Mark B. Hazuka

Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: A prospective phase III randomized study of the southwest oncology group

PURPOSE This phase III randomized trial was designed to determine if granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the hematologic toxicity and morbidity induced by chemoradiotherapy in limited-stage small-cell lung cancer (SCLC). METHODS This multicenter prospective trial randomized 230 patients to receive chemotherapy and radiotherapy (RT) with or without GM-CSF given on days 4 to 18 of each of six cycles. The primary end point was hematologic toxicity. Secondary end points included the following: nonhematologic toxicities; days of (1) fever, (2) antibiotics, (3) hospitalization, and (4) infection; number of transfusions; drug doses delivered; and response rates and survival. RESULTS There was a statistically significant increase in the frequency and duration of life-threatening thrombocytopenia (P < .001) in patients randomized to GM-CSF. GM-CSF patients had significantly more toxic deaths (P < .01), more nonhematologic toxicities, more days in hospital, a higher incidence of intravenous (IV) antibiotic usage, and more transfusions. Patients randomized to GM-CSF had higher WBC and neutrophil nadirs (P < .01), but no significant difference in the frequency of grade 4 leukopenia or neutropenia. Patients randomized to GM-CSF had a lower complete response rate (36% v 44%), but the differences were not significant (P = .29). There were no significant differences in survival (median, 14 months on GM-CSF and 17 months on no GM-CSF; P = .15). CONCLUSION GM-CSF, as delivered in this study, should not be included with concurrent chemoradiotherapy treatment programs for limited-stage SCLC. The simultaneous use of hematopoietic colony-stimulating factors (CSFs) and chemoradiotherapy should be performed only in experimental settings. Chemoradiotherapy programs with cisplatin and etoposide ([VP-16] PE) and simultaneous chest RT produce grade 4 neutropenia and thrombocytopenia in a small-enough proportion of patients that prophylactic hematopoietic growth factors are clinically unnecessary.

Brain metastases: results and effects of re-irradiation

Re-irradiation for recurrent manifestations of brain metastases has been reported to be of benefit by either increasing the duration of survival or improving the quality of life. The records of 455 patients with brain metastases treated by radiation therapy at the University of Colorado Health Sciences Center from 1975 through 1986 were reviewed. Of these, 44 patients (9.7%) were re-irradiated because of suggestive neurological findings and/or imaging studies diagnostic of recurrent disease. The primary site distribution was as follows: lung (non-small cell)--15 (34%), lung (small cell)--9 (20%), melanoma--5 (11%), breast--4 (9%), genitourinary--4 (9%), unknown--4 (9%), lymphoma--2 (4%), and endometrium--1 (2%). Retreated patients received at least two courses of irradiation and one received three. The median interval between the first and second courses was 34 weeks (7.8 months). For the initial course of treatment, all patients were treated to the whole-brain with megavoltage X rays to a dose of 30-36 Gy (median 30 Gy) at 1.5 to 4.0 Gy/fraction (median 3.0 Gy/fraction). Retreatment also consisted of whole-brain irradiation (37/42 patients) to additional doses of 6-36 Gy (median 25 Gy) at 2.0 to 4.0 Gy/fraction (median 3.0 Gy/fraction). The total cumulative doses to the brain, therefore, varied from 38-75 Gy with a median of 60 Gy. Survival data were available for 42 of 44 patients retreated. All patients died with disease. The overall median survival following the initial course of irradiation was 40 weeks (9.2 months) with 10 patients (24%) living beyond 1 year. The median survival following retreatment, however, was only 8 weeks with one patient surviving greater than 1 year. Only 12 patients (27%) showed partial neurological improvement with re-irradiation and over one-half (55%) either failed to respond or deteriorated during or soon following retreatment. Brain necropsies were performed in 8 patients. Three of these had developed brain necrosis and two most likely died as a direct consequence. It is concluded that retreatment of brain metastases is seldom worthwhile. Survival is usually short and most importantly, the quality of survival frequently is not improved.

Role of recombinant interferon alfa-2a maintenance in patients with limited-stage small-cell lung cancer responding to concurrent chemoradiation: a Southwest Oncology Group study.

PURPOSE This study was designed to determine if recombinant interferon alfa-2a (rIFN alpha-2a) could prolong remission duration and/or survival in patients with limited-stage small-cell lung cancer (SCLC) who achieved an objective response to chemoradiotherapy. A secondary end point was to assess the toxicity of chronic IFN administration. PATIENTS AND METHODS One hundred seventy-one of 215 eligible patients achieved an objective response and were eligible to receive rIFN alpha-2a (3 million units [MU]/m2 subcutaneously three times per week escalated to 9 MU/m2 as tolerated) or observation for 2 years. RESULTS One hundred thirty-two of 140 registered patients were eligible. Sixty-four patients were randomized to receive IFN and 68 to observation alone. The median time from randomization to progression was 9 months on the IFN arm and 10 months on the observation arm (P = .72). The overall median survival time was 16 months on the observation arm versus 13 months on the IFN arm (P = .77). Significant toxicities occurred in the rIFN alpha-2a arm. Grade 3 or higher toxicities included malaise, fatigue, and/or lethargy (30%), leukopenia (14%), neutropenia (13%), dyspnea (13%), nausea (11%), and respiratory infection (6%). Forty-three patients discontinued treatment due to intolerable side effects. CONCLUSION rIFN alpha-2a in the dose and schedule used in this study failed to prolong response duration or survival in patients with limited-stage SCLC who had previously responded to an induction chemoradiotherapy program. Failure may have been partly related to poor tolerance and inability to complete therapy.

Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer

PURPOSE A phase II study was conducted by the Southwest Oncology Group (SWOG) to assess the efficacy and toxicity of concurrent carboplatin, etoposide, and thoracic radiation (XRT) in a defined population of poor-risk patients with stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with stage III NSCLC were eligible if they were excluded from cisplatin-based protocols because of poor pulmonary or renal function, history of congestive heart failure, hearing loss, peripheral neuropathy, or weight loss. Carboplatin 200 mg/m2 daily intravenously days 1, 3, 29, and 31 and etoposide 50 mg/m2 daily intravenously days 1 through 4 and 29 through 32 were administered. Beginning day 1, XRT was delivered at 1.8 to 2.0 Gy daily to a total dose of 61 Gy. RESULTS Within a period of 1 year, 63 patients were registered and 60 were eligible. Patient characteristics were age 47 to 79 years, performance status 0 to 1 (82%) and 2 (18%), and stages IIIA (60%) and IIIB (40%) NSCLC. The most common grades 3 and 4 toxicities included leukopenia (50%), thrombocytopenia (23%), and esophagitis (15%). There were no treatment-related deaths. The overall confirmed response rate was 29%, and median overall survival was 13 months (95% confidence interval, 11 to 14 months). The 2-year survival rate was 21%. CONCLUSION This chemoradiotherapy regimen is well tolerated in poor-risk patients and yields a median survival similar to that of good-risk patients who received cisplatin-based chemoradiotherapy. This chemoradiotherapy regimen will be compared with XRT alone in poor-risk patients with stage III NSCLC in a randomized phase III trial.

Spinal cord ependymomas treated with surgery and radiation therapy. A review of 11 cases.

Between 1971 and 1990, 11 patients with primary spinal cord ependymomas were treated with surgery and postoperative irradiation or surgery alone at the University of Colorado Health Sciences Center. Of the 11 patients, 6 (54%) were subclassified with myxopapillary ependymomas that were located in the lumbosacral region of the spinal cord: 2 patients underwent complete resections, 8 had subtotal resections, and 1 had a biopsy only; 8 patients received postoperative irradiation (range: 4,500–5,482 cGy) with 7 of 8 patients treated to involved spinal fields. With a mean follow-up of 7.4 years, 3 patients (27%) have developed recurrent disease, 2 in the combined treatment group, and 1 in the surgery alone group. The 5− and 10-year actuarial survival rates were 100% and 80%, respectively. Eight of nine patients (89%) demonstrated clinical improvement after postoperative irradiation which suggests that the irradiation may have contributed to the improvement. The present study supports the long-term survival of patients with spinal cord ependymomas. Results from this series and a review of the literature indicate that complete surgical resection is only possible in about one-quarter of cases. Local spinal irradiation should continue to be utilized when surgery is incomplete.

Daily low-dose cisplatin plus concurrent high-dose thoracic irradiation in locally advanced unresectable non-small-cell lung cancer: results of a phase II Southwest Oncology Group study.

PURPOSE This single-arm phase II trial was designed to evaluate the efficacy and toxicity of continuous-course, high-dose thoracic irradiation (RT) combined with concurrent daily low-dose cisplatin followed by high-dose cisplatin consolidation in patients with locally advanced unresectable non-small-cell lung cancer (NSCLC). The daily chemotherapy regimen was designed to optimize the radiosensitizing properties of cisplatin. PATIENTS AND METHODS Sixty-five patients from 21 participating institutions were entered onto the study between April 1989 and May 1991. Protocol therapy consisted of daily intravenous (i.v.) cisplatin (5 mg/m2) plus concurrent continuous-course RT (61 Gy over 6 1/2 weeks) both delivered Monday through Friday each week. After a 3- to 4-week rest period, this was followed by three 28-day cycles of cisplatin at 100 mg/m2 or subsequently 50 mg/m2 administered i.v. on days 1 and 8 of each cycle. RESULTS Sixty-four patients were eligible; the majority had unresectable stage IIIa (36%) or IIIb (55%) NSCLC. The remaining 9% had recurrent disease confined to the chest (five patients) or stage II disease (one patient). The feasibility of this regimen is demonstrated by the fact that only five patients (8%) were unable to complete daily cisplatin and RT because of toxicity. Esophagitis (16%), leukopenia (14%), nausea (8%), and vomiting (6%) were the most common severe (grade 3) toxicities. There was only one life-threatening toxicity (grade 4 nausea) and no treatment-related deaths. The objective response rate was 39%, and six patients (9%) achieved a radiographic complete response (CR). The median survival duration for all patients was 14 months, and the 1- and 2-year actuarial survival rates were 56% and 24%, respectively. For stage IIIa patients, the median survival duration and 2-year survival rate were 17 months and 38%, as compared with 10 months and 14% for stage IIIb patients, respectively. CONCLUSION Daily low-dose cisplatin plus concurrent high-dose continuous-course RT is a well-tolerated out-patient regimen. The survival results are encouraging and appear to be equivalent to more toxic combined approaches. These results warrant further testing of combined daily platinum analogs with RT.

Aids-related non-hodgkin's lymphoma: The outcome and efficacy of radiation therapy☆

The records of all 16 patients with AIDS-related lymphoma treated with radiation therapy at our institutions were reviewed. All patients were male with a median age of 32 years, and all but one had biopsy proven high-grade NHL. Eleven had lymphoma involving the central nervous system and five had lymphoma involving other sites. Seven of the 11 patients with CNS involvement had primary CNS lymphoma. All patients were treated with megavoltage X rays to doses ranging from 1050 cGy in 1 1/2 weeks to 5037 cGy in 6 weeks. Of those patients with CNS lymphoma, only one responded completely and four responded partially to irradiation. All patients died within a range of 0.2 to 5.3 months (median survival = 2.2 months) from starting radiation therapy. In contrast, 3 of 5 patients (60%) with NHL outside the CNS responded completely and 1 responded partially to involved-field irradiation. These patients survived a median of 12.6 months with one achieving long-term lymphoma-free survival at 40 months. This long-term survivor presented with Stage IE lymphoma as his only manifestation of AIDS. We conclude that AIDS-related lymphomas respond less favorably to radiation therapy than lymphomas in non-immunosuppressed patients. Furthermore, CNS lymphomatous involvement is an ominous occurrence in the AIDS patient. In our experience, cranial irradiation failed to provide significant palliation or survival prolongation in this group of patients. Instead, long-term survival is possible in AIDS patients with limited NHL outside the CNS, and it is in these patients that combination chemotherapy plus involved-field radiation therapy may play a curative role.

Mediastinoscopy incisional metastasis. A radiotherapeutic approach.

Tumor seeding of the mediastinoscopy tract has been described. Although it is a rare occurrence, it can present the radiation oncologist with a therapeutic dilemma. Two cases of mediastinoscopy scar recurrences are reported. Their response to treatment and a review of previous cases are included.

Treatment-related central nervous system toxicity: MR imaging evaluation with CT and clinical correlation

Thirteen patients with abnormal brain MR scans attributable to treatment-induced injury were retrospectively reviewed. All patients were treated with radiation therapy and 62% received chemotherapy. Five patients were graded as having severe white matter (WM) changes, four had moderate WM changes, and four had mild WM changes. CT was generally equivalent to MR in evaluation of severe and moderate WM abnormalities, whereas MR was superior to CT in detection of mild WM abnormalities. In general, the severity of changes depicted by MR/CT correlated with the extent of neurologic dysfunction. The most severe changes were seen in those patients treated with combination irradiation and chemotherapy.