Publications by authors named "Mark Saunders"

116 Publications

Kevin Kealy, M.V.M., M.R.C.V.S., D.V.R. (1921-2021).

Authors:
Mark Saunders

Vet Radiol Ultrasound 2021 Sep 28. Epub 2021 Sep 28.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/vru.13013DOI Listing
September 2021

Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME-RT).

Radiat Oncol 2021 Aug 26;16(1):163. Epub 2021 Aug 26.

Institute of Cancer Sciences, Glasgow Royal Infirmary, University of Glasgow, Room 2.57, Level 2, New Lister Building, Glasgow, G31 2ER, UK.

Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response.

Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m oxaliplatin, 350 mg folinic acid and 400 mg/m bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m 5-FU infusion over 46-48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease.

Discussion: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13014-021-01888-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393812PMC
August 2021

Accelerated Hypofractionated Image-Guided vs Conventional Radiotherapy for Patients With Stage II/III Non-Small Cell Lung Cancer and Poor Performance Status: A Randomized Clinical Trial.

JAMA Oncol 2021 Aug 12. Epub 2021 Aug 12.

Department of Radiation Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas.

Importance: A significant subset of patients with stage II/III non-small cell lung cancer (NSCLC) cannot receive standard concurrent chemoradiotherapy owing to the risk of toxic effects outweighing potential benefits. Without concurrent chemotherapy, however, the efficacy of conventional radiotherapy is reduced.

Objective: To determine whether hypofractionated image-guided radiotherapy (IGRT) would improve overall survival in patients with stage II/III NSCLC who could not receive concurrent chemoradiotherapy and therefore were traditionally relegated to receiving only conventionally fractionated radiotherapy (CFRT).

Design, Setting, And Participants: This nonblinded, phase 3 randomized clinical study enrolled 103 patients and analyzed 96 patients with stage II/III NSCLC and Zubrod performance status of at least 2, with greater than 10% weight loss in the previous 6 months, and/or who were ineligible for concurrent chemoradiotherapy after oncology consultation. Enrollment occurred at multiple US institutions. Patients were enrolled from November 13, 2012, to August 28, 2018, with a median follow-up of 8.7 (3.6-19.9) months. Data were analyzed from September 14, 2018, to April 11, 2021.

Interventions: Eligible patients were randomized to hypofractionated IGRT (60 Gy in 15 fractions) vs CFRT (60 Gy in 30 fractions).

Main Outcomes And Measures: The primary end point was 1-year overall survival.

Results: A total of 103 patients (96 of whom were analyzed [63 men (65.6%); mean (SD) age, 71.0 (10.2) years (range, 50-90 years)]) were randomized to hypofractionated IGRT (n = 50) or CFRT (n = 46) when a planned interim analysis suggested futility in reaching the primary end point, and the study was closed to further accrual. There was no statistically significant difference between the treatment groups for 1-year overall survival (37.7% [95% CI, 24.2%-51.0%] for hypofractionated IGRT vs 44.6% [95% CI, 29.9%-58.3%] for CFRT; P = .29). There were also no significant differences in median overall survival, progression-free survival, time to local failure, time to distant metastasis, and toxic effects of grade 3 or greater between the 2 treatment groups.

Conclusions And Relevance: This phase 3 randomized clinical trial found that hypofractionated IGRT (60 Gy in 15 fractions) was not superior to CFRT (60 Gy in 30 fractions) for patients with stage II/III NSCLC ineligible for concurrent chemoradiotherapy. Further studies are needed to verify equivalence between these radiotherapy regimens. Regardless, for well-selected patients with NSCLC (ie, peripheral primary tumors and limited mediastinal/hilar adenopathy), the convenience of hypofractionated radiotherapy regimens may offer an appropriate treatment option.

Trial Registration: ClinicalTrials.gov Identifier: NCT01459497.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2021.3186DOI Listing
August 2021

Three Versus Six Months of Adjuvant Doublet Chemotherapy for Patients With Colorectal Cancer: A Multi-Country Cost-Effectiveness and Budget Impact Analysis.

Clin Colorectal Cancer 2021 09 15;20(3):236-244. Epub 2021 Apr 15.

Health Economics and Health Technology Assessment, Institute of Health and Wellbeing, University of Glasgow, Glasgow, Scotland.

Background: The Short Course Oncology Treatment (SCOT) trial demonstrated non-inferiority, less toxicity, and cost-effectiveness from a UK perspective of 3 versus 6 months of oxaliplatin-based chemotherapy for patients with colorectal cancer. This study assessed the cost-effectiveness of shorter treatment and the budget impact of implementing trial findings from the perspectives of all countries recruited to SCOT: Australia, Denmark, New Zealand, Spain, Sweden, and the United Kingdom.

Patients And Methods: Individual cost-utility analyses were performed from the perspective of each country. Resource, quality of life, and survival estimates from the SCOT trial (N = 6065) were used. Probabilistic sensitivity analysis and subgroup analyses were undertaken. Using undiscounted costs from these cost-utility analyses, the impact on country-specific healthcare budgets of implementing the SCOT trial findings was calculated over a 5-year period. The currency used was US dollars (US$), and 2019 was the base year. One-way and scenario sensitivity analysis addressed uncertainty within the budget impact analysis.

Results: Three months of treatment were cost saving and cost-effective compared to 6 months from the perspective of all countries. The incremental net monetary benefit per patient ranged from US$8972 (Spain) to US$13,884 (Denmark). The healthcare budget impact over 5 years for the base-case scenario ranged from US$3.6 million (New Zealand) to US$61.4 million (UK) and totaled over US$150 million across all countries.

Conclusion: This study has widened the transferability of results from the SCOT trial, showing that shorter treatment is cost-effective from a multi-country perspective. The vast savings from implementation could fully justify the investment in conducting the SCOT trial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clcc.2021.04.001DOI Listing
September 2021

Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study.

BMC Cancer 2021 Apr 1;21(1):354. Epub 2021 Apr 1.

Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK.

Background: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers.

Methods: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS).

Results: Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, K, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025).

Conclusions: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, K, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-021-08097-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017714PMC
April 2021

Duration of Adjuvant Doublet Chemotherapy (3 or 6 months) in Patients With High-Risk Stage II Colorectal Cancer.

J Clin Oncol 2021 02 13;39(6):631-641. Epub 2021 Jan 13.

University of Glasgow, Institute of Cancer Sciences, Scotland, United Kingdom.

Purpose: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers.

Patients And Methods: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required.

Results: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68).

Conclusion: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.01330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078416PMC
February 2021

The Impact of Changes in Service Delivery in Patients With Colorectal Cancer During the Initial Phase of the COVID-19 Pandemic.

Clin Colorectal Cancer 2021 06 5;20(2):e120-e128. Epub 2020 Dec 5.

Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; Manchester Cancer Research Centre, Manchester, United Kingdom.

Background: The Coronavirus disease 2019 (COVID-19) pandemic has imposed significant changes in cancer service delivery resulting in increased anxiety and distress in both patients and clinicians. We aimed to investigate how these changes have been perceived by patients diagnosed with colorectal cancer and identify determinants of increased anxiety.

Patients And Methods: An anonymized 32-item survey in the specialized lower gastrointestinal cancer outpatient clinics at a tertiary cancer center in North West England between May 18 and July 1, 2020. Self-reported anxiety was based on the General Anxiety Disorder-7 screening tool.

Results: Of 143 participants who completed the survey (response rate, 67%), 115 (82%) were male, and the median age group was 61 to 70 years. A total of 112 (78%) participants had telephone consultation (83% met needs), and 57 (40%) had radiologic scan results discussed over the phone (96% met needs). In total, 23 (18%) participants were considered to have anxiety (General Anxiety Disorder-7 score ≥ 5), with 7 (5.5%) scoring for moderate or severe anxiety. Those concerned about getting COVID-19 infection, and worried COVID-19 would have effect on their mental health, and affect their experience of cancer care, were most likely to have anxiety (P < .05, multivariate analysis). The majority did not feel they needed support during this phase of the pandemic. Participants felt that friends and family had been very supportive, but less so the primary care services (P < .05).

Conclusions: The findings of this survey suggest that some of the service changes implemented may have already improved the overall experience of cancer care among patients with colorectal cancer at our institute. Reassuringly, the incidence of participants with moderate to severe anxiety levels during the peak of COVID-19 in the United Kingdom was much lower than anticipated. Importantly, patients were much more concerned about their cancer treatment than COVID-19, emphasizing the need to continue to provide comprehensive cancer care even with a "second wave" of COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clcc.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718777PMC
June 2021

Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials.

Lancet Oncol 2020 12;21(12):1620-1629

Department of Health Science Research, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: A prospective, pooled analysis of six randomised phase 3 trials was done to investigate disease-free survival regarding non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer; non-inferiority was not shown. Here, we report the final overall survival results.

Methods: In this prospective, pooled analysis of six randomised phase 3 trials, we included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-1 recruited between June 20, 2007, and Dec 31, 2015, across 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials, who started any treatment (modified intention-to-treat). Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or capecitabine and oxaliplatin (CAPOX) in different doses and methods every 3 weeks, at the treating physician's discretion. The primary endpoint was disease-free survival (time to relapse, secondary colorectal primary tumour, or death due to all causes), and overall survival (time to death due to all causes) was the prespecified secondary endpoint. The non-inferiority margin for overall survival was set as a hazard ratio (HR) of 1·11. Pre-planned subgroup analyses included regimen and risk group. Non-inferiority was declared if the one-sided false discovery rate adjusted (FDRadj) p value was less than 0·025.

Findings: With median follow-up of 72·3 months (IQR 72·2-72·5), 2584 deaths among 12 835 patients were observed. 5064 (39·5%) patients received CAPOX and 7771 (60·5%) received FOLFOX. 5-year overall survival was 82·4% (95% CI 81·4-83·3) with 3 months of therapy and 82·8% (81·8-83·8) with 6 months of therapy (HR 1·02 [95% CI 0·95-1·11]; non-inferiority FDRadj p=0·058). For patients treated with CAPOX, 5-year overall survival was 82·1% (80·5-83·6) versus 81·2% (79·2-82·9; HR 0·96 [0·85-1·08]); non-inferiority FDRadj p=0·033), and for patients treated with FOLFOX 5-year overall survival was 82·6% (81·3-83·8) and 83·8% (82·6-85·0; HR 1·07 [0·97-1·18]; non-inferiority FDRadj p=0·34). Updated disease-free survival results confirmed previous findings (HR 1·08 [95% CI 1·02-1·15]; non-inferiority FDRadj p=0·25). Data on adverse events were not further recorded.

Interpretation: Non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0·4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration.

Funding: US National Cancer Institute.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(20)30527-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786835PMC
December 2020

Early Adaptation of Colorectal Cancer Cells to the Peritoneal Cavity Is Associated with Activation of "Stemness" Programs and Local Inflammation.

Clin Cancer Res 2021 02 30;27(4):1119-1130. Epub 2020 Nov 30.

Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, England, United Kingdom.

Purpose: At diagnosis, colorectal cancer presents with synchronous peritoneal metastasis in up to 10% of patients. The peritoneum is poorly characterized with respect to its superspecialized microenvironment. Our aim was to describe the differences between peritoneal metastases and their matched primary tumors excised simultaneously at the time of surgery. Also, we tested the hypothesis of these differences being present in primary colorectal tumors and having prognostic capacity.

Experimental Design: We report a comprehensive analysis of 30 samples from peritoneal metastasis with their matched colorectal cancer primaries obtained during cytoreductive surgery. We tested and validated the prognostic value of our findings in a pooled series of 660 colorectal cancer primary samples with overall survival (OS) information and 743 samples with disease-free survival (DFS) information from publicly available databases.

Results: We identified 20 genes dysregulated in peritoneal metastasis that promote an early increasing role of "stemness" in conjunction with tumor-favorable inflammatory changes. When adjusted for age, gender, and stage, the 20-gene peritoneal signature proved to have prognostic value for both OS [adjusted HR for the high-risk group (vs. low-risk) 2.32 (95% confidence interval, CI, 1.69-3.19; < 0.0001)] and for DFS [adjusted HR 2.08 (95% CI, 1.50-2.91; < 0.0001)].

Conclusions: Our findings indicated that the activation of "stemness" pathways and adaptation to the peritoneal-specific environment are key to early stages of peritoneal carcinomatosis. The analysis suggested that this 20-gene peritoneal signature may hold prognostic information with potential for development of new precision medicine strategies in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-3320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611320PMC
February 2021

Three-dimensional (3D) magnetic resonance volume assessment and loco-regional failure in anal cancer: early evaluation case-control study.

BMC Cancer 2020 Nov 30;20(1):1165. Epub 2020 Nov 30.

Division of Molecular & Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.

Background: The primary aim was to test the hypothesis that deriving pre-treatment 3D magnetic resonance tumour volume (mrTV) quantification improves performance characteristics for the prediction of loco-regional failure compared with standard maximal tumour diameter (1D) assessment in patients with squamous cell carcinoma of the anus undergoing chemoradiotherapy.

Methods: We performed an early evaluation case-control study at two UK centres (2007-2014) in 39 patients with loco-regional failure (cases), and 41 patients disease-free at 3 years (controls). mrTV was determined using the summation of areas method (Vol). Reproducibility was assessed using intraclass concordance correlation (ICC) and Bland-Altman limits of agreements. We derived receiver operating curves using logistic regression models and expressed accuracy as area under the curve (ROC).

Results: The median time per patient for Vol quantification was 7.00 (inter-quartile range, IQR: 0.57-12.48) minutes. Intra and inter-observer reproducibilities were generally good (ICCs from 0.79 to 0.89) but with wide limits of agreement (intra-observer: - 28 to 31%; inter-observer: - 28 to 46%). Median mrTVs were greater for cases (32.6 IQR: 21.5-53.1 cm) than controls (9.9 IQR: 5.7-18.1 cm, p < 0.0001). The ROC for mrT-size predicting loco-regional failure was 0.74 (95% CI: 0.63-0.85) improving to 0.82 (95% CI: 0.72-0.92) when replaced with mrTV (test for ROC differences, p = 0.024).

Conclusion: Preliminary results suggest that the replacement of mrTV for mrT-size improves prediction of loco-regional failure after chemoradiotherapy for squamous cell carcinoma of the anus. However, mrTV calculation is time consuming and variation in its reproducibility are drawbacks with the current technology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-07613-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706015PMC
November 2020

The Glasgow Microenvironment Score associates with prognosis and adjuvant chemotherapy response in colorectal cancer.

Br J Cancer 2021 02 23;124(4):786-796. Epub 2020 Nov 23.

School of Medicine, University of Glasgow, Glasgow, UK.

Background: The Glasgow Microenvironment Score (GMS) combines peritumoural inflammation and tumour stroma percentage to assess interactions between tumour and microenvironment. This was previously demonstrated to associate with colorectal cancer (CRC) prognosis, and now requires validation and assessment of interactions with adjuvant therapy.

Methods: Two cohorts were utilised; 862 TNM I-III CRC validation cohort, and 2912 TNM II-III CRC adjuvant chemotherapy cohort (TransSCOT). Primary endpoints were disease-free survival (DFS) and relapse-free survival (RFS). Exploratory endpoint was adjuvant chemotherapy interaction.

Results: GMS independently associated with DFS (p = 0.001) and RFS (p < 0.001). GMS significantly stratified RFS for both low risk (GMS 0 v GMS 2: HR 3.24 95% CI 1.85-5.68, p < 0.001) and high-risk disease (GMS 0 v GMS 2: HR 2.18 95% CI 1.39-3.41, p = 0.001). In TransSCOT, chemotherapy type (p = 0.013), but not duration (p = 0.64) was dependent on GMS. Furthermore, GMS 0 significantly associated with improved DFS in patients receiving FOLFOX compared with CAPOX (HR 2.23 95% CI 1.19-4.16, p = 0.012).

Conclusions: This study validates the GMS as a prognostic tool for patients with stage I-III colorectal cancer, independent of TNM, with the ability to stratify both low- and high-risk disease. Furthermore, GMS 0 could be employed to identify a subset of patients that benefit from FOLFOX over CAPOX.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-020-01168-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884404PMC
February 2021

Louis Corwin, Jr. (1926-2019).

Vet Radiol Ultrasound 2021 Jan 20;62(1):133. Epub 2020 Nov 20.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/vru.12923DOI Listing
January 2021

Blood-based mutation testing: concordance with tissue-based testing and mutational changes on progression.

Future Oncol 2020 Oct 27;16(28):2177-2189. Epub 2020 Jul 27.

Department of Medical & Clinical Oncology, The Christie Hospital, 550 Wilmslow Road, Manchester M20 4BX, UK.

To determine the concordance between plasma and tissue mutation status in metastatic colorectal cancer patients to gauge whether blood-based testing is a viable alternative. We also evaluated the change in mutation status on progression. testing was performed on plasma from patients commencing first-line therapy (OncoBEAM™ RAS CEIVD kit). Results were then compared with formalin-fixed paraffin embedded tumor samples. The overall percentage agreement (concordance) was 86.0% (86/100), which demonstrates that blood-based testing is an alternative to tissue-based testing. Reproducibility was 100% between three laboratories and 20% showed changes in their mutational status on progression. These results show good concordance between tissue and plasma samples and suggest the need for longitudinal plasma testing during treatment to guide management decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0523DOI Listing
October 2020

Blood-based mutation testing: concordance with tissue-based testing and mutational changes on progression.

Future Oncol 2020 Oct 27;16(28):2177-2189. Epub 2020 Jul 27.

Department of Medical & Clinical Oncology, The Christie Hospital, 550 Wilmslow Road, Manchester M20 4BX, UK.

To determine the concordance between plasma and tissue mutation status in metastatic colorectal cancer patients to gauge whether blood-based testing is a viable alternative. We also evaluated the change in mutation status on progression. testing was performed on plasma from patients commencing first-line therapy (OncoBEAM™ RAS CEIVD kit). Results were then compared with formalin-fixed paraffin embedded tumor samples. The overall percentage agreement (concordance) was 86.0% (86/100), which demonstrates that blood-based testing is an alternative to tissue-based testing. Reproducibility was 100% between three laboratories and 20% showed changes in their mutational status on progression. These results show good concordance between tissue and plasma samples and suggest the need for longitudinal plasma testing during treatment to guide management decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0523DOI Listing
October 2020

International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct.

J Clin Oncol 2020 08 12;38(22):2510-2518. Epub 2020 Jun 12.

Royal Marsden Hospital, London, United Kingdom.

Purpose: To compare cisplatin plus fluorouracil (FU) versus carboplatin plus paclitaxel in chemotherapy-naïve advanced anal cancer to establish the optimal regimen.

Patients And Methods: Patients who had not received systemic therapy for advanced anal cancer were randomly assigned 1:1 to intravenous cisplatin 60 mg/m (day 1) plus FU 1,000 mg/m (days 1-4) every 21 days or carboplatin (area under the curve, 5; day 1) plus paclitaxel 80 mg/m (days 1, 8, and 15) every 28 days for 24 weeks, until disease progression, intolerable toxicity, or withdrawal of consent. Primary end point was objective response rate (ORR). Primary and secondary end points were assessed in a hierarchic model to compare the regimens and pick the winner.

Results: We conducted an international multicenter randomized phase II study in 60 centers between December 2013 and November 2017. Median follow-up was 28.6 months. A total of 91 patients were randomly assigned: 46 to cisplatin plus FU and 45 to carboplatin plus paclitaxel. ORR was 57% (95% CI, 39.4% to 73.7%) for cisplatin plus FU versus 59% (95% CI, 42.1% to 74.4%) for carboplatin plus paclitaxel. More serious adverse events were noted in the cisplatin plus FU arm (62%) compared with the carboplatin plus paclitaxel arm (36%; = .016). Median progression-free survival was 5.7 months (95% CI, 3.3 to 9.0 months) for cisplatin plus FU compared with 8.1 months (95% CI, 6.6 to 8.8 months) for carboplatin plus paclitaxel. Median overall survival was 12.3 months for cisplatin plus FU (95% CI, 9.2 to 17.7 months) compared with 20 months (95% CI, 12.7 months to not reached) for carboplatin plus paclitaxel (hazard ratio, 2.00; 95% CI, 1.15 to 3.47; = .014).

Conclusion: This is the first international randomized trial to our knowledge conducted in chemotherapy-naïve advanced anal cancer. Although there was no difference in ORR, the association with clinically relevant reduced toxicity and a trend toward longer survival suggest that carboplatin plus paclitaxel should be considered as a new standard of care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.03266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406334PMC
August 2020

Cytoreductive surgery (CRS) with hyperthermic intraoperative peritoneal chemotherapy (HIPEC) versus standard of care (SoC) in people with peritoneal metastases from colorectal, ovarian or gastric origin: protocol for a systematic review and individual participant data (IPD) meta-analyses of effectiveness and cost-effectiveness.

BMJ Open 2020 05 12;10(5):e039314. Epub 2020 May 12.

Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK.

Introduction: There is uncertainty about whether cytoreductive surgery (CRS)+hyperthermic intraoperative peritoneal chemotherapy (HIPEC) improves survival and/or quality of life compared with standard of care (SoC) in people with peritoneal metastases who can withstand major surgery.

Primary Objectives: To compare the relative benefits and harms of CRS+HIPEC versus SoC in people with peritoneal metastases from colorectal, ovarian or gastric cancers eligible to undergo CRS+HIPEC by a systematic review and individual participant data (IPD) meta-analysis.

Secondary Objectives: To compare the cost-effectiveness of CRS+HIPEC versus SoC from a National Health Service (NHS) and personal social services perspective using a model-based cost-utility analysis.

Methods And Analysis: We will perform a systematic review of literature by updating the searches from MEDLINE, Embase, Cochrane library, Science Citation Index as well as trial registers. Two members of our team will independently screen the search results and identify randomised controlled trials comparing CRS+HIPEC versus SoC for inclusion based on full texts for articles shortlisted during screening. We will assess the risk of bias in the trials and obtain data related to baseline prognostic characteristics, details of intervention and control, and outcome data related to overall survival, disease progression, health-related quality of life, treatment related complications and resource utilisation data. Using IPD, we will perform a two-step IPD, that is, calculate the adjusted effect estimate from each included study and then perform a random-effects model meta-analysis. We will perform various subgroup analyses, meta-regression and sensitivity analyses. We will also perform a model-based cost-utility analysis to assess whether CRS+HIPEC is cost-effective in the NHS setting.

Ethics And Dissemination: This project was approved by the UCL Research Ethics Committee (Ethics number: 16023/001). We aim to present the findings at appropriate international meetings and publish the review, irrespective of the findings, in a peer-reviewed journal.

Prospero Registration Number: CRD42019130504.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-039314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228534PMC
May 2020

Histological phenotypic subtypes predict recurrence risk and response to adjuvant chemotherapy in patients with stage III colorectal cancer.

J Pathol Clin Res 2020 10 13;6(4):283-296. Epub 2020 May 13.

Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

Histological 'phenotypic subtypes' that classify patients into four groups (immune, canonical, latent and stromal) have previously been demonstrated to stratify survival in a stage I-III colorectal cancer (CRC) pilot cohort. However, clinical utility has not yet been validated. Therefore, this study assessed prognostic value of these subtypes in additional patient cohorts along with associations with risk of recurrence and response to chemotherapy. Two independent stage I-III CRC patient cohorts (internal and external cohort) were utilised to investigate phenotypic subtypes. The primary endpoint was disease-free survival (DFS) and the secondary endpoint was recurrence risk (RR). Stage II-III patients, from the SCOT adjuvant chemotherapy trial, were utilised to further validate prognostic value and for exploratory analysis assessing associations with adjuvant chemotherapy. In an 893-patient internal cohort, phenotypic subtype independently associated with DFS (p = 0.025) and this was attenuated in stage III patients (p = 0.020). Phenotypic subtype also independently associated with RR (p < 0.001) in these patients. In a 146-patient external cohort, phenotypic subtype independently stratified patients by DFS (p = 0.028), validating their prognostic value. In 1343 SCOT trial patients, the effect of treatment type significantly depended on phenotypic subtype (p = 0.011). Phenotypic subtype independently associated with DFS in stage III patients receiving FOLFOX (p = 0.028). Furthermore, the immune subtype significantly associated with better response to FOLFOX compared to CAPOX adjuvant chemotherapy in stage III patients (p = 0.013). In conclusion, histological phenotypic subtypes are an effective prognostic classification in patients with stage III CRC that associates with risk of recurrence and response to FOLFOX adjuvant chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cjp2.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578335PMC
October 2020

Temporal improvements in loco-regional failure and survival in patients with anal cancer treated with chemo-radiotherapy: treatment cohort study (1990-2014).

Br J Cancer 2020 03 14;122(6):749-758. Epub 2020 Jan 14.

Division of Cancer Sciences, School of Medical Sciences, Faculty of Biological, Medicine and Health, University of Manchester, Manchester, UK.

Background: We evaluated oncological changes in patients with squamous cell carcinoma of the anus (SCCA) treated by chemoradiotherapy (CRT) from a large UK institute, to derive estimates of contemporary outcomes.

Methods: We performed a treatment-cohort analysis in 560 patients with non-metastatic SCCA treated with CRT over 25 years. The primary outcomes were 3-year loco-regional failure (LRF), 5-year overall survival (OS), and 5-year cancer-specific survival (CSS). We developed prediction models; and overlaid estimates on published results from historic trials.

Results: Age distributions, proportions by gender and cT stage remained stable over time. The median follow-up was 61 (IQR: 36-79) months. Comparing the first period (1990-1994) with the last period (2010-2014), 3-year LRF declined from 33 to 16% (P < 0.001); 5-year OS increased from 60% to 76% (P = 0.001); and 5-year CCS increased from 62% in to 80% (P = 0.001). For 2020, the models predicted a 3-year LRF of 14.7% (95% CIs: 0-31.3); 5-year OS of 74.7% (95% CIs: 54.6-94.9); and 5-year CSS of 85.7% (95% CIs: 75.3-96.0). Reported oncological outcomes from historic trials generally underestimated contemporary outcomes.

Conclusions: Current and predicted rates for 3-year LRF and 5-year survivals are considerably improved compared with those in historic trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-019-0689-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078229PMC
March 2020

First-line trifluridine/tipiracil plus bevacizumab for unresectable metastatic colorectal cancer: SOLSTICE study design.

Future Oncol 2020 Feb 9;16(4):21-29. Epub 2020 Jan 9.

University Hospital of Pisa, Pisa, Italy.

Trifluridine/tipiracil (TT) is an orally administered combination of the thymidine-based nucleoside analogue trifluridine and the thymidine phosphorylase inhibitor tipiracil hydrochloride, which increases the bioavailability of cytotoxic trifluridine. Encouraging antitumor activity of first-line TT + bevacizumab (TT-B) has been observed in a Phase II study in patients with unresectable metastatic colorectal cancer ineligible for combination oxaliplatin- or irinotecan-based therapy. Here, we describe the design of SOLSTICE (NCT03869892), an open-label, Phase III trial in unresectable metastatic colorectal cancer patients who are not candidates for, or do not require, intensive therapy. The 854 patients were randomized 1:1 to receive first-line TT-B versus capecitabine + bevacizumab. The primary objective is to demonstrate superior progression-free survival with TT-B over capecitabine + bevacizumab. The first patient was enrolled in March 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2019-0786DOI Listing
February 2020

3-month versus 6-month adjuvant chemotherapy for patients with high-risk stage II and III colorectal cancer: 3-year follow-up of the SCOT non-inferiority RCT.

Health Technol Assess 2019 12;23(64):1-88

Gloucestershire Oncology Centre, Cheltenham General Hospital, UK.

Background: Oxaliplatin and fluoropyrimidine chemotherapy administered over 6 months is the standard adjuvant regimen for patients with high-risk stage II or III colorectal cancer. However, the regimen is associated with cumulative toxicity, characterised by chronic and often irreversible neuropathy.

Objectives: To assess the efficacy of 3-month versus 6-month adjuvant chemotherapy for colorectal cancer and to compare the toxicity, health-related quality of life and cost-effectiveness of the durations.

Design: An international, randomised, open-label, non-inferiority, Phase III, parallel-group trial.

Setting: A total of 244 oncology clinics from six countries: UK (England, Scotland, Wales and Northern Ireland), Denmark, Spain, Sweden, Australia and New Zealand.

Participants: Adults aged ≥ 18 years who had undergone curative resection for high-risk stage II or III adenocarcinoma of the colon or rectum.

Interventions: The adjuvant treatment regimen was either oxaliplatin and 5-fluorouracil or oxaliplatin and capecitabine, randomised to be administered over 3 or 6 months.

Main Outcome Measures: The primary outcome was disease-free survival. Overall survival, adverse events, neuropathy and health-related quality of life were also assessed. The main cost categories were chemotherapy treatment and hospitalisation. Cost-effectiveness was assessed through incremental cost comparisons and quality-adjusted life-year gains between the options and was reported as net monetary benefit using a willingness-to-pay threshold of £30,000 per quality-adjusted life-year per patient.

Results: Recruitment is closed. In total, 6088 patients were randomised (3044 per group) between 27 March 2008 and 29 November 2013, with 6065 included in the intention-to-treat analyses (3-month analysis,  = 3035; 6-month analysis,  = 3030). Follow-up for the primary analysis is complete. The 3-year disease-free survival rate in the 3-month treatment group was 76.7% (standard error 0.8%) and in the 6-month treatment group was 77.1% (standard error 0.8%), equating to a hazard ratio of 1.006 (95% confidence interval 0.909 to 1.114; -value for non-inferiority = 0.012), confirming non-inferiority for 3-month adjuvant chemotherapy. Frequent adverse events (alopecia, anaemia, anorexia, diarrhoea, fatigue, hand-foot syndrome, mucositis, sensory neuropathy, neutropenia, pain, rash, altered taste, thrombocytopenia and watery eye) showed a significant increase in grade with 6-month duration; the greatest difference was for sensory neuropathy (grade ≥ 3 was 4% for 3-month vs.16% for 6-month duration), for which a higher rate of neuropathy was seen for the 6-month treatment group from month 4 to ≥ 5 years ( < 0.001). Quality-of-life scores were better in the 3-month treatment group over months 4-6. A cost-effectiveness analysis showed 3-month treatment to cost £4881 less over the 8-year analysis period, with an incremental net monetary benefit of £7246 per patient.

Conclusions: The study achieved its primary end point, showing that 3-month oxaliplatin-containing adjuvant chemotherapy is non-inferior to 6 months of the same regimen; 3-month treatment showed a better safety profile and cost less. For future work, further follow-up will refine long-term estimates of the duration effect on disease-free survival and overall survival. The health economic analysis will be updated to include long-term extrapolation for subgroups. We expect these analyses to be available in 2019-20. The Short Course Oncology Therapy (SCOT) study translational samples may allow the identification of patients who would benefit from longer treatment based on the molecular characteristics of their disease.

Trial Registration: Current Controlled Trials ISRCTN59757862 and EudraCT 2007-003957-10.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 23, No. 64. See the NIHR Journals Library website for further project information. This research was supported by the Medical Research Council (transferred to NIHR Evaluation, Trials and Studies Coordinating Centre - Efficacy and Mechanism Evaluation; grant reference G0601705), the Swedish Cancer Society and Cancer Research UK Core Clinical Trials Unit Funding (funding reference C6716/A9894).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3310/hta23640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936167PMC
December 2019

Beyond Bergmann's rule: Global variability in human body composition is associated with annual average precipitation and annual temperature volatility.

Am J Phys Anthropol 2019 09 18;170(1):75-87. Epub 2019 Jul 18.

Childhood Nutrition Research Centre, UCL Great Ormond Street Institute of Child Health, London, UK.

Objectives: Human populations exhibit substantial geographical variability in body size and shape. However, the ecological stresses underlying this morphological variability remain poorly understood. The prevailing evolutionary explanation, "Bergmann's rule" assumes that morphological variability represents an adaptive response to average thermal conditions. We hypothesized that other climate factors-annual average precipitation, a marker of ecological productivity and inter-annual temperature volatility, a marker of infectious disease spikes-may also contribute to variability in body composition.

Materials And Methods: We explored this hypothesis by examining associations between these climate factors and geographic variability in body composition across 133 male and 105 female populations from nonindustrialized settings. We used monthly climate data over 113 years (1901-2013) to develop new climate indices for all worldwide land areas. We stratified our analyses by hot/cold setting (>/<20°C).

Results: In hot environments, lean mass increased as predicted in association with ecological productivity, and decreased in association with ecological volatility. Conversely, levels of body fat increased in association with temperature volatility and precipitation. However, in cold settings, equivalent associations were only partially consistent with our hypotheses, and there was suggestive evidence of sex differences in these associations.

Discussion: Beyond associations with mean annual temperature predicted by Bergmann's rule, variability in human body composition is also associated with mean annual temperature and inter-annual temperature volatility, with these associations further differing between hot and cold settings. Collectively, our results suggest that associations of human body composition with climate are complex for both physique (fat-free mass) and energy stores (adiposity).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajpa.23890DOI Listing
September 2019

An evaluation of cetuximab dosing strategies using pharmacokinetics and cost analysis.

J Pharm Pharmacol 2019 Aug 24;71(8):1222-1230. Epub 2019 May 24.

The Christie NHS Foundation Trust, Manchester, UK.

Objectives: Cetuximab dosing is based on body surface area (BSA), an approach that is associated with significant wastage due to available vial sizes. NHS England recently introduced an alternative strategy for cetuximab dosing based on dose banding. The aim of this work was to investigate approaches to cetuximab dosing to improve its cost-effectiveness.

Methods: A simulation study using a population pharmacokinetic model was used to assess the performance of dosing strategies using exposure, probability of target attainment and cost. Two dosage regimens (500 and 400/250 mg/m ) were investigated; 5% and 10% dose banding, fixed and optimised dosing strategies were evaluated and compared to BSA strategy.

Key Findings: The percentage of the total cost associated with wastage for the 400/250 mg/m regimen were 8.75%, 5.13%, 3.61%, 9.2% and 0% for BSA; 5 and 10% bands; fixed and optimal strategies, respectively. Similar results were obtained for 500 mg/m regimen. In comparison with BSA strategy, other strategies have comparable or improved performance. Optimised strategy showed consistent performance and ensures equal exposure and probability of target attainment.

Conclusions: Cost-effectiveness of cetuximab treatment can be improved with alternative strategies by reducing wastage without compromising exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jphp.13108DOI Listing
August 2019

Association analyses identify 31 new risk loci for colorectal cancer susceptibility.

Nat Commun 2019 05 14;10(1):2154. Epub 2019 May 14.

Wellcome Centre for Human Genetics, McCarthy Group, Roosevelt Drive, Oxford, OX3 7BN, UK.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-09775-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517433PMC
May 2019

Considering tumour volume for motion corrected DWI of colorectal liver metastases increases sensitivity of ADC to detect treatment-induced changes.

Sci Rep 2019 03 7;9(1):3828. Epub 2019 Mar 7.

University of Manchester, Wolfson Molecular Imaging Centre, Manchester, UK.

ADC is a potential post treatment imaging biomarker in colorectal liver metastasis however measurements are affected by respiratory motion. This is compounded by increased statistical uncertainty in ADC measurement with decreasing tumour volume. In this prospective study we applied a retrospective motion correction method to improve the image quality of 15 tumour data sets from 11 patients. We compared repeatability of ADC measurements corrected for motion artefact against non-motion corrected acquisition of the same data set. We then applied an error model that estimated the uncertainty in ADC repeatability measurements therefore taking into consideration tumour volume. Test-retest differences in ADC for each tumour, was scaled to their estimated measurement uncertainty, and 95% confidence limits were calculated, with a null hypothesis that there is no difference between the model distribution and the data. An early post treatment scan (within 7 days of starting treatment) was acquired for 12 tumours from 8 patients. When accounting for both motion artefact and statistical uncertainty due to tumour volumes, the threshold for detecting significant post treatment changes for an individual tumour in this data set, reduced from 30.3% to 1.7% (95% limits of agreement). Applying these constraints, a significant change in ADC (5 and 20 percentiles of the ADC histogram) was observed in 5 patients post treatment. For smaller studies, motion correcting data for small tumour volumes increased statistical efficiency to detect post treatment changes in ADC. Lower percentiles may be more sensitive than mean ADC for colorectal metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-40565-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405765PMC
March 2019

Biological Contamination Prevention for Outer Solar System Moons of Astrobiological Interest: What Do We Need to Know?

Astrobiology 2019 08 14;19(8):951-974. Epub 2019 Feb 14.

15Eurospace, Paris, France.

To ensure that scientific investments in space exploration are not compromised by terrestrial contamination of celestial bodies, special care needs to be taken to preserve planetary conditions for future astrobiological exploration. Significant effort has been made and is being taken to address planetary protection in the context of inner Solar System exploration. In particular for missions to Mars, detailed internationally accepted guidelines have been established. For missions to the icy moons in the outer Solar System, Europa and Enceladus, the planetary protection requirements are so far based on a probabilistic approach and a conservative estimate of poorly known parameters. One objective of the European Commission-funded project, Planetary Protection of Outer Solar System, was to assess the existing planetary protection approach, to identify inherent knowledge gaps, and to recommend scientific investigations necessary to update the requirements for missions to the icy moons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ast.2018.1996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767865PMC
August 2019

Interleukin-1 receptor antagonist levels predict favorable outcome after bermekimab, a first-in-class true human interleukin-1α antibody, in a phase III randomized study of advanced colorectal cancer.

Oncoimmunology 2019;8(3):1551651. Epub 2018 Dec 12.

XBiotech, Austin, TX, USA.

Bermekimab is a true human monoclonal antibody that targets interleukin-1alpa (IL-1α), an inflammation-mediating alarmin. IL-1 receptor antagonist (IL-1Ra) is a natural molecule that blocks IL-1α activity by occupying the IL-1 receptor. The effect of endogenous IL-1Ra levels on the effectiveness of bermekimab is unknown. We investigated whether pre-treatment levels of circulating IL-1Ra, assessed by an enzyme-linked immunoassay, correlated with achievement of the primary outcome endpoint (effect on lean body mass and symptoms at week 8) in a Phase III study (2:1 randomization) of bermekimab versus placebo (each with best supportive care) in advanced colorectal cancer. Patients who responded to bermekimab in terms of achieving the primary endpoint had lower levels of IL-1Ra than non-responders (N = 204 patients; median = 843 vs. 1035 pg/ml, p=0.0092); no such relationship was observed in the placebo arm (N = 100 patients; 901 vs. 984 pg/ml, p = 0.55). Multivariate analysis corroborated that, in the bermekimab group, patients with lower baseline IL-1Ra levels were more likely to achieve the primary endpoint (odds ratio (OR) 1.7 (95% confidence interval (CI), 1.1 to 2.6), p = 0.017); in contrast, in the placebo arm, pre-treatment plasma IL-1Ra levels were not associated with outcome (OR 1.2 (95% CI 0.6 to 2.5), p = 0.57). The current findings demonstrate that, in a randomized phase III trial, patients with advanced colorectal cancer and lower levels of circulating IL-1Ra are more responsive to treatment with the IL-1α-targeting antibody bermekimab and these observations define a potential biomarker for anti-IL-1α therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2018.1551651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350690PMC
December 2018

Pattern Recognition Receptor Polymorphisms as Predictors of Oxaliplatin Benefit in Colorectal Cancer.

J Natl Cancer Inst 2019 08;111(8):828-836

See the Notes section for the full list of authors' affiliations.

Background: Constitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification.

Methods: We performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided.

Results: Our validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P = .07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P = .66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P = .27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P = .40).

Conclusion: In this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djy215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695319PMC
August 2019

A core outcome set for clinical trials of chemoradiotherapy interventions for anal cancer (CORMAC): a patient and health-care professional consensus.

Lancet Gastroenterol Hepatol 2018 12;3(12):865-873

Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Cancer Research Centre and National Institute for Health Research, Manchester Biomedical Research Centre, University of Manchester, Manchester, UK; Colorectal and Peritoneal Oncology Centre, Christie National Health Service Foundation Trust, Manchester, UK.

Chemoradiotherapy is the primary treatment for patients with squamous cell carcinoma of the anus, but variations in the reported outcomes have restricted between-study comparisons. Treatment-related morbidity is considerable; however, no trial has comprehensively quantified long-term side-effects or quality of life. Therefore, we established the first international health-care professional and patient consensus to develop a core outcome set, using the Core Outcome Measures in Effectiveness Trials method. We used the results from our previous systematic review and combined them in this Review with patient interviews to derive a comprehensive list of outcomes, followed by a two-round Delphi survey completed by 149 participants (55 patients and 94 health-care professionals) from 11 countries. The Delphi results were discussed at a consensus meeting of health-care professionals and patients. Agreement was reached on 19 outcomes across four domains: disease activity, survival, toxicity, and life impact. Implementation of the Core Outcome Research Measures in Anal Cancer (CORMAC) set in future trials will serve as a framework to achieve standardisation, facilitate selection of health-area-specific evaluation tools, reduce redundancy of outcome lists, allow between-study comparisons, and ultimately enhance the relevance of trial findings to health-care professionals, trialists, and patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2468-1253(18)30264-4DOI Listing
December 2018

SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer.

Br J Cancer 2018 11 13;119(11):1332-1338. Epub 2018 Nov 13.

Gloucestershire Oncology Centre, Cheltenham General Hospital, Cheltenham, UK.

Background: The Short Course Oncology Therapy (SCOT) study is an international, multicentre, non-inferiority randomised controlled trial assessing the efficacy, toxicity, and cost-effectiveness of 3 months (3 M) versus the usually given 6 months (6 M) of adjuvant chemotherapy in colorectal cancer.

Methods: In total, 6088 patients with fully resected high-risk stage II or stage III colorectal cancer were randomised and followed up for 3-8 years. The within-trial cost-effectiveness analysis from a UK health-care perspective is presented using the resource use data, quality of life (EQ-5D-3L), time on treatment (ToT), disease-free survival after treatment (DFS) and overall survival (OS) data. Quality-adjusted partitioned survival analysis and Kaplan-Meier Sample Average Estimator estimated QALYs and costs. Probabilistic sensitivity and subgroup analysis was undertaken.

Results: The 3 M arm is less costly (-£4881; 95% CI: -£6269; -£3492) and entails (non-significant) QALY gains (0.08; 95% CI: -0.086; 0.230) due to a better significant quality of life. The net monetary benefit was significantly higher in 3 M under a wide range of monetary values of a QALY. The subgroup analysis found similar results for patients in the CAPOX regimen. However, for the FOLFOX regimen, 3 M had lower QALYs than 6 M (not statistically significant).

Conclusions: Overall, 3 M dominates 6 M with no significant detrimental impact on QALYs. The results provide the economic case that a 3 M treatment strategy should be considered a new standard of care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-018-0319-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265336PMC
November 2018

Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer.

Nat Commun 2018 11 7;9(1):4672. Epub 2018 Nov 7.

Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute & Manchester Centre for Cancer Biomarker Sciences, Manchester, M20 4BX, UK.

Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, K (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-07174-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220185PMC
November 2018
-->