You are here: Home: CCU 5 | 2006: Axel Grothey, MD

Tracks 1-15

Track 1 Introduction Track 2 OPTIMOX2: Maintenance therapy or chemotherapy-free intervals after FOLFOX Track 3 Clinical trial incorporating a maintenance or chemotherapy-free interval strategy with bevacizumab Track 4 Selection of FOLFOX or FOLFIRI with bevacizumab as first-line therapy Track 5 Therapeutic approach with curative intent for patients with metastatic disease Track 6 Treatment of patients with synchronous primary and metastatic disease Track 7 Clinical management of potentially resectable hepatic-only metastases Track 8 NSABP-C-09: CAPOX with or without hepatic arterial infusion of floxuridine for resected or ablated liver metastases Track 9 Ongoing adjuvant clinical trials evaluating FOLFOX with biologic therapy Track 10 Tolerability and side effects of biologic therapies in the adjuvant setting Track 11 Potential rationale for efficacy of adjuvant bevacizumab Track 12 Selection of adjuvant chemotherapeutic regimens Track 13 Use of adjuvant fluoropyrimidine monotherapy Track 14 NSABP-R-04: Preoperative radiation therapy and oral versus intravenous 5-FU with or without oxaliplatin for rectal cancer Track 15 Use of postoperative adjuvant therapy for rectal cancer

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Track 3

DR GROTHEY: I believe the most important trial in this regard was the OPTIMOX2 trial (Maindrault-Goebel 2006), which was based on a prior trial conducted in France, the OPTIMOX1 trial (Tournigand 2006). OPTIMOX1 was a Phase III trial comparing FOLFOX4 continued until patients either developed toxicities or their disease progressed to a stop-and-go regimen — with the stop-and-go related to oxaliplatin — meaning that patients were treated with a limited duration of FOLFOX then continued on a maintenance therapy of 5-FU alone, and oxaliplatin was to be reintroduced at a planned interval.

OPTIMOX2 went one step further by introducing the complete chemotherapy- free interval — giving patients a complete break from all treatment until their disease progressed and comparing it to maintenance therapy.

The problem with this trial for our current practice, beyond the fact that it did not include bevacizumab, was that this trial design allowed tumors to grow back to their initial size. Patients who had a response to FOLFOX-based therapy and discontinued FOLFOX after three months of therapy were then followed and tumors were allowed to progress back to their initial presentation. I believe this would currently be quite a hard sell to patients.

Within these limitations, and based on the fact that only 200 patients were assigned in this trial, no significant difference appeared in the duration of disease control as defined by the study. We don’t have any data on overall survival yet, and we don’t have quality-of-life data, but at least withholding therapy did not appear to harm patients.

Track 4

DR GROTHEY: If we are treating in the neoadjuvant potentially curative setting, an abundance of data support FOLFOX over FOLFIRI and oxaliplatin over irinotecan, particularly the recent data coming from MD Anderson about the effects of liver toxicity on therapy and postoperative, postliver resection mortality or morbidity (Vauthey 2006).

Outside of that, I believe whether you use FOLFOX or FOLFIRI is “a wash.” Outside of a clinical trial, I talk to my patients about which toxicity they would prefer. It’s either the neurotoxicity or the higher risk of developing early onset diarrhea. From an efficacy point of view, FOLFOX and FOLFIRI are not different in the palliative setting.

DR LOVE: We don’t have direct comparisons of FOLFOX/bevacizumab versus FOLFIRI/bevacizumab, but can you make any indirect conclusions from the BICC-C trial data and the TREE trial data?

DR GROTHEY: Yes. The TREE trials (Hochster 2006, 2005) and the BICC-C trial (Fuchs 2006) were similar. The TREE-1 and BICC-C trials both started the year before bevacizumab was approved, so both trials did not include bevacizumab in their first phase, and both trials evaluated what is the best fluoropyrimidine, in combination with either oxaliplatin in the TREE trials or irinotecan in the BICC-C trial.

After bevacizumab was approved in the United States, the TREE trial, which evaluated oxaliplatin combinations, was amended to include bevacizumab in all three treatment arms. The capecitabine dose in arm three was reduced to account for toxicities observed in TREE-1, and the BICC-C trial discontinued the capecitabine and irinotecan arm and added bevacizumab to FOLFIRI and IFL.

What we have now is a cross-trial comparison. When you compare FOLFOX and FOLFIRI with bevacizumab in TREE-2 and in the BICC-C trial, it’s interesting to see that the progression-free survival in both trials — a crosstrial comparison for FOLFOX with bevacizumab and FOLFIRI with bevacizumab — was 9.9 months, exactly identical. The response rates were 54 to 55 percent, almost identical (1.1).

We have data on FOLFOX with bevacizumab in terms of overall survival, which was 26 months in TREE-2. For FOLFIRI with bevacizumab, the endpoint for overall survival in the BICC-C Phase II trial had not yet been reached, but the survival curve suggested that it will be beyond two years. So we have similar data on FOLFIRI and FOLFOX using almost all efficacy parameters.

Track 9

DR GROTHEY: Recently we have moved from 5-FU to FOLFOX as standard of care in the adjuvant setting for colon cancer and, for most purposes, also in rectal cancer. So the new question is how to integrate the biologic agents that we know work in the palliative setting — cetuximab and bevacizumab. Both of these biologics have demonstrated efficacy in established colorectal cancer tumors, but it has not been determined whether they play any role in the adjuvant setting.

We can’t immediately transfer all our knowledge and our experience from the palliative setting into the adjuvant setting. This was demonstrated by the relative failure of irinotecan to show benefit in the adjuvant setting (Saltz 2004), whereas in the palliative setting FOLFOX and FOLFIRI are equivalent.

Cetuximab is an EGFR antibody, and bevacizumab is a VEGF inhibitor. Both are being tested in the United States in ongoing cooperative group trials. NSABP-C-08 is evaluating FOLFOX with or without bevacizumab as adjuvant therapy for Stage II and III colon cancer. NCCTG-N0147 is evaluating FOLFOX with or without cetuximab in the adjuvant setting.

ECOG has a Stage II trial (E5202) observing patients at molecular high risk as defined by microsatellite instability and loss of heterozygosity at the 18q chromosome. Those patients will be randomly assigned to FOLFOX with or without bevacizumab — analogous to the C-08 trial.

For every patient that we see right now in the adjuvant setting, Stage II and Stage III, there is an adjuvant trial available (1.2). These trials are being mirrored by European trials that are similar in design: The AVANT trial is evaluating bevacizumab, and the PETACC trial is evaluating cetuximab.

Track 14

DR GROTHEY: The NSABP-R-04 trial was initially designed simply to compare capecitabine to continuous infusion 5-FU, but over time this question became more and more secondary. We want to optimize not only local control but also the systemic effects of therapy so that micrometastases can be treated as early as possible. So evaluating an oxaliplatin-based combination made sense because we also know that oxaliplatin is a good radiosensitizer and has systemic efficacy at a dose of 50 mg/m² on a weekly basis.

The standard of care right now outside of a clinical trial would be to use continuous infusion 5-FU. A growing body of evidence suggests that capecitabine at a dose of 825 mg/m² BID from Monday to Friday with weekend breaks throughout radiation can be safely administered, and this
regimen has similar efficacies in Phase II cross-trial comparisons.

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Editor:
Neil Love, MD

Interviews:

Axel Grothey, MD
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Daniel G Haller, MD
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Charles S Fuchs, MD, MPH
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Neal J Meropol, MD
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