Gastric cancer: Translating novels concepts into clinical practice.

The overall 5-year survival of gastric cancer (GC) has change only little in the last decades and it remains the fifth leading cause of cancer-related death worldwide. However, in the past few years a more effective combination chemotherapy has raised the bar of curability of about 10% in resectable disease. Morever, a deeper knowledge of GC biology have unveiled biomarkers to help personalize adjunctive treatments in patients candidate to surgery. Despite a plateau in efficacy of fist-line treatment, incremental survival advantages have been recorded in unresectable advanced disease. The growing number of effective drugs in second and later lines along with a more judicious delivery of cytotoxics and early supportive interventions have enabled more patients to proceed beyond first-line. The continuum of care has become a reality in a considerable proportion of patients that offer opportunities to improve outcomes. Finally, the advent of the immune checkpoint inhibitors has brought great expectations in molecularly-defined subset of patients. This Review summarizes the state-of-the art in the management of GC together with novel concepts that have entered clinical development with the potential of change practice in the foreseeable future.

The Italian Rare Pancreatic Exocrine Cancer Initiative.

INTRODUCTION: Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available. METHODS: A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway-oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays. CONCLUSIONS: We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices.

Systemic Chemotherapy for Advanced Rare Pancreatic Histotype Tumors: A Retrospective Multicenter Analysis.

OBJECTIVES: Two issues were put forth by clinicians in the management of the advanced stages of rare variants of pancreatic ductal adenocarcinoma and other exocrine histotypes with peculiar clinical and pathological features: Do chemotherapy regimens recommended in pancreatic ductal adenocarcinoma patients have a clinical activity in rare pancreatic tumors? Or should other chemotherapy combinations be considered in this subset of patients? METHODS: We conducted a multicenter retrospective study that collected data from 2005 to 2016 at 14 Italian cancer centers with the aim to evaluate tumor response and time to progression for first- and second-line and overall survival. RESULTS: Of approximately 4300 exocrine pancreatic cancer patients, 79 advanced cases affected by rare histological types were identified, with pancreatic acinar cell cancer (n = 23), pancreatic adenosquamous cancer (n = 16), and mucinous cystic neoplasm with an associated invasive mucinous cystadenocarcinoma (n = 15) most represented. Survival analyses for each subgroup in relation with the different chemotherapy regimens showed the lack of statistical significance correlations. CONCLUSIONS: Because of the lack of clinical trials in patients affected by these rare pancreatic histotypes, only their molecular classification would help clinicians in future therapeutic choice.

Clinical outcome and molecular characterisation of chemorefractory metastatic colorectal cancer patients with long-term efficacy of regorafenib treatment.

Background: To investigate the potential predictors of response to regorafenib, in chemorefractory metastatic colorectal cancer (mCRC) patients with long-term efficacy from regorafenib treatment. Methods: Retrospective, single institution analysis of patients with chemorefractory mCRC treated with regorafenib, in clinical practice setting. 123 patients were treated and stratified into two groups according to number of cycles received (<7 and ≥7). Overall survival (OS), progression-free survival (PFS) and safety were evaluated. 20 tumour samples (10 poor and 10 long responders) were analysed with the OncoMine Comprehensive Assay for 143 genes. Results: A good Eastern Cooperative Oncology Group performance status, a lung limited metastatic disease and a long history of metastatic disease were significantly associated with better OS and PFS from treatment with regorafenib. Mutations were mostly found in TP53, KRAS and PIK3CA as well as in NRAS, ERBB2, SMAD4 and PTEN genes. BCL2L1, ERBB2, KRAS, MYC, GAS6 gene amplifications were detected as well as ALK rearrangement. No significant correlation between molecular alterations and response to regorafenib was observed. However, HER2 gene alterations were found in three poor responder patients, suggesting a potential role in regorafenib resistance. Conversely, GAS6 amplification and SMAD4 mutation, detected in two long responder patients, might suggest a role of epithelial-mesenchymal transition phenotype in regorafenib response. Conclusion: A subgroup of long responder patients to regorafenib treatment was identified and a comprehensive molecular characterisation was performed; however, further research efforts are essential to confirm our data.

Sequential Treatment with Pazopanib and Everolimus in Metastatic Renal Cell Carcinoma.

In metastatic renal cell carcinoma, complete response to first-line antiangiogenic agents is rare and resistance to therapy often develops. Protocols for sequential treatment with angiogenesis and mTOR inhibitors are under evaluation to improve outcomes. In this observational, real-world study, patients received a first-line therapy with pazopanib until discontinuation for disease progression or toxicity, then a second-line with everolimus. Primary endpoints were overall survival (OS) for sequence, progression free survival (PFS) for each agent, and safety. Thirty-one patients were included in the analysis: 73.3% of patients underwent nephrectomy before treatment, 25.8% had at least three comorbidities. At the beginning of therapy, the median age was 68 years, with more than 60% of patients older than 65 years. The median OS for sequence was 26.5 months (95% CI 17.4-nc); median PFS was 10.6 months (95% CI 6.3-12.1) with pazopanib and 5.3 months (95% CI 3.8-6.7) with everolimus. The median persistence in pazopanib therapy was 8.1 months (Interquartile Range IQR 5.3-12.7), with 31% of patients who required dose reduction, while persistence in everolimus was 4.4 months (IQR 3.4-6.5). Sequence was well tolerated with a different profile of adverse events for each agent. These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance.

A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases.

BACKGROUND: The discordance in oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) status between primary and recurrent breast cancer is being intensively investigated and a large amount of data have been produced. However, results from different studies are heterogeneous and often conflicting. To highlight this issue, a meta-analysis of published data was performed. METHODS: A literature search was performed using Medline, and all the studies published from 1983 to 2011 comparing changes in ER, PgR and/or HER2 status in patients with matched breast primary and recurrent tumours were included. We used random-effects models to estimate pooled discordance proportions. RESULTS: We selected 48 articles, mostly reporting retrospective studies. Thirty-three, 24 and 31 articles were focused on ER, PgR and HER2 changes, respectively. A total of 4200, 2739 and 2987 tumours were evaluated for ER, PgR and HER2 discordance, respectively. The heterogeneity between study-specific discordance proportions was high for ER (I(2)=91%, p<0.0001), PgR (I(2)=79%, p<0.0001) and HER2 (I(2)=77%, p<0.0001). Pooled discordance proportions were 20% (95% confidence interval (CI): 16-35%) for ER, 33% (95% CI: 29-38%) for PgR and 8% (95% CI: 6-10%) for HER2. Pooled proportions of tumours shifting from positive to negative and from negative to positive were 24% and 14% for ER (p=0.0183), respectively. The same figures were 46% and 15% for PgR (p<0.0001), and 13% and 5% for HER2 (p=0.0004). CONCLUSION: Our findings strengthen the concept that changes in receptor expression may occur during the natural history of breast cancer, suggesting clinical implications and a possible impact on treatment choice.

Peripherally inserted central catheter tip position: a novel empirical-ultrasonographical index in a modern surgical oncology department.

BACKGROUND: The correct positioning of ultrasound-guided, peripherally inserted central catheters (UGPICCs) is essential to avoid multiple complications. We describe for the first time a retrospective study to evaluate a novel and easy transabdominal ultrasound-guided approach, so-called "Marano index," to place the UGPICCs tip correctly, making oncological surgeons able to obtain a high successful initial placement rate without postinsertion chest radiography. METHODS: We examined the placement of UGPICCs applying, in 53 patients, the "Marano index." The tip catheter location was controlled by postprocedural chest radiography. Sensitivity, positive predictive value, and accuracy of index application also were calculated and compared with radiographic findings. RESULTS: The ultrasonographic-guided insertion was successful in all patients (100%). The identification of catheter inside the inferior vena cava was registered in 50 patients (94.3%), and in all cases it was clear the precise catheter placement, after Marano index application, with the real tip position and the concordance between postprocedural radiography in 100% of cases. The overall accuracy of this novel empirical-ultrasonographical index was 94%, with positive predictive value of 94% and sensitivity of 100%. CONCLUSIONS: This technique, once validated in a larger cohort, would allow the insertion of UGPICC without radiologic confirmation in selected patients with an adequate ultrasound body habitus. This would avoid unneeded radiation exposure from chest X-rays and would potentially save cost and time. This strategy provides only minimal deviation from the current practice and it is hence technically easy to learn and perform accurately with basic training by digestive oncological surgeons.

Natural history of malignant bone disease in gastric cancer: final results of a multicenter bone metastasis survey.

BACKGROUND: Bone metastasis represents an increasing clinical problem in advanced gastric cancer (GC) as disease-related survival improves. In literature, few data on the natural history of bone disease in GC are available. PATIENTS AND METHODS: Data on clinicopathology, skeletal outcomes, skeletal-related events (SREs), and bone-directed therapies for 208 deceased GC patients with evidence of bone metastasis were statistically analyzed. RESULTS: Median time to bone metastasis was 8 months (CI 95%, 6.125-9.875 months) considering all included patients. Median number of SREs/patient was one. Less than half of the patients (31%) experienced at least one and only 4 and 2% experienced at least two and three events, respectively. Median times to first and second SRE were 2 and 4 months, respectively. Median survival was 6 months after bone metastasis diagnosis and 3 months after first SRE. Median survival in patients who did not experience SREs was 5 months. Among patients who received zoledronic acid before the first SRE, the median time to appearance of first SRE was significantly prolonged compared to control (7 months vs 4 months for control; P: 0.0005). CONCLUSIONS: To our knowledge, this retrospective analysis is the largest multicenter study to demonstrate that bone metastases from GC are not so rare, are commonly aggressive and result in relatively early onset of SREs in the majority of patients. Indeed, our large study, which included 90 patients treated with ZOL, showed, for the first time in literature, a significant extension of time to first SRE and increase in the median survival time after diagnosis of bone metastasis. Taken together, these data may support the beneficial effects of ZOL in GC patients.

Emerging VEGF-receptor inhibitors for colorectal cancer.

INTRODUCTION: Targeted agents have dramatically improved and enriched the therapeutical choices for patients with metastatic colorectal cancer (mCRC). By better understanding the role of the angiogenic pathway in colorectal cancer (CRC), new therapies have been developed. Bevacizumab, the first anti-angiogenetic agent approved for the treatment of mCRC provide a proof of concept since it has improved the progression-free survival and overall survival when combined with cytotoxic chemotherapy. AREAS COVERED: This review is focused on the most recent findings on the VEGF signaling pathway and new therapeutic drugs explored in clinical trials. EXPERT OPINION: Despite the advantage offered by bevacizumab, the median overall survival of mCRC patient exceeds 21 months; thus, investigational efforts are needed. Several antiangiogenic agents for the treatment of mCRC are being tested in preclinical and clinical Phase I/II trials. Unfortunately a discrete number of Phase III trials produced negative results. Recently aflibercept and regorafenib, two new antiangiogenic drugs, have been approved as the new-targeted agents for the treatment of mCRC, according to the positive findings from the VELOUR and the CORRECT studies. In order to maximize clinical impact it will be important to validate predictive biomarkers and best combination treatments to offer for mCRC patients; further research and intense investigation is still required.

Optimized granulocyte colony-stimulating factor prophylaxis in adult cancer patients: from biological principles to clinical guidelines.

INTRODUCTION: Chemotherapy-induced neutropenia, the depth and length of which are correlated to the risk of febrile neutropenia (FN) and neutropenia sepsis, remains a serious problem in medical oncology. Granulocyte colony-stimulating factors (G-CSF) stimulate the proliferation and survival of neutrophils and their precursors, thereby reducing the incidence, duration and severity of neutropenic events across a broad range of malignancies and regimens, often enabling the delivery of full chemotherapy dose intensity. AREAS COVERED: In this review, areas covered include the physiologic role of G-CSF in granulopoiesis, as well as a related biological model of bone marrow kinetics after chemotherapy. Information relating to the application of clinical guidelines for optimization of prophylaxis of FN in adult cancer patients was critically summarized. The literature and pharmacological data were obtained through an electronic search. EXPERT OPINION: There are relevant physiological and clinical evidences for the use of G-CSF to prevent FN and to ameliorate the myelotoxicities of cancer chemotherapy. In particular, biological models are in favor of the prophylactic rather than therapeutic use of G-CSF therapy. Use of a single dose of pegfilgrastim per cycle in appropriate patients provides a more convenient and potentially more effective strategy for assisting neutrophil recovery. While biosimilars may cost less, future developments in their regulation will need to address multiple issues. In the interim, physicians should remember that small differences in biochemical and biophysical characteristics might translate into differences in potency and immunogenic potential.

Detection of erbB2 copy number variations in plasma of patients with esophageal carcinoma.

BACKGROUND: Mortality is high in patients with esophageal carcinoma as tumors are rarely detected before the disease has progressed to an advanced stage. Here, we sought to isolate cell-free DNA released into the plasma of patients with esophageal carcinoma, to analyze copy number variations of marker genes in the search for early detection of tumor progression. METHODS: Plasma of 41 patients with esophageal carcinoma was prospectively collected before tumor resection and chemotherapy. Our dataset resulted heterogeneous for clinical data, resembling the characteristics of the tumor. DNA from the plasma was extracted to analyze copy number variations of the erbB2 gene using real-time PCR assays. RESULTS: The real-time PCR assays for erbB2 gene showed significant (P = 0.001) copy number variations in the plasma of patients with esophageal carcinoma, as compared to healthy controls with high sensitivity (80%) and specificity (95%). These variations in erbB2 were negatively correlated to the progression free survival of these patients (P = 0.03), and revealed a further risk category stratification of patients with low VEGF expression levels. CONCLUSION: The copy number variation of erbB2 gene from plasma can be used as prognostic marker for early detection of patients at risk of worse clinical outcome in esophageal cancer.