In vitro study of radiosensitivity in colorectal cancer cell lines associated with Lynch syndrome.

Introduction: Lynch syndrome patients have an inherited predisposition to cancer due to a deficiency in DNA mismatch repair (MMR) genes which could lead to a higher risk of developing cancer if exposed to ionizing radiation. This pilot study aims to reveal the association between MMR deficiency and radiosensitivity at both a CT relevant low dose (20 mGy) and a therapeutic higher dose (2 Gy). Methods: Human colorectal cancer cell lines with (dMMR) or without MMR deficiency (pMMR) were analyzed before and after exposure to radiation using cellular and cytogenetic analyses i.e., clonogenic assay to determine cell reproductive death; sister chromatid exchange (SCE) assay to detect the exchange of DNA between sister chromatids; γH2AX assay to analyze DNA damage repair; and apoptosis analysis to compare cell death response. The advantages and limitations of these assays were assessed in vitro, and their applicability and feasibility investigated for their potential to be used for further studies using clinical samples. Results: Results from the clonogenic assay indicated that the pMMR cell line (HT29) was significantly more radio-resistant than the dMMR cell lines (HCT116, SW48, and LoVo) after 2 Gy X-irradiation. Both cell type and radiation dose had a significant effect on the yield of SCEs/chromosome. When the yield of SCEs/chromosome for the irradiated samples (2 Gy) was normalized against the controls, no significant difference was observed between the cell lines. For the γH2AX assay, 0, 20 mGy and 2 Gy were examined at post-exposure time points of 30 min (min), 4 and 24 h (h). Statistical analysis revealed that HT29 was only significantly more radio-resistant than the MLH1-deficient cells lines, but not the MSH2-deficient cell line. Apoptosis analysis (4 Gy) revealed that HT29 was significantly more radio-resistant than HCT116 albeit with very few apoptotic cells observed. Discussion: Overall, this study showed radio-resistance of the MMR proficient cell line in some assays, but not in the others. All methods used within this study have been validated; however, due to the limitations associated with cancer cell lines, the next step will be to use these assays in clinical samples in an effort to understand the biological and mechanistic effects of radiation in Lynch patients as well as the health implications.

Potential risks associated with the use of ionizing radiation for imaging and treatment of colorectal cancer in Lynch syndrome patients.

The aim of this review is to investigate the literature pertaining to the potential risks of low-dose ionizing radiation to Lynch syndrome patients by use of computed tomography (CT), either diagnostic CT colonography (CTC), standard staging CT or CT surveillance. Furthermore, this review explores the potential risks of using radiotherapy for treatment of rectal cancer in these patients. No data or longitudinal observational studies of the impact of radiation exposure on humans with Lynch syndrome were identified. Limited experimental studies utilizing cell lines and primary cells exposed to both low and high radiation doses have been carried out to help determine radio-sensitivity associated with DNA mismatch repair gene deficiency, the defining feature of Lynch syndrome. On balance, these studies suggest that mismatch repair deficient cells may be relatively radio-resistant (particularly for low dose rate exposures) with higher mutation rates, albeit no firm conclusions can be drawn. Mouse model studies, though, showed an increased risk of developing colorectal tumors in mismatch repair deficient mice exposed to radiation doses around 2 Gy. With appropriate ethical approval, further studies investigating radiation risks associated with CT imaging and radiotherapy relevant doses using cells/tissues derived from confirmed Lynch patients or genetically modified animal models are urgently required for future clinical guidance.

Additional Treatments to the Local tumour for metastatic prostate cancer-Assessment of Novel Treatment Algorithms (IP2-ATLANTA): protocol for a multicentre, phase II randomised controlled trial.

INTRODUCTION: Survival in men diagnosed with de novo synchronous metastatic prostate cancer has increased following the use of upfront systemic treatment, using chemotherapy and other novel androgen receptor targeted agents, in addition to standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit. In this setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the addition of sequential multimodal local and metastasis-directed treatments compared with standard care alone. METHODS: A phase II, prospective, multicentre, three-arm randomised controlled trial incorporating an embedded feasibility pilot. All men with new histologically diagnosed, hormone-sensitive, metastatic prostate cancer, within 4 months of commencing ADT and of performance status 0 to 2 are eligible. Patients will be randomised to Control (standard of care (SOC)) OR Intervention 1 (minimally invasive ablative therapy to prostate±pelvic lymph node dissection (PLND)) OR Intervention 2 (cytoreductive radical prostatectomy±PLND OR prostate radiotherapy±pelvic lymph node radiotherapy (PLNRT)). Metastatic burden will be prespecified using the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) definition. Men with low burden disease in intervention arms are eligible for metastasis-directed therapy, in the form of stereotactic ablative body radiotherapy (SABR) or surgery. Standard systemic therapy will be administered in all arms with ADT±upfront systemic chemotherapy or androgen receptor agents. Patients will be followed-up for a minimum of 2 years. PRIMARY OUTCOME: PFS. Secondary outcomes include predictive factors for PFS and overall survival; urinary, sexual and rectal side effects. Embedded feasibility sample size is 80, with 918 patients required in the main phase II component. Study recruitment commenced in April 2019, with planned follow-up completed by April 2024. ETHICS AND DISSEMINATION: Approved by the Health Research Authority (HRA) Research Ethics Committee Wales-5 (19/WA0005). Study results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03763253; ISCRTN58401737.

Single-centre Experience of Use of Radium 223 with Clinical Outcomes Based on Number of Cycles and Bone Marrow Toxicity.

BACKGROUND: Bone is the most common site of metastatic disease in advanced prostate cancer. Radium-223 (223Ra) is a calcium-mimetic alpha-particle emitter, which has been shown to have activity in prostate cancer with clinical benefit in patients with symptomatic bone metastasis. The recommended schedule is six cycles of 223Ra, 5 kBq/kg, at 4-weekly intervals. Although previous studies have assessed clinical outcomes in patients who received six cycles of Ra223, there is very little information about outcomes of patients receiving fewer courses of treatment. PATIENTS AND METHODS: Patients with hormone-refractory metastatic prostate cancer treated from May 2014 to August 2016 were included in this retrospective study. A total of 113 patients were identified with a median age of 76 (range=52-92) years. The median number of cycles administered was 5 (range=1-6) with 54 (48%) completing six cycles of treatment. Eighty-five patients (75%) received 223Ra prior to docetaxel chemotherapy and 28 (25%) received it after receiving docetaxel. RESULTS: Eleven patients developed grade 2/3 thrombocytopenia, and none of these received further 223Ra. Only 25% of patients who had a haemoglobin level of 10 g/dl or below at the start of the treatment were able to complete six courses of 223Ra. Of the patients who completed fewer than six cycles of 223Ra (1-5 cycles), the survival was 121 days, compared to 398 days in men who received six cycles (odds ratio(OR)=4.767, 95% confidence internal(CI)=1.07-21.25; p=0.0005). CONCLUSION: Careful selection of patients is essential to obtain good clinical outcomes from 223Ra therapy. When fewer than six cycles were delivered then a beneficial survival effect was not seen.

Baseline Multiparametric MRI for Selection of Prostate Cancer Patients Suitable for Active Surveillance: Which Features Matter?

INTRODUCTION: Increasing evidence has supported the use of multiparametric magnetic resonance imaging (mpMRI) for the detection of prostate cancer. However, its role in selecting patients clinically suitable for active surveillance (AS) is still in development. We aimed to find relevant mpMRI features that might be helpful for refinement of the selection of low-risk prostate cancer patients for AS. We also evaluated the interobserver variability in reporting prostate mpMRI features. PATIENTS AND METHODS: From 2008 to 2012, 135 patients were selected for AS using Epstein criteria. Baseline mpMRI studies were performed within 3 months of recruitment and reviewed by 2 radiologists who were unaware of the patients' outcomes. The radiologists recorded the mpMRI features using the Prostate Imaging Reporting and Data System (PI-RADS) guidelines. The overall likelihood of the presence of significant prostate cancer was also determined using the Likert and PI-RADS, version 2 (v2), scores. Univariate and multivariate analyses, receiver operating characteristic curves, and Kaplan-Meier survival curves were calculated for the mpMRI features with respect to patient withdrawal from the AS program and failure-free survival (FFS). The interobserver agreement was also evaluated. RESULTS: At a median follow-up time of 31 months (range, 6-80 months), 84 patients (62.2%) were participating in the AS program. In 2 multivariate models, the variables significantly associated with outcomes for both readers were the index lesion size (hazard ratio [HR], 2.34 and 3.13, respectively) and overall PI-RADS, v2, score (HR, 2.51 and 3.21, respectively). The interobserver agreement was higher for the overall Likert and PI-RADS, v2, scores. CONCLUSION: Overall, the PI-RADS, v2, score and index lesion size were strongly associated with FFS. Overall, the Likert and PI-RADS, v2, scoring systems have been confirmed to be useful, although further improvements are needed.

Factors Implicated for Delay of Adjuvant Chemotherapy in Colorectal Cancer: A Meta-analysis of Observational Studies.

BACKGROUND: The survival benefit of administering adjuvant chemotherapy (AC) in colorectal cancer is well established, as is the impact of its timing. Although various factors have been associated with treatment delay, their implications remain controversial. We determined clinicopathological factors associated with delay in transition to AC via systematic review and meta-analysis. METHODS: Studies assessing factors for delay in initiating AC were identified from MEDLINE, EMBASE, and Cochrane Databases. Studies were included only if relevant clinicopathological factors were adequately described and appropriate comparative groups were balanced. For each study, the odds ratio (OR) and 95 % confidence interval (CI) were estimated, regarding response to early versus delayed AC initiation. RESULTS: We identified 15 eligible studies involving 67,537 patients. Twelve studies were multicentre studies and three were single-center cohort studies. Meta-analysis demonstrated age >75 years [4 studies, OR = 1.44 (95 % CI 1.32-1.58)], marital status-single [3 studies, OR = 1.32 (95 % CI 1.20-1.44)], low socioeconomic status (SES) [7 studies, OR = 1.67 (95 % CI 1.32-2.12)], worse comorbidity status [5 studies, OR = 1.47 (95 % CI 1.14-1.90)], low tumour grade [7 studies, OR = 1.06 (95 % CI 1.02-1.11)], prolonged length of stay [3 studies, OR 2.37 (95 % CI 2.10-2.68)], and readmission [3 studies, OR = 3.23 (95 % CI 1.66-6.26)] were significant predictors of delayed initiation of AC. Laparoscopy compared to an open surgical approach was a significant predictor of earlier AC initiation [5 studies, OR = 0.70 (95 % CI 0.51-0.97)]. CONCLUSIONS: Laparoscopy is associated with earlier initiation of AC, encouraging its increased adoption. Social isolation and low SES merit consideration of approaches that counter the lack of social support and deprivation to improve cancer outcomes.

Transdermal oestrogen therapy as a second-line hormonal intervention in prostate cancer: a bad experience.

OBJECTIVE: To compare transdermal oestrogen with oral diethylstilbestrol (DES) as a second- or third-line hormonal therapy in the treatment of prostate cancer. PATIENTS AND METHODS: In all, 32 assessable patients who, having already had a relapse on at least one line of hormonal therapy, received transdermal oestrogen therapy as an alternative to oral DES, when DES became unavailable. RESULTS: Whereas DES had controlled the prostate-specific antigen (PSA) level for a median of 29 weeks in a group of 15 patients in remission, all but one had an increase in PSA level (median 86% increase above the starting PSA level) within a median of 8 weeks after introducing transdermal therapy. This increase was reversed in seven of the 12 patients who recommenced DES therapy. CONCLUSION: Although the use of transdermal oestrogen is currently attracting enthusiasm as a first-line treatment for prostate cancer, these results show that for second- or third-line therapy further cautious research with careful monitoring is necessary.