Enrico Cortesi

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

BACKGROUNDnIn 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.nnnAIMnThe 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.nnnPATIENTS, MATERIALS AND METHODSnA 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.nnnRESULTSnAt 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.nnnCONCLUSIONnReducing the charge of therapy in this population did not diminish the efficacy of treatment. Further studies with this strategy, including biologicals, are warranted.

Early detection, prevention and management of cutaneous adverse events due to sorafenib: Recommendations from the Sorafenib Working Group

Cutaneous adverse events commonly reported with tyrosine kinase inhibitors (TKIs) in the treatment of malignancies, represent an important clinical concern since they can limit the optimal use of these novel drugs. Although there are numerous reports in the literature of these events there are no practical guidelines on how they should be managed. The Sorafenib Working Group (SWG) was established with the objective of developing recommendations to allow the early detection, prevention and management of cutaneous adverse events in everyday clinical practice. The SWG was a multidisciplinary team made up of experts in the field who were closely involved in the sorafenib clinical development program. This review provides an overview of the nature and incidence of cutaneous adverse events which manifest with sorafenib treatment and provides recommendations for their early detection and effective management in clinical practice.

Treatment of peritoneal carcinomatosis from breast cancer by maximal cytoreduction and HIPEC: a preliminary report on 5 cases.

Although peritoneal carcinomatosis from breast cancer is a rare event it frequently causes morbidity and mortality. Current literature provides scarce information on its management. We report outcomes in 5 patients (mean age 59.4 years) with peritoneal carcinomatosis from breast cancer treated with maximal cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) by the closed technique, at 40 °C for 1 h with cisplatin 75 mg/m(2). The primary breast cancer was a ductal carcinoma in 3 patients and a lobular carcinoma in 2. Mean peritoneal cancer index was 20.2. In 4 of the 5 patients surgery achieved macroscopic complete cytoreduction. One patient died of disease at 56 months, 4 are alive and disease-free at 13, 45, 74 and 128 months. These encouraging outcomes suggest that cytoreduction and HIPEC is a promising approach to offer to highly selected patients with peritoneal carcinomatosis from breast cancer and that this approach merit investigation in a larger series.

A Phase II Study of Cetuximab/Irinotecan in Patients with Heavily Pretreated Metastatic Colorectal Cancer: Predictive Value of Early Specific Toxicities

BACKGROUNDnThis study was designed to evaluate the predictive value of early specific toxicities on efficacy of weekly irinotecan/cetuximab administered as salvage therapy in patients with metastatic colorectal cancer (CRC) refractory to oxaliplatin and irinotecan.nnnPATIENTS AND METHODSnSeventy patients received a regimen composed of weekly irinotecan 125 mg/m2 as a 1-hour intravenous infusion and cetuximab 400 mg/m2 infused over 2 hours as the initial dose and 250 mg/m2 infused over 1 hour for subsequent administrations. A single treatment cycle was composed of 4 weekly irinotecan infusions followed by 2 weeks of rest. The predictive value of adverse events (AEs) attributable to cetuximab (rash) and major toxicities attributable to irinotecan (gastrointestinal [GI] and hematologic) were observed after the first cycle of treatment and, therefore, correlated to activity and efficacy of cetuximab and weekly irinotecan.nnnRESULTSnSixty-six of 70 patients received >or= 1 cycle of chemotherapy and were therefore evaluable for response. Overall, toxicity observed was generally mild and manageable. According to an intent-to-treat analysis, a partial response was exhibited in 15.7% of patients, with a median progression-free survival (PFS) and median overall survival time of 4 months and 9 months, respectively. As expected, PFS (P = .01) and median survival (P = .04) correlated strongly with the presence and severity of the rash. Surprisingly, the presence of at least moderate hematologic and GI toxicity was associated with improved PFS (P = .03).nnnCONCLUSIONnOur data suggest that irinotecan-induced AEs might predict a better outcome in advanced CRC. This finding would identify a different subset of patients-those likely to benefit from a renewed sensitivity to irinotecan induced by cetuximab.

Negative prognostic factors and resulting clinical outcome in patients with metastatic renal cell carcinoma included in the Italian nivolumab-expanded access program

AIMnWe report the outcomes observed with nivolumab in metastatic renal cell carcinoma patients with poor prognostic features enrolled in the Italian expanded access program.nnnPATIENTS & METHODSnNivolumab was available for patients who relapsed after at least one prior systemic treatment in the advanced or metastatic setting.nnnRESULTSnOf 389 patients, 32 (8%) had brain metastasis, 129 (33%) had liver and 193 (50%) had bone metastasis. These subpopulations achieved a disease control rate of 53, 45 and 47%, respectively. Fifty-one patients had G4 tumor, and they showed 23% objective response rate. The safety profile of the subgroups was in line with the expanded access program population. No new safety signals were reported.nnnCONCLUSIONnPatients with poor prognostic features may derive relevant benefits from nivolumab.

Safety and efficacy of nivolumab for metastatic renal cell carcinoma: real-world results from an expanded access programme

To report the safety and efficacy results of patients enrolled in the Italian Nivolumab Renal Cell Cancer Expanded Access Programme.

The Role of Systemic Chemotherapy

Development of peritoneal carcinomatosis (PC) in metastatic solid tumors is associated with poor prognosis and is usually more frequent in gynecological and gastrointestinal (GI) malignancies. No standard systemic or local treatment can eradicate PC definitively, and chemotherapy (CHT) and surgery alone seem unable to improve patient survival, so that PC is usually considered a terminal condition [1]. PC is commonly observed in ovarian cancer (OC), in which the spread of disease is primarily locoregional and then to visceral sites. In this pathology, complete PC removal is associated with improved survival. In GI tumors, such as gastric and colorectal cancer (CRC), PC is seen less frequently, and its cytoreduction is not considered mandatory due to the high percentage of short-term recurrence and no effect on survival rates [2]. Systemic CHT has a limited impact on the peritoneum, probably because the peritoneal cavity is a “pharmacological sanctuary” in which intravenously administered drug diffusion is difficult. This is due to a blood-peritoneal barrier, composed of stromal tissues between mesothelial and endothelial cells, of ∼90-μm thickness, which is difficult to overcome by many systemic agents [3]. Given this low effectiveness of systemic therapies or surgery alone and the necessity to improve the local action of drugs, in recent decades, new multimodal approaches have been developed based on the association of cytoreductive surgery (CRS) with intravenous (IV) (neoadjuvant or adjuvant) and/or intraperitoneal (IP) administration of CHT (IP-CHT). Different combinations and integrations of these treatments have been proposed and evaluated in randomized or nonrandomized trials in many cancer types.

BRAFV600E mutation positive metastatic melanoma in a young woman treated with anti-BRAF/anti MEK combination: a case report.

Compassionate Use program. Just after one month of treatment she reported clinical benefit in terms of deambulation improvement and pain relief. During the second month of therapy the treatment with Dabrafenib was withdrawn for some days, due to two episodes of hyperpyrexia up to 39°C, treated with Paracetamol. Progressively the antiBRAF drug was reintroduced with no further interruption. The CT/PET performed after three and six month of treatment showed a good response to the therapy with a dimensional decrease and SUV reduction of more than 50% in all target lesions. Currently the patient is continuing the treatment; her ECOG PS is 0. She does not require any antalgic drugs. Our aim is obtain the maximum reduction to allow a surgical approach.