Phase III trial of chemotherapy using 5-fluorouracil and streptozotocin compared with interferon α for advanced carcinoid tumors: FNCLCC–FFCD 9710

The aim of this randomized multicenter phase III trial was to compare chemotherapy and interferon (IFN) in patients with metastatic carcinoid tumors. Patients with documented progressive, unresectable, metastatic carcinoid tumors were randomized between 5-fluorouracil plus streptozotocin (day 1–5) and recombinant IFN-α-2a (3 MU×3 per week). Primary endpoint was progression-free survival (PFS). From February 1998 to June 2004, 64 patients were included. The two arms were well matched for median age, sex ratio, PS 0–1, previous chemotherapy, surgery, or radiotherapy. The median PFS for chemotherapy was 5.5 months versus 14.1 for IFN (hazard ratio=0.75 (0.41–1.36)). Overall survival (OS), tolerance, and effects on carcinoid symptoms were not significantly different. Despite a trend in favor of IFN, there was no difference in PFS and OS in advanced metastatic carcinoid tumors and therapeutic effect of both treatments was mild.

Download Full-text

Phase III Trial Comparing Concurrent Biochemotherapy With Cisplatin, Vinblastine, Dacarbazine, Interleukin-2, and Interferon Alfa-2b With Cisplatin, Vinblastine, and Dacarbazine Alone in Patients With Metastatic Malignant Melanoma (E3695): A Trial Coordinated by the Eastern Cooperative Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2008.17.5448 ◽

2008 ◽

Vol 26 (35) ◽

pp. 5748-5754 ◽

Cited By ~ 208

Author(s):

Michael B. Atkins ◽

Jessie Hsu ◽

Sandra Lee ◽

Gary I. Cohen ◽

Lawrence E. Flaherty ◽

...

Keyword(s):

Overall Survival ◽

Metastatic Melanoma ◽

Interleukin 2 ◽

Progression Free Survival ◽

Response Rates ◽

Interferon Alfa ◽

Phase Iii ◽

Phase Iii Trial ◽

Free Survival ◽

Median Progression Free Survival

Purpose Phase II trials with biochemotherapy (BCT) have shown encouraging response rates in metastatic melanoma, and meta-analyses and one phase III trial have suggested a survival benefit. In an effort to determine the relative efficacy of BCT compared with chemotherapy alone, a phase III trial was performed within the United States Intergroup. Patients and Methods Patients were randomly assigned to receive cisplatin, vinblastine, and dacarbazine (CVD) either alone or concurrent with interleukin-2 and interferon alfa-2b (BCT). Treatment cycles were repeated at 21-day intervals for a maximum of four cycles. Tumor response was assessed after cycles 2 and 4, then every 3 months. Results Four hundred fifteen patients were enrolled, and 395 patients (CVD, n = 195; BCT, n = 200) were deemed eligible and assessable. The two study arms were well balanced for stratification factors and other prognostic factors. Response rate was 19.5% for BCT and 13.8% for CVD (P = .140). Median progression-free survival was significantly longer for BCT than for CVD (4.8 v 2.9 months; P = .015), although this did not translate into an advantage in either median overall survival (9.0 v 8.7 months) or the percentage of patients alive at 1 year (41% v 36.9%). More patients experienced grade 3 or worse toxic events with BCT than CVD (95% v 73%; P = .001). Conclusion Although BCT produced slightly higher response rates and longer median progression-free survival than CVD alone, this was not associated with either improved overall survival or durable responses. Considering the extra toxicity and complexity, this concurrent BCT regimen cannot be recommended for patients with metastatic melanoma.

Download Full-text

Phase III Trial of Two Investigational Schedules of Ifosfamide Compared With Standard-Dose Doxorubicin in Advanced or Metastatic Soft Tissue Sarcoma: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2006.09.7717 ◽

2007 ◽

Vol 25 (21) ◽

pp. 3144-3150 ◽

Cited By ~ 178

Author(s):

Paul Lorigan ◽

Jaap Verweij ◽

Zsuzsa Papai ◽

Sjoerd Rodenhuis ◽

Axel Le Cesne ◽

...

Keyword(s):

Overall Survival ◽

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Standard Dose ◽

Single Agent ◽

Progression Free Survival ◽

Phase Iii ◽

Advanced Soft Tissue Sarcoma ◽

Phase Iii Trial ◽

Free Survival

Purpose Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin. Patients and Methods This randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m2 every 21 days, ifosfamide 9 g/m2 over 3 days continuous infusion, or ifosfamide 3 g/m2 per day in 3 hours over 3 days. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, and toxicity. Results The study included 326 patients. Grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in the ifosfamide arms. Progression-free survival, overall survival, and response rates were not significantly different between the three arms. An independent data monitoring committee reviewed the interim data and recommended early closure of the trial for futility (ie, no significant difference would be shown). Conclusion Single-agent doxorubicin remains the treatment of choice for patients with advanced soft tissue sarcoma.

Download Full-text

Randomized Phase III Trial of Platinum-Doublet Chemotherapy Followed by Gefitinib Compared With Continued Platinum-Doublet Chemotherapy in Japanese Patients With Advanced Non–Small-Cell Lung Cancer: Results of a West Japan Thoracic Oncology Group Trial (WJTOG0203)

Journal of Clinical Oncology ◽

10.1200/jco.2009.23.3445 ◽

2010 ◽

Vol 28 (5) ◽

pp. 753-760 ◽

Cited By ~ 107

Author(s):

Koji Takeda ◽

Toyoaki Hida ◽

Tosiya Sato ◽

Masahiko Ando ◽

Takashi Seto ◽

...

Keyword(s):

Overall Survival ◽

Progression Free Survival ◽

Sequential Therapy ◽

Small Cell ◽

Phase Iii ◽

Small Cell Lung ◽

Phase Iii Trial ◽

Free Survival ◽

Doublet Chemotherapy ◽

Platinum Doublet

Purpose Gefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase. We conducted a phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Chemotherapy-naïve patients with advanced stage (IIIB/IV) NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function were randomly assigned to either platinum-doublet chemotherapy up to six cycles (arm A) or platinum-doublet chemotherapy for three cycles followed by gefitinib 250 mg orally once daily, until disease progression (arm B). Patients were stratified by disease stage, sex, histology, and chemotherapy regimens. The primary end point was overall survival; secondary end points included progression-free survival, tumor response, safety, and quality of life. Results Between March 2003 and May 2005, 604 patients were randomly assigned. There was a statistically significant improvement in progression-free survival in arm B (hazard ratio [HR], 0.68; 95% CI, 0.57 to 0.80; P < .001); however, overall survival results did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.03; P = .11). In an exploratory subset analysis of overall survival by histologic group, patients in arm B with adenocarcinoma did significantly better than patients in arm A with adenocarcinoma (n = 467; HR, 0.79; 95% CI, 0.65 to 0.98; P = .03). Conclusion This trial failed to meet the primary end point of OS in patients with NSCLC. The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib, especially for patients with adenocarcinoma.

Download Full-text

A multicenter randomized phase III study for newly diagnosed maximally resected glioblastoma comparing carmustine wafer implantation followed by chemoradiotherapy with temozolomide with chemoradiotherapy alone; Japan Clinical Oncology Group Study JCOG1703 (MACS study)

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyz169 ◽

2019 ◽

Vol 49 (12) ◽

pp. 1172-1175

Author(s):

Tomohiro Kadota ◽

Ryuta Saito ◽

Toshihiro Kumabe ◽

Junki Mizusawa ◽

Hiroshi Katayama ◽

...

Keyword(s):

Overall Survival ◽

Progression Free Survival ◽

Phase Iii ◽

Newly Diagnosed ◽

Phase Iii Trial ◽

Free Survival ◽

Carmustine Wafer ◽

Newly Diagnosed Glioblastoma ◽

Secondary Endpoints ◽

Phase Iii Study

Abstract A randomized phase III trial in Japan commenced in June 2019. The present standard treatment for newly diagnosed glioblastoma is maximal resection followed by chemoradiotherapy with temozolomide. The purpose of this study is to confirm the superiority of maximal resection with carmustine wafer implantation followed by chemoradiotherapy with temozolomide over the standard maximal resection followed by chemoradiotherapy with temozolomide in terms of overall survival for newly diagnosed glioblastoma. A total of 250 patients will be accrued from 35 Japanese institutions in 5.5 years. Patients with >90% surgical resection will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is overall survival and the secondary endpoints are progression-free survival, loco-regional progression-free survival and incidence of adverse events. This trial has been registered in the Japan Registry of Clinical Trial, as jRCT1031190035 [https://jrct.niph.go.jp/en-latest-detail/jRCT1031190035].

Download Full-text

Preliminary results of a randomized phase III trial comparing streptozotocin plus fluorouracil versus interferon for metastatic carcinoid tumors (FNCLCC - FFCD 9710)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4090 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4090-4090

Author(s):

J. F. Seitz ◽

L. Dahan ◽

P. Rougier ◽

J. L. Raoul ◽

E. Gamelin ◽

...

Keyword(s):

Interferon Alpha ◽

Survival Rates ◽

Progression Free Survival ◽

Median Number ◽

Carcinoid Tumors ◽

Phase Iii ◽

Expected Improvement ◽

Metastatic Carcinoid ◽

Female Ratio ◽

Phase Iii Trial

4090 Background: Streptozotocin and 5 FU in combination is widely used for the treatment of advanced carcinoids tumors. Interferon is an effective treatment of the malignant carcinoids tumors. This randomized multicenter phase III trial compared those treatments in patients with metastatic carcinoïd tumors. Methods: Patients with metastatic carcinoid tumors, clinical or biological progression, WHO status 0–2 (PS) and age ≤ 75 years were randomized 1:1 between interferon alpha 2a recombinant (3MU × 3 per weeks) and 5FU (400 mg/m2/day day1 to day5) plus streptozotocin (500 mg/m2/day day1 to day5) every 6 weeks. Stratification was done according to center, PS and anterior treatment. Primary endpoint was progression free-survival (PFS). It was required to include 120 pts and to observe 38 progressions to detect an expected improvement in 1year PFS from 55% to 80% (bilateral α = 5 % and β = 20 %). Secondary endpoints included 1-year and 2-year overall survival (OS). Intent to treat analyses were performed. Results: From February 1998 to june 2004, in 23 centers, 63 patients has been included, 32 in 5FU-STZ arm and 32 in interferon arm: median age (59 years [37–77] vs 63 [39–75]), male/female ratio (1.2 vs 1), PS 0–1 (91% vs 97%), anterior chemotherapy (13% vs 16%), surgery (69% vs 59%), radiotherapy (6% vs 0%) are well balanced between arms. The median number of 5FU-STZ and Interferon cycles was respectively 5 and 4. After a median follow-up of 26 months, the median OS for interferon was 44.3 months versus 37.7 months for chemotherapy: HR = 0.90 [0.43–1.90]; 1- year and 2-year survival rates were 89% and 72% for interferon versus 84% and 73% for chemotherapy. Conclusions: Interferon alpha 2a does not prolong OS in advanced metastatic carcinoid tumors as compared to the combination of 5FU-streptozotocin. After checking clinical and biological progression, PFS analyses will be presented at the meeting. No significant financial relationships to disclose.

Download Full-text

Once-a-Week Versus Once-Every-3-Weeks Cisplatin Chemoradiation for Locally Advanced Head and Neck Cancer: A Phase III Randomized Noninferiority Trial

Journal of Clinical Oncology ◽

10.1200/jco.2017.74.9457 ◽

2018 ◽

Vol 36 (11) ◽

pp. 1064-1072 ◽

Cited By ~ 78

Author(s):

Vanita Noronha ◽

Amit Joshi ◽

Vijay Maruti Patil ◽

Jaiprakash Agarwal ◽

Sarbani Ghosh-Laskar ◽

...

Keyword(s):

Overall Survival ◽

Head And Neck ◽

Locally Advanced ◽

Progression Free Survival ◽

Phase Iii ◽

Absolute Difference ◽

Comparable Efficacy ◽

Advanced Head ◽

Adjuvant Setting ◽

Free Survival

Purpose Chemoradiation with cisplatin 100 mg/m2 given once every 3 weeks is the standard of care in locally advanced head and neck squamous cell cancer (LAHNSCC). Increasingly, low-dose once-a-week cisplatin is substituted because of perceived lower toxicity and convenience. However, there is no level 1 evidence of comparable efficacy to cisplatin once every 3 weeks. Patients and Methods In this phase III randomized trial, we assessed the noninferiority of cisplatin 30 mg/m2 given once a week compared with cisplatin 100 mg/m2 given once every 3 weeks, both administered concurrently with curative intent radiotherapy in patients with LAHNSCC. The primary end point was locoregional control (LRC); secondary end points included toxicity, compliance, response, progression-free survival, and overall survival. Results Between 2013 and 2017, we randomly assigned 300 patients, 150 to each arm. Two hundred seventy-nine patients (93%) received chemoradiotherapy in the adjuvant setting. At a median follow-up of 22 months, the estimated cumulative 2-year LRC rate was 58.5% in the once-a-week arm and 73.1% in the once-every-3-weeks arm, leading to an absolute difference of 14.6% (95% CI, 5.7% to 23.5%); P = .014; hazard ratio (HR), 1.76 (95% CI, 1.11 to 2.79). Acute toxicities of grade 3 or higher occurred in 71.6% of patients in the once-a-week arm and in 84.6% of patients in the once-every-3-weeks arm ( P = .006). Estimated median progression-free survival in the once-a-week arm was 17.7 months (95% CI, 0.42 to 35.05 months) and in the once-every-3-weeks arm, 28.6 months (95% CI, 15.90 to 41.30 months); HR, 1.24 (95% CI, 0.89 to 1.73); P = .21. Estimated median overall survival in the once-a-week arm was 39.5 months and was not reached in the once-every-3-weeks arm (HR, 1.14 [95% CI, 0.79 to 1.65]; P = .48). Conclusion Once-every-3-weeks cisplatin at 100 mg/m2 resulted in superior LRC, albeit with more toxicity, than did once-a-week cisplatin at 30 mg/m2, and should remain the preferred chemoradiotherapy regimen for LAHNSCC in the adjuvant setting.

Download Full-text

Phase III Trial of Infusional Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared With Infusional Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) As First-Line Treatment for Metastatic Colorectal Cancer: The Gruppo Oncologico Nord Ovest

Journal of Clinical Oncology ◽

10.1200/jco.2006.09.0928 ◽

2007 ◽

Vol 25 (13) ◽

pp. 1670-1676 ◽

Cited By ~ 735

Author(s):

Alfredo Falcone ◽

Sergio Ricci ◽

Isa Brunetti ◽

Elisabetta Pfanner ◽

Giacomo Allegrini ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Progression Free Survival ◽

Phase Iii ◽

Peripheral Neurotoxicity ◽

Phase Iii Trial ◽

Free Survival ◽

Secondary Resection ◽

Phase Iii Study ◽

Grade 3

Purpose The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 200 mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI). Methods Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no prior chemotherapy for advanced disease. The primary end point was response rate (RR). Results A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral neurotoxicity (0% v 19%; P < .001), and grade 3 to 4 neutropenia (28% v 50%; P < .001) were observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to 4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators, were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and 58%, (RR, 41% v 66%; P = .0002). RR confirmed by an external panel was 34% versus 60% (P < .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm (6% v 15%; P = .033, among all 244 patients; and 12% v 36%; P = .017 among patients with liver metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032). Conclusion The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the neoadjuvant setting are warranted.

Download Full-text

Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2016.70.6994 ◽

2017 ◽

Vol 35 (17) ◽

pp. 1905-1912 ◽

Cited By ~ 61

Author(s):

Emanuele Zucca ◽

Annarita Conconi ◽

Giovanni Martinelli ◽

Reda Bouabdallah ◽

Alessandra Tucci ◽

...

Keyword(s):

Overall Survival ◽

Randomized Trial ◽

Lymphoid Tissue ◽

Progression Free Survival ◽

Phase Iii ◽

Free Survival ◽

Final Sample ◽

Phase Iii Study ◽

To Receive

Purpose There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m2/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m2 intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. Results At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination ( P = .0009). Progression-free survival was also significantly better with the combination ( P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. Conclusion Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.

Download Full-text