Potential benefit of ß-glucans as adjuvant therapy in immuno-oncology: a review.

Fungal compounds have long been used for centuries as food supplements. ß-glucans have been identified as the most interesting molecules with beneficial effects in several chronic diseases. In vitro studies have shown that they are able to elicit the immune cells maturation and activation with the result of an increased release of proinflammatory cytokines and chemokines and a stimulation of anti-bacterial activity of macrophages and neutrophils. As ß-glucans enhance pathogen elimination through non-self antigens identification, they can also direct immune response against tumor cells. These compounds also stimulate the activity on adaptive immune cells and they have been regarded as biological response modifiers. In this way, ß-glucans can be exploited as adjuvant cancer therapy, in particular by a synergic action with chemotherapy or immunotherapy. In the immuno-oncology era, the need is to identify innovative drugs that can simultaneously target and inhibit different biological processes relevant for cancer cells survivors. Recent clinical studies showed promising results about the combination of ß-glucans and immune checkpoint inhibitors for patients affected by different solid tumors. This review aims to investigate molecular mechanisms of action of ß-glucans and is focused on their application in clinical practice as immune-adjuvants for treatment of cancer patients.

Weighing the prognostic role of hyponatremia in hospitalized patients with metastatic solid tumors: the HYPNOSIS study.

Previous works linked low sodium concentration with mortality risk in cancer. We aimed at weighing the prognostic impact of hyponatremia in all consecutive patients with metastatic solid tumors admitted in a two-years period at our medical oncology department. Patients were included in two cohorts based on serum sodium concentration on admission. A total of 1025 patients were included, of whom 279 (27.2%) were found to be hyponatremic. The highest prevalence of hyponatremia was observed in biliary tract (51%), prostate (45%) and small-cell lung cancer (38.9%). With a median follow-up of 26.9 months, median OS was 2 months and 13.2 months for the hyponatremia versus control cohort, respectively (HR, 2.65; P < 0.001). In the multivariable model, hyponatremia was independently associated with poorer OS (HR, 1.66; P < 0.001). According to the multivariable model, a nomogram system was developed and validated in an external set of patients. We weighed over time the influence of hyponatremia on survival of patients with metastatic solid tumors and pointed out the possibility to exploit serum sodium assessment to design integrated prognostic tools. Our study also highlights the need for a deeper characterization of the biological role of extracellular sodium levels in tumor development and progression.

The value of lactate dehydrogenase serum levels as a prognostic and predictive factor for advanced pancreatic cancer patients receiving sorafenib.

Although lactate dehydrogenase (LDH) serum levels, indirect markers of angiogenesis, are associated with a worse outcome in several tumours, their prognostic value is not defined in pancreatic cancer. Moreover, high levels are associated even with a lack of efficacy of tyrosine kinase inhibitors, contributing to explain negative results in clinical trials. We assessed the role of LDH in advanced pancreatic cancer receiving sorafenib. Seventy-one of 114 patients included in the randomised phase II trial MAPS (chemotherapy plus or not sorafenib) and with available serum LDH levels, were included in this analysis. Patients were categorized according to serum LDH levels (LDH ≤ vs.> upper normal rate). A significant difference was found in progression free survival (PFS) and in overall survival (OS) between patients with LDH values under or above the cut-off (PFS: 5.2 vs. 2.7 months, p = 0.0287; OS: 10.7 vs. 5.9 months, p = 0.0021). After stratification according to LDH serum levels and sorafenib treatment, patients with low LDH serum levels treated with sorafenib showed an advantage in PFS (p = 0.05) and OS (p = 0.0012). LDH appears to be a reliable parameter to assess the prognosis of advanced pancreatic cancer patients, and it may be a predictive parameter to select patients candidate to receive sorafenib.

Sorafenib does not improve efficacy of chemotherapy in advanced pancreatic cancer: A GISCAD randomized phase II study.

BACKGROUND: The RAF-MEK-ERK pathway is commonly activated in pancreatic cancer because of a high frequency of KRAS-BRAF mutations. A phase II randomized trial was designed to investigate the activity of sorafenib in combination with chemotherapy in advanced pancreatic cancer. METHODS: Locally advanced or metastatic pancreatic adenocarcinoma patients were randomized in a 1:1 ratio to receive cisplatin plus gemcitabine with sorafenib 400mg bid (arm A) or without sorafenib (arm B). RESULTS: One hundred and fourteen patients were enrolled; of these, 43 (74.6%) patients progressed in arm A and 44 (82.4%) in arm B. Median progression-free survival was 4.3 months (95% CI: 2.7-6.5) and 4.5 months (95% CI: 2.5-5.2), respectively (HR=0.92; 95% CI: 0.62-1.35). Median overall survival was 7.5 (95% CI: 5.6-9.7) and 8.3 months (95% CI: 6.2-8.7), respectively (HR=0.95; 95% CI: 0.62-1.48). Response rates were 3.4% in arm A and 3.6% in arm B. CONCLUSIONS: Sorafenib does not significantly enhance activity of chemotherapy in advanced pancreatic cancer patients, and therefore should not be assessed in phase III trials.

Second-line chemotherapy with irinotecan, 5-fluorouracil and leucovorin (FOLFIRI) in relapsed or metastatic gastric cancer: lessons from clinical practice.

AIMS AND BACKGROUND: Soon after the approval of irinotecan for second-line therapy of advanced gastric cancer, the FOLFIRI regimen represented a possible treatment choice in clinical practice. However, there was still scarce data on the efficacy of irinotecan in this setting. We retrospectively evaluated the efficacy of FOLFIRI as second-line treatment in advanced gastric cancer patients progressing after platinum-based chemotherapy. METHODS: Patients with metastatic gastric cancer progressing after platinum-based chemotherapy who received FOLFIRI as second-line chemotherapy were included in our analysis. RESULTS: Thirty patients were consecutively treated (20 males and 10 females). Median age was 62 years (range, 36-78). All patients had metastatic disease. In 17 cases (56.6%), peritoneal tumor diffusion was present. Six patients (20%) had previously received 5-fluorouracil-based adjuvant chemotherapy. The median number of cycles administered was 4 (range, 1-12). Partial remission was obtained in 1 case (3%) and stable disease in 8 patients (27%). Median progression-free survival and overall survival were 2.7 months and 5.5 months, respectively. The most common toxicities (grade 2-3) observed were neutropenia (13.3%), diarrhea (10%) and vomiting (30%). Ten patients (10%) received 3 or less courses of chemotherapy. In these cases, treatment was stopped before scheduled for accelerated worsening of clinical conditions. CONCLUSIONS: FOLFIRI resulted scarcely active in metastatic gastric cancer patients pre-treated with platinum-based chemotherapy. In this setting, the real benefit of a second-line chemotherapy with the FOLFIRI regimen should be carefully re-considered, especially according to the clinical condition of the patient and possible treatment-related side effects.

Evolving strategies for the treatment of hepatocellular carcinoma: from clinical-guided to molecularly-tailored therapeutic options.

Hepatocellular carcinoma (hepatocellular carcinoma, HCC) is the commonest primary liver cancer (80-90%) and represents the leading cause of cancer-related death, after lung and stomach cancer. The process of neoplastic transformation proceeds through the accumulation of mutations in the genes governing cell proliferation and apoptosis. It is currently difficult to determine the natural history of patients with untreated early-stage HCC, since most with early-stage tumor patients undergoes curative therapy. Survival rates at 3 years is 65% in patients with Child-Pugh A, and single untreated lesion. This proportion increases to 70% at 5 years after radical treatment. In patients included in randomized controlled clinical trials with advanced disease, survival at 1 and 2 years is respectively 72% and 50%. Surgery is the only potentially curative treatment for HCC. In carefully selected patients, resection and transplantation in fact, allow a 5 years survival from 60% to 70%. Unfortunately most patients in Western countries present with an intermediate or advanced HCC at diagnosis with the consequent inability to use curative treatments. These patients are therefore candidates to palliative therapies that include arterial embolization and chemoembolization and systemic treatments including chemotherapy, immunotherapy and hormonal therapy. Only recently the molecular targeted drug, Sorafenib, has been introduced among the therapeutic options for these patients.

Trans-arterial chemo-embolization (TACE), with either lipiodol (traditional TACE) or drug-eluting microspheres (precision TACE, pTACE) in the treatment of hepatocellular carcinoma: efficacy and safety results from a large mono-institutional analysis.

More data about TACE and pTACE seem necessary to better define the global treatment strategy for HCC. Aim of our analysis was to evaluate the role of TACE, either with lipiodol (traditional) or drug-eluting microspheres in terms of response rate (RR), time to progression (TTP), overall survival (OS) and toxicity in HCC.Patients with HCC undergoing traditional TACE or pTACE (either alone or in combination with other treatment options) were eligibleOne hundred and fifty patients were analyzed. In the global patient population median OS was 46 months for lipiodol TACE and 19 months for pTACE (p < 0.0001), TTP was 30 months versus 16 months for patients receiving TACE or pTACE respectively (p = 0.003). These results were confirmed also among the group of patients who received exclusive TACE or pTACE. Neither RR nor toxicity was different between TACE or pTACE.At multivariate analysis, age, the Okuda stage, type of TACE and number of TACE proved to be independent prognostic factors influencing overall survival.In our experience, lipiodol TACE showed a better OS and TTP over pTACE, without difference in toxicity profile and RR. Among the staging systems analyzed only the Okuda stage seemed able to reliably predict patients outcome.

Mucinous rectal adenocarcinoma can be associated to tumor downstaging after preoperative chemoradiotherapy.

PURPOSE: The aim of this study was to evaluate downstaging as primary end point, and progression-free survival and overall survival as secondary end points, in rectal adenocarcinoma patients treated with preoperative chemoradiation. METHODS: One hundred and thirty-six extraperitoneal adenocarcinoma patients (33 low rectum T2, 74 T3, 29 T4 [without sacral invasion], 25 with mucinous subtype) were treated with posterior pelvis preoperative radiotherapy (5040 cGy total dose, 180 cGy/fr, 5 fr/w, 10-15 MV linac X-rays) and concomitant 5-fluorouracil-based chemotherapy. After 6 to 8 weeks patients underwent surgery and prechemoradiation clinical stage was compared with pathologic stage to evaluate downstaging in each patient. Seventy-four patients received adjuvant chemotherapy. Median follow-up was 39 months (4-84). RESULTS: Forty-four patients had macroscopic complete response, 52 patients had partial response, 37 patients showed no change and 3 patients had progression. At multivariate analysis only histotype showed correlation with downstaging (hazard ratio = 0.350 and 0.138 - 0.885 95 percent confidence interval) because of the evidence for poor downstaging in mucinous subtype. There were no significant differences in overall survival and progression-free survival between adenocarcinoma and mucinous subtype. CONCLUSIONS: The main finding is that mucinous histology is associated with poor downstaging after preoperative chemoradiation but this poor response was not associated with worse outcome in this small study. The good outcome for mucinous histology is at odds with other reports in the literature and requires further study.