A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience.

We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p<0.0001), while overall survival was positively affected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical benefit (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order.

ESAS and FACT-B in eribulin-treated metastatic breast cancer patients: a multicenter, prospective and observational study.

AIM: Quality of life (QoL) is a critical issue for women with metastatic breast cancer (MBC). Eribulin mesylate represents a novel and active drug for pretreated MBC. Regretfully, few data exploring health-related (HR) QoL are available in unselected populations. PATIENTS & METHODS: A multicenter prospective observational study was conducted in 50 MBC patients treated with eribulin mesylate, in order to evaluate HRQoL and patients' well-being by using the Edmonton symptoms assessment scale (ESAS) and Functional Assessment of Cancer Therapy-Breast questionnaires. RESULTS: A significant ESAS score improvement was observed with a 10% median decrease. No differences were revealed for the QoL scores. CONCLUSION: The analysis of ESAS and Functional Assessment of Cancer Therapy scores showed that eribulin mesylate contributes to preserve QoL in MBC patients.

Bevacizumab as first-line treatment in HER2-negative advanced breast cancer: pros and cons.

PURPOSE: Bevacizumab, a humanized, anti-vascular endothelial growth factor-A monoclonal antibody, has shown efficacy in a number of cancers. However, its use in metastatic breast cancer (MBC) remains controversial. METHODS: A literature review using the PubMed database was performed to update the currently available clinical trials evidence on bevacizumab in the first-line treatment of breast cancer. In addition, the proceedings of selected oncology annual meetings were searched for relevant presentations. RESULTS: This article reviews the available evidence for bevacizumab as first-line therapy for MBC and discusses its current and future applicability in the management of MBC. Three phase III trials (ECOG-2100, AVADO, RIBBON-1) demonstrated that the addition of bevacizumab to chemotherapy is well-tolerated and improves progression-free survival and objective response rates in the first-line setting. These findings were supported by a large clinical practice-based study (ATHENA) and a recent clinical trial in which bevacizumab added to paclitaxel showed notable activity in triple-negative MBC. However, bevacizumab has thus far not demonstrated a significant benefit in overall survival. CONCLUSIONS: The addition of bevacizumab to chemotherapy is well-tolerated and produces substantial improvements in overall response rate and progression-free survival, compared with chemotherapy alone, in advanced HER2-negative breast cancer. Nevertheless, it has thus far not demonstrated a significant benefit in overall survival. Whether prolongation of progression-free survival is enough to consider bevacizumab efficacious is unclear. Based on the available clinical trials results, bevacizumab is a part of the complex therapeutic strategy of advanced HER2-negative breast cancer.

Treatment of Metastatic Colorectal Cancer Patients ≥75 Years Old in Clinical Practice: A Multicenter Analysis.

BACKGROUND: Colorectal cancer patients have a median age of incidence >65years although they are largely under-represented in phase-III trials. This large population contains patients unfit for treatment, those suitable for monotherapy or for doublets and the impact of chemotherapy outside clinical trial is unclear. The aim of the study was to retrospectively analyse Overall Survival(OS) of elderly metastatic colorectal cancer(mCRC) patients treated with chemotherapy in daily practice. METHODS: Kaplan-Meir method was used for OS, the log-rank or Tarone-Ware test for differences between subgroups, Cox's proportional hazard model to assess the impact of known prognostic factors and treatment. RESULTS: 751 patients with mCRC observed between January 2000 and January 2013 were collected. Median age was 79 year(75-93); Male/Female 61/39%, ECOG-PS 0-1/2 85/15%; colon/rectum 74/26%; multiple metastatic sites 34%, only liver metastasis in 41% of patients. KRAS status was studied in 35% of patients: 44% of them showed gene mutation. 20.5% of patients did not received any kind of treatment including surgery. Comorbidities observed: cardiovascular 34%, diabetes 14%, hypertension 50%. Primary tumor was resected in 80.6%; surgery of liver metastasis was done in 19% of patients (2.3% of patients >80years). 78% of patients underwent chemotherapy. Median follow up was 12 months(range 1-124). Median OS was 17 months (CI 95%15-19);median OS in no-treated patients was 5 months (4-6); mOS of patients with at least one treatment was 20 months (18-22). In KRAS mutated group median OS was 19months (15-23) while in KRAS wild type patients median OS was 25 months (20-30). At multivariate analysis sex(Female), age(<80y), performance status(0-1), chemotherapy, Surgery of metastasis, Surgery of primary tumor and Site of metastasis(liver) were prognostic factors for OS. CONCLUSION: The results of our study show that in clinical practice treatment has a positive impact on OS of elderly patients, confirmed at multivariate analysis, included patients with age >80 years old or with a poor performance status (respectively p<0.0001 and p<0.0001). KRAS analysis deserve further evaluation.

Safety and efficacy of bevacizumab in combination with first-line chemotherapy in advanced breast cancer: data from the Italian cohort of the ATHENA trial.

AIMS AND BACKGROUND: The ATHENA international study investigated the safety and efficacy of bevacizumab plus first-line chemotherapy in locally recurrent/metastatic breast cancer in routine oncology practice. The present paper focuses on the outcomes of the Italian cohort of the study. METHODS: A subgroup analysis was carried out to report on the safety (primary endpoint) and efficacy (secondary endpoint) outcomes of patients recruited from Italian Centers. RESULTS: A total of 278 patients were included. Median age was 57 years (range, 26-85), and ECOG performance status was 0 or 1 in 96% of the patients. Bevacizumab was predominantly combined with a taxane monotherapy: paclitaxel (41.4%), docetaxel (21.9%), or a taxane-based combination therapy (12.2%). The most frequent grade ≥3 adverse events previously associated with bevacizumab were hypertension (3.2%), proteinuria (2.9%), and cardiac disorders (0.7%). Median time to progression was 10.9 months. Median overall survival was 29.9 months, and 1-year survival probability was 85%. Objective responses were observed in 62.6% of the patients, and an additional 30% achieved stable disease. CONCLUSIONS: Results from the study support the safety and efficacy of bevacizumab in combination with chemotherapy for the treatment of locally recurrent/metastatic breast cancer in the context of routine oncology practice in Italy.

Non-pegylated liposomal Doxorubicin-cyclophosphamide in sequential regimens with taxanes as neoadjuvant chemotherapy in breast cancer patients.

PURPOSE: Chemotherapy regimens containing anthracyclines and taxanes represent the landmark of neoadjuvant systemic therapy of breast cancer. In advanced breast cancer patients liposomal anthracyclines (LA) have shown similar efficacy and less cardiac toxicity when compared to conventional anthracyclines. We performed this retrospective analysis in order to evaluate the efficacy and tolerability of neoadjuvant regimens including LA outside of clinical trials in routine clinical practice. METHODS: Fifty operable or locally advanced, HER2 negative, breast cancer patients were retrospectively identified in 5 Italian cancer centres. Nineteen patients had received 4 cycles of non-pegylated liposomal doxorubicin (NPLD) and cyclophosphamide, followed by 4 cycles of docetaxel, every 3 weeks. In 25 patients the reverse sequence was employed, and a third subgroup of 6 patients received 4 cycles of NPLD/cyclophosphamide every 3 weeks followed by 4 cycles of weekly carboplatin and paclitaxel. RESULTS: We observed 10 pathological complete responses (pCR) (20.0%, 95%CI, 9% to 31%), and 35 (70%, 95%CI, 57.3% to 82.7%) partial responses (pPR), whereas no patients progressed onto therapy. In the small subset of triple negative tumors the pCR rate was 37.5%, and in tumors expressing ER and/or PgR it was 16.7%. A pCR rate of 26.5% was observed in tumors with high Ki-67, whereas in tumors with low Ki-67 only one (6.2%) pCR was observed (p=0.14). Treatments were well tolerated. The most common toxicities were myelosuppression and palmar-plantar erytrodysesthesia; 4 asymptomatic and transient LVEF decrease have been recorded, without any case of clinical cardiotoxicity. CONCLUSIONS: NPLD-cyclophosphamide and taxanes sequential regimens were proven effective and well tolerated in breast cancer patients with contra-indication to conventional anthracyclines undergoing neoadjuvant chemotherapy, even outside of clinical trials in everyday clinical practice.

Evaluation of relapse-free survival in T3N0 colon cancer: the role of chemotherapy, a multicentric retrospective analysis.

BACKGROUND: Adjuvant chemotherapy (AC) in Stage II Colon Cancer (CC) is still under debate. Choice should be based on patients and disease characteristics. According to guidelines AC should be considered in high-risk T3N0 patients. No data are available for better option in low-risk patients. The aim of the study is to retrospectively evaluate relapse-free survival (RFS) and disease-free survival (DFS) according to treatment received in T3N0 CC. METHODS: RFS and DFS are evaluated with Kaplan-Meier method. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15, respectively. RESULTS: 834 patients with T3N0 CC were recruited. Median age was 69 (29-93), M/F 463/371, 335 low-risk patients (40.2%), 387 high-risk (46.4%), 112 unknown (13.4%); 127 (15.2%) patients showed symptoms at diagnosis. Median sampled lymph nodes were 15 (1-76); 353 (42.3%) patients were treated with AC. Median follow up was 5 years (range 3-24). The 5-years RFS was 78.4% and the 5-years DFS was 76.7%. At multivariate analysis symptoms, lymph nodes, and adjuvant chemotherapy were prognostic factors for RFS. AC is prognostic factor for all endpoints. In low-risk group 5-years RFS was 87.3% in treated patients and 74.7% in non-treated patients (p 0.03); in high-risk group was respectively 82.7% and 71.4% (p 0.005). CONCLUSIONS: Data confirmed the role of known prognostic factors and suggest the relevance of adjuvant chemotherapy also in low-risk stage II T3N0 CC patients. However, the highest risk in low-risk subgroup should be identified to be submitted to AC.

Effectiveness of neoadjuvant trastuzumab and chemotherapy in HER2-overexpressing breast cancer.

PURPOSE: Trastuzumab and chemotherapy is the current standard of care in HER2+ early or locally advanced breast cancer, but there are scanty literature data of its real world effectiveness. METHODS: We retrospectively reviewed 205 patients with HER2+ breast cancer diagnosed in 10 Italian Medical Oncology Units between July 2003 and October 2011. All patients received neoadjuvant systemic therapy (NST) with trastuzumab in association with chemotherapy. Many different chemotherapy regimens were used, even if 90 % of patients received schemes including anthracyclines and 99 % received taxanes. NST was administered for more than 21 weeks (median: 24) in 130/205 (63.4 %) patients, while trastuzumab was given for more than 12 weeks (median: 12 weeks) in 101/205 (49.3 %) patients. pCR/0 was defined as ypT0+ypN0, and pCR/is as ypT0/is+ypN0. RESULTS: pCR/0 was obtained in 24.8 % and pCR/is in 46.8 % of the patients. At multivariate logistic regression, nonluminal/HER2+ tumors (P < 0.0001) and more than 12 weeks of neoadjuvant trastuzumab treatment (P = 0.03) were independent predictors of pCR/0. Median disease-free survival (DFS) and cancer-specific survival (CSS) have not been reached at the time of analysis. At multivariate analysis, nonluminal/HER2+ subclass (DFS: P = 0.01 and CSS: P = 0.01) and pathological stage II-III at surgery (DFS: P < 0.0001 and CSS: P = 0.001) were the only variables significantly associated with a worse long-term outcome. CONCLUSIONS: Our data set the relevance of molecular subclasses and residual tumor burden after neoadjuvant as the most relevant prognostic factors for survival in this cohort of patients.

Prolonged control of bone metastases in non-small-cell lung cancer patients treated with gefitinib.

We describe two non-small-cell lung cancer (NSCLC) patients in which treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKIs) gefitinib produced a prolonged control of bone disease. In the first patient, a 48-year-old male with adenocarcinoma (ADC) of the lung and multiple bone metastases, the bone scan became completely negative following treatment with gefitinib for 9 months. The patient remained alive and with no evidence of bone metastases for 20 months, despite two local recurrences that were surgically removed. Similarly, the bone scan of the second patient, a 49-year-old male with ADC of the lung and bone metastases, became negative after 6 months on gefitinib. The molecular mechanisms potentially involved in this phenomenon are discussed.

Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial.

BACKGROUND: The rationale for combining anticancer drugs has not been applied consistently to use of intravesical agents for treatment of superficial bladder cancer, for which immunotherapeutic BCG and chemotherapeutic mitomycin seem to be a potentially effective combination. We aimed to do a prospective, randomised comparison of BCG alone with that of sequential BCG and electromotive mitomycin in patients with stage pT1 bladder cancer. METHODS: After transurethral resection and multiple biopsies, 212 patients with stage pT1 bladder cancer were randomly assigned to: 81 mg BCG infused over 120 min once a week for 6 weeks (n=105); or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for three cycles (n=107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval; secondary endpoints were time to progression; overall survival; and disease-specific survival. Analyses were done by intention to treat. This trial has been submitted for registration at the US National Cancer Institute website . FINDINGS: Median follow-up was 88 months (IQR 63-110). Patients assigned sequential BCG and electromotive mitomycin had higher disease-free interval than did those assigned BCG alone (69 months [95% CI 55-86] vs 21 months [15-54]; difference between groups 48 months [42-54], log-rank p=0.0012). Patients assigned sequential BCG and electromotive mitomycin also had lower recurrence (41.9% [32.7-51.5] vs 57.9% [48.7-67.5]; difference between groups 16.0% [2.7-29.3], log-rank p=0.0012); progression (9.3% [3.8-14.8] vs 21.9% [17.9-25.9]; difference between groups 12.6% [3.0-22.2], log-rank p=0.004); overall mortality (21.5% [13.5-29.5] vs 32.4% [23.4-41.4], difference between groups 10.9% [0.6-21.2], log-rank p=0.045); and disease-specific mortality (5.6% [1.2-10.0] vs 16.2% [6.1-23.3], difference between groups 10.6% [2.5-18.7], log-rank p=0.01). Side-effects were mainly localised to the bladder. INTERPRETATION: BCG-induced inflammation might increase the permeability of the bladder mucosa such that mitomycin can reach the target tissue more easily and exert its anticancer effect.