An Italian multicenter retrospective real-life analysis of patients with brain metastases from renal cell carcinoma: the BMRCC study.

BACKGROUND: The treatment of patients with brain-spread renal cell carcinoma (RCC) is an unmet clinical need, although more recent therapeutic strategies have significantly improved RCC patients' life expectancy. Our multicenter, retrospective, observational study investigated a real-world cohort of patients with brain metastases (BM) from RCC (BMRCC). PATIENTS AND METHODS: A total of 226 patients with histological diagnosis of RCC and radiological evidence of BM from 22 Italian institutions were enrolled. Univariate and multivariate models were performed to investigate the impact of clinicopathological features and multimodal treatments on both overall survival (OS) from the BM diagnosis and intracranial progression-free survival (iPFS). RESULTS: The median OS from the BM diagnosis was 18.8 months (interquartile range: 6.2-43 months). Multivariate analysis confirmed the following as positive independent prognostic factors: a Karnofsky Performance Status >70% [hazard ratio (HR) = 0.49, 95% confidence interval (CI) 0.26-0.92, P = 0.0026] and a single BM (HR = 0.51, 95% CI 0.31-0.86, P = 0. 0310); in contrast, the following were confirmed as worse prognosis factors: progressive extracranial disease (HR = 1.66, 95% CI 1.003-2.74, P = 0.00181) and only one line of systemic therapy after the BM occurrence (HR = 2.98, 95% CI 1.62-5.49, P = 0.029). Subgroup analyses showed no difference in iPFS according to the type of the first systemic treatment [immunotherapy (IT) or targeted therapy (TT)] carried out after the BM diagnosis (HR = 1.033, 95% CI 0.565-1.889, P = 0.16), and revealed that external radiation therapy (eRT) significantly prolonged iPFS when combined with IT (10.7 months, 95% CI 4.9-48 months, P = 0.0321) and not when combined with TT (9.01 months, 95% CI 2.7-21.2 months, P = 0.59). CONCLUSIONS: Our results suggest a potential additive effect in terms of iPFS for eRT combined with IT and encourage a more intensive multimodal therapeutic strategy in a multidisciplinary context to improve the survival of BMRCC patients.

Therapeutic implications of resistance to molecular therapies in metastatic colorectal cancer.

Metastatic colorectal cancer (mCRC) patients carrying KRAS mutated tumors do not benefit from epidermal growth factor receptor (EGFR)-targeted cetuximab- or panitumumab-based therapies. Indeed, the mutational status of KRAS is currently a validated predictive biomarker employed to select mCRC patients for EGFR targeted drugs. When patients fail standard 5-fluorouracil-, oxaliplatin-, irinotecan- and bevacizumab-based therapies, EGFR-targeted salvage therapy can be prescribed only for those individuals with KRAS wild-type cancer. Thus, clinicians are now facing the urgent issue of better understanding the biology of KRAS mutant disease, in order to devise novel effective therapies in such defined genetic setting. In addition to KRAS, recent data point out that BRAF and PIK3CA exon 20 mutations hamper response to EGFR-targeted treatment in mCRC, potentially excluding from treatment also patients with these molecular alterations in their tumor. This review will focus on current knowledge regarding the molecular landscape of mCRC including and beyond KRAS, and will summarize novel rationally-developed combinatorial regimens that are being evaluated in early clinical trials.

The impact of chemotherapy on overall survival and quality of life of patients with metastatic colorectal cancer: a review of phase III trials.

The treatment aims for advanced colorectal cancer (ACRC) patients are to prolong overall survival and to improve or maintain quality of life. Phase III studies published between 1997 and 2006 comparing different first or subsequent lines of treatment regimens were collected in order to evaluate the impact of these regimens on the overall survival and quality of life of ACRC patients. Our review shows that a first-line polychemotherapy regimen including oxaliplatin or irinotecan, in comparison with monochemotherapy, can improve overall survival. Second-line therapy and/or a cross-over between the first-line treatment arms can further modify the disease course. Hence, from the very beginning the treatment of ACRC patients must embrace a strategic approach taking into account all new agents available. Quality of life (QoL) was assessed in 52.3% of the first-line studies, while this was done in the whole group of studies evaluating pre-treated patients. QoL appears to be unrelated to the toxicity profile.

Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study).

BACKGROUND: The purpose of this phase II study was to evaluate the efficacy and safety of cetuximab combined with FOLFIRI as a first-line treatment of advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. PATIENTS AND METHODS: Untreated patients with confirmed advanced gastric or gastroesophageal adenocarcinoma received cetuximab at an initial dose of 400 mg/m(2) intravenously (i.v.) followed by weekly doses of 250 mg/m(2), CPT 11 180 mg/m(2) i.v. on day 1, LFA 100 mg/m(2) i.v. followed by 5-FU 400 mg/m(2) i.v. bolus, and 600 mg/m(2) i.v. 22-h continuous infusion on days 1 and 2 (FOLFIRI) every 2 weeks, for a maximum of 24 weeks, then cetuximab alone was allowed in patients with a complete response, partial response, or stable disease. Antitumor activity was assessed by computed tomography (CT) and positron emission tomography (PET) at baseline and after 6 weeks, and further by CT alone or CT and PET every 6 weeks. RESULTS: Thirty-eight patients were enrolled (median age 63.5 years, range 39-83; median Karnofsky performance status 90, range 70-100; stomach 89.5% and GEJ 10.5%; locally advanced disease 13.2% and metastatic disease 86.8%). All 38 patients were assessed for safety and survival, and 34 patients were assessed for overall response rates (ORR). The ORR was 44.1% [95% confidence interval (CI) 27.5% to 60.9%]. The median time-to-progression was 8 months (95% CI 7-9). At the median follow-up time of 11 months, 55.3% of patients were alive, with a median expected survival time of 16 months (95% CI 9-23). Grade 3-4 toxicity included neutropenia (42.1%), acne-like rash (21.1%), diarrhea (7.9%), asthenia (5.3%), stomatitis (5.3%), and hypertransaminasemia (5.3%). There was one (2.6%) treatment-related death. CONCLUSIONS: The combination of cetuximab and FOLFIRI is active in gastric and GEJ adenocarcinoma. The higher toxicity appears to be limited to neutropenia.