Angelo Nacci

Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: The CAPPA-2 study

Platinum-based chemotherapy is the standard treatment for patients with advanced non-small cell lung cancer (NSCLC), but the evidence of its efficacy among ECOG performance status (PS)2 patients is weak because these patients are usually excluded from clinical trials; concern exists about tolerability and feasibility of standard chemotherapy in these patients. No prospective randomized trial has tested the addition of cisplatin to single-agent chemotherapy in patients with advanced NSCLC and PS2. CAPPA-2 was a multicenter, randomized phase 3 study for first-line treatment of PS2 patients with advanced NSCLC. Patients, aged 18-70, were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes (TNM VI edition) and adequate organ function. Patients in standard arm received gemcitabine 1200 mg/m(2) days 1 and 8. Patients in experimental arm received cisplatin 60 mg/m(2) day 1 plus gemcitabine 1000 mg/m(2) days 1 and 8. All treatments were repeated every 3 weeks, up to 4 cycles, unless disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). To have 80% power of detecting hazard ratio (HR) 0.71, corresponding to an increase in median OS from 4.8 to 6.8 months, 285 deaths were required. The study was stopped in June 2012 after the enrolment of 57 patients, due to the slow accrual and the report of positive results from a similar study. Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin plus gemcitabine (HR 0.52, 95% CI 0.28-0.98, p = 0.039). Combination chemotherapy produced longer PFS (median 1.7 vs. 3.3 months, HR 0.49, 95% CI 0.27-0.89, p = 0.017) and higher response rate (4% vs. 18%, p = 0.19), without substantial increase in toxicity. The addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC.

Recent advances in the treatment of hormone receptor positive HER2 negative metastatic breast cancer

Endocrine therapy is the recommended systemic therapy for hormone receptor (HR) positive metastatic breast cancer (MBC). However so far the limited number of endocrine agents and the onset of endocrine resistance have severely limited the therapeutic options for this patients. In the last years many targeted agents have been investigated to prevent or overcome endocrine resistance; only a few of them have been found effective in HR positive MBC, such as everolimus, CK4/6 inhibitors and HDAC inhibitors. Furthermore, translational medicine studies using next generation sequencing technologies have evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with targeted agents benefit. In some studies predictive biomarkers have been identified and many ongoing studies are evaluating the efficacy of targeted drugs in HR positive MBC patients selected for biomarkers or stratified by pathways amplification.

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.

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

Abstract 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.

Updating data about a first-line modified schedule of gemcitabine with a lower dose than standard in very elderly or PS 2 patients with advanced non-small cell lung cancer.

e18031 Background: Monochemotherapy with gemcitabine (Gem) is often the treatment of choice in elderly or poor performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Our study was aimed to assess the efficacy and tolerability of a modified schedule of Gem using a lower dose than standard. METHODS From May 2009 through December 2010, fifty patients (43 males and 7 females with a median age of 76 years (64 to 85) with advanced NSCLC (stage IIIB 34,0% and IV 66,0%) were enrolled. Histology were: squamous 39,6%, adenocarcinoma 31,2%, large cell 6,2 %, undifferentiated 4,2 %, undetermined 18,8%. Only eight patients (16,0%) had a WHO PS 0 whereas nineteen (38,0%) were PS 1 and eleven (46,0%) PS 2. All patients received first-line chemotherapy with 6 cycles of Gem 1000 mg/sq on days 1 and 8 every 4 weeks. RESULTS At the time of analysis 35 patients were evaluable for response. Partial response (PR) was achieved in 7 patients (20,0%), stable disease > 12 weeks (SD) in 16 (45,7%) whereas 12 had progressive disease (34,3%). Importantly, the clinical benefit rate (PR + SD) was 65,7%. Quality of life was mesured with EORTC QoL 3.0 Questionary. Both pain and PS improved in 6 patients (17,1%) whereas 19 (54,2%) had an improvement in pain with no worsening of PS. We observed only grade 2 NCCTs version 3 haematological toxicities including anemia, leucopenia, neutropenia and trombocytopenia. Not febrile neutropenia occurred in 4 patients (11,4%). Overall, we did not observe any not-haematological treatment-related event. CONCLUSIONS Our data show that a modified schedule of Gem with a lower dose intensity than standard may be beneficial in terms of both disease control and tolerability when employed in elderly or PS 2 patients with advanced NSCLC. These data are similar to published data in elderly. At ASCO meeting we present all data about 50 pts enrolled.

Optimizing outcomes in patients (pts) with HER2+ metastatic breast cancer (MBC) through continuous inhibition of HER2 activity: A single institution study.

e11067 Background: Anti-HER2 therapies are effective in HER2+ breast cancer; even if resistance occurs, continued HER2 inhibition is required for antitumor effect. There are no definitive data on the clinical benefit of continued trastuzumab (T) beyond progression in MBC and the optimal duration of T in pts with long-term control of disease. This study explores outcomes of MBC pts treated with T in multiple sequential lines. METHODS From 2001 to 2009 we evaluated OS and cardiac toxicity in 50 pts with HER2+ (ASCO/CAP criteria) MBC who received T-based therapy for ≥ 12 months. OS was measured from the beginning of T-based CT to the last follow up visit or death. Cardiac event was any decline in LVEF by >10% from baseline or drop to <50%, III/IV NYHA CHF, new onset angina myocardial infarction, significant arrhytmias or sudden cardiac death. RESULTS Median age was 59 (33-79), visceral disease in 60% and multiple site in 34%; 8 (16%) pts developed brain metastasis during T. All had overexpression of HER2 by IHC, FISH was centrally assessed in 78% and not amplified in 8%. T was administered for a median duration of 23 months (12-120). All pts received a median of 2 CT regimens (1-8); 9 out of 25 pts with endocrine responsive disease received endocrine therapy plus T after at least 1 CT regimen; 20 pts (40%) experienced CR and received T alone as maintenance for a median duration of 9 months (3-46); 23 (46%) pts received lapatinib, when the drug was licensed in Italy, after failure of at least two T-based CT lines. Median OS was 34 months (12-120). There were 3 cardiac events (6%) and consisted in asymptomatic decrease in LVEF to less than 50%; T-based CT was interrupted in 1 patient because of LVEF decrease to ≤ 40%. CONCLUSIONS T in multiple sequential lines demonstrated highly favorable outcomes in MBC pts. Overall the incidence of cardiac dysfunction was low.