Francesco De Rosa

Metronomic Capecitabine in Advanced Hepatocellular Carcinoma Patients: A Phase II Study

UNLABELLED Anti-angiogenic treatment with targeted agents is effective in advanced hepatocellular carcinoma (HCC). This trial evaluated the safety and efficacy of metronomic capecitabine in patients with HCC. METHODS This single-institution phase II trial included 59 previously untreated patients with advanced HCC and 31 patients resistant to or intolerant of sorafenib. The treatment schedule was capecitabine 500 mg twice daily until progression of disease, unacceptable toxicity level, or withdrawal of informed consent. Progression-free survival (PFS) was chosen as the primary endpoint. RESULTS A total of 59 previously untreated and 31 previously treated patients with HCC were enrolled. The first cohort achieved a median PFS of 6.03 months and an overall survival (OS) of 14.47 months. Two patients achieved a complete response, 1 patient achieved partial response, and in 30 patients, stable disease was the best outcome. The second cohort achieved a median PFS of 3.27 months and a median OS of 9.77 months. No complete or partial responses were observed, but 10 patients had stable disease. An unscheduled comparison of the first cohort of patients with 3,027 untreated patients with HCC from the Italian Liver Cancer (ITA.LI.CA) database was performed. One-to-one matching according to demographic/etiologic/oncologic features was possible for 50 patients. The median OS for these 50 capecitabine-treated patients was 15.6 months, compared with a median OS of 8.0 months for the matched untreated patients (p = .043). CONCLUSION Metronomic capecitabine is well tolerated by patients with advanced HCC and appears to have activity both in treatment-naive patients and in those previously treated with sorafenib.

Incidence of bacterial and fungal infections in newly diagnosed acute myeloid leukaemia patients younger than 65 yr treated with induction regimens including fludarabine: retrospective analysis of 224 cases

Objectives:  Infections are the major cause of morbidity and mortality in patients with acute myeloid leukaemia (AML). They primarily occur during the first course of induction chemotherapy and may increase the risk of leukaemia relapse, due to a significant delay in consolidation therapy. The intensification of induction chemotherapy and the use of non‐conventional drugs such as fludarabine are considered responsible for the increased risk of infections.

Neoadjuvant Treatment in Rectal Cancer: Actual Status

Neoadjuvant (preoperative) concomitant chemoradiotherapy (CRT) has become a standard treatment of locally advanced rectal adenocarcinomas. The clinical stages II (cT3-4, N0, M0) and III (cT1-4, N+, M0) according to International Union Against Cancer (IUCC) are concerned. It can reduce tumor volume and subsequently lead to an increase in complete resections (R0 resections), shows less toxicity, and improves local control rate. The aim of this review is to summarize actual approaches, main problems, and discrepancies in the treatment of locally advanced rectal adenocarcinomas.

Adjuvant Systemic Chemotherapy After Putative Curative Resection of Colorectal Liver and Lung Metastases

OBJECTIVE Marginal statistical evidence of efficacy of adjuvant and/or perioperative chemotherapy after resection of colorectal metastases exists, but formal recommendations are still lacking. The present study evaluated the adjuvant systemic chemotherapy after the first resection of liver and lung colorectal cancer metastases. PATIENTS AND METHODS We retrospectively reviewed data of 181 consecutive unselected patients with R0 resection of colorectal metastases treated simultaneously at 2 institutions from 1997 to 2004. Patients > 75 years old, with an Eastern Cooperative Oncology Group Performance Status Score ≥ 2 or unfit for adjuvant chemotherapy were excluded from the analysis. The decision on chemotherapy after surgery was left to the patient in the absence of conclusive data on the efficacy of adjuvant chemotherapy in this setting. A total of 151 patients (131 with liver metastases, 20 with lung metastases), 78 of whom underwent adjuvant chemotherapy, were evaluable for disease-free survival (DFS) and overall survival. The main prognostic factors for DFS after resection of colorectal cancer metastases were investigated in univariate and multivariate analyses. RESULTS At the univariate analysis, the number of resected lesions, lesion volume, disease-free interval and adjuvant systemic chemotherapy were the only significant prognostic factors. At multivariate analysis, only adjuvant chemotherapy and disease-free interval were independent prognostic factors (hazard ratios 1.66 and 1.62, respectively). The median DFS of patients who underwent systemic adjuvant chemotherapy was 16 months compared with 9.7 months for patients with observation alone (hazard ratio 1.56). Estimated 5-year DFS was 17.4% and 10.5% for treated and untreated patients, respectively. CONCLUSION Adjuvant chemotherapy after metastasectomy in patients with colorectal cancer showed a significant benefit for DFS.

Durable complete response of hepatocellular carcinoma after metronomic capecitabine.

Background Hepatocellular carcinoma (HCC) is a highly vascular tumor which is poorly responsive to standard systemic chemotherapy. Recently, various antiangiogenic targeted agents have shown promising activity at different levels of evidence in patients with advanced HCC, suggesting that such treatments might be effective. Case report Since chemotherapy administered with metronomic schedules inhibits angiogenesis, we treated a 64-year-old man with advanced HCC with metronomic capecitabine. After only two months of treatment the HCC nodules disappeared on ultrasonography. This finding was confirmed by a computed tomography scan. After more than three years the patient is still in treatment with minimal toxicity and maintains a complete remission. Conclusions Our case report suggests that metronomic capecitabine may be effective in advanced HCC patients while being also well tolerated. This is important, given the frequent comorbidities of HCC patients. Free full text available at www.tumorionline.it

Antitumoral Efficacy of the Protease Inhibitor Gabexate Mesilate in Colon Cancer Cells Harbouring KRAS, BRAF and PIK3CA Mutations

The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor gabexate mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that gabexate mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of gabexate mesilate and cetuximab in combination was found to be not superior than that observed with gabexate mesilate as single agent. Overall, these preliminary findings suggest that gabexate mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as mono-therapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexate mesilate mechanism of action in CRC cells are therefore warranted.

Can the tyrosine kinase inhibitors trigger metabolic encephalopathy in cirrhotic patients

Sorafenib is the standard treatment of advanced hepatocarcinoma (HCC) in cirrhotic patients with preserved liver function. It shares many adverse effects with other tyrosine‐kinase (TK) inhibitors and antiangiogenic drugs. TK inhibitors could have a direct toxicity on CNS, both by interfering with TK‐related pathways and by inhibiting angiogenesis.

Durable Complete Response to Frontline Docetaxel in an Advanced Prostate Cancer Patient with Favourable CYP1B1 Isoforms: Suggestion for Changing Paradigms?

Docetaxel is currently indicated for androgen-independent, metastatic prostate cancer; there is also evidence demonstrating the role of CYP1B1 in modulating the activity of the drug. We present the case of a man with residual disease after radical prostatectomy treated successfully with docetaxel chemotherapy. After only two cycles of therapy, a complete remission was obtained and then consolidated with additional cycles of docetaxel and radiotherapy. Prospective genetic analysis had shown that the patient had a favourable CYP1B1 genotype. He has been disease free since August 2006. Prospective trials investigating this strategy are warranted.

Current status and perspectives in immunotherapy for metastatic melanoma

Metastatic melanoma was the first malignancy in which immune checkpoint inhibitors demonstrated their successful efficacy. Currently, the knowledge on the interaction between the immune system and malignant disease is steadily increasing and new drugs and therapeutic strategies are overlooking in the clinical scenario. To provide a comprehensive overview of immune modulating drugs currently available in the treatment of melanoma as well as to discuss of possible future strategies in the metastatic melanoma setting, the present review aims at analyzing controversial aspects about the optimal immunomodulating treatment sequences, the search for biomarkers of efficacy of immunocheckpoint inhibitors, and innovative combinations of drugs currently under investigation.

Skewing effect of sulprostone on dendritic cell maturation compared with dinoprostone

BACKGROUND Dendritic cells (DCs) are the most efficient antigen-presenting cells and act at the center of the immune system owing to their ability to control both immune tolerance and immunity. In cancer immunotherapy, DCs play a key role in the regulation of the immune response against tumors and can be generated ex vivo with different cytokine cocktails. METHODS We evaluated the feasibility of dinoprostone (PGE2) replacement with the molecular analog sulprostone, in our good manufacturing practice (GMP) protocol for the generation of DC-based cancer vaccine. We characterized the phenotype and the function of DCs matured in the presence of sulprostone as a potential substitute of dinoprostone in the pro-inflammatory maturation cocktail consisting of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β) and IL-6. RESULTS We found that sulprostone invariably reduces the recovery, but does not significantly modify the viability and the purity of DCs. The presence of sulprostone in the maturation cocktail increases the adhesion of single cells and of clusters of DCs to the flask, making them more similar to their immature counterpart in terms of adhesion and spreading proprieties. Moreover, we observed that sulprostone impairs the expression of co-stimulatory molecules and the spontaneous as well as the directed migration capacity of DCs. DISCUSSION These findings underscore that the synthetic analog sulprostone strongly reduces the functional quality of DCs, thus cannot replace dinoprostone in the maturation cocktail of monocyte-derived DCs.