PracticeUpdate Oncology May 2019

EDITOR’S PICKS 14

Increasing the Dose Intensity of Chemotherapy byMore Frequent Administration or Sequential Scheduling The Lancet

Take-home message • This meta-analysis was designed to compare the impact of dose- intense versus standard-schedule chemotherapy for patients with early breast cancer. The risk of recurrence at 10 years was lower in the dose- intense group compared with the standard-schedule group (28.0% vs 31.4%; P < .0001). Both 10-year breast cancer mortality and all-cause mortality were also significantly lower in the dose-intense group compared with the standard-schedule group. • The use of dose-intense chemo- therapy for patients with breast cancer appears to reduce the risk of recurrence and cancer death. Neil Majithia MD Abstract BACKGROUND Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in low- er-dose concurrent treatment schedules, might enhance efficacy. METHODS To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracy- cline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). FINDINGS Individual patient data were provided for 26 of 33 relevant trials identified, compris- ing 37 298 (93%) of 40070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cyto- toxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-in- tense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-sched- ule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82-0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9% vs 21·3%; RR 0·87, 95% CI 0·83-0·92; p<0·0001), as was all-cause mortality (22·1% vs 24·8%; RR 0·87, 95% CI 0·83- 0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year

COMMENT By Lee S. Schwartzberg MD, FACP

T he concept of manipulating a chemotherapy schedule to improve outcomes, uti- lizing dose-dense and/or sequential dosing, is based on mathematical models of tumor cell killing derived from the Norton–Simon hypothesis. This model sug- gests that the fraction of cell killing by cytotoxic agents will be improved by exposing cancer to chemotherapy more frequently and by giving all of one drug to eradicate a sensitive clone completely followed by an agent that kills a different clone of cells, rather than administering them together or in an alternating fashion. One way to clinically replicate the preclinical model is to give standard doses of chemo- therapy in a shortened cycle time, termed dose-density. In order to achieve this with cytotoxics, growth factor support is typically required. Many clinical trials have tested this kinetic approach over the past 20 years, but results from individual trials, usually testing anthracycline and taxane regimens, have not always shown clear-cut results from a dose-dense or sequential program. The Early Breast Cancer Trialist Collaborative Group has now published in The Lancet a patient-level meta-analysis of this approach, bringing together 37,000+ patients from 26 clinical trials representing various dose-dense or sequential approaches. Overall, dose-intense treatment reduced 10-year recurrence risk by 14%, with an absolute 10-year recurrence risk of 28.0% for the intense regimen compared with 31.4% for standard. Moreover, dose intensity also improved 10-year breast cancer- related mortality and overall mortality. Importantly, deaths without recurrence were numerically less for dose-intense therapy despite the use of growth factors to support the regimens, demonstrating the safety of such treatment. For studies in the meta-analysis that used both dose-dense and sequential treatment in the regimen design, the improvement was even greater: 30.4% recurrence com- pared with 35.0% at 10 years for the standard treatment (HR, 0.82, which is highly statistically significant). The dose-dense and sequential strategies worked equally well in ER+ and ER− tumors, but the contribution of adding anti-HER2 therapy in the HER2+ subgroups cannot be ascertained, as many of the trials predated use of anti- HER2 therapy. These results validate the ongoing use of dose-dense/sequential methods in neo- adjuvant/adjuvant therapy in early-stage breast cancer. The findings also provide reassurance that long-term, non-breast cancer mortality is not greater with this approach, and call into question whether continuing with other standard regimens without dose-density or sequencing is optimal.

risk 4·1% vs 4·6%; RR 0·88, 95% CI 0·78-0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemo- therapy given 3-weekly (10-year risk 24·0% vs 28·3%; RR 0·83, 95% CI 0·76-0·91; p<0·0001), in the six trials (n=11 028) of sequential versus con- current anthracycline plus taxane chemotherapy (28·1% vs 31·3%; RR 0·87, 95% CI 0·80-0·94; p=0·0006), and in the six trials (n=6532) testing both shorter intervals and sequential administra- tion (30·4% vs 35·0%; RR 0·82, 95% CI 0·74-0·90; p<0·0001). The proportional reductions in recur- rence with dose-intense chemotherapy were similar and highly significant (p<0·0001) in oes- trogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics.

INTERPRETATION Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giv- ing the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes. Increasing the Dose Intensity of Chemotherapy by More Frequent Administration or Sequential Scheduling: A Patient-Level Meta-Analysis of 37,298 Women With Early Breast Cancer in 26 Randomised Trials. Lancet 2019 Feb 07;[EPub Ahead of Print], Early Breast Cancer Trialists' Col- laborative Group (EBCTCG)

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