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clinic

THE BELGIAN JOURNAL OF MEDICAL ONCOLOGY IS THE OFFICIAL JOURNAL OF THE BELGIAN SOCIETY OF MEDICAL ONCOLOGY (BSMO) AND THE BELGIAN ASSOCIATION FOR CANCER RESEARCH (BACR)

Belgian Journal of Medical OncologyVOLUME 13 | ISSUE 6

OCTOBER 2019

Low Grade Glioma: towards a personalised treatment S. Dingenen, L. Renard, T.M. Lawson,  N. Whenham

Introducing a Castrate Resistant Prostate Cancer (CRPC) Model Care Pathway in Belgian Hospitals – towards national standardisation? T. Vermassen, T. Roumeguere, Y. Neybuch, L. Hoekx, I. Fele, B. Sautois, W. Everaerts, D. De Maeseneer, F. Lecouvet, N. Lumen, P. Ost, S. Rorive, S. Stroobants, P. Dirix, S. Rottey

State of the art in the treatment of soft tissue sarcomas C. Gennigens, G. Jerusalem

Adjuvant chemotherapy of colon cancer: 3 versus 6 months C. Debeuckelaere, L. Triest, T. Vandamme, B. Van den Heuvel, K. Papadimitriou, M. Rasschaert, H. Prenen, M. Peeters

Appropriateness of treatment options in patients with metastatic castration-resistant prostate cancer with a focus on radium-223: outcomes of a Belgian multidisciplinary Consensus MeetingP. Ost, D. Schrijvers, L. Duck, M. Gizzi, K. Goffin, S. Joniau, S. Rottey, T. Roumeguère, E. Seront, N. Withofs, B. Tombal

Difficulties in diagnosis and treatment of a rare malignancy, malignant peritoneal mesotheliomaB. Dullens, C. Bourgain, W. Ceelen, W. Wynendaele, X. Mortiers, T. Adams, H. Vandeursen

Case report: Seeding metastases after percutaneous vertebroplasty procedure for pathological fracture: a rare complicationC. Debeuckelaere, A. Van Goethem, G. Maleux, H. Prenen

Highlights of the 2019 annual meeting of the European Neuroendocrine Tumour Society (ENETS)W. Lybaert, T. Vandamme, G. Boons, K. Vandenborne, L. De Backer, M. Peeters

New oncology reimbursements in BelgiumP. Specenier

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BELGIAN JOURNAL OF MEDICAL ONCOLOGY

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INTRODUCTION J. De Grève

REVIEW ONCOLOGYLow Grade Glioma: towards a personalised treatmentS. Dingenen, L. Renard, T.M. Lawson, N. Whenham

Introducing a Castrate Resistant Prostate Cancer (CRPC) Model Care Pathway in Belgian Hospitals – towards national standardisation?T. Vermassen, T. Roumeguere, Y. Neybuch, L. Hoekx, I. Fele, B. Sautois, W. Everaerts, D. De Maeseneer, F. Lecouvet, N. Lumen, P. Ost, S. Rorive, S. Stroobants, P. Dirix, S. Rottey

PRACTICE GUIDELINESState of the art in the treatment of soft tissue sarcomasC. Gennigens, G. Jerusalem

PHARMACOTHERAPYAdjuvant chemotherapy of colon cancer: 3 versus 6 monthsC. Debeuckelaere, L. Triest, T. Vandamme, B. Van den Heuvel, K. Papadimitriou, M. Rasschaert, H. Prenen, M. Peeters

Appropriateness of treatment options in patients with metastatic castration-resistant prostate cancer with a focus on radium-223: outcomes of a Belgian multidisciplinary Consensus MeetingP. Ost, D. Schrijvers, L. Duck, M. Gizzi, K. Goffin, S. Joniau, S. Rottey, T. Roumeguère, E. Seront, N. Withofs, B. Tombal

ONCOCASEDifficulties in diagnosis and treatment of a rare malignancy, malignant peritoneal mesotheliomaB. Dullens, C. Bourgain, W. Ceelen, W. Wynendaele

Case report: Seeding metastases after percutaneous vertebroplasty procedure for pathological fracture: a rare complicationC. Debeuckelaere, A. Van Goethem, G. Maleux, H. Prenen

CONGRESS NEWSHighlights of the 2019 annual meeting of the European Neuroendocrine Tumour Society (ENETS)W. Lybaert, T. Vandamme, G. Boons, K. Vandenborne, L. De Backer, M. Peeters

REIMBURSEMENT NEWSNew oncology reimbursements in BelgiumP. Specenier

CALENDAR OF EVENTS

TABLE OF CONTENTS 211COLOPHON

The Belgian Journal of Medical Oncology (BJMO) is the official scientific journal of the Belgian Society of Medical Oncology (BSMO) and the Belgian Association for Cancer Research (BACR). The BJMO aims to be a peer-reviewed cancer journal covering all aspects of the diagnostic and clinical management of cancer patients. Subscriptions are free for all specialists who are active in the fields of oncolo-gy, radiotherapy and adherent fields.

PUBLISHER AND EDITORIAL OFFICEAriez International B.V.Ms. E. van Zanten, MScc/o Oude Houtlei 118-120, 9000 Gent, BelgiumTel: 0031-75-642 94 20E-mail: editor@bjmo.be

FOUNDED BY L. Dirix, MD, PhD, medical oncologist, St Augustinus Hos-pital, Wilrijk.

EDITOR-IN-CHIEFJ. De Grève, MD, PhD, Professor in Oncology, head of de-partment of medical oncology, University Hospital Brus-sels, Brussels.

EDITORIAL BOARDA. Awada, MD, PhD, Professor in Oncology, Jules Bordet Institute, Brussels, J-F. Baurain, MD, PhD, Professor in Oncology, Cliniques Universitaires Saint-Luc, Brussels, F. Cornelis, MD, medical oncologist, Cliniques Universitaires Saint-Luc, Brussels, H. Denys, MD, PhD, medical oncologist, University Hospital Gent, Gent, M. De Ridder, MD, PhD, Professor in Radiation Oncology, UZ Brussel, Brussels, M. Dicato, MD, haematologist-oncologist, Centre Hospitalier de Luxembourg, Luxembourg, P. Dirix, MD, PhD, radiation oncologist, University Hospitals Leuven, Leuven,L. Duck, MD, PhD, medical oncologist, Clinique Saint-Pierre, Ottignies, C. Duhem, MD, haematologist-oncologist, Centre Hospitalier de Luxembourg, Luxembourg, F. Duhoux, MD, PhD, medical oncologist, Cliniques Universitaires Saint-Luc, Brussels, A. Hendrix, MD, medical oncologist, Gent University Hospital, Gent, M. Ignatiadis, MD, PhD, medical oncologist, Jules Bordet Institute, Brussels,G. Jerusalem, MD, PhD, medical oncologist, CHU Sart-Tilman, Liège, J. Kerger, MD, PhD, medical oncologist, Jules Bordet Institute, Brussels, J-P. Machiels, MD, PhD, Professor in Oncology, Cliniques Universitaires Saint-Luc, Brussels, J. Mebis, MD, PhD, medical oncologist, Jessa Ziekenhuis, Hasselt, P. Pauwels, MD, PhD, pathologist, University Hospital Antwerp, Edegem, H. Prenen, MD, PhD, Professor in Oncology, University Hospitals Leuven, Leuven, S. Rottey, MD, PhD, medical oncologist, Gent University Hospital, Gent, D. Schrijvers, MD, PhD, medical oncologist, Ziekenhuis-netwerk Antwerpen, Antwerp,P. Specenier, MD, PhD, Professor in Oncology, University Hospital Antwerp, Edegem, J-L. Van Laethem, MD, PhD, Professor in Gastroenterology, Université Libre de Bruxelles, Brussels, H. Van Poppel, MD, PhD, Professor in Urology, University Hospitals Leuven, Leuven, D. Verhoeven, MD, PhD, medical oncologist, AZ KLINA, Brasschaat, J.B. Vermorken, MD, PhD, Professor in Oncology, University Hospital Antwerp, Edegem, H. Wildiers, MD, PhD, Professor in Oncology, University Hospitals Leuven, Leuven.

SUBSCRIPTIONSFor paid subscriptions, please refer to the publisher: abon@ariez.com.

Publication Frequency: 8 issues per year.Edition: 3,000 copies.

COPYRIGHT© Ariez International B.V. Zaandam, The Netherlands.No information from this publication may be copied, com-mercialised by third parties without written permission of the publisher in advance. The Editorial Board and the publisher cannot be held responsible for the content of articles or the content of advertisements and cannot be held responsible for or liable to potential claims of third parties regarding damage suffered following publication of this issue.

COVER ILLUSTRATION Science Photo

ISSN-NUMBER 1784-7141

VOLUME13OCTOBER2019

Increased spending on cancer care and cancer drugs: justified?

DEAR COLLEAGUES,

The rising expenditures for cancer therapy and especially cancer medicine

has recently come under public scrutiny. Immunotherapy, but also other

therapies are responsible for this evolution.

While it is evident that the payer should go for the least possible cost, it is

also obvious that innovative therapeutic options that affect cancer patient survival and quality of life justify an increased budget

and we should be pleased about this, not apologise for it. So far, the cancer patient has been underserved when compared

to other major health domains taking into account the impact of the disease on patients’ lives (Disability-Adjusted Life Years,

DALY). A diverse array of remedies are proposed to decrease the cost (pay for performance, open-source products, etc.). Some

realistic, some utopic, but all rather complicated in application. The most obvious and effective solution is never part of the

options envisioned: competitive market access based on quality and price for innovative drugs that are sometimes quite

comparable in efficacy and toxicity. In other economic sectors, R&D is an upfront investment and risk taken by companies

leading to new products that enter the market in a competitive environment and pricing, without an a priori guarantee on

price setting or budget. Why can we not apply this liberal market principle to medicines? Somewhere in the past, payers and

governments have been convinced that pharma should be an exception. It is unclear why and why it should remain this way

at a moment when society faces an untenable situation that endangers our current social justice in treatment access.

The current issue covers low-grade glioma, prostate cancer, soft tissue sarcoma, colorectal cancer, peritoneal mesothelioma,

ENETS and new reimbursements.

Enjoy the reading,

Jacques De Grève, MD, PhD

6

J. DE GRÈVE

212INTRODUCTION

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SUMMARYThis review is designed to help the management of low grade glioma and is based on literature regarding molecular characterisation, surgery, radiotherapy, chemotherapy and neurocognitive preservation.(BELG J MED ONCOL 2019;13(6): 213-218)

1Medical Oncology, Ambroise Paré, Mons, 2Radiotherapy, Cliniques Saint-Luc, Brussels, 3Neurosurgery, Cliniques Saint-Luc, Brussels, 4Medical

Oncology, Clinique Saint-Pierre Ottignies and Cliniques Saint-Luc, Brussels.

Please send all correspondence to: N. Whenham, MD, Clinique Saint-Pierre, Department of Oncology and Haematology, Avenue Reine Fabiola

9, 1340 Ottignies, Belgium, tel: +32 10437241, email: nicolas.whenham@uclouvain.be.

Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest.

Keywords: low grade glioma, radiotherapy, surgery, systemic treatment and molecular subtype.

S. Dingenen, MD1, L. Renard, MD2, T.M. Lawson, MD3, N. Whenham, MD4

Low Grade Glioma: towards a personalised treatment

INTRODUCTIONDiffuse infiltrating low grade glioma (LGG) (grade II) include

astrocytomas and oligodendrogliomas and account for about

5% of all primary brain tumours. They are slow growing tu-

mours with a malignant potential of transformation in ana-

plastic tumours and glioblastomas.1 The treatment goal is to

prolong overall survival while maintaining a good quality of

life and neurocognitive functions. In this context, it is im-

portant to distinguish between patients eligible for an initial

conservative approach and patients who need an immedi-

ate aggressive multimodal treatment. The optimal sequence

and treatment modality of LGG is highly controversial since

only few randomised studies exist and guidelines are thus

difficult to make.

RISK FACTORS AND A NEW MOLECULAR CLASSIFICATIONClassical negative prognostic factors (age above 40 years,

astrocytoma histology, maximal tumour diameter ≥ 6 cm,

tumour crossing the midline and presence of neurologic

deficit before surgery) are important to guide the optimal

therapy choice.2 The modified 2016 WHO classification was

the first to use molecular parameters in combination with

histological information to define tumours of the central

nervous system and thus significantly changed daily prac-

tice.3 The histologic separation between astrocytomas and

oligodendrogliomas is complemented by recent evidence

for two molecular subtypes, characterised by IDH, ATRX

and TP53 mutations. Astrocytic tumours lack the 1p/19q

co-deletion while the oligodendroglial tumours, who are

associated with better prognosis, are characterised by an

IDH mutation and the 1p/19q co-deletion.3,4,5 1p/19q co-

deleted gliomas without IDH mutation (confirmed by se-

quencing of IDH1 and IDH2 if immunohistochemistry for

IDH1 R132 is negative) are rather associated with IDH-

wildtype astrocytomas and are characterised by a more ag-

gressive clinical course. LGG can thereby be assigned to

one of the three molecular classes: IDH-mutant astrocyto-

ma, IDH-wildtype astrocytoma and 1p/19q co-deleted oli-

godendroglioma. If molecular testing cannot be performed,

the term ‘not otherwise specified (NOS)’ should be added

(Table 1 and 2).3 The same molecular classification is pro-

posed for anaplastic gliomas (grade III). It is still unclear

if the molecular classification, next to the classical grad-

ing classification, will become more and more important

in daily clinical practice.

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SURGERYJakola et al. showed that early surgical resection was asso-

ciated with better overall survival outcomes, compared to

biopsy and watchful waiting.6 However, the ‘wait and scan’

approach may also be proposed in patients with good clinical

condition and not yet histologically proven lesions.7 In 2008,

a retrospective study by Smith et al. provided evidence that a

more aggressive resection predicts significant improvement

in progression free survival (PFS) and overall survival (OS)

compared with a simple debulking.8 Yordanova et al. report-

ed that a supratotal resection (resection extending beyond the

MRI signal abnormalities) in non-eloquent regions may pre-

clude anaplastic transformation.9 Unfortunately, the fact that

diffuse gliomas are often located in a functional zone make

this a challenging approach.10 A good anatomo-functional

knowledge of the brain is thus needed to allow a maximised

safe resection. In this context, advanced techniques such as

functional MRI, neuro-navigation, intraoperative MRI, diffu-

sion tensor imaging, neuro-navigated transmagnetic stimula-

tion and awake surgery are major tools for the neurosurgeon.

However, one should be trained to the pitfalls and limits of

each technique, especially regarding functional anatomy and

individual variability.11 The use of these modern techniques

in neurosurgery allows experienced teams to perform a max-

imal safe resection of the tumour until the junction of the elo-

quent zone with a positive impact on survival outcomes and

a low frequency of permanent neurological deficits (2%).12-14

RADIOTHERAPYRadiotherapy (RT) is a standard therapy in low-grade glio-

ma but the optimal timing is uncertain. Results of the EO-

RTC 22845 trial demonstrated that early radiotherapy (RT

54 Gy in fractions of 1.8 Gy), versus deferred radiotherapy

until progression, was associated with prolonged PFS but no

difference in OS. At 5 years, 55% of the irradiated patients

were still free from progression, compared to 35% of the pa-

tients in the control group. The majority of patients (65%) in

the group without postoperative RT received RT at progres-

sion. The absence of a survival benefit (7.4 versus 7.2 years)

is probably due to the effectiveness of salvage radiotherapy in

the control group at recurrence (Table 3).15 Furthermore, two

randomised trials demonstrated no advantage and more tox-

icity for higher radiation doses. Schedules like 50 to 54 Gy

with 1.8 or 2 Gy per fraction are considered as the standard

of care for the treatment of LGG.16,17

CHEMOTHERAPYRTOG 9802 is a prospective randomised trial showing an

indisputable benefit of the procarbazine, lomustine, vincris-

tine (PCV) chemotherapy combination after radiotherapy in

selected patients. Patients with favourable risk factors (gross

total resection and < 40 years) were observed after operation

(no randomisation). For this population the PFS at 5 years

was 48% and the OS at 5 years was 93%.18 Of note, the study

received some critique concerning the definition of favour-

able and unfavourable risk factors. For example, patients with

< 1 cm residual disease, initial tumour diameter < 4 cm and

oligodendroglioma histology are commonly observed after

surgery.18 The group of patients with unfavourable risk factors

in the RTOG 9802 trial harboured all patients above 40 years

old and patients younger than 40 years without a gross total

resection. These selected patients were randomly assigned to

receive radiotherapy followed by chemotherapy (up to six cy-

cles of PCV) or RT alone. The initial publication of the study

results showed an absence of OS benefit despite the increase

in PFS. In the post-analysis with a follow-up of 11 years, the

TABLE 1. Astrocytic and oligodendroglial tumour classification.3

Tumour Genotype

Diffuse astrocytoma IDH Mutant

IDH Wild-type

NOS

Oligodendroglioma IDH Mutant and 1p/19q co-deleted

NOS

TABLE 2. Median overall survival in LGG.4

Genotype mOS

IDH Mutant 1p/19q co-deleted 15 years

IDH Mutant 1p/19q non co-deleted 10 years

IDH Wild-type 2 years

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addition of PCV to RT conferred an impressive advantage in

both PFS and median OS (13.3 versus 7.8 years).19 Benefit for

chemotherapy is delayed and seems to be reserved for pa-

tients alive after 4 years (late divergence in survival curves).

The small number of patients in each subgroup and the in-

complete data unfortunately preclude definitive conclusions

about molecular predictive factors. However, the benefit of

chemotherapy appears to be the largest in IDH mutated glio-

mas, particularly in oligodendrogliomas (Table 3).19,20

EORTC 22033-26033 is a phase III intergroup trial com-

paring RT alone versus dose-intense temozolomide (TMZ)

monotherapy in supratentorial LGG with at least one high

risk factor (age >40 years, progressive disease, tumour >5 cm

or crossing the midline, neurological symptoms). The study

could not show a significant difference in PFS. However, non

co-deleted tumours were associated with longer PFS with RT

alone than with TMZ. Results for OS are awaited (Table 3).21

RTOG 0424 is a phase II study in which 129 patients with

LGG with risk factors (age >40 years, astrocytoma histology,

bi-hemispheric tumour, preoperative tumour diameter > 6

cm, preoperative neurologic altered functional status) were

treated with concurrent radiation with daily TMZ followed

by monthly TMZ. The 3-year OS rate was 73% and thus sig-

nificantly higher than the historical control OS rate of 54% in

specified controls treated with radiation alone. The 5-year OS

rate was 57.1% and the median OS has not yet been reached.

The 3-year PFS was 59.2% and median PFS was 4.5 years.22

On the basis of these studies and other positive trials in ana-

plastic glioma (EORTC 26951, RTOG 9402, EORTC 26053-

22054), guidelines for personalised treatment according

molecular biology can be proposed.20

- Diffuse IDH wild-type astrocytomas are aggressive tumours

despite low grade histology. Biological and molecular profile

as well as prognosis are comparable to grade IV glioblasto-

ma.21 No randomised trial exists in this condition. Most like-

ly, the same postoperative regimens as in high grade gliomas

have to be considered.

- Diffuse IDH mutant astrocytomas: The upcoming EORTC

trial 1635 investigates the role of radiotherapy and TMZ ver-

sus initial active surveillance in this molecular category. It is

TABLE 3. Summary of important randomised trials.15,18,19,21

Study Design Population Results

EORTC 22845 Phase III randomised trial of early vs. delayed radia-tion therapy for LGG

314 patients with supraten-torial LGG

Median follow up: 7.8 years Median PFS: p =0.003-5.3 years RT group -3.4 years control group Median survival: p=0.873-7.4 years RT group-7.2 years control group

RTOG 9802 Phase III randomised trial to evaluate effects of radi-otherapy alone vs. radio-therapy + chemotherapy PCV in the cohort of LGG patients considered to be the unfavourable risk group

251 adult patients with age ≥ 40 years, irrespective of extent of resection, and those of 18-39 years of age that had undergone subto-tal resection or biopsy alone

Initial publication Median follow up: 4 years Median PFS: p=0.06-4.5 years RT group -not reached RT + PCV group Absence of OS benefit p=0.33 Post-analysis: Median follow up: 11 years Median overall survival:p = 0.002-7.8 years RT group -13.3 years RT + PCV group

EORTC 22033-26033 Phase III randomised trial comparing radiotherapy alone vs. dose intense TMZ therapy

477 adult patients with su-pratentorial grade II glioma with at least one high risk factor

Median follow up: 4 years Median PFS: p= 0.22-39 months in the TMZ arm -46 months in the RT groupMedian PFS in IDH-mutant non co-deleted: p=0.0043-36 months in the TMZ arm -55 months in the RT groupResults for OS are awaited

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216

unclear whether TMZ is equally effective as PCV. Recent data

about the efficacy of adjuvant TMZ for grade III glioma sug-

gested that radiotherapy followed by TMZ is an acceptable al-

ternative to PCV. Moreover, a better tolerability is expected.23

- IDH mutant and 1p/19q co-deleted oligodendrogliomas with

unfavourable clinical factors: based on data of the RTOG

9802 trial and data of large phase III studies in anaplastic ol-

igodendrogliomas, radiation therapy plus chemotherapy PCV

is the standard for this population.18,24,25

NEUROCOGNITIVE TOXICITYIn addition to OS and PFS, cognitive deterioration and quali-

ty of life after treatment must be taken into account.26 The tu-

mour itself, depending on its size and location, has a negative

impact on neurocognitive functioning. Teixidor et al. report-

ed that surgery can temporarily exacerbate baseline deficits,

although most patients recovered and reached the level of

preoperative cognitive function within three months.27 More-

over, intraoperative functional mapping can minimise the

risk of permanent deficit to less than 2%.28,12

Radiation leukoencephalopathy may appear months to years

after treatment and can lead to deterioration in personality,

gait and balance, urinary continence, attention, memory and

executive function.29 It should be noted that these data main-

ly come from the era before modern radiotherapy techniques

like IMRT and image guided radiotherapy and that these side

effects are nowadays most likely less pronounced. Most LGG

patients have good neurocognitive function after focal radio-

therapy but these data are often based on imperfect and lim-

ited tools as MMSE. In the future, more discriminating tests

of cognition should be used for a better evaluation and cog-

nitive function should be considered as a major endpoint in

clinical trials.30 A neuropsychological assessment is recom-

mended before and after resection. Early postoperative cogni-

tive rehabilitation should be encouraged.13 Radiotherapy has

nevertheless a positive effect on seizure control.

Chemotherapy also has a potential negative impact.26 Never-

theless, there is no proof that adding chemotherapy to surgery

and radiotherapy increases neurocognitive deterioration.31,32

CONCLUSIONEarly and maximal surgical resection, taking into account

functional limitations, is the first therapeutic option to con-

sider in LGG.

The modified WHO 2016 classification has enabled the ma-

jority of LGG to be assigned to one of the three classes of low

grade glioma: IDH-mutant astrocytoma, IDH-mutant and

1p/19q-co-deleted oligodendroglioma and IDH-wildtype as-

trocytoma. Further studies are needed to clarify whether mo-

lecular testing will replace the classical grading.

For young patients of < 40 years with complete resection and

a good prognosis, initial observation after surgery is consid-

ered to be the standard of care in order to postpone toxici-

ty of oncologic therapies. The EORTC 22845 results showed

that the ‘wait and see’ approach does not have a negative im-

pact on overall survival.

For patients older than 40 years, or younger patients with re-

sidual disease, an adjuvant treatment should be discussed in

a multidisciplinary consultation. This should be done on an

individual basis, taking into account other clinical risk fac-

KEY MESSAGES FOR CLINICAL PRACTICE

1. The modified 2016 WHO classification integrates molecular biology to the classification of brain tumours. LGGs are now classified in three subtypes: IDH mutant astrocytoma, IDH wild-type astrocytoma and oligodendroglioma (IDH mutant and 1p/19q co-deleted).

2. Maximal safe surgery improves survival.

3. Initial observation after surgery is an acceptable option in patients with good prognostic factors in order to postpone toxicity of radiotherapy and chemotherapy.

4. RTOG 9802 is a large randomised trial that demonstrates a clear benefit in OS with chemotherapy PCV after radiotherapy in selected patients (>40 years or no gross total resection).

5. TMZ has a better tolerance profile and may be considered as an acceptable alternative to PCV in astrocytomas. PCV remains the standard of care for oligodendroglial tumours when a postoperative treatment is indicated.

VOLUME13OCTOBER20196

217REVIEW ONCOLOGY

tors, molecular biology and patient’s preference. When an ad-

juvant treatment is decided, the standard of care should be

radiotherapy followed by chemotherapy.

Some neuro-oncologists prefer chemotherapy alone as initial

treatment to avoid possible neurocognitive damages associat-

ed with radiotherapy. However, there are no clear data sup-

porting the attitude neither in terms of disease control or in

terms of cognitive preservation. Moreover, benefit of salvage

RT at the time of relapse is unclear in comparison with the

initial combined therapy.

In conclusion, as the management of LGG is complex and

controversial, all cases must be discussed in a multidisci-

plinary committee before treatment. Physicians have to dis-

cuss the estimated risks and benefits of adjuvant therapies

in term of PFS, OS and neurocognitive preservation with

their patients.

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19. Van den Bent MJ. Practice changing mature results of RTOG 9802: another

positive PCV trial makes adjuvant chemotherapy part of standard of care in low

grade glioma, Neuro-Oncology 2014;16(12):1570–4.

20. Sasaki H, Yoshida K. Treatment recommendations for adult patients with dif-

fuse gliomas of Grades II and III according to the new who classification in 2016,

Neurol Med chir 2017;57:658-66.

21. Baumert BG, Hegi ME, Van den Bent MJ, et al. Temozolomide chemother-

apy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033):

a randomised, open-label, phase 3 intergroup study, Lancet Oncol.

2016;17(11):1521-32.

22. Fisher BJ, Hu C, Macdonald DR, et al. Phase 2 study of temozolomide-based

chemoradiation therapy for high-risk low-grade gliomas: preliminary results of

Radiation Therapy Oncology Group 0424., Int J Radiat Oncol Biol Phys.

2015;91(3):497-504.

23. Van den Bent MJ, Baumert B, Erridge EC, et al. Interim results from the CAT-

NON trial (EORTC study 26053-22054) of treatment with concurrent and adju-

vant temozolomide for 1p/19q non-codeleted anaplastic glioma: a phase 3 ran-

domised open-label intergroup study, Lancet 2017;390:1645-53.

24. Van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine,

lomustine and vincristine chemotherapy in newly diagnosed anaplastic oligo-

dendroglioma: long-term follow up of EORTC brain tumour group study, J Clin

Oncol. 2013;31:344-55.

25. Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiation for

anaplastic oligodendrioglioma; long term results of RTOG 9402, J Clin On-

col.2013;31:337-43.

26. Boele FW, Douw L, Reijneveld JC, et al, Health-related quality of life in sta-

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27. Teixidor P, Gatignol P, Leroy M, et al. Assessment of verbal working memo-

ry before and after surgery for low grade glioma, J Neurooncol 2006;81:305-13.

28. Duffau H. Surgery of low grade glioma: towards a functionnal neurooncolo-

gy. Curr Opin Oncol 2009;21:543-9.

29. Surma-aho O, Niemela M, Vilkki J, et al. Adverse long term effects of brain

radiotherapy in adult low grade glioma patients. Neurol 2001;56:1285-90.

30. Brown PD, Buckner JC, O’Fallon JR, et al. Effects of radiotherapy on cogni-

tive function in patients with low grade glioma measured by the folstein mini-men-

tal state examination, J Clin Oncol 2003;21:2519-24.

31. Correa DD, DeAngelis LM, Shi W, et al. Cognitive functions in low grade dis-

ease and treatment effects, J Neurooncol 2007;81:175-84.

32. Correa DD, Shi W, Thaler HT, et al. Longitudinal cognitive follow-up in low

grade glioma, J Neurooncol 2008;86:321-7.

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SUMMARYCastrate-resistant prostate cancer (CRPC) is characterised by complex strategies for therapy and follow-up. In order to standardise CRPC cancer care on a national basis, an integrated care pathway was devised, based on clinical governance principles and acknowledged best practice, in order to reduce length of hospital stay, reduce costs of patient care, improve patient outcomes (e.g. Quality-of-Life, complications), etc. Therefore, a steering group of Belgian experts, consisting of medical oncologist, urologists, radiation oncologists, oncology nurses, pathologists and nuclear medicines, was assembled to discuss the need for an integrated care path-way for CRPC in Belgium. This was made possible through the financial support of Astellas Belgium. An exten-sive integrated care pathway was discussed with various stages, depending on the disease status of the pa-tient. Belgian implementation could lead towards further standardisation of cancer care for CRPC patients although several important matters still have to be discussed or adapted. Further assessment and inter-hospi-tal deliberation seems required to ensure a national implementation of the CRPC integrated care pathway.(BELG J MED ONCOL 2019;13(6): 219-226)

1Department of Medical Oncology, Ghent University Hospital, 2Drug Research Unit Ghent, Ghent University Hospital, 3Department of Urology,

Erasme University Hospital, 4Department of Medical Oncology, Hôpital de Jolimont, 5Department of Urology, Antwerp University Hospital, 6Department of Medical Oncology, Liege University Hospital (CHU), 7Department of Urology, Leuven University Hospital, 8Department of

Radiology, Cliniques Universitaires Saint Luc, 9Department of Urology, Ghent University Hospital, 10Department of Radiation Oncology, Ghent

University Hospital, 11Department of Pathology, Erasme University Hospital, 12Department of Nuclear Medicine, Antwerp University Hospital, 13Department of Radiation Oncology, Antwerp University Hospital.

Please send all correspondence to: S. Rottey, MD, PhD, Department of Medical Oncology, Ghent University Hospital, C. Heymanslaan 10, 9000

Ghent, Belgium, tel: +32 93322692, email: sylvie.rottey@ugent.be.

Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest.

Keywords: castrate-resistant prostate cancer, integrated care pathway, national standardisation.

Acknowledgements: This ICP project was made possible with the financial support of Astellas Pharma. Astellas Pharma did not have any

active role in the discussion of the ICP, nor in the writing of all documents.

T. Vermassen, PhD1,2, T. Roumeguere, MD, PhD3, Y. Neybuch, MD4, L. Hoekx, MD5, I. Fele3, B. Sautois, MD, PhD6, W. Everaerts, MD, PhD7, D. De Maeseneer, MD1, F. Lecouvet, MD, PhD8, N. Lumen, MD, PhD9, P. Ost, MD, PhD10, S. Rorive, MD, PhD11, S. Stroobants, MD, PhD12, P. Dirix, MD, PhD13, S. Rottey, MD, PhD1,2

Introducing a Castrate Resistant Prostate Cancer (CRPC) Model Care Pathway in Belgian Hospitals – towards national standardisation?

INTRODUCTIONIntegrated Care has become a buzzword for seamless patient

management since the late 1990s. However, as it is current-

ly applied, the term is often used incorrectly. True integrat-

ed care seeks to combine and integrate checklists, standards,

evidence and patient data with case management activities

and outcome data. Furthermore, the pathway should facil-

itate regular audit so that a demonstrable improvement in

VOLUME13OCTOBER20196

220

both the process and outcome of care can be achieved. Ma-

ny integrated care projects fail to achieve these objectives and

are in reality nothing more than guidelines or protocols un-

der a different name. In order to deliver true integrated care,

clinical governance principles and acknowledged best prac-

tice have been applied to this project.1,2

The typical Integrated Care Pathway (ICP) comprises a flow

chart illustrating the normal patient journey for a defined

clinical condition, a document summarising and clarifying

the relevant evidence base and a series of forms that provide

the day-to-day record and process check for the care of each

patient. The opportunities provided by an effectively used

and appropriately developed ICP are summarised in Table 1.

If applied properly, an ICP can result in several benefits such

as a reduction in length of hospital stay, reduction in costs of

patient care, improved patient outcomes (e.g. Quality-of-Life,

complications), increased patient satisfaction with service,

improved communication between staff, increased patient

and physician involvement and reduction in time spent on

paperwork.

MODEL CARE PATHWAY FOR CASTRATION RESISTANT PROSTATE CANCER (CRPC) IN BELGIUMAs the advantages of an effective ICP are clearly described,

a steering group of Belgian experts was assembled, consist-

ing of medical oncologists, urologists, radiologists, radiation

oncologists, oncology nurses, pathologists and nuclear med-

icines, to discuss the need for an ICP for prostate cancer in

Belgium. Believing that it would be impossible to cover the

entire ICP for prostate cancer, starting from primo-diagno-

sis until the end of metastatic treatment, the steering group

decided to focus on an ICP for CRPC patients from moment

of castration-resistance until end of treatment of metastatic

CRPC patients.

The currently established ICP for CRPC patients is depict-

ed in Figure 1. This ICP has been designed in 2018 to facili-

tate the implementation of guidance and best practice in the

management of CRPC according to the state-of-the-art and

related to the Belgian situation. The ICP is intended to rep-

resent a model pathway for Belgian physicians and hospitals

that can be amended or modified to suit the capability and

capacity of any institution or region. Its main purpose is to

facilitate communication across the multidisciplinary team

and to ensure that an appropriate care plan is implemented

for each patient. During this patient journey, several stages

can be traversed from start of the ICP until patients finally

exit the ICP. Several documents accompany each stage of the

patient journey. These documents have been added as supplemen-

tary information, available online.

CONFIRMATION OF DIAGNOSIS AND METASTATIC STATUSAt the moment the patient visits the healthcare specialist, it

is imperative that the disease status is correctly identified. In

this matter, only patients who have evidence of disease pro-

gression during treatment with androgen deprivation therapy

(ADT) will be considered to have castration-resistant disease

and can enter the ICP. During this first stage, clinicians are

required to gather all information needed to determine the

actual disease status of the patient and to decide on further

treatment options.

At first, general physical examination is required in order to

REVIEW ONCOLOGY

FIGURE 1: Integrated Care Pathway for CRPC patients.

The model pathway follows the patient journey shown in the

diagram. For each part in the patient journey accompanying

documents have been worked out in order to facilitate

collection of all needed and available data. These documents

can easily be adapted or modified according to the needs

and choice of the user (These documents have been added

as supplementary information, available online).

VOLUME13OCTOBER2019

221

assess general and urological symptoms (especially ureter-

al obstruction and bladder outlet obstruction). In addition,

it is also imperative to assess the presence of any neurologi-

cal symptoms as well as the presence of pain (preferable us-

ing the Visual Analog Scale).3 For completion of the patient

history, previous and current therapies should be recorded.

Next, disease progression can be identified. This should be

done by either laboratory analyses, namely increase in serum

prostate-specific antigen (PSA) in the context of testosterone

in the castration range, which usually precedes the onset of

clinical symptoms by several months, as well as by imaging

to prove the occurrence of new metastases and/or progres-

sion of existing metastases. Different imaging modalities can

be used to describe the presence of metastatic disease, such

as CT/PET imaging (thoracic and abdominopelvic for assess-

ment of soft tissue lesions and observation of ‘flare’ phenom-

enon), whole body MRI (assessment of bone and soft tissue

lesions) and bone scan (progression in case of appearance of

at least two new lesions, confirmed at least six weeks later due

to possible ‘flare’ phenomenon).4-6 Please note that it is high-

ly advised to perform imaging at regular intervals in asymp-

tomatic patients with a stable PSA concentration. This as the

PREVAIL trial has indicated that 1 in 4 patients in this pa-

tient population does have radiographic progression despite

no progression in PSA concentration.7

Patients with non-metastatic disease should be categorised as

M0 CRPC patients. Although no international accepted cri-

teria exist to define CRPC, the EAU guidelines stipulate the

following definition: castrate serum testosterone < 50 ng/dL

or 1.7 nmol/L plus either biochemical progression (defined as

three consecutive rises in PSA one week apart resulting in two

50% increases over the nadir, and a PSA > 2 ng/mL) or radio-

logical progression (defined as the appearance of new lesions:

either two or more new bone lesions on bone scan or a soft tis-

sue lesion). Symptomatic progression alone is not sufficient.8-10

Next to the determination of the (metastatic) CRPC status,

other tests can be performed in order to complete patient re-

cords and improve patient care. First, histology assessment

can provide new information and may be mandatory for in-

clusion in clinical trials. Secondly, neuron-specific enolase /

chromogranin A can be determined as both are linked with

development of CRPC and poor survival in patients diag-

nosed with CRPC who have normal PSA concentrations.

Thirdly, bone mineral density should be considered to as-

sess possible ADT induced osteoporosis. Lastly several oth-

er laboratory tests, such as serum creatinine, liver enzymes,

haemoglobin, alkaline phosphatase, lactate dehydrogenase

and electrolytes, should be conducted in compliance with

good clinical practice and to determine possible treatment-re-

lated toxicities and prognostic factors.11-24

Based on all gathered data, disease status can be determined

and treatment can be initiated. Please note that it is essential

that all possible treatment options are discussed in a multi-

disciplinary team meeting (clinicians, oncology nurses, pa-

thologists, etc.) in order to select the most optimal treatment

modality for the patient.25 If applicable, consider if patient can

participate in a clinical trial or other potential study/project.

Subsequently, the family physician must be informed of the

outcome of the multidisciplinary team meeting and he/she

should be invited to participate herein.

TABLE 1. Opportunities provided by an ICP.1,2

• Support multidisciplinary care

• Encourage simple record-keeping

• Allow locally determined standards to be set

• Facilitate clinical audit

• Decrease unwanted variance from the normal pattern in patient care

• Enhance communication between clinical staff, and with patients leading towards improved patient satisfaction

• Provide a structured plan for patient care

• Describe the expected progress for a “typical” patient

• Outline the normal timescale of events

• Present the procedures to be followed, in the right order therefore improving quality standards

• Is backed up by evidence

• Incorporate guidelines based on best practice

VOLUME13OCTOBER20196

222TREATMENT INITIATION FOR NON-METASTATIC CRPC AND ASSESSMENTFirstly, a full clinical evaluation must be performed includ-

ing ECOG performance status determination and, for elderly

patients, G8 assessment. This tool was developed by the In-

ternational Society of Geriatric Oncology (SIOG) PCa Work-

ing Group (PCWG) which recommended that treatment of

elderly patients should be based on a systematic evaluation

of health status.17

At treatment initiation, clinical evaluation was already done

during stage 1 of the patient pathway (see Confirmation of di-

agnosis and metastatic status) whereas this can change during

the course of the therapy. In this matter, PSA evaluation is

of utmost importance for follow-up of patients diagnosed

with non-metastatic CRPC. It is the opinion of internation-

al experts that second-line hormonal therapies should not

be given to chemotherapy-naïve men with non-metastat-

ic CRPC who are at low risk of developing metastases, for

whom watchful waiting is considered to be a preferred op-

tion.26 This risk of developing metastases is defined by low

PSA concentrations in combination with a long PSA dou-

bling time.6,27 Again, results of all clinical evaluations should

be discussed in a multidisciplinary meeting to determine

the most appropriate evidence-based treatment.25 Several

phase III trials have been / are being conducted in search for

novel therapies in these patient cohorts. Currently available

treatment options, to be administered depending on patient

symptoms, consists of corticosteroids (low cost and favour-

able toxicity profile with no proven survival benefit), deno-

sumab, abiraterone acetate and enzalutamide.28-33 However,

despite positive results in clinical trials, the current guide-

lines do not (yet) support the use of these cancer-directed

treatments in non-metastatic CRPC.29,34 As the need for novel

therapeutics to delay the onset of metastatic disease is high,

enrolment of patients with non-metastatic CRPC into clini-

cal trials is recommended.

Once decided, the clinician, assisted by the oncology nurse,

can explain all viable treatment options to the patient and

come to a treatment decision in accordance with the patient

(joint decision making). During this process, it is important

to inform the patient what to expect from the administered

therapy, which are the possible (and most reported) side ef-

fects, which are the possible interactions with other medica-

tions and who to contact in case of questions or occurrence

of side effects (oncology nurse or prescriber). If desirable,

all information can be assembled into a patient information

booklet.

During therapy, patients with non-metastatic CRPC will un-

dergo repeated review and follow-up until disease progres-

sion. Depending on the status of the patient, the response

to therapy (i.e. PSA concentration and PSA doubling time),

symptomatic improvement, good psychological coping and

good treatment compliance, follow-up should be scheduled

every one, two or three months. It is also recommended to

perform regular imaging, in patient with M0 CRPC who re-

ceive any form of systemic treatment.34 Interim contacts with

the oncology nurse can also be scheduled if desired or need-

ed. Also make sure the family physician is informed follow-

ing every follow-up visit of the patient.

METASTATIC CRPC CONFIRMATION OF DIAGNOSIS AND TREATMENT INITIATIONUnfortunately, almost all prostate cancer patients will suffer

from metastatic CRPC throughout the course of their dis-

ease.35 As stated for the confirmation of absence of metastases

in non-metastatic CRPC, several imaging modalities can be

used to confirm the metastatic disease status, as has been de-

scribed above (see Confirmation of diagnosis and metastatic sta-

tus). Depending on the visceral and/or bone metastatic status,

several first-line treatment options have been shown to im-

prove OS, namely docetaxel, abiraterone, enzalutamide and

radium-223. Cabazitaxel is an approved second line option

after docetaxel. 8,36-49 In addition, several pain management

therapies and bone therapies (zoledronic acid, denosumab,

calcium / vitamin D) should be considered in order to im-

prove patient’ comfort. Imperative when giving bone therapy,

is that possible occurrence of bone therapy-induced compli-

cations such as osteonecrosis of the jaw are strictly monitored

(e.g. via expert stomatologic control).17,31,50 Lastly, clinical tri-

als should also be considered.

It is important to stress the role of the multidisciplinary

team in this phase of the process. Due to the extent of first-

line treatment options available for patients with metastatic

CRPC, it is greatly recommended to discuss every patient in

order to select the optimal treatment regimen per patient.25

Which therapy is given greatly depends on the physical con-

ditions of the patient. In this matter, ECOG and/or Karnofsky

performance status, pain assessment as well as the G8 health

status screening tool have to be checked whether or not pa-

tients are fit enough to receive systemic therapy for their ill-

ness or should receive best supportive care (BSC).

Comparable to patients with non-metastatic CRPC, joint deci-

sion making will lead to the optimal and preferred treatment

choice for the patient. Depending on the type of treatment

initiated, the patient should be thoroughly informed. Next to

all above-mentioned essential information that has to be re-

ported to the patients, special attention must be given to the

risk of spinal cord compression.51

Next, if desired by the patient, psychological support as well

as support at home can be provided. If possible, and if ap-

REVIEW ONCOLOGY

VOLUME13OCTOBER2019

223propriate, introduce end of life planning with the patient

covering the following basics: vital testament, legal issues,

financial issues, religious issues and BSC. The role of the on-

cology nurse in this stadium of the process is very import-

ant as he/she will function as the primary point of contact

with the patient and as liaison between patients and the at-

tending physician.

Finally, follow-up / assessment should be planned. Depend-

ing on the status of the patient, the response to therapy (i.e.

PSA concentration and PSA doubling time), symptomatic im-

provement, good psychological coping and good treatment

compliance, follow-up should be scheduled every one, two

or three months. It is also recommended to perform regu-

lar imaging (every 6 months at least), in patients who receive

any form of systemic treatment.34 Interim contacts with the

oncology nurse can also be scheduled if desired or needed.

Also make sure the family physician is informed following

every follow-up visit of the patient.

METASTATIC CRPC TREATMENT ASSESSMENT/ESCALATIONDuring follow-up for treatment of metastatic CRPC, a full

clinical evaluation must be performed as described previ-

ously (see Confirmation of diagnosis and metastatic status) with

special attention to pain assessment and treatment-related

adverse events. Comparable to assessment in patients with

non-metastatic CRPC, several biochemical test are manda-

tory to evaluate the disease status: testosterone / PSA (eval-

uation biochemical disease progression), serum creatinine

(possible bilateral ureteral obstruction or bladder retention),

liver enzymes (assessment treatment toxicity), calcium / vi-

tamin D (assessment of possible induced osteoporosis), CRP

(adverse prognostic factor in metastatic CRPC) and INR (eval-

uate blood coagulation in case of disseminated intravascular

coagulation or treatment with oral anticoagulants in com-

bination with enzalutamide).8,17,52 Additionally, presence of

new metastases or progression of metastases already present

at first-line metastatic treatment initiation can be monitored

using CT imaging and bone scan. If required, a MRI scan

of the given segment of the axial skeleton can be performed

whereas whole body MRI is not recommended.4-6

Patient having a clinically good evaluation and who do not

progress on their current therapy should be followed-up at

regular time intervals (1-3 months). Unfortunately, patients

will be faced with disease progression at some time during

their first-line therapy. At that point, it has to be decided,

by means of multidisciplinary team meeting, if further-line

treatment is a viable option for the patient in question based

on the patient’s disease, physical conditions, ECOG and/or

Karnofsky performance status, pain assessment and, if need-

ed the G8 health status screening tool.25 Patients in whom

systematic therapy is not / no longer an option, should re-

ceive BSC.

If second-line therapy is initiated, numerous treatment mo-

dalities are available, namely and depending on first-line

treatment received, docetaxel, abiraterone, enzalutamide, ra-

dium-223 and cabazitaxel.53-60 Comparable to first-line treat-

ment initiation, choice for therapy should be made via joint

decision making in which patients are sufficiently informed

concerning risk and possible expectations (contact with on-

cology nurse). In addition, pain management therapies and

bone therapies should be considered in order to improve pa-

tient comfort and clinical trials should also be considered

with great attention to possible bone therapy-induced com-

plications.17,31,50 If not yet done earlier in the process, intro-

duce psychological support, support at home or end of life

planning.

Follow-up and reassessment of patients at regular time in-

terval should be continued as long as patients are treated for

their metastatic CRPC. In case of third- or further-line thera-

pies, multidisciplinary meetings are vital to discuss the most

optimal treatment modality at that time. Research has proven

that enzalutamide shows an objective response rate of 23% in

fourth- or fifth-line therapy.61 Whether a docetaxel re-chal-

lenge is useful in further-line remains to be determined.62

Eventually, all patients will progress in such matter that no

therapeutic options remain and BSC should be offered.

BEST SUPPORTIVE CAREAlong the pathway, patients with metastatic CRPC will no

longer benefit from therapy or are no longer fit to receive

therapy. At that time, only BSC (palliative care) should be

offered to the patients. The World Health Organization de-

fines palliative care as ‘an approach that improves the quality of

life of patients and their families facing the problem associated with

life-threatening illness, through the prevention and relief of suffer-

ing by means of early identification and impeccable assessment

and treatment of pain and other problems, physical, psychosocial

and spiritual.63 Therefore in order to offer BSC to our patients,

physicians can perform a full clinical evaluation at final fol-

low-up to assess general symptoms, ongoing adverse events,

co-morbidities and (treatment-related) complications.

In general, BSC should be considered at home. If desired by

the patient, further follow-up can be planned with the attend-

ing physician. Depending on the clinical evaluation and the

needs of the patient, additional therapy (e.g. analgesics, ra-

diotherapy, etcetera) can be prescribed for symptom manage-

ment, pain management, and anxiety or depression.8 Contact

with the oncology nurse is further encouraged so patients

still have a link with the attending physician and medication

VOLUME13OCTOBER20196

224

can be adjusted in case of increased pain, anxiety, etcetera.

In terms of patient comfort, following items (if applica-

ble) should be addressed: referral to pain clinic, social sup-

port, psychological support, mobility, Quality-of-Life (e.g.

increased focus on spiritual need64), family support, assis-

tance at home, nutritional needs, complications and end of

life planning.

EXITThe ICP recognises that on some occasions patients leave the

pathway (either permanently or temporarily). This informa-

tion should be recorded into the patient medical file. Possible

reasons for exiting the ICP are: admitted to hospital, trans-

ferred care elsewhere, death and lost to follow-up.

PITFALLS ACCORDING TO THE STEERING GROUP TOWARDS NATIONAL IMPLEMENTATION OF THE CRPC ICPThe steering group reached a consensus that implementation

of such an ICP could indeed improve patient care with high-

er standardisation throughout CRPC patient care. However,

several items are in need of review in order to enable full im-

plementation of an ICP in Belgian hospitals:

Need of ICP in hospitals already exhibiting high levels of

standards for care? Probably only parts of ICP should be im-

plemented, can be adapted to every centre and can have dif-

ferent accents for every multidisciplinary team.

Practical implementation: will the ICP be able to integrate

within electronic patient files already implemented in the

hospital? Or will this lead to more (repetitive) administra-

tive work?

What about inconsistencies between types of electronic pa-

tient files used throughout Belgian hospitals and, in aspect

to data sharing between hospitals, will this be in compliance

with current GDPR requirements?

High need for constant review of the ICP as the field of pros-

tate cancer is continuously changing. ICP and accompany-

ing guidelines should be reviewed at least every 12 months.

CONCLUSIONSWe propose the implementation of an ICP for CRPC in Bel-

gium. This could lead towards improved patient care and

high standardisation throughout Belgian centres. It has been

agreed within the steering committee that the proposed ICP

is acceptable for Belgian implementation and could lead to-

wards further standardisation of cancer care for CRPC pa-

tients in Belgium, although several important matters have

to be discussed / adapted in order to allow implementation

of the ICP. Further assessment and inter-hospital delibera-

tion seems required to ensure a national implementation of

the CRPC ICP.

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KEY MESSAGES FOR CLINICAL PRACTICE

1. Castrate-resistant prostate cancer (CRPC) is characterised by complex strategies for therapy and follow-up.

2. Implementation of an integrated care pathway (ICP) for CRPC could lead towards improved patient care and high standardisation throughout Belgian centres.

3. Various stages of the ICP can be used depending on the disease status of the patient.

4. ICP can easily be integrated in the electronic patient files used throughout hospitals.

5. Further assessment and inter-hospital deliberation seems required to ensure a national implementation of the CRPC ICP.

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29. Luo J, Beer T, Graff J. Treatment of nonmetastatic castration-resistant pros-

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33. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, dou-

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2018;36(6 Suppl);3-3.

34. Parker C, Gillessen S, Heidenreich A, et al. Cancer of the prostate: ESMO

clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol

2015;26 Suppl 5;v69-77.

35. Scher H, Solo K, Valant J, et al. Prevalence of prostate cancer clinical states

and mortality in the United States: Estimates using a dynamic progression mod-

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trone plus prednisone for advanced prostate cancer: Updated survival in the

TAX327 study. J Clin Oncol 2008;26(2);242-5.

37. Horgan A, Seruga B, Pond G, et al. Tolerability and efficacy of docetaxel in

older men with metastatic castrate-resistant prostate cancer (mCRPC) in the

TAX327 trial. J Geriatr Oncol 2014;5(2):119-26.

38. Tannock I, de Wit R, Berry W, et al. Docetaxel plus prednisone or mitoxan-

trone plus prednisone for advanced prostate cancer. N Engl J Med

2004;351(15):1502-12.

39. Rathkopf D, Smith M, de Bono J, et al. Updated interim efficacy analysis and

long-term safety of abiraterone acetate in metastatic castration-resistant pros-

tate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol

2014;66(5):815-25.

40. Ryan C, Smith M, de Bono J, et al. Abiraterone in metastatic prostate can-

cer without previous chemotherapy. N Engl J Med 2013;368(2):138-48.

41. Ryan C, Smith M, Fizazi K, et al. Abiraterone acetate plus prednisone versus

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tion-resistant prostate cancer (COU-AA-302): Final overall survival analysis of a

randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol

2015;16(2):152-60.

42. Smith M, Rathkopf D, Mulders P, et al. Efficacy and safety of abiraterone ac-

etate in elderly (75 years or older) chemotherapy naive patients with metastatic

castration resistant prostate cancer. J Urol 2015;194(5):1277-84.

43. Beer T, Armstrong A, Rathkopf D, et al. Enzalutamide in men with chemo-

therapy-naive metastatic castration-resistant prostate cancer: Extended analy-

sis of the phase 3 PREVAIL study. Eur Urol 2017;71(2):151-54.

44. Beer T, Armstrong A, Rathkopf D, et al. Enzalutamide in metastatic prostate

cancer before chemotherapy. N Engl J Med 2014;371(5):424-33.

45. Graff J, Baciarello G, Armstrong A, et al. Efficacy and safety of enzalutamide

in patients 75 years or older with chemotherapy-naive metastatic castration-re-

sistant prostate cancer: Results from PREVAIL. Ann Oncol 2016;27(2):286-94.

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radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol

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47. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and surviv-

al in metastatic prostate cancer. N Engl J Med 2013;369(3):213-23.

48. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on

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line therapy for patients with metastatic castration-resistant prostate cancer: A

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52. Ito M, Saito K, Yasuda Y, et al. Prognostic impact of c-reactive protein for de-

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53. de Bono J, Logothetis C, Molina A, et al. Abiraterone and increased surviv-

al in metastatic prostate cancer. N Engl J Med 2011;364(21):1995-2005.

54. Fizazi K, Scher H, Molina A, et al. Abiraterone acetate for treatment of met-

astatic castration-resistant prostate cancer: Final overall survival analysis of the

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cet Oncol 2012;13(10):983-92.

55. Harland S, Staffurth J, Molina A, et al. Effect of abiraterone acetate treatment

on the quality of life of patients with metastatic castration-resistant prostate can-

cer after failure of docetaxel chemotherapy. Eur J Cancer 2013;49(17):3648-57.

56. Sternberg CN, Molina A, North S, et al. Effect of abiraterone acetate on fa-

tigue in patients with metastatic castration-resistant prostate cancer after

docetaxel chemotherapy. Ann Oncol 2013;24(4):1017-25.

57. Scher H, Fizazi K, Saad F, et al. Increased survival with enzalutamide in pros-

tate cancer after chemotherapy. N Engl J Med 2012;367(13):1187-97.

58. Hoskin P, Sartor O, O’Sullivan J, et al. Efficacy and safety of radium-223 di-

chloride in patients with castration-resistant prostate cancer and symptomatic

bone metastases, with or without previous docetaxel use: A prespecified sub-

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and palliation of tumour-related pain in men with metastatic castration-resistant

prostate cancer treated in the TROPIC trial. Ann Oncol 2013;24(9):2402-8.

60. de Bono J, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or

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ALL PUBLISHED BJMO ARTICLES ARE AVAILABLE ON OUR WEBSITE:

WWW.ARIEZ.COMAs well as all published articles from our other medical journals.

REVIEW ONCOLOGY

VOLUME13OCTOBER20196

227

SUMMARYSoft tissue sarcomas represent 75% of all sarcomas and constitute a group of more than 50 different histo-logical subtypes, with an even greater number of molecular subtypes. Localised STSs are generally treated by surgery followed, or preceded, by radiotherapy and according to criteria linked with the risk of local re-currence. Metastatic STSs are principally treated by systemic treatments such as chemotherapy and targe-ted drugs. The most important drugs used are doxorubicin, ifosfamide, dacarbazine, gemcitabine/docetaxel, eribulin and trabectedin; but also pazopanib. The place of localised treatments (surgery, radiotherapy, ra-diofrequency, etc.) in this setting is reserved for oligometastatic disease. A multidisciplinary approach is mandatory, with centralisation of all cases in reference centres, as early as at the time of clinical diagnosis of a suspected sarcoma. This ‘centralised’ approach, for this rare and complex disease, has an impact on the oncologic outcomes (quality of resection and overall survival) of patients.(BELG J MED ONCOL 2019;13(6): 227-233)

1Department of Medical Oncology, CHU Sart-Tilman, Liège, Belgium, 2Liège University, Liège, Belgium.

Please send all correspondence to: C. Gennigens, MD, department of Medical Oncology, University Hospital (CHU de Liège), Avenue de l’hôpital

1, 4000 Liège, Belgium, tel: +32 43667801, email: Christine.gennigens@chuliege.be.

Conflict of interest: C. Gennigens reports grants and personal fees from Roche, Pfizer, Pharmamar, Lilly, Novartis, Astra-Zeneca, Ipsen;

personal fees from Janssen-CILAG, BMS and MSD; grants from Eisai; outside the submitted work. G. Jerusalem reports grants, personal fees

and non-financial support from Novartis; grants, personal fees and non-financial support from Roche; personal fees and non-financial support

from Pfizer; personal fees and non-financial support from Lilly; personal fees from Celgene; personal fees and non-financial support from Amgen;

personal fees and non-financial support from BMS; personal fees from Puma Technology; personal fees and non-financial support from Astra-

Zeneca; personal fees from Daiichi Sankyo; personal fees from Abbvie, outside the submitted work.

Keywords: Chemotherapy, diagnosis, radiotherapy, soft-tissue sarcoma, surgery.

C. Gennigens, MD1, G. Jerusalem, MD, PhD1,2

State of the art in the treatment of soft tissue sarcomas

INTRODUCTIONAdult sarcomas represent a group of rare and highly het-

erogeneous malignant tumours of mesenchymal origin, that

account for approximately 1% of adult malignancies. The ma-

jority of sarcomas arise from soft tissue (75%); the remaining

sarcomas are 15% gastrointestinal stromal tumours (GISTs)

and 10% bone sarcomas. The world-age standardised inci-

dence rates are in the range of 1.5-3/100,000/year for soft tis-

sue and 0.5-2/100,000/year for bone sarcomas.1

Soft tissue sarcomas (STSs) constitute a group of more than

50 different histological subtypes, classified according to the

soft tissue of origin, with an even greater number of molecu-

lar subtypes. The most common histologies are leiomyosar-

coma (LMS), undifferentiated pleomorphic sarcoma (UPS)

and liposarcoma (LPS).2

Most of these tumours appear in the limbs; however, they

can occur in any part of the body (abdominal cavity, retro

peritoneum, thorax or head and neck). The incidence of de

novo metastatic disease is around 10%; twenty-five to 30%

of patients will develop metastases after the initial curative

treatment. The majority of these metastases are located in

the lungs. Hardly any patients with resectable oligometa-

static disease can be potentially cured, or given prolonged

remission. Although the majority of patients with metasta-

PRACTICE GUIDELINES

VOLUME13OCTOBER2019

228ses will unfortunately die, systemic therapy is recommended

in fit patients, as it probably prolongs survival (in first-line,

no randomised trials comparing chemotherapy versus only

best supportive care exist) and offers palliation that decreas-

es symptoms and improves quality of life.

DIAGNOSISOne of the most important first steps in the optimal care of

STSs is to ‘think about sarcoma’. Indeed, if the surgeon op-

erates without this idea, the risk of unplanned excision in-

creases and this is associated with a negative impact on the

survival of the patient. In addition, it is mandatory to have

an early discussion within a specialised Multidisciplinary Tu-

mour Board (MDTB) before any ‘technical’ acts and/or treat-

ments take place, once more with the goal of improving the

survival rate of patients.3

Ultrasound could be an interesting option for initial evaluation

of soft tissue mass (dimension, depth, internal echotexture

and vascularity, etc.). In localised STSs, magnetic resonance

imaging (MRI) is the main imaging modality used in the ex-

tremities, pelvis and trunk. Assessment of tumour extent is

essential for surgical planning. Misjudgement of tumour mar-

gin may up-stage or down-stage of tumour and may influence

patient prognosis. On conventional MRI, it is not clear if per-

itumoural high signal intensity represents tumour infiltra-

tion or simply reactive change. Diffusion Weighted Imaging

(DWI) could be interesting, revealing additional information

regarding peritumoural tissue, especially at the cellular level

with impact on the assessment of tumour extent. Dynamic

Contrast Enhanced (DCE) MRI gives information on tissue

perfusion, vascularisation and capillary permeability; it al-

so differentiates between the tumour and the peritumoural

oedema. Computed tomography can also play a role in retro-

peritoneal tumours and for all the distant staging. 18F 2-flu-

oro-2-deoxy-D-glucose (18F-FDG) positron emission tomography

is probably a valuable exam in initial staging of the sarcoma,

in identifying the target area of biopsy, detecting metastasis

and in assessing treatment response but its precise role is

not yet fully established. Concerning lung metastases, it has

lower sensitivity but higher specificity compared to CT alone.

Following appropriate imaging assessment, the standard ap-

proach to diagnosis consists of multiple percutaneous core

needle biopsies, using 14–16G needles, with a co-axial tech-

nique. These biopsies should be carried out by a radiologist,

or a surgeon, after a multidisciplinary discussion. It should

be planned in such a way that the biopsy pathway and the

scar can be safely removed by definitive surgery (except for

retroperitoneal sarcomas (RPSs) where the biopsies should

be performed via a posterior/lateral approach and never by a

trans-peritoneal one). The biopsy entrance point can be tat-

tooed. The collection of fresh frozen tissue is encouraged to

allow for further molecular tests, if necessary. The role of fine

needle aspiration biopsy is limited, because of small amount

of tissue, not allowing for the evaluation of tissue architecture,

and additional analyses such as molecular testing. The debate

is still ongoing between core needle biopsy or open biopsy.

But, image guided core needle biopsy can be performed with

less complications, less risk of contamination, morbidity and

cost compared to open biopsy, giving good tissue samples.4

Pathological diagnosis should be made according to the 2013

World Health Organization classification. In all cases where

the first diagnosis was not made in a reference centre/net-

work, a pathological expert validation is recommended; this

is due to the therapeutic implications of a misdiagnosis, in

particular for benign lesions, carcinomas or sarcomas re-

quiring chemotherapy at an early phase. This principle is

accurately described in the following trial based on the his-

tological data of 1,463 patients collected in France and Ita-

ly over a 2-year period. Initial diagnoses were systematically

compared with second opinions (SO) from regional and na-

tional experts. The results showed full concordance between

primary diagnosis and SO in 56% of cases, partial concor-

dance (identical diagnosis of connective tumour but different

grade or histological subtype) in 35% of cases and complete

disagreement (benign versus malignant, different histologi-

cal type or invalidation of the diagnosis of sarcoma) in 8% of

all cases. In conclusion, more than 40% of first histological

diagnoses were modified at second reading, possibly result-

ing in different treatment decisions.5

After definitive surgery, the pathologist should share informa-

tion on whether the tumour was intact and should include an

appropriate description of the tumour margins (i.e. the dis-

tance in millimetres between the tumour edge and the closest

inked margins) and the grade of the tumour. Of note, defini-

tive diagnosis may require cytogenetic or molecular analysis

for chromosomal translocations.

REFERENCE CENTRESThe management of sarcomas should be organised in refer-

ence centres for sarcomas and/or in reference networks shar-

ing multidisciplinary expertise. This ‘centralised approach’

should begin as early as at the time of the clinical diagnosis

of a suspected sarcoma. In practice, the referral of all patients

with a lesion likely to be a sarcoma should be recommended.

The results of the trial published by JY Blay et al. on the bene-

fits of a pre-therapeutic specialised Multidisciplinary Tumour

Board (MDTB) supports this principle. Indeed, compliance

with clinical practice guidelines and the relapse-free surviv-

al of sarcoma patients are significantly better when the initial

treatment is guided by these specialised MDTB.3

VOLUME13OCTOBER20196

229PRACTICE GUIDELINES

In an oral session at ESMO 2018, JY Blay et al. presented re-

search, based on 35,784 patients, about the impact of treatment

in reference centres. The Local-Recurrence-Free-Survival

(LRFS), RFS at 2 years (66% and 59% respectively), overall

survival (OS) and quality of resection (53% R0 vs. 15.9%) are

better in these centres. This trial demonstrated a 36% reduc-

tion of the risk of death and a 46% reduction in the risk of re-

lapse. In conclusion, treatment in reference centres is “clearly

the simplest and cheapest way to improve survival from these

orphan tumours”.6

MANAGEMENT OF LOCAL/REGIONAL DISEASESURGERYSurgery is the standard treatment for all patients with a lo-

calised STS. It must be carried out by an expert surgeon who

has been specifically trained in the treatment of this disease.

The standard surgical procedure is a wide, en bloc excision

with clear negative margins (R0).

Reoperation in reference centres must be considered in the

case of R1 resections, if adequate margins can be achieved

without major morbidity. In the case of R2 surgery, reopera-

tion in reference centres is also mandatory, probably follow-

ing preoperative treatment if adequate margins cannot be

achieved or if surgery is mutilating. Isolated hyperthermic

limb perfusion could be considered in this latter case, but in

a very select number of cases.

NEO-ADJUVANT OR ADJUVANT TREATMENTSRadiotherapy

The standard treatment of localised STS is a wide excision

followed by radiotherapy (RT) in cases of high-grade (G2–3)

and deep tumours with a size of more than 5 cm.

For extremity STS, early studies showed that wide local ex-

cision (WLE) alone was associated with local recurrence

rates as high as 30-50%. Due to this, amputation became

common practice until the use of perioperative RT allowing

limb-sparing surgery. Another very old trial compared ampu-

tation with WLE and RT in patients with high-grade extrem-

ity STS. Despite a local recurrence rate of 15% with WLE and

RT and 0% with amputation, there was no difference in OS.7

Because of the lack of survival benefit, WLE and RT became

the standard for primary high-grade extremity STS.

The timing of RT (preoperative or postoperative), remains a

controversial issue and only one, dated, randomised trial has

explored this question. In this trial, O-Sullivan et al. demon-

strated, by studying 180 patients with limb sarcoma, that lo-

cal control and survival are not influenced by the timing of

RT, but that there are more early complications in the preop-

erative arm and more late complications in the postoperative

arm.8 Indeed, preoperative RT lowered the rates of long-term

fibrosis and improved joint mobility compared with post-

operative RT; this may be attributed to the smaller volume

of irradiated tissue and the lower RT doses. A disadvantage

of preoperative RT, is the increased rate of wound compli-

cations. The doses and the volumes of RT are different be-

tween the two treatments: 50Gy (tumour plus a margin) in 5

weeks (and smaller volumes) in the preoperative setting and

66Gy over 7 weeks in the postoperative setting. The timing

should be influenced by the tumour’s characteristics, such

as site of origin, preservation function, the histologic sub-

type (myxoid liposarcoma is known for its exceptional sen-

sitivity to radiation), grade and size, as well as the patient’s

characteristics such as old age, smoking, obesity, diabetes

and vascular insufficiency, all known to have a negative ef-

fect on wound healing.

The place of RT in the RPSs is still under investigation. The

results of the STRASS trial (NCT01344018) are eagerly await-

ed. This phase III study is comparing surgery vs. RT followed

by surgery, in non-metastatic RPS.

Chemotherapy

While adjuvant and neo-adjuvant chemotherapy (CT) for

paediatric sarcomas (rhabdomyosarcoma, ewing’s sarcoma

and osteosarcoma) has been established, it’s role in adult-

type sarcomas remains controversial. There is no consensus

on the current role of adjuvant chemotherapy in adult STSs.

It is a major issue because more than half of the high-risk pa-

tients with adequate local control of the disease develop dis-

tant metastases. More than 20 studies on adjuvant therapy

have been performed, but these trials have reported conflict-

ing data; most of them have been small-scale, lacked statis-

tical power to detect small changes in OS, enrolled different

risk patients and treated patients with different CT regimens.

Meta-analyses by the Sarcoma Meta-Analysis Collaboration

were made (first in 1997 and updated in 2008 with 18 ran-

domised trials and 1,953 patients) and showed odds ratios

(OR) for local recurrence of 0.73, and for distant and overall

recurrence of 0.67, all in favour of CT with doxorubicin plus

ifosfamide. However, the impact of this chemotherapy on

survival is modest, with an absolute risk reduction of death

from 46% to 40% (p<0.05).9

Another pooled analysis of two large studies, by EORTC, on

819 patients treated with doxorubicin plus ifosfamide-based

CT, was negative. RFS and OS were only improved in the in-

completely resected group (R1).10

Adjuvant CT could be proposed to high-risk individual pa-

tients (deep, grade 3 and more than 5 cm tumour), taking

into account the site of the disease, size, grade, histological

subtype and chemosensitivity but also the comorbidities and

VOLUME13OCTOBER2019

230the age of patients; all factors to be considered in the frame-

work of a shared decision making process. “SARCULATOR”

(www.sarculator.com) could be a useful tool in prognosis.

CT can also be used in a neo-adjuvant setting, with goals

such as reducing the size of the tumour and therefore facil-

itating its removal, providing chemosensitivity information

and killing microscopic metastatic disease.

A recent Italian trial, including 289 patients, compared pre-

operative CT with full-dose epirubicin plus ifosfamide vs. his-

tology-tailored CT. This trial was prematurely ended due to

interim analysis that showed a statistically significant benefit

in terms of both RFS and OS in favour of the epirubicin and

ifosfamide CT arm. Indeed, RFS is 62% (vs. 38% in the con-

trol group) and OS rates at 3 years were 64% vs. 89% in fa-

vour of epirubicin plus ifosfamide. In myxoid-round-cell LPS,

the trabectedin arm showed equivalent results to the epiru-

bicin plus ifosfamide arm and could thus be an alternative

treatment option in this specific histology.11

MANAGEMENT OF ADVANCED/METASTATIC DISEASESURGERYThe majority of metastases are located in the lungs. In cases

of metachronous lung metastases, without extrapulmonary

disease, surgery is recommended if all the metastases can

be removed. In cases of synchronous metastases, without

extrapulmonary disease, CT is the standard treatment, fol-

lowed by resection of residual lung metastases. Other local

treatments in case of oligometastatic disease, such as radiof-

requency ablation or radiosurgery, must not be overlooked.

CHEMOTHERAPYSome patients with metastatic STS may remain asymptom-

atic for a long period, even without treatment. This group

of patients may just be watched closely, particularly if they

have a low disease burden. STSs have various responses to

therapy because of multiple histological types. Selection of a

treatment regimen must be based on several factors, includ-

ing histology, disease biology and patient preferences.

First-line

For the majority of patients with unresectable metastatic dis-

ease, systemic therapy is administered with palliative inten-

tion. For more than 30 years, doxorubicin-based CT has been

the cornerstone and standard treatment, regardless of his-

tology subtypes.

In comparison with doxorubicin alone, doxorubicin plus if-

osfamide increase the response rate (RR) but without impact

on OS.12 This lack of OS advantage and the higher rates of

toxicities do not support its routine use in the setting of ad-

vanced incurable disease unless there is a need to decrease

tumour bulk, improve symptoms or lead to resection, espe-

cially in CT sensitive subtypes. It is important to underline

the fact that ifosfamide is not useful in LMS. In this latter case,

doxorubicin plus dacarbazine could be proposed.

A recent phase Ib/II study compared doxorubicin with or

without olaratumab (an antibody directed against platelet-de-

rived growth factor receptor alpha) in a metastatic setting

and demonstrated a statistically significant higher OS (14.7

vs. 26.5 months) in the combination arm, without significant

benefit in PFS and RR.13 The results of the phase III (AN-

NOUNCE) study have just been revealed and showed that

there was no difference in OS between the two arms. There-

fore, olaratumab should not be proposed to new patients out-

side clinical trials.

The GEDDIS phase III study compared doxorubicin with

the combination of gemcitabine and docetaxel. The combi-

nation failed to show any improvement in PFS and objective

response rate; no differences in efficacy were found between

histology subtype groups, such as LMS or non-LMS.14

Second and later lines

Best supportive care alone is an alternative for unfit patients,

especially if standard late-line therapies have already been

used on the patient. Inclusion in clinical trials should be fa-

voured for fit patients.

Patients who have already received standard-dose (9 g/m2) if-

osfamide (if they did not progress on it previously) could still

receive high-dose ifosfamide (14 g/m2), in some specific sub-

types sensitive to this drug (synovialsarcomas, MPNST).15,16

Trabectedin is an option for third line (or before, in case of pa-

tients not able to receive doxorubicin and/or ifosfamide) and

beyond, and is effective in several sarcoma subtypes but es-

pecially in L-sarcomas (Lipo- and Leiomyo-sarcomas).17 Ef-

ficacy of Eribulin was shown in a randomised phase III trial

which studied eribulin vs. dacarbazine in patients with LPS

and LMS. The median OS was 13.5 vs. 11.5 months in favour

of eribulin, but a subgroup analysis showed that it reached

15.6 months (vs. 8.4 months) in LPSs and even 22.2 months

in pleomorphic LPS subtype.18 Eribulin is only reimbursed

in LPS histology. Gemcitabine/docetaxel seemed to be more ef-

fective than gemcitabine alone as second-line CT19, but these

data have not been confirmed (equivalence in response rate,

PFS and OS) in a second randomised trial conducted in LMS

only.20 In both trials, toxicity was superior in the combina-

tion arm.

Gemcitabine in combination with dacarbazine demonstrated,

in a phase II trial, a better objective response (49 vs. 25%) and

mOS (16.8 vs. 8.2 months) than dacarbazine alone.21

Pazopanib is another option; the PALETTE phase III ran-

VOLUME13OCTOBER20196

231PRACTICE GUIDELINES

domised trial, studying 369 patients with non-adipogenic

sarcomas, showed a PFS benefit of 3 months in the pazo-

panib arm (4.6 months vs. 1.6 months in the placebo arm).22

The future is, nevertheless, a ‘niche’ approach with specif-

ic drugs (CT or targeted therapies) for specific sarcoma sub-

types. Table 1 attempts to summarise potential treatment

pathways, mainly based on early phase studies. It must how-

ever be noted that the majority of these drugs are not cur-

rently reimbursed.

Radiotherapy

RT should be used as a palliative resource in all cases when

appropriate to the clinical need (e.g. bone lesions at risk of

fracture, painful metastases, etc.).

Immunotherapy

Immunotherapy has been one of the major breakthroughs

in oncology, but for STS the efficacy remains controversial.

Tumour PD-L1 expression has been reported in up to 65%

of different subtypes of sarcomas and the degree of PD-L1

expression in tumour specimens from 105 cases of STS has

been correlated with poorer prognosis and more aggressive

disease.31

In the SARC028 phase II study, 40 patients with high-grade,

metastatic STS, and 40 patients with bone sarcoma, were en-

rolled to receive pembrolizumab until progression. This trial

suggested a potential benefit for UPS, with a response rate of

40%, higher than other histological subtypes.32

CONCLUSIONSSTS is not a single disease but represents a group of more

than 50 different histological and molecular subtypes. Given

the implications of a misdiagnosis, an expert validation by a

pathologist is recommended in all cases when the first diag-

nosis was made outside a centre of excellence.

Localised STSs are treated by surgery followed, or preceded,

by RT in some cases. Neo- or adjuvant CT is still a contro-

versial subject. Metastatic STSs require systemic treatments

(doxorubicin, ifosfamide, trabectedin, gemcitabine/docetaxel,

eribulin, dacarbazine) such as chemotherapy or targeted

therapies (pazopanib). Doxorubicin is the cornerstone of

treatment, especially in first-line treatment.

A multidisciplinary approach is mandatory, with centralisa-

tion of all cases in reference centres, as early as at the time

of the clinical diagnosis of a suspected sarcoma. This ‘cen-

tralised’ approach, for this rare and complex disease, has an

impact on the oncologic outcomes (quality of resection and

overall survival) of patients. Belgium should copy the beau-

tiful example of France with its NETSARC network.3,33

REFERENCES1. Stiller CA, Botta L, Brewster DH, et al. Survival of adults with cancers of bone

or soft tissue in Europe-Report from the EUROCARE-5 study. Cancer Epidemi-

ol. 2018;56:146-53.

2. Sbaraglia M, Dei Tos AP. The pathology of soft tissue sarcomas. Radiol.Med.

2019;124(4):266-81.

3. Blay JY, Soibinet P, Penel N, et al. Improved survival using specialized multi-

TABLE 1. ‘Niche’ approach with specific drugs in sarcoma subtypes.

Histology Targets Agents

Dermatofibrosarcoma protuberans

PECOMAS

Giant Cell Tumor

Well-differentiated/dedifferentiated LPS

Pigmented villonodular synovitis and diffu-se-type giant cell tumour

Inflammatory myofibroblastic tumour

Alveolar STS

Angiosarcoma

Solitary fibrous tumour

t(17-22) PDFGR

mTOR/TSC1,2

RANK/RANKL

CDK4 ?

t(1-2) CSF1

ALK translocations

VEGFR?

Imatinib23

Rapamycin inhibitors24

Denosumab25

Palbociclib?26

Imatinib/ Anti-CSF127

Crizotinib28

Anti-VEGFR?

Paclitaxel29, Gemcitabine

Dacarbazine30, Sunitinib

VOLUME13OCTOBER2019

232

disciplinary board in sarcoma patients. Ann Oncol 2017;28:2852-9.

4. Patel DB, Matcuk GR, Jr. Imaging of soft tissue sarcomas. Chin Clin.Oncol.

2018;7(4):35.

5. Ray-Coquard I, Montesco MC, Coindre JM, et al. Sarcoma: concordance be-

tween initial diagnosis and centralized expert review in a population-based study

within three European regions. Ann Oncol 2012;23:2442-9.

6. Blay JY, Toulmonde M., Penel N, et al. Natural history of sarcomas and im-

pact of reference centers in the nationwide NETSARC study on 35,784 patients

(pts) from 2010 to 2017. Annals of Oncology 29 (suppl_8), vii576-vii595. 2018.

7. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sar-

comas of the extremities: prospective randomized evaluations of (1) limb-spar-

ing surgery plus radiation therapy compared with amputation and (2) the role of

adjuvant chemotherapy. Ann Surg 1982; 196:305-15.

8. O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative

radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet

2002;359:2235-41.

9. Pervaiz N, Colterjohn N, Farrokhyar F, et al. A systematic meta-analysis of ran-

domized controlled trials of adjuvant chemotherapy for localized resectable soft-

tissue sarcoma. Cancer 2008;113:573-81.

10. Lecesne A, Ouali M, Leahy MG, et al. Doxorubicin-based adjuvant chemo-

therapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III

clinical trials. Ann Oncol 2014;25:2425-32.

11. Gronchi A, Ferrari S, Quagliuolo V, et al. Histotype-tailored neoadjuvant che-

motherapy versus standard chemotherapy in patients with high-risk soft-tissue

sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled,

phase 3, multicentre trial. Lancet Oncol 2017;18:812-22.

12. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensi-

fied doxorubicin plus ifosfamide for first-line treatment of advanced or metastat-

ic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol

2014;15:415-23.

13. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus

doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b

and randomised phase 2 trial. Lancet 2016;388:488-97.

14. Seddon B, Strauss SJ, Whelan J, et al. Gemcitabine and docetaxel versus

doxorubicin as first-line treatment in previously untreated advanced unresect-

able or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled

phase 3 trial. Lancet Oncol 2017;18:1397-410.

15. Le Cesne A, Antoine E, Spielmann M, et al. High-dose ifosfamide: circum-

vention of resistance to standard-dose ifosfamide in advanced soft tissue sar-

comas. J.Clin.Oncol. 1995;13(7):1600-8.

16. Lee SH, Chang MH, Baek KK, et al. High-dose ifosfamide as second- or

third-line chemotherapy in refractory bone and soft tissue sarcoma patients. On-

cology 2011;80(3-4):257-61.

17. Demetri GD, von MM, Jones RL, et al. Efficacy and Safety of Trabectedin or

Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of

Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clin-

ical Trial. J Clin Oncol 2016;34:786-93.

18. Schöffski P, Chawla S, Maki RG, et al. Eribulin versus dacarbazine in previ-

ously treated patients with advanced liposarcoma or leiomyosarcoma: a ran-

domised, open-label, multicentre, phase 3 trial. Lancet 2016;387:1629-37.

19. Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcit-

abine and docetaxel compared with gemcitabine alone in patients with meta-

static soft tissue sarcomas: results of sarcoma alliance for research through col-

laboration study 002 [corrected]. J Clin Oncol 2007;25:2755-63.

20. Pautier P, Floquet A, Penel N, et al. Randomized multicenter and stratified

phase II study of gemcitabine alone versus gemcitabine and docetaxel in pa-

KEY MESSAGES FOR CLINICAL PRACTICE

1. STS is not a single disease but represents a group of more than 50 different histological and molecular subtypes.

2. Localised STSs are treated by surgery followed, or preceded, by radiotherapy according to criteria linked with the risk of local recurrence (size, grade, depth).

3. Metastatic STSs require systemic treatments such as chemotherapy (doxorubicin - the cornerstone in first-line, ifosfamide, trabectedin, gemcitabine/docetaxel, eribulin, dacarbazine) or targeted therapies (pazopanib).

4. The future is, nevertheless, a ‘niche’ approach with specific drugs (CT or targeted therapies) for specific sarcoma subtypes.

5. A multidisciplinary approach is mandatory, with centralisation of all cases in reference centres, as early as at the time of the clinical diagnosis of a suspected sarcoma. This ‘centralised’ approach, for this rare and complex disease, has an impact on the oncologic outcomes (quality of resection and overall survival) of patients.

VOLUME13OCTOBER20196

233PRACTICE GUIDELINES

tients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des

Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group Study

(TAXOGEM study). Oncologist 2012;17:1213-20

21. Garcia-Del-Muro X, Lopez-Pousa A, Maurel J, et al. Randomized phase II

study comparing gemcitabine plus dacarbazine versus dacarbazine alone in pa-

tients with previously treated soft tissue sarcoma: a Spanish Group for Research

on Sarcomas study. J.Clin.Oncol. 2011;29(18):2528-33.

22. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-

tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled

phase 3 trial. Lancet 2012;379:1879-86.

23. Stacchiotti S, Pantaleo MA, Negri T, et al. Efficacy and Biological Activity of

Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP). Clin Cancer

Res 2016;22:837-46.

24. Flechter E, Zohar Y, Guralnik L, et al. Long-lasting stable disease with mTOR

inhibitor treatment in a patient with a perivascular epithelioid cell tumour: A case

report and literature review. Oncol Lett 2016;12:4739-43.

25. Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of denosumab

for adults and skeletally mature adolescents with giant cell tumour of bone: in-

terim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol

2013;14:901-8.

26. Dickson MA, Schwartz GK, Keohan ML, et al. Progression-Free Survival

Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treat-

ed With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial. JAMA Oncol

2016;2:937-40.

27. Brahmi M, Vinceneux A, Cassier PA. Current Systemic Treatment Options

for Tenosynovial Giant Cell Tumour/Pigmented Villonodular Synovitis: Targeting

the CSF1/CSF1R Axis. Curr Treat Options Oncol 2016;17:10.

28. Schöffski P, Sufliarsky J, Gelderblom H, et al. Crizotinib in patients with ad-

vanced, inoperable inflammatory myofibroblastic tumours with and without an-

aplastic lymphoma kinase gene alterations (European Organisation for Research

and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospec-

tive, non-randomised phase 2 trial. Lancet Respir Med 2018;6:431-41.

29. Penel N, Bui BN, Bay JO, et al. Phase II trial of weekly paclitaxel for unresect-

able angiosarcoma: the ANGIOTAX Study. J Clin Oncol 2008;26:5269-74.

30. Stacchiotti S, Tortoreto M, Bozzi F, et al. Dacarbazine in solitary fibrous tu-

mour: a case series analysis and preclinical evidence vis-a-vis temozolomide

and antiangiogenics. Clin Cancer Res 2013;19:5192-201.

31. Pollack SM, He Q, Yearley JH, et al. T-cell infiltration and clonality correlate

with programmed cell death protein 1 and programmed death-ligand 1 expres-

sion in patients with soft tissue sarcomas. Cancer 2017;123:3291-304.

32. Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-

tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, sin-

gle-arm, open-label, phase 2 trial. Lancet Oncol 2017;18:1493-501

33. Casali PG, Abecassis N, Bauer S, et al. Soft tissue and visceral sarcomas:

ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and fol-

low-up. Ann.Oncol. 2018;29(Supplement_4):iv51-iv67.

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SUMMARYFor over a decade, oxaliplatin-based adjuvant chemotherapy has been the gold standard for resected early colon cancer. Oxaliplatin is known to cause polyneuropathy, which affects quality of life dramatically. In re-cent years, there has not been any progress in the development of novel agents to replace oxaliplatin as adjuvant therapy. Consequently, there is a growing interest to investigate whether a shorter course of che-motherapy is sufficient. This article will discuss the history of adjuvant treatment in early-resected colon cancer, the toxicity of oxaliplatin, the results from the IDEA meta-analysis and future prospects. (BELG J MED ONCOL 2019;13(6): 234-239)

1Gastroenterology department, ASZ Aalst, Aalst, Belgium, 2Department of Oncology, Antwerp University Hospital, Edegem, Belgium.

Please send all correspondence to: C. Debeuckelaere, MD, ASZ Gastroenterology department, Merestraat 80, 9300 Aalst, Belgium,

email: celine.debeuckelaere@asz.be.

Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest.

Keywords: adjuvant treatment, chemotherapy, colon cancer, duration of chemotherapy, IDEA collaboration.

C. Debeuckelaere, MD1, L. Triest, MD2, T. Vandamme, MD2, B. Van den Heuvel, MD2, K. Papadimitriou, MD2, M. Rasschaert, MD2, H. Prenen, MD, PhD2, M. Peeters, MD, PhD2

Adjuvant chemotherapy of colon cancer: 3 versus 6 months

PHARMACOTHERAPY

INTRODUCTIONColorectal cancer is the third most common cancer world-

wide. Eighty percent of the patients have localised disease at

time of diagnosis and are candidates for surgical resection.

The 5-year survival rate after resection alone is 85-95% in

stage I, 60-80% in stage II and 30-60% in stage III. The risk

of recurrence depends on the pathological stage of the prima-

ry tumour: 30% in stage II and 50% in stage III. The goal of

adjuvant treatment after surgery is to reduce the risk of recur-

rence and improve overall survival (OS). Current guidelines

recommend adjuvant chemotherapy for stage III tumours and

high-risk stage II tumours.1,2 Fluoropyrimidines are the back-

bone of adjuvant chemotherapy for nearly 30 years. Adding

oxaliplatin improved overall survival and disease-free surviv-

al (DFS) but led to increased toxicity.2,3 Especially late onset

polyneuropathy causes an important burden on quality of life

of these patients. As we know that the incidence and severity

of polyneuropathy is correlated with the cumulative dose of

oxaliplatin, it is important to select the right population for

adjuvant treatment and to determine the optimal treatment

duration.4 Identifying prognostic and predictive biomarkers

could help to determine subgroups within stage III and high-

risk stage II patients that benefit from adjuvant treatment.

ADJUVANT TREATMENT THROUGHOUT HISTORYThe first use of adjuvant treatment is based on the results of a

trial in 1990 with levamisole and fluorouracil for 12 months,

in comparison to follow-up in patients with resected colon

cancer with stage II and stage III. The trial showed a signifi-

cant improvement in OS and DFS in the chemotherapy group

in stage III patients. The results in stage II patients were com-

parable but too preliminary to draw any conclusions.5 In the

next few years, fluoropyrimidines were introduced. It was

proven that 6 months of 5-fluoro-uracil/levamisole (5FU/

LV) was superior to 12 months of 5FU/LV in high-risk stage

II and stage III patients.6 The introduction of oxaliplatin to

our standard practice was based on the findings of three tri-

VOLUME13OCTOBER2019

235als: MOSAIC, NSABP C-07 and NO16968. The MOSAIC trial

was a randomised phase III trial in 2,246 patients with cura-

tive resection for stage II and III colon cancer that compared

5FU/LV with 5FU/LV plus oxaliplatin. The rate of DFS at

three years was 78.2% in the group given 5FU/LV plus oxal-

iplatin and 72.9 % in the 5FU/LV group.3,7 The second trial,

NSABP C-07, compared the combination of oxaliplatin and

weekly bolus of 5FU/LV (FLOX) with a weekly bolus of 5FU/

LV alone. For stage III patients there was a benefit in 5-year

DFS (64.4% vs. 57.8%) and 5-year OS (76.5% vs. 73.8%).8,9

The third and last trial, NO16968, compared capecitabine

and oxaliplatin (CAPOX) three-weekly with bolus 5FU/LV

for stage III colon cancer. Also in this study, the combina-

tion of 5FU and oxaliplatin was proven to be more efficacious

with an improvement of 5-year OS (73% vs. 67%).10 Based on

these trials, 6 months of oxaliplatin with fluoropyrimidine is

still the backbone of adjuvant treatment in resected stage III

colon cancer patients since 2004. Interestingly, adding ox-

aliplatin to fluoropyrimidines is not beneficial throughout

the overall population of stage III colon cancer. Low risk pa-

tients (low grade (well or moderately differentiated, or grade

1 or 2 tumours), T1/2 tumours and involvement of ≤ 4 lymph

nodes) have a 5-year DFS of 75% when treated with adjuvant

5-FU alone in comparison with 17% in high risk patients (>

5 lymph nodes, high grade (poorly differentiated, anaplastic,

and grade 3 or 4 tumours), T4 tumours).11 Subgroup analy-

sis of MOSAIC, NSABP C-07 and NO16968 showed no ben-

efit of adding oxaliplatin in patients aged above 70. There

have not been any prospective studies in this population.9,10,12

Moreover, the addition of oxaliplatin is not recommended in

stage II patients. In an updated analysis of the MOSAIC trial,

there was no significant difference in OS and DFS between

both treatment arms.7 There is no evidence for irinotecan or

biological agents (anti-VEGF and anti-EGFR agents) in the

adjuvant setting.13-19

OXALIPLATIN AND NEUROTOXICITYThe addition of oxaliplatin came at the cost of potential

polyneuropathy from which recovery is often incomplete

and affects quality of life dramatically. The neurotoxicity

of oxaliplatin has rather unique characteristics and is the

dose-limiting toxicity (DLT).4 There are two distinct forms of

oxaliplatin-induced neurotoxicity: the acute and mostly re-

versible sensory neuropathy and the chronic cumulative sen-

sory neurotoxicity. The acute form appears during or shortly

after the first administration of oxaliplatin. It consists of dis-

tal or perioral paraesthesia or dysesthesias. They are usually

completely reversible within a few hours or days. Typical fea-

ture for acute neuropathy is that it aggravates or is triggered

by exposure to cold. Preventive measures to cold should be

discussed before starting treatment with oxaliplatin.20 The

chronic form is due to cumulative sensory neurotoxicity and

is of clinical relevance, as it is an important reason for dose re-

duction or even cessation of oxaliplatin. In the MOSAIC trial,

12% of patients experienced grade 3 neurotoxicity one year

after treatment. Grade 1 and 2 neurotoxicity two years after

oxaliplatin was approximately 50%.3 Neurotoxicity is an im-

portant adverse event that affects quality of life. In a survey,

86 patients with colorectal cancer receiving oxaliplatin and

capecitabine, completed a detailed questionnaire after each

chemotherapy cycle. Grade 3 dysesthesia and paraesthesia

was seen in 5 and 7%. After 3 months (6 cycles) 80% of the

patients still received full dose. After 6 months of treatment,

62.5% needed a dose reduction or discontinuation of oxal-

iplatin.21 Shortening the duration of adjuvant therapy would

lead to fewer patients with invalidating neuropathy and low-

er grade of neuropathy.

SHORTENING THE DURATION: THE IDEA COLLABORATIONIt would be beneficial to minimise the duration of the adju-

vant treatment to prevent or minimise neurotoxicity and re-

duce the use of health care resources.

The IDEA project (International Duration Evaluation of Adju-

vant chemotherapy) pooled the results of 6 prospective phase

III trials that analysed the efficacy of 3 months FOLFOX or

CAPOX versus 6 months of therapy in stage III colon cancer,

with three years DFS as the primary endpoint. It includes the

TOSCA (Three or Six Colon adjuvant) trial, SCOT trial (Short

Course Oncology Treatment), IDEA France trial, the inter-

group Cancer and Leukemia Group B/Southwest Oncology

Group (CALGB/SWOG) Trial 80702, HORG trial (Hellenic

Oncology Research Group) and the ACHIEVE trial (Adju-

vant Chemotherapy for colon cancer with High Evidence).

Non-inferiority could be claimed if the upper limit of the

two-sided 95% confidence interval of the hazard ratio did

not exceed 1.12. The margin of 1.12 was chosen on the basis

of clinical acceptability, since it corresponded to a worsen-

ing of 2.7% in the 3-year DFS. In total 12,834 patients with

stage III disease were included in 12 countries and received

either 3 or 6 months of FOLFOX or CAPOX. In some trials

patients with stage II or rectal cancer were included and other

chemo schemes were used. Nevertheless, these patients were

not included in the pooled analysis for the IDEA trial. Differ-

ent schemes of FOLFOX or CAPOX were used in a non-ran-

domised way. The decision was up to the treating physician.

There were great differences in the use of CAPOX and FOLF-

OX. In the CALGB/SWOG trial all patients were treated with

FOLFOX and in the IDEA France only 10% received CAPOX.

The majority of patients in the SCOT and ACHIEVE received

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236

CAPOX, respectively 66.5% and 75.1%. Overall 40% of the

patients received CAPOX and 60% FOLFOX (Table 1).

As mentioned above, the primary endpoint was 3-year DFS

but several trials had additional secondary endpoints, which

were not included in the IDEA paper.22 The results show that

in the overall population the endpoint was not met. The dif-

ference in 3-year DFS between 3 months and 6 months of

treatment was 0.9% in favour of 6 months of chemotherapy

(95% CI: -2.4 to 0.6), a difference of limited clinical relevance.

In post hoc analysis, patients were divided in risk groups.

The high risk (T4 and/or N2) and low risk group (T1-3, N1)

had clear differences in 3-year survival, respectively 60% and

80%. In the CAPOX group, non-inferiority was confirmed

for all patients, independent of disease stage and risk group.

In patients treated with FOLFOX, 6 months of therapy re-

sulted in a higher DFS, particularly in the higher-risk group.

Non-inferiority could not be proven in the low-risk group.

As there was no randomisation for CAPOX or FOLFOX, no

statements could be made about superiority of CAPOX to

FOLFOX. Based on the consistent findings in different trials,

one could claim that adding another 3 months of CAPOX

did not improve survival outcomes. The IDEA group suggest-

ed some hypothesis for the difference between CAPOX and

FOLFOX: as CAPOX is an oral treatment, adherence might

be worse in the last few months. The absence of benefit of 3

more months of CAPOX could be due to a reduced overall

dose intensity in the 6 months’ group. Although the docu-

mented dose intensity of capecitabine in the 6-month group

did not differ significantly from the 5FU, the data was not

based on rigorous diary-based documentation. An alterna-

tive hypothesis relates to the different dosing of oxaliplatin in

the CAPOX and FOLFOX regimen (respectively 130mg/m2

of BSA every 3 weeks and 85mg/m2 every 2 weeks) and the

fluoropyrimidine dosage (capecitabine twice daily 2 weeks

of every 3 weeks with CAPOX and 46-hour infusion of flu-

orouracil every 2 weeks with FOLFOX). The daily dose of a

fluoropyrimidine for two weeks might be more effective than

a short infusion. Another observation, the choice between

FOLFOX and CAPOX was investigator-driven. It seems that

the patients receiving CAPOX had a better performance sta-

tus (81% of the patients had an ECOG 0 vs. 77.6% in the

FOLFOX group).22 The IDEA collaboration provided informa-

tion that allows personalised treatment strategies based on

patient’s risk profiles and preferences. In lower-risk groups

treated with CAPOX, 3 months of therapy is recommended,

as it is non-inferior in efficacy and less toxic. When treating

the high-risk group with FOLFOX, 6 months of treatment is

recommended. Regarding CAPOX in high-risk patients and

FOLFOX in low risk patients, non-inferiority was not prov-

en with 3 months of chemotherapy, albeit the absolute differ-

ence of 3-years DFS is very small and possibly not clinically

significant (Table 2).

DIFFERENCE BETWEEN STAGE II AND STAGE IIIThere is still debate about the benefit of adjuvant treatment

in stage II patients. The QUASAR trial included 2,291 stage

II colon cancers between May 1994 and December 2003 in

19 countries. Patients were randomised in a chemotherapy

group and an observation group. In the chemotherapy group,

PHARMACOTHERAPY

TABLE 1: Characteristics of individual trials in the IDEA collaboration.22,24-27

Trial Enrolling countries

Stage III patients

% stage II patients

% rectal involvement

% patients receiving FOLFOX

% patients receiving CAPOX

Median follow-up (months)

TOSCA Italy 2402 35 13.4 65 35 61.7

SCOT UK, Denmark,

Spain, Austra-

lia, Sweden,

New Zealand

3983 18 18 33 67 36.8

IDEA FRANCE France 2010 0.1 0 90 10 51.3

C80702 US, Canada 2440 0 0 100 0 34.9

HORG Greece 708 N/A N/A 42 58 47.5

ACHIEVE Japan 1277 0 21 25 75 36.7

N/A: not available

VOLUME13OCTOBER2019

237

patients received mainly fluorouracil-based treatment. Re-

sults showed a benefit in OS and recurrence rate (RR) with

30 weeks of chemotherapy. Although the survival benefit was

statistically significant, as the mortality risk in this group is

rather low, the absolute risk reduction of the mortality risk

was only 3.6% in 5-year OS. Importantly, these benefits were

not observed in patients aged 70 or more. Unfortunately, they

could not make a difference between high-risk and low-risk

stage II colon cancers, due to the lack of pathological data.23

Despite this data, the present ESMO guidelines state that

high-risk stage II patients should receive adjuvant treatment.

High risk is here defined as one of the following negative prog-

nostic factors: pT4 stage, vascular, lymphatic or peri-neural

invasion, inadequate number of lymph nodes analysed (<12),

grade G3 or presentation with perforation or occlusion.1,2 The

sub analysis of the MOSAIC trial and NSABP trial showed

no benefit of adding oxaliplatin to 5FU as adjuvant treatment

in stage II disease, even for the high risk stage II patients.7,16

In the IDEA collaboration three trials included stage II co-

lon cancer patients (TOSCA, HORG and SCOT). The TOSCA

and SCOT trials could not prove non-inferiority of 3 months

of treatment compared to 6 months.26,27 The question still re-

mains whether 6 months of therapy and/or doublet chemo-

therapy (e.g. CAPOX) is needed in this specific population.

FUTURE PROSPECTS: SELECTION OF PATIENTS BASED ON PREDICTIVE AND PROGNOSTIC FACTORSIn addition to research into new treatment options in the

adjuvant setting, there is a need to optimise the selection

of patients who will benefit from adjuvant treatment. For

example, it is known that patients with stage II colon can-

cer and MMR deficiency have a better OS and possibly lack

benefit of adjuvant chemotherapy, especially 5-FU based

chemotherapy.28,29

In the search for new prognostic biomarkers, the loss of

staining for transcription factor CDX2 is identified as a neg-

ative prognostic marker in stage II and III colon cancer pa-

tients. CDX2 negative tumours have a worse 5-year DFS.30

The role of CDX2 in the decision-making about adjuvant

treatment still needs to be confirmed in prospective trials.

Another interesting biomarker could be “liquid biopsies” or

circulating tumour DNA (ctDNA). At present, it is not yet

clear how to use this information in the discussion about

3 months or 6 months of adjuvant treatment. In a cohort

of patients with stage II colon cancer who did not undergo

chemotherapy, ctDNA was measured. If ctDNA was posi-

tive, the RR was 100% at 3 years. In contrast, if ctDNA was

negative, the patients were at low risk of radiologic recur-

rence at 3 years (3-year recurrence free survival (RFS) of

91%).31 In a study on stage III colon cancer, ctDNA was test-

ed postoperative and after the completion of adjuvant treat-

ment. Patients with positive ctDNA after surgery, despite

receiving adequate adjuvant treatment, still had a signifi-

cantly lower recurrence-free survival compared to patients

with negative ctDNA. Secondly, if ctDNA remained positive

or became positive at the end of chemotherapy, their recur-

rence was even higher.32 Future trials will attempt to assess

and monitor ctDNA during treatment to better understand

the correlation with RR and consequently try to determine

the need of adjuvant treatment and duration according to

ctDNA. Another approach to risk stratify patients in the fu-

ture is the immune-score, based on the density of two dis-

tinct lymphocyte populations (CD8+ cytotoxic T cells and

CD3+ T memory cells) at the centre and the invasive mar-

gins of the tumour. In a recent validation study, time to re-

currence was significantly longer for patients with stage II

and III colon cancer with high immune-score and was inde-

pendent of patient age, sex, T stage, N stage, microsatellite

instability, and existing prognostic factors. It has therefore

been suggested to integrate the immune-score in the well-

known TNM classification.33

TABLE 2: Summary results HR IDEA trial. (Adapted from M. Buyse, ESMO 2017)

HR 3 vs. 6 months (95% CI)

CAPOX FOLFOX ALL

Low risk

(T1-3 N1)

0.85 (0.71-1.01)

1.10 (0.96-1.26)

1.01 (0.9-1.12)

High risk (T4 or N2)

1.02 (0.89-1.17)

1.20 (1.07-1.35)

1.12 (1.03-1.23)

All 0.95 (0.85-1.06)

1.16 (1.06-1.26)

1.07 (1.00-1.15)

VOLUME13OCTOBER20196

238

CONCLUSIONSThe ultimate goal of adjuvant treatment is to reduce the risk

of disease recurrence. Adjuvant treatment remains recom-

mended in stage III and high-risk stage II cancer. Fluoropy-

rimidines and oxaliplatin are still the backbone of adjuvant

treatment in stage III colon cancer. Single agent fluoropyrimi-

dine is a valid option for patients at high risk of toxicities and

stage II colon cancer. The IDEA collaboration attempted to

answer the question about duration of adjuvant chemother-

apy. However, the meta-analysis could not prove non-inferi-

ority for the 3-months regimen, the results provide a valuable

base to explore personalisation of treatment regimen and du-

ration. High-risk stage III patients (T4 and/or N2) should be

treated for 6 months, if FOLFOX is the chosen adjuvant che-

motherapy. In contrast, low risk (T1-3 N1) stage III patients

can be treated with only 3 months of CAPOX. The duration

of FOLFOX in the low risk group and CAPOX in the high

risk group is still unclear. At present, information about ad-

juvant treatment in stage II colon cancer is still insufficient.

Hopefully in the future prognostic and predictive biomark-

ers can aid in better selecting patients that will benefit from

adjuvant treatment.

REFERENCES1. Sargent D, Sobrero A, Grothey A, et al. Evidence for Cure by Adjuvant Thera-

py in Colon Cancer: Observations Based on Individual Patient Data from 20,898

Patients on 18 Randomized Trials. J Clin Oncol 2009;27(6):872–7.

2. Labianca R, Nordlinger B, Beretta GD, et al. Early colon cancer: ESMO Clin-

ical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J

Eur Soc Med Oncol 2013; 24 Suppl 6(suppl 6):vi64-72.

3. André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, Fluorouracil, and Leu-

covorin as Adjuvant Treatment for Colon Cancer. N Engl J Med 2004; 350(23):

2343-51.

4. Raymond E, Chaney SG, Taamma A, et al. Oxaliplatin: a review of preclinical

and clinical studies. Ann Oncol Off J Eur Soc Med Oncol 1998;9(10):1053–71.

5. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for ad-

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6. Haller DG, Catalano PJ, Macdonald JS, et al. Phase III study of fluorouracil,

leucovorin, and levamisole in high-risk stage II and III colon cancer: final report

of Intergroup 0089. J Clin Oncol 2005; 23(34):8671–8.

7. André T, de Gramont A, Vernerey D, et al. Adjuvant Fluorouracil, Leucovorin,

and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Out-

comes According to BRAF Mutation and Mismatch Repair Status of the MOSA-

IC Study. J Clin Oncol 2015; 33(35):4176–87.

8. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin Combined With Week-

ly Bolus Fluorouracil and Leucovorin As Surgical Adjuvant Chemotherapy for

Stage II and III Colon Cancer: Results From NSABP C-07. J Clin Oncol

2007;25(16):2198–204.

9. Yothers G, O’Connell MJ, Allegra CJ, et al. Oxaliplatin As Adjuvant Therapy

for Colon Cancer: Updated Results of NSABP C-07 Trial, Including Survival and

Subset Analyses. J Clin Oncol 2011;29(28):3768–74.

10. Schmoll H-J, Tabernero J, Maroun J, et al. Capecitabine Plus Oxaliplatin

Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Co-

lon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Tri-

PHARMACOTHERAPY

KEY MESSAGES FOR CLINICAL PRACTICE

1. Adjuvant treatment remains recommended in stage III and high-risk stage II cancer.

2. The combination of fluoropyrimidines and oxaliplatin is still the gold standard of adjuvant treatment in stage III colon cancer.

3. Single agent fluoropyrimidine is an acceptable option for patients at high risk of toxicities and stage II colon cancer.

4. The IDEA meta-analysis did not meet its primary endpoint. However, the results provide evidence to carefully modify the current standard of care in certain subgroups: • High-risk stage III patients (T4 and/or N2): if FOLFOX is the chosen chemotherapy, a duration of 6 months

is appropriate. • Low risk stage III patients (T1-3 N1): if CAPOX is the chosen chemotherapy, a duration of 3 months should

suffice. • The duration of FOLFOX in the low-risk group and CAPOX in the high-risk group is still unclear.

5. There is currently insufficient information about the duration of adjuvant treatment in stage II colon cancer.

VOLUME13OCTOBER2019

239al. J Clin Oncol 2015;33(32):3733–40.

11. Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based

adjuvant therapy for stage II and III colon cancer: who benefits and by how much?

J Clin Oncol 2004;22(10):1797–806.

12. Tournigand C, André T, Bonnetain F, et al. Adjuvant Therapy With Fluoroura-

cil and Oxaliplatin in Stage II and Elderly Patients (between ages 70 and 75 years)

With Colon Cancer: Subgroup Analyses of the Multicenter International Study

of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon

Cancer Trial. J Clin Oncol 2012; 30(27):3353–60.

13. Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan Fluorouracil Plus Leucov-

orin Is Not Superior to Fluorouracil Plus Leucovorin Alone As Adjuvant Treatment

for Stage III Colon Cancer: Results of CALGB 89803. J Clin Oncol

2007;25(23):3456–61.

14. Van Cutsem E, Labianca R, Bodoky G, et al. Randomized Phase III Trial Com-

paring Biweekly Infusional Fluorouracil/Leucovorin Alone or With Irinotecan in

the Adjuvant Treatment of Stage III Colon Cancer: PETACC-3. J Clin Oncol

2009;27(19):3117–25.

15. Papadimitriou CA, Papakostas P, Karina M, et al. A randomized phase III tri-

al of adjuvant chemotherapy with irinotecan, leucovorin and fluorouracil versus

leucovorin and fluorouracil for stage II and III colon cancer: A Hellenic Coopera-

tive Oncology Group study. BMC Med 2011;9(1):10.

16. Allegra CJ, Yothers G, O’Connell MJ, et al. Phase III Trial Assessing Bevaci-

zumab in Stages II and III Carcinoma of the Colon: Results of NSABP Protocol

C-08. J Clin Oncol 2011;29(1):11–6.

17. de Gramont A, Van Cutsem E, Schmoll H-J, et al. Bevacizumab plus oxalipl-

atin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a

phase 3 randomised controlled trial. Lancet Onco 2012;13(12):1225–33.

18. Taieb J, Tabernero J, Mini E, et al. Oxaliplatin, fluorouracil, and leucovorin with

or without cetuximab in patients with resected stage III colon cancer (PETACC-8):

an open-label, randomised phase 3 trial. Lancet Oncol 2014;15(8):862–73.

19. Huang J, Nair SG, Mahoney MR, et al. Comparison of FOLFIRI With or With-

out Cetuximab in Patients With Resected Stage III Colon Cancer; NCCTG (Alli-

ance) Intergroup Trial N0147. Clin Colorectal Cancer 2014;13(2):100–9.

20. Extra JM, Marty M, Brienza S, et al. Pharmacokinetics and safety profile of

oxaliplatin. Semin Oncol 1998;25(2 Suppl 5):13–22.

21. Leonard GD, Wright MA, Quinn MG, et al. Survey of oxaliplatin-associated

neurotoxicity using an interview-based questionnaire in patients with metastat-

ic colorectal cancer. BMC Cancer 2005;5(1):116.

22. Grothey A, Sobrero AF, Shields AF, et al. Duration of Adjuvant Chemothera-

py for Stage III Colon Cancer. N Engl J Med 2018; 378(13):1177–88.

23. QUASAR Collaborative Group, Gray R, Barnwell J, McConkey C, et al. Ad-

juvant chemotherapy versus observation in patients with colorectal cancer: a

randomised study. Lancet 2007; 370(9604):2020–9.

24. Iveson TJ, Kerr RS, Saunders MP, et al. 3 versus 6 months of adjuvant ox-

aliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an

international, randomised, phase 3, non-inferiority trial. Lancet Oncol

2018;19(4):562–78.

25. Lonardi S, Sobrero A, Rosati G, et al. Phase III trial comparing 3–6 months

of adjuvant FOLFOX4/XELOX in stage II–III colon cancer: safety and compliance

in the TOSCA trial. Ann Oncol;28(12):3110–3110.

26. Kotaka M, Yamanaka T, Yoshina T, et al. Safety data from the phase III Jap-

anese ACHIEVE trial: part of an international, prospective, planned pooled anal-

ysis of six phase III trials comparing 3 versus 6 months of oxaliplatin-based ad-

juvant chemotherapy for stage III colon cancer. ESMO open 2018; 3(3)

27. André T, Vernerey D, Mineur L, et al. Three Versus 6 Months of Oxaliplatin-

Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Dis-

ease-Free Survival From a Randomized, Open-Label, International Duration Eval-

uation of Adjuvant (IDEA) France, phase III Trial. J Clin Oncol 2018;36(15):1469-1477.

28. Sargent DJ, Marsoni S, Monges G, et al. Defective Mismatch Repair As a

Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in

Colon Cancer. J Clin Oncol 2010;28(20):3219–26.

29. Hutchins G, Southward K, Handley K, et al. Value of Mismatch Repair, KRAS,

and BRAF Mutations in Predicting Recurrence and Benefits From Chemothera-

py in Colorectal Cancer. J Clin Oncol 2011;29(10):1261–70.

30. Dalerba P, Sahoo D, Paik S, et al. CDX2 as a Prognostic Biomarker in Stage

II and Stage III Colon Cancer. N Engl J Med 2016;374(3):211–22.

31. Tie J, Wang Y, Tomasetti C, et al. Circulating tumour DNA analysis detects

minimal residual disease and predicts recurrence in patients with stage II colon

cancer. Sci transl 2016;8(346): 346ra92–346ra92.

32. Tie J, Cohen J, Wang Y, et al. Serial circulating tumour DNA (ctDNA) analy-

sis as a prognostic marker and a real-time indicator of adjuvant chemotherapy

(CT) efficacy in stage III colon cancer (CC). Abstract 3516 ASCO 2018 J Clin On-

col 2018; 36(15_suppl):3516-3516.

33.Pagès F, Mlecnik B, Marliot F, et al. International validation of the consensus

Immunoscore for the classification of colon cancer: a prognostic and accuracy

study. Lancet 2018;391(10135):2128–39.

VOLUME13OCTOBER20196

240PHARMACOTHERAPY

SUMMARYThe treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) has changed dramatically with the approval of a variety of therapeutic agents including abiraterone acetate, cabazitaxel, docetaxel, enzalutamide and radium-223 dichloride and the introduction of docetaxel and abiraterone acetate in combination with androgen deprivation therapy in newly diagnosed metastatic prostate cancer. Evidence on the optimal sequence of these therapies is scarce. In practice, the most appropriate treatment (sequence) depends on patient and disease characteristics. This article summarises the recommendations of a multidisciplinary group of Belgian experts in sequencing treatments for patients with mCRPC, with a focus on radium-223 dichloride. (BELG J MED ONCOL 2019;13(6): 240-250)

1Department of Radiotherapy, UZ Ghent, Ghent, 2Department of Medical Oncology, ZNA Middelheim, Antwerp, 3Department of Medical Oncology

Clinique Saint-Pierre, Ottignies, 4Department of Oncology-Hematology, Grand Hôpital de Charleroi, Charleroi, 5Department of Nuclear Medicine,

UZ Leuven, Leuven, 6Department of Urology, UZ Leuven, Leuven, 7Department of Medical Oncology, UZ Ghent, Ghent, 8Department of Urology,

Cliniques universitaires de Bruxelles, Hôpital Erasme-ULB, Brussels, 9Department of Oncology, CH Jolimont, Haine-Saint-Paul, 10Department of

Nuclear Medicine and Oncological Imaging, CHU de Liège, Liège, 11Service d’Urologie, Cliniques universitaires Saint-Luc, Brussels, Belgium.

*Authors contributed equally to the manuscript.

Please send all correspondence to: P. Ost, MD, PhD, Department of Radiotherapy, UZ Ghent, De Pintelaan 185, 9000 Ghent, Belgium, tel: +32

93322411, email: Piet.Ost@UGent.be.

Conflict of interest: All authors, with the exception of B. Tombal, received a consultancy honorarium from Bayer. Bayer SA-NV Belgium set up

an expert meeting that was managed by Ismar Healthcare NV in which the mCRPC treatment landscape and the manuscript concept were

discussed. Bayer SA-NV Belgium also provided funding to Ismar Healthcare NV for survey development, data analysis, drafting the manuscript

and manuscript submission.

Keywords: abiraterone acetate, bone metastases, cabazitaxel, docetaxel, enzalutamide, metastatic castration-resistant prostate cancer,

patient selection, radium-223, targeted alpha therapy, treatment monitoring, treatment selection, treatment sequence.

Acknowledgments: The authors are grateful to Ismar Healthcare NV for their assistance in development of the voting tool, survey data analysis

and editorial assistance, which was funded by Bayer SA-NV Belgium. The survey was conducted exclusively by the expert panel and each

author is entirely responsible for the overall scientific content of the manuscript.

P. Ost, MD, PhD1*, D. Schrijvers, MD, PhD2*, L. Duck, MD3, M. Gizzi, MD4, K. Goffin, MD, PhD5, S. Joniau, MD, PhD6, S. Rottey, MD, PhD7, T. Roumeguère, MD8, E. Seront, MD, PhD9, N. Withofs, MD, PhD10, B. Tombal, MD, PhD11*

Appropriateness of treatment options in patients with metastatic castration-resistant prostate cancer with a focus on radium-223: outcomes of a Belgian multidisciplinary Consensus Meeting

VOLUME13OCTOBER2019

241INTRODUCTION Castration-resistant prostate cancer (CRPC) is defined by bi-

ochemical or radiological progression despite castrate tes-

tosterone levels (<50 ng/dl or 1.7 nmol/l).1 Bone metastases

are the most frequent metastatic site in metastatic CRPC

(mCRPC), present in 60-90% of patients. Many patients

will present with complications from their skeletal metasta-

ses, usually defined as symptomatic skeletal events (SSEs).2-4

These SSEs are a major cause of morbidity, pain, decreased

quality of life (QoL), patient disability and increased treat-

ment cost. In addition, the development of bone metasta-

ses is associated with a rise in mortality.3 Around 40% of

mCRPC patients with bone metastases also have nodal dis-

ease, although this seems to have a limited impact on over-

all survival.5 Visceral metastases usually develop later in the

course of the disease and are associated with bone and nod-

al metastases in the majority of patients.6

Radium-223 dichloride (radium-223) is a targeted alpha

therapy that prolongs overall survival (OS) in patients with

mCRPC.2 It attacks the cycle of cancer growth caused by the

interplay between prostate cancer (PCa) tumour cells and

the bone microenvironment. Approval of radium-223 was

based on data from the pivotal phase III ALSYMPCA trial,

randomising patients to radium-223 or placebo.2 Patients on

radium-223 had improved OS (14.9 versus 11.3 months; haz-

ard ratio (HR) 0.70, 95% confidence interval (CI): 0.58-0.83,

P<0.001) irrespective of prior docetaxel use (57% of patients

received prior docetaxel) and a significantly longer median

time to first SSE (15.6 versus 9.8 months) that was more ev-

ident in patients receiving bisphosphonates.2,7 In addition,

the survival advantage was associated with a significantly

higher proportion of patients experiencing a meaningful im-

provement in QoL and a slower decline in QoL over time.8

Treatment with radium-223 was well-tolerated with a low in-

cidence of myelosuppression.2 However, one of the main lim-

itations of ALSYMPCA lies in the fact that the other approved

OS prolonging agents (abiraterone acetate, enzalutamide,

cabazitaxel) were not available for study participants. None-

theless, according to the European Society for Medical On-

cology Magnitude of Clinical Benefit Scale (ESMO-MCBS),

radium-223 has the highest clinical benefit of all treatments

for mCRPC patients.9

Radium-223 was initially indicated for treatment of patients

with mCRPC, symptomatic bone metastases and no known

visceral metastases. However, the European Medicines Agen-

cy (EMA) authorisation and Belgian reimbursement criteria

for radium-223 have been changed after the publication of

the ERA-223 trial. This phase III study investigated the com-

bination of radium-223 and abiraterone acetate in patients

with asymptomatic/mildly symptomatic chemotherapy-naïve

mCRPC.10 In an unplanned ad-hoc analysis an increased risk

of fractures in the radium-223 plus abiraterone acetate group

compared to the placebo plus abiraterone acetate group was

noted, while no significant difference in survival was ob-

served between the 2 groups. Of note, 61% of patients were

not receiving bone health agents10, while the interim analysis

of the PEACE III trial suggested that administration of bone

health agents to patients receiving an androgen receptor path-

way inhibitor (ARPI) combined with radium-223 provides

good control of fractures.11

The EMA changed the indication of radium-233 in 2018 to

“treatment of men with mCRPC, symptomatic bone metas-

tases and no known visceral metastases, in progression af-

ter ≥2 prior lines of systemic therapy for mCRPC (other than

luteinising hormone-releasing hormone [LHRH] analogues),

or ineligible for any available systemic mCRPC treatment”.12

Interestingly, the indication in the label was left unchanged

despite a review of the data in the United States, Switzer-

land, Canada and Japan.

In Belgium, the reimbursement criteria were recently up-

dated: “Radium-223 is reimbursed in mCRPC patients with

symptomatic bone metastases and no known visceral metas-

tases in progression after at least 2 prior systemic treatments

(other than LHRH analogues) or ineligible to an available

systemic mCRPC treatment”.13 The European Association of

Urology (EAU) guidelines recommend radium-223 as a first-

and second-line (in case of progression following docetaxel)

mCRPC treatment option.1

Next to radium-223, four other life-prolonging therapies are

approved and reimbursed in Belgium for mCRPC treatment:

docetaxel and the ARPIs abiraterone acetate and enzalut-

amide in first- and second-line treatment, and cabazitaxel

in second-line treatment after docetaxel.14-19 This creates an

everyday dilemma for physicians when it comes to choosing

the most appropriate therapy for individual patients since the

evidence regarding treatment sequencing is mostly retrospec-

tive.20,21 In addition, based on several large trials, docetaxel

and abiraterone acetate can be administered together with

ADT in newly diagnosed metastatic patients, thus creating a

new paradigm. Guidelines recommend to base the choice of

life-prolonging first- or second-line treatment for mCRPC on

(pre-treatment) performance status, symptoms, co-morbid-

ities, location and extent of disease, patient preference, and

(in case of first-line treatment) on the previous treatment for

metastatic hormone-sensitive PCa (mHSPC).1,22

The present paper reports the recommendations of a Bel-

gian multidisciplinary expert panel on the management of

mCRPC in routine clinical practice. The aim is to provide

guidance on the appropriateness of therapeutic options in

different treatment lines with focus on radium-223. In addi-

VOLUME13OCTOBER20196

242

tion, practical considerations for the use of radium-223 are

discussed.

METHODSThe multidisciplinary expert panel consisted of 11 Belgian

physicians, including 3 urologists, 5 medical oncologists, 1

radiation oncologist and 2 nuclear medicine physicians. They

were asked to rate the appropriateness of treatment options

for different mCRPC patient scenarios. The patient scenari-

os consisted of 5 index cases including ‘what if’ scenarios in

which a patient or disease characteristic changed versus the

index case. The following assumptions were made for all pa-

tient scenarios: patients have a testosterone level <50 ng/dl

while receiving ADT, drugs are prescribed at the registered

dose and with the recommended accompanying treatment

(e.g. prednisone or supplements), patients have normal val-

ues for alkaline phosphatase (ALP), i.e. 23 to 126 U/L, and

stage is defined based on standard imaging, i.e. 99mTc-meth-

ylene diphosphonate (99mTc-MDP) bone scan for detection of

bone metastases and contrast-enhanced computed tomogra-

phy (CT) of the chest, abdomen and pelvis for detection of

metastatic lymph nodes and visceral metastases. The process

consisted of an individual rating round using an online vot-

ing tool and a plenary meeting to discuss the results. Panel

members were asked to rate according to their clinical judge-

ment. Assessment of appropriateness was based on the rules

typically used in RAND-UCLA studies.23 The RAND-UCLA

method is a scientifically validated approach for calculating

the level and extent of expert agreement and treatment ap-

propriateness. The appropriateness scale ranged from 1 (ex-

tremely inappropriate) to 9 (extremely appropriate) with 5

being equivocal or uncertain (Figure 1A). Based on the extent

of agreement and median panel score, the individual ratings

were converted to panel statements (appropriate, inappro-

priate, and uncertain) for each treatment option. Disagree-

ment was defined as at least one third of the panellists rated

each extreme segment (Figure 1B). In case of disagreement,

the panel outcome was translated as uncertain. In absence

of disagreement, a treatment was defined as appropriate in

case the median panel score was 7-9, inappropriate in case

the median panel score was 1-3, or uncertain in case the me-

dian panel score was 4-6 (Figure 1C).

RESULTS AND DISCUSSIONPATIENTS WITH A HISTORY OF RADICAL LOCAL THERAPY PLUS ADT, PROGRESSING TO MCRPCDetails of the different patient scenarios and appropriateness

outcomes on mCRPC treatments in this setting are displayed

in Tables 1A, B.

Index case one concerned a patient who had received radi-

otherapy (RT) plus ADT for localised PCa and experienced

symptomatic progression during first-line mCRPC treatment

with abiraterone acetate with a PSA doubling time (PSA-DT)

of 9 months (Table 1A).

The expert panel considered both docetaxel and radium-223

appropriate second-line mCRPC treatment options for this

patient. As studies have shown little benefit of sequential

ARPI treatment, enzalutamide and continuation of abirater-

one acetate were considered inappropriate by the panel.24,25

PHARMACOTHERAPY

9-point scale

Agreement: If at least 3/4th of the panellists rated in one segmentDisagreement: If at least 1/3th of the panellists rated in each extreme segmentIndeterminate: Every other scenario

1-3:4-6:

7-9:

Inappropriate: not recommended in this patientUncertain: no strong arguments in favour or against this treatmentin this patientAppropriate: treatment is a recommended option in this patient(the expected benefits outweigh the expected risk or negativeconsequences by a sufficient margin)

A

AgreementB

A treatment option is:- Appropriate: no disagreement and median score 7-9- Inappropriate: no disagreement and median score 1-3- Uncertain: all other cases

AppropriatenessC

Inappropriate

21 3

Equivocal/uncertain

54 6

Appropriate

87 9

Agreement 1 2 3 4 5 6 7 8 9

Disagreement 1 2 3 4 5 6 7 8 9

Indeterminate 1 2 3 4 5 6 7 8 9

Agreement DisagreementIndeterminate

Appropriate

Uncertain

Inappropriate

Median

7-9

4-6

1-3

FIGURE 1. Appropriateness scale for individual ratings (A),

assessment of agreement between the panellists (as example)

(B), and assessment of appropriateness of a treatment option

according to the panellists (C).

VOLUME13OCTOBER2019

243

Index case one: second-line mCRPC treatment

RT + ADT Abiraterone ?

• Man, 73 years old, GS 3+4 (ISUP G2), PSA 12 ng/ml, cT2b cN1 cM0

• Primary RT + 3 years ADT

° PSA nadir of 0.5 ng/ml at 6 months

• 28 months after start of ADT:

° PSA 4 ng/ml (confirmed rise)

° Testosterone level <35 ng/dl

° 2 bone metastases on bone scintigraphy confirmed by CT scan, without other lesions

° No symptoms

° Normal ALP

• Starts abiraterone + prednisone + denosumab + calcium and Vitamin D

° PSA nadir of 0.4 ng/ml

• 16 months after start of abiraterone:

° PSA 4 ng/ml (confirmed rise >2 ng/ml)

° PSA-DT 9 months

° 8 bone metastases with 1 symptomatic lesion on Th1 (paracetamol 1g 3x/day BPI score 3)

° No visceral metastases or lymph node metastases >2 cm

° ALP 120 U/L (normal range 35-105 U/L)

° Rest of bloodwork normal

° ECOG 1

Treatment

Abiraterone conti-nued

Docetaxel Enzalutamide Radium-223

Index case one

A What if PSA-DT <6 months

BWhat if number of bone

metastases <6

TABLE 1A: Appropriateness of mCRPC treatment options in two patient cases with a history of radiotherapy plus androgen deprivation therapy with ‘what if’ scenarios.

PLATO, a phase IV randomised, double-blind, placebo-con-

trolled trial, investigated the efficacy of abiraterone acetate

alone or combined with enzalutamide in mCRPC patients

with rising PSA during enzalutamide treatment.24 No signif-

icant differences between both groups were observed in me-

dian progression-free survival and secondary endpoints, and

the clinical benefit of abiraterone acetate following enzalut-

amide was very limited. In addition, a multi-centre, phase II

study randomised 202 treatment-naïve mCRPC patients to

abiraterone acetate or enzalutamide with a cross-over at PSA

progression.25 The results showed limited benefits from the

sequential use of ARPIs.

Radium-223 was considered uncertain in case of rapidly

progressing disease (PSA-DT <6 months), which may be ex-

plained by an increased risk of visceral metastases or the in-

ability to administer 6 cycles of radium-223. Docetaxel was

considered uncertain in case of fewer bone metastases (<6),

while the number of bone metastases did not impact the ap-

propriateness of radium-223.

When looking specifically at the appropriate treatment op-

tions of index case one, namely docetaxel and radium-223,

it should be noted that in the Belgian situation, the patient

should be considered ineligible to docetaxel in order to be

reimbursed for radium-223 in this setting, e.g. a PSA-DT >6

months or when he is too frail to receive docetaxel.13

Index case two described a patient who had received RT plus

Grey boxes in schematic overview indicate castration-resistant state. red: inappropriate; yellow: uncertain; green: appropriate

ADT: androgen deprivation therapy; ALP: alkaline phosphatase; ARPI: androgen receptor pathway inhibitor; BPI: Brief Pain

Inventory; CT: computed tomography; ECOG PS: Eastern Cooperative Oncology Group Performance Status; GS: Gleason

score; ISUP: International Society of Urological Pathologists; mCRPC: metastatic castration-resistant prostate cancer; PSA:

prostate-specific antigen; PSA-DT: prostate-specific antigen doubling time; RT: radiation therapy.

VOLUME13OCTOBER20196

244PHARMACOTHERAPY

adjuvant ADT for locally advanced PCa, was treated with

first-line abiraterone acetate for mCRPC and progressed af-

ter second-line docetaxel (Table 1B). The expert panel con-

sidered cabazitaxel and radium-223 appropriate third-line

mCRPC treatment options for this patient. Although both

agents are reimbursed in this setting in Belgium13, it was dis-

cussed that in clinical practice these are prescribed for two

different patient profiles: while radium-223 should be con-

sidered for patients with bone-dominant disease, cabazitax-

el holds a place for men with rapidly progressing disease.

Docetaxel rechallenge and ARPIs were considered uncer-

tain treatment options. If the patient would have progressed

during, instead of after, second-line docetaxel treatment, the

panel considered cabazitaxel an appropriate third-line treat-

ment option, ARPIs and radium-223 uncertain treatment

options and docetaxel an inappropriate option. There was

consensus among the panellists that every patient should be

given the possibility to maximise the number of treatment

Index case two: third-line mCRPC treatment

RT + ADT Abiraterone Docetaxel ?

• Man 68 years old, GS 3+4 (ISUP G2), PSA 12 ng/ml, cT3a cN1 cM0

• Primary RT + 3 years ADT

° PSA nadir of 0.5 ng/ml at 6 months

• 28 months after start of ADT:

° PSA nadir of 0.5 ng/ml at 6 months

° PSA 4 ng/ml (confirmed rise)

° Testosterone level <35 ng/dl

° 2 bone metastases on bone scintigraphy confirmed by CT scan, without other lesions

° No symptoms

° Normal ALP

• Starts abiraterone + prednisone + denosumab + calcium and Vitamin D

° PSA nadir of 0.5 ng/ml at 6 months

• 16 months after start of abiraterone:

° PSA 4 ng/ml (confirmed rise)

° PSA-DT 4 months

° 8 bone metastases with 1 symptomatic lesion on Th1 (paracetamol 1g 3x per day, BPI score 3)

° No visceral metastases or lymph node metastases >2 cm

° ALP 120 U/L (normal range 35-105 U/L)

° Rest of bloodwork normal

° ECOG 1

• Starts docetaxel for 9 cycles

° PSA nadir of 0.2 ng/ml and stable disease at the end of treatment

• PSA progression and progression of bone metastases 6 months after docetaxel discontinuation

° No visceral metastases or lymph node metastases >2 cm

Treatment

ARPI CabazitaxelDocetaxel rechal-

lengeRadium-223

Index case two

A What if the patient

progresses during the

docetaxel treatment (PSA

and bone metastases)

TABLE 1B: Appropriateness of mCRPC treatment options in two patient cases with a history of radiotherapy plus androgen deprivation therapy with ‘what if’ scenarios.

Grey boxes in schematic overview indicate castration-resistant state. red: inappropriate; yellow: uncertain; green: appropriate

ADT: androgen deprivation therapy; ALP: alkaline phosphatase; ARPI: androgen receptor pathway inhibitor; BPI: Brief Pain

Inventory; CT: computed tomography; ECOG PS: Eastern Cooperative Oncology Group Performance Status; GS: Gleason

score; ISUP: International Society of Urological Pathologists; mCRPC: metastatic castration-resistant prostate cancer; PSA:

prostate-specific antigen; PSA-DT: prostate-specific antigen doubling time; RT: radiation therapy.

VOLUME13OCTOBER2019

245

Index case three: first-line mCRPC treatment

De novo

mHSPC

ADT +

docetaxel?

• Man, 68 years old, GS 4+4 (ISUP G4), PSA 12 ng/ml, cT3a cN1 cM1b (4 bone metastases with 1 beyond pelvis/spine on bone

scintigraphy), asymptomatic

• Primary treatment: ADT + 6 cycles docetaxel

° PSA nadir of 0.5 ng/ml at 6 months

• 24 months after start of ADT + docetaxel:

° PSA 4 ng/ml (confirmed rise)

° PSA-DT 6 months

° 8 bone metastases with 1 symptomatic lesion on Th1 (paracetamol 1g 3x/day, BPI score 3)

° No visceral metastases or lymph node metastases >2 cm

° ALP-levels 120 U/L (normal range 35-105 U/L)

° Rest of bloodwork normal

° Testosterone level <35 ng/dl

° ECOG 1

Treatment

ARPI Cabazitaxel Docetaxel Radium-223

Index case three

A What if BPI score >3 at

progression

Index case four: second-line mCRPC treatment

De novo

mHSPC

ADT +

docetaxelEnzalutamide ?

• Man, 68 years old, GS 4+4 (ISUP G4), PSA 12 ng/ml, cT3a cN1 cM1b (4 bone metastases with 1 beyond pelvis/spine on bone

scintigraphy), asymptomatic

• Primary treatment: ADT + 6 cycles docetaxel

° PSA nadir of 0.5 ng/ml at 6 months

• 24 months after start of ADT + docetaxel

° PSA 4 ng/ml (confirmed rise)

° PSA-DT 6 months

° 4 bone metastases with 1 symptomatic lesion on Th1 (paracetamol 1g 3x/day, BPI score 3)

° No visceral metastases or lymph node metastases >2 cm

° ALP-levels 120 U/L (normal range 35-105 U/L)

° Rest of bloodwork normal

° Testosterone level <35 ng/dl

° ECOG PS 1

• Starts enzalutamide. 18 months after start of enzalutamide:

° Increasing PSA with PSA-DT >6 months

° Progressive bone metastases: 8 bone metastases with 1 symptomatic lesion on Th1 (paracetamol 1g 3x/day, max BPI score 3)

° No visceral metastases or lymph node metastases >2 cm

Treatment

Abiraterone Cabazitaxel DocetaxelEnzalutamide

continuedRadium-223

Index case four

A

What if the response to

enzalutamide is less than

3 months

B

What if the response to en-

zalutamide is 18 months,

and PSA-DT is 3 months

TABLE 2A: Appropriateness of mCRPC treatment options in three patient cases with de novo mHSPC progressing to mCRPC with ‘what if’ scenarios.

VOLUME13OCTOBER20196

246PHARMACOTHERAPY

lines. This is important as a current treatment choice may

impact future treatment options.

DE NOVO MHSPC PATIENTS PROGRESSING TO MCRPCThe different patient scenarios and appropriateness out-

comes on mCRPC treatments for this setting are shown in

Tables 2A, B. The expert panel agreed that if a patient has re-

ceived ADT plus docetaxel or ADT plus abiraterone acetate

for mHSPC, this should be counted as one line of system-

ic therapy referring to the Belgium reimbursement criteria.

Index case three concerned a patient who presented with

bone metastases at diagnosis and was treated with ADT plus

6 cycles docetaxel (Table 2A). After 24 months, he became

castration-resistant with a brief pain inventory (BPI) score

of 3. Overall, the expert panel considered first-line mCRPC

treatment (or second-line systemic treatment) with an AR-

PI appropriate while docetaxel rechallenge was considered

uncertain. This is in line with a retrospective analysis of the

GETUG-15 trial, suggesting that abiraterone acetate and en-

zalutamide still have anti-cancer activity in mCRPC patients

who have received ADT plus docetaxel in mHSPC setting.

Docetaxel rechallenge seems to have a rather limited activity

in this setting.26 The experts also considered radium-223 an

appropriate first-line mCRPC treatment option while caba-

zitaxel was considered uncertain. The treatment recommen-

dations by the expert panel were independent of the level of

pain at progression (BPI score >3; Table 2A).

When looking at the appropriate treatment options of index

case three in the Belgian situation, an ARPI is not reimbursed

if the patient is considered eligible for docetaxel.13 Further-

more, radium-223 is only reimbursed if the patient is consid-

ered ineligible for any available systemic treatment.

Index case four concerned a patient with presence of bone

metastases at diagnosis who was treated with ADT plus 6 cy-

cles docetaxel (Table 2A). He progressed to mCRPC after 24

Index case five: first-line mCRPC treatment

De novo

mHSPC

ADT +

abiraterone?

• Man, 68 years old, GS 4+4 (ISUP G4), PSA 12 ng/ml, cT3a cN1 cM1b (4 bone metastases with 1 beyond pelvis/spine on bone

scintigraphy), asymptomatic

• Primary treatment: ADT + abiraterone + prednisone

° PSA nadir of 0.4 ng/ml at 6 months

• 24 months after start of ADT + abiraterone:

° PSA 4 ng/ml (confirmed rise)

° PSA-DT 6 months

° 8 bone metastases with 1 symptomatic lesion on Th1 (paracetamol 1g 3x/day, BPI score 3)

° No visceral metastases or lymph node metastases >2 cm

° ALP-levels 120 U/L (normal range 35-105 U/L)

° Rest of bloodwork normal

° Testosterone level <35 ng/dl

° ECOG PS 1

Treatment

Abirateronecontinued

Docetaxel Enzalutamide Radium-223

Index case five

A What if PSA-DT is 11

months

TABLE 2B: Appropriateness of mCRPC treatment options in three patient cases with de novo mHSPC progressing to mCRPC with ‘what if’ scenarios.

Grey boxes in schematic overview indicate castration-resistant state. red: inappropriate; blue: uncertain; green: appropriate

ADT: androgen deprivation therapy; ALP: alkaline phosphatase; ARPI: androgen receptor pathway inhibitor; BPI: Brief Pain

Inventory; ECOG PS: Eastern Cooperative Oncology Group Performance Status; GS: Gleason score; ISUP: International

Society of Urological Pathologists; mCRPC: metastatic castration-resistant prostate cancer; PSA: prostate-specific antigen;

PSA-DT: prostate-specific antigen doubling time.

VOLUME13OCTOBER2019

247months, was treated with enzalutamide but progressed after

18 months with a PSA-DT >6 months. The expert panel con-

sidered radium-223 and cabazitaxel appropriate second-line

mCRPC treatment options. Treatment with an ARPI was con-

sidered inappropriate and docetaxel uncertain for reasons

discussed earlier.24-26 The panel recommendations were also

in favour of appropriateness of radium-223 and cabazitaxel

in case of a shorter response to enzalutamide (3 months) or

a shorter PSA-DT (3 months).

Focussing on the appropriate treatment options of index case

four, namely cabazitaxel and radium-223, it should be not-

ed that radium-223 but not cabazitaxel would be reimbursed

in Belgium.13

Index case five concerned a patient with presence of bone

metastases at diagnosis treated with ADT plus abiraterone

acetate (Table 2B). He became castration-resistant after 24

months with a PSA-DT of 6 months. The expert panel con-

sidered both docetaxel and radium-223 appropriate first-line

mCRPC treatment options for this patient. Both enzaluta-

mide and continuation of abiraterone acetate were considered

inappropriate by the panel as studies have shown little ben-

efit of sequential ARPI treatment.24,25 Treatment recommen-

dations for this case were similar if the patient progressed

slower (PSA-DT 11 months; Table 2B).

When looking specifically at the appropriate treatment op-

tions of index case five, namely docetaxel and radium-223,

it should be noted that in the Belgian situation radium-223

is only reimbursed in this setting if the patient is considered

ineligible for docetaxel, e.g. a PSA-DT >6 months or when he

is unwilling to receive docetaxel.13

PRACTICAL CONSIDERATIONS FOR THE USE OF RADIUM-223INITIATION OF RADIUM-223 Selection of patients suitable for radium-223

In general, mCRPC treatment should be tailored to the pa-

tient and discussed by a multidisciplinary team in order to

achieve the most appropriate and broadest range of treat-

ment options. Close interaction between different disciplines

and departments, more particularly nuclear medicine, radi-

ation oncology, medical oncology and urology services, fa-

cilitates the identification of patients eligible for radium-223

treatment.27 In addition, patient preferences and expectations

should be taken into account.

According to the expert panel, the best window of oppor-

tunity for radium-223 includes patients with bone predom-

inant disease (≥2 bone metastases on bone scan) before any

development of visceral disease and/or malignant lymphad-

enopathy >3 cm in their minor axis.

In addition, there was consensus that patients should be

able to receive 6 cycles of radium-223 to obtain the highest

survival benefit; starting radium-223 if it is likely that the

patient will not be able to receive 6 cycles was generally con-

sidered inappropriate. Prospective and retrospective studies

(ALSYMPCA, EAP, BELFIGO) have shown that earlier use

of radium-223 in mCRPC patients increases the likelihood

of completing therapy and better outcomes.28-30 Indeed, re-

ceiving 5-6 cycles of radium-223 was associated with longer

overall survival compared to 1-4 cycles.28,29 Patients who dis-

continued radium-223 after 1-4 cycles most often did be-

cause of disease progression and were more likely to have

more advanced or more rapidly progressing mCRPC at the

start. Since patients with more advanced or more rapidly pro-

gressing disease seem to be less likely to complete the rec-

ommended 5-6 cycles, radium-223 should be considered as

early as appropriate in the treatment course of patients with

mCRPC and bone metastases.31

Baseline measurements

Prior to the start of radium-223 treatment, bone metastasis os-

teoblastic activity must be confirmed by functional bone im-

aging and data concerning symptoms should be collected.32

Haematological evaluation must be performed at baseline

with the absolute neutrophil count measuring ≥1.5 x 109/l,

the platelet count ≥100 x 109/l and haemoglobin ≥10.0 g/dl.12

Bone health

Guidelines recommend to offer bone protective agents to

mCRPC patients with skeletal metastases to prevent osseous

complications.1,22 When prescribing either denosumab or bi-

sphosphonates, calcium and vitamin D supplementation to-

gether with preventive dental care should be offered as well.

Caution is advised in patients with dental problems due to

an increased risk of osteonecrosis of the jaw.1,22 Painful bone

metastases should be treated early on with palliative meas-

ures such as external beam radiation therapy (EBRT) and ad-

equate use of analgesics. Radium-223 can be safely used in

combination with EBRT in case of painful focal bone metas-

tases that require rapid pain palliation and with bone pro-

tective agents (bisphosphonates and denosumab) to prevent

osseous complications.2

Contraindications

Following the interim analysis of the phase III ERA-223 tri-

al, combination therapy with radium-223 and abiraterone is

currently contra-indicated.12

MONITORING DURING RADIUM-223 TREATMENTHaematological evaluation of patients must be performed pri-

or to every injection (or cycle) of radium-223 with the abso-

VOLUME13OCTOBER20196

248PHARMACOTHERAPY

lute neutrophil count ≥1.0 x 109/l and the platelet count ≥50

x 109/l.12 The panellists agreed that during radium-223 treat-

ment a CT of chest, abdomen and pelvis together with blood

tests could in general be performed every 3 months, taking

into account that the precise timing of these exams is usu-

ally individualised. According to the expert panel, standard

biomarkers in the blood (e.g. PSA, ALP and lactate dehydro-

genase [LDH]) may increase during radium-223 treatment.

Therefore, patients should be informed that a PSA rise dur-

ing radium-223 treatment does not imply a lack of efficacy of

radium-223. In addition, it has been shown in the ALSYMP-

CA trial that dynamic changes in ALP and LDH during ra-

dium-223 treatment might be useful for monitoring, but do

not serve as surrogates for survival.33 The EAU guidelines

state that PSA alone is not reliable enough for monitoring

disease activity in advanced CRPC, since visceral metasta-

ses may develop in men without rising PSA.1 According to

the PCWG3 (Prostate Cancer Working Group 3) on-treat-

ment evaluations should look at the general clinical status of

the patient, including physical examinations, symptom as-

sessments, and laboratory studies.34 The PCWG3 also rec-

ommends that a combination of bone scintigraphy and CT

scans, PSA measurements and an assessment of the clinical

benefit should be performed in assessing men with mCRPC.

In addition, at the 2017 Advanced Prostate Cancer Consen-

sus Conference (APCCC) 75% of the experts suggested bone

scintigraphy and CT scans for monitoring mCRPC patients

treated with radium-223.35 In general, in line with the cur-

rent EAU guidelines, the panellists agreed to only start a sub-

sequent treatment if the patient progresses, i.e. has two of the

following factors: PSA, radiological or clinical progression.1

FOLLOW-UP AFTER RADIUM-223There was consensus among the panellists to perform a bone

scan at least one month after the last radium-223 injection.

Once the last cycle is terminated, the majority of panellists

recommend to monitor the patient every three months (in-

cluding ALP, LDH, PSA, full blood count, CT and bone scan)

until a new treatment is initiated. If there is a clinical indi-

cation of progressive disease, examinations should be per-

formed earlier.

With regard to the next line of treatment, a pre-specified

subgroup analysis from ALSYMPCA showed that docetax-

el following radium-223 is still feasible and well-tolerated in

patients with mCRPC.36 An interim analysis of REASSURE, a

global prospective trial, confirmed the safety of radium-223 in

routine clinical practice and showed again that it is safe to use

docetaxel after radium-223.37 The panellists agreed that both

chemotherapy and ARPIs can still be safely administered af-

ter radium-223 treatment. Overall, they concluded that every

patient with metastatic PCa should be given the possibility to

receive as many life-prolonging treatment options as possible.

CONCLUSIONSNo clear guidelines exist on how to sequence the different

therapeutic options for patients with mCRPC. These pa-

KEY MESSAGES FOR CLINICAL PRACTICE

1. Every patient with metastatic PCa should be given the possibility to receive as many life-prolonging treatment options as possible.

2. Radium-223 is an anti-cancer drug associated with overall survival benefit and a delayed time to the occurrence of SSEs, is well-tolerated and is administered for a determined period. The overall survival benefit is comparable to the survival benefit of other agents in the mCRPC setting.

3. Radium-223 is indicated for mCRPC patients with symptomatic bone metastases and no known visceral metastases, in progression after ≥2 prior lines of systemic therapy for mCRPC, or ineligible for any available systemic mCRPC treatment. Because radium-223 should be administered before progression to visceral metastases and/or lymph nodes >3 cm, it should be given as early in the disease course as possible. Both ARPIs and docetaxel can still be given after radium-223 treatment.

4. Completion of 6 cycles of radium-223 is of paramount importance in order to achieve the best clinical benefit related with this treatment. Heavily pre-treated patients are less likely to complete 6 cycles of radium-223.

5. mCRPC patients with bone metastases should receive bone health agents, irrespective of the life-prolonging treatment.

VOLUME13OCTOBER2019

249tients should be discussed by a multidisciplinary team in

order to achieve the most appropriate treatment. As stated

in the EAU guidelines, the choice of first- or second-line

treatment should be based on (pre-treatment) performance

status, symptoms, co-morbidities, location and extent of

disease, patient preference, and (in case of first-line treat-

ment) on the previous treatment for mHSPC. Every pa-

tient with metastatic PCa should be given the possibility

to receive as many life-prolonging treatment options as

possible. Since radium-223 should be administered before

progression to visceral metastases and/or lymph nodes >3

cm, it should be given as early as appropriate in the dis-

ease course.

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251ONCOCASE

SUMMARYThis article describes two cases of malignant peritoneal mesothelioma (MPM), which highlights the diversity of the disease and the diagnostic pitfalls. The risk factors, symptoms, molecular pathogenesis and the daily clinical relevance are discussed. (BELG J MED ONCOL 2019;13(6): 251-254)

1Department of Medical Oncology, University Hospital Leuven, Leuven, 2Department of Pathology, Imelda Hospital Bonheiden, Bonheiden, 3Deparment of Abdominal Surgery, University Hospital Ghent, Ghent, 4Department of Medical Oncology, Imelda Hospital Bonheiden, Bonheiden,

Belgium.

Please send all correspondence to: W. Wynendaele, MD, PhD, Department of Medical Oncology, Imelda Hospital Bonheiden, Imeldalaan 9,

2820 Bonheiden, Belgium, tel: +32 15504625, email: Wim.wynendaele@imelda.be.

Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest.

Keywords: cisplatin-pemetrexed, cytoreductive surgery, intraperitoneal chemotherapy, malignant peritoneal mesothelioma.

B. Dullens, MD1, C. Bourgain, MD, PhD2, W. Ceelen, MD, PhD3, W. Wynendaele, MD, PhD4

Difficulties in diagnosis and treatment of a rare malignancy, malignant peritoneal mesothelioma

INTRODUCTIONMPM is a rare disease caused by asbestos exposure. This

article describes two cases that demonstrate the frequent

occurrence of atypical symptoms and the complexity of its

differential diagnosis. This article gives an overview on the

recent literature and daily clinical practice in the diagnosis

and treatment of MPM.

CASE ONEA 61-year-old man was admitted to the emergency depart-

ment because of dyspepsia, abdominal pain and diarrhoea.

Physical examination revealed painless abdominal disten-

tion. There was no significant medical history. The patient

worked in a fibre cement company during his youth and

smoked 41 pack-years.

Blood work-up showed no significant abnormalities. Ab-

dominal CT showed diffuse peritoneal metastasis, an

omental cake and ascites. Thoracic CT and esophagogas-

troduodenoscopy were within normal range. An ultra-sound

guided punction of a peritoneal implant was performed.

Anatomopathological examination revealed malignant epi-

thelial cells with a tubulopapillary growth pattern. Immu-

nohistochemistry showed positive staining for Cytokeratin

(Ck) 7, GATA-3, Wilms-Tumour 1 (WT-1) and Calretinin.

Ca 19.9, Ck20, thyroid transcription factor 1 (TTF-1) and

CDX-2 were negative.

These pathology findings, together with the history of as-

bestos exposure, confirmed the diagnosis of an epithelioid

MPM. After a multidisciplinary meeting, chemotherapy was

proposed because the patient was unfit for hyperthermic in-

traperitoneal chemotherapy (HIPEC) with cytoreductive sur-

gery (CRS).

Chemotherapy with cisplatin/pemetrexed was initiated. Af-

ter three cycles of chemotherapy, CT evaluation showed un-

altered disease. After the fifth cycle of chemotherapy, the

patient presented with a bowel obstruction, caused by peri-

toneal implants. Because of the persisting obstruction, the

weak general condition, the irreversible cause and the bad

VOLUME13OCTOBER2019

252prognosis, the multidisciplinary team proposed palliative

care. The patient declined palliative care and insisted on ex-

ploring remaining therapy options. He underwent HIPEC

with CRS as a last resort. This was complicated with post-op-

erative peritonitis and septic shock. Intravenous antibiotics

were given and revision laparoscopy was performed with

drainage of multiple abdominal collections. After revision

surgery there was a slow but favourable evolution and the

patient went to a rehabilitation centre. At the first postoper-

ative control, no abnormalities were observed. Two months

later, the patient died at home after a rapid physical deterio-

ration with refusal of any further treatment.

CASE TWOA 38-year-old female was admitted to the emergency depart-

ment with complaints of abdominal pain and nausea. Phys-

ical investigation was without abnormalities. There was no

significant medical history and there was no asbestos expo-

sure reported.

Blood work-up was without abnormalities. A colonoscopy re-

vealed an intraluminal mass at the hepatic flexure. Biopsies

of this mass showed normal colon mucosa. Abdominal CT

confirmed the same intraluminal mass with signs of invag-

ination and torsion. In addition, there was evidence for dif-

fuse malignant peritoneal infiltration.

The CT findings lead to a laparoscopic right colectomy. An-

atomicopathological investigation showed an epithelial tu-

mour with papillary structures. Immunohistochemical panel

revealed positive expression of Ck7, WT-1, P16, Calretinin

and BerEP4. In some nuclei a weak expression for oestrogen

receptor and p53 were observed. MRI whole body showed

no extra-abdominal lesions. At this point, the anatomico-

pathological and radiology findings were most suggestive for

a high-grade serous tubo-ovarian carcinoma with peritone-

al metastasis, FIGO IIIC. Because the disease was inopera-

ble, neo-adjuvant chemotherapy with carboplatin/taxol was

initiated. Re-evaluation after three cycles of chemotherapy

showed a partial response, but the disease was still consid-

ered inoperable.

A second opinion of the tissue sample of the colectomy by

another pathologist brought an unexpected finding to light.

At re-evaluation, the tissue sample was most compatible

to epithelioid MPM, instead of ovarian carcinoma. There-

fore, chemotherapy was adjusted to cisplatin/pemetrexed.

Re-evaluation after 3 cycles showed further response. The

patient was referred to a centre specialised in CRS with in-

traperitoneal chemotherapy (IPC).

CRS and HIPEC with cisplatin were successfully performed.

Afterwards, the patient started maintenance chemotherapy

with pemetrexed 500mg/m2 every 3 weeks. This treatment

strategy was based on an expert opinion. Further adjuvant

cisplatin was impossible because of a decreased renal func-

tion after CRS and HIPEC. The most recent evaluation, af-

ter 1.5 year of maintenance therapy, showed a stable disease.

DISCUSSIONMPM is a rare and aggressive malignancy with an incidence

of 0.2 to 3 cases per million people in industrialised coun-

tries.1 Mesotheliomas arise from serous surfaces, such as the

peritoneum, pleura, pericardium and tunica vaginalis testes.2

Of all diagnosed mesotheliomas, 10-30% is peritoneal. It is

the second most common site of mesothelioma.3

MPM can present itself with various non-specific symptoms

of which abdominal pain, ascites, weight loss, anorexia, ab-

dominal mass, fever, diarrhoea and vomiting are the most fre-

quent. Because of the non-specific presentation, diagnosis of

MPM is often delayed. Associated paraneoplastic syndromes

are thrombocytosis, hypoglycaemia, venous thrombosis and

wasting syndrome.2

Exposure to asbestos is the predominant risk factor. Some re-

ports suggest that previous radiation therapy is another risk

factor, as well as exposure to mineral fibres, the Simian virus

40 and having Mediterranean familial fever.2

Molecular pathogenesis of MPM is still unclear, evidence sug-

gests frequent alterations in 3 genes: BRCA1 associated pro-

tein in 57% of the cases, cyclin-dependent kinase inhibitor

2A (CDKN2A) in 29% and neurofibromin 2 (NF-2) in 35%.

In the future, these gene alterations may be used to guide

treatment decisions since CDKN2A and NF2 alterations are

correlated to a poor clinical outcome.4

When there is clinical suspicion of MPM, an abdominal CT

must be performed. Screening for metastatic localisation is

not recommended unless there is clinical suspicion. MRI

and PET-CT have no place in conventional practice.3 His-

topathologic and immunohistochemical analysis is essential

to confirm the diagnosis of MPM.2 Because of the high false

negative rate, cytological fluid analysis is not recommended

for diagnosing MPM.5

Histopathologic analysis can show three major types of MPM.

The epithelioid type is the most common and has the best

prognosis. It is composed of epithelioid polygonal, cuboidal

or oval cells that can mimic non-malignant reactive mesothe-

lial cells and grow in a tubulopapillary or trabecular pattern.

The rarer sarcomatoid type has a worse prognosis and is most

often composed of spindle cells but can also consist of lym-

phohistiocytoid cells or rhabdomyosarcomatous, osteosarco-

matous or chondrosarcomatous elements. Lastly, the mixed

type or biphasic MPM consist of a mixture of the two pre-

vious types.5,6 The initial histopathological findings together

with the considered differential diagnosis are important to

VOLUME13OCTOBER20196

253

select the correct immunohistochemical markers. There is

no standard immunohistochemical panel.5 Markers that are

frequently used and stain positive are CK5 and 6, calretinin

and WT-1. TTF-1 and BerEP4 typically stain negative.3 Dif-

ferential diagnosis that have to be considered are peritoneal

carcinomatosis, serous papillary carcinomatosis, tuberculous

peritonitis and peritoneal lymphomatosis.5

As MPM is a rare disease, there are limited prospective da-

ta. The international consensus is CRS and IPC as first line

treatment in carefully selected patients. Selection criteria for

CRS and IPC are a good performance status, invasion depth,

anatomic tumour site and absence of metastatic disease.6,7

Most frequently used regimens for IPC are HIPEC and ear-

ly postoperative intraperitoneal chemotherapy (EPIC), or a

combination of these two.8 Multiple drug regimens have been

studied for IPC. Best studied regimens are cisplatin and mito-

mycin monotherapy or a combination of cisplatin with doxo-

rubicin or docetaxel.9 Two retrospective studies showed an

advantage of cisplatin over mitomycin in overall survival

(OS).6 The median OS in the largest multicentre registration

of 405 patients, treated with CRS and IPC, was 53 months.

Prognostic factors, independently associated with improved

survival, were epithelial subtype, absence of lymph node me-

tastasis and completeness of CRS.10 The use of perioperative

or (pseudo-)adjuvant systemic chemotherapy has been stud-

ied but efficacy has never been proven.

If patients are progressive after CRS and IPC or if they do not

qualify for this approach, systemic chemotherapy is an alter-

native therapy. Most data on systemic chemotherapy refer to

pleural mesothelioma, the effectiveness is considered simi-

lar.6 In 2002, a meta-analysis of all data published on cyto-

toxic therapy for mesothelioma from 1965 until 2001 showed

cisplatin as most active single-agent.11 In practice, cisplatin

is never administered as a single agent. The combination of

cisplatin/pemetrexed proved to be more efficient in a phase

III study. The median survival time of cisplatin/pemetrexed

in malignant pleural mesothelioma was 12.1 months ver-

sus 9.3 months in cisplatin monotherapy. Response rate and

time to progression were also in favour for cisplatin/peme-

trexed.12 Carboplatin is better tolerated and can be an alter-

native for cisplatin.6 Interesting remark, a recent phase III

study of pleural mesothelioma, published in 2017, showed an

improved overall survival and progression free survival for

bevacizumab associated to cisplatin/pemetrexed.13 Extrapo-

lation of these results to MPM is suggested.

If MPM is progressive despite CRS with IPC or platinum with

pemetrexed, limited options are left. Patients can be enrolled

in ongoing studies with immunotherapy and molecular tar-

geted therapy, or an attempt with second-line chemothera-

py can be made. There are no valuable prospective data in

this situation. Best supportive care and palliation should be

an option at all time.

CONCLUSIONMPM is a rare disease that is difficult to diagnose. In case of

suspicion for MPM, a tissue sample should be obtained for

histopathologic and immunohistochemical analysis. If the

diagnosis is confirmed, cytoreductive surgery with IPC is

the first line therapy in carefully selected patients. If patients

have a progressive disease after CRS with IPC, or in case of

contra-indications, chemotherapy with cisplatin/pemetrexed

can be considered. Study inclusion and best supportive care

are alternatives in daily practice.

REFERENCES1. Boffetta P. Epidemiology of peritoneal mesothelioma: a review. Ann Oncol

2007;18(6):985-90.

2. Bridda A, Padoan I, Mancarelli R, et al. Peritoneal mesothelioma: a review.

MedGenMed 2007;9(2):32.

3. García-Fadrique A, Mehta A, Mohamed F, et al. Clinical presentation, diagno-

sis, classification and management of peritoneal mesothelioma: a review. J Gas-

trointest Oncol 2017;8(5):915-924.

4. Singhi AD, Krasinskas AM, Choudry HA, et al. The prognostic significance of

BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma. Mod Pathol

2016;29(1):14-24.

5. Husain AN, Colby TV, Ordóñez NG, et al. Guidelines for pathologic diagno-

ONCOCASE

KEY MESSAGES FOR CLINICAL PRACTICE

1. MPM is a rare disease with an atypical presentation. When there is suspicion of MPM, always obtain a tissue sample for histopathologic and immunohistochemical investigation.

2. CRS with IPC is first line therapy. If patients have a progressive disease after CRS with IPC, or in case of contra-indications, chemotherapy with cisplatin/pemetrexed is an option. Best supportive care and study inclusion should be considered at all times.

VOLUME13OCTOBER2019

254sis of malignant mesothelioma 2017 update of the consensus statement from

the international mesothelioma interest group. Arch Pathol Lab Med

2018;142(1):89-108.

6. Kim J, Bhagwandin S, Labow DM. Malignant peritoneal mesothelioma: a re-

view. Ann Transl Med 2017;5(11):236.

7. Yan TD, Haveric N, Carmignani CP, et al. Abdominal computed tomography

scans in the selection of patients with malignant peritoneal mesothelioma for

comprehensive treatment with cytoreductive surgery and perioperative intraper-

itoneal chemotherapy. Cancer 2005;103(4):839-49.

8. Yan TD, Welch L, Black D, et al. A systematic review of the efficacy of cytore-

ductive surgery combined with perioperative intraperitoneal chemotherapy for

diffuse malignancy peritoneal mesothelioma. Ann Oncol 2007;18(5):827-34.

9. Russell MC, Staley CA. Cytoreductive surgery and hyperthermic intraperito-

neal chemotherapy for malignant peritoneal mesothelioma. J Oncol Pract

2016;12(10):938-939.

10. Yan TD, Deraco M, Baratti D, et al. Cytoreductive surgery and hyperthermic

intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-insti-

tutional experience. J Clin Oncol 2009;27(36):6237-42.

11. Berghmans T, Paesmans M, Lalami Y, et al. Activity of chemotherapy and im-

munotherapy on malignant mesothelioma: a systematic review of the literature

with meta-analysis. Lung Cancer 2002;38(2):111-21.

12. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of peme-

trexed in combination with cisplatin versus cisplatin alone in patients with malig-

nant pleural mesothelioma. J Clin Oncol 2003;21(14):2636-44.

13. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed

pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study

(MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet

2016;387(10026):1405-1414

VOLUME13OCTOBER20196

255ONCOCASE

SUMMARYPercutaneous balloon vertebroplasty (PVP) is an effective treatment for pathological vertebral compression fractures in oncological patients. The procedure is considered safe and the analgesic effect is fast and long lasting. Seeding metastases after PVP are a rare complication. At present, there is no standard of care how to prevent or treat this complication. Further research is necessary to determine preventive measures. (BELG J MED ONCOL 2019;13(6): 255-257)

1Gastroenterology department, ASZ Aalst, Aalst, 2Department of Medical Oncology, GZA/AZ Klina, Antwerp, 3Radiology, Leuven University

Hospital, Leuven, 4Departmant of Oncology, Antwerp University Hospital, Antwerp.

Please send all correspondence to: C. Debeuckelaere, MD, ASZ Gastroenterology department, Merestraat 80, 9300 Aalst, Belgium, email:

celine.debeuckelaere@asz.be.

Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest.

Keywords: pathological vertebral fracture, percutaneous vertebroplasty, seeding metastasis.

C. Debeuckelaere, MD1, A. Van Goethem, MD2, G. Maleux, MD, PhD3, H. Prenen, MD, PhD4

Case report: Seeding metastases after percutaneous vertebroplasty procedure for pathological fracture: a rare complication

INTRODUCTIONThis article reports the case of a 64-year old male patient with a

sigmoid adenocarcinoma that developed a pathological verte-

bral fracture, treated with percutaneous balloon vertebroplasty

(PVP). Later on, he developed seeding metastases: a rare com-

plication of PVP. This case-report will address the procedure

and possible complications of PVP and stresses the lack of da-

ta about possible preventive measures and treatment options.

CASE REPORTA 64-year old male patient was diagnosed with a sub stenot-

ic adenocarcinoma of the sigmoid in 2014 and underwent

a laparoscopic sigmoid resection at time of diagnosis. He

was staged pT3N1M0, although there was some doubt about

possible metastases to the lungs on CT scan. Nevertheless,

he was treated with adjuvant chemotherapy with modified

FOLFOX for 6 months (October 2014 till March 2015). In

September 2015, a metastasectomy of the lung lesions was

done and confirmed the diagnosis of metastases. Unfortu-

nately, three months later, CT scan showed new lung lesions

and he was started on modified FOLFIRI and bevacizumab.

Because of a pathological fracture of his L3 vertebra in De-

cember 2017, he was referred to the interventional radiolo-

FIGURE 1. Percutaneous balloon vertrebroplasty with

SpineJack device of pathological vertebral fracture.

VOLUME13OCTOBER2019

256

gy department for percutaneous balloon vertebroplasty with

SpineJack devices (5.0) (Figure 1). Two months after the pro-

cedure, the patient complained of increasing pains in the L2/

L3 dermatome regions. Clinically we observed 2 firm skin

nodules (Figure 2), laterally of the spine at level L3, suspi-

cious for seeding metastasis after the percutaneous vertebro-

plasty. He was referred to the radiotherapy department for

antalgic radiotherapy of the seeding metastases. Unfortu-

nately, in the meantime he had developed more respiratory

complaints and his general condition had deteriorated. CT

scan of thorax and abdomen showed a mixed response. As

he had become very frail, the decision was made not to start

oral chemotherapy (regorafenib or TAS 102). He deteriorat-

ed rapidly and died before receiving radiotherapy.

DISCUSSIONThere is not much literature about seeding metastases af-

ter PVP of spinal metastasis. There are only a few cases re-

ported. Percutaneous vertebroplasty (PVP) is known to be

an effective treatment for pathological vertebral compression

fractures in oncological patients. The indication for PVP as

treatment for spinal metastases is analgesia and spinal stabi-

lisation. Analgesic effect can be achieved within the first 48

hours after the procedure and can last for at least 6 months.1

This effect is secondary to prevention of micro movements

in the fractured vertebrae.2 Overall, it is a safe procedure al-

though complications such as cement leakage into the spi-

nal canal, pulmonary embolism, bleeding, spondylitis and

fractures are known.3,4 Major complications, such as un-

planned surgery or permanent sequelae, occur in less than

1% of cases. Interestingly, there is evidence that complica-

tions are more common after treating pathological spinal

fractures than after non-oncological fractures, respective-

ly in <5% and 1% of the patients.5 Overall, the incidence of

needle tract seeding after biopsy is probably underestimated,

as patients might die before the metastases become apparent

and outcomes might not be reported.1,6 In order to prevent

needle-tract seeding (NTS) after PVP, some have made the

suggestion to use a non-aspiration technique, as aspiration

is also linked with tumour cell dissemination. Also low-

pressure injection of polymethyl methacrylate (PMMA) is

recommended to prevent leakage of cancer cells after remov-

ing the needle.6 At present there is no standard of care how

to prevent or treat this complication. Research on preven-

tive measures with radiofrequency ablation, freezing tech-

niques and chemical agents is ongoing but none of them are

routinely used.7-9

REFERENCES1. Chen YJ, Chang GC, Chen WH, et al. Local metastases along the tract of nee-

dle: a rare complication of vertebroplasty in treating spinal metastases. Spine

2007;32(21):615-8.

2. Barragan-Campos HM, Vallée JN, Lo D, et al. Percutaneous vertebroplasty

for spinal metastases: complications. Radiology 2006;238(1):354-62.

FIGURE 2. Two skin nodules, suspicious for seeding

metastases after PVP.

KEY MESSAGES FOR CLINICAL PRACTICE

1. Seeding metastases is a rare complication after percutaneous vertebroplasty of a pathological vertebral fracture.

2. There is little data about preventive measures and possible treatments. Further investigation is necessary.

VOLUME13OCTOBER20196

257ONCOCASE

3. Laredo JD, Hamze B. Complications of percutaneous vertebroplasty and

their prevention. Skeletal Radiol 2004;33(9):493-505.

4. Hulme PA, Krebs J, Fergyson SJ, et al. Vertebroplasty and kyphoplasty: a

systematic review of 69 clinical studies. Spine 2006;31(17):1983-2001.

5. Mc Graw JK, Cardella J, Barr JD, et al. Society of Interventional radiology qual-

ity improvement guidelines for percutaneous vertebroplasty. J Vasc Interv Radi-

ol 2003;14(7):827-31.

6. Lee CH, Lee JW, Hyun SJ, et al. Needle-tract seeding after percutaneous

vertebroplasty: a case report. Spine 2014;39(12):752-6.

7. Azlan CA, Mohd Nasir NF, Saifizul AA, et al. A low cost solution for post-biop-

sy complications using available RFA generator and coaxial core biopsy needle.

Australas Phys Eng Sci Med 2007;30(4):288-91.

8. Ivorra A. Electrochemical prevention of needle-tract seeding. Ann Biomed Eng

2011; 39(7):2080-9.

9. Mu F, Liu SP, Zhou XL, et al. Prevention of needle-tract seeding by two-step

freezing after lung cancer biopsy. Pathol Oncol Res 2013;19(3):447-50.

VOLUME13OCTOBER2019

258

1Medical Oncology, AZ Nikolaas-AZ Lokeren-UZA, Waasland-Antwerpen, 2Center for Oncological Research (CORE), University of Antwerp, 3NET-nurse Multidisciplinary Oncological Center Antwerp (MOCA), UZA, Edegem, 4Datamanager Multidisciplinary Oncological Center Antwerp

(MOCA), UZA, Edegem, 5Medical Oncology, UZA, Edegem, Belgium.

Please send all correspondence to: W. Lybaert, MD, Department of Medical Oncology, AZ Nikolaas, Moerlandstraat 1, 9100 Sint-Niklaas,

Belgium, tel: +32 37606060, email: willem.lybaert@aznikolaas.be.

Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest.

Keywords: NET G3 pancreatic NENs to all NENs, NET G3 CAPTEM and PRRT, FDG-PET + 68Ga-DOTATATE in poorly differentiated tumours,

pembrolizumab in NETs grade 1/2, combination anti-CTLA-4/PD-1 checkpoint blockade in high-grade neuroendocrine tumours, lenvatinib in

panNETs and giNETs, running trials in NETs and NECs, QoL in NET oncological studies.

Acknowledgement: Special word of thanks to IPSEN for delivering contributing articles.

W. Lybaert, MD1, T. Vandamme, MD2, G. Boons2, K. Vandenborne3, L. De Backer4, M. Peeters, MD, PhD5

NETwerk Antwerpen-Waasland, ENETS Centre of Excellence

Highlights of the 2019 annual meeting of the European Neuroendocrine Tumour Society (ENETS)MARCH 6-8TH, 2019, BARCELONA

NEW WHO CLASSIFICATION OF NEUROENDOCRINE TUMOURS (NETS) AND NEUROENDOCRINE CARCINOMAS (NECS) ANNO 2019In the first joint session between ENETS and the European

Society of Pathology, the pathology of neuroendocrine neo-

plasms (NENs) was discussed with a focus on high-grade

NENs. Aurel Perren discussed the grading of NENs according

to the World Health Organization (WHO) classification sys-

tem, which is based on proliferation markers such as Ki-67

and mitotic count. Since 2017, the differentiation grade was

reintroduced as an additional parameter for the classifica-

tion of pancreatic NEN (PNEN). Well-differentiated PNENs

are termed pancreatic neuroendocrine tumours (PNETs) and

can be Grade (G) 1, G2 or G3 based on their proliferation

rate, while neuroendocrine carcinomas (NECs) are poorly

differentiated neoplasms with a high proliferation rate (G3).

If other NENs are highly proliferative, e.g. G3, they are still

NECs by definition, while G1 and 2 GEP-NENs are termed

NETs.1 However, the adaptations implemented for PNENs

are expected to be extended to the other NENs, including

lung NENs.2

In the talk of Jean-Yves Scoazec, the difficulties in classifying

neoplasms as NET or NEC were discussed. The main hur-

dles in this identification include limited availability of tissue

material, poor microscopic slide quality, tumour heterogene-

ity, difficulties in assessing differentiation grade of NENs or

overlap in morphological features.3 In addition, there are also

inter-observer inaccuracies when performing Ki-67% or mi-

totic index estimations. Nevertheless, given the big differenc-

es in tumour behaviour, prognosis and patient management

between different tumour classes, it is very important that a

correct diagnosis is made. Molecular analysis of NETs and

NECs has indicated differences on the genetic level between

the two entities and these differences might provide an inter-

esting additional tool to distinguish and classify them. The

latter was recently reviewed by Gitta Boons et al.4

For oesophageal and appendiceal NENs, genetic data are lack-

ing. Although data are available for G1 and G2 siNEN, data

on G3 NECs of the small intestine are lacking, mainly due

VOLUME13OCTOBER20196

259CONGRESS NEWS

to the rarity of these neoplasms. For gastric NENs the avail-

able genetic data are limited, but multiple studies have high-

lighted mutations or loss of TP53 in NECs. In contrast, TP53

is unaffected in NETs. In addition, mutations were found in

KRAS, RB1, SMAD4 and BRAF in gastric NECs. However,

the small number of cases in these studies imply that vali-

dation of these mutations is still needed.5-9 The largest part

of the colorectal NENs are NECs, and colorectal NECs were

found to harbour mutations in APC, KRAS, BRAF and TP53

and these tumour types often display microsatellite instabili-

ty.6,9 In contrast, mutations in these genes were not observed

in colorectal NETs.10

PNECs and PNETs can also be distinguished based on their

genetic profiles. In fact, also G3 PNETs, who show overlap

with PNECs regarding Ki-67 values, show a distinct genet-

ic profile. The most frequently affected genes in PNECs are

TP53, KRAS, RB1 and CDKN2A/p16 while in PNETs, MEN1,

DAXX, ATRX and mTOR pathway genes are most frequent-

ly affected.11-13 Mutations in these genes also translate into

an altered protein expression profile in these tumour types,

which can be detected via immunohistochemistry (IHC).14

Some genes, however, have been found to be mutated in both,

including LRP1B, ARID1A, CDKN2A, APC and TP53.11 In

2016, Tang et al. studied 33 G3 NENs and showed that in two

thirds of the cases, pathologists did not reach consensus on

the differentiation state of the NENs based on morpholog-

ic analysis alone.3 The use of a Ki-67 cut-off of 55%, where

lower levels would indicate a WD-NET and higher levels a

PD-NEC, did not enable discrimination of WD-NETs and

PD-NECs. This led to a misclassification of approximately

30% of WD-NETs and 30% of PD-NECs.3,15 To address this,

the additional value of IHC staining for p53, SMAD4, Rb,

ATRX and DAXX was evaluated, next to an extended patho-

logical review. DAXX or ATRX loss allowed correct classifi-

cation in 50% of the morphologically ambiguous WD-NET

cases, while abnormal expression of p53 or Rb allowed cor-

rect classification of 90% of the morphologically ambiguous

PD-NEC cases. SMAD4 evaluation didn’t provide additional

value when p53 and Rb were evaluated. Tang et al. demon-

strated that, next to additional clinical information and pres-

ence of G1/2 regions, which points towards a G3 WD-NET,

also IHC analysis can aid in making the correct diagnosis. In

more than 60% of the cases IHC analysis could differentiate

between a WD-NET and a PD-NEC.3

As discussed, genetic differences have been found between

NETs and NECs, which could be interesting as markers in

cases were histology is inconclusive. However, additional

studies with larger sample sizes will be required to further

assess the potential of molecular analyses in the differenti-

ation between NETs and NECs and thereby guide patient

Metastatic NEN G3Treatment algorythm

NET G3(Ki-67: 21-60%)

Uncertain G3(Ki-67: 21-60%)

NEC(Ki-67: 21-60%)

NEC(Ki-67: >60%)

First line:NET G2 options:- CAPTEM- Everolimus- Sunitinib if pancreatic- PRRT if SRI positive- EP if rapid PD.- Metastatic surgery

First line:Depends on clinical situation,tumor growth, tumor burden,primary etc:- EP- Other options depending- on the primary- CAPTEM- FOLFIRI/FOLFOX- PRRT?

First line:- EP

Second line:- FOLFIRI, CAPTEM of FOLFOX

MSI high = immunotherapy?CRC primary: FOLFIRINOXCRC primary: FOLFOX/CRC primary: FOLFIRI first line?

NET likepresentation

NEC likepresentation Rapid growth

FIGURE 1. Treatment algorithm for metastatic NEN G3 tumours.

VOLUME13OCTOBER2019

260

management. In addition, overlap between genetic profiles of

exocrine tumours and NECs has been described, especially

in pancreas and colon, suggesting that NECs might have an

exocrine genetic signature. The latter might be relevant for

treatment and should be explored further.9,10

Halfdan Sorbye discussed the potential difference in response

to treatment in G3 NETs in comparison to NECs, using a re-

cently published treatment algorithm (Figure 1). Interestingly,

novel data indicate that response could be dependent on Rb

expression and KRAS mutation status in G3 PNEN. G3 PNET

patients had a low response rate to platinum-based chemo-

therapy, while PNEC patients showed a good response. In

this analysis, 55% of PNEC patients did not show Rb expres-

sion and 49% harboured mutations in KRAS. In contrast, no

abnormal Rb expression or KRAS mutations were observed

in G3 PNETs. Rb expression and KRAS mutations were both

predictive for response to platinum-based chemotherapy in

G3 PNENs, while Rb expression was also predictive for re-

sponse within the PNEC population.16 Additionally, more da-

ta were presented at ENETS indicating that there might be

a role for peptide receptor radiotherapy (PRRT) in G3 NETs.

COMBINING 68GA-DOTATATE AND 18F-FDG PET/CT BETTER PREDICTS SURVIVAL IN PATIENTS WITH GASTROENTEROPANCREATIC NETSA retrospective study was presented to define the role of

combination of 68Ga-DOTATATE and 18F-FDG PET/CT in

prognosis and management of patients with advanced gas-

troenteropancreatic NETs. An adagio in NET-diagnostics is

doing gallium-PET for well differentiated tumours (i.e. grade

1 and 2 NETs) and FDG-PET for poorly differentiated tu-

mours (i.e. grade 3 NECs). The presented study included 52

patients with midgut (58%) and pancreatic (27%) prima-

ry tumours who had undergone both 68Ga-DOTATATE and 18F-FDG PET/CT within 90 days of each other. Most (87%)

patients had hepatic metastases and the median follow-up

was 42 months. Patients were divided according to 3 groups

based on PET-positivity:

1. 68Ga-positive plus FDG-negative (N= 17; well differentiat-

ed, low grade tumours)

2. 68Ga-positive plus FDG-positive (N= 29; less well differ-

entiated tumours)

3. 68Ga-negative plus FDG-positive (N= 6; poorly differenti-

ated tumours).

Results showed that the combined 68Ga/FDG-assessment (p=

0.0005) and age (p< 0.0001) were independently associat-

ed with overall survival (OS). In 31 (60%) patients, clinical

management was changed by the results of dual scanning

and provided additional information to guide the biopsy in

three cases.17

In conclusion, instead of just reserving FDG-PET for the

poorly differentiated tumours, by adding 68Ga-DOTATATE

for a larger subset of patients, prognosis can be estimated

more accurately. Prospective studies are needed to confirm

these data.

These data were nicely replicated in a poster presented by

Karfis et al.18 This study included 88 patients who underwent

90

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G1

G2

G3

G1

G2

G3

C1

C2

C3

C1

C2

C3

mPFS = 19.4 vs 17.9 vs 5.8 monthsG1 vs G2: p=0.89, HR: 1.31 (95%CI, 0.75 - 2.31)G2 vs G3: p<0.001, HR: 2.76 (95%CI, 1.32 - 5.79)

mOS = 59.2 vs 44.2 vs 22.8 monthsG1 vs G2: p=0.93, HR: 0.97 (95%CI, 0.46 - 2.05)G2 vs G3: p=0.10, HR: 1.82 (95%CI, 0.81 - 4.09)

mPFS = 40.1 vs 14.9 vs 5.6 monthsG1 vs G2: p=0.004, HR: 2.13 (95%CI, 1.64 - 3.58)G2 vs G3: p=0.007, HR: 2.48 (95%CI, 0.95 - 6.49)

mOS = 103.2 vs 41.7 vs 12.4 monthsC1 vs C2: p=0.049, HR: 2.15 (95%CI, 1.05 - 4.37)C2 vs C3: p=0.001, HR: 3.21 (95%CI, 1.12 - 9.18)

FIGURE 2. Combined Ga-DOTATATE and FDG PET imaging improves the prognostic stratification of metastatic gastro-

enteropancreatic neuroendocrine neoplasms (GEP-NENs).18

VOLUME13OCTOBER20196

261both a 68Ga-DOTATATE and 18F-FDG PET/CT scan within

90 days of each other. Patients were classified into three cat-

egories according to histological grade (G1, G2 and G3) and

into three categories according to combined PET-imaging: C1

(all lesions FDG-/Ga-DOTATATE positive), C2 (all or part of

FDG positive lesions are Ga-DOTATATE positive as well) and

C3 (all or part of FDG positive lesions are Ga-DOTATATE

negative). Stratification according to histological grade did

not show significant statistical difference in median progres-

sion-free survival (PFS) between G1 and G2 patients and in

median OS between G1, G2 and G3 patients. The survival

curves were completely separated between C1, C2 and C3

patients not only regarding mPFS, but also mOS (Figure 2).18

IMMUNOTHERAPY IN NETS: WHERE DO WE STAND?ENETS 2019 again featured the presentation of several neg-

ative trials evaluating single agent immunotherapy (previ-

ously presented at ESMO 2018 [spartalizumab] and ASCO

GI 2019 [pembrolizumab]). Earlier findings from the phase

I KEYNOTE-028 trial, which studied pembrolizumab in a

number of solid tumours, showed activity of immunothera-

py in some patients with heavily pre-treated NETs.

A phase II basket trial, KEYNOTE-158, studied the efficacy

and safety of pembrolizumab in 10 different tumour types,

including NETs. Earlier this year (ASCO GI) Jonathan Stros-

berg presented an analysis of 107 patients from the NET

cohort of KEYNOTE-158. This cohort included grade 1/2

NETs of the lung, appendix, small intestine, colon, rectum

or pancreas, with disease progression on or intolerance to

at least 1 line of standard therapy.19 Patients in this study re-

ceived 200 mg of pembrolizumab every 3 weeks for 2 years

or until progression, intolerable toxicity, or physician or

patient decision. Tumour imaging was performed every 9

weeks for the first year and then every 12 weeks. The me-

dian age of patients enrolled was 59 years, 67.3% had re-

ceived 2 or more prior therapies and 16% of participants

had a PD-L1-positive NET. The primary endpoint was ORR,

with duration of response, PFS, OS and safety as secondary

study objectives. After a median follow-up of 18.6 months,

the ORR was 3.7%, with no complete responses and 4 par-

tial responses (3 in patients with a NET of the pancreas and 1

in a patient with a gastrointestinal NET). All 4 patients with

a response to pembrolizumab had PD-L1-negative disease.

In addition to the partial responses, 61 patients had stable

disease as their best response. Three of the four responses

were ongoing after 9 months of follow-up. The median PFS

was 4.1 months with a 6-month PFS of 38.2%. At 6 months,

84.6% of patients was still alive. Treatment-related adverse

events occurred in approximately three-quarters of patients,

and 20.6% of patients had grade 3/4 adverse events. The

most commonly reported adverse event was fatigue.19

In conclusion, pembrolizumab monotherapy showed only

limited anti-tumour activity in grade 1/2 NETs and prob-

ably will not find its way in routine clinical practice. May-

be other approaches under study like combination therapy,

e.g. immunotherapy plus angiogenesis inhibition, or peptide

receptor radionuclide therapy (PRRT), are more promising.

A positive premature light at the horizon came from the

AACR Meeting 2019 in Atlanta. IN fact, results of a phase

II ‘basket trial’ showed that combined anti-CTLA-4/PD-

1 checkpoint blockade had promising activity in heavily

pre-treated patients with high-grade neuroendocrine tu-

mours (NETs).20 Among the 32 patients in the NET cohort,

including patients with both low- and high-grade disease,

24% achieved an objective response with ipilimumab plus

nivolumab, with 1 complete response. Regardless of primary

site, it appeared that the majority of patients who conferred

benefit in terms of tumour shrinkage in this study had high-

grade neuroendocrine carcinoma. A post-hoc analysis by

tumour grade found that none of the 14 patients with low-

er intermediate-grade NETs responded to ipilimumab plus

nivolumab, while 44% of those with high-grade disease did

(8 of 18 patients), The latter group included patients with

lung, gastrointestinal tract and gynaecologic primary tu-

mours. Prior studies using anti-PD-1 checkpoint inhibitor

alone in high-grade disease yielded response rates of around

5%. Interestingly, some of the responses in this study have

lasted over a year. After 6 months of therapy, 31% of patients

was free of progression and the median OS was reported

at 11 months. In summary, this combination might repre-

sent a promising strategy for patients who have almost no

hope of responding to any form of therapy. Of note, in this

study ipilimumab was administered every 6 weeks at 1 mg/

kg, which is lower than the approved dose in cancers such

as melanoma and kidney cancer. This strategy aimed at re-

ducing potential toxicities. Nivolumab was administered at

240 mg every 2 weeks and the combination was given until

progressive disease or unacceptable toxicity. The most com-

mon high-grade immune toxicities were liver function ab-

normalities in 9% of patients and colitis in 6%. No cases of

pneumonitis were reported and there were no deaths due

to adverse events.20

ANY PROMISING TARGETED THERAPIES FOR GRADE 1/2 NETS ON THE HORIZON?Jaume Capdevila updated the results of the phase II TALENT

trial, which studies the efficacy of lenvatinib 24 mg/day in

metastatic patients with grade 1/2 advanced pancreatic (pan)

NETs and gastrointestinal (gi)NETs. The ORR with current

CONGRESS NEWS

VOLUME13OCTOBER2019

262

targeted agents like sunitinib and everolimus in NETs ranges

between 2-9%. In contrast, the ORR with lenvatinib in pan-

NETs was 40.4% and 18.5% in giNETs (Figure 3). The median

PFS in pan- and giNETs was 15.8 and 15.4 months, respec-

tively. Dose reductions/interruptions were needed in 91.8%

with a median dose of lenvatinib of 20 mg/day. No new tox-

icities were reported.21

In conclusion, lenvatinib showed the highest reported ORR

with a targeted agent in panNETs and giNETs with prom-

ising PFS in a pre-treated population. The benefit was ob-

served across subgroups analyses, including patients treated

with prior targeted agents.

PROMISING ONGOING CLINICAL TRIALS IN NETS AND NECSEnrique Grande summarised the most promising running tri-

als in the domain of NETs and NECs (Figure 4). These trials

mostly focus on new angiogenesis inhibitors, combination

immunotherapy approaches and optimal sequencing of ex-

isting therapeutics. As you can appreciate, lots of exciting da-

ta to be expected in the coming years.22

WHAT MATTERS IN NURSING CARE IN NETS?With respect to nursing, ENETS provided the following take

home messages

1. NPF (NET Patient Foundation) project 2019-2020:

MIND THE GAP. For many patients with NETs, the ‘what

comes next’ question is the hardest part of their disease.

Living with uncertainty is a consistent and persistent chal-

lenge for these patients. The reality of ‘chronic cancer’ can

be an anxiety ridden place, and we have to help the pa-

tient carry, not only the physical, but also the psychologi-

cal burden of disease.

2. Sexual aspects of QoL. Living with and having treatment

for a NET can have a big effect on how patients feel about

sex (NPF). The reported NPF survey is based on a response

given by patients (26 females, 22 males) undergoing PRRT

and their responses were analysed from January 2018 to

January 2019. The authors concluded that it was difficult

to assess whether PRRT affects the sexual function during

the actual therapy. The ratio from patients who felt unaf-

fected by the therapy to patients who did experience an

impact on their sexuality was 3:2. It will be worth repeat-

ing the survey/analysis for a longer time frame to get more

significant results.

3. Physical activity during cancer treatment: why and

how? It has already been established that exercise at mod-

erate intensity can reduce cancer-related fatigue, increase

health-related QoL, prevent deterioration or improve

strength and fitness. In addition to this, there is limited ev-

idence that exercise can reduce the risk of relapse and im-

prove survival in breast, prostate and colon cancer. It also

reduces nausea and pain and improves sleep and the ability

to complete the chemotherapy treatment. Several exercise

recommendations have been formulated, including aero-

bics and muscle strengthening physical activity. It is also

recommended to adapt the exercise during chemothera-

py treatment and to start on a lower intensity and slow-

ly increase the exercise intensity and duration. The main

message is that any physical activity is better than none.

From a caregiver perspective, both written and oral in-

formation can be given on the importance of exercise. Pa-

tients can next be referred to a physiotherapist or another

exercise specialist, perform a pre-exercise fitness assess-

ment and provide supervised exercise in groups.

FIGURE 3. ORR in the phase II TALENT trial evaluating lenvatinib 24 mg/day in metastatic patients with grade 1/2 advanced

pancreatic (pan)NETs (top) and gastrointestinal (gi)NETs (bottom).21

Max

imum

cha

nge

from

bas

elin

e (%

)

Baseline

0

ORR (95 CI): 40.4% (27.3 - 54.9)

OVERALL RESPONSE RATE: PANCREATIC NETS(CENTRAL RADIOLOGY REVIEW)

50-5

0-1

0010

0

SDPR

PD

CRBest Response RECIST 1.1

Max

imum

cha

nge

from

bas

elin

e (%

)

Baseline

0

ORR (95 CI): 18.5% (9.7 - 31.9)

OVERALL RESPONSE RATE: GASTROINTESTINAL NETS(CENTRAL RADIOLOGY REVIEW)

50-5

0-1

0010

0

SDPR

PD

CRBest Response RECIST 1.1

VOLUME13OCTOBER20196

263

4. Carcinoid syndrome: Carcinoid syndrome has a major

impact on QoL. In this respect, the hypothesis was raised

that SIRT might improve the QoL in patients with carci-

noid syndrome caused by neuroendocrine liver metasta-

ses. A large international retrospective study including 244

patients of whom 60% had symptoms (flushing 43%, di-

arrhoea 40%) concluded that:

a. QoL is an important consideration in treating patients

with NET.

b. Oncology trials mainly focus on OS and PFS and as a re-

sult QoL is poorly reported in NET oncological studies.

c. Using a NET specific QoL questionnaire will provide

more robust data for NET patients.

d. QoL data is becoming an important factor in demon-

strating cost-effectiveness in the current health economy.

5. Disease-related consequences for patients: First of all,

disease-related symptoms such as diarrhoea, flushes and

fatigue can have important social consequences for pa-

tients. In addition to this, patients also experience prom-

inent psychological and existential issues. These include

the feeling that they wish to play their part in a society

but feel left out, financial consequences, insecurities in

performing their activities of daily living, fear of disease

progression and worries about their loved ones. Howev-

er, patients do seem to be able to diminish the burden of

these consequences. In this respect, a good balance be-

tween activity and rest is important. In addition, patients

should focus on living with NET instead of having NET.

It is self-evident that an adequate social support, a stable

financial situation, meaningful activities and enjoying life

in general are also factors that influence the disease-relat-

ed consequences for patients. The main conclusion should

be that it is important to talk about the social consequenc-

es of their disease.

6. Genetic counselling. A genetic study entails important

emotional implications for the patient as well as for the

relatives in risk. Therefore, a genetic counselling profes-

sional should have an in-depth knowledge on the disease,

have thorough knowledge on the genetics involved in the

disease and have insights into prevention management.

However, it is perhaps as important to have the necessary

communication skills to share this knowledge with the

patient and his/her relatives. Genetic professionals should

see the patient and family members as a whole, holistical-

ly, evaluating the psycho-emotional consequences of the

entire process for everybody who is likely to be affected

by the outcome of the genetic analysis. Nurse profession-

als are key to guide patients through this genetic counsel-

ling process.

7. How to differentiate between side effects of treatment

and symptoms of NET? Interdisciplinary systemic algo-

rithms on diagnosis and treatment of symptoms are in

place, but collaboration between different specialties is of

pivotal importance. Patient reported outcome (PRO) rep-

resent an interesting tool to identify unmet needs. Impor-

tantly, nurses can also help patients in case of symptoms

2018

PancreaticNETs

E2201Spartalizumab

TALENTLenvatinib

2019

SANET-pSurufatinib vs

Placebo

SUNEVOSunitinib +

Evofosfamide

2020

DUNEDurva + Treme

RESUNETSurufatinib

2021

SEQTOREve vs STZ-5FU

COMPETEEve vs 177Lu-edo

2022

CABATENCabo + Atezo

CABINETCabo vsPlacebo

Non-PancreaticNETs

E2201Spartalizumab

TALENTLenvatinib

SANET-pSurufatinib vs

Placebo

AXINETAxi + Oct vs Oct

DUNEDurva + Treme

COMPETEEve vs 177Lu-edo

CABINETCabo vsPlacebo

TELEFIRSTLAN w/woTelotristat

NECsE2201

Spartalizumab

NABNECNab-pac + carbovs Carbo-Etop

DUNEDurva + Treme

CABATENCabo + Atezo

SENECAFOLFIRI vsCAPTEM

EVINECEverolimus

Phase II TrialPhase III Trial

FIGURE 4. Ongoing clinical trials in NETs/NECs.

CONGRESS NEWS

VOLUME13OCTOBER2019

264

for which no quick-fix is possible: just being present, avail-

able and willing to listen can be of great help to patients

8. Person-centred care. A systematic way to create a culture

that recognises the patient as an expert in his own life and

make a room for that is the meeting with health care ser-

vices. Patient concern inventory (PCI) is one example of

identifying unmet needs.

REFERENCES1. Lloyd RV, et al. WHO Classification of Tumours of Endocrine Organs. 4th edi-

tion ed. Lyon, France: IARC Press; 2017.

2. Rindi G, et al. A common classification framework for neuroendocrine neo-

plasms: an International Agency for Research on Cancer (IARC) and World Health

Organization (WHO) expert consensus proposal. Modern pathology: an official

journal of the United States and Canadian Academy of Pathology, Inc.

2018;31(12):1770-86.

3. Tang LH, et al. A Practical Approach to the Classification of WHO Grade 3

(G3) Well Differentiated Neuroendocrine Tumour (WD-NET) and Poorly Differen-

tiated Neuroendocrine Carcinoma (PD-NEC) of the Pancreas. The American

Journal of Surgical Pathology. 2016;40(9):1192-202.

4. Boons G, et al. Clinical applications of (epi)genetics in gastroenteropancreat-

ic neuroendocrine neoplasms: moving towards liquid biopsies. Reviews in En-

docrine and Metabolic Disorders. Accepted.

5. Makuuchi R, et al. Comprehensive analysis of gene mutation and expression

profiles in neuroendocrine carcinomas of the stomach. Biomedical Research.

2017;38(1):19-27.

6. Pizzi S, et al. Genetic alterations in poorly differentiated endocrine carcino-

mas of the gastrointestinal tract. Cancer. 2003;98(6):1273-82.

7. Furlan D, et al. Different molecular profiles characterize well-differentiated en-

docrine tumours and poorly differentiated endocrine carcinomas of the gastro-

enteropancreatic tract. Clinical cancer research: an official journal of the Amer-

ican Association for Cancer Research. 2004;10(3):947-57.

8. Nishikura K, et al. Carcinogenesis of gastric endocrine cell carcinoma: anal-

ysis of histopathology and p53 gene alteration. Gastric cancer: official journal of

the International Gastric Cancer Association and the Japanese Gastric Cancer

Association. 2003;6(4):203-9.

9. Sahnane N, et al. Microsatellite unstable gastrointestinal neuroendocrine car-

cinomas: a new clinicopathologic entity. Endocrine-related cancer. 2015;22(1):35-

45.

10. Takizawa N, et al. Molecular characteristics of colorectal neuroendocrine car-

cinoma; similarities with adenocarcinoma rather than neuroendocrine tumour.

Human pathology. 2015;46(12):1890-900.

11. Konukiewitz B, et al. Pancreatic neuroendocrine carcinomas reveal a closer

relationship to ductal adenocarcinomas than to neuroendocrine tumours G3.

Human pathology. 2018;77:70-9.

12. Jiao Y, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently

KEY MESSAGES FOR CLINICAL PRACTICE

1. The NET G3 category might soon be extended from pancreatic NENs to all NENs, including tumours of lung origin. Genetic characterisation might help differentiate between NET and NEC.

2. The optimal treatment of NET G3 should be studied further, however CAPTEM-chemotherapy and PRRT seem to be effective in this population and genetics can guide treatment.

3. The use of 68Ga-DOTATATE in combination with FDG-PET in a larger subset of patients allows for a more accurate estimation of the prognosis.

4. Pembrolizumab monotherapy showed only limited anti-tumour activity in NETs grade 1/2 and probably will not find its way in routine clinical practice.

5. Combining anti-CTLA-4/PD-1 checkpoint blockade showed promising activity in heavily pre-treated patients with high-grade neuroendocrine tumours.

6. Lenvatinib showed the highest reported ORR with a targeted agent in panNETs and giNETs with promising PFS in a pre-treated population.

7. Ongoing trials in NETs and NECs are mostly focusing on new angiogenesis inhibitors, combination immunotherapy approaches and optimal sequencing of existing therapeutics.

8. QoL is poorly reported in NET oncological studies. Using a NET specific QoL questionnaire will provide more robust data for NET patients. A dedicated NET nurse can play a pivotal role to guide patients with NET.

VOLUME13OCTOBER20196

265altered in pancreatic neuroendocrine tumours. Science. 2011;331(6021):1199-

203.

13. Scarpa A, et al. Whole-genome landscape of pancreatic neuroendocrine tu-

mours. Nature. 2017;543(7643):65-71.

14. Yachida S, et al. Small cell and large cell neuroendocrine carcinomas of the

pancreas are genetically similar and distinct from well-differentiated pancreatic

neuroendocrine tumours. Am J Surg Pathol. 2012;36(2):173-84.

15. Sorbye H, et al. Predictive and prognostic factors for treatment and survival

in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO

G3): the NORDIC NEC study. Annals of oncology: official journal of the Europe-

an Society for Medical Oncology/ESMO. 2013;24(1):152-60.

16. Hijioka S, et al. Rb Loss and KRAS Mutation Are Predictors of the Response

to Platinum-Based Chemotherapy in Pancreatic Neuroendocrine Neoplasm with

Grade 3: A Japanese Multicenter Pancreatic NEN-G3 Study. Clinical cancer re-

search: an official journal of the American Association for Cancer Research.

2017;23(16):4625-32.

17. Furtado O’Mahony L, et al. Combination of 68Ga-DOTATATE and 18F-FDG PET/

CT in Advanced Gastroenteropancreatic Neuroendocrine Tumours (GEPNET) –

Clinical and Prognostic Implications. Presented at ENETS 2019, Barcelona,

Spain.

18. Karfis I, et al. Combined Ga-DOTATATE and FDG PET Imaging Improves Prog-

nostic Stratification In Metastatic GastroEnteroPancreatic Neuroendocrine Neo-

plasias (GEP-NENs). Presented at ENETS 2019, Barcelona, Spain.

19. Strosberg JR, et al. Pembrolizumab treatment of advanced neuroendocrine

tumours: Results from the phase II KEYNOTE-158 study. Oral presentation at

ASCO GI 17-19 January 2019, San Francisco.

20. Patel S, et al. Immune Checkpoint Inhibitor Combination Efficacious For Pa-

tients With High-grade Neuroendocrine Carcinoma. Presented at AACR 2019,

Atlanta.

21. Capdevila J, et al. Progression-free survival (PFS) and subgroups analyses

of lenvatinib in patients (pts) with G1/G2 advanced pancreatic (panNETs) and

gastrointestinal (giNETs) neuroendocrine tumours (NETs): Updated results from

the phase II TALENT trial (GETNE 1509). Oral presentation at ENETS 2019, Bar-

celona, Spain.

22. Grande E. Clinical Trials Updates. Oral presentation at ENETS 2019, Barce-

lona, Spain.

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Overview of Belgian reimbursement news(BELG J MED ONCOL 2019;13(6):266-267)

Department of Oncology, University Hospital Antwerp, Edegem, Belgium.

Please send all correspondence to: P. Specenier, MD, PhD, Antwerp University Hospital, Department of Oncology, Wilrijkstraat 10, 2650

Edegem, Belgium, tel: +32 3 8214014, email: pol.specenier@uza.be.

Conflict of interest: The author has nothing to disclose and indicates no potential conflict of interest.

Keywords: dabrafenib, lenvatinib, trametinib.

P. Specenier, MD, PhD

New oncology reimbursements in Belgium

DABRAFENIB-TRAMETINIB (TAFINLAR®-MEKINIST®)Dabrafenib-trametinib (Tafinlar®-Mekinist®) can be re-

imbursed as adjuvant therapy for patients with completely

resected stage III BRAFv600 mutated melanoma. The effica-

cy and safety of dabrafenib in combination with trametinib

were studied in a phase III, multicentre, randomised, dou-

ble-blind, placebo-controlled study (COMBI-AD) in patients

with stage III (stage IIIA with lymph node metastasis >1 mm,

IIIB, or IIIC) cutaneous melanoma with a BRAF V600 E/K

mutation, following complete resection. Patients were ran-

domised 1:1 to receive either combination therapy or two

placebos for a period of twelve months. At the time of pri-

mary analysis, the median duration of follow-up (time from

randomisation to last contact or death) was 2.83 years in the

dabrafenib and trametinib combination arm and 2.75 years

in the placebo arm. The study showed a statistically signifi-

cant difference for the primary outcome of relapse-free sur-

vival (RFS) between treatment arms, with a median RFS of

16.6 months for the placebo arm and not yet reached for the

combination arm (hazard ratio [HR]: 0.47; 95% confidence

interval [CI]: 0.39, 0.58; p=1.53×10-14). Based on updated da-

ta with an additional ten months of follow-up compared to

the primary analysis (minimum follow-up of 40 months), the

RFS benefit was maintained with an estimated HR of 0.49;

95% CI: 0.40, 0.59). Based on 153 events corresponding to a

26% information fraction of the total target of 597 overall sur-

vival (OS) events, the estimated hazard ratio for OS was 0.57

(95% CI: 0.42, 0.79; p=0.0006). These results did not meet

the pre-specified boundary to claim statistical significance at

this first OS interim analysis (HR=0.50; p=0.000019). Sur-

vival estimates at one and two years from randomisation were

97% and 91% in the combination arm and 94% and 83% in

the placebo arm, respectively.

LENVATINIB (LENVIMA®)Lenvatinib (Lenvima®) can be reimbursed for patients with

advanced hepatocellular carcinoma with an ECOG PS 0 or

1 and a Child-PUGH A liver function who have received no

prior systemic therapy. No more than 50% of the liver should

be involved by tumour and there should be no clear invasion

of van porta or biliary duct.

The clinical efficacy and safety of lenvatinib have been evalu-

ated in an international, multicentre, open-label, randomised

non-inferiority phase III study (REFLECT) in patients with

unresectable hepatocellular carcinoma (HCC). Patients were

eligible to participate if they had a liver function status of

Child-Pugh class A and Eastern Cooperative Oncology

Group Performance Status (ECOG PS) 0 or 1. Patients who

had prior systemic anticancer therapy for advanced/unre-

sectable HCC or any prior anti-VEGF therapy were excluded.

Target lesions previously treated with radiotherapy or locore-

gional therapy had to show radiographic evidence of disease

progression. Patients with ≥50% liver occupation, clear in-

vasion into the bile duct or a main branch of the portal vein

(Vp4) on imaging were also excluded.

VOLUME13OCTOBER20196

267In total, 954 patients were randomised 1:1 to receive either

lenvatinib (12 mg [baseline body weight ≥60 kg] or 8 mg

[baseline body weight <60 kg]) given orally once daily or

sorafenib 400 mg given orally twice daily. The primary effi-

cacy endpoint was OS. Lenvatinib was non-inferior for OS to

sorafenib with HR = 0.92 (95% CI: 0.79, 1.06) and a median

OS of 13.6 months vs 12.3 months.

ABEMACICLIB (VERZENIOS®)Abemaciclib (Verzenios®) can be reimbursed for the treat-

ment of women with locally advanced or hormone-receptor

HER2-negative metastatic breast cancer:

• in association with a non-steroidal aromatase inhibitor in

patients:

º who received an adjuvant therapy with tamoxifen and

who recur during or within twelve months after adju-

vant therapy or

º who received an adjuvant hormonal therapy and who

recur >12 months after the end adjuvant therapy or

º symptomatic, previously untreated patients with de no-

vo metastases

• in association with fulvestrant in patients:

º who received an adjuvant therapy with an aromatase in-

hibitor and who recur during or within twelve months

after adjuvant therapy or

º who already received a hormonal treatment for ad-

vanced or metastatic disease

The efficacy and safety of Verzenios in combination with an

aromatase inhibitor (anastrozole or

letrozole) was evaluated in MONARCH 3, a randomised,

double-blind, placebo-controlled phase III study in women

with hormone-receptor positive, HER2-negative locally ad-

vanced or metastatic breast cancer who had not received prior

systemic therapy in this disease setting. Patients were ran-

domised in a 2:1 ratio to receive either Verzenios 150 mg or

placebo twice daily plus a non-steroidal aromatase inhibitor.

Progression-free survival (PFS) was significantly prolonged

in the Verzenios plus aromatase inhibitor arm, with a HR of

0.540 (95% CI: 0.418, 0.698); p=0.000002. Median PFS was

28.18 months and 14.46 months, respectively. Overall sur-

vival was not mature at the final PFS analysis. The HR was

1.057 (95% CI: 0.683, 1.633), p=0.8017.

The efficacy and safety of Verzenios in combination with ful-

vestrant was evaluated in MONARCH 2, a randomised, dou-

ble-blind, placebo-controlled phase III study in women with

hormone-receptor positive, HER2-negative locally advanced

or metastatic breast cancer. Patients were randomised in a 2:1

ratio to receive either Verzenios 150 mg or placebo twice daily

plus fulvestrant. Median PFS was significantly prolonged in

the Verzenios plus fulvestrant arm with a HR of 0.553 (95%

CI: 0.449, 0.681); p<0.000001. Median PFS was 16.4 months

and 9.3 months, respectively. Overall survival was not ma-

ture at the final PFS analysis. The HR was 0.854 (95% CI:

0.598, 1.221); p=0.3886.

LINKS:https://www.ema.europa.eu/en/medicines/human/EPAR/

tafinlar#product-information-section

https://www.ema.europa.eu/en/medicines/human/EPAR/

lenvima#product-information-section

https://www.ema.europa.eu/en/search/

search?search_api_views_fulltext=verzenios

PELMEG® (PEGFILGRASTIM)Pelmeg® (prefilled syringe) is available and reimbursed in Bel-

gium since September first. This launch follows European

Commission (EC) approval in November 2018. Pelmeg® is a

pegfilgrastim biosimilar and is the fourth biosimilar medicine

to be commercialised by Mundipharma. Pelmeg® is indicat-

ed for the reduction of the duration of neutropenia and the

incidence of febrile neutropenia in adult patients treated with

cytotoxic chemotherapy for malignancy (with the exception of

chronic myeloid leukaemia and myelodysplastic syndromes).1

It is administered as a subcutaneous injection once per

chemotherapy cycle, at least 24 hours after cytotoxic

chemotherapy.1

The approval of Pelmeg® was based on a robust regulato-

ry submission of rigorous analytical, biofunctional, preclinical

and clinical studies to demonstrate biosimilarity in terms of

its quality, safety and efficacy profile compared with the refer-

ence pegfilgrastim.2 As such, it is indicated in the exact same

way as subcutaneous (pre-filled syringe) Neulasta®.3

REFERENCES1. European Medicines Agency. Pelmeg® (pegfilgrastim) Summary of Prod-

uct Characteristics. Available at: https://www.ema.europa.eu/docu-

ments/product-information/pelmeg-epar-product-information_en.pdf.

Last accessed January 2019.

2. European Medicines Agency. Pelmeg® (pegfilgrastim) European Public

Assessment Report. Available at: https://www.ema.europa.eu/en/med-

icines/human/EPAR/pelmeg#overview-section. Last accessed January

2019.

3. SmPC of Neulasta®.

BE/PMG-19018 -date of preparation: April 2019.

REIMBURSEMENT NEWS

Caregivers delivering care to breast cancer patients wish to provide the highest quality breast care possible within their existing financial and personnel resources. Due to the complexity of the care pathway, this care should be delivered by a multidiscipli-nary team working in a breast cancer unit.

This book was written by 125 experts from 25 countries

coming from the five continents. Nine members of the

Belgian Society of Medical Oncology and three members

of the Quality task force participated in this effort. Profes-

sor Paridaens participated by photographic poetry. Diffe-

rent disciplines present ideas for developing a breast unit

wherever you live. Although the basics in diagnosis and

treatment are well known, providing, monitoring, and

assessing the breast cancer care offered is challenging for

most sites. The authors provide thorough descriptions of high-quality breast cancer care, define

targets to strive for, methods to assess one’s care, and ideas on how to improve within one’s resour-

ces. A global view of quality of breast cancer care shows specific best practices applicable to many

centres operating in various health care systems with different financial and political situations.

Foundation hallmarks of innovation, communication, patient-centred care, multidisciplinary, and

budget considerations guide specific recommendations for each component of care. This book

provides a comprehensive overview that takes into global and local considerations so that optimally

“integrated” breast cancer care can be organised. Individually, each component of care (e.g. ima-

ging, surgery, systemic treatment, genetic assessment, etc.) is discussed from both theoretical and

practical aspects. Each discipline may identify a desired level of care that is possible, while the local

resources define what is achievable. The choice of a final recommendation for each component of

care is facilitated by experienced experts laying out rational and practical approaches to each step.

This book discusses how to integrate the different disciplines into breast cancer care. Beyond

treatment, it provides practical considerations regarding accreditation and certification, and it

comments about the influence of budget and value over treatment. Finally, it demonstrates how best

practices may be altered by the emerging involvement of patients, technologies, and transitions of

future societal values. This book is highly recommended to all interested in breast cancer manage-

ment by the BSMO task force of breast cancer and by the task force of quality management.

2

BREAST CANCER

GLOBAL QUALITY CARE

edited byDidier Verhoeven | Cary Kaufman | Robert Mansel | Sabine Siesling

Published by OXFORD UNIVERSITY PRESS

VOLUME13OCTOBER2019

269

2019Congress Calendar

OCTOBER3-5 OCTOBER ESHNR 2019Palermo, Sicily, Italy

http://www.eshnr.eu/meetings/future-

meetings/

9-13 OCTOBER 28th EADV CongressMadrid, Spain

https://www.eadv.org/calendar/2019

9 OCTOBER13th Respiratory Oncology Update MeetingDolce La Hulpe, La Hulpe, Brussels,

Belgium

https://www.update-respiratoryonco.be/

23-26 OCTOBER 51st SIOP 2019Lyon, France

https://siop19.kenes.com/

25-26 OCTOBER Palliative and Supportive Care in

Oncology SymposiumSan Francisco, California, United States

https://pallonc.org/about/dates-overview

NOVEMBER2-5 NOVEMBER 21st ESGO CongressAthens, Greece

https://www.esgo.org/esgo2019/

7-9 NOVEMBER 7th Trends in Head and Neck

Oncology (THNO-7)Athens, Greece

https://congresscare.com/congress/7th-

trends-in-head-and-neck-oncology/

13-15 NOVEMBER

BSIR Annual Meeting Manchester, United Kingdom

https://www.bsir.org/meetings/

14-15 NOVEMBER Oncologiedagen voor Nederland en

Vlaanderen 2019 Papendal, Arnhem, The Netherlands

http://www.nvmodagen.nl

14-16 NOVEMBER

19th SIOG Annual ConferenceGeneva, Switzerland

https://www.siogconference.org

14-16 NOVEMBER Advanced Breast Cancer 5th ESO-EMSO International Consensus

Conference Lisbon, Portugal

http://www.abc-lisbon.org/

14-17 NOVEMBER 11th European Multidisciplinary Congress on Urological Cancers

(EMUC19) Vienna, Austria

https://emuc.org/

17-19 NOVEMBER3rd International Oncology

Leadership Conference (IOLC)University of Antwerp, Antwerp, Belgium

http://oncologyleadership.org/register

21-23 NOVEMBER

27th COGI Congress

Paris, France

http://cogi-congress.org/

DECEMBER 7-10 DECEMBER

61st ASH Annual MeetingOrlando, Florida, United States

http://www.hematology.org/

10-14 DECEMBER 42nd San Antonio Breast Cancer

Symposium San Antonio, Texas, United States

https://www.sabcs.org/