Mortality due to cancer treatment delay: systematic review and meta-analysis

Abstract

Objective: To quantify the association of cancer treatment delay and mortality for each four week increase in delay to inform cancer treatment pathways.

Design: Systematic review and meta-analysis.

Data sources: Published studies in Medline from 1 January 2000 to 10 April 2020.

Eligibility criteria for selecting studies: Curative, neoadjuvant, and adjuvant indications for surgery, systemic treatment, or radiotherapy for cancers of the bladder, breast, colon, rectum, lung, cervix, and head and neck were included. The main outcome measure was the hazard ratio for overall survival for each four week delay for each indication. Delay was measured from diagnosis to first treatment, or from the completion of one treatment to the start of the next. The primary analysis only included high validity studies controlling for major prognostic factors. Hazard ratios were assumed to be log linear in relation to overall survival and were converted to an effect for each four week delay. Pooled effects were estimated using DerSimonian and Laird random effect models.

Results: The review included 34 studies for 17 indications (n=1 272 681 patients). No high validity data were found for five of the radiotherapy indications or for cervical cancer surgery. The association between delay and increased mortality was significant (P<0.05) for 13 of 17 indications. Surgery findings were consistent, with a mortality risk for each four week delay of 1.06-1.08 (eg, colectomy 1.06, 95% confidence interval 1.01 to 1.12; breast surgery 1.08, 1.03 to 1.13). Estimates for systemic treatment varied (hazard ratio range 1.01-1.28). Radiotherapy estimates were for radical radiotherapy for head and neck cancer (hazard ratio 1.09, 95% confidence interval 1.05 to 1.14), adjuvant radiotherapy after breast conserving surgery (0.98, 0.88 to 1.09), and cervix cancer adjuvant radiotherapy (1.23, 1.00 to 1.50). A sensitivity analysis of studies that had been excluded because of lack of information on comorbidities or functional status did not change the findings.

Conclusions: Cancer treatment delay is a problem in health systems worldwide. The impact of delay on mortality can now be quantified for prioritisation and modelling. Even a four week delay of cancer treatment is associated with increased mortality across surgical, systemic treatment, and radiotherapy indications for seven cancers. Policies focused on minimising system level delays to cancer treatment initiation could improve population level survival outcomes.

Fig 1

PRISMA (preferred reporting items for systematic reviews and meta-analyses) 2009 flow diagram for systematic review of treatment delay and survival for curative surgery, systemic treatment, and radiotherapy for bladder, breast, colon, rectum, lung, cervix, and head and neck cancer. HR=hazard ratio

Fig 2

Forest plot and pooled hazard ratios for association of each four week delay in surgery and overall survival by cancer site. Small purple diamonds represent the hazard ratio for each study and whiskers represent 95% confidence interval. Large purple diamonds represent summary effect estimates with the centre being the estimate and the ends representing 95% confidence intervals. NSCLC=non-small cell lung cancer

Fig 3

Forest plot and pooled hazard ratios for association of each four week delay in adjuvant and neoadjuvant systemic treatment and overall survival by cancer site. Small purple diamonds represent the hazard ratio for each study and whiskers represent 95% confidence interval. Large purple diamonds represent summary effect estimate with the centre being the estimate and the ends representing 95% confidence intervals. NSCLC=non-small cell lung cancer

Fig 4

Forest plot of hazard ratios for association of each four week delay in radical and adjuvant radiotherapy and overall survival by cancer site. Purple diamonds represent the hazard ratio for each study and whiskers represent 95% confidence interval