Opportunity for palliative care Research

Dr Sushmita PathyAssociate Professor

Department of Radiation OncologyDr BRA Institute Rotary Cancer HospitalAll India Institute Of Medical Sciences

New Delhi INDIA

Dr. Sushmita PathyAdditional ProfessorDepartment Of Radiation OncologyInstitute Rotary Cancer HospitalAll India Institute Of Medical SciencesNew Delhi INDIA.

Role of Radiotherapy in Multidisciplinary Management of Rectal Cancers

Burden of Rectal cancer

• Colorectal cancer third most common cancer worldwide.

• More than 50% of the cases occur in more developed regions.

• Highest Australia/New Zealand (ASR 44.8 & 32.2) lowest in Western Africa.

• Mortality High in the less developed regions • India Highest in Mizoram (ASR - 4.5/Lakh

population) Lowest in Dindigul, AP cancer registry (ASR – 1.4/Lakh population)

Globocan 2012& CI5 vol X

Need of Multidisciplinary Approach

• Surgery is the gold standard

• Proven benefits of total mesorectal excision

• Parallel to improvement in surgical technique adjuvant therapy reduce local recurrence rate

• Dramatic changes in management of rectal cancers.

Multidisciplinary management: Paradigm shift

Adjuvant Therapy: Rectal Cancer

• High rate of local recurrence locally advanced disease. Tumor fixation is a limitation

• Adjuvant radiotherapy preop/post op significant increase in loco-regional control

• Sphincter sparing procedure . Organ preservation

• No improvement with DFS,OS and distant metastasis

• Role of adjuvant chemo-radiotherapy was evaluated to improve treatment outcome .

Adjuvant TherapyDescription

GITSG (1988) 4 arm trial S/S+RT/S+CT/S+CRT227 patients B2 ,C(R0 resection)10 yr OS 45 % vs 27%,LRR 10% vs 25%Significant benefit with CRT

NSABP R-01(1988) 3 arm RCT500 patientsPT3/T4N+ S/S+CT/S+RTS+CT: Improved DFS& OSS+RT: Reduction in LRR 16% vs 25 % favouring RT No survival benefit

Preoperative vs Postoperative approach

o Pre-operative RT o Tumour downstaging and improve resection,o Better toleranceo Higher biologically effective dose intact vascularity. Evaluation of patients on basis of pathological

features not possibleo Post operative RTo Hypoxic post surgical bed Chemotherapy and RT less

effectiveo Higher morbidity : small bowel,large treatment volume Selectively treat patients with high risk histopath

features

Short Course Preoperative Radiotherapy

Study

Swedish Rectal cancer TrialFolkesson J et al JCO 2005

•PreopRT vs sug alone•1168 •25Gy/5Fr/5days→Sug •Med FU 13 years•OS 38% vs30%, p 0.008•LRR 9%vs 26% p 0.008

Dutch study CKVO 95-04Willem VG et al Lancet oncol 2011

PreopRTvs TME alone 1861 patients 25Gy/5Fr/5days→TMEMed FU 10 years OS 48%vs 49% p 0.86LR 5% vs 11% p 0.0001

Adverse effects Of Preoperative Radiotherapy

Study

Swedish rectal cancer trial : Long term follow –up Birgisson JCO 2005

•Increase in risk for early admissions(6 months) inirradiated patients RR1.64•Bowel frequency,•Incontinence,•UrgencyOver all quality of life rated good

Swedish rectal cancer trial : Late GI toxicity Birgisson Br J sug 2008

•Increased RR 2.49of late small bowel obstruction ,(post op anast leakage)• Abdominal Pain RR 2.09

Long course Preoperative chemoradiation

• Neoadjuvant CTRT :Standard of care• Tumour downstaging• Improved resection.• Increased sphincter preservation• Higher pCR/local control

• German rectal cancer Trial :• Preop CRT vs Post op CRT• T3/4,N+• Reduction in local failure 6%vs 13% • Improvement in sph preservation ( p=0.004) favouring

preop CRT . Saur et al NEJM 2004

Preoperative chemoradiotherapyTrial No of Patients

Randomisation

Median F/U

LR OS Toxicity

GERMANcT3-4cN+

823 Pre op CRT-405

Post op CRT-395

134 months(90-184

mo)

10yr7.1%

Vs10.1%

P - 0.048

10yr59.6%

Vs59.9%

P – 0.85

-

EORTC 22921

4arm study

1011 1.Pre op RT

Sx+/- CT

2. Pre op CRTSx +/-CT

10.4 Yrs(7.8-13.1)

10yrs22.4% vs 11.8% vs 14.5% vs

11.7%P –0.0017

10yr49%vs

50.7%vs51.8%vs48.4%

P – 0.91

No sign. toxicity

Sauer R et al. German CAO/ARO/AIO-94 JCO 2012Bosset J et.al. EORTC 22921 Lancet Oncol 2014

Long vs Short Course Chemoradiotherapy

Study No of Patients

Randomisation

Median F/U 3 yr LRR 5 yr OS Toxicitylate

Australian Intergroup trial 2012

326T3 N0-2

M0

SC – 163

LC – 163

5.9yrs 7.5%Vs

4.4%

P – 0.24

74%Vs

70%

P – 0.62

G 3-45.8 vs 8.2

P-0.53

Polish rectal cancer group

2006

312 SC:156LC 156

48 mths Higher pCR in

CRT

67.2%Vs 66.2%

10.1%Vs 7.1%

Tumour downstaging/higher pCR/ LRR No conclusive evidence of survival benefit/sph sparing

MULTIDISCIPLINARY MANAGEMENT : WHERE ARE WE GOING?

• Benefits of RT/CRT Vs Burden

• Identify the patients at low risk of local recurrence, and ideally may not benefit from neo-adjuvant therapy

• Prognostic role of circumferential resection margin (CRM)

• ESMO sub-categorize rectal tumours (favourable, intermediate ,high risk ) based on MRI finding

(Low risk ?? Benefit )

OPTIMAL TIMING PREOP RT/CRT AND SURGERY

• Short course: 25Gy/5fractions/5 days 11days/3-4 weeks Improved pCR Oncological outcome ? Acute radiation reaction subside after RT

• Long Course(CRT):45-50.4 Gy/25 fractions/5 weeks More pronounced tumor regression pCR with prolonged interval Oncological outcome ? Data lacking No reason to delay beyond 6-8 weeks

• Glimelius Front oncol 2014

Positioning & immobilisation• Supine/prone • Pelvic thermoplastic mask• CECT simulation

Target volumes:• Primary tumour + clinically +ve

nodes >1cm• Entire mesorectum• Lymphnodes

Dose:• Shortcourse:25Gy/5Fr/1wk• Long course 45Gy/25Fr/5wk• Postop adjuvant* :

50.4Gy/28Fr/5.5 wk*high risk histopath ≥ pT3,N+,LVSI,Margin positivity

INNOVATIONS IN RADIATION THERAPY

• Three dimensional RT standard of care • New advances RT minimize toxicity and maximize

efficacy.

• Intensity Modulated and Image guided RT anatomically sculpt dose delivery reduce CTV-PTV margin and irradiated volume of small bowel

• Proton therapy reduces bone marrow exposure : Reduces hematological toxicity. Better tolerance to chemotherapy

Three dimensional conformal Radiotherapy

• Preplanning and localization.• Computed tomography imaging for three

dimensional planning. • Target and critical structure delineation

Contouring of the target volume including gross tumour volume ,clinical target volume, planning target volume /OAR.

• Beam and field designing• Dose calculation.• Plan optimization and evaluation.• Treatment documentation and set up verification.

• Organs at risk (OAR) : Dose constraintsSmall bowel Bladder Femoral head

No more than 180 cc above 35 Gy No more than 100 cc above 40 GyNo more than 65 cc above 45 Gy

No more than 40% volume > 40 Gy No more than 15% volume > 45 Gy

No more than 40% volume > 40 GyNo more than 25% volume > 45 Gy

•

• 48 M with complaints of bleeding per rectum & pain lower abdomen CECT : irregular wall thickening of distal rectum and proximal anal canal . No significant prerectal LN Colonoscopy growth starting 4 cm from anal verge, upper extent 8 cm.

• Pre op CTRT 45Gy/25#/ 5week with concurrent capecitabine

Plan evaluation : Dose volume histogram

Mid rectal cancer: planned for preoperative chemo radiotherapy with intensity modulated

radiotherapy

Samuelian et al IJROBP 2012

Technique CRT vs IMRT GI toxicity(Gr 2) 62% 32%Diarrhoea 48 % 23%Enteritis 30% 10%(p=0.02) No diff in pCR rates

IMRT Vs CRT

Samuelian JM et al IJROBP 2012

IMRT-IGRT- SIMULATANEOUS INTEGRATED BOOST

Preoperative IMRT-IGRT with simulataneous boost 46 Gy in daily fractions of 2 Gy. Horseshoe shaped distribution of the dose to spare the small bowel. Simultaneous integrated boost till 55.2 Gy is prescribed on the tumor. Local recc <3%. Grade ≥2 diarrhoea 18% Acute toxicity <1% and <10% late grade 3 toxicity Sermeus et al World J Gastro 2014 De Ridder et al IJROBP 2007

PROTON THERAPY

•Bragg peak is the characteristic of proton beam

•Spread out Bragg peak (SOBP) summation of multiple beam•Sharp dose fall off spares tissue surrounding target•No exit dose

COMPARISON PROTON/3DCRT/IMRT

Colaco et al J Gastrointest oncol 2014

COMPARISION PROTON/3DCRT/IMRT

Colaco et al J Gastrointest oncol 2014

RADIOTHERAPY IN PALLIATIVE SETTING

Symptom based management • Haemostatic Radiotherapy

• Local palliative Radiotherapy

• Bone metastasis

• Cord compression

• Brain metastasis

Conclusion

• Multimodal treatment approach in rectal cancers result in a better outcome.

• Preop RT /Postop CRT improves local control and survival over surgery alone for locally advanced tumors

• Neoadjuvant CRT : Tumor down staging improved resection/ sph preservation /local control: Current standard of care No evidence of survival benefit . Optimal combination challenge.

Conclusion

• Long term data from RCT assess late toxicity of short vs long course therapy.

• Newer RT techniques provide improved dose delivery with sparing of OAR.

• Selection of patients who will benefit from neoadjuvant therapy will influence future directions

Thank you