Clinical activity and tolerability of FOLFIRI and cetuximab in elderly patients with metastatic colorectal cancer in the CAPRI-GOIM first-line trial.

BACKGROUND: In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups. METHODS: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by age-groups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (≥65; ≥70 and ≥75 years). RESULTS: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were >65 years, 86 >70 years and 35 >75 years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were >65 years, 46 >70 and 17 >75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were ≥65 years; 29 were ≥70; 9 were ≥75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade ≥3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients ≥75 years and grade ≥3 fatigue (31% vs 20%, p=0.01) in patients <75 years. CONCLUSIONS: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade ≥3 diarrhoea and neutropaenia in patients ≥75 years and grade ≥3 fatigue in patients <75 years. TRIAL REGISTRATION NUMBER: 2009-014041-81.

Panitumumab after progression on cetuximab in KRAS wild-type metastatic colorectal cancer patients: a single institution experience.

AIMS AND BACKGROUND: Few data describe the activity of panitumumab after cetuximab-irinotecan-based regimen failure in patients with KRAS wild-type metastatic colorectal cancer (WT MCRC). METHODS: The aim of this study is to assess if panitumumab has some activity in this setting. RESULTS: We retrospectively analyzed 25 patients with KRAS WT MCRC who received panitumumab from July 2009 to January 2013 after progression on cetuximab. All patients had previously received cetuximab and irinotecan (20 patients) or oxaliplatin (5 patients). We withdrew cetuximab for intolerance in 4 patients (16%). Twenty-one patients (84%) who had previously responded to cetuximab (overall response rate [ORR] plus stable disease ≥5 months) received panitumumab off-label after progression on cetuximab because they were strongly motivated to continue treatment without chemotherapy. The median number of cycles of panitumumab was 7 (range 1-54). Only 20 patients were evaluable for ORR (5 patients received 1-2 cycles and then died). We observed 1 (5%) partial response, 5 (25%) stable disease, median duration 9 months. Median progression-free survival (PFS) and overall survival (OS) were 5 (3-28) and 8 (5-41) months, respectively. All patients were evaluable for toxicity. No patients developed anemia or neutropenia. One patient (4%) developed grade 2 thrombocytopenia, 8 patients (32%) grade 2-3 dry skin or rash, and 2 patients (8%) grade 2 nausea-vomiting (Common Terminology Criteria for Adverse Events version 4.03). CONCLUSIONS: Our data, with all the limits of a retrospective analysis, show longer PFS and OS as compared to other series in the same setting, demonstrating that panitumumab has treatment effectiveness in patients with KRAS WT MCRC who progressed on prior cetuximab. Further confirmatory prospective studies with a larger series of patients are necessary.

Clinical outcomes and cardiac safety of continuous antiHer2 therapy in c-erbB2-positive metastatic breast cancer patients.

BACKGROUND: To explore clinical outcomes and cardiac safety of continuous antiHer2 therapy. PATIENTS AND METHODS: This retrospective study evaluates overall survival (OS), time to treatment failure (TTF), and cardiac safety of 80 consecutive Her2-positive metastatic breast cancer (MBC) patients that received ≥ 12 months of therapy with trastuzumab, followed by lapatinib-based or trastuzumab-based therapy. RESULTS: All patients received trastuzumab as first antiHer2 therapy; 54% received lapatinib in the second or subsequent line. Median OS was 34 months (12-120 months). Median OS was 48 months in the subgroup of 43 patients who received lapatinib and 26 months in the 37 patients who did not. Median TTF was shorter for lapatinib. There were three cardiac events and trastuzumab-based chemotherapy (CT) was interrupted in one patient because left ventricular ejection fraction (LVEF) decreased to ≤ 40%. CONCLUSION: Continuous antiHer2 therapy provides good clinical outcomes, especially in those patients who received lapatinib. Cardiac dysfunction was a rare event, reversible, associated to trastuzumab and not related to treatment duration.

Poly (ADP-ribose) polymerase (PARP): rationale, preclinical and clinical evidences of its inhibition as breast cancer treatment.

INTRODUCTION: The chance to take advantage of genetic defects of cancer cells is a promising clinical tool in breast cancer therapy. Among the genetic aberrations, dysfunctions in DNA repair mechanisms are quite common and suitable for an attractive antitumor effect. Poly (ADP-ribose) polymerase I (PARP-1) is an enzyme with many functions in transcriptions and cell cycle regulation and in coordination of cellular response to DNA damage. Its involvement in tumorigenesis is witnessed by the overexpression found in different primary human tumors, where the increased enzymatic activity leads to cancer cell protection against DNA damage and instability. Therefore, activity of PARP and the opportunity to block it, mainly in cancer cells also deficient in other mechanisms of repair, are promising. AREAS COVERED: In this review, areas covered include the main DNA repair mechanisms, the role of PARP enzymatic activity in diverse cell pathways as well as the preclinical and clinical data with PARP inhibitors. EXPERT OPINION: Despite the theoretical role of PARP inhibitors as therapeutic strategy in specific subtypes of breast cancer (hereditary BRCA1/BRCA2 mutation-related cancers and sporadic triple-negative breast cancer), questions are still open. More exhaustive knowledge is needed about other important functions of PARPs in cellular homeostasis and about escape mechanisms of cancer cells to inhibitory effect of PARP inhibitors.

Metronomic chemotherapy against cancer: from paradigm to clinical practice?

We describe two paradigmatic cases where metronomic antitumor chemotherapy was successfully employed in patients not suitable for standard treatments. The first patient was affected by advanced soft tissue sarcoma but she also had ischemic cardiopathy. She received oral cyclophosphamide 50 mg once daily and methotrexate 2.5 mg bid twice weekly, obtaining a significant clinical response with a progression-free survival of 7 months. The second patient was over 70 years of age and suffered from metastatic gastric cancer. Because of his poor performance status he was given capecitabine 1500 mg daily, achieving a complete remission with a current disease-free survival of 13 months. In both cases no significant toxicities were observed.