Dose-Dense Chemotherapy for Premenopausal Breast Cancer Improves Survival

Multiple research studies demonstrate effectiveness of dose dense chemotherapy treatment for early stage breast cancer.

Dose-Dense Chemotherapy for Premenopausal Breast Cancer Improves Survival

by Dr. C.H. Weaver M.D. updated 10/2018

Premenopausal women who have been diagnosed with breast cancer have improved survival if their chemotherapy doses are delivered every two weeks, compared to every three weeks. Dose-dense chemotherapy (chemotherapy with a shortened interval between doses), has demonstrated improvement in outcomes compared to conventional chemotherapy in patients with high-risk, early breast cancer.

Chemotherapy following surgery is a standard treatment option for premenopausal women diagnosed with breast cancer. A standard regimen includes chemotherapy delivered every 3 weeks. The delivery of chemotherapy at closer time intervals, such as every 2 weeks, is referred to as “dose-dense.”

Premenopausal women with breast cancer are unique in several ways when compared to the majority of breast cancer cases, which include postmenopausal women. Breast cancer in premenopausal women tends to be more aggressive than that in postmenopausal women. In addition, treatment may cause ovarian suppression, leading to a type of early menopause. In turn, this early menopause is associated with a reduced quality of life due to side effects such as hot flashes, sweats, breast pain or sensitivity, vaginal dryness, vaginal discharge, lack of sexual desire, and weight gain. Importantly, treatment for breast cancer in premenopausal women may cause infertility, a highly emotional issue for many patients.

Different therapeutic strategies for premenopausal women with breast cancer continue to be explored to determine which treatments can achieve optimal survival rates, while minimizing associated side effects.

Researchers from Europe recently conducted a meta-analysis from two large phase III clinical trials comparing dose-dense chemotherapy (every 2 weeks) to standard delivery of chemotherapy (every 3 weeks) to treat premenopausal women with breast cancer.

The two trials, referred to as the MIGI and GIM2 studies included 3,305 premenopausal patients with breast cancer that had spread to their lymph nodes, or who were otherwise at a high risk of developing a cancer recurrence. The average patient age was 44 years.

  • Overall survival was improved by nearly 30% among the women treated with dose-dense chemotherapy compared to those treated with standard-dose chemotherapy.
  • At 10 years, survival for women with hormone-negative breast cancer (cancer that is not stimulated to grow from exposure to female hormones) was improved by 35% among those treated with dose-dense chemotherapy, compared to those treated with standard-dose chemotherapy.
  • At 10 years, survival for women with hormone-positive breast cancer (cancer that is stimulated to grow from exposure to female hormones) had a 22% increase in survival if treated with dose-dense chemotherapy versus standard-dose chemotherapy.
  • Importantly, dose-dense chemotherapy was not associated with an increased risk of developing amenorrhea (early menopause) from treatment.
  • The development of amenorrhea was not significantly associated with improved survival; however, there was a trend of increased survival among women with hormone-positive breast cancer and the development of amenorrhea.

Follow-up Data on Dose-dense Chemotherapy Confirm Benefit in Early Breast Cancer

Researchers in Germany conducted a Phase III clinical trial in 1,284 patients under the age of 65 who had at least four involved axillary (underarm) lymph nodes. Patients were assigned to receive either dose-dense or conventional chemotherapy with epirubicin, cyclophosphamide, and paclitaxel.

  • At five years relapse-free survival was 70% in the dose-dense arm, compared with 62% in the conventional-dose arm.
  • At five years overall survival was 82% in the dose-dense arm and 77% in the conventional-dose arm.
  • Quality of life declined during dose-dense therapy, but was recovered three months following completion of therapy.
  • 7% of patients in the dose-dense arm were hospitalized for febrile neutropenia (a low white blood cell count accompanied by fever), compared with just 2% in the conventional-dose arm.

Dose-Dense Chemotherapy Results of The Intergroup 9741

The final report on this trial was issued after the patients had been followed for a median of 6.5 years. The Intergroup 9741 trial enrolled 2,005 women with lymph node-positive breast cancer. Patients were first randomly assigned to receive concurrent Adriamycin® (doxorubicin), Taxol® (paclitaxel), and Cytoxan® (cyclophosphamide) or concurrent Adriamycin and Cytoxan followed by Taxol. Patients then underwent a second round of randomization in order to determine whether they would receive their chemotherapy on a conventional schedule (every three weeks) or a dose-dense schedule (every two weeks).

  • Among women with hormone receptor-negative breast cancer, cancer-free survival was significantly better among those who received dose-dense chemotherapy. There was a suggestion of improvement in overall survival.
  • Among women with hormone receptor-positive breast cancer, survival was similar across treatment groups.
  • Risk of acute myeloid leukemia or myelodysplastic syndrome was similar (less than 1%) in each treatment group.
  • The dose-dense regimen did not appear to increase the risk of heart problems.

The researchers concluded that after long-term follow-up, dose-dense chemotherapy remains safe and effective as adjuvant therapy in breast cancer. The benefit, however, appears to be most substantial for patients with estrogen receptor-negative breast cancer.

A single Neulasta® Injection Allows Optimal Delivery of Dose-Dense Chemotherapy in Breast Cancer

Dose-dense therapeutic approaches are associated with a higher risk of some side effects, and dose-dense doxorubicin, cytoxan and a taxane (paclitaxel or Taxotere®) is associated with a higher risk of neutropenia which can lead to life threatening infections and prevent the optimal delivery of the chemotherapy.

Neutropenia occurs when white blood cells (immune cells) are destroyed by chemotherapy, leaving the immune system unable to fight bacterial, viral and fungal infections. Chemotherapy-induced neutropenia can become a serious condition for several reasons. First, many patients who develop neutropenia require a dose reduction in their treatment, which can compromise delivery of treatment and reduce survival rates. In order to achieve optimal outcomes, it is important that patients receive their planned doses of the chemotherapy drug(s) at the planned time. In addition, patients who develop neutropenia may require hospitalization and even minor infections can become life threatening. Therefore, it is imperative during dose-dense therapy that protective measures against neutropenia are taken so that patients are able to receive optimal chemotherapy.

Neupogen® and Neulasta® are referred to as growth factors and they stimulate the production of white blood cells. Clinical studies have indicated that early treatment with growth factors such as Neulasta® or Neupogen® prevents neutropenia, thereby allowing patients to receive their planned dose of chemotherapy on time. Neulasta® requires administration only once during a chemotherapy cycle, whereas Neupogen® requires daily injections. Clinical trials have indicated that Neulasta® is as effective as Neupogen® in reducing the incidence and/or severity of neutropenia in patients undergoing treatment for cancer and further trials are being conducted to determine the true clinical efficacy of treatment with Neulasta®. Many researchers believe that Neulasta® should replace Neupogen® for the prevention and/or treatment of neutropenia.

The results from a clinical trial that included 73 patients treated with dose-dense chemotherapy for breast cancer who received Neulasta® once per chemotherapy cycle prevented the development of febrile neutropenia (neutropenia accompanied by fever) and kept all patients out of the hospital for complications associated with neutropenia. Only 10% of patients developed severe neutropenia (Grades 3-4). When referencing these results to previous trials utilizing Neupogen® for the same treatment regimens, Neulasta® demonstrated just as effective prevention against neutropenia. Importantly for patients, Neulasta was administered with 1 injection compared to over 2 weeks of daily injections for Neupogen.

Neulasta® is as effective as Neupogen® in preventing neutropenia associated with dose-dense regimens for the treatment of breast cancer. Since chemotherapy-induced neutropenia is a common and serious side effect of most dose-dense chemotherapy regimens, Neulasta® may play an integral part in allowing patients to tolerate therapy and ultimately, providing patients with an optimal long-term outcomes. Patients with breast cancer who are to undergo dose-dense therapy may wish to speak with their physician regarding the addition of Neulasta® in their treatment regimen.

References:

  1. Citron ML, Berry DA, Cirrincione C, Hudis C, et al. Randomized 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. Journal of Clinical Oncology 2003; 21: 1-9.
  2. Hudis C, Citron M, Berry D, et al. Five year follow-up of INT C9741: dose-dense (DD) chemotherapy (CRx) is safe and effective. Proceedings from the 28th San Antonio Breast Cancer Symposium. December 2005. Abstract #41.
  3. Venturini M, Del Mastro L, Aitini E et al. Dose-Dense Adjuvant Chemotherapy in Early Breast Cancer Patients: Results From a Randomized Trial. Journal of the National Cancer Institute. 2005;97:1724-33.
  4. Kummel S, Krocker J, Kohls A et al. Randomised Trial: Survival Benefit and Safety of Adjuvant Dose-Dense Chemotherapy for Node-Positive Breast Cancer. British Journal of Cancer. April 11, 2006. Early Online Publication.
  5. Moebus V, Leuck H, Thomssen C, et al. Dose-dense sequential chemotherapy with epirubicin, paclitaxel and cyclophosphamide in comparison to conventional dosed chemotherapy in high-risk breast cancer patients ³4+LN), mature results of an AGO-trial. Proceedings from the 2006 San Antonio Breast Cancer Symposium. Oral presentation December 17 2006. Abstract# 53.
  6. Lambertini M, et al. Dose-dense adjuvant chemotherapy, treatment-induced amenorrhea and overall survival in premenopausal breast cancer patients: a pooled analysis of the MIG1 and GIM2 phase III studies. Oral Abstract session at the 10th annual European Breast Cancer Conference. 2016; Abstract 5. Available at: . Accessed March 15, 2016.
  7. Schwartzberg L, Henry D, Sabbath K, et al. Randomized comparison of early vs. standard intervention with darbepoetin alfa for chemotherapy-induced anemia in early-stage breast cancer. Proceedings from the 2006 annual San Antonio Breast Cancer Symposium. December 2006. Abstract #6079.
  8. Schwartzberg LS, Tauer KT, Barry FV. Dose-dense chemotherapy (DDC) supported by pegfilgrastim (Peg) and an erythropoietic agent (EA) in operable breast cancer. Proceedings from the 27th annual San Antonio Breast Cancer Symposium (SABCS). December 2004. Abstract #6035.

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