Phase II study of trastuzumab in combination with S-1 plus cisplatin in HER2-positive gastric cancer (HERBIS-1)

Background:

S-1, an oral fluoropyrimidine, plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. To date, no studies have evaluated the efficacy and safety of trastuzumab combined with SP in patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC.

Methods:

Patients with HER2-positive AGC received S-1 (80–120 mg per day) orally on days 1–14, cisplatin (60 mg m⁻²) intravenously on day 1, and trastuzumab (course 1, 8 mg kg⁻¹; course 2 onward, 6 mg kg⁻¹) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary end points included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and adverse events.

Results:

A total of 56 patients were enrolled. In the full analysis set of 53 patients, the confirmed RR was 68% (95% confidence interval (CI)=54–80%), and the disease control rate was 94% (95% CI=84–99%). Median OS, PFS, and TTF were estimated as 16.0, 7.8, and 5.7 months, respectively. Major grade 3 or 4 adverse events included neutropaenia (36%), anorexia (23%), and anaemia (15%).

Conclusions:

Trastuzumab in combination with SP showed promising antitumour activity and manageable toxic effects in patients with HER2-positive AGC.     

Cediranib with mFOLFOX6 vs bevacizumab with mFOLFOX6 in previously treated metastatic colorectal cancer

Background:

Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signalling with activity against all three VEGF receptors. Bevacizumab is an anti-VEGF-A monoclonal antibody with clinical benefit in previously treated metastatic colorectal cancer (mCRC).

Methods:

Patients with mCRC who had progressed following first-line therapy were randomised 1 : 1 : 1 to modified (m)FOLFOX6 plus cediranib (20 or 30 mg day⁻¹) or bevacizumab (10 mg kg⁻¹ every 2 weeks). The primary objective was to compare progression-free survival (PFS) between treatment arms.

Results:

A total of 210 patients were included in the intent-to-treat (ITT) analysis (cediranib 20 mg, n=71; cediranib 30 mg, n=73; bevacizumab, n=66). Median PFS in the cediranib 20 mg, cediranib 30 mg and bevacizumab groups was 5.8, 7.2 and 7.8 months, respectively. There were no statistically significant differences between treatment arms for PFS (cediranib 20 mg vs bevacizumab: HR=1.28 (95% CI, 0.85–1.95; P=0.29); cediranib 30 mg vs bevacizumab: HR=1.17 (95% CI, 0.77–1.76; P=0.79)) or overall survival (OS). Grade ⩾3 adverse events were more common with cediranib 30 mg (91.8%) vs cediranib 20 mg (81.4%) or bevacizumab (84.8%).

Conclusion:

There were no statistically significant differences between treatment arms for PFS or OS. When combined with mFOLFOX6, the 20 mg day⁻¹ dose of cediranib was better tolerated than the 30 mg day⁻¹ dose.     

Phase I/II trial of a biweekly combination of S-1 plus docetaxel in patients with previously treated non-small cell lung cancer (KRSG-0601)

Background:

Combination of S-1, an oral fluorouracil derivative, plus docetaxel against non-small cell lung cancer (NSCLC) showed promising efficacy but clinically problematic emesis. A phase I/II study utilising a new schedule for this combination was conducted.

Methods:

A biweekly regimen of docetaxel on day 1 with oral S-1 on days 1–7 was administered to previously treated NSCLC patients. Doses of docetaxel/S-1 were escalated to 30/80, 35/80, and 40/80 mg m⁻², respectively, and its efficacy was investigated at the recommended dose below maximum tolerated dose (MTD).

Results:

In phase I study employing 13 patients, dose-limiting toxicities were febrile neutropenia and treatment delay, with the respective MTDs for docetaxel 40 mg m⁻²/S-1 80 mg m⁻². In the phase II study, 34 patients were treated with docetaxel 35 mg m⁻²/S-1 80 mg m⁻² for a median cycle of 6. The response and disease control rates were 34.3% (95% confidence interval (CI), 18.6–50.0%) and 62.9% (95% CI, 46.8–72.9%), respectively. Median progression-free survival was 150.5 days. Haematologic grade 4 toxicities were observed in neutropenia (11.8%) and thrombocytopenia (2.9%). Regarding non-haematologic toxicities, including emesis, there were no grade 3/4 side effects.

Conclusion:

Combination of 1-week administration of S-1 with biweekly docetaxel is safe and active for NSCLC.     

A phase I dose-escalation study of eribulin and S-1 for metastatic breast cancer

Background:

We evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, recommended dose for phase II (P2RD), and preliminary anticancer activity of a combination eribulin and S-1 therapeutic in metastatic breast cancer patients pretreated with anthracycline and taxane.

Method:

Patients aged 20–74 years were recruited. In level 1, patients received S-1 (65 mg m⁻²) from day 1 to 14, and eribulin (1.1 mg m⁻²) on day 1 and 8 in a 21-day cycle. In level 2, eribulin was increased to 1.4 mg m⁻². In level 3, S-1 was increased to 80 mg m⁻².

Results:

Twelve patients were enrolled into three cohorts. Planned dose escalation was completed, with one case exhibiting dose-limiting toxicity (grade 3 hypokalaemia) at level 3, without reaching the MTD. The P2RD was determined to be level 2 (eribulin 1.4 mg m⁻² and S-1 65 mg m⁻²). The most common grade 3 or 4 toxicity was neutropenia (83.3%), followed by febrile neutropenia (25.0%). Five of eleven patients (41.7%) with measurable disease had a partial response. Pharmacokinetics were characterised by dose-dependent elimination and nonlinear exposure.

Conclusion:

Dose level 3 was not tolerated owing to febrile neutropenia development. Thus, intermediate dose level 2 was recommended for further evaluation. Preliminary antitumour activity warrants further investigation in this setting.     

S-1 plus irinotecan and oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: a prospective phase II study and pharmacogenetic analysis

Background:

S-1 is an oral fluoropyrimidine that mimics infusional 5-fluorouracil. The aim of this phase II trial was to explore the clinical efficacy of the triplet regimen TIROX, which consists of S-1, irinotecan and oxaliplatin.

Methods:

Forty-two chemo-naive patients with metastatic colorectal cancer (mCRC) were planned to be enrolled and be treated with irinotecan 150 mg m⁻² followed by oxaliplatin 85 mg m⁻² on day 1 and S-1 80 mg m⁻² per day from day 1 to 14 every 3 weeks. Polymorphisms in the UGT1A1, UGT1A6, UGT1A7 and CYP2A6 genes were analysed.

Results:

Between July 2007 and February 2008, 43 patients were enrolled. An objective response was noted in 29 patients (67.4%, 95% confidence interval: 53.4–81.4), of which 2 achieved durable complete responses. The median progression-free survival was 10.0 months and the median overall survival was 19.2 months. Significant grade 3 or 4 adverse events were neutropenia (45.2%), febrile neutropenia (9.5%), diarrhoea (7.1%) and vomiting (9.5%). Increased gastrointestinal toxicities were associated with the presence of UGT1A6*2 or UGT1A7*3 and an improved tumour response was noted in those without variant alleles of CYP2A6 or UGT1A1*60.

Conclusion:

The combination of S-1, irinotecan and oxaliplatin showed favourable efficacy and tolerability in untreated patients with mCRC.     

Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer

Background:

A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting.

Methods:

Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m⁻² twice daily) on days 1–14 plus paclitaxel (60 mg m⁻²) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m⁻² twice daily) on days 1–21 plus cisplatin (60 mg m⁻²) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

Results:

A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7% P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin.

Conclusion:

S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials.     

Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma,a phase II study

Background:

Adrenocortical carcinoma (ACC) is a rare disease with a poor response to chemotherapy. Cisplatin is the most widely investigated drug in the treatment of ACC and in vitro studies have indicated activity of taxanes. The objectives of this study were to evaluate the efficacy and toxicity of cisplatin combined with docetaxel as first-line treatment of advanced ACC.

Methods:

Patients with advanced ACC were included in this phase II trial investigating the response to a combination of cisplatin (50 mg m⁻²) and docetaxel (60 mg m⁻²) administered with a 3-week interval.

Results:

Nineteen patients were included in this study. The response rate was 21% (95% CI: 3–39%). No patients obtained a complete response, 32% had stable disease, and 37% progressed while on treatment. The median progression-free survival (PFS) was 3 months (95% CI: 0.7–5.3 months) and 1 year PFS was 21% (95% CI: 3–39%). Median survival was 12.5 months (95% CI: 6–19 months). The predominant grade 3/4 toxicity was neutropenia (35%); febrile neutropenia occurred in 5% of cycles.

Conclusion:

This study could not demonstrate that the combination of cisplatin and docetaxel has higher efficacy than other regimens reported in previous studies.     

A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study

Background:

This randomised phase II trial compared gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer.

Methods:

Patients were randomly assigned to 4-week treatment with gemcitabine alone (1000, mg m⁻² gemcitabine by 30-min infusion on days 1, 8, and 15) or gemcitabine and S-1 combination therapy (1000, mg m⁻² gemcitabine by 30-min infusion on days 1 and 15 and 40 mg m⁻² S-1 orally twice daily on days 1–15). The primary end point was progression-free survival (PFS).

Results:

Between July 2006 and February 2009, 106 patients were enrolled. The PFS in gemcitabine and S-1 combination arm was significantly longer than in gemcitabine arm (5.4 vs 3.6 months), with a hazard ratio of 0.64 (P=0.036). Overall survival (OS) for gemcitabine and S-1 combination was longer than that for gemcitabine monotherapy (13.5 vs 8.8 months), with a hazard ratio of 0.72 (P=0.104). Overall, grade 3 or 4 adverse events were similar in both arms.

Conclusion:

Gemcitabine and S-1 combination therapy demonstrated longer PFS in advanced pancreatic cancer. Improved OS duration of 4.7 months was found for gemcitabine and S-1 combination therapy, though this was not statistically significant.     

Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205

Background:

Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer.

Methods:

Two dose levels (I/II) were defined: capecitabine 850/1000 mg m⁻² twice daily on days 1–14; oxaliplatin 100/130 mg m⁻² on day 1; bevacizumab 7.5 mg kg⁻¹ on day 1; imatinib 300 mg day⁻¹ on days 1–21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS).

Results:

Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities.

Conclusion:

The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy.     

A randomised,double-blind,placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer

Background:

The purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer.

Methods:

We undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1 : 1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m⁻² as a 90-min infusion, leucovorin at 200 mg m⁻² as a 2-h infusion, and a bolus injection of 5-FU 400 mg m⁻² followed by a 46-h continuous infusion of 5-FU at 2400 mg m⁻². The XELIRI regimen consisted of irinotecan at 250 mg m⁻² as a 90-min infusion with capecitabine 1000 mg m⁻² twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity.

Results:

Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5–7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4–8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade ⩾3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively).

Conclusions:

The addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity.     

Adjuvant chemotherapy for gastric cancer: a randomised phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201)

Background:

This phase 3 study evaluated the efficacy of new adjuvant chemotherapy (MFP), which intensified the mitomycin-C (MMC) plus short-term doxifluridine (Mf) for gastric cancer.

Patients and methods:

A total of 855 patients (424 in Mf, 431 in MFP) with pathological stage II–IV (M0) gastric cancer after D2 gastrectomy were randomly assigned to receive either Mf (MMC 20 mg m⁻², followed by oral doxifluridine 460–600 mg m⁻² per day for 3 months) or MFP (MMC 20 mg m⁻², followed by oral doxifluridine 460–600 mg m⁻² per day for 12 months with 6 monthly infusions of 60 mg m⁻² of cisplatin) chemotherapy.

Results:

With a median follow-up of 6.6 years, there was no difference between the two groups in recurrence-free survival (RFS) (5-year RFS 61.1% in Mf and 57.9% in MFP; hazard ratio 1.10 (95% CI 0.89–1.35); P=0.39) and overall survival (OS) (5-year OS 66.5% in Mf and 65.0% in MFP; hazard ratio 1.11 (95% CI 0.89–1.39); P=0.33).

Conclusion:

Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients.     

Phase II study of gemcitabine,oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer

Background:

Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer.

Methods:

Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0–2 were treated with panitumumab 6 mg kg⁻¹, GEM 1000 mg m⁻² (10 mg m⁻² min⁻¹) and OX 85 mg m⁻² on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival.

Results:

Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5–24 months) and median overall survival 20.3 months (95% CI 9–25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%.

Conclusions:

The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.     

Phase I–II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma

Background:

This phase I–II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma.

Methods:

The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single-agent plitidepsin 3.2 mg m⁻² (n=20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m⁻² on days 1, 8 and 15 q4wk combined with DTIC 800 mg m⁻² q4wk (n=38).

Results:

The overall response rate with plitidepsin/DTIC was 21.4% all responders had normal serum lactate dehydrogenase (LDH) levels and performance status ⩽1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug–drug pharmacokinetic interactions were found.

Conclusion:

This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m⁻² fortnightly and DTIC 800 mg m⁻² q4wk is recommended.     

A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas

Background:

This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy.

Methods:

Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m⁻² and cisplatin 25 mg m⁻² on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand–foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m⁻², cisplatin 20 mg m⁻² and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57–77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome.

Results:

A total of 39 patients were accrued. The most common grade 3–4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34–66%). Median PFS and overall survival were 6.5 (95% CI: 3.5–8.3) and 14.4 months (95% CI: 11.6–19.2 months), respectively. No correlation was observed between pERK and outcomes.

Conclusion:

The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased.     

Neoadjuvant FOLFIRI+bevacizumab in patients with resectable liver metastases from colorectal cancer: a phase 2 trial

Background:

Preoperative treatment of resectable liver metastases from colorectal cancer (CRC) is a matter of debate. The aim of this study was to assess the feasibility and activity of bevacizumab plus FOLFIRI in this setting.

Methods:

Patients aged 18–75 years, PS 0–1, with resectable liver-confined metastases from CRC were eligible. They received bevacizumab 5 mg kg⁻¹ followed by irinotecan 180 mg m⁻², leucovorin 200 mg m⁻², 5-fluorouracil 400 mg m⁻² bolus and 5-fluorouracil 2400 mg m⁻² 46-h infusion, biweekly, for 7 cycles. Bevacizumab was stopped at cycle 6. A single-stage, single-arm phase 2 study design was applied with 1-year progression-free rate as the primary end point, and 39 patients required.

Results:

From October 2007 to December 2009, 39 patients were enrolled in a single institution. Objective response rate was 66.7% (95% exact CI: 49.8–80.9). Of these, 37 patients (94.9%) underwent surgery, with a R0 rate of 84.6%. Five patients had a pathological complete remission (14%). Out of 37 patients, 16 (43.2%) had at least one surgical complication (most frequently biloma). At 1 year of follow-up, 24 patients were alive and free from disease progression (61.6%, 95% CI: 44.6–76.6). Median PFS and OS were 14 (95% CI: 11–24) and 38 (95% CI: 28–NA) months, respectively.

Conclusion:

Preoperative treatment of patients with resectable liver metastases from CRC with bevacizumab plus FOLFIRI is feasible, but further studies are needed to define its clinical relevance.     

Phase I/II study of 131I-MIBG with vincristine and 5 days of irinotecan for advanced neuroblastoma

Background:

¹³¹I-metaiodobenzylguanidine (MIBG) is an active radiopharmaceutical in neuroblastoma. A previous study demonstrated that MIBG could be combined with vincristine and prolonged irinotecan, although 25% of first courses had grade 3 diarrhoea. The current phase I/II study evaluated MIBG with vincristine and 5 days of higher-dose irinotecan.

Methods:

Patients 1–30 years old with advanced neuroblastoma were eligible. Patients received cefixime on days −1 to +6, irinotecan (50 mg m⁻² per dose IV) on days 0–4, vincristine (2 mg m⁻²) on day 0, MIBG (555 or 666 MBq kg⁻¹) on day 1, and peripheral blood stem cells on day 13. UGT1A1 genotyping was performed in consenting patients.

Results:

Thirty-two patients (12 phase I ; 20 phase II) received 42 courses. No dose-limiting toxicities were seen during dose escalation and the recommended administered activity was 666 MBq kg⁻¹. Myelosuppression and diarrhoea were the most common toxicities, with grade 3 diarrhoea in 6% of first courses. Patients homozygous for UGT1A1*28 had more grade 4 thrombocytopenia (80% vs 37% P=0.14). Responses (five complete and four partial) occurred in 9 out of 32 (28%) patients.

Conclusions:

MIBG (666 MBq kg⁻¹) with vincristine and this irinotecan schedule is tolerable and active, with less severe diarrhoea compared with a regimen using more protracted irinotecan.     

A phase II trial of dose-dense chemotherapy,followed by surgical resection and/or thoracic radiotherapy,in locally advanced thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9606)

Background:

This study aimed to evaluate the safety and efficacy of dose-dense weekly chemotherapy, followed by resection and/or thoracic radiotherapy.

Methods:

Patients with histologically documented thymoma with unresectable stage III disease received 9 weeks of chemotherapy: cisplatin 25 mg m⁻² on weeks 1–9; vincristine 1 mg m⁻² on weeks 1, 2, 4, 6 and 8; and doxorubicin 40 mg m⁻² and etoposide 80 mg m⁻² on days 1–3 of weeks 1, 3, 5, 7 and 9. Patients went on to surgery and post-operative radiotherapy of 48 Gy; those with unresectable disease received 60 Gy radiotherapy.

Results:

total of 23 patients were entered. The main toxicities of the chemotherapy regimen were neutropenia and anaemia, and 57% of patients completed the planned 9 weeks of therapy. There were no toxic deaths. Of the 21 eligible patients, 13 (62%) achieved a partial response (95% confidence interval: 38–82%). Thirteen patients underwent a thoracotomy and nine (39%) underwent complete resection. Progression-free survival at 2 and 5 years was 80 and 43%, respectively. Overall survival at 5 and 8 years was 85 and 69%, respectively. Survival did not seem to be affected by resection.

Conclusion:

In thymoma patients, weekly dose-dense chemotherapy has activity similar to that of conventional regimens. Although some patients could achieve complete resection, the role of surgery remains unclear.     

Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102)

Background:

A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival.

Methods:

Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1–5, vincristine 0.7 mg m⁻² day 5, mitomycin 7 mg m⁻² day 5, cisplatin 14 mg m⁻² days 1–5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival.

Results:

A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80% P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85).

Conclusion:

Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.     

Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma

Background:

The aim of this open label phase II study ({"type":"clinical-trial","attrs":{"text":"NCT00407459","term_id":"NCT00407459"}}NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM).

Methods:

Eligible patients received pemetrexed 500 mg m⁻², carboplatin area under the plasma concentration–time curve (AUC) 5 mg ml⁻¹ per minute and bevacizumab 15 mg kg⁻¹, administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated.

Results:

Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7–46.0%). Forty-four (57.9%, 95% CI 46.0–69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3–4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred.

Conclusion:

The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.