Dose intensification of chemotherapy for early breast cancer in the age of de-escalation
Authors: Sara A Hurvitz
Journal: The Lancet (2019)

60 years ago, the first randomised trial of adjuvant chemotherapy for breast cancer began.1Fisher B Ravdin RG Ausman RK Slack NH Moore GE Noer RJ Surgical adjuvant chemotherapy in cancer of the breast: results of a decade of cooperative investigation.Ann Surg. 1968; 168: 337-356Google Scholar Although the overall results were negative, the study did demonstrate a benefit in premenopausal women, especially those with nodal involvement. Henceforth began a race to eliminate clinically occult metastases and improve cure rates. This ambitious but worthy goal at times led to massive overtreatment, as was the case with myeloablative chemotherapy followed by autologous stem-cell rescue. Fortunately, major strides in molecular subtyping of breast cancer have substantially improved our ability to assess risk of disease recurrence, develop and use safer and more effective targeted therapies, and move towards an era of biologically rational treatment recommendations. Recent results from TAILORx represent a milestone achievement in reducing unnecessary exposure to cytotoxic chemotherapy in those who will be unlikely to derive benefit,2Sparano JA Gray RJ Makower DF et al.Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer.N Engl J Med. 2018; 379: 111-121Google Scholar marking the entry into an era of de-escalation, where treatment is customised to a patient's risk to avoid overtreatment. So how are we to assimilate information from the meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) in The Lancet,3Early Breast Cancer Trialists' Collaborative Group (EBCTCG)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; (published online Feb 7.)http://dx.doi.org/10.1016/S0140-6736(18)33137-4Google Scholar which seemingly contradicts this "less is more" approach, with its results demonstrating, rather convincingly, that increasing the dose intensity of adjuvant chemotherapy will benefit patients? Two theories provide a rationale for dose intensification. The Goldie-Coldman hypothesis predicts that development of chemotherapy-resistant tumour clones could be prevented by use of dose-intense alternating drugs.4Coldman AJ Goldie JH Impact of dose-intense chemotherapy on the development of permanent drug resistance.Semin Oncol. 1987; 14: 29-33Google Scholar The Norton-Simon hypothesis, based on Gompertzian kinetics, predicts that smaller tumours grow more rapidly than larger tumours.5Norton L A Gompertzian model of human breast cancer growth.Cancer Res. 1988; 48: 7067-7071Google Scholar, 6Simon R Norton L The Norton-Simon hypothesis: designing more effective and less toxic chemotherapeutic regimens.Nat Clin Pract Oncol. 2006; 3: 406-407Google Scholar As chemotherapy shrinks the tumour, an increase in growth between cycles occurs; thus, shorter intervals between each cycle should be more effective. These theories led to the development of multiple trials starting in the 1990s to test whether increasing the intensity of curative-intent chemotherapy by reducing the intervals between cycles, or by treating with drugs sequentially at full dose rather than concurrently at reduced doses, improves outcomes. Although some trials showed significant benefit with dose intensity,7Citron ML Berry DA Cirrincione C et al.Randomised trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741.J Clin Oncol. 2003; 21: 1431-1439Google Scholar, 8Del Mastro L De Placido S Bruzzi P et al.Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2×2 factorial, randomised phase 3 trial.Lancet. 2015; 385: 1863-1872Google Scholar, 9Burnell M Levine MN Chapman JA et al.Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer.J Clin Oncol. 2010; 28: 77-82Google Scholar others did not meet statistical significance, possibly because of underpowering. In the EBCTCG's meta-analysis3Early Breast Cancer Trialists' Collaborative Group (EBCTCG)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; (published online Feb 7.)http://dx.doi.org/10.1016/S0140-6736(18)33137-4Google Scholar of trials comparing 2-weekly dose-dense versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy, the primary outcomes were recurrence and breast cancer mortality. With the inclusion of 37 298 patients treated in 26 trials and with a median follow-up of 7·4 years, the EBCTCG meta-analysis3Early Breast Cancer Trialists' Collaborative Group (EBCTCG)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; (published online Feb 7.)http://dx.doi.org/10.1016/S0140-6736(18)33137-4Google Scholar showed a significant 3·4% absolute reduction (14% relative risk reduction) in breast cancer recurrences with dose intensification versus with standard-schedule chemotherapy (28·0% vs 31·4%, first-event rate ratio [RR] 0·86 [95% CI 0·82–0·89], p<0·0001). Additionally, the absolute 10-year breast cancer mortality was improved by 2·4% (18·9% vs 21·3%, RR 0·87 [95% CI 0·83–0·92], p<0·0001) and all-cause mortality was decreased by 2·7% (both with 13% relative risk reduction). Notably, patients included in this analysis had higher-risk disease as more than three-quarters had lymph-node-positive disease. Reassuringly, death without recurrence was similar when comparing the two treatment approaches. Although these results are meaningful, several limitations should be recognised as we translate these findings into practice. First, the benefits of dose intensification have not been established in the era of targeted therapy. Given that these studies enrolled women from 1985 to 2011, HER2 status was only known for 50% of tumours. Of those tested, 16% (n=2994) were HER2 positive. Use of trastuzumab was not reported but was probably uncommon since adjuvant trastuzumab was not approved until 2006. The remaining 18 625 patients did not have HER2 testing; thus, no HER2-directed therapy would have been given. Therefore, the majority of patients with HER2-positive breast cancer did not receive targeted therapy. Although the authors report that women with HER2-positive and HER2-negative disease benefit similarly from dose intensification, it is impossible to know whether dose intensification benefits trastuzumab-treated patients or those who receive more than one HER2-targeted therapy (pertuzumab, neratinib, or trastuzumab-emtansine). Similarly, if other targeted therapies such as CDK4/6 inhibitors and PARP inhibitors show significant benefit in the curative setting for high-risk oestrogen receptor (ER)-positive or BRCA-mutated breast cancer, prospective studies will be required to establish whether dose-intensive chemotherapy is better than standard chemotherapy in those settings. Second, it is premature to conclude that patients older than 70 years or those with node-negative disease benefit from dose intensification, given the small number of patients in those groups and the fact that no significant benefit was observed for these patients. Moreover, gene-expression profiling was not used in these studies; thus, the benefit, if any, of a dose-intense approach for women with lymph-node-negative, high-risk, ER-positive disease is impossible to know. Finally, the use of dose intensification has not been studied in non-anthracycline, taxane-based regimens, which are being increasingly evaluated and used in women with node-negative, ER-positive disease.10Jones S Holmes FA O'Shaughnessy J et al.Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735.J Clin Oncol. 2009; 27: 1177-1183Google Scholar, 11Ejlertsen B Tuxen MK Jakobsen EH et al.Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial.J Clin Oncol. 2017; 35: 2639-2646Google Scholar, 12Harbeck N Gluz O Clemens M et al.Prospective WSG phase III PlanB trial: final analysis of adjuvant 4×EC→4× doc vs. 6× docetaxel/cyclophosphamide in patients with high clinical risk and intermediate-to-high genomic risk HER2-negative, early breast cancer.J Clin Oncol. 2017; 35: 504Google Scholar, 13Blum JL Flynn PJ Yothers G et al.Anthracyclines in early breast cancer: the ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology).J Clin Oncol. 2017; 35: 2647-2655Google Scholar With these caveats in mind, the results of this meta-analysis are undoubtedly clinically important. In modern practice, if anthracycline-based chemotherapy is warranted, these data provide convincing evidence that a dose-intense approach should be considered. The data are strongest in node-positive disease but should be applied with caution in women with node-negative disease, in elderly patients, and in those with HER2-positive disease. As chemotherapy regimens continue to evolve and new targeted therapies enter the curative scene, prospective studies will be warranted to validate the dose-intense approach in these settings. I have received research funding paid to my institution and fees for abstract and manuscript writing from Ambrx, Amgen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Genentech/Roche, Immunomedics, Lilly, Macrogenics, Medivation, Merrimack, Novartis, Pfizer, OBI Pharma, Pieris, PUMA, and Seattle Genetics, outside of the submitted work. 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 trialsIncreasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes. Full-Text PDF Open Access