Antiangiogenic scheduling of lower dose chemotherapy in elderly patients with advanced colorectal cancer
Authors: Ignazio Ugo Carreca, Fernanda Bellomo, Giuseppe Bronte, Dario Piazza, Sergio Rizzo, Salvatore Russo, Annapaola Carreca, Lodovico Balducci
Journal: Clinical Cancer Research (2006)

B78  Background: in elderly patients (EP) decreased functionality of multiple organ systems may affect pharmacokinetics and pharmacodynamics of drugs. Colorectal cancer (CRC) incidence arise in EP who show enhanced susceptibility to cytotoxic therapy, especially for bone-marrow, mucosal, CNS and neuroperipheral (NPH) toxicity (TOX). A way to prevent these effects could be metronomic chemotherapy, which is a variation of dose-dense therapy, with a cumulative dose significantly lower than maximum tolerated dose. Aim: to determine tolerability and efficacy of a new schedule of capecitabine (XEL) in combination with oxaliplatin (OX) with antiangiogenic intent, compared with the standard XELOX schedule. Methods: a totally of 45 EP (median age: 70; range: 67-75) with stage C Dukes CRC were treated after written informed consent obtained. 23 pts (Group A) received XEL 1000 mg/sqm b.i.d from day 2 to day 15 + OX 130 mg/sqm infused i.v. on day 1 (Schedule A). Another group of 22 pts (Group B) received XEL 1000 mg b.i.d (flat dose) from day 2 to day 15 + OX 130 mg/sqm infused i.v. on day 1 (Schedule B). We evaluated GFR of each patient. Drug9s dosage was calculated according to patients9 body surface adjusted with Kintzel-Dorr formula. All patients were evaluated for Clinical Response according to WHO criteria and common treatment-related adverse events as haematological, liver, mucosal, CNS and NPH TOX, nausea and vomiting and hand/foot syndrome, according to the NCI-CTC. All patients were also evaluated for ADL/IADL both with ECOG Performance Status and number of comorbidities, such as haematological, liver, heart diseases and diabetes. Plasma VEGF concentrations were analyzed by ELISA, at baseline (B) and at the end of treatment (E). Results: both Group A and B were evaluated at the end of treatment. Group A pts received about 80% of expected dose only. Group B received full expected dose. Clinical evaluation at the end of treatment showed in pts of Group A: 1 Complete Response, 5 Partial Responses (PR) and 7 Stable Diseases (SD) with a Response Rate of 23% and Clinical Benefit (CB) of 59%. In Group B pts 3 PR and 13 SD were achieved with 13% RR and 70% CB. Main toxicities were haematological, neurological, liver and HFS. There were no grade 3/4 toxicities in Group B. VEGF9s mean values (pg/ml): Group A: baseline = 563 (386 - 789); end = 489 (281 - 648); p=0,062. Group B: baseline = 522 (331 - 750); end = 336 (208 - 697); p=0,001. Conclusions: XEL flat dose + OX (schedule B) seems to be safe and highly effective in CRC EP compared to standard dose chemotherapy (A). Further, XEL flat dose (Lokich, Canc. Invest., 2004) improves PTS compliance for oral delivery (no needs to different tablets for size and concentration to reach the expected dose). No delivery delay occurred in schedule B pts. Even if RR was lower in Group B pts, their CB was higher then Group A pts. These results and our previous findings could confirm that treating cancer with a low continuous dose seems to be a suggestive choice to turn cancer into chronic disease by switching on the antiangiogenic mechanism as demonstrated in the recent paper of Kerbel (Science, May 2006). Authors believe that larger randomized clinical studies will be necessary to assess time to treatment failure and overall survival.