Multicentric phase II trial of gemcitabine plus epirubicin plus paclitaxel as first-line chemotherapy in metastatic breast cancer

In this phase II, multicentre trial, patients with metastatic breast cancer (MBC) were treated with a combination of gemcitabine, epirubicin and paclitaxel (GET). The primary objective of this study was to determine the tolerability and activity in terms of complete responce (CR) and overall response rate of the GET combination in this patient population. Patients with no prior treatment for MBC, and at least one bidimensionally measurable lesion received gemcitabine 1000 mg m(-2) intravenously (i.v.) over 30 min on days 1 and 4, followed by epirubicin i.v. at 90 mg m(-2) on day 1, and paclitaxel 175 mg m(-2) over 3 h on day 1, every 21 days, up to eight courses. From May 1999 to June 2000, 48 patients were enrolled from seven Italian institutions. A total of 297 chemotherapy courses were administered with a median of six cycles patient(-1) (range 1-8). Seven patients (15%) obtained CR and 27 patients (56%) had partial responce, for an overall response rate of 71% (95% CI: 58.3-83.7). After a median follow-up of 23.7 months (range 7.0-34.4), median progression-free survival was 10.5 months (95% CI: 9.2-11.7), and median overall survival 25.9 months. The main haematological toxicity consisted of grade 3 or 4 neutropenia that occurred in 62% of cycles (22% grade 4 and 40% grade 3). The GET combination is active and well tolerated as first-line chemotherapy for MBC.     

拓扑替康与顺铂联合方案治疗晚期复发性上皮性卵巢癌的多中心临床研究

目的研究拓扑替康(topotecan)与顺铂联合化疗治疗晚期复发性上皮性卵巢癌的疗效和毒性反应.方法我们于2000年10月至2001年6月联合应用拓扑替康1.0mg/(m2*d),第1-5天与顺铂20mg/(m2*d),第1-3天,共治疗30例晚期复发性卵巢癌.平均用药2.4个疗程.结果总有效率为33.3%(10/30),其中CR4例,PR6例;疗效稳定为36.7%(11/30);进展为30.0%(9/30),其中3例于随访中死亡.至随访截止,中位无进展期5月,中位生存期6.5月.毒性反应以骨髓抑制为主,Ⅲ-Ⅳ度白细胞下降为56.7%(17/30),以中性粒细胞下降为主;Ⅲ-Ⅳ度血小板下降为30.0%(9/30);Ⅲ-Ⅳ度血红蛋白下降为30.0%(9/30).无严重并发症发生.恶心、呕吐发生率为86.7%,脱发占83.3%.结论本方案抗肿瘤效应肯定,但血液学毒副反应较大,可作为二线化疗方案选择性应用于晚期复发性上皮性卵巢癌患者.     

吉西他滨联合洛铂与联合顺铂方案治疗术后辅助化疗失败的卵巢癌患者的疗效对比

目的:观察吉西他滨联合洛铂与联合顺铂方案治疗术后辅助化疗失败的卵巢癌患者的疗效及安全性。方法:自2011年6月21日至2016年5月30日,我科收治的初治失败的卵巢癌患者共73例入组,随机分为吉西他滨联合洛铂组（GL组）与吉西他滨联合顺铂组（GP组）,比较两方案在平均化疗周期数、总有效率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）、总生存期（OS）及不良反应发生率等方面的差异。结果:两组患者的平均化疗周期数GL组（4.73±1.305）周期,GP组(4.03±1.341)周期,P=0.027,差异有统计学意义。ORR、DCR间的比较差异均无统计学意义（P=0.345;P=0.127）。GL组中位PFS为6.0个月（95%可信区间5.722~6.278个月）,GP组5.0个月（95%可信区间4.209~5.791个月）,P=0.414,无统计学差异。GL组中位OS为10.0个月（95%可信区间8.675~11.325个月）,GP组9.0个月（95%可信区间8.296~9.704个月）,P=0.308,无统计学差异。不良反应中,GL组轻中度血小板降低较多（P=0.006）,GP组有较多的轻中度肝功能异常（P=0.007）、中重度恶心（P=0.043）及中重度呕吐（P=0.019）。其余不良反应两组间无统计学差异。结论:GL方案对于初治失败的卵巢癌患者而言是安全有效的,可达到与GP方案类似的治疗效果,不良反应较GP方案轻,但需要注意血小板降低。     

Phase II study of gemcitabine plus oxaliplatin as first-line chemotherapy for advanced non-small-cell lung cancer

This phase II study evaluated the response rate and tolerability of gemcitabine-oxaliplatin chemotherapy in non-small-cell lung cancer (NSCLC) patients. Chemonaive patients with stage IIIB or IV NSCLC received gemcitabine 1000 mg m(-2) on days 1 and 8, followed by oxaliplatin 130 mg m(-2) on day 1. Cycles were repeated every 21 days for up to six cycles. From February 2002 to May 2004, 60 patients were enrolled into the study in seven Italian institutions. We observed one complete response (1.7%) and 14 partial responses (23.3%), for an overall response rate of 25.0% (95% confidence interval, 14.7-37.9%). The median duration of response was 5.9 months (range 1.5-17.1 months). With a median follow-up of 6.7 months, median time to progressive disease and overall survival were 2.7 (range 1.9-3.4 months) and 7.3 months (range 7.2-8.6 months), respectively. The main grade 3-4 haematological toxicities were transient neutropenia in 11.7% and thrombocytopenia in 8.3% of the patients. Nausea/vomiting was the main grade 3-4 nonhaematological toxicity, occurring in 10.0% of the patients. Two (3.3%) patients developed grade 3 neurotoxicity. Our results show that gemcitabine-oxaliplatin chemotherapy is active and well tolerated in patients with advanced NSCLC, deserving further study, especially for patients not eligible to receive cisplatin.     

A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer

Background: Most patients with advanced ovarian cancer will relapse following platinum-based combination chemotherapy and be considered for second-line treatment. Gemcitabine, a nucleoside analogue, is active against a range of solid tumors. This phase II study investigated the activity of single-agent gemcitabine in patients with recurrent ovarian cancer.Patients and methods: Thirty-eight patients with FIGO stage III (34%) or IV (64%) ovarian cancer who were previously treated with platinum-containing regimens were enrolled. Patients received 1200 mg/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle.Results: Patients completed an average of 3.6 cycles. Two complete and three partial responses were seen in 36 evaluable patients, for an overall response rate of 13.9% (95% CI: 4.7%–29.5%). The median survival time was 6.7 months. Toxicities were generally mild. The most common were grade 3–4 neutropenia and grade 3 leukopenia reported in 23.7% and 10.5% of patients, respectively. One patient had grade 4 pulmonary toxicity.Conclusion: Single-agent gemcitabine is active and well tolerated in patients with recurrent ovarian cancer.     

A phase II feasibility study of carboplatin followed by sequential weekly paclitaxel and gemcitabine as first-line treatment for ovarian cancer

A total of 53 women with chemotherapy-na?ve stage Ic-IV ovarian cancer were treated with four cycles of carboplatin area under the curve 7 every 3 weeks, followed by four cycles of paclitaxel 70 mg m(-2) (days 1, 8, and 15) and gemcitabine 1000 mg m(-2) (days 1 and 8) every 3 weeks. In all, 37 (70%) had stage III/IV disease, with 22 (42%) having tumour >2 cm; 38 patients (72%) completed all planned treatment; 27 of the 32 (84%) patients with radiologically evaluable disease had partial or complete responses; and 30 of the 39 patients (77%) with elevated cancer antigen (CA) 125 had a greater than 75% fall in this value. At a median follow-up of 28 months, 31 patients had relapsed with a median progression-free survival of 19.5 months. In total, 79% of patients were alive at 2 years. Common Toxicity Criteria grade 3/4 haematological toxicity, predominantly neutropenia, was seen in 57% of the patients. A certain degree of pulmonary toxicity was observed; eight patients had symptomatic breathlessness, +/- decreased diffusing capacity of the lung for carbon monoxide, and interstitial chest X-ray changes during the weekly phase. In all cases, this toxicity was reversible. No significant neurotoxicity was seen. This regimen is generally well tolerated with encouraging efficacy. However, the observation of pulmonary toxicity, potentially a feature of the weekly taxane-gemcitabine regimen, was of some concern. Alternative schedules, including 3-weekly taxanes, are currently being evaluated.     

盐酸拓扑替康治疗顺铂耐药复发卵巢癌的临床研究

目的:评价盐酸拓扑替康治疗一线顺铂耐药复发卵巢癌的近期和远期疗效及安全性。方法:对一线含顺铂方案化疗耐药复发卵巢癌患者采用盐酸拓扑替康1.25mg/m2静滴(1~5)d,每21 d重复。治疗每2周期后评价疗效,CR或PR病例继续化疗直至疾病进展或毒性不能耐受。结果:共入组患者52例,可评价临床疗效49例,可评价血清CA12-5疗效48例,可评价毒性52例。临床和CA12-5总有效率分别为22.5%和29.2%,中位缓解期为6月,中位无疾病进展生存时间和总生存时间分别为10月和16月。主要毒副作用为中性粒细胞减少和白细胞减少,两者III/IV度毒性分别为44.2%和53.8%。非血液学毒性轻微。结论:盐酸拓扑替康单药治疗一线含顺铂方案化疗耐药复发卵巢癌疗效肯定,耐受性良好。     

拓扑替康联合顺铂治疗晚期卵巢癌的近期疗效观察

目的:观察拓扑替康(TPT)联合顺铂(PDD)治疗晚期卵巢癌的疗效、毒副反应。方法:对45例临床确诊的晚期卵巢癌病人进行化疗,TPT0.75mg/m2,PDD20mg/m2,连用5天为1个疗程,21天为1周期,2个周期结束后评价疗效。结果:45例病人化疗后,总有效率44.44%(20/45),其中初治病人有效率68.75%(11/16),复治病人有效率31.03%(9/29)。化疗后毒副作用主要表现为骨髓抑制,白细胞下降75.56%(34/45),Ⅲ度以上46.67%(21/45);血小板下降44.44%(20/45),Ⅲ度以上24.44%(11/45)。结论:TPT联合PDD治疗晚期卵巢癌,疗效肯定;尤其是对复发病人仍有效,可做为复发卵巢癌的二线或三线化疗。     

A phase II study of sequential carboplatin, paclitaxel and topotecan in patients with previously untreated advanced ovarian cancer

We evaluated the sequential use of carboplatin, paclitaxel and topotecan in patients with advanced, previously untreated ovarian cancer. In total, 43 patients with advanced ovarian cancer and >1 cm residual disease were treated with sequential carboplatin (area-under-the-curve (AUC) 5 days 1 and 22), paclitaxel (175 mg m(-2) days 43 and 64) and topotecan (1.5 mg m(-2) daily for 5 days from days 85, 106, 127 and 148). Median age of patients was 61 years. Median follow-up was 22.2 months (range 0.76-50.6 months). In all, 34 (79%) patients received all eight cycles of treatment and nine (21%) withdrew. Of the 29 evaluable patients, 19 (66%) responded according to WHO and 30 of 36 (83%) patients according to CA125. The best overall response (CA125 and/or WHO) was 77% (33 of 43 patients). The response rates to sequential drugs based on >50% fall in CA125 were as follows: carboplatin, 77% (30 of 39 patients); paclitaxel, 65% (15 of 23 patients); topotecan, 38% (five of 13 patients). Two patients responded to paclitaxel and one to topotecan after failure to respond to preceding chemotherapy. Median survival and time to progression was 22.24 and 10.61 months, respectively. This study demonstrates that sequential chemotherapy with just two initial courses of carboplatin is a reasonable way to introduce new agents into first-line therapy for poor prognostic ovarian cancer patients.     

Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study

Targeting the epidermal growth factor receptor pathway in pancreatic cancer seems to be an attractive therapeutic approach. This study assessed the efficacy of cetuximab plus the combination of gemcitabine/oxaliplatin in metastatic pancreatic cancer. Eligible subjects had histological or cytological diagnosis of metastatic pancreatic adenocarcinoma. The primary end point was response according to RECIST. Patients received cetuximab 400 mg m⁻² at first infusion followed by weekly 250 mg m⁻² combined with gemcitabine 1000 mg m⁻² as a 100 min infusion on day 1 and oxaliplatin 100 mg m⁻² as a 2-h infusion on day 2 every 2 weeks. Between January 2005 and August 2006, a total of 64 patients (22 women (34%), 42 men (66%); median age 64 years (range 31–78)) were enrolled at seven study centres. On October 2007, a total of 17 patients were alive. Sixty-two patients were evaluable for baseline and 61 for assessment of response to treatment in an intention-to-treat analysis. Six patients had an incomplete drug combination within the first cycle of the treatment plan (n=4 hypersensitivity reactions to the first cetuximab infusion, n=2 refused to continue therapy). Reported grade 3/4 toxicities (% of patients) were leukopaenia 15%, anaemia 8%, thrombocytopaenia 10%, diarrhoea 7%, nausea 18%, infection 18% and allergy 7%. Cetuximab-attributable skin reactions occurred as follows: grade 0: 20%, grade 1: 41%, grade 2: 30% and grade 3: 10%. The intention-to-treat analysis of 61 evaluable patients showed an overall response rate of 33%, including 1 (2%) complete and 19 (31%) partial remissions. There were 31% patients with stable and 36% with progressive disease or discontinuation of the therapy before re-staging. The presence of a grade 2 or higher skin rash was associated with a higher likelihood of achieving objective response. Median time to progression was 118 days, with a median overall survival of 213 days. A clinical benefit response was noted in 24 of the evaluable 61 patients (39%). The addition of cetuximab to the combination of gemcitabine and oxaliplatin is well tolerated but does not increase response or survival in patients with metastatic pancreatic cancer.     

Phase II study of liposomal doxorubicin and gemcitabine in the salvage treatment of ovarian cancer

In total, 70 patients were enrolled into this phase II study, to evaluate the activity of the pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) combination in recurrent ovarian cancer patients. PLD, 30 mg m(-2), was administered on day 1 by 60' i.v. infusion, followed by GEM, 1000 mg m(-2), given by 30' i.v. on days 1 and 8; cycles were repeated every 21 days. In all, 67 patients are so far evaluable for response. Seven complete responses (10.4%, 95% CI: 3.1-17.7), 16 partial responses (23.9%, 95% CI: 13.7-34.1), 26 disease stabilisations (38.8%, 95% CI: 27.1-50.5) and 18 progressions (26.9%, 95% CI: 16.3-37.5) have been registered. Within the resistant population (n=36), the response rate was 25% (95% CI: 10.9-39.1). Within the group of platinum-sensitive patients (n=31), the response rate was 45.2% (95% CI: 27.7-62.7). A total of 443 courses are evaluable for toxicity. Grade 3-4 hematological toxicity was registered in 30 patients (42.8%), mainly represented by neutropenia (35.6%); palmar-plantar erythrodysesthesia affected 24 patients (34.2%), but it was of grade 3 in only seven of them (10%).     

Gemcitabine and vinorelbine as second-line treatment in patients with metastatic breast cancer progressing after first-line taxane-based chemotherapy: A phase II study conducted by the Hellenic Cooperative Oncology Group

Background:Gemcitabine and vinorelbine have shown activity inbreast cancer. A phase II trial was initiated in order to evaluate theresponse rate (RR) and time to progression (TTP) of the combination of the twodrugs in patients with metastatic breast cancer progressing after first-linetaxane-based chemotherapy. Patients and methods:Thirty-one patients were treated with thecombination of gemcitabine 1000 mg/m² days 1 + 8 and vinorelbine30 mg/m² days 1 + 8. The cycles were repeated every three weeks. Results:Of 27 evaluable patients 1 (4%, 95%confidence interval (95% CI): 0.1%–19%) achievedcomplete remission (CR), five (18%; 95% CI:6%–38%) partial remission (PR), eleven (40%;95% CI: 22%–61%) stable disease and ten patientsprogressed. The median duration of response was six months (range 4–10+)and the median duration of disease stabilization was five months (range2–22+). With a median follow-up of 16 months (range 0.4–22+) themedian TTP was 3.5 months (range 0.4–22+) and the median survival was9.5 months (range 0.4–22+). Grade 3–4 toxicities weregranulocytopenia 15 patients (48%), rash 3 patients (10%),neuropathy 1 patient (3%) and thrombocytopenia 1 patient (3%).In conclusion the combination of gemcitabine/vinorelbine in the dosesadministered in this group of patients had a response rate of 22% andneeds to be further evaluated in metastatic breast cancer.     

吉西他滨加顺铂治疗复发性卵巢癌的临床观察

目的：探讨复发性卵巢癌治疗方法,评估吉西他滨联合顺铂治疗复发性卵巢癌的疗效及不良反应。方法：56例复发性卵巢癌,用吉西他滨1000mg/m2,第1、8天,顺铂35mg/m2,第1、8天静滴,21天为1周期。结果：56例患者总有效率60.7%,其中CR10例（17.9%）,PR24例（42.9%）。中位疾病进展时间5.5个月（2.5-20个月）,中位生存期12.5个月。其中32例铂类耐药和24例铂类敏感患者的有效率、中位生存期分别为56.3%和66.7%（P=0.95）、10.5和14.5个月（P=0.003）。不良反应主要是白细胞减少和血小板减少。结论：吉西他滨加顺铂是治疗复发性卵巢癌的有效方案,不仅可用于铂类敏感患者,也可用于铂类耐药患者,其不良反应可以接受。     

Phase II study of gemcitabine in ovarian cancer

This phase II study evaluated the response rate and toxicity of single-agent gemcitabine in 40 women with epithelial ovarian cancer, previously treated with platinum-based chemotherapy. Patients had stage III or IV disease and progressive disease 1–12 months after the last treatment. Gemcitabine 1250 mg/m² was administered on days 1, 8 and 15 of each 28-day cycle as a 30-minute infusion.The overall response rate to gemcitabine was 22% (95% confidence intervals: 10–39%). Responses to gemcitabine were observed in patients with platinum-refractory disease, which suggests no cross resistance to platinum. Gemcitabine was well tolerated and no grade 4 toxicity was seen.This study confirms that gemcitabine is active and well tolerated in pre-treated women with ovarian cancer.     

Combined paclitaxel and gemcitabine as first-line treatment in metastatic non-small cell lung cancer: a multicentre phase II study

The efficacy and toxicity of combined paclitaxel and gemcitabine was evaluated in 54 chemotherapy-naive patients with metastatic non-small cell lung cancer (NSCLC). Gemcitabine i.v. 1000 mg/m(2)was administered on days 1 and 8 and paclitaxel 200 mg/m(2)as a continuous 3-hour infusion on day 1. Treatment was repeated every 21 days. Patients had a median age of 53 years. ECOG performance status was 0 or 1 in 48 patients. 41 patients (75.9%) had initial stage IV disease; histology was mainly adenocarcinoma (46.3%). 2 patients (4.3%) achieved a complete response and 15 (31.9%) achieved a partial response giving an overall response rate of 36.2% (95% CI: 22.4-49.9%); 19 patients (40.4%) had stable disease and 10 (21.3%) had progressive disease. The median survival time was 51 weeks (95% CI: 46.5-59.3), with a 1-year survival probability of 0.48 (95% CI: 0.34-0.63). Grade 3/4 neutropenia and febrile neutropenia occurred in 15.2% and 2.2% of courses, respectively. Grade 3/4 thrombocytopenia was rare (1.8% of courses). Peripheral neurotoxicity developed in 25 patients (47.2%), mostly grade 1/2. Arthalgia/myalgia was observed in 30 patients (56.6%), generally grade 1 or 2. Grade 3 abnormal levels of serum glutamate pyruvate transaminase (SGPT) and serum glutamate oxaloacetate transaminase (SGOT) occurred in 5 patients (9.4%) and 1 patient (1.9%), respectively. Combined paclitaxel and gemcitabine is an active and well-tolerated regimen for the treatment of advanced NSCLC, and warrants further investigation in comparative, randomized trials.     

吉西他滨联合顺铂方案二线治疗晚期卵巢癌的临床研究

目的 对紫杉类和卡铂药物一线化疗后复发的晚期卵巢癌患者进行吉西他滨联合顺铂方案化疗,评估其疗效及毒性.方法 紫杉类和卡铂一线化疗后复发的晚期卵巢癌患者接受吉西他滨1.0 g/m2,i.v.,dl,d8;顺铂25mg/m2,i.v.,d1～d3; 21天为1个疗程,至少应用2个疗程,然后评价临床疗效和毒性,并进行随访.结果 30例患者治疗总缓解率53.3％.其中完全缓解3例,部分缓解13例,无缓解14例;中位疾病进展时间6.8个月（3～18.7个月）,中位生存期11.8个月.毒性反应主要是骨髓抑制和胃肠道反应,Ⅲ～Ⅳ度毒性反应发生率为60％.结论 一线接受紫杉类和卡铂化疗后复发的晚期卵巢癌患者行吉西他滨联合顺铂化疗是有效方案,毒性可耐受.     

A phase II study of gemcitabine plus paclitaxel in patients with metastatic breast cancer and prior anthracycline treatment

Aim: To investigate the efficacy and safety of gemcitabine‐paclitaxel in Chinese patients with metastatic breast cancer following anthracycline failure in a multicenter, open‐label, single‐arm, phase II clinical trial. Methods: Chinese female patients with unresectable, locally recurrent or metastatic breast cancer who had relapsed after neo‐adjuvant anthracycline‐based chemotherapy were included. All patients had measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 at baseline. Gemcitabine (1250 mg/m²)‐paclitaxel (175 mg/m²) was administered on a 3‐weekly schedule until disease progression, and patients were followed up for 12 months (post‐enrolment). The primary end point was objective response rate; secondary end points included duration of response, progression‐free survival and overall survival. Results: Overall 60 patients were enrolled. Their mean age was 46.9 (SD ± 9.0) years and 90% of patients had metastatic disease. All patients had previously received chemotherapy. A total of 48 patients (80%) completed the 12‐month follow up, and 40 patients (67%) completed at least six cycles of study therapy. The objective response rate (complete response + partial response) was 50% (95% CI: 36.6–63.4). Median duration of response was 5.6 months (95% CI: 4.4–7.6) and median progression‐free survival was 7.6 months (95% CI: 5.8–8.8). Overall survival at 12 months was 87% (95% CI: 77.9–95.2). Laboratory toxicities were primarily hematologic, including Grade 3 and 4 neutropenia (n = 27 [45%]) and leukopenia (n = 18 [30%]). Eight patient deaths (13%) were not treatment‐related. Conclusion: Gemcitabine‐paclitaxel combination therapy is an active and well‐tolerated chemotherapy regimen, with expected and manageable toxicity in Chinese patients with metastatic breast cancer.     

Dose finding study for combination treatment with topotecan and gemcitabine of patients with recurrent ovarian cancer after failure of first-line chemotherapy with Paclitaxel and platinum

OBJECTIVES: Topotecan and gemcitabine have shown mono-activity against different solid tumors including recurrent ovarian cancer after failure of platinum- and paclitaxel-containing therapies. Both drugs affect DNA replication, topotecan additionally inhibits the DNA repair process. Efficacy profiles and different mechanisms of action make the combination of both drugs a promising regimen. Therefore the following dose-finding study was conducted to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) of this combination. Based on the monotherapy schedules topotecan was given on day 1-5, and gemcitabine on day 1 + 8 every 21 days. PATIENTS AND METHODS: Patients with histologically proven ovarian cancer who relapsed after platinum- and paclitaxel-containing therapy were enrolled. 3 different dose levels were investigated. No individual dose escalation or primary use of cytokines were allowed. RESULTS: 23 patients were enrolled, 50% were pretreated with at least 2 platinum-containing therapies; 80 courses were analyzed for toxicity. Thrombocytopenia and leucopenia were the major DLTs. The MTD for phase II trials is 0.50 mg/m(2) topotecan and 800/600 mg/m(2) gemcitabine. In this dose level only one therapy-related non-hematological adverse event >grade 2 (grade 3 mycotic stomatitis) and one grade 4 thrombocytopenia occurred. Responses were observed in 6 and stable disease in 4 out of 12 evaluable patients. Median survival was 15.3 (95% CI: 13.2-28.6) months. CONCLUSIONS: The results of this phase I study demonstrate the feasibility and tolerability of this new combination in heavily pretreated patients. Based on these results a phase II study was initiated to evaluate the efficacy of this regimen.     

A phase II study of sequential neoadjuvant gemcitabine plus doxorubicin followed by gemcitabine plus cisplatin in patients with operable breast cancer: prediction of response using molecular profiling

This study examined the pathological complete response (pCR) rate and safety of sequential gemcitabine-based combinations in breast cancer. We also examined gene expression profiles from tumour biopsies to identify biomarkers predictive of response. Indian women with large or locally advanced breast cancer received 4 cycles of gemcitabine 1200 mg m(-2) plus doxorubicin 60 mg m(-2) (Gem+Dox), then 4 cycles of gemcitabine 1000 mg m(-2) plus cisplatin 70 mg m(-2) (Gem+Cis), and surgery. Three alternate dosing sequences were used during cycle 1 to examine dynamic changes in molecular profiles. Of 65 women treated, 13 (24.5% of 53 patients with surgery) had a pCR and 22 (33.8%) had a complete clinical response. Patients administered Gem d1, 8 and Dox d2 in cycle 1 (20 of 65) reported more toxicities, with G3/4 neutropenic infection/febrile neutropenia (7 of 20) as the most common cycle-1 event. Four drug-related deaths occurred. In 46 of 65 patients, 10-fold cross validated supervised analyses identified gene expression patterns that predicted with >or=73% accuracy (1) clinical complete response after eight cycles, (2) overall clinical complete response, and (3) pCR. This regimen shows strong activity. Patients receiving Gem d1, 8 and Dox d2 experienced unacceptable toxicity, whereas patients on other sequences had manageable safety profiles. Gene expression patterns may predict benefit from gemcitabine-containing neoadjuvant therapy.     

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer.

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m(-2) d(-1) on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m(-2) d(-1), experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m(-2) d(-1)) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m(-2) d(-1)). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m(-2)d(-1) in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose.