Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma

This phase III randomized study compared concurrent cisplatin-radiotherapy (CRT) versus radiotherapy (RT) alone in patients with locoregionally advanced nasopharyngeal carcinoma. A total of 350 patients were randomly assigned to receive external RT alone or concurrently with cisplatin at a dosage of 40 mg/m(2) weekly. The primary endpoint was overall survival, and the median follow-up was 5.5 years. The 5-year overall survival was 58.6% (95% confidence interval [CI] = 50.9% to 66.2%) for the RT arm and 70.3% (95% CI = 63.4% to 77.3%) for the CRT arm. In Cox regression analysis adjusted for T stage, age, and overall stage, the difference in overall survival was statistically significantly in favor of concurrent CRT (P = .049, hazard ratio [HR] = 0.71 [95% CI = 0.5 to 1.0]). Subgroup analysis demonstrated that there was no difference between overall survival in the arms for T1/T2 stage (P = .74, HR = 0.93 [95% CI = 0.59 to 1.4]), whereas there was a difference between the arms for T3/T4 stage (P = .013, HR = 0.51 [95% CI = 0.3 to 0.88]), favoring the CRT arm. The regimen of weekly concurrent CRT is a promising standard treatment strategy for locoregionally advanced nasopharyngeal carcinoma patients.     

Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Fran?ais de Pneumo-Cancérologie NPC 95-01 Study.

PURPOSE: We conducted a phase III study to compare the survival impact of concurrent versus sequential treatment with radiotherapy (RT) and chemotherapy (CT) in unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomly assigned to one of the two treatment arms. In the sequential arm, patients received induction CT with cisplatin (120 mg/m2) on days 1, 29, and 57, and vinorelbine (30 mg/m2/wk) from day 1 to day 78, followed by thoracic RT at a dose of 66 Gy in 33 fractions (2 Gy per fraction and 5 fractions per week). In the concurrent arm, the same RT was started on day 1 with two concurrent cycles of cisplatin 20 mg/m2/d and etoposide 50 mg/m2/d (days 1 to 5 and days 29 to 33); patients then received consolidation therapy with cisplatin 80 mg/m2 on days 78 and 106 and vinorelbine 30 mg/m2/wk from days 78 to 127. RESULTS: Two hundred five patients were randomly assigned. Pretreatment characteristics were well balanced between the two arms. There were six toxic deaths in the sequential arm and 10 in the concurrent arm. Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm (log-rank test P = .24). Two-, 3-, and 4-year survival rates were better in the concurrent arm (39%, 25%, and 21%, respectively) than in the sequential arm (26%, 19%, and 14%, respectively). Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm (32% v 3%). CONCLUSION: Although not statistically significant, clinically important differences in the median, 2-, 3-, and 4-year survival rates were observed, with a trend in favor of concurrent chemoradiation therapy, suggesting that is the optimal strategy for patients with locally advanced NSCLC.     

Chemo‐radiotherapy for advanced non‐small cell lung cancer: concurrent or sequential? It's no longer the question: a systematic review

There has been conflicting evidence concerning the best sequence of radiotherapy (RT) and chemotherapy (CT) for advanced non‐small‐cell‐lung‐cancer (NSCLC). To investigate whether current clinical trials can clarify this schedule and offer further bases for clinical decision making, we performed a systematic review of 11 trials (2,043 patients; concurrent–1,019, sequential–1,024) that compared concurrent RT‐CT with sequential arm in advanced NSCLC patients. Primary end point was overall survival (OS). Pooled median ratios (MRs) and progression‐free‐survival ratios (FRs) for median survival and progression‐free survival (PFS) were calculated using the weighted sum of the log ratio of MR and FR of individual study. Pooled odds ratios (ORs) for the objective response rate, relapse control rate, and toxic events were calculated using the Mantel‐Haenszel estimate. Results confirmed that concurrent RT‐CT determined a statistically significant increase in median survival time (16.3 vs. 13.9 months; MR = 1.17,95%CI:1.09–1.26), response rate (64.0% vs. 56.3%; OR = 1.38,95%CI:1.10–1.72), and tumor‐relapse control (OR = 0.82,95%CI:0.69–0.97), though at the expense of increased hematological toxicity (neutropenia and thrombocytopenia) and non‐hematological toxicity (nausea/vomiting, stomatitis, and esophagitis). Similar results were obtained from the sensitivity analysis of all Phase‐III/trials designed to evaluate the primary end point of OS. Subgroup analysis revealed that concurrent strategy was mainly associated with improved loco‐regional control (OR = 0.68,95%CI:0.52–0.87). However, no difference in PFS is shown. While careful interpretation of our conclusions is required because of potential bias, the present study, to some extent, exhibits the superiority of the concurrent arm over the sequential in the treatment of advanced NSCLC. Further improvements will be obtained by optimizing the conditions for a concurrent regimen.     

Standard thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer: a phase III trial of the Japan Clinical Oncology Group (JCOG9812)

BACKGROUND: The purpose of this study was to evaluate whether radiotherapy with carboplatin would result in longer survival than radiotherapy alone in elderly patients with unresectable stage III non-small cell lung cancer (NSCLC). METHODS: Eligible patients were 71 years of age or older with unresectable stage III NSCLC. Patients were randomly assigned to the radiotherapy alone (RT) arm, irradiation with 60 Gy; or the chemoradiotherapy (CRT) arm, the same radiotherapy and additional concurrent use of carboplatin 30 mg/m(2) per fraction up to the first 20 fractions. RESULTS: This study was terminated early when 46 patients were registered from November 1999 to February 2001. Four patients (one in the RT arm, three in the CRT arm) were considered to have died due to treatment-related causes. The JCOG Radiotherapy Committee assessed these treatment-related deaths (TRDs) and the compliance with radiotherapy in this trial. They found that 60% of the cases corresponded to protocol deviation and 7% were protocol violation in dose constraint to the normal lung, two of whom died due to radiation pneumonitis. As to the effectiveness for the 46 patients enrolled, the median survival time was 428 days [95% confidence interval (CI) = 212-680 days] in the RT arm versus 554 days (95% CI = 331 to not estimable) in the CRT arm. CONCLUSIONS: Due to the early termination of this study, the effectiveness of concurrent use of carboplatin remains unclear. We re-planned and started a study with an active quality control program which was developed by the JCOG Radiotherapy Committee.     

放疗联合方克顺铂同步或序贯化疗治疗老年晚期食管癌的临床研究

目的评价放疗联合方克顺铂同步或序贯化疗治疗老年食管癌的疗效及毒副反应。方法将62例〉70a的老年食管癌病人随机分成两组,同步放化疗组（31例）：放疗d1即同时开始化疗;序贯放化疗组31例：入组后先予化疗2个周期,再单独予放疗,放疗结束后再化疗2～3个周期,放疗采用6～Coy常规分割放疗,1．8～2．0Gy／次,5次／wk,总剂量64～68Gy／6～7wk完成。结果同步组和序贯组的有效率分别为93．6％、83．9％,1a、3a局部控制率分别为77．4％与67．7％和48．4％与38．7％,两组比较差异无统计学意义（χ^2=3．02,P=0．065）。同步组和序贯组的1a、3a生存率分别为74．2％与64．5％和45．1％与32.3％,两组比较差异无统计学意义（χ^2=2．32,P=0．073）。同步组的血液学毒性、放射性食管炎以及放射性肺炎均高于序贯组,多数为1以级。结论老年晚期食管癌病人同步治疗组较序贯治疗组的疗效提高,生存期延长,毒副作用增加,但病人可以耐受。     

Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer.

PURPOSE: A phase III study was performed to determine whether concurrent or sequential treatment with radiotherapy (RT) and chemotherapy (CT) improves survival in unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were assigned to the two treatment arms. In the concurrent arm, chemotherapy consisted of cisplatin (80 mg/m(2) on days 1 and 29), vindesine (3 mg/m(2) on days 1, 8, 29, and 36), and mitomycin (8 mg/m(2) on days 1 and 29). RT began on day 2 at a dose of 28 Gy (2 Gy per fraction and 5 fractions per week for a total of 14 fractions) followed by a rest period of 10 days, and then repeated. In the sequential arm, the same CT was given, but RT was initiated after completing CT and consisted of 56 Gy (2 Gy per fraction and 5 fractions per week for a total of 28 fractions). RESULTS: Three hundred twenty patients were entered onto the study. Pretreatment characteristics were well balanced between the treatment arms. The response rate for the concurrent arm was significantly higher (84. 0%) than that of the sequential arm (66%) (P =.0002). The median survival duration was significantly superior in patients receiving concurrent therapy (16.5 months), as compared with those receiving sequential therapy (13.3 months) (P =.03998). Two-, 3-, 4-, and 5-year survival rates in the concurrent group (34.6%, 22.3%, 16.9%, and 15.8%, respectively) were better than those in the sequential group (27.4%, 14.7%, 10.1%, and 8.9%, respectively). Myelosuppression was significantly greater among patients on the concurrent arm than on the sequential arm (P =.0001). CONCLUSION: In selected patients with unresectable stage III NSCLC, the concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach.     

多西他赛加顺铂诱导化疗联合同期放化疗局部晚期非小细胞肺癌的临床观察

目的 评价TP方案诱导化疗联合同期放化疗局部晚期非小细胞肺癌的近期疗效和不良反应。方法 病理证实的局部晚期非小细胞肺癌86例,随机分成同期放化疗联合TP方案诱导化疗(ICCRT) 组和单纯同期放化疗(CCRT) 组。放疗均采用调强放疗。治疗结束后比较两组疗效、生存率和不良反应。结果 86例患者的随访率为100%。ICCRT组和CCRT组的有效率分别为80%和70%(χ²=1.26,P=0.261),1、2、3年总生存率分别为85%和65%、50%和40%、44%和33%(χ²=3.90,P=0.048),主要不良反应白细胞减少(43例和32例,χ²=3.48,P=0.062)、放射性食管炎(26例和20例,χ²=0.12,P=0.730)、血红蛋白减低(26例和16例,χ²=2.34,P=0.126)和放射性肺炎(13例和9例,χ²=0.37,P=0.541)。结论 ICCRT能明显提高局部晚期非小细胞肺癌的总生存率,且与CCRT相比并不增加局部不良反应。     

A randomized phase II trial evaluating standard (50 mg/min) versus low (10 mg/min) infusion duration of gemcitabine as first-line treatment in advanced non-small-cell lung cancer patients who are not eligible for platinum-based chemotherapy

PURPOSE: Gemcitabine is one of the most active drugs against non-small-cell lung cancer (NSCLC). Preclinical data suggested that gemcitabine efficacy could be improved by increasing the dose or by increasing the infusion duration. This study has been designed in order to explore two different approaches of gemcitabine dose intensification in patients with advanced NSCLC. PATIENTS AND METHODS: A total of 121 chemonaive patients with locally advanced or metastatic NSCLC not suitable for a platinum-based chemotherapy were randomly allocated to chemotherapy with gemcitabine 1500 mg/m2 on days 1 and 8 every 3 weeks by standard 30 min intravenous infusion (arm A), or gemcitabine 10 mg/m2/min for 150 min on days 1 and 8 every 3 weeks by intravenous infusion at fixed dose rate (arm B). RESULTS: One hundred and seventeen patients were fully analyzed. No difference in response rate (16.1% versus 9.9%, p=0.28), median time to disease progression (4 months versus 4.5 months, p=0.34) median survival (9.8 months in both arms), and 1-year survival (42.6% versus 39.0% p=0.98) was detected in arms A and B, respectively. No treatment-related deaths occurred. Main hematological toxicities were grade 3-4 neutropenia observed in 17.9% of patients in group A and in 49.2% of individuals in group B (p=0.0002). The incidence of febrile neutropenia was 3.3% in arm A and 0% in arm B (p=0.17). Grade 3-4 thrombocytopenia was more frequently observed in arm B patients (9.9% versus 1.8%, p=0.057). Non-hematological toxicity was similar in both arms, and consisted in grade 1-2 gastrointestinal toxicity observed in 48.2% of patients in arm A and 41.0% in arm B. CONCLUSION: Intensification of standard doses or prolonged infusion schedule did not result in efficacy improvement. Gemcitabine infusion duration does not warrant further investigation in patients with advanced NSCLC.     

诱导性同步放化疗治疗侵袭性肺上沟瘤

目的分析同步放化疗(CRT)在NSCLC外科治疗的地位.方法回顾性总结1987～1996年外科手术的30例累及胸顶部的NSCLC,单纯手术组10例,手术+放疗组(RT)9例,含铂方案化疗+放疗组(CRT)11例.结果单纯手术组2、4年生存率分别为30%和20%, RT组为22% 和11%,CRT组为73% 和53%.单因素分析根治性(是与否比较,P=0.027)和诱导性治疗(单纯手术和RT与CRT比较,P=0.0173)是有意义的预后因素.多因素分析仅诱导性治疗,P=0.023 8,是有意义的预后因素.结论与诱导性放疗和单纯手术相比,CRT可提高累及胸顶部的NSCLC患者的生存率.     

全身化疗同步或序贯脑放疗治疗非小细胞肺癌脑转移患者的疗效与毒副反应

目的 探讨全身化疗同步脑放疗或序贯脑放疗治疗非小细胞肺癌(NSCLC)脑转移患者的疗效和毒副反应.方法 采用前瞻对照方法,将60例NSCLC脑转移患者分为全身化疗同步脑放疗组(同步组)和全身化疗序贯脑放疗组(序贯组),每组各30例.结果 共59例患者完成治疗,总体客观缓解率(ORR)为22.0%,脑转移灶的ORR为35.6%,中位无进展生存期(PFS)为3个月,中位生存期(MST)为16个月,1年和2年总生存率分别为55.0%和24.4%.同步组和序贯组的总体ORR分别为20.0%和24.1%,脑转移灶的ORR分别为43.3%和27.6%,中位PFS分别为3和4个月,MST分别为16和13个月,差异均无统计学意义(均P>0.05).同步组和序贯组的1年生存率分别为58.5%和52.9%(P=0.365),2年生存率分别为37.2%和18.9%,同步组明显优于序贯组(P=0.011).同步组白细胞减少的发生率低于序贯组,差异有统计学意义(P=0.029);其他毒副反应的发生率差异无统计学意义(P>0.05).结论 全身化疗同步脑放疗治疗NSCLC脑转移可以取得较好疗效,且患者耐受性良好.

Abstract：

Objective To evaluate the efficacy, survival and toxicity in patients with brain metastases from non-small cell lung cancer ( NSCLC), treated with concurrent systemic chemotherapy and whole brain radiation therapy (WBRT) or sequential systemic chemotherapy/WBRT.Methods A total of 60 NSCLC patients with brain metastases were divided into two groups in this prospective clinical study:concurrent systemic chemotherapy and WBRT group (concurrent group ) and sequential systemic chemotherapy/WBRT group (sequential group).Results Of 59 assessable patients, the overall response rate was 22.0%, and the brain response rate was 35.6%;the median progression-free survival time was 3.0 months, and the overall 1- and 2-year survival rates were 55% and 24.4%, respectively, with a median survival time of 16.0 months.The overall response rate was 20.0% in the concurrent group and 24.1% in sequential group (P > 0.05 ).The brain response rates of 43.3% in concurrent group and 27.6% in sequential group were also not significantly different (P > 0.05 ).The median progression-free survival time for the patients in the concurrent group was 3.0 months versus 4.0 months in the sequential group, and the median survival time was 16.0 months versus 13.0 months ( all P >0.05 ).The 1- and 2-year survival rates were 58.5% and 37.2% versus 52.9% and 18.9%, respectively, with a significant difference in the 2-year survival rate between the two groups ( P = 0.011 ).In the sequential group, leukopenia was more frequent during chemotherapy than that in the concurrent group ( P = 0.029).Conclusion Concurrent systemic chemotherapy and WBRT is effective with tolerable adverse events in treating brain metastasis from NSCLC with an encouraging survival, and deserves further large sample and randomized multicenter clinical trials.     

Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group.

PURPOSE: This randomized study compared the results achieved by concurrent chemoradiotherapy (CRT) versus radiotherapy (RT) alone for nasopharyngeal carcinoma (NPC) with advanced nodal disease. PATIENTS AND METHODS: Patients with nonkeratinizing/undifferentiated NPC staged T1-4N2-3M0 were randomized to CRT or RT. Both arms were treated with the same RT technique and dose fractionation. The CRT patients were given cisplatin 100 mg/m2 on days 1, 22, and 43, followed by cisplatin 80 mg/m2 and fluorouracil 1,000 mg/m2/d for 96 hours starting on days 71, 99, and 127. RESULTS: From 1999 to January 2004, 348 eligible patients were randomly assigned; the median follow-up was 2.3 years. The two arms were well-balanced in all prognostic factors and RT parameters. The CRT arm achieved significantly higher failure-free survival (72% v 62% at 3-year, P = .027), mostly as a result of an improvement in locoregional control (92% v 82%, P = .005). However, distant control did not improve significantly (76% v 73%, P = .47), and the overall survival rates were almost identical (78% v 78%, P = .97). In addition, the CRT arm had significantly more acute toxicities (84% v 53%, P < .001) and late toxicities (28% v 13% at 3-year, P = .024). CONCLUSION: Preliminary results confirmed that CRT could significantly improve tumor control, particularly at locoregional sites. However, there was significant increase in the risk of toxicities and no early gain in overall survival. Longer follow-up is needed to confirm the ultimate therapeutic ratio.     

Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial.

PURPOSE: Nasopharyngeal carcinoma (NPC) is highly sensitive to both radiotherapy (RT) and chemotherapy. This randomized phase III trial compared concurrent cisplatin-RT (CRT) with RT alone in patients with locoregionally advanced NPC. PATIENTS AND METHODS: Patients with Ho's N2 or N3 stage or N1 stage with nodal size > or = 4 cm were randomized to receive cisplatin 40 mg/m(2) weekly up to 8 weeks concurrently with radical RT (CRT) or RT alone. The primary end point was progression-free survival (PFS). RESULTS: Three hundred fifty eligible patients were randomized. Baseline patient characteristics were comparable in both arms. There were significantly more toxicities, including mucositis, myelosuppression, and weight loss in the CRT arm. There were no treatment-related deaths in the CRT arm, and one patient died during treatment in the RT-alone arm. At a median follow-up of 2.71 years, the 2-year PFS was 76% in the CRT arm and 69% in the RT-alone arm (P =.10) with a hazards ratio of 1.367 (95% confidence interval [CI], 0.93 to 2.00). The treatment effect had a significant covariate interaction with tumor stage, and a subgroup analysis demonstrated a highly significant difference in favor of the CRT arm in Ho's stage T3 (P =.0075) with a hazards ratio of 2.328 (95% CI, 1.26 to 4.28). For T3 stage, the time to first distant failure was statistically significantly different in favor of the CRT arm (P =.016). CONCLUSION: Concurrent CRT is well tolerated in patients with advanced NPC in endemic areas. Although PFS was not significantly different between the concurrent CRT arm and the RT-alone arm in the overall comparison, PFS was significantly prolonged in patients with advanced tumor and node stages.     

Randomized phase II study of carboplatin/gemcitabine versus vinorelbine/gemcitabine in patients with advanced nonsmall cell lung cancer: West Japan Thoracic Oncology Group (WJTOG) 0104

BACKGROUND: Combined gemcitabine and carboplatin (GC) and combined gemcitabine and vinorelbine (GV) are active and well tolerated chemotherapeutic regimens for patients with advanced nonsmall cell lung cancer (NSCLC). The authors conducted a randomized Phase II study of GC versus GV to compare them in terms of efficacy and toxicity. METHODS: One hundred twenty-eight patients with Stage IIIB or IV NSCLC were randomized to receive either carboplatin at an area under the curve of 5 on Day 1 combined with gemcitabine 1000 mg/m2 on Days 1 and 8 (n = 64 patients) or vinorelbine 25 mg/m2 combined with gemcitabine 1000 mg/m2 on Days 1 and 8 (n = 64 patients) every 3 weeks. RESULTS: Response rates were 20.3% for the GC patients and 21.0% for the GV patients. In the GC arm, the median survival was 432 days, and the a 1-year survival rate was 57.6%; in the GV arm, the median survival was 385 days, and the 1-year survival rate was 53.3% in the GV arm. The median progression-free survival was 165 days in the GC arm and 137 days in the GV arm. Severe hematologic toxicity (Grade 4) was significantly more frequent in the GC arm (45.3% vs. 25.8% in the GV arm; P = .022). Most notably, the incidence of Grade 3 or 4 thrombocytopenia was significantly higher in the GC arm (81.3% vs. 6.5% in the GV arm; P < .001). Conversely, severe nonhematologic toxicity (Grade 3 or 4) was more common in the GV arm (7.8% vs. 19.4% in the GC arm; P = .057). CONCLUSIONS: Although the GV and GC regimens had different toxicity profiles, there was no significant difference in survival among patients with NSCLC in the current study.     

Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study.

PURPOSE: To study the efficacy of concurrent chemoradiotherapy (CRT) and adjuvant chemotherapy (AC) for nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Patients with Ho's stage T3 or N2/N3 NPC or neck node > or = 4 cm were eligible. Patients were randomly assigned to have radiotherapy (RT) or CRT with uracil and tegafur and to have AC or no AC after RT/CRT. AC comprised alternating cisplatin, fluorouracil, vincristine, bleomycin, and methotrexate for six cycles. There were four treatment groups: A, RT; B, CRT; C, RT and AC; D, CRT and AC. For CRT versus RT, groups B and D were compared with groups A and C. For AC versus no AC, groups C and D were compared with groups A and B. RESULTS: Three-year failure-free survival (FFS) and overall survival (OS) for CRT versus RT were 69.3% versus 57.8% and 86.5% versus 76.8%, respectively (P =.14 and.06; n = 110 v 109). Distant metastases rate (DMR) was significantly reduced with CRT (14.8% v 29.4%; P =.026). Locoregional failure rates (LRFR) were similar (20% v 27.6%; P =.39). Three-year FFS and OS for AC versus no AC were 62.5% versus 65% and 80.4% versus 83.1%, respectively (P =.83 and.69; n = 111 v 108). DMR and LRFR were not reduced with AC (P =.34 and.15, respectively). Cox model showed CRT to be a favorable prognostic factor for OS (hazard ratio, 0.42; P =.009). CONCLUSION: An improvement in OS with CRT was observed but did not achieve statistical significance. The improvement seemed to be associated with a significant reduction in DMR. AC did not improve outcome.     

Preliminary results of a randomized study (NPC-9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma

PURPOSE: To compare the benefit achieved by concurrent chemoradiotherapy (CRT) and/or accelerated fractionation (AF) vs. radiotherapy (RT) alone with conventional fractionation (CF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: All patients were irradiated with the same RT technique to > or =66 Gy at 2 Gy per fraction, conventional five fractions/week in the CF and CF+C (chemotherapy) arms, and accelerated six fractions/week in the AF and AF+C arms. The CF+C and AF+C patients were given the Intergroup 0099 regimen (concurrent cisplatin plus adjuvant cisplatin and 5-fluorouracil). RESULTS: Between 1999 and April 2004, 189 patients were randomly assigned; the trial was terminated early because of slow accrual. The median follow-up was 2.9 years. When compared with the CF arm, significant improvement in failure-free survival (FFS) was achieved by the AF+C arm (94% vs. 70% at 3 years, p = 0.008), but both the AF arm and the CF+C arm were insignificant (p > or = 0.38). Multivariate analyses showed that CRT was a significant factor: hazard ratio (HR) = 0.52 (0.28-0.97), AF per se was insignificant: HR = 0.68 (0.37-1.25); the interaction of CRT by AF was strongly significant (p = 0.006). Both CRT arms had significant increase in acute toxicities (p < 0.005), and the AF+C arm also incurred borderline increase in late toxicities (34% vs. 14% at 3 years, p = 0.05). CONCLUSIONS: Preliminary results suggest that concurrent chemoradiotherapy with accelerated fractionation could significantly improve tumor control when compared with conventional RT alone; further confirmation of therapeutic ratio is warranted.     

A randomized phase II trial of sequential gemcitabine plus vinorelbine followed by gemcitabine plus ifosfamide versus gemcitabine plus cisplatin in the treatment of chemo-naive patients with stages III and IV non-small cell lung cancer (NSCLC)

BACKGROUND: Third-generation platinum-based combinations are established as first-line treatment for advanced non-small cell lung cancer (NSCLC). Non-platinum regimens could be an alternative if they show similar efficacy with better tolerability. This randomized phase II trial compared the objective tumor response rate (ORR) of sequential gemcitabine plus vinorelbine followed by gemcitabine plus ifosfamide versus gemcitabine plus cisplatin. Secondary objectives included time to disease progression (TTP), overall survival and toxicity. METHODS: Chemo-naive patients with stages III and IV NSCLC and Karnofsky performance status >70 were assigned to receive either (a) gemcitabine 1000mg/m(2) plus vinorelbine 25mg/m(2) on days 1 and 8 for 2 cycles, followed by gemcitabine 1000mg/m(2) on days 1 and 8 plus ifosfamide 2000mg/m(2) on day 1 (GV-GI arm) for 2 cycles or (b) gemcitabine 1250mg/m(2) on days 1 and 8 with cisplatin 70mg/m(2) on day 1 (GC arm) for 4 cycles. RESULTS: Between July 2001 and January 2003, 102 patients were enrolled (50 on the GV-GI arm and 52 on the GC arm). Patient characteristics were balanced between arms (GV-GI arm: median age 59 years, 84% male, 22 stage IIIB, 24 stage IV, 4 stage IIIA; GC arm: median age 56 years, 87% male, 27 stage IIIB, 23 stage IV, 2 stage IIIA). Of the 101 patients evaluable for response, ORR was significantly higher on the GC arm than on the GV-GI arm (25% versus 6%, respectively; p=0.007). No complete responses occurred. TTP was longer on the GC arm than on the GV-GI arm (median 135 and 79 days, respectively), although this difference was not statistically significant (p=0.065). Survival was not significantly different between the arms (median 293 and 197 days, respectively; p=0.16). Although significantly more thrombocytopenia was reported on the GC arm (22% and 4%, respectively; p=0.02), it did not lead to more transfusions (15 transfusions in 5 patients versus 14 transfusions in 6 patients, respectively). There was no significant difference in other safety parameters between treatment arms. CONCLUSIONS: GC appears to produce better response in advanced NSCLC than GV-GI, with a trend towards longer TTP. Except for more thrombocytopenia with GC, similar toxicity profiles were observed.     

Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol.

PURPOSE: This phase II noncomparative randomized trial was conducted to determine the optimal sequencing and integration of paclitaxel/carboplatin with standard daily thoracic radiation therapy (TRT), in patients with locally advanced unresected stage III non-small-cell lung cancer (NSCLC). Survival data were compared with historical standard sequential chemoradiotherapy data from the Radiation Therapy Oncology Group. PATIENTS AND METHODS: Patients with unresected stages IIIA and IIIB NSCLC, with Karnofsky performance status > or = 70% and weight loss < or = 10%, received two cycles of induction paclitaxel (200 mg/m2)/carboplatin (area under the plasma concentration time curve [AUC] = 6) followed by TRT 63.0 Gy (arm 1, sequential) or two cycles of induction paclitaxel (200 mg/m2)/carboplatin (AUC = 6) followed by weekly paclitaxel (45 mg/m2)/carboplatin (AUC = 2) with concurrent TRT 63.0 Gy (arm 2, induction/concurrent), or weekly paclitaxel (45 mg/m2)/carboplatin (AUC = 2)/TRT (63.0 Gy) followed by two cycles of paclitaxel (200 mg/m2)/carboplatin (AUC = 6; arm 3, concurrent/consolidation). RESULTS: With a median follow-up time of 39.6 months, median overall survival was 13.0, 12.7, and 16.3 months for arms 1, 2, and 3, respectively. During induction chemotherapy, grade 3/4 granulocytopenia occurred in 32% and 38% of patients on study arms 1 and 2, respectively. The most common locoregional grade 3/4 toxicity during and after TRT was esophagitis, which was more pronounced with the administration of concurrent chemoradiotherapy on study arms 2 and 3 (19% and 28%, respectively). CONCLUSION: Concurrent weekly paclitaxel, carboplatin, and TRT followed by consolidation seems to be associated with the best outcome, although this schedule was associated with greater toxicity.     

Treatment Characteristics and Real-World Progression-Free Survival in Patients With Unresectable Stage III NSCLC Who Received Durvalumab After Chemoradiotherapy: Findings From the PACIFIC-R Study

IntroductionThe phase 3 PACIFIC trial established consolidation therapy with durvalumab as standard of care for patients with unresectable, stage III NSCLC and no disease progression after definitive chemoradiotherapy (CRT). The observational PACIFIC-R study assesses the real-world effectiveness of durvalumab in patients from an early access program. Here, we report treatment characteristics and a preplanned analysis of real-world progression-free survival (rwPFS).MethodsPACIFIC-R (NCT03798535) is an ongoing, international, retrospective study of patients who started durvalumab (intravenously; 10 mg/kg every 2 wk) within an early access program between September 2017 and December 2018. The primary end points are investigator-assessed rwPFS and overall survival (analyzed by Kaplan–Meier method).ResultsAs of November 30, 2020, the full analysis set comprised 1399 patients from 11 countries (median follow-up duration, 23.5 mo). Patients received durvalumab for a median of 11.0 months. Median rwPFS was 21.7 months (95% confidence interval: 19.1–24.5). RwPFS was numerically longer among patients who received concurrent versus sequential CRT (median, 23.7 versus 19.3 mo) and among patients with programmed cell death-ligand 1 expression greater than or equal to 1% versus less than 1% (22.4 versus 15.6 mo). Overall, 16.5% of the patients had adverse events leading to treatment discontinuation; 9.5% of all patients discontinued because of pneumonitis or interstitial lung disease.ConclusionsConsolidation durvalumab after definitive CRT was well tolerated and effective in this large, real-world cohort study of patients with unresectable, stage III NSCLC. As expected, rwPFS was longer among patients who received concurrent versus sequential CRT and patients with higher programmed cell death-ligand 1 expression. Nevertheless, favorable rwPFS outcomes were observed regardless of these factors.     

CODEL: phase III study of RT,RT + TMZ,or TMZ for newly diagnosed 1p/19q codeleted oligodendroglioma. Analysis from the initial study design

BackgroundWe report the analysis involving patients treated on the initial CODEL design.MethodsAdults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm.ResultsThirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months.ConclusionsTMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.     

Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: a Spanish Lung Cancer Group trial.

BACKGROUND: Docetaxel is a widely accepted second-line treatment in advanced non-small-cell lung cancer (NSCLC) with a risk of myelotoxicity. This study evaluated the efficacy and toxicity profile of two docetaxel regimens in NSCLC patients who had failed first-line non-docetaxel-based chemotherapy. PATIENTS AND METHODS: A total of 259 patients from 33 Spanish centers were randomized to receive either docetaxel 75 mg/m(2) administered every 3 weeks (3W arm) or docetaxel 36 mg/m(2) given weekly (1W arm) for 6 weeks followed by 2 weeks of rest. The primary end point was 1-year survival; secondary end points were median survival, time to progression, response and toxicity. RESULTS: One-year survival was 27% in the 3W and 22% in the 1W arm. Median time to progression was also similar in the two arms. Median survival was 6.6 months in the 3W arm versus 5.4 months in the 1W arm (P = 0.075). Response rates were 9.3% in the 3W arm and 4.8% in the 1W arm. More patients in the 1W arm experienced mucositis [1W, nine patients (7.2%); 3W, two patients (1.6%); P = 0.032], while febrile neutropenia was significantly higher in the 3W arm [3W, 10 patients (7.8%); 1W, one patient (0.8%); P = 0.010]. CONCLUSIONS: Both weekly and 3-weekly docetaxel were effective and well-tolerated, with different toxicity profiles. In general, there was no indication to recommend the weekly schedule. However, the significant lower rate of febrile neutropenia observed in the weekly schedule makes it a good alternative for patients at risk of severe neutropenia.