Neoadjuvant treatment Evolution and Current Status

Neoadjuvant treatment Evolution and Current Status Dr Andrew See Radiation Oncologist 2017 Rectal Cancer Symposium Friday 10 th November 2017 2 1

Major Randomised Trials Supporting Neoadjuvant CRT Trial # Pts p CR 5-Yr LRC Metastases 5-Yr OS CAA/ARO/AIO-94, Sauer et al. (2004) 394 8% 6% 36% 4yr, 74% Polish Trial Bujko et al. (2004) FFCD 9203 Gerard et al. (2006) EORTC 22921, Bosset et al. (2005, 2006) 157 16% 4yr, 15.6% 34.6% 4yr, 66% 375 11.4% 8% 36% 66% 505 13.4% 8.7% 34% 65% 3 CAO / ARO / AIO-94 Sauer et al. for the German Rectal Cancer Study Group NEJM 2004; 351 : 1731-1740, October 21, 2004 4 2

Short Course Studies: 25Gy in 5 fractions with Surgery the following week Randomized Phase III Trials of Preoperative Radiotherapy vs Surgery Alone as initial therapy for Resectable Rectal Cancer CONTROL PREOPERATIVE RADIATION SWEDISH (1997) DUTCH (2001) MRC CR07 (2006) No Local Relapse Rate at 5 year No Local Relapse Rate at 5 year 585 26% 583 9% p<0.01 924 11.4% 937 5.8% P<0.001 676 17% 674 5% p<0.0001 TOTAL 2185 17.3% 2194 6.9% Hazard Ratio CI at 95% NR NR 3.42 2.05-5.71 2.47 1.61-3.79 PREOPERATIVE RADIATION REDUCES SIGNFICANTLY LOCAL RELAPSES EVEN IN TME RESECTED PATIENTS 5 Short Course Studies: 25Gy in 5 fractions with Surgery the following week Randomized Phase III Trials of Preoperative Radiotherapy vs Surgery Alone as initial therapy for Resectable Rectal Cancer CONTROL No Survival (5 year) PREOPERATIVE RADIATION No Survival Hazard Ratio CI at 95% SWEDISH (1997) DUTCH (2001) MRC CR07 (2006) 585 48% 583 58% p<0.004 924 63.5% 937 64.2% p<0.84 676 62% 674 72% p<0.07 0.79 0.66-0.92 1.02 0.83-1.25 1.25 0.98-1.59 PREOPERATIVE RADIATION MAY NOT HAVE A SIGNIFICANT EFFECT ON SURVIVAL 6 3

Dutch 12-Year Update For stage III with negative CRM, 10-year OS: 50% in the preop RT group vs 40% in the surgery-alone group (p=0.032) Willem van Gijn, Corrie AM Marijnen, Iris D Nagtegaal et al. Lancet Oncology 12;6 June 2011 (575-582) 7 Short course vs Long course 8 4

TROG 01.04 SELECTIVE Preop rectal adenocarcinoma MR or U/S defined ct 3 N 0-2 Lower border <12cm of verge N=326, 2001-2006 Primary end point 3-yr LRR R A N D O M I S E S/C: Radiotherapy alone 25Gy in 5 fractions Surgery *** 3-7 days later 6 cycles Adjuvant Chemotherapy L/C CRT: 50.4Gy in 28 fractions with IVI 5FU 225mg/m 2 /day Surgery *** 4-6 weeks later 4 cycles Adjuvant Chemotherapy Ngan SY, Burmeister B, Fisher RJ et al. J Clin Oncol. 2012 Sep 24. [Epub] Adjuvant Chemotherapy 4 or 6 monthly courses of 5FU 425mg/m 2 and FA 20mg/m 2 daily for 5 days 4 to 6 weeks after surgery 9 TROG 01.04 Downstaging 45% v 28%; p=0.002 *** pcr rates 15% v 1% No difference in sphincter preservation rate distal APR rates 79% vs 77% for SC and LC, resp (p=0.87) No difference in local recurrence 3-yr LRR 7.5% vs 4.5%, favouring LC (p=0.24) 79 patients with distal tumours cumulative incidence of LR 12.5% vs 0% favouring LC ***** No significant difference in OS or DFS at 3 years Between RT and CRT Groups Ngan SY, Burmeister B, Fisher RJ et al. J Clin Oncol. 2012 Sep 24. [Epub] 10 5

TROG 01.04 Ngan SY, Burmeister B, Fisher RJ et al. J Clin Oncol. 2012 Sep 24. [Epub] 11 TROG 01.04 Short course Long course No of Patients % No of Patients % ALL PATIENTS (316) 114 152 Any complication 84 53 79 50 Abdominal wound complications 16 10 14 8.9 Bowel obstruction 9 5.7 7 4.5 Prolonged Ileus 6 3.8 9 5.7 Deep vein Thrombosis 5 3.2 2 1.3 Other 55 35 49 31 APR Patients (n=107) Perineal wound complications 23 39 23 44 NON APR Patients (LAR) (n=208) 99 109 Anastomotic Breakdown 7 7.1 4 3.7 Ngan SY, Burmeister B, Fisher RJ et al. J Clin Oncol. 2012 Sep 24. [Epub] 12 6

S/C vs L/C CRT: Polish Trial SELECTIVE T3,T4 M0 Resectable Adenoca No sphincter involvement Tumour palpable on DRE Powered for Sphincter preservation n=316 (1999-2002) R A N D O M I S E S/C: Radiotherapy alone 25Gy in 5 fractions Surgery *** 7 days later Adjuvant Chemotherapy optional L/C CRT: 50.4Gy in 28 fractions with bolus 5FU/LV 325mg/m 2 /day x 5 in 1 st and 5 th weeks Surgery *** 4-6 weeks later Adjuvant Chemotherapy optional Bujko K et al. Br J Surg, 2006 Oct;93(10):1215-23 Adjuvant Chemotherapy Bolus 5-FU/LV x 4m (CRT group) or x 6m (RT group) 13 S/C vs L/C CRT: Polish Trial Incr rate of pcr in CRT group 16.1% CRT v 0.7% RT (p<0.001) Incidence of Local Recurrence No difference in sphincter preservation rate RT 61.2% v. CRT 58% (p=0.57) No difference in local recurrence RT 10.6% v. CRT 15.6% (p=0.210) No difference in distant mets RT 31.4% v. CRT 34.6% (p=0.540) Bujko K et al. Br J Surg, 2006 Oct;93(10):1215-23 14 7

S/C vs L/C CRT: Polish Trial No significant difference in OS or DFS at 4 years between RT and CRT Groups Bujko K et al. Br J Surg, 2006 Oct;93(10):1215-23 15 57 year old man with rectal cancer, T2-weighted axial image shows extramural venous invasion and extension into lateral rectal vein (arrow). ct3n2, emvi+ CRM involved. Suitable for LAR. Taylor, F.G.M. et al. Am. J. Roentgenol. 2008; 191: 1827-1835 16 8

The anatomic considerations for extra-levator abdominoperineal excision (ELAPE) are shown J Joshua Smith and Julio Garcia-Aguilar JCO 2015; 33:1797-1808 17 Non-Operative Approach? 18 9

Non-operative Personalised Rx Ageing population Recognition of harm with intervention 80yr+ 30 day mortality 14% 95yr+ 30 day mortality 25% (Dutch 6 mo RIP 50%) National screening programs more early lesions Anal Cancer Non operative management is standard of care 19 Rectal Cancer GOOD BAD UGLY T1/T2/T3a N0 / M0 <3cm Mobile polyp T3b <5mm N1 / M0 >3cm CRM negative T3c+/T4 N2 / M0 >3cm CRM positive 20 10

Habr - Gama 361 Low Rectal Cancers Chemo-Radiotherapy Positive biopsy / Significant Ulcer 8 Weeks Assessment No Tumour SURGERY OBSERVATION (111) (Most ct3n0) At 5 years 88% DFS 83% OS 23 patients LR within 1 year Med 48w interval At 5 years 100% DFS 92% OS Habr-Gamr A et al. Annals of Surgery; 2004;240(4);711-718 Habr-Gamr A. Colorectal Dis 2006 Sep;8 Suppl 3;21-4 21 Habr-Gamr The definition of ccr was inconsistent, with only partial concordance with pcr Results suggested that pts who are observed, but subsequently fail to sustain ccr may fare worse than those who undergo immediate tumour resection Proof of principle in small low rectal cancers, where clinical assessment is easy, should not be extrapolated uncritically to more advanced cancers where nodal involvement is common Robert Glynne-Jones 2012 July 99(7);897-909 BJS Epub. 2012 April 27 Critical appraisal of the wait and see approach in rectal cancer for clinical complete responders after chemoradiation 22 11

Response is heterogeneous in the tumour Significant no. of advanced cancers do not have residual cancer cells in mucosa, submucosa after chemoradiation Dis Colon Rectum 2013 23 Perils of MRI assessment response post induction Rx 24 12

Interpreting Clinical Response after CRT Endoscopic evaluation unreliable T2W MRI concordance only 50% Size and volume change (GROW Maastricht IJROB 93(5) 2015) Multiparametric MRI DWI via ADC drop increases sensitivity to 84% Meta-analysis (v d Paardt et al Radiology 2013) DCE via K-trans (measure of capillary permeability obtained using DCE- MR CALC by measuring accumulation of gadolinium based contrast agent in the extra-vascular tissues. PET Imaging High accuracy when SUV combined with DWI (Korean paper) 25 26 13

TREC Low risk T1,T2 Short course CRT Not usual CRT patients 27 28 14

STAR-TReC TRIAL PROTOCOL Saving the rectum by watchful waiting or TransAnal surgery after (chemo)radiotherapy versus Total mesorectal excision for early Rectal Cancer Rectal Cancer Stage: ct1-3a/b N0 V0 M0 MDT review Default Treatment TME RANDOMISE Target rate > 6 per month 1 control 2 cases UK / Netherlands / Denmark International Clinical Network (> 35 Units) Standard surgery Organ Preservation Select: (1) CRT or (2) SCPRT or (3) RANDOMISE WK 1 Standard surgery TME 25 x 2Gy Capecitabine 625 mg/m 2 BD 5 x 5Gy WK 11-13 Clinical complete Evaluate clinical radiotherapy response (endoscopy and MRI) Clinical incomplete No response WK 13-15 Watch and wait TEMS TME WK >20 Reverse temporary stoma to restore Intestinal continuity (if required) High risk histology (ypt2/t3) CONVERT to TME 29 Triple response assessment Clinical complete response Watchful waiting 1. No sign of residual tumour on MRI (MRycT0) 2. Node-negative status (MR ycn0): no suspected malignant lymph nodes at contrast-enhanced MRI 3. No tumour palpable upon DRE (if at primary staging the tumour was indeed palpable) 4. No tumour found at sigmoidoscopy: only a scar remains 30 15

Triple response assessment Clinical partial response Local excision using single port trans-anal surgery technique 1. Residual tumour confined to the bowel wall (MR yct1-2) on MRI 2. Node-negative status (MR ycn0): no malignant lymph nodes at contrast enhanced MRI 3. Pronounced downsizing on DRE (small tumour, without fixation to surrounding structures) 4. Pronounced downsizing at sigmoidoscopy: small area of residual mucosal tumour 31 Triple response assessment No response Total mesorectal excision 1. Evidence of progression or minimal downsizing of the tumour in bowel wall (MR yct2+) 2. node positive status (MRycN1+): malignant lymph nodes at contrast-enhanced MRI 3. Evidence of progression or minimal downsizing upon DRE 4. Evidence of progression or minimal downsizing at sigmoidoscopy 32 16

Clinical Surveillance Recommended follow-up CEA assessed annually Baseline post-operative MRI and sigmoidoscopy at 3 months MRI annually for the first 3 years Sigmoidoscopy at 6,9,12,18 and 27 months Colonoscopy at 36 months (all patients) 33 Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial Evaluating 3-year disease free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation Chemotherapy, and total meso-rectal excision or nonoperative management J Joshua Smith and Julio Garcia-Aguilar JCO 2015; 33:1797-1808 34 17

Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial Evaluating 3-year disease free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation Chemotherapy, and total meso-rectal excision or nonoperative management Clinical complete response 35 Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial Evaluating 3-year disease free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation Chemotherapy, and total meso-rectal excision or nonoperative management Clinical near-complete response 36 18

Oxaliplatin trials STAR-01 trial (Preoperative Fluorouracil (FU)- Based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer ACCORD 12/0405 Prodige2 trial (Radiation therapy and capecitabine with or without oxaliplatin in treating patients who are undergoing surgery for stage II or stage III rectal cancer NSABP R 04 trial CAO/ARO/AIO-04 (Neoadjuvant Chemoradiotherapy and adjuvant chemotherapy with 5-flurouracil and oxaliplatin versus 5-Fluorouracil alone in rectal cancer Higher pcr rate with no increase in toxicity Median FU 50m, DFS at 3 years was 75.9% vs 71.2% (HR 0.79, 95% CI 0.64-0.98; p=0.03) 39 ARISTOTLE SELECTIVE Preop rectal adenocarcinoma 1:1 RAND Locally advanced N=920 Primary end point DFS R A N D O M I S E L/C: CRT: 45Gy in 25 fractions CAP 900mg/m 2 BD Mo-FR Surgery Adjuvant Chemotherapy L/C CRT: 45Gy in 25 fractions CAP 650mg/m 2 BD Mo-Fr Irinotecan 60mg/m 2 weekly (wk1-4) Surgery Adjuvant Chemotherapy Adjuvant Chemotherapy Postop Chemotherapy based on declared policy 40 20

Induction Chemotherapy? 41 Induction Chemotherapy Benefits Early treatment of potential systemic disease? Improve survival Chemotherapy difficult to give post op Biological test with opportunity to de-escalate / intensify according to interval response Reduces acute radiotherapy side effects More complete downstaging Opportunity for rapid drug evaluation (i.e. pcr endpoint) 42 21

Trials for review EXPERT Completed Phase II High risk EXPERT C Completed Phase III High risk FORARC Completed Phase III Intermediate SPANISH GCR-3 Completed Rand Phase II High risk MSKCC Phase II Completed Phase II Intermediate Selective RT PROSPECT Ongoing Phase III Intermediate Selective RT RAPIDO Ongoing Phase III High risk MSKCC TIMING Trial Completed Phase II Intermediate 43 INDUCTION CHEMOTHERAPY EXPERT Patients with MRI defined poor-risk rectal cancer <1mm CRM T3 c/d T4 N2 D1 D22 x4 T M E x4 77 patients pcr > 20% intention to treat 5% mortality Capecitabine: 2000mg/M 2 Capecitabine: 1650mg/M 2 Capecitabine: 1650mg/M 2 Oxaliplatin: 130mg/M 2 Radiation: 45Gy in 25 + 9Gy Boost RMH Chau I, Brown G, Cunningham D et al. JCO 2005;24(4):668. 44 22

INDUCTION CHEMOTHERAPY EXPERT C Patients with MRI defined poor-risk rectal cancer D1 D22 D1 D22 x4 x4 R D1 D22 D1 D22 T M E Phase II N=164 x4 x4 Capecitabine: 2000mg/M 2 Capecitabine: 1650mg/M 2 Capecitabine: 1650mg/M 2 Oxaliplatin: 130mg/M 2 Radiation: 45Gy in 25 + 9Gy Boost Cetuximab: 400mg/M 2 D1 then 250mg/M 2 weekly 45 The addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P=1.0; odds ratio, 1.22 OS (HR, 0.27; P=0.034) Cetuximab led to a significant increase in OS in patients with KRAS / BRAF wild-type rectal cancer 46 23

cii-iii R Ca, excluding T4, candidates for sphincter-sparing surgery FOLFOX / Bev x 4 FOLFOX x 2 Phase II n=32 Response by EUS T M E 17/32 (53%) were female, Clinical stages T2-3, N0-2 2 patients withdrawn after cycle 1-2 (MI and cardiac rhythm disturbance attributed to CFI 30 completed induction therapy and surgery without RT Median age of 30 patients: 51 years (26-81) FOLFOX x 6 - recommended Schrag D, W.M., Goodman KA, Gonen M, Cercek A, Reidy DL, et al, J Clin Oncol, 2010. 28(Suppl): p. 15S 47 32/32 had R0 resections 8/32 (25%) had a pcr 1/32 post-op death 0/32 have had LR 3/32 have had distant recurrence (pulmonary metastases) 48 24

PROSPECT trial (Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients with Locally Advanced Rectal Cancer Undergoing Surgery Trial Number: N1048-CALGB81001-ACOSOGZ6052 J Joshua Smith and Julio Garcia-Aguilar JCO 2015; 33:1797-1808 49 PROSPECT trial (Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients with Locally Advanced Rectal Cancer Undergoing Surgery Trial Number: N1048-CALGB81001-ACOSOGZ6052 ct2n1, ct3n0, or ct3n1 (stage IIA, IIIA, or IIIB) as determined by examination CT, and either MRI or US Candidate for sphincter preservation, TME before neoadjuvant therapy No encroachment on the meso-rectal fascia based on preoperative imaging i.e. NOT LOW, NOT cn2, NOT CRM +ve The study is open across US and 293 patients were enrolled as of Feb 20 2015 50 25

Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation Lars Pahlman Department of Surgery Colorectal Unit, University Hospital Uppsala Sweden 51 CRT Surgery Chemo 4m TME+ CAPOX x 8 5 x 5Gy Chemo 5m Surgery CAPOX x 6 52 26

At least one of T4 overgrowth to adjacent organs T4b peritoneal involvement EMVI+ vascular invasion N2 > 4 nodes which look abnormal N+ lateral nodes > 1cm MRF + 53 54 27

Polish Colorectal Study Group SELECTIVE Preop rectal adenocarcinoma 1:1 RAND Fixed ct3 or ct4 cancer N=515 Median FU 35m Primary end point R0 resection R A N D O M I S E SC: 5 x 5 Gy Three cycles FOLFOX 4 Surgery*** Adjuvant Chemotherapy 50.4Gy in 28 fractions 5-day cycle of bolus 5-FY/Leucovorin W1,5 Oxaliplatin 50mg/M 2 once weekly W1,5 Surgery Adjuvant Chemotherapy BUJKO et al. Ann Oncol 2016 Feb 15 Adjuvant Chemotherapy Postop Chemotherapy based on declared policy 55 Preoperative acute toxicity lower in group A than group B R0 resection rates (primary endpoint) 77% vs 71%, p=0.07 pcr 16% vs. 12%, p=0.17 Cumulative incidence of local failure 22% vs. 21%, p=0.82 Cumulative incidence distant metastases 30% vs. 27%, p=0.26 Postoperative complications 29% vs. 25%, p=0.15 Late complications 20% vs. 22%, p=0.54 56 28

3 year overall survival 73% vs. 65%, p=0.046 3 year disease free survival 53% vs. 52%, p=0.85 57 TIMING: Timing of Rectal Cancer Response to CRT Trial: a multicentre, phase 2 trial Phase 2, non-randomised trial consisting of four sequential study groups of patients with stage II-III locally advanced rectal cancer. All patients receive CRT w 5FU 45.0Gy + boost 5.4Gy Group 1: TME 6-8 weeks after CRT pcr rate 18% Group 2: TWO cycles of mfolfox6 Between CRT and TME pcr rate 25% Group 3: THREE cycles of mfolfox6 Between CRT and TME pcr rate 30% Group 4: FOUR cycles of mfolfox6 Between CRT and TME pcr rate 38% 2004 2012, 259 met criteria for analysis mfolfox6 Toxicity Group 2: 3% G3 AE; 1% G4 AE Group 3: 18% G3 AE Group 4: 28% G3 AE; 8% G4 AE (The most common > G3 AE s neutropenia and lymphopenia Across all study groups 25 grade 3 or worse surgery related complications occurred (10 in G1, 5 in G2, 3 in G3, 7 in G4) Julio Garcia Aguilar Lancet Oncology 2015;16;957-966 58 29

Rectal Cancer Treatment LOW ct1-2 N0 ct3n0 (<5mm EMI and MRF>1mm) TME INT HIGH ct1-3 N1 ct3 N0(>5mm EMI and MRF>1mm) including sacral side upper rectum S/C RT EMVI+ Breached CRM Threatened CRM (<1mm) N2 Lateral node > 1cm Extra-meso-rectal node ct3 MRF < 1mm ct4b upper rectum > T3b MRF- middle or lower L/C CRT Low tumours encroaching on inter-sphincteric plane or with levator involvement, APE required 59 30