RTOG/Intergroup Phase III Study: No Overall Survival Advantage for Chemo-Radiation Followed by Surgery Over Chemo-Radiation Alone for Patients with Stage IIIA (N2) Non-Small-Cell Lung Cancer
Philadelphia, PA - July 27, 2009 - Performing surgery following concurrent chemotherapy and radiotherapy for patients with stage IIIA (N2) non-small-cell lung cancer does not lead to better overall survival rates than chemotherapy and radiotherapy alone, according to a landmark Radiation Therapy Oncology Group (RTOG) study published online today and in an upcoming edition of The Lancet.
Surgery following radiotherapy and chemotherapy did not improve overall survival; however it did produce better progression free survival rates than chemotherapy and radiation alone. Radiotherapy plus chemotherapy, with or without surgery, may both be viable treatment options for patients with stage IIIA (N2) non-small-cell lung cancer. The patients who did appear to have a benefit from added surgery were those in which a selection of the lung (lobe) was removed, rather than the entire lung.
"This is a one-of-a-kind study in a common form of lung cancer, where the difference in the two groups of patients being compared was the use of surgery. Survival for each group was better than past experience, so patients deserve to learn about both options. And, from our study we know that for selected patients, using all 3 treatment modalities available - chemotherapy, radiation, and surgery - may yield a superior outcome in delay relapse and improved survival," said RTOG 9309 Principal Investigator Kathy Albain, MD, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center.
In this randomized controlled trial, the authors compared concurrent chemotherapy and radiotherapy followed by surgery with standard concurrent chemotherapy and radiotherapy without surgery, the current standard for this group of patients.
Those patients with stage IIIA (N2) non-small-cell lung cancer were randomly assigned to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/mē on days 1, 8, 29, and 36] and etoposide [50 mg/mē on days 1-5 and 29-33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals.
If no progression, patients in group 1 underwent surgery and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS).
202 patients (median age 59 years, range 31-77) were assigned to group 1 and 194 (61 years, 32-78) to group 2. Median OS was 23.6 months in group 1 versus 22.2 months in group 2 (a non-statistically significant difference).The 5 year survival rate was 27% for group 1 and 20% for group 2.
Progression free survival (PFS) was significantly better in group 1 than in group 2, median 12.8 months versus 10.5 months; the PFS rate at 5 years for group 1 was 22% and for group 2 was 11%.
Lower white blood cell counts (neutropenia) and esophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus 4 (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy.
The authors suggest the reason for an absence of effect of surgery could be inadequate power in the trial or reduced delivery of later chemotherapy (cycles 3 and 4) in the surgery group. However they say the mostly likely reason could be increased mortality following pneumonectomy, mainly due to acute respiratory distress syndrome and other respiratory causes.
The authors conclude: "Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA (N2) non-small-cell lung cancer... medically healthy patients with stage IIIA (N2) non-small-cell lung cancer should be assessed by a team skilled in multimodality treatment, and treatment options can be considered during assessment. On the basis of the findings of our study, patients should be counseled about the risks and potential benefits of definitive chemotherapy plus radiotherapy with and without a surgical resection (preferably by lobectomy)."
"This trial is a major step forward in understanding how to integrate complex multi-disciplinary management of patients with this very challenging stage of lung cancer. All the co-authors, investigators, and participating patients and families should be strongly commended for this landmark trial," said Walter J. Curran, Jr., MD, the RTOG Group Chair, and the Lawrence W. Davis Professor and chairman of the Department of Radiation Oncology in the Emory School of Medicine and chief medical officer of the Emory Winship Cancer Institute.
Non-small-cell lung cancer makes up some 80% of lung cancers, and its most common cause is long-term exposure to tobacco smoke. Of all cases of non-small-cell lung cancer, the disease is locally advanced in the chest only in about 30% (stage IIIA), where front-line surgery cannot cure the disease because it has already spread to lymph nodes in the centre of the chest (N2).
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