Biweekly Schedule of Docetaxel and Cisplatin in High Risk Patients With Unresectable Non-small Cell Lung Cancer (NSCLC)
Condition: Non-small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Study type: Interventional
Phase: Phase 2

Summary: 
      The rationale of phase II study of biweekly docetaxel and cisplatin in patients with
      unresectable NSCLC are follows:

      First, the optimal dose and schedule of combination with docetaxel and cisplatin are still
      controversial (3 weekly versus weekly).

      Platinum-based combination chemotherapy improves the survival of patients with advanced
      non-small cell lung cancer (NSCLC) in the first-line setting.

      Combination chemotherapy with docetaxel and cisplatin is one of the standard platinum-based
      regimens for treating NSCLC. However, usual standard 3 weekly regimen with docetaxel and
      cisplatin have consistently produced frequent Grade 3-4 neutropenia, and febrile neutropenia.

      Although weekly docetaxel and cisplatin is better tolerated than chemotherapy every 3 weeks,
      especially in the first line setting in terms of myelosuppression, the optimal dose and
      schedule for administration of the two drugs has not yet been determined.

      Both 3-weekly docetaxel plus cisplatin and weekly schedule showed similar response rates but
      had different toxicity profiles. The most frequent grade 3 or 4 toxicities were neutropenia
      in the 3 weekly schedule and fatigue or asthenia in the weekly schedule.

      Second, docetaxel and cisplatin have different action and mechanism. Docetaxel showed
      characteristic early bone marrow suppression 5-7 days after infusion compared with usual 14
      days after infusion of cisplatin. Thus, nadir period is not overlapped when the investigators
      administered both drugs concomittantly.

      Third, there are many feasible reports of biweekly administration of docetaxel in patients
      with NSCLC, breast cancer, stomach cancer, and ovarian cancer with better safety profiles.

      Therefore,the investigators designed this phase II study to evaluate the efficacy and
      toxicity of biweekly schedule of docetaxel and cisplatin in patients with unresectable NSCLC
      and test the hypothesis that biweekly schedule of docetaxel and cisplatin is better tolerated
      than both standard 3 week and weekly schedule in terms of hematologic (neutropenia) and
      non-hematologic toxicities (asthenia, interstitial pneumonitis. Additionally the
      investigators will evaluate polymorphism associated with this study.
    

Detailed description: 
      Study design is followings: The sample size was calculated according to Simon's two stage
      optimal design. Assuming a response rate of 40%, a probability of error of 5% and a power of
      80%, a total of 48 patients (43 patients plus 5 patients to compensate a 10% drop-out rate)
      were enrolled. In the initial stage, 13 evaluable patients were to be entered into the study
      and evaluated for their response. If ≥ 3 responses were observed during the first stage, then
      30 additional patients were to be entered in the second stage. The statistical evaluation was
      performed based on the intention to-treat analysis.

      The combination chemotherapy consisted of docetaxel of 40mg/m2 as a 1-hour infusion followed
      by cisplatin 40mg/m2 as a 30-minutes intravenous infusion and both drugs were given on days
      1, and 15 in an outpatient setting. Patients also received adequate hydration with at least
      1,500ml of half saline or normal saline before cisplatin administration. All the patients
      received antiemetic therapy that consisted of intravenous 5-HT3 antagonist and dexamethasone
      before docetaxel administration. The treatment cycles were repeated every 4 weeks until the
      maximum six cycles.

      The patients whose absolute neutrophil count and platelet count were greater than or equal to
      1.500 and 100,000/mm3, respectively, and who had lower than or equal to grade 1
      non-hematologic toxicity (excluding alopecia) received chemotherapy on day 1 of each cycle.

      On days 15 of each cycle, the minimum requirements to receive chemotherapy were an absolute
      neutrophil count between 1000 and 1,500/mm3, a platelet count ≥75,000/mm3 and no grade ≥2
      nonhematologic toxicity (excluding alopecia).

      If these conditions were not met on days 1, or 15, then chemotherapy was postponed for 1
      week. A delay of more than 3 weeks resulted in withdrawal from the study.

      If there were any grade 3 to 4 hematologic toxicities at the nadir of the previous cycle, or
      febrile neutropenia with or without documented infection, then administration of both drugs
      in the subsequent cycles was reduced by 25% from the planned dose.

      The Administration of granulocyte-colony stimulating factor (G-CSF) was allowed in the
      presence of febrile neutropenia, and grade 3 or 4 neutropenia.

      In the presence of grade 3 or 4 non-hematologic toxicity (except nausea, vomiting and
      alopecia), the treatment was postponed until resolution of the toxicity and then both drug
      doses were reduced by 25% for the next cycle. Treatment was stopped at any time for
      documented disease progression, unacceptable toxicity or according to the patient's own
      refusal.

      The pretreatment baseline evaluation included a complete medical history and physical
      examination, a complete blood cell count (CBC) with the differentials, chemistry profiles and
      performance status. Chest X-rays, chest and upper abdominal computed tomography (CT) scans,
      brain CT scan or magnetic resonance imaging, a radionuclide bone scan and other diagnostic
      procedures were performed as clinically indicated.

      During treatment, a limited history taking, physical examination, assessment of toxicity, a
      complete blood cell count with the differentials and blood chemistry tests were repeated
      weekly. A chest X-ray was performed every 4 weeks before each cycle.

      Appropriate imaging studies, including CT scans of the chest and upper abdomen, were
      performed every two cycles to assess the treatment response, and sooner if needed for
      documenting disease progression. The objective tumor responses were assessed according to the
      RECIST criteria. The response rate was calculated as the ratio of the number of patients who
      achieved a complete or partial response to the number of enrolled patients. Overall survival
      (OS) and Time to progression (TTP) were calculated from the start of therapy until death and
      progression, respectively, or until the last follow-up. Toxicities were evaluated according
      to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale version 3.0.
    

Intervention name(s): Docetaxel and Cisplatin
Intervention type(s): Drug
Intervention description(s): splitted administration of docetaxel and cisplatin.
Other intervention name(s): Docetaxel (Sanofi-Aventis); Cisplatin
Intervention MeSH terms: Cisplatin; Docetaxel
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: biweekly; docetaxel; cisplatin; non-small cell lung cancer