NIHR Signal Delaying chemotherapy after breast cancer surgery may reduce survival chances

Published on 31 January 2017

Delaying chemotherapy after breast cancer surgery may slightly decrease a woman’s chances of survival. A review found about a 5% increase in the relative risk of death.

Many women are offered chemotherapy soon after breast cancer surgery, called adjuvant chemotherapy. Chemotherapy is usually started after the surgical wounds have healed but the effect of any delay to this was unclear. These researchers calculated the risk from outcomes for almost 30,000 women treated with adjuvant chemotherapy, from studies in Europe and North America.

The absolute risk of death for any woman will depend on her individual cancer stage and characteristics. A four week delay could add several percentage points to her overall risk of death. This could have meaningful impact for the individual, but may not be enough to remove the benefit entirely. The review didn’t examine delays longer than four months. 

NICE recommend adjuvant chemotherapy for breast cancer should be started within 31 days of surgery. This review reinforces that guidance.

Share your views on the research.

Why was this study needed?

Breast cancer is the most common cancer in the UK, with 55,200 new cases recorded in 2014. The majority of breast cancers (75%) are treated by surgery. Many women receive adjuvant chemotherapy soon after surgery to treat any small areas of cancer that were not apparent at the time of surgery. Previous trials have demonstrated that adjuvant chemotherapy started within three months of surgery can reduce risk of recurrent cancer and improve overall survival.

If the treatment plan includes adjuvant chemotherapy, the UK recommendation is for this to start within one month of surgery. However, it’s unclear how many women are treated in this timeframe.

Until now, there’s been no good information about how delays between surgery and chemotherapy might affect women’s chances of surviving breast cancer.  Previous research studies have reported an association between delay and survival, but many were based just on cancer registry data and may have been at risk of bias.

What did this study do?

This systematic review included 14 studies assessing how waiting time between breast cancer surgery and the start of chemotherapy affected survival. Five were randomised controlled trials and nine were observational cohorts, either hospital-based or general population samples.

Five randomised controlled trials and three cohorts including 26,265 participants were pooled in meta-analysis looking at the link between a four-week delay in start of chemotherapy and overall survival. These studies were categorized as ‘high validity’, meaning they included information on patients’ age, cancer stage, hormone receptor status, and made it clear that chemotherapy was to aid treatment, not as palliative care after surgery had failed.

Results were pooled using a fixed effect and a random effects model, which allows for the fact that the effect varied between the individual studies. Researchers analysed the randomised studies separately from the observational studies.

What did it find?

  • A four-week increase in time from surgery to start of chemotherapy was linked to a 4% to 8% increase in chances of death depending on the choice of analytical model. In the fixed effect model of high quality studies, the overall survival was increased by 4% for those people not delayed by more than 4 weeks (relative risk 1.04, 95% confidence interval [CI] 1.01 to 1.08) and in the random effects model by 8% (relative risk 1.08, 95% confidence interval [CI] 1.01 to 1.15). The authors concluded that the 5% estimate of the increased risk was reasonable.
  • This finding was mainly dependent on the results of three cohort studies (14,029 participants). None of the five individual randomised controlled trials (12,236 participants) showed a statistically significant effect of time to start of chemotherapy upon overall survival. This reduces our confidence in the accuracy of the results.
  • Seven studies also reported effect of chemotherapy delay on the outcome of survival before cancer recurrence. These studies found suggestion that four-week delay also slightly increased risk of cancer recurrence (RR 1.05, 95 % CI 1.01 to 1.10), but this fell short of statistical significance when only the five ‘high validity’ studies were pooled (RR 1.06, 95 % CI 0.99 to 1.12).

What does current guidance say on this issue?

The NICE guideline on early and locally advanced breast cancer recommends: “Start adjuvant chemotherapy or radiotherapy as soon as clinically possible within 31 days of completion of surgery in patients with early breast cancer having these treatments”. This is in line with the findings of the study.

NICE suggest doctors consider using online tools to support their estimations on individual prognosis and the likely benefit of adjuvant treatment.

What are the implications?

There may be various reasons why a woman is not ready to start chemotherapy within four weeks. This study suggests there are compelling reasons to avoid non-essential delays.

However, absolute risk will vary depending on cancer stage and characteristics. For example, if a woman’s 10-year risk of death is 20%, with prompt chemotherapy this could increase to 21% with four-week delay. A 60% risk could increase to 65%. Therefore risks need to be balanced for the individual and electronic tools, such as Predict, are available to help with this.

The key message for hospitals and commissioners is to manage waiting lists and clinics in a way that minimises unnecessary delays in starting chemotherapy after surgery.

Citation and Funding

Raphael MJ, Biagi JJ, Kong W, et al. The relationship between time to initiation of adjuvant chemotherapy and survival in breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat. 2016;160(1):17-28

No funding information was provided for this study.

Bibliography

NHS Choices. Breast cancer (female). London: Department of Health; page last reviewed in 2016.

NICE. Early and locally advanced breast cancer: diagnosis and treatment. CG80. London: National Institute for Health and Care Excellence; 2009

Wishart GC, Azzato EM, Greenberg DC, et al. PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer. Breast Cancer Res. 2010;12(1):R1.

Why was this study needed?

Breast cancer is the most common cancer in the UK, with 55,200 new cases recorded in 2014. The majority of breast cancers (75%) are treated by surgery. Many women receive adjuvant chemotherapy soon after surgery to treat any small areas of cancer that were not apparent at the time of surgery. Previous trials have demonstrated that adjuvant chemotherapy started within three months of surgery can reduce risk of recurrent cancer and improve overall survival.

If the treatment plan includes adjuvant chemotherapy, the UK recommendation is for this to start within one month of surgery. However, it’s unclear how many women are treated in this timeframe.

Until now, there’s been no good information about how delays between surgery and chemotherapy might affect women’s chances of surviving breast cancer.  Previous research studies have reported an association between delay and survival, but many were based just on cancer registry data and may have been at risk of bias.

What did this study do?

This systematic review included 14 studies assessing how waiting time between breast cancer surgery and the start of chemotherapy affected survival. Five were randomised controlled trials and nine were observational cohorts, either hospital-based or general population samples.

Five randomised controlled trials and three cohorts including 26,265 participants were pooled in meta-analysis looking at the link between a four-week delay in start of chemotherapy and overall survival. These studies were categorized as ‘high validity’, meaning they included information on patients’ age, cancer stage, hormone receptor status, and made it clear that chemotherapy was to aid treatment, not as palliative care after surgery had failed.

Results were pooled using a fixed effect and a random effects model, which allows for the fact that the effect varied between the individual studies. Researchers analysed the randomised studies separately from the observational studies.

What did it find?

  • A four-week increase in time from surgery to start of chemotherapy was linked to a 4% to 8% increase in chances of death depending on the choice of analytical model. In the fixed effect model of high quality studies, the overall survival was increased by 4% for those people not delayed by more than 4 weeks (relative risk 1.04, 95% confidence interval [CI] 1.01 to 1.08) and in the random effects model by 8% (relative risk 1.08, 95% confidence interval [CI] 1.01 to 1.15). The authors concluded that the 5% estimate of the increased risk was reasonable.
  • This finding was mainly dependent on the results of three cohort studies (14,029 participants). None of the five individual randomised controlled trials (12,236 participants) showed a statistically significant effect of time to start of chemotherapy upon overall survival. This reduces our confidence in the accuracy of the results.
  • Seven studies also reported effect of chemotherapy delay on the outcome of survival before cancer recurrence. These studies found suggestion that four-week delay also slightly increased risk of cancer recurrence (RR 1.05, 95 % CI 1.01 to 1.10), but this fell short of statistical significance when only the five ‘high validity’ studies were pooled (RR 1.06, 95 % CI 0.99 to 1.12).

What does current guidance say on this issue?

The NICE guideline on early and locally advanced breast cancer recommends: “Start adjuvant chemotherapy or radiotherapy as soon as clinically possible within 31 days of completion of surgery in patients with early breast cancer having these treatments”. This is in line with the findings of the study.

NICE suggest doctors consider using online tools to support their estimations on individual prognosis and the likely benefit of adjuvant treatment.

What are the implications?

There may be various reasons why a woman is not ready to start chemotherapy within four weeks. This study suggests there are compelling reasons to avoid non-essential delays.

However, absolute risk will vary depending on cancer stage and characteristics. For example, if a woman’s 10-year risk of death is 20%, with prompt chemotherapy this could increase to 21% with four-week delay. A 60% risk could increase to 65%. Therefore risks need to be balanced for the individual and electronic tools, such as Predict, are available to help with this.

The key message for hospitals and commissioners is to manage waiting lists and clinics in a way that minimises unnecessary delays in starting chemotherapy after surgery.

Citation and Funding

Raphael MJ, Biagi JJ, Kong W, et al. The relationship between time to initiation of adjuvant chemotherapy and survival in breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat. 2016;160(1):17-28

No funding information was provided for this study.

Bibliography

NHS Choices. Breast cancer (female). London: Department of Health; page last reviewed in 2016.

NICE. Early and locally advanced breast cancer: diagnosis and treatment. CG80. London: National Institute for Health and Care Excellence; 2009

Wishart GC, Azzato EM, Greenberg DC, et al. PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer. Breast Cancer Res. 2010;12(1):R1.

The relationship between time to initiation of adjuvant chemotherapy and survival in breast cancer: a systematic review and meta-analysis

Published on 16 September 2016

Raphael, M.J.,Biagi, J. J.,Kong, W.,Mates, M.,Booth, C. M.,Mackillop, W. J.

Breast Cancer Research and Treatment , 2016

BACKGROUND: It is known that adjuvant chemotherapy improves survival in women with breast cancer. It is not known whether the interval between surgery and the initiation of chemotherapy influences its effectiveness. PURPOSE: To determine the relationship between time to initiation of adjuvant chemotherapy and survival in women with breast cancer, through a systematic review of the literature and meta-analysis. METHODS: Systematic review of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Database of Controlled Trials, Google Scholar, and abstracts presented at major international oncology conferences. The primary meta-analysis included only high-validity studies which directly measured the time from surgery to initiation of adjuvant chemotherapy and which controlled for major prognostic factors. Outcomes reported in the original studies were converted to a regression coefficient (beta) and standard error corresponding to a 4-week delay in the initiation of chemotherapy. These relative risks were combined in both fixed- and random-effects models. Homogeneity was assessed by the Cochran chi 2 statistic and the I 2 statistic. Potential publication bias was investigated using standard error-based funnel plots. RESULTS: Meta-analysis of 8 high-validity studies demonstrated that a 4-week increase in TTAC was associated with a significant increase in the risk of death in both the fixed-effects model (RR 1.04; 95 % CI, 1.01-1.08) and random-effects model (RR 1.08; 95 % CI, 1.01-1.15). The association remained significant when the most highly weighted studies were sequentially removed from this analysis, and also when additional, lower validity studies were included in this analysis. Funnel plots showed no significant asymmetry to suggest publication bias. CONCLUSIONS: Increased waiting time from surgery to initiation of adjuvant chemotherapy is associated with a significant decrease in survival. Avoidance of unnecessary delays in the initiation of adjuvant chemotherapy has the potential to save the lives of many women with breast cancer.

Expert commentary

Delays to starting adjuvant chemotherapy following surgery for breast cancer are an increasing concern due to heavily overloaded chemotherapy units. The ideal time window for commencing chemotherapy is unknown, but generally the aim would be to start as soon as the surgical wound has sufficiently healed.

This meta-analysis looks at observational evidence from chemotherapy trials to determine the effect of delays to starting treatment and finds a small but significant increase in the risk of death for each four week delay.

With the advent of genomic testing for patients with borderline clinical indications for chemotherapy, which can take at least a couple of weeks to turn around, we might see further delays to starting treatment that could negate the already relatively small benefits of chemotherapy for these patients. It also serves as a useful reminder for NHS institutions to adequately resource chemotherapy units to allow prompt treatment for all patients.

Dr Mark Beresford, Consultant Oncologist and Clinical Lead for Radiotherapy, Royal United Hospital Bath; Visiting Senior Lecturer, Bath University