Track 1

DR LOVE: Axel, what are your thoughts about this poll question?

DR GROTHEY: I was happy about the audience answers because I have been trying to educate physicians to stop treatment before patients develop toxicities.

For an oxaliplatin-based regimen, this approach has evolved, and it’s already the standard approach based on the Phase III data from the OPTIMOX1 trial, which demonstrated we can safely discontinue oxaliplatin without compromising efficacy (Tournigand 2006; [3.1]).

For irinotecan, we have limited information based on the Italian GISCAD trial presented at ASCO 2006. Discontinuation of irinotecan-based therapy — in an on-and-off schedule of two months on FOLFIRI followed by two months off FOLFIRI (a complete chemotherapy break) — did not influence progression-free survival or toxicity (Labianca 2006; [3.2]), which was interesting.

The data are more solid for an oxaliplatin-based regimen, which is what we use more often as first-line therapy in the United States. Because oxaliplatin is associated with cumulative toxicity, it makes sense to “OPTIMOXize” FOLFOX, meaning to stop oxaliplatin after a certain number of cycles.

At the 2007 ASCO GI Symposium, Aimery de Gramont discussed the history of the OPTIMOX trials and updated the results from the OPTIMOX2 trial. The problem Aimery faced when he developed the FOLFOX regimen was that more patients stopped oxaliplatin-based therapy because of toxicity than because of disease progression (Green 2005).

So the OPTIMOX1 trial in patients with metastatic colorectal cancer compared the continuation of FOLFOX4 until disease progression or toxicity to a stop-and-go strategy for oxaliplatin, which used induction therapy with six cycles of FOLFOX7 followed by six months of maintenance therapy with 5-FU/leucovorin and planned reintroduction of FOLFOX7. He demonstrated that when you stop oxaliplatin for six months, this does not compromise overall outcome in terms of the response rate, progression-free survival, duration of disease control and overall survival (Tournigand 2006; [3.1]).

The OPTIMOX2 trial randomly assigned patients with metastatic colorectal cancer to an OPTIMOX1-like treatment arm of induction, maintenance, reintroduction or a treatment arm consisting of induction, a complete chemotherapy-free interval and reintroduction. It was a Phase II trial comparing maintenance therapy to a complete break of any tumor-directed therapy (Maindrault-Goebel 2006; [3.3]).

The response rates were the same for the patients treated with maintenance therapy and those treated with a chemotherapy-free interval because they received the same induction therapy regimen. There is no question, and response occurs early (Maindrault-Goebel 2006).

It’s clear that when you receive some tumor-targeted therapy (ie, chemotherapy that can inhibit tumor growth), progression-free survival is significantly longer than if you stop therapy completely (Maindrault-Goebel 2006; [3.3]).

If progression-free survival is your primary endpoint, you must be sure patients receive their therapy and only discontinue the treatment components that create toxicity.

DR LOVE: How is this approach being integrated into the current randomized trials in the metastatic setting?

DR GROTHEY: We still have a hard time adopting this stop-and-go approach in our ongoing Phase III trials that use an oxaliplatin-based regimen up front. At some point patients will discontinue treatment not for progression but for toxicity, which then affects overall outcome if not dealt with in the right way. Right now, the ongoing Intergroup trial is being amended to include a more or less OPTIMOX-like approach as the standard.

Track 2

DR LOVE: What do we know about incorporating biologics into this type of strategy?

DR GROTHEY: We have limited data about how biologics would affect this concept of maintenance therapy or chemotherapy-free intervals. We’re currently conducting a trial led by the Mayo Clinic, which is evaluating a FOLFOX regimen with bevacizumab in a stop-and-go design.

In this trial, patients receive FOLFOX and bevacizumab for four months or eight cycles (3.4). Then we apply a planned discontinuation of oxaliplatin while 5-FU/bevacizumab is continued for four months, followed by the reintroduction of oxaliplatin.

This trial has accrued more than half of the target accrual goal, so we should have some data next year to determine whether continuing biologics as an integral component of maintenance therapy allows us to deliver more treatment and delay tumor progression without affecting toxicity.

Currently, various trials use biologic agents in the maintenance phase to delay tumor progression. The idea is, you might induce a response by using conventional chemotherapy in combination with one or two biologic agents and maintain the response by using biologic agents to allow for a long-term delay in progression and limit toxicity.

Tracks 3-4

DR LOVE: Neal, in practice do you use treatment-free intervals or prefer some type of maintenance therapy?

DR MEROPOL: In general, I provide complete treatment-free holidays. It is a tremendous added benefit for the patient not to have to come in to the office. While we have no secure data addressing the survival impact of a complete holiday, in the absence of data to the contrary and with the data from the OPTIMOX1, OPTIMOX2 and GISCAD studies suggesting no detriment, at least in short-term outcomes, I’m pretty comfortable discussing with a patient the possibility of a complete holiday from treatment.

DR HALLER: A question I have for the panel members is, what defines the end of the holiday, assuming you don’t want to wait until the patient is symptomatic?

DR GOLDBERG: So many different considerations are relevant — including the patient’s psychology. For some patients, the thought that they have cancer and are not actively on treatment is so detrimental to their quality of life that they’d rather put up with the toxicities and the office visits.

DR VENOOK: I favor absolute holidays, but they are not appropriate for everyone. Palliation means trying to improve the patient’s quality of life, and stopping therapy can often help to do that. However, the issue is complex, and my default position is probably to continue the chemotherapy. Also, we need a data set on whether discontinuing bevacizumab will be a problem.

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Editor and Moderator:
Neil Love, MD