Induction chemotherapy followed by concominant chemoradiotherapy (CT/XRT) versus CT/XRT alone for regionally advanced unresectable non-small cell cancer: Initial analysis of a randomized phase III trial

Reviewer: S. Jack Wei, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 6 de junio del 2004

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Presenter: Everett V. Vokes
Presenter's Affiliation: Cancer and Leukemia Group B
Type of Session: Scientific

Background

  • Induction chemotherapy has been shown to improve survival in patients with stage IIIB non-small cell lung cancer (NSCLC) compared to radiation (RT) alone
  • Concurrent chemoradiotherapy (CT/XRT) has also been shown to be superior to sequential chemotherapy and RT
  • Despite these findings, the majority of patients with stage III NSCLC recur with distant metastatic disease
  • This trial was designed to examine effect of induction chemotherapy followed by concurrent CT/XRT compared to CT/XRT alone for unresectable NSCLC patients

Materials and Methods

  • 366 patients with inoperable stage IIIA and selected stage IIIB NSCLC were randomized between October 1998 and May 2002 to either immediate CT/XRT (Arm A) or induction chemotherapy followed by CT/XRT (Arm B)
  • Eligible patients had an ECOG performance status of 0-1; however, unlike other CALGB studies, inclusion criteria did not restrict patients with excessive weight loss
  • CT/XRT consisted of weekly carboplatin (AUC = 2) and paclitaxel (50 mg/m2) given concurrently with radiotherapy (66 Gy to the chest)
  • Induction chemotherapy consisted of 2 cycles of carboplatin (AUC = 6) and paclitaxel (200 mg/m2) given every 21 days followed by identical CT/XRT
  • The study was designed to accrue 360 patients with an 290 expected deaths in order to detect a 40% difference in median survival with 80% power.
  • Patients were stratified by measurable vs. evaluable disease

Results

  • 331 patients were evaluated (Arm A, n=161. Arm B, n=170)
  • Patient groups were well balanced with regards to gender, age, PS, measurable disease, and stage
  • A higher percentage of patients in the Arm A had >5% weight loss (32% vs. 21%)
  • Response rates were similar between the two groups (p=ns):
    • Complete Response: Arm A = 7%, Arm B = 12%
    • Partial Response: Arm A = 58%, Arm B = 48%
    • Overall Response: Arm A = 66%, Arm B = 61%
  • Median survival: 11.4 mo (Arm A) vs. 13.7 mo (Arm B) (p=0.154) with 254 of 290 expected deaths
  • Three-year overall survival (OS): 18% (Arm A) vs. 24% (Arm B)
  • Median failure-free survival: 7.0 mo (Arm A) vs. 7.8 mo (Arm B) (p=0.11)
  • On multivariate analysis, only performance status and weight loss affected survival
  • When patients with >5% weight loss were excluded from the study, there was still no difference in OS (15.9 mo (Arm A) vs. 14.3 mo (Arm B))
  • The patterns of failure were similar between both arms with the majority of patients failing distantly
  • Grade 3/4 toxicity was experienced by 61%/24% of patients in Arm A compared to 24%/41% in Arm B
  • There was no difference between the two groups with regards to grade 4 neutropenia, grade 3/4 fatigue, grade 3 esophagitis, and grade 4 dyspnea

Author's Conclusions

  • The median survival in both arms of this study is low compared to other published studies of concurrent CT/XRT for unresectable NSCLC.  The reason for this is unclear
  • Although induction chemotherapy appeared to improved median survival somewhat, this did not reach statistical significance
  • Increased toxicity was seen with the additional of induction chemotherapy
  • It is possible that induction chemotherapy results in toxicity that interferes with the delivery of definitive CT/XRT
  • CT/XRT without induction chemotherapy remains the standard treatment for unresectable NSCLC

Clinical/Scientific Implications

The role of induction chemotherapy in addition to concurrent CT/XRT has been an issue of wide controversy.  Results from previous studies have been mixed, and some studies such as the LAMP trial seemed to indicate that induction chemotherapy does not improve outcomes in these patients, and may even be detrimental.  The current study, while showing an absolute increase in median survival and three-year OS with the addition of induction chemotherapy, did not reach statistical significance on either measure.  Previous studies have shown a median survival of approximately 16 months with the use of concurrent CT/XRT.  It is somewhat concerning that the standard arm from this study has a lower-than-expected survival.  The reason for this is unclear, but this unexpectedly low survival may affect the ability to accurately compare the treatment arms in this study.  Given the lack of definitive benefit of induction chemotherapy in this study and the conflicting results of previous studies, induction chemotherapy should not be part of the standard treatment of unresectable NSCLC.   Future studies should address additional questions such as the role of consolidation chemotherapy following concurrent CT/XRT in this population of patients.

Oncolink's ASCO Coverage made possible by an unrestricted Educational Grant from Bristol-Myers Squibb Oncology.



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