R. Maisano

FOLFOX-4 Regimen as First-Line Chemotherapy in Elderly Patients with Advanced Gastric Cancer: A Safety Study

Abstract Gastric cancer is often diagnosed in advanced stage (AGC) and in elderly patients. Current chemotherapies induce severe toxicity and are difficult to deliver. Some authors have shown the activity and safety of oxaliplatin with various 5-fluorouracil (FU) and leucovorin (LV) infusions in AGC. The aim of our study was to evaluate the feasibility of the FOLFOX-4 regimen in elderly patients with AGC. From 6/2003 to 7/2005, 33 patients (median age 74 years, range 66-79 years) were enrolled into the study. 31 patients were assessable for the safety analysis and for response. We recorded complete response in 4 patients (13%), partial response in 6 patients (19%), 9 (29%) stable disease and 12 progressive disease for an overall response rate of 32% (95% CI, 16% to 48%). At median follow-up of 20 months the median time to progression was 6.4 months. The therapy was well tolerated, the main G1/2 toxicities were nausea, vomiting and diarrhea. Only 2 patients suffered from severe vomiting. Severe hematologic toxicities were uncommon. Anemia G3 was recorded in 3 patients, neutropenia G3 in 6 patients and febrile neutropenia in 1 patient. G1 and G2 neurotoxicity were a common event while G3 sensorial neuropathy was not reported. We conclude that although our patients were elderly and most had a PS 2, the regimen was manageable, easy to deliver, well accepted by the patients and active.

Carboplatin and Gemcitabine Combination in Metastatic Triple-Negative Anthracycline- and Taxane-Pretreated Breast Cancer Patients: A Phase II Study

Abstract Triple-negative breast cancer (TNBC) is characterized by lack of hormone receptors and HER-2 and shares many features with BRCA1-associated cancer. Preclinical data indicate cisplatin sensitivity, suggesting that these tumors may have defects in the BRCA1 pathway. The carboplatin and gemcitabine (CG) combination is active in unselected anthracycline/taxane pretreated metastatic breast cancer patients, so we carried out a phase II study to evaluate the activity of the CG combination in pretreated metastatic TNbC patients. From 10/2004 to 3/2009 we enrolled 31 patients. Median age was 57 years and 29 patients out of 31 had visceral involvement. The overall response rate (ORR) was 32% (1 complete response /9 partial responses), in addition 5 patients obtained stable disease for ≥12 weeks. After a median follow-up of 34 months, all patients progressed with a median time to progression of 5.5 months and median overall survival of 11 months. Dose reductions, delays and omissions occurred in 75 (60%), 36 (29%) and 22 (18%) cycles. Grade 3/4 neutropenia occurred in 17 and febrile neutropenia in 4 patients. Ten patients had Grade 3/4 thrombocytopenia. Non hematological toxicities were manageable. The CG combination is a reasonable option for the treatment of metastatic pre-treated TNBC patients.

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.

Mucinous histology of colon cancer predicts poor outcomes with FOLFOX regimen in metastatic colon cancer

Abstract Mucinous adenocarcinoma (MA) of colorectal cancer seems associated with reduced responsiveness to chemotherapy. The overexpression of markers of resistance to fluorouracil and oxaliplatin has recently been demonstrated. We revised the outcomes of metastatic MA of the colon treated with FOLFOX. From January 2002 to December 2009, we treated 198 patients with metastatic colon cancer, of which 21 (10·6%) had diagnosis of MA and were compared with 42 control patients with non-mucinous adenocarcinoma (NMA). In MA group, three patients [14%; inhibitory concentration 95: ±7·5%] reached partial response, and in NMA group, two patients obtained complete response and 16 obtained partial response with an overall response rate of 43% (inhibitory concentration 95: ±7·6%) with a significant statistical difference (P = 0·027). Median progression-free survival for MA group was 4 months with respect to 8 months for NMA (P = 0·0001); regarding overall survival, we registered a median of 8 months with respect to 18 months for MA and NMA (P = 0·001). In multivariate analysis, MA histology, Eastern Cooperative Oncology Group performance status 2, more than two metastatic sites, and peritoneal metastatic involvement resulted in negative independent prognostic factors. Also in our study, MA is connected to poor prognosis and reduced activity of chemotherapy. In the absence of randomised studies, it may be convenient to analyse this subgroup of patients within the large trials carried out on colorectal cancer.

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.

Alkaline phosphatase levels as a prognostic factor in metastatic colorectal cancer treated with the FOLFOX 4 regimen: a monoinstitutional retrospective study

AIMS AND BACKGROUND Metastatic colorectal cancer has a heterogeneous behavior, and a set of patients will have minimal response and rapid disease progression. To understand this heterogeneity, studies have evaluated biological and clinical prognostic factors. Alkaline phosphatase seems to be a key prognostic factor, so we have reviewed the outcomes of our patients with respect to alkaline phosphatase levels. METHODS AND STUDY DESIGN Between January 2003 and December 2008, we treated with the FOLFOX 4 regimen 103 consecutive patients with metastatic colorectal cancer. Thirty-two patients had alkaline phosphatase > or =300 U/l. RESULTS Median time to progression was 4 months for patients with high alkaline phosphatase levels and 8 months for those with low alkaline phosphatase levels. Median overall survival was 8 and 17.5 months, respectively. Only 3 patients in the high alkaline phosphatase group obtained partial response (9.4%) compared to 3 complete responses and 24 partial responses (41.5%) in low alkaline phosphatase group. Toxicity was substantially different, with more grade 3-4 neutropenia, diarrhea and oral mucositis in the high than low alkaline phosphatase group. CONCLUSIONS Alkaline phosphatase is an uncomplicated and potent prognostic factor. Patients with high alkaline phosphatase levels had a poor prognosis.

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.