Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). High-dose chemotherapy with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors. Standard combination versus alternating chemotherapy in small cell lung cancer: a randomised clinical trial including 394 patients. 'Petites Cellules' Group. Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study. Dose intensity of chemotherapy in patients with relapsed Hodgkin's lymphoma. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. Alternating versus sequential chemotherapy in small cell lung cancer. A randomized German multicenter trial. High-dose melphalan with autologous stem-cell rescue in metastatic rhabdomyosarcoma.
Approximately 60% of patients with small-cell lung cancer (SCLC) develop brain metastases. Whole-brain radiotherapy (WBRT) gives symptomatic improvement in more than 50% of these patients. Because brain metastases are a sign of systemic progression, and chemotherapy was found to be effective as well, it becomes questionable whether WBRT is the only appropriate therapy in this situation.
                In a phase III study, SCLC patients with brain metastases were randomized to receive teniposide with or without WBRT. Teniposide 120 mg/m(2) was given intravenously three times a week, every 3 weeks. WBRT (10 fractions of 3 Gy) had to start within 3 weeks from the start of chemotherapy. Response was measured clinically and by computed tomography of the brain.
                One hundred twenty eligible patients were randomized. A 57% response rate was seen in the combined-modality arm (95% confidence interval [CI], 43% to 69%), and a 22% response rate was seen in the teniposide-alone arm (95% CI, 12% to 34%) (P<.001). Time to progression in the brain was longer in the combined-modality group (P=.005). Clinical response and response outside the brain were not different. The median survival time was 3.5 months in the combined-modality arm and 3.2 months in the teniposide-alone arm. Overall survival in both groups was not different (P=.087).
                Adding WBRT to teniposide results in a much higher response rate of brain metastases and in a longer time to progression of brain metastases than teniposide alone. Survival was poor in both groups and not significantly different. Concurrent platinum etoposide chemotherapy given in combination with hyperfractionated thoracic radiation therapy (HTRT) in limited disease (LD) small cell lung cancer (SCLC) is associated with a high response rate and significant prolongation of survival. Given these results, the Hellenic Cooperative Oncology Group (HeCOG) performed a multicenter randomized phase II study in patients with LD SCLC to evaluate the timing of HTRT (early vs. late) when given concurrently with chemotherapy.
                To be eligible for the study, patients were required to have histologically or cytologically proven LD SCLC, confined to one hemithorax and/or ipsilateral mediastinal or supraclavicular lymphnodes and absence of pleural effusion or controlateral supraclavicular lymphnode involvement. Moreover, patients had to have a good performance status and adequate haematological, liver and renal function. Patients with LD SCLC were randomized to receive HTRT either concurrently with the first (Group A) or with the fourth (Group B) cycle of chemotherapy. Chemotherapy consisted of carboplatin administered at an AUC of six given as an i.v. 1-hour-infusion immediately followed by etoposide at a dose of 100 mg/m2 i.v. as a two-hour infusion for three consecutive days every three weeks up to a total of six cycles. Prophylactic cranial irradiation was also given to patients achieving a complete response.
                42 and 39 patients, were eligible for efficacy evaluation in group A and B respectively. The overall response rate was 76% in group A and 92.5% in group B (P = 0.07) with a complete response rate of 40.5% and 56.5%, respectively. After a median follow-up of 35 months, time to progression was 9.5 months in group A and 10.5 in group B (NS) while overall median survival was 17.5 and 17 months respectively (NS). The 2-year survival was 36% in group A and 29% in group B (NS) and the 3-year survival 22% and 13%, respectively (NS). The distant relapse rate was 38% in group A and 61% in group B (P = 0.046). Severe grade 3 4 anemia was recorded in 19% of group A and 12.5% of group B (NS), while severe leucopenia was recorded in 35.5% and 20.5% (P = 0.09) and neutropenic fever in 5% and 2.5% (NS), respectively. Severe thrombocytopenia did not differ significantly between the two treatment groups being 21.5% and 23%, respectively. Severe grade 2-3 esophageal toxicity was 19% in group A and 23% in group B (NS), while grade 3 lung toxicity was 5% and 7.5% (NS), respectively. No toxicity-related deaths were recorded.
                Concurrent administration of HTRT with carboplatin etoposide is associated with a high response and survival rate. Although a trend for higher response rate was recorded in the group of patients who received late HTRT, the overall median, 2-year and 3-year survival rates did not differ significantly between the two treatment groups. The toxicity of this promising therapeutic approach was acceptable. Comparative phase III studies with an adequate number of patients are recommended in order to answer this question. We treated 49 patients with recurrent or poor-prognosis CNS malignancies with high-dose chemotherapy regimens followed by autologous marrow rescue with or without peripheral-blood stem-cell augmentation to determine the toxicity of and event-free survival after these regimens.
                Nineteen patients had medulloblastomas, 12 had glial tumors, seven had pineoblastomas, five had ependymomas, three had primitive neuroectodermal tumors, two had germ cell tumors, and one had fibrosarcoma. Thirty-seven received chemotherapy with cyclophosphamide 1.5 g/m2 daily x 4 and melphalan 25 to 60 mg/m2 daily x 3. Nine received busulfan 37.5 mg/m2 every 6 hours x 16 and melphalan 180 mg/m2 (n = 7) or 140 mg/m2 (n = 2). Three received carboplatin 700 mg/m2/d on days -7, -5, and -3 and etoposide 500 mg/m2/d on days -6, -4, and -2. All patients received standard supportive care.
                Eighteen of 49 patients survive event-free 22+ to 55+ months (median, 33+) after transplantation, including nine of 16 treated before recurrence and nine of 33 treated after recurrence. There was one transplant-related death from pulmonary aspergillosis. Of five patients assessable for disease response, one had a partial remission (2 months), one has had stable disease (55+ months), and three showed progression 2, 5, and 8 months after transplantation.
                The toxicity of these regimens was tolerable. Certain patients with high-risk CNS malignancies may benefit from such a treatment approach. Subsequent trials should attempt to determine which patients are most likely to benefit from high-dose chemotherapy with autologous stem-cell rescue. to compare standard and alternating administration of chemotherapy combinations in small cell lung cancer (SCLC) patients.
                in a multicenter clinical trial, 394 previously untreated SCLC patients were randomised to receive, every 4 weeks, eight courses of either a standard regimen with CCNU, cyclophosphamide, adriamycin (CCA) and VP16 or an alternating regimen (CCA regimen alternating with cisplatin-vindesine-VP16).
                overall response rate was higher in the standard group (78%) than in the alternating group (64%) (P = 0.0001). Complete response rate was also higher in the standard group (32%) than in the alternating group (18%) (P = 0.004). The median survival in the overall SCLC population was 306 days in the standard group and 272 days in the alternating group (P = 0.08). In limited SCLC patients, median survival was higher in the standard group (421 days) than in the alternating group (328 days) (P = 0.01). Grade III/IV haematological toxicity was lower in patients in the alternating group (25 versus 47%) (P < 0.001).
                the standard regimen was better than the alternating regimen for patients with limited forms of SCLC. The alternating regimen, associated with better haematological safety and ensuring a fairly similar survival, may be considered in patients with extensive SCLC. Pleiomorphic resistance mechanisms to chemotherapy make it difficult to define a non-cross-resistant chemotherapy regimen. The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia. High-dose chemotherapy (HDCT) followed by autologous stem-cell transplantation (PBSCT) has become the standard treatment for patients with relapsed Hodgkin's lymphoma (HL). The intensity of treatment needed is unclear. This European intergroup study evaluated the impact of sequential high-dose chemotherapy (SHDCT) before myeloablative therapy.
                Patients with histologically confirmed, relapsed HL were treated with two cycles of dexamethasone, cytarabine, and cisplatin, and those without disease progression were randomly assigned. In the standard arm (A), patients received myeloablative therapy with carmustine, BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by PBSCT. Patients in the experimental arm (B) also received sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM. Freedom from treatment failure (FFTF) was the primary end point. Remission rates, overall survival (OS), and toxicity of treatment were secondary end points.
                From a total of 284 patients included, 241 responding patients were randomly assigned after two cycles of dexamethasone, cytarabine, and cisplatinum. Patients treated in arm B had longer treatment duration and experienced more toxicity and protocol violations (P < .05). Mortality was similar in both arms (20% and 18%). With a median observation time of 42 months, there was no significant difference in terms of FFTF (P = .56) and OS (P = .82) between arms. FFTF at 3 years was 62% (95% CI, 56% to 68%) and OS was 80% (95% CI, 75% to 85%). Patients with stage IV, early relapse, multiple relapse, anemia, or B symptoms had a higher risk of recurrence (P < .001).
                Compared with conventional high-dose chemotherapy, additional SHDCT is associated with more adverse effects and does not improve the prognosis of patients with relapsed HL. The importance of the timing of thoracic irradiation (TI) in the combined modality therapy of limited-stage small-cell lung cancer (SCLC) was assessed in a randomized trial.
                All 308 eligible patients received cyclophosphamide, doxorubicin, and vincristine (CAV) alternating with etoposide and cisplatin (EP) every 3 weeks for three cycles of each chemotherapy regimen. Patients randomized to early TI received 40 Gy in 15 fractions over 3 weeks to the primary site concurrent with the first cycle of EP (week 3), and late TI patients received the same radiation concurrent with the last cycle of EP (week 15). After completion of all chemotherapy and TI, patients without progressive disease received prophylactic cranial irradiation (25 Gy in 10 fractions over 2 weeks).
                Although complete remission rates were not significantly different between the two arms, progression-free survival (P = .036) and overall survival (P = .008) were superior in the early TI arm. Patients in the late TI arm had a higher risk of brain metastases (P = .006).
                The early administration of TI in the combined modality therapy of limited-stage SCLC is superior to late or consolidative TI. A total of 306 patients with small cell lung cancer (SCLC) were randomized to receive chemotherapy in a sequential or alternating mode. Sequential chemotherapy consisted of eight cycles of cyclophosphamide, Adriamycin (doxorubicin), and vincristine (CAV) and alternating chemotherapy consisted of three cycles (1, 3, 5) of etoposide, vindesine, and ifosfamide (EVI); three cycles (2, 4, 6) of cisplatin, Adriamycin, and vincristine (PAV); and two cycles (7, 8) of cyclophosphamide, methotrexate, and CCNU (CMC). Responsive patients received prophylactic cranial irradiation after three cycles and chest irradiation after eight cycles of chemotherapy. No maintenance therapy was applied to patients achieving complete remission. Minimum follow-up was 2 years. Of the 302 patients evaluable, overall response rate was 59% in the sequential arm and 70% in the alternating arm. Patients treated with CAV had a complete response rate of 21% in contrast to 36% for those receiving alternating therapy. The median survival for all patients was 9.8 versus 11.3 months, for limited disease 11.1 versus 13.4 months, and for extensive disease 8.9 versus 9.9 months, all in favor of the alternating treatment. Two-year survival rate for all patients was 6% versus 9%, for limited disease 11% versus 14%, and for extensive disease 3% versus 6%, all preferring the alternating treatment mode. Progression-free survival demonstrated a strong correlation to the extent of response irrespective of the treatment regimen applied. Toxicity included 11 lethal and 8 life-threatening complications with a higher frequency in the alternating treatment arm. These results suggest that alternating treatment of SCLC with different drug combinations is more effective than sequential application of CAV. The European Collaborative MMT4-91 trial was conducted as a prospective nonrandomized study to evaluate the potential benefit of high-dose melphalan as consolidation of first complete remission in children with stage IV rhabdomyosarcoma.
                Fifty-two patients in complete remission after six courses of chemotherapy received "megatherapy": 42 received melphalan alone, whereas 10 received melphalan in combination with etoposide, carboplatin/etoposide, or thiotepa/busulfan and etoposide. The outcome of this group of patients was compared with that observed in 44 patients who were also in complete remission after six courses of identical chemotherapy (plus surgery or radiotherapy) but went on to receive a total of up to 12 courses of conventional chemotherapy (four cycles). No differences were found between the two groups regarding clinical characteristics, chemotherapy received before complete remission, or response to chemotherapy. In particular, there was no significant difference between the groups for site of primary tumor, histologic subtype, age at presentation, presence of bone or bone marrow metastases, or number of metastases.
                The 3-year event-free survival (EFS) and overall survival (OS) rates were 29.7% and 40%, respectively, for those receiving high-dose melphalan or other multiagent high-dose regimens and 19.2% and 27.7%, respectively, for those receiving standard chemotherapy. The difference was not statistically significant (P =.3 and P =.2 for EFS and OS, respectively). There was a significant prolongation in the time from the last day of high-dose chemotherapy or the end of chemotherapy cycle 4 to the time of relapse in those receiving megatherapy (168 days for patients receiving megatherapy v 104 days for those receiving standard therapy; P =.05).
                The addition of a high-dose alkylating agent to consolidation therapy may have prolonged progression-free survival in this poor-risk patient group, but it did not significantly improve the ultimate outcome.
Given the paucity of robust studies assessing the clinical effects of treatments, available evidence is insufficient to judge the effectiveness and safety of chemotherapy for the treatment of BM from SCLC. Published studies are insufficient to address the objectives of this review. According to the available evidence included in this review, chemotherapy does not improve specific brain PFS and OS in patients with SCLC. The combined treatment of teniposide and brain radiation therapy contributed to outcome in terms of increased complete remission and shorter time to progression (though not OS).