Editor’s Note In our faces

In the late 1980s, under the entertaining tutelage of coach Jimmy Johnson, the University of Miami football team defied the staid college football establishment. Instead of wearing the required coats and ties to a Fiesta Bowl dinner, the players showed up wearing combat fatigues. Prior to each game, the team stood jaw-to-jaw with their opponents and brashly told them exactly what was about to transpire.

Radiation oncologist Chris Crane was a member of the University of Miami undergraduate student body at that time, and his best friend was the team’s placekicker. Perhaps it was his exposure to this type of blunt talk that later led Chris, as a faculty member at MD Anderson Cancer Center, to unflinchingly “tell it like he sees it,” including his very public challenge in a JCO editorial of the rectal cancer research plans of our most august cooperative group.

I attended the June 2003 NSABP meeting in Orlando when R-04 was presented and discussed and was somewhat surprised and disappointed to hear about the initial plans. In an interview for this program during the meeting, NSABP chair Norman Wolmark defended the study but also noted that the group wished to address additional important research questions in rectal cancer. Shortly after that, the protocol was amended to also evaluate the role of oxaliplatin as neoadjuvant therapy with combined radiation therapy and either capecitabine or infusional 5-FU (1.1).

Having been on the medical school faculty of the University of Miami during the Jimmy Johnson, Vinnie Testaverde, Jerome Brown and Michael Irvin era, I can empathize with Chris’s desire to shake things up in the name of progress. However, during our conversation at ASCO, we were both much more interested in reflecting on new avenues of clinical research, such as Chris Willett’s fascinating translational work in rectal cancer evaluating bevacizumab.

The other two interviewees for this program — medical oncologists Neal Meropol and Axel Grothey — provide a review of other key ASCO developments in colorectal cancer. Probably the most important paper from the meeting was Norm Wolmark’s “late-breaking” presentation of the efficacy data from NSABPC- 07 comparing “Roswell Park” bolus 5-FU/leucovorin to the same regimen plus oxaliplatin (FLOX).

These data looked much like the first presentation of the MOSAIC trial two years ago, when the addition of oxaliplatin to infusional 5-FU demonstrated a diseasefree survival advantage, prompting the FDA to bless the strategy.

Immediately following this talk, Rich Goldberg jumped to the microphone and asked whether these data meant that oncologists “can send our infusional pumps back to the manufacturer.” Norm — as always, the wry pundit — replied, “I don’t know why you would ask a surgeon, but the data speak for themselves. We’ve demonstrated that adding oxaliplatin to a weekly 5-FU bolus template shows a benefit that is of similar magnitude to an infusional 5-FU regimen. I would hope people would examine these data and make their own decisions.”

There were also many questions about the relevance of these findings with the FLOX regimen and how they impact the current NSABP adjuvant trial C-08, which uses FOLFOX as the control arm versus FOLFOX plus bevacizumab.

During the same 2003 interview with Norm at the NSABP meeting when we talked about R-04, he elaborated on the group’s plans at that time for C-08. The study was intended to be a three-by-two factorial design comparing in the first randomization FOLFOX versus FLOX versus CAPOX (capecitabine plus oxaliplatin), followed by a second randomization to bevacizumab or control. Subsequently, with considerable input (and muscle) from CTEP and the FDA, the study was simplified to its current design (1.2).

The downsizing of C-08 means that an answer about the role of adjuvant bevacizumab will be obtained more quickly; however, if an advantage is observed for adding the anti-VEGF agent, physicians and patients will then have to decide if the results can be generalized to more user-friendly regimens, including capecitabine.

Many similar dilemmas exist in other common solid tumors, including the following:

1. Should chemotherapy regimens with proven safety and efficacy in metastatic non-small cell lung cancer be utilized in the adjuvant setting if no specific adjuvant data exist for that regimen (for example, docetaxel/carboplatin)?
2. Can chemotherapeutic agents other than paclitaxel/carboplatin be combined with bevacizumab for metastatic non-small cell lung cancer (for example, doublets such as docetaxel/carboplatin or gemcitabine/carboplatin)?
3. Can agents other than paclitaxel be combined with bevacizumab in metastatic breast cancer (for example, docetaxel, nab paclitaxel, capecitabine or vinorelbine)?

Chris Crane’s “in your face” critique of R-04 brings into question the entire concept of evidence-based medicine, which in my opinion means utilizing credible laboratory and clinical research data as the basis for treatment decisions. However, credible evidence goes well beyond the realm of Phase III studies.

Chris’s point is that we often have extensive Phase II data on capecitabine, including safety findings, and Phase III trials from similar settings, and that these data may form enough of an evidence base to change practice without going through the expense and delay of implementing large Phase III studies.

The other major colorectal randomized trial reported at ASCO that ties into the concept of “How much evidence is enough to change practice?” was ECOGE3200. Discussed on the last issue of this audio series by principal investigator Bruce Giantonio, the E3200 data set reinforced the initial findings reported last November via an NCI press release and during Bruce’s ASCO GI presentation in January.

Essentially, this study demonstrated a progression-free and overall survival benefit for the addition of bevacizumab to FOLFOX in the second-line metastatic setting. What is interesting about the E3200 data is that oncologists had already made a leap of faith and have been utilizing this regimen up front for more than a year based on positive data combining bevacizumab with 5-FU alone and with IFL. The FDA made this leap much easier by approving bevacizumab with any infusional 5-FU regimen.

The delicate balance between regulatory bodies like the FDA, third-party payers including Medicare, clinical researchers and medical oncologists in practice represents an imperfect system that every now and then benefits when gadflies like “The U’s” Chris Crane shake things up a bit and make us reconsider where we’ve been, where we are and where we’re headed.

— Neil Love, MD
NLove@ResearchToPractice.net

Select publications

Crane CH, Sargent DJ. Substitution of oral fluoropyrimidines for infusional fluorouracil with radiotherapy: How much data do we need? J Clin Oncol 2004;22(15):2978-81. No abstract available

De Gramont A et al. Oxaliplatin/5FU/LV in the adjuvant treatment of stage II and stage III colon cancer: Efficacy results with a median follow-up of 4 years. Presentation. ASCO 2005;Abstract 3501.

Giantonio BJ et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. Presentation. ASCO 2005;Abstract 2.

Twelves C et al. Updated efficacy findings from the X-ACT phase III trial of capecitabine (X) vs bolus 5-FU/LV as adjuvant therapy for patients (pts) with Dukes’ C colon cancer. Presentation. ASCO 2005;Abstract 3521.

Wolmark N et al. A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP Protocol C-07. Presentation. ASCO 2005;Abstract LBA3500.