Antonio Bernardo

First-line chemotherapy with vinorelbine, gemcitabine, and carboplatin in the treatment of brain metastases from non-small-cell lung cancer: a phase II study.

On the basis of the hypothesis that responsiveness of brain metastases (BM) to chemotherapy is primarily determined by the chemosensitivity of primary tumor, rather than the ability of cytotoxic agents to penetrate the blood–brain barrier, we addressed the role of a new combination regimen with Vinorelbine (VNR), Gemcitabine (GEM), and Carboplatin (CBDCA) as a primary treatment modality in non-small-cell lung cancer (NSCLC) patients with BM. Twenty-two consecutive chemotherapy-naïve patients with documented BM from NSCLC and at least 1 evaluable extracerebral lesion were enrolled in this phase II study. Vinorelbine (25 mg/m2) and GEM (1000 mg/m2) were given on day 1, combined with a fixed daily dose of CBDCA at AUC=5.0 for three consecutive days. The cycle was repeated every three weeks in an outpatient setting. A total of 116 cycles was given (median 4, range 3–9 per patient). Specific evaluation of BM by contrast-enhanced computed tomography (CT) scan showed an overall response rate of 45% in 20 evaluable patients (95% confidence interval, 26–66%), with 3 (15%) complete and 6 (30%) partial remissions; in addition, three minor regressions, five disease stabilizations, and three progressions were found. Patients who responded for the brain also had a response at the extracerebral sites, and a benefit by a remission of symptoms and improvement of performance index was observed in 77% of the whole group. Median time to response was 10 weeks (range 6–12 weeks) and median response duration was 25 weeks (range 12–32 weeks). Median survival time was 33 weeks (range 18–62+weeks) in the whole group and 48 weeks in responders (range 26–62+weeks). The adopted schedule was well tolerated and easy to use in the outpatient setting, with good patient compliance. Our results, which are consistent with the study hypothesis, suggest that BM respond to chemotherapy in the same way as systemic disease and primary tumor, and further support the need for reconsideration of the role of chemotherapy in such a clinical setting. Controlled trials comparing chemotherapy with radiotherapy or concomitant sequential chemo-radiotherapy would be appropriate.

Which patients with metastatic breast cancer benefit from subsequent lines of treatment? An update for clinicians.

The outcome of patients with metastatic breast cancer (MBC) has clearly improved over the past decades and the proportion of women living with their disease for several years is increasing. However, the usefulness of multiple lines of treatment is still debated and under evaluation. The available data from both randomized trials and large retrospective series are reviewed and discussed in order to analyze management practices, with emphasis on potential prognostic and predictive factors for clinical outcome. At present, evidence-based medicine provides some support for the use of second-line and to a lesser degree and in selected cases, third-line chemotherapy in human epidermal growth factor receptor 2 (HER2) negative MBC. Beyond third-line treatment, messages from recently reported retrospective studies also suggest a clear potential gain for women receiving further therapies after disease progression, since each line can contribute to a longer survival. In HER2-positive disease, the data from observational and retrospective studies support a clinical benefit from the use of trastuzumab beyond disease progression and emerging evidences from randomized controlled trials are leading to the introduction of newer HER2-targeted therapies in multiple lines. The question ‘How many lines of treatment should we give patients?’ clearly needs further research through prospective, high-quality clinical trials, aiming for a better definition of factors with prognostic and predictive role. In the meantime, the ‘optimal’ treatment strategy should probably be to use as many therapeutic options as possible, either in sequence or combination, to keep the best efficacy/toxicity balance, considering MBC as a chronic disease.

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer patients: prospective evaluation of activity, safety, and quality of life

Background A prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC). Patients and methods Fifty-two women with HER2-negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m2 as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal. Results All of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%–61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52–86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0–11.6 months, range 5–21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment. Conclusion Our results showed that single-agent nab-paclitaxel 260 mg/m2 every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen is a valid therapeutic option for that ‘difficult to treat’ patient population represented by women who at the time of disease relapse have already received the most active agents in the adjuvant and/or metastatic setting (ie, conventional taxanes).

Restaging clear cell renal carcinoma with 18F-FDG PET/CT.

Aim The aim of our retrospective study was to assess the usefulness of 18F-FDG PET/CT in the restaging of clear cell renal cell carcinoma (RCC) patients. Patients and Methods Sixty-nine patients (median age = 62 years; range = 36–86 years) affected by clear cell RCC (TNM at staging: T1, 42 patients; T2, 13 patients; T3, 11 patients; T4, 3 patients; Fuhrman grade: G2, 47 patients; G3, 20 patients; G4, 2 patients) underwent whole-body 18F-FDG PET/CT to restage the disease after nephrectomy for clinical or radiological suspicion of metastases. Areas of abnormal uptake at PET/CT were classified, taking the liver uptake as reference, as follows: 1 = faint uptake, lower than liver; 2 = moderate uptake, equal to liver; and 3 = high uptake, higher than liver. Validation of 18F-FDG PET/CT results was established by (1) biopsy (23 patients) and (2) other imaging modalities (addressed BS; c.e.CT; MRI; 18F-fluoride PET/CT; subsequent 18F-FDG PET/CT), and/or clinical and radiological follow-up of 12 months (46 patients). Results 18F-FDG PET/CT was positive in 42 patients and negative in 27 patients. Sixteen patients presented single lesions and 26 patients presented multiple localizations of the disease. On a patient basis, 40 patients resulted true positive, 2 patient false positive, 23 patients true negative, and 4 patients false negative. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 90%, 92%, 91%, 95%, and 85%, respectively. On a lesion basis, PET/CT detected 114 areas of abnormal uptake in 42 positive patients of which 112 resulted to be true positive. FDG uptake of the true positive lesions resulted to be high in 83 cases, moderate in 17 lesions, and finally faint in 12 lesions. Conclusions 18F-FDG PET/CT demonstrated a good sensitivity in the restaging of clear cell RCC. Most of the lesions showed intense activity. According to our results, it seems that the use of 18F-FDG PET/CT in the restaging of RCC is feasible because the number of false-negative cases is limited.

Patterns of Care and Clinical Outcomes of First-Line Trastuzumab-Based Therapy in HER2-Positive Metastatic Breast Cancer Patients Relapsing After (Neo)Adjuvant Trastuzumab: An Italian Multicenter Retrospective Cohort Study

BACKGROUND We evaluated the patterns of care and clinical outcomes of metastatic breast cancer patients treated with first-line trastuzumab-based therapy after previous (neo)adjuvant trastuzumab. MATERIALS AND METHODS A total of 416 consecutive, HER2-positive metastatic breast cancer patients who had received first-line trastuzumab-based therapy were identified at 14 Italian centers. A total of 113 patients had presented with de novo stage IV disease and were analyzed separately. Dichotomous clinical outcomes were analyzed using logistic regression and time-to-event outcomes using Cox proportional hazards models. RESULTS In the 202 trastuzumab-naïve patients and 101 patients with previous trastuzumab exposure, we observed the following outcomes, respectively: overall response rate, 69.9% versus 61.3% (adjusted odds ratio [OR], 0.62; p = .131), clinical benefit rate, 79.1% versus 72.5% (adjusted OR, 0.73; p = .370), median progression-free survival (PFS), 16.1 months versus 12.0 months (adjusted hazards ratio [HR], 1.33; p = .045), and median overall survival (OS), 52.2 months versus 48.2 months (adjusted HR, 1.18; p = .404). Patients with a trastuzumab-free interval (TFI) <6 months, visceral involvement, and hormone receptor-negative disease showed a worse OS compared with patients with a TFI of ≥6 months (29.5 vs. 48.3 months; p = .331), nonvisceral involvement (48.0 vs. 60.3 months; p = .270), and hormone receptor-positive disease (39.8 vs. 58.6 months; p = .003), respectively. CONCLUSION Despite the inferior median PFS, trastuzumab-based therapy was an effective first-line treatment for patients relapsing after (neo)adjuvant trastuzumab. Previous trastuzumab exposure and the respective TFI, type of first site of disease relapse, and hormone receptor status should be considered in the choice of the best first-line treatment option for HER2-positive metastatic breast cancer patients.

Intravenous or Oral Vinorelbine Plus Capecitabine As First-Line Treatment in HER2– Metastatic Breast Cancer: Joint Analysis of 2 Consecutive Prospective Phase II Trials

BACKGROUND The purpose of this study was to assess the activity and safety of the combination of vinorelbine (VNR) and capecitabine (CAP) as first-line treatment in HER2-negative (HER(-)) metastatic breast cancer (MBC). PATIENTS AND METHODS Patients (42) enrolled in trial A received intravenous (i.v.) VNR 25 mg/m2 on days 1 and 8 of a 21-day cycle combined with CAP 1000 mg/m2 twice daily for 14 consecutive days followed by 1 week of rest. Trial B (46 patients) followed trial A when the oral formulation of VNR became available at our institution. Patients received oral VNR (60 mg/m(2) on days 1-8) combined with the same CAP schedule as in trial A. RESULTS The response rate (RR) in trial A was 73.2% (95% confidence interval [CI], 56.4-82.8), including 12.2% complete responses (CRs). Clinical benefit was achieved in 78% of patients (95% CI, 63.2-87.9). In trial B, overall RR was 76% (95% CI, 62.0-86.0), with 13% CRs and clinical benefit of 80.4% (95% CI, 66.8-89.3). In trial A, median progression-free survival (PFS) was 8.2 months (range, 6-14+ months) and median overall survival (OS) was 32.4 months (range, 17-36+ months). In trial B, median PFS and OS were 8.8 months (range, 8-21+ months) and 34.3 months (14-39+ months), respectively. Treatment-related toxicity was manageable. Quality of life assessment showed a statistically significant difference regarding body image (p = .001), sexual functioning (p = .02), and future perspectives (p = .03) in women receiving chemotherapy fully by the oral route. CONCLUSION This joint analysis shows that both tested schedules can produce high objective RRs with encouraging PFS, manageable toxicity profile, and suggested benefit on some aspects of quality of life for the fully oral combination.

Targeted chemotherapy with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in metastatic breast cancer: which benefit for which patients?

The therapeutic goals in metastatic breast cancer (MBC) remain palliative in nature, aimed at controlling symptoms, improving or maintaining quality of life and prolonging survival. The advent of new drugs and new formulations of standard agents has led to better outcomes in patients with advanced or metastatic disease. These developments have also allowed a tailored therapeutic approach, in which the molecular biology of the tumour, the treatment history, and patient attitudes are taken into account in the decision-making process. Targeting drug delivery to the tumour is a promising mean of increasing the therapeutic index of highly active agents such as the taxanes, and nanoparticle albumin-bound paclitaxel (nab-paclitaxel), the first nanotechnology-based drug developed in cancer treatment, is one such advance. Data from randomized trials support the efficacy of single-agent nab-paclitaxel as first-line and further treatment lines in MBC at the registered 3-weekly schedule of 260 mg/m2, but emerging evidence suggests its activity as a weekly regimen or combined with other agents in various clinical scenarios. Thus, nab-paclitaxel seems to offer flexibility in terms of dosing schedules, allowing physicians to tailor the dose according to different clinical situations. This paper reviews the clinical trial background for nab-paclitaxel in MBC, focusing on specific ‘difficult-to-treat’ patient populations, such as taxane-pretreated or elderly women, as well as those with triple-negative, HER2-positive and poor-prognostic-factors disease. Moving beyond evidence-based information, ‘real life’ available experiences are also discussed with the aim of providing an update for daily clinical practice.

Uncommon dihydropyrimidine dehydrogenase mutations and toxicity by fluoropyrimidines: a lethal case with a new variant

DPD is the rate-limiting enzyme involved in the metabolism of 5-fluorouracil and its prodrugs, capecitabine and tegafur. Many cases of severe toxicities by fluoropyrimidines are reported in the literature, sometimes with lethal outcome, due to a poor or null metabolizer phenotype. The exon 14-skipping mutation IVS14+1G>A and the c.2846A>T are the most common deficient variants. However, many additional variants of the DPYD gene with unclear functional significance have been reported. We describe a patient with metastatic breast cancer who received capecitabine and trastuzumab at standard doses. Six days after beginning capecitabine, the patient developed fever, leucopenia and neutropenia, mucositis, hand-foot syndrome, multiple organ dysfunction and eventually died. Since the toxicity profile was compatible with capecitabine administration, complete exon sequencing of DPYD was carried out and the patient was found to be compound heterozygous for the rare mutation c.257C>T in exon 4, c.496A>G in exon 6, the new variant c.1850C>T in exon 14 and c.2194G>A in exon 18. Given the marginal role of c.496A>G and c.2194G>A in DPD deficiency, the cause of death was suggested to be dependent on the novel c.1850C>T in combination with c.257C>T. The complexity of DPD pharmacogenetics suggests the need to develop cost-effective screening approaches to identify patients at risk of severe toxicities.

Nab-Paclitaxel in Advanced HER2-negative Breast Cancer Patients: Efficacy and Safety Beyond Clinical Trials.

BACKGROUND Few data are available regarding efficacy and safety of nanoparticle albumin-bound (nab)-paclitaxel in advanced breast cancer patients outside a controlled trial, especially for the weekly schedule. PATIENTS AND METHODS We prospectively collected data of advanced breast cancer patients who were candidates to be treated with weekly (125 mg/m2 for 3 consecutive weeks followed by a 1-week rest) or every 3 weeks (260 mg/m2) schedules of nab-paclitaxel, according to physicians decision. RESULTS The study enrolled 209 patients, of whom 92 (39.3%) received weekly nab-paclitaxel. The median age was 58 (range, 31-84) years; 21.8% of the patients were classified as triple-negative breast cancer (estrogen-recetor/progesteron-receptor-negative). The median number of cycles was 5.5. The overall response rate was 32.1% in the whole population, without any significant difference according to schedule, previous paclitaxel exposure, presence of visceral metastases, or line of treatment. The median time to disease progression was 6 months (95% confidence interval, 1-34), with no differences according to the schedule of treatment. Severe adverse events (Grade 3-4) were observed in 60.6% of the patients. The main toxicities were alopecia (53.4%), neutropenia (3%), and sensory neuropathy (2.1%). CONCLUSION Our real-life data indicate that both schedules of nab-paclitaxel are manageable and safe in advanced breast cancer patients, even if previously treated with other taxanes.

Vinflunine in Advanced Transitional Cell Cancer of the Urothelial Tract: A Potential Option for Maintenance Therapy? A Case Series

Introduction: Vinflunine is a microtubule inhibitor approved in Europe as second-line treatment of advanced transitional cell cancer of the urothelium (TCCU). The inability to continue with a first-line platinum-based regimen beyond 6 cycles suggested investigating the use of vinflunine as switch maintenance therapy in patients with response or stable disease after first-line therapy. Methods: Patients with advanced TCCU and documented disease control after 3-6 cycles of first-line platinum-based chemotherapy received vinflunine maintenance therapy within 6 weeks of the last cycle. Our analysis aimed to examine the performance of vinflunine in terms of activity and safety in such a patient population. Results: 28 consecutive patients were studied. After a median follow-up of 25 months, vinflunine was associated with a median progression-free survival of 9 months (range 4 to > 16 months) and a disease control rate of 64%; median overall survival was not reached. Treatment was well tolerated, with no unexpected safety events. The most common adverse events of grade ≥ 3 were neutropenia (21%) and constipation (14%); no toxicity-related death occurred. Conclusions: Our results suggest that vinflunine may be a suitable maintenance treatment option for TCCU patients who received a maximum of 6 cycles of platinum-based chemotherapy commonly used as first-line treatment.