Neoadjuvant Chemotherapy Followed by Preoperative Radiochemotherapy (hfRTCT) Plus Surgery or Surgery Plus Postoperative Radiotherapy in Stage III Non-Small Cell Lung Cancer: Results of a Randomized Phase III Trial of the German Lung Cancer Cooperative Group
Reviewer: S. Jack Wei, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 6, 2004
Presenter: C. Buche Presenter's Affiliation: German Lung Cancer Cooperative Group Type of Session: Plenary
The optimal treatment for patients with stage III non-small cell lung cancer (NSCLC) is controversial.
Ideally, patients with NSCLC should undergo surgical resection of their disease; however, the role of pre-operative radiation is unclear.
This study was designed to examine the effects of the addition of radiation therapy to preoperative chemotherapy on resectability, tumor control, survival, and toxicity
Materials and Methods
Eligible patients included histologically-confirmed stage IIIA or IIB NSCLC.
Patients with T3N0-1 disease and patients with T4 tumors due to esophageal or myocardial invasion and those with pleural effusions were excluded.
Patients were <70 years old with ECOG performance status of 0-1.
All patients received pre-operative chemotherapy consisting of cisplatin (55 mg/m2 d1-4) and etoposide (100 mg/m2 d1-4) x 3 cycles.
Eligible patients were then randomized to:
Arm A: Hyperfractionated radiochemotherapy (hfRTCT) consisting of radiation therapy (1.5 Gy bid to 45 Gy) and chemotherapy (carboplatin and vindesin d1,8,15) followed by surgical resection if possible. Patients who were unresectable following preoperative hfRTCT received an additional radiation boost of 24 Gy to the gross disease.
Arm B: Surgical resection if possible followed by radiation therapy. If a complete (R0) resection was performed, patients received 54 Gy (1.8Gy/d). If an incomplete resection was performed, patients received 68.4 Gy (1.8Gy/d).
Patients were stratified by treating institution and stage.
Primary endpoints was progression-free-survival (PFS)
Secondary endpoints included overall survival (OS), response, resectability, and treatment toxicity.
Between 10/95 and 7/03, 558 patients were registered.
6% of patients were ineligible.
Median follow-up was 52 months.
Treatment groups were well-balanced with regards to age (median = 59), Gender (83% male), performance status (ECOG 0 = 87%), histology (majority squamous cell carcinoma), and stage (Arm A stage IIIB 69%, Arm B stage IIIB 65%).
Response rate before surgery
p=NS for all
Operable Stage IIIB Resulting in Complete Resection
Grade III/IV Leukopenia
Grade III/IV Hematotoxicity
Grade III/IV Esophagitis
Grade III/IV Pneumonitis
Progression Free Survival
Patterns of Recurrence
Local + Distant
p=NS for all
On subgroup analysis, there continued to be no difference for OS or PFS between the two treatment arms for stage IIIA patients, stage IIIB patients, and patients receiving complete resections
Due to the experimental design, there was an increased time to surgery from first initiation of chemotherapy for patients receiving hfRTCT compared to those receiving post-operative radiation therapy, 166 days vs. 111 days.
The addition of hfRTCT before surgery has no benefit with regards to resectability, OS, and PFS.
hfRTCT results in increased esophagitis and hematotoxicity.
hfRTCT before surgery has no benefit over chemotherapy alone before surgery.
The current study examines the role of pre-operative radiation therapy in addition to chemotherapy before surgery in stage III NSCLC. Although the results of this study seem to argue that there is no benefit to pre-operative radiation in these patients compared to preoperative chemotherapy alone, this interpretation of the data should be viewed with some caution. Both treatment arms in this trial received radiation, making the central issue in this trial an issue of timing of radiation therapy, either before or after surgery, and not a question purely about the addition of preoperative radiation therapy. However, even the question of radiation timing is difficult to interpret from this study due to the significantly different manner in which the radiation was delivered preoperatively vs. postoperatively. Patients receiving preoperative radiation were treated with combined hyperfractionated chemoradiotherapy while those treated postoperatively were treated with radiation therapy delivered in standard fractions. It is not surprising that a higher rate of toxicity was seen in the preoperative radiation arm given then more intense nature of the treatment, particularly with regards to esophagitis.
It is important to note that the tumors in this study were quite large and locally advanced. Although patients with esophageal or myocardial invasion or with pleural effusions were excluded, patients with invasion of the carina, the great vessels, trachea, and pericardium were all included in this study. Even with the locally advanced nature of many of these patients, over half of all patients in this study (two-thirds were stage IIIB) were able to undergo surgical resection, and the addition of preoperative radiation therapy resulted in a complete resection rate of 84% for stage IIIB patients who were able to undergo resection.
Despite these findings, the true importance of surgical resection in these patients is still unclear. Recently reported data from RTOG 93-09 shows no significant difference in outcome for patients with stage IIIA NSCLC treated with either definitive chemoradiotherapy compared to preoperative chemoradiotherapy followed by surgical resection, While this study adds to growing body of literature regarding stage IIIB NSCLC patients, the optimal treatment for these patients is still very much in debate.
Mar 26, 2010 - Adding adjuvant chemotherapy to surgery alone or surgery plus radiotherapy improves survival modestly among patients with non-small-cell lung cancer, according to a pair of meta-analyses published online March 24 in The Lancet.