Lung Cancer Update 2006 (4)

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 2003 appeared to suggest that surgery after induction chemoradiation therapy was not any better than definitive chemoradiation therapy, although it was associated with a trend toward improved progression-free survival.

If you evaluate the data carefully, however, you notice a high mortality rate for patients who underwent pneumonectomy. The overall operative mortality rate was seven percent, but the operative mortality rate in patients requiring pneumonectomy was 14 percent.

A subsequent unplanned analysis of the trial was presented by Dr Albain at a follow-up ASCO 2005 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-only group favoring combined chemoradiation therapy with surgery.

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Lung Cancer Update 2007 (4)

DR HANNA: In 2003, SWOG published results from the SWOG-S9504 Phase II trial. The study included 83 patients with Stage IIIB disease who were treated with cisplatin/etoposide for two cycles concurrently with 61 Gray of radiation, followed by three cycles of consolidation docetaxel.

The median survival time was 26 months. This patient population should have had a median survival time of about 13 months with Stage IIIB and chemoradiation treatment only. Instead, they had a five-year survival of 29 percent. Historically, that group should have had a five-year survival of five, seven, eight percent.

This engendered a lot of enthusiasm and became a de facto standard for many physicians, based upon a single, relatively small Phase II trial. We sought to confirm that this strategy was effective. We did a randomized Phase III study that included patients with both Stage IIIA and Stage IIIB disease.

A total of 243 patients entered our trial. All patients received cisplatin/etoposide and concurrent radiation with 59.4 Gray. Then, after a rest period of four to eight weeks — and as long as they had not progressed and remained eligible — patients were randomly assigned to either three cycles of docetaxel consolidation or observation.

We reported several provocative findings. No difference in progression-free survival between the two randomized arms was seen, and there was no difference in median survival, three-year survival or overall survival. The p-value was 0.9. The curves were completely superimposable.

Lung Cancer Update 2007 (3)

DR WAKELEE: The Hoosier Oncology Group (HOG) trial, which evaluated chemotherapy with cisplatin/etoposide and concurrent radiation therapy with or without consolidation chemotherapy for unresectable Stage IIIA and IIIB disease, was the most practice-changing presentation in lung cancer at ASCO. 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.

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 beyond the standard chemoradiation intervention. 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 are 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.

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