02_Rectal_cancer_New Paradigms_KAG -day 3

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Rectal Cancer: New Paradigms beyond Standard Chemotherapy and Radiation:

Rectal Cancer: New Paradigms beyond Standard Chemotherapy and Radiation Karyn A. Goodman, M.D. Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center

1990 NCI Consensus Statement:

1990 NCI Consensus Statement “Combined postoperative chemotherapy and radiation therapy improves local control and survival in stage II/III rectal cancer patients and is recommended.” Therapeutic advances over the last 2 decades Improvements in surgical technique Move to neoadjuvant therapy Advances in radiotherapy planning and delivery JAMA;1990;264

Total Mesorectal Excision:

Total Mesorectal Excision Sharp dissection of entire mesorectum and rectal tumor en bloc Smooth Contour = Fascial Plane

Dutch CVKO 95-04 Study:

Dutch CVKO 95-04 Study 1805 patients w/T1-3 rectal ca (54% w/T1-2) Relative reduction of 50% in LR with pre-op short course RT v. TME alone 10 yr LR 10 yr OS Op mortality RT + TME 5.1% 47.6% 3% TME 11.1% 48.8% 4% Kapiteijn , NEJM;2001; Peeters , Ann Surg;2007; van Gijn , Lancet Oncol , 2011 1 wk break

Dutch CVKO 95-04 Study:

Dutch CVKO 95-04 Study In unplanned subgroup analysis: Preop RT yields OS advantage at 10 years (50% vs. 40%) in Stage III patients with negative circumferential margins van Gijn , Lancet Oncol , 2011

German Rectal Cancer Study :

German Rectal Cancer Study Statistically significant increase in sphincter preservation among patients receiving preoperative chemoradiotherapy Surgery: TME Preoperative 5FU +5040cGy pelvic RT Postoperative 5FU +5580 cGy pelvic RT Surgery: TME Locally Advanced Rectal Cancer Sauer, NEJM;2004

Neoadjuvant Chemoradiation: Overview of Emerging Options:

Neoadjuvant Chemoradiation : Overview of Emerging Options Incorporating new chemotherapy agents Phase III data evaluating role of Oxaliplatin with concurrent 5-FU based chemoradiation Incorporating novel RT techniques Intensity modulated radiotherapy Tailoring therapies for rectal cancer Selective use of radiotherapy Total neoadjuvant therapy Non-operative management

Phase III trials adding Oxaliplatin to 5-FU-based chemoradiation:

Phase III trials adding Oxaliplatin to 5-FU-based chemoradiation 8 STAR 01 : 50.4 Gy FU ± oxaliplatin ACCORD 12 : Cap45Gy vs CapOx50Gy NSABP R04 : 45 Gy + boost FU vs Cape ± oxaliplatin CAO/ARO 04 : 50.4 Gy FU ± oxaliplatin

Randomized Trials of Oxaliplatin:

Randomized Trials of Oxaliplatin STAR-01 ACCORD- 12 NSABP-R04 CAO/ARO-04 N° Pts 720 596 1,608 1,265 Cum Dose Oxaliplatin 360 mg/m 2 250 mg/m 2 250 mg/m 2 200 mg/m 2 Dose RT (Gy) 50.4 45-50 50.4-55.8 50.4 Tox G3-4 7 v. 24% 11 v. 25% 7 v. 15% 22 v. 23% ypCR 16% 13 v. 19% 19 v. 21% 13 v. 17%* Sph Sav S 78% 75% 62% 88% Gerard , J Clin Oncol;2010; Aschele, J Clin Oncol;2011; Rodel, Proc ASCO 2011; Roh, Proc ASCO 2011

ACCORD 12 Secondary Outcomes:

ACCORD 12 Secondary Outcomes Endpoint Cap45 Capox50 P-value LR 6 % 4 % NS DFS 69 % 74 % NS OS 88 % 88 % NS Gerard , Proc ASTRO, 2011

Neoadjuvant Chemoradiation: Overview of Emerging Options:

Neoadjuvant Chemoradiation : Overview of Emerging Options Incorporating new chemotherapy agents Phase III data evaluating role of Oxaliplatin with concurrent 5-FU based chemoradiation Incorporating novel RT techniques Intensity modulated radiotherapy Tailoring therapies for rectal cancer Selective use of radiotherapy Total neoadjuvant therapy Non-operative management

Advances in RT Techniques:

Advances in RT Techniques Multiple dosimetric studies have compared conventional fields (bony anatomy) and IMRT planning Target coverage and bowel volume irradiated better for all plans compared to conventional Urbano M, IJROBP, 2006; Callister M, Proc ASTRO, 2006; Guerrero Urbano MT, IJROBP 2006; Arbea L, Radiat Oncol , 2010; Tho LM, IJROBP. 2006 Conventional Pelvic RT Fields IMRT

RTOG 0822: Phase II Rectal IMRT Trial:

RTOG 0822: Phase II Rectal IMRT Trial cT3-4NxM0 or cTxN1-2M0 Rectal Cancer IMRT capecitabine + oxaliplatin Surgery LAR or APR + Adjuvant Chemo FOLFOX Garofalo M, ASTRO 2011 Primary endpoint : Comparison of Grade 2+ GI toxicity to RTOG 0247 (non-IMRT)

RTOG 0822:

RTOG 0822 68 analyzable patients 90% T3, 55% N+ 51% Grade 2+ GI toxicity compared to 58% on RTOG 0247 (NS) Criticism: Increased toxicity associated with concurrent oxaliplatin Central review of RT contours and plans Contouring based on RTOG anorectal atlas Only 5 (7%) had unacceptable volumes Garofalo M, ASTRO 2011

IMRT v. Conventional Pelvic RT:

IMRT v. Conventional Pelvic RT 92 rectal cancer pts treated from 2004-2009 61 – CRT, 31 – IMRT 45/50.4 Gy for CRT 45/50 Gy for IMRT using an integrated boost Samuelian JM, IJROBP, 2012

IMRT v. Conventional Pelvic RT:

IMRT v. Conventional Pelvic RT IMRT (%) CRT (%) P value Grade 2+ GI toxicity 48 62 .006 Grade 2+ Diarrhea 23 30 .62 Grade 2+ enteritis 10 38 .10 pCR 19 28 NS Samuelian JM, IJROBP, 2012

Neoadjuvant Chemoradiation: Overview of Emerging Options:

Neoadjuvant Chemoradiation : Overview of Emerging Options Incorporating new chemotherapy agents Phase III data evaluating role of Oxaliplatin with concurrent 5-FU based chemoradiation Incorporating novel RT techniques Intensity modulated radiotherapy Tailoring therapies for rectal cancer Selective use of radiotherapy Total neoadjuvant therapy Non-operative management

Selective Use of Radiotherapy:

Selective Use of Radiotherapy Can radiotherapy be avoided in a subset of patients with negative margins after TME?

MRC CR07:

MRC CR07 Surgery: TME Preoperative RT 25Gy/5 fx Selective post-op 5FU + 45Gy pelvic RT Surgery: TME 1350 pts with operable Rectal Cancer Pre-op RT Selective post-op CRT 3 yr LR 4.4% 10.6% p<0.0001 3 yr DFS 77.5% 71.5% p=0.013 3 yr OS 80.3% 78.6% p=0.40 12% CRM + Sebag-Montefiore, Lancet;2009

CR-07 PR Bowel Dysfunction:

CR-07 PR Bowel Dysfunction No Difference in Defecation Dysfunction 25% at baseline and in f/u for both arms Incontinence Increased Over Baseline Doubling of dysfunction with preop RT (25 to 50%) Stephens et al.; J Clin Oncol , 2010

Selective Use of Radiotherapy:

Selective Use of Radiotherapy Can radiotherapy be avoided in a subset of patients after a good clinical response to neoadjuvant chemotherapy?

MSKCC Pilot Study:

MSKCC Pilot Study 32 patients enrolled 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 infusional 5FU) 30 completed induction therapy and surgery without RT Median age of 30 patients: 51 years (26 – 81 years) 5FU/XRT Complete Restaging TME Surgery FOLFOX + Bev x6 No progression Any progression

MSKCC Pilot Results :

MSKCC Pilot Results Of 32 patients accrued to pilot study 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 mets ) 1 patient has died

PROSPECT Trial:

PROSPECT Trial A phase II/III study: Randomized phase II of 366 patients with early stopping rule if failure to complete R0 resections or if high rate of Local Recurrence Phase III component to include 644 additional patients

PowerPoint Presentation:

FOLFOX x 8 TME 5FUCMT FOLFOX x 6 TME “Selective Arm” Response  20% “Standard Arm” PROSPECT Trial Schema Response <20% RANDOMIZE 1:1 5FUCMT TME FOLFOX x 2 FOLFOX x 6

Key Inclusion Criteria:

Key Inclusion Criteria Tumor tissue located at 5-12 cm from anal verge Baseline Clinical staging: T2N1, T3N0, T3N1 MRI or ERUS (MRI preferred) Candidate for sphincter sparing surgery Physical exam by primary surgeon Surgeon is TME credentialed

Total Neoadjuvant Therapy :

Total Neoadjuvant Therapy Distant recurrence rates now exceed local recurrence rates Move systemic therapy upfront to address micrometastatic disease earlier Particularly in high-risk patients node positive disease bulky primary tumors Two phase II studies have evaluated induction chemotherapy followed by CRT

MRI to Risk Stratify Rectal Cancer:

MRI to Risk Stratify Rectal Cancer Determine extent of extramural tumor 1 Identify risk of CRM positivity 2 1- Mercury Study group, Radiology, 2007 2- Mercury Study group, British Medical Journal, 2006

Induction Chemotherapy:

Induction Chemotherapy 105 patients with poor-risk rectal cancer defined by MRI: tumor within 1mm or beyond mesorectal fascia T3 low-lying tumor at or below the levators Tumor extending ≥ 5 mm into perirectal fat T4 or N2 CAPOX x 12 wks  54Gy + Cape  TME  CAPOX x 12 wks 97 underwent surgery, 20% pCR rate 3-year PFS and OS: 68% and 83% 3-year RFS after complete resection was 74% Chua, Lancet Oncol;2010

Induction Chemotherapy:

Induction Chemotherapy 108 pts with poor-risk rectal cancer based on MRI: tumors extending to within 2mm or beyond mesorectal fascia ≤ 6 cm from anal verge cT3 or resectable cT4, any cT3N+ Surgery: TME Capecitabine + 5040cGy Capecitabine + 5040cGy Induction CAPOX X 4 Cycles Randomized Phase II Trial Surgery: TME CAPOX X 4 Cycles Path CR 13.5 % 14.3% Dose intensity Cape 0.67 0.91 Oxali 0.73 0.94 Fernandez- Martos , J Clin Oncol;2010

Induction Chemotherapy at MSKCC:

Induction Chemotherapy at MSKCC Retrospectively reviewed the records of all patients with clinical stage II/III rectal cancer (T3/4, N1-2) based on endorectal ultrasound or MRI treated with ICT followed by CRT and TME Of ~300 patients treated with pre-operative CMT at MSKCC between 2007 and 2012, 57 received some or all of their planned FOLFOX as initial therapy

Patient Characteristics:

Patient Characteristics Number of Patients Total = 57 % Male Female 30 27 52 % 47% Age, years - Median Range 52 25-82 Performance Status (ECOG ) 0 1 39 18 68 % 31% Initial Diagnosis Stage T3N0 T3N1 T3N2 T3 N/A T4N0 T4N1 9 29 7 4 1 2 15% 50% 12% 7% 1% 3% Initial Imaging Stage with MRI* T3N1 T3N2 3 2 5% 3%

Results:

Results 57 patients received a median of 7 cycles ICT Out of the 57 patients, 53 received 5-FU based CRT median RT dose = 50Gy Toxicities were as would be expected for systemic FOLFOX and from CRT 4 patients achieved an excellent response to chemotherapy alone, declined radiation, and proceeded directly to TME

Results:

Results 45 patients who underwent TME Median 6.5 cycles of ICT 100% R0 resections Response to treatment Total number of patients with TME N=45 Pathologic Complete Response 13 ( 29%) > 90% treatment effect 21 ( 47%)

Results:

Results 12 did not to undergo TME; 9 had clinical response managed non-operatively 1 refused recommended surgery despite incomplete tumor regression, 1 was deferred due to comorbidities 1 developed distant metastatic disease A total of 18 patients had either 13 pCR 5 complete clinical response leading to non-operative management

Non-operative Therapy:

Non-operative Therapy Can surgery be avoided in the setting of complete clinical response to preoperative treatment?

Prognostic Factors: Tumor Regression:

Prognostic Factors: Tumor Regression Tumor Regression Grade 4 ( pCR ) No local recurrence, 86% 5-year DFS Tumor Regression Grade 2-3 4% local recurrence, 75% 5-year DFS Tumor Regression Grade 0-1 6% local recurrence, 63% 5-year DFS Rodel , J Clin Oncol;2005

Paradigm shift?:

Paradigm shift? Anal Cancer Distal rectal cancer Definitive surgery (before 1970’s) Definitive surgery (before 1990’s) Preoperative chemoradiation (1970’s) Preoperative chemoradiation (Present) Definitive chemoradiation (Present) Definitive chemoradiation ?

Non-operative Therapy: Brazilian Data:

Non-operative Therapy: Brazilian Data Habr -Gama, Ann Surg 2004 Clinical complete response: 71 pts Pathologic complete response: 22 pts Mean followup : 57 months 48 months Local recurrence: 2.8% 0% Pelvic recurrence: 0% 0% Distant metastasis: 4.2% 14% 5-year OS: 100% 88% 265 pts treated with pre-operative CRT 71 pts (27%) had a cCR 194 pts (73%) incomplete response  surgery 22 pts had a pCR

:

2006 Update: 361 patients, 99 with clinical CR (27%) Mean followup : 60 months Local recurrence: 5% 4 surgical salvage 1 brachytherapy salvage No subsequent recurrence Mean interval to recurrence: 52 months Pelvic recurrence: 0% Distant metastasis: 8% 5-year OS: 93% Habr -Gama J Gastrointest Surg 2006 Non-operative Therapy: Brazilian Data

MSKCC Experience:

MSKCC Experience Retrospective review of stage I-III rectal cancer pts treated at MSKCC between Jan 2006 and Aug 2010 57 (22%) pCR 32 cCR and NOM 265 Rectal Resection & TME 208 (78%) no pCR vs. NOM pts compared to resected pts found to have pCR Smith, Ann Surg. 2012

Clinical Features:

Clinical Features cCR & NOM pCR & RR P value Number of patients 32 57 Median follow up (range) 28m (9-70m) 42 (1-70m) Age (median in years) 70 60 0.009* Co-morbidity : Yes No 15 (47%) 17 (53%) 16 (28%) 41 (72%) 0.07 Ϯ Distance from the anal verge (range) 6cm (0.5-12) 7cm (2-12) 0.02* c T stage: 3 2 22 (69%) 10 (31%) 39 (78%) 11 (22%) 0.3 Ϯ c N stage: Positive Negative 18 ( 56%) 14 (44%) 31 (61%) 20 (39%) 0.7 Ϯ Pre-treatment AJCC Stage : III II I 18 ( 56%) 6 (19%) 8 (25%) 31 (61%) 18 (35%) 2 (4%) 0.01* Ϯ Chi -squared test *T-test

Results:

Results 6 NOM patients recurred locally at a median time of 11 months post CRT (range 7-14months) 0 pCR patients recurred locally 3 distant recurrences in each group NOM 2 yr LR = 21% pCR 2 yr LR = 0% no pCR 2 yr LR = 5% NOM 2 yr DFS = 88% pCR 2 yr DFS = 98 % no pCR 2 yr DFS = 82% P=0.27 P<0.001

Summary:

Summary 26 of 32 NOM pts (81%) achieved durable cCR and successfully avoided rectal resection with a median follow up of 28 months The 6 local failures occurred at 7-14 months post-radiation and were all successfully treated locally by salvage resection Compared to patients who achieved pCR with RR & TME: NOM patients were older, had less advanced cancers and more distal tumors NOM patients appeared to have similar rates of distant recurrence and survival Smith, Ann Surg. 2012

Counterarguments to Non-operative Management:

Counterarguments to Non-operative Management Clinical response is not always predictive of pathologic response Only 25% of clinical CR demonstrate pathologic CR in MSKCC series ( Hiotis J Am Coll Surg 2002) Primary tumor response is not always predictive of lymph node response 7% of pathologic CR in primary tumor have pathologically positive mesorectal nodes in MSKCC series ( Stipa Ann Surg Oncol 2004 )

Conclusions:

Conclusions Pre-operative chemoradiation remains standard of care for T3+ or N+ rectal cancer Reduces local recurrence risk Allows for sphincter preservation 5-FU based chemotherapy remains standard, oxaliplatin concurrent with RT only adds toxicity

Conclusions:

Conclusions New conformal techniques can reduce toxicity of pelvic RT May be a role for selective RT after response to induction chemotherapy Trimodality therapy necessary for high-risk patients Need better methods to risk stratify patients Molecular biomarkers, functional imaging

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