The effect of time before diagnosis and treatment on colorectal cancer outcomes: systematic review and dose–response meta-analysis

ABSTRACT BACKGROUND This systematic review and meta-analysis aimed to evaluate existing evidence on the relationship between diagnostic and treatment intervals and outcomes for colorectal

cancer. METHODS Four databases were searched for English language articles assessing the role of time before initial treatment in colorectal cancer on any outcome, including stage and

survival. Two reviewers independently screened articles for inclusion and data were synthesised narratively. A dose–response meta-analysis was performed to examine the association between

treatment interval and survival. RESULTS One hundred and thirty papers were included in the systematic review, eight were included in the meta-analysis. Forty-five different intervals were

considered in the time from first symptom to treatment. The most common finding was of no association between the length of intervals on any outcome. The dose–response meta-analysis showed a

U-shaped association between the treatment interval and overall survival with the nadir at 45 days. CONCLUSION The review found inconsistent, but mostly a lack of, association between

interval length and colorectal cancer outcomes, but study design and quality were heterogeneous. Meta-analysis suggests survival becomes increasingly poorer for those commencing treatment

more than 45 days after diagnosis. REGISTRATION This review was registered, and the protocol is available, in PROSPERO, the international database of systematic reviews, with the

registration ID CRD42021255864. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your

institution Subscribe to this journal Receive 24 print issues and online access $259.00 per year only $10.79 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access

to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read

our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS TREATMENT INTERVAL IN CURATIVE TREATMENT OF COLON CANCER, DOES IT IMPACT (CANCER FREE) SURVIVAL? A NON-INFERIORITY

ANALYSIS Article 12 December 2023 A SYSTEMATIC REVIEW OF META-ANALYSES ASSESSING THE VALIDITY OF TUMOUR RESPONSE ENDPOINTS AS SURROGATES FOR PROGRESSION-FREE OR OVERALL SURVIVAL IN CANCER

Article Open access 11 September 2020 ONE-YEAR MORTALITY OF COLORECTAL CANCER PATIENTS: DEVELOPMENT AND VALIDATION OF A PREDICTION MODEL USING LINKED NATIONAL ELECTRONIC DATA Article Open

access 24 August 2020 DATA AVAILABILITY Data used in this review is provided in Supplementary Appendices; any additional data are available upon request to the corresponding author.

REFERENCES * Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers

in 185 countries. CA Cancer J Clin. 2021;71:209–49. Article  PubMed  Google Scholar  * Xi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol.

2021;14:101174. Article  PubMed  PubMed Central  Google Scholar  * Emery J, Brown G, Macrae F, Bell C, Tse J, Skinner I, et al. Guidelines: colorectal cancer/the symptomatic patient. Sydney:

Cancer Council Australia; 2017. * Neal RD. Do diagnostic delays in cancer matter? Br J Cancer. 2009;101:S9–s12. Article  PubMed  PubMed Central  Google Scholar  * Weller D, Vedsted P, Rubin

G, Walter FM, Emery J, Scott S, et al. The Aarhus statement: improving design and reporting of studies on early cancer diagnosis. Br J Cancer. 2012;106:1262–7. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Aslam MI, Chaudhri S, Singh B, Jameson JS. The "two-week wait" referral pathway is not associated with improved survival for patients with colorectal

cancer. Int J Surg. 2017;43:181–5. Article  PubMed  Google Scholar  * Olesen F, Hansen RP, Vedsted P. Delay in diagnosis: the experience in Denmark. Br J Cancer. 2009;101:S5–8. Article 

PubMed  PubMed Central  Google Scholar  * Walter F, Webster A, Scott S, Emery J. The Andersen Model of Total Patient Delay: a systematic review of its application in cancer diagnosis. J

Health Serv Res Policy. 2012;17:110–8. Article  PubMed  PubMed Central  Google Scholar  * Ramos M, Esteva M, Cabeza E, Campillo C, Llobera J, Aguiló A. Relationship of diagnostic and

therapeutic delay with survival in colorectal cancer: a review. Eur J Cancer. 2007;43:2467–78. Article  PubMed  Google Scholar  * Ramos M, Esteva M, Cabeza E, Llobera J, Ruiz A. Lack of

association between diagnostic and therapeutic delay and stage of colorectal cancer. Eur J Cancer. 2008;44:510–21. Article  PubMed  Google Scholar  * Hanna TP, King WD, Thibodeau S, Jalink

M, Paulin GA, Harvey-Jones E, et al. Mortality due to cancer treatment delay: systematic review and meta-analysis. BMJ. 2020;371:m4087. Article  PubMed  Google Scholar  * Whittaker TM,

Abdelrazek MEG, Fitzpatrick AJ, Froud JLJ, Kelly JR, Williamson JS, et al. Delay to elective colorectal cancer surgery and implications for survival: a systematic review and meta-analysis.

Colorectal Dis. 2021;23:1699–711. Article  PubMed  PubMed Central  Google Scholar  * Franssen RFW, Strous MTA, Bongers BC, Vogelaar FJ, Janssen-Heijnen MLG. The association between treatment

interval and survival in patients with colon or rectal cancer: a systematic review. World J Surg. 2021;45:2924–37. Article  PubMed  PubMed Central  Google Scholar  * Hangaard Hansen C,

Gögenur M, Tvilling Madsen M, Gögenur I. The effect of time from diagnosis to surgery on oncological outcomes in patients undergoing surgery for colon cancer: a systematic review. Eur J Surg

Oncol. 2018;44:1479–85. Article  CAS  PubMed  Google Scholar  * Neal RD, Tharmanathan P, France B, Din NU, Cotton S, Fallon-Ferguson J, et al. Is increased time to diagnosis and treatment

in symptomatic cancer associated with poorer outcomes? Systematic review. Br J Cancer. 2015;112:S92–107. Article  PubMed  PubMed Central  Google Scholar  * Castelo M, Sue-Chue-Lam C, Paszat

L, Kishibe T, Scheer AS, Hansen BE, et al. Time to diagnosis and treatment in younger adults with colorectal cancer: a systematic review. PLoS ONE. 2022;17:e0273396. Article  CAS  PubMed 

PubMed Central  Google Scholar  * Tørring ML, Frydenberg M, Hamilton W, Hansen RP, Lautrup MD, Vedsted P. Diagnostic interval and mortality in colorectal cancer: U-shaped association

demonstrated for three different datasets. J Clin Epidemiol. 2012;65:669–78. Article  PubMed  Google Scholar  * Rupassara KS, Ponnusamy S, Withanage N, Milewski PJ. A paradox explained?

Patients with delayed diagnosis of symptomatic colorectal cancer have good prognosis. Colorectal Dis. 2006;8:423–9. Article  CAS  PubMed  Google Scholar  * Crawford SC, Davis JA, Siddiqui

NA, de Caestecker L, Gillis CR, Hole D, et al. The waiting time paradox: population based retrospective study of treatment delay and survival of women with endometrial cancer in Scotland.

BMJ. 2002;325:196. Article  PubMed  PubMed Central  Google Scholar  * Crippa A, Discacciati A, Bottai M, Spiegelman D, Orsini N. One-stage dose-response meta-analysis for aggregated data.

Stat Methods Med Res. 2019;28:1579–96. Article  PubMed  Google Scholar  * Orsini N, Spiegelman D Meta-analysis of dose-response relationships. Handbook of meta-analysis. Boca Raton, FL:

Chapman and Hall/CRC; 2020. p. 395-428. * Li Y, Gu M, Jing F, Cai S, Bao C, Wang J, et al. Association between physical activity and all cancer mortality: dose-response meta-analysis of

cohort studies. Int J Cancer. 2016;138:818–32. Article  CAS  PubMed  Google Scholar  * Wang F, Yeung KL, Chan WC, Kwok CC, Leung SL, Wu C, et al. A meta-analysis on dose-response

relationship between night shift work and the risk of breast cancer. Ann Oncol. 2013;24:2724–32. Article  CAS  PubMed  PubMed Central  Google Scholar  * Drosdowsky A, Lamb KE, Bergin RJ,

Boyd L, Milley K, IJ MJ, et al. A systematic review of methodological considerations in time to diagnosis and treatment in colorectal cancer research. Cancer Epidemiol. 2023;83:102323.

Article  PubMed  Google Scholar  * Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for

reporting systematic reviews. BMJ. 2021;372:n160. Article  PubMed  PubMed Central  Google Scholar  * Veritas Health Innovation. Covidence systematic review software, Melbourne, Australia,

2023. * The Joanna Briggs Institute. Critical Appraisal Tools. 2023. https://joannabriggs.org/critical-appraisal-tools. * Parmar MK, Torri V, Stewart L. Extracting summary statistics to

perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–34. Article  CAS  PubMed  Google Scholar  * Tierney JF, Stewart LA, Ghersi D, Burdett S,

Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8:16. Article  PubMed  PubMed Central  Google Scholar  * PlotDigitizer. 2022.

https://plotdigitizer.com/. * Il'yasova D, Hertz-Picciotto I, Peters U, Berlin JA, Poole C. Choice of exposure scores for categorical regression in meta-analysis: a case study of a

common problem. Cancer Causes Control. 2005;16:383–8. Article  PubMed  Google Scholar  * Taylor K. Wanting a particular reference category in categorical risk data. University of Oxford;

2022. https://www.cebm.ox.ac.uk/resources/data-extraction-tips-meta-analysis/reference-category-risk-data. * R Core Team. R: a language and environment for statistical computing. Vienna: R

Foundation for Statistical Computing, 2021. * Crippa A, Orsini N. Multivariate dose-response meta-analysis: the dosresmeta R package. J Stat Softw. 2016;72:1–15. Article  Google Scholar  *

Gleason F, Chu DI, Kennedy GD, Kenzik KM. Early elective surgery after colon cancer diagnosis has higher risk of readmission and death. Ann Surg. 2021;273:188–94. Article  PubMed  Google

Scholar  * Kaltenmeier C, Shen C, Medich DS, Geller DA, Bartlett DL, Tsung A, et al. Time to surgery and colon cancer survival in the United States. Ann Surg. 2021;274:1025–31. Article 

PubMed  Google Scholar  * Lo BD, Caturegli G, Stem M, Biju K, Safar B, Efron JE, et al. The impact of surgical delays on short- and long-term survival among colon cancer patients. Am Surg.

2021;87:1783–92. Article  PubMed  Google Scholar  * Harrell FE. Regression modeling strategies: with applications to linear models, logistic regression, and survival analysis. Berlin:

Springer; 2001. * Abdulaal A, Arhi C, Ziprin P. Effect of health care provider delays on short-term outcomes in patients with colorectal cancer: multicenter population-based observational

study. Interact J Med Res. 2020;9:e15911. Article  PubMed  PubMed Central  Google Scholar  * Ahmed RN, Rai L, Samo KA, Saeed S, Salam A, Khan H, et al. Factors affecting delay in diagnosis

of colorectal cancer: a cross‐sectional study from a tertiary care hospital of Karachi, Pakistan. Int J Clin Pract. 2021;75:e14529. Article  PubMed  Google Scholar  * Amri R, Bordeianou LG,

Sylla P, Berger DL. Treatment delay in surgically-treated colon cancer: does it affect outcomes? Ann Surg Oncol. 2014;21:3909–16. Article  PubMed  Google Scholar  * Arbman G, Nilsson E,

Störgren-Fordell V, Sjödahl R. A short diagnostic delay is more important for rectal cancer than for colonic cancer. Eur J Surg. 1996;162:899–904. CAS  PubMed  Google Scholar  * Arhi CS,

Burns EM, Bottle A, Bouras G, Aylin P, Ziprin P, et al. Delays in referral from primary care worsen survival for patients with colorectal cancer: a retrospective cohort study. Br J Gen

Pract. 2020;70:e463–e71. Article  PubMed  PubMed Central  Google Scholar  * Auvinen A. Social class and colon cancer survival in Finland. Cancer 1992;70:402–9. Article  CAS  PubMed  Google

Scholar  * Bagaria SP, Heckman MG, Diehl NN, Parker A, Wasif N. Delay to colectomy and survival for patients diagnosed with colon cancer. J Invest. Surg. 2019;32:350–7. Article  PubMed 

Google Scholar  * Bako G, Hill G, Ferenczi L, Hanson J. Factors influencing the survival of patients with cancer of the colon or rectum. Chronic Dis Can. 1988;9:101–4. Google Scholar  *

Barillari P, De Angelis R, Valabrega S, Indinnimeo M, Gozzo P, Ramacciato G, et al. Relationship of symptom duration and survival in patients with colorectal carcinoma. Eur J Surg Oncol.

1989;15:441–5. CAS  PubMed  Google Scholar  * Bassett ML, Bennett SA, Goulston KJ. Colorectal cancer. A study of 230 patients. Med J Aust. 1979;1:589–92. Article  CAS  PubMed  Google Scholar

  * Ben-Ishay O, Brauner E, Peled Z, Othman A, Person B, Kluger Y. Diagnosis of colon cancer differs in younger versus older patients despite similar complaints. Isr Med Assoc J.

2013;15:284–7. PubMed  Google Scholar  * Bharucha S, Hughes S, Kenyon V, Anderson ID, Carlson GL, Scott NA. Targets and elective colorectal cancer: outcome and symptom delay at surgical

resection. Colorectal Dis. 2005;7:169–71. Article  CAS  PubMed  Google Scholar  * Bjerkeset T, Søreide O. Symptoms in colorectal adenocarcinomas and their relation to tumor characteristics

and survival. Dig Surg. 1988;5:61–5. Article  Google Scholar  * Cerdán-Santacruz C, Cano-Valderrama O, Cárdenas-Crespo S, Torres-García AJ, Cerdán-Miguel J. Colorectal cancer and its delayed

diagnosis: have we improved in the past 25 years? Rev Esp Enferm Dig. 2011;103:458–63. Article  PubMed  Google Scholar  * Chapuis PH, Dent OF, Fisher R, Newland RC, Pheils MT, Smyth E, et

al. A multivariate analysis of clinical and pathological variables in prognosis after resection of large bowel cancer. Br J Surg. 1985;72:698–702. Article  CAS  PubMed  Google Scholar  *

Chen FW, Sundaram V, Chew TA, Ladabaum U. Advanced-stage colorectal cancer in persons younger than 50 years not associated with longer duration of symptoms or time to diagnosis. Clin

Gastroenterol Hepatol. 2017;15:728–37.e3. Article  PubMed  Google Scholar  * Clarke AM, Jones IS. Diagnostic accuracy and diagnostic delay in carcinoma of the large bowel. NZ Med J.

1970;71:341–7. CAS  Google Scholar  * Comber H, Cronin DP, Deady S, Lorcain PO, Riordan P. Delays in treatment in the cancer services: impact on cancer stage and survival. Ir Med J.

2005;98:238–9. CAS  PubMed  Google Scholar  * Cubiella J, Lorenzo M, Baiocchi F, Tejido C, Conde A, Sande-Meijide M, et al. Impact of a colorectal cancer screening program implantation on

delays and prognosis of non-screening detected colorectal cancer. World J Gastroenterol. 2021;27:6689–700. Article  PubMed  PubMed Central  Google Scholar  * Curtis NJ, West MA, Salib E,

Ockrim J, Allison AS, Dalton R, et al. Time from colorectal cancer diagnosis to laparoscopic curative surgery-is there a safe window for prehabilitation? Int J Colorectal Dis.

2018;33:979–83. Article  CAS  PubMed  Google Scholar  * Davidson JTT, Abelson JS, Glasgow SC, Hunt SR, Mutch MG, Wise PE, et al. Delaying definitive resection in early stage (I/II) colon

cancer appears safe up to 6 weeks. Am J Surg. 2021;222:402–7. Article  PubMed  Google Scholar  * de Roos MAJ, Hugen N, Hazebroek EJ, Spillenaar Bilgen EJ. Delayed surgical resection of

primary left-sided obstructing colon cancer is associated with improved short- and long-term outcomes. J Surg Oncol. 2021;124:1146–53. Article  PubMed  Google Scholar  * de Sousa JB, Souza

CS, Fernandes MB, de Castro Durães L, de Almeida RM, Dos Santos AC, et al. Do young patients have different clinical presentation of colorectal cancer causing delay in diagnosis? Int J

Colorectal Dis. 2014;29:519–27. Article  PubMed  Google Scholar  * Delisle M, Helewa RM, Ward MA, Hochman DJ, Park J, McKay A. The association between wait times for colorectal cancer

treatment and health care costs: a population-based analysis. Dis Colon Rectum. 2020;63:160–71. Article  PubMed  Google Scholar  * Deng SX, An W, Gao J, Yin J, Cai QC, Yang M, et al. Factors

influencing diagnosis of colorectal cancer: a hospital-based survey in China. J Dig Dis. 2012;13:517–24. Article  PubMed  Google Scholar  * Di Girolamo C, Walters S, Gildea C, Benitez

Majano S, Rachet B, Morris M. Can we assess cancer waiting time targets with cancer survival? A population-based study of individually linked data from the National Cancer Waiting Times

monitoring dataset in England, 2009-2013. PLoS ONE. 2018;13:e0201288. Article  PubMed  PubMed Central  Google Scholar  * Dregan A, Møller H, Charlton J, Gulliford MC. Are alarm symptoms

predictive of cancer survival?: population-based cohort study. Br J Gen Pract. 2013;63:e807–12. Article  PubMed  PubMed Central  Google Scholar  * Duff SE, Wood C, McCredie V, Levine E,

Saunders MP, O'Dwyer ST. Waiting times for treatment of rectal cancer in North West England. J R Soc Med. 2004;97:117–8. Article  CAS  PubMed  PubMed Central  Google Scholar  * Edwards

GC, Gamboa AC, Feng MP, Muldoon RL, Hopkins MB, Abdel-Misih S, et al. What’s the magic number? Impact of time to initiation of treatment for rectal cancer. Surgery. 2022;171:1185–92. Article

  PubMed  Google Scholar  * Eldar S, Kemeny MM, Terz JJ. Extended resections for carcinoma of the colon and rectum. Surg Gynecol Obstet. 1985;161:319–22. CAS  PubMed  Google Scholar  * Fegiz

G, Barillari P, Ramacciato G, De Angelis R, Gozzo P, Indinnimeo M, et al. Right colon cancer: long-term results after curative surgery and prognostic significance of duration of symptoms. J

Surg Oncol. 1989;41:250–5. Article  CAS  PubMed  Google Scholar  * Fernández-de Castro JD, Baiocchi Ureta F, Fernández González R, Pin Vieito N, Cubiella Fernández J. The effect of

diagnostic delay attributable to the healthcare system on the prognosis of colorectal cancer. Gastroenterol Hepatol. 2019;42:527–33. Article  PubMed  Google Scholar  * Fisher DA, Zullig LL,

Grambow SC, Abbott DH, Sandler RS, Fletcher RH, et al. Determinants of medical system delay in the diagnosis of colorectal cancer within the Veteran Affairs Health System. Dig Dis Sci.

2010;55:1434–41. Article  PubMed  PubMed Central  Google Scholar  * Flemming JA, Nanji S, Wei X, Webber C, Groome P, Booth CM. Association between the time to surgery and survival among

patients with colon cancer: a population-based study. Eur J Surg Oncol. 2017;43:1447–55. Article  CAS  PubMed  Google Scholar  * Garcia-Botello S, Martín-Arevalo J, Cozar-Lozano C,

Benitez-Riesco A, Moro-Valdezate D, Pla-Martí V, et al. Does delaying curative surgery for colorectal cancer influence long-term disease-free survival? A cohort study. Langenbeck’s Arch

Surg. 2021;406:2383–90. Article  Google Scholar  * Gómez-Domínguez E, Trapero-Marugán M, del Pozo AJ, Cantero J, Gisbert JP, Maté J. The colorectal carcinoma prognosis factors. Significance

of diagnosis delay. Rev Esp Enferm Dig. 2006;98:322–9. Article  PubMed  Google Scholar  * Gonzalez-Hermoso F, Perez-Palma J, Marchena-Gomez J, Lorenzo-Rocha N, Medina-Arana V. Can early

diagnosis of symptomatic colorectal cancer improve the prognosis? World J Surg. 2004;28:716–20. Article  PubMed  Google Scholar  * Goodman D, Irvin TT. Delay in the diagnosis and prognosis

of carcinoma of the right colon. Br J Surg. 1993;80:1327–9. Article  CAS  PubMed  Google Scholar  * Gort M, Otter R, Plukker JT, Broekhuis M, Klazinga NS. Actionable indicators for short and

long term outcomes in rectal cancer. Eur J Cancer. 2010;46:1808–14. Article  PubMed  Google Scholar  * Graffner H, Olsson SA. Patient’s and doctor’s delay in carcinoma of the colon and

rectum. J Surg Oncol. 1986;31:188–90. Article  CAS  PubMed  Google Scholar  * Grass F, Behm KT, Duchalais E, Crippa J, Spears GM, Harmsen WS, et al. Impact of delay to surgery on survival in

stage I-III colon cancer. Eur J Surg Oncol. 2020;46:455–61. Article  PubMed  Google Scholar  * Guzmán Laura KP, Bolíbar Ribas I, Alepuz MT, González D, Martín M. Impact on patient care time

and tumor stage of a program for fast diagnostic and treatment of colorectal cancer. Rev Esp Enferm Dig. 2011;103:13–9. Article  PubMed  Google Scholar  * Hafström L, Johansson H, Ahlberg

J. Does diagnostic delay of colorectal cancer result in malpractice claims? A retrospective analysis of the Swedish board of malpractice from 1995-2008. Patient Saf Surg. 2012;6:13. Article

  PubMed  PubMed Central  Google Scholar  * Helewa RM, Turner D, Park J, Wirtzfeld D, Czaykowski P, Hochman D, et al. Longer waiting times for patients undergoing colorectal cancer surgery

are not associated with decreased survival. J Surg Oncol. 2013;108:378–84. Article  PubMed  Google Scholar  * Holliday HW, Hardcastle JD. Delay in diagnosis and treatment of symptomatic

colorectal cancer. Lancet. 1979;1:309–11. Article  CAS  PubMed  Google Scholar  * Irvin TT, Greaney MG. Duration of symptoms and prognosis of carcinoma of the colon and rectum. Surg, Gynecol

Obstet. 1977;144:883–6. CAS  PubMed  Google Scholar  * Iversen LH, Antonsen S, Laurberg S, Lautrup MD. Therapeutic delay reduces survival of rectal cancer but not of colonic cancer. Br J

Surg. 2009;96:1183–9. Article  CAS  PubMed  Google Scholar  * Janssen RM, Takach O, Nap-Hill E, Enns RA. Time to endoscopy in patients with colorectal cancer: analysis of wait-times. Can J

Gastroenterol Hepatol. 2016;2016:8714587. Article  PubMed  PubMed Central  Google Scholar  * Järvinen HJ, Turunen MJ. Colorectal carcinoma before 40 years of age: prognosis and predisposing

conditions. Scand J Gastroenterol. 1984;19:634–8. Article  PubMed  Google Scholar  * Jolly KD, Scott JP, MacKinnon MJ, Clarke AM. Diagnosis and survival in carcinoma of the large bowel. Aust

NZ J Surg. 1982;52:12–6. Article  CAS  Google Scholar  * Jullumstrø E, Lydersen S, Møller B, Dahl O, Edna TH. Duration of symptoms, stage at diagnosis and relative survival in colon and

rectal cancer. Eur J Cancer. 2009;45:2383–90. Article  PubMed  Google Scholar  * Keddie N, Hargreaves A. Symptoms of carcinoma of the colon and rectum. Lancet. 1968;2:749–50. Article  CAS 

PubMed  Google Scholar  * Khattak I, Eardley NJ, Rooney PS. Colorectal cancer–a prospective evaluation of symptom duration and GP referral patterns in an inner city teaching hospital.

Colorectal Dis. 2006;8:518–21. Article  CAS  PubMed  Google Scholar  * Khorana AA, Tullio K, Elson P, Pennell NA, Grobmyer SR, Kalady MF, et al. Time to initial cancer treatment in the

United States and association with survival over time: an observational study. PLoS ONE. 2019;14:e0213209. Article  CAS  PubMed  PubMed Central  Google Scholar  * Khubchandani M.

Relationship of symptom duration and survival in patients with carcinoma of the colon and rectum. Dis Colon Rectum. 1985;28:585–7. Article  CAS  PubMed  Google Scholar  * Kim TJ, Kim ER,

Hong SN, Chang DK, Kim YH. Long-term outcome and prognostic factors of sporadic colorectal cancer in young patients: a large institutional-based retrospective study. Medicine 2016;95:e3641.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Kiran PR, Glass RE. Duration of symptoms and spread of colorectal cancer: a short history does not mean early disease. Ann R Coll Surg

Engl. 2002;84:381–5. Article  CAS  PubMed  PubMed Central  Google Scholar  * Korsgaard M, Pedersen L, Sørensen HT, Laurberg S. Delay of treatment is associated with advanced stage of rectal

cancer but not of colon cancer. Cancer Detect Prev. 2006;30:341–6. Article  PubMed  Google Scholar  * Kucejko RJ, Holleran TJ, Stein DE, Poggio JL. How soon should patients with colon

cancer undergo definitive resection? Dis Colon Rectum. 2020;63:172–82. Article  PubMed  Google Scholar  * Kyle SM, Isbister WH, Yeong ML. Presentation, duration of symptoms and staging of

colorectal carcinoma. Aust NZ J Surg. 1991;61:137–40. Article  CAS  Google Scholar  * Langenbach MR, Sauerland S, Kröbel KW, Zirngibl H. Why so late?!–delay in treatment of colorectal cancer

is socially determined. Langenbeck’s Arch Surg. 2010;395:1017–24. Article  Google Scholar  * Langenbach MR, Schmidt J, Neumann J, Zirngibl H. Delay in treatment of colorectal cancer:

multifactorial problem. World J Surg. 2003;27:304–8. Article  PubMed  Google Scholar  * Law CW, Roslani AC, Ng LL. Treatment delay in rectal cancer. Med J Malays. 2009;64:163–5. CAS  Google

Scholar  * Lee YH, Kung PT, Wang YH, Kuo WY, Kao SL, Tsai WC. Effect of length of time from diagnosis to treatment on colorectal cancer survival: a population-based study. PLoS ONE.

2019;14:e0210465. Article  CAS  PubMed  PubMed Central  Google Scholar  * Leiva A, Esteva M, Llobera J, Macià F, Pita-Fernández S, González-Luján L, et al. Time to diagnosis and stage of

symptomatic colorectal cancer determined by three different sources of information: a population based retrospective study. Cancer Epidemiol. 2017;47:48–55. Article  PubMed  Google Scholar 

* Lim BS, Dennis CR, Gardner B, Newman J. Analysis of survival versus patient and doctor delay of treatment in gastrointestinal cancer. Am J Surg. 1974;127:210–4. Article  CAS  PubMed 

Google Scholar  * Lino-Silva LS, Guzmán-López JC, Zepeda-Najar C, Salcedo-Hernández RA, Meneses-García A. Overall survival of patients with colon cancer and a prolonged time to surgery. J

Surg Oncol. 2019;119:503–9. Article  PubMed  Google Scholar  * MacArthur C, Smith A. Factors associated with speed of diagnosis, referral, and treatment in colorectal cancer. J Epidemiol

Commun Health 1984;38:122–6. Article  CAS  Google Scholar  * Maguire A, Porta M, Malats N, Gallén M, Piñol JL, Fernandez E. Cancer survival and the duration of symptoms. An analysis of

possible forms of the risk function. ISDS II Project Investigators. Eur J Cancer. 1994;30a:785–92. Article  CAS  PubMed  Google Scholar  * Majumdar SR, Fletcher RH, Evans AT. How does

colorectal cancer present? Symptoms, duration, and clues to location. Am J Gastroenterol. 1999;94:3039–45. Article  CAS  PubMed  Google Scholar  * Marble K, Banerjee S, Greenwald L.

Colorectal carcinoma in young patients. J Surg Oncol. 1992;51:179–82. Article  CAS  PubMed  Google Scholar  * McDermott F, Hughes E, Pihl E, Milne BJ, Price A. Symptom duration and survival

prospects in carcinoma of the rectum. Surg Gynecol Obstet. 1981;153:321–6. CAS  PubMed  Google Scholar  * McDermott FT, Hughes ES, Pihl E, Milne BJ, Price AB. Prognosis in relation to

symptom duration in colon cancer. Br J Surg. 1981;68:846–9. Article  CAS  PubMed  Google Scholar  * Mulcahy H, O’Donoghue D. Duration of colorectal cancer symptoms and survival: the effect

of confounding clinical and pathological variables. Eur J Cancer. 1997;33:1461–7. Article  CAS  PubMed  Google Scholar  * Murchie P, Raja EA, Brewster DH, Campbell NC, Ritchie LD, Robertson

R, et al. Time from first presentation in primary care to treatment of symptomatic colorectal cancer: effect on disease stage and survival. Br J Cancer. 2014;111:461–9. Article  CAS  PubMed

  PubMed Central  Google Scholar  * Nilsson E, Bolin S, Sjödahl R. Carcinoma of the colon and rectum. Delay in diagnosis. Acta Chir Scand. 1982;148:617–22. CAS  PubMed  Google Scholar  *

Olsson L, Bergkvist L, Ekbom A. Symptom duration versus survival in non-emergency colorectal cancer. Scand J Gastroenterol. 2004;39:252–8. Article  CAS  PubMed  Google Scholar  * Ortiz-Ortiz

KJ, Ríos-Motta R, Marín-Centeno H, Cruz-Correa M, Ortiz AP. Factors associated with late stage at diagnosis among Puerto Rico’s government health plan colorectal cancer patients: a

cross-sectional study. BMC Health Serv Res. 2016;16:1–10. Article  Google Scholar  * Öztürk E, Kuzu MA, Öztuna D, Işık Ö, Canda AE, Balık E, et al. Fall of another myth for colon cancer:

duration of symptoms does not differ between right- or left-sided colon cancers. Turk J Gastroenterol. 2019;30:686–94. Article  PubMed  Google Scholar  * Påhlman L, Glimelius B, Enblad P.

Clinical characteristics and their relation to surgical curability in adenocarcinoma of the rectum and rectosigmoid. A population-based study on 279 consecutive patients. Acta Chir Scand.

1985;151:685–93. PubMed  Google Scholar  * Patel R, Anderson JE, McKenzie C, Simpson M, Singh N, Ruzvidzo F, et al. Compliance with the 62-day target does not improve long-term survival. Int

J Colorectal Dis. 2018;33:65–9. Article  PubMed  Google Scholar  * Pearson C, Fraser J, Peake M, Valori R, Poirier V, Coupland VH, et al. Establishing population-based surveillance of

diagnostic timeliness using linked cancer registry and administrative data for patients with colorectal and lung cancer. Cancer Epidemiol. 2019;61:111–8. Article  PubMed  PubMed Central 

Google Scholar  * Pescatori M, Maria G, Beltrani B, Mattana C. Site, emergency, and duration of symptoms in the prognosis of colorectal cancer. Dis Colon Rectum. 1982;25:33–40. Article  CAS

  PubMed  Google Scholar  * Pita-Fernández S, González-Sáez L, López-Calviño B, Seoane-Pillado T, Rodríguez-Camacho E, Pazos-Sierra A, et al. Effect of diagnostic delay on survival in

patients with colorectal cancer: a retrospective cohort study. BMC Cancer. 2016;16:664. Article  PubMed  PubMed Central  Google Scholar  * Polissar L, Sim D, Francis A. Survival of

colorectal cancer patients in relation to duration of symptoms and other prognostic factors. Dis Colon Rectum. 1981;24:364–9. Article  CAS  PubMed  Google Scholar  * Porta M, Gallén M,

Malats N, Planas J. Influence of "diagnostic delay" upon cancer survival: an analysis of five tumour sites. J Epidemiol Commun Health 1991;45:225–30. Article  CAS  Google Scholar 

* Porter GA, Inglis KM, Wood LA, Veugelers PJ. Access to care and satisfaction in colorectal cancer patients. World J Surg. 2005;29:1444–51. Article  PubMed  Google Scholar  * Pruitt SL,

Harzke AJ, Davidson NO, Schootman M. Do diagnostic and treatment delays for colorectal cancer increase risk of death? Cancer Causes Control. 2013;24:961–77. Article  PubMed  PubMed Central 

Google Scholar  * Ratcliffe R, Kiff RS, Hoare EM, Kingston RD, Walsh SH, Jeacock J. Early diagnosis in colorectal cancer still no benefit? Ann Chir. 1989;43:570–4. CAS  PubMed  Google

Scholar  * Redaniel MT, Martin RM, Ridd MJ, Wade J, Jeffreys M. Diagnostic intervals and its association with breast, prostate, lung and colorectal cancer survival in England: historical

cohort study using the Clinical Practice Research Datalink. PLoS ONE. 2015;10:e0126608. Article  PubMed  PubMed Central  Google Scholar  * Ristvedt SL, Birnbaum EH, Dietz DW, Fleshman JW,

Kodner IJ, Read TE. Delayed treatment for rectal cancer. Dis colon rectum. 2005;48:1736–41. Article  PubMed  PubMed Central  Google Scholar  * Robinson E, Mohilever J, Zidan J, Sapir D.

Colorectal cancer: incidence, delay in diagnosis and stage of disease. Eur J Cancer Clin Oncol. 1986;22:157–61. Article  CAS  PubMed  Google Scholar  * Roder D, Karapetis CS, Olver I, Keefe

D, Padbury R, Moore J, et al. Time from diagnosis to treatment of colorectal cancer in a South Australian clinical registry cohort: how it varies and relates to survival. BMJ Open.

2019;9:e031421. Article  PubMed  PubMed Central  Google Scholar  * Roland CL, Schwarz RE, Tong L, Ahn C, Balch GC, Yopp AC, et al. Is timing to delivery of treatment a reliable measure of

quality of care for patients with colorectal adenocarcinoma? Surgery. 2013;154:421–8. Article  PubMed  Google Scholar  * Roncoroni L, Pietra N, Violi V, Sarli L, Choua O, Peracchia A. Delay

in the diagnosis and outcome of colorectal cancer: a prospective study. Eur J Surg Oncol. 1999;25:173–8. Article  CAS  PubMed  Google Scholar  * Rowejones DC, Aylett SO. Delay in treatment

in carcinoma of colon and rectum. Lancet. 1965;2:973–6. Article  CAS  PubMed  Google Scholar  * Rubin M, Zer M, Dintsman M. Factors influencing delay in treatment of cancer of rectum and

colon in Israel. Isr J Med Sci. 1980;16:641–5. CAS  PubMed  Google Scholar  * Sandar M, Hsiang LG, Yew CK, Guat LB. Use of population-based cancer registry data to determine the effect of

timely treatment on the survival of colorectal cancer patients. J Registry Manag. 2015;42:130–8. PubMed  Google Scholar  * Sey MS, Gregor J, Adams P, Khanna N, Vinden C, Driman D, et al.

Wait times for diagnostic colonoscopy among outpatients with colorectal cancer: a comparison with Canadian Association of Gastroenterology targets. Can J Gastroenterol. 2012;26:894–6.

Article  PubMed  PubMed Central  Google Scholar  * Shin DW, Cho J, Kim SY, Guallar E, Hwang SS, Cho B, et al. Delay to curative surgery greater than 12 weeks is associated with increased

mortality in patients with colorectal and breast cancer but not lung or thyroid cancer. Ann Surg Oncol. 2013;20:2468–76. Article  PubMed  Google Scholar  * Simunovic M, Rempel E, Thériault

ME, Baxter NN, Virnig BA, Meropol NJ, et al. Influence of delays to nonemergent colon cancer surgery on operative mortality, disease-specific survival and overall survival. Can J Surg.

2009;52:E79–e86. PubMed  PubMed Central  Google Scholar  * Singh H, Shu E, Demers A, Bernstein CN, Griffith J, Fradette K. Trends in time to diagnosis of colon cancer and impact on clinical

outcomes. Can J Gastroenterol. 2012;26:877–80. Article  PubMed  PubMed Central  Google Scholar  * Stapley S, Peters TJ, Sharp D, Hamilton W. The mortality of colorectal cancer in relation to

the initial symptom at presentation to primary care and to the duration of symptoms: a cohort study using medical records. Br J Cancer. 2006;95:1321–5. Article  CAS  PubMed  PubMed Central

  Google Scholar  * Strous MTA, Janssen-Heijnen MLG, Vogelaar FJ. Impact of therapeutic delay in colorectal cancer on overall survival and cancer recurrence - is there a safe timeframe for

prehabilitation? Eur J Surg Oncol. 2019;45:2295–301. Article  PubMed  Google Scholar  * Stubbs RS, Long MG. Symptom duration and pathologic staging of colorectal cancer. Eur J Surg Oncol.

1986;12:127–30. CAS  PubMed  Google Scholar  * Terhaar sive Droste JS, Oort FA, van der Hulst RW, Coupé VM, Craanen ME, Meijer GA, et al. Does delay in diagnosing colorectal cancer in

symptomatic patients affect tumor stage and survival? A population-based observational study. BMC Cancer. 2010;10:332. Article  PubMed  PubMed Central  Google Scholar  * Thompson MR, Asiimwe

A, Flashman K, Tsavellas G. Is earlier referral and investigation of bowel cancer patients presenting with rectal bleeding associated with better survival? Colorectal Dis. 2011;13:1242–8.

Article  CAS  PubMed  Google Scholar  * Tiong J, Gray A, Jackson C, Thompson-Fawcett M, Schultz M. Audit of the association between length of time spent on diagnostic work-up and tumour

stage in patients with symptomatic colon cancer. ANZ J Surg. 2017;87:138–42. Article  PubMed  Google Scholar  * Tørring ML, Falborg AZ, Jensen H, Neal RD, Weller D, Reguilon I, et al.

Advanced-stage cancer and time to diagnosis: an International Cancer Benchmarking Partnership (ICBP) cross-sectional study. Eur J Cancer Care. 2019;28:e13100. Article  Google Scholar  *

Tørring ML, Frydenberg M, Hansen RP, Olesen F, Hamilton W, Vedsted P. Time to diagnosis and mortality in colorectal cancer: a cohort study in primary care. Br J Cancer. 2011;104:934–40.

Article  PubMed  PubMed Central  Google Scholar  * Tørring ML, Frydenberg M, Hansen RP, Olesen F, Vedsted P. Evidence of increasing mortality with longer diagnostic intervals for five common

cancers: a cohort study in primary care. Eur J Cancer. 2013;49:2187–98. Article  PubMed  Google Scholar  * Tørring ML, Murchie P, Hamilton W, Vedsted P, Esteva M, Lautrup M, et al. Evidence

of advanced stage colorectal cancer with longer diagnostic intervals: a pooled analysis of seven primary care cohorts comprising 11720 patients in five countries. Br J Cancer.

2017;117:888–97. Article  PubMed  PubMed Central  Google Scholar  * Trepanier M, Paradis T, Kouyoumdjian A, Dumitra T, Charlebois P, Stein BS, et al. The impact of delays to definitive

surgical care on survival in colorectal cancer patients. J Gastrointest Surg. 2020;24:115–22. Article  PubMed  Google Scholar  * Turnbull PR, Isbister WH. Colorectal cancer in New Zealand: a

Wellington study. Aust NZ J Surg. 1979;49:45–8. Article  CAS  Google Scholar  * Turunen MJ, Peltokallio P. Delay in the diagnosis of colorectal cancer. Ann Chir Gynaecol. 1982;71:277–82.

CAS  PubMed  Google Scholar  * Van Hout AM, de Wit NJ, Rutten FH, Peeters PH. Determinants of patient’s and doctor’s delay in diagnosis and treatment of colorectal cancer. Eur J

Gastroenterol Hepatol. 2011;23:1056–63. Article  PubMed  Google Scholar  * Viiala CH, Tang KW, Lawrance IC, Murray K, Olynyk JK. Waiting times for colonoscopy and colorectal cancer

diagnosis. Med J Aust. 2007;186:282–5. Article  PubMed  Google Scholar  * Walming S, Block M, Bock D, Angenete E. Timely access to care in the treatment of rectal cancer and the effect on

quality of life. Colorectal Dis. 2018;20:126–33. Article  CAS  PubMed  Google Scholar  * Wanis KN, Patel SVB, Brackstone M. Do moderate surgical treatment delays influence survival in colon

cancer? Dis Colon Rectum. 2017;60:1241–9. Article  PubMed  Google Scholar  * Wattacheril J, Kramer JR, Richardson P, Havemann BD, Green LK, Le A, et al. Lagtimes in diagnosis and treatment

of colorectal cancer: determinants and association with cancer stage and survival. Aliment Pharmacol Ther. 2008;28:1166–74. Article  CAS  PubMed  PubMed Central  Google Scholar  * Wheeler,

Wakefield, Mortensen NJMcC, Kettlewell. Delays experienced by patients with symptomatic colorectal cancer. Colorectal Dis. 1999;1:174–6. * Young CJ, Sweeney JL, Hunter A. Implications of

delayed diagnosis in colorectal cancer. Aust NZ J Surg. 2000;70:635–8. Article  CAS  Google Scholar  * Yun YH, Kim YA, Min YH, Park S, Won YJ, Kim DY, et al. The influence of hospital volume

and surgical treatment delay on long-term survival after cancer surgery. Ann Oncol. 2012;23:2731–7. Article  CAS  PubMed  Google Scholar  * Zhang JK, Fang LL, Wu XM, Liu JC, Zhang CD, Dai

DQ. Factors associated with delaying medical assessment of patients and impacting the prognosis of rectal cancer. Eur J Cancer Prev 2015;24:391–9. Article  CAS  PubMed  Google Scholar  *

Burke JR, Brown P, Quyn A, Lambie H, Tolan D, Sagar P. Tumour growth rate of carcinoma of the colon and rectum: retrospective cohort study. BJS Open. 2020;4:1200–7. Article  PubMed  PubMed

Central  Google Scholar  * Ng J, Stovezky YR, Brenner DJ, Formenti SC, Shuryak I. Development of a model to estimate the association between delay in cancer treatment and local tumor control

and risk of metastases. JAMA Netw Open. 2021;4:e2034065. Article  PubMed  PubMed Central  Google Scholar  * Cohen J. The cost of dichotomization. Appl Psychol Meas. 1983;7:249–53. Article 

Google Scholar  * Royston P, Altman DG, Sauerbrei W. Dichotomizing continuous predictors in multiple regression: a bad idea. Stat Med. 2006;25:127–41. Article  PubMed  Google Scholar  *

Petrova D, Špacírová Z, Fernández-Martínez NF, Ching-López A, Garrido D, Rodríguez-Barranco M, et al. The patient, diagnostic, and treatment intervals in adult patients with cancer from

high- and lower-income countries: a systematic review and meta-analysis. PLoS Med. 2022;19:e1004110. Article  PubMed  PubMed Central  Google Scholar  * Siciliani L, Moran V, Borowitz M. What

works? Waiting policies in the health sector. Eurohealth Observer. 2015;21:14–7. Google Scholar  * Australian Government Department of Health. Optimal cancer care pathways. Canberra:

Commonwealth of Australia; 2016. Download references FUNDING AD is supported by a NHMRC Postgraduate Scholarship. RJB is supported by a Victorian Cancer Agency, Early Career Research

Fellowship (ECRF20015). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of General Practice and Centre for Cancer Research, The University of Melbourne, Parkville, VIC, Australia

Allison Drosdowsky, Rebecca J. Bergin, Kristi Milley, Lucy Boyd & Jon D. Emery * Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia

Karen E. Lamb, Amalia Karahalios & Maarten J. IJzerman * Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia Rebecca J. Bergin * Primary Care Collaborative

Cancer Clinical Trials Group (PC4), Carlton, VIC, Australia Kristi Milley & Jon D. Emery Authors * Allison Drosdowsky View author publications You can also search for this author

inPubMed Google Scholar * Karen E. Lamb View author publications You can also search for this author inPubMed Google Scholar * Amalia Karahalios View author publications You can also search

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publications You can also search for this author inPubMed Google Scholar * Jon D. Emery View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS All

authors have significantly contributed to the conceptualisation, design, conduct and reporting (writing and reviewing) of this systematic review. CORRESPONDING AUTHOR Correspondence to

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citation * Received: 19 December 2022 * Revised: 28 June 2023 * Accepted: 24 July 2023 * Published: 01 August 2023 * Issue Date: 05 October 2023 * DOI:

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