Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer.

Background: There is no standard treatment after progression on second-line chemotherapy for metastatic breast cancer (MBC). We compared vinflunine with physician's choice of alkylating agent (AA) for patients with heavily pretreated MBC. Patients and methods: In this open-label phase III trial, patients with MBC were included if they had received at least two prior chemotherapy regimens for MBC and had received anthracycline, taxane, antimetabolite and vinca alkaloid therapy. Patients were no longer candidates for these chemotherapies because of resistance and/or intolerance. Patients were randomised to either vinflunine 280 mg/m2 intravenously every 3 weeks (q3w) or AA monotherapy q3w. Stratification factors were performance status, number of prior chemotherapy lines for MBC, disease measurability and study site. The primary end point was overall survival (OS). Results: A total of 594 patients were randomised (298 to vinflunine, 296 to AA). There was no difference between treatment arms in OS (hazard ratio 1.04, P = 0.67; median 9.1 months for vinflunine versus 9.3 months for AA), progression-free survival (hazard ratio 0.94, P = 0.49; median 2.5 versus 1.9 months, respectively) or overall response rate (6% versus 4%, respectively). However, the disease control rate was significantly higher with vinflunine than AA (44% versus 35%, respectively; P = 0.04). The most common adverse events (any grade) were haematological and gastrointestinal disorders and asthenia in both arms. The most common grade 3/4 adverse events were neutropenia (19% versus 11% with vinflunine versus AA, respectively) and asthenia (10% versus 4%). Conclusions: Vinflunine 280 mg/m2 q3w did not improve OS compared with the physician's choice of AA as third- or later-line therapy for MBC. Vinflunine demonstrated an acceptable safety profile, suggesting that vinflunine 320 mg/m2 merits evaluation. ClinicalTrials.gov: NCT01091168.

Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT.

BACKGROUND: Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation. DESIGN AND METHODS: We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling. RESULTS: Distributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72-1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69-1.84) who are less likely to develop chemotherapy-induced amenorrhea. CONCLUSION: Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected. CLINICALTRIALS.GOV: NCT00066690 and NCT00066703.

Improved Natural Killer cell activity and retained anti-tumor CD8(+) T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy.

BACKGROUND: Locally advanced HER2-overexpressing breast cancer (BC) patients achieve a high rate of pathological complete responses (pCR) after neoadjuvant chemotherapy (NC). The apparently unaltered immune proficiency of these patients together with the immune-modulating activities of NC drugs suggest a potential contribution of host immunity in mediating clinical responses. We thus performed an extensive immunomonitoring in locally advanced BC patients undergoing NC to identify immunological correlates of pCR induction. METHODS: The immune profile of 40 HER2-positive and 38 HER2-negative BC patients was characterized at diagnosis and throughout NC (Paclitaxel and Trastuzumab, or Docetaxel and Epirubicin, respectively). The percentages of circulating immune cell subsets including T and B lymphocytes, Natural Killer (NK) cells, regulatory T cells, T helper 17 lymphocytes, were quantified by multiparametric flow cytometry. NK cells functional activity was evaluated through the analysis of NF-kB nuclear translocation by Multispectral flow cytometry, and with the in vitro monitoring of Trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC). CD8(+) T cell responses against six different tumor-associated antigens (TAA) were characterized by IFN-γ ELISPOT and IFN-γ/IL-2 DualSpot assays. RESULTS: After NC, HER2-positive patients showed a significant increase in the number of NK cells and regulatory T cells irrespective of the pathological response, whereas patients undergoing a pCR disclosed higher percentages of T helper 17 cells. Notably, a significant increase in the number of activated NK cells was observed only in HER2-positive patients achieving a pCR. Characterization of anti-tumor T cell responses highlighted sustained levels of CD8(+) T cells specific for survivin and mammaglobin-A throughout NC in patients undergoing a pCR in both arms. Moreover, HER2-positive patients achieving a pCR were characterized by a multi-epitopic and polyfunctional anti-tumor T cell response, markedly reduced in case of partial response. CONCLUSIONS: These results indicate that maintenance of functional T cell responses against selected antigens and improvement of NK cell proficiency during NC are probably critical requirements for pCR induction, especially in HER2-positive BC patients. Trail registration: TRIAL REGISTRATION NUMBER: NCT02307227, registered on ClinicalTrials.gov ( http://www.clinicaltrials.gov , November 26, 2014).

Retreatment with trastuzumab-based therapy after disease progression following lapatinib in HER2-positive metastatic breast cancer.

BACKGROUND: Preclinical data suggest that treatment with lapatinib reinduces sensitivity to trastuzumab in human epidermal growth factor receptor 2(HER2)-positive breast cancer cells. PATIENTS AND METHODS: Between January 2007 and November 2010, 179 HER2-positive metastatic breast cancer patients were treated with lapatinib and capecitabine at nine Italian institutions. We evaluated the clinical outcome of 69 patients (38.5%) retreated with trastuzumab after lapatinib progression. RESULTS: Visceral metastases were identified in 51 (74%) and brain metastases in 16 patients (23%). All patients were pretreated with both trastuzumab- and lapatinib-based therapy. We observed with retreatment with trastuzumab-based therapy: 1 complete remission (2%), 18 partial remission (29%) and 10 stable disease ≥6 months (14%) and 47% of clinical benefit (CB). Median duration of response was 8.1 months [95% confidence interval (CI) 5.5-10.7]. No unexpected toxic effects occurred. At a median follow-up of 13 months, median progression-free survival was 4.9 months (95% CI 4.2-5.6) and overall survival (OS) 19.4 months (95% CI 14.0-25.0). Median OS was longer for patients experiencing CB (not reached versus 13.4 months for patients without CB, P = 0.002). Brain involvement was associated with lower median OS (17.3 versus 23.3 months for patients without brain disease; P = 0.021). CONCLUSION: Retreatment with trastuzumab-based therapy showed CB in 47% of patients progressing during lapatinib-based therapy, leading to a prolonged OS.

Incidence of febrile neutropenia and neutropenic infections in elderly patients receiving anthracycline-based chemotherapy for breast cancer without primary prophylaxis with colony-stimulating factors.

There is concern about the potential increase of hematological toxicity in elderly patients treated with chemotherapy. Recently, primary prophylaxis with colony-stimulating factors (CSFs) was proposed for elderly patients receiving moderately toxic chemotherapy. However, evidence for the benefits of this primary prophylaxis for elderly breast cancer patients is currently lacking. We retrospectively analyzed the incidence of febrile neutropenia (FN) and neutropenic infections in elderly breast cancer patients receiving anthracycline-based chemotherapy without primary prophylaxis with colony-stimulating factors. In addition, we assessed the direct costs of hospitalization for these complications. Febrile neutropenia or neutropenic infection occurred in 13% of the 46 patients. Further studies are needed to adequately evaluate the risk of neutropenic complications (NC) in elderly patients receiving standard-dose chemotherapy for breast cancer and the potential benefits of primary prophylaxis with colony-stimulating factors.

Ifosfamide in advanced/disseminated breast cancer.

Ifosfamide is an alkylating agent active in various tumor types including breast cancer. The availability of mesna (sodium 2-mercaptoethanesulfonate) has increased its safety, avoiding the main dose-limiting side effect, urotoxicity. Interesting activity as a single agent, with response rates ranging from 7 to 30%, is reported in pretreated patients; more attractive data derived from phase II studies on ifosfamide combined with drugs known to be active in advanced breast cancer show response rates always over 35%. This review has taken in consideration papers published after 1995 and available on PubMed medline: the data indicate a potential usefulness of ifosfamide in the clinical management of advanced breast cancer, even if the exact therapeutic role of the drug in this setting should be derived from randomized studies not yet available.

Treatment of older breast cancer patients with high recurrence risk.

Adjuvant treatment of elderly women affected by breast cancer who have a high risk of recurrence is one of the most questionable issues in clinical oncology. The use of tamoxifen in women with hormone receptor-positive tumors is a relatively simple therapeutic option considering the favourable toxicity profile, whereas the administration of adjuvant chemotherapy is more complicated and a variety of aspects need to be considered. The estimated life expectancy, the presence and degree of comorbid conditions, the geriatric assessment and estimated benefit from treatment should be taken into account. Due to the lack of data from clinical trials in women over the age of 70, the approach is still experimental. Clinical trials evaluating the role of adjuvant chemotherapy in high risk patients are currently being developed and hopefully in the near future, more convincing data on the best drugs, regimens and benefits for the treatment of elderly breast cancer patients will become available.

Fourteen-day infusion of ifosfamide in the management of advanced breast cancer refractory to protracted continuous infusion of 5-fluorouracil.

AIMS AND BACKGROUND: Ifosfamide is an active drug in advanced breast cancer. Short-term continuous infusion schedules have been evaluated with encouraging results. The aim of the study was to evaluate in patients with advanced breast cancer a 14-day infusion schedule previously tested at our center in soft tissue sarcomas. METHODS: From July 1998 to February 2000, 26 consecutive patients with heavily pretreated breast cancer, progressing during protracted continuous infusion of fluorouracil, were treated with ifosfamide at the dose of 800 mg/m2/day for 14 consecutive days by means of an elastomeric pump via an in-dwelling Groshong catheter. The median age of the patients was 52 years (range, 32-67) and median PS was 1 (range, 1-3). All patients were pretreated with anthracyclines or taxanes; the median number of chemotherapy lines in the metastatic phase was 2 (range, 1-4). Predominant metastatic sites wen soft tissues in 5 patients, lung in 6, liver in 7 and serosal cavities in 3. RESULTS: Twenty-four patients were assessable for response Two complete responses and 2 partial remissions were noted for an overall 16.6% response rate. The duration of response was 3+, 5, 8 and 10 months, respectively. Stabilization or mi nor response was observed in 2 more patients. The main tox ic effect was myelosuppression (grade 1-2 in 15 patients grade 3-4 in 4). Other toxicities included nausea in 14 patients (grade 3 in 2) and grade 1-2 vomiting in 2 patients. Hair lost or alopecia was universal. CONCLUSIONS: The regimen yielded some clinically useful re sponses with acceptable toxicity. Its evaluation in less ad vanced cases appears to be warranted.

Combination chemotherapy with navelbine and continuous infusion of 5-fluorouracil in metastatic, chemotherapy refractory breast cancer.

BACKGROUND: The protracted continuous infusion (PCI) of 5-fluorouracil (5-FU) has proven in several studies an active and well tolerated treatment for advanced, pretreated breast cancer. Navelbine has also activity in this setting. PATIENTS AND METHODS: Heavily pretreated patients with metastatic breast carcinoma were eligible for the study. Treatment consisted of 5-FU 250 mg/m2 given as a PCI by an elastomeric pump and navelbine 20 mg/m2 on days 1 and 8, every four weeks. Eighty-three patients (median age 54 years; range 32-82 years) entered the study. The median number of metastatic tumour sites was 2, with visceral involvement in 56 patients. Apart from five patients with contraindications, all patients had been pretreated with anthracyclines. Thirty-one patients had received taxanes and seventy-four bolus 5-FU. RESULTS: A median of 5 cycles (range 1-14) per patient was administered. The median duration of 5-FU infusion was 17 weeks (range, 4-90). In the 80 evaluable patients (3 not yet evaluable) 12 complete remissions and 24 partial remissions occurred (response rate, 45%). Median duration of response was 9 months. Toxicity was mild. Median survival was 20 months. CONCLUSIONS: PCI-5-FU combined with navelbine offers a reasonable chance of tumour regression with modest side effects in patients with heavily pretreated breast cancer.

Treatment of multiple myeloma and acute myelogenous leukemia in the elderly: an update.

The optimal management of hematopoietic malignancies in the elderly requires the development of specific therapeutic strategies based on the peculiar clinico-biologic features of aged patients. Multiple myeloma arising in elderly patients remains at this time an incurable disease, while attention to supportive therapy and palliation can make a great impact on the quality of life. Fortunately advances have been made in last years in this field. Therapy at the time of diagnosis is usually recommended for patients with symptomatic disease, or for those who may be asymptomatic, but have evidence of high tumor burden of a biologically aggressive disease, and may be expected to progress and develop complications over a short period of time. Melphalan combined with prednisone remains the standard therapy choice in elderly patients. Radiotherapy maintains an important place in the palliation of destructive bone disease in poorly controlled myeloma, particularly in elderly patients. In Acute Myelogenous Leukemia, age has been concordantly reported as an adverse prognostic indicator in affecting both remission rates and survival. The overall unsatisfactory therapeutic results appear connected with host-related factors, and intrinsic differences in the biology of leukemia. Patients with standard risk should be included in collaborative trials aimed at improving the long-term results of conventional therapy. Patients with high risk and unfavorable prognostic factors, could be enrolled in controlled studies aimed at better assessing, in the elderly, the long term results of newer drug combinations. A watch and wait strategy, consisting of transfusion support and leukocytosis control, should be limited to patients with extremely poor performance status (PS), very limited life-expectancy and/or severe comorbidity displaying unfavorable biologic factors, including secondary Acute Myelogenous Leukemia.