Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung

Combination chemotherapy is frequently used in the therapy of advanced non-small-cell lung cancer (NSCLC), but late complications are rarely recognized because of the short survival of most patients. Of 119 patients with advanced NSCLC treated with cisplatin and other drugs, four patients developed acute nonlymphocytic leukemia (ANLL). All four patients received etoposide and cisplatin with or without vindesine. Leukemia was diagnosed at 13, 19, 28, and 35 months after start of treatment. Three patients had morphologic and/or cytogenetic features of acute leukemia with significant monoblastic involvement; the fourth patient had trilineage dysplasia and cytogenetic abnormalities more commonly associated with therapy-related leukemia. Detailed analysis of the subgroup who survived longer than 1 year (24 patients) suggests that high cumulative doses of etoposide are leukemogenic; the median etoposide dose was 6,795 mg/m2 (first year only) in the four leukemic patients compared with 3,025 mg/m2 in the 20 nonleukemic patients (P less than .01). The rate of ANLL was 0.30 per person-year after the first year (95% confidence limits 0.11 to 0.90), with a cumulative risk of 15% +/- 11% at 2 years, and 44% +/- 24% at 2.5 years. We conclude that high doses of etoposide are potentially leukemogenic, and can induce a syndrome with features of acute monoblastic leukemia de novo that is distinct from other secondary leukemias.     

Cyclic alternating chemotherapy for small cell carcinoma of the lung

Eighty-two previously untreated patients with small cell cancer of the lung were treated with six cycles of two alternating drug regimens: a new combination of mitomycin, methotrexate, and etoposide; and cyclophosphamide, doxorubicin, and vincristine. No maintenance chemotherapy was used. Consolidative thoracic irradiation and prophylactic cranial irradiation were employed. The median survival time for 32 limited-disease patients was 59 weeks, and for 50 extensive-disease patients was 35 weeks. Four-year survival was 12% for limited-disease patients and 2% for extensive-disease patients. These results were not superior to conventional combination chemotherapy regimens.     

Cyclic alternating combination chemotherapy for small cell bronchogenic carcinoma.

Sixty-one protocol-eligible patients with small cell bronchogenic carcinoma received cyclic alternating combination chemotherapy with two or three non-cross-resistant drug combinations. No chest or prophylactic brain radiation therapy was used. Twenty-eight months after starting treatment, disease-free survival was 23% for patients achieving a complete response (CR) and 13% overall. Initial treatment consisted of high-dose cyclophosphamide, methotrexate, and CCNU (CMC) for 6 weeks. Patients then received vincristine, adriamycin, and procarbazine (VAP) for 6 weeks. The addition of VAP increased the CR rate from 42% to 74% in limited-disease patients and from 24% to 36% in extensive-disease patients. Half of the patients were randomized to a third combination of VO-16-213 and ifosfamide. These patients were cycled at 6-week intervals through the three drug regimens while the remaining patients were cycled between CMC and VAP. The addition of VP-16-213 and ifosfamide did not increase the CR rate or prolong survival. Only complete responders survived beyond 24 months. Sequential use of non-cross-resistant drug combinations represents one method for increasing the CR rate.     

Non-cross-resistant chemotherapy and consolidation radiotherapy for small cell carcinoma of the lung

Fifty-six patients with small cell carcinoma of the lung were treated with a two-cyclic induction course of hexamethylmelamine, vincristine, doxorubicin, and cyclophosphamide. Patients with limited disease (LD) who responded and patients with extensive disease (ED) who had a complete response received prophylactic whole-brain radiotherapy, as well as radiotherapy to thoracic and abdominal sites of disease. Concurrently with radiotherapy, consolidation chemotherapy was given with doxorubicin, cyclophosphamide, methotrexate, and etoposide. The complete response rate was 35% for ED patients and 68% for LD patients. The median survival time for complete responders was 54 weeks for ED patients and 65 weeks for LD patients. The toxicity of the program was moderate, and the effectiveness was comparable to that of other reported combined-modality treatment programs.     

"Salvage" radiation therapy for intrathoracic small cell carcinoma of the lung progressing on combination chemotherapy

Thirty-two patients with small cell carcinoma of the lung were given chest radiotherapy to progressive intrathoracic tumor after failing chemotherapy. Two-thirds of these patients received split-course treatment at a dose of 4000 rad in 10 fractions. Sixteen of 25 evaluable patients (64%) had an objective response, but only five responders did not progress within the port during life. Median time to local progression was 16 weeks. Two patients, one of whom was given concurrent chemotherapy, survived greater than 18 months, and one is free of disease at 31+ months. Short-term palliation of chest disease and occasional long-term survival are possible with this regimen, although most patients will die with systemic disease within several months. Small cell carcinoma of the lung is less responsive to irradiation as second-line therapy than as initial therapy, but doses of greater than or equal to 4000 rad can offer symptomatic relief in many cases and, rarely, survival beyond 18 months.     

Intensive induction chemotherapy for small cell anaplastic carcinoma of the lung

The role of intensive induction chemotherapy in small cell cancer of the lung remains unclear. Twenty-eight newly diagnosed patients with small cell lung cancer were randomized to receive either high-dose or standard-dose cyclophosphamide, vincristine, and semustine in a trial where the dose of induction chemotherapy was the sole treatment variable. Complete responses (CR) were achieved in 57% of patients receiving high-dose therapy as compared to 21% of patients receiving standard-dose therapy (P less than 0.05). There was a higher rate of severe toxicity in the high-dose group (P less than 0.01). The overall median survival was not improved (36 weeks for the high-dose group vs 43 weeks for the standard-dose group); however, the median survival in patients achieving CR was prolonged (92 weeks for the high-dose group vs 50 weeks for the standard-dose group). These effects were most pronounced in patients with extensive disease; a CR after induction was achieved in five of nine patients treated with high doses but not in any of those treated with standard doses (P less than 0.05). A small group of patients appear to benefit by achieving a long-term remission with intensive induction chemotherapy, but this effect may be offset by increased morbidity.     

Intermittent high-dose cyclophosphamide chemotherapy for small cell carcinoma of the lung.

Twenty-three patients with small cell carcinoma of the lung (15 with limited disease and eight with extensive disease) were randomized into one of two induction schedules of high-dose cyclophosphamide (CY), 60 mg/kg iv, given either on Days 1 and 2 or on Days 1 and 8. Following the high-dose CY, patients were treated with a sequence of three monthly courses of COMB (CY, 800 mg/m2; vincristine [Oncovin], 1.4 mg/m2; methotrexate, 20 mg/m2; and BCNU, 60 mg/m2) alternating with high-dose CY. The overall response rate to the high-dose CY was 70% with 17% being complete responses (CRs). COMB produced no additional responses. There was no significant difference in response rate with either high-dose CY schedule. There was no unexpected morbidity associated with the intensive regiment despite marked myelosuppression. The high-dose CY administered on Days 1 and 8 appeared less toxic than that given on Days 1 and 2. Laboratory studies demonstrated that small cell carcinoma cells respond to drug-induced humoral stimulation in vitro; and that tumor proliferation in vivo temporally coincides with increased serum stimulatory activity. This study demonstrates that high-dose CY is a safe and effective induction therapy for small cell carcinoma of the lung although the low CR rate obtained is disappointing.     

Cisplatin combination chemotherapy in advanced lung cancer in the aged

Eleven aged patients over 65 years of age with advanced lung cancer (mean age = 70.8 +/- 1.4, non-small cell:small cell = 9:2, stage III:IV = 5:6) were treated with combination chemotherapy consisting of cisplatin (50 or 80 mg/m2) and vincaloids (vindesine 3 mg/m2 or etoposide 80 mg/m2). To evaluate this cisplatin combination therapy, the aged group was compared with a young group consisting of eleven patients (mean age = 53.3 +/- 1.7, non-small cell:small cell = 9:2, stage III:IV = 5:6) matched for cell type, stage and dose regimen. The mean dose of cisplatin was 58.2 mg/m2 in the aged and 63.6 mg/m2 in the younger group. A notable reduction in tumor size was observed in 9.1% of the aged and 27.3% of the young, while one-year survival rate was 63.6% in the aged and 72.7% in the young. The common side effects were nausea and vomiting, while diarrhea was seen in 18.2% of the aged. Neutropenia, anemia and thrombocytopenia were found in both groups and the time course of myelosuppression in the aged (18.2 +/- 0.8 days) was significantly shorter than that in the younger patients (22.0 +/- 1.4 days, p less than 0.05). With regard to nephrotoxicity, creatinine clearance rate in the aged decreased remarkably from 56.9 to 38.9 ml/min, while there was no significant change in BUN, serum creatinine and urine NAG between the aged and the young. Disorders of electrolytes such as hypokalemia and hyponatremia were seen in 45.5% of the aged. We conclude that advanced lung cancer in the aged was effectively treated with cisplatin combination therapy with tolerable nephrotoxicity and myelosuppression.     

Intensive alternating chemotherapy regimen in small cell carcinoma of the lung

Fifty-five patients with small cell carcinoma of the lung (SCCL) were treated with alternating courses of CAV (cyclophosphamide, doxorubicin, and vincristine) and VHM (etoposide, hexamethylmelamine, and methotrexate) at 21-day intervals. One regimen contained high-dose cyclophosphamide (2400 mg/m2 iv), while the second contained an increased dose of etoposide (250 mg/m2 iv on Days 1-3). Patients achieving a complete response (CR) received a minimum of six cycles of therapy or two cycles beyond the achievement of CR. These patients as well as those with partial response with disease limited to the lung then received radiotherapy to the lung primary (5100 rads in 300-rad fractions) as well as prophylactic cranial radiotherapy (3000 rads in 300-rad fractions). All therapy was subsequently stopped until relapse. There were no deaths during the aplastic periods induced by the intensive chemotherapy. CR was achieved in 57% of the patients and partial response was achieved in 38%. The actuarial median survival for the 27 patients with extensive disease was 13.5 months and for the 28 patients with limited disease was 13 months. Survival at this point appears comparable to less intensive regimens in which maintenance therapy was given. We conclude that prolonged intensive induction chemotherapy in SCCL is well-tolerated. Studies are needed to examine in a randomized trial the role of alternating combinations and maintenance therapy in SCCL.     

Vinblastin and mitomycin-C combination chemotherapy for patients with non small cell lung cancer.

Thirty-four patients with non small cell lung cancer were treated with a combination of vinblastin and mitomycin-C. Major radiological response was observed in 61.5% of cases. Median survival of the treated patients was 6 months and it was 7 months for those showing a major response. Fourteen of the 21 responders survived for 6 months or more, and 4 survived for more than a year. Leucopenia was a common side effect, and it did not produce any major infective complication. We did not find any advantage of this regimen over other less expensive drugs used in our earlier trials.     

Vindesine and etoposide chemotherapy in the management of patients with small cell lung cancer and poor prognosis.

Twenty-five patients with histologically proven small cell lung cancer who were in too poor physical condition to receive 'aggressive' chemotherapy were treated with vindesine and etoposide (VE). The median survival was 195 days, and there were 4 survivors of greater than 460 days. Eight patients died before the second pulse of chemotherapy, and these all had a Karnofsky score of less than or equal to 20 at diagnosis. Toxicity of the chemotherapy regimen was minimal, and the results suggest that VE chemotherapy may be suitable for the treatment of patients with small cell lung cancer who are unsuitable for more toxic chemotherapy.     

Lithium carbonate in patients with small cell lung cancer receiving combination chemotherapy

Lithium administration has been shown to attenuate the leukopenia associated with systemic chemotherapy. The results of a randomized trial of lithium in 45 patients with small cell lung cancer who received combination chemotherapy and radiation therapy are reported. Patients randomized to receive lithium were started on 300 mg three times daily for 18 days of every 21 day chemotherapy cycle. Patients who received lithium experienced significantly less mid-cycle leukocyte and neutrophil count depression and spent fewer days with leukopenia and neutropenia than control patients regardless of age or extent of disease. Patients who received lithium spent fewer days hospitalized and fewer days with fever in the presence of severe neutropenia than control patients. The cumulative risk of fever with signs of infection was greater in control patients regardless of age, disease extent or the presence of marrow involvement. Patients who were given lithium received significantly more chemotherapy than control patients. Patient survival was greatest in those with limited disease, in complete responders and in those who received more than 75 percent of their induction chemotherapy although it did not differ between the two study groups. The majority of patients required either reduction or discontinuation of lithium. Those who received lithium continuously demonstrated a higher objective response rate and longer survival than either patients in whom the lithium had to be discontinued or those randomized to the control group. Infection was an important cause of death in the control group and cardiovascular events occurred frequently in the lithium group, but the major cause of death in this patient population remains progressive malignant disease.     

Cisplatin and vinca alkaloid combination chemotherapy of advanced non-small-cell lung cancer in the aged

Fifteen patients aged over 65 years of age with advanced non-small-cl lung cancer (mean age = 70.7, stage IIIb: IV = 4:11) were treated with combination chemotherapy consisting of Cisplatin (50 or 80 mg/m2) and a vinca-alkaloid (Vindesine 3 mg/m2 or Etoposide 80 mg/m2). The effectiveness and side effects of this cisplatin therapy in different combinations of vinca-alkaloid regimens (Vindesine vs Etoposide) were examined. The mean dose of Cisplatin in the Etoposide combination group (75.2 mg/m2) was significantly higher than that in the Vindesine combination group (54.3 mg/m2) (p less than 0.01). A notable reduction the tumor size was observed in 25% of the Etoposide group, only. The 6-month survival rate and one-year survival rate were respectively 85.7%, 57.1% in the Vindesine + Cisplatin group, and 87.5%, 50% in the Etoposide + Cisplatin group. The common side effects were nausea, vomiting, anorexia, and alopecia. These symptoms were either alleviated by antiemetic drugs or followed by spontaneous recovery. Leucopenia, anemia and thrombocytopenia were found in both groups, and there was no difference in the time course of myelosuppression between the two groups. The extent of nephrotoxicity was assessed by creatinine clearance rate. Its decrease in the Vindesine group (60.1----38.9 ml/min) was higher than that in the Etoposide group (64.9----48.9 ml/min), while there was no significant change in BUN, serum creatinine and urine NAG between the two groups. There were no cases in which chemotherapy schedules had to be interrupted due to myelosuppression and nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cisplatin, vindesine, and bleomycin (DVB) combination chemotherapy for esophageal carcinoma

Forty-six patients with epidermoid carcinoma of the esophagus have been treated with a three-drug combination of cisplatin, vindesine, and bleomycin. Of the 40 patients currently evaluable for response, 21 have had partial remissions (52%). At least four of these responses were almost complete, with only microscopic disease found on endoscopy or review of the resected specimen. Toxic effects have, in general, been manageable. The major toxic effects included nausea and vomiting, nephrotoxicity, and myelosuppression. There were two drug-related deaths: one due to renal failure and one due to sepsis. The three-drug combination appears to be substantially more effective than either the two-drug combination of cisplatin and bleomycin or vindesine alone. Effects on survival cannot yet be evaluated.     

Cisplatin bolus and 5-FU infusion chemotherapy for non-small cell lung cancer

Patients with unresectable non-small cell lung cancer were treated with combination chemotherapy: cisplatin (100 mg/m2) on Day 1 and 5-FU (1 g/m2 continuous infusion) on Days 1-5, initially every third week, then every 4-6 weeks. Group 1 consisted of 19 patients without prior therapy and Group 2 consisted of 15 patients with prior therapy. Using standard criteria, seven patients (37%) in Group 1 achieved partial remissions lasting 2 to greater than 31 months (median, 10). Patients with squamous cell carcinoma or good performance status were somewhat more likely to respond. Three patients (20%) in Group 2 achieved partial remissions lasting 5-7 months. Mucositis (grade II in six patients, grade III-IV in seven patients) was the dose-limiting toxicity, especially in Group 2. These responses to cisplatin bolus and 5-FU infusion in patients with non-small cell lung cancer were not greater than those achieved with other cisplatin-containing regimens. However, this combination does have activity and might be effectively combined with radiation therapy as has been done for carcinomas of other sites.     

Intensive induction chemotherapy in 54 patients with small cell carcinoma of the lung

Fifty-four patients with localized and extensive small cell carcinoma of the lung and no prior therapy were treated with intensive induction chemotherapy. The induction regimen consisted of two courses of high-dose cyclophosphamide, doxorubicin, and VP-16-213. The objective response rate was 78% (42 responses among 54 patients), with 14 complete (26%) and 28 partial (52%) responses. The median survival time for the entire group of patients is 378 days, with a projected 2-year survival rate of 22%. The most significant determinant of survival was the attainment of a complete response. Tumor progression in most relapsing patients occurred at the sites of initial involvement. Toxicity was significant, as expected, but treatment-related mortality did not exceed that of less intense regimens. Despite the use of such intensive induction regimens, the major challenge in the therapy for small cell carcinoma remains the achievement of more durable complete remissions.     

紫杉醇顺铂方案联合同步放疗治疗顺铂依托泊苷化疗不敏感局限期小细胞肺癌的临床疗效

目的探讨紫杉醇顺铂联合同步放疗对顺铂依托泊苷(EP)不敏感局限期小细胞肺癌的治疗作用。方法 EP两周期化疗结束2 w后评估为无变化和疾病进展的患者为研究对象,在知情同意下随机分为继用EP方案化疗联合同步放疗组(观察组)和改用紫杉醇顺铂联合同步放疗组(对照组)。观察两组的毒副作用,评估治疗结束后4 w的近期临床有效率(RR),以疾病无进展生存时间(PFS)为随访终点。结果观察组的RR为37.5%(6/16),对照组为76.5%(13/17),两组差异显著。中位PFS:观察组为6.0个月,对照组为12.0个月,两组差异显著。两组骨髓抑制、放射性食管炎及放射性肺炎等不良反应无统计学差异。结论紫杉醇顺铂联合同步放疗对EP两周期化疗不敏感局限期小细胞肺癌有效。