Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy

To evaluate the single agent activity, pharmacokinetics and tolerability of the novel tubulin targeted agent vinflunine (VFL) (320 mg m(-2) q 21 days) as second-line chemotherapy in patients with metastatic breast carcinoma (MBC). All patients had disease progression after anthracycline/taxane (A/T) therapy. They could have received a nonanthracycline adjuvant treatment and subsequently received a first-line A/T combination for advanced/metastatic disease; or relapsed >6 months after completion of adjuvant A/T therapy and were subsequently treated with the alternative agent; or relapsed within 6 months from an adjuvant A/T combination. Objective response was documented in 18 of 60 patients enrolled (RR: 30% (95% confidence interval (CI): 18.9-43.2%)). Among the responders, seven patients had relapsed during a period of <3 months from taxane-based regimen yielding a RR of 33.3%. The median duration of response was 4.8 months (95% CI: 4.2-7.2), median progression-free survival was 3.7 months (95% CI: 2.8-4.2) and median overall survival was 14.3 months (95% CI: 9.2-19.6). The most frequent adverse event was neutropenia (grade 3 in 28.3% and grade 4 in 36.7% of patients). No febrile neutropenia was observed. Fatigue (grade 3 in 16.7% of patients) and constipation (grade 3 in 11.7% of patients) were also common; these were non-cumulative and manageable permitting achievement of a good relative dose intensity of 93.5%. Vinflunine is an active agent with acceptable tolerance in the management of MBC patients previously treated with (A/T)-based regimens. These encouraging phase II results warrant further investigation of this novel agent in combination with other active agents in this setting or in earlier stages of disease.     

Accelerated chemotherapy in the treatment of urothelial cancer

To evaluate an alternative treatment for advanced or metastatic urothelial cancers, a dose-intensive combination chemotherapy regimen using carboplatin, methotrexate, vincristine and cisplatin was given to 60 patients over a 3-year period (1990 to 1993). There were 26 patients with locally advanced disease and 34 with metastatic disease; 49 patients were evaluable for response. A complete response was noted in four patients (8%) and a partial response in 15 (31%), for an overall response rate of 39%. The median survival was 12 months. Two- and 5-year survival rates were 25.5% (95% confidence interval CI) 15.2-37.0) and 7.3% (95% CI 2.2-16.4) respectively. Failure-free survival was 15.3% (95% CI 7.5-25.6) at 2 years and 5.9% (95% CI 1.6-14.4) at 5 years, with a median of 8 months. For the responders, the median duration of response was 14 months, with a range of 2-59+ months. Toxicity included myelosuppression (28% grade 4/5 neutropenia, 19% grade 4 thrombocytopenia), peripheral neuropathy (54% grade 1 and 23% grade 2/3) and ototoxicity (21% grade 1, 19% grade 2). This schedule of dose-intensified platinum-based chemotherapy for bladder cancer resulted in significant neurotoxicity without evidence of enhanced response rates or survival. Regimens such as methotrexate, vinblastine, doxorubicin and cisplatin should remain standard. Accelerated regimens may be useful in situations were it is necessary to administer chemotherapy over a short time (e.g. as part of combined modality treatment).     

A phase II monocentric study of oxaliplatin in combination with gemcitabine (GEMOX) in patients with advanced/metastatic transitional cell carcinoma (TCC) of the urothelial tract.

BACKGROUND: The aim of the study was to evaluate the activity and the safety of the gemcitabine-oxaliplatin (GEMOX) combination as first-line treatment in advanced/metastatic transitional cell carcinoma (TCC) of the urothelial tract. MATERIALS AND METHODS: Patients with metastatic or unresectable TCC, PS < or =2, creatinine < or =1.5 upper limit of normal range (UNL) and measurable disease according to RECIST criteria were treated with a combination of gemcitabine (1500 mg/m(2)) followed by oxaliplatin (85 mg/m(2)) on day 1 and 15 of a 28-day cycle. RESULTS: A total of 123 cycles were administered to 30 patients (median 4, range 1-8). Three complete responses (CR) and 11 partial responses (PR) were observed. Overall response rate (ORR) was 47% (95% CI 28% to 66%). Median overall survival (OS) was 15 months (95% CI 8-31). Grade 3 and 4 neutropenia were reported in three and one patient, respectively; grade 3 anaemia in three patients; grade 3 and 4 thrombocytopenia in two and one patient, respectively; grade 1, 2 and 3 peripheral neuropathy in 14, 11 and two patients, respectively; grade 2 and 3 fatigue in 13 and seven patients respectively. CONCLUSIONS: The GEMOX combination is active in advanced/metastatic TCC with minimal toxicity and needs to be evaluated in a selected population of unfit patients and compared with other non-cisplatin-containing regimens.     

Phase II study of IV vinflunine in patients with chemotherapy naive metastatic malignant melanoma

This phase II study evaluated vinflunine in chemotherapy naive patients with metastatic melanoma. Vinflunine was administered at 350 mg/m(2) every 3 weeks, but after 9 patients this was reduced to 320 mg/m(2) based on interim analyses of all phase II trials. A partial response was observed in 1 of the first 9 patients (11.1%) treated at 350 mg/m(2), which gives a 3.0% [95% confidence interval (CI): 0.08-15.8] response rate in 33 patients. No change was the best response in 13 patients (39.4%) with progressive disease in 16 (48.5%) and 3 were not evaluable for response. The time to response was 1.4 months and duration was 6 months. At 350 mg/m(2) grade 4 neutropaenia occurred in 3 patients (33.3%) and grade 3 in 2 patients (22.2%) while at 320 mg/m(2) grade 4 neutropaenia occurred in 6 patients (25%) and grade 3 in 3 patients (12.5%) with 2 episodes of grade 3 febrile neutropaenia. Two patients (8.3%) had grade 3 anaemia. These results do not show activity at this dose and schedule for vinflunine in patients with chemotherapy naive metastatic melanoma.     

Vinflunine -- an active chemotherapy for treatment of advanced non-small-cell lung cancer previously treated with a platinum-based regimen: results of a phase II study

A multicentre, single-arm, phase II trial designed to determine the efficacy of single-agent vinflunine in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with a platinum-based regimen. The objectives were to assess efficacy in terms of tumour response rate (primary end point), duration of response, progression-free survival (PFS) and overall survival (OS), and to evaluate the toxicity associated with this treatment. Patients with advanced NSCLC with progressive disease having failed prior platinum-based first-line treatment for advanced disease. Five responses out of the 63 treated patients were documented by WHO criteria and validated by an independent panel review (IRP), yielding a response rate of 7.9% (95% CI: 2.6-17.6) in the intent-to-treat analysis and 8.3% (95% CI: 2.8-18.4) in the evaluable population. Disease control was achieved in 35 out of 60 evaluable patients (58.3%). The median duration of response (complete response+partial response), according to modified WHO criteria was 7.8 months (95% CI: 4.6-NR). Median PFS was 2.6 months (95% CI: 1.4-3.8), and the median survival was 7.0 months (95% CI: 5.8-9.2). Grades 3-4 neutropenia was reported in 50% of patients; febrile neutropenia was observed in two patients (3.2%); grades 3-4 myalgia and grade 3 constipation were experienced by 10 (15.9%) and six (9.5%) of patients, respectively. Constipation was manageable, non-cumulative and could be prevented with laxative prophylaxis. The encouraging results from this phase II study with vinflunine warrant further investigations in phase III trials as second- or first-line treatment of advanced non-small-cell lung carcinoma, as a single agent or in combination with other active drugs.     

A phase II trial of a combination of pemetrexed and gemcitabine in patients with metastatic breast cancer: an NCCTG study.

PURPOSE: This phase II study was undertaken to define the efficacy and toxicity of pemetrexed in combination with gemcitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients with measurable metastatic breast cancer who had previously received an anthracycline and a taxane in either the adjuvant or metastatic setting were treated with gemcitabine 1250 mg/m2 (intravenous; days 1 and 8) and pemetrexed 500 mg/m2 (intravenous; day 8) every 21 days. RESULTS: Fifty-nine patients received a median of five cycles (range one to 22) of treatment and were followed until death or for a median of 28 months (range 19.4-36.6) among living patients. Fourteen partial responses for an overall response rate of 24% [95% confidence interval (CI) 16% to 39%] were documented. Nine (15%; CI 5% to 32%) patients had stable disease for >6 months. The median survival time was 10.3 months (95% CI 8.3-18.9) and the 1 year survival rate was 49% (95% CI 38% to 64%). The median time to progression was estimated to be 3.7 months (95% CI 2.3-5.3). The most common grade 3 or 4 toxicities were neutropenia and thrombocytopenia in 83% and 27% of patients, respectively. Fourteen percent of patients experienced febrile neutropenia. Other common grade 3 or 4 non-hematological toxicities included fatigue (17%), dyspnea (15%), rash (7%) and anorexia (5%). CONCLUSIONS: The combination of pemetrexed and gemcitabine is clinically active, with an overall response rate of 24% in patients with metastatic breast cancer who have previously been treated with an anthracycline and a taxane. Myelosuppression (66% grade 4 neutropenia and 14% febrile neutropenia) was the major treatment-related toxicity observed for this combination.     

Weekly chemotherapy with docetaxel, gemcitabine and cisplatin in advanced transitional cell urothelial cancer: a phase II trial.

PURPOSE: To evaluate the efficacy and toxicity of a combination of weekly docetaxel, gemcitabine and cisplatin in advanced transitional cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Thirty-five chemotherapy-na?ve (adjuvant and neoadjuvant chemotherapy was allowed) patients with advanced TCC received intravenous docetaxel 35 mg/m2, gemcitabine 800 mg/m2 and cisplatin 35 mg/m2, on days 1 and 8 every 3 weeks. Prophylactic granulocyte-colony stimulating factor was given from days 3 to 6 and days 10 to 15, anti-emetics were used routinely. RESULTS: Most (27) patients (77.1%) had a performance status of 0 to 1 and eight (22.9%) had received prior adjuvant or neoadjuvant cisplatin-based chemotherapy. In the intention-to-treat analysis, the objective response rate was 65.6% [23/35 patients, 95% confidence interval (CI) 47.8% to 80.9%]. Ten patients (28.5%) achieved a complete response (95% CI 14.6% to 46.3%) and 13 (37.1%) a partial response (95% CI 21.5% to 55.0%). Median survival time was 15.5 months, median duration of response was 10.2 months and median time to progression was 8.9 months. Ten patients (28.5%) developed grade 3/4 neutropenia, including five (14.3%) who experienced febrile neutropenia, which was successfully treated. Grade 3/4 anaemia and thrombocytopenia occurred in 20% and 25.7% of patients, respectively; four patients required platelet transfusions. There were no treatment-related deaths. CONCLUSIONS: Weekly docetaxel, gemcitabine plus cisplatin is a highly effective treatment for chemotherapy-na?ve advanced TCC, and causes only moderate toxicity. This regimen should be considered as a suitable option that deserves further prospective evaluation through randomised phase III trials.     

The combination of capecitabine and irinotecan in treating 5-Fluorouracil- and Oxaliplatin-pretreated metastatic colorectal cancer

Purpose Since the combination of capecitabine and irinotecan has successfully been used as a first-line treatment in metastatic colorectal cancer (MCRC), we expected promising results when given as a second-line treatment to metastatic colorectal patients who had been pretreated with 5-Fluorouracil and Oxaliplatin. Methods Thirty-three MCRC patients participated in this study and received an oral dose of 1,000 mg/m² capecitabine twice daily on days 1–14 and a dose of 100 mg/m² irinotecan infused over 90 min on days 1 and 8, every 3 weeks. Results The overall response rate in intent-to-treat was 33.3% (95% CI, 21.5–58.3%), including one complete response (3.0%) and ten partial responses (30.3%); 12 patients (36.4%) had disease stabilization and only 9 (27.3%) progressed. The median time to progression was 6.7 months (95% CI, 4.8–8.6 months). After a median follow-up time of 12 months, nine patients (27.3%) were still alive with metastatic disease. The median response duration for all patients was 6.7 months (95% CI, 3.9–9.5 months) and the median overall survival was 13.4 months (95% CI, 11.0–15.8 months) with a 1-year survival rate of 55.4%. Myelosuppression was commonly observed; NCI-CTC (v 2.0) grade 3/4 neutropenia, however, occurred in eight (24%) patients and grade 3 anemia was seen in one patient (3%). The most common (grade 3/4) non-hematological toxicity was diarrhea (15%) and the other severe grade 3/4 toxicities included nausea/vomiting in one patient (3%), stomatitis in one patient (3%), hand-foot syndrome in one patient (3%). Conclusions The combination of capecitabine and irinotecan is an effective and well-tolerated regimen for second-line treatment of metastatic colorectal cancer. However, further phase III trials are required to clarify its use in the treatment of metastastic colorectal cancer patients who have been pretreated with 5-fluorouracil and oxaliplatin.     

Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial

The aim of this international phase II trial was to determine the efficacy and safety profile of weekly vinorelbine plus trastuzumab as first-line chemotherapy for women with HER 2-overexpressing metastatic breast cancer. Sixty-nine patients with tumours overexpressing HER 2 received vinorelbine: 30 mg m-2 week-1 and trastuzumab: 4 mg kg-1 on day 1 as a loading dose followed by 2 mg kg-1 week-1 starting on day 8. Sixty-two patients were evaluable for response and 69 patients were evaluable for toxicity. The overall response rate was 62.9%. The median time to response was 8.4 weeks, the median duration of response was 17.5 months, the median progression-free survival was 9.9 months (95% CI, 5.6-12.1) and the one-year progression-free survival was 39.1%. The median survival for all patients was 23.7 months (95% CI, 18.4-32.6). This regimen was safe: grade 3-4 neutropenia were observed over 17.7% of courses in 83.8% of patients, with only two episodes of febrile neutropenia (0.1%) in two patients (2.9%). Only one patient discontinued treatment due to grade 3 symptomatic cardiac dysfunction that resolved with therapy. Vinorelbine plus trastuzumab is one of the most active treatment regimens for patients with HER 2-positive metastatic breast cancer and demonstrates a very favourable safety profile allowing prolonged treatment with long-term survival. This study has been presented in part at the following conferences: The San Antonio Breast Cancer Symposium, San Antonio, TX, USA, 2003; The American Society of Clinical Oncology, Orlando, FL, USA, 2005.     

Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study

OBJECTIVE: Patients with advanced biliary tract cancers have a dismal prognosis. The aim of this study was to evaluate the efficacy and safety of gemcitabine as a single agent in the treatment of patients with unresectable biliary tract cancers. METHODS: From May 2002 to April 2004, 23 chemotherapy-na?ve patients with locally advanced or metastatic biliary tract adenocarcinomas were enrolled. The median age was 59 years (range 37-76). Fifteen patients (65.2%) had cholangiocarcinomas and eight (34.8%) had gallbladder adenocarcinomas. Patients received gemcitabine 1000 mg/m(2) over 60 min once a week for 2 weeks followed by a week off therapy. Treatment was discontinued when unacceptable toxicities occurred or there was evidence of disease progression. RESULTS: A total of 110 cycles of chemotherapy were performed with a median of four cycles (range 1-10). The median follow-up was 13.4 months. Among the 23 patients, six (26.1%) had a partial response, eight (34.8%) had stable disease and nine (39.1%) had disease progression despite treatment. The overall response rate was 26.1% [95% confidence interval (CI) 22.08-30.12]. The median time to disease progression was 8.1 months (95% CI 3.33-12.87) and the median overall survival was 13.1 months (95% CI 1.64-24.56). Toxicities were generally mild and treatment was well tolerated. Of the 23 patients, one patient experienced a grade 3-4 neutropenia and one a grade 3-4 thrombocytopenia; however, no cases of febrile neutropenia or treatment-related deaths were noted. CONCLUSION: In this phase II trial, therapy with gemcitabine was well tolerated and clinically active in patients with locally advanced or metastatic biliary tract cancers.     

Phase II multicentre study of docetaxel plus 5-fluorouracil in patients with anthracycline-pretreated metastatic breast cancer

The purpose of the study was to determine the efficacy and safety of docetaxel plus continuous infusion of 5-fluorouracil (5-FU) in patients with metastatic breast cancer previously treated with anthracyclines. A total of 41 patients with histologically proven metastatic breast cancer and performance status 0-2, who had received at least one anthracycline-containing regimen, received docetaxel 85 mg m(-2) followed by continuous infusion of 5-FU 750 mg m(-2) day(-1) for 5 days every 3 weeks for up to eight cycles. All patients received corticosteroid premedication, but there was no prophylactic colony-stimulating factor support. The most frequent metastatic sites were the liver (61%), bone (29%), and lung (29%). All 41 patients were assessable for toxicity and 30 were eligible and assessable for efficacy. The objective response rate was 70.0% (95% CI: 53.6-86.4%) for the per protocol group and 53.7% (95% CI: 38.4-68.9%) for the intent-to-treat (ITT) population. For the ITT population, median duration of response was 8.4 months (95% CI: 6.7-12.2 months), median time to progression was 6.7 months (95% CI 5.5-8.6 months), and median survival was 17 months (95% CI: 12.3-not recorded months). Grade 3/4 neutropenia occurred in 54% of patients, with febrile neutropenia in 24% of patients and 5% of cycles, but infections were rare. Stomatitis was frequent, grade 3 in 24% of patients and grade 4 in one patient (2%), but manageable. Diarrhoea was rare, grade 3 in 7% of patients and 1% of cycles. Other grade 3/4 nonhaematological toxicities were infrequent. In conclusion, this docetaxel/5-FU regimen is highly active and well tolerated in patients with anthracycline-pretreated metastatic breast cancer. The efficacy is particularly promising, as one-third of patients were either second-line and/or anthracycline-resistant/refractory.     

Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy.

BACKGROUND: An every-2-week regimen of gemcitabine and paclitaxel was adapted for patients with advanced transitional cell carcinoma (TCC) who had received prior cisplatin-based chemotherapy. METHODS: Forty-one patients with advanced or metastatic TCC who had received prior cisplatin-based systemic chemotherapy were treated with an outpatient regimen of gemcitabine 2500-3000 mg/m(2) and paclitaxel 150 mg/m(2) every 2 weeks. RESULTS: Forty of 41 patients had measurable disease. Response was observed in 24 patients (60%; 95% confidence interval [CI], 45-75%). Eleven (28%) achieved complete response, and 13 (33%) obtained partial response. Twenty of 25 patients (80%; 95% CI, 64-96%) who had been previously treated in the neoadjuvant or adjuvant setting responded versus 4 of 15 (27%; 95% CI, 5-49%) in patients who received prior methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC) for metastatic disease. The median duration of survival for patients given gemcitabine and paclitaxel after failing neoadjuvant or adjuvant M-VAC was 12 months (range, 2-43+), as compared with only 8 months (range, 2-28) for patients who had been treated after failure of prior therapy for metastatic disease. For all patients, the median duration of response was 6.4 months (range, 2-43.3+ months), and the median survival was 14.4 months (range, 2-43+). Thirteen patients (32%) developed World Health Organization Grade 3-4 neutropenia, with febrile neutropenia in 3 (7%) patients. Granulocyte colony-stimulating factor was given to 10 (24%) patients. There was no Grade 3-4 anemia or thrombocytopenia. CONCLUSIONS: The combination of gemcitabine and taxol in previously treated patients with recurrent TCC is highly effective and produces objective durable responses. This every-2-week schedule is a well tolerated outpatient regimen with minimal toxicity.     

Multicenter phase II study of docetaxel plus oxaliplatin combination chemotherapy in patients with advanced gastric cancer: Daegu Gyeongbuk Oncology Group

The present study was conducted to evaluate the efficacy and safety of a combination regimen of docetaxel plus oxaliplatin in patients with advanced gastric cancer. Patients with previously untreated metastatic or recurrent, measurable gastric cancer received intravenous docetaxel 65 mg m(-2) plus oxaliplatin 120 mg m(-2) on day 1 based on a 3-week cycle. Forty-two patients were enrolled in the current study, among whom 39 were assessable for efficacy and all assessable for toxicity. One complete response and 18 partial responses were confirmed, giving an overall response rate of 45.2% (95% confidence interval (CI); 31.7-59.7%). At a median follow-up of 7.7 months, the median time to progression and median overall survival was 5.7 (95% CI; 4.3-7.2) months and 9.9 (95% CI; 7.8-12.0) months, respectively. Grade 3/4 neutropenia occurred in 11 patients (26.1%) and febrile neutropenia was observed in four patients (9.5%). The common non-haematologic toxicity was fatigue (grade 1/2, 61.9%) and nausea (grade 1/2, 47.7%). The combination of docetaxel and oxaliplatin was found to be well tolerated and effective in patients with advanced gastric cancer.     

Phase II trial of gemcitabine combined with cisplatin in patients with inoperable biliary tract carcinomas

Objectives The aim of this phase II study was to evaluate the response rate to gemcitabine combined with cisplatin in patients with locally advanced, metastatic or recurrent biliary tract cancer who had received no prior chemotherapy. Methods The treatment consisted of cisplatin 70 mg/m² in intravenous infusion followed by gemcitabine 1,250 mg/m² in 30-min intravenous infusion on days 1 and 8, repeated every 3 weeks until disease progression, unacceptable toxicity, patient’s refusal or up to 8 cycles. Results Thirty-nine patients with advanced biliary cancer were enrolled between March 2003 and August 2003. Fourteen patients (40%) had gall bladder cancer and 20 patients (57%) had cholangiocarcinoma. Thirty-two patients (91%) had metastatic disease at study entry with liver being the most commonly involved site of metastasis. About 84.5 and 94.2% of the initially planned dose were administered for gemcitabine and cisplatin, respectively. In the ITT population (n = 35), six partial responses were observed for an objective response rate of 17.1% (95% CI; 4.7–29.6%). Ten patients (28.6%) had stable disease, 16 (45.7%) progressed, and three (8.6%) were not evaluable. For the 35 patients in the ITT population, the median overall survival time was 8.6 months (95% CI; 6.1–10.4 months). The median time to disease progression was 3.2 months (95% CI; 2.3–4.9 months) and the median time to treatment failure was 3.1 months (95% CI; 1.9–4.1 months). Among the six tumor responders, the median duration of tumor response was 7.3 months (95% CI; 5.6–11.0 months). The most common grade 3/4 maximum toxicities were nausea (3.4%) and vomiting (2.7%). Conclusion The combination chemotherapy with gemcitabine and cisplatin in this trial demonstrated moderate antitumor activity with favorable toxicity profile. Supported by Korean Cancer Study Group.     

Phase II study of weekly docetaxel in patients with metastatic breast cancer.

BACKGROUND: This study was conducted to investigate the efficacy and toxicity of weekly docetaxel administration in patients with metastatic breast cancer. PATIENTS AND METHODS: Thirty-seven women were treated with 1 h infusions of docetaxel at 40 mg/m2/week after pre-medication with 8 mg dexamethazone. Each cycle consisted of three consecutive weekly treatments followed by a 1 week rest. All patients were assessed for toxicity; five patients were not assessable for clinical response, time to progression (TTP) and overall survival (OS) because of early treatment failure, but they were included in intention-to-treat analysis. RESULTS: Patients received a median of four cycles (range, 1-9), with a median dose intensity of 28 mg/m2/week (range 22-30) and a median relative dose intensity of 0.95 (range 0.73-1.0). No patients showed complete response, whereas 14 had partial response, which accounted for 38% of objective response rate [95% confidence interval (CI) 22% to 53%]. In addition, three patients (8%, 95% CI 0% to 17%) had stable disease over 6 months. Clinical responses were achieved at a median of three cycles (range 1-4 cycles). The median TTP and OS were 5 and 12 months, respectively. The weekly docetaxel regimen was generally well tolerated. About half of the patients experienced grade > or = 1 neutropenia; only 19% had grade 3/4 neutropenia, including one case of grade 4. No febrile neutropenia was observed and fluid retention syndrome was uncommon. Non-hematologic toxicity, however, such as asthenia/fatigue, nail damage, tearing or hearing disorders, was seen with successive treatment cycles. CONCLUSIONS: Weekly docetaxel at 40 mg/m2/week is an active and feasible regimen for patients with metastatic breast cancer.     

Bevacizumab combined with chemotherapy in the second-line treatment of metastatic colorectal cancer: results from the phase II BEVACOLOR study

BackgroundThis prospective phase II study assessed the efficacy and safety of bevacizumab plus chemotherapy regimens commonly used in the second-line treatment of metastatic colorectal cancer (mCRC).MethodsPatients with mCRC who progressed or relapsed after first-line oxaliplatin-based or irinotecan-based treatment received bevacizumab 2.5 mg/kg/week plus chemotherapy until disease progression. The primary endpoint was disease-control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety.ResultsFifty-three patients (66% men; median age, 62 years old) received second-line bevacizumab plus folinic acid, fluorouracil, and irinotecan (FOLFIRI; 57%), folinic acid, fluorouracil, oxaliplatin (FOLFOX; 26%), irinotecan (15%), or capecitabine plus irinotecan (XELIRI; 2%). The DCR was 87% (95% CI, 77%-97%); ORR was 32% (95% CI, 19%-46%). Median PFS was 6.5 months (95% CI, 5.8-7.8 months) and median OS 19.3 months, (95% CI, 14.2-25.1 months).The most frequent grade 3/4 adverse events included neutropenia (21%), diarrhea (15%), asthenia, and vomiting (9% each). Five patients (9%) had grade 3/4 targeted toxicities: grade 3 hypertension (n = 2), grade 3 venous thromboembolism (n = 2), and grade 4 arterial thromboembolism (n = 1). None of these events led to death during the study.ConclusionBevacizumab plus standard second-line chemotherapy is highly active in patients with mCRC and has an acceptable safety profile.     

Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer.

PURPOSE: This Nordic multicenter phase II study evaluated the efficacy and safety of oxaliplatin combined with the Nordic bolus schedule of fluorouracil (FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer. PATIENTS AND METHODS: Eighty-five patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1, followed by a 3-minute bolus injection with FU 500 mg/m(2) and, 30 minutes later, by a bolus injection with FA 60 mg/m(2) every second week. The same doses of FU and FA were also given on day 2. RESULTS: Fifty-one of 82 assessable patients achieved a complete (n = 4) or partial (n = 47) response, leading to a response rate of 62% (95% CI, 52% to 72%). Nineteen patients showed stable disease, and 12 patients had progressive disease. Thirty-eight of the 51 responses were radiologically confirmed 8 weeks later (confirmed response rate, 46%; 95% CI, 36% to 58%). The estimated median time to progression was 7.0 months (95% CI, 6.3 to 7.7 months), and the median overall survival was 16.1 months (95% CI, 12.7 to 19.6 months) in the intent-to-treat population. Neutropenia was the main adverse event, with grade 3 to 4 toxicity in 58% of patients. Febrile neutropenia developed in seven patients. Nonhematologic toxicity consisted mainly of neuropathy (grade 3 in 11 patients and grade 2 in another 27 patients). CONCLUSION: Oxaliplatin combined with the bolus Nordic schedule of FU+FA (Nordic FLOX) is a well-tolerated, effective, and feasible bolus schedule as first-line treatment of metastatic colorectal cancer that yields comparable results compared with more complex schedules.     

Irinotecan is active in chemonaive patients with metastatic gastric cancer: a phase II multicentric trial

To assess the response rate and the tolerance of irinotecan as first-line therapy, 40 patients with metastatic gastric cancer received irinotecan 350 mg m(-2) every 3 weeks administered as a 30 min infusion. Among the 35 patients evaluable for response, two complete and five partial responses were recorded (response rate: 20.0% (95% CI:8.4-36.9%)). In total, 16 patients achieved stable disease and 12 progressive disease. In all, 66 percent of the patients benefited from tumour growth control. The median time to progression was 3.0 months (95% CI: 2.3-4.4%). The median overall survival was 7.1 months (95% CI: 5.2-9.0%). The probability of being alive at 6 months and 9 months was 61.0 and 32.4%, respectively. The median number of cycles per patient was 3 (range 1-14), and the relative dose intensity was 0.98. The most common grade 3-4 toxicities by patients were diarrhoea 20%, asthenia 10%, nausea 7.5%, vomiting 5.0%, abdominal pain 5%, neutropenia 38.5%, leucopenia 28.2%, anaemia 12.8% and thrombocytopenia 5.1%. Febrile neutropenia occurred in 12.5% of patients. These findings indicate that irinotecan is active and well tolerated in patients with metastatic gastric adenocarcinoma and warrants further evaluation in this clinical setting.     

Carboplatin plus gemcitabine repeating doublet therapy in recurrent breast cancer

PurposeThe combination of cisplatin plus gemcitabine is active in metastatic breast cancer. Carboplatin plus gemcitabine, widely used in ovarian and non–small-cell lung cancers, has also been used in breast cancer. This trial examined the efficacy and toxicity of split-dose carboplatin plus gemcitabine in advanced breast cancer.Patients and MethodsPatients with measurable disease, recurrent after adjuvant and ≤ 1 previous treatment for systemic disease, received carboplatin area under the curve = 2.0 (Calvert) plus gemcitabine 800 mg/m², both drugs administered days 1 and 8 every 21 days. Of 15 patients accrued, 13 are fully evaluable.ResultsThere were 2 complete (13.3%) and 6 partial (40%) responses, for an overall response rate by intention to treat of 53.3% (95% CI, 28%-82%). The median time to progression was 4.5 months (95% CI, 2.03-6.97 months), and median overall survival was 28.8 months (95% CI, 9.4-48.2 months). There were 2 patients with grade 3 (13.3%) anemia, 7 patients with grade 3 (46.6%) and 4 patients (26.6%) with grade 4 neutropenia, 4 patients with grade 3 (26.6%) and 3 patients (20%) with grade 4 thrombocytopenia.ConclusionThe repeating doublet of split-dose carboplatin plus gemcitabine reveals activity comparable to that of cisplatin plus gemcitabine, is well tolerated, and warrants evaluation in patients with recurrent breast cancer.     

Clinical outcomes of African American patients with advanced or metastatic non-small cell lung cancer on Nivolumab in a single community-based cancer center

African Americans (AA) have the highest incidence and mortality rates with lung cancer. They are diagnosed at an earlier age with more advanced disease. Programmed cell death protein-1 inhibitor, Nivolumab, was approved as a second-line agent after failure of platinum-based therapy for advanced or metastatic non-small cell lung cancer (NSCLC). The original studies leading to the approval of Nivolumab had insufficient AA patients, thus there is still inadequate knowledge on treatment outcomes among AA patients. Our primary study endpoints were to determine the median overall survival, 1-year overall survival rate, median progression-free survival, and 1-year progression-free survival rate of patients with advanced or metastatic non-small cell lung cancer on Nivolumab. Our secondary study endpoints were to determine the overall tumor response rate, median time to response, median duration of response, and incidence of treatment-related adverse events of grade 3 or 4. In this retrospective study, we reviewed the charts of 38 patients, 29 of which were AA, with advanced or metastatic NSCLC who received Nivolumab from March 1, 2015 until November 30, 2017 from a single community-based cancer center and compared our results with historical data. Adenocarcinoma was the most common histology (71%) among all patients. Seven (18%) continued to use Nivolumab while 21 (55%) discontinued the treatment mainly due to progression of the disease. The median overall survival was 21.4 months (95% CI 13.5–27.4) and 17.6 months (95% CI 11.5–27.6) for all the patients and AA, respectively. Both have statistically significant difference (P?<?0.001) compared to the historical studies of Borghaei et al. and Brahmer et al. At 1 year, the overall survival rate was 73% (95% CI 50–86) and 66% (95% CI 40–82) for all patients and AA, respectively. The median progression-free survival was also statistically significant (P?<?0.001) between all the patients 6.3 months (95% CI 2.8–8), AA 6.0 months (95% CI 2.3–8.0), and the said historical studies. The 1-year progression-free survival rate was 23% (95% CI 10–39) and 28% (95% CI 12–47) for all patients and AA, respectively. Overall tumor response rate which includes complete and partial responses was 21% (95% CI 10–37) and 24% (95% CI 10–43) for all patients and AA, respectively. The median time to response was 3 and 2.8 months for all patients and AA, respectively. The median duration of response was 3.8 and 4.0 months for all patients and AA, respectively. Treatment-related adverse events of grade 3 or 4 were reported in 8 and 10% in all patients and AA, respectively, similar to the rates previously shown. AA patients with advanced or metastatic NSCLC on Nivolumab had increased overall survival and progression-free survival with similar grade 3 or 4 treatment-related adverse events. Providing adequate access to immunotherapy is indispensable to maximize survival benefit for AA patients.