The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

Abstract Aim The SARS‐CoV‐2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non‐delayed surgery. Methods This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January–April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. Results Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90–1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69–1.27, P = 0.672). Longer delays were not associated with poorer outcomes. Conclusion One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID‐19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long‐term survival attributable to delays is likely to be due to micro‐metastatic disease.


INTRODUC TI ON
Globally, colorectal cancer is the third most commonly diagnosed cancer type and the second largest cause of cancer death [1]. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has affected all aspects of healthcare and has led to variable delays to the delivery of colorectal cancer surgery across the globe [2,3]. It is estimated that over 28 million operations were cancelled in the initial 3 months of disruption alone [4,5]. This creates a unique 'natural experiment' to explore the effects of treatment delay on outcomes of colorectal cancer surgery.
Although there is no international guidance on the optimal timing for colorectal cancer resection, it is generally perceived as a time critical intervention. In the UK, the National Health Service sets a target of 4 weeks from a treatment decision to definitive treatment in cancer care, but global practice and policy varies significantly. A number of modelling studies and systematic reviews have explored the impact of delays on long-term survival in colorectal cancer, but it is unclear whether this is related to poorer initial cancer control (i.e., lower rates of complete resection) or micro-metastatic disease spread [6].
Understanding the effects of surgical delay during the SARS-CoV-2 pandemic will help inform future prioritization of surgical waiting lists during post-pandemic recovery and postoperative surveillance by the multidisciplinary team.
This study aimed to explore the association between delayed surgery for colorectal cancer in patients not undergoing neoadjuvant therapy and surgical resectability during the SARS-CoV-2 pandemic.

Study design and setting
This was an international prospective cohort study which included consecutive patients with a decision for elective curative surgery from the multidisciplinary team meeting, tumour board or equivalent. Any hospital worldwide undertaking elective colorectal cancer surgery was eligible for inclusion in this analysis. Each participating site recruited consecutive eligible patients for a period of 3 months following the emergence of COVID-19 in their local area (first notification of SARS-CoV-2 ranging between January and April 2020).
Each site obtained ethical approval according to local regulations, and the COVIDSurg-Cancer study (overall inclusion by cancer type available in Table S12) was pre-registered with Clini calTr ials.gov (identifier NCT04384926).

Patient inclusion, pathways and follow-up
All patients with a decision for curative cancer surgery or who would normally have been offered curative surgery in the pre-pandemic setting but an alternative treatment was offered due to  were included. Patients were excluded from this study if they had (1) planned palliative surgery, (2) a suspected cancer that was later found to be benign on histopathology, (3) a suspected benign tumour that was later found to be cancerous or (4) received endoscopic treatment only (e.g., transanal endorectal microsurgery).
From all the included patients, some of them did receive their planned curative surgery but some ended up not receiving it during the study period. For patients who were operated, follow-up data were collected at 30 days after surgery. For patients who remained non-operated, their last known status was recorded. All follow-up was completed by 31 August 2020 with a minimum follow-up of 3 months for all included patients. The characteristics of non-operated patients were described and reasons for the nonperformance of the planned surgery were reported. This allows a comprehensive understanding of the whole sample and an informed discussion on how treatment pathways that were in place during the study influenced the patient groups that we are comparing.
Of all the operated patients, some required surgical resection alone and some required neoadjuvant therapy (chemotherapy and/ or radiotherapy prior to surgery). Due to differences in disease biology, and potential effects of treatment intervals in patients undergoing neoadjuvant therapy, the patients who received neoadjuvant therapy were excluded from the main analysis as their disease behaviour is expected to be fundamentally different. However, tumour location and the type of neoadjuvant treatment are reported in the supplement for completeness.

Delay to surgery
The main analysis on surgical delays focused on patients who received their planned surgery with curative intent, without having received neoadjuvant therapy. Delay to surgery was defined according to the number of weeks from the date of the decision for curative surgery to the date when the patient received surgery. For the primary analysis, patients who were operated more than 4 weeks after their decision for surgery were classified as delayed and those who were operated within 4 weeks were defined as non-delayed. This 4-week cut-off was informed by UK National Institute for Clinical Excellence guidance and standards for timely delivery of cancer care [7].

What does this paper add to the literature?
This was a prospective cohort study of 5453 patients with a decision for curative colorectal cancer surgery. Surgical delays of up to 12 weeks were not associated with worse rates of complete resection. Any reduction in long-term survival attributable to delays is likely to be due to micrometastatic disease and should be the focus of postoperative surveillance programmes.

Outcomes
The primary outcome measure for the study was complete resection, defined as disease amenable to surgical removal at the time of surgery with a negative circumferential resection margin (R0, no microscopic or macroscopic disease within 1 mm of the circumferential resection margin). Patients whose disease became unresectable during the study period or whose surgical resection was achieved with positive resection margins (R1 or R2) were classified as having an incomplete resection.
Secondary outcomes were also compared between patients undergoing delayed and non-delayed surgery. These included the 30-day postoperative mortality rate, 30-day major postoperative complication rate (defined as Clavien-Dindo Grade III-V complications) [8], stage change from baseline (clinical) to pathology (according to the American Joint Committee on Cancer [AJCC] 8th edition of the TNM staging system [9], defined as upstaged for any increase in stage, downstaged for any decrease in stage and no change for patients remaining at the same stage group), detection of new metastatic disease (clinically, intra-operatively or on radiological imaging that was not present at the time of decision for surgery) and the rate of emergency surgery (i.e., as all patients had an initial plan for elective surgery at study entry, emergency surgery can be interpreted as a cancer-related complication requiring emergency intervention).
The indications for emergency surgery are presented.

Data variables
Baseline information was collected for each patient at the point of entry to the study. This included age, sex, American Society

Data handling and statistics
All the data collected were non-identifiable and uploaded to a secure online server hosted by the University of Birmingham, using the Research Electronic Data Capture (REDCap) system. Data management and analysis used RStudio version 4.0.3 with the 'readr', 'tidyverse', 'dplyr', 'gmodels', 'Hmisc' and 'finalfit' packages (R Foundation for Statistical Computing). Unadjusted categorical data were compared using the chi-squared test with Fisher's exact modification where required. A P value <0.05 was considered statistically significant. Logistic regression models were used to explore the association between delay to surgery and complete resection, adjusting for clinically plausible patient and disease factors selected a priori. All missing data were recorded and are reported in the tables and figures.
Reflecting differences in treatment timelines and capacity across different resource settings, we performed a sensitivity analysis exploring longer delays of 6, 8 and 12 weeks from treatment decision to surgery, and the primary outcome measure.
Given that patients undergoing emergency surgery could have shown distinct clinical features at the time of decision for surgery that made them more likely to receive an urgent intervention, a pre-planned subgroup analysis was performed for patients undergoing planned (elective) surgery only. Further subgroup analyses were performed looking exclusively at colon cancers, rectal cancers, early disease and advanced disease. For this purpose, early disease stage was defined as organ confined, non-nodal, non-metastatic (T1-3 N0 M0) and advanced disease was defined as reaching the serosa, nodal or metastatic disease (T4, N+ or M1). A sensitivity analysis of the adjusted and unadjusted results was conducted to explore the impact of longer delays in resectability: 0-4, 5-8, 9-12 and more than 12 weeks from decision to surgery.

Outcomes of delayed surgery
Delayed patients did not have lower rates of complete resection, compared to non-delayed patients. In the unadjusted analysis, delayed patients were more likely to have resectable disease (93.7% vs. 91.9%, P = 0.032) and less likely to develop new metastases (6.2% vs. 10.1%, P < 0.001) than non-delayed patients. Changes in disease stage from baseline to pathological staging were more common in delayed patients, including both upstaging and downstaging ( Table 2). Delayed patients were also less likely to have had emergency surgery (4.5% vs. 22.9%, P < 0.001) whilst waiting for their planned surgery, mainly due to obstructive symptoms.
Other indications for emergency surgery in this cohort are shown in Table S3. There were no significant differences in 30-day major postoperative complications (9.3% vs. 9.8%, P = 0.648) or postoperative mortality rates (1.5% vs. 2.2%, P = 0.126). After adjustment for case mix, delay was not associated with significantly lower rates of complete resection (OR = 1.18, 95% CI 0.90-1.55, P = 0.224) ( Figure 2). The full adjusted model can be found in Table S4.

Subgroup analysis
In the subgroup analysis of patients undergoing elective surgery only, delay was not associated with lower rates of complete resection (OR = 0.94, 95% CI 0.69-1.27, P = 0.672) (logistic regression F I G U R E 1 Flowchart of patient inclusion, with outcomes stratified by delay versus non-delay. Delay was defined as a time from decision to treat to surgery of >4 weeks

All colorectal patients (n=5453)
model available in Figure S2). Demographic trends of delayed patients were also similar to the main analysis (Table S5). When looking at colon and rectal cancers in isolation, a delay of 4 weeks was not associated with a reduced rate of complete resection in colon

DISCUSS ION AND CON CLUS IONS
During the first wave of the SARS-CoV-2 pandemic, one in 15 patients did not receive their planned operation for colorectal cancer.
In those who did undergo surgery, delays of more than 4 weeks did not appear to be associated with reduced rates of complete resection. This was robust to several sensitivity and subgroup analyses.
Although there are inherent biases in this study design, including selection bias in those that were exposed to treatment delay, this study represents a unique natural experiment to better understand the pathobiology of survival after colorectal cancer surgery.
Whilst long-term oncological outcome data are not yet available for this cohort, these data provide important insight into the potential mechanism for the relationship between long-term survival and in multimodal cancer treatment showed a negative impact on longterm oncological outcomes [6]. This study suggests that a delay to surgery does not affect short-term patho-oncological outcomes. It raises the hypothesis that any decrease in long-term survival observed is unlikely to be due to initial cancer control and may be related to micro-metastatic disease spread. Patients whose surgery is delayed might therefore benefit from closer follow-up strategies for early detection of relapse and metastatic disease. Further research is required to understand the effectiveness of enhanced follow-up pathways on long-term survival, alongside their performance in different tumour biology patterns (not captured in this study).
The clinical features of non-operated patients suggest clinical selection based on a perceived high risk of surgical complications, given that these patients had worse performance status, were more likely to be underweight and had more advanced disease. Although these decisions probably aimed to protect frail patients from the additional risk conveyed by perioperative SARS-CoV-2 infection, they might have exposed some patients with advanced disease to a risk of progression to palliative disease. Changes in the management of colorectal cancer during the COVID-19 pandemic have been described by several research groups, including reduction of the number of patients receiving surgery and shorter treatment regimens [16][17][18].
This study provides further insight on the drivers of these clinical decisions and on which patients might have been more impacted by them.
Advanced (non-organ confined) and rectal cancers were also more likely to be operated promptly, as opposed to early and colon cancers which were more likely to be delayed. This suggests that additional features of the disease were perceived by surgical teams as justifying early surgery, which might explain why non-delayed pa- This study has several important limitations. Longer-term follow-up of this cohort will be required to explore the true clinical impact of treatment delay for these patients. The second is the risk of selection bias in the comparison of delayed and non-delayed patients. We attempted to overcome this through multivariable modelling and several subgroup and sensitivity analyses, but the analysis may still be subject to residual bias from unmeasured confounders.
Third, patients who remained non-operated may have had a poorer prognosis at baseline and/or may have been subject to disease progression and other cancer-related sequelae which could lead to underestimation of the impact of delay (7% of the cohort overall).
Fourth, we were unable to explore the impact of treatment delay in patients with prior neoadjuvant therapy, who pose a biologically distinct treatment group. Finally, histological data were not collected and therefore we were unable to explore whether molecular subtypes or mutational status differed between the groups, and whether this impacted resection.
SARS-CoV-2 waves are not the only pressure that health systems face, and many factors can cause delays in the delivery of surgical care. These findings can inform clinical decision making, management of surgical waiting lists and patient informed consent before surgery. Guidance on management of colorectal cancer should also take these findings into account when designing follow-up strategies for patients who are operated for colorectal cancer. The possibility of performing cancer resection with a few weeks of delay without a negative impact on local control could be important for patients who may benefit from longer periods of pre-habilitation and pre-conditioning before surgery, in order to achieve a better fitness status and optimize perioperative outcomes.

CO N FLI C T O F I NTE R E S T
There are no conflicts of interest to declare.

E TH I C A L S TATEM ENT
This study was approved in every participating country and hospital as per local requirements. National and hospital leads were responsible and guaranteed the necessary approvals ahead of data upload.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data-sharing requests will be considered by the management group upon written request to the corresponding author. If agreed, deidentified participant data will be available, subject to a data-sharing agreement.

S U PP O RTI N G I N FO R M ATI O N
Additional supporting information may be found in the online version of the article at the publisher's website.