Select Excerpts from the Interview

Track 2

DR LOVE: Would you comment on ECOG-E4599, which evaluated bevacizumab in combination with chemotherapy in patients with metastatic disease?

DR ALBAIN: The addition of bevacizumab makes carboplatin/paclitaxel a better regimen. If you want to utilize carboplatin and paclitaxel in the front-line setting and the patient meets the criteria for ECOG-E4599 (nonsquamous histology and no history of uncontrolled hypertension, bleeding or clotting), you should probably also administer bevacizumab (Sandler 2005; [2.1]).

DR LOVE: How do you approach the selection of chemotherapy in the first-line setting for patients with metastatic NSCLC, and where does bevacizumab fit in?

DR ALBAIN: Our goal is to enroll our patients on clinical trials. In the Southwest Oncology Group, we’ve just finished a study (SWOG-S0342) with cetuximab, either concurrent with or sequenced after carboplatin and paclitaxel.

As I mentioned previously, if you want to use carboplatin and paclitaxel as your main regimen in this patient population, then you should add bevacizumab (Sandler 2005).

There is a preclinical rationale for the combination of bevacizumab with a taxane, and a lot of work is being done to evaluate other potentially additive and/or synergistic combinations. So, hopefully, there’ll be more agents to work with. I also use other regimens: cisplatin/docetaxel, cisplatin/ gemcitabine, and a number of others.

DR LOVE: How do you decide between those options on a case-by-case basis? What are some of the factors you consider?

DR ALBAIN: I consider the patient’s overall performance status and comorbid illnesses. So if the patient, for example, has diabetes that’s quite difficult to control, you may stay away from a regimen that requires steroids for a few days. There are a lot of things that play into the decision-making in advanced lung cancer. Patients often have a spectrum of other illnesses that go along with prior smoking — poor lung function, et cetera.

Track 7

DR LOVE: Where do you see things heading with the next generation of adjuvant trials in NSCLC?

DR ALBAIN: We do need an adjuvant bevacizumab trial, and one is being designed right now and will be conducted by the Intergroup. I believe that we also have to get erlotinib back in trials, because I can’t imagine that it wouldn’t be helpful for minimal residual disease as opposed to very advanced chemotherapy-refractory disease.

DR LOVE: What are your thoughts about the report by Herbst and Sandler evaluating the combination of bevacizumab and erlotinib (Herbst 2005; [2.2])?

DR ALBAIN: That’s a very interesting trial, and we’re participating in the follow-up study. It’s an extremely provocative result, and it is worth testing the combination of agents. Combining targeted agents is going to be important for those tumors that aren’t driven by a dominant single pathway.

Tracks 9-10

DR LOVE: Would you talk about the RTOG-9309 study?

DR ALBAIN: RTOG-9309 evolved because of the large number of Phase II trials conducted in the late 1980s and early 1990s that showed the feasibility of sending patients for a resection following chemoradiotherapy.

Other trials were studying chemotherapy alone, but at least in the Southwest Oncology Group’s series of pilot studies, we were evaluating a concurrent chemoradiotherapy program that showed a lot of promise.

That was brought into two studies — the first a trimodality study with surgery after the chemoradiation and the second with straight chemoradiation. These trials not only showed feasibility, but they also raised some concerns about a higher rate of acute respiratory distress syndrome (ARDS) after surgery.

Additionally, these trials identified a group of patients who — even though they had high-volume disease prior to therapy — at the time of surgery would have no remaining disease in their mediastinal nodes. The pilot study observed patients with Stage IIIA (pN2) and IIIB (nonpleural effusion) disease. The big debate, then, was whether surgery really contributes to survival.

Thus, SWOG started a Phase III trial while several other Phase III trials were going on. The Intergroup decided to shut all of them down and start a new one (RTOG-9309), which was identical to the SWOG design but was run by the RTOG. RTOG-9309 limped along in its accrual for a number of years. It was an extremely difficult study to discuss with patients because you had to inform them of the possibility of a higher rate of postoperative death. The trial finally recorded enough events for reporting, which were fewer than projected because of the long duration of accrual.

The first report showed a marked improvement in progression-free survival with the addition of surgery. Reproducing what we had seen in the pilot study, those patients with mediastinal nodes that were no longer positive after chemoradiotherapy seemed to have the best outcome.

The overall survival, however, showed no difference; the tail of the curve was a little bit separated, but the p-value was not significant (Albain 2003).

A final survival report was planned when more data were available, and we presented it at ASCO 2005. We showed the same overall results in terms of progression-free survival and overall survival (Albain 2005; [2.3]).

We looked very carefully at the postoperative deaths. We found — just as we had in the pilot trial — that the majority of the postoperative deaths occurred in patients who had undergone a pneumonectomy. These deaths were predominantly from ARDS, just as other postoperative deaths we have reported. The trial was not able to show an overall survival advantage because of these postoperative deaths (Albain 2005).

Our statistician performed an exploratory analysis matching the patients who had undergone pneumonectomies to a similar group in the nonsurgical arm.

The same process was followed with the patients who had undergone lobectomies. A dramatic split favored the lobectomy group over chemoradiotherapy alone, whereas the patients who had pneumonectomies had a worse survival rate than a matched group that did not receive surgery (Albain 2005; [2.4]).

That analysis was exploratory, but it answered the question, “What do I do in practice?” These were the types of patients for whom the standard of care would be chemotherapy and radiation. These were not the patients with very minimal N2 disease, who could still undergo surgery.

If I see a patient with mediastinal disease who fits the criteria for the study, is suited to undergoing a lobectomy, is fit and has a good performance status and good pulmonary function, we discuss the study results.

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