key: cord-0687143-oslhq59j
authors: Whittaker, Thomas M; Abdelrazek, Mohamed E. G.; Fitzpatrick, Aran J.; Froud, Joseph L. J.; Kelly, Jack R.; Williamson, Jeremy S.; Williams, Gethin L.
title: Delay to elective colorectal cancer surgery and implications for survival: a systematic review and meta‐analysis
date: 2021-03-25
journal: Colorectal Dis
DOI: 10.1111/codi.15625
sha: 1e7a7608e4efa36eab55c898b56585d3ea5e7e46
doc_id: 687143
cord_uid: oslhq59j

AIM: The Covid‐19 pandemic has delayed elective colorectal cancer (CRC) surgery. The aim of this study was to see whether or not this may affect overall survival (OS) and disease‐free survival (DFS). METHOD: A systematic review was carried out according to PRISMA guidelines (PROSPERO ID: CRD42020189158). Medline, EMBASE and Scopus were interrogated. Patients aged over 18 years with a diagnosis of colon or rectal cancer who received elective surgery as their primary treatment were included. Delay to elective surgery was defined as the period between CRC diagnosis and the day of surgery. Meta‐analysis of the outcomes OS and DFS were conducted. Forest plots, funnel plots and tests of heterogeneity were produced. An estimated number needed to harm (NNH) was calculated for statistically significant pooled hazard ratios (HRs). RESULTS: Of 3753 articles identified, seven met the inclusion criteria. Encompassing 314 560 patients, three of the seven studies showed that a delay to elective resection is associated with poorer OS or DFS. OS was assessed at a 1 month delay, the HR for six datasets was 1.13 (95% CI 1.02–1.26, p = 0.020) and at 3 months the pooled HR for three datasets was 1.57 (95% CI 1.16–2.12, p = 0.004). The estimated NNH for a delay at 1 month and 3 months was 35 and 10 respectively. Delay was nonsignificantly negatively associated with DFS on meta‐analysis. CONCLUSION: This review recommends that elective surgery for CRC patients is not postponed longer than 4 weeks, as available evidence suggests extended delays from diagnosis are associated with poorer outcomes. Focused research is essential so patient groups can be prioritized based on risk factors in future delays or pandemics.

Outcomes after cancer surgery have been negatively affected by the economic recession in 2007 and the recent SARS-CoV-2 (Covid- 19) pandemic [1, 2] . Both have had a detrimental effect globally. Surgery, the cornerstone of any curative treatment, has inevitably been delayed. Under 'normal' circumstances, any treatment for colorectal cancer (CRC) should start within 2 months of the diagnosis at the latest and ideally within 1 month [3] .

Covid-19 will continue to have a devastating effect on healthcare systems as the pandemic enters further waves of global infection. A recent multicentre observational study encompassing 24 countries reported that infection with Covid-19 in the perioperative period was associated with a significant mortality [4] . This, as well as the pressure on high-dependency beds, led to elective CRC surgery being delayed or cancelled. National and international learned societies suggested optimal treatment strategies to surgeons and their multidisciplinary teams. Some guidelines recommended that elective cancer surgery be deferred until such time that the environment was safe [5] . There were projections that nearly 40% of cases would be postponed during the initial 12 weeks of the Covid-19 pandemic [6] .

Systematic reviews and a meta-analysis in the literature confirm that a delay in diagnosis is associated with an increased risk of the patient presenting with an advanced stage of CRC [7] . This conclusion may be less relevant in the context of the current healthcare crisis where access to secondary care has been challenging, even with the rapid adoption of the faecal immunochemical screening test (FIT). Indeed, a recent systematic review demonstrated that delayed colonoscopy following a positive FIT was associated with a higher incidence of advanced CRC [8] . One large-scale cohort study recommended that any treatment should be within 30 days of the diagnosis [9] . This may be more relevant to rectal than colonic cancer in terms of long-term survival [10] .

Although common sense dictates that delay leads to poorer outcome in CRC, evidence is surprisingly scant, contradictory and difficult for surgeons and their patients to decipher. There is therefore a need for clarification of this risk, especially at a time when it has been reported that during the Covid-19 pandemic just 20% of UK hospitals are providing treatment within 31 days of the decision to treat [11] .

The aim of this systematic review was to determine how detrimental delay to treatment of resectable nonmetastatic CRC is in terms of overall survival (OS) and disease-free survival (DFS).

A systematic review was conducted utilizing the Cochrane collaboration-specified protocol and reported as per the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines [12, 13] .

The PICO model was used to identify the criteria for searching for and selecting studies [14] . Studies reporting patients over the age of 18 years diagnosed with colon or rectal cancer receiving elective surgery as their primary treatment and reporting the time elapsed from diagnosis to surgical intervention were included. Studies were not initially excluded based on the year of publication, but this detail was considered during the full article screening process. Publications in languages other than English were excluded. Those studies which included neoadjuvant chemoradiotherapy were excluded, since this strategy is likely to have extended the time between diagnosis and surgery. There were no randomized controlled trials to include in the meta-analysis, presumably due to the ethical implications of delaying necessary treatment. Nonrandomized cohort studies and trial registries were included, as well as grey literature, including conference abstracts. wait OR delay* adj3 surg* OR delay* adj3 colo* OR delay* adj3 survival* AND colorectal surg* OR colo* neoplas* OR rect* neoplas* OR colo* canc* OR rect* canc* OR colo* adj3 canc* OR rect* adj3 canc* OR colo* surg* OR rect* surg* OR colo* adj3 surg* OR rect* adj3 surg* OR resect* AND survival* OR overall survival* OR 5 year survival* All search terms were modified in accordance with the search system of each database used. Duplicates were removed and then article titles and abstracts were screened by two independent authors using the reference management software EndNote X9.

Two authors independently evaluated full-text versions of selected studies and performed data extraction and assessment of methodological quality. Any disagreements were discussed between all authors until consensus was established.

Extracted data included: first author, year of study, study type and design, number of participants, patient demographics, disease characteristics, surgical modality and treatment outcomes.

Also extracted was the time elapsed between diagnosis and surgical intervention, which was defined on an individual study basis due to lack of homogeneity in methodology, with no minimum or maximum value established. Treatment outcomes measured were OS and DFS, and outcome events were captured when two or more studies presented extractable data. Data were extracted at maximal follow-up. The study protocol was registered with the PROSPERO database (record ID CRD42020189158) before data extraction and analyses.

Quality assessment of the selected studies was conducted using the risk of bias in nonrandomized studies of interventions tool (ROBINS-I) [15] .

Meta-analyses were produced using Revman v.5.3 [16] . Where hazard ratios (HRs) were available, meta-analysis was performed using a random effects generic inverse variance model to create forest plots for OS and DFS and reported with 95% per cent confidence intervals (CIs). This model was chosen as the outcomes were adjusted for varied confounders in each study (listed in Table 3 ). The random effects model produced pooled HRs as well as heterogeneity chi-square and I 2 scores [17] . Funnel plots were utilized to assess publication bias.

For statistically significant pooled HRs, an estimated number needed to harm (NNH) was calculated according to the Cochrane Handbook for Systematic Reviews of Interventions [12, 18] (Figure 1 ).

As the outcomes are detrimental to patients, the difference in risk is described as NNH as opposed to number needed to treat. The assumed control risk in patients not delayed (interval <30 days) for OS is from Bagaria et al. [19] . This study was selected as it is a large-scale cohort study presenting mortality risk in the control group (<30 days delay to surgery) used in all analyses.

The search conducted across Medline, EMBASE and Scopus yielded 5506 results. After the removal of duplicates using EndNote X9 software, 3753 titles and abstracts were screened, leaving 39 articles which were then reviewed in full. A total of seven articles ful- Table 1 . Following this, reference lists of the final seven studies were screened; however, no articles fulfilled the inclusion criteria [19] [20] [21] [22] [23] [24] [25] . One study was excluded as it did not match the time frames required for statistical analysis [10] . Two of the included studies received funding for their work. Trepanier et al. [24] was supported by research scholarships from the Quebec Health Sciences Research Fund and the Canadian Institute for Health Research, and Shin et al. [22] received a grant from the Ministry of Health and Welfare, Korea.

The selected studies had a range of epidemiological characteristics with variation in several categories including the number of patients, country or delay cut-off times. Study publication dates ranged from 2013 to 2020. The sample sizes for the included studies ranged from 408 to 187 319 patients. Six articles selected for this review are retrospective cohort studies [19] [20] [21] [22] [23] [24] whilst one is a prospective cohort study [25] . The seven studies varied in geographical location, with three from the USA [19] [20] [21] , two from Canada [24, 25] and one each from the Netherlands [23] and South Korea [22] . Four studies were limited to colon cancer [19] [20] [21] 25] , This was because rectal cancers differ in pathology, epidemiology and treatment [26] [27] [28] (Table 2) . All the included studies performed confounder adjustments; the variables chosen for each study can be seen in Table 3 . 

Outcome data for each study are presented in Table 3 . There was wide heterogeneity between studies in categorizing delay from diagnosis to surgery. According to the data that could be extracted from each study, two categories of delay were chosen: 1 month and 3 months.

Seven studies containing 314 560 patients reported outcomes of OS.

Six studies with comparable delay times of approximately 1 month demonstrated a pooled HR of 1.13 (95% CI 1.02-1.26, p = 0.020) [20] [21] [22] [23] [24] [25] associated with delay. HRs for 1 month and over for each study were pooled to create comparable time frames (Figure 4) . A single study reported a possible reduction in risk with delay (HR 0.82, 95% CI 0.63-1.08) [25] . One study could not be included in this analysis due to noncomparable categorization of delay [19] .

A funnel plot ( Figure 5 ) analysing studies which reported the effects of a 1 month delay to surgery on OS demonstrated slight asymmetry in studies with a high standard error. Further analyses to quantify publication bias were incompatible due to the number of studies being below 10 [29] . There was moderate heterogeneity between studies reporting a 4 week delay (I 2 = 51%). The calculated estimated NNH for a 1 month delay to surgery was 35.

Reviews of Interventions [12] for calculation of the number needed to harm (ACR, assumed control rate; NNT, number needed to treat; OR, odds ratio). The formula describes NNT, but as per convention in this study it is described as 'number needed to harm' as the outcome is a detriment to the patient NNT ACR -OR × ACR 1

Three studies containing 193 950 patients reported outcomes following a delay of 12 weeks or longer to surgery and were suitable for comparison [19, 21, 22] , The pooled HR associated with a 12 week delay to surgery was 1.57 (95% CI 1.16-2.12, p = 0.004) ( Figure 6 ).

were not compatible due to the small number of studies [29] . There was a high degree of heterogeneity in studies reporting a 12 week

Four studies could not be included in the 12 week delay forest plot as the delay categories did not correspond appropriately [20, [23] [24] [25] . A study using data from a US national database used a spline curve to extrapolate collected data and forecast that a delay of 12 weeks was associated with a 1.4 times greater risk of mortality [20] . A study from the Netherlands set the upper limit of delay at 

Three publications evaluated DFS as an outcome for surgical delay [23] [24] [25] . HRs for 1 month and over for each study were pooled to Ironically, there may be an upside to treatment delay as it has

given the opportunity to implement and study prehabilitation which can decrease pulmonary and other morbidity after major abdominal surgery [37] . Prehabilitation programmes of 2-6 weeks' duration can safely counterbalance the detrimental effects of delay to surgery of 1 month [37] . Extending this any longer would need to be justified by focused research and would not currently be supported by our study.

Our review suggests that increased comorbidity and anaesthetic risk were commonly quoted as the reason for surgical delay (Table 2) .

This period allows time for optimization of patients' comorbidities and prehabilitation which are strategies which improve postoperative outcomes across surgical disciplines [38, 39] . However, none of the studies that were included in the analysis documented the use of a prehabilitation programme.

The psychological impact of delay to surgery must not be underestimated. Longer waiting times for elective general surgery are associated with a prolonged period of decreased health and has considerable impact on the psychological well-being and social life of patients [40] . Preoperative psychological distress may affect wound healing, length of stay and lung function [41] .

There are several limitations to this study. Whilst confounder adjustment was reported in all studies, it is difficult to control for some confounding factors. These include disease-specific factors such as tumour stage, lymphovascular invasion and differentiation. In one study, no record of comorbidity was available [25] . In another, the use of adjuvant chemotherapy was not reported or described [21] .

The reasons for surgical delay were not explicitly stated for each patient and it is likely that some would affect survival. Advanced comorbidity and frailty are major potential confounders since they may prompt further medical or anaesthetic assessment, further delay to surgery and perhaps lead to spurious associations with poorer outcome. No randomized studies were available for analysis for obvious reasons, and only a single study was conducted prospectively.

This systematic review and meta-analysis evaluated the current accessible data on the risk of delay to elective surgery for CRC. The quality of available data is weak but there is some evidence that a delay of 3 months or more has a deleterious effect on OS of CRC F I G U R E 6 A random effects generic inverse variance forest plot and calculated pooled hazard ratio for the effects of a 12-week delay to curative colorectal cancer surgery on overall survival patients. The enforced delays to treatment of CRC during the Covid-19 pandemic should provide prospective data to answer this question and hopefully improve patient care in the future [42] .

No ethical approval was required for this paper.

None.

No funding was received for this paper.

TW contributed to the data collection, analysis of the data, interpretation and drafting of the manuscript. MA contributed to data collection, statistical analysis and drafting of the manuscript. AF, JF and JK contributed to data collection, manuscript revision and study analysis. JW contributed to data interpretation, study design and manuscript drafting. GW contributed to study design, data collection and interpretation and drafting of the manuscript. All authors read and approved the final version.

The data used in these studies to generate our meta-analysis can be found in the Medline, Scopus and EMBASE databases.

Thomas M Whittaker https://orcid.org/0000-0002-0594-9691

Mohamed E. G. Abdelrazek https://orcid. org/0000-0002-3469-6494

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How to cite this article

Delay to elective colorectal cancer surgery and implications for survival: a systematic review and meta-analysis