You are here: Home: CCU 5 | 2006: Daniel G Haller, MD

Tracks 1-11

Track 1 Introduction Track 2 US BRiTE registry trial: Side effects and toxicity of bevacizumab in clinical practice Track 3 Predicting risk of bevacizumab-associated arterial thrombotic events Track 4 Acquired hypertension as a predictor of response to bevacizumab Track 5 Cetuximab-associated rash: Implications for adjuvant therapy Track 6 Preoperative versus postoperative chemoradiation therapy for rectal cancer Track 7 The importance of downstaging rectal cancer Track 8 Rationale for incorporating oxaliplatin with preoperative radiation therapy for rectal cancer Track 9 Selection of oral versus infusional fluoropyrimidine therapy Track 10 Geographic variability in the tolerability of fluoropyrimidines Track 11 Use of preoperative response to chemoradiation therapy to determine postoperative adjuvant therapy for rectal cancer

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Track 2

DR HALLER: I believe American oncologists are doing a wonderful job of selecting patients. The BRiTE registry showed that the toxicity profile of bevacizumab for the average patient in the community is similar to those in clinical trials. This is important information to have. Sometimes we worry that patients in trials are so extraordinarily selected that toxicity findings will not apply to our patients.

We know that 20 percent of patients with metastatic disease should not receive bevacizumab because of the high risk of arterial thrombotic events, perforation or other adverse events. I believe 80 percent might be the correct number of patients to be receiving bevacizumab.

DR LOVE: Where are we in terms of understanding the side effects and toxicity of bevacizumab?

DR HALLER: We know that the toxicity profile we saw in the AVF2107 trial is somewhat predictive of what we see in clinical practice (Hurwitz 2003; Hedrick 2006; [2.1]). As a practitioner, that is comforting — I can tell a patient what to expect.

Track 8

DR HALLER: Our preclinical rationale is something we have inferred from laboratory evidence — that platinates will be synergistic with radiation therapy. This is why platinums and fluoropyrimidines have been used in head and neck cancer, lung cancer, cervical cancer and other settings.

Our clinical rationale stems from two US trials, CALGB 89901 and ECOG 1297 (Ryan 2006; Rosenthal 2003). These trials incorporated infusional 5-FU and either biweekly or weekly oxaliplatin and showed pathologic complete response rates in the mid 20 percent range, compared to about 10 percent in other trials, including the German study with preoperative 5-FU and radiation therapy (Sauer 2004).

Indeed, across a series of Phase I-II trials, we see reliable pathologic complete response rates from the midteens up to about 40 percent. To me, the consistency of the data is important.

At our institution, we collected data from a large series of patients who were not enrolling in a study but received preoperative 5-FU with or without oxaliplatin. When we examined these cases retrospectively, we saw that the pathologic complete response rates were equivalent to those seen in the ECOG trial (Dolinsky 2006).

The data were so intriguing to our radiation oncologists and surgeons that they hesitated to refer a patient unless they believed the patient might receive oxaliplatin as part of a “standard” regimen.

Track 10

DR HALLER: As American oncologists, we all thought we were doing something wrong. What was it about our patients that made them appear to suffer so much more toxicity from capecitabine than the patients described in trials? Dr Hans Schmoll and I co-chaired a study that compared CAPOX with either the Roswell or the Mayo Clinic 5-FU regimens in 1,800 patients with Stage III colon cancer (Schmoll 2005). When we evaluated toxicity differences by region, we saw on the surface that the US population clearly had more toxicity.

When we combined our data with two trials of the Mayo Clinic regimen versus capecitabine in advanced disease (Hoff 2001; van Cutsem 2001), the toxicity profile was consistent across the board. We then reviewed historically the IMPACT data (IMPACT 1995), which were a compilation of 5-FU and leucovorin regimens versus surgery alone in colon cancer, and saw that Europeans had less toxicity with any 5-FU and leucovorin regimen.

At ASCO this year Dr Schmoll presented toxicity data for the CAPOX study (Schmoll 2006), and I presented a poster on capecitabine in both the metastatic and adjuvant settings with or without oxaliplatin (Haller 2006).

For US patients versus non-US patients, the hazard ratios were about 1.8 for almost any toxicity you could name, including myelosuppression, a nonself-reported toxicity, and some self-reported toxicities such as diarrhea and mucositis (2.2).

So it is no longer unclear whether Americans have more toxicity — it is now a known truth. Possible explanations for these differences include differences in pharmacogenetic factors or differences in external environmental factors, such as diet. Dr Carmen Allegra has shown that certain foods or supplements — and American diets are very high in folates — may be contributing to toxicity.

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Neil Love, MD

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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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