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: Roberto Santiago, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 20, 2003
Presenter: Andrew Turrisi, M.D. Presenter's Affiliation: RTOG Type of Session: Plenary
Patients with stage IIIa NSCLC have a poor prognosis.
Although definitive chemoradiotherapy (especially when delivered concurrently) remains standard for most patients with pathologic N2 disease, small phase III trials support the use of chemotherapy followed by surgery in selected patients. In addition, phase II studies have suggested that induction chemoradiotherapy followed by surgical resection is feasible in a significant proportion of patients with IIIa disease and yields encouraging results.
This study investigates the use of surgical resection in stage IIIA patients to determine if it improves outcome over CRT alone. Study endpoints are: progression free, median and overall survival, as well as pattern of failure.
Materials and Methods
429 medically fit patients were accrued over 92 mo.
All patients had proven NSCLC, stage T1-3pN2M0.
Pretreatment FEV1 was >2L and the expected postoperative FEV1 was > 800cc.
Prior to any treatment, patients were randomized to:
Induction chemoradiotherapy followed by surgical resection followed by two cycles of PE chemotherapy (after 2-4 week treatment break) or
Induction chemoradiotherapy followed by consolidative chemoradiotherapy to 61 Gy followed by two 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.
All patients were treated with induction chemoradiotherapy consisting of daily radiation to 45 Gy (1.8 Gy fractions) with two cycles of concurrent cisplatin (50 mg/m2 day 1, 8) and etoposide (50 mg/m2 days 1-5)
RT target volume mandated initial sites of disease and subcarinal nodes in all fields.
The arms were well balanced.
Median follow-up of the 392 eligible patients (201 in the surgical arm; 191 in the nonsurgical arm) was 69 months.
88% of patients had a KPS of 90-100 and 78% had weight loss of less than 5%.
32% had squamous carcinoma and only 16% had T3 primary tumors.
Induction chemotherapy and radiation was delivered as per protocol in 95% of patients.
However, consolidative chemotherapy was delivered as planned in 58% of patients in the surgical arm vs. 79% in the non-surgical arm (p = 0.037).
RT was delivered as planned in 97% of the surgical arm and 81% of the non-surgical arm, p = 0.002.
Complete resection was obtained in 88% of patients randomized to surgery.
Local Failure was significantly better in the surgical arm: 4% vs. 13%
Progression Free Survival was also significantly better in the surgical arm: 15% vs. 28% at 3 years and a median PFS of 14.0 mo vs. 11.7 mo
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%
However, more patients died of cancer in the non-surgical arm (71% vs. 81%) and more patients died of treatment related causes in the surgical arm (11% vs. 2%)
The overall survival was worse initially for the surgical arm, but by year 3, a 5% absolute survival benefit was noted for the surgical arm; the hazard ratios crossed at 22 months.
Patients achieving a path complete response (54 pts) had a 3yr-OS of 53% and median survival significantly longer than those who did not: 36.7 mo vs. 22.1 mo.
Esophagitis occurred in 39%.
There were 3 treatment-related deaths in the CRT arm (all during consolidative chemotherapy) compared to 14 in the surgery arm (10 during consolidative chemotherapy and 12/14 in patients who required pneumonectomy).
Brain Mets were relatively common: 16% in the surgical arm and 21% in the non-surgical arm.
Advancing T stage and weight loss were predictive for a poor outcome.
Surgery reduces progression and improves local control but is associated with more treatment death.
Despite more chemotherapy, the [no S] group had more cancer death.
Despite significantly improved PFS, surgery does not improve overall median survival, p = 0.51 perhaps because of a strong trend to treatment related death.
Patients with pathological CR at time of surgery survive better.
Longer follow-up may demonstrate benefit.
Both treatment arms performed well (actually, better than expected) producing a 3-year overall survival over 30% in each arm despite the older PE chemotherapy.
There was poorer protocol compliance to RT fields in the non-surgical arm; this was related to geographical misses during the oblique off-cord irradiation.
This study demonstrates that, in patients with potentially resectable stage IIIa NSCLC and an excellent performance/minimal weight loss, induction chemoradiotherapy followed by surgical resection confers a PFS advantage, when compared to definitive chemoradiotherapy. However, the phrase "potentially resectable" and the fact that these were very fit patients cannot be overemphasized. Only 16% of tumors were T3. In short, these are not the representative of the typical locally-advanced NSCLC patient. It is interesting that improved local control can lead to improved caused-specific survival. However, the potential benefit for improved overall survival is negated by the increase treatment related mortality. We are hopeful that new RT techniques as well as less toxic systemic therapies will improve the therapeutic ratio an yield better survival. There was no mention of how these patients were staged. This is another important issue, as it has been shown that clinical (radiologic) staging is somewhat inaccurate. It would also be interesting to compare results in patients treated with surgical resection to those in patients treated with chemoradiotherapy using higher doses of radiation. 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.
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