Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients.

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Last Modified: June 3, 2006

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Presenter: J.P. Pignon
Presenter's Affiliation: Institut Gustave-Roussy, Villejuif, France
Type of Session: Scientific

Background

  • Lung cancer is the number one cause of cancer death in America.
  • A meta-analysis published in 1995 demonstrated a small but significant survival benefit with adjuvant cisplatin based chemotherapy in patients who received surgery for their diagnosis of non-small cell lung cancer (NSCLC).
  • Since then, some randomized trials and literature based meta-analyses have confirmed this benefit, and others have not.
  • The main objective of this meta-analysis was to identify trial characteristics associated with a benefit of adjuvant cisplatin based chemotherapy in NSCLC
  • For this study, individual patient data was pooled from large, recent randomized trials.

Materials and Methods

  • Randomized trials with a sample size >300 patients that were reported after the previously mentioned NSCLC meta-analysis from 1995 were included.
  • Included trials either compared cisplatin based chemotherapy to observation or cisplatin based chemotherapy and radiation to radiation alone.
  • Patients had to have completely resected lung cancer.
  • Trials with concurrent chemoradiotherapy were excluded.
  • The primary endpoint was overall survival.
  • The authors were looking for a variation in chemotherapy’s effect based on age, gender, performance status, type of surgery, histology, stage, choice of drugs, planned radiation, and planned dose of cisplatin.
  • Five trials fit all of the inclusion criteria (ALPI, ANITA, BLT, IALT, JBR10).
  • Median follow-up is 5.1 years (3.1-5.9).

Results

  • The chemotherapy arms significantly outperformed the no chemotherapy arms (HR 0.89, 95%CI 0.82-0.96, p=0.004).
  • At 3 years, the chemotherapy patients had an absolute survival improvement of 3.9% (61% vs. 57.1%); at 5 years, the curves continued to separate and the chemotherapy patients had an absolute survival improvement of 5.3% (48.8% vs. 43.5%).
  • In a post-hoc analysis, the cisplatin/vinorelbine arms marginally outperformed the other drug combinations (HR 0.80, 95%CI 0.70-0.91); this became significant when the other combinations were pooled (p=0.04).
  • However, the protocol doses of cisplatin were higher in the cisplatin/vinorelbine trials than the other trials.
  • The benefit of chemotherapy varied by stage; chemotherapy appeared detrimental in stage IA patients (HR 1.41, 95%CI 0.96-2.09), had no effect in stage IB patients (HR 0.92, 95%CI 0.78-1.10), and improved survival in stage II (HR 0.83, 95%CI 0.73-0.95) and stage III patients (HR 0.83, 95%CI 0.73-0.95).
  • Chemotherapy also conferred a disease free survival benefit (HR 0.84, 95%CI 0.78-0.90, p<0.001).

Author's Conclusions

  • Cisplatin based adjuvant chemotherapy improves overall survival and disease free survival in patients with NSCLC.
  • Vinorelbine associated with 320 to 400 mg/m2 of cisplatin appears to be the most promising drug combination.
  • Despite the large numbers of patients, multivariate analyses were not able to study the respective roles of the associated drug and cumulative cisplatin doses.
  • Cisplatin based chemotherapy is certainly effective for stages II and III NSCLC.
  • There was no variation seen in chemotherapy effect with respect to any other factors studied.
Clinical/Scientific Implications

The authors presented a well performed meta-analysis of a large number of lung cancer patients. This research adds further weight to the concept that adjuvant cisplatin based chemotherapy improves overall survival in patients with resected NSCLC. This study showed the greatest benefit in patients with stage II or III disease, and failed to demonstrate a benefit in patients with stage IB disease. This is in keeping with other research that has been published and presented at ASCO. It is interesting that the combination of cisplatin/vinorelbine appeared to outperform the other cisplatin based doublets. However, the total dose of cisplatin is a confounding variable in this analysis. In order to prove that vinorelbine makes up the other half of the most active doublet for adjuvant treatment of NSCLC, more research will need to be performed. However, a valid conclusion of this study is that cisplatin/vinorelbine is an effective regimen.


News
Majority of randomized controlled oncology trials assess treatments available outside trials

Nov 2, 2010 - Most recent oncology randomized controlled trials evaluate drugs that are available "off-protocol therapy" in the United States, and this can adversely impact trial enrollment, according to a study published online Oct. 25 in the Journal of Clinical Oncology.



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