Summary Background We compared standard adjuvant anthracycline chemotherapy with anthracycline–taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the ...final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety. Methods BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18–70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov , number NCT00688740. Findings Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90–126), disease-free survival was 62% (95% CI 58–65) for patients in the TAC group and 55% (51–59) for patients in the FAC group (hazard ratio HR 0·80, 95% CI 0·68–0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72–79) for patients in the TAC group and 69% (65–72) for patients in the FAC group (HR 0·74, 0·61–0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3–4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC. Interpretation Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation. Funding Sanofi.
Summary Background Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles. On the basis of promising results from a phase 1/2 trial ...assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer (NSCLC), we aimed to assess efficacy and safety of this combination in a phase 3 trial. Methods In our double-blind, placebo-controlled, randomised phase 3 trial (BeTa), we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment. Patients were randomly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab (bevacizumab group) or erlotinib plus placebo (control group) according to a computer-generated randomisation sequence by use of an interactive voice response system. The primary endpoint was overall survival in all enrolled patients. Patients, study staff, and investigators were masked to treatment assignment. We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses. This trial is registered with ClinicalTrials.gov , number NCT00130728. Findings Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group (hazard ratio HR 0·97, 95% CI 0·80–1·18, p=0·7583). Median overall survival was 9·3 months (IQR 4·1–21·6) for patients in the bevacizumab group compared with 9·2 months (3·8–20·2) for controls. Progression-free survival seemed to be longer in the bevacizumab group (3·4 months 1·4–8·4) than in the control group (1·7 months 1·3–4·1; HR 0·62, 95% CI 0·52–0·75) and objective response rate suggested some clinical activity of bevacizumab and erlotinib. However, these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done, to control type I error rate. In the bevacizumab group, 130 (42%) of 313 patients with safety data had a serious adverse event, compared with 114 (36%) controls. There were 20 (6%) grade 5 adverse events, including two arterial thromboembolic events, in the bevacizumab group, and 14 (4%) in the control group. Interpretation Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC. Funding Genentech.
Background Primary analysis from the pivotal ERIVANCE BCC study resulted in approval of vismodegib, a Hedgehog pathway inhibitor indicated for treatment of adults with metastatic or locally advanced ...basal cell carcinoma (BCC) that has recurred after surgery or for patients who are not candidates for surgery or radiation. Objective An efficacy and safety analysis was conducted 12 months after primary analysis. Methods This was a multinational, multicenter, nonrandomized, 2-cohort study in patients with measurable and histologically confirmed locally advanced or metastatic BCC taking oral vismodegib (150 mg/d). Primary outcome measure was objective response rate (complete and partial responses) assessed by independent review facility. Results After 12 months of additional follow-up, median duration of exposure to vismodegib was 12.9 months. Objective response rate increased from 30.3% to 33.3% in patients with metastatic disease, and from 42.9% to 47.6% in patients with the locally advanced form. Median duration of response in patients with locally advanced BCC increased from 7.6 to 9.5 months. No new safety signals emerged with extended treatment duration. Limitations Limitations include low prevalence of advanced BCC and challenges of designing a study with heterogenous manifestations. Conclusion The 12-month update of the study confirms the efficacy and safety of vismodegib in management of advanced BCC.
Background Vismodegib, a first-in-class Hedgehog pathway inhibitor, was US Food and Drug Administration (FDA) approved for advanced basal cell carcinomas (BCCs) based on a single, nonrandomized, ...phase-II trial. Consequently, additional clinical data are critical to confirm the efficacy and safety of vismodegib. Objective We sought to assess efficacy and safety of vismodegib, while providing early drug access to patients with advanced BCC and limited treatment options. Methods This was an open-label, multicenter study in patients with advanced BCC inappropriate for radiotherapy or surgery. Patients received 150 mg vismodegib daily until disease progression or intolerable toxicity. Tumor response was assessed via Response Evaluation Criteria in Solid Tumors version 1.0. Results A total of 119 patients with advanced BCC took vismodegib for a median of 5.5 months. Objective responses occurred in 46.4% of locally advanced BCC and 30.8% of patients with metastatic BCC. Response was negatively associated with prior systemic therapy in patients with locally advanced BCC ( P = .002). Mean follow-up for safety was 6.5 months, with muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%), and diarrhea (25.2%) as the most common adverse events. Limitations Abbreviated follow-up time because of study termination upon FDA approval was a limitation. Conclusion This study provides important clinical data supporting the efficacy and safety of vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes.
Summary Background Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to ...assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). Methods We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov , number NCT00412061. Findings 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7–21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4–14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59–1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62% vs 14%), rash (37% vs 12%), fatigue (31% vs 23%), and diarrhoea (27% vs 16%). Interpretation Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. Funding Novartis Pharmaceuticals.
Summary Background Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to ...compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma. Methods We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov , number NCT01108445. Findings Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months 80% CI 5·8–11·4 vs 5·6 months 5·5–6·0; hazard ratio 1·41 80% CI 1·03–1·92; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3–4 adverse events were hypertension (12 24% of 51 patients in the sunitinib group vs one 2% of 57 patients in the everolimus group), infection (six 12% vs four 7%), diarrhoea (five 10% vs one 2%), pneumonitis (none vs five 9%), stomatitis (none vs five 9%), and hand-foot syndrome (four 8% vs none). Interpretation In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors. Funding Novartis and Pfizer.
Abstract Background The purposes of this phase 1/2 trial were: 1) to define tolerable doses of ixabepilone and sorafenib when used in combination, and 2) to evaluate the efficacy and toxicity of this ...combination in the treatment of patients with HER2-negative metastatic breast cancer (MBC). Methods Eligible patients had HER2-negative MBC, and had received no previous chemotherapy in the metastatic setting. All patients received ixabepilone intravenously on day 1 of each 21-day treatment cycle; sorafenib was administered orally twice daily. Patients in phase 2 received the maximum doses identified in phase 1. Patients were reevaluated after completion of 3 treatment cycles; treatment continued until disease progression or intolerable toxicity. 67 patients were required in phase 2 to demonstrate increased median PFS from 4.2 to 6.2 months (90% power, alpha=0.05). Results Ten patients entered the phase 1 portion; the maximum tolerated doses were: ixabepilone 32 mg/m2 and sorafenib 400 mg orally twice daily. 76 patients were treated at the phase 2 dose. The median PFS was 4.8 months (95% CI 3.5, 6.3). The overall response rate was 37%. The regimen was difficult to tolerate for many patients. Twenty patients discontinued due to toxicity, and dose reductions were frequent. Common toxicities included neutropenia, fatigue, rash, and neuropathy. Conclusions The combination of ixabepilone and sorafenib was poorly tolerated as first-line treatment of patients with MBC. The activity of the combination was similar to the activity previously reported with single agent ixabepilone or taxanes. Further development of this combination is not recommended.
Abstract Background Triple-negative breast cancer (TNBC) is a subtype with poor prognosis, and treatment options limited to chemotherapy. As the epidermal growth factor receptor (EGFR) is ...overexpressed in up to 70% of these tumors, this phase 2 trial was designed to evaluate the efficacy and safety of panitumumab in combination with gemcitabine and carboplatin as first- or second-line treatment for metastatic TNBC. Methods Adult women with metastatic TNBC with a maximum of one prior chemotherapy regimen were eligible. Patients received gemcitabine 1500 mg/m2 IV, carboplatin AUC = 2.5 IV, and panitumumab 6 mg/kg IV every 2 weeks. Treatment continued until disease progression or unacceptable toxicity, with disease evaluations every 6 weeks. The primary endpoint was PFS. Archival tissue was collected for correlative analysis, to include PIK3CA, p53, PTEN, EGFR, and K-ras status. Results Between 5/2010 and 8/2012, 71 women (median age 54 years; 14% de novo stage IV) were treated. At median follow-up of 11 months, the median PFS was 4.4 months (95% CI: 3.2, 5.5 months). The objective response rate was 42% (CR 1, PR 29). Treatment-related toxicity included: rash (70%), fatigue (52%), neutropenia (45%; 2 episodes of febrile neutropenia), and thrombocytopenia (45%). Conclusion While the addition of panitumumab was feasible, the results of this trial do not support addition of panitumumab to gemcitabine and carboplatin in the treatment of patients with TNBC.
Primary Malignant Mediastinal Tumors Adkins, R. Benton; Maples, Michael D.; Hainsworth, John D.
The Annals of thoracic surgery
38, Številka:
6
Journal Article
Recenzirano
Thirty-eight patients with primary malignant mediastinal tumors of all cell types are the basis for this review. Eleven of these patients had germ cell tumors. Five germ cell tumors were seminomas, ...two were malignant teratomas, and two were endodermal sinus tumors. Mean survival for all patients with germ cell tumors was 3.3 years. Eight children had surgical excision of mediastinal neuroblastomas, and all but 1 are alive for a mean survival of 6.7 years. Seven patients had lymphoproliferative disorders; 6 of these patients had nodular sclerosing Hodgkin's disease, and 1 had lymphoblastic (thymic) lymphoma. Mean survival was 5.1 years. There were five carcinomas of various cell types and one angiopericytoma. None of the patients with these lesions survived more than 2 years. Four patients had thymoma with an average survival of 3.7 years. Two patients had carcinoid tumors of thymic origin; neither survived more than 1 year.
In 1972, we reported 5-year disease-free survival of 26% in a series of patients with primary mediastinal tumors. Our experience since 1970 shows current survival of 47.3% and 5-year disease-free survival of 34.2%. We use combined methods of therapy, including aggressive surgical resection, combination chemotherapy, and often mediastinal irradiation for most types of mediastinal tumors. Primary mediastinal malignancies should be treated aggressively using a multidisciplinary approach, since many of these tumors are curable.
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