Inequalities in the recovery of colorectal cancer services during the COVID-19 pandemic: a national population-based study.

AIM: Evidence is lacking on whether there were inequalities in the recovery of colorectal cancer (CRC) services within the English National Health Service (NHS) following the COVID-19 pandemic. The aim of this study was to evaluate recovery according to patient age and socioeconomic status. METHOD: Using routinely collected data, CRC patients diagnosed and treated in the English NHS were identified for two timeframes: the 'initial pandemic period' (April-June 2020) and the 'pandemic period' (April 2020-March 2022). Poisson models evaluated changes in numbers of diagnoses, major resections, adjuvant chemotherapy and neoadjuvant radiotherapy use for each timeframe, relative to the equivalent pre-pandemic timeframe (April-June 2019 and April 2018-March 2020, respectively), stratified by age and socioeconomic status. Tumour stage at presentation was evaluated over time. RESULTS: Substantial deficits in diagnoses, major resections and adjuvant chemotherapy were identified in the initial pandemic period, whilst the use of neoadjuvant radiotherapy increased. Overall, these deficits recovered. Patients outside screening age, and in the most deprived group, had greater deficits in diagnoses and major resections. There was no evidence of stage migration by June 2021. CONCLUSIONS: CRC services showed recovery to baseline during the pandemic. However, evident inequalities must be addressed in ongoing recovery efforts. Long-term outcomes will fully establish the impact of the pandemic on CRC patients.

What is the impact of hospital and surgeon volumes on outcomes in rectal cancer surgery?

AIM: Evidence for a positive volume-outcome relationship for rectal cancer surgery is unclear. This study aims to evaluate the volume-outcome relationship for rectal cancer surgery at hospital and surgeon level in the English National Health Service (NHS). METHOD: All patients undergoing a rectal cancer resection in the English NHS between 2015 and 2019 were included. Multilevel multivariable logistic regression was used to model relationships between outcomes and mean annual hospital and surgeon volumes (using a linear plus a quadratic term for volume) with adjustment for patient characteristics. RESULTS: A total of 13 858 patients treated in 166 hospitals were included. Six hospitals (3.6%) performed fewer than 10 rectal cancer resections per year, and 381 surgeons (45.0%) performed fewer than five such resections per year. Patients treated by high-volume surgeons had a reduced length of stay (p = 0.016). No statistically significant volume-outcome relationships were demonstrated for 90-day mortality, 30-day unplanned readmission, unplanned return to theatre, stoma at 18 months following anterior resection, positive circumferential resection margin and 2-year all-cause mortality at either hospital or surgeon level (p values > 0.05). CONCLUSION: Almost half of colorectal surgeons in England do not meet national guidelines for rectal cancer surgeons to perform a minimum of five major resections annually. However, our results suggest that centralizing rectal cancer surgery with the main focus of increasing operative volume may have limited impact on NHS surgical outcomes. Therefore, quality improvement initiatives should address a wider range of evidence-based process measures, across the multidisciplinary care pathway, to enhance outcomes for patients with rectal cancer.

Impact of patient choice and hospital competition on patient outcomes after rectal cancer surgery: A national population-based study.

BACKGROUND: The objective of the current national cohort study was to analyze the correlation between choice and competition on outcomes after cancer surgery in rectal cancer. METHODS: The analysis included all men who underwent rectal cancer surgery in the English National Health Service between March 2015 and April 2019 (n = 13,996). Multilevel logistic regression was used to assess the effect of a rectal cancer surgery center being located in a competitive environment (based on the number of centers within a threshold distance) and being a successful competitor (based on the ability to attract patients from other hospitals) on eight patient-level outcomes: 30- and 90-day emergency readmissions, 30-day re-operation rates, 90-day postoperative mortality, length of stay >14 days, circumferential resection margin status, rates of primary procedure with a permanent stoma, and rates of persistent stoma 18 months after anterior resection. RESULTS: With adjustment for patient characteristics, patients who underwent surgery in centers located in a stronger competitive environment were less likely to have an abdominoperineal excision or a Hartman's procedure (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.55-0.97, p = .04). Additionally, individuals who received treatment at hospitals that were successful competitors had a lower risk of a 90-day readmission following rectal cancer surgery (OR, 0.86; 95% CI, 0.76-0.97, p = .03) and were less likely to have a persistent stoma at 18 months after anterior resection (OR, 0.75; 95% CI, 0.61-0.93, p = .02). CONCLUSIONS: Hospitals located in areas of high competition are associated with better patient outcomes and improved processes of care for rectal cancer surgery.

Measuring variation in the quality of systemic anti-cancer therapy delivery across hospitals: A national population-based evaluation.

AIM: To date, there has been little systematic assessment of the quality of care associated with systemic anti-cancer therapy (SACT) delivery across national healthcare systems. We evaluated hospital-level toxicity rates during SACT treatment as a means of identifying variation in care quality. METHODS: All colorectal cancer (CRC) patients receiving SACT within 106 English National Health Service (NHS) hospitals between 2016 and 2019 were included. Severe acute toxicity rates were derived from hospital administrative data using a validated coding framework. Variation in hospital-level toxicity rates was assessed separately in the adjuvant and metastatic settings. Toxicity rates were adjusted for age, sex, comorbidity, performance status, tumour site, and TNM staging. RESULTS: Eight thousand one hundred and seventy three patients received SACT in the adjuvant setting, and 7,683 patients in the metastatic setting. Adjusted severe acute toxicity rates varied between hospitals from 11% to 49% for the adjuvant cohort, and from 25% to 67% for the metastatic cohort. Compared to the national mean toxicity rate in the adjuvant cohort, six hospitals were more than two standard deviations (2SD) above, and four hospitals were more than 2SD below. In the metastatic cohort, six hospitals were more than 2SD above, and seven hospitals were more than 2SD below the national mean toxicity rate. Overall, 12 hospitals (12%) had toxicity rates more than 2SD above the national mean, and 11 (10%) had rates more than 2SD below. CONCLUSION: There is substantial variation in hospital-level severe acute toxicity rates in both the adjuvant and metastatic settings, despite risk-adjustment. Ongoing reporting of this performance indicator can be used to focus further investigation of toxicity rates and stimulate quality improvement initiatives to improve care.

Outcomes of colorectal cancer resection in patients with inflammatory bowel disease: a national population-based analysis in England and Wales.

AIM: The aim was to compare early postoperative outcomes and 2-year cancer-specific mortality following colorectal cancer (CRC) resection in patients with and without inflammatory bowel disease (IBD) in England and Wales. METHOD: Records for patients in the National Bowel Cancer Audit who had major CRC resection between April 2014 and December 2017 were linked to routinely collected hospital level administrative datasets and chemotherapy and radiotherapy datasets. Multivariable regression models were used to compare outcomes with adjustment for patient and tumour characteristics. RESULTS: In all, 63 365 patients were included. 1285 (2.0%) had an IBD diagnosis: 839 (65.3%) ulcerative colitis, 435 (33.9%) Crohn's disease and 11 (0.9%) were indeterminate. IBD patients were younger, had more advanced cancer staging and a higher proportion of right-sided tumours. They also had a higher proportion of emergency resection, total/subtotal colectomy, open surgery and stoma formation at resection, with longer hospital admissions and higher rates of unplanned readmission and reoperation. Fewer rectal cancer patients with IBD received neoadjuvant radiotherapy (24.8% vs. 36.0%, P = 0.005) whilst similar proportions of Stage III colon cancer patients received adjuvant chemotherapy. Ninety-day postoperative mortality was similar, but unadjusted 2-year cancer-specific mortality was significantly higher in patients with IBD (subdistribution hazard ratio 1.35, 95% CI 1.18-1.55). Risk adjustment for patient and tumour factors reduced this association (adjusted subdistribution hazard ratio 1.22, 95% CI 1.05-1.43). CONCLUSION: Patients with IBD and CRC are a distinct patient group who develop CRC at a younger age and undergo more radical surgery. They have worse cancer survival, with the difference in prognosis appearing after the early postoperative period.

Development and validation of a coding framework to identify severe acute toxicity from systemic anti-cancer therapy using hospital administrative data.

BACKGROUND: The capture of toxicities from systemic anti-cancer therapy (SACT) in real-world data will complement results from clinical trials. The aim of this study was to develop and validate a comprehensive coding framework to identify severe acute toxicity in hospital administrative data. METHODS: A coding framework was developed to identify diagnostic codes representing severe acute toxicity in hospital administrative data. The coding framework was validated on a sample of 23,265 colon cancer patients treated in the English National Health Service between 1 June 2014 and 31 December 2017. This involved comparing individual toxicities according to the receipt of SACT and according to different SACT regimens, as well as assessing the associations of predictive factors and outcomes with toxicity. RESULTS: The severe acute toxicities captured by the developed coding framework were shown to vary across clinical groups with an overall rate of 26.4% in the adjuvant cohort, 53.4% in the metastatic cohort, and 12.5% in the comparison group receiving no chemotherapy. Results were in line with regimen-specific findings from clinical trials. For example, patients receiving additional bevacizumab had higher rates of bleeding (12.5% vs. 2.7%), gastrointestinal perforation (5.6% vs. 2.9%) and fistulation (1.4% vs. 0.5%), and allergic drug reactions (1.4% vs. 0.5%). Severe acute toxicity was associated with pre-existing renal (p = 0.001) and cardiac disease (p = 0.038), and urgency of surgery (p = 0.004). Severe toxicity also predicted lower rates of completion of chemotherapy (p = <0.001) and an increased likelihood of altered administration route (p = <0.001). CONCLUSION: These results demonstrate that the developed coding framework captures severe acute toxicities from hospital administrative data of colon cancer patients. A similar approach can be used for patients with other cancer types, receiving different regimens. Toxicity captured in administrative data can be used to compare treatment outcomes, inform clinical decision making, and provide opportunities for benchmarking and provider performance monitoring.

Survival outcomes associated with completion of adjuvant oxaliplatin-based chemotherapy for stage III colon cancer: A national population-based study.

The impact of cycle completion rates of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer in real-world practice is unknown. We assessed its impact, and that of treatment modification, on 3-year cancer-specific mortality. Four thousand one hundred and forty-seven patients with pathological stage III colon cancer undergoing major resection from 2014 to 2017 in the English National Health Service were included. Chemotherapy data came from linked national administrative datasets. Competing risk regression analysis for 3-year cancer-specific mortality was performed according to completion of <6, 6-11, or 12 5-fluoropyrimidine and oxaliplatin (FOLFOX) cycles, or <4, 4-7, or 8 capecitabine and oxaliplatin (CAPOX) cycles, adjusted for patient, tumour and hospital-level characteristics. Median age was 64 years. Thirty-two per cent of patients had at least one comorbidity. Forty-two per cent of patients had T4 disease, and 40% had N2 disease. Compared to completion of 12 FOLFOX cycles, cancer-specific mortality was higher in patients completing <6 cycles [subdistribution hazard ratios (sHR) 2.17; 95% CI 1.56-3.03] or 6-11 cycles (sHR 1.40; 95% CI 1.09-1.78) (P < .001). Compared to completion of 8 CAPOX cycles, cancer-specific mortality was higher in patients completing <4 cycles (sHR 2.02; 95% CI 1.53-2.67) or 4-7 cycles (sHR 1.63; 95% CI 1.27-2.10) (P < .001). Dose reduction and early oxaliplatin discontinuation did not impact mortality in patients completing all cycles. Completion of all cycles of chemotherapy was associated with improved cancer-specific survival in real-world practice. Poor prognostic factors may have affected findings, however, patients completing <50% of cycles had poor outcomes. Clinicians may wish to facilitate completion with treatment modification in those able to tolerate it.

Validity of chemotherapy information derived from routinely collected healthcare data: A national cohort study of colon cancer patients.

BACKGROUND: We used a structured approach to validate chemotherapy information derived from a national routinely collected chemotherapy dataset and from national administrative hospital data. METHODS: 10,280 patients who had surgical resection with stage III colon cancer were included. First, we compared information derived from the national chemotherapy dataset (SACT) and from the administrative hospital dataset (HES) in the English NHS with respect to receipt of adjuvant chemotherapy (ACT). Second, we compared regimen and number of cycles in linked patient-level records. Third, we carried out a sensitivity analysis to establish to what extent the impact of ACT receipt differed according to data source. RESULTS: 6,012 patients (58 %) received ACT according to either dataset. Of these patients, 3,460 (58 %) had ACT records in both datasets, 1,649 (27 %) in SACT alone, and 903 (15 %) in HES alone. Of the 3,460 patients with records in both datasets, 3,320 (96 %) had matching regimens. There was good agreement on cycle number with similar proportions of patients recorded with a single cycle (6 % in SACT vs. 7 % in HES) and slightly fewer patients recorded with more than 8 cycles in SACT (32 % in SACT vs. 35 % in HES). 3-year cancer-specific mortality was similar for patients receiving ACT, regardless of whether a patient received ACT according to SACT alone (16.6 %), according to HES alone (16.8 %), or according to either SACT or HES (17.1 %). CONCLUSION: Routinely collected national chemotherapy data and administrative hospital data are highly accurate in recording regimen and number of chemotherapy cycles. However, chemotherapy information should ideally be captured from both datasets to avoid under-capture, particularly of oral chemotherapy from administrative hospital data, and to minimise bias.

Balancing the efficacy and toxicity of chemotherapy in colorectal cancer.

As the therapeutic options for the treatment of colorectal cancer have expanded over the past 20 years, so has the complexity of decision making. The goals of treatment in the palliative, adjuvant and neoadjuvant settings vary and it is not only the efficacy of drugs that influence treatment decisions. Age, performance status, the presence of significant comorbidities and the different treatment regimens and strategies provide medical oncologists with an array of options to attempt to maximize patients' quality of life and longevity.

Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial.

PURPOSE: Predicting efficacy and toxicity could potentially allow individualization of cancer therapy. We investigated putative pharmacogenetic markers of chemotherapy toxicity in a large randomized trial. PATIENTS, MATERIALS, AND METHODS: Patients were randomly assigned to different sequences of chemotherapy for advanced colorectal cancer. First-line therapy was fluorouracil (FU), irinotecan/FU (IrFU) or oxaliplatin/FU (OxFU). Patients allocated first-line FU had planned second-line irinotecan alone, IrFU, or OxFU. The primary toxicity outcome measure was toxicity-induced delay or dose reduction; the secondary outcome was Common Terminology Criteria of Adverse Events grade >or= 3 toxicity. DNA was analyzed in 1,188 patients; 1,036 were assessable for the primary outcome, including 688 treated with FU, 270 with IrFU (first or second line), 280 with OxFU (first or second line), 184 with irinotecan alone, and 454 with any irinotecan-containing regimen. Ten polymorphisms were assessed: thymidylate synthase-enhancer region (TYMS-ER), thymidylate synthase 1494 (TYMS-1494), dihydropyrimidine dehydrogenase (DPYD), methylenetetrahydrofolate reductase (MTHFR), mutL homolog 1 (MLH1), UDP glucuronyltransferase (UGT1A1), ATP-binding cassette group B gene 1 (ABCB1), x-ray cross-complementing group 1 (XRCC1), glutathione-S-transferase P1 (GSTP1), and excision repair cross-complementing gene 2 (ERCC2). Results Using the primary outcome measure, no polymorphism was significantly associated (P < .01) with the toxicity of any regimen or with the difference in toxicity of IrFU or OxFU versus FU alone. Trends (of doubtful significance) were seen for associations of XRCC1, ERCC2, and GSTP1 with toxicity during irinotecan regimens: XRCC1, primary end point, any irinotecan-containing regimen (P = .045); ERCC2, secondary end point, irinotecan alone (P = .003); GSTP1, secondary end point; IrFU (P = .039); and irinotecan alone (P = .05). There was no evidence of association of UGT1A1*28 with irinotecan toxicity. CONCLUSION: These results do not support the routine clinical use of the evaluated polymorphisms, including UGT1A1*28. Further investigation of XRCC1, ERCC2, and GSTP1 as potential predictors of irinotecan toxicity is warranted.

Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial.

PURPOSE: Candidate predictive biomarkers for irinotecan and oxaliplatin were assessed in 1,628 patients in Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (FOCUS), a large randomized trial of fluorouracil alone compared with fluorouracil and irinotecan and compared with fluorouracil and oxaliplatin in advanced colorectal cancer. METHODS: The candidate biomarkers were: tumor immunohistochemistry for MLH1/MSH2, p53, topoisomerase-1 (Topo1), excision repair cross-complementing gene 1 (ERCC1), O-6-methylguanine-DNA-methyltranserase (MGMT), and cyclooxygenase 2 (COX2); germline DNA polymorphisms in GSTP1, ABCB1, XRCC1, ERCC2, and UGT1A1. These were screened in more than 750 patients for interaction with benefit from irinotecan or oxaliplatin; two markers (Topo1 and MLH1/MSH2) met criteria to be taken forward for analysis in the full population. Primary end points were progression-free survival (PFS) and overall survival. RESULTS: One thousand three hundred thirteen patients (81%) were assessable for Topo1 immunohistochemistry (low, < 10%; moderate, 10% to 50%; or high, > 50% tumor nuclei). In patients with low Topo1, PFS was not improved by the addition of either irinotecan (hazard ratio [HR], 0.98; 95% CI, 0.78 to 1.22) or oxaliplatin (HR, 0.85; 95% CI, 0.68 to 1.07); conversely, patients with moderate/high Topo1 benefited from the addition of either drug (HR, 0.48 to 0.70 in all categories; interaction P = .005; overall, P = .001 for irinotecan; P = .05 for oxaliplatin). High Topo1 was associated with a major overall survival benefit with first-line combination chemotherapy (HR, 0.60; median benefit, 5.3 months); patients with moderate or low Topo1 did not benefit (HR, 0.92 and 1.09, respectively; interaction P = .005). MLH1/MSH2 did not show significant interaction with treatment, although the low rate of loss (4.4%) limits the power of the study for this biomarker. CONCLUSION: Topo1 immunohistochemistry identified subpopulations that did or did not benefit from irinotecan, and possibly also from oxaliplatin. If verified independently, this information will contribute to the individualization of treatment for colorectal cancer.

Molecular markers of chemotherapeutic response and toxicity in colorectal cancer.

Outcomes in colorectal cancer have improved over the last 15 years; this is in part due to the optimization of 5-fluorouracil schedules and the introduction of new and effective chemotherapeutic agents, such as irinotecan and oxaliplatin. However, not all patients respond to these agents and a proportion may suffer severe side effects from particular chemotherapy drugs. These observations have resulted in a concerted research effort to identify markers of chemotherapy efficacy and toxicity. Here we review the evidence for using molecular markers to individualize chemotherapy treatment in colorectal cancer.

Phase I and pharmacokinetic study of intravenous irinotecan plus oral ciclosporin in patients with fuorouracil-refractory metastatic colon cancer.

PURPOSE: To assess the safety and toxicity profile of escalating doses of intravenous irinotecan, in combination with a fixed dose of oral ciclosporin (Cs) and to determine the pharmacokinetic profile of irinotecan and its metabolites. PATIENTS AND METHODS: Patients with fluorouracil-refractory metastatic colorectal cancer received escalating doses of intravenous irinotecan from 40 to 125 mg/m(2) every 2 weeks in combination with a fixed dose of oral Cs (5 mg/kg bid for 3 days). Pharmacokinetic analysis of plasma irinotecan and its metabolites SN38 and SN38G was performed during paired cycles with and without Cs. RESULTS: Thirty-seven patients were treated. Dose-limiting toxicity of grade 4 neutropenia was seen at an irinotecan dose of 125 mg/m(2). There was no grade 4 diarrhea, and only one patient experienced grade 3 diarrhea. Toxicities caused by Cs were generally mild. Pharmacokinetic studies demonstrated that irinotecan clearance was reduced from 13.4 to 5.8 L/h/m(2) and area under the curve (AUC)(0-tn) was increased 2.2-fold by the coadministration of Cs. Similar significant increases in AUC(0-24h) were seen for both SN38 and SN38G (2.2-fold and 2.3-fold, respectively) in the presence of Cs. Antitumor activity was seen at every irinotecan dose level. CONCLUSION: The maximum tolerated irinotecan dose and recommended dose for phase II studies is 100 mg/m(2) every 2 weeks. Dose-limiting diarrhea was not seen during this study, supporting the hypothesis that pharmacokinetic modulation of irinotecan by Cs may improve its therapeutic index. Further studies using this combination are warranted.