Giuseppe Fornarini

Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised ‘GISCAD’ trial

BACKGROUND In advanced colorectal cancer, chemotherapy is usually administered without pauses and until progression but patients can experience cumulative toxicity and cannot tolerate a heavy therapeutic charge. AIM The aim of the present trial was to evaluate whether an intermittent chemotherapy with levo-leucovorin + 5-fluorouracil (5-FU) + irinotecan (CPT-11) was at least as effective as the same regimen given continuously, both administered until progression, in patients affected with advanced colorectal cancer and not previously exposed to chemotherapy for metastatic disease. PATIENTS, MATERIALS AND METHODS A total of 337 patients from 27 institutions were randomised between levo-leucovorin, 100/mg/m(2) i.v. + 5-FU; 400 mg/m(2) i.v. bolus + 5-FU; 600 mg/m(2) 22-h continuous infusion, days 1 and 2 + CPT-11; 180 mg/m(2) day 1, administered every 2 weeks 2 months on and 2 months off (arm A) and the same regimen administered continuously (arm B), until progression in both arms. The main end point was overall survival (OS), the secondary progression-free survival (PFS) and toxicity. RESULTS At a median follow-up of 41 months, OS was 18 months in arm A and 17 months in arm B [hazard ratio (HR), 0.88]. Also PFS was comparable in the two groups (6 months in both, with HR, 1.03), and even grades 3-4 toxicity (mainly myelosuppression, fever and diarrhoea) was similar. Second-line oxaliplatin-based treatment was administered in a similar percentage (66%) in the two arms. The median chemotherapy-free period (drug holiday) in arm A was 3.5 months. CONCLUSION Reducing the charge of therapy in this population did not diminish the efficacy of treatment. Further studies with this strategy, including biologicals, are warranted.

Incidence and clinical implications of venous thromboembolism in advanced colorectal cancer patients: the 'GISCAD-alternating schedule' study findings.

AIM OF THE STUDY To investigate the incidence and clinical implications of venous thromboembolism (VTE) in advanced colorectal cancer (ACC) patients treated and followed-up through a prospective randomised trial, comparing FOLFIRI chemotherapy given as an intermittent or as a continuous schedule. PATIENTS, MATERIALS AND METHODS A total of 266 patients were randomised by 15 experimental centres: 168 (63.2%) were males, median age: 64.6 years, age range: 37-76 years. Almost all (95.5%) patients had metastatic disease, while the remainder were classified with locally advanced irresectable disease. For 138 (51.9%) of the patients, the chemotherapy treatment was intermittent FOLFIRI and the remaining patients received continuous treatment. All toxicities, including VTE, were prospectively collected. RESULTS During the study protocol, the central data management gathered two cases of VTE. Our analysis retrieved 27 (10.2%) patients who developed a VTE, almost all (89%) during the course of chemotherapy treatment: 20 out of 27 during FOLFIRI, the remaining 7 during following lines or follow-up. VTE was the most frequent grade 3/4 toxicity. The incidence of VTE was significantly increased in the patients receiving continuous rather than intermittent treatment (HR 2.67, 95% CI 1.17-6.10; p<0.02). CONCLUSION VTE is a common complication among advanced colorectal cancer patients and yet this type of toxicity is widely underestimated. In this randomised trial, VTE was the most frequent grade 3/4 toxicity. Use of an intermittent schedule is associated with a reduced risk of developing VTE.

BRCA1 and BRCA2 mutations in central and southern Italian patients

Statement of findingsProtein truncation test (PTT) and single-strand conformation polymorphism (SSCP) assay were used to scan the BRCA1 and BRCA2 genes in 136 unrelated Italian breast/ovarian cancer patients. In the sample tested, BRCA1 and BRCA2 equally contributed to site-specific breast cancer patients who reported one to two breast cancer-affected first-/ second-degree relative(s) or who were diagnosed before age 40 years in the absence of a family history of breast/ovarian cancer. BRCA1 and BRCA2 mutations were mostly found in patients with disease diagnosis before and after age 50 years, respectively. Moreover, in cases with familial clustering of site-specific breast cancer, BRCA1 mostly accounted for tumours diagnosed before age 40 years and BRCA2 for tumours diagnosed after age 50 years. The BRCA1 and BRCA2 mutation spectrum was consistent with a lack of significant founder effects in the sample of patients studied.

Clinical Outcomes of Castration-resistant Prostate Cancer Treatments Administered as Third or Fourth Line Following Failure of Docetaxel and Other Second-line Treatment: Results of an Italian Multicentre Study

BACKGROUND The availability of new agents (NAs) active in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel treatment (abiraterone acetate, cabazitaxel, and enzalutamide) has led to the possibility of using them sequentially to obtain a cumulative survival benefit. OBJECTIVE To provide clinical outcome data relating to a large cohort of mCRPC patients who received a third-line NA after the failure of docetaxel and another NA. DESIGN, SETTING, AND PARTICIPANTS We retrospectively reviewed the clinical records of patients who had received at least two successive NAs after the failure of docetaxel. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The independent prognostic value of a series of pretreatment covariates on the primary outcome measure of overall survival was assessed using Cox regression analysis. RESULTS AND LIMITATIONS We assessed 260 patients who received one third-line NA between January 2012 and December 2013, including 38 who received a further NA as fourth-line therapy. The median progression-free and overall survival from the start of third-line therapy was, respectively, 4 mo and 11 mo, with no significant differences between the NAs. Performance status, and haemoglobin and alkaline phosphatase levels were the only independent prognostic factors. The limitations of the study are mainly due its retrospective nature and the small number of patients treated with some of the sequences. CONCLUSIONS We were unable to demonstrate a difference in the clinical outcomes of third-line NAs regardless of previous NA therapy. PATIENT SUMMARY It is debated which sequence of treatments to adopt after docetaxel. Our data do not support the superiority of any of the three new agents in third-line treatment, regardless of the previously administered new agent.

Real-world cabazitaxel safety: the Italian early-access program in metastatic castration-resistant prostate cancer.

AIM Cabazitaxel is a novel taxane that is approved for use in metastatic castration-resistant prostate cancer based on the Phase III TROPIC study, which showed improved overall survival with cabazitaxel/prednisone versus mitoxantrone/prednisone. A global early-access program was initiated in order to provide early access to cabazitaxel in docetaxel-pretreated patients and to obtain real-world data. PATIENTS & METHODS We report interim safety results from an Italian prospective, single-arm, multicenter, open-label trial of 218 patients receiving cabazitaxel 25 mg/m2 every 3 weeks plus prednisolone 10 mg/day, until disease progression, unacceptable toxicity, investigators decision or death. RESULTS Patients completing treatment received a median of six cabazitaxel cycles. The most common grade 3/4 adverse events were neutropenia (33.9%), leukopenia (15.6%), anemia (6%) and asthenia (6%). No peripheral neuropathy or nail disorders were observed. CONCLUSION These results confirm that cabazitaxel has a manageable safety profile in daily clinical practice and support its use in patients with prostate cancer who progress during or after a docetaxel-based therapy.

Bevacizumab in the treatment of metastatic colorectal cancer

Angiogenesis is essential for tumor growth and metastasis, and has become a useful target for novel biological agents. Vascular endothelial growth factor (VEGF) is one of the most important angiogenesis regulators. Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody recently approved in Europe and the USA for first- and second-line therapy (in combination with chemotherapy) for metastatic colorectal cancer. It has a proven impact on survival, as demonstrated in large Phase III clinical trials. Treatment with bevacizumab is generally well tolerated, with hypertension and arterial thromboembolic events being the main side effects. Currently, its role in the adjuvant setting, in combination with chemotherapy, is being evaluated in large Phase III clinical trials.

Two doses of NGR-hTNF in combination with capecitabine plus oxaliplatin in colorectal cancer patients failing standard therapies

Background: asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF), an agent selectively damaging the tumour vasculature, showed a biphasic dose–response curve in preclinical models. Previous phase I trials of NGR-hTNF indicated 0.8 and 45 μg/m2 as optimal biological and maximum-tolerated dose, respectively. Patients and methods: Two sequential cohorts of 12 colorectal cancer (CRC) patients who had failed standard therapies received NGR-hTNF 0.8 or 45 μg/m2 in combination with capecitabine–oxaliplatin (XELOX). Results: Median number of prior treatment lines was 3 in the low-dose and 2 in the high-dose cohort. Overall, 21 patients had been pretreated with oxaliplatin-based regimens. No grade 3–4 NGR-hTNF-related toxicities were observed. Grade 1–2 chills were reported in 43% and 40% of cycles in the low-dose and high-dose cohorts, respectively. In the low-dose cohort, one patient achieved a partial response and five had stable disease for a median of 4.6 months. In the high-dose cohort, six patients had stable disease for a median of 3.6 months. Three-month progression-free survival (PFS) rates were 50% and 33% in the low-dose and high-dose cohort, respectively. Three patients in low-dose cohort experienced PFS longer than PFS on last prior therapy. Conclusions: Both NGR-hTNF doses were safely combined with XELOX in pretreated CRC patients. Hint of activity was apparent only with low-dose NGR-hTNF.

Standard vs adapted sunitinib regimen in elderly patients with metastatic renal cell cancer: results from a large retrospective analysis.

BACKGROUND There are no data on the patterns of care and outcome of elderly patients with mRCC treated with sunitinib. In a retrospective study, we assessed the routine use of first-line sunitinib in mRCC patients aged ≥ 70 years. PATIENTS AND METHODS We reviewed the clinical files of 185 patients aged ≥ 70 years with mRCC treated with first-line sunitinib in 17 Italian oncology units from February 2006 to September 2011. One hundred twenty-three patients (66.5%) received a standard 50 mg/d for a 4 weeks on/2 weeks off regimen (SR), and 62 patients (33.5%) received an AR consisting of 37.5 mg/d for a 4 weeks on/2 weeks off in 67.7% of cases. RESULTS Median age was 74 years. Patients treated with an AR were older than those treated with the SR (P < .0001). In the overall population, the median progression-free survival (PFS) was 11 months, and the median overall survival (OS) was 25.5 months. Grade 3-4 toxicities occurred in 87 of 123 SR (70.7%) and 32 of 62 AR (51.6%), respectively; dose reductions were required in 82 SR (66.7%) and 26 AR (41.9%), respectively; discontinuations because of therapy-related adverse events occurred in 25 SR (20.3%) and 15 AR (24.2%), respectively. In multivariate analysis, only performance status and the Heng score were predictors of either PFS or OS. CONCLUSION Sunitinib is active and feasible in elderly patients with mRCC. A sunitinib AR could be considered as an option in selected older mRCC patients. The optimal treatment of frail patients with mRCC remains to be established.

Intra-arterial liver chemotherapy and hormone therapy in malignant insulinoma: case report and review of the literature.

Background Malignant insulinoma is a rare tumor. Metastatic disease confined to the liver can be treated with various locoregional treatments. Case report We report a case of a young woman who developed liver metastases twelve years following resection of a pancreatic insulinoma positive to anti-insulin antibodies. With five cycles of intra-arterial locoregional chemotherapy (fluorouracil and epirubicin) to the liver and monthly hormone therapy (octreotide) the patient obtained a clinical complete response. After twelve months she is still disease free. Conclusion Locoregional therapy for insulinoma metastatic to the liver might represent the treatment of choice; hepatic intra-arterial chemotherapy is an interesting therapeutic approach which deserves attention. The role of somatostatin analogs is limited to symptom control.

First-Line PAzopanib in NOn–clear-cell Renal cArcinoMA: The Italian Retrospective Multicenter PANORAMA Study

Introduction Pazopanib is a standard first‐line treatment for metastatic clear‐cell renal cell carcinoma (ccRCC). Very few data on its activity in non–clear‐cell renal cell carcinoma (nccRCC) are currently available. The aim of this study was to retrospectively analyze efficacy and toxicity of pazopanib in nccRCC patients. Patients and Methods Records from advanced nccRCC patients (consecutive sample) treated with first‐line pazopanib between 2010 and 2015 at 17 Italian centers were reviewed. Response rate, progression‐free survival (PFS), and overall survival (OS) were evaluated. Univariate and descriptive analyses were performed. Results Thirty‐seven patients with nccRCC were treated with first‐line pazopanib; 51% had papillary histology, 24% chromophobe, 22% unclassified, and 3% had Xp11.2 translocation. Dose reductions/temporary interruptions for toxicity were required in 46% of cases. Grade (G) 3/4 toxicity was seen in 32%, G1/2 in 89% of cases; 81% achieved disease control, with 10 partial responses (27%) and 20 cases of stable disease (54%); 16% of patients had disease progression as best response. Median PFS and OS were 15.9 and 17.3 months, respectively. In univariate analysis, nephrectomy (P = .020), Memorial Sloan Kettering Cancer Center (MSKCC) score (P < .001), basal neutrophil/lymphocyte ratio (NLR; P = .009) and performance status (PS) (P = .001) were associated with PFS; MSKCC score (P < .001), International Metastatic Renal Cell Carcinoma Database Consortium score (P = .003), PS (P < .0001), nephrectomy (P = .002), histology (P = .035), dose reductions/interruptions (P = .039), best response to treatment (P < .001), and NLR (P = .008) were associated with OS. Conclusion In nccRCC patients, treatment with pazopanib was effective and feasible; dose reductions required for toxicity were similar as expected in ccRCC. Micro‐Abstract In this retrospective study we focused on a subgroup of rare tumors, such as non–clear‐cell renal cancers, with the aim to provide evidence of activity and feasibility of a multityrosine kinase inhibitor, pazopanib, as a first‐line treatment alternative to the widely used sunitinib. Our conclusions support the use of pazopanib in this subgroup, awaiting prospective results of ongoing clinical trials.