Ten-year follow-up of Southwest Oncology Group 8269: a phase II trial of concomitant cisplatin-etoposide and daily thoracic radiotherapy in limited small-cell lung cancer.

PURPOSE: To report the long-term follow-up of Southwest Oncology Group-8269, a phase II North American cooperative group trial of concurrent cisplatin, etoposide, vincristine (PEV), and thoracic radiotherapy (TRT) for limited small-cell lung cancer (L-SCLC). METHODS: 114 eligible patients from 47 institutions enrolled between April, 1985 and March 1986. Patients had documented L-SCLC. Induction chemotherapy consisted of three cycles of PEV. TRT was administered at 1.8 Gy/fraction in 25 daily fractions to a total dose of 45 Gy, to begin concomitantly. Consolidative chemotherapy included two cycles of vincristine, methotrexate, etoposide, doxorubicin and cyclophosphamide. Prophylactic cranial irradiation (PCI) was concurrent with the 3rd cycle of chemotherapy. The PCI dose was 30 Gy in 15 fractions of 2 Gy/fraction. RESULTS: As of May 2000, 5 of 114 remain alive and progression-free with a minimum follow-up interval of 13.2 years, as of May 2000. The median follow-up interval is 14.2 years. Thirty eight patients died of causes other than SCLC and five patients are still alive and progression-free. Of the remaining 71 patients dying of SCLC, local failure (LF) occurred in 24% (17 patients), distant metastasis (DM) occurred in 35% (25 patients), simultaneous LF and DM occurred in 25% (18 patients), and was indeterminate in 16% (11 patients). Thus, LF was a component of failure in 49%. Twenty patients had the CNS as the initial site of failure. Eleven patients (10%) developed fatal second primary cancers, including two with acute myelogenous leukemia, two with squamous cell lung cancer, one each with breast, pancreas, prostate, renal cell, and myelodysplasia. One patient developed both a melanoma and non-Hodgkin's lymphoma. CONCLUSION: There are long-term survivors with concomitant TRT and PEV. LF and DM are common. Pattern of failure suggests needs to improve local and systemic control.

Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160).

OBJECTIVE: The rate of complete resection (50%) and the 5-year survival (30%) for non-small cell lung carcinomas of the superior sulcus have not changed for 40 years. Recently, combined modality therapy has improved outcome in other subsets of locally advanced non-small cell lung carcinoma. This trial tested the feasibility of induction chemoradiation and surgical resection in non-small cell lung carcinoma of the superior sulcus with the ultimate aim of improving resectability and survival. METHODS: Patients with mediastinoscopy-negative T3-4 N0-1 superior sulcus non-small cell lung carcinoma received 2 cycles of cisplatin and etoposide chemotherapy concurrent with 45 Gy of radiation. Patients with stable or responding disease underwent thoracotomy 3 to 5 weeks later. All patients received 2 more cycles of chemotherapy and were followed up by serial radiographs and scans. Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed for significance by Cox regression analysis. RESULTS: From April 1995 to September 1999, 111 eligible patients (77 men, 34 women) were entered in the study, including 80 (72.1%) with T3 and 31 with T4 tumors. Induction therapy was completed as planned in 102 (92%) patients. There were 3 treatment-related deaths (2.7%). Cytopenia was the main grade 3 to 4 toxicity. Of 95 patients eligible for surgery, 83 underwent thoracotomy, 2 (2.4%) died postoperatively, and 76 (92%) had a complete resection. Fifty-four (65%) thoracotomy specimens showed either a pathologic complete response or minimal microscopic disease. The 2-year survival was 55% for all eligible patients and 70% for patients who had a complete resection. To date, survival is not significantly influenced by patient sex, T status, or pathologic response. CONCLUSIONS: (1) This combined modality treatment is feasible in a multi-institutional setting; (2) the pathologic complete response rates were high; and (3) resectability and overall survival were improved compared with historical experience, especially for T4 tumors, which usually have a grim prognosis.

Induction chemotherapy before surgery for early-stage lung cancer: A novel approach. Bimodality Lung Oncology Team.

OBJECTIVE: This phase II trial assessed the feasibility, as measured by response rate, toxicity, resectability rate, and surgical morbidity and mortality rates, of perioperative paclitaxel and carboplatin chemotherapy in patients with early-stage non-small cell lung carcinoma. METHODS: All patients required negative mediastinoscopy results and adequate medical parameters to undergo induction chemotherapy and an operation. Superior sulcus patients were excluded. Chemotherapy consisted of paclitaxel 225 mg/m(2) over 3 hours and carboplatin (area under the curve = 6) every 21 days for 2 cycles preoperatively. Three postoperative cycles of chemotherapy were planned for patients undergoing complete resection. RESULTS: Between June 1996 and July 1998, 94 patients were entered into the study. Sixty-five (69%) were men, and the median age was 64 years (range, 34-79 years). After induction chemotherapy, 53 of 94 (56%; 95% confidence interval, 46%-67%) had a major objective response, 88 (94%) underwent surgical exploration, and 81 (86%; 95% confidence interval, 78%-92%) underwent complete resection. Reasons for not undergoing an operation included disease progression (n = 3), clinically unresectable status (n = 1), death (n = 1), and patient lost to follow-up (n = 1). Two postoperative deaths occurred. Six (6%; 95% confidence interval, 0%-13%) pathologic complete responses were observed. Ninety (96%) patients received the planned preoperative chemotherapy versus 45% receiving postoperative chemotherapy. No unexpected chemotherapy or surgical morbidity occurred. The 1-year survival is currently estimated at 85%, and the median survival has not yet been reached. CONCLUSIONS: Induction chemotherapy with paclitaxel and carboplatin is feasible and produces a high response rate with acceptable morbidity and mortality rates in early-stage non-small cell lung carcinoma. A prospective randomized trial comparing 3 cycles of induction chemotherapy and surgery with surgery alone in early-stage non-small cell lung carcinoma is planned.

Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study.

PURPOSE: Prior studies show that increased levels of the DNA repair protein O6 methylguanine-DNA methyltransferase (MGMT), also referred to as O6-alkylguanine-DNA alkyltransferase (AGT) correlate with the resistance of glioma cell lines to nitrosoureas. The observed nitrosourea sensitivity of MGMT-deficient lines (methyl excision repair negative [MER-]) and those repair-proficient lines pretreated with MGMT-specific inhibitors (eg, O6 benzylguanine) has raised the possibility that tumor MGMT levels may be an important predictor of survival in patients with gliomas. PATIENTS AND METHODS: We correlated the MGMT level in malignant astrocytoma tissues, obtained from patients treated with radiotherapy and bis-chloroethylnitrosourea (BCNU) on a prior prospective trial (Southwest Oncology Group [SWOG] 8737), with overall and failure-free survival. RESULTS: Of 64 assessable patients with malignant astrocytoma (63% glioblastoma, 37% anaplastic astrocytoma), 64% had high (> 60,000 molecules/nucleus) MGMT levels. The overall median survival for patients with high versus low MGMT levels was 8 and 29 months, respectively (P=.0002), and median failure-free survival 3 and 6 months, respectively (P=.008). Subset analysis by histology (high v low MGMT levels) for anaplastic astrocytoma was 14 versus 62 months (n=24) and for glioblastoma was 7 versus 12 months (n=40). The overall hazards ratio (risk for death) for high versus low MGMT levels was 3.41; in young patients, the hazards ratio was higher (age 18 to 40 years, 4.19; age 41 to 60 years, 3.08) but became equal by MGMT level at age older than 60 years (1.11). Multivariate analysis showed that MGMT was independent of other known prognostic factors (age, performance status, histology). CONCLUSION: The MGMT level in tumor tissue specimens may be a predictive marker of survival in patients with malignant astrocytoma that is independent of other previously described prognostic variables.

Concurrent cisplatin, prolonged oral etoposide, and vincristine plus chest and brain irradiation for limited small cell lung cancer: a phase II study of the Southwest Oncology Group (SWOG-9229).

PURPOSE: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting. METHODS AND MATERIALS: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m2 i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m2 (days 1-14, 29-42, and 57-70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy. RESULTS: Among 56 eligible patients, 93% had SWOG performance status 0-1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimum follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3). CONCLUSION: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.

Phase II study of Didemnin B in central nervous system tumors: a Southwest Oncology Group study.

Didemnin B 6.3 mg/m2 was administered intravenously to 48 patients with recurrent or progressive central nervous system tumors. One patient of 39 (2.9%, 95% confidence limits 0.1 to 13.5) eligible patients had a confirmed partial response utilizing standard solid tumor criteria which lasted 14 months. Toxicity was significant. Nausea and vomiting and lethargy were the most frequent toxicities, but multiple severe toxicities were seen. Further investigation of Didemnin B at this dose is not warranted in patients with central nervous system malignancies.