Nicola Caristi

Emerging Targeted Therapies for Castration-Resistant Prostate Cancer

Until recently, few therapeutic options were available for patients with castration-resistant prostate cancer (CRPC). Since 2010, four new molecules with a demonstrated benefit (sipuleucel-T, cabazitaxel, abiraterone, and denosumab) have been approved in this setting, and to-date several other agents are under investigation in clinical trials. The purpose of this review is to present an update of targeted therapies for CRPC. Presented data are obtained from literature and congress reports updated until December 2011. Targeted therapies in advanced phases of clinical development include novel androgen signaling inhibitors, inhibitors of alternative signaling pathways, anti-angiogenic agents, inhibitors that target the bone microenvironment, and immunotherapeutic agents. Radium-223 and MDV3100 demonstrated a survival advantage in phase III trials and the road for their introduction in clinical practice is rapidly ongoing. Results are also awaited for phase III studies currently underway or planned with new drugs given as monotherapy (TAK-700, cabozantinib, tasquinimod, PROSTVAC-VF, ipilimumab) or in combination with docetaxel (custirsen, aflibercept, dasatinib, zibotentan). The optimal timing, combination, and sequencing of emerging therapies remain unknown and require further investigation. Additionally, the identification of novel markers of response and resistance to these therapies may better individualize treatment for patients with CRPC.

The Risk of Toxicities from Trastuzumab, Alone or in Combination, in an Elderly Breast Cancer Population

Background: Breast cancer in the elderly is associated with high recurrence and death rates, due mostly to undertreatment. Human epidermal growth factor receptor type 2 (HER2) overexpression is infrequent in older patients. Trastuzumab-based chemotherapy is often withheld from elderly patients because of its cardiotoxicity. Patients and Methods: Medical records of consecutive HER2-positive breast cancer patients aged ≥70 years old treated between 2005 and 2010 in the participating centers were retrospectively reviewed. All patients underwent multidimensional geriatric assessment (MGA). Results: Among 59 patients identified, 51 patients were evaluable (median age 76 years). The rate of any adverse event was 20% (10/51). The most relevant cardiac adverse event consisted of symptomatic congestive heart failure (CHF; n = 1, 2%) followed by asymptomatic decreases of left ventricular ejection fraction (LVEF; n = 6, 12%). Other toxicities included moderate hypersensitivity reactions during trastuzumab infusions (n = 3, 6%). Hypertension, obesity, prior anthracyclines exposure and concurrent chemotherapy were associated with a higher incidence of toxic events. Previous radiotherapy, concurrent endocrine therapy and different trastuzumab-based regimens did not seem to influence toxicity. Conclusions: Our data suggest that trastuzumab has a good safety profile in nonfrail women aged 70 years and older. These favorable findings may be related to a limited number of anthracycline pretreatments, patient selection and a close cardiologic monitoring.

Current knowledge and future directions on bisphosphonate-related osteonecrosis of the jaw in cancer patients

Background: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe adverse event of long-term use of bisphosphonates that heavily affects the quality of life of cancer patients. Objective: To review epidemiologic data, pathobiology, risk factors, diagnosis and management of BRONJ. Methods: Articles were identified by searching the PubMed and MEDLINE databases and recent meetings abstracts. Results/conclusion: BRONJ pathobiology is thought to be related to bisphosphonate-induced suppression of normal bone remodeling and impairment of bone blood flow. Dental extractions, daily masticatory traumas, oral infections, chemotherapy and antiangiogenic drugs can also play an active role. Collaboration between oncologists and dentists is essential to prevent BRONJ. A conservative approach based on pain control, oral rinses, antibiotics and limited debridement represents the current management. Optimization of therapy based on reduction of bisphosphonate doses or exposure time, newer bisphosphonates and biomolecular agents could favorably impact on BRONJ incidence.

Oxaliplatin and raltitrexed in the treatment of inoperable malignant pleural mesothelioma: Results of a pilot study

Aims and Background The treatment of inoperable malignant pleural mesothelioma is a challenge for the oncologist. Available chemotherapy regimens achieve poor results, therefore new agents or combinations are needed. In a phase I study, the combination of oxaliplatin and raltitrexed was shown to be active against malignant pleural mesothelioma. We herein report the results of a pilot study about the treatment of this disease. Methods From April 1999 to June 2000, we enrolled 11 chemotherapy-naïve patients with inoperable malignant pleural mesothelioma suitable to receive the following combination chemotherapy: raltitrexed, 3 mg/m2 iv, and oxaliplatin, 130 mg/m2, as a 2-hr infusion every 3 weeks. Results Four partial responses, 1 regression of disease (objective response rate, 45%; 95% Cl, 15.6-74.4%), 4 stable diseases and 2 progressions of disease were observed. An improvement in disease-related symptoms was recorded in all responders and in 2 patients with stable disease. Toxicity was mild, with no toxic-related death and only 1 episode of grade 4 neurotoxicity. Conclusions We consider the combination promising and worthy of further studies.

A Modified Weekly Docetaxel Schedule as First-Line Chemotherapy in Elderly Metastatic Breast Cancer: A Safety Study

Abstract Standard dose docetaxel is burdened by severe toxicity. Weekly schedules have been shown to be active as standard scheme with reduced side effects. In 20-30% of elderly patients (pts) the classic 6-week schedule induces grade 3/4 fatigue and other cumulative toxicities. We carried out this safety study in order to evaluate whether a modified weekly docetaxel schedule would improve the toxicity profile. Twenty-one untreated elderly (≥70 years) pts suffering from metastatic breast cancer were enrolled in the study. Pts were treated with a weekly dose of 35 mg/m2 docetaxel for 6 weeks, followed by a 2-week rest. Further cycles were performed with this modified schedule: docetaxel days 1, 8 and 15 every 29 days. All pts received at least the first cycle (6 weeks). A total of 261 doses were delivered. No toxic deaths occurred. The toxicity was mild: we recorded 1 episode of grade 3neutropenia and severe asthenia in only 2 pts (10%). We recorded an overall response rate of 33% (1 CR, 6 PR). Our data showed a reduced incidence of severe asthenia (2/21), obtained with a light modification of a weekly docetaxel schedule.

Activity of pegylated liposomal doxorubicin in combination with gemcitabine in triple negative breast cancer with skin involvement: two case reports.

Breast carcinoma (BC) is a heterogeneous disease in terms of histology, therapeutic response, dissemination patterns to distant sites and patient outcomes. Triple-negative breast cancer (TNBC), defined by the lack of protein expression of estrogen and progesterone receptors and the absence of HER2 protein overexpression (ER–/PR–/HER2–) has significant clinical implications due to their poor prognosis and the lack of targeted agents. Skin involvement is one of the most distressing presentations of locally recurrent breast cancer and few studies have identified effective agents in this setting. In fact, the increasing use of anthracycline/taxane-based chemotherapy in the neoadjuvant and/or adjuvant settings has led to investigate new cytotoxic therapies such as the combination of pegylated liposomal doxorubicin (PLD) with gemcitabine. Here, we report two cases of disseminated TNBC with extensive cutaneous metastases and a remarkable response to PLD in combination with gemcitabine. Further investigations are needed to confirm the efficacy of this regimen in skin involvement and TNBC.

Gefitinib in lung cancer therapy: clinical results, predictive markers of response and future perspectives.

Over the past few years, epidermal growth factor receptor has emerged as one of the most important targets in tumorgenesis and several drugs targeting signal transduction pathways have been developed. The first among these agents to be approved for the treatment of NSCLC was gefitinib, a potent, selective and reversible inhibitor of HER1/EGFR tyrosine kinase activity. The review summarizes its clinical development and the new therapeutic options, with particular focus on predictive markers of susceptibility to this drug.

Protective Effect of Leuprolide on Ovarian Function in Young Women Treated with Adjuvant Chemotherapy for Early Breast Cancer : A Multicenter Phase II Study

Abstract The aim of this study was to evaluate the protective effect of concomitant leuprolide treatment on ovarian function in young women undergoing adjuvant chemotherapy for early breast cancer. 19 women, median age 36.5 years (range 26-40 years), with operable breast cancer and negative hormonal receptors, received six cycles of FEC 100 regimen as adjuvant chemotherapy and co-treatment with leuprolide. Menstrual resumption was gained in all patients in a median time of 5 months (range 3-8). Follicle-stimulating hormone and estradiol assessment was performed in all patients. The return to pre-menopausal values was achieved within 6 months of the last leuprolide administration. At a median follow-up of 3 years (range 1-5 years), no patient relapsed and four full-term pregnancies were recorded in four women, each of whom delivered a healthy infant. Our data are in agreement with similar experiences and confirm the activity of GnRH therapy in preventing ovarian failure.

Cisapride and dexamethasone in the prevention of delayed emesis after cisplatin administration

Abstract Management of delayed emesis (DE) remains unsatisfactory, and only 50% of the patients achieve complete protection. Cisapride is a strong prokinetic gastrointestinal drug that could have a role in the prevention of DE. We enrolled 31 adult naive outpatients who were scheduled to receive cisplatin chemotherapy at doses of ≥75 mg/m2. All patients received the same prophylactic treatment for acute emesis (20 mg dexamethasone and 8 mg ondansetron i.v.) and, as preventive therapy for DE, oral cisapride, 10 mg every 8 h on days 2–4, combined with dexamethasone i.m., 8 mg twice daily on days 2 and 3, and 4 mg twice daily on day 4. All patients were evaluable for activity. Complete protection from acute vomiting was 80.7%, from nausea 71% and from nausea/vomiting 64.5%. The overall protection from DE (days 2–4) was 74.1% for vomiting, 64.5% for nausea and 58% for nausea/vomiting. In our study the combination of cisapride and dexamethasone was effective, giving 58% of complete protection from DE, and it is therefore worthy of further studies.

Oral Vinorelbine as First Line Chemotherapy in Unfit Elderly Patients with Hormone-Refractory Prostate Cancer

Abstract Hormone-refractory prostate cancer (HRPC) is a rapidly progressive disease which produces considerable morbidity and involves mostly men over 70, often comorbid and with poor tolerance to chemotherapy. Low-toxicity chemotherapy is a reasonable option in this setting. Vinorelbine and a corticosteroid show activity and clinical benefit responses in HRPC. An oral regimen is preferable for elderly patients. This study aimed to evaluate safety, prostate-specific antigen (PSA) response, clinical benefit and progression-free survival in chemonaive elderly HRPC patients. 33 men, median age 78.2, were treated with oral vinorelbine 60 mg/m2 days 1 and 8 every 3 weeks, escalable to 80 mg/m2 after the first cycle, and prednisone 5 mg b.i.d. The main toxicity was hematopoietic (mild at 60 mg/m2 and moderate at 80 mg/m2). Of 27 evaluable patients, 9 (33%) had PSA responses and 9 had clinical benefit, PSA-correlated in 5 cases (56%). Median progression-free survival was 13.4 weeks, median overall survival 45 weeks. Oral vinorelbine plus prednisone is safe and has moderate activity, with biochemical and clinical responses in about one-third of patients and could be an option in unfit elderly HRPC patients.