People whose treatment for cancer is delayed by even one month have 6% to 13% higher risk of dying – a risk that keeps rising the longer treatment does not begin – suggests a Canadian and UK systematic review involving 1.2m patients.
“The new work reinforces the critical need for system level efforts to minimise waiting times for cancer treatments,” The BMJ writes in an editorial.
The researchers found there was a significant impact on a person’s mortality if their treatment was delayed, whether surgical, systemic therapy (such as chemotherapy), or radiotherapy for seven types of cancer – including cancers of the breast, bowel, and head and neck.
The team of researchers from the London School of Hygiene & Tropical Medicine, King’s College London and Queen’s University – Canada, led by Dr’s Timothy Hanna and Ajay Aggarwal, carried out a systematic review and analysis of 34 studies into cancer treatment delays and mortality risk between January 2000 and April 2020.
Of the 1.2m patients studied, the association between delay of treatment and increased mortality was significant for 13 of the 17 types of conditions known as indications.
Globally, health systems have problems with cancer treatment delays and it is already widely accepted that such delays can have adverse consequences on a patient’s outcome. But the precise impact of delays from diagnosis to receipt of treatment on mortality has not been thoroughly analysed.
The need for better understanding of the impact of treatment delay on outcomes has come into focus during the COVID-19 pandemic because many countries have experienced deferral of elective cancer surgery and radiotherapy as well as reductions in the use of systemic therapies, while health systems have directed resources to preparing for the pandemic.
The researchers analysed data on surgical interventions, systemic therapy (such as chemotherapy), or radiotherapy for seven forms of cancer – bladder, breast, colon, rectum, lung, cervix, and head and neck – that together, represent 44% of all incident cancers globally.
They measured the risk to overall survival per four-week delay for each indication and delays were measured from diagnosis to first treatment, or from the completion of one treatment to the start of the next.
Analysis of the results showed that across all three treatment approaches, a treatment delay of four weeks was associated with an increase in the risk of death.
For cancer surgery, this was a 6-8% increase in the risk of death for every four-week treatment delay including for breast cancer, meaning that a 3-month delay would increase the risk of death by approximately 25%. The impact was even more marked for some radiotherapy and drug treatment indications, such as bowel cancer chemotherapy with a 13% risk of death for a 4-week delay (rising to a 44% increase risk of death for a 12-weeks delay).
A surgical delay of 12 weeks for all patients with breast cancer for a year (for example during COVID-19 lockdown and recovery) would lead to 1,400 excess deaths in the UK, 6,100 in the US, 700 in Canada, and 500 in Australia, assuming surgery was the first treatment in 83% of cases, and mortality without delay was 12%.
Aggarwal said: “There has never been a systematic attempt to look at all the evidence on what delays in different types of treatment mean for cancer patient outcomes. Because we know this is happening to cancer patients during the COVID-19 pandemic it is essential to understand the real impact.
“The concern is that at the start of lockdown health systems such as in the UK suggested that some surgeries, for example bowel cancer surgery, could be safely deferred by up to 12 weeks. Our study suggests that this is not the case and could in fact increase the risk of premature death.
“As we move towards the second COVID-19 wave in many countries, the results emphasise the need to prioritise cancer services including surgery, drug treatments and radiotherapy as even a 4-week delay can significantly increase the risk of cancer death.”
The researchers acknowledge that their study had limitations such as the fact that it was based on data from observational research which cannot perfectly establish cause, and it was possible that patients with longer treatment delays were destined to have inferior outcomes for reasons of having multiple illnesses or treatment morbidity.
Nevertheless, their analysis was based on a large amount of data and they ensured that they only included high quality studies that had high validity, meaning they accurately measured what they were investigating.
Dr Timothy Hanna concludes: “A four-week delay in treatment is associated with an increase in mortality across all common forms of cancer treatment, with longer delays being increasingly detrimental.
“In light of these results, policies focused on minimising system level delays in cancer treatment initiation could improve population level survival outcomes.”
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 (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.
TP Hanna, WD King, S Thibodeau, M Jalink, GA Paulin, E Harvey-Jones, DE O’Sullivan, CM Booth, R Sullivan, A Aggarwal
London School of Hygiene & Tropical Medicine material