Landmark trials in chemotherapy in colon cancer

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PROF.S.SUBBIAH et al.
COLON CANCER -
CHEMOTHERAPY TRIALS
Department of Surgical Oncology
Centre for Oncology
GRH,Royapettah

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STAGING

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CHEMOTHERAPY IN COLON CANCER

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CHEMOTHERAPY REGIMENS

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ADJUVANT CHEMOTHERAPY FOR RESECTABLE
COLON CANCER
STAGE ADJUVANT TREATMENT
Stage 1 and MSI-H Stage II No Adjuvant treatment
Low risk MSS or p MMR Stage II Observation or Capecitabine or 5-FU/LV
High risk MSS or p MMR Stage II 3 m CAPEOX or 3-6 m FOLFOX or
6 m Capecitabine/5FU-LV
Low risk stage III 3 m CAPEOX or 3-6 m FOLFOX or
6 m Capecitabine/5FU-LV
High risk stage III 3 m CAPEOX or 3-6 m FOLFOX or
6 m Capecitabine/5FU-LV

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HIGH RISK FEATURES
• Poorly differentiated or undifferentiated
• LVI
• PNI
• Close/indeterminate/positive margins
• Tumor budding
• Less than 12 nodes sampled
• Bowel obstruction
• Perforation

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5-FU TRIALS

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• Clear benefit in terms of 5-year DFS for stage III patients who received
chemotherapy.
• 33% reduction in mortality in patients receiving 1 year of adjuvant 5-fluorouracil
plus levamisole, compared with surgery alone.
• Subsequently, the INT-0089 trial showed that 6 months of 5-fluorouracil plus
leucovorin (5- FU/LV) was equivalent to 1 year of 5-fluorouracil plus levamisole.
• there was no further benefit of the addition of levamisole.

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ORAL FluoroP – X-ACT Trial

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• Compared the efficacy and safety of the oral fluoropyrimidine
capecitabine with bolus 5-fluorouracil as adjuvant therapy for
stage III colon cancer.
• A total of 1987 patients were enrolled at 164 centers worldwide.
• Disease-free survival (primary study endpoint) in the
capecitabine arm was at least equivalent to that in the 5-FU/LV
arm.
• Significantly fewer fluoropyrimidine-related grade 3/4 adverse
events
• Savings in direct costs as well as uniquely effective oral
outpatient treatment.

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MOSAIC TRIAL

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• 2246 patients with resected high-risk stage II and III colon cancer
were randomized
• LV-5FU (bolus leucovorin, bolus and infusional 5-fluorouracil every 2
weeks) or the same regimen plus oxaliplatin (FOLFOX4) for 6 months.
• DFS at 3 years for oxaliplatin showed a 23% reduction in the risk of
relapse compared with LV-5FU (22% vs. 27%; p = 0.002).
• In a post hoc analysis, oxaliplatin improved 10-year OS in patients
with stage III disease (67% vs. 59%; p = 0.016)

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The addition of oxaliplatin did not improve OS for stage II patients,
either as a whole or for the subset with one or more high-risk factors.

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NSABP C-07 TRIAL

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• 2407 patients with stage III and high risk, stage II colon cancer
• 6 months of bolus 5-fluorouracil/leucovorin (FULV) administered
weekly, or the same regimen plus oxaliplatin (FLOX).
• Improved 3-year DFS with the addition of oxaliplatin, which resulted
in a 20% reduction in the risk of relapse (33% vs. 27%; p0.004).
The addition of oxaliplatin did not improve DFS or OS in patients with
high-risk, stage II colon cancer or those aged 70 years and older

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NO16968 TRIAL
• 1886 patients with resected stage III colon cancer to 5-FU/LV alone or
to the combination of capecitabine plus oxaliplatin (CapeOx).
• Primary endpoint-improved 3-year DFS with CapeOx, which resulted
in a 20% reduction in the risk of relapse compared with FULV (31% vs.
38%; p = 0.0045).
• In a post hoc analysis, the use of CapeOx was associated with
improved OS at 7 years (67% vs. 73%; p = 0.004)

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These results(MOSAIC,NSABP C-07 and NO16968) suggest that
• Adjuvant oxaliplatin plus FU and leucovorin is useful after surgery
for stage III colon cancer.
• A similar conclusion cannot be drawn for stage II disease as a whole,
although there is some evidence from the results that patients
classified as having high-risk stage II disease may also benefit from
such treatment.

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ADJUVANT CHEMO IN STAGE II-QUASAR TRIAL
Stage II colon cancer have a favorable long-term prognosis and the
benefits from adjuvant chemotherapy, if any, are negligible

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• The QUASAR trial randomized 3239 patients with resected colorectal
cancer (CRC), of whom 91% had stage II disease and 71% had colon
cancer as opposed to rectal cancer, to receive 5-FU/LV or to
observation.
• Survival benefit for those treated with chemotherapy
• 64% had fewer than 12 lymph nodes sampled-indicating high risk
disease-which may have benefitted from adjuvant chemo

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MSI- CALGB 9581 TRIAL
MMR status was prognostic but not predictive of benefit or
detrimental effect of chemotherapy in Stage II Cancer

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CHEMOTHERAPY IN ELDERLY-TRIALS
• Adjuvant chemotherapy usage declines with the age of patient
• Subset analysis of major adjuvant therapy trials
• MOSAIC, NSABP C-07, C-08, XELOXA, AVANT, TOSCA-IDEA
• 5-FU/LV-Benefits similar in young and elderly
• Oxaliplatin addition to 5-FU/Capecitabine- benefit not proven in
stage II/III Cancer

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END POINTS FOR ADJ CHEMOTHERAPY-
ACCENT TRIAL

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Appropriate end points of clinical trials
• DFS after 2 and 3 years
• OS after 6 years
Atleast 6 years are required for follow up for overall survival in modern
adjuvant colonic cancer clinical trials

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Since oxaliplatin is associated with cumulative neurotoxicity, a
shorter duration of therapy could spare toxic effects and health
expenditures.
DURATION OF ADJUVANT CHEMOTHERAPY-
IDEA COLLABORATION

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IDEA COLLABORATION
International Duration Evaluation of Adjuvant Therapy (IDEA)
collaboration aimed to
• combine data from 6 randomized trials
• to investigate whether a 3-month (3m) of
oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT)
is non-inferior to the 6-month(6m)
• for 3-year disease free survival (DFS) in stage III colon cancer
(CC).

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CONCLUSION:
Among patients with stage III colon cancer receiving adjuvant
therapy with FOLFOX or CAPEOX
• noninferiority of 3 months of therapy, as compared with 6
months, was not confirmed in the overall population.
• However, in patients treated with CAPEOX, 3 months of therapy
was as effective as 6 months, particularly in the lower-risk
subgroup

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These data suggest that the choice of treatment regimen, duration of
therapy, and characteristics of the patients may be balanced against
the substantial risk of increased toxicity of longer oxaliplatin-based
therapy, including persistent neurotoxicity

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ADJUVANT REGIMENS NOT RECOMMENDED-
NEGATIVE TRIALS
TRIALS REGIMENS NOT RECOMMENDED FOR STAGE II/III
CALGB 89803 IRINOTECAN (FOLFIRI)
NSABP C-08 BEVACIZUMAB with FOLFOX
AVANT BEVACIZUMAB addition to usual regimens
QUASAR 2 BEVACIZUMAB with CAPECITABINE
INTERGROUP N0147,PETACC 8 CETUXIMAB with FOLFOX
NSABP C-07 FLOX

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FOLFOX VS FLOX

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FLOX no longer recommended as adjuvant treatment due to high
GI toxicity

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NEOADJUVANT THERAPY-FOxTROT TRIAL
NAC has an established role in many solid tumours but its utility
has not previously been formally evaluated in colon cancer.
5 FU and Oxaliplatin in Treating Operable colon Tumors

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• 1053 patients entered at 98 hospitals in the UK, Denmark and
Sweden. Of 699 allocated NAC/AC, 674 (97%) started and 612
(88%) completed 6 wks NAC.
• Serious perioperative morbidity(anastomotic leaks) was lower
after NAC.
• Marked histological downstaging after NAC
• 3.8 % NAC/AC pts had pCR and 32 (4.6%) had near-complete
tumour regression
• Incomplete (R1/R2) resections were reduced

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For bulky nodal disease or clinically T4b,Neoadjuvant chemotherapy
with FOLFOX or CAPEOX may be considered prior to surgery

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RADIOTHERAPY IN COLON CANCER
• Neoadjuvant or adjuvant RT delivered concurrently with 5-FU based
chemotherapy
• Select patients –T4 penetrating to a fixed structure or patients with
recurrent disease
• Additional boost by IORT or 10-20 Gy of EBRT
• Also for locally unresectable or medically inoperable using IMRT/SBRT

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TAKE HOME POINTS
5-FU +
Levamisole
5-FU + LV
Oral
FluoroP
Oxaliplatin+
FluoroP

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TAKE HOME POINTS
STAGE ADJUVANT TREATMENT
Stage I No Adjuvant treatment
Low risk Stage II Observation
High risk Stage II 6 m Capecitabine or 3 m CAPEOX
Benefit of Oxaliplatin not proven
Low risk stage III 3 m CAPEOX or 3-6 m FOLFOX
High risk stage III 3 m CAPEOX or 3-6 m CAPEOX or
6 m FOLFOX
Elderly >70 years 5-FU or Capacitabine alone
Neoadjuvant therapy- Data are limited. Considered for T4 Tumors at high risk
of involvement of resection margins

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REFERENCES
• NCCN GUIDELINES
• DEVITA
• JOURNAL-LANDMARK SERIES