Interfraction interval in patients with stage III non-small-cell lung cancer treated with hyperfractionated radiation therapy with or without concurrent chemotherapy: final results in 536 patients

We investigated the influence of interfraction interval (IFI) on treatment outcome in patients with stage III non-small-cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (Hfx RT) with or without concurrent chemotherapy (CHT). During 3 randomized phase III and 1 phase II study, a total of 536 patients were treated with Hfx RT alone or with concurrent carboplatin/etoposide. Two hundred eighty-five patients were treated with IFI of 4.5-5.0 hours, while 251 patients were treated with IFI of 5.5-6.0 hours. "Shorter" (4.5-5.0 hours) IFI led to better overall survival (OS) (P = 0.0000) and local recurrence-free survival (LRFS) (P = 0.0000). Multivariate analyses showed IFI to be an independent prognosticator of both OS and LRFS. These results were confirmed when we separated all patients (n = 536) into those treated with Hfx RT only (n = 127) and those treated with concurrent RT/CHT (n = 409). Various RT-related high-grade acute toxicity was not different between the 2 IFI, but patients treated with shorter IFI had a significantly higher incidence of hematological toxicity (P = 0.002). None of the late high-grade toxicities were different between the 2 interfraction intervals. Using regression analysis, it was shown that IFI was not a significant predictor of any of acute or late high-grade (> or =3) toxicity. IFI is an important prognosticator of OS and LRFS in patients with stage III NSCLC treated with Hfx RT with or without concurrent carboplatin/etoposide. IFI led to higher incidence only of hematological toxicity, but was not predictive of any acute or late high-grade (> or =3) toxicity. A carefully designed randomized trial seems necessary to give better insight into the issue of optimal IFI in this disease.     

Induction chemotherapy followed by concurrent chemoradiation for patients with non-operable stage III non-small-cell lung cancer

Combined modality treatment with chemotherapy (CT) and radiotherapy (RT) in stage III non-small-cell lung cancer is considered as standard therapy. As concomitant CT appears to be beneficial, the choice of anticancer agents and the role of induction chemotherapy is still unresolved. We present our experience based on an induction CT scheme with carboplatin plus paclitaxel followed by RT and concomitant CT. 31 patients with non-operable stage IIIA or IIIB NSCLC without pleural effusion were included in this study: 30 males, 1 female; median age 66 years (range: 50-81); 32% with non-operable stage IIIA and 68% with stage IIIB without pleural effusion; 61% squamous cell carcinoma, 32% adenocarcinoma and 7% other histologies. Regarding performance status (PS), 9.7% PS 0 and 90% PS 1 were included. Patients received 3 courses of induction CT with carboplatin AUC=6 and paclitaxel 175 mg/m(2), administrated i.v. on day 1 of each 21-day cycle, followed by thoracic irradiation (total dose 60-65 Gy, daily fractions 1.8-2 Gy) with two concurrent courses of carboplatin/paclitaxel. 16.2% of the patients achieved complete response, 48.4% partial response, 25.8% stable disease and 9.6% progression of disease. Median progression-free and overall survival was 12 and 18 months, respectively. The most frequent haematological toxicities were grade (G) 3 anaemia in 19.3%, G3 neutropenia in 9.6% and G4 neutropenia in 12.9%. Esophageal G2 toxicity (RTOG) was observed in 28.1% of cases. The induction CT followed by concomitant chemoradiation used in this study appears feasible, safe and effective when administered to an unselected inoperable NSCLC stage III patient cohort in the everyday routine clinical practice. Further, our results are comparable to previously published phase III studies.     

Maintenance chemotherapy for non-small-cell lung cancer

Currently, platinum-based combination chemotherapy is the standard first-line chemotherapy for non-small-cell lung cancer (NSCLC). Historically, platinum-based chemotherapy has been recommended for up to six cycles even for responders, and second-line chemotherapy has been considered when disease progression is confirmed. In spite of extensive investigations into maintenance chemotherapy, no positive data have been obtained; however, the results of recent clinical trials suggest both the safety and efficacy of maintenance chemotherapy in patients with NSCLC, although it is still controversial. In this review, we summarize the major clinical trials of maintenance chemotherapy in patients with NSCLC, and discuss its clinical validity and present future perspectives.     

长春瑞滨和卡铂联合同步放疗治疗晚期非小细胞肺癌观察

目的：评价国产长春瑞滨(盖诺)和卡铂联合同步放疗治疗晚期非小细胞肺癌的疗效及毒副反应。方法：106例Ⅲ期NSCLC患，分为二组，化放组在放疗的同时及放疗后进行4周期化疗，化疗用药盖诺25mg／m^2在每个周期的第1、8天静脉滴注给予；卡铂300mg／m^2第1天静脉滴注。单放组行单纯放疗。结果：化放组有效率71．4％，单放组有效率为42．0％。化放组的有效率明显高于单放组(P=0．008)。化放组和单放组的1、2年生存率分别为77．39％、30．33％和58．65％、15．75％，中位生存时间分别为18个月和13个月，其差异有显性(P=0．0407)。结论：盖诺和卡铂联合同步放疗是治疗晚期非小细胞肺癌的安全有效的治疗方法，值得进一步临床研究。     

Prospective evaluation of early lung toxicity following three-dimensional conformal radiation therapy in non-small-cell lung cancer: preliminary results

PURPOSE: Radiation pneumonitis is the restricting complication following lung cancer irradiation. The correlation between dose-volume histograms (DVHs) and pneumonitis, with a clinical, radiological, and respiratory function evaluation was assessed. Special endpoint was the evaluation of respiratory function after three-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS: Fifty-four patients with non metastatic non-small-cell lung cancer (NSCLC) were treated with a curative intent with 3D-CRT (66 Gy). Thirty-one patients were treated postoperatively (pneumonectomy in 9 patients) for residual tumor or massive nodal involvement (N2 or N3); 23 patients were treated with exclusive radiotherapy. Clinical evaluation, CT scan, and pulmonary functional tests were performed before and 6 weeks after irradiation. The DVHs were calculated applying lung density heterogeneity. RESULTS: Twenty patients had radiation pneumonitis. Irradiation significantly decreased total lung capacity. Volume of the PTV2 (more than 200 cm(3)) was a significant prognostic factor for lung complication. CONCLUSION: DVHs combined with initial pulmonary functional tests can predict pulmonary toxicity and could allow us to adjust volume that received total highest dose with acceptable toxicity.     

Adjuvant chemotherapy for resected non-small-cell lung cancer

Because of the high rate of distant disease recurrence, the 5-year survival of patients who have undergone complete surgical resection of localized non-small-cell lung cancer (NSCLC) is approximately 50%. Initial results from early studies of adjuvant postoperative chemotherapy reported an adverse effect of alkylating agent and older chemotherapy regimens on survival. Cisplatin-based combinations were the first to show a survival advantage. A 1995 meta-analysis of these studies suggested a 13% reduction in the hazard ratio for death (HR = 0.87), leading to a 5% survival benefit at 5 years. Still, these trials involved limited numbers of patients (N = 1,394), and the results failed to reach statistical significance (P = .08). Of the five largest subsequent randomized trials of platinum-based adjuvant therapy, three showed a significant survival advantage. Although it is impossible to determine the reasons for the differing outcomes of these studies, several key features distinguish them, and the data suggest that medically fit patients with resected stage IB or II NSCLC should be offered chemotherapy with a platinum/new drug combination.     

晚期非小细胞肺瘤的双途径化疗

目的研究不同的化疗方法治疗晚期非小细胞肺癌（NSCLC）并观察其疗效和毒副反应。方法将55例晚期NSCLC患者分4组,A组经皮肺穿刺瘤体内注射卡铂（PCI）+支气管动脉灌注（BAI）双途径化疗13例,B组PCI+VP-16静滴12例,C组单纯BAI18例,D组传统静脉化疗12例进行临床对比观察。结果近期有效率A组为76.9%,B组为58%高于C组33.3%,明显高于D组的16.7%（P<0.01）。一年生存率A组69.2%,B组75%,优于C组的38.9%,更明显优于D组8.3%（P<0.01）。一般状况的改善A、B、C三组明显优于D组（P<0.01）;而毒副反应均明显低于D组（P<0.01）。结论PCI是一种安全、简便的直接介入疗法,联合BAI或VP-16静滴双途径化疗是晚期NSCLC较为理想有效的综合性治疗手段,且PCI+VP-16疗法较PCI+BAI疗法更安全、简便、费用少,并发症少。     

Second-line chemotherapy for non-small-cell lung cancer: recent data with pemetrexed

Bronchoalveolar carcinoma (BAC) is a subtype of non-small-cell lung cancer (NSCLC) with unique clinical and pathologic characteristics. The most recent classification system defines BAC as a primary lung cancer that tends to be peripheral and grow in a lepedic fashion along the alveolar septae without parenchymal invasion. Most of the clinical information on BAC comes from retrospective institutional reviews; however, recent studies have focused more specifically on BAC. In particular, clinical trials of molecular-targeted anticancer therapies against the epidermal growth factor receptor have led to a deeper understanding of the distinct features of this cancer and suggest that BAC may require a therapeutic paradigm different from that of other NSCLCs.     

Induction chemotherapy for resectable non-small-cell lung cancer

Lung cancer remains the leading cause of cancer death in American men and women. Non-small-cell lung cancer (NSCLC) accounts for 85% of these cases. Although surgery is the best curative approach for resectable NSCLC, long-term survival for patients with operable disease remains poor. More than half of patients who initially present with stage I to IIIA disease experience relapse of metastatic disease. Postoperative adjuvant therapy has been evaluated in several randomized trials, and provides a survival benefit. It appears reasonable to look to induction chemotherapy, or preoperative chemotherapy, to provide a similar improvement in survival with early treatment of micrometastatic disease. Multiple trials of induction therapy have been carried out with encouraging results. The use of various induction regimens with chemotherapy alone or chemotherapy combined with radiotherapy for stage IIIA NSCLC is under investigation. Randomized trials are under way to better define the role of induction therapy in the multimodality treatment of NSCLC.     

Five-year results of a phase II trial of hyperfractionated radiotherapy and concurrent daily cisplatin chemotherapy for stage III non-small-cell lung cancer

The purpose of this study was to evaluate the 5-year results for a phase II trial of hyperfractionated radiotherapy (RT) and concurrent daily cisplatin chemotherapy. Between August 1994 and December 1999, 63 patients with stage IIIA and stage IIIB non-small-cell lung cancer were treated with RT to a dose of 69.6 Gy at 1.2 Gy twice daily with daily cisplatin at 6 mg/m. Thirty-seven patients elected to receive consolidation carboplatin and paclitaxel chemotherapy. Recurrence and survival outcomes were evaluated by Kaplan-Meier analysis. Acute and late side effects were scored by the Radiation Therapy Oncology Group (RTOG) grading system. Radiographic complete or partial tumor response was achieved in 34 of 63 (54%) of cases. Median absolute survival was 20.1 months. Median time to local recurrence and distant metastases were 10.6 and 8.6 months, respectively. Overall survival rates were 57%, 35%, and 23% at 1, 3, and 5 years, respectively. Survival was significantly greater for patients receiving consolidation chemotherapy (50% versus 20% at 3 years). Only 5 patients (7%) experienced Grade 3 or 4 esophagitis. There were 16 cases of Grade 1 or 2 pneumonitis; steroid therapy resolved symptoms in 9 patients. This regimen of hyperfractionated RT and chemotherapy achieved significant response, and 5-year survival rates with acceptable toxicity.     

Outcomes of concurrent radiotherapy with weekly docetaxel and platinum-based chemotherapy in stage III non-small-cell lung cancer

PurposeThe present study evaluated the outcomes of concurrent weekly docetaxel and platinum-based drug doublet in association with concurrent thoracic radiotherapy (TR) in the curative treatment of stage III locally advanced non-small-cell lung cancer (NSCLC).Patients and MethodsPatients with stage IIIA/B NSCLC were retrospectively included. Patients received weekly docetaxel and either cisplatin or carboplatin intravenous injections during concurrent TR (60 to 66 Gy). Patients who received induction chemotherapy with the same drug doublet were also included. The endpoints were: disease control rate (DCR), overall recurrence rate, survival rates [disease-free survival (DFS) and overall survival (OS)] and toxicity.ResultsEighty-nine consecutive patients treated with this association were included. Median follow-up time was 57.8 months. DCR was 76.5% at the first follow-up CT scan (6 to 12 weeks after the end of concurrent treatment). Median DFS and OS was 14.3 and 29.9 months respectively. Three-year survival was 43%. The overall recurrence rate was 65.9%. During overall treatment, grade 3 to 4 adverse events occurred in 29.2% of patients, the most common being esophagitis (12.4% of patients). Only 13.5% of patients presented with a grade 3 or higher adverse event after the end of concurrent treatment.ConclusionsWeekly docetaxel and platinum-based drug doublet combined with TR yielded promising results in stage III NSCLC, with high survival rates. The toxicity of this association is acceptable, with mainly manageable esophagitis. These findings warrant validation in a prospective study before considering this association for standard of care.     

Stage III non-small-cell lung cancer treated with high-dose hyperfractionated radiation therapy and concurrent low-dose daily chemotherapy with or without weekend chemotherapy: retrospective analysis of 301 patients

We investigated the outcome in patients with stage III non-small-cell lung cancer (NSCLC) treated with high-dose hyperfractionated radiation therapy (Hfx RT) and concurrent chemotherapy (CHT) consisting of carboplatin (C) and etoposide (E). During three prospective randomized phase III and one prospective phase II study enrolling a total of 536 patients, 301 patients were treated with high-dose Hfx RT (69.6 Gy) and either low-dose daily CE (50 mg each) (n = 163) or daily CE (30 mg each) accompanied by "weekend" CE (100 mg of each on Saturdays and Sundays) (n = 138). The median survival time for all 301 patients is 22 months and 5-year survival is 24%. Median local recurrence-free survival (LRFS) time is 21 months and 5-year local recurrence-free survival is 32%. The median time to distant metastasis is 25 months, and 5-year distant metastasis-free survival (DMFS) is 35%. Only the type/schedule of CHT administration did not influence overall survival, LRFS, and DMFS. On multivariate analyses using these three endpoints, age stage, interfraction interval, and type/schedule of CHT administration did not predict survival, LRFS, and DMFS, while gender, KPS, and weight loss did. Only high grade hematologic toxicity was more frequent in weekend CHT group. High dose Hfx RT and concurrent low-dose daily CE with or without weekend CE is an active treatment approach in stage III NSCLC that led to high overall survival, LRFS, and DMFS rates.     

Cisplatin-based combination chemotherapy for elderly patients with non-small-cell lung cancer

Purpose: To compare the response rates, toxicities and survival durations of elderly patients (70 years of age or more) with those of younger patients ( less than 70 years of age) with non-small-cell lung cancer (NSCLC) treated with cisplatin-based chemotherapy. Patients and methods: We analyzed retrospectively the data of 203 assessable patients entered on a prospective randomized trial of cisplatin-based combination chemotherapy. Chemotherapy consisted of three dosage regimens: (1) vindesine and cisplatin (VP); (2) mitomycin, vindesine and cisplatin (MVP); or (3) etoposide and cisplatin alternating with vindesine and mitomycin (EP/VM). Results: A greater proportion of elderly patients had localized disease and more squamous cell carcinoma than non-elderly patients. The overall response rates were 44% in the elderly group and 28% in the non-elderly group. In the EP/VM arm, the response rate was significantly better in the elderly group than in the non-elderly group. The frequency of grade 4 leukocytopenia in the MVP and EP/VM arms in the elderly group was significantly greater than in the non-elderly group (P < 0.05). No differences were found in nonhematological toxicities between the two groups. There was no difference in overall survival between the groups. Conclusion: Elderly patients treated with mitomycin-containing regimens have higher hematologic toxicities than younger patients. The results of this study are consistent with the previously reported pharmaco logic data on mitomycin suggesting altered pharmacokinetics in elderly patients. The improved response rate in the elderly patients was probably because more elderly patients had earlier disease, squamous cell carcinoma and better performance status. Cisplatin-based chemotherapy was tolerable for most elderly NSCLC patients with good performance status. Received: 30 October 1996 / Accepted: 20 March 1997