Colorectal CancerAn oncologists perspective

SpR Teaching Dec 2012Erica Beaumont

Summary

• Neoadjuvant Radiotherapy for rectal cancer• Neoadjuvant Chemotherapy for colon cancer• Adjuvant chemotherapy• Liver metastases• Palliative treatments

The MDT

Neoadjuvant Radiotherapy

• Operable rectal cancer (SCPRT)

• Inoperable / threatened CRM (CRT)

• Modern Context– MRI staging– TME

• Gina Brown et al. Radiol 1999;211:215-222

• MERCURY study gp. Diagnostic accuracy of preop MRI in prediciting curative

resection of rectal cancer: prospective observational study. BMJ 2006; 333: 779

MERCURY Study

• 428 pts

• MRI mesorectal fascia involvement by tumour significantly predicted for local recurrence

• DFS and OS showed that avoidance of preop RT safe in patients with MRI defined good prognosis disease (3% local recurrence)

• Allows stratification of patients and better targeting of preoperative radiotherapy for reduced patient toxicity and morbidity

• Phase II/III trials to identification of key imaging predictors of patients at risk of developing metastatic disease on initial staging

MERCURY staging study in rectal cancer Bmj, 2006; Salerno,Daniels et al. Dis Colon Rectum, 2009).

TME Surgery

• Total mesorectal excision reduces local recurrence rates

• 30-40% without TME, 3.7% with TME  

• TME varies between surgeons (experience, training technique )

• How can oncologists assess quality of surgery? Surgeons objectively assess Sx?

Heald Lancet 1986;  1(8496):1479-82Heald Lancet 1993;  341(8843):457-60 

Quality of Surgery

• Quirke

– Raised awareness of importance the circumferential resection margin and quality of TME specimen

– Developed graded assessment of TME

– Used in Dutch study & CR07

Quality of TME in Dutch Study

Influence of quality of TME surgery

Quality of TME and outcome CR07

3 yr LR 3 yr DFS

Plane of Sx N Pre Post HR Pre Post HR

Musc prop 141 9% 29% 2.76 79% 65% 1.75

Intra meso 382 6% 12% 2.02 78% 75% 1.13

Mesorectal 596 1% 6% 4.47 87% 80% 1.53

Potential benefits of neoadjuvant RT

• Improving survival• Reducing risk of local recurrence• Improving the chance of sphincter

saving surgery• Increasing the chance of complete

resection in advanced disease

Post Op RT

• Decrease rel risk LR by 30-40%

• Absolute decrease 25.8% vs 16.7% (p<0.00002)

• Rectal cancer † decreases by 8.6%

*Lancet Meta-analysis 2001. CRC collaborative gp. >2000 pts 8 post op RCTs

Pre op RT

• >6000 pts 14 RCTs

• Decrease relative risk LR of 50-60%

• Absolute decrease 22.2% vs 12.5% (p< 0.00001)

• Rectal cancer † decrease by 22%

Lancet meta-analysis 2001

Short Course Preoperative RTSCPRT

SCPRT – Swedish studies

• >1100 pts with resectable rectal Ca Sx vs RT 25/5 + Sx (1986-1990)

– Not TME– 25/5#/1W– 5 yr LR 27% vs 12% – 5 yr OS 48% vs 58% – Only pre op study showing survival benefit – Benefits maintained - most recent update JCO 2005

Swedish Rectal Cancer Trial. N Engl J Med 1997; 336: 980-7

SCPRT – Dutch study

• Sx vs preop RT 25/5 + Sx in operable Rectal cancer

• 1748 pts underwent complete resection• 2yr LR 8.2% vs 2.4% *

• Longer FU relative benefit maintained• Also assessed importance of CRM and quality of

surgery* *

* Kapiteijn et al. Preop RT combined with TME for resectable rectal cancer. NEJM 2001; 345: 638

* * Nagtegaal et al. Dutch CCG co-operative. Macroscopic evaluation of rectal cancer specimen. 2002; 20: 1729

Risk factors for LR

Influence of CRM on LR & OS

• A – LR with AR• B – LR with APR• C – OS with AR• D – OS with APR

Grey = CRM -

Black = CRM +

Low rectal cancers have worse outcomes

APR v AR in Dutch study

• OS– 38.5% v 57.6% (p=0.008)

• CRM+– 30.4% v 10.7% (p=0.002)

• Perforation rate– 13.7% v 2.5% (p<0.001)

SCPRT – CR07

• SCPRT vs selective post op CRT with TME Sx• 1350 pts

– 674 25/5 SCPRT– 676 Sx alone of whom 11% CRM +

• 3 yr LR 4.7% v 11.1% (HR 2.47, 95% CI 1.61-3.79)

• 3 yr DFS 79.5% v 74.9% (HR 1.31, 95% CI 1.02-1.67)

• Benefit consistent for all levels & stages

JCO 2006 ASCO Proceedings Part I. Vol 24; No. 18S: 3511

Side effects of SCPRT

• Minimal acute toxicity

• Poor wound healing (esp perineal)

• Bowel dysfunction – faecal incontinence

• Less of a problem for patients post APR

Who should have SCPRT?

• To reduce local recurrence in:

– Low rectal cancers (APR)– Bulky T3– Node positive disease

Long Course Chemoradiotherapy

Polish study• 312 pts with rectal cancer palpable by

DRE

• Primary end point – sphincter preservation

• Secondary endpoints –LR, toxicity

• Operation specified by surgeon pre RT

• Randomised to 25/5 vs 45/25 + 5FU wk 1&5

• Reassessed to decide on final operation post RT

Bujko et al. Radioth Oncol 2004; 72: 15

Polish study

• No difference in sphincter-preservation rates

• More acute Gd 3 & 4 toxicity with CRT– 18% v 3% (p=0.001)

• More pCR, less N+ & CRM+ with CRT– 16.1% v 0.7%, 31.6% v 47.6%, 4.4%v 12.9%

Polish study

• No difference late toxicity– 28.3% v 27%

• No difference in 4 yr LR– 15.6% v 10.6% (p=0.21)

Why give CRT?

• Downstage inoperable tumours (but is there a role for SCPRT?)

• Downstage tumours where there is a threatened CRM (by primary or node)

Practicalities of RT

• Tattoos

• Empty rectum, full bladder

• CT scan

• SCPRT: 5 daily treatments the week before surgery

• CRT: 25-28 daily treatments with bd capecitabine chemotherapy

Toxicities of RT

• Acute: sore skin, tiredness, nausea, diarrhoea, PR bleeding, urinary

• Late: bowel dysfunction, urinary, small bowel stricture, infertility, menopause, poor wound healing, vaginal stricture, impotence, pelvic bone fragility, risk of second malignancy

Planning RT

• CT scan

• Fields vs volumes

• Aristotle trial

• Include – mesorectum– Extension of tumour beyond mesorectum

(+margin)– Sup: sacral promontory– Inf: obturator foramen, or 2-3cm below tumour

Adjuvant Radiotherapy

• Post-op if positive margin (R1 resection)

• Only if no pre-op RT given

• Not as effective as pre-op RT

• Better than nothing

Neoadjuvant chemotherapy for colon cancer

FOXTROT trial

• Ongoing

• Initial data: 150 patients

• Locally advanced (T3/4) colon tumours on CT

• 3 cycles (6 weeks) FOLFOX chemo and Surgery vs Surgery alone

FOXTROT

• No diff post-op morbidity (p=0.8)

• Decreased T and N stage with neoadjuvant chemo (p=0.04)

• Decreased margin involvement (p=0.002)

Lancet Oncol 2012; 13:1152-60

Adjuvant Chemotherapy

Rectal Cancer

• All data extrapolated from colon cancer

• SCPRT – does not downstage cancer

• CRT – downstages cancer

• Treat on initial clinical staging

• Chronicle trial failed to recruit

• Good prognostic group: ypT0 ypN0 M0– Distant metastases 8.9%, 5yr DFS 85%

Colon cancer

• Initial studies done with 5FU

• Intergroup 035 (5FU vs no chemo)– 5yr OS benefit for Dukes C 13%– 5yr OS benefit for Dukes B 3-5%

• X-ACT (capecitabine vs 5FU)– 4% benefit for cap

• MOSAIC (5FU /oxaliplatin vs 5FU)– 3yr DFS benefit of 5%

Current Practice

• Node positive tumours– 5FU / Oxaliplatin– If less fit / elderly, Cap alone

• High risk node negative tumours– EMVI, T4, R1, Emergency presentation, <12

nodes– Cap / 5FU alone– 5FU / Oxalipatin if lots of risk factors

What does this mean for patients?

• 6 months treatment (SCOT trial ongoing)

• Tiredness, nausea, diarrhoea, stomatitis

• Palmar plantar syndrome

• Neuropathy, orolaryngeal spasm

• Haematological toxicity

• Cardiac toxicity

• Thromboembolic disease

• DPD deficiency

Follow Up

• Often CNS led

• Risk stratified

• Regular CT scans– Timing controversial– To assess for resectable liver mets

Treatment of liver metastases

Liver only disease

• Assessment– CT, MRI Liver, PET

• Resectable– Refer for surgery, ?chemo upfront– EPOC B

• Unresectable– K-Ras status– Chemotherapy for 3 months and reassess– SIRT (FOXFIRE trial)

Chemotherapy

• FOLFOX

• Every 2 weeks for 6 cycles, PICC line

• If k-ras wild-type and unresectable for Cetuximab

• mAb EGFR

• Celim study: ph 2 (Lancet Oncol 2010)– RR: 68% with FOLFOX and Cetuximab– Resectability increased from 32% to 60%

Why liver resection?

• Historically 50% colorectal cancer patients develop liver mets

• 30% present with liver mets

• Resection can give 5yr OS rates of 21-43%

After liver resection

• 3 months adjuvant chemotherapy

• 6 monthly CT scans

• Further liver resections may be possible

Presentation with liver mets

• 2 problems: liver and primary

• Which will kill patient first?

• Risk of obstruction – surgery vs stent?

• Will delaying chemo harm patient?

• Risk of micrometastatic disease elsewhere

• Synchronous resections?

• Controversial area

Lung metastases

• Extrapolate from liver data

• Resection of <5 lung mets

• No adjuvant chemo

• PULMIC study

Palliative Treatments

Primary in situ

• Does resecting the primary give an advantage?

• Assess for obstruction

• Stents

• May prevent use of bevacizumab (anti-angiogenesis Ab)

Chemotherapy

• In fit patients (PS 0-1), multiple lines of chemotherapy can give 18-24 months survival

• Chemo drugs: 5FU / Capecitabine, Oxaliplatin, Irinotecan

• Biological therapies: Cetuximab, Bevacizumab, Panitumumab

• New agents: Aflibercept, Regorafenib

Liver therapies

• RFA

• Chemoembolisation

• SIRT

Radiotherapy

• Rectal cancer– 25Gy/5# can downstage– 8Gy/1# can stop bleeding– Hard to give if has had RT pre-op

• Bone mets

• Back pain from para-aortic disease

• Lung met with haemoptysis