A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study.

BACKGROUND: The aim of the present study was to evaluate the clinical activity of imatinib mesylate in patients with recurrent and refractory c-kit-expressing small-cell lung cancer. PATIENTS AND METHODS: Patients with c-kit-expressing SCLC (> or =1+ by immunohistochemistry) were enrolled in two groups. Arm A included patients with disease progression <3 months and arm B included patients with disease progression > or =3 months after previous treatment. Imatinib was administered at a dose of 400 mg b.i.d. continuously, with a cycle length of 28 days. A single stage Simon design with a planned interim analysis was used to evaluate the 16-week progression free rate in each arm. RESULTS: A total of 29 evaluable patients were entered into the study (seven in arm A, median age 68; 22 in arm B, median age 64.5). Median number of treatment cycles was one in both arms. Grade 3+ non-hematologic adverse events were seen in 15 (52%) patients, with nausea, vomiting, dyspnea, fatigue, anorexia and dehydration each occurring in at least 10% of patients. Median survival was 3.9 and 5.3 months and median time to progression was 1 and 1.1 months for arms A and B, respectively. Enrollment to arm A was temporarily suspended prior to reaching interim analysis due to striking early disease progression (29%), early deaths (29%) and patient refusal (42%). No objective responses and no confirmed stable disease > or =6 weeks were seen in either arm. Accrual was permanently terminated to both arms as only one patient was progression-free at 16 weeks. CONCLUSION: Imatinib failed to demonstrate any clinical activity in spite of patient selection for c-kit-expressing SCLC. Our results strengthen the collective evidence that prediction of efficacy of novel therapeutic agents based on target expression, rather than pathway activation (for example, through activating mutations), may not be a valid paradigm for drug development.

Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma.

PURPOSE: We conducted a randomized prospective trial in selected patients with fully resected high-risk stage I and II malignant melanoma. PATIENTS AND METHODS: Interferon alfa-2a (IFN-alpha 2a) 20 x 10(6) U/m2 was administered three times each week for 12 weeks by the intramuscular route. Both the treatment group (n = 131) and the control group (n = 131) were evenly balanced with regard to relevant prognostic discriminants. RESULTS: The median disease-free survival (DFS) time was 2.4 years for the IFN-alpha 2a group and 2.0 years for the observation group (log-rank P = 0.19). The median survival times were 6.6 years for IFN-alpha 2a and 5.0 years for observation (log-rank P = .40). For stage I patients (n = 102), there was no apparent therapeutic advantage from IFN-alpha 2a therapy. The DFS for stage II patients was a median of 10.8 months in the control group versus 17 months in the treatment group. The overall survival time was 4.1 years for the treatment group versus 2.7 years for the control group. The differences in DFS for stage II patient were significant in a Cox model. These results must be interpreted cautiously because of subset analysis. A severe flu-like toxicity occurred in 44% of patients, 13% lost at least 10% of their baseline weight, and 45% experienced a worsening of Eastern Cooperative Oncology Group (ECOG) performance score. CONCLUSION: Our findings indicate trends that suggest a possible benefit for selected patients with high-risk malignant melanoma. The results will require further study in a larger patient population for confirmation.

Phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in advanced/recurrent endometrial carcinoma.

A phase II combination chemotherapy protocol combining methotrexate, vinblastine, doxorubicin, and cisplatin was designed to evaluate tumor response and survival in patients with advanced/recurrent endometrial carcinoma. Thirty patients with advanced/recurrent endometrial carcinoma were assigned to chemotherapy treatment at 4-week intervals with methotrexate 30 mg/m2 i.v. Days 1, 15, and 22; vinblastine 3 mg/m2 i.v. Days 2, 15, and 22; doxorubicin 30 mg/m2 i.v. Day 2; and cisplatin 70 mg/m2 i.v. Day 2. After a median of four cycles (maximum number two cycles beyond complete regression; minimum six cycles for stable partial regression), we observed objective regression in 20 patients (67%) (95% CI, 50, 84) with complete regression in 8 patients (27%) and partial regression in 12 patients (40%). Median overall survival was 9.9 months (range, 0.3-34.2), and median survival of responders was 11.0 months (range, 2.6-34.2) from initial date of response. Toxicity was substantial with two treatment-related deaths and consisted predominantly of neutropenia (grade 3 or greater in 93% of the patients), alopecia, nausea, emesis, stomatitis, and azotemia. In conclusion, MVAC is a highly active outpatient chemotherapy regimen in patients with advanced/recurrent endometrial carcinoma, achieving a high complete and partial response rate. Toxicity is substantial in this elderly patient population.

Diagnostic features and treatment of the Askin tumor--malignant small cell tumor of the thoraco-pulmonary region: a case report.

The Askin tumor is one of a group of small round cell tumors and is found mainly in the thoraco-pulmonary region of children and young adults. The treatment of the patient and the differentiation of this tumor from other small round cell tumors, especially Ewing's sarcoma and neuroblastoma by light microscopy, immunohistochemical methods, and electron microscopy is discussed.

Myelodysplastic syndromes. A clinical and pathologic analysis of 109 cases.

A total of 109 patients with myelodysplastic syndromes (MDS) was analyzed to determine the clinical and pathologic features of the five recently defined French-American-British Cooperative Group (FAB) subtypes, and to assess the utility of this classification system in predicting survival, evolution to acute nonlymphocytic leukemia (ANLL), and cause of death. All patients with MDS presented with anemia; additional cytopenias were present in patients with refractory anemia with excess blasts (RAEB), chronic myelomonocytic leukemia (CMML) and refractory anemia with excess blasts in transformation to ANLL (RAEB/Tr). Thirty-two patients received some form of antileukemic therapy for MDS. ANLL developed in 16 of the 77 remaining untreated patients, including 18% (2/11), 0% (0/21), 22% (5/23), 33% (2/6), and 44% (7/16) of patients with refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), RAEB, CMML, and RAEB/Tr, respectively (P = 0.02). The FAB subtype was highly predictive of survival with median survivals ranging from 71 months for RARS to 5 months for RAEB/Tr (P = less than 0.0001). Patients with RAEB, CMML, and RAEB/Tr frequently died of direct consequences of MDS, while patients with RA and especially RARS generally survived or died from unrelated disorders (P = less than 0.0001). MDS encompass a spectrum of disorders. RA and RARS, are relatively indolent and often do not lead to the patient's demise. RAEB, CMML, and RAEB/Tr are aggressive disorders which are often responsible for the patient's death whether or not actual progression to overt leukemia occurs. FAB subtype predicts survival, evolution to ANLL, and cause of death, although the five morphologic subtypes appear to separate into only two disease groups, especially with regard to survival and cause of death.