Two Studies Extend Value of Adjuvant Chemotherapy to Early Lung Cancer

NEW ORLEANS–Chemotherapy following surgery improves survival for early-stage non-small-cell lung cancer, according to two studies presented here at the ASCO Annual Meeting. The studies provide convincing evidence that the current standard of care—surgery, followed by observation—should be changed, investigators and independent observers said.Figure: Gary M. Strauss, MD, MPH: “I hope that these trials demonstrate that treatment is better than no treatment.” Future trials, he said, should be head-to-head comparisons of various regimens, because the principle of adjuvant therapy is now established.One of the studies was coordinated by Cancer and Leukemia Group B (CALGB); the other by the National Cancer Institute of Canada (NCIC) Clinical Trials Group. Using different platinum-based chemotherapy regimens, both showed a significant survival benefit—15% after five years for the Canadian study and 12% after four years for the US trial. “These studies will lead to a change in practice,” said Bruce Johnson, MD, Director of the Lowe Center for Thoracic Oncology at Boston's Dana-Farber Cancer Institute, who moderated an ASCO news briefing at which the studies were discussed. “Adding these agents…appears to prolong survival.” The leader of the American study, Gary M. Strauss, MD, MPH, of Brown Medical School in Providence, RI, said, “I hope that these trials demonstrate that treatment is better than no treatment.” The Canadian lead investigator, Timothy L. Winton, MD, of the NCIC in Kingston, Ontario, said, “I think the results should and will change the standard of care.” “It's the best news for lung cancer patients in a long time,” he said in an interview. Reluctance about Chemotherapy in Earlier Stages Although adjuvant chemotherapy is the standard of care in more advanced disease, surgeons, medical oncologists, and patients have been reluctant to accept it in earlier stages, because of the perceived risk of toxicity balanced against a small and possibly non-existent benefit. As a “simple surgeon,” Dr. Winton said, it will now be easier to persuade his fellow surgeons they should follow resection with adjuvant chemotherapy.Figure: Timothy L. Winton, MD, said that as a “simple surgeon,” he will now find it easier to persuade his fellow surgeons they should follow resection with adjuvant chemotherapy. It will also be easier to persuade patients—“Patients often march into my office and expect me to cut out their cancer and leave it behind forever.”It will also be easier to persuade patients, he said. “Patients often march into my office and expect me to cut out their cancer and leave it behind forever.” But the fact is that a large proportion of patients relapse, because resection often leaves behind tumor cells that no current technique can find and remove. “Surgery alone—which has been the traditional treatment—is well recognized as not being the be-all and end-all,” he said. In the future, Dr. Winton said, “A physician will be remiss if he doesn't speak to this and offer it to the patient.” ‘Paradigm-Shifting’ “I think these two trials are really what we call paradigm-shifting studies,” said Frances Shepherd, MD, the Scott Taylor Chair in Lung Cancer Research at Princess Margaret Hospital in Toronto. Dr. Shepherd, who was involved in the Canadian study, presented data earlier that showed significant benefits of targeted therapy in late-stage, relapsed lung cancer patients. “The magnitudes of difference—12% and 15%—are enormous,” Dr. Shepherd said. She added that earlier non-randomized studies—which usually suggested a 4% or 5% benefit—“were not enough in patients' minds, in surgeons' minds and in many medical oncologists' minds, to justify the risk. “A 15% improvement in the cure rate is totally different.” US Study: 344 Patients In the US study, 344 patients with Stage IB disease, who had undergone complete resection, were randomized to chemotherapy with paclitaxel and carboplatin or to no further treatment. The study was closed early by the independent data safety monitoring board, Dr. Strauss said, because the results were so strikingly in favor of the chemotherapy. The treatment reduced deaths from lung cancer by 49%, and overall mortality by 38%, Dr. Strauss said. As well, four-year survival in the treatment arm was 71% compared with 59%—a 12% absolute benefit. Earlier adjuvant chemotherapy studies in early-stage lung cancer had been inconclusive, he said, but this study shows “an unequivocal effect.” Future trials, he said, should be head-to-head comparisons of various regimens, because the principle of adjuvant therapy is now established. Canadian Study: 482 Patients The Canadian study examined a different platinum-based regimen in a slightly different population: 482 patients with Stage I or II disease were randomized to either no treatment after surgery or to cisplatin and vinorelbine. Overall survival was significantly prolonged: 94 months on average for those on treatment, compared with 73 months. As well, the average time to relapse has not yet been reached in the treatment arm, compared with 46.7 months for those not getting treatment. After five years, Dr. Winton said, 69% of treated patients were alive, compared with 54% of those who were just followed—a 15% survival benefit. Toxicity Limited Toxicity in both studies was limited, the investigators said. In the US study, slightly more than half the patients suffered either Grade III or IV neutropenia, but there were no therapy-related deaths. The Canadian study saw “common” Grade IV neutropenia, with febrile neutropenia in 7% of those in the study. Two deaths were attributed to the study drugs, one from febrile neutropenia and the other from pulmonary fibrosis.

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