Phase II,multicentre, randomised trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine as first-line chemotherapy in patients with HER2-negative metastatic breast cancer

BackgroundPaclitaxel plus gemcitabine (PG) combination chemotherapy is a preferred chemotherapeutic regimen for patients with metastatic breast cancer (MBC). Eribulin mesylate is a halichondrin non-taxane inhibitor of microtubule dynamics. A recent pooled analysis with eribulin showed improved overall survival (OS) in various MBC patient subgroups pretreated with anthracycline and taxane. Furthermore, eribulin may have less neurotoxicity than paclitaxel.Patients and methodsThis study was a prospective randomised phase II, open-label, two-arm, multicentre study comparing eribulin plus gemcitabine (EG) with PG chemotherapy as a first-line treatment for patients with human epidermal growth factor receptor 2-negative MBC. We hypothesised that EG chemotherapy would not be inferior to PG chemotherapy. The primary end-point was progression-free survival (PFS), which was estimated to be 70% at 6 months for each arm. The secondary end-points were as follows: OS, neuropathic scale, toxicity and clinical benefit rate.ResultsA total of 118 patients (median age: 50, 24–66) were enrolled between March 2015 and March 2016 and were randomly assigned to PG (n = 59) or EG (n = 59) chemotherapy. The mean number of metastatic sites was 3 (range 1–8). The 6-month PFS rates for both arms were 72% for EG and 73% for PG (P = 0.457). There was no significant difference in OS between the two groups (not reached versus 21.2 months, P = 0.2234). The median number of chemotherapy cycles for both groups was 10 for EG and 8 for PG (range 2–32). Clinical benefit rates were 44% for EG and 49% for PG. Major toxicities were neutropenia and neurotoxicity. Grade II or above neurotoxicity was more common with PG than with EG (13.6% for EG versus 45.8% for PG, P < 0.0001).ConclusionEG chemotherapy had similar clinical benefits to PG chemotherapy in terms of PFS but less neurotoxicity.Trial registrationKCSG BR13-11; ClinicalTrials.gov, NCT02263495.     

A randomized phase II study of paclitaxel and bevacizumab with and without gemcitabine as first-line treatment for metastatic breast cancer

Background

The addition of bevacizumab to paclitaxel improved progression-free survival (PFS) of patients with metastatic breast cancer (MBC). We examined the efficacy and safety of adding gemcitabine to paclitaxel/bevacizumab (PB).

Patients and Methods

In this multicenter, open-label, randomized phase II trial, women with locally advanced or MBC were randomly assigned to receive paclitaxel 90 mg/m² (days 1, 8, 15) and bevacizumab 10 mg/kg (days 1, 15) with or without gemcitabine 1500 mg/m² (days 1, 15) in 28-day cycles. Patients with prior cytotoxic therapy for MBC were ineligible. The primary endpoint was investigator-assessed overall response rate (ORR); secondary endpoints were PFS, overall survival (OS), safety, and quality of life.

Results

Ninety-four patients received PB, and 93 received paclitaxel/bevacizumab/gemcitabine (PB+G). The ORRs were 48.9% (95% confidence interval [CI], 38.5%-59.5%) and 58.7% (95% CI, 47.9%-68.9%; P = .117) with PB and PB+G, respectively. The median PFS was 8.8 months (95% CI, 8.1-10.4 months) and 11.3 months (95% CI, 9.7-12.7 months; P = .247; hazard ratio, 0.82); the median OS was 25.0 months (95% CI, 18.8-not assessable [N/A] months) and 24.3 months (95% CI, 20.3-N/A months; P = .475; hazard ratio, 0.84), with PB and PB+G, respectively. There was significantly more grade 3-4 neutropenia (P = .001) and dyspnea (P = .014) with PB+G. Patients treated with PB experienced more improvement in total FACT-B (Functional Assessment of Cancer Therapy-Breast) (P = .021), FACT-B Social/Family Well-being (P = .041), and Breast Cancer-Additional Concerns (P = .008) scores than patients treated with PB+G.

Conclusion

The addition of gemcitabine to PB was not associated with a statistically significant improvement in ORR. Treatment with PB+G increased the incidence of severe neutropenia and dyspnea, although the regimen generally was well tolerated.     

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.     

Phase II study of a gemcitabine and cisplatin combination regimen in taxane resistant metastatic breast cancer

Purpose: To determine the safety and efficacy of gemcitabine and cisplatin in patients with taxane resistant metastatic breast cancer. Patients and methods: Thirty-three taxane resistant metastatic breast cancer patients were treated with gemcitabine 1,250 mg/m² IV infusion over 30 min on days 1 and 8, and with cisplatin 75 mg/m² by IV infusion over 1 h on day 1 in 21 day cycles. Results: Of the 30 evaluable patients, there were 9 (30%) partial responses and no complete response, an overall objective response rate of 30%. Median time to progression and median survival duration for all study subjects were 7 (95% CI 5.1–8.9 months) and 15 months (95% CI 10.5–19.5 months), respectively. Toxicities included grade 3 and 4 leucopenia in 10 (30%), thrombocytopenia in 6 (18%), anemia in 2 (6%) and oral mucositis in 2 (6%). No grade 3 or 4 peripheral neuropathy, renal dysfunction, hepatic dysfunction, or nausea/vomiting was observed, and no treatment-related deaths occurred. Conclusion: The described gemcitabine plus cisplatin combination was found to be an active and tolerable salvage regimen in patients with taxane resistant metastatic breast cancer.     

吉西他滨为主的方案治疗难治性乳腺癌的临床研究

目的：观察以吉西他滨（ＧＥＭ）为主的方案治疗复发的难治性乳腺癌的疗效和不良反应。方法：４６例晚期复治的乳腺癌患者,应用ＧＥＭ为主的联合方案治疗,持续至疾病进展或出现不可耐受的不良反应,每２周期按照ＲＥＣＩＳＴ标准（１.０版）进行疗效评价,按ＮＣＩ ＣＴＣ（３.０版）评价毒性并随访生存情况。结果：在４６例可评价的患者中,获得ＣＲ２例,ＰＲ９例,ＳＤ２４例,ＰＤ１１例,有效率（ＲＲ）２３.９％,总的疾病控制率（ＤＣＲ）为７６.１％;中位肿瘤进展时间（ｍＴＴＰ）为５.７个月（９５％ＣＩ：３４５～７.９５个月）,中位总生存期（ｍＯＳ）为１２.０个月（９５％ＣＩ：７.４０～１６.６０个月）。主要不良反应为骨髓抑制和皮疹。结论：吉西他滨为主的联合方案治疗难治性乳腺癌具有较好的疗效,不良反应可以耐受,值得推广应用。     

A phase II study of weekly docetaxel in patients with anthracycline pretreated metastatic breast cancer

Background: Docetaxel has significant activity in metastatic breast cancer and weekly schedules are associated with less myelosuppression than 3-weekly schedules. We evaluated the toxicity and the activity of weekly docetaxel in anthracycline-pretreated patients. Patients and methods: A total of 42 patients were studied. Treatment consisted of docetaxel 35 mg/m² weekly as a 30-min infusion for 6 weeks followed by a 2-week rest, with dexamethasone 8 mg i.v. pre-medication and 4 mg orally 12-hourly for 48 h following treatment. Results: The median age of the patients was 53 years (range 34–74). Twenty-six (62%) patients had received prior chemotherapy for advanced disease. Patients received a median 10 weeks of treatment (range 1–24). 11 had a partial response (ORR 26%; 95% CI 13–39%), five of whom had relapsed <12 months since the end of previous anthracycline-based chemotherapy. In addition six patients (14%) had stable disease for >16 weeks. Myelosuppression was rare with only 2 patients (5%) experiencing grade 3 neutropenia (no grade 4 neutropenia). Non-haematological grade III toxicities were as follows: fatigue 17%, neuropathy 0%, hyperlacrimation 5%, stomatitis 7%, diarrhoea 14%, and cutaneous toxicity 19%. Skin toxicity consisted of limb/palmar–plantar erythematous reactions, or fixed-plaque erythrodysaesthesia. Conclusions: Weekly docetaxel has moderate activity in women with anthracycline pre-treated breast cancer. Although the level of myelosuppression is lower than 3-weekly regimens, this weekly regimen cannot be recommended due to the significant non-haematological toxicities associated with the treatment.     

A phase-I study evaluating the combination of pegylated liposomal doxorubicin and paclitaxel as salvage chemotherapy in metastatic breast cancer previously treated with anthracycline

Purpose The two main goals of this phase-I study were to determine the maximum-tolerated dose (MTD) and to characterize the toxicity of the combination of pegylated liposomal doxorubicin (PLD; Lipo-Dox) and paclitaxel (PTX) administered on a 3-week schedule in patients with metastatic breast cancer (MBC) who had previously been treated with anthracycline-based therapy. Methods This phase-I study was performed via a two-staged dose escalation schema. The initial doses were PLD 30 mg/m² and PTX 150 mg/m², administered intravenously once every 21 days. The dose of PLD was escalated in increments of 5 mg/m² until the MTD was reached, at which time the PTX was then increased in increments of 10 mg/m² until the MTD was reached. Results Twenty-three patients received between 1 and 13 treatment cycles. In stage I of the study, 14 patients received a fixed dose of PTX 150 mg/m² while PLD escalated from 30 mg/m². At 40 mg/m², PLD resulted in dose-limiting toxicities (DLT) including febrile neutropenia and palmar-plantar erythrodysesthesia that occurred in two of five patients. In stage II of the study, nine patients received fixed dose of PLD 35 mg/m² and escalating doses of PTX starting at 160 mg/m². At PTX 170 mg/m² and dose-limiting neutropenic fever occurred in two of five patients. Out of 19 evaluable patients, 10 (52.6%) achieved objective response (one complete response and nine partial response), and 5 had stable disease. Conclusions The maximal tolerated doses of PLD and PTX are 35 and 160 mg/m², respectively, administered every 3 weeks. The combination of PLD (30–35 mg/m²) and PTX (150–160 mg/m²) constitutes an active regimen with mild toxicity that merits further study.     

Phase ii trial of a metronomic schedule of docetaxel and capecitabine with concurrent celecoxib in patients with prior anthracycline exposure for metastatic breast cancer

Background

This phase ii clinical trial examined the activity of a metronomic dosing schedule of docetaxel and capecitabine chemotherapy in patients with advanced breast cancer. Patients also received daily oral celecoxib in an effort to improve outcome measures and to ameliorate some of the common side effects of chemotherapy.

Methods

Patients received docetaxel at a starting dose of 15 mg/m² weekly, oral capecitabine 1250 mg/m² once daily, and oral celecoxib 200 mg twice daily. The primary endpoint was clinical benefit: percentage of patients experiencing either an objective response or stable disease (sd) for more than 6 months. In the absence of significant neutropenia, the dose of docetaxel was escalated after 4 and 8 weeks of treatment. Therapy was given until disease progression or development of unacceptable toxicity. The level of thymidine phosphorylase expression in peripheral white blood cells of patients was measured before and during treatment to determine the effect on this capecitabine-activating enzyme.

Results

Of 47 patients enrolled, 38 (81%) completed treatment to a disease endpoint. No complete responses were achieved, but 13 of the 38 patients (34%) experienced a partial response, and another 3 patients (8%) experienced sd for more than 6 months. The clinical benefit rate was therefore 42% (95% confidence interval: 27% to 57%). The median time to disease progression for all evaluable patients was 3.6 months (range: 0.9–21.7 months). The most common nonhematologic toxicities were diarrhea, plantar– palmar erythrodysesthesia, fatigue, mucositis, and vomiting. Most patients (89%) received combination chemotherapy until disease progression.

Conclusions

The present study demonstrates that metronomic docetaxel–capecitabine chemotherapy with daily celecoxib can produce significant anticancer activity, with predictable toxicity. Efficacy fell short of expectations, with outcome measures being similar to those obtained when the study agents are given in conventional dosing. Furthermore, there is mounting evidence to indicate that a low dose of taxanes fails to induce thymidine phosphorylase expression, an effect believed to be important in achieving therapeutic synergism when taxanes are given concurrently with capecitabine.     

Paclitaxel plus vinorelbine: An active regimen in metastatic breast cancer patients with prior anthracycline exposure

Purpose:To evaluate the anti-tumour activity and tolerance of thecombination of paclitaxel plus vinorelbine in metastatic breast cancer (MBC)patients previously treated with anthracyclines. Patients and methods:Fifty-six MBC patients who have had at leastone previous anthracycline-containing chemotherapy regimen were enrolled inthis phase II trial. Patients received paclitaxel (135 mg/m² overone-hour infusion) and vinorelbine (30 mg/m²) both on day 1 of eachthree-week course of therapy (maximum eight courses or until diseaseprogression was evident). Results:Six complete and nineteen partial responses were observedamong the fifty-four assessable patients (response rate of 46%,95% CI: 33%–60%). Responses were observed in alldisease sites and in all subsets of patients. The response rates whenpaclitaxel plus vinorelbine were used as first, second and third-linechemotherapy for metastases were 67%, 41% and 35%,respectively. The response rate among anthracycline-refractory patients was46% (6 of 13). Median time to progression in the overall patient groupwas 28 weeks. The main toxicities (CTC grade 2 or more) were alopecia,myelosuppression and peripheral neuropathy (85%, 46% and19% of patients, respectively). Nine patients (17%) hadneutropenic fever in fifteen of the three hundred twenty-eight coursesadministered (5%). Conclusions:The combination of paclitaxel and vinorelbine on day1 every three weeks is active in MBC patients with prior anthracyclineexposure. The regimen is safe, well tolerated and convenient for the patients.     

High efficacy of gemcitabine and cisplatin in patients with predominantly anthracycline- and taxane-pretreated metastatic breast cancer

Background: Effective and tolerable regimens are sought specifically in patients who have been pretreated with anthracyclines and taxanes. Gemcitabine and cisplatin demonstrated synergistic activity in vitro and provides a new mechanism of drug interaction. Patients and methods: Previously treated patients with metastatic breast cancer (MBC) were enrolled in a multicentre phase II study. Treatment consisted of gemcitabine (750 mg/m²) and cisplatin (30 mg/m²) given on day 1 and 8 every 3 weeks. Results: Thirty-eight patients were recruited, all of whom had previously received chemotherapy (35 pretreated with taxanes, 33 pretreated with anthracyclines). A median of 5 cycles of the study treatment was delivered. There were 2 complete and 13 partial responses, for an overall response rate of 40% (95% confidence interval: 23–56%). Thirteen patients (35%) had stable disease. Tumour response appeared independent of previously applied chemotherapy. Median time-to-progression was 6 months and median overall survival was 13.5 months. Main toxicities were leucopenia and thrombocytopenia (grade 3/4 in 26 and 16% of cycles, respectively). Non-haematological toxicity was rarely severe. Conclusions: Combination chemotherapy with gemcitabine and cisplatin given on 2 out of 3 weeks is well tolerated and active in heavily pretreated patients with MBC, even after prior exposure to anthracyclines and taxanes. V. Heinemann, H.J. Stemmler contributed equally     

Tau expression and efficacy of paclitaxel treatment in metastatic breast cancer

Purpose  Paclitaxel is widely used for the treatment of patients with metastatic breast cancer (MBC). Although several mechanisms of paclitaxel resistance have been demonstrated, useful markers of paclitaxel resistance have not been available in clinical practice. Methods  In this study, the clinical significance of tau expression in MBC cases was established by identifying candidates with paclitaxel administration. Tissue specimens obtained from 35 patients were examined. Status of tau expression was determined by immunohistochemistry. Results  Fifteen cases were classified as tau-negative and 20 cases were classified as tau-positive, respectively. Sixty percent of tau-negative expression showed favorable response. Conversely, 85% of tau-positive expression showed progressive or stable disease after paclitaxel administration. Time to disease progression in tau-negative and tau-positive groups was 9.4 ± 6.6 and 6.0 ± 3.7 months, respectively. Conclusions  Patients with tau-positive expression may derive less benefit than tau-negative from paclitaxel therapy in MBC. No financial support was received for this study.     

Metastatic breast cancer with resistance to both anthracycline and docetaxel successfully treated with weekly paclitaxel

We report the case of a 38-year-old woman who underwent surgery for stage III-b breast cancer, and whose liver metastasis failed to respond to both docetaxel (administered at 30–40 mg/m² every 2 weeks as a 1-h intravenous infusion) and epirubicin (administered as a 40–60 mg/m² bolus hepatic arterial infusion). For subsequent treatment, this patient was managed with weekly paclitaxel. The regimen showed some usefulness for the treatment of the liver metastasis, as indicated by an improvement in performance status and tolerable toxicity. This case demonstrates that weekly paclitaxel may be well tolerated and useful for patients with extensive metastatic breast cancer that was resistant to treatment. Our findings also suggest that paclitaxel could be used as a salvage therapy in patients with anthracycline- and docetaxel-resistant breast cancer. Received: February 2, 2000 / Accepted: October 16, 2000     

Monotherapy with paclitaxel as third-line chemotherapy against anthracycline-pretreated and docetaxel-refractory metastatic breast cancer

We describe a patient with anthracycline-pretreated and docetaxel-refractory metastatic breast cancer who achieved a complete response after third-line chemotherapy with paclitaxel. A 59-year-old woman underwent modified radical mastectomy for advanced cancer in her left breast after local arterial neoadjuvant chemotherapy with anthracycline. Postoperatively anthracycline-containing adjuvant therapy was administered. Pulmonary metastases occurred 15 months after surgery, which did not respond to 4 cycles of second-line chemotherapy with docetaxel, given at 60 mg/m(2) every 3 weeks. Therefore 210 mg/m(2) of paclitaxel was given every 3 weeks as third-line monotherapy and induced a complete response with grade 3 neutropenia and hair loss as the major adverse effects. We suggest that paclitaxel is potentially effective as third-line monotherapy for anthracycline-resistant and docetaxel-refractory metastatic breast cancer.     

Phase II study of 5-fluorouracil and paclitaxel in patients with gemcitabine-refractory pancreatic cancer

Purpose  There is no effective salvage regimen for failed gemcitabine-based chemotherapy. This study evaluated the efficacy and toxicity of 5-fluorouracil and paclitaxel in patients with gemcitabine-refractory pancreatic cancer. Methods  Between January 2004 and December 2007, 28 patients with pancreatic cancer previously treated with gemcitabine-based chemotherapy were enrolled. 5-Fluorouracil 1,000 mg/m² was infused (days 1, 2, and 3) and paclitaxel 175 mg/m² (day 1) was administered every 4 weeks. The primary endpoint of this study was efficacy and toxicity and the secondary endpoint was time to progression and overall survival. Results  A total of 75 cycles were given, for a mean of 2.68 cycles per patient. The response could be evaluated in 20 patients. Two patients (10%) obtained a partial response, and four patients (20%) had stable disease. The median time to progression and overall survival was 2.5 and 7.6 months, respectively. Grade 3/4 hematological toxicity included neutropenia in six patients (21.4%), anemia in one (3.6%), and thrombocytopenia in one (3.6%). One (3.6%) patient experienced grade 4 neuropathy, and two (7.2%) patients experienced grade 3 diarrhea. Conclusion  The 5-fluorouracil and paclitaxel combination treatment seems to be effective in patients with advanced pancreatic cancer that did not respond to a gemcitabine-based regimen.     

Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy

BackgroundPaclitaxel and gemcitabine (PG) combination chemotherapy is effective as a maintenance chemotherapeutic regimen in metastatic breast cancer (MBC) patients because it increases progression-free survival (PFS), which increases overall survival (OS). The primary purpose of our study was to investigate the association between genetic polymorphisms in the genes involved in PG pathways and clinical outcomes in MBC patients treated with PG chemotherapy.MethodsA total of 324 MBC patients were enrolled in this prospective multicenter trial of PG as the first-line chemotherapy. Eighty-five of the 324 patients from two institutes were available for analysis of single nucleotide polymorphisms (SNPs). Germline DNA was extracted from peripheral blood mononuclear cells. Thirty-eight SNPs in 15 candidate genes selected from pathways that may influence the metabolism and transport of, or sensitivity, to PG were analysed.ResultsThe median PFS and OS of all 324 patients were 8.7 months (95% confidence interval [CI]: 7.5–9.6 months) and 26.9 months (95% CI: 23.6–30.1 months), respectively. An SNP in SLC28A3 (rs7867504, C/T) was associated with OS (CC or CT versus TT: 37 versus 21 months, p = 0.027, hazard ratio [HR] 2.6, 95% CI: 1.1–6.3). SLC29A1 GA haplotype had a significantly shorter OS (p = 0.030, HR 3.391, 95% CI: 1.13–10.19). RRM1 (ribonucleotide reductase large subunit M1) SNP (rs9937), and haplotypes ATAA and ATGA were significantly associated with neurotoxicity.ConclusionGenetic polymorphisms in SLC28A3, SLC29A1 and RRM1 can influence the clinical outcome of MBC patients treated with PG chemotherapy. Further studies on the functional mechanisms relating to these germline polymorphisms in these genes are warranted.     

吉西他滨联合长春瑞滨治疗晚期三阴性乳腺癌的临床观察

目的：观察吉西他滨联合长春瑞滨（ＧＮ方案）治疗ＥＲ、ＰＲ、ＨＥＲ ２均阴性（三阴性）晚期转移性乳腺癌的疗效与安全性。方法：２００４年１月～２００８年１月共３７例经免疫组化证实ＥＲ、ＰＲ、ＨＥＲ ２均阴性的晚期转移性乳腺癌复治患者参与研究。患者接受吉西他滨联合长春瑞滨方案治疗：吉西他滨１ ０００ｍｇ／ｍ２,静脉滴注３０ｍｉｎ,ｄ_１、ｄ_８;长春瑞滨２５ｍｇ／ｍ^２静脉滴注１５ｍｉｎ,ｄ_１、ｄ_８。２１天重复。结果：全组３７例共完成１３６个周期的治疗,中位数４个周期,范围２～６个周期,均可评价疗效。完全缓解１例（２.７％）,部分缓解８例（２１.６％）,病情稳定２０例（５１.４％）,病情进展９例（２１.６％）,客观有效率为２４.３％;中位疾病进展时间（ｍＴＴＰ）６个月（９５％ ＣＩ：４～８个月）,中位生存期（ＯＳ）２４个月（９５％ ＣＩ：１１～３７个月）,１年生存率为（６６.２４±８.４３）％,３年生存率为（２８.７７±１１.９６）％。毒副反应主要为Ⅰ ～Ⅱ度骨髓抑制、末梢神经毒性、胃肠道反应、流感样症状、轻度肝功能损伤等。结论：吉西他滨联合长春瑞滨治疗晚期三阴性乳腺癌患者,初步观察有一定的疗效,其毒副作用患者可以耐受。     

First-line paclitaxel and cisplatin used sequentially or in combination in metastatic breast cancer: A phase II randomized study

Introduction

Breast cancer (BC) is the commonest cancer among females worldwide. Some patients present initially at advanced stages and more than 50% of them will develop metastasis (MBC) at some point. Compared to single agents, combination chemotherapy produces higher response rates (RR), longer progression-free survival (PFS) than single agents. This is associated with remarkably higher toxicities. At the same time, overall survival (OS) is comparable. This study aimed to compare safety and efficacy of combination and sequential chemotherapy.

Phase II study of weekly gemcitabine in patients with metastatic breast cancer relapsing or failing both an anthracycline and a taxane

A phase II study was performed to investigate the efficacy and tolerability of gemcitabine as third-line chemotherapy for patients with metastatic breast cancer, previously treated with both an anthracycline - and taxane-containing regimen. Twenty-three patients were treated with gemcitabine 1200mg/m² in a 30-min infusion on day 1, 8 and 15 of a 28 day cycle. Seventy-four percent of the patients had visceral metastases. No complete or partial responses were observed. Six patients (26%) had stable disease with a median duration of 4.0 months. The median time to progression was 1.9 months and the median survival time was 7.8 months. Neutropenia grade 3 and 4 was observed in four patients (18%). Non-hematological toxicity grade 3 included nausea and vomiting in 14%, skin toxicity in 9% and elevation of transaminases in 23% of the patients. Gemcitabine is ineffective as third-line single agent therapy in patients failing anthracycline and taxane treatment for metastatic breast cancer.     

Phase I-II study of gemcitabine and paclitaxel in pretreated patients with stage IIIB-IV non-small cell lung cancer

Gemcitabine and paclitaxel are among the most active new agents in non-small cell lung cancer (NSCLC) and are worth considering for second-line chemotherapy. In this phase I–II study, we combined gemcitabine and paclitaxel for second-line treatment of advanced NSCLC. Gemcitabine doses were kept fixed at 1000 mg/m² on day 1 and 8, and paclitaxel doses were escalated from 90 mg/m² on day 1 of the 21-day cycle. Thirty-seven patients were treated at six different dose levels. Grade 4 neutropenia was dose-limiting toxicity (DLT), since it occurred in two out of six patients treated at paclitaxel 240 mg/m²; the paclitaxel dose level just below (210 mg/m²) was selected for phase II evaluation. Non-hematologic toxicity was mild. One complete response (CR) (3%) and 13 partial responses (PR) (36%) were observed in 36 evaluable patients for an overall response rate of 39% (95% C.I., 23–57%). Median duration of response was 35 weeks (range, 8–102). All of the observed objective responses occurred in the 19 patients who had previously responded to the first-line therapy. Median survival was 40 weeks (range, 8–108 weeks). The combination of gemcitabine and paclitaxel is a feasible, well-tolerated, and active scheme for second-line treatment of advanced NSCLC; further evaluation, at least in selected patients, such as those previously responding to first-line chemotherapy, is definitely warranted.     

Alternating weekly administration of paclitaxel and gemcitabine: a phase II study in patients with advanced non-small-cell lung cancer

Background We sought to evaluate toxicity and efficacy of an alternating week schedule of paclitaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC).Methods Patients (n=27, mean age 56 years, range 27–73 years) received paclitaxel (100 mg/m² i.v. infusion over 1 h) on days 1 and 15 alternating with gemcitabine (1000 mg/m²) on days 8 and 22 of a 36-day cycle. Responses were evaluated after three cycles, and after the proposed six cycles.Results In total, 116 cycles were administered (mean 4.25 cycles per patient). Haematological toxicity was slight: febrile neutropenia (n=1) and neutropenia grade III–IV (n=5). Non-haematological toxicities included arthromyalgia grade II (n=6) and neurotoxicity grade III (n=1). Objective response was 29%, stable disease 25% and disease progression 46%. Median duration of response was 8 months (95% CI 5–11 months), median progression-free survival was 7 months (95% CI 4–11 months), median overall survival was 13 months (95% CI 7–17 months) and survival at 1 year was 52%.Conclusions A regimen of alternating weekly paclitaxel and gemcitabine is feasible in patients with advanced NSCLC, showing a lower toxicity profile compared with other platinum-based combinations, which makes this novel scheme attractive for these patients.