Phase III comparison of concurrent chemotherapy plus radiotherapy (CT/RT) and CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Initial results from intergroup trial 0139 (RTOG 93-09)
Reviewer: Ryan Smith, MD
Last Modified: June 1, 2003
Presenter: K.S. Albain Presenter's Affiliation: RTOG Type of Session: Scientific
Patients with Stage IIIA NSCLC have a poor prognosis, though chemoradiation (CRT) remains the standard of care for pathologic N2 disease.
Many have advocated surgical treatment in those who are resectable with a good performance status
Phase II studies (SWOG 8805 and SWOG 9019) have shown that surgical resection is feasible and shows good results
This study investigates the use of surgical resection in stage IIIA patients to determine if it improves outcome over CRT alone
Materials and Methods
429 patients were accrued over 7 years
Patients who were stage T1-3pN2M0 were eligible, if their FEV1 was >2L or expected postoperative FEV1 > 800cc
All patients were treated with cisplatin 50 mg/m2 day 1, 8 and etoposide 50 mg/m2 days 1-5 (PE chemotherapy) x2 with concurrent daily radiation to 45 Gy (1.8 Gy fractions)
Patients were randomized, prior to beginning treatment, to:
Arm 1: surgical resection followed by PE chemotherapy x 2 (after 2-4 week treatment break)
Arm 2: consolidative radiation therapy to 61 Gy with 2 more cycles of PE chemotherapy
Re-evaluation was performed prior to beginning the additional (randomized) therapy to insure no progression had occurred: On Arm 1, this re-evaluation occurred 2-4 weeks after induction therapy. On Arm 2, this evaluation was done 7 days before completion of induction therapy, so that no break in treatment would occur
Median follow-up was 69 months, with 392 patients availiable for analysis
88% of patients had a KPS of 90-100 and 78% had weight loss of less than 5%. Only 16% had T3 primary tumors
Induction chemotherapy and radiation was delivered as per protocol in 95% of patients
Consolidative chemotherapy was delivered in 58% of patients on the surgical arm and 79% in the non-surgical arm
Complete resection was obtained in 88% of patients randomized to surgery
There were 3 treatment-related deaths in the CRT arm compared to 14 in the surgery arm. Ten of these were post-operative, and the majority (12/14) in patients who required pneumonectomy
Those treated by surgical resection had a better outcome with progression free survival of 14 mo vs. 11.7 months and 3 year PFS of 29% vs. 19%
There was no difference in overall survival, with median survival times of 22.1 months and 21.7 months (p=.51). Three-year overall survival rates were 38% and 33%
There were crossing hazard ratios at 22 months. The overall survival was worse initially for the surgical arm, but by year 3, the absolute survival benefit for the surgical arm was 5%
There was no difference in patterns of failure
Predictive for a poor outcome was advancing T stage and weight loss (no difference based on pathologic response at surgery)
Both arms had treatment outcomes that yield 3 year survivals that were better than expected
There was mortality with the surgical arm-especially with pneumonectomy
PFS was better in the surgical arm, though there is no overall survival benefit as of yet. However, the PFS curves have acheived a plateau, so hopefully this will eventually confer a survival benefit
Stage IIIA NSCLC represents an aggressive disease in which the majority of the patients will fail within the first 5 (and even 2), years. Chemoradiation has been the standard of care, though many have been advocating surgical resection for quite some time, based on results from SWOG 8850 (which is a phase II trial that showed a 26% 3 year survival) and SWOG 9109. This study demonstrates that, in patients with excellent performance status and virtually no weight loss, the addition of surgical resection confers a PFS advantage, which may translate into an overall survival benefit soon. However, some words of caution should be mentioned. First, patients must qualify for resection, which in the advanced NSCLC population, is difficult. This is evidenced by an intergroup study requiring over 7 years to accrue just over 400 patients. In addition, there was no mention of how these patients were pathologically staged, or if clinical staging was relied upon. This is an important distinction, as it has been shown that clinical (radiologic) staging is somewhat inaccurate. It would also be interesting to compare patients treated with surgical resection to those who received higher doses chemoradiation-closer to 66 Gy, which is commonly used. Also, it was not mentioned how many patients did not qualify for the additional therapy (i.e. who progressed during induction CRT). This again speaks to the importance of careful selection of patients. Based on earlier studies, nodal response was predictive of outcome, so it may be possible that if only patients who had responses were analyzed, the results would be even more significant. Regardless, this is the first large, randomized study that shows a benefit with neoadjuvant chemotherapy and radiation therapy followed by surgical resection in patients with stage IIIA NSCLC. Though there is no overall survival benefit as of yet, with the plateau of the PFS curve, it may only be a matter of time. These results will be updated at ASTRO 2003. These updated data of this landmark study are highly anticipated.
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Nov 23, 2014 - In patients with stage IIIA(N2) non-small cell lung cancer, lung resection, preferably by lobectomy, should be considered in addition to chemotherapy and radiotherapy, according to a study published online July 27 in The Lancet.