Introduction: Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. In the last 10 years, clinical trials have established ...multitargeted tyrosine kinase inhibitors (TKIs) as the standard first-line treatment in patients with metastatic disease. Multiple agents are now available for treatment in subsequent lines.The mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus alone or with lenvatinib) are among the most effective options.
Areas covered: This paper provides a complete and updated overview on mTOR inhibitors for the treatment of advanced RCC. The authors revised the results of the most recent completed clinical trials and provided information about ongoing trials.
Expert opinion: mTOR pathway still represents an important driver for RCC management. Combination of everolimus and lenvatinib is considered a category 1 choice with cabozantinib and nivolumab for subsequent therapy in metastatic RCC according to NCCN guidelines v2.2017. These three treatments (levantinib/everolimus, cabozantinib, and nivolumab) all resulted in a superior efficacy compared to everolimus alone. Moreover, mTOR inhibitors, and in particular temsirolimus for poor risk patients, are available choices for treatment in non-clear cell carcinomas together with TKIs.
Abstract Introduction Major pathologic regression after neoadjuvant therapy is a strong and favorable prognostic factor in several types of cancer (breast, rectal and bladder). This information is ...less clear and has yet to be systematically evaluated in upper gastrointestinal tumors. We performed a meta-analysis to evaluate the prognostic impact of tumor regression after preoperative therapy on disease-free survival (DFS) and overall survival (OS) in gastroesophageal cancer patients. Methods we searched for relevant articles in PubMed, SCOPUS, Web of Science, CINAHL, LILACS, Ovid, Cochrane Library, Google Scholar and Embase up to June 2, 2016. Data of tumor regression (complete or near-complete pathologic response) that independently correlated with OS and DFS in multivariate analysis were extracted, and the proper hazard ratios (HRs) with corresponding 95% confidence intervals (95% CIs) were pooled according to the random effect model. Results a total of 17 studies—which included 3,145 patients—were considered in the final analysis. Major pathologic response was significantly related with better OS (HR 0.46, 95% CI 0.32–0.66, P<0.001) and DFS (HR=0.40, 95%CI 0.26-0.62, P<0.001). Pathologic complete response (pCR) or major tumor regression were associated with the same degree of benefit in outcome compared to no or minimal pathologic regression, regardless of histology. Conclusion major pathologic response is associated with a significant improvement in OS compared to no response or minor pathologic changes after neoadjuvant therapy in gastroesophageal cancers. This should be considered a robust prognostic factor to guide postoperative treatment and follow-up.
No structured modality for providing information and support to patients in oncology wards has been validated in clinical trials.
This is a pragmatic, two-arm, cluster randomized trial, with the ...oncology ward as random assignment unit. Centers were allocated to implement a Point of Information and Support (PIS) or to a control group. The PIS included a library for cancer patients and a specifically trained oncology nurse. End points, measured at patient level, were psychological distress and satisfaction with received information. Both intent-to-treat and per-protocol analyses considering clustering were performed.
Thirty-eight Italian cancer centers were randomly assigned, and 6 months after PIS creation, 3,286 unselected, consecutive cancer patients were surveyed (1,654 in the experimental group and 1,632 in the control group). Three thousand one hundred ninety-seven (97%) questionnaires were collected and deemed valid. Fifty-two percent of centers (11 of 21 centers) in the experimental arm did not implement the PIS in accordance with the protocol. Overall, 34% of patients showed moderate to severe psychological distress, and only 9% declared dissatisfaction. Intent-to-treat analysis did not yield significant differences. Although the per-protocol analysis did show a reduction in psychological distress (28.9% for functioning PIS v 33.3% for no PIS) and dissatisfaction (6.4% for functioning PIS v 9.3% for no PIS), differences did not reach significance.
This is the first cluster randomized trial aiming to demonstrate that a structured modality of providing information reduces psychological distress. We did not find this, but we believe results should be interpreted cautiously, particularly because of the low compliance with PIS implementation. Context analysis preceding such interventions is essential.
Despite the efforts of the scientific community, the prognosis of metastatic colorectal cancer (mCRC) remains poor. Actionable gene fusions such as Neurotrophic Tropomyosin Receptor Kinases (NTRK) ...rearrangements are rare but might represent a new target to improve outcomes in this setting. The first-generation TRK inhibitors, larotrectinib and entrectinib, have demonstrated efficacy and safety in mCRC cancer patients exhibiting NTRK pathogenic fusions. Moreover, second-generation molecules are emerging, able to overcome the acquired resistance to NTRK blocking.
This review aims to report the current knowledge and the available evidence on NTRK fusion in mCRC, with a focus on molecular bases, clinical characteristics, prognostic meaning, and new therapeutic approaches, from the perspective of the clinical oncologist.
Considering the limited options associated with the treatment of mCRC patients, the possibility of identifying new molecular biomarkers is an urgent clinical need. The availability of new molecular targets and the combinations of different agents might represent the true breakthrough point, allowing for change in the clinical course of colorectal cancer patients.
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Background: The potential of monitoring circulating tumor DNA (ctDNA) dynamics to guide clinical decisions in metastatic colorectal cancer (mCRC) patients (pts) treated with I and II line ...systemic anti-cancer therapy (SACT) has not been widely tested. Methods: 862 serial plasmas were collected 4-weekly from baseline (BL) until disease progression in 75 mCRC pts undergoing SACT. ctDNA was tested using a custom (RMH GI; 20 genes) or a commercial (Roche Avenio; 77 genes) ctDNA next generation sequencing (NGS) panel. White blood cells were sequenced to rule out clonal hematopoiesis. Whole exome sequencing (WES) was performed on tissue biopsies. ctDNA normalization was defined as ≥99% clearance after 1 month of therapy (Mo1) in the 3 variants with the highest allele frequency in BL ctDNA. Results: 83 paired samples from 75 pts were available for analysis (for 8 pts, I and II line bloods were available). 12 pairs (14.4%) showed no variants in either BL or Mo1. In the remaining 71 comparisons (65 pts), 37 (52.1%) showed ctDNA normalization at Mo1. Among normalized pts there was a higher proportion of cases with a baseline ECOG performance status (PS) 0-1 (97.3% vs 82.4%, p = 0.0362) in comparison to non-normalized pts, whilst no other clinic-pathologic characteristics, including age, sex, prior primary tumor resection, sidedness, RAS/RAF genotype, type of regimen and number of metastatic sites were significantly associated with ctDNA dynamics. Pts with normalized ctDNA had significantly longer overall survival (OS), 45.6 months (95% confidence interval CI: 30.0 - not reached, 14 events) and progression-free survival (PFS), 13.9 months (95%CI: 11.2-18.3; 30 events) compared to non-normalized pts OS = 22.6 months (95%CI: 16.6-31.2, 24 events) (Log-rank p = 0.01) and PFS = 10.7 months (95%CI: 7.53-13.8; 32 events) (Log-rank p = 0.036) respectively. In addition, pts with normalized ctDNA had higher overall response rate (ORR) of 72.9% (27/37 responses; 95%CI: 53.0-84.1) compared to 38.2% (13/34 responses; 95%CI: 22.1 – 56.4) in non-normalized pts. In a multivariate model, ctDNA normalization was confirmed as an independent predictor of decreased risk of death (hazard ratio HR 0.47, 95%CI: 0.23-0.96; p = 0.04) and higher probability of achieving an objective response from front-line treatment (odds ratio OR 3.03, 95%CI: 1.08-8.49; p = 0.0351). Only 23/50 (46%) of variants detected in ctDNA were detected by WES in paired tissues in 12 pts for whom liquid/solid biopsy was available. Conclusions: ctDNA monitoring represents an early indicator of benefit from systemic therapy in mCRC pts. A significant fraction of variants detected in ctDNA was not detected in paired tissues.
IntroductionOur group previously demonstrated the feasibility of the HuCare Quality Improvement Strategy (HQIS), aimed at integrating into practice six psychosocial interventions recommended by ...international guidelines. This trial will assess whether the introduction of the strategy in oncology wards improves patient’s health-related quality of life (HRQoL).Methods and analysisMulticentre, incomplete stepped-wedge cluster randomised controlled trial, conducted in three clusters of five centres each, in three equally spaced time epochs. The study also includes an initial epoch when none of the centres are exposed to the intervention, and a final epoch when all centres will have implemented the strategy. The intervention is applied at a cluster level, and assessed at an individual level with cross-sectional model. A total of 720 patients who received a cancer diagnosis in the previous 2 months and about to start medical treatment will be enrolled. The primary aim is to evaluate the effectiveness of the HQIS versus standard care in terms of improvement of at least one of two domains (emotional and social functions) of HRQoL using the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items) questionnaire, at baseline and at 3 months. This outcome was chosen because patients with cancer generally exhibit low HRQoL, particularly at certain stages of care, and because it allows to assess the strategy’s impact as perceived by patients themselves. The HQIS comprises three phases: (1) clinician training—to improve communication-relational skills and instruct on the project; (2) centre support—four on-site visits by experts of the project team, aimed to boost motivation, help with context analysis and identification of solutions; (3) implementation of Evidence-Based Medicine (EBM) recommendations at the centre.Ethics and disseminationEthics committee review approval has been obtained from the Ethics Committee of Parma. Results will be disseminated at conferences, and in peer-reviewed and professional journals intended for policymakers and managers.Trial registration number NCT03008993; Pre-results.
CDX2 is a homeobox gene encoding transcriptional factors for intestinal organogenesis and represents a specific marker of colorectal adenocarcinoma (CRC) differentiation. We have evaluated if CDX2 ...expression is associated with better overall and disease-free survival (OS and DFS) in patients with CRC. PubMed, SCOPUS, EMBASE, The Cochrane Library, and Web of Science (from inception to July 2017) were systematically reviewed for relevant studies on adult patients with CRC where OS and DFS were calculated according to CDX2 expression in uni- or multivariate analysis were included. Hazard ratio (HR) for mortality and/or disease progression was calculated. The search produced 16 studies suitable for inclusion (6291 individual patients). The meta-analysis showed a reduced risk of death for patients with CDX2-positive CRC in 14 studies (HR, 0.5; 95% confidence interval CI, 0.38-0.66; P < .001 according to random effect model). In 6 studies where only DFS data was available, CDX2 expression led to a 52% lower risk of relapse or death (HR, 0.48; 95% CI, 0.39-0.59; P < .001 according to random effect model). The results did not change as a function of ethnicity, type of study, CDX2 detection modality, or stage. Interestingly, in stages II to III, CDX2 expression was associated with a 70% lower risk of death (HR, 0.3; 95% CI, 0.12-0.77; P = .01). CDX2 expression confirms to be a strong prognostic factor in stage II and III CRC. In this setting, along with other clinical and pathologic factors, the lack of expression of CDX2 may be considered an important variable when deciding for adjuvant chemotherapy.
The use of adjuvant treatment (AT) in resected biliary tract cancers (BTC) is still controversial. No efficacy comparison has been performed between chemotherapy (CT) and chemoradiotherapy (CTRT). A ...systematic review of the available evidence regarding adjuvant chemotherapy (AC) in resected BTC was performed.
PubMed, EMBASE, Web of Science, SCOPUS and The Cochrane Library databases were searched for relevant articles published. Only studies including at least 50 patients affected by tumors of gallbladder, intrahepatic, perihilar, and distal bile ducts were considered. Data were pooled using a random-effects model. The primary endpoint of the study was overall survival (OS).
Thirty studies were analyzed with a total of 22,499 patients, 3967 of whom received AC. Eleven cohorts included Western patients and 19 were Asiatic. Surgeries were classified as R0 with negative margins, R1 with positive microscopic and R2 with positive macroscopic margins. Weighted mean OS difference among experimental (AC) and control arm was 4.3 months (95% CI 0.88–7.79, P = 0.014). AC reduced the risk of death by 41% (Hazard ratio HR = 0.59, 95% CI 0.49–0.71; P < 0.001).
AC administration gives an OS benefit in resected BTC. The results of prospective randomized studies are awaited in order to define the standard AT in BTC.
Combination of docetaxel, cisplatin, and 5-fluorouracil (DCF) is an active but not well-tolerated regimen for advanced gastric cancer (GC) with standard 3-weekly doses. Several modified schedules ...(mDCFs) have been designed to reduce acute toxicities and improve feasibility as first-line therapy in patients with metastatic GC. The objective of this systematic review was to evaluate overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade (G) greater than or equal to 3 adverse event of mDCF chemotherapy in this setting. MEDLINE, SCOPUS, Embase, Web of Science, LILACS, CINAHL, Google Scholar, and the Cochrane Library were searched for studies with mDCF schedules in advanced GC. Pooled median OS, PFS, ORR (the primary endpoints), and G3 or G4 adverse events (secondary endpoints) were presented according to random effect model. Twenty-four studies were included for a total of 1311 patients, with weekly or biweekly (n=11) and reduced doses 3-weekly (n=13) schedules. The median pooled PFS and OS were 7.2 months 95% confidence interval (CI)5.9–8.8 and 12.3 months (95% CI10.6–14.3), respectively. Among 23 studies with available data for ORR, the pooled result was 49% (95% CI43.4–54.4). The incidence of grade 3/4 neutropenia, thrombocytopenia, anemia, febrile neutropenia, stomatitis, diarrhea, nausea+vomiting, and neurotoxicity were 29.1, 5.6, 8.9, 7.6, 6.6, 4.9, and 9.9%, respectively. mDCF chemotherapy with splitted weekly or biweekly schedules, or reduced 3-weekly doses, is a very effective and well-tolerated regimen in metastatic GC. By providing a 50% ORR, such regimens may be particularly indicated for younger and fit patients for cytoreductive purposes (conversion therapy) or in case of symptomatic tumor burden.
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Background: The EDOI Study (EUDRACT 2018-003833-14) was designed to evaluate venous thromboembolism (VTE), a common complication of cancer and cancer therapy. VTE contributes to mortality and ...morbidity, and may interfere with therapy. When drafting the protocol, the standard treatment for VTE consisted of low-molecular weight heparin followed by vitamin K antagonists. DOACs are as effective as vitamin K antagonists in the treatment of VTE. Edoxaban has been confirmed to be effective and safe in the treatment of VTE. Adverse events (AEs) associated with DOACs can delay or interfere with chemotherapy; to date, data regarding the impact of Edoxaban treatment on cancer treatment AEs are scanty. Methods: In this multicentric, phase IV study, patients receiving an antineoplastic treatment (and candidates for at least 3 additional months of treatment) and diagnosed with VTE, received Edoxaban as per clinical practice. Patients received between 6 and 12 months of Edoxaban and were evaluated at baseline and after 1, 3 and 6 months. Primary endpoint was the impact of Edoxaban-related AEs on antineoplastic therapy, defined as delays/interruptions/reductions due to adverse drug reactions (ADR) related to Edoxaban (bleeding, hepatobiliary toxicity, renal toxicity, anemia, hypersensitivity reactions). As secondary endpoint, we assessed patient-reported outcomes (PROs) during treatment with Edoxaban (health-related quality of life: FACT-G, expectations and satisfaction with anticoagulant treatment: PACT-Q2 and ACTS). For each tool, mean scores at each time point were calculated. Results: One hundred and fifty patients were enrolled, 147 patients were evaluable. The Incidence density rate of antineoplastic therapy delay/interruption/reduction due to ADR related to Edoxaban was 0,8% per person-month (90% CI: 0,4; 1,5% and 95% CI: 0,4; 1,6%). For all the patient-reported outcomes, mean scores were maintained at different time points. Conclusions: The results of the study clearly show that the edoxaban treatment is well tolerated and has no relevant impact on the delivery of cancer treatments. Results in terms of quality of life and patients’ satisfaction with anticoagulant treatment are reassuring. Clinical trial information: EUDRACT 2018-003833-14 . Table: see text
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