Long-term results of the French randomized trial comparing neoadjuvant chemotherapy followed by surgery versus surgery alone in resectable non-small cell lung cancer

Reporter: J. Nicholas Lukens, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 5 de junio del 2010

Presenter: V. Westeel, MD, on behalf of the Intergroupe Francophone de Cancerologie Thoracique

Background

  • This is an update of a previously reported French Phase III randomized trial (DePierre, JCO 2002) comparing neo-adjuvant chemotherapy followed by surgery to surgery alone for patients with resectable non-small cell lung cancer (NSCLC).
  • There had been several studies demonstrating a benefit to pre-operative chemotherapy in patients with Stage IIIA NSCLC (Roth, Lung Cancer,1998; Rosell, N Engl J Med, 1994); however, this area of research remains complex and controversial.
  • Overall survival (OS) rates for patients with T2N0 and Stage II disease remain relatively poor (5 year OS of 50% and <50%, respectively); this study included a broader patient population, including those with Stage I (except T1N0), II, and IIIA disease
  • The study initially demonstrated:
    • A delayed benefit of pre-operative chemotherapy on OS (8.6% benefit at 4 years), and
    • An interaction with stage, with a positive effect of pre-operative chemotherapy on survival in Stage I and II patients, but not Stage IIIA.
  • The objective of this update was to evaluate the survival beyond 10 years of this cohort of patients treated with pre-operative chemotherapy, and to asses the durability of the survival benefit seen.

Methods

  • Inclusion criteria: resectable Stage I (except T1N0), II, or IIIA non-small-cell lung cancer (NSCLC), ECOG Performance Status of 0-2.
  • Patients randomized to pre-operative chemotherapy (PCT) consisting of 2 cycles of Mitomycin, Ifosfamide, and Cisplatin, followed by surgery, and an additional 2 cycles post-operatively for objective responders, versus surgery alone.
  • In both arms, patients with pT3 or pN2 disease, or incomplete surgery, received adjuvant thoracic radiotherapy (up to 60 Gy).
  • Primary endpoint: Overall Survival (OS), powered for a difference in OS of 15% at 2 years
  • Follow-up: CT Chest and fiberoptic bronchoscopy every 6 months for first 2 years, then annually until 7 years, then annual follow-up with procedures at the discretion of the investigator beyond 7 years.

Results

  • 355 patients were randomized as part of this study (179 in PCT arm versus 176 in surgery arm)
  • Median follow-up was 13.8 years
  • Comparing the 2 groups, there were more N2+ patients in the PCT arm compared to the surgery arm (42% versus 28%, respectively, p=0.065)
  • Compliance with follow-up CT Chest fell to 22% after 5 years
  • The 8% overall survival benefit with PCT at 5 years was maintained at 10 years, although this did not reach statistical significance (10 year OS 29.4% for PCT versus 20.8% for surgery, P=0.12)
    • Multivariate analysis showed that age, T and N stage were significantly correlated with overall survival; therefore,
    • Adjusting for age, T and N stage in multivariate analysis, neo-adjuvant chemotherapy led to a significant improvement in OS (HR 0.69, P=0.0055)
    • OS was significantly improved with PCT in patients who underwent lobectomy (p = 0.04), but not in those who underwent pneumonectomy.
  • The 10-year recurrence-free survival rate was 38.2% in the S arm, versus 54.6% in the PCT arm (p = 0.001).
  • Interestingly, there was a lower rate of bone metastases in the patients treated with neo-adjuvant chemotherapy compared to surgery alone (5% vs. 13%, p=0.004), but there was no difference in the rate of brain metastases.
  • At exploratory subgroup analyses:
    • The 10-year OS rate for patients with Stage I and II disease was 23.1% in the surgery arm, vs. 37.6% in the PCT arm (p = 0.04).
    • The survival difference between the two arms for patients with stage IIIA disease was not significant.
  • The rate of non-cancer deaths was identical in the two arms.
  • The mortality rate from second malignant neoplasms was also similar (6.9% in the S arm and 5% in the PCT arm).

Author’s Conclusions

  • Neoadjuvant chemotherapy did not significantly increase long-term survival by univariate analysis.
  • However, an 8% survival benefit in favor of neo-adjuvant chemotherapy remained stable beyond 10 years, and the multivariate analysis suggested a long-term benefit of neoadjuvant chemotherapy.

Clinical Implications

  • This study has several limitations which limit its applicability in current clinical practice:
    • The treatment arms were not balanced, with more patients in the pre-operative chemotherapy arm having N2+ disease
    • The chemotherapy regimen used in the trial is not standard in the United States, and is a combination of neo-adjuvant and adjuvant chemotherapy; furthermore, it is unclear how many patients in the PCT arm received all 4 planned cycles of chemotherapy.
  • Nevertheless, the trial is suggestive of a benefit to neo-adjuvant chemotherapy in early stage NSCLC, especially when considered in light of another recently published Phase III study:
    • Pisters et al., (JCO 2010, SWOG 9900): Phase III trial of induction Carbo/Taxol in early stage NSCLC: This trial demonstrated a trend towards improved overall survival with use of neoadjuvant chemotherapy, but the trial was closed early after a benefit to adjuvant chemotherapy was reported in other studies.
    • When taken together, these studies suggest that there may be an overall survival benefit to pre-operative chemotherapy in early stage (Stage IB to IIIA) NSCLC that did not reach significance due to lack of power.
  • The finding on subgroup analysis of a survival benefit in T2N0 and Stage II patients, but not in Stage IIIA patients, is difficult to reconcile with other (smaller) Phase III data demonstrating a survival advantage in Stage IIIA patients;
    • This calls into question the dictum that pre-operative chemotherapy should be reserved for Stage IIIA patients
    • Additional studies would be needed to clarify the role of neo-adjuvant chemotherapy in Stage IIIA disease
  • Numerous studies have demonstrated an overall survival benefit with adjuvant chemotherapy, especially in node-positive disease (Pignon, JCO, 2008; Butts, JCO, 2010 – JBR-10)
    • Therefore, it remains to be determined whether pre-operative or adjuvant chemotherapy represents the optimal approach in this subset of patients, and further research is warranted.
  • In summary, this is an intriguing study that is a valuable contribution to the literature. It raises many questions that do not have ready answers, and which will hopefully be addressed in future trials.

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