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Treatment Principles Histological Staging Chemotherapy Trials

Palliative Curative

◦Surgery◦Surgery + neoadjuvant Tx◦Surgery + neoadjuvant + adjuvant Tx◦Surgery + adjuvant Tx◦(Radiotherapy)

Dukes A = T1/T2, N0 Dukes B = T3/T4, N0 Dukes C = Any T, Node positive (Dukes D = Any T, Any N, M1)

Applies to rectal and colon cancers

Surgery alone provides high cure rate for early stage disease

5yr survival rates Stage I = 80-90% 5yr survival rates Stages II or III = <70%

Pts who have undergone a potentially curative resection, disease recurrence is thought to be due to micrometastases present at the time of surgery.

The aim of adjuvant therapy is to eradicate these.

Rectal cancer adjuvant therapy = chemotherapy +/- radiotherapy

Colon cancer adjuvant therapy = chemotherapy

Don’t forget neoadjuvant CRT or DXT or chemo alone

After recovery from surgery In general, six to eight weeks No trials specifically looking at effects of

delay Delay beyond 2 months may compromise

the effectiveness of chemo.

Operations:1. Anterior resection2. Low anterior resection3. Abdomino-perienal excision of rectum

(APER)4. TART / TEMS

After surgery alone:◦ <10% T1-2◦ 15-35% T3N0◦ 45-65% T3-T4, node positive

Figures above before the use of TME excision (Now <10%)

Meta-analysis of RCTs in 1980s showed:◦ Improved local control◦ Increased time to local recurrence

With adjuvant RT in stage II or III disease 5yr risk of LR 17% vs 28% (surgery alone)

However, no survival benefit (58 vs 59%)

RCTs in 1980s & 1990s showed survival advantage if 5-Fluorouracil (5FU)-based chemo added to RT Trials used chemo high risk of leukaemia = methyl-CCNU

2012 Meta-analysis of 9,221 pts (21 trials) sig reduction in risk of ◦ disease relapse (HR for relapse 0.75, 95% CI 0.68-

0.83), and ◦ death (HR for death 0.83, 95% CI 0.76-0.91) ◦ (chemo alone vs no chemo)

5FU sensitises tissues to RT◦ Miller et al 2002, showed improved survival and

decreased metastases, but no difference in LR◦ Smalley et al 2006, showed no difference

?higher risk of acute reaction with infusion, plus cost, inconvenience and risks of CVP line

Orally active fluoropyrimidine which is converted to 5FU

Can be used as neoadjuvant or adjuvant therapy in combination with RT

However, no long term studies available comparing infusional 5FU and capecitabine

No specific trails for rectal cancer, but has been shown to improve outcomes in colon cancer

‘Sandwich’ technique◦ 1 or 2 cycles of chemo (2 months)◦ Combined modality (6 weeks)◦ Additional chemo (2 months)

No trial have shown disadvantage or benefit for giving RT early or in the middle of sequence

Increased bowel movements (inc nighttime, incontinence)

Diarrhoea Acute toxicity Chronic bowel injury Anastomotic strictures

T3N0 – 5-FU-based CRT T1-T2N1 – 5-FU-based CRT for node positive

disease

Stage I – surgery alone Stage II or III – sig local control & survival

benefit for adjuvant CRT

Fluoropyrimidine as radiation sensitiser (5FU)

Leucovorin,oxaliplatin

3 or 4 field approach (PA, left & right lateral +/- AP)

Lower level of L5 to 5cm below anastomosis or perineum (APER)

1.5cm beyond bony pelvis laterally Prone position Full bladder

1.8Gy, five fractions per week to a total dose of 45Gy

Field size then reduced and a ‘boost’ dose is delivered to the tumour bed

Avoid excess radiation to small bowel

Operations◦Right hemicolectomy (extended)◦Left hemicolectomy (extended)◦Subtotal colectomy◦Sigmoid colectomy◦Total colectomy

Stage III Disease (node +ve)◦ ~30% rel reduction in risk of disease recurrence◦ 22-32% rel reduction in mortality

Stage II Disease (node –ve)◦ Benefits less certain, and chemo use is varaible.

Fluoropyrimidine-based chemo◦ Multiple trials have included stage II & III pts◦ QUASAR & IMPACT B2 trial looked at stage II

disease only Non-significant trend towards improved survival

comapred to observation alone Neither trial enrolled enough pts though

Intergroup 2004◦ 3302 pts with stage II or III colon cancer◦ Stat sig improvement in 5-yr DFS (76 vs 72%)◦ No sig difference in overall survival (81 vs 76%)

Ontario Group 2004◦ Systematic review, 4187 pts◦ 5-10% sig improvement in DFS◦ No sig diff in overall survival◦ASCO does not support the routine use of

adjuvant chemotherapy for stage II colon cancer

6 months of adjuvant 5-FU/LV versus FOLFOX (Oxaliplatin, leucovorin, 5-FU/capecitabine) in pts with resected stage II or stage III colon cancer

Min 6 yrs FU◦ Stat sig increase in overall survival (76 vs 79%,

HR for death 0.84, p=0.046), but this was limited to stage III disease.

◦ Stage II = 87% both Tx arms◦ DFS 80 vs 84%, p=0.26

Worse prognosis:◦ T4 primary◦ Poorly differentiated◦ Lymphovascular or perineural invasion◦ Bowel obstruction or perforation◦ Close or positive margins◦ <13 LN sampled◦ High pre-op CEA level

Worse prognosis:◦ T4 primary◦ Poorly differentiated◦ Lymphovascular or perineural invasion◦ Bowel obstruction or perforation◦ Close or positive margins◦ <13 LN sampled◦ High pre-op CEA level

5yr DFS with 0, 1 or ≥2 = 95%, 85%, 57%

No evidence that these high-risk factors are more likely to benefit from chemo

Factors with a poorer prognosis are not necessarily predictive of chemo response

However, ASCO 2002 suggested that adjuvant therapy be discussed in medically fit pts with high-risk clinicpathological features

Various research studies ongoing to identify factors which may influence prognosis & response to chemotherapy

Only one identified is microsatellite instability (MSI = biologic footprint of DNA mismatch repair deficiency) which is assd with resistance to 5-FU, but these tend to be less aggressive cancers

Adjuvant! Online Estimates risk of recurrence & death based

on clinicopathologic features www.adjuvantonline.com US SEER tumor registry

Role is poorly defined Subgroups to offer:

◦ Est local recurrence risk ≥ 30%◦ Ascending or descending colon primary with T4

disease or positive resection margin

5-FU-based chemo does NOT exceed an absolute improvement in 5yr survival of 5%

Should NOT be standard care However, risks & benefits should be

discussed (SE, risk of recurrence or death) ‘High-risk factors’ RT for limited no. of pts.

International Multicentre Pooled Analysis of Colon Cancer Trails◦ 1526 pts with Dukes’ B or C◦ Observation vs 6 cycles of 5-FU/LV

Significant 22% reduction in death ◦ 3yr overall survival 83% vs 78%◦ Benefit almost entirely limited to stage III disease

FOLFOX vs 5-FU/LV alone Stat sig improvement in overall survival 5yr DFS 73% vs 69%, HR 0.80, p= 0.023)

Febrile neutropaenia (1.8% vs 0.2%) Grade 3 or 4 diarrhoea (10.8% vs 6.6%) 92% developed peripheral neuropathy

(severe in 13%)

2407 pts with stage II or III FOLFOX vs 5-FU/LV

5yr DFS 69% vs 64%, HR 0.82 Overall survival not significant

◦ 80% vs 78%, HR 0.88

Toxicity for both groups

Diet Exercise Aspirin (and other NSAIDs)

Adjuvant systemic therapy initiated within 6-8 weeks of surgery

6/12 of oxaliplatin-based regimen (if pt likely to tolerate it) ◦ Contraindications inc pre-existing neuropathy

Or, 5-FU/LV (but ?less favourable outcomes)

RT for high risk local recurrence (T4 & penetration to a fixed structure, or postive resection margins)

Rectal cancer = chemotherapy +/- radiotherapy

Stage II colon cancer = chemotherapy if high risk & fit

Stage III colon cancer = oxaliplatin-based chemotherapy

Stage IV disease = chemotherapy

Don’t forget lifestyle changes?!? Don’t forget neoadjuvant treatment