89 Background: Oxaliplatin hypersensitivity is not uncommon in patients with gastrointestinal (GI) cancers receiving chemotherapy. The use of oral premeditations (dexamethasone, cetirizine and famotidine) starting 24 hours before treatment and continuing for a total of three days, further intravenous premedication (dexamethasone, chlorphenamine and famotidine) 30 minutes before treatment and the gradual administration of oxaliplatin over 6.5 hours in four separate escalating doses (desensitisation protocol) is commonly used in such cases. While desensitisation is an option, especially in severe cases, responses and survival outcomes upon rechallenge are not well described. Methods: A retrospective chart review of patients with various GI malignancies who received oxaliplatin-based desensitisation chemotherapy after a severe drug reaction between October 2019 and October 2022 at a single cancer centre was performed. Clinicopathological characteristics and oncological outcomes were assessed. Results: Forty-four patients with a median age of 61 years (range 38-81) were studied. The majority had a diagnosis of CRC (n=22; 50%), followed by oesophago-gastric (n=19; 4%), appendiceal (n=1), cholangiocarcinoma (n=1), and cancer of unknown primary (n=1). More than two thirds of patients (n=32, 73%) were treated with palliative intent. The most common regimens associated with oxaliplatin hypersensitivity reactions after a median of 3 cycles (range 1-10) were FOLFOX (n=24, 55%), CAPOX (n=18, 41%), FLOT (n=1) and FOLFOXIRI (n=1). Seven patients (16%) had another reaction after desensitisation, leading to discontinuation of treatment. Thirty-seven patients (84%) completed treatment as planned. Treatment outcomes after desensitisation included 5 (11%) patients with no evidence of disease (NED) after adjuvant treatment, 16 (37%) patients with disease control, including 3 (7%) partial responders (PR) and 13 (30%) patients with stable disease (SD), and 23 (52%) patients with progressive disease (PD). Conclusions: Oxaliplatin desensitisation is feasible with low discontinuation rates and leads to acceptable oncological outcomes. All patients should be offered desensitisation to allow continuation of active systemic therapy.

BACKGROUND:Early onset Colorectal Cancer (EOCRC), defined as those diagnosed under the age of 50, has been increasing rapidly since 1970. UK data on EOCRC are currently limited and better understanding of the condition is needed. MATERIALS AND METHODS:A single-center retrospective study of patients with EOCRC treated over 9 years (2013-2021) at a large UK cancer center was performed. Clinicopathological features, risk factors, molecular drivers, treatment, and survival were analyzed. RESULTS:In total, 203 patients were included. A significant increase in cases was reported from 2018-2019 (n = 33) to 2020-2021 (n = 118). Sporadic EOCRC accounted for 70% of cases and left-sided tumors represented 70.9% (n = 144). Median duration of symptoms was 3 months, while 52.7% of the patients had de-novo metastatic disease. Progression-free survival after first-line chemotherapy was 6 months (95% CI, 4.85-7.15) and median overall survival (OS) was 38 months (95% CI, 32.86-43.14). In the advanced setting, left-sided primary tumors were associated with a median OS benefit of 14 months over right-sided primaries (28 vs 14 months, P = .009). Finally, primary tumor resection was associated with median OS benefit of 21 months compared with in situ tumors (38 vs 17 months, P < .001). CONCLUSIONS:The incidence of EOCRC is increasing, and survival outcomes remain modest. Raising public awareness and lowering the age for colorectal cancer screening are directions that could improve EOCRC clinical outcomes. There is also a need for large prospective studies to improve the understanding of the nature of EOCRC and the best therapeutic approaches.

BACKGROUND:Cytoreductive surgery (CRS) is effective for colorectal cancer peritoneal metastases (CRPM) at increasing overall survival (OS) compared to systemic anticancer treatment (SACT) alone. The addition of Oxaliplatin heated intraperitoneal chemotherapy (HIPEC) has been shown in a randomized controlled trial to result in increased complications without significant OS benefit. This study evaluates outcomes for CRPM patients undergoing CRS+HIPEC with Oxaliplatin (Ox) 368mg/m2 (30 min), versus Mitomycin C (MMC) 35mg/m2 (90min).  METHODS: A prospective CRPM real-world database was used to collect outcomes for patients undergoing CRS+HIPEC at a single center. OS, recurrence-free (RFS), peritoneal RFS (PeRFS) were compared amongst all patients with histologically proven CRPM, those with completeness of cytoreduction (CC) score =0/1, and those with CC score=0/1 who were SACT naïve.  RESULTS: Between April 2005 and April 2021, 409 patients underwent CRS+HIPEC: 271 (66%) had MMC, 138 (34%) Ox. Of these, 395 (97%) had histologically confirmed CRPM, 336 (85%) achieved CC=0/1, 188 (47%) were SACT naïve; median OS =39.5, 44.4, and 47.2 months respectively. MMC versus Ox median OS in CC0/1=43.7 (95% CI 35.9-48.3) versus 50.1 (39.7-70.2) months, P = .28; Median OS in SACT naïve=45.7 (39.4-65.9) versus 59.9 (38.3-82.0) months, P = .31; multivariable analysis for CC0/1, SACT naïve patients showed Ox was comparable to MMC: HR=0.90, (0.64-1.27) P = .55 versus HR=0.88, (0.53-1.44) P = .60, respectively. Ox resulted in a significantly improved PeRFS in CC0/1 patients (MMC=9.0 versus Ox=12.6months, P = .01). A multivariable model for PeRFS showed a HR=0.63, (0.43-0.95), P = .03 for Ox.  CONCLUSION: This study suggests a role for Ox HIPEC in CRPM which should be explored further in clinical trials.

PICO-SM was a prospective longitudinal study investigating the psychological impact of the COVID-19 pandemic on patients with colorectal cancer treated in a large UK tertiary cancer centre. Here, we present the impact of the third wave of the pandemic (December 2021 to February 2022), when the Omicron variant became prevalent in the UK, and the complete longitudinal comparison across the entire duration of this study. Patients were invited to complete a questionnaire, including screening psychometric tools. In total, n = 312 patients were included in the final analysis. Specifically, in this Omicron-predominant wave, n = 96 patients were studied in detail: the mean age was 64 years, 64% were male, 33% reported poor well-being, 27% anxiety, 11% depressive symptoms, and 3% trauma-related symptoms. The participants who had investigations cancelled (OR 9.22, 95% CI 1.09-77.85; p = 0.041) or felt that the pandemic would affect their mental health (OR 3.82, 95% CI 1.96-7.44; p < 0.001) had an increased risk of anxiety according to a multivariate analysis. Similarly, independent predictors of poor well-being included concern that the pandemic would affect their cancer treatment (OR 4.59, 95% CI 1.03-20.56; p = 0.046) or mental health (OR 3.90, 95% CI 1.38-11.03; p = 0.010). The psychological distress experienced by patients, particularly anxiety, remained high during the third wave of the COVID-19 pandemic. These results align with our previously reported findings, emphasising the importance of continuing cancer treatment amidst an ongoing humanitarian emergency.

Treatment guidelines provided by PRODIGE-7 recommend perioperative systemic chemotherapy before cytoreductive surgery (CRS) for colorectal cancer peritoneal metastases (CRPM). Toxicity with multimodal treatment needs to be better defined. Chemotherapy response and impact on survival have not been reported. We assessed CRPM patients who received systemic oxaliplatin/irinotecan before CRS (preoperative) with Mitomycin C (35 mg/m2, 90 min) or Oxaliplatin (368 mg/m2, 30 min) heated intraperitoneal chemotherapy (HIPEC). Secondary analysis was performed from a prospective database. Overall survival (OS) in chemotherapy responders (R) and nonresponders (NR) was compared. Toxicity was assessed by rate of adverse events (AEs). From April 2005 to April 2021, 436 patients underwent CRS + HIPEC; 125 (29%) received preoperative chemotherapy. The 112 (90%) received oxaliplatin (64, 57%) or irinotecan (48, 43%). R, defined as complete (CR) or partial response on preoperative imaging and/or postoperative histology, was seen in 71, 63% (53.8-72.3); 16, 14% (8.4-22.2) had CR. Median OS in R versus NR was 43.7 months (37.9-49.4) versus 23.9 (16.3-31.4) p = 0.007, HR 0.51 (0.31-0.84). OS multivariable analysis showed HR 0.48 (0.25-0.95), p = 0.03 for chemotherapy response corrected by peritoneal cancer index, completeness of cytoreduction score. CRS led to 21% grade 3-4 AEs versus 4% for preoperative chemotherapy. HIPEC grade 3-4 AEs were 0.5%. Preoperative chemotherapy response is an independent predictor for OS in CRPM. Perioperative chemotherapy is used in the multimodal treatment of colorectal cancer peritoneal metastases (CRPM). Preoperative chemotherapy response is an independent predictor for overall survival in patients with CRPM. Grade 3-4 adverse events related to mitomycin C (35 mg/m2) and Oxaliplatin (368 mg/m2) heated intraperitoneal chemotherapy are rare (0.5%).

The COVID-19 pandemic has resulted in unprecedented changes to the lives of patients with cancer. To evaluate the impact of the COVID-19 pandemic on the mental health and well-being of patients with colorectal cancer, we conducted a prospective longitudinal questionnaire study at a UK tertiary cancer centre. In total, 216 participants were included: mean age 65 years, 57% (n = 122) male, 92% (n = 198) of white ethnicity. Amongst participants who completed the screening psychometric questionnaire, 24% (n = 48/203) reported anxiety (GAD-7 ≥ 5), 15% (n = 31/204) depressive symptoms (PHQ-9 ≥ 10), 3% (n = 5/190) probable post-traumatic stress disorder (PC-PTSD-5 ≥ 4), and 31% (n = 66/213) poor well-being (WHO-5 < 50). In the subgroup (n = 95/216, 44%) who consented to and completed a follow-up survey 6 months later, there was a significant increase in the number of participants at risk of depression (4% vs. 13%, p = 0.021). Self-reported concern about the COVID-19 pandemic impacting one's mental health is associated with increased likelihood of anxiety, depression, and poor well-being, in respective multivariate analyses. In conclusion, screening for the mental health impact of the COVID-19 pandemic is essential to ensure timely action from all key stakeholders and to avoid potentially longer-term detrimental consequences.

39 Background: The role of heated intraperitoneal chemotherapy (HIPEC) in colorectal cancer peritoneal metastases (CRPM) is confounded by cytoreductive surgery (CRS) or receipt of peri-operative systemic anticancer therapy (SACT). Following Prodige-7, the role of Oxaliplatin HIPEC in addition to CRS has been debated. We evaluated a patient series undergoing CRS with Oxaliplatin (368mg/m2 for 30 mins) or Mitomycin C (MMC) (35mg/m2 for 90 mins) HIPEC stratified by extent of CRS and SACT. Methods: Data collected retrospectively from a prospective database of CRPM patients undergoing CRS +/- HIPEC at a single UK Peritoneal Tumour Centre included sex, primary tumour detail: site, TNM stage, SACT: adjuvant, peri-operative, operation details: peritoneal cancer index (PCI), cytoreductive score (CC), HIPEC agent, molecular profile: RAS, BRAFV600E, PIK3CA, microsatellite status, date of last follow-up or recurrence/death to 1st July 2022. Univariable and multivariable (MVA) analysis were performed for overall survival (OS) and recurrence free survival (RFS). Outcomes were compared among three patient groups: 1. all comers (all patients who underwent CRS +/- HIPEC), 2. CC0-1 (those who achieved CC0-1) and 3. SACT naïve (CC0-1 and no SACT pre-CRS, adjuvant SACT post primary resection allowed if completed > 6 months). Results: From April 2005 to April 2021, 409 patients received HIPEC: 271 (66%) MMC, 138 (34%) Oxaliplatin; 395 patients (97%) had CRPM (all comers); 336 (85%) achieved CC0-1; 187 (47%) were SACT naïve. Median OS for all comer, CC0-1 and SACT naïve groups were 39, 44 and 47 months respectively. MMC vs Oxaliplatin HIPEC median OS was 44 (95% CI 38-49) vs 50 (95% 40-60) months, p=0.3 in CC0-1. Median OS in SACT naïve was 46 (95% CI 34-58) vs 60 (95% CI 38-82) months, p=0.3. Oxaliplatin HIPEC showed a trend to benefit PCI <15 and SACT naïve (table). OS MVA in CC0-1 and SACT naïve showed Oxaliplatin HIPEC was comparable to MMC HR: 0.85, 95% CI (0.60-1.19) p=0.3, HR: 0.83, 95% CI (0.51-1.35) p=0.5, respectively. Oxaliplatin HIPEC had a significant benefit on local RFS in CC0-1 (MMC vs Oxaliplatin RFS 9 vs 12 months p=0.01; distant RFS 10 vs 12 months p=0.5, local and distant RFS 6 vs 8 months p=0.3). Local RFS MVA showed a HR: 0.64, 95% CI (0.41-0.99), p=0.04 for Oxaliplatin HIPEC when corrected by PCI, N stage and grade. Conclusions: The study shows a trend to better OS with Oxaliplatin HIPEC in selected patients with low volume CRPM not requiring SACT. CRS with Oxaliplatin HIPEC is beneficial in local RFS, suggesting there is a role for local control in CRPM with Oxaliplatin HIPEC. This needs to be further explored in clinical trials. [Table: see text]

Background: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases with a focus on terminology, diagnosis and management.Methods: This project was a multi-organisational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis and management. Statements were refined during an online Delphi process and those with 70% agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising twelve key statements.Results: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term "early metachronous metastases" applies to those absent at presentation but detectedwithin 12 months of diagnosis of the primary tumour with "late metachronous metastases" applied to those detected after 12 months. Disappearing metastases applies to lesions which are no longer detectable on MR scan after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways including systemic chemotherapy, synchronous surgery and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed.Conclusions: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.

BACKGROUND:Since the beginning of the COVID-19 pandemic, multiple changes to the provision of cancer care has been introduced to maximize patient safety and protect staff. We aimed to identify factors influencing clinicians' decision on treatment modification during the initial phase of the pandemic, and to assess its impact on outcomes in patients with colorectal cancer.PATIENTS AND METHODS:Electronic records of patients seen in a large United Kingdom tertiary cancer center was reviewed. The frequency and type of changes to systemic anticancer therapy , as well as the factors predicting clinicians' decision were assessed.RESULTS:A total of 418 patients; mean age 63 ± 12 years and 57% male were included. More than half of the patients had modification to their treatment; with treatment delay (21%) or cancellation (10%), being the most common. Majority of patients on neoadjuvant treatment (97%) proceeded with treatment, with some form of treatment modification in 20%. Half of patients on adjuvant treatment had their treatment plan modified. Overall, a change in treatment was more likely in older patients (OR 1.028 [95% CI 1.010-1.047]; P = .002), and in patients who had already received higher number of cycles of systemic anticancer therapy (OR 1.040 [95% CI 1.016-1.065]; P = .001). A change in treatment was less likely further out of the first national lockdown (OR 0.837 [95% CI 0.758-0.925]; P < .001). Patients on third-line treatment were most likely to have alterations to their treatment plan (69%, n=33/48).CONCLUSION:During the first wave of COVID-19 in the United Kingdom, clinicians adapted clinical practice in accordance to local and national guidance, especially amongst older patients and those on third-line treatment. Further real-world data are needed to document the important impact of changes to treatment on outcomes in patients with cancer.

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 trans , 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 trans , offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

BackgroundThe 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 MethodsAn 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.ResultsOf 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).ConclusionsThe 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.

Abstract Background The standard first- and second- line chemotherapy backbone regimens for metastatic colorectal cancer (mCRC) are 5-fluorouracil (5-FU)/capecitabine-based with addition of irinotecan or oxaliplatin. Until recently, evidence for optimal sequencing post second-line was sparse. Trifluridine/tipiracil (indicated for mCRC and gastric cancer after standard chemotherapies) was made available to UK patients via a named patient programme (NPP) before receiving marketing authorisation in Europe in 2016, allowing characterisation of UK treatment pathways, and evaluation of trifluridine/tipiracil in a UK non-trial population. Methods Data collected routinely for the NPP were analysed to describe the patient demographics, clinical characteristics and treatment pathways. Patients eligible for the programme were adults (≥18 years) with histologically or cytologically confirmed mCRC who had previously received chemotherapy treatment(s). Results Of the 250 eligible patients enrolled in the NPP, 194 patients received ≥1 dose of trifluridine/tipiracil and 56 patients did not receive trifluridine/tipiracil. The following results are reported first for patients who received trifluridine/tipiracil and second for those who did not receive trifluridine/tipiracil: median (IQR) age was 63.0 (54.0–69.0) and 62.0 (54.8–69.0) years; Eastern Cooperative Oncology Group performance status score was 0 for 28 and 14%, 1 for 65 and 70%, 2 for 7 and 16%. In terms of previous systemic treatments 47 and 43% had 2 prior lines of therapy. FOLFOX-, FOLFIRI- and CAPOX-based therapies were the most common first-line regimens in patients receiving trifluridine/tipiracil (37, 35 and 21%, respectively), and in patients not receiving trifluridine/tipiracil (41, 30 and 20%, respectively). Second-line treatment regimens in patients receiving and not receiving trifluridine/tipiracil were most commonly FOLFIRI-based (48 and 41%, respectively) and FOLFOX-based (19 and 21%, respectively). Patients received a median of 2 cycles of trifluridine/tipiracil with a median treatment duration of 1.8 (95% CI: 1.8–2.4) months. In patients who discontinued treatment due to disease progression, the median progression-free duration was 2.8 (95% CI: 2.4–2.9) months. Conclusions The results highlight the number of treatment pathways used to treat mCRC in routine UK clinical practice prior to the marketing authorisation and National Institute for Health and Care Excellence approval of trifluridine/tipiracil and highlight the lack of clinical guidelines for mCRC.

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 trans ( 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.

e15043 Background: Trifluridine/tipiracil (TAS-102), an oral combination of a nucleoside analogue and thymidine phosphorylase inhibitor, showed significant survival benefit in the RECOURSE study. We assessed TAS-102 clinical activity in an unselected patient population with refractory metastatic colorectal cancer in the UK Expanded Access Programme (EAP). Methods: Pharmacy databases were used to identify patients treated with TAS-102 on the UK EAP at three tertiary referral Cancer Centres (Manchester, Cardiff and Southampton) between December 2015 and December 2016. Case notes, laboratory tests and histopathology were reviewed to ascertain survival data and prognostic variables. Results: Of the 78 patients treated with TAS-102, median ECOG PS was 1, 56% of patients were male and median age was 64 years (range 27- 80 years). 31 patients had 3 or more metastatic sites of disease. 26 patients were RAS mutant and 1 patient was B-RAFmutant. Median number of cycles of TAS-102 was 2 cycles (range 1-11 cycles) with one third of patients requiring a dose reduction due to toxicity. 39% of patients developed grade 3 or 4 neutropenia and 12% febrile neutropenia. Response assessment was not performed in 12 patients due to death prior to assessment (6 patients) or withdrawal of patient consent for TAS-102 treatment (6 patients). Where best disease response was assessed by RECIST 1.1 criteria, 26.6% patient showed clinical benefit (stable disease or partial response) whereas 73.3% of patients had confirmed progressive disease. Median follow-up period was 5.2 months with 45 deaths in the study period. Median overall survival (OS) was 6.6 months. OS was significantly worse for patients with hypoalbuminemia (Albumin < 30g/dl) at cycle 1 day 1 TAS-102 (p = 0.028). Anaemia, renal or liver impairment and number of metastatic sites of disease had no impact on patient survival. RAS mutant colorectal cancer patients showed a trend to improved outcome on TAS-102 which did not reach statistical significance within the study follow-up period. Conclusions: TAS-102 shows modest clinical benefit in treatment refractory metastatic colorectal cancer patients on the UK expanded access programme.

Up to a fifth of patients with colorectal cancer (CRC) present with synchronous hepatic metastases. In patients with CRC who present without intestinal obstruction or perforation and in whom comprehensive whole-body imaging confirms the absence of extrahepatic disease, evidence indicates a state of equipoise between several different management pathways, none of which has demonstrated superiority. Neoadjuvant systemic chemotherapy is advocated by current guidelines, but must be integrated with surgical management in order to remove the primary tumour and liver metastatic burden.. Surgery for CRC with synchronous liver metastases can take a number of forms: the 'classic' approach, involving initial colorectal resection, interval chemotherapy and liver resection as the final step; simultaneous removal of the liver and bowel tumours with neoadjuvant or adjuvant chemotherapy; or a 'liver-first' approach (before or after systemic chemotherapy) with removal of the colorectal tumour as the final procedure. In patients with rectal primary tumours, the liver-first approach can potentially avoid rectal surgery in patients with a complete response to chemoradiotherapy. We overview the importance of precise nomenclature, the influence of clinical presentation on treatment options, and the need for accurate, up-to-date surgical terminology, staging tests and contemporary management options in CRC and synchronous hepatic metastatic disease, with an emphasis on multidisciplinary care.

Background: There is a lack of real-world data on the clinical practice, resource use and outcomes of irinotecan in metastatic colon cancer (mCRC). This multi-centre, retrospective, highly detailed, observational study, funded by Sanofi, describes patient characteristics, chemotherapy treatment pathways and outcomes in second-line irinotecan-based chemotherapy following oxaliplatin-containing regimens. Methods: Hospital databases identified patients who commenced irinotecan-based chemotherapy (2nd line) on or after 01/01/2008, following prior treatment with an oxaliplatin-based regimen (1st line), for the treatment of mCRC or who had relapsed within 6 months of completion of adjuvant oxaliplatin. Demographics and chemotherapy information, adverse events, resource use and outcomes were captured retrospectively by the routine clinical team from start of chemotherapy for colorectal cancer to current time or death. Results: Data collected from 97 patients (71% male) who received 105 irinotecan-based chemotherapy regimens in 4 centres in England and Wales. Mean(SD) age at diagnosis of mCRC 62.4(9.9) years. Mean(SD) BSA was 1.8(0.2)m2; weight 72.4(14.3)kg. Median (Interquartile range, IQR) time from mCRC diagnosis to death was 22.34 months (15.6-30.9); 12.0 (0.03-43.5) months from commencing irinotecan-based regimen (98% patients deceased at data collection). Median (IQR) time to progression from commencing irinotecan-based chemotherapy 4.7 (0.03-31.3) months. Median (IQR) time to death from commencing irinotecan-based chemotherapy was 10.2 (0.03-43.5) months (n = 95); 17.4 (5.1-43.5) months for those receiving subsequent 3rd line chemotherapy (n = 42), 7.2 (0.03-21.1) months without subsequent 3rd line chemotherapy (n = 53). Oxaliplatin-based regimens used 1st line for mCRC (n = 96) (not mutually exclusive): 65 (68%) oxaliplatin + infusional 5-fluorouracil and folinic acid combinations (FOLFOX), 32 (33%) oxaliplatin + oral 5-fluorouracil combinations (XELOX), 4(4%) FOLFOX/XELOX with bevacizumab. Patients received irinotecan-based regimens following progression/recurrence after oxaliplatin (n = 97) (not mutually exclusive): 69 (71%) irinotecan + infusional combinations (FOLFIRI), 13 (13%) irinotecan + oral combinations (XELIRI), 10 (10%) irinotecan-based chemotherapy with biological agents, 7 (7%) irinotecan monotherapy, 4 (4%) aflibercept/placebo + FOLFIRI. 43 (44%) patients received 3rd and/or subsequent lines of chemotherapy (not mutually exclusive): 18 (42%) re-challenged with oxaliplatin, 15 (35%) irinotecan combinations, 15 (35%) mitomycin combinations, 3 (7%) single-agent capecitabine, 2 (5%) single-agent irinotecan, 2 (5%) single-agent panitumumab and 9 (21%) clinical trial drugs. In terms of toxicity, 26/105 (25%) irinotecan regimens were stopped prematurely due to adverse events, 32/97 (33%) patients underwent dose reduction of irinotecan, and 26/97 (27%) patients experienced delayed cycles (≥7 days) when receiving irinotecan (not mutually exclusive). Conclusion: FOLFIRI was the most common irinotecan-based regimen used 2nd line in mCRC, with lower than expected use of irinotecan monotherapy in clinical practice given its recommendation by NICE. Mitomycin or re-challenge with oxaliplatin or irinotecan were the most common post-irinotecan chemotherapy options for mCRC. The male preponderance in second line treatment of mCRC is similar to that seen in clinical trials, and is unexplained. Further strategies need to be evaluated to re-visit optimal dosing and scheduling for irinotecan in this group of patients as in clinical practice one third of all patients undergo dose-reduction, and a quarter of all patients experience delayed cycles and a quarter discontinued irinotecan prematurely.

AIMS:Variants in UGT1A1 have previously been associated with toxicity from irinotecan chemotherapy. We conducted a pragmatic prospective cohort study to establish the relevance of UGT1A1 variants in the prediction of severe diarrhea and neutropenia in patients with colorectal cancer receiving irinotecan in a routine clinical setting.MATERIALS & METHODS:Genotyping of UGT1A1*28 and c.-3156G>A was undertaken in an unselected, prospective cohort of 96 individuals treated with irinotecan at a single major UK oncology centre. Data on cytotoxic drugs received, and toxicity for all irinotecan treatment cycles were collected from case notes. Over 95% (92/96) of patients received an intermediate dose of irinotecan (180 mg/m(2), twice weekly). Irinotecan was given in combination with other cytotoxic drugs in 93/96 subjects and Grade 3 or 4 toxicity occurred in 23% of subjects.RESULTS:No association was found between UGT1A1*28 or c.-3156G>A and neutropenia. However, individuals carrying two copies of UGT1A1*28 (p = 0.04; OR: 14; 95% CI: 1.1-185) or c.-3156G>A (p = 0.03) had a significantly increased risk of diarrhea over all cycles.CONCLUSION:Our findings indicate that UGT1A1 genotyping is not a good predictor of hematological toxicity in patients treated with intermediate irinotecan doses. However, it may be useful in the identification of patients at risk of severe diarrhea.