Capecitabine and Vinorelbine as an All-Oral Chemotherapy in HER2-Negative Locally Advanced and Metastatic Breast Cancer

BACKGROUND: The oral formulation of vinorelbine together with capecitabine allows for an all-oral combination chemotherapy which promises to raise quality of life of patients with advanced breast cancer. PATIENTS AND METHODS: Patients with HER2-negative, locally advanced, inoperable or metastatic breast cancer were included in this prospective observational trial (treatment schedule: capecitabine 500 mg/m2 twice daily, days 1-14; vinorelbine 60 mg/m2, days 1+8; repeated in 3-week cycles). RESULTS: All 32 patients (median age 50 years) were evaluable for toxicity, and 30 patients for response. Twentyfour patients received therapy as first-line treatment, and 8 patients as beyond first-line treatment. Median time to progression was 8 months, and median overall survival was 32 months. Complete response was observed in 1 patient (3%), partial response in 10 patients (33%), and disease stabilization for more than 6 months (SD > 6) in 10 patients (33%). This results in an overall response rate (ORR) of 37% and a clinical benefit rate (ORR + SD > 6) of 70%. The only grade 3/4 toxicities were neutropenia (19%) and hand-foot syndrome (9%). CONCLUSIONS: The all-oral combination of capecitabine/vinorelbine at this schedule appears to be an effective, well-tolerated regimen for treatment of advanced breast cancer, and offers a promising alternative to single-agent capecitabine and vinorelbine as well as intravenous polychemotherapy.     

Role of gemcitabine in metastatic breast cancer patients: a short review

Many active cytotoxic drugs, given according to a number of different regimens are approved for the treatment of metastatic breast cancer patients. However, these therapies have not changed the outcome of patients affected by this malignancy. As a consequence, the balance between chemotherapy-induced side effects and relief of cancer-related symptoms must be carefully considered in this setting. Gemcitabine is an antimetabolite that is incorporated as a triphosphate into DNA. As a single agent, it yields responses rates ranging from 14% to 37% in chemotherapy-na?ve patients and from 12% to 30% in patients previously treated with anthracyclines and/or taxanes. In combination with paclitaxel, it produces a significantly higher response rate (41.4% vs. 26.2%), longer time to progression (6.1 vs. 4 months) and significantly higher overall survival (18.6 vs. 15.8 months) than paclitaxel alone. In addition, a phase III study revealed that gemcitabine plus docetaxel is as effective as capecitabine plus docetaxel, but causes significantly less non-haematologic toxicity. Lastly, in another phase III trial, progression free survival was significantly longer with the combination of gemcitabine plus vinorelbine than with vinorelbine alone (6 vs. 4 months), but without a significant difference in overall survival; the incidence of haematologic toxicity was higher in the group treated with combined therapy. Novel gemcitabine combinations are being investigated in phase II studies.     

Combined Chemotherapy with Mitomycin C, Folinic Acid, and 5-Fluorouracil (MiFoFU) as Salvage Treatment for Patients with Liver Metastases from Breast Cancer - a Retrospective Analysis

BACKGROUND: The aim of this study was to analyze the activity and tolerability of a combined chemotherapy with mitomycin C, folinic acid, and 5-fluorouracil (MiFoFU) in patients with hepatic metastases from breast cancer, and in particular in patients with impaired liver function. PATIENTS AND METHODS: We retrospectively studied the charts of 44 patients who were treated with a MiFoFU combination therapy because of progressive metastatic breast cancer. Predominant site of metastases was the liver. Primary endpoints were response and time to progression (TTP); secondary endpoints were overall survival (OS) and tolerability. RESULTS: Median age prior to treatment was 59 years. A median of 6 treatment cycles were administered per patient. Clinical benefit rate amounted to 64%. A mean TTP of 9 months and a mean OS of 14 months were found. Main clinical signs of nonhematological toxicity were stomatitis, nausea, and diarrhea. Grade III/IV hematotoxicity was seen in only 9 patients. 16 patients showed clinical signs of liver dysfunction. A clinical benefit could be achieved in 8 of these patients. CONCLUSION: MiFoFU combination chemotherapy is a well-tolerated treatment alternative in the palliative therapy of patients with liver metastases from breast cancer. Particularly in patients with hepatic dysfunction, this regimen seems to represent a helpful treatment option.     

Multicenter Phase II Study with Weekly Bendamustine and Paclitaxel as First- or Later-Line Therapy in Patients with Metastatic Breast Cancer: RiTa II Trial

The combination of bendamustine (B) and paclitaxel (P) as anthracycline-free treatment option in patients with advanced breast cancer has been evaluated in the previous RiTa I trial. The regimen of weekly B 70 mg/m(2) and P 90 mg/m(2) with a pause every 4th week was established as an effective regimen with low toxicity. The aim of the present RiTa II study was to investigate the potential of BP as anthracycline-free combination therapy. The primary objective was to determine the progression-free survival (PFS); secondary endpoints were safety, tolerability, overall response rate (ORR) and overall survival (OS). 26 patients were available, 15 received BP as first-line, 11 as beyond first-line treatment. 27% patients had triple-negative breast cancer (TNBC). Median PFS and OS were 7.3 months (95% confidence interval (CI): 5.5-10.9) and 14.9 months (95% CI: 9.9-22.9), respectively. The 1-year PFS rate was 20.3% and the 1-year OS rate 71.2%. The ORR was 42.3%, including 4 complete and 7 partial remissions. TNBC patients reached an ORR of 71.4%. Anthracycline-pretreated patients showed an ORR of 43.8%, confirming bendamustine's lack of cross-resistance to anthracycline agents. BP represents a favorable option with moderate toxicity in pretreated metastatic breast cancer and offers a possibility for application in anthracycline-pretreated and TNBC patients.     

Phase II study of lapatinib in combination with vinorelbine in patients with HER2 positive recurrent or metastatic breast cancer: A multicentric Turkish Oncology Group (TOG) trial

BackgroundThe aim of this explorative phase II study was to evaluate the activity and safety of lapatinib in combination with intravenous vinorelbine in women with HER2 positive metastatic or recurrent breast cancer.MethodsTwenty-nine patients were enrolled. The primary objectives were response and clinical benefit (CB) rates, secondary objectives were toxicity, response duration and progression free survival. Patients received 1250 mg oral lapatinib continuously once daily and intravenous vinorelbine 20–25 mg/m² on days 1 and 8, every 3 weeks.ResultsAlthough 25 patients were evaluable for response, according to intend to treat analysis of 28 patients; 14% had confirmed partial response (PR) and 36% had stable disease more than 24 weeks with a CB rate of 50%. Sixty four percent of the patients suffered from grade 3–4 hematologic and 18% from grade 3 extra-hematologic toxicities.ConclusionThe results of this trial provide evidence to further investigate the potential of this combination for patients unsuitable for trastuzumab or who become refractory to trastuzumab.     

Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d'Etudes des Tumeurs Uro-Génitales) study

PURPOSE: Collecting duct carcinoma of the kidney is a rare and aggressive neoplasm of the distal collecting tubules for which there is no established treatment. Since the histology of collecting duct carcinoma is similar to that of urothelial carcinoma, the standard chemotherapy regimen defined by a gemcitabine and platinum salts combination was prospectively investigated in patients with metastatic collecting duct carcinoma. MATERIALS AND METHODS: A total of 23 patients with metastatic collecting duct carcinoma with no prior systemic chemotherapy were treated with 1,250 mg/m(2) gemcitabine on days 1 and 8 plus 70 mg/m(2) cisplatin or carboplatin (AUC 5) in patients with renal insufficiency on day 1. The drugs were repeated every 21 days for 6 cycles according to toxicity and efficacy. The objective response rate was the primary end point. RESULTS: There were 1 complete and 5 partial responses for an objective response rate of 26% (95% CI 8 to 44). Median progression-free and overall survival was 7.1 (95% CI 3 to 11.3) and 10.5 months (95% CI 3.8 to 17.1), respectively. Toxicity was mainly hematological with grade 3-4 neutropenia and thrombocytopenia in 52% and 43% of patients, respectively. The severity of granulocytopenia and the number of metastatic sites were associated with overall survival on univariate and multivariate analyses. CONCLUSIONS: To our knowledge this is the first prospective, multicenter, phase II study showing that the platinum salts combination is an active and safe regimen as first line treatment in patients with metastatic collecting duct carcinoma. This platinum based chemotherapy should be considered the standard regimen in these patients.     

Gemcitabine plus vinorelbine chemotherapy in patients with advanced bladder carcinoma who are medically unsuitable for or who have failed cisplatin-based chemotherapy

Objective: To evaluate the efficacy and toxicity of gemcitabine plus vinorelbine chemotherapy in patients with advanced bladder carcinoma who are unsuitable for or who have failed cisplatin-containing chemotherapy.Patients and Methods: Thirty-one patients with advanced transitional cell carcinoma (TCC) of the bladder were scheduled to receive gemcitabine and vinorelbine chemotherapy. Twenty-one patients had received no prior chemotherapy and their creatinine clearance was below 50 ml/min (group 1), and the remaining 10 patients did not respond to previous cisplatin-containing chemotherapy (group 2).Results: In group 1, objective response rate was 47.6%, including 2 (9.5%) complete and 8 (38.9%) partial responses. In group 2, partial response was observed in 2 (20%) patients. The median survival time for patients in group 1 and 2 were 15 months (range 3–23) and 7 months (range 3–21), respectively. Grades 3 or 4 leukopenia developed in 16.1% of patients. Overall, 12.9% of the patients suffered from grade 3 nonhematologic toxicity.Conclusion: Our preliminary data indicate that the combination of gemcitabine and vinorelbine is active and well tolerated especially in patients with advanced TCC who are unsuitable for cisplatin-based chemotherapy.     

Anti-tumor activity of capecitabine and vinorelbine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: findings from the EORTC 10001 randomized phase II trial

The aim of this randomized phase II study was to evaluate the anti-tumor activity and safety of capecitabine and vinorelbine in patients with metastatic breast cancer pretreated with taxanes and anthracyclines. We planned to randomize 72 patients to capecitabine 1250 mg/m(2) orally bid days 1-14 or vinorelbine 30 mg/m(2) i.v. days 1 and 8, both given every 3 weeks. The study was stopped due to poor accrual with 47 patients enrolled. Responses were seen in 2/23 patients treated with capecitabine (8.7%; 95% CI 1.1-29.0) and 3/24 patients treated with vinorelbine (12.5%; 95% CI 2.7-32.4). Median progression-free survival was 2.8 and 2.6 months, and median overall survival was 9.3 and 11.0 months, in the capecitabine and vinorelbine arms, respectively. There was more hematologic toxicity, neurotoxicity, and nausea/vomiting with vinorelbine and more diarrhea and hand-foot syndrome with capecitabine. The anti-tumor activity of capecitabine and vinorelbine seems to be comparable, but the toxicity profiles are different.     

Gemcitabine-oxaliplatin combination in heavily pretreated metastatic breast cancer: a pilot study on 43 patients

To investigate the efficacy and the safety of gemcitabine and oxaliplatin combination in metastatic breast cancer (MBC), in patients heavily treated with anthracycline and taxane. A retrospective study including all MBC patients, treated by two different schedules of GemOx between February 2001 and December 2003 in the medical oncology department of Saint-Louis hospital. Forty-three consecutive patients were included. Median involved organs was 2. The median number of regimen of previous metastatic chemotherapy administered was 3. The median number of cycle administered was 5, with a median dose by cycle of 1,000 or 2,000 mg/m(2) of gemcitabine (D1D2 or D1D8 schedule, respectively) and 100 mg/m(2) of oxaliplatin. Of the 40 evaluable patients, three achieved a partial response giving an overall response rate of 7.5% and 11 demonstrated stable disease, giving a stabilization rate of 27.5%. Median overall survival in all treated patients was 10.6 months and median progression-free survival in all evaluated patients was 3.0 and 10.5 months for the partial responders. Hematotoxicity was prevalent, sometimes severe, with grades 3 and 4 neutropenia, thrombocytopenia, and anemia in 42%, 19%, and 14% of the patients. Grades 3 and 4 peripheral neuropathy were developed by 9% of the patients, but was not limiting. The present study reports the results of two exploratory schedules of the GemOx combination in advanced breast cancer patients. The D1D8 schedule was the most promising and deserves further clinical studies.     

Phase II trial of weekly intravenous gemcitabine administration with interferon and interleukin-2 immunotherapy for metastatic renal cell cancer

PURPOSE: Since metastatic renal cell carcinoma has a poor prognosis and treatment strategies, including hormone therapy, chemotherapy and immunotherapy, have little impact on the quality of life and global survival statistics, new interest has recently focused on the combination of immuno-chemotherapy using pyrimidine analogues, such as gemcitabine. MATERIALS AND METHODS: In a phase II study 16 patients with metastatic renal cell carcinoma were treated with 1,000 mg./m. gemcitabine intravenously on days 1, 8, 15 and 28 for 6 months, 3 MU (1 MU = 1 x 10(6) IU) interferon (IFN)-alpha intramuscularly 3 times a week and 4.5 million IU interleukin (IL)-2 subcutaneously daily for 5 days a week for 2 consecutive weeks every month for 6 months. Responding and nonprogressing cases were maintained on immunotherapy consisting of IFN-alpha and IL-2 for further 6 months. RESULTS: In 15 evaluable patients overall response rate (1 complete response plus 3 partial response) was 28% while stable disease was achieved in 7 (47%). Median survival duration was 20 months (range, 9 to 26+) and median time to tumor progression was 14 months (6 to 26+). The complete response lasted 24+ months and partial response lasted 16 months. The regimen was well tolerated with only 1 case of neutropenia (WHO grade 3), while anorexia, fatigue and flu-like symptoms were the most common toxicity problems but were never greater than grade 2. CONCLUSIONS: Despite the small sample size, this study demonstrates that gemcitabine combined with standard doses of IFN-alpha and low doses of IL-2 is effective treatment for metastatic renal cell carcinoma. This biotherapy was well tolerated and resulted in an optimum objective response and relatively long-term survival.     

Phase II study of gemcitabine plus vinorelbine in the treatment of cisplatin-resistant nasopharyngeal carcinoma

BACKGROUND: A phase II study was conducted to evaluate the safety and efficacy of a gemcitabine plus vinorelbine combination (GV) for patients with cisplatin-resistant nasopharyngeal carcinoma (NPC). METHODS: Thirty-nine eligible patients received vinorelbine, 20 mg/m(2), followed by gemcitabine, 1,000 mg/m(2), on days 1 and 8 of each 21-day cycle. RESULTS: Grade 3/4 neutropenia and thrombocytopenia occurred in 44% and 18% of patients, respectively, but there was only one episode of febrile neutropenia. Nonhematologic toxicities were mild and did not lead to any treatment withdrawal. The overall response rate was 36% (95% confidence interval [CI], 20% to 52%) in an intent-to-treat analysis, with one complete response (3%) and 13 partial responses (33%). The median response duration, progression-free survival, and overall survival were 5.1, 5.6, and 11.9 months, respectively. CONCLUSION: Given the moderately high activity and favorable toxicity profile, GV is a reasonable choice for patients with cisplatin-resistant NPC.     

A prospective, open label, randomized phase II trial of weekly docetaxel versus weekly vinorelbine as first line chemotherapy in patients with androgen independent prostate cancer

PURPOSE: In previous phase I to III studies docetaxel and vinorelbine have shown promising activity in androgen independent prostate cancer. In the present trial we assessed the efficacy and tolerability of single agent low dose docetaxel vs vinorelbine in patients with advanced androgen independent prostate cancer. MATERIALS AND METHODS: A total of 40 chemotherapy naive patients with histologically proven androgen independent prostate cancer, adequate androgen ablation, and clinical and/or biochemical progression were randomly assigned to receive either 25 mg/m(2) docetaxel (arm A) or 25 mg/m(2) vinorelbine (arm B) weekly. Treatment was continued until clinical and/or biochemical progression. In cases of progression patients switched to the alternative treatment arm. The primary end point was time to disease progression. Secondary end points included prostate specific antigen response rates in sequential treatment, analgesic response and toxicity. RESULTS: The current analysis showed a doubled risk of progression in treatment arm B. The median time to first disease progression was 14.5 months for arm A vs 4.4 months for arm B. The proportion of patients with a greater than 50% prostate specific antigen decrease on first line therapy was significantly higher in arm A (62.5%) compared to arm B (11.1%) (p = 0.0033). After progression to docetaxel second line vinorelbine yielded a greater than 50% prostate specific antigen response rate of 28.6% vs 62.5% for second line docetaxel. Clinically significant toxicity occurred more often in arm B with neutropenia grade 4 seen in 22% and grade 3 in 28% of patients (p = 0.0005) during the first treatment phase. CONCLUSIONS: While weekly application of both cytotoxic agents was well tolerated, this study demonstrates the superiority of docetaxel vs vinorelbine as monotherapy in the treatment of androgen independent prostate cancer.     

GN之后序贯口服N治疗晚期乳腺癌的临床观察与分析

目的比较GN(吉西他滨/长春瑞滨)4疗程后序贯GN×4(GN×8组)或序贯口服N×4方案(GN×4-N组)治疗对晚期乳腺癌(MBC)的疗效及不良反应。方法选取2014年1月至2015年12月确诊的晚期乳腺癌患者61人,采用GN×4疗程后序贯GN×4或序贯口服N×4方案化疗,比较患者的总有效率(ORR)及1年生存率。结果 GN×8组ORR为35.5%(11/31),其中CR 6.5%(2/31),PR 29%(9/31);GN×4-N组ORR为33.3%(10/30),其中CR 6.7%(2/30),PR 26.7%(8/30),两组ORR差异无统计学意义(P=0.925),GN×8组1年生存率为67.7%;GN×4-N组1年生存率为65.5%,两组1年生存率差异无统计学意义(P=0.576)。两组均无化疗相关死亡病例,主要不良反应为骨髓抑制及胃肠道反应。结论 GN4疗程后序贯GN×4或序贯口服N×4方案对于MBC均有较好的有效率,不良反应均可耐受。但从药物经济学及患者的生活质量上讲,GN×4-N更符合晚期治疗患者"低毒高效、服用方便"的原则。     

A phase II study of mitomycin,fluorouracil, folinic acid,and irinotecan (MFI) for the treatment of transitional cell carcinoma of the bladder

Background and objectivesCisplatin-based chemotherapy is standard care for metastatic transitional cell carcinoma (TCC) of the urinary tract. However it is not appropriate for all patients, particularly those with poor renal function. There is no clear consensus on the optimal regimen for these individuals or for those after cisplatin failure. Here we present data using mitomycin, 5-fluorouracil, and irinotecan (MFI) in these patients.Materials and methodsPatients with TCC, who had either received cisplatin-based chemotherapy previously or who were not deemed fit for cisplatin therapy (creatinine clearance was less than 60 ml/min) were eligible for treatment with the experimental combination chemotherapy regimen MFI.ResultsThirty-six patients were treated with MFI between 2001 and 2004. Overall response rate was 19% and median overall survival (OS) was 5.4 months (95% CI 3.3–8.4 months). The response rate and overall survival in both groups was 19% and 5.4 months, respectively, (95% CI 2.9–7.1 months) in the pretreated and 2.5– 9.3 months in the untreated. The most common toxicity was malaise (grade 3 or 4 = 28%).ConclusionsMFI appear to be a combination which requires further investigation in patients where cisplatin and gemcitabine are not applicable.     

Combined epirubicin and vinorelbine as first-line therapy in metastatic breast cancer: a pilot study performed by the Danish Breast Cancer Cooperative Group

This pilot study investigated the tolerability and efficacy of increasing doses of epirubicin and vinorelbine as first-line chemotherapy for metastatic breast cancer. Acute toxicity was manageable at all dose levels for combinations of epirubicin 60-90 mg/m2 on day 1 and vinorelbine 15-25 mg/m2 on days 1 and 8 repeated every 3 weeks. Myelotoxicity was the most frequent toxic event, with a significant increase in grade 4 leukopenia from 0% at dose level 1 (60+15 mg/m2) to 26% at dose level 6 (90+25 mg/m2). Signs of acute or chronic cardiotoxicity grades 2-4 were seen in 15% of the patients and included arrhythmia and decreased function. No significant association was established between dose and nonhematological toxicity. Objective responses were observed in 49 of the 99 evaluable patients (49.5%, 95% CI 39.9-59.2), 18 being complete and 31 partial responses. Responses were observed at all six dose levels.In conclusion, acute toxicity was manageable at all dose levels for combinations of epirubicin 60-90 mg/m2 on day 1 and vinorelbine 15-25 mg/m2 on days 1 and 8. In the treatment of advanced breast cancer, improvement of the antitumor efficacy by the addition of vinorelbine to epirubicin remains to be demonstrated in a randomized phase III trial.     

Results of a phase I trial of intravenous vinorelbine plus oral capecitabine as first-line chemotherapy of metastatic breast cancer

The management of metastatic breast cancer becomes increasingly intricate, requiring new drugs and combinations. We present here the results of a phase I study evaluating the maximal tolerated dose of vinorelbine combined with capecitabine as first-line chemotherapy. Vinorelbine was administered intravenously on days 1 and 15, and capecitabine was given orally twice daily from day 1 to 14 (three cycles every 21 days). Three out of six patients receiving vinorelbine at 25mg/m2/day and capecitabine at 2000 mg/m2/day presented with a dose-limiting toxicity, consisting of protracted grade 3 neutropenia, hand-foot syndrome and/or liver test disturbances. Despite of a dose reduction in vinorelbine (20mg/m2/day), one patient among four developed a dose-limiting febrile neutropenia. This regimen cannot be recommended as first-line treatment of metastatic breast cancer. These findings are not in agreement with previous publications of this schedule, or with promising results using both drugs orally.     

A multicenter phase II clinical study of oxaliplatin, folinic acid, and 5-fluorouracil combination chemotherapy as second-line treatment for advanced colorectal cancer: A Japanese experience

Purpose

This multicenter phase II study was designed to determine the efficacy and tolerability of oxaliplatin, levoforinate, and infusional 5-fluorouracil (FOLFOX4) as a second-line therapy for Japanese patients with unresectable advanced or metastatic colorectal cancer.

Methods

A total of 53 patients with progressive disease after first-line chemotherapy were enrolled in the study. The treatment was repeated every 2 weeks until disease progression or unacceptable toxicity occurred, or the patient chose to discontinue the treatment.

Results

Four patients were ineligible and one did not receive the protocol therapy. Therefore, the response rate, overall survival (OS), and progression-free survival (PFS) were evaluated in 48 patients; toxicity was evaluated in 52 patients, excluding the patient who had not received the protocol therapy. A partial response was observed in 10 patients. The overall response rate was 20.8% (95% confidence interval [CI], 10.5%?C35.0%). The median PFS was 5.6 months (95% CI, 4.1?C7.0 months) and the median OS was 19.6 months (95% CI, 11.4?C24.3 months). The most frequently encountered grade 3/4 hematological symptom was neutropenia (43.1%). The toxicity profile was generally predictable and manageable.

Conclusion

The results showed good tolerability and efficacy for second-line FOLFOX4 in patients with advanced colorectal cancer, thus indicating the promise of this regimen as an effective second-line therapy for advanced colorectal cancer in the Japanese population.     

长春瑞滨和表阿霉素联合新辅助化疗方案治疗局部晚期乳腺癌的临床研究

目的评估长春瑞滨和表阿霉素的联合新辅助化疗方案在局部晚期乳腺癌治疗中的临床疗效和毒性反应.方法2001年9月至2004年12月,158例经空芯针活检组织学诊断证实的局部晚期乳腺癌患者在术前接受新辅助化疗,方案为长春瑞滨25 mg/m^2（第1、8天）,表阿霉素60mg/m^2（第1天）,每3周为1个疗程共3个疗程.结果原发病灶临床有效率为81.6%,其中23.4%（37/158）达到临床完全缓解（cCR）,58.2%（92/158）达到临床部分缓解;疾病稳定（SD）16.5%（26/158）,疾病进展（PD）1.9%（3/158）.病理完全缓解29例（18.3%）,其中15例术后标本未见肿瘤残留,14例仅残留原位癌组织.68例新辅助化疗前区域淋巴结细针穿刺活检阳性的病例,化疗后18例（26.5%）手术标本中未见区域淋巴结转移.最常见的毒性反应包括中性粒细胞减少症、脱发和恶心呕吐,共有111例患者（70.3%）发生3～4度中性粒细胞减少症.无因新辅助化疗引起的败血症和死亡病例.结论长春瑞滨和表阿霉素的联合新辅助化疗方案在局部晚期乳腺癌治疗中疗效显著且耐受性良好.     

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinoma

What’s known on the subject? and What does the study add? Metastatic bladder cancer is a devastating disease that often proves fatal. Systemic chemotherapy with MVAC (methotrexate, vinblastine, adriamycin, cisplatin) has been the first choice of treatment for many years but toxicity can be severe and overall survival poor. The search for more effective drug combinations continues. Clinical data indicate that gemcitabine has activity in this disease in terms of tumour response and overall survival. This systematic review comprehensively presents the available clinical evidence on gemcitabine chemotherapy for the management of metastatic bladder cancer. Limited data from randomized trials suggest that cisplatin plus gemcitabine may be considered a viable first‐line option for this disease and that the less toxic combination of gemcitabine plus carboplatin may be suitable for patients with poor renal function or low performance status. Data from observational studies highlight the wide variation in drug combinations and schedules used and the need for a systematic approach to clinical research with gemcitabine.

OBJECTIVE

? To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer.

MATERIALS AND METHODS

? The Medical Literature Analysis and Retrieval System Onlinedatabase (MEDLINE), the Excerpta Medicadatabase (EMBASE), the Cumulative Index to Nursing and Allied Health Literature database(CIHNAL), the Cochrane database of randomized trials, the Literatura Latino‐Americana e do Caribe emCiências da Saúdedatabase (LILACS), and Web of Science were searched to identify trials of gemcitabine for metastatic bladder cancer. Also searched were international guidelines on metastatic prostate cancer, trial registries, and recent systematic reviews. Data on trial design, survival, tumour response and toxicity outcomes were extracted from relevant studies.

RESULTS

? This review identified six randomized trials of combined chemotherapy with gemcitabine for the management of unresectable, locally advanced or metastatic bladder cancer. ? One trial compared gemcitabine plus cisplatin (GCis) with methotrexate/vinblastine/doxorubicin/cisplatin(MVAC) and found no difference in overall survival (OS; hazard ratio 1.09) but a better safety profile with GCis, which was suggested as the treatment of choice. ? A second trial evaluated GCis against gemcitabine plus carboplatin (GCarbo) and reported similar median OS (12.8 vs 9.8 months), disease progression (8.3 vs 7.3 months) and tumour response rates (66% vs 56%) for the two patient groups. ? A third trial compared GCis with GCis plus paclitaxel (GCisPac) and showed no significant difference in median OS (12.3 vs 15.3 months) and response rates (44% vs 43%) but greater toxicity with GCisPac. ? A fourth trial assessed GCarbo against methotrexate plus carboplatin plus vinblastine in patients unfit for cisplatin‐based chemotherapy and found similar tumour response rates for each regime (38% vs 20%) but the triplet regime was more toxic. ? Two other randomized studies compared a 2‐weekly maintenance regime of gemcitabine plus paclitaxel with a 3‐weelky regime given for a maximum of six cycles and found that the maintenance schedule did not confer any additional survival benefit. ? In all, 53observational studies of gemcitabine chemotherapy were identified that varied considerably in the drug combinations used and schedules. Overall response rates (17–78%) and median OS (6.4–24.0 months) were variable with no combination being clearly superior.

CONCLUSIONS

? Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer. ? GCis may be considered an alternative regime to MVAC. ? GCarbo should be considered for patients unfit for cisplatin‐based therapy.     

A multicenter phase II clinical study of oxaliplatin, folinic acid, and 5-fluorouracil combination chemotherapy as first-line treatment for advanced colorectal cancer: A Japanese experience

Purpose

This multicenter phase II study was designed to determine the efficacy and tolerability of oxaliplatin in combination with levofolinate and infusion 5-fluorouracil (FOLFOX4) as first-line therapy for Japanese patients with unresectable metastatic colorectal cancer.

Methods

Sixty consecutive patients with histologically confirmed advanced or metastatic colorectal cancer were enrolled in the study. Treatment was repeated every 2 weeks until disease progression or unacceptable toxicity occurred.

Results

Two patients were ineligible. Toxicity was evaluated in 60 patients, who had received a part or all of the protocol therapy. A partial response was observed in 20 patients. The overall response rate was 34.5% (95% CI, 22.5%?C48.1%) and the tumor control rate (partial response + stable disease) was 82.8%. The median progression-free survival was 6.9 months (95% CI, 5.1?C9.8 months), and the median overall survival was 31.5 months (95% CI, 18.1?C40.1 months). There were no toxicity-related deaths. Grade 3 or 4 neutropenia occurred in 48.3% of patients and often caused a delay in the subsequent treatment course. Mild to moderate cumulative peripheral sensory neuropathy affected 71.7% of patients.

Conclusion

The results showed good tolerability and efficacy for first-line FOLFOX4 in the treatment of patients with advanced colorectal cancer, indicating the promise of this regimen as first-line therapy for advanced colorectal cancer in the Japanese population.