RECTAL CANCER The (neo)adjuvant story

RECTAL CANCERThe (neo)adjuvant story

Mark Rother MD FRCPCMedical Oncologist

Peel Regional Cancer CenterCredit Valley Hospital

Case• 62 year old man (father of your life long best friend)

has rectal bleeding

• You get him in to see a GI specialist and a colonoscopy finds a non obstructing adenocarcinoma 6 cms from anal verge

• CT Thorax/Abd/Pelvis – No mets

• Your friend calls you for advice on the next step? He has been reading up!

• He thinks his Dad will need surgery, chemo and radiation based on his reading

• He finds it all very confusing but knows you are an expert in GI oncology and will clarify it for him and his dad.

Questions?

• More Tests- MRI? EUS? Role of PET/CT?

• Surgery- When? What type? Who should do it?

• Radiation- Before/After surgery? Long protracted or intensive short type? With chemo or without?

• Chemotherapy- What type? How long for? New drugs? Clinical trials? Must he get a PICC?

OVERVIEW

• Introduction• Postoperative Chemoradiation• Preoperative Radiotherapy(no chemo)• Preoperative Chemoradiation• Preoperative vs Postoperative Chemoradiation• Optimizing Preoperative Chemoradiation• Postoperative chemotherapy after neoadjuvant CRT • Future Approaches

OVERVIEW


Rectal Cancer

• Estimated 6000 new cases per year in Canada (30% of colorectal cancer)

• Local and Systemic Relapse Risk

• Prototype of a multimodality approach– Surgery– Radiation– Chemotherapy

Definition- Rectal Cancer• Discriminating between colon and rectal cancer is

critical

• Colon is 150 cm long but rectum is about the last 12-15 cm

• Anatomically, the upper boundary of the rectum is located at the rectosigmoid junction, slightly below the sacral promontory. On clinical grounds, the peritoneal reflection is the more important landmark

• In the post-operative setting the location of the tumour relative to the peritoneal reflection should be part of the surgical and pathological report

• Identification of rectal tumours prior to surgery is generally obtained by measuring the distance between the inferior edge of the tumour and the anal verge(12-15cm)

Definition - Rectal Cancer

Adjuvant therapy

• Adjuvant therapy needs to address the local and systemic recurrence risk

• Under-treatment : pelvic recurrences and complications

• Over-treatment : therapy related complications - bowel, bladder and sexual dysfunction

Challenges in Adjuvant Therapy for Rectal Cancer

• Data from randomized trials limited.

• Debate on pre vs post op radiation and radiation dose and schedule is confusing

• Chemotherapy concurrently with XRT-What and How?

• Decisions on adjuvant chemo if received pre-op therapy.

OVERVIEW


OLDER APPROACH TO RECTAL CANCER(but still commonly done)

• Surgical resection

• Pathology assessment and risk estimation

• Treatment based on TMN

• Post operative Chemoradiation

1990 NCI Consensus Statement

• Combined postoperative chemotherapy and radiation improves local control and survival in patients with stage II and III rectal cancer and is recommended:– GITSG– NCCTG-MAYO

JAMA 1990: 264:1444-1450

GITSG(227) NEJM 1985

Surgery/5FU/mCCNU/RT

LR 11% OS 56%

Surgery/5FU/mCCNU

LR 21% OS 46%

Surgery/RT LR 20% OS 43%

Surgery

LR 24% OS 32%

NCCTG(204) NEJM 1991

Surgery/5FU/mCCNU/RT LR 14% OS 58%

Surgery/RT LR 25% OS 48%

1990 NCI Consensus Statement

NCCTG Intergroup Study• 660 patients with resected stage II/III rectal

cancer

O’Connell NEJM 1994

http://content.nejm.org/content/vol331/issue8/images/large/03f1.jpeg

2x2 study design:

PVI 5-FU vs bolus(with rads)

- Improved PFS (p=0.02)

- Improved OS (p=.01)

MeCCNU: no benefit

NCCTG Intergroup Trial

O’Connell NEJM 1994

CP1050909-25

R

Bolus 5FU

IIIII

Bolus 5FU-Levamisole

Bolus 5FU-Leucovorin

Bolus 5FU-Leucovorin-Levamisole Tepper et al. JCO 2002

Intergroup 0114 : Post-operative CT – CRT- CT

Tepper, J.E. et al. J Clin Oncol; 20:1744-1750 2002

Intergroup 0114 -OS by treatment arm

R

Intergroup 0144: Post operative CT – CRT - CT

b5FU – XRT+PVI5FU – b5FU

IIIII

PVI5FU – XRT+PVI5FU – PVI5FU

b5FU/LV – XRT+b5FU/LV – b5FU/LV

Smalley, JCO2006

Smalley, S. R. et al. J Clin Oncol; 24:3542-3547 2006

Intergroup 0144 - Overall survival and relapse-free survival

Advantages of Postoperative Treatment

• Accurate pathologic staging

• Shorter delay to definitive surgery

• Potentially less surgical morbidity?– Not complicated by prior XRT-chemo

Long-Term Effects of Postoperative Chemoradiation Surgery alone

Chemoradiation

# BMs/day 2 (1-7) 7 (1-20)

Nocturnal BMs 18% 46%

Continence 93% 44%

Antidiarrheals 5% 53%

OVERVIEW


Preop RT(25 Gy in 5 fractions)

Immediate surgery

R LR 11%, 5yr OS 58%

LR 27%, 5yr OS 48%

Swedish Rectal Cancer Study

NEJM 1997

Preop RT + TME(25 Gy in 5 fractions)

TME alone

R

Dutch Colorectal Group (NEJM 2001)

Kapiteijn NEJM 2001

LR 5.6%

LR 10.9%

MRC CR-07 (NCIC CO-16)

Lancet 2009; 373: 821–28

Lancet 2009; 373: 821–28

MRC CR07

Lancet 2009; 373: 821–28

MRC CR07

What about Short-course XRT?• 2500 cGy in 5 fractions

• Northern Europe approach

• No concurrent chemo(5FU) radiosensitizer

• Surgery within a 1-2 weeks

• No downstaging(not for T4 or concern re CRM)

• Concerns re long term bowel function

• Studies ongoing with 6 week delay(?downstaging)-Stockholm lll

OVERVIEW


Preoperative Chemoradiotherapy

•North American/Southern Europe approach

•For patients with locally advanced disease-T3/T4 or N+

•More protracted RT course 5-6 weeks(45-50.4 cGy)

•Concurrent 5FU based chemotherapy

•Followed by Surgery 4 - 6 weeks later

Bosset NEJM 2006

Bosset NEJM 2006

PolishPolish Study ResultsStudy Results• 25/5 vs Chemoradiation Therapy

• pCR 1% vs. 19%

• Similar SSS,DFS,OS

• Similar late toxicity

• Await similar design TROG study

TROG Study-ASCO 2010

OVERVIEW


• INT- 0147 - terminated prematurely due to poor accrual

• NSABP R-03 - terminated prematurely due to poor accrual

• German Trial- CAO/ARO/AIO 94 - completed accrual

Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer

Rolf Sauer, M.D., Heinz Becker, M.D., et al. for the German Rectal Cancer Study Group

Volume 351:1731-1740 October 2004

http://content.nejm.org/

• 421 receive preoperative and 402 receive postoperative

chemoradiotherapy.

• The overall five-year survival rates were 76 percent and 74 percent (P=0.80).

• The five-year incidence of local relapse 6 percent for preoperative and 13 percent in the postoperative group (P=0.006).

• Grade 3 or 4 acute toxicity occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001)

Sauer NEJM 2004

Results -Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer

Rolf Sauer, M.D., Heinz Becker, M.D., et al. for the German Rectal Cancer Study Group

Sauer NEJM 2004 Sauer NEJM 2004

Sauer NEJM 2004

Sphincter Preserving SurgeryITT Analysis

Pre-randomization:“APR Necessary“

Postoper. RCT Preoper. RCT n= 394 n = 405

85 109

17/85 (20%) 43/109 (39%)

85-17= 68 109-43= 66

Sphincterpreserved p = 0.004

APR actually done

German Rectal Study Conclusions• Preop CRT significantly improves local control

• Preop CRT improves sphincter preservation in low-lying tumours

• Preop CRT reduced acute and chronic toxicity

• Preop CRT should be the standard adjuvant treatment in cT3/4 or cN+ rectal cancer

CAVEAT •18% of tumours in the post operative group

were overstaged clinically (i.e. Stage 1 on pathology)

• Mandates excellent preoperative radiologic assessment

Accurate preoperative local tumor staging is critical in directing patient management

All modalities remain poor in assessment of regional lymph node involvement

CT still the workhorse for distant metastatic disease, complications/sequelae and surveillance

Preoperative Rectal Staging

OVERVIEW


5FU as a radiosensitizer

• Improves local control, pCR (FFCD,EORTC)

• Potentially improves control at distant sites (treats micro metastasis earlier)

• PVI is the optimal schedule

Capecitabine as a Radiosensitizer?

• Mimics infusional 5FU

• Convenient versus PVI

• Intratumoral thymidine phosphorylase activity upregulated with XRT

Oral vs Infusional 5FU N PCR (%) SSS (%)

Phase2, UFT 400mg/m2/d X 5/7 – S – 5FU/LVX4 (1)

94 9% 25%

Phase1 – RP2D Capecitabine 825mg/m2 BID X 7/7 (2)

36 -- --

Phase 2, Capecitabine 825mg/m2 BID X 7/7 – S – C X 4/12 (3)

53 24% 59%

Phase 2, Capecitabine 825mg/m2 BID X 7/7 – S – C X 4/12 (4)

95 12% 74%

Matched-Pair Analysis (PVI vs Capecitabine) (5)

89/89 12%/21% 70%/78%Similar OS

1 – Fernandez, JCO2004 2 – Dunst, JCO 20023 – DePaoli, Ann Oncol 2006 4 – Kim, IJROBP 20055 – Das, IJROBP, 2006

Capecitabine versus 5-fluorouracil-based (neo-)adjuvant chemo-radiotherapy for locally advanced rectal cancer:

Long term results of a randomized phase III trial

R. Hofheinz, F. Wenz, S. Post, on behalf of the German MARGIT study

Study Design

Mar 2002-July2005Post-Op

Treatment

Post July 2005

After Publication of Sauer TrialNeoadjuvant

TreatmentArms Added

Overall survival (OS)Primary endpoint (Median Follow-up 52 mon.)

Disease free survival (DFS)Secondary endpoint (Median Follow-up 52 mon.)

NSABP-R04

1200 pts

***Capecitabine is 825 mg /m2 bid for 5/7(Rad days)

Oxaliplatin No Oxaliplatin

Capecitabine

5FU

Roh et al ASCO 2011

NSABP-R04

Roh et al ASCO 2011

NSABP-R04

Roh et al ASCO 2011

5FU-Oxaliplatin-XRT

•Over 15 phase I/II trials have demonstrated pCR rates ranging from 20-40% (compared to 10-20% expected with XRT+5-FU)

•Increased likelihood for sphincter preservation?

•More efficacious systemic therapy for micrometastases given preoperatively?

NSABP-R04

Roh et al ASCO 2011

NSABP-R04Pathologic Complete Response by Treatment

Oxaliplatin vs NoneSphincter Saving Surgery by Treatment

Oxaliplatin vs None

Roh et al ASCO 2011

STAR TRIAL

Aschele C et al. J Clin Oncol July 2011

STAR TRIAL RESULTS

5-FU CRT 5-FU/Oxal CRT p-value

Path CR 16% 16% 0.94

Gr 3-4 toxicity

Any

Diarrhea

8%

4%

24%

15%

<0.0001

<0.0001

Grade 2-3 neurosensory

0.5% 36% <0.0001

Aschele C et al. J Clin Oncol July 2011

ACCORD 12/0405-Prodige 2

Eligibility

• T3-4, N0-2, M0 resectable (or T2 distal anterior) rectal cancer, DRE accessible

CAPOX/RT50RT 50 Gy x 5 wksCAPE 800 mg/m2 BID/day*OXA 50 mg/m2 weekly

CAPE/RT45RT 45 Gy x 5 wksCAPE 800 mg/m2 BID/day*

Adjuvant chemotherapy (Center discretion)

(6 weeks)

Total Mesorectal Excision (TME)

R

*Except weekend

Gerard JP et al. J Clin Oncol 2010;28(10):1638-44.

ACCORD 12 TRIAL RESULTS

CAP/RT CAPOX/RT p-value

Path CR 14% 19% 0.11

Gr 3-4 toxicity

Any

Diarrhea

Neuropathy

11%

3%

0.4%

25%

13%

5%

<0.001

<0.001

<0.002

Standard of care remains 5-FU based neoadjuvant CRT without oxaliplatin.

Gerard JP et al. J Clin Oncol 2010;28(10):1638-44.

OVERVIEW


Decline in the rates of local failure:1980-2010 The war we are winning

35

30

25

20

15

10

5

0

Loca

l fai

lure

(%)

sx only sx RT sx CTRT CTRT TME

Deline in the rates of distant failures: 1980-2010 The war we are losing

40

35

30

25

20

15

10

5

0

Dis

tant

met

asta

ses

(%)

sx only sx RT sx CTRT CTRT TME

Gunderson, L. L. et al. J Clin Oncol; 22:1785-1796 2004

(NCCTG 794751, 864751; NSABP R01, R02; INT 0114) n=3791

CT

No CT

Postoperative chemotherapy in Rectal Cancer (no preoperative treatment in these studies)

Lancet 2007 Lancet 2007; 370: 2020–29; 370: 2020–29

Recurrence free survival

Overall survival

Postoperative chemotherapy in Rectal Cancer QUASAR STUDY-Rectal Cohort(29%) n=948

Postoperative chemotherapy in Rectal Cancer

ECOG 3201

Stage II/IIRectal Cancer

Preop or Postop CRT (MD Choice)

R

5FU/LV

FOLFOX4

FOLFIRI

Closed at 225 of planned 3150

Bosset NEJM 2006

Bosset NEJM 2006

Collette, L. et al. J Clin Oncol; 25:4379-4386 2007

Who benefits from post operative 5FU?(ypT downsized)

Postoperative chemotherapy after neoadjuvant CRT

5FU/FA:-Only trend in EORTC study(negative)-Only level 1 study to date -Standard in postoperative CRT era-QUASAR,INT 0114/0144

Xeloda:-Only extrapolation from stage 3 colon cancer(X-ACT)

FOLFOX: -Only extrapolation from stage 3 colon cancer(MOSAIC,CO7)

Postoperative chemotherapy after neoadjuvant CRT • All patients should get some chemo regardless of ypT

ypN statusplan set preoperatively

• Duration should be 4 months

• Choice of Xeloda vs FOLFOX individualized

• If no downstaging- FOLFOX?

• If short-course preop-XRT – 6 months

STUDIES OF CHEMOTHERAPY IN RECTAL CANCER

Pre-op: STAR( 5FU +/- OXALIPLATIN)-Published JCO 2011

ACCORD(XELODA +/- OXALIPLATIN)- Published JCO 2010 NASBP R-04( 5FU vs. XELODA +/- OXALIPLATIN)-ASCO 2011

Post-op: SCRIPT (XELODA vs. Nil)-Closed for accrual issues CHRONICLE (XELOX vs. Nil)- Closed for accrual issues

E5204 (FOLFOX +/-AVASTIN)- Closed for accrual issues Pre and Post-op: CAO/ARO/AIO 04(5FU+/-Oxaliplatin---PRE/POST)- report 2011

PETACC-6(XELODA +/- OXALIPATIN---PRE/POST)-ongoing

Operable Rectal Cancer-Clinical Stage2/3

↓ Preop CRT/5 day rads ↓ TME surgery ↓ Randomization Observation Capecitabine CLOSED DUE TO POOR ACCRUAL

SCRIPT STUDY

CHRONICLE STUDY

CLOSED DUE TO POOR ACCRUAL

ECOG 5204 Phase III Trial (NCIC CRC.4)

Stage II/III R

mFOLFOX6 X 12

mFOLFOX6 + Bev X 12

Accrual: 2100 planned- CLOSED DUE TO ACCRUAL -2009

CAO/ARO/AIO 04

Rodel et al ASCO 2011

CAO/ARO/AIO 04


CAO/ARO/AIO 04


CAO/ARO/AIO 04


Conclusion

PETACC 6

ONGOING

OVERVIEW

• Introduction• Postoperative Chemoradiation• Preoperative Radiotherapy(no chemo)• Preoperative Chemoradiation• Preoperative vs Postoperative

Chemoradiation• Optimizing Preoperative Chemoradiation• Post operative adjuvant chemotherapy• Future Approaches

Newer approaches-Phase 2


Newer approaches-Phase 2EXPERT trial





Patients with progressive orstable disease XRT + 5-FU FOLFOX + Bev

FOLFOX + Bev x 4 FOLFOX x 2

Patients with clinical regression Surgery*

Newly diagnosed clinical stage II or III rectal adenocarinoma

*Post-operative treatment atdiscretion of physician.FOLFOX x 6 recommended; nopost-operative Bev provided.

Schrag D et al. Proc ASCO 2010;Abstract 3511.


• 31 patients with Stage II/III (no T4) rectal • 27/27 patients had regression and proceeded

to surgery with no XRT

• 27 had R0 resection and 7/27 (26%) pCR

• One pt with 14/14 nodes offered post-op XRT


Schrag D et al. Proc ASCO 2010;Abstract 3511.

CALGB Phase II/III “PROSPECT” study


• Accurate preoperative imaging -MRI Staging

• Multidisciplinary Tumour Board discussion

• Use of preoperative radiation with or without chemotherapy

• Surgical concept of TME resections

• Pathologists “auditing” the surgical procedure -TME quality, CRM, nodal recovery • Postoperative chemotherapy

SUMMARY APPROACH TO RECTAL CANCER-2011

Questions

RECTAL CANCER The (neo)adjuvant story

Documents