Gemcitabine In Metastatic Breast Cancer Research Articles

2506 A Fatal Case of Gemcitabine-Induced Acute Liver Failure

INTRODUCTION: Gemcitabine is a common chemotherapeutic agent with broad anti-tumor activity. Gemcitabine induced acute liver failure (ALF) is exceedingly rare, resulting in severe steatohepatosis and high mortality. We report the ninth case of Gemcitabine induced ALF. CASE DESCRIPTION/METHODS: A 65 year-old female on her second cycle of palliative Gemcitabine for metastatic breast cancer presented with five days of weakness, nausea and vomiting after chemotherapy. She was afebrile but hypotensive. She was not visibly jaundiced, sclerae anicteric, and without palpable hepatomegaly. Her initial labs were significant for elevated direct bilirubin, ALP and transaminitis suggestive of a cholestatic pattern (Figure 1). Notably, she had no hepatic dysfunction one month prior to presentation. Ultrasound revealed fatty infiltration of the liver without evidence of obstruction or acute cholecystitis. She developed worsening steatohepatitis with direct bilirubin predominance (Figure 2). CT abdomen revealed fatty replacement of the liver without obstruction or metastasis. Her course was complicated by severe thrombocytopenia, anemia, and renal failure. She deteriorated despite supportive care, becoming increasingly jaundiced and encephalopathic, expiring on hospital day 5. Table 1. DISCUSSION: Chemotherapy agent Gemcitabine is a deoxycitadine analog that incorporates into DNA resulting in apoptosis. Generally well-tolerated, common side effects include myelosuppression and transient elevations in LFTs. However, gemcitabine is implicated as the causative agent of a rare, severe and highly fatal cholestatic ALF. Gemcitabine induced ALF appears idiosyncratic, without clear correlation between dose or duration of treatment. In Gemcitabine induced ALF, imaging shows fatty infiltration of hepatic parenchyma and biopsy reveals hepatocyte ballooning and marked cholestasis. These cases are often rapidly fatal, complicated by thrombocytopenia, coagulopathy and renal failure. Our literature review revealed two cases of patient survival; in one case, Gemcitabine was promptly recognized as the offending agent and high dose steroid therapy was initiated. This may represent a treatment strategy where thus far no others exist. As drug induced hepatotoxicity is the most common cause of ALF in the USA, clinicians should be aware of this hepatotoxic potential, especially given the high mortality rate of Gemcitabine induced ALF.

Tumor Lysis Syndrome: A Rare Complication of Chemotherapy for Metastatic Breast Cancer

Tumor lysis syndrome (TLS) is a fatal complication of chemotherapy treatment. It is rarely seen in the treatment of solid tumors particularly in breast cancer. We presented the case of a chemo-naïve 58-year-old Caucasian woman who developed tumor lysis syndrome (TLS) after a single treatment dose of gemcitabine for metastatic breast cancer. Despite optimal management, the patient clinically deteriorates and is referred to inpatient hospice. Although targeted chemotherapy options have become increasingly effective, physicians should be aware of the rare, yet often fatal complications of TLS. Similarly, physicians should be able to quickly recognize the development of TLS to ensure swift and effective prophylaxis or treatment.

Caveolin-1 expression predicts efficacy of weekly nab-paclitaxel plus gemcitabine for metastatic breast cancer in the phase II clinical trial

BackgroundNanoparticle albumin-bound (nab)-paclitaxel has better efficacy, safety profiles, and no need to use prophylactic steroids compared with solvent-based paclitaxel. We performed a single arm, phase II study to evaluate the efficacy and safety of weekly nab-paclitaxel and gemcitabine combination in patients with metastatic breast cancer (MBC) and explored role of tumor/stromal Caveolin-1 (Cav-1) as a predictive biomarker for the efficacy.MethodsNab-paclitaxel (125 mg/m2) and gemcitabine (800 mg/m2) were administered on days 1, 8, and 15 in a 4-week cycle. The primary end point was objective response rate (ORR). Secondary end points were progression free survival (PFS), overall survival (OS) and safety profile. Exploratory study included immunohistochemical detection of Cav-1.ResultsAmong 85 patients enrolled in the study, ORR was 52.4%. After a median follow-up of 17.2 months, median PFS was 7.9 months (95%CI, 6.6–9.2) and median OS was 25.8 months (95% CI, 20.4–31.1). The most common toxicities were neutropenia (75.0% for all grades; 45.2% for grade 3 or worse) and the most common non-hematologic toxicity was peripheral neuropathy (50.0% for all grades, 7.14% for grade 3 or worse). Higher tumor Cav-1 level and lower stromal Cav-1 level were significantly associated with longer PFS of nab-paclitaxel and gemcitabine.ConclusionsThe regimen had substantial antitumor activity and was well tolerated in MBC patients. Tumor/stromal Cav-1 level may be a good predictor for the efficacy of nab-paclitaxel and gemcitabine.Trial registrationNCT01550848. Registered 12 March 2012.

Successful Remission of Hemolytic-Uremic Syndrome during the Third-line Weekly Gemcitabine for Metastatic Breast Cancer

Sequential palliative chemotherapy for metastatic breast cancer incorporating weekly gemcitabine administered as three-weeks-on, one-week-off schedule is widely adopted throughout the East Asia region. Hemolytic-uremic syndrome (HUS) associated with weekly gemcitabine for a breast cancer patient is extremely rare. We report here a case of 43-year-old woman with metastatic breast cancer who received weekly gemcitabine as a third-line palliative chemotherapy for her disease. She developed HUS after a cumulative dose of 11,000 mg/m2 gemcitabine, evidenced by microangiopathic hemolytic anemia (MAHA) with schistocytes seen in peripheral blood smear, decreased haptoglobin level (<0.29 mmol/L), thrombocytopenia, negative direct Coombs test, and acute kidney injury. Owing to the ease of administration of weekly gemcitabine, gemcitabine-induced thrombocytopenia, multifactorial anemia in metastatic breast cancer, and possibility of cancer progression, HUS could have gone unnoticed. Breast cancer oncologist should be cognizant of this rare HUS even during weekly gemcitabine treatment.

P3-091 - Efficacy and Tolerability of Gemcitabine for Metastatic Breast Cancer

ABSTRACT Backgroud Metastatic breast cancer (MBC) still remains incurable and the goals of treatment are to prolong survival while controlling symptoms and minimizing toxicity. We evaluated the efficacy and tolerability of Gemcitabine (GEM) in MBC patients at our institute. Methods Clinical data from 17 MBC patients treated with GEM alone or with trastuzumab (in HER2 overexpressing patients) were retrospectively examined. Patient and tumor characteristics, best overall response, time to progression (TTP), adverse effects (CTCAE) were examined. Results Median age was 62 (40–81) and 5 (29%) received trastuzumab in combination with GEM. 15 were recurrent MBC after surgery and 9 (60%) had had adjuvant chemotherapy, with 7 receiving an anthracycline or a taxane. Median number of previous treatments was 3 regimens (range: 1 ∼ 8 regimens). Best overall response was 1 CR (5.9%), 1 PR (5.9%), 4 SD (23.5%), 11 PD (64.7%) with a response rate of 11.7% and a clinical benefit rate of 17.6%. Median TTP was 3 months (range: 1–8 months). Adverse effects were three cases of grade 2 diarrhea, one case of fatigue, three cases of grade 3 neutropenia. Dose modification and delayed administrations were caused by neutropenia, diarrhea, and fatigue. Among the six responders, GEM was administered earlier (first or second line as MBC treatment) in four cases, but for the others, GEM was the sixth and seventh regimen. Conclusion GEM was well tolerated and could be a choice of treatment even in later regimens in MBC.

Gemcitabine and capecitabine in previously anthracycline-treated metastatic breast cancer: a multicenter phase II study (SOLTI 0301 trial)

BackgroundOn the basis of clinical activity of capecitabine and gemcitabine for metastatic breast cancer, we carried out a multicenter phase II clinical trial on the combination of these two agents in advanced anthracycline-pretreated breast cancer patients. Main objectives were to assess its efficacy and safety profile. Patients and methodsSeventy-six anthracycline-pretreated breast cancer patients were evaluated and were stratified according to previous treatment of advanced disease (group-1: not previously treated and group-2: previously treated). Study treatment consisted of gemcitabine 1000 mg/m2, i.v., as 30 min-infusion, days 1 and 8 every 21 days, plus oral capecitabine 830 mg/m2 b.i.d., days 1–14 every 21 days. ResultsOverall response rate was 61% for group-1, 48.5% for group-2 and 55.2% for the whole population. Clinical benefit rate was 73% for group-1, 80% for patients in group-2 and 76% for all patients. Median time to progression was 13.0 months for group-1, 8.2 months for group-2 and 11.1 months for the whole population. Most frequent grade 3–4 observed toxic effects per patient were neutropenia (60%), asymptomatic liver toxicity (13.5%), asthenia (14%) and hand–foot syndrome (16%). Only one patient presented febrile neutropenia. No treatment-related deaths occurred. ConclusionCombination of gemcitabine and capecitabine is an active and safe regimen in anthracycline-pretreated breast cancer patients.

The clinical effectiveness and cost-effectiveness of gemcitabine for metastatic breast cancer: a systematic review and economic evaluation

To assess the clinical effectiveness and cost-effectiveness of gemcitabine, used in combination with paclitaxel, as a second-line treatment for people with metastatic breast cancer who have relapsed following treatment with anthracycline-based chemotherapy. Electronic databases were searched from inception to March 2006. Clinical advisers were also consulted. A systematic review of the literature was undertaken to appraise the clinical and cost-effectiveness of gemcitabine. A Markov state transition model was developed for the economic evaluation. The systematic review identified only one randomised controlled trials (RCT), and this has not yet been fully published. The methodological quality and quality of reporting of the included trial were assessed to be poor using standard criteria, but this may be due to the lack of information in the limited publications rather than being a fair reflection of the trial's quality. This RCT compared gemcitabine and paclitaxel therapy with paclitaxel monotherapy in 529 patients with metastatic breast cancer who had previously received anthracyclines, but no prior chemotherapy for metastatic breast cancer. Approximately 71% of the gemcitabine/paclitaxel patients survived for 1 year, compared with 61% of the paclitaxel group. The hazard ratio showed a 26% lower chance of survival in the paclitaxel group, and time to progressive disease was also shorter in this group. The overall response rate was higher in the gemcitabine/paclitaxel group than in the paclitaxel group. Adverse events, particularly neutropenia, were more common with gemcitabine/paclitaxel combination therapy than with paclitaxel therapy alone. The economic model was run for a simulation of 1000 patients, assuming that chemotherapy continued until patients' disease progressed. This base-case analysis found an incremental cost-effectiveness ratio (ICER) of 58,876 pounds per quality-adjusted life-year (QALY) gained and 30,117 pounds per life-year gained. The model was re-run with treatment restricted to a maximum of six cycles per patient, reflecting normal practice. This yielded an ICER of 38,699 pounds per QALY gained and 20,021 pounds per life-year gained. The review of clinical effectiveness is based on data from a single RCT that has not yet been fully published. While only tentative conclusions can be drawn from this, the evidence may indicate that treatment with gemcitabine and paclitaxel confers an improved outcome for patients in terms of survival and disease progression, but at the cost of increased toxicity. An economic model developed for this review reflects high costs per QALY for this treatment combination. The base-case analysis shows high ICERs, with costs per QALY gained close to 60,000 pounds. Adopting a more realistic treatment protocol, with chemotherapy limited to a maximum of six cycles, gives a more favourable cost-effectiveness estimate. However, this was still higher than would usually be considered to be a cost-effective treatment from the NHS's perspective. Future research recommendations include an update of this review in 12-18 months' time, by which time the included RCT should be fully published. It would also be useful to compare gemcitabine with currently used treatments for metastatic breast cancer, including capecitabine and vinorelbine.

Gemcitabine in metastatic breast cancer

10735 Background: Gemcitabine (GEM) has shown efficacy in metastatic breast cancer (MBC). We conducted studies with GEM-based regimens to assess the efficacy and toxicity of GEM combined with other drugs in MBC. GEM was combined with docetaxel (DXL) in pre-treated MBC with an anthracycline-based regimen and GEM was combined with doxorubicin (DXR) in chemonaive patients (pts) with MBC. The studies’ objectives were to show clinically relevant hematologic toxicity and response rates among pts treated with GEM-DXL either in combination in pre-treated pts with anthracycline regimen or GEM-DXR in chemonaive pts with MBC to assess the efficacy of GEM in MBC either in neoadjuvant or first-line treatment. Methods: For GEM-DXL: 42 pts were enrolled; GEM: 1250 mg /m2 D1 &amp; D8, DXL: 75 mg /m2 D1, every 21 days with classical premedication for DXL. For GEM-DXR: 51 pts were enrolled; GEM: 1250 mg /m2 D1 &amp; D 8, DXR: 25 mg/m2 D1 &amp; D8, every 21 days. Results: See table below. In the GEM-DXR group, surgery was performed in 30 pts, and 13 (43.2%) had histologically complete response. The median TTP in this group was 13.3 months (range, 2–53). Conclusions: GEM in MBC is very efficient and produced an interesting objective response and clinical benefit. This activity is consistent in either chemonaive pts or in pts with relapsing breast cancer. [Table: see text] No significant financial relationships to disclose.

A phase II trial of a biweekly combination of paclitaxel and gemcitabine in metastatic breast cancer

BackgroundMany emerging new drugs have recently been trialled for treatment of early and advanced breast cancer. Among these new agents paclitaxel and gemcitabine play a crucial role, mostly in patients with relapsed and metastatic disease after failure of chemotherapy with antracyclines.MethodsA phase II study was started in order to evaluate the activity and toxicity of a combination of paclitaxel and gemcitabine in a biweekly schedule on metastatic breast cancer patients previously treated with antracyclines.ResultsTwenty-five patients received paclitaxel (150 mg/mq) by 3-hours infusion, followed by gemcitabine (2000 mg/mq) given as a 60 min i.v. infusion (day 1–14) for a maximum of eight cycles. In all patients treatment was evaluated for toxicity and efficacy; four patients (16%) achieved a complete response, 12 (48%) a partial response giving an overall objective response rate of 64%. Stable disease was documented in 5 patients (20%) and progressive disease occurred in 4 patients (16%).ConclusionThe schedule of treatment was safe and tolerable from a haematological and non-haematological point of view. These data confirm that the combination of gemcitabine and paclitaxel on a biweekly basis is an effective and well-tolerated regimen in breast cancer patients with prior therapeutic exposure to antracyclines.

Weekly Docetaxel and Gemcitabine as First-Line Treatment for Metastatic Breast Cancer: Results of a Multicenter Phase II Study

Objectives: We conducted a multicenter phase II study to evaluate the clinical efficacy, toxicity, and dose intensity of a new weekly schedule of docetaxel and gemcitabine as first-line treatment of metastatic breast cancer patients. Methods: We enrolled 58 patients, 52% of whom had received a previous anthracycline-containing chemotherapy. The treatment schedule was: docetaxel 35 mg/m² and gemcitabine 800 mg/m² i.v. on days 1, 8, 15 every 28 days. Results: All patients were assessable for toxicity and 56 for efficacy. Overall response rate was 64.3% with 16.1% of complete responses and 48.2% of partial responses. Median survival was 22.10 months (95% CI: 15.53–28.67) and median time to tumor progression was 13.6 months (95% CI: 10.71–16.49). The most common hematological toxicity was neutropenia (no febrile neutropenia), which occurred in 28 patients (48.3%) but grade 3–4 in only 8 patients (14%). Alopecia, the most common nonhematological toxicity, occurred in 20 (34.5%) patients, but only 5 patients (8.6%) experienced grade 3 alopecia. Conclusion: The activity of docetaxel and gemcitabine in metastatic breast cancer is confirmed. The promising results of the employed schedule, in agreement with other published studies, need to be further confirmed within a phase III study.

Gemcitabine in metastatic breast cancer

Gemcitabine is a pyrimidine antimetabolite which has shown activity in metastatic breast cancer both as a single agent, but also in various combination regimens. It is characterized by a unique mechanism of action which includes cytotoxic self-potentiation, masked DNA chain termination and potent inhibition of DNA repair. The clinical application of gemcitabine is supported by a favorable toxicity profile. In metastatic breast cancer, several Phase II trials document the activity of gemcitabine in pretreated and unpretreated patients. In a single Phase III trial performed in elderly patients not pretreated, gemcitabine was inferior to epirubicin. High activity has, however, been obtained by the combination of gemcitabine with taxanes such as paclitaxel or docetaxel. In a randomized trial performed in anthracycline-pretreated patients, the combined use of gemcitabine and paclitaxel induced a significant improvement not only of response rate and time to disease progression, but also caused a significant increase in quality of life and survival when compared with paclitaxel alone. The combination of gemcitabine with vinorelbine and cisplatin has been validated in numerous Phase II trials and promises reliable activity in anthracycline- and/or taxane-pretreated patients. Triple-agent regimens such as gemcitabine/epirubicin/paclitaxel provided consistently high response rates in Phase II trials, but failed to show superiority over the 5-fluorouracil/epirubicin/cyclophosphamide regimen in a randomized Phase III trial. Based on high response rates and pathological complete remission rates achieved by preoperative induction therapy with gemcitabine/epirubicin/taxane regimens, ongoing trials focus on the incorporation of gemcitabine into neoadjuvant and adjuvant regimens.

Monthly docetaxel and weekly gemcitabine in metastatic breast cancer: A phase II trial

Docetaxel and gemcitabine are active against breast cancer. The purpose of this phase II study was to evaluate the efficacy and safety of monthly docetaxel combined with weekly gemcitabine in patients with chemotherapy-pretreated metastatic breast cancer. Thirty-nine patients were enrolled, of whom thirty had received prior chemotherapy in the adjuvant setting, seven for metastatic disease, and two for both, including prior anthracycline in 33 patients. Treatment was gemcitabine 800 mg/m2 days 1, 8, 15 and docetaxel 100 mg/M2 on day 1, with cycles repeated every four weeks. Response rate was 79% (95% confidence interval (CI): 63%-91%), with 2 complete and 29 partial responses. Twenty-five of the responders remained progression-free for more than six months. Median survival was 24.5 months. Delivered dose intensity of gemcitabine was lower than expected (63% of planned). The predominant hematologic toxicity was grade 4 neutropenia in 36 patients, complicated by fever in three patients. With the exception of asthenia, severe non-hematological toxicities were infrequent. Monthly docetaxel, combined with weekly gemcitabine, has significant but manageable hematologic toxicity. Despite frequent dose adjustments, this doublet is very active in metastatic breast cancer, producing a high proportion of durable responses associated with favorable survival.