Bioclinical parameters driving decision-making of subsequent lines of treatment in metastatic castration-resistant prostate cancer.

Different options are available as second-line treatment of metastatic castrate-resistant prostate cancer: cabazitaxel, abiraterone, and enzalutamide. Phase III studies evaluating cabazitaxel and the two hormonal agents have been shown to significantly prolong overall survival compared to mitoxantrone and placebo, respectively. Several studies have also demonstrated feasibility and activity of docetaxel rechallenge in case of a sufficient progression-free interval (3-6 months), good performance status, and previous acceptable safety profile, thus providing an additional treatment option in clinical practice. Clinical and biological parameters should be considered to tailor II line treatment. In clinical practice, we can primarily evaluate patients' fitness according to age, performance status, symptomatic disease, comorbidities, and expected safety profile of each drug. Different prognostic/predictive factors may be considered, such as presence of bone-limited or visceral metastases, length of androgen deprivation therapy (ADT) before chemotherapy, time to progression after docetaxel, Gleason score, PSA doubling time, and serum testosterone, even if their clinical relevance is still debated. This review will discuss current options of innovative drugs sequencing and selection according to bioclinical parameters.

General principles of chemotherapy.

BACKGROUND AND OBJECTIVE: Over the last 50 years, medical treatment of solid cancers gained major advances in terms of effectiveness through breakthrough knowledge of cancer biology, technology development and identification of fundamental active drugs. STATE OF THE ART: We conventionally discriminate between medical treatment of the advanced or metastatic disease and of the early disease, namely adjuvant and neoadjuvant or primary treatment, if administered after or before surgery. New drugs or treatment associations can be sequentially introduced in medical treatment of cancer patients in phase I, II and III clinical trials. No drug or drug association can be proposed in the adjuvant or neoadjuvant setting of treatment without proven effectiveness in the advanced disease. Primary endpoints of medical treatment according to the phase of the disease are safety, activity and efficacy. Different options of medical treatment may be selected for each tumor according to the specific phase of disease. In some metastatic cancers, such as colorectal cancer, the activity of medical treatment justified the development of strategies integrating also surgical resection of metastases, specifically liver, with the objective to increase efficacy. PERSPECTIVES: Open question in first and subsequent lines of treatment in advanced cancer patients, particularly in MCRC patients, is the proper individualization of medical treatment according to prognostic and predictive bio-markers.

Triplet schedule of weekly 5-fluorouracil and alternating irinotecan or oxaliplatin in advanced colorectal cancer: a dose-finding and phase II study.

A weekly administration of alternating irinotecan or oxaliplatin associated to 5-Fluorouracil in advanced colorectal cancer was planned in order to evaluate a new schedule maintaining dose intensities of each drug as in double combinations and tolerability of the triplet association. The following weekly schedule was administered: irinotecan, days 1 and 15; oxaliplatin, days 8 and 22; 5-fluorouracil (5-FU) over 12-h (from 10:00 p.m. to 10:00 a.m.) timed flat infusion, days 1-2, 8-9, 15-16 and 22-23, every 4 weeks. Dose- finding and phase II study were planned. Thirteen patients were enrolled in the dose-finding study and 23 in the phase II study. The recommended doses of our study are: irinotecan 160 mg/m(2); oxaliplatin 80 mg/m(2); 5-FU 900 mg/m(2). The dose-limiting toxicity was diarrhea (35% of patients) but no cases of febrile neutropenia were observed. In 30 patients assessable for response two complete (6.7%) and 18 partial (60%) responses were observed, for an overall response rate of 66.7% (alpha 0.05, CI+/-17). The triplet association using this weekly alternating schedule is an active and well-tolerated outpatient regimen. Surgical removal of residual disease was considered in 5 patients and a radical resection was performed in 5 patients (147 %).