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Comparison of Four Chemotherapy Regimens for Advanced Non–Small-Cell Lung Cancer

Comparison of Four Chemotherapy Regimens for Advanced Non–Small-Cell Lung Cancer,10.1056/NEJMoa011954,New England Journal of Medicine,Joan H. Schiller

Comparison of Four Chemotherapy Regimens for Advanced Non–Small-Cell Lung Cancer   (Citations: 1202)
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Journal: New England Journal of Medicine - N ENGL J MED , vol. 346, no. 2, pp. 92-98, 2002
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    • ... Platinum-based doublet chemotherapy is the current standard of care for patients with preserved functional status. Patients treated with platinum-based regimens have a mean survival of 8–10 months. Despite advances in the treatment of advanced NSCLC, the advent of third-generation cytotoxic agents including gemcitabine and docetaxel has reached a therapeutic plateau ...

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    • ...2 whereas patients in advanced stages rarely survive more than 5 years despite aggressive chemotherapy, molecular-targeted therapy or chemoradiotherapy...

    Yasumitsu Moriyaet al. Tumor suppressive microRNA133a regulates novel molecular networks in l...

    • ...The clinical management of advanced non-small-cell lung cancer (NSCLC) remains challenging. Initial therapies for advanced NSCLC with platinum-based regimens have shown consistent overall response rates of 30–40% with progression-free intervals of 4–5 months and 1-year survival rates of 35–40% [,...

    Fu-Tsai Chunget al. Low-Dose Weekly Docetaxel Is as Tolerable as Pemetrexed in Previously ...

    • ...Approximately onethird of patients obtain an objective response with the firstline chemotherapy, and another 20–30% achieve temporary disease stabilization [4, 5]. After failure of the first-line chemotherapy, many patients still have a good performance status and remain to be candidates to receive further chemotherapy...

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    • ...The main characteristics of the two trials and the overall Nicolucci score are detailed in table 2.2Table 2. Characteristics of the selected trialsT02
      Efficacy and Safety AnalysesThere were 1,576 patients (768 treated with bevacizumab-containing regimens, and 808 treated with chemotherapy alone) included in the primary analysis, and 1,921 patients (1,113 treated with a bevacizumab-containing regimen and 808 treated with chemotherapy alone) were included in the secondary analysis (table 2). A large heterogeneity was documented in both analyses for 6-month progression-free interval (I2 = 88.164%, p = 0.004) and overall survival (I2 = 73.541, p = 0.052). The reasons of this heterogeneity were of either methodological or/and clinical nature, and can be summarized as follows:• The primary end point of the E4599 trial was overall survival and the primary end point of the AVAiL trial was progression-free survival.• The E4599 trial was a 2-arm trial and the AVAiL trial was a 3-arm trial.• Two different schedules of treatment were used as comparators in the 2 trials: carboplatin-paclitaxel in the E4599 trial, and cisplatin-gemcitabine in the AVAiL trial.• In the AVAiL trial, the number of patients over 65 years and the number of males were significantly lower than in the E4599 trial (31 vs. 43%, p < 0.0001; and 31 vs. 54%, p < 0.0001, respectively).• In the secondary analysis patients treated with either bevacizumab 7.5 mg/kg or bevacizumab 15 mg/kg were included in the same experimental arm.In the primary analysis, the odds ratio for 1-year survival rate was 0.874 (95% CI = 0.588–1.299%, p = 0.507), with an absolute risk reduction of death of 3.3% (95% CI = –6.5 to 13.2%) and a NNT = 30 in favor of the patients treated with a bevacizumab 15 mg/kg-containing regimen (fig. 1a). Likewise, the odds ratio for 6-month progression-free interval was 0.534 (95% CI = 0.294–0.971%, p = 0.04) with an absolute risk reduction of progression of 15.2% (95% CI = 0.07–29.6%) and a NNT = 7 in favor of the patients treated with a bevacizumab 15 mg/kg-containing regimen (fig. 2a).
      1Fig. 1. Absolute 1-year risk reduction of death. a Patients treated with bevacizumab 15 mg/kg. b Patients treated with bevacizumab 15 mg/kg and 7.5 mg/kg. B-CHT = Bevacizumab plus chemotherapy; CHT = chemotherapy.F01
      2Fig. 2. Absolute risk reduction of 6-month progression. a Patients treated with bevacizumab 15 mg/kg. b Patients treated with bevacizumab 15 mg/kg and 7.5 mg/kg. B-CHT = Bevacizumab plus chemotherapy; CHT = chemotherapy.F02
      The absolute risk of treatment-related death was 2.4% (95% CI = 0.8–3.9%, p = 0.003), with a NNH = 41 against the bevacizumab 15 mg/kg-containing regimens. The absolute risk of bleeding was 3.3% (95% CI = 1.6–4.9%, p < 0.001), with a NNH = 30 against the bevacizumab 15 mg/kg-containing regimen. The absolute risk of hemoptysis was 2.4% (95% CI = –0.1 to 5%, p = 0.058), with a NNH = 42 against the bevacizumab 15 mg/kg-containing regimen. The absolute risk of hypertension was 6.6% (95% CI = 4.6–8.6%, p < 0.001), with an NNH = 15 against the bevacizumab 15 mg/kg-containing regimen. The absolute risk of proteinuria was 2.1% (95% CI = 0.3–3.8%, p = 0.024), with a NNH = 47 against the bevacizumab 15 mg/kg-containing regimen. The absolute risk of neutropenia was 7.3% (95% CI = 3.2–11.4%, p < 0.001), with a NNH = 13 against the bevacizumab 15 mg/kg-containing regimen. The absolute risk of febrile neutropenia was 1% (95% CI = –0.8 to 2.7%, p = 0.281), with a NNH = 100 against the bevacizumab 15 mg/kg-containing regimen. The absolute risk of thrombocytopenia was 1.5% (95% CI = 0.2–2.7%, p = 0.021), with a NNH = 66 against the bevacizumab 15 mg/kg-containing regimen. The absolute risk of anemia was 1% (95% CI = 0.1–2%, p = 0.045), with a NNH = 100 in favor of bevacizumab 15 mg/kg-containing regimen. The absolute risk of grade III–IV side effects is detailed in figure 3a. The main outcomes and side effects expressed as NNT, NNH and NNH/NNT ratio are detailed in table 3a.3Table 3. Efficacy, safety and risk/benefit ratio of the bevacizumab-chemotherapy combination in the pooled analysisT03
      3Fig. 3. Absolute risk of grade III–IV side effects. a Patients treated with bevacizumab 15 mg/kg. b Patients treated with bevacizumab 7.5 mg/kg and 15 mg/kg. B-CHT = Bevacizumab plus chemotherapy; CHT = chemotherapy.F03
      In the secondary analysis, the odds ratio for 1-year survival rate was 0.852 (95% CI = 0.612–1.184%, p = 0.339), with an absolute risk reduction of death of 4% (95% CI = –4.2 to 12.2%) and a NNT = 25 in favor of the patients treated with bevacizumab (7.5 + 15 mg/kg)-containing regimens (fig. 1b). Likewise, the odds ratio for 6-month progression-free interval was 0.516 (95% CI = 0.307–0.868%, p = 0.013) with an absolute risk reduction of progression of 16% (95% CI = 3.4–28.6%) and a NNT = 6 in favor of the patients treated with bevacizumab (7.5 + 15 mg/kg)-containing regimens (fig. 2b).The absolute risk of treatment-related death was 1.9% (95% CI = –0.2 to 4.1%, p = 0.082), with a NNH = 53 against the bevacizumab (7.5 + 15 mg/kg)-containing regimens. The absolute risk of bleeding was 3.1% (95% CI = 1.6–4.6%, p < 0.001), with a NNH = 32 against the bevacizumab 15 mg/kg-containing regimens. The absolute risk of hemoptysis was 1.9% (95% CI = 0.6–3.1%, p = 0.003), with a NNH = 53 against the bevacizumab 15 mg/kg-containing regimen. The absolute risk of hypertension was 6.1% (95% CI = 4.4–7.9%, p < 0.001), with an NNH = 16 against the bevacizumab (7.5 + 15 mg/kg)-containing regimens. The absolute risk of proteinuria was 1.8% (95% CI = –0.4 to 4%, p = 0.118), with a NNH = 56 against the bevacizumab (7.5 + 15 mg/kg)-containing regimens. The absolute risk of neutropenia was 3.1% (95% CI = –20.1 to 26.3%, p = 0.793), with a NNH = 32 against chemotherapy. The absolute risk of febrile neutropenia was 0.9% (95% CI = –1 to 2.8%, p = 0.366), with a NNH = 111 against the bevacizumab (7.5 + 15 mg/kg)-containing regimens. The absolute risk of thrombocytopenia was 1.3% (95% CI = 0.1–2.6%, p = 0.038), with a NNH = 77 against the bevacizumab (7.5 + 15 mg/kg)-containing regimens. The absolute risk of anemia was 1% (95% CI = 0.1–2%, p = 0.045), with a NNH = 100 in favor of the bevacizumab 15 mg/kg-containing regimen (fig. 3b).
      DiscussionIn the past years, the treatment of lung cancer had been based on the distinction between small cell lung cancer and NSCLC, and the treatment of NSCLC was based on doublets of a platinum and gemcitabine, vinorelbine, docetaxel or paclitaxel [...

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