Between February 1999 and August 2000, 57 patients with unresectable MPM were enrolled onto this study at participating institutions from the SWOG. Patients were required to have histologically confirmed MPM of the pleura with bidimensionally measurable disease, SWOG performance status 0–2, and no prior chemotherapy or radiotherapy for any reason. Patients may have undergone prior surgery at least four weeks before study enrollment, and should have recovered from all side effects associated with surgery.
Adequate bone marrow function (total leukocyte count ≥ 3,000,/μl, and platelet count ≥ the institutional lower limit of normal), hepatic function (bilirubin ≤ 2 mg/dl and aspartate aminotransferase or alanine aminotransferase ≤ 2.5 times the institutional upper limit of normal) and renal function (estimated creatinine clearance ≥ 60 ml/min, and serum creatinine ≤ twice the institutional upper limit of normal) were required. Patients with prior malignancies (other than non-melanoma skin cancer, and adequately treated cervical cancer) were excluded if the disease free interval from the other malignancy was less than five years. Pregnant or nursing mothers were excluded. Patients with reproductive potential were required to use an effective contraceptive method. This study was approved by each individual institutional review board, and written informed consent was obtained from each patient in accordance with institutional and federal guidelines.
All patients received gemcitabine 1,000 mg/m2 over 30 minutes and cisplatin 30 mg/m2 over 30 minutes on days 1,8 and 15 of a 28-day cycle. An appropriate anti-emetic regimen was administered according to the institutional standards of care.
The study used NCI Common Toxicity Criteria version 2.x for toxicity and adverse event reporting. NCI CTC (National Cancer Institute Common Toxicity Criteria) Grade 3 non-hematological toxicity required a 50% reduction of the doses of both drugs, or withholding the doses based on the judgement of the treating investigator. NCI CTC Grade 4 non-hematological toxicity required withholding the medications till resolution of such toxicity, and a reinitiation of chemotherapy with a 50% dose reduction. Grade 2 diarrhea or mucositis required the gemcitabine dose to be withheld, and grade 3 or 4 diarrhea or mucositis required withholding the dose and a 50% reduction of the subsequent doses.
The gemcitabine dose was reduced by 25% for an absolute neutrophil count (ANC) less than 1,500/μl or a platelet count less than 100,000/μl. It was reduced by 50% for an ANC less than 1,250/μl or a platelet count less than 75,000/μl. Gemcitabine was withheld if the ANC was less than 1,000/μl or a platelet count less than 50,000/μl. In the event of a dose being held, because of cytopenias, the drug could be reinitiated with a 25% reduction for all subsequent cycles.
Cisplatin dose modification was performed on the day of treatment, and was based on the estimated creatinine clearance. If the estimated creatinine clearance was less than 60 ml/min, a 50% dose reduction was required. If the creatinine clearance decreased to less than 40ml/min, cisplatin was discontinued. Grade 2 peripheral neuropathy required a 50% dose reduction of cisplatin and grade 3 peripheral neuropathy required the discontinuation of cisplatin. Patients requiring discontinuation of cisplatin due to the above toxicities were continued on single agent gemcitabine.
Growth factor support with granulocyte colony stimulating factor, (G-CSF Neupogen ®; Amgen, California) was not permitted in the first cycle. However, it could be used for patients who developed grade 3 or 4 neutropenia, or neutropenic fever, for all subsequent cycles of chemotherapy. If an adequate neutrophil count was maintained with the initial cycle of G-CSF supported chemotherapy, dose escalation to the original dose level with subsequent cycles of chemotherapy was allowed.
All patients entered into the study underwent a baseline clinical history, physical examination, laboratory evaluation, CT scan of the chest, chest x-ray, and an audiogram. Patient examination and laboratory evaluation was performed weekly prior to each treatment. Staging studies were repeated after every two cycles for tumor assessment.
Tumor response was defined as complete response, partial response, stable disease or progression according to the SWOG criteria(11
). Complete response (CR) was defined as the disappearance of all measurable and evaluable disease. Partial response (PR) was defined as a 50% or greater decrease in the sum of the products of the perpendicular diameters of all measurable lesions. Stable disease (SD) was defined as a response which did not qualify for complete response, partial response or progression. Progressive disease was defined as a 50% increase or an increase of 10cm2
(whichever was smaller) in the sum of products of all measurable lesions over the smallest observed (over baseline if no decrease), clear worsening of any evaluable disease, reappearance of any lesion which had disappeared, appearance of a new lesion, or failure to return for evaluation due to death or deteriorating condition. All measurable, evaluable and non-evaluable lesions were assessed using the same technique (CT scan, MRI, Plain X-ray or palpable lesion greater than 2 cm.) as baseline. All responses were confirmed a minimum of three weeks later with the same imaging modality. Patients were removed from the protocol treatment if they experienced unacceptable toxicity, disease progression, delay in treatment of greater than three weeks due to toxicity, or if they required radiation to any site for symptom relief, withdrew consent, or completed two cycles after complete response. Responding patients were continued on chemotherapy till disease progression or undue toxicity. In patients with a complete response, chemotherapy was given for two cycles beyond best response.
The primary endpoint of this study was the median overall survival calculated from study entry date. Accrual of 50 patients was required to allow for assessment of 1-year survival to within ±14% of actual survival (95% C.I). Response rates and rates of specific toxicities could also be estimated to within ± 14% (95% C.I.). Any toxicity with at least a 5% probability was likely to be seen at least once (92% chance)