Editor’s Note Three tenors

By strange happenstance, during this year’s ASCO meeting in New Orleans, I had the rare opportunity to interview three clinical investigators who recently presented clinical trial results that have permanently changed oncologic practice. On this program, Aimery de Gramont, Herbert Hurwitz and James Cassidy discuss the background, rationale, methods and initial findings of arguably the three most important Phase III clinical trial data sets in colorectal cancer treatment in more than a decade.

For over a year, I had attempted to arrange an interview with Aimery de Gramont. However, due to the length of our recording sessions and Dr de Gramont’s relatively brief US visits, the time was never right for us to sit down and talk. Fortunately for our listeners, I was finally able to secure a time slot with the French researcher during the ASCO 2004 meeting. Unfortunately, as we began the discussion, the Louisiana skies opened and a spectacular thunderstorm ensued. When recording on location at meetings, we frequently confront aberrant noises such as sirens and train whistles. Usually, these can be edited out. In this case, though, the relentless booming and crackling are here to stay.

I actually like the dramatic audio accent the storm adds to our discussion of the MOSAIC trial, a landmark study that Dr de Gramont first presented at last year’s ASCO meeting. The definitive paper on MOSAIC had just been published in the New England Journal of Medicine during the week I interviewed Dr de Gramont, and I was particularly interested in his reaction to Robert Mayer’s accompanying editorial. As the clouds thundered outside, this very thoughtful investigator reviewed the clear-cut benefits associated with adjuvant FOLFOX in Stage III patients, and data his group had just reported that afternoon on its benefits in patients with higher-risk Stage II disease. The MOSAIC trial results have not only dramatically altered the nonprotocol approach to adjuvant systemic therapy, but also the design of subsequent adjuvant trials as evidenced by the many new randomized studies with variations of FOLFOX as the control arm.

Like Dr de Gramont, Herb Hurwitz is another busy trialist who is difficult to catch up with, and again I felt fortunate to meet with him in New Orleans. It is always amusing to conduct interviews at ASCO because everyone is frenzied with multiple simultaneous commitments. Dr Hurwitz — a very deep-thinking person who chooses words carefully — was able to take a deep breath and then calmly and concisely weave a fascinating research yarn.

The disappointments during Judah Folkman’s angiogenesis chronicle have long preceded the bevacizumab story, and for years many believed that anti-angiogenic treatment would not play out clinically. This perception was reinforced in December 2002 at the San Antonio Breast Cancer Symposium when Kathy Miller presented the disappointing results from the randomized trial that added “bev” to capecitabine in women with previously treated metastatic breast cancer. I had been chatting with Kathy for some time as that critical study accrued and then finally reported results, and when we sat down for an interview, it was obvious she was disappointed, but hopeful that another ongoing first-line ECOG trial of bev plus paclitaxel as first-line therapy in women with metastatic breast cancer would be positive.

After that inauspicious anti-VEGF debut in December 2002, all hell broke loose at the ASCO 2003 meeting. Soft-spoken Herb calmly presented a biologic blockbuster — bevacizumab added more to IFL in terms of progression-free and overall survival than the addition of irinotecan to 5-FU and leucovorin, which led to the IFL FDA indication.

With these now landmark results, which were published with MOSAIC in the June 3rd issue of the New England Journal of Medicine, the Folkman anti-angiogenesis legacy is clearly alive. Or is it? Researchers like Lee Ellis have postulated that the benefits encountered with bevacizumab were actually related to the normalization of the vasculature within tumors, allowing for greater penetration of cytotoxic agents, rather than cutting off the blood supply. Who knows? The bottom line is that more patients are staying alive and feeling better, and adjuvant bevacizumab trials are on their way.

The final member of the memorable investigator trio appearing on this program, James Cassidy, met with me shortly after presenting perhaps the most anticipated GI research report at the 2004 ASCO meeting, the initial results from the X-ACT trial demonstrating at least equivalence in tumor control for capecitabine compared to the Mayo Clinic regimen of 5-FU and leucovorin as adjuvant therapy. Not only does this study obviate the need for a commonly utilized but inconvenient parenteral regimen, but for the first time, we have clinical trial evidence that capecitabine is much more than oral 5-FU. The original objective of this study was to demonstrate equivalence in efficacy with improved tolerability and convenience. X-ACT surprised even Dr Cassidy with tantalizing relapse-free and overall survival advantage for capecitabine, although only RFS was statistically significant. Perhaps the promise of intratumoral prodrug-activation via thymidine phosphorylase has now truly been fulfilled. In any event, patients have one more effective, relatively nontoxic alternative as adjuvant therapy.

I always feel privileged to have the opportunity to chat with the great minds in our field, but it was particularly striking to have the chance to listen to these three humble but visionary research leaders. After years of inertia in the treatment of this very important cancer, the work of these and other investigators is rapidly altering the colorectal cancer treatment landscape.

— Neil Love, MD
NLove@ResearchToPractice.net