Peripheral cytokine levels as a prognostic indicator in gastric cancer : a review of existing literature

Although strong connections exist between the carcinogenesis of gastric cancer and chronic inflammation, gastric cancer is unique in that the chronic gastritis which frequently precedes carcinogenesis is strongly associated with H. pylori infection. The interplay between H. pylori virulence factors and host immune cells is complex but culminates in the activation of inflammatory pathways and transcription factors such as NF-κB, STAT3, and AP-1, all of which upregulate cytokine production. Due to the key role of cytokines in modulating the immune response against tumour cells as well as possibly stimulating tumour growth and proliferation, different patterns of cytokine secretion may be associated with varying patient outcomes. In relation to gastric cancer, interleukin-6, 8, 10, 17A, TNF, and IFN-γ may have pro-tumour properties, although interleukin-10, TNF, and IFN-γ may have anti-tumour effects. However, due to the lack of studies investigating patient outcomes, only a link between higher interleukin-6 levels and poorer prognosis has been demonstrated. Further investigations which link peripheral cytokine levels to patient prognosis may elucidate important pathological mechanisms in gastric cancer which adversely impact patient survival and allow treatments targeting these processes to be developed

Web-based patient-reported outcome measures for personalized treatment and care (PROMPT-Care) : multicenter pragmatic nonrandomized trial

Background: Despite the acceptability and efficacy of e–patient-reported outcome (ePRO) systems, implementation in routine clinical care remains challenging. Objective: This pragmatic trial implemented the PROMPT-Care (Patient Reported Outcome Measures for Personalized Treatment and Care) web-based system into existing clinical workflows and evaluated its effectiveness among a diverse population of patients with cancer. Methods: Adult patients with solid tumors receiving active treatment or follow-up care in four cancer centers were enrolled. The PROMPT-Care intervention supported patient management through (1) monthly off-site electronic PRO physical symptom and psychosocial well-being assessments, (2) automated electronic clinical alerts notifying the care team of unresolved clinical issues following two consecutive assessments, and (3) tailored online patient self-management resources. Propensity score matching was used to match controls with intervention patients in a 4:1 ratio for patient age, sex, and treatment status. The primary outcome was a reduction in emergency department presentations. Secondary outcomes were time spent on chemotherapy and the number of allied health service referrals. Results: From April 2016 to October 2018, 328 patients from four public hospitals received the intervention. Matched controls (n=1312) comprised the general population of patients with cancer, seen at the participating hospitals during the study period. Emergency department visits were significantly reduced by 33% (P=.02) among patients receiving the intervention compared with patients in the matched controls. No significant associations were found in allied health referrals or time to end of chemotherapy. At baseline, the most common patient reported outcomes (above-threshold) were fatigue (39%), tiredness (38.4%), worry (32.9%), general wellbeing (32.9%), and sleep (24.1%), aligning with the most frequently accessed self-management domain pages of physical well-being (36%) and emotional well-being (23%). The majority of clinical feedback reports were reviewed by nursing staff (729/893, 82%), largely in response to the automated clinical alerts (n=877). Conclusions: Algorithm-supported web-based systems utilizing patient reported outcomes in clinical practice reduced emergency department presentations among a diverse population of patients with cancer. This study also highlighted the importance of (1) automated triggers for reviewing above-threshold results in patient reports, rather than passive manual review of patient records; (2) the instrumental role nurses play in managing alerts; and (3) providing patients with resources to support guided self-management, where appropriate. Together, these factors will inform the integration of web-based PRO systems into future models of routine cancer care

Health-related quality of life during chemoradiation in locally advanced rectal cancer : impacts and ethnic disparities

Aims: There is limited data on health-related quality of life (HRQoL) in locally advanced rectal cancer. We assessed HRQoL before, during and after neoadjuvant chemoradiation, correlated this to corresponding clinician-reported adverse events (CR-AEs) and explored disparities between patients of Asian ethnicity versus Caucasians. Correlation between HRQoL and treatment response was also assessed. Methods: A consecutive sample of patients was recruited. HRQoL was assessed with the EORTC QLQ-C30 before chemoradiation, week three of chemoradiation and one-week pre-surgery. Clinical variables including CR-AEs were recorded at these time-points. Patients self-reported socio-demographic variables. Treatment response was assessed by the tumour regression grade. HRQoL data were analysed with multilevel models. Results: Fifty-one patients were recruited. HRQoL completion rates were ≥86%. Cognitive and role functioning worsened significantly during treatment. Emotional, role and social functioning improved significantly at pre-surgery. Fatigue and nausea/vomiting worsened during treatment while fatigue, appetite loss, diarrhoea and financial difficulties improved from treatment to pre-surgery. Almost 30% of the cohort were Asian ethnicity. Differences were found in multiple HRQoL domains between Asians and Caucasians, with Asians faring worse. Significant differences were evident in physical, role and cognitive functioning, and in seven out of the 8 symptom scales. The correlation between patient-reported outcomes and clinician-reported outcomes was weak, with diarrhoea having the strongest correlation (r = 0.58). Vomiting during treatment correlated with poor response, whilst baseline constipation correlated with good response. Conclusion: Chemoradiation for locally advanced rectal cancer affects multiple HRQoL domains. Our findings highlight the importance of psychological aspects of treatment. Significant differences were identified between the Asian and Caucasian populations, with Asians consistently performing worse. Poor correlations between patient and clinician reporting strongly support the inclusion of patient-reported outcomes in clinical studies. HRQoL domains of vomiting and constipation are potential biomarkers of treatment response

Nutritional status, management and clinical outcomes in patients with esophageal and gastro-oesophageal cancers : a descriptive study

Aim: The aims of this study were to investigate the nutritional management practice and nutritional status of patients with oesophageal and gastro-oesophageal cancers, and to propose strategies for improving their nutritional and clinical outcomes. Methods: All patients diagnosed with oesophageal and gastro-oesophageal cancers and treated with chemotherapy and/or radiotherapy at the Liverpool Cancer Therapy Centre (between August 2010 and February 2014) were included in this retrospective study. Patient and tumour characteristics, nutritional status and management were compared to clinical outcomes. Results: A total of 69 patients met the inclusion criteria. The median weight loss prior to treatment commencement was 10.5% (Interquartile Range (IQR) = 6.6–15.4). A decline in nutritional status continued throughout the treatment course. The median percentage of weight loss during treatment was 3.53% (IQR = 0.00–6.84). Seven and 19 patients required nutrition intervention using a feeding tube or stent insertion to manage dysphagia, respectively. In patients treated with a curative intent, radiotherapy was completed in 100% of those with a nasogastric tube insertion as compared to 80% who had a stent insertion. There was a higher percentage of patients from culturally and linguistically diverse (CALD) background, experiencing significant weight loss when compared with their non-CALD counterparts (P = 0.04). Conclusions: Patients with oesophageal and gastro-oesophageal cancers commonly present with significant weight loss and this continues during the course of their anti-cancer treatment. A standardised protocol of nutrition management for these cancer patients is recommended, focusing on assisting patients from CALD backgrounds

The value of first‐line chemotherapy and targeted therapy in the treatment of breast cancer

Objective: To investigate the value (survival benefit and cost) of first-line chemotherapy and targeted therapy in breast cancer at a population level. Methods: Based on guideline recommendations, a model of optimal utilisation was constructed for first-line chemotherapy and targeted therapy in breast cancer, calculating the survival benefit and average cost of all regimens recommended for each treatment indication at 5 years and at 10 years. Results: Survival benefits from chemotherapy and targeted therapy differ markedly depending on the treatment indications. The cost per life-year gained at 5 years is $38,044 for stages I and II,$33,749 for stage III and $151,668 for patients presenting with stage IV breast cancer. The cost per life-year gained at 10 years is$ 13,587 for early breast cancer. The most expensive chemotherapy indication in breast cancer is the treatment of metastatic HER2-positive breast cancer costing $330,978 per LYG for a survival benefit of 11% at 5 years falling to zero survival benefit at 10 years. Conclusion: There are large differences in value between the different indications for first-course chemotherapy and targeted therapy in the treatment of breast cancer that should be considered when pricing cancer drugs

The prognostic value of fluorodeoxyglucose positron emission tomography metabolic tumor volume in solitary colorectal liver metastasis

Background: Management of colorectal liver metastasis (CRLM) is evolving but surgery remains the most effective treatment in improving survival. Optimal preoperative patient selection is important and semi-quantitative F-18 fluorodeoxyglucose positron emission tomography (PET) parameters may provide valuable prognostic information. Methods: Sixty-one patients with solitary CRLM as first site of distant dissemination and preoperatively staged with PET were retrospectively studied. Various semi-quantitative PET parameters, pathological size of the hepatic lesion and clinical variables were correlated with survival outcome. The data were analyzed with nonparametric Kruskal–Wallis test and univariate Cox regression. Kaplan–Meier estimates of overall survival and disease-free survival (DFS) were log-rank tested. Results: Mean follow-up for the 61 subjects was 48 months. The 1- and 3-year survival rates were 98.7% and 72.2%. The median DFS was 16 months with recurrence in 10 (16.4%) patients following surgery. Univariate analysis found a statistically significant increased risk of death for higher mean PET tumor diameter (hazard ratio [HR] 2.95, P = 0.014), mean metabolic tumor volume (HR 3.0, P = 0.009) and median pathological size of hepatic lesion (HR 2.97, P = 0.022).Maximum standardized uptake value of the liver metastasis and calculated standardized uptake value ratio between tumor and normal liver parenchyma (tumor background ratio) were not predictive of overall survival. None of the PET parameters or clincopathological variables statistically correlated with DFS. Conclusion: Semiquantitative PET variables are potentially valuable prognostic biomarkers in CRLM. Volumetric data like metabolic tumor volume enable better estimation of tumor burden and its utility may improve preoperative risk stratification and optimize outcome

An Australian three-centre feasibility study of neoadjuvant modified FOLFIRINOX and stereotactic body radiotherapy for locally advanced pancreatic cancer with collection of baseline circulating tumor cells

Purpose/Objective(s): Stereotactic body radiotherapy (SBRT) has an increasing role for treatment of locally advanced pancreatic adenocarcinoma (LAPC). Selection of appropriate cases may be improved with identification of useful prognostic and predictive clinical biomarkers. This study aimed to establish the feasibility and safety of neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) chemotherapy followed by SBRT for patients with LAPC (including borderline resectable), and to identify a role for circulating tumor cells (CTCs) in prognostication. Materials/Methods: Eligible patients were enrolled to a three-center prospective pilot study (MASTERPLAN Pilot ACTRN12617001642370). Eligibility criteria included age > 18 years, histological confirmation of PA, ECOG 0-1, with confirmation of borderline resectable (BRPC) or unresectable LAPC according to NCCN guidelines. The initial patient cohort was enrolled in a sub-study, to collect peripheral blood CTCs at baseline (bCTCs) which was correlated with overall survival (OS), progression free survival (PFS) and locoregional relapse free survival (LRFS). Patients received 4 cycles of mFOLFIRINOX (oxaliplatin, irinotecan, 5- fluorouracil), followed by insertion of pancreatic fiducials and 5 fractions of SBRT to a dose of 30Gy with a simultaneous integrated boost to 45Gy, determined by proximity to organs at risk. Acute toxicity was collected to 3 months post-SBRT. Results: Between April 2018 and October 2019, 12 patients were enrolled (initial 10 to the bCTC sub-study). The median follow-up from diagnosis was 10 months (range 4-18). Three patients did not commence treatment after enrollment, and 2 patients did not proceed to SBRT after mFOLFIRINOX. Seven patients with a median age of 62 years completed trial therapy. The median CA19.9 at baseline was 225kU/L (range 1-2558), 72% had BRPC and 57% were lymph node positive. One patient with BRPC proceeded to resection with positive surgical margins. At the time of evaluation, two further patients with BRPC were awaiting re-evaluation prior to surgery. Of those alive at 6 and 12 months follow up, local control was achieved in 83.3% and 66.7% of patients respectively. The first patient experienced acute Grade 3 neutropenia. Thereafter, G-CSF was administered with mFOLFIRINOX and no further Grade 3 toxicities were seen. Six patients experienced Grade 2 acute toxicity, and no patients developed Grade 4 toxicity. Nine patients had bCTCs collected, and of these, 6 completed trial therapy. The median number of CTCs was 11 per 8mls blood (range 1-12), and in this study bCTCs did not significantly correlate with OS, PFS or LRFS, however due to small numbers interpretation of this data is limited. Conclusion: Neoadjuvant mFOLFIRINOX with G-CSF and SBRT to 30- 45Gy is feasible and safe. A role of bCTCs in prognostication was not identified in this small study

[In Press] Utility of multigene panel next-generation sequencing in routine clinical practice for identifying genomic alterations in newly diagnosed metastatic nonsmall cell lung cancer

Background: The standard of care in newly diagnosed metastatic non-small cell lung cancer (NSCLC) is to test for aberrations in three genes for driver mutations – ALK, ROS1 and epidermal growth factor receptor (EGFR) – and also for immunohistochemistry to be performed for programmed death-ligand 1 expression level. Next-generation sequencing (NGS), with or without RNA fusion testing, is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) Tiers I–V and X. Aim: Our aim was to analyse NSCLC tumour samples for the prevalence of Tiers I–V mutations to establish guidance for current and novel treatments in patients with metastatic disease. Methods: NGS was performed employing the Oncomine Precision Assay (without RNA fusion testing) that interrogates DNA hotspot variants across 45 genes to screen 210 NSCLC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022. Results: In our cohort, 161 of 210 (77%) had at least one gene mutation identified, with 41 of 210 (20%) having two or more concurrent mutations. Tier I mutations included 42 of 210 (20%) EGFR mutations (EIA) and five of 210 (3%) MET exon 14 skipping mutations (EIB). Non-Tier I variants included 22 of 210 (11%) KRAS G12C hotspot mutations (EIIB), with a further 47 of 210 (22%) having non-G12C KRAS (EX) mutations. NGS testing revealed an additional 15% of cases with Tier II ESCAT mutations in NSCLC. Forty-six percent of patients also demonstrated potential Tier III and IV mutations that are currently under investigation in early-phase clinical trials. Conclusions: In addition to identifying patients with genomic alterations suitable for clinically proven standard-of-care therapeutic options, the 45-gene NGS panel has significant potential in identifying potentially actionable non-Tier 1 mutations that may become future standard clinical practice in NSCLC