Michela Roberto

Circulating tumor cells count predicts survival in colorectal cancer patients

Background & Aims: Respiratory complications represent an important adverse event of endoscopic procedures. We screened for respiratory complications aer endoscopic procedures using a questionnaire and followed-up patients suggestive of respiratory infection. Method: In this prospective observational, multicenter study performed in Outpatient practices of gastroenterology we investigated 15,690 patients by questionnaires administered 24 hours aer the endoscopic procedure. Results: 832 of the 15,690 patients stated at least one respiratory symptom aer the endoscopic procedure: 829 patients reported coughing (5.28%), 23 fever (0.15%) and 116 shortness of breath (SOB, 0.74%); 130 of the 832 patients showed at least two concomitant respiratory symptoms (107 coughing + SOB, 17 coughing + fever, 6 coughing + coexisting fever + SOB) and 126 patients were followed-up to assess their respiratory complaints. Twenty-nine patients (follow-up: 22.31%, whole sample: 0.18%) reported signs of clinically evident respiratory infection and 15 patients (follow-up: 11.54%; whole sample: 0.1%) received therefore antibiotic treatment. Coughing or vomiting during the endoscopic procedure resulted in a 156.12-fold increased risk of respiratory complications (95% CI: 67.44 - 361.40) and 520.87-fold increased risk of requiring antibiotic treatment (95% CI: 178.01 - 1524.05). All patients of the follow-up sample who coughed or vomited during endoscopy developed clinically evident signs of respiratory infection and required antibiotic treatment while this occurred in a signicantly lower proportion of patients without these symptoms (17.1% and 5.1%, respectively). Conclusions: We demonstrated that respiratory complications following endoscopic sedation are of comparably high incidence and we identied major predictors of aspiration pneumonia which could inuence future surveillance strategies aer endoscopic procedures.

A metronomic schedule as salvage chemotherapy for upper gastrointestinal tract cancer

In recent years, metronomic chemotherapy, consisting of continuous administration of low doses of cytotoxic agents, has being used as rescue therapy for different tumours. The aim of this study was to retrospectively assess the efficacy and safety of low-dose metronomic, oral capecitabine in pretreated or frail patients with recurrent upper gastrointestinal tract cancer. Patients with pretreated upper gastrointestinal tract cancer or who were not candidates for standard chemotherapy because of toxicity concerns received capecitabine at 1500 mg per day continuously until disease progression or occurrence of toxicity. Forty-seven patients (25 oesophagogastric cancer, 22 pancreatobiliary cancer; 25 men, 22 women; median age 69 years, range 42–90) were included in the study. Forty-five percent of the patients had received at least two previous lines of treatment and the median number of previous treatments was 1 (range 0–5). Twelve (31.6%) patients achieved clinical benefit (one partial response, 11 stable disease), whereas nine (23.7%) patients were progression free for at least 6 months. In an exploratory analysis, there was a significant relationship between performance status and clinical benefit (hazard ratio=8.25; P=0.01). The median overall survival was 5 months. A good performance status was associated with a longer survival (hazard ratio=0.26; P<0.01). No severe toxicity or treatment-related death was reported. Metronomic capecitabine showed good safety and moderate activity in frail or pretreated patients with advanced, upper gastrointestinal tract cancer.

High-doses of proton pump inhibitors in refractory gastro-intestinal cancer: A case series and the state of art

BACKGROUND In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose to modulate tumour microenvironment acidification thus restoring chemotherapeutic sensitivity. Moreover, several clinical data supports the role of cytotoxic drugs at low-dose continuously delivered as anticancer therapy. METHODS Clinical records of three patients affected with gastrointestinal cancer refractory to standard treatments, who had received a combination of high-dose rabeprazole and metronomic chemotherapy were reviewed. RESULTS The first case, a 78-year-old man was treated for lung metastasis from colon adenocarcinoma. The second case, a 73-year-old man was treated for metastatic rectal cancer to the liver. The third one, a 68-year-old man, underwent the combination regimen for colon cancer with lung, liver and peritoneal metastases. CONCLUSIONS Despite the failure of previous standard chemotherapy for metastatic disease, good clinical outcome was shown in these patients treated with an unconventional association of high-dose PPIs and metronomic chemotherapy.

The TYMS-TSER polymorphism is associated with toxicity of low-dose capecitabine in patients with advanced gastrointestinal cancer

Low doses of drugs delivered at close, regular intervals are increasingly being used to manage patients with different neoplasms. Despite the good tolerability, treatment-related adverse events still occur following metronomic protocols. The aim of this study was to retrospectively investigate whether polymorphisms of different genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with the outcome of a low-dose capecitabine schedule. Genotyping of DPYD IVS14+1 G>A, MTHFR C677T, and A1298C single-nucleotide polymorphisms was performed by pyrosequencing technology. A PCR technique was used for genotyping TYMS-TSER. Using peripheral blood mononuclear cells, we also evaluated the 5-FU degradation rate, which determines the net result of all the enzymatic transformation of 5-FU, in terms of the amount of drug consumed by the cells in a time unit. The association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. Eighty-four patients with metastatic gastrointestinal cancer, who had been treated with a low-dose fluoropyrimidine schedule, as a rescue therapy were included in the study. The TSER 2R/2R genotype was significantly associated with both hematologic (odds ratio=7.90, P=0.002) and gastrointestinal toxicity (odds ratio=3.24, P=0.009). Because DPYD IVS14 G>A single-nucleotide polymorphism was not observed in the cohort, it was excluded from the statistical analysis. No significant association was detected between clinical outcome and both MTHFR polymorphisms and the 5-FU degradation rate. In the advanced setting of cancer care, high attention should be paid toward avoiding toxicity and worsening of quality of life. Although metronomic chemotherapy is generally well tolerated, treatment toxicity nonetheless does occur. Our data suggest a possible role of the TSER 2R/2R polymorphism as a predictive marker of toxicity in patients treated with low-dose capecitabine.

Recent advances for the treatment of pancreatic and biliary tract cancer after first-line treatment failure

Here, we evaluate clinical trials on chemotherapy for patients with pancreatic or biliary tract cancer after first-line treatment failure. Clinical trials on conventional and innovative medical treatments for progressive pancreatic and biliary cancer were analyzed. Metronomic chemotherapy, which consists of the administration of continuative low-dose of anticancer drugs, was also considered. A significant extension of overall survival was achieved with second-line, regimens in patients with gemcitabine-refractory pancreatic cancer. Moreover, many Phase II studies, including chemotherapy and target molecules and immunotherapy, have reported promising results, in both pancreatic and biliary cancer. However, data in these patients’ setting are very heterogeneous, and only few randomized studies are available.

The sexist behaviour of immune checkpoint inhibitors in cancer therapy

Background Immune checkpoint inhibitors, targeting the molecules CTLA-4, PD-1 and PD-L1, showed efficacy against several type of cancers and are currently used in clinical practice. An important biological variable that influences innate and adaptive immunity is the sex, acting through genetic, hormonal and environmental factors. The overall differences between sexes could be crucial to evaluate the response to ICIs. Materials and methods We performed a meta-analysis of Phase II-III Clinical Trials published up to June 2017 in which anti-CTLA-4, anti-PD-1 and anti-PD-L1 were studied. We extracted the OS and PFS HR differentiated by sex from subgroups analysis of each trial. We analyzed the three classes of drugs separately. Results We selected 36 Phase II-III Clinical Trials, 9 of which reported results for OS and 6 for PFS. We analyzed 2 Clinical Trials for OS with anti-CTLA-4, including 1178 patients, observing a benefit for males vs females (HR 0.65, 95% CI 0.55-0.77 vs HR 0.79, 95% CI 0.65-0.96, p 0.078). Not statistically significant results were observed with anti-PD-1 neither for OS (males vs females: HR 0.72, 95% CI 0.64-0.83 vs HR 0.81, 95% CI 0.70-0.94, p 0.285) neither for PFS (males vs females: HR 0.66, 95% CI 0.52-0.82 vs HR 0.85, 95% CI 0.66-1.09, p 0.158). We cannot perform a meta-analysis for anti-PD-L1 due to the lack of data. Conclusions Different mechanisms could be involved in sex differences with regard to immunotherapy. These differences could be relevant to identify immunological targets in order to draw studies exploring novel combinations of immunotherapy agents.

Exploring the Prognostic Role of Microsatellite Instability in Patients With Stage II Colorectal Cancer: A Systematic Review and Meta-Analysis

Micro‐Abstract Many studies have disclosed the prognostic effect of microsatellite instability (MSI) and/or loss of mismatch repair proteins in colorectal cancer. Nevertheless, little evidence supports their role in decision‐making of adjuvant therapy for the stage II. This systematic review evaluated the prognostic and/or predictive role of MSI status in patients with stage II colorectal cancer. Only 2 articles fulfilled the eligibility criteria, suggesting a prognostic role of MSI on disease‐free survival but not supporting the hypothesis of a predictive effect. Background: Many studies have disclosed the prognostic effect of microsatellite instability (MSI) and/or loss of mismatch repair proteins in colorectal cancer. Nevertheless, little evidence supports their role in the decision‐making of adjuvant therapy for patients with stage II disease. Materials and Methods: The aim of this systematic review was to evaluate the prognostic and/or predictive role of MSI status in patients with stage II colorectal cancer on disease‐free survival and overall survival. MEDLINE, EMBASE, and Cochrane libraries were searched to identify eligible studies. Results: Only 2 of 389 articles identified fulfilled the eligibility criteria. In both treated and untreated patients, high‐level MSI improved disease‐free survival compared with low‐level MSI, suggesting a prognostic role but not supporting the hypothesis of a predictive effect of MSI. Conclusions: Further studies are needed to explore the predictive role of MSI/mismatch repair proteins, because available data do not allow definitive conclusions.

A nomogram to predict 5-fluorouracil toxicity: when pharmacogenomics meets the patient

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients’ characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFR A1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27–87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3–4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYD heterozygous mutated patients (83.3% of the patients). Age, DPYD status, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.

Lean body mass wasting and toxicity in early breast cancer patients receiving anthracyclines

Background Sarcopenia refers to the reduction of both volume and number of skeletal muscle fibers. Lean body mass loss is associated with survival, quality of life and tolerance to treatment in cancer patients. The aim of our study is to analyse the association between toxicities and sarcopenia in early breast cancer patients receiving adjuvant treatment. Materials and Methods Breast cancer patients who have received anthracycline-based adjuvant treatment were retrospectively enrolled. CT scan images performed before, during and after adjuvant chemotherapy were used to evaluate lean body mass at third lumbar vertebra level with the software Slice Omatic V 5.0. Results 21 stage I–III breast cancer patients were enrolled. According to the skeletal muscle index at third lumbar vertebra cut-off ≤38.5 cm2/m2, 8 patients (38.1%) were classified as sarcopenic before starting treatment, while 10 patients (47.6%) were sarcopenic at the end of treatment. A lower baseline L3 skeletal muscle index is associated with G3-4 vs G0-2 toxicities (33.4 cm2/m2 (31.1–39.9) vs 40.5 cm2/m2 (33.4–52.0), p = 0.028). Similarly skeletal muscle cross sectional area was significantly lower in patients with G3-4 toxicities (86.7 cm2 (82.6–104.7) vs 109.0 cm2 (83.3–143.9), p = 0.017). L3 skeletal muscle index is an independent predictor of severe toxicity (p = 0.0282) in multivariate analysis. Conclusion Lean body mass loss is associated with higher grade of toxicity in early breast cancer patients receiving adjuvant chemotherapy.

Tackling pancreatic cancer with metronomic chemotherapy

Pancreatic tumours, the majority of which arise from the exocrine pancreas, have recently shown an increasing incidence in western countries. Over the past few years more and more new selective molecules directed against specific cellular targets have become available for cancer therapy, leading to significant improvements. However, despite such advances in therapy, prognosis of pancreatic cancer remains disappointing. Metronomic chemotherapy (MCT), which consists in the administration of continuous, low-dose anticancer drugs, has demonstrated the ability to suppress tumour growth. Thus, it may provide an additional therapeutic opportunity for counteracting the progression of the tumour. Here we discuss evidence arising from preclinical and clinical studies regarding the use of MCT in pancreatic cancer. Good results have generally been achieved in preclinical studies, particularly when MCT was combined with standard dose chemotherapy or antinflammatory, antiangiogenic and immunostimolatory agents. The few available clinical experiences, which mainly refer to retrospective data, have reported good tolerability though mild activity of metronomic schedules. Further studies are therefore awaited to confirm both preclinical findings and the preliminary clinical data.