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ABSTRACT Introduction Colorectal cancer (CRC) may behave differently depending on the patient's age at diagnosis. This study evaluated the effect of decade of life at diagnosis on the five‐year cancer‐specific and the five‐year stage‐specific survivals (5YCSS and 5YSSS, respectively). The authors hypothesised that both 5YCSS and 5YSSS would be poorer at extremes of age (EoA) compared to middle decades of life (MDoL). Methods Data was sourced from Queensland Oncology Repository (QOR) and held by Cancer Alliance Queensland. Patients diagnosed between 01 January 2001 and 31 December 2021 were allocated into 10‐year age groups and survivals were compared. Descriptive statistics, Pearson chi‐square, Cox regression analysis, logistic regression, and Cramer's V were used. A p ‐value < 0.05 was considered significant. Results Out of 56 768 patients, 44 836 were included in the 5YCSS analysis and 29 906 were included in the 5YSSS analysis. The highest 5YCSS of 74.20% belonged to patients 50–59 years, who were selected as the reference group. In comparison, patients under 30 years had a lower 5YCSS of 66.22% ( p < 0.005) and patients older than 80 years had the lowest 5YCSS of 58.78% ( p < 0.001). Over 80 years and under 30 years Stage IV patients had the lowest 5YSSS of 3.57% and 15.87%, respectively. Conclusion Patients diagnosed at EoA had a poorer 5YCSS compared to patients diagnosed in MDoL. Stage IV patients at EoA had poorer 5YSSS compared to patients in MDoL. This finding may be a result of more aggressive behaviour of CRC in young patients, within each stage, and increased frailty and comorbidity in older patients.

BACKGROUND:There is uncertainty when determining the optimal treatment for malignant polyps. Clinicians must balance the oncological risk of a malignant polyp with the risk of morbidity and mortality from surgery. This study developed an online risk-calculator using machine-learning techniques to predict the risk of an adverse outcome from a malignant colorectal polyp following polypectomy. METHODS:Retrospective data collection of a population-wide database of all malignant polyps from 2011 to 2020 was performed. Utilizing an artificial intelligence-based machine learning approach a generalized linear mixed (GLM) model was developed to predict the risk of an adverse outcome after polypectomy. The presence of an adverse outcome was determined by assessing for the presence of residual disease or lymphatic disease if colorectal resection was undertaken. Delayed disease recurrence was also assessed as an additional adverse outcome. Patient and pathological details from the Queensland Cancer Registry were collected and included in the calculator development. RESULTS:The following variables were included in the final model: age, gender, polyp location (right colon, left colon, rectum), depth of tumour invasion, lymphovascular space invasion, tumour grade, associated polyp type, mismatch repair immunohistochemistry status and margin status. Based on ROC analysis, the AUC for the final GLM model was 0.76. The mean accuracy of the GLM model was 0.76 (95% CI: 0.72-0.80). CONCLUSION:This web-based nomogram will facilitate the discussion of whether individual patients with malignant colorectal polyps can be safely managed with polypectomy or whether the patient should undergo colorectal resection. This nomogram is now available at https://malignantpolyp.com/risk-calculator.

Purpose Given the evolving literature regarding the optimal surgical approach to mitigate post-operative recurrence of Crohn’s disease (CD), this survey study aimed to elucidate the practices and preferences of colorectal surgeons in Australia and New Zealand (ANZ) in their surgical management of CD. Methods Colorectal surgical consultants and fellows ( n = 337) registered with the Colorectal Surgical Society of Australia and New Zealand (CSSANZ) were invited by email in April 2022 to participate in a cross-sectional survey consisting of basic demographics and 12 questions relating to their usual surgical practice and preferred operative strategy. Results A total of 135 responses were received (39.9%). Regarding anastomotic configuration, 47% ( n = 68) preferred the side-to-side anastomosis (STSA), 19% ( n = 28) the end-to-end anastomosis (ETEA), and 15% ( n = 21) the Kono S anastomosis. Most respondents preferred to resect at the proximal junction of the abnormal mesentery (75%, n = 97), while radical resection of the mesentery was preferred in 10% ( n = 13) and close intestinal resection through abnormal mesentery in 15% ( n = 20). The preferred surgical approach was by far laparoscopic (93%, n = 125) with extraction from the midline peri-umbilical port (80%, n = 108). Conclusion Amongst participating colorectal surgeons, there was a clear consensus on the approach, where the dominant practice was laparoscopy with a midline peri-umbilical extraction. Similarly, most respondents preferred some degree of mesenteric resection. However, anastomotic configuration and technique were domains of resection in CD lacking unanimity despite clear guidelines, highlighting an area requiring further attention.

Aim Anastomotic leak (AL) is the anathema of colorectal surgery and its occurrence constitutes a serious risk to patients and places a substantial burden on the health system. The analysis of extravasated intraluminal substances in drain fluid has shown promise for the early detection of AL. The aim of this study is to assess the measurement of drain fluid iodine as a biomarker of AL. Method This prospective, observational, 2b exploration cohort study measured the iodine in drain fluid of patients undergoing a low colorectal anastomosis and without a diverting ileostomy (DI) when the rectal tube was flushed with Gastrografin (R). Iodine was measured by dual-energy computed tomography (DECT) and inductively coupled plasma mass spectroscopy (ICPMS). Results Sixty-six patients underwent a rectal resection and low colorectal anastomosis. Five patients experienced an AL. Four had grade C AL and returned to the operating theatre for peritoneal lavage and DI. The fifth was diagnosed at 30 days postoperatively and underwent image-guided drainage (grade B). The mean drain fluid iodine was significantly elevated in patients who experienced an AL compared with those who did not, as measured by DECT and ICPMS. The mean iodine value was 6.05 mg/mL vs. 0.088 mg/mL (p < 0.0001) for DECT and 41 437 mu mol/L vs. 3.81 mu mol/L (p < 0.0001) for ICPMS. Conclusion This study showed that drain iodine can be used as a sensitive indicator of early AL in patients undergoing a rectal resection with an extraperitoneal colorectal anastomosis and omission of a DI and when the rectal tube is flushed with Gastrografin following surgery.

AIM:Long-term survival outcomes in young-onset colorectal cancer patients are contradictory and inconsistent. Some studies report overall survival to be significantly superior compared with older adults, while others report worse survival. Worldwide, the incidence of young-onset colorectal cancer has, alarmingly, nearly doubled since the 1990s, in stark contrast to that in those over 50 years of age. Long-term survival in young-onset colorectal cancer has not been explored in the Australian population. The aim of this study was to investigate cancer-specific and overall survival up to 10 years. METHOD:This was a retrospective population-based cohort study. All colorectal cancer diagnoses between 2001 and 2020 in the state of Queensland, Australia were reviewed. Young-onset colorectal cancer (20-49 years) was compared with late-onset colorectal cancer (50 years+). RESULTS:There were 52 697 adults diagnosed with colorectal cancer in Queensland. Young-onset colorectal cancer accounted for 7.7% of these. Young-onset colorectal cancer had a greater proportion of Stage III and IV disease than the late-onset group (66% vs. 59%, p < 0.001). Despite this, young-onset colorectal cancer had statistically significant improved overall survival at all time points to 10 years (p < 0.001). Stage-for-stage cancer-specific survival to 10 years was superior in all stages in young-onset colorectal cancer (p < 0.001). CONCLUSION:Both stage-for-stage cancer-specific and overall survival were superior in young-onset colorectal cancer compared with those aged 50 years and above, up to 10 years.

Purpose Stenting is a useful treatment option for malignant colonic obstruction, but its role remains unclear. This study was designed to establish how stents have been used in Queensland, Australia, and to review outcomes. Methods Patients diagnosed with colorectal cancer in Queensland from January 1, 2008, to December 31, 2014, who underwent colonic stent insertion were reviewed. Primary outcomes of 5-year survival, 30-day mortality, and overall length of survival were calculated. The secondary outcomes included patient and tumor factors, and stoma rates. Results In total, 319 patients were included, and distant metastases were identified in 183 patients (57.4%). The 30-day mortality rate was 6.6% (n=21), and the 5-year survival was 11.9% (n=38). Median survival was 11 months (interquartile range, 4–27 months). A further operation (hazard ratio [HR], 0.19; P<0.001) and chemotherapy and/or radiotherapy (HR, 0.718; P=0.046) reduced the risk of 5-year mortality. The presence of distant metastases (HR, 2.052; P<0.001) and a comorbidity score of 3 or more (HR, 1.572; P=0.20) increased mortality. Surgery was associated with a reduced risk of mortality even in patients with metastatic disease (HR, 0.14; P<0.001). Twenty-two patients (6.9%) ended the study period with a stoma. Conclusion Colorectal stenting was used in Queensland in several diverse scenarios, in both localized and metastatic disease. Surgery had a survival advantage, even in patients with metastatic disease. There was no survival difference according to whether patients were socioeconomically disadvantaged, diagnosed in a major city or not, or treated at private or public hospitals. Stenting proved a valid treatment option with low stoma rates.

BACKGROUND:The management of Crohn's disease (CD) complicated by ileosigmoid fistula (ISF) remains a challenge, and Australian outcomes have not previously been reported. METHODS:A retrospective review of a tertiary colorectal inflammatory bowel disease unit, across public and private sites, from 2005 to 2023 to identify adult patients having undergone operative management of ISF. RESULTS:Twenty-nine patients underwent surgery for ISF in the study period. Seventeen were male and the median age was 40 years. The pre-operative diagnosis of ISF was made in 76%, and patients were more likely to undergo resectional surgery if the pre-operative diagnosis was made endoscopically. Sixty-nine percent of cases were performed electively, with 76% completed laparoscopically with an 18.5% conversion rate to an open approach. The ISF was oversewn in three patients, repaired primarily in 14 patients, managed with segmental wedge resection in eight patients and resected via an anterior resection in four patients. The rate of stoma formation at the index procedure was 20.7% overall and 22% in patients being acutely managed with steroids. Emergent cases were more likely to be defunctioned with a stoma. Morbidity was 17.2% with a single anastomotic leak. CONCLUSION:ISF in CD remains difficult to diagnose pre-operatively, but can be safely managed laparoscopically without formal resection, and with limited use of diverting stoma formation. The specific surgical approach to the sigmoid in ISF is difficult to pre-determine and often requires decisions to be made intra-operatively.

The accumulation of evidence by which we make decisions can be slow and the accrual can create potential temporary deviations away from the final outcome as the journey continues. In this perspective is presented an important example involving ileocolic resection and Crohn's disease for consideration. Many surgeons will have read the Luglio1 randomized controlled trial (RCT) from 2021 investigating the Kono S anastomosis after ileocolic resection for Crohn's disease (CD) and some will have altered their practice and will have taken up the Kono S anastomosis as their preferred anastomotic configuration. On the face of it, the findings of an endoscopic recurrence (i2 or greater) rate of 22.2% in the Kono S group vs. 62.8% in the stapled side to side (SSTS) (p < 0.001) is strong evidence of the superiority of the new technique. This coupled with the retrospective cohort studies of very low surgical recurrence out of Japanese centres that have reported five-year surgery free rates of 95.0% in the Kono S vs. 81.3% in the end to end group (p < 0.001),2 make the case compelling. Certainly, it is imperative to study this anastomotic configuration rigorously, but it is important to wait for high level evidence before it is adopted as the gold standard. It is important to remember that the primary outcome in the Luglio study was evidence of endoscopic recurrence graded at i2 (more than 5 ulcers in the ileum or anastomosis) and that this is a surrogate outcome for more important clinical outcomes such as surgical recurrence, need for new medical therapy or indeed quality of life.3 These long term outcomes are not yet available. In an attempt to better predict the future disease course after an ileocolic resection, Rutgeerts developed an endoscopic score in 1984 based on a number of endoscopic findings.3, 4 This score was later modified to account for the observation that ulceration along the staple line of a SSTS may not behave the same way as 'true' ileal aphthous ulcers. The modified Rutgeerts score separates >5 ulcers at the staple line (i2a) and >5 ulcers in the terminal ileum (i2b). The i2b lesions have a greater likelihood of progressing to more severe endoscopic disease, and thus are considered a more important predictor of disease course.5 Surgical recurrence is an important outcome but is also highly subjective. The criteria for resection are not defined and of course are interpreted in light of the individual patient's symptoms and wishes. These are framed by their gastroenterologist's approaches to treatment and susceptible to temporal bias as more therapeutic options become available on the PBS. Practice in 2024 is very different to practice in 2014. This highlights the imprudence of historical cohorts as comparator groups in IBD studies. An excellent example of temporal bias is the presentation of outcomes of the extent of mesenteric resection in ileal CD when retrospective cohorts are used. The Coffey et al. study of radical mesenteric resection used historical controls to conclude that a radical resection of the mesentery led to a near five-year surgical recurrence rate of 2.9% vs. 40% in the conservative group (p = 0.003).6 These findings were largely repudiated this year at ECCO with the presentation of the results of the RCT of radical vs. conservative mesenteric resection (the SPICY trial).7 In this study the investigators randomized 130 patients to an extended mesenterectomy vs. a mesentery sparing resection. The authors found no difference in the primary outcome of endoscopic recurrence at 6 months, graded as i2b or greater (42.4% vs. 43.1%; p = 1.0). Whilst this is a surrogate outcome for clinical and surgical recurrence, it is certainly objective. The five-year surgical outcomes are awaited. The Luglio RCT of 74 patients now stands in stark contrast to the interim outcomes of the much larger North American RCT of the Kono S vs. the SSTS anastomosis.8 The interim results of this study were presented by Koiana Trencheva, also at the ECCO meeting this year and reported endoscopic recurrence rates of 25.9% vs. 27.8% (p = 0.775) in this interim study of the 250 patients who had reached their primary outcome of i2b or greater at post-operative colonoscopy at 3–6 months. There are still 32 patients who haven't as yet reached their primary outcome and the final publication and long term outcomes are eagerly awaited. The Kono S anastomosis comprises three elements that have not been independently studied. These are: 1 the supporting column; 2 the mesenteric preservation; and 3 the stricturoplasty-like anastomotic configuration that excludes the mesentery from the anastomosis.9 Stefan Holubar et al. from the Cleveland Clinic reported on the safety of a combination of mesenteric resection with the other two elements.10 RCTs studying this combination are proceeding in the Cleveland Clinic, the United Kingdom and Australia.11 Some of the shine is certainly coming off the Kono S anastomosis. The original cohort studies have reported extraordinarily low surgical recurrence and the construct is supported by the Luglio RCT. However, larger and well-constructed RCTs are providing conflicting evidence to cohort series. These studies need to be interpreted in the context of primary outcomes of endoscopic recurrence which are a surrogate for important and relevant clinical outcomes. IBD patients are a heterogenous cohort and thus it is important that randomized studies are conducted to do the heavy lifting to control bias. In an ideal world, all eligible patients would be enabled to be entered into an RCT to expeditiously advance evidence but there are substantial administrative barriers to these multicentre studies.12 It is paramount that we investigate new operative techniques thoroughly and wait for good quality, long term evidence before we embrace these techniques as a new gold standard. David A. Clark: Conceptualization; writing – original draft; writing – review and editing. Open access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians.

PURPOSE:The estimation of the risk posed by malignant polyps for residual or lymphatic disease plays a central role. This study investigated colorectal surgeons' assessment of these risks associated with malignant polyps. METHODS:A cross-sectional questionnaire was electronically administered to colorectal surgeons in Australia and New Zealand in October 2022. The questionnaire contained 17 questions on demographics, when surgeons consider colorectal resection appropriate, and the risk assessment for 5 hypothetical malignant polyps. RESULTS:The mean risk of residual or lymphatic disease that would prompt surgeons to recommend colonic resection was 5%. However, this increased to a mean risk of 10% if the malignant polyp was located in the rectum, and the only resection option was abdominoperineal resection with end-colostomy. There was high concordance between the estimated risk of residual or lymphatic disease by colorectal surgeons and the Association of Coloproctology of Great Britain and Ireland (ACPGBI) guidelines for the 5 hypothetical malignant polyps, with the ACPGBI estimated risk lying within the 95% confidence interval for 4 of the 5 malignant polyps. Nonetheless, 96.6% of surgeons felt that an online risk calculator would improve clinical practice. CONCLUSION:Colorectal surgeons in Australia and New Zealand accurately estimated the risk posed by malignant polyps. An online risk calculator may assist in better conveying risk to patients.

BACKGROUND:Over 42 000 Australians live with a stoma, and this number increases annually. Pregnancy in stoma patients is a rare but complex condition and there is limited published literature regarding surgical and obstetric complications in pregnant stoma patients. The aim of this paper was to review stoma outcomes, perinatal morbidity and mortality, and early postpartum period in pregnant stoma patients. METHODS:Data was retrospectively obtained on women of childbearing age, with a stoma, who had been pregnant and birthed in the last nine years at the Royal Brisbane and Women's Hospital between January 2014 to December 2022. Data recorded included patient demographics, type of stoma, indication for stoma, need for additional abdominal surgeries, method of conception, pregnancy complications, length of stay, neonatal outcomes and post pregnancy stomal complications. RESULTS:In total, there were 16 births from 13 mothers with stomas. Of 10 births to IBD patients, 40% experienced a serious stomal complication. Caesarean section (CS) rate was 90% for IBD and 83% for non-IBD. In-vitro fertilisation rates were 40% in IBD patients and 0% in non-IBD patients. The average gestational age at delivery was 36 weeks in IBD and 35 weeks in non-IBD patients. Neonates delivered to IBD mothers had a birth weight under 2500g in 40% of cases and in non IBD mothers at 33.3% (p = 0.62). Of the sixteen births there was five complications (31.25%) associated with the stoma either during pregnancy or during the sixty-day postpartum period. CONCLUSION:Pregnancy in stoma patients is a rare occurrence and appears to be associated with high rates of CS, preterm delivery, low birth weight and stomal complication.

BACKGROUND:Colorectal cancer is the third most common cancer and the second highest cause of cancer mortality in Australia. Despite advances in colorectal surgery, anastomotic leak still occurs in low-risk patients and is a substantial cause of morbidity and mortality. Many operative strategies are used to assess anastomotic integrity such as an air leak test or intraoperative flexible sigmoidoscopy, however an objective anastomotic checklist is yet to be developed and studied. This study aims to develop a photodocumentary anastomotic specific checklist and determine its feasibility for implementation. METHODS:Patients undergoing left sided colorectal resections with primary anastomosis without a de-functioning ileostomy were prospectively included between May 2021 and December 2022. A photographic checklist assessing anastomotic perfusion, integrity via either air test or endoscopic image, evidence of complete operative doughnut specimens and the assessment of tension was implemented. The feasibility of an anastomotic checklist was externally validated by four independent colorectal surgeons from Australia, New Zealand and United States of America. RESULTS:The anastomotic checklist was completed in 44 patients. Mean age was 62 years, with 43% male and mean BMI 28. Operations included high anterior resection (45%), low anterior resection (18%), ultra-low anterior resection (20%), reversal of Hartmann's (11%). Median length of stay was 4 days. Complications post operatively were documented in six patients with anastomotic leak in 2% and wound infection in 6.8%. Intraclass correlation coefficients were poor amongst all reviewers with air leak and tension having no inter-reviewer correlation. CONCLUSION:The introduction of an anastomotic checklist was a feasible tool to systematically assess and document anastomotic integrity. Unfortunately, with the small sample size there was significant discrepancy in inter-observer variability, and this led to poor correlation regarding which patients were typically high risk requiring a temporary ileostomy. Larger studies on the implementation of an anastomotic checklist will be needed to evaluate if it is an inherently feasible approach and if there is an effect on anastomotic leak.

Aim: Surgery for constipation is usually reserved for patients with severe and refractory symptoms because of concerns about perioperative morbidity and unpredictable functional outcomes. The aim of this paper is to identify the long-term outcomes of patients who have undergone total colectomy and ileorectal anastomosis for severe constipation.Method: Patients who had undergone a total colectomy and ileorectal anastomosis for severe constipation were identified from a prospectively maintained database and sent a postal survey assessing functional symptoms, patient satisfaction and the impact of symptoms on quality of life. Information regarding the surgery, perioperative complications and hospitalizations were also collected. Functional outcomes of the surgery were evaluated with the Gastrointestinal Quality of Life Index, St Marks incontinence score, Wexner continence score, obstructed defaecation syndrome score and Cleveland Clinic constipation score.Results: Seventy-one questionnaires were posted and 32 (45%) patients responded. The mean time since surgery was 15.3 years (range 2.9-30.4 years) Most patients were happy with the surgery. Ongoing symptoms were common, the most frequent of these were abdominal pain, experienced by 23 patients (71.9%), and faecal incontinence, experienced by 17 patients (53%). Fourteen patients (43.8%) required subsequent hospital admission due to bowel obstruction and eight patients (25%%) had subsequent surgery for adhesions. There was an association between patient quality of life and subsequent surgeries.Conclusion: Most patients were happy and viewed their life as improved following total colectomy for severe constipation. This is despite a high rate of ongoing functional symptoms.

Ileostomy formation may be permanent or intended as temporary to defunction a high‐risk pelvic anastomosis to reduce the risk of septic consequences of anastomotic leak. However, these procedures have a high rate of readmission, most commonly due to dehydration and associated with acute kidney injury (AKI).

The management of malignant polyps is a treatment dilemma in selecting between polypectomy and colorectal resection. To assist clinicians, guidelines have been developed by the Association of Coloproctology of Great Britain and Ireland (ACPGBI) to provide treatment recommendations. This study compared management strategy based on the ACPGBI risk categorization for malignant polyps. Univariable and multivariable statistical analysis was undertaken to assess the factors predicting management strategy. A population-wide analysis was performed of 1646 malignant polyps and the factors that predicted their management strategy, from Queensland, Australia, from 2011 to 2019. Overall, 31.55% of patients with very low or low risk disease proceeded to resection. Of those with high or very high risk disease, 36.69% did not proceed to resection. In very low and low risk polyps, age ( P  = 0.003) and polyp location ( P  < 0.001) were significantly different between the colorectal resection group and the polypectomy alone group. In those with very high or high risk polyps age ( P  < 0.001), type of facility (public or private) for the colonoscopy ( P  = 0.037), right colonic polyps compared to left colonic polyps ( P  = 0.015) and rectal polyps ( P  < 0.001) and mismatch repair mutations present ( P  = 0.027) were predictive of resection in high risk disease using a multivariable model. Over 30% of patients with very low and low risk malignant polyps proceeded to resection, against the advice of guidelines. Furthermore, over 35% of patients with very high or high risk malignant polyps did not proceed to resection. Education strategies may improve management decision choices. Furthermore, improvements in data collation will improve the understanding of management choices in the future.

BACKGROUND:Malignant polyps represent the early development of colorectal adenocarcinoma. During 2020, there was widescale rationing of health-care resources in response to the COVID-19 pandemic. In particular there was deferral of some colonoscopy procedures required for timely malignant polyp detection. This study sought to assess how these deferrals affected the diagnosis of malignant polyps.METHODS:A population wide analysis was performed of 2079 malignant polyps, diagnosed in Queensland, Australia from 2011 to 2020. A regression analysis, with 95% prediction intervals, was produced to determine whether there was a significant impact on the number of malignant polyps diagnosed in 2020 compared to previous years. Univariate statistical analysis of patient, procedural, and pathological variables was also performed.RESULTS:In 2020 there were 211 malignant polyps diagnosed, which was significantly lower than was predicted by the univariate regression analysis (r2  = 0.85, 95% prediction interval: 255.07-323.91, P < 0.001). These malignant polyps were less likely to be diagnosed in a private setting (P < 0.001), and exhibited significantly less depth of submucosal invasion (P = 0.017). There was no significant difference in the management strategy (polypectomy, resection or trans-anal resection) between 2011 and 2019 and 2020.CONCLUSION:Because of the significant decrease in the number of malignant polyps, and the natural history of the disease, it is expected that there will be an increase in more advanced colorectal adenocarcinomas presenting in 2021 and beyond. This has implications for healthcare resources, particularly in light of the ongoing strain on health departments as a result of the COVID-19 pandemic.

Significance: Reactive oxygen species (ROS) are critical to normal cellular function with redox homeostasis achieved by balancing ROS production with removal through detoxification mechanisms. Many of the conventional chemotherapies used to treat colorectal cancer (CRC) derive a proportion of their cytotoxicity from ROS generation, and resistance to chemotherapy is associated with elevated detoxification mechanisms. Furthermore, cancer stem cells demonstrate elevated detoxification mechanisms making definitive treatment with existing chemotherapy challenging. In this article, we review the roles of ROS in normal and malignant colonic cell biology and how existing and emerging therapies might harness ROS for therapeutic benefit.Recent Advances: Recent publications have elucidated the contribution of ROS to the cytotoxicity of conventional chemotherapy alongside the emerging approaches of photodynamic therapy (PDT), sonodynamic therapy (SDT), and radiodynamic therapy (RDT), in which ROS are generated in response to excitatory light, sound, or X-ray stimuli to promote cancer cell apoptosis.Critical Issues: The majority of patients with metastatic CRC have a very poor prognosis with a 5-year survival of similar to 13% making the need for new or more effective treatments an imperative.Future Directions: Modulation of ROS through a combination of new and emerging therapies may improve the efficacy of current chemotherapy providing novel approaches to treat the otherwise resistant disease.