Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: IFCT-0501 randomized phase III study in advanced non-small cell lung cancer (NSCLC)

Reporter: Samuel Swisher-McClure
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2010

Presenter: E. A. Quoix, on behalf of IFCT; Hôpitaux Universitaires, Strasbourg, France


  • Lung cancer is the most common cause of cancer mortality in the US, accounting for 30% of cancer-related deaths in men and 26% of cancer-related deaths in women.
  • Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases diagnosed, and, unfortunately, the majority of patients have advanced disease at the time of presentation.
  • The incidence of lung cancer in the elderly is increasing over time and a recent analysis of available SEER data reported that 47% of all lung cancers are diagnosed in patients over age 70 (Owonikoko et al. JCO, 2007).
  • Aging is associated with changes in organ function that may alter pharmacokinetics, as well as decreased bone marrow reserve that can limit tolerance of anti-neoplastic therapy.
  • The majority of previously published chemotherapy trials enrolled younger patients limiting the applicability of those findings to the elderly population.
  • There have been few trials specifically addressing treatment of elderly patients
    • An Italian Phase III trial conducted in 191 elderly patients (Age ? 70 years) with Stage IIIB or IV NSCLC showed that single agent vinorelbine significantly improved quality of life and overall survival compared to supportive care alone with a median overall survival of 27 vs. 21 weeks (Elderly Lung Cancer Vinorelbine Italian Study Group (ELVIS). JNCI, 1999).
    • Phase II data also supports the use of Gemcitabine monotherapy among elderly patients with advanced NSCLC. The Multicenter Italian Lung Cancer in the Elderly Study (MILES) enrolled 233 patients and reported response rates of 16% and a median survival of 28 weeks with single agent Gemcitabine.
    • A Japanese Phase III trial randomized 91 patients with advanced NSCLC age ? 70 years to either docetaxel or vinorelbine monotherapy (Kudoh et al. JCO, 2006). That study reported significant improvements in response rate and progression free survival in the docetaxel arm (RR= 22.7% v 9.9%; P = .019 and 5.5 months v 3.1 months; P < .001). However there was no statistically significant difference in overall survival between the two groups (14.3 months v 9.9 months; hazard ratio, 0.780; 95% CI, 0.561 to 1.085; P = .138).
    • Platinum based chemotherapy regimens are the current standard approach for younger patients with advanced NSCLC. Retrospective subset analyses have been performed to examine the outcomes of elderly patients who received platinum based chemotherapy as part of previously conducted large randomized trials (Shepherd et al. NEJM, 2005). The reported results demonstrated no significant differences in overall survival for those patients ? 65 years vs. < 65 years when controlling for other factors.
  • Based upon these results, the authors performed a randomized study in elderly patients with advanced NSCLC comparing monotherapy with gemcitabine or vinorelbine to combination therapy with carboplatin and paclitaxel.


  • This trial was a prospective multi-institutional Phase III randomized controlled trial
  • Inclusion Criteria:
    • Patients aged 70 to 89 years
    • PS 0-2
    • Diagnosis of advanced NSCLC, defined as either Stage III disease not amenable to radiation or Stage IV disease.
    • No prior therapy for NSCLC other than surgery or palliative radiotherapy
    • Estimated life expectancy at least 12 weeks
    • Adequate hematologic, renal, and hepatic function.
  • Exclusion Criteria:
    • Symptomatic brain metastases
    • Prior mediastinal radiation
    • History of prior malignancy within the last 5 years
    • Serious active infection
    • Underlying motor or sensory neuropathy
  • Patients enrolled in the study were randomized to one of two chemotherapy regimen:
    • Arm A: Monotherapy with gemcitabine (1,150 mg/m2) or vinorelbine (30 mg/m2,) administered on days 1 and 8 in 3 week cycles for planned total of 5 cycles
    • Arm B: Combination therapy with carboplatin AUC 6 every 4 weeks + paclitaxel 90 mg/m2administered on days 1,8, and 15 with a planned total of 4 cycles
  • In the event of significant toxicity or progressive disease, patients were started on second line therapy with erlotinib (150 mg/d).
  • Patients were stratified by age (? 80 vs. > 80), PS (0-1 vs. 2), and disease stage (III vs. IV).
  • Response assessments were performed on weeks 6, 12, and 18 in both arms and then every 3 months until progression.
  • The primary endpoint was overall survival (OS)
    • Target enrollment of 522 patients which would provide 80% power to detect a 10% improvement in 1 year survival with a two sided type-I error of < 0.05
    • There were 3 planned interim analyses to be conducted
    • Measurements of overall survival were done by intention-to-treat analysis
    • Secondary endpoints included:
    • Progression free survival (PFS)
    • Response Rate (RR)
    • Grade 3/4 Toxicities (NCIC-CTCAE)


  • 451 pts were enrolled between 04/2006 to 12/2009 (16 patients were ineligible).
    • The 2 arms were well-balanced for patient characteristics.
    • 73.8% of patients were male
    • Median age was 77.2 years (range 70-89).
    • PS was 0-1 in 73.6% of patients.
    • 79.6% of patients had Stage IV disease, and 20.4% of patients had Stage III disease
    • Histology: 30% Squamous Cell Carcinoma, 50% Adenocarcinoma, 15 % other
    • Approximately 20% of patients were non-smokers
    • There were no significant differences between the two groups in baseline Mini-Mental Status Examination (MMSE), Charlson Comorbidity Index Score, or ability to complete activities of daily living (ADL).
  • At time of the second planned interim analysis (after ~2/3rd of the expected deaths), 451 pts had been randomized, out of the 522 initially planned. The results at that time favored arm B with observed improvement in overall survival and a calculated p-value < 0.001. These results met the pre-determined stopping criteria for the trial.
  • Median follow-up was 21.3 months
  • 62.9% of patients in arm B and 53.1% of patients in arm A completed therapy as planned
  • Response rate was significantly better in Arm B vs. Arm A (29.1% vs. 10.9%, p < 0.00001)
  • There was an significant improvement in OS and PFS in arm B vs. arm A
    • Median OS: 10.3 months vs. 6.2 months, 1 year survival 45.1% vs. 26.9% (p = 0.00004)
    • A multivariate analysis of survival was performed, yielding a Hazard ratio of 0.60 (95%CI 0.46-0.78, p = 0.0001) favoring arm B.
    • Median PFS was 6.1 months (95% CI 5.5- 6.9) vs. 3.0 months (95%CI 2.6-3.9)
  • Grade 3-4 Hematological toxicities were significantly more frequent in arm B (17.9% vs. 54.1%, p < 0.00001).
  • Death attributed to treatment related toxicities was more common in arm B (6.6% vs. 1.8%, p = 0.035)

Authors’ Conclusions

  • Initial therapy with combination carboplatin/paclitaxel confers a significantly longer survival in elderly patients with advanced NSCLC compared to the current standard single agent therapy.
  • Toxicity rates are acceptable.
  • The authors reported this regimen as the new treatment paradigm for patients with advanced NSCLC aged ? 70 years.

Clinical Implications

  • Approximately half of all patients diagnosed with advanced NSCLC are over the age of 70. However, relatively few clinical trials have specifically addressed the optimal care for this unique group of patients.
  • Previously recommended therapy for these patients consisted of monotherapy with vinorelbine, gemcitabine, or docetaxel.
  • The current study was a well-conducted phase III randomized trial demonstrating significant improvements in overall survival and progression free survival associated with combination Carboplatin/Paclitaxel chemotherapy as compared to monotherapy.
  • The results of the study are likely to change the standard initial therapy for this group of patients.
  • The authors did observe significantly increased rates of Grade 3-4 Hematologic toxicities in patients receiving Carboplatin/Paclitaxel. These included neutropenia, neutropenic fever, and thrombocytopenia.
  • There were also more treatment related deaths in the combination therapy arm. However, the observed rate of 6.6% in arm B remains acceptable.
  • These results should be interpreted carefully when considering treatment options for patients over age 70. The current study was limited to patients with PS of 0-2 and many patients ? 70 years of age may not meet those criteria.
  • Future trials may further examine the use of targeted therapies for these patients in order to minimize the risk of potential toxicities.


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