May 2007 GI Updates

We would like to acknowledge and thank Dr Berry for providing us with the latest oncology GI meeting updates

ASCO GI Symposium Updates

At this year’s ASCO GI Symposium there were key updates for the 2000 patient “NO16966” trial: a randomised 2x2 factorial phase III trial of capecitabine and oxaliplatin vs FOLFOX4 + bevacizumab or placebo in first-line metastatic colorectal cancer.

This trial examined 2 key questions in the treatment of metastatic colorectal cancer:

• Can capecitabine replace the infusional 5FU component of combination chemotherapy with oxaliplatin?

  The primary outcome was progression free survival. Median PFS for the patients on FOLFOX4 was 8.5 months vs 8 months for capecitabine/oxalipatin (HR 1.04, 97.5% CI 0.93 -1.16, which was below the non-inferiority upper limit of 1.23) Investigators reported response rates- 49% for FOLFOX4 and 46% for capecitabine/oxaliplatin (39% vs 36% were the response rates confirmed by the independent review committee)

  In terms of toxicity, capecitabine oxaliplatin had more grade 3/4 diarrhea (20% vs 12% ) and slightly more hand foot syndrome (6 vs 1 %) thank FOLFOX4. FOLFOX4 had more grade 3/4 neutropenia (43 vs 7%).

  You can access the full slide set here

  BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS:
  This is an important trial for Canadian oncologists. It confirms that capecitabine can be substituted for the infusional 5FU component of combination chemotherapy with oxaliplatin without sacrificing any efficacy. It also provides information about the differential toxicity profile of the 2 regimens that will allow oncologists to have more informed discussions with their patients as they make decisions about therapy for metastatic colorectal cancer. However, this trial will not resolve issues around the differential funding and access available for capecitabine and oxaliplatin across the country.
  

• Does bevacizumab add to the efficacy of first line chemotherapy with oxaliplatin based combination chemotherapy?

  Dr Leonard Saltz presented an update on the second component of this trial. The median PFS for chemotherapy and bevacizumab was 9.4 months vs 8 months for chemotherapy alone which was statistically significant. Dr Saltz raised the following question: Why was the PFS benefit smaller than had been seen with prior studies? There is no definitive answer to this question. However Dr. Saltz’s subsequent discussion outlined some hypotheses. One hypothesis relates to the duration of exposure to bevacizumab. Most patients in this trial had their bevcizumab discontinued when their chemotherapy was discontinued (on average at about the 6 month time point – presumably because of oxaliplatin neurotoxicity) Even though patients with neurotoxicity were permitted to stop oxaliplatin and continued with bevacizumab and a fluoropyrimidine, this rarely happened. In other bevacizumab trials like the pivotal IFL +/- bevacizumab trial patients were able to have longer exposure to bevacizumab because of the absence of a dose-limiting toxicity like neurotoxicity.

  This hypothesis is interesting to consider but does not explain why the response rates - that were reported for the first time at this meeting – showed that chemotherapy + bevacizumab had very similar response rates to chemotherapy + placebo (47% vs 49% investigator reported responses, 38% vs 38% for independent review committee confirmed responses)

  You can access Dr Saltz’s full presentation here

  BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS:
  This was a major study whose results have anxiously been awaited because it was the first randomized trial to assess the value of adding bevacizumab to a commonly used first line combination chemotherapy regimen. Although the results show a statistically significant improvement in PFS, the improvement was more modest than what we may have hoped for our patients. As further data becomes available we may be able to reconcile the results of this trial with other studies of bevacizumab in metastatic colorectal cancer.