Select Excerpts from the Interview

Track 2

DR LOVE: Can you provide an overview of the clinical and research issues involved in the management of Stage IIIA non-small cell lung cancer?

DR PASS: The question of how to treat Stage IIIA lung cancer has been a vexing one. A number of studies have been performed using induction therapy for Stage IIIA nodal disease, two of which, despite very small accrual, were highly touted for the positive survival advantage seen among patients who received induction cisplatin-based therapy.

By the same token, Phase II trials studying the combination of chemotherapy and radiation therapy resulted in a randomized trial that evaluated whether induction chemoradiation therapy was better than definitive chemoradiation therapy without surgery for Stage IIIA disease.

The RTOG-9309 study presented by Dr Kathy Albain at ASCO appeared to suggest that surgery after induction chemoradiation therapy was not any better than definitive chemoradiation therapy, although it was associated with a trend in improved progression-free survival (Albain 2005; [3.1]).

If you look at the data carefully, however, you notice a high mortality rate for patients who underwent pneumonectomy. The overall operative mortality rate was seven percent, of which the operative mortality rate due to pneumonectomies was 14 percent. One of the reasons for the pneumonectomies was that the trial design was not stratified by lymph node size.

A subsequent unplanned analysis of the trial was presented by Dr Albain at a follow-up ASCO meeting, in which the authors carefully matched patients treated with definitive chemoradiation therapy to patients with lobectomies and not pneumonectomies. Sure enough, they found a fairly dramatic survival advantage in the lobectomy group (3.2).

The next trial, RTOG-0412, was then planned to ask a new question: What is the role of radiation therapy in Stage IIIA disease?

To avoid the pneumonectomy issue, the trial was designed to carefully stratify nodal disease into microscopic or clinically apparent disease and also to indicate by mediastinoscopy the number of stations involved. Essentially, this was to ensure against including patients with bulkier disease in this trial.

Although this trial has brought some controversy, the role of radiation therapy is an important issue because we still do not know whether induction chemotherapy alone or induction chemoradiation therapy is better.

Track 7

DR LOVE: Could you talk more about the design of the RTOG-0412 trial you are co-chairing?

DR PASS: The study is designed to enroll approximately 580 patients to try to show a 10 percent increase in survival for patients treated with induction chemoradiation therapy over those treated with induction chemotherapy alone (3.3).

This trial involves multiple types of treatment, and all patients are treated surgically, so patients don’t feel that they are losing out by not having surgery. However, we truly don’t know whether the response rate or long-term survival is different between the induction chemoradiation group and the induction chemotherapy group.

We are also offering a new chemotherapy regimen in the trial. The advantage of our trial is that it will be easier to sell to patients because they will all be treated surgically.

In addition, the surgery will be made safer by defining disease that is amenable to lobectomy, which allows for less resection. If a patient needs a pneumonectomy, we will allow it, but we’re trying to decrease the number of pneumonectomies.

DR LOVE: Can you talk about the chemotherapy regimen that’s used and why it was chosen?

DR PASS: The cisplatin/docetaxel induction regimen was the one used by Dr Betticher in the Swiss Trials, which showed promising response rates and intermediate five-year survival rates (Betticher 2006).

This combination was followed up at the IASLC meeting, and the outcomes held up and were similar to the Roth or Rosell numbers we had from before. The issue, therefore, became whether this new regimen could be combined with radiation therapy. We combined these regimens but reduced the doses to make them more compatible.

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