Evidence Statements

• An individual participant data (IPD) meta-analysis examined the effect of increasing chemotherapy dose intensity on recurrence risk and survival in women with high-risk early breast cancer.¹ Included studies were subdivided by the method of dose intensification.  Trial participants were treated between 1985 and 2011 so, in the majority of trials, targeted therapies, e.g. for HER2 positive or ER+ patients, were not routinely used. Few women (<2%) included in the relevant trials were aged 70 or older. 
• A subanalysis within the meta-analysis brought together eight trials (IPD data available for seven, n=10,004) of increasing dose intensity by reducing the time interval between cycles whilst keeping the drugs, doses and number of cycles the same. Recurrence was lower in the dose-dense group (rate ratio (RR) =0.83, 95% CI 0.76 to 0.91, p<0.0001) as was breast cancer mortality (RR=0.86, 95% CI 0.77 to 0.96, p=0.005). This benefit was seen without evidence of statistically significant impact on death without recurrence (RR=0.96, 95% CI 0.76 to 1.20, p>0.1).
• In subgroup analyses tumour grade, nodal status and hormone receptor status did not statistically affect the proportional reductions in recurrence. The HER2 status was known for 70% of the study population, of which 20.8% were HER2 positive. There was wide uncertainty around the estimate of effect in the HER2 positive subgroup although Chi-squared testing indicated statistical homogeneity in intervention effect across the HER2 positive and HER2 negative groups. 
• There were only minor differences in toxicities between dose-dense and standard chemotherapies.  In four trials there were higher rates of anaemia and stomatitis in the dose-dense chemotherapy arm compared with control. Diarrhoea and vomiting symptoms at grade 3 or above (variously categorised across trials) were also experienced by a higher proportion of study participants receiving dose-dense chemotherapy in two and four trials respectively. 
• Data from two trials indicated that quality of life was worse during treatment with dose-intense therapy but was similar in both treatment arms when measured after the end of the treatment phase.
• In five trials where data were available, there was no statistically significant difference in the proportion of patients not completing all cycles of chemotherapy: 12.3% (dose dense group) vs 12.8% (standard chemo group), RR=0.96, 95% CI 0.84 to 1.09, p>0.1.
• In the context of NHS Scotland high-risk early breast cancer is defined as where chemotherapy provides >5% additional 10-year survival benefit according to PREDICT or using similar criteria.
• In regard to the size of predicted benefit from dose dense adjuvant chemotherapy the authors of the meta-analysis note that “…this reduction is only moderate but since the standard chemotherapy comparator is already known to reduce the risk of breast cancer death by about a third,² preventing a further 10–15% of deaths would imply that, compared to no chemotherapy, dose-intense adjuvant chemotherapy schedules with anthracycline and taxane could prevent about 40% of deaths from breast cancer during the first decade.”

For patients with early breast cancer, are chemotherapy regimens with fluorouracil superior to regimens without fluorouracil in the adjuvant setting?

Evidence statements

• One randomised controlled trial (n=2,091) was identified.¹ Women with high-risk early breast cancer receiving adjuvant chemotherapy were randomised to four cycles of epirubicin and cyclophosphamide, with or without fluorouracil, followed by four cycles of paclitaxel. Around half the participants (n=1,002) received chemotherapy every two weeks with the remaining participants having chemotherapy every three weeks (n=1,089).
• The primary outcome was disease-free survival. Median follow up period was 15.1 years.
• No statistically significant differences were identified between the time to event distribution curves between those receiving regimens with or without fluorouracil, hazard ratio (HR)=1.12 (95% CI 0.98 to 1.29, p=0.11). 
• Similarly, there was no statistically significant difference in overall survival between groups having fluorouracil-containing regimens and those receiving regimens without fluorouracil, HR=1.13 (95% CI 0.94 to 1.36, p=0.18). 
• In a post-hoc subgroup analysis examining hormone receptor-positive and HER2-negative (HR=1.09, 95% CI 0.90 to 1.33, p=0.37) HER2-positive (HR=1.01, 95% CI 0.75 to 1.35, p=0.96), and triple-negative breast cancer HR=0.62, 95% CI 0.37 to 1.04, p=0.07), none of the subtypes showed a disease-free survival benefit from fluorouracil-containing regimens compared with the regimens without fluorouracil. 
• Rates of neutropenia, fever, nausea and vomiting were statistically significantly higher in patients receiving fluorouracil. No information was provided on whether hospitalisation was required for these events. Treatment-related serious adverse events were similar across study groups. There were no treatment-related deaths. 

References

1. Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, et al. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. The Lancet Oncology. 2022;23(12):1571-82.