Intensive weekly chemotherapy for good-prognosis patients with small-cell lung cancer.

A weekly, intensive chemotherapy regimen has been used to treat 70 patients with small-cell lung cancer (SCLC). Forty-five patients had limited disease (LD) and 25 extensive disease (ED) with good prognostic features. The regimen consisted of cisplatin 50 mg/m2 intravenously (IV) day 1 and etoposide 75 mg/m2 IV days 1 and 2, alternating weekly with ifosfamide 2 g/m2 IV day 8 and doxorubicin 25 mg/m2 IV day 8, for a total of 12 weeks. Dose modifications were made according to defined hematologic criteria. Responding patients with limited disease subsequently received mediastinal radiotherapy. Overall response to chemotherapy was 91% with a complete response (CR) rate of 50%. Forty-five patients with limited disease (LD) achieved an overall response rate of 91% with a CR rate of 51%, and 25 patients with extensive disease (ED) achieved an overall response rate of 92% with a CR rate of 48%. Median survival for the whole group was 54 weeks (LD, 58 weeks; ED, 42 weeks). Hematologic toxicity was predictable, without the wide fluctuations in WBC count seen in conventional 3-weekly regimens. In all, one quarter of treatment courses were delayed, most frequently because of leukopenia. Dose reductions were required in 63% of cases. The average delivered dose intensity was calculated and shown to be 73% of projected. Nonhematologic toxicity was mild with nausea and vomiting being the most common. This weekly schedule of chemotherapy has proved to be active and well tolerated and is currently being compared with conventional 3-weekly chemotherapy in a randomized study.     

免疫治疗在广泛期小细胞肺癌中的临床应用

小细胞肺癌(small cell lung cancer,SCLC)是临床难治肿瘤之一,约75%～80%患者发现时已发展为广泛期SCLC(extensive stage-SCLC,ES-SCLC),中位生存期不足1年。随着免疫检查点抑制剂在多种实体瘤的成功应用,ES-SCLC的免疫治疗也出现大量的临床研究,但同时对于不同阶段的治疗策略也提出了更高的要求和挑战。本文对近年开展的初治和经治ES-SCLC患者免疫治疗相关临床研究进行综述,涉及了PD-1、PD-L1、CTLA-4抑制剂,免疫检查点抑制剂的单药治疗和联合治疗模式,以及预测疗效的生物标志物,总结最佳治疗模式,深入思考未来研究的方向,以期提高疗效,改善患者生存。     

A model to select chemotherapy regimens for phase III trials for extensive-stage small-cell lung cancer

BACKGROUND: Many more phase II studies have favorable outcomes than the subsequent phase III trials. We used historical data from phase II and phase III studies for patients with extensive-stage small-cell lung cancer (SCLC) to generate a statistical model to provide assistance in selecting chemotherapy regimens from phase II studies for subsequent use in phase III randomized studies. METHODS: Information from 21 phase III trials for patients with extensive-stage SCLC initiated during the period from 1972 through 1990 was reviewed to identify those that were preceded by phase II studies of the same regimen. We used data from all the trial pairs to develop a statistical model in which the number of patients, the median survival of patients, and the number of deaths observed in the phase II trial are used to estimate the statistical power of the subsequent phase III trial. All statistical tests were two-sided. RESULTS: Nine phase II studies were identified that preceded phase III trials of the same regimen. The regimens from two phase II studies with the greatest expected power in the phase III trial (0. 62 and 0.58) both demonstrated significantly prolonged survival when compared with standard treatment in subsequent phase III trials (P<. 001 and P =.002, respectively). The regimens from six of the other phase II studies, for which the median power expected in the phase III trial was 0.28 (range, 0.19-0.52), showed no difference when compared with standard treatment in a phase III trial. CONCLUSIONS: Phase II studies for particular regimens that have an expected power of greater than 0.55 provide a reasonable basis for proceeding with a phase III trial.     

Alternating chemotherapy with or without VP-16 in extensive-stage small-cell lung cancer

In this study, we evaluated the role of alternating chemotherapy with or without etoposide (VP-16) in patients with extensive-stage small-cell carcinoma (SCC) of the lung. All patients received initial treatment with CMC [cyclophosphamide, methotrexate, and chloroethyl-cyclohexyl-nitrosourea (CCNU)]. Four weeks after initial treatment, patients were stratified by performance score, central nervous system (CNS) metastasis, age, and response to initial CMC therapy and randomized to receive AO (doxorubicin and vincristine) or AVO (doxorubicin, VP-16, and vincristine) alternating with CMC. One hundred eighty-two eligible patients were treated with the initial cycle of CMC and 98 responded (54%). One hundred fifty-four patients were randomized to either AO/CMC or AVO/CMC. The response rates to AO/CMC and AVO/CMC were similar (72 vs. 68%). The time to progression and survival were not significantly different on the two treatment regimens. Toxicity was significantly greater for patients receiving AVO/CMC with six treatment-related deaths. Etoposide as used in this regimen did not significantly influence response rates, time to progression, or survival of patients with extensive small-cell lung cancer.     

Intensive chemotherapy with autologous bone marrow transplantation for small-cell lung cancer

Summary Since 1980, 75 patients with small-cell lung cancer (SCLC) have been entered into four consecutive studies of high-dose chemotherapy using autologous bone marrow transplantation (ABMT) to assist haematological recovery. In the first study, 25 patients were treated with cyclophosphamide (160–200 mg/kg) as the sole chemotherapy; in the second (26 patients), the cycle of high-dose cyclophosphamide (with or without 800–1,200 mg/m² etoposide) was repeated as induction treatment. In the first study, response was high [14 complete responses (CR), 7 partial responses (PR)] but was not increased by repeating the cycle (15 CR, 8 PR), and survival was slightly worse in the second trial. In the third study, 15 patients were treated with doxorubicin, vincristine and etoposide for two cycles and then with 200 mg/kg cyclophosphamide. Although high-dose cyclophosphamide increased the complete response rate, the additional responses were short-lived. In the final study, an attempt was made to increase the initial CR rate by combination chemotherapy using carboplatin (400–600 mg/m²), etoposide (120 mg/ m²x4) and either high-dose cyclophosphamide (40 mg/kg x4) or melphalan (140 mg/m²). Although all nine patients responded, none underwent a CR. The long-term survival (up to 7 years) does not appear to be different from that in comparably selected cases treated with conventional chemotherapy.This work was supported by the Cancer Research Campaign     

Clinical correlation of extensive-stage small-cell lung cancer genomics

BackgroundGenomic studies in small-cell lung cancer (SCLC) lag far behind those carried out in nonsmall-cell lung cancer (NSCLC). To date, most SCLC studies have evaluated patients with surgically resectable disease. Here we sought to evaluate the genomic mutation spectrum of ‘every-day’ SCLC patient tumors with extensive stage disease (ES-SCLC) and to correlate mutations with the main clinical outcomes of response to chemotherapy, progression-free (PFS) and overall (OS) survival.Patients and methodsA total of 50 SCLC patient tumors were examined in this study; targeted exome sequencing was obtained on 42 patients and whole-exome sequencing on 8 patients. Mutated genes were correlated with clinical outcomes using Kaplan–Meier methods (PFS, OS) and logistic regression (chemo-response). RB1 protein expression was detected by either western blotting of cultured cell lysates or immunohistochemistry of tumor specimens.ResultsIn all, 39 patients had ES-SCLC; 15 patients had either primary refractory/resistant disease and 21 patients had sensitive disease. The two most frequently mutated genes were TP53 (86%) and RB1 (58%); other frequently mutated genes (>10% patients) were involved in epigenetic regulation as well as the mTOR pathway. We identified a number of low-frequency, targetable mutations, including RICTOR, FGFR1, KIT, PTCH1 and RET. Using multivariate analysis, RB1 was the only significant factor (P = 0.038) in predicting response to first-line chemotherapy, with an odds ratio of 5.58 comparing mutant RB1 with wild-type. Patients with mutant RB1 had both better OS (11.7 versus 9.1 months P = 0.04) and PFS (11.2 versus 8.6 months, P = 0.06) compared with patients with wild-type RB1. Interestingly, ∼25% of SCLC cell lines and tumor specimens expressed RB1 protein, possibly representing the subgroup with wild-type RB1.ConclusionsWe found that SCLC tumors harboring no mutation in RB1 had a poor response to chemotherapy.     

Tumor lysis syndrome in extensive-stage small-cell lung cancer

Tumor lysis syndrome is a constellation of metabolic complications that occurs in the setting of treatment of hematologic malignancies. On occasion, it has been reported to occur after therapy for solid tumors associated with large tumor burdens and aggressive therapy. We herein report the rare occurrence of acute tumor lysis syndrome in a woman with extensive-stage small-cell lung cancer after cytotoxic therapy.     

High-dose induction chemotherapy with cyclophosphamide, etoposide, and cisplatin for extensive-stage small-cell lung cancer

To exploit possible dose-response and combination drug synergism, 20 previously untreated patients with extensive-stage small-cell lung cancer (SCLC) received one or two courses of high-dose induction chemotherapy consisting of cyclophosphamide (100 mg/kg), etoposide (1,200 mg/m2), and cisplatin (120 mg/m2) (HDCEP). HDCEP was followed by four cycles of standard-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1.4 mg/m2) (CAV). Response was determined after HDCEP and following CAV. Reevaluation included repeat bronchoscopy and chest computerized tomography (CT), as well as repetition of all initially abnormal studies. All patients were evaluable for response and toxicity. Overall response to HDCEP was 90%, with a complete response (CR) rate of 65% (95% confidence limits, 44% to 86%) and a partial response (PR) rate of 25% (95% confidence limits, 6% to 44%). All patients either maintained or improved their initial response while receiving CAV. Median duration of response was 6 months (range, 2 to 12 months) and median survival was 9.5 + months (range, 2 to 21 + months). All 37 courses of HDCEP were associated with leukopenia (less than 1,000/microL), 92% with thrombocytopenia (less than 20,000/microL), and 84% with fever of greater than 38.5 degrees C. Additional toxicities included bacteremia (24%), nausea and emesis (59%), mucositis (57%), diarrhea (38%), and hemorrhagic cystitis (5%). There were two treatment-related deaths due to infection. A third patient died 4 months after completing HDCEP with pulmonary fibrosis. Although response duration and median survival were not improved, HDCEP produced a high CR rate in ambulatory patients with extensive-stage SCLC.     

Chemotherapy for extensive-stage small-cell lung cancer with idiopathic pulmonary fibrosis

Background

Idiopathic pulmonary fibrosis (IPF) is associated with an independent increased risk of lung carcinogenesis. The benefit of chemotherapy for extensive-stage small-cell lung cancer (ED-SCLC) in cases of IPF remains unknown. This study was conducted to elucidate the efficacy of chemotherapy for ED-SCLC in patients with IPF.

Methods

This was a retrospective observational study of ED-SCLC patients with IPF (all with distant metastasis) who received systemic chemotherapy. The response rate, toxicity, overall survival, and progression-free survival (PFS) were investigated.

Results

Eleven patients treated with chemotherapy between January 2005 and December 2011 were the subjects of this study. The overall response rate with the 1st regimen was 63.6 %. The median overall survival was 7.0 months, and the median PFS was 4.7 months.

Conclusion

Our results suggest that ED-SCLC patients with IPF may benefit from chemotherapy. A prospective study will be needed to confirm this in the future.     

A phase II study of weekly alternating chemotherapy in extensive-stage small cell lung cancer

Despite the recent development of new chemotherapeutic agents with activity in small cell lung cancer (SCLC), the long-term prognosis of patients with extensive-stage disease remains poor and has not improved in the past 20 years. The present study was designed to evaluate the activity and toxicity of weekly, alternating-regimen chemotherapy in patients with extensive-stage SCLC. Patients with previously untreated extensive-stage SCLC and performance status 0-2 were treated with cyclophosphamide 250 mg/m², etoposide 100 mg/m², and cisplatin 50 mg/m² on day 1; vincristine 1 mg/m² on day 8; and ifosfamide 1.2 gm/m² on days 8 and 9 with the entire treatment repeated every 14 days. Eighteen patients received chemotherapy for a median of 14 weeks (range, 1-35 weeks). Seventeen patients (94%) required dose delays and 16 patients (89%) required at least one dose reduction due to toxicity. Twelve patients (67%) exhibited an objective response (1 complete response, 11 partial response) with a median duration of response of 18 weeks (range, 8-32 weeks). Median survival was 33 weeks (range, 1-57 weeks) with a 1-year survival rate of 22%. Toxicity was primarily hematologic, including grade 3-4 leukopenia (82% of patients) and anemia (53% of patients). Only 2 patients developed grade 3 peripheral neuropathy and none exhibited grade 3-4 renal insufficiency. This regimen of weekly alternating combination chemotherapy resulted in tolerable toxicity as well as response and survival rates comparable to those achieved with standard chemotherapy in patients with extensive-stage SCLC. However, weekly chemotherapy regimens for the treatment of SCLC remain investigational.     

Second-line treatment of small-cell lung cancer. The case for systemic chemotherapy

Small-cell lung cancer is an aggressive tumor associated with high rates of regional or distant metastases at diagnosis. Although highly chemosensitive to agents given in the first-line setting (e.g., etoposide and cisplatin), most patients relapse and have a poor prognosis. Treatment options for relapsed patients include radiotherapy for limited-stage disease and chemotherapy or combined modalities for advanced-stage disease. In clinical practice, however, some oncologists maintain that chemotherapy provides an insufficient survival benefit to justify the sometimes debilitating toxicity associated with the more active regimens in particular. Other potential barriers to further treatment include patient comorbidities, performance status, site(s) of progression, progression-free interval, and previous treatments. However, numerous clinical trials demonstrate that some patients benefit from treatment, achieving prolonged survival, symptom palliation, improved quality of life, and the opportunity, albeit rare, for durable remission. Additionally, several novel chemotherapeutics are available that alone or in combination help patients lead an improved quality of life. Finally, alternative routes and schedules--oral formulations, weekly administration, and prolonged treatment vacations--have been developed to deliver chemotherapy to patients with poor performance status or multiple comorbidities. This article reviews the advantages and disadvantages of treating recurrent small-cell lung cancer and summarizes the utility of several active agents.     

不同放化疗组合方案对广泛期SCLC预后影响

目的 探讨不同放化疗组合方案对广泛期SCLC预后的影响。方法 回顾分析2011—2015年收治的322例广泛期SCLC患者,均接受依托泊苷+顺铂或卡铂标准方案化疗;根据RECIST标准将化疗后疗效分为CR、PR、SD、PD,排除化疗后进展的90例,共入组232例。根据化疗有效后是否行放疗将患者分为放疗组(187例)和无放疗组(45例)。根据放疗的早晚分为早放疗组(化疗≤3个周期接受放疗,65例)和晚放疗组(化疗>3个周期接受放疗,122例)。根据放疗和化疗顺序分为同步放化疗组(45例)和序贯放化疗组(142例)。Kaplan-Meier计算生存率,Logrank检验差异,Cox模型多因素预后分析。结果 中位OS、PFS、LRFS全组分别为13.2、 8.7、14.6个月;无放疗组分别为 8.7、5.6、5.9个月,有放疗组分别为15.0、9.8、19.2个月(P=0.00、0.00、0.00);早放疗组分别15.4、8.0、19.2个月,晚放疗组分别为14.6、10.8、18.1个月(P=0.720、0.426、0.981);同步放化疗组分别为19.4、10.8、19.8个月,序贯放化疗组分别为13.8、9.8、17.8个月(P=0.036、0.656、0.768)。接受放疗患者不良反应较无放疗患者增加(P=0.038),但≥3级严重不良反应相似(P=0.126)。     

Phase II study of cisplatin/etoposide and endostar for extensive-stage small-cell lung cancer

Purpose  

To investigate the efficacy and safety of endostar, a novel recombinant human endostatin, plus cisplatin, and etoposide in patients with extensive-stage small-cell lung cancer (ED-SCLC).     

Phase I trial of aggressive weekly chemotherapy in small-cell carcinoma of the lung

We have treated 10 patients with small-cell carcinoma of the lung with an aggressive weekly chemotherapy regimen. Treatment consisted of cyclophosphamide and doxorubicin (Adriamycin) on day 1, methotrexate on day 8, followed by leucovorin on days 9, 10, and 11 cis-platinum on day 15, VP-16 on days 15, 16, and 17, vincristine on days 1, 8, 15, and 22, and trimethoprim/sulfa twice daily. Cycles were repeated every 28 days. The primary toxicity was hematologic. One treatment-related death occurred. All other patients tolerated treatment without irreversible toxicity. There have been three complete responses and seven partial responses. This very active regimen is tolerated with acceptable toxicity even in patients with poor performance status.     

Topotecan for the treatment of small-cell lung cancer

Lung cancer is the most prevalent and yet the most preventable malignancy worldwide. Owing to the propensity of small-cell lung cancer to early relapse and its relative resistance to subsequent treatment there is a need to improve currently available therapies. Topotecan has provided an efficacious and tolerable therapeutic option for patients with recurrent small-cell lung cancer, and the oral formulation has also been shown to be beneficial, even in elderly patients of poor performance status. Herein we review the role of topotecan in the treatment of small-cell lung cancer.     

Pilot phase II study of weekly chemotherapy with paclitaxel and carboplatin for refractory or relapsed small-cell lung cancer

Purpose: The safety and efficacy of weekly chemotherapy with paclitaxel and carboplatin for the treatment of patients with refractory or relapsed small-cell lung cancer (SCLC) were evaluated. Patients and methods: Paclitaxel (100 mg/m²) and carboplatin (with a target area under the concentration versus time curve of 2 mg min/ml using the Calvert formula) were administered to patients with previously- treated SCLC on days 1 and 8 at every 3–4 weeks. Results: A total of 29 patients (pts) [male/female, 26/3 pts; median age 62.7 years (43–74); performance status 0/1/2, 9/10/10 pts] were enrolled between March 2000 and June 2002. The mean number of cycles administered per pt was 3 (1–7). The overall response rate was 69% (95% confidence interval 52–86%), and 83% (15/18) in sensitive pts and 45% (5/11) in refractory pts (P<0.01). The overall median survival time was 29.6 weeks with a 1-year survival rate of 37% [34.1 weeks in sensitive pts and 23.1 weeks in refractory pts (P=0.085), 46.9 weeks in PS 0–1 and 16.3 weeks in PS 2 (P<0.001)]. The median time to progressive disease was 16.4 weeks [21.7 weeks in sensitive pts and 15.3 weeks in refractory pts (P=0.32)]. Hematologic toxicities observed included grade ≥3 neutropenia in 55%, grade ≥3 anemia in 36%, and grade ≥3 thrombocytopenia in 3%. Non-hematologic toxicities were mild except for grade 3 diarrhea in three pts and grade 3 pneumonitis in one pt. Conclusion: Weekly chemotherapy with paclitaxel and carboplatin was well- tolerated and gave a high-response rate in pts with refractory or relapsed small-cell lung cancer.     

Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress.

PURPOSE: All cooperative group studies performed in North America for patients with extensive-stage small-cell lung cancer (SCLC) were evaluated to determine the pattern of the clinical trials and the outcome of patients over the past 20 years. PATIENTS AND METHODS: Phase III trials for patients with extensive-stage SCLC were identified through a search of the National Cancer Institute Cancer Therapy Evaluation Program database from 1972 to 1993. Patients with extensive-stage SCLC treated during a similar time interval listed in the Surveillance, Epidemiology, and End Results (SEER) database were also examined. Trends were tested in the number of trials over time, the number and sex of patients entered onto the trials, and the survival time of patients treated over time. RESULTS: Twenty-one phase III trials for patients with extensive-stage SCLC were initiated between 1972 and 1990. The median of the median survival times of patients treated on the control arms of the phase III trials initiated between 1972 and 1981 was 7.0 months; for those patients enrolled onto control arms between 1982 and 1990, the median survival time was 8.9 months (P =.001). Analysis of the SEER database of patients with extensive-stage SCLC over the same time period shows a similar 2-month prolongation in median survival time. CONCLUSION: Analysis of 21 phase III trials initiated in North America and the SEER database from 1972 to 1994 demonstrates that there has been a modest improvement in the survival time of patients with extensive-stage SCLC.