A prognostic model in patients with advanced biliary tract cancer receiving first-line chemotherapy.

BACKGROUND: Standard treatment of advanced biliary tract cancer (aBTC) is represented by first-line chemotherapy (CT1). However, some patients do not gain any benefit from CT1, contributing to the overall dismal prognosis of aBTC. The present study aimed to devise a prognostic model in aBTC patients receiving CT1. METHODS: A large panel of clinical, laboratory, and pathology variables, available before the start of CT1, were retrospectively assessed in a multi-centric cohort to determine their prognostic value on univariate and multivariate regression analysis. The variables that showed a significant correlation with overall survival (OS) were computed in a three-tier prognostic score. External validation of the prognostication performance was carried out. RESULTS: Clinical histories of 935 patients (median OS 10.3 months), with diagnosis dates ranging from 2001 to 2017, were retrieved from 14 institutions. According to multivariate analysis, Eastern Cooperative Oncology Group performance status, carbohydrate antigen 19.9, albumin levels, and neutrophil/lymphocyte ratio were strongly associated with OS (p <0.01). The prognostic score could generate a highly significant stratification (all between-group p values ≤0.001) into groups of favorable (comprising 51.5% of the sample), intermediate (39.2%), and poor prognosis (9.3%): median OS was 12.7 (CI95% 11.0-14.4), 7.1 (CI95% 5.8-8.4), and 3.2 months (CI95% 1.7-4.7), respectively. This OS gradient was replicated in the validation set (129 patients), with median OS of 12.7 (CI95% 11.0-14.3), 7.5 (CI95% 6.1-8.9), and 1.4 months (CI95% 0.1-2.7), respectively (all between-group p values ≤0.05). CONCLUSION: A prognostic score, derived from a limited set of easily-retrievable variables, efficiently stratified a large population of unselected aBTC patients undergoing CT1. This tool could be useful to clinicians, to ascertain the potential benefit from CT1 at the start of treatment.

Selecting patients for gastrectomy in metastatic esophago-gastric cancer: clinics and pathology are not enough.

AIM: To evaluate the impact on overall survival (OS) of gastrectomy in asymptomatic metastatic esophago-gastric cancer. PATIENTS & METHODS: Five hundred and thirteen patients were included. The role of surgery and other clinico-pathological factors was evaluated by univariate and Cox regression analyses. OS was the primary end point. RESULTS: Multivariate analysis confirmed that gastrectomy was a predictor of longer OS (p < 0.001), as well as preserved performance status and benefit from first-line chemotherapy. None of the investigated clinico-pathological variables identified preferable candidates for surgery (all p > 0.05). CONCLUSION: Palliative gastrectomy might play a role in asymptomatic metastatic esophago-gastric cancer patients with good performance status who received benefit from first-line chemotherapy. Future prospective trials integrating tumor biology among inclusion criteria may help defining the optimal candidates.

MGMT promoter methylation status in brain metastases from colorectal cancer and corresponding primary tumors.

BACKGROUND: Brain metastases (BM) from colorectal cancer are usually associated with poor prognosis. The aim of this retrospective study is to evaluate MGMT promoter methylation in BM and their corresponding primary colorectal cancer tumors. MATERIALS & METHODS: MGMT promoter methylation status was assessed by pyrosequencing in 53 consecutive patients resected for BM. A concordance analysis between BM and matched primary tumor was performed in 39 cases. RESULTS: MGMT methylation was found in 34 (64.2%) BM and in 25 corresponding primary tumors (64.1%). Median survival after neurosurgery was independent from MGMT promoter methylation (163 days for those with methylated MGMT versus 193 days for the unmethylated). CONCLUSION: Epigenetic MGMT promoter methylation was common and the concordance between primary and secondary lesions was high.

Prognostic role of KRAS, NRAS, BRAF and PIK3CA mutations in advanced colorectal cancer.

AIM: To explore the prognostic value of extended mutational profiling for metastatic colorectal cancer (mCRC). MATERIALS & METHODS: We retrospectively reviewed survival results of 194 mCRC patients that were assigned to four molecular subgroups: BRAF mutated; KRAS mutated codons 12-13 only; any of KRAS codons 61-146, PIK3CA or NRAS mutations and all wild-type. Point mutations were investigated by pyrosequencing. RESULTS: BRAF (5.2%) and KRAS 12-13 (31.9%) mutations were associated with poorer survival (HR 2.8 and 1.76, respectively). Presenting with right-sided colon cancer, not resected primary tumor, WBC >10 × 10(9)/l, receiving less chemotherapy or no bevacizumab were all associated with inferior outcome. The all-wild-type subgroup (39.2%) reported the longest survival. CONCLUSION: Extended mutational profile combined with clinical factors may impact on survival in mCRC.

Risk of unplanned visits for colorectal cancer outpatients receiving chemotherapy: a case-crossover study.

AIM: This study was conducted to evaluate the impact of chemotherapy on the risk of unplanned visit in a cohort of colorectal cancer outpatients. Chief complaints for unplanned visits and risk factors for hospital admission were also analyzed. PATIENTS AND METHODS: Clinical data of 229 consecutive colorectal cancer patients who were unexpectedly presented to our acute oncology clinic between 2006 and 2009 were reviewed. A case-crossover statistical analysis was applied to study the association between exposure to chemotherapy (trigger event) and the occurrence of unplanned visit (acute outcome) in three time windows (7, 15, and 21 days from the closest previous chemotherapy treatment). Cox model was used to assess the risk factors for hospitalization. RESULTS: There were 469 unplanned visits registered. Most of the patients had Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 (80 %) and advanced cancer stage (78 %). The majority of unplanned visits (72 %) occurred within 30 days since last chemotherapy. The most frequent presenting complaints were pain, fatigue, and anorexia. The two time windows associated with higher risk of visit were 15 and 21 days from last treatment, both for early (odds ratio [OR] 3.8, CI 1.4-10.2 and OR 3.8, CI 1.4-10.2) and advanced disease stage (OR 1.71, CI 1-2.9 and OR 3, CI 1.5-5.9). Of the unplanned visits, 10 % resulted in hospital admission. Presenting with multiple symptoms and with deteriorated PS were both predictors for hospitalization. CONCLUSION: Chemotherapy exposition triggers the need for unplanned visits over the second and third week after treatment. The prompt and effective management of unexpected events may be cost- and time-saving and reduce pressure on oncology services.

From trial highlights to clinical context: putting American Society of Clinical Oncology gastrointestinal news into practice.

Celebrating its tenth anniversary, the Gastrointestinal Cancers Symposium is a world class, international conference focused on research and multidisciplinary management of digestive tract malignancies, co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the American Gastroenterological Association Institute and the Society of Surgical Oncology. This premium meeting was held from 24 to 26 January 2013 in San Francisco (CA, USA) and, in line with its principal mission, it sought to globally embrace prevention, screening, diagnostics, translational research and multimodal treatment, moving on three major anatomic tracks (upper gastrointestinal cancers, pancreatic/hepatobiliary tumors and colorectal malignancies). Over 2000 healthcare professionals gathered at this valuable 3day scientific event, which included plenary educational sessions and oral presentations of the top-rated abstracts, as well as the exposition of nearly 600 posters. This short article offers a summarized opinion-based overview of the most significant studies presented at the meeting that are likely to impact on clinical practice as well as new drug development, as best exemplified by the three most important messages of the whole meeting: the value of nanoparticle albumin-bound paclitaxel in metastatic pancreatic cancer; that of ramucirumab in second-line gastric cancer; and that of capecitabine and bevacizumab in elderly advanced colorectal cancer patients.

Clinical insights and prognostic factors from an advanced biliary tract cancer case series: a real-world analysis.

Advanced biliary tract cancer (aBTC) comprises a heterogeneous group of rare malignancies with dismal prognosis. Given the scarcity of prospective evidence, the aim of this study was to derive clinically useful insights and prognostic factors from a large, real-world series of aBTC. Clinicopathologic variables and treatment outcomes were retrospectively collected involving 940 patients diagnosed with aBTC between 2001 and 2017, and treated with first-line chemotherapy (CT1) at 14 Italian medical oncology institutions. Median overall survival (OS) was 10.3 months (CI95% 9.5-11.1). CT1 with gemcitabine-Platinum salts doublets achieved OS of 11.7 months vs 7.5 with gemcitabine alone (HR 0.67, p < 0.001). However, a clear temporal trend towards improved OS could not be demonstrated. Radical surgery of recurrent disease achieved a relapse-free survival of 5.9 months. A substantial minority (44.5%) of patients were able to receive a second-line chemotherapy, which achieved a response rate of 7.6%, and disease control in 30% of patients with no significant differences between combination regimens and monotherapies. In a large retrospective series of real-world aBTC, outcomes of standard CT1 closely resembled those of the registrational trials. A limited set of easily retrievable independent prognostic factors was defined. Further research is needed on second-line regimens.

Maintenance Therapy in Colorectal Cancer: Moving the Artillery Down While Keeping an Eye on the Enemy.

The survival improvement in metastatic colorectal cancer, achieved with more intensive chemotherapy regimens, has recently led clinicians to question the optimal duration of therapies and to consider the role of maintenance. Indeed, patients whose disease is controlled after induction chemotherapy may benefit from continuing a less intensive regimen in order to reinforce the results achieved with up-front treatment. In addition, the more favorable toxicity profile of maintenance approaches would ensure a better quality of life. After discussing the rationale and the difference of pursuing a maintenance strategy with chemotherapeutic and/or biologic agents, we present significant available data from the literature and comment on the current implications and future directions of maintenance therapy. The current roles of depotentiated treatment schedules, antiangiogenic compounds, epidermal growth factor receptor inhibitors, and novel targeted therapies are also reviewed. Finally, we address elements that may foster clinical and social debate on this topic, suggesting potential aspects that need to be further investigated.

Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: A critical insight.

Advanced gastric cancer ranks second as the global leading cause of cancer-related death and improvements in systemic chemotherapy have reached a plateau. Advanced molecular sequencing techniques help identifying patients more likely to respond to targeted agents; nevertheless we are still far from major breakthroughs. Although antiangiogenic drugs have produced notable advances, redundant pathways or mechanisms of resistance may limit their efficacy. Novel compounds have been recently developed to specifically target VEGF receptors, PlGF, FGF, MET, and angiopoietin. Ramucirumab, a monoclonal antibody specifically directed against the VEGFR-2, has emerged as a novel therapeutic opportunity. REGARD and RAINBOW were the first phase III studies to report the value of this strategy in gastric cancer patients, and other ongoing trials are testing novel antiangiogenic compounds. The aim of our review is to present the state-of-the-art of novel antiangiogenic compounds in advanced gastric cancer, underlying the biology, their mechanism of action, and their clinical results.

Bevacizumab and first-line chemotherapy for older patients with advanced colorectal cancer: final results of a Community-based Observational Italian Study.

BACKGROUND: Although the efficacy and safety of combining first-line chemotherapy with bevacizumab in elderly patients with colorectal cancer (CRC) is supported by the results of a phase III trial, real-practice data are limited. PATIENTS AND METHODS: Our multi-center, community-based observational study included 233 elderly patients with CRC (median age=73 years, range=70-84 years). Baseline comorbidities and geriatric evaluation were also analyzed. Pre-specified end-points of the study were safety, tolerability and outcome results. RESULTS: The incidence of both chemotherapy-induced and specific bevacizumab-related toxicities was low, and not influenced by baseline concurrent morbidities. Median progression free survival (PFS) and median overall survival (OS) were 9.9 months and 23.6 months, respectively. Fifty-six percent of patients received second-line chemotherapy. CONCLUSION: The upfront treatment of older patients with CRC with chemotherapy and bevacizumab is safe and efficacious in a real-world setting. No un expected toxicities were reported. Multi-dimensional geriatric evaluation is under-used in clinical practice.

Timing and extent of response in colorectal cancer: critical review of current data and implication for future trials.

The identification of new surrogate endpoints for advanced colorectal cancer is becoming crucial and, along with drug development, it represents a research field increasingly studied. Although overall survival (OS) remains the strongest trial endpoint available, it requires larger sample size and longer periods of time for an event to happen. Surrogate endpoints such as progression free survival (PFS) or response rate (RR) may overcome these issues but, as such, they need to be prospectively validated before replacing the real endpoints; moreover, they often bear many other limitations. In this narrative review we initially discuss the role of time-to-event endpoints, objective response and response rate as surrogates of OS in the advanced colorectal cancer setting, discussing also how such measures are influenced by the tumor assessment criteria currently employed. We then report recent data published about early tumor shrinkage and deepness of response, which have recently emerged as novel potential endpoint surrogates, discussing their strengths and weaknesses and providing a critical comment. Despite being very compelling, the role of such novel response measures is yet to be confirmed and their surrogacy with OS still needs to be further investigated within larger and well-designed trials.

Panitumumab after progression on cetuximab in KRAS wild-type metastatic colorectal cancer patients: a single institution experience.

AIMS AND BACKGROUND: Few data describe the activity of panitumumab after cetuximab-irinotecan-based regimen failure in patients with KRAS wild-type metastatic colorectal cancer (WT MCRC). METHODS: The aim of this study is to assess if panitumumab has some activity in this setting. RESULTS: We retrospectively analyzed 25 patients with KRAS WT MCRC who received panitumumab from July 2009 to January 2013 after progression on cetuximab. All patients had previously received cetuximab and irinotecan (20 patients) or oxaliplatin (5 patients). We withdrew cetuximab for intolerance in 4 patients (16%). Twenty-one patients (84%) who had previously responded to cetuximab (overall response rate [ORR] plus stable disease ≥5 months) received panitumumab off-label after progression on cetuximab because they were strongly motivated to continue treatment without chemotherapy. The median number of cycles of panitumumab was 7 (range 1-54). Only 20 patients were evaluable for ORR (5 patients received 1-2 cycles and then died). We observed 1 (5%) partial response, 5 (25%) stable disease, median duration 9 months. Median progression-free survival (PFS) and overall survival (OS) were 5 (3-28) and 8 (5-41) months, respectively. All patients were evaluable for toxicity. No patients developed anemia or neutropenia. One patient (4%) developed grade 2 thrombocytopenia, 8 patients (32%) grade 2-3 dry skin or rash, and 2 patients (8%) grade 2 nausea-vomiting (Common Terminology Criteria for Adverse Events version 4.03). CONCLUSIONS: Our data, with all the limits of a retrospective analysis, show longer PFS and OS as compared to other series in the same setting, demonstrating that panitumumab has treatment effectiveness in patients with KRAS WT MCRC who progressed on prior cetuximab. Further confirmatory prospective studies with a larger series of patients are necessary.

Evidence-based appraisal of the upfront treatment for unresectable metastatic colorectal cancer patients.

Colorectal cancer (CRC) is a significant health problem, with around 1 million new cases and 500000 deaths every year worldwide. Over the last two decades, the use of novel therapies and more complex treatment strategies have contributed to progressively increase the median survival of patients with unresectable advanced CRC up to approximately 30 mo. The availability of additional therapeutic options, however, has created new challenges and generated more complicated treatment algorithms. Moreover, several clinically important points are still in debate in first-line, such as the optimal treatment intensity, the most appropriate maintenance strategy, the preferred biologic to be used upfront in patients with KRAS wild-type CRC, and the need for more detailed information on tumor biology. In this moving landscape, this review analyses why the first-line treatment decision is crucial and how the choice may impact on further treatment lines. In addition, it focuses on results of major phase III randomized trials.