Editor’s Note One year later

According to Norman Wolmark, colorectal cancer control took its most significant step forward in more than a decade during the 2003 ASCO meeting in Chicago. In an interview for this audio series, the NSABP chairperson noted that for the first time in his memory, more attendees were present at the ASCO GI session than the breast cancer assembly. Whether the audience anticipated the monumental nature of the data or simply had a heightened interest in colorectal cancer, one thing is certain: Two stunning presentations from ASCO have had an immediate and permanent impact on daily patient care and clinical trial design.

First, Aimery de Gramont presented the initial findings of the MOSAIC adjuvant trial, which demonstrated a significant three-year disease-free survival advantage for the oxaliplatin-containing FOLFOX4 regimen compared to 5-FU/leucovorin. While we await more mature analyses of overall survival, many oncologists have immediately embraced the many variations of FOLFOX as off-protocol adjuvant treatment options, and for some, the use of adjuvant regimens containing oxaliplatin has become a new standard of care.

In a recent program, Richard Goldberg previewed an upcoming 2004 ASCO presentation from his group that will document the close historical correlation between three-year disease-free survival and five-year overall survival in adjuvant trials. This will likely provide an even greater incentive for the use of adjuvant FOLFOX in both clinical practice and research trials.

When I interviewed Dr Wolmark during the NSABP meeting just weeks after the 2003 ASCO meeting, he described a new adjuvant study NSABP protocol C-08 that had just been presented to the group. Of interest, all three of the control arms for this study contained oxaliplatin. In this issue of Colorectal Cancer Update, Dr Roy Smith updates us on the evolution of this trial which is still being finalized and several other new trials being launched by the NSABP.

The original adjuvant trial discussed in June 2003 was a three-by-two factorial design attempting to answer two important research questions: What is the optimal oxaliplatin-containing regimen, and what is the adjuvant role of the anti-VEGF factor bevacizumab? The NSABP wished to compare FLOX, the experimental arm of its prior study (C-07), to FOLFOX6 and CAPOX. Although the results of C-07 are not yet available, based on the MOSAIC results, the NSABP trialists were betting that C-07 would show FLOX to be superior to 5-FU/leucovorin.

The NSABP meeting generated a great deal of enthusiasm about CAPOX as adjuvant therapy. This regimen substitutes the oral fluoropyrimidine prodrug capecitabine for continuous infusion 5-FU. The CAPOX regimen not only offers the possibility of less hassle for patients and doctors, but perhaps an even greater antitumor effect based on the intratumoral activation of this agent.

Dr Smith notes that since this original concept was presented last year, C-08 has been refined and now focuses only on FOLFOX and the bevacizumab question. The rapid evolution of clinical and laboratory research in colorectal cancer has created an imprimatur to complete trials quicker. One of the major reasons that this trial was streamlined was to decrease accrual numbers so it could be completed more expeditiously.

Although the CAPOX arm of the proposed NSABP-C-08 trial was dropped, this patient-friendly regimen is still the basis for another fascinating study that is winding its way through regulatory processes, NSABP-C-09, which compares CAPOX alone to CAPOX plus intrahepatic infusion of floxuridine in patients who have had resection or ablation of hepatic metastases. In this issue, Nancy Kemeny comments on C-09 and her own landmark research on therapy for patients with liver-only disease.

Another NSABP trial discussed last year and still lumbering through the system is R-04, a study combining preoperative radiation therapy with capecitabine or infusional 5-FU. Bruce Minsky provides an update on clinical research in rectal cancer and discusses the possibility that capecitabine might be not only more convenient but perhaps also more effective in this setting.

The other groundbreaking news at the 2003 ASCO meeting was the significant progression-free and overall survival advantage associated with the addition of bevacizumab to IFL in patients with metastatic disease as presented by Herb Hurwitz. This paper, a milestone in colorectal cancer research, spawned a plethora of new trials evaluating this agent in the adjuvant setting, including NSABP-C-08.

Bruce Giantonio updates us on the ongoing clinical research with "bev" and notes that his own ECOG trial will answer perhaps the most pressing current question related to this antiangiogenic agent whether combining it with oxaliplatin will produce treatment benefits similar to those seen with the combination of bevacizumab and IFL. Those data from ECOG-3200 are not yet available, but the hope is that the synergism between irinotecan and bevacizumab will generalize to other cytotoxic agents. Clearly the NSABP-C-08 adjuvant trial has this as its premise, which is particularly salient in view of the apparent lack of benefit seen with adjuvant IFL.

Personally, I find it somewhat disappointing that some of these trials are not yet up and running. As discussed by Dr Smith, large cooperative studies often take years to activate. I have no doubt there are excellent reasons to explain this, particularly to ensure that participating patients are protected. On the other hand, people with this disease and their doctors want answers now, and frankly, it is troubling that they have to wait so long.

Neil Love, MD
NLove@ResearchToPractice.net