Concetta Elisa Onesti

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.

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.

What to expect from high throughput genomics in metastatic breast cancers

Breast cancer is a heterogeneous disease and its genomic characteristics have been widely studied in the last years. Although several progresses have been made, metastatic disease is still incurable in the majority of patients. Recent genomic studies have shown that a large number of candidate targets exist in breast cancer. Currently only two drivers have been validated (ER and HER2), but several others seem to be associated with objective response, such as PIK3CA mutations, FGFR1 amplifications, AKT1 mutations, EGFR amplifications and ERBB2 mutations. Beside driver identification, many other applications can be developed for genomics such as identification of lethal subclones, DNA repair defects or immune response against tumor. Most of the precision medicine programs currently use targeted sequencing. Nevertheless, whole exome sequencing, RNA sequencing, gene expression analysis, phosphoprotein detection, SNP arrays and ctDNA sequencing have been also proposed in clinical trials.

Gastric Metastases From Testicular Cancer: Case Report and Review of Literature

Testicular germ cell tumors represent approximately 1 % of all cancers in man and are the most common malignancy between 15and 35-year olds [1, 2]. Testicular malignancy has a common precursor and reflects a continuum of differentiation potential of early neoplastic germ cell. They are classified into seminomas (classic and spermatocytic) and non-seminomas (embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma). Seminomas are characterized by a more favorable clinical outcome compared to nonseminomas [3]. Pure seminomatous cancers account for 40 % of cases, while non-seminomatous and mixed tumors represent about 60 % of cases [1]. Approximately one half of patients with non-seminomatous germ cell tumors present at stage IV [2, 4]. Generally, these tumors metastasize to the retroperitoneal lymph nodes and, less commonly, to the lungs, liver, and brain [5]. Gastrointestinal metastases are very rare and may present with bowel obstruction or, less frequently, with hemorrhage [6]. We present the case of a 44-year-old man affected by a mixed testicular cancer, who began with symptoms related to bleeding from gastric metastasis.

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.

Molecular Detection of EMT Markers in Circulating Tumor Cells from Metastatic Non-Small Cell Lung Cancer Patients: Potential Role in Clinical Practice

Background Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related mortality; nevertheless, there are few data regarding detection of circulating tumor cells (CTCs) in NSCLC, compared to other kinds of cancers in which their prognostic roles have already been defined. This difference is likely due to detection methods based on the epithelial marker expression which ignore CTCs undergoing epithelial-mesenchymal transition (CTCsEMT). Methods After optimization of the test with spiking experiments of A549 cells undergoing TGF-β1-induced EMT (A549EMT), the CTCsEMT were enriched by immunomagnetic depletion of leukocytes and then characterized by a RT-PCR assay based on the retrieval of epithelial and EMT-related genes. Blood samples from ten metastatic NSCLC patients before starting treatment and during chemotherapy were used to test this approach by longitudinal monitoring. Ten age- and sex-matched healthy subjects were also enrolled as controls. Results Recovery experiments of spiked A549EMT cells showed that the RT-PCR assay is a reliable method for detection of CTCsEMT. CTCsEMT were detected in three patients at baseline and in six patients after four cycles of cysplatin-based chemotherapy. Longitudinal monitoring of three patients showed that the CTCsEMT detection is related to poor therapeutic response. Conclusions The RT-PCR-based approach for the evaluation of CTCsEMT phenotype could be a promising and inexpensive tool to predict the prognosis and the therapeutic response in NSCLC patients.