[Show abstract][Hide abstract] ABSTRACT: We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy.
This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC. Patients received three biweekly cycles of OXATOM/FUFA during RT. Bevacizumab was given 2 weeks before the start of chemo-radiotherapy, and on the same day of chemotherapy for 3 cycles (concomitant-schedule A) or 4 days prior to the first and second cycle of chemotherapy (sequential-schedule B). Primary end point was pathological complete tumor regression (TRG1) rate.
The accrual for the concomitant-schedule was early terminated because the number of TRG1 (2 out of 16 patients) was statistically inconsistent with the hypothesis of activity (30%) to be tested. Conversely, the endpoint was reached with the sequential-schedule and the final TRG1 rate among 46 enrolled patients was 50% (95% CI 35%-65%). Neutropenia was the most common grade ≥3 toxicity with both schedules, but it was less pronounced with the sequential than concomitant-schedule (30% vs. 44%). Postoperative complications occurred in 8/15 (53%) and 13/46 (28%) patients in schedule A and B, respectively. At 5 year follow-up the probability of PFS and OS was 80% (95%CI, 66%-89%) and 85% (95%CI, 69%-93%), respectively, for the sequential-schedule.
These results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.
[Show abstract][Hide abstract] ABSTRACT: Background: Elderly patients (65 years and over) develop often, sometimes predominantly , esophageal, gastro esophageal junction, gastric and pancreatic cancer (gastrointestinal non colorectal cancer). Most clinical trials exclude elderly patients from accrual considering aging a potential risk factor. In fact an elderly patient can develop greater toxicity than a younger patient from oncologic treatments (chemotherapy, radiotherapy, target therapies) due to a worse function of vital organs. Methods: We analyzed the current scientific literature, searching articles since 1990, about gastrointestinal non colorectal cancer in elderly patients, to establish if they need a specific management, different from younger patients. Results: Data from analyzed studies, both gastro esophageal and pancreatic cancer, are contradictory. In some reports elderly patients don't seem to bring greater toxicity than younger. Other trials consider that dose-adjustment to renal function is need in elderly patients, but these trials are very few. Other trials may include several biases such as accrual of "only fit" elderly patients. Conclusions: It is very important in elderly patients with higher risk of toxicity, to distinguish the aim of cancer treatment: is it curative or palliative? Furthermore, in this type of patients the most important target is probably maintaining the quality of life especially in gastric and pancreatic cancer that often started as advanced disease. For these valuation chronological age alone is not sufficient. Another very important factor in elderly cancer patients is the geriatric assessment including not only age but also functional, social and mental status.
[Show abstract][Hide abstract] ABSTRACT: Background:
Preoperative treatment of resectable liver metastases from colorectal cancer (CRC) is a matter of debate. The aim of this study was to assess the feasibility and activity of bevacizumab plus FOLFIRI in this setting.
Patients aged 18–75 years, PS 0–1, with resectable liver-confined metastases from CRC were eligible. They received bevacizumab 5 mg kg−1 followed by irinotecan 180 mg m−2, leucovorin 200 mg m−2, 5-fluorouracil 400 mg m−2 bolus and 5-fluorouracil 2400 mg m−2 46-h infusion, biweekly, for 7 cycles. Bevacizumab was stopped at cycle 6. A single-stage, single-arm phase 2 study design was applied with 1-year progression-free rate as the primary end point, and 39 patients required.
From October 2007 to December 2009, 39 patients were enrolled in a single institution. Objective response rate was 66.7% (95% exact CI: 49.8–80.9). Of these, 37 patients (94.9%) underwent surgery, with a R0 rate of 84.6%. Five patients had a pathological complete remission (14%). Out of 37 patients, 16 (43.2%) had at least one surgical complication (most frequently biloma). At 1 year of follow-up, 24 patients were alive and free from disease progression (61.6%, 95% CI: 44.6–76.6). Median PFS and OS were 14 (95% CI: 11–24) and 38 (95% CI: 28–NA) months, respectively.
Preoperative treatment of patients with resectable liver metastases from CRC with bevacizumab plus FOLFIRI is feasible, but further studies are needed to define its clinical relevance.
British Journal of Cancer 04/2013; 108(8). DOI:10.1038/bjc.2013.140 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Anti-EGFR monoclonal antibodies have shown efficacy in the treatment of metastatic colorectal cancer (mCRC). One of the mechanism is the antibody-dependent cell-mediated cytotoxicity (ADCC) in which Fc region of the antibody binds to the Fc gamma receptors (FcγR) expressed by immune cells. The present study investigated the association between single nucleotide polymorphisms of FcγRIIa and FcγRIIIa and clinical outcome in mCRC treated with anti-EGFR antibodies.
Seventy-four consecutive patients with mCRC were analyzed. The genotypes for FcγRIIa-131 histidine (H)/arginine (R), FcγRIIIa-158 valine (V)/phenylanaline (F) polymorphisms were evaluated by directly sequencing. Multiplex allele-specific polymerase chain reaction was performed for FcγRIIIa-158 valine (V)/phenylanaline (F). Correlations between FcγR polymorphisms, baseline patient and tumor features were studied by contingency tables and the chi-square test. The Kaplan-Meier product limit method was applied to the progression-free survival (PFS) curves. Univariate analysis was performed with the log-rank test. Cox proportional-hazards regression was used to analyze the effect of multiple risk factors on PFS.
FcγRIIIa polymorphisms were significantly associated with response to anti-EGFR-based therapy in 49 patients with kras wt tumors (p=0.035). There was not association with response for FcγRIIa polymorphisms. Furthermore, obtained results suggested that prognosis is particularly unfavorable for patients carrying the FcγRIIIa-158F/F genotype (median PFS V/V, V/F, F/F: 18.2 vs 17.3 vs 9.4 months). No prognostic ability was identified for FcγRIIa polymorphisms.
In mCRC patients the presence of FcγRIIIa-F can predict resistance to anti-EGFR therapy and unfavorable prognosis.
Journal of Translational Medicine 11/2012; 10(1):232. DOI:10.1186/1479-5876-10-232 · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In many cases, early-stage breast cancer is now curable, and metastatic disease can be chronic consequent to the advent of new therapeutic tools. Unfortunately, some treatments have been associated with adverse cardiovascular effects. Indeed, in many breast cancer survivors, the risk of cardiovascular disease is higher than the risk of cancer recurrence. The clinical challenge of preventing cardiovascular complications in patients undergoing antineoplastic treatment has two aims, more effective life-saving treatment of patients, and prevention of morbidity and cardiovascular mortality in the short term and long term. The aim of the present study is to review the rapidly evolving therapeutic strategies designed to treat early-stage breast cancer. The review highlights the need for more data on the impact of new biological drugs (targeted therapy) on the cardiovascular apparatus. Finally, given the complexity of targeted and other novel treatments, cancer patients are best managed through a multidisciplinary approach.
Journal of Cardiovascular Medicine 12/2010; 11(12):861-8. DOI:10.2459/JCM.0b013e328336b4c1 · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The standard treatment of CRC patients with hepatic metastases is systemic chemotherapy; however, 5-year survival is disappointingly poor despite recent advances. On the other hand, in patients who undergo immediate radical surgical resection of hepatic metastases, 5-year survival reaches 30-40%. Unfortunately, only 15-20% of patients with hepatic metastases are initially eligible for a radical surgical approach. The majority of patients undergoing liver resection relapse after surgery. For this reason, new onco-surgery approaches have been investigated in recent years and the addition of biological agents to chemotherapy, such as bevacizumab and cetuximab, and the improvements of surgical techniques have opened a new scenario in the management of colorectal liver metastases. Recently, the EORTC trial has demonstrated that perioperative chemotherapy (Folfox regimen) is feasible and improves progression-free survival in patients with resectable liver metastases. Chemotherapy and surgery can finally collaborate. In the unresectable setting, the association of chemotherapy with bevacizumab and cetuximab is particularly promising in improving resectability rate. In particular, K-RAS is a molecular response predictive factor that could be particularly useful in selecting the best treatment option in patients with unresectable liver disease.
Cancer Chemotherapy and Pharmacology 03/2010; 66(2):209-18. DOI:10.1007/s00280-010-1297-x · 2.57 Impact Factor