Early death during chemotherapy in patients with small-cell lung cancer: derivation of a prognostic index for toxic death and progression.
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Based on an increased frequency of early death (death within the first treatment cycle) in our two latest randomized trials of combination chemotherapy in small-cell lung cancer (SCLC), we wanted to identify patients at risk of early non-toxic death (ENTD) and early toxic death (ETD). Data were stored in a database and logistic regression analyses were performed to identify predictive factors for early death. During the first cycle, 118 out of 937 patients (12.6%) died. In 38 patients (4%), the cause of death was sepsis. Significant risk factors were age, performance status (PS), lactate dehydrogenase (LDH) and treatment with epipodophyllotoxins and platinum in the first cycle (EP). Risk factors for ENTD were age, PS and LDH. Extensive stage had a hazard ratio of 1.9 (P = 0.07). Risk factors for ETD were EP, PS and LDH, whereas age and stage were not. For EP, the hazard ratio was as high as 6.7 (P = 0.0001). We introduced a simple prognostic algorithm including performance status, LDH and age. Using a prognostic algorithm to exclude poor-risk patients from trials, we could minimize early death, improve long-term survival and increase the survival differences between different regimens. We suggest that other groups evaluate our algorithm and exclude poor prognosis patients from trials of dose intensification. (+info)
Defining and analysing symptom palliation in cancer clinical trials: a deceptively difficult exercise.
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The assessment of symptom palliation is an essential component of many treatment comparisons in clinical trials, yet an extensive literature search revealed no consensus as to its precise definition, which could embrace relief of symptoms, time to their onset, duration, degree, as well as symptom control and prevention. In an attempt to assess the importance of these aspects and to compare different methods of analysis, we used one symptom (cough) from a patient self-assessment questionnaire (the Rotterdam Symptom Checklist) in a large (>300 patient) multicentre randomized clinical trial (conducted by the Medical Research Council Lung Cancer Working Party) of palliative chemotherapy in small-cell lung cancer. The regimens compared were a two-drug regimen (2D) and a four-drug regimen (4D). No differences were seen between the regimens in time of onset of palliation or its duration. The degree of palliation was strongly related to the initial severity: 90% of the patients with moderate or severe cough at baseline reported improvement, compared with only 53% of those with mild cough. Analyses using different landmark time points gave conflicting results: the 4D regimen was superior at 1 month and at 3 months, whereas at 2 months the 2D regimen appeared superior. When improvement at any time up to 3 months was considered, the 4D regimen showed a significant benefit (4D 79%, 2D 60%, P = 0.02). These findings emphasize the need for caution in interpreting results, and the importance of working towards a standard definition of symptom palliation. The current lack of specified criteria makes analysis and interpretation of trial results difficult, and comparison across trials impossible. A standard definition of palliation for use in the analysis of clinical trials data is proposed, which takes into account aspects of onset, duration and degree of palliation, and symptom improvement, control and prevention. (+info)
Coexpression of transcripts encoding EPHB receptor protein tyrosine kinases and their ephrin-B ligands in human small cell lung carcinoma.
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The EPH family is the largest subfamily of receptor protein tyrosine kinases, consisting of the EPHA and EPHB subgroups. Ephrin-B1, ephrin-B2, and ephrin-B3 are ligands of the EPHB subgroup and are encoded by the EFNB1, EFNB2, and EFNB3 genes, respectively. We have shown previously that EPHB2 transcripts are expressed in six small cell lung carcinoma (SCLC) cell lines. In this study, we examined the expression of EPHB1, EPHB2, EPHB3, EPHB4, and EPHB6 in 4 SCLC tumor specimens and 14 cell lines including 3 cell lines derived from these tumor specimens. To investigate whether potential autocrine loops of EPHB receptors and ephrin-B ligands exist in SCLC, the expression of EFNB1, EFNB2, and EFNB3 was also examined. Our data show that transcripts encoding multiple members of the EPHB subgroup and the ephrin-B subgroup are coexpressed in SCLC cell lines and tumors. These results suggest that the EPHB subgroup receptor kinases may modulate the biological behavior of SCLC through autocrine and/or juxtacrine activation by ephrin-B ligands that are expressed in the same or neighboring cells. (+info)
Combined modality therapy of lung cancer.
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Combined modality therapy for lung cancer was first demonstrated to be successful in limited-stage small cell lung cancer. Concurrent administration of chemotherapy with chest and elective brain irradiation appears to produce the best results, with cisplatin/etoposide as the core chemotherapy. Using such programs, 2-year survival in the 40% range and 5-year survivals in excess of 20% may be expected, based on the results of multiple studies. Attempts to improve on these results through the use of altered schemes of chest irradiation or the delivery of high-dose consolidation chemotherapy are ongoing but to date have not been shown to affect survival significantly. We remain at a plateau in the effectiveness of combined modality therapy for small cell lung cancer, with little evidence that it impacts survival at all in extensive-stage disease. The incorporation of new agents in combination chemotherapy regimens, more "specific" immunotherapy directed at tumor-associated antigens, and the potential adjunctive use of broad-spectrum neuropeptide antagonists offer promise for the future. In non-small cell lung cancer, the sequential use of platinum-based chemotherapy and chest irradiation appears superior in survival to standard, daily fractionated radiation therapy used alone, with long-term survival increased from 5-10% to 15-20%. Concurrent administration of chemotherapy with cisplatin/etoposide and chest irradiation produces 2-year survival in the range of 30%, about twice that would be expected for radiation therapy alone, but has not been compared to it in the setting of a randomized trial. Low-dose cisplatin on a daily basis has been combined as a "sensitizer" with chest irradiation, producing initial results that appeared encouraging. However, these have not been reproduced in subsequent, randomized trials. Another approach to combined modalities has been to give chemotherapy or chemotherapy/radiation therapy as induction, followed by surgical resection, with or without subsequent additional treatment. Most patients (80-85%) can be resected, with encouraging survival at 2 and 3 years in the Southwest Oncology Group experience (37 and 26%, respectively). However, toxicity is greater, and such an approach is associated with an overall mortality risk in the range of 10%. A current intergroup study attempts to define the role of surgery in this setting. The major recent development that is likely to influence the future of combined modality therapy for this disease is the advent of multiple new chemotherapeutic agents, such as the taxanes, gemcitabine, vinorelbine, and the topoisomerase-I inhibitors, which have activity in stage IV disease. The immediate challenge is how to combine these agents with platinum analogues, radiation, and surgery. Aiding this process may be the use of molecular biological "markers" that may predict the chance of success or failure with a given systemic agent. The next decade is likely to see substantial improvements in the outcome of treatment for patients with stages I-III non-small cell lung cancer, based on the systemic exploration of combined modalities. (+info)
Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin.
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We conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m(-2). Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m(-2) dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered. (+info)
Fractionated administration of irinotecan and cisplatin for treatment of lung cancer: a phase I study.
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A combination chemotherapy of irinotecan (CPT-11) and cisplatin (CDDP) has been reported to be active for lung cancer. In the previous trial, however, diarrhoea and leucopenia became the major obstacle for sufficient dose escalation of CPT-11 to improve the treatment outcome. We conducted a phase I study to investigate whether the fractionated administration of CDDP and CPT-11 at escalated dose was feasible and could improve the treatment outcome. Twenty-four previously untreated patients with unresectable non-small-cell lung cancer (NSCLC) or extensive disease of small-cell lung cancer (SCLC) were eligible. Both CDDP and CPT-11 were given on days 1 and 8, and repeated every 4 weeks. The dose of CDDP was fixed at 60 mg m(-2) and given by 1-h infusion before CPT-11 administration. The starting dose of CPT-11 was 40 mg m(-2), and the dose was escalated by an increase of 10 mg m(-2). The maximally tolerated dose of CPT-11 was determined as 60 mg m(-2) because grade 4 haematological or grade 3 or 4 non-haematological toxicities developed in six patients out of 11 patients evaluated. Diarrhoea became a dose-limiting toxicity. The objective response rates were 76% for NSCLC and 100% for SCLC. The recommended dose of CPT-11 and CDDP in a phase II study will be 50 mg m(-2) and 60 mg m(-2) respectively. (+info)
Anti-amphiphysin I antibodies in patients with paraneoplastic neurological disorders associated with small cell lung carcinoma.
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Patients with stiff man syndrome and breast cancer develop anti-amphiphysin I antibodies that primarily recognise the C terminus of the protein. Anti-amphiphysin I antibodies have also been identified in a few patients with paraneoplastic neurological disorders (PND) and small cell lung cancer (SCLC). The frequency of anti-amphiphysin I antibodies in patients with SCLC and PND was analysed and the epitope specificity of these antibodies was characterised. Anti-amphiphysin I antibodies were evaluated by immunohistochemistry on human and rat cerebellum and immunoblots of rat brain homogenates. Serum samples included 134 patients with PND and anti-Hu antibodies (83% had SCLC), 44 with SCLC and PND without anti-Hu-antibodies, 63 with PND and either Yo, Ri, or Tr antibodies, 146 with SCLC without PND, and 104 with non-PND. Positive serum samples were confirmed with immunoblots of recombinant human amphiphysin I and immunoreacted with five overlapping peptide fragments covering the full length of the molecule. Serum samples positive for anti-amphiphysin I antibodies included those from seven (2.9%) patients with PND and two (1.4%) with SCLC without PND. Six of the seven anti-amphiphysin I antibody positive patients with PND had SCLC (three with Hu-antibodies), and one had anti-Hu-antibodies but no detectable tumour. The PND included encephalomyelitis/sensory neuropathy (five patients), cerebellar degeneration (one), and opsoclonus (one). All anti-amphiphysin I antibodies reacted with the C terminus of amphiphysin I, but seven also recognised other fragments of the molecule. In conclusion, anti-amphiphysin I antibodies are present at low frequency in patients with SCLC irrespective of the presence of an associated PND. All anti-amphiphysin I antibody positive serum samples have in common reactivity with the C terminus of the protein. (+info)
Paclitaxel and carboplatin in the treatment of small-cell lung cancer patients resistant to cyclophosphamide, doxorubicin, and etoposide: a non-cross-resistant schedule.
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PURPOSE: To evaluate the efficacy of paclitaxel and carboplatin (PC) in small-cell lung cancer (SCLC) patients resistant to cyclophosphamide, doxorubicin, and etoposide (CDE). PATIENTS AND METHODS: We performed a phase II study with PC in SCLC patients who relapsed within 3 months after first-line treatment with CDE. Paclitaxel administration (175 mg/m2 by a 3-hour intravenous infusion) was followed by a 30-minute infusion of carboplatin (area under the curve 7; Chatelut formula) once every 3 weeks for five cycles. Dexamethasone, clemastine, and ranitidine were standard premedication before every cycle. RESULTS: Included were 35 patients (median age, 59 years; 16 with limited disease and 19 with extensive disease; Eastern Cooperative Oncology Group performance status of < or = 1; median time off treatment 6 weeks) who were previously treated with CDE (n = 33), oral etoposide (n = 2), and reinduction CDE (n = 15); only one patient had received three CDE treatments of five cycles. The CDE regimen was followed by local thoracic radiotherapy in seven patients. Hematologic toxicity of grade 3 or 4, for leukopenia was 27% and 6%, for thrombocytopenia 21% and 13%, and for anemia 17% and 0%, respectively, for a total of 132 cycles. Two patients had neutropenic fever; no toxic death occurred. Nonhematologic toxicity was paresthesia CTC grade 3, diarrhea grade 4, and myalgia grade 3 in one patient each. Reversible paresthesia (CTC grade 1 and 2) in toes and fingers was reported in 69% of patients. Thirty-four patients were assessable for response: complete response in two patients, partial response in 23 patients, stable disease in eight patients, and progressive disease in one patient (response rate, 73.5%; 95% confidence interval, 59% to 88%). One patient was found to have atypical carcinoid at pathologic review and was excluded. Median time to progression was 21 weeks (range, 3 to 40 weeks). Median survival was 31 weeks (range, 6 to 112 weeks). One-year survival was 9%. CONCLUSION: Second-line PC in CDE-resistant SCLC patients yields a high response rate and seems non-cross-resistant to CDE. Toxicity was mild in these poor-prognosis patients. (+info)