Select Excerpts from the Interview

Track 1

DR LOVE: What were some of the practice-changing presentations at ASCO this year?

DR WAKELEE: The Hoosier Oncology Group (HOG) trial, which evaluated chemotherapy with cisplatin/etoposide and concurrent radiation therapy for unresectable Stage IIIA and IIIB disease, was the most practice-changing presentation in lung cancer at ASCO (Hanna 2007).

All patients in the study received chemotherapy and radiation therapy, and then they were randomly assigned to either consolidation docetaxel using the standard SWOG-S9504 protocol or nothing. The trial showed no difference in survival between the two arms, with strikingly overlapping survival curves.

Criticisms include the fact that it was a relatively small study, and it was stopped early because of an interim analysis showing that there was no way statistically to obtain a separation of the curves. The study begs the question of what consolidation chemotherapy is achieving in that situation. Other studies that evaluated induction chemotherapy with additional chemoradiation therapy in a similar patient population also didn’t show any benefit with chemotherapy. Again, it’s bringing into the forefront this question of what to do with Stage III disease.

For several years, everyone has been comfortable with the SWOG-S9504 regimen. Now we have to question that. However, I have a hard time believing that two cycles of a platinum doublet with radiation therapy is enough to cure Stage III disease when we know we need more than that to improve survival for earlier stages. I don’t believe the question is dead, but I believe we need to move away from simply building on S9504.

Many people are still using a weekly carboplatin-based regimen and a taxane with the radiation therapy. To say that we shouldn’t administer any chemotherapy after that is a somewhat frightening proposition, considering that these patients are not receiving much chemotherapy at all during the radiation therapy.

The median survival from those Phase II trials, excluding the CALGB study, is in keeping with what we’re seeing with these cisplatin/etoposide/radiation therapy regimens with or without docetaxel. We still have a lot of questions in Stage III disease, but as a general practice, consolidation docetaxel cannot be considered a standard anymore.

Track 3

DR LOVE: What are your thoughts on the AVAiL study data presented at ASCO?

DR WAKELEE: This was a European study of gemcitabine and cisplatin with or without bevacizumab (Manegold 2007; [3.1]). It evaluated two doses of bevacizumab: 7.5 mg/kg or 15 mg/kg. The 15-mg/kg dose was the dose used in the ECOG-E4599 carboplatin/paclitaxel study (Sandler 2005). AVAiL was initially an overall survival study, but they changed it to include progression-free survival.

A statistically significant improvement was demonstrated in progression-free survival — not a big difference, but a real difference statistically — with both the 7.5-mg/kg and the 15-mg/kg doses. The trial wasn’t powered to compare 15 mg/kg to 7.5 mg/kg — only both of those doses to placebo. Overall survival data weren’t mature yet.

DR LOVE: People may now question whether you can get away with using 7.5 mg/kg.

DR WAKELEE: That is the big question. I’m cautious still. We don’t have the survival data yet. We have no real way of evaluating any difference between 15 mg/kg and 7.5 mg/kg, even if we could do it statistically. I don’t believe it’s wrong to consider using 7.5 mg/kg, but I’m not ready to make the change in my practice. Certainly we won’t be making a change in the ECOG-E1505 adjuvant trial, in which we’re still using the 15-mg/kg dose every three weeks.

Track 4

DR LOVE: What do you consider reasonable nonprotocol options for chemotherapy regimens to combine with bevacizumab for metastatic disease?

DR WAKELEE: In the United States, carboplatin/paclitaxel with bevacizumab is approved. Given the AVAiL data (Manegold 2007), gemcitabine/cisplatin would certainly be reasonable now.

We’re conducting an ongoing trial with carboplatin/gemcitabine. I wouldn’t say that regimen is “ready for prime time” — not until we have the toxicity data, given the increased thrombocytopenia and neutropenia with that regimen. Substituting docetaxel for paclitaxel is reasonable because we don’t have any toxicity differences that would be of concern.

Track 6

DR LOVE: Will you provide an update on the ECOG-E1505 adjuvant study that you chair?

DR WAKELEE: We activated the study recently, and we are more comfortable than ever with our choice of regimens that investigators can select: cisplatin/ gemcitabine, cisplatin/vinorelbine and cisplatin/docetaxel, all with and without bevacizumab (3.2).

At this point, we’re still sticking with the 15-mg/kg dose of bevacizumab because that’s the dose for which we have known survival benefit. The bevacizumab is administered at the 15-mg/kg dosing every three weeks starting with the first cycle of chemotherapy and then continuing for one year.

DR LOVE: Are patients with Stage IB disease included in the study?

DR WAKELEE: We are limiting patients with Stage IB disease to those whose tumors are four centimeters or larger. We know from subset analyses of the larger adjuvant trials that patients with Stage IB disease don’t seem to benefit overall.

The CALGB IB trial was statistically negative overall, but those whose tumors were four centimeters or larger did show a survival benefit (Strauss 2006). That’s why we came up with the 4-cm cutoff.

At this point we’re not limiting to any NSC histology. We’re also not excluding patients receiving anticoagulation. Based on the safety data that have emerged in colorectal cancer — and now hints that have emerged in the AVAiL study — patients who have had any sort of stroke or transient ischemic attack are excluded. Patients who have had any other arterial thrombotic events, such as myocardial infarction, within six months are also excluded.

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