Everolimus Plus Exemestane in Advanced Breast Cancer: Safety Results of the BALLET Study on Patients Previously Treated Without and with Chemotherapy in the Metastatic Setting.

BACKGROUND: The BALLET study was an open-label, multicenter, expanded access study designed to allow treatment with everolimus plus exemestane in postmenopausal women with hormone receptor-positive metastatic breast cancer progressed following prior endocrine therapy. A post hoc analysis to evaluate if previous chemotherapy in the metastatic setting affects the safety profile of the combination regimen of everolimus and exemestane was conducted on the Italian subset, as it represented the major part of the patients enrolled (54%). PATIENTS AND METHODS: One thousand one hundred and fifty-one Italian patients were included in the present post hoc analysis, which focused on two sets of patients: patients who never received chemotherapy in the metastatic setting (36.1%) and patients who received at least one chemotherapy treatment in the metastatic setting (63.9%). RESULTS: One thousand one hundred and sixteen patients (97.0%) prematurely discontinued the study drug, and the main reasons reported were disease progression (39.1%), local reimbursement of everolimus (31.1%), and adverse events (AEs) (16.1%). The median duration of study treatment exposure was 139.5 days for exemestane and 135.0 days for everolimus. At least one AE was experienced by 92.5% of patients. The incidence of everolimus-related AEs was higher (83.9%) when compared with those that occurred with exemestane (29.1%), and the most commonly reported everolimus-related AE was stomatitis (51.3%). However, no significant difference in terms of safety related to the combination occurred between patients without and with chemotherapy in the metastatic setting. CONCLUSION: Real-life data of the Italian patients BALLET-related cohort were an adequate setting to state that previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane. IMPLICATIONS FOR PRACTICE: With the advent of new targeted agents for advanced or metastatic breast cancer, multiple lines of therapy may be possible, and components of the combined regimens can overlap from one line to another. Thus, it is important to assess even the potential of cumulative and additive toxic effects among the drugs. Previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane. The continuous monitoring of the safety signals of this drug combination from general clinical practice is important, in particular for stomatitis.

Cardioprotective effect of dexrazoxane in patients with breast cancer treated with anthracyclines in adjuvant setting: a 10-year single institution experience.

BACKGROUND AND OBJECTIVE: Anthracyclines are highly effective and widely used cytotoxic agents, but their application is often limited by cumulative dose-dependent cardiotoxicity. Dexrazoxane has been shown in several clinical trials to prevent the development of this serious toxicity. The aim of our study was to analyze the incidence of cardiac dysfunction over a 10-year period in patients with breast cancer who were treated with anthracycline-based regimens with addition of dexrazoxane, mainly in an adjuvant setting. METHODS: We conducted a retrospective analysis on a population of women with breast cancer treated at our institution between January 1993 and October 2003. We reviewed patients' medical records and data on patient characteristics, treatment history, and adverse events that were collected, starting from the time of first visit before starting therapy, with the use of software created and designed for clinical records management in our institution (1999 OK-DH). Patients underwent an ECG assessment prior to starting chemotherapy, and were clinically monitored for cardiac failure. Those who developed signs and symptoms suggestive of cardiac dysfunction underwent further ECG. If clinical findings indicated, echocardiography and further cardiologic investigations were performed. The main outcome measure was the development of signs and symptoms indicative of congestive heart failure (CHF). RESULTS: A total of 318 female patients were treated with an anthracycline (doxorubicin or epirubicin)-based combination chemotherapy regimen during this time, in most cases in the adjuvant setting (n = 285). Most patients (n = 302) had early-stage disease and only 16 women presented with metastatic disease with good life expectancy (at least 1 year). All patients received dexrazoxane 1000 mg/m(2) intravenously prior to anthracycline administration during each chemotherapy cycle. The median follow-up duration was 35 months. During this time, five patients (1.57%) developed signs and symptoms of CHF. No patient at our institution died of heart failure during the period analyzed. Dexrazoxane was well tolerated, with no reports of adverse events associated with this drug. CONCLUSIONS: The reported incidence of cardiotoxicity in this study represents a marked reduction compared with historical data for patients receiving anthracycline-based chemotherapy without dexrazoxane. Dexrazoxane appears to have a cardioprotective effect in women with early-stage or advanced breast cancer treated with anthracycline-based combination chemotherapy, mainly as an adjuvant treatment. Prospective, randomized, controlled clinical trials in adjuvant setting should be performed to confirm these results.

Comparing the efficacy and safety of fixed versus weight-based dosing of epoetin alpha in anemic cancer patients receiving platinum-based chemotherapy.

Fixed dosing is potentially more convenient than weight-based dosing for both patients and physicians. Therefore, this open-label, randomized (1:1), multicenter study was conducted to compare the effectiveness, safety, and quality-of-life benefits of fixed vs. weight-based dosing of epoetin alpha in anemic cancer patients undergoing chemotherapy. Five hundred forty-six anemic patients undergoing platinum-based chemotherapy for solid malignancies were enrolled. Patients received epoetin alpha, either a fixed dose of 10,000 IU or a weight-based dose of 150 IU/kg, administered subcutaneously 3 times weekly for up to 12 weeks. Endpoints were transfusion requirements over days 29-84, change in hemoglobin (Hb) level from baseline, and change in quality-of-life (QOL) scores from baseline as measured using the Cancer Linear Analog Scale (CLAS). Five hundred and thirty-two patients received at least 1 dose of epoetin alpha, and 510 of these (255 in each treatment group) were considered evaluable for efficacy. At day 84, rates for freedom from transfusion were similar between the fixed-dose and the weight-based dose group (84% vs. 87%, respectively, p=0.32), as calculated by the lifetable method. These rates were also similar between patients in the 45-63 kg weight group receiving the fixed 10,000 IU dose or 7,000-9,000 IU on a per-weight basis (83% vs. 87%, respectively), and those in the 70-100 kg weight group receiving the fixed 10,000 IU dose or 11,000-15,000 IU on a per-weight basis (85% vs. 83%, respectively). Mean Hb increases from baseline to last observation were 2.10 g/dl [95% confidence intervals (CI95) 1.85-2.35] in the 10,000 IU group (from 9.64-11.74 g/dl) and 2.06 g/dl (CI95 1.82-2.30) in the 150 IU/kg group (from 9.70-11.76 g/dl). QOL results were similar for both groups and cumulative data have been reported. For 275 patients (in both groups combined) with CLAS QOL scores both at baseline and 29-98 days thereafter, the QOL index (average of scores for the 3 QOL parameters: energy level, ability to do daily activities and overall QOL) increased by 10.4 mm (CI95 7.5-13.2), from 46.2 mm at baseline to 56.6 mm at the final observation. QOL improvements were directly associated with Hb increases (p<0.001, multiple linear regression analysis) within all chemotherapy response classes. Epoetin alpha was well tolerated in both groups. Fixed (10,000 IU) and weight-based (150 IU/kg) dosing regimens of epoetin alpha demonstrated similar efficacy in maintaining freedom from transfusion, increasing Hb levels, and improving QOL in anemic cancer patients undergoing platinum-based chemotherapy. QOL improvements were directly associated with Hb increases. These findings support the use of a fixed-dose regimen of epoetin alpha, which may offer greater convenience for physicians and patients than weight-based dosing with this agent.

Chemotherapy with or without low-dose interleukin-2 in advanced non-small cell lung cancer: results from a phase III randomized multicentric trial.

Non-small cell lung cancer (NSCLC) is associated with IL-2-dependent cell-mediated immunodeficiency. As IL-2 is the main lymphocyte growth factor, a phase III randomized multicenter trial was conducted to evaluate the impact of subcutaneous low-dose IL-2 added to standard chemotherapy (CT) on overall survival (OS) in advanced NSCLC patients. Patients (n=241) with histologically confirmed stage IIIb or IV non-operable NSCLC underwent stratified randomization on the basis of center, ECOG PS, stage of disease and percentage of weight loss. Patients received gemcitabine (1000 mg/m2) on days 1 and 8 + cisplatin (100 mg/m2) on day 2 every 21 days for a maximum of 6 cycles [chemotherapy (CT) arm]. In the CT+IL-2 arm, patients also received low-dose subcutaneous IL-2 3,000,000 IU/die on days 3-5, 9-11, 15-17. The study had 90% power to detect a 20% absolute increase in 1-year OS with 118 patients/arm. An overall response (OR) rate of 12.8% (14% in the CT+IL-2 arm and 11.4% in CT arm) was observed. Stable disease was 70 and 66.7%, and progressive disease 16 and 21.8% in the CT+IL-2 and CT arms, respectively. No differences in response were found in any subgroup analysis. At a median follow-up of 32 months, 1-year OS was 45% for the CT+IL-2 arm vs. 51% for the CT arm (p=0.456 log-rank). Median progression-free survival was 6.6 months in the CT+IL-2 arm vs. 6.9 months in the CT arm (p=0.573, log-rank). A higher number of grade 4 toxicities were reported with CT+IL-2. The most common grade ≥3 adverse events were gastrointestinal toxicity (mainly nausea and diarrhea) and myelosuppression. No relevant differences in clinical outcome were observed from the addition of IL-2 to CT. Future studies investigating the role of T-regulators in chemoimmunotherapeutic regimens could be performed.

Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory nonseminomatous germ cell tumor.

OBJECTIVE: Cisplatin-refractory germ cell tumors (GCTs) represent a subset of germinal neoplasms with a poor prognosis. Conventional-dose chemotherapy induces objective response in 10-20% of these patients with rare durable complete remissions. We investigated the activity and tolerance of a chemotherapeutic regimen with oxaliplatin and gemcitabine. PATIENTS AND METHODS: Treatment consisted of oxaliplatin 130 mg/m(2) day 1, and gemcitabine 1,250 mg/m(2), days 1 and 8, every three weeks. RESULTS: Eighteen patients were enrolled and were assessable for response and toxicity. Primary site was testis in twelve cases, retroperitoneum in four, and mediastinum in two. Seven patients (39%) were cisplatin-refractory, while eleven (61%) absolutely cisplatin-refractory. A median of three cycles (range, 1-6) per patient were given. One patient achieved a clinical complete remission, one a partial remission with negative marker in whom complete surgical resection of residual masses yielded mature teratoma only, and one a partial remission with positive marker in whom complete surgical resection of residual masses yielded viable tumor cells. These three cases were characterized by testicular primary embryonal carcinoma. They remained disease-free at 44+, 20+, and 18+ months of follow-up. CONCLUSION: The oxaliplatin-gemcitabine combination is a safe and active standard-dose regimen for patients with cisplatin-refractory testicular primary GCT.

Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial.

BACKGROUND: To determine whether a dose-dense regimen improves outcome in early breast cancer patients, we compared outcomes with the same fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapeutic regimen administered every 3 weeks (FEC21) or administered every 2 weeks (FEC14 including support with filgrastim, a granulocyte colony-stimulating factor) in a multicenter phase III randomized trial. METHODS: A total of 1214 patients with early-stage breast cancer were randomly assigned to receive six cycles of FEC14 (604 patients) or of FEC21 (610 patients). Study endpoints were overall survival and event-free survival. Associations were assessed by multivariable analysis with adjustment for age; tumor size; grade; proliferative rate; and menopausal, lymph node, estrogen receptor, and progesterone receptor status. All statistical tests were two-sided. RESULTS: Patients in the FEC14 arm had fewer dose reductions or treatment delays or discontinuation (26%) than those in the FEC21 arm (33%) (difference = 7%, 95% confidence interval [CI] = 2% to 12%; P = .008). FEC14 therapy, compared with FEC21 therapy, was associated with more asthenia (36% versus 29%, difference = 7%, 95% CI = 2% to 12%; P = .01), bone pain (33% versus 4%, difference = 29%, 95% CI = 25% to 33%; P < .001), anemia (38% versus 19%, difference = 19%, 95% CI = 14% to 24%; P < .001), and thrombocytopenia (8% versus 2%, difference = 6%, 95% CI = 4% to 9%; P < .001), but with less leukopenia (12% versus 45%, difference = 33%, 95% CI = 28% to 37%; P < .001). No acute myelogenous leukemia or myelodysplastic syndrome was observed. At a median follow-up of 10.4 years, no statistically significant difference in the hazard of death (hazard ratio [HR] = 0.87, 95% CI = 0.67 to 1.13) or recurrence (HR = 0.88, 95% CI = 0.71 to 1.08) was found between FEC14 and FEC21 groups after adjustment by multivariable analysis. Although the study was underpowered for subset analysis, we found no evidence that the effect of the treatment type was associated with any of the potential prognostic factors. CONCLUSION: Our results support the long-term safety of FEC14 chemotherapy as an adjuvant treatment of breast cancer. However, this therapy was not associated with improved outcome, but because of the limited statistical power of our study, we cannot rule out a modest improvement in outcome associated with FEC14 therapy.