pmb definition guideline for metastatic (including ... definition project... · pmb definition...

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PMB definition guideline for metastatic (including advanced) oesophageal cancer


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Disclaimer:

The metastatic stage oesophageal cancer benefit definition has been developed for the majority of

standard patients. These benefits may not be sufficient for outlier patients. Therefore Regulation 15(h) and

15(I) may be applied for patients who are inadequately managed by the stated benefits. The benefit

definition does not describe specific in-hospital management such as theatre, anaesthetists, anaesthetist

drugs and nursing care. However, these interventions form part of care and are prescribed minimum

benefits.

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Table of contents

1. Introduction ………………......................................................................................................5

2. Scope and purpose…...........................................................................................................5

3. Epidemiology and burden of Disease................................................................................. .6

4. Investigation, diagnosis and staging ……………………………………………….....................6

5. Treatment options for metastatic stage oesophageal cancer.............................................. .7

6. Follow up Care ………………...............................................................................................10

7. References…...................................................................................................................... 13

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Abbreviations

5FU Fluorouracil

AC Adenocarcinoma

ASCO American Society of Clinical Oncology

A-YLLs Absolute Years of Life Lost

CMS Council for Medical Schemes

CT Computed tomographic

DTPs Diagnosis treatment pairs

FBC Full Blood Count

GEJ Gastro-oesophageal junction

ICD International Classification of Diseases

IMRT Intensity-modulated radiation therapy

NCR National Cancer Registry

OC oesophageal cancer

PEG Percutaneous endoscopic gastrostomy

PMB Prescribed minimum benefit

SCC Squamous cell carcinoma

SEMS self-expanding metal stents

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1. Introduction

1.1. The legislation governing the provision of the prescribed minimum benefits (PMBs) is contained in

the Regulations enacted under the Medical Schemes Act, 131 of 1998 (the Act). In respect of some

of the diagnosis treatment pairs (DTPs), medical scheme beneficiaries find it difficult to know their

entitlements in advance. In addition, medical schemes interpret these benefits differently, resulting

in a lack of uniformity of benefit entitlements.

1.2. The benefit definition project is coordinated by the Council for Medical Schemes (CMS) and aims

to define the PMB package as well as to guide the interpretation of the PMB provisions by relevant

stakeholders.

2. Scope and purpose

2.1. This is a recommendation for the diagnosis, treatment and care of individuals with metastatic

oesophageal cancer in any clinically appropriate setting as outlined in the Act.

2.2 The purpose is to improve clarity in respect of funding decisions by medical schemes, taking into

consideration evidence based medicine, affordability and in some instances cost-effectiveness.

Table 1: Possible ICD10 codes for identifying metastatic oesophageal cancer

ICD 10 code WHO description

C15.0 Malignant neoplasm, cervical part of oesophagus

C15.1 Malignant neoplasm, thoracic part of oesophagus

C15.2 Malignant neoplasm, abdominal part of oesophagus

C15.3 Malignant neoplasm, upper third of oesophagus

C15.4 Middle third of oesophagus

C15.5 Malignant neoplasm, lower third of oesophagus

C15.8 Malignant neoplasm, overlapping lesion of oesophagus

C15.9 Malignant neoplasm, oesophagus, unspecified

3. Epidemiology

3.1. Despite improved screening and treatment modalities, more than 50% of oesophageal cancer is

diagnosed in the advanced stages of disease (Shah, 2015). Many patients progress to metastatic disease

following treatment with curative intent. Although an improvement has been seen in reduction in Absolute

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Years of Life Lost (A-YLLs) from 2005 to 2015, oesophageal cancer still remains ranked 7th in terms of A-

YLLs in the world (Global Burden of Disease Cancer Collaboration, 2016).

3.2. The prognosis remains poor in advanced or metastatic disease and the aim of treatment is to improve

survival and quality of life through palliative therapy (Berry, 2014).

3.3. In South Africa, patients typically present in late stages of disease and as a result oesophageal cancer

ranks as the 3rd most common cause of cancer death in the country (Global Burden of Disease Cancer

Collaboration, 2016).

3.4. Very little original research has been published in South Africa on oesophageal cancer (Loots, Sartorius,

Madiba, Mulder & Clarke, 2016).

4. Investigation, diagnosis and staging

4.1. Staging of OC is conventionally as per the American Joint Committee on Cancer (AJCC)/Union for

International Cancer Control (UICC) TNM staging system (7th Edition) , however this has recently been

updated to the 8th Edition which is published as 3 separate recommendations for staging (Rice, T.W.,

Ishwaran ,H., Hofstetter, W.L., Kelsen,D.P., Apperson-Hansen, C., Blackstone, 2016: 897-905; Rice et

al, 2016: 913-919; Rice et al , 2016: 906-912).

4.2. The diagnosis and staging of inoperable metastatic oesophageal cancer focuses more on distant

metastases and lymph nodes. The most common organ metastases are in the liver, lung and bone

(Varghese, Hofstetter, Rizk, Low, Darling, Watson, Mitchell & Krasna, 2013).

4.3. Chest x-ray is PMB level of care for the detection of pulmonary metastases

4.4. CT of the chest and abdomen is recommended as the optimal test for staging metastatic oesophageal

cancer (Varghese et al, 2013).

4.5. PET-CT is only recommended for locally advanced disease if the patient has already had a baseline PET

scan or if considering radical local therapy

4.6. Barium studies are recommended in localising disease, to exclude suspicion of a tracheoesophageal

fistula or confirming aspiration as in tight strictures or planning treatment thereof (Varghese et al, 2013).

4.7. Full blood count, liver function tests and renal function tests are PMB level of care

Table 2: Diagnosis and staging work-up for advanced metastatic (inoperable) oesophageal cancer

Description Frequency

Clinical assessment Consultations with

primary care practitioner, gastroenterologist,

oncologist, surgeon

2 consultations per speciality

Imaging: Radiology Chest x-ray 1

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CT study of chest and abdomen

OR

1

PET-CT (FDG ) - )- if the patient has already

had a baseline PET scan or if considering

radical local therapy

1

Barium swallow with contrast

1

Imaging: Procedures Upper gastro-intestinal endoscopy 1

Bronchoscopy - Only on specialist motivation 1

Histological

assessment

Histology / Cytology 1

Pathology Full Blood Count (FBC) 1

Liver function test 1

Renal function 1

5. Treatment options for metastatic stage oesophageal cancer

Treatment in locally advanced and metastatic oesophageal cancer is largely based on systemic therapies or

palliative management. Improvement in overall survival is unlikely and therefore quality of life issues are important

with a focus on managing pain, dysphagia and bleeding.

The use of radical therapy vs palliative therapy in locally advanced disease is based on patient factors (age,

performance status, symptoms, anthropometric measures, biochemistry and haem) as well as tumor factors

(location, size, length risk of occult metastases). Patients who have localized disease and are amenable to radical

therapy may be candidates for treatments such as chemoradiotherapy (definitive), chemotherapy followed by

assessment for surgery or radiotherapy. In this instance a PET-CT scan is recommended to rule out metastatic

disease if the CT is unclear to avoid protracted, unnecessary treatment.

5.1. Surgical management

The following surgical interventions of oesophageal cancer are PMB level of care for metastatic

disease:

- Dilatation

- Stenting

- Percutaneous endoscopic gastrostomy (PEG)

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5.1.1. Dilatation may be used to facilitate endoscopic ultrasound where strictures limit access or pre-

stenting (American Society for Gastrointestinal Endoscopy Standards of Practice Committee,

2013).

5.1.2. Dilatation may be used in severe obstruction where the patient is still able to swallow liquids

however the risk of perforation is high and symptom alleviation is better achieved with stenting.

(American Society for Gastrointestinal Endoscopy Standards of Practice Committee, 2013;

NCCN Guidelines Version 2, 2016)

5.1.3. The most recent Cochrane Systematic Review (2014) of the treatment of dysphagia in

oesophageal cancer does not recommend dilatation either as monotherapy or in combination

with other modalities as a comparative intervention to stenting and other modalities such as

brachytherapy however dilatation is used pre-stenting (Dai, Li, Xie, Liu, Zhang, Zhou, Pan &

Yang, 2014).

5.1.4. Self-expanding metal stents (SEMS) are a recommended palliation therapy for patients with

dysphagia and/or fistula. Metal stents are preferred over plastic stents with lower adverse events

and improved clinical benefits (Dai et al, 2014; Spaander, Baron, Siersema, Fuccio,

Schumacher, Escorsel, Garcia-Pagán, Dumonceau, Conio, de Ceglie, Skowronek, Nordsmark,

Seufferlein, Van Gossum, Hassan, Repici & Bruno, 2016).

5.2. Chemotherapy for locally advanced unresectable oesophageal cancer

5.2.1. The recurrence rate in patients who receive chemotherapy for metastatic oesophageal cancer

is generally high with a decline in performance status following first-line treatment thereby

limiting treatment options as second line therapy. Higher response rates (up to 65 percent) are

reported in phase II trials evaluating combination therapy in patients with advanced

oesophageal and gastric cancer. However, almost without exception, response rates have

been lower in the setting of randomized trials. Furthermore, whether higher response rates

seen with combination as compared with single agent chemotherapy translate into longer

response duration or survival remains uncertain. The decision rests with the clinicians’

assessment and is based on clinical condition.

5.2.2. The medicines listed below may be used in recognised combinations.

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Table 4: Chemotherapy options in metastatic oesophageal cancer

Indication Treatment description Medicine details

Oesophageal cancer:

Definitive

1st line chemotherapy Cisplatin

Carboplatin

Paclitaxel/ docetaxel

Fluorouracil (5FU) with leucovorin

Capecitabine

2nd line chemotherapy Cisplatin

Oxaliplatin

Carboplatin

Paclitaxel or Docetaxel

Fluorouracil (5FU) with leucovorin

Capecitabine

5.2.3. First line chemotherapy is generally given as combination therapy of a platinum agent (cisplatin

or carboplatin) and a fluoropyrimidine (5FU or Capecitabine) (Mohammad, ter Veer, Ngai, Mali,

Van Oijen & Laarhoven, 2015).

5.2.4. First-line double therapy is preferred over triple therapy as the overall survival benefits are limited

with triple therapy with significantly increased Grade 3-4 adverse events (Mohammad et al,

2015), (NCCN Guidelines Version 2,2016).

5.2.5. Outcome studies are limited for chemotherapy in squamous cell carcinoma with cisplatin and

fluorouracil the preferred first-line treatment regimen (Lordick, Mariette, Haustermans,

Obermannová & Arnold, 2016). Evidence for second-line therapy is also limited and based

mostly on phase II studies (Wang and Huang, 2016).

5.2.6. Patients with adenocarcinoma are more likely to respond to chemotherapy with cisplatin and

fluorouracil as the preferred first-line treatment regimen (Lordick et al, 2016).

5.2.7. The use of a taxane (Paclitaxel/Docetaxel) as second or third-line treatment in adenocarcinoma

has shown statistically significant improvement in overall survival and reduction in hazard ratio

for death (Janowitz, Thuss-Patience, Marshall, Kang, Connell, Cook, Dunn, Park & Ford, 2016).

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5.2.8. Taxanes may be used in combination as first-line therapy or monotherapy as second-line

treatment (Lordick et al, 2016; NCCN Guidelines Version 2, 2016).

5.2.9. Capecitabine has been shown to be well tolerated as first-line treatment in combination with

cisplatin or paclitaxel (Lee, Kim, Kim, Lee, Park, Im, & Park, 2015).

5.2.10. Perioperative chemotherapy is recommended in locally advanced adenocarcinoma of the

thoracic oesophagus with the combination of a platinum agent and fluorouracil being the best

studied (Lordick et al, 2016; Malthaner, Wong, Spithoff, Rumble & Zuraw, 2016).

5.3. Radiation therapy

5.3.1. Brachytherapy compared to SEMS has shown to have gradual improvement over SEMS in

managing dysphagia and quality of life with time and is suggested as an alternative to SEMS

based on performance status (Dai et al, 2014; NCCN Guidelines Version 2, 2016).

5.3.2. Single dose brachytherapy may be recommended as palliative treatment in metastatic disease

with improved tolerability and symptom relief compared to stenting (Lordick et al, 2016).

5.3.3. Few studies have evaluated the cost-effectiveness of brachytherapy as palliative treatment with

2 studies suggesting similar total medical costs with another showing significantly higher costs

for the brachytherapy group. Brachytherapy can be combined with external beam radiotherapy

or offered after stent insertion. External beam may also be combined with stent insertion (Homs,

Steyerberg, Eijkenboom, Tilanus, Stalpers, Bartelsman, Van Lanschot, Wijrdeman, Mulder,

Reinders, Boot, Aleman, Kuipers, & Siersema, 2004; Polinder, Homs, Siersema, Steyerberg,

2004; Wenger, Johnsson, Bergquist, Nyman, Ejnell, Lagergren, Ruth & Lundell, 2005).

Table 5. Radiation therapy in locally advanced oesophageal cancer

Conventional Radiation therapy

Palliation: 5#: conventional single volume / Conventional multiple volumes

Palliation: 10#: conventional single volume / Conventional multiple volumes

Brachytherapy: single dose brachytherapy in palliative setting

6. Follow up care

6.1. Follow-up and surveillance in metastatic disease should focus on patient quality of life with optimal

symptom management and patient support (Lordick et al, 2016).

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6.2. The American Society of Clinical Oncology (ASCO) recommends in its Choosing Wisely campaign of

2013 to “avoid using positron emission tomography or positron emission tomography–computed

tomography scanning as part of routine follow-up care to monitor for cancer recurrence in asymptomatic

patients who have finished initial treatment to eliminate the cancer unless there is high-level evidence that

such imaging will change the outcome” (Schnipper, Lyman, Blayney, Hoverman, Raghavan, Wollins &

Schilsky, 2013).

6.3. The use of PET as a follow-up to detect recurrence in oesophageal does not improve survival outcomes

at 2 years (Healy, Yin, Reddy & Wong, 2016).

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Table 6: Frequency of interventions considered to be PMB level of care in metastatic oesophageal cancer during therapy and up to 10 years post diagnosis

Frequency during

therapy

Up to 2 years

post diagnosis

3-5 years post diagnosis Recurrent work up – only if there is suspicion of

disease recurrence

Frequency per year

Clinical assessment Consultations Depends on the

treatment intervention

Every 6 months

for the first 2

years

Once per annum

Pathology Full Blood Count

(FBC)

6 2 1 √

Liver function test 6 2 1 √

Renal function 6 0 0 √

Imaging: Radiology CT study of chest

and abdomen

1 1 1 √

Chest x-ray AND Only if symptomatic Only if

symptomatic

Only if symptomatic √

Contrast swallow Only if required Only if

symptomatic

Only if symptomatic √

PET scan 0 0 0 Only done for locally advanced if a PET was done in

the initial work up. Not for metastatic disease.

This guideline will be due for update on 31 December 2018

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7. References

American Society for Gastrointestinal Endoscopy Standards of Practice Committee. 2013. Endosocopy in the

assesment and treatment of esophageal cancer. Gastrointestinal Endoscopy, 77(3): 328-34.

Berry, M. 2014. Esophageal cancer: staging system and guidelines for staging and treatment. A review. Journal

of Thoracic Diseases, 6(S3):S289-S297.

Dai, Y., Li, C., Xie, Y., Liu, X., Zhang, J., Zhou, J., Pan, X. & Yang, S. 2014. Interventions for dysphagia in

oesophageal cancer. Cochrane Database of Systematic Reviews, 10: CD005048.

Global Burden of Disease Cancer Collaboration. 2016. Global, Regional, and National Cancer Incidence,

Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer

Groups, 1990 to 2015. A Systematic Analysis for the Global Burden of Disease Study. Journal of the American

Medical Association- Oncology, E1-E25.

Healy, M.A., Yin, H., Reddy, R.M. & Wong, S.L. 2016. Use of Positron Emission Tomography to Detect

Recurrence and Associations With Survival in Patients With Lung and Esophageal Cancers. Journal of the

National Cancer Institute, 108:7.

Homs, M.Y., Steyerberg, E.W., Eijkenboom, W.M., Tilanus, H.W., Stalpers, L.J., Bartelsman, J.F., van Lanschot,

J.J., Wijrdeman, H.K., Mulder, C.J., Reinders, J.G., Boot, H., Aleman, B.M., Kuipers, E.J. & Siersema, P.D. 2004.

Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal

cancer: multicentre randomised trial. Lancet, 364 (9444): 1497-504.

Janowitz, T., Thuss-Patience, P., Marshall, A., Kang, J.H., Connell, C., Cook, N., Dunn, J., Park, S.H. & Ford, H.

2016. Chemotherapy vs supportive care alone for relapsed gastric, gastroesophageal junction, and oesophageal

adenocarcinoma: a meta-analysis of patient-level data. British Journal of Cancer, 114(4): 381-7.

Lee, S.J., Kim, S., Kim, M., Lee, J., Park, Y.H., Im, Y.H. & Park, S.H. 2015. Capecitabine in combination with

either cisplatin or weekly paclitaxel as a first-line treatment for metastatic esophageal squamous cell carcinoma:

a randomized phase II study. BioMed Central Cancer, 15: 693.

Loots, E., Sartorius, B., Madiba, T.E., Mulder, C.J. & Clarke, D.L. 2016. Is Clinical Research in Oesophageal

Cancer in South Africa in Crisis? A Systematic Review. World Journal of Surgery, Vol. ePub ahead of print.

Lordick, F., Mariette, C., Haustermans, K., Obermannová, R. & Arnold, D. 2016. Oesophageal Cancer: ESMO

Clinical Practice Guidelines. Annals of Oncology, 27 (5):v50-v57.

Malthaner, R.A., Wong, R.K.S., Spithoff, K., Rumble, R.B. & Zuraw, L. 2016. Gastrointestinal Cancer Disease

Site Group. Preoperative or postoperative therapy for resectable esophageal cancer. Program in Evidence-

based Care Evidence-based Series No: 2-11 Version 4. 2008.

Mohammad, N., ter Veer, E., Ngai, L., Mali, R., van Oijen, M. & Laarhoven, H. 2015. Optimal first-line

chemotherapeutic treatment in apteints with locally advanced or metastatic esophagogastric carcinoma: triplet

versus doublet chemotherapy: a systematic literature review and meta-analysis. Cancer Metastatis Review,

34:421-441.

National Comprehensive Cancer Network. 2016. Esophageal and Esophagogastric junction cancers. NCCN

Guidelines Version 2.

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Polinder, S., Homs, M.Y., Siersema, P.D., Steyerberg, E.W. & Group. 2004. Dutch SIREC Study. Cost study of

metal stent placement vs single-dose brachytherapy in the palliative treatment of oesophageal cancer. British

Journal of Cancer, 90(11): 2067-72.

Rice, T.W., Ishwaran, H., Kelsen, D.P., Hofstetter, W.L., Apperson-Hansen, C., Blackstone, E.H. & Investigators.

2016. Worldwide Esophageal Cancer Collaboration. Recommendations for neoadjuvant pathologic staging

(ypTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging

manuals. Diseases of the Esophagus, 29(8): 906-912.

Rice, T.W., Ishwaran, H., Blackstone, E.H., Hofstetter, W.L., Kelsen, D.P., Apperson-Hansen, C. & Investigators.

2016. Worldwide Esophageal Cancer Collaboration. Recommendations for clinical staging (cTNM) of cancer of

the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Diseases of the

Esophagus, 29(8): 913-919.

Rice, T.W., Ishwaran, H., Hofstetter, W.L., Kelsen, D.P., Apperson-Hansen, C., Blackstone, E.H. & Investigators.

2016. Worldwide Esophageal Cancer Collaboration. Recommendations for pathologic staging (pTNM) of cancer

of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Diseases of the

Esophagus, 29(8): 897-905.

Schnipper, L.E., Lyman, G.H., Blayney, D.W., Hoverman, J.R., Raghavan, D., Wollins, D.S. & Schilsky, R.L.

2013. American Society of Clinical Oncology top five list in oncology. Journal of Clinical Oncology, 31(34):4362-

70.

Shah, M. 2015. Update on Metstatic Gastric and Esophageal Cancers. Journal of Clinical Oncology, 33(16):

1760-1769.

Spaander, M.C., Baron, T.H., Siersema, P.D., Fuccio, L., Schumacher, B., Escorsel,l À., Garcia-Pagán, J.C.,

Dumonceau, J.M., Conio, M., de Ceglie, .A., Skowronek, J., Nordsmark, M., Seufferlein, T., Van Gossum, A.,

Hassan, C., Repici, A. & Bruno, M.J.2016. Esophageal stenting for benign and malignant disease: European

Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy, 48(10): 939-48.

Varghese, T.K., Hofstetter, W.L., Rizk, N.P., Low, D.E., Darling, G.E., Watson, T.J., Mitchell, J.D. & Krasna, M.J.

2013. The Society of Thoracic Surgeons guidelines on the diagnosis and staging of patients with esophageal

cancer. Annals of Thoracic Surgery, 96: 346-356.

Wang, X. & Huang, J. 2016. Irinotecan plus fluorouracil-based regimen as second or third-line chemotherapy for

recurrent or metastatic esophageal squamous cell carcinoma. Thoracic Cancer, 7: 246–250.

Wenger, U., Johnsson, E., Bergquist, H., Nyman, J., Ejnell, H., Lagergren, J., Ruth, M. & Lundell, L. 2005. Health

economic evaluation of stent or endoluminal brachytherapy as a palliative strategy in patients with incurable

cancer of the oesophagus or gastro-oesophageal junction: results of a randomized clinical trial. European

Journal of Gastroenterology and Hepatology, 17(12): 1369-77.

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