A real-world study of cardiac events in > 3700 patients with HER2-positive early breast cancer treated with trastuzumab: final analysis of the OHERA study.

PURPOSE: Cardiac dysfunction risk associated with intravenous trastuzumab (H IV) treatment may differ in real-world practice versus randomized trials. We investigated cardiac events in patients with HER2-positive early breast cancer (EBC) treated with H IV as adjuvant therapy in routine practice. METHODS: The observational study of cardiac events in patients with HER2-positive EBC treated with Herceptin (OHERA; NCT01152606) enrolled patients with stage I-IIIb disease eligible for H IV in the adjuvant setting per the European Summary of Product Characteristics (SmPC). Primary outcomes were symptomatic congestive heart failure incidence (CHF; New York Heart Association class II-IV) and cardiac death. Patient visits/assessments were per local practice. RESULTS: 3733 Patients received ≥ 1 H IV dose per local practice; 88.9% received H IV for > 300 days (median follow-up: ~ 5 years). Prior to disease recurrence (if any), symptomatic CHF occurred in 106 patients (2.8%); 6 (0.2%) cardiac deaths occurred (5 in patients with cardiac disease history). Median time to symptomatic CHF onset was 5.7 months (95% CI 5.3-6.5); 77/106 (72.6%) patients with symptomatic CHF achieved resolution. CHF incidence was higher in patients ≥ 65 years, and those with pre-existing cardiac conditions, hypertension, or left ventricular ejection fraction ≤ 55% at baseline. CONCLUSIONS: OHERA is the largest prospective observational study to investigate the cardiac safety of H IV as adjuvant EBC therapy in a real-world setting. Symptomatic CHF and cardiac event incidences were consistent with randomized trials in this setting and baseline risk factors identified in the H IV European SmPC.

Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study.

Background: Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer. Patients and methods: Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results: Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP. Conclusion: Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information: NCT01506609.

Randomised phase II study of axitinib or bevacizumab combined with paclitaxel/carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer.

BACKGROUND: Efficacy and safety of first-line axitinib/paclitaxel/carboplatin versus bevacizumab/paclitaxel/carboplatin in advanced non-squamous non-small-cell lung cancer (NSCLC) was evaluated. PATIENTS AND METHODS: Patients with stage IIIB/IV disease stratified by adjuvant therapy and gender were randomised 1 : 1 to axitinib (5 mg twice daily) or bevacizumab [15 mg/kg every 3 weeks (Q3W)], both with paclitaxel (200 mg/m(2) Q3W)/carboplatin (AUC 6 mg min/ml Q3W). RESULTS: The trial was discontinued after preliminary analysis. Median progression-free survival (primary end point) for axitinib (N = 58) and bevacizumab (N = 60), respectively, was 5.7 and 6.1 months [hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.68-1.76; one-sided stratified P = 0.64]; median overall survival was 10.6 and 13.3 months (HR 1.12, 95% CI 0.74-1.69; one-sided stratified P = 0.70). Objective response rates (95% CI) were 29.3% (18.1-42.7) and 43.3% (30.6-56.8), respectively; risk ratio 0.676 (95% CI 0.41-1.11; one-sided stratified P = 0.94). The most common grade 3/4 adverse events included neutropenia (28% versus 20%), fatigue (14% versus 7%), and hypertension (14% versus 5%). Patient-reported outcomes based on the EORTC QLQ-C30 were similar between arms. CONCLUSIONS: In patients with advanced non-squamous NSCLC, axitinib/paclitaxel/carboplatin did not improve efficacy versus bevacizumab/paclitaxel/carboplatin, and was less well tolerated.

Phase I-II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma.

BACKGROUND: This phase I-II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma. METHODS: The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single-agent plitidepsin 3.2 mg m(-2) (n = 20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m(-2) on days 1, 8 and 15 q4wk combined with DTIC 800 mg m(-2) q4wk (n = 38). RESULTS: The overall response rate with plitidepsin/DTIC was 21.4%; all responders had normal serum lactate dehydrogenase (LDH) levels and performance status ≤ 1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug-drug pharmacokinetic interactions were found. CONCLUSION: This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m(-2) fortnightly and DTIC 800 mg m(-2) q4wk is recommended.

A randomized, double-blind, phase II study of erlotinib with or without sunitinib for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC).

BACKGROUND: Combined inhibition of vascular, platelet-derived, and epidermal growth factor receptor (EGFR) pathways may overcome refractoriness to single agents in platinum-pretreated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This randomized, double-blind, multicenter, phase II trial evaluated sunitinib 37.5 mg/day plus erlotinib 150 mg/day versus placebo plus erlotinib continuously in 4-week cycles. Eligible patients had histologically confirmed stage IIIB or IV NSCLC previously treated with one or two chemotherapy regimens, including one platinum-based regimen. The primary end point was progression-free survival (PFS) by an independent central review. RESULTS: One hundred and thirty-two patients were randomly assigned, and the median duration of follow-up was 17.7 months. The median PFS was 2.8 versus 2.0 months for the combination versus erlotinib alone (HR 0.898, P = 0.321). The median overall survival (OS) was 8.2 versus 7.6 months (HR 1.066, P = 0.617). Objective response rates (ORRs) were 4.6% and 3.0%, respectively. Sunitinib plus erlotinib was fairly well tolerated although most treatment-related adverse events (AEs) were more frequent than with erlotinib alone: diarrhea (55% versus 33%), rash (41% versus 30%), fatigue (31% versus 25%), decreased appetite (30% versus 13%), nausea (28% versus 14%), and thrombocytopenia (13% versus 0%). CONCLUSIONS: The addition of sunitinib to erlotinib did not significantly improve PFS in patients with advanced, platinum-pretreated NSCLC.

Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy.

BACKGROUND: This phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Patients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers. RESULTS: Seventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen. CONCLUSIONS: Bosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population.

First-line bevacizumab-containing therapy for breast cancer: results in patients aged≥70 years treated in the ATHENA study.

BACKGROUND: There are limited data on treatment outcomes in the growing population of elderly patients with locally recurrent/metastatic breast cancer (LR/mBC). To gain information on first-line bevacizumab combined with chemotherapy in the elderly, we analyzed data from the ATHENA trial in routine oncology practice. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor-2-negative LR/mBC received first-line bevacizumab with standard chemotherapy until disease progression, unacceptable toxicity, or physician/patient decision. We carried out a subgroup analysis of safety and efficacy in patients aged≥70 years. Possible correlations between tolerability and baseline comorbidities or Eastern Cooperative Oncology Group status were explored. RESULTS: Bevacizumab was combined with single-agent paclitaxel in 46% of older patients. Only hypertension and proteinuria were more common in older than in younger patients (grade≥3 hypertension: 6.9% versus 4.2%, respectively; grade≥3 proteinuria: 4.0% versus 1.5%, respectively). Grade≥3 arterial/venous thromboembolism occurred in 2.9% versus 3.3%, respectively. Further analysis revealed no relationship between baseline presence and severity of hypertension and risk of developing hypertension during bevacizumab-containing therapy. Median time to progression was 10.4 months in patients aged≥70 years. CONCLUSIONS: These findings suggest that bevacizumab-containing therapy is tolerable and active in patients aged≥70 years. Hypertension was more common than in younger patients but was manageable. We find no evidence precluding the use of bevacizumab in older patients, including those with hypertension, although age may influence chemotherapy choice.

Methotrexate in the treatment of mycosis fungoides - a multicenter observational study in 79 patients.

OBJECTIVE: The first report concerning methotrexate (MTX) in the treatment of Mycosis fungoides (MF) was published in 1964 by Wright. The mechanism of MTX action in the treatment of primary cutaneous T-cell lymphoma (CTCL) has been not explained in detail yet (the anti-inflammatory, immunomodulating, immunosuppressive, and cytostatic actions have been under discussion). PATIENTS AND METHODS: This is a retrospective analysis of 79 MF patients in 4 dermatology clinical centers in Poland. Data are presented in terms of the duration, use of MTX, the effectiveness of treatment with MTX in terms of time required to achieve remission, the disease stage, route of administration, age at diagnosis and the dosage. Moreover, the occurrence of side effects depending on the route of administration and duration of therapy with MTX was analyzed. RESULTS: The analysis has revealed that 56 patients (70,9%) had achieved remission on the MTX. The remission began in the 1st month of therapy in 20% of patients, lasted 4 to 6 months in 50% of cases. At least 12 months' remission was confirmed in 25% of patients (2-year-long only in 10% and 3-year-long in 5% of patients). The time to remission was related to the stage of disease at diagnosis as well as to minimal and maximal dose of MTX. The total therapeutic dose of MTX was found important for the course of the disease: higher total dose had prolonged the remission. CONCLUSIONS: Despite the common use of MTX in MF patients, relatively few clinical studies have been published. The response of MF subjects to MTX seems to depend on the stage and, more importantly, the dose of MTX treatment. Methotrexate appears to be an effective treatment at every stage of MF; however, it is not devoided of side effects such as infections and elevated level of aminotransferases, which are most common.

Prognostic factors in Hodgkin's disease: multivariate analysis of 327 patients from a single institution.

On the basis of a retrospective study of 327 patients with Hodgkin's disease (HD), the prognostic significance of several factors, accepted previously and recently proposed, has been analyzed with regard to response to treatment and the survival time. Multivariate regression analysis strongly decreased the number of potentially prognostic parameters. The only independent, pretreatment factors negatively influenced by either time of survival or response to treatment were the following: age at diagnosis of more than 45 years, advanced (IIIB/IV) clinical stage, poor clinical status according to Karnofsky's scale (score less than 70), presence of systemic symptoms, mixed cellularity/lymphocyte depletion histological type, multisite peripheral nodal localization of the disease, abdominal lymphadenopathy, and large primary tumor mass (bulky disease). Short time to achieve complete remission (during the first four courses of chemotherapy) has proven to be significantly positive predictive factor. Cumulative dose of cytostatics lower than programmed was a significantly negative prognostic factor that correlated with a shorter time of survival. Lack of or a too-low dose of radiotherapy had the same predictive value. High activity of serum lactate dehydrogenase correlated moderately with poor response to the first-line treatment but did not influence the survival time. Other clinical, morphological, and biochemical parameters influenced neither the prognosis nor the response to treatment. Additionally, immunohistochemical examinations for proliferating cell nuclear antigen and the protein products of the p53 and bcl-2 genes were performed on the lymph nodes obtained from the patients with HD. High expression of proliferating cell nuclear antigen, p53, and BCL-2 correlated with poor response to the treatment and/or short time of survival. Statistical analysis has led us to the conclusion that the pretreatment expression of these oncoproteins can be taken into consideration as a new prognostic factor in HD.

[Radiotherapy instead of second-line chemotherapy in patients with Hodgkin's disease in partial remission after treatment with cytostatics]. / Radioterapia zamiast chemioterapii "drugiej linii" u chorych na ziarnice zlosliwa w czesciowej remisji po leczeniu cytostatykami.

Radiotherapy was given to 32 patients with Hodgkin's disease (clinical stage IIA-IIIA) in whom chemotherapy given as the first treatment produced partial remission or minimal regression with disappearance of all systemic symptoms (27 cases) or recurrence developed after earlier treatment with cytostatic agents (5 cases). For a more accurate determination of the extent of lesions before radiotherapy in 24 cases laparotomy was done with splenectomy. Radiotherapy given in place of a second course of chemotherapy led in 24 cases (75%) to complete remission lasting from 8 to 62 months, mean 23.2 months. Twenty-one patients are still in continuing remission. These results point to the usefulness of considering the possibility of using radiation energy for the treatment of patients with advanced Hodgkin's disease (phase IIP-IIIP) in whom cytostatic drugs given as a first-line therapy failed to produce complete remission after 4-6 treatment courses, but caused some regression of symptoms with disappearance of systemic signs.

[ARDS (adult respiratory distress syndrome) after chemotherapy and radiotherapy. Complications in two patients treated for non-Hodgkin's lymphoma]. / ARDS (adult respiratory distress syndrome) po chemioterapii i radioterapii. Opis powiklan u dwóch chorych leczonych z powodu chlloniaka zlosliwego.

Complications were described in two patients with non Hodgkins lymphoma (large cell anaplastic lymphoma and histiocytoma malignum) after completion of chemotherapy and radiotherapy. Both patients died. In one of them it was established at autopsy that the cause of death was ARDS, while in the second case it was the clinical course which suggested the same diagnosis.

[Comparison of computed tomography results and pathological findings after laparotomy with splenectomy in Hodgkin's disease]. / Porównanie wyników tomografii komputerowej i patologicznej oceny zmian w jamie brzusznej po laparotomii ze splenektomia w ziarnicy zlosliwej.

In 69 patients (pts) with Hodgkin's disease (HD) in I-IIIA clinical stage results of abdominopelvic computed tomography (CT) were compared with pathological staging. Concordance (specificity) of CT scan with results of macroscopic evaluation of HD lesions in the abdomen during laparotomy with splenectomy was 83%. Accuracy CT results and microscopic findings was 80%. False positive results of CT were found in 11.6% of patients and false negative in 8.6%. Specificity and sensitivity of CT versus to pathological staging were 84% and 63% respectively. The results presented here confirm, that pathological staging after laparotomy with splenectomy in HD was some advantage in precise prediction of some patients to radiotherapy and planning of irradiated fields.

Intermediate-dose Ara-C plus G-CSF for stem cell mobilization in patients with lymphoid malignancies, including predicted poor mobilizers.

The optimal protocol for mobilization of hematopoietic stem cells in patients with lymphoid malignancies has not been determined so far. We retrospectively analyzed the efficacy and safety of Ara-C at a dose of 1.6 g/m(2) compared with CY at a dose of 4.0 g/m(2), both combined with filgrastim. Seventy and forty-five patients, respectively, were included, among whom 60% were defined as 'predicted poor mobilizers'. The use of Ara-C was associated with significantly higher peak number of circulating CD34(+) cells compared with CY (P<0.0001). In the Ara-C group, 95% of patients with multiple myeloma (MM) collected at least 5 × 10(6) CD34(+) cells/kg required for tandem transplantation, and 97% of lymphoma patients collected at least 2 × 10(6) CD34(+) cells/kg, needed for a single autologous hematopoietic SCT (autoHSCT), which was achieved with a single leukapheresis in 91% of cases. Results for the CY group were significantly inferior (P<0.0001). No patient mobilized with Ara-C experienced febrile neutropenia, whereas 35% required platelet transfusions. Among patients who proceeded to autoHSCT, the time of both neutrophil and platelet recovery was significantly shorter for those mobilized with Ara-C than CY. We conclude that intermediate-dose Ara-C+filgrastim is a very effective and relatively safe mobilization protocol for patients with lymphoid malignancies.

[Thymoma and thymoma-like tumors of the anterior mediastinum--therapeutic problems in observed patients]. / Grasiczaki i guzy przedniego sródpiersia--problemy lecznicze u obserwowanych chorych.

In the last years, 11 patients with tumors of anterior mediastinum were treated at the Oncologic Centre in Lódz. Lymphocytic-epithelial thymoma was diagnosed in 6 patients whereas thymoma was suspected in 5 patients. Therapy was a problem mainly in these 5 patients, especially if lymphoma was considered in the differential diagnosis. The authors suggest that therapy should start with cytostatic agents in all patients with mediastinal tumors and morphology which not justifies thymoma diagnosis. Radiotherapy may follow in these cases in which 1-2 chemotherapy cycles failed.