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Abstract Background Retrospective studies show improved outcomes in colorectal cancer patients if taking statins, including overall survival, pathological response of rectal cancer to preoperative chemoradiotherapy (pCRT), and reduced acute and late toxicities of pelvic radiation. Major tumour regression following pCRT has strong prognostic significance and can be assessed in vivo using MRI-based tumour regression grading (mrTRG) or after surgery using pathological TRG (pathTRG). Methods A double-blind phase 2 trial will randomise 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 18+ sites in New Zealand and Australia. Patients will receive simvastatin 40 mg or placebo daily for 90 days starting 1 week prior to standard pCRT. Pelvic MRI 6 weeks after pCRT will assess mrTRG grading prior to surgery. The primary objective is rates of favourable (grades 1–2) mrTRG following pCRT with simvastatin compared to placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4–5). Secondary objectives include comparison of: rates of favourable pathTRG in resected tumours; incidence of toxicity; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection; cancer outcomes and pathological scores for radiation colitis. Tertiary objectives include: association between mrTRG and pathTRG grouping; inter-observer agreement on mrTRG scoring and pathTRG scoring; studies of T-cell infiltrates in diagnostic biopsies and irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Trial recruitment commenced April 2018. Discussion When completed this study will be able to observe meaningful differences in measurable tumour outcome parameters and/or toxicity from simvastatin. A positive result will require a larger RCT to confirm and validate the merit of statins in the preoperative management of rectal cancer. Such a finding could also lead to studies of statins in conjunction with chemoradiation in a range of other malignancies, as well as further exploration of possible mechanisms of action and interaction of statins with both radiation and chemotherapy. The translational substudies undertaken with this trial will provisionally explore some of these possible mechanisms, and the tissue and data can be made available for further investigations. Trial registration ANZ Clinical Trials Register ACTRN12617001087347. (www.anzctr.org.au, registered 26/7/2017) Protocol Version: 1.1 (June 2017).

Aims: The peritoneal regression grading score (PRGS) and peritoneal cytology (PC) assess response to chemotherapy in peritoneal metastasis (PM) in a setting of palliative treatment by pressurized intraperitoneal aerosol chemotherapy (PIPAC). Progression has been defined as an increase of PRGS between first and third PIPAC procedures (iPRGS). iPRGSand positive peritoneal cytology were not associated with prognostic impact. These results may be explained by a lack of statistical power. Also, it is not known whether the mean or the highest PRGS among taken peritoneal biopsies bears the highest clinical value. We therefore conducted the largest prospective study to investigate the prognostic impact of PGRS, PC, and their combination, designated as combined progression index (CPI). Methods and results: Patients with PM who underwent >3 PIPAC (n = 112) between December 2016 and February 2019 were prospectively included. A significant difference in OS and PFS according to CPI (used highest value of PRGS) was found (OS: CPI−, 83.3, 95% CI [49.8; NA] vs. CPI+, 48.1, 95% CI [38.5; 66.4] months; and PFS (respectively, 59.7, 95% CI [43.0; 96.0] vs. 33.7, 95% CI [30.4; 44.2] months). PRGS or PC had no independent prognostic impact. CPI+ was an independent predictor of worse prognosis, in OS (HR = 5.24, 95% CI [2.07; 13.26]), and PFS (HR = 4.41, 95% CI [1.40; 13.88]). Conclusions: The CPI based on highest PRGS and PC was found to be independently associated with a worse prognosis for OS and for PFS in the setting of peritoneal metastasis. These results indicate that it should be of interest to systematically take peritoneal fluid for cytological examination and to implement the CPI in the therapeutic decision‐making process in the context of PIPAC. [ABSTRACT FROM AUTHOR]

Aims: In the adjuvant setting, when compared to gemcitabine, patients with pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX (Folinic Acid, Fluorouracil, Irinotecan, and Oxaliplatin) show superior survival. In this study, we quantitatively assess the pathological tumour response to chemoradiation in pancreatectomy specimens and reassess guidelines for tumour regression grading. Methods and results: We evaluated 92 patients with borderline resectable/locally advanced PDAC following pancreatectomy and neoadjuvant treatment with FOLFIRINOX and radiation. Demographic data, CAP tumour regression grade (TRG) and overall survival (OS) were recorded. A quantitative analysis of residual tumour was performed on the slide with the highest tumour burden to derive a tumour‐to‐tumour bed ratio. On univariate analysis, only lymph node status (P = 0.043) and CAP TRG (P = 0.038) correlated with OS. Sixteen per cent of patients showed a complete pathological response. The optimal tumour‐to‐tumour bed ratio cut‐point was 11.6%, and on a multivariate model was the only pathological parameter that correlated with OS (P = 0.016) (hazard ratio = 2.27). Conclusions: The high proportion of patients with PDAC showing complete and near‐complete pathological responses supports the use of FOLFIRINOX and radiation in the neoadjuvant setting. Several traditional pathology parameters fail to predict OS in patients treated with chemoradiation, while a quantitative tumour‐to‐tumour bed ratio is a powerful predictor of OS. The data support a two‐tiered approach to TRG based on tumour‐to‐tumour bed ratio, and quantitative analysis merits further consideration. [ABSTRACT FROM AUTHOR]

Background: Retrospective studies show improved outcomes in colorectal cancer patients if taking statins, including overall survival, pathological response of rectal cancer to preoperative chemoradiotherapy (pCRT), and reduced acute and late toxicities of pelvic radiation. Major tumour regression following pCRT has strong prognostic significance and can be assessed in vivo using MRI-based tumour regression grading (mrTRG) or after surgery using pathological TRG (pathTRG).Methods: A double-blind phase 2 trial will randomise 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 18+ sites in New Zealand and Australia. Patients will receive simvastatin 40 mg or placebo daily for 90 days starting 1 week prior to standard pCRT. Pelvic MRI 6 weeks after pCRT will assess mrTRG grading prior to surgery. The primary objective is rates of favourable (grades 1-2) mrTRG following pCRT with simvastatin compared to placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4-5). Secondary objectives include comparison of: rates of favourable pathTRG in resected tumours; incidence of toxicity; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection; cancer outcomes and pathological scores for radiation colitis. Tertiary objectives include: association between mrTRG and pathTRG grouping; inter-observer agreement on mrTRG scoring and pathTRG scoring; studies of T-cell infiltrates in diagnostic biopsies and irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Trial recruitment commenced April 2018.Discussion: When completed this study will be able to observe meaningful differences in measurable tumour outcome parameters and/or toxicity from simvastatin. A positive result will require a larger RCT to confirm and validate the merit of statins in the preoperative management of rectal cancer. Such a finding could also lead to studies of statins in conjunction with chemoradiation in a range of other malignancies, as well as further exploration of possible mechanisms of action and interaction of statins with both radiation and chemotherapy. The translational substudies undertaken with this trial will provisionally explore some of these possible mechanisms, and the tissue and data can be made available for further investigations.Trial Registration: ANZ Clinical Trials Register ACTRN12617001087347. (www.anzctr.org.au, registered 26/7/2017) Protocol Version: 1.1 (June 2017). [ABSTRACT FROM AUTHOR]

Aims: The four‐tiered peritoneal regression grading score (PRGS) assesses the response to chemotherapy in peritoneal metastasis (PM). The PRGS is used, for example, to assess the response to pressurised intraperitoneal aerosol chemotherapy (PIPAC). However, the reproducibility of the PRGS is currently unknown. We aimed to evaluate the inter‐ and intraobserver variability of the PRGS. Methods and results: Thirty‐three patients who underwent at least three PIPAC treatments as part of the PIPAC‐OPC1 or PIPAC‐OPC2 clinical trials at Odense University Hospital, Denmark, were included. Prior to each therapy cycle, peritoneal quadrant biopsies were obtained and three haematoxylin and eosin (H&E)‐stained step sections were scanned and uploaded to a pseudonymised web library. For determining interobserver variability, eight pathologists assessed the PRGS for each quadrant biopsy, and Krippendorff's alpha and intraclass correlation coefficients (ICCs) were calculated. For determining intraobserver variability, three pathologists repeated their own assessments and Cohen's kappa and ICCs were calculated. A total of 331 peritoneal biopsies were analysed. Interobserver variability for PRGS of each biopsy and for the mean and maximum PRGS per biopsy set was moderate to good/substantial. The intraobserver variability for PRGS of each biopsy and for the mean and maximum PRGS per biopsy set was good to excellent/almost perfect. Conclusions: Our data support the PRGS as a reproducible and useful tool to assess response to intraperitoneal chemotherapy in PM. Future studies should evaluate the prognostic and predictive role of the PRGS. [ABSTRACT FROM AUTHOR]

Routine implementation of risk-adapted therapeutic strategies is one of the highest priorities in the management of locally advanced rectal cancer (LARC). Refinement of risk stratification and better treatment selection have the potential to minimise undesirable treatment-related side effects and improve oncological outcome of patients with this disease. Pathological extramural venous invasion (pEMVI) and tumour regression grade (pTRG) within the resection specimens have been historically regarded as prognostic factors for LARC. More recently, studies have increasingly reported suggesting that these parameters can be detected by high-resolution magnetic resonance imaging (i.e. mrEMVI and mrTRG) significantly widening the opportunities to assess individual patient risk and adapt the treatment plan accordingly. In this article, we review the available evidence on the prognostic role of pEMVI, pTRG, mrEMVI and mrTRG in LARC. Moreover, we discuss how using these prognostic factors in clinical practice may potentially promote the implementation of selected therapeutic strategies in this setting. [ABSTRACT FROM AUTHOR]

Aims: High-dose chemoradiation is now considered the standard treatment of locally advanced rectal cancer. To provide feedback on the effect of this treatment, several regression grading systems have been proposed. For a grading system to be useful it has to be reproducible. The aim of this study was to test the reproducibility of a five-point grading system, proposed originally by Mandard, and to describe the sources of disagreement. Methods and results: Tumour regression was assessed independently by two observers on 100 consecutive chemoradiated rectal cancer specimens. The grading system was extremely reproducible, with weighted and unweighted kappa values of 0.89 and 0.82, respectively. The most frequent source of disagreement was assessment of the relative amount of fibrosis. Displacement of epithelium was a minor source of disagreement. Conclusions: The five-point grading system of Mandard is extremely reproducible. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To explore the utility of tumour regression grading (TRG, the amount of residual tumour cells in relation to extension of fibrosis) after chemoradiation of rectal cancer. Materials and methods: Of 131 patients who received preoperative chemoradiation in the frame of the randomized trial, pathological complete response (pCR, TRG0), good regression (TRG1), moderate regression (TRG2), and poor regression (TRG3) were recorded in 17%, 31%, 31%, and 22% of patients, respectively. Results: The rates of ypN-positive category for TRG0, TRG1, TRG2, and TRG3 groups were 5%, 23%, 45%, and 46%, respectively, p =0.001. When ypT-category and TRG were evaluated by the logistic regression analysis, only ypT-category remained significant for independent prediction of the risk for mesorectal nodal metastases, p =0.006. The 4-year (median follow-up) disease-free survival (DFS) for TRG0, TRG1, TRG2, and TRG3 groups were 91%, 67%, 54%, and 47%. When patients with persistent disease (TRG1 vs. TRG2 vs. TRG3) were analyzed separately, TRG had no prognostic value for DFS, p =0.402. Conclusions: TRG in patients with residual cancer had no prognostic value for the incidence of nodal disease and for DFS. Our findings and literature data question the need for the inclusion of TRG assessment into a routine pathological report. [Copyright &y& Elsevier]

Presents information on a study which examined the usefulness of tumor regression grading in quantifying the effect of preoperative radiotherapy on patients with rectal carcinoma. Preoperative evaluation of the patients with rectal carcinoma; Pathologic features of tumors in different treatment groups; Results and discussion; Conclusions.

Colorectal liver metastases (CRLM) affect about 50% of colorectal cancer patients. With the improvement of neoadjuvant chemotherapy and the introduction of targeted therapy, resectability of CRLM and survival rates have improved over time. However, 60-70% of patients still recur. Several pathological and molecular parameters have been described as prognostic factors after CRLM resection. These parameters encompass not only tumoral features, but also non-tumoral ones, such as chemotherapy related liver injury, or factors related to tumour environment, namely Immunoscore. This review summarizes these prognostic indicators to clarify which patho-molecular parameters should be addressed in the pathological report., (© Acta Gastro-Enterologica Belgica.)