You are here: Home: CCU GI Think Tank 2007: Section 1

Tracks 1-9

Track 1 Use of oxaliplatin as a radio-sensitizer, systemic therapy or both Track 2 NSABP-R-04: Preoperative radiation therapy and capecitabine or 5-FU with or without oxaliplatin for operable rectal cancer Track 3 Use of preoperative versus postoperative chemotherapy in rectal cancer Track 4 Importance of preoperative staging in the determination of optimal therapy for rectal cancer Track 5 Preoperative chemoradiation therapy with oxaliplatin for select patients with locally advanced rectal cancer Track 6 Rationale for NSABP-R-04 design Track 7 Preoperative staging and the use of neoadjuvant chemoradiation therapy versus postoperative chemotherapy Track 8 Incorporating biologic agents in preoperative therapy of rectal cancer Track 9 Use of preoperative oxaliplatin-containing chemoradiation therapy for rectal cancer

Track 1

DR HALLER: I would say “in between” because I wear two different hats: one as a person who conducted a Phase I/II trial in this area and uses it off protocol and another as the GI Intergroup co-chair with a protocol (NSABPR-04; [1.2]) specifically addressing this question.

Separate Phase I or II studies evaluating this regimen have been conducted worldwide (1.1), and some clear conclusions have emerged. First, it is evident that you can add oxaliplatin to a fluoropyrimidine and radiation therapy on a weekly or biweekly schedule or once every three weeks and at different doses. The dose depends on whether you consider oxaliplatin a radiosensitizer, a systemic agent or both. That is, you’re administering adjuvant therapy and local therapy to make the radiation therapy work better.

If you want to use oxaliplatin as a radiosensitizer, you probably want to use it more frequently, as in CALGB-89901 (Ryan 2006). If you believe it’s more of a systemic agent, you certainly want to administer the maximal dose.

It turns out if you administer oxaliplatin weekly, not everybody gets through all the dosing. So although the total dose that could be delivered is high, the actual dose administered with the weekly regimens is much lower than with the every two-week or every three-week regimens. We have defaulted to a weekly regimen because CALGB data suggested that oxaliplatin was more of a radiosensitizer.

In the German preoperative trial, the pathologic complete response (CR) rate was found to correlate with disease-free survival (Rödel 2005). For patients who have received radiation therapy alone or radiation therapy with 5-FU, the pathologic CR rate is in the range of about eight to 10 percent (Sauer 2004). In the 5-FU/oxaliplatin studies, the pathologic CR rates range anywhere from about 18 percent to 48 percent.

Track 2

DR HALLER: The primary comparison in NSABP-R-04 was capecitabine versus infusional 5-FU (1.2). It started to become a fairly pedestrian question because many physicians had already diverted to using capecitabine. However, it remains an important question because you have to lower the dose of capecitabine from the “standard systemic dose.” You need to ensure that you’re maintaining — for a patient being treated with curative intent — the same rates obtained with infusional 5-FU.

DR LOVE: What is the dosing schedule for capecitabine in NSABP-R-04?

DR HALLER: It’s 825 mg/m² twice a day on Monday through Friday. As the study was just about to be launched, the whole oxaliplatin issue came along. Many of us thought the trial would be better as a two-by-two design asking two important questions. We will have the definitive answer from NSABPR- 04, but I would guess that the oxaliplatin combinations would have better pathologic CR rates. Whether that translates into better long-term outcomes — including acute and late toxicities, sphincter preservation, type of surgery and overall survival — is where NSABP-R-04 comes into play.

DR LOVE: What do we know about the safety and tolerability of adding oxaliplatin to a fluoropyrimidine in the neoadjuvant setting?

DR HALLER: In most of the studies, more diarrhea occurred with the weekly regimen, which is why more doses were dropped (1.1). Patients received more oxaliplatin when it was administered less frequently because they didn’t face dose reductions and delays. In treating patients with rectal cancer, it’s important that you not interfere with the radiation therapist administering treatment at the standard dose and schedule. If you had six treatment interruptions for hospitalizations and such, you may see an inferior outcome because the radiation therapy was unintentionally administered in a split-course fashion.

Track 5

DR GROTHEY: I was intrigued that approximately two thirds of the people here tonight would consider oxaliplatin — at least for some patients — outside of a clinical trial, in the neoadjuvant setting with, so far, only Phase II data. The question I pose to Dan is, do we really need the data from the NSABPR-04 study if two thirds of us are already using this approach?

DR HALLER: We certainly know that capecitabine is a feasible agent, but the dose that you can administer during radiation therapy is considerably lower than the dose you would normally administer systemically to most patients. So I do want to see that the lower capecitabine dose is equivalent to infusional 5-FU.

Track 9

DR GOLDBERG: We participated in the CALGB study, and I had several patients who showed good responses to oxaliplatin and 5-FU on protocol. I participate in the NSABP-R-04 trial, but I don’t use oxaliplatin in this setting off study.

DR GROTHEY: I’ve used oxaliplatin outside of clinical trials in the neoadjuvant setting for patients with large tumors for whom I wanted to use the radiosensitization activity of oxaliplatin. Also, for patients who present with presumably curable metastatic disease, this utilizes the most active therapy up front and still provides patients with the benefits of local tumor control, preservation of sphincter function, et cetera.

DR HOCHSTER: For a couple of patients who have presented in my practice like that, we’ve used FOLFOX without bevacizumab and saved radiation therapy for postoperative treatment. The question is about the combination with radiation. What will the increased acute and the long-term toxicities be when you add these agents and a biologic together with radiation therapy?

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Neil Love, MD