taxane and Thrombocytopenia

The two commercially available taxanes (paclitaxel and docetaxel) are widely employed in standard oncologic practice. Toxicity of the agents includes bone marrow suppression (principally neutropenia), complete alopecia, and hypersensitivity reactions. While both drugs can cause neurotoxicity and myalgias/arthralgias, this is a greater clinical concern with paclitaxel. Docetaxel can be associated with the development of significant fluid retention (e.g., edema, ascites, pleural effusions), the incidence and severity of which appear to be limited by prophylactic treatment with corticosteroids both before and after each treatment. If patients are monitored closely (e.g., for hypersensitivity reactions, bone marrow suppression) the taxanes have a favorable side effect profile, and it is currently uncommon for treatment to be discontinued because of the development of excessive toxicity.

Topics: Antineoplastic Agents, Phytogenic; Arthralgia; Bridged-Ring Compounds; Docetaxel; Drug Hypersensitivity; Humans; Neutropenia; Paclitaxel; Peripheral Nervous System Diseases; Taxoids; Thrombocytopenia

The antibody-drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial.. EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to trastuzumab emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m. Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either trastuzumab emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with trastuzumab emtansine than with control (29·9 months [95% CI 26·3-34·1] vs 25·9 months [95% CI 22·7-28·3]; hazard ratio 0·75 [95% CI 0·64-0·88]). 136 (27%) of 496 patients crossed over from control to trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months [IQR 19·5-26·1]). Of those patients originally randomly assigned to trastuzumab emtansine, 254 (51%) of 495 received capecitabine and 241 [49%] of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with trastuzumab emtansine), fewer grade 3 or worse adverse events occurred with trastuzumab emtansine (233 [48%] of 490) than with capecitabine plus lapatinib control treatment (291 [60%] of 488). In the control group, the most frequently reported grade 3 or worse adverse events were diarrhoea (103 [21%] of 488 patients) followed by palmar-plantar erythrodysaesthesia syndrome (87 [18%]), and vomiting (24 [5%]). The safety profile of trastuzumab emtansine was similar to that reported previously; the most frequently reported grade 3 or worse adverse events in the trastuzumab emtansine group were thrombocytopenia (70 [14%] of 490), increased aspartate aminotransferase levels (22 [5%]), and anaemia (19 [4%]). Nine patients died from adverse events; five of these deaths were judged to be related to treatment (two in the control group [coronary artery disease and multiorgan failure] and three in the trastuzumab emtansine group [metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukaemia]).. This descriptive analysis of final overall survival in the EMILIA trial shows that trastuzumab emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming trastuzumab emtansine as an efficacious and tolerable treatment in this patient population.. F Hoffmann-La Roche/Genentech.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Anemia; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Breast Neoplasms; Breast Neoplasms, Male; Bridged-Ring Compounds; Capecitabine; Diarrhea; Disease-Free Survival; Female; Hand-Foot Syndrome; Humans; Lapatinib; Male; Maytansine; Middle Aged; Quinazolines; Receptor, ErbB-2; Response Evaluation Criteria in Solid Tumors; Retreatment; Survival Rate; Taxoids; Thrombocytopenia; Trastuzumab; Vomiting; Young Adult

In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial.. Eligible patients for the TH3RESA trial were men and women (aged ≥18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, left ventricular ejection fraction of at least 50%, and adequate organ function. Patients were randomly assigned (2:1) by an interactive voice and web response system with permuted block randomisation in blocks of six to receive trastuzumab emtansine (3·6 mg/kg intravenously every 21 days) or treatment of physician's choice administered per local practice. Randomisation was stratified by world region, number of previous regimens for advanced breast cancer, and presence of visceral disease. On Sept 12, 2012, the study protocol was amended to allow patients with disease progression to crossover from treatment of physician's choice to trastuzumab emtansine. The coprimary endpoints for TH3RESA were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. We report results from a preplanned second interim analysis of overall survival, which was planned for when approximately 67% (n=330) of 492 expected deaths had occurred. This study is registered with ClinicalTrials.gov, number NCT01419197.. Between Sept 14, 2011, and Nov 19, 2012, 602 patients were enrolled from 146 centres in 22 countries and randomly assigned to trastuzumab emtansine (n=404) or treatment of physician's choice (n=198). At data cutoff (Feb 13, 2015), 93 (47%) of 198 patients in the physician's choice group had crossed over to trastuzumab emtansine. Overall survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice (median 22·7 months [95% CI 19·4-27·5] vs 15·8 months [13·5-18·7]; hazard ratio 0·68 [95% CI 0·54-0·85]; p=0·0007). As the stopping boundary for overall survival was crossed, this overall survival analysis serves as the final and confirmatory analysis of overall survival and the study was terminated according to the protocol. The incidence of grade 3 or worse adverse events was 161 (40%) of 403 patients in the trastuzumab emtansine group and 87 (47%) of 184 patients in the treatment of physician's choice group. Of the most common grade 3 or worse adverse events (affecting ≥2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with trastuzumab emtansine were diarrhoea (three [1%] of 403 patients in the trastuzumab emtansine group vs eight [4%] of 184 patients in the treatment of physician's choice group), neutropenia (ten [3%] vs 29 [16%]), and febrile neutropenia (one [<1%] vs seven [4%]); whereas those that were more frequent with trastuzumab emtansine were thrombocytopenia (24 [6%] of 403 patients vs five [3%] of 184 patients) and haemorrhage of any type (17 [4%] of 403 vs one [<1%] of 184). Serious adverse events were reported in 102 (25%) of 403 patients in the trastuzumab emtansine group and 41 (22%) of 184 in the physician's choice group. Deaths from adverse events were reported in three patients (2%) in the physician's choice group (of which one was judged to be treatment related) and nine (2%) in the trastuzumab emtansine group (of which three were judged to be treatment related).. In patients who had progressed on two or more HER2-directed regimens, trastuzumab emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of trastuzumab emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy.. F Hoffman-La Roche/Genentech.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Breast Neoplasms, Male; Bridged-Ring Compounds; Chemotherapy-Induced Febrile Neutropenia; Diarrhea; Early Termination of Clinical Trials; Female; Hemorrhage; Humans; Lapatinib; Male; Maytansine; Middle Aged; Neoplasm Metastasis; Neutropenia; Practice Patterns, Physicians'; Quinazolines; Receptor, ErbB-2; Retreatment; Survival Rate; Taxoids; Thrombocytopenia; Trastuzumab

To determine the safety and efficacy of gemcitabine and cisplatin in patients with taxane resistant metastatic breast cancer.. 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.. 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.. The described gemcitabine plus cisplatin combination was found to be an active and tolerable salvage regimen in patients with taxane resistant metastatic breast cancer.

Topics: Adult; Aged; Alopecia; Anemia; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Deoxycytidine; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Gemcitabine; Humans; Infusions, Intravenous; Leukopenia; Middle Aged; Neoplasm Metastasis; Recurrence; Severity of Illness Index; Stomatitis; Survival Rate; Taxoids; Thrombocytopenia; Treatment Outcome

Second-line chemotherapy for patients with nonsmall cell lung carcinoma has been ineffective due to the lack of activity of older agents following platinum-based therapy. This Phase II trial evaluated the feasibility, toxicity, and efficacy of two active new agents, gemcitabine and vinorelbine, used in combination as second-line therapy for patients with nonsmall cell lung carcinoma.. Patients with advanced nonsmall cell lung carcinoma who had progressive disease after previous chemotherapy or combined-modality therapy were eligible for this trial. All patients received vinorelbine 20 mg/m(2) followed by gemcitabine 1000 mg/m(2) on Days 1, 8, and 15 of each 28-day cycle. Patients were reevaluated for a response after two treatment courses: responding patients and those with stable disease received a maximum of six courses. Fifty-five patients were treated between January 1998 and November 1998; 47 patients (85%) had previously received both a taxane and a platinum agent.. Objective responses were seen in 9 of 50 evaluable patients (18%), including 8 partial responses and 1 complete response. Twenty-four additional patients (48%) had either minor response or stable disease. The median time to progression for patients with objective response or stable disease was 5 months. The median survival was 6.5 months with an actuarial 1-year survival of 20%. The treatment was well tolerated with uncommon nonhematologic toxicity and no alopecia. Grade 3 neutropenia and thrombocytopenia occurred in 27% and 22% of patients, respectively, but Grade 4 neutropenia was uncommon (occurring in 9% of patients) and only 4 patients required hospitalization for treatment of neutropenia and fever.. The combination of vinorelbine and gemcitabine is active and well tolerated as second-line therapy for patients with advanced nonsmall cell lung carcinoma. This regimen merits further evaluation as a first-line therapy for patients with this disease.

Topics: Actuarial Analysis; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Disease Progression; Feasibility Studies; Female; Fever; Gemcitabine; Humans; Lung Neoplasms; Male; Middle Aged; Neutropenia; Platinum Compounds; Remission Induction; Survival Rate; Taxoids; Thrombocytopenia; Vinblastine; Vinorelbine

Lung carcinoma is the most common malignancy and the leading cause of cancer deaths worldwide. Although clinical factors including age, performance status and stage influence the likelihood of benefit from and tolerability of chemotherapy, the genetic profile of individual patients may be an independent predictor of response and toxicity. The present study aimed to identify pharmacogenetic markers associated with clinical response and toxicity in patients with advanced non-small cell lung cancer (NSCLC) treated primarily with carboplatin and paclitaxel.. Genomic DNA samples from 90 adult male patients diagnosed with stage IIIB/IV NSCLC were genotyped for SNPs in candidate genes of relevance to platinating agents and paclitaxel and analyzed for association with survival and toxicities in univariate and multivariate models.. After adjusting for performance status and stage, SNPs in the drug transporters ABCB1 and ABCC1, as well as within NQO1 were associated with progression-free survival. With respect to hematological and nonhematological toxicities, SNPs in drug transporters (ABCB1 and ABCG2) were associated with thrombocytopenia, nausea and neutropenia, whereas SNPs in the DNA repair pathway genes ERCC4 and XPC were significantly associated with neutropenia and sensory neuropathy, respectively.. Our study evaluated and identified SNPs in key candidate genes in platinating agent and taxane pathways associated with outcome and toxicity in advanced NSCLC. If validated in large prospective studies, these findings might provide opportunities to personalize therapeutic strategies.

Topics: Aged; Aged, 80 and over; ATP Binding Cassette Transporter, Subfamily B; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; DNA-Binding Proteins; Female; Genetic Association Studies; Humans; Male; Middle Aged; Multidrug Resistance-Associated Proteins; NAD(P)H Dehydrogenase (Quinone); Nausea; Neoplasm Staging; Neutropenia; Paclitaxel; Polymorphism, Single Nucleotide; Taxoids; Thrombocytopenia