Significant improvements in disease free survival reported in women with breast cancer

December 12, 2002

San Antonio, 12 December 2002 - New data from a large phase III study of 2005 women with node-positive breast cancer show that when Taxol® (paclitaxel) (T) is given with standard chemotherapy, doxorubicin (A) and cyclophosphamide (C), in a 2-weekly dose-dense regimen the rate of recurrence is significantly reduced by 26% (p=0.010) and the rate of death is reduced by 31% (p=0.013), compared to standard 3-weekly administration, with an acceptable toxicity profile. The results of the study are reported for the first time at the 25th Annual San Antonio Breast Cancer Symposium, 9-14 December 2002, USA.

"Chemotherapy treatment is very difficult for patients, both physically and mentally. To be able to complete adjuvant treatment faster with the hope for better long-term survival is a huge boost for breast cancer patients," said Dr Marc Citron, Clinical Professor of Medicine Albert Einstein College of Medicine, New York, NY, the principal investigator of the study. "The dose-dense treatment approach used in this study allows patients to receive their chemotherapy doses on time, giving them the best opportunity to recover and continue with their everyday lives."

Based on positive results from previous studies (CALGB 9344, Hudis et al) , AC plus Taxol® became standard adjuvant therapy in the USA and investigators of CALGB 9741 used this foundation to determine if additional improvements in treatment outcome could be gained through varying the schedule and dose-density of Taxol®. CALGB 9741 was designed to compare concurrent AC-T vs sequential A-C-T either in a 2-weekly dose-dense schedule or in a 3-weekly conventional schedule in women with axillary node-positive operable breast cancer. The cumulative dose of treatment in each of the arms was identical, Taxol® (175mg/m2), doxorubicin (60mg/m2) and cyclophosphamide (600mg/m2).

2005 patients were randomized into four study arms and received either A-C-T for 36 weeks (arm 1); A-C-T for 24 weeks (arm 2); AC-T for 24 weeks (arm 3); AC-T for 16 weeks (arm 4).

In addition, all patients receiving chemotherapy in the dose-dense arms (arms 2 and 4) received Neupogen® (filgrastim) prophylactically to boost their production of infection-fighting white blood cells. Researchers found that the women in the dose-dense arms of the study who were given Neupogen were less prone to infection than those who did not receive Neupogen.

Grade 4 granulocytopenia (<500>After 36 months of median follow-up, the primary endpoint of disease-free survival favored the dose-dense regimens (arms 2 and 4) with a 26% proportional reduction in risk of recurrence (p=0.010). Disease-free survival at 4 years was 82% for the dose dense regimens, compared to 75% for conventional 3-weekly therapy. Similar impressive results were seen in the secondary endpoint of overall survival with a 31% proportional reduction in mortality (p=0.013) with dose-dense therapy, and 4-year overall survival of 92% versus 90% with conventional therapy.

"We are both excited and encouraged by these results," said Richard L Schilsky, MD, University of Chicago Cancer Center and Chairman of the CALGB. "There has been a compelling theoretical rationale for dose-dense scheduling of chemotherapy, and now we are beginning to see the benefits of this approach in the clinic."

Whether the treatment was administered concurrently (combination therapy AC-T) or sequentially (single agents A-C-T) made no difference to disease-free survival (p=0.58) or overall survival (p=0.48), only dose-density made an impact. In addition, the duration of dose-dense treatment of 16 weeks (compared to 24 to 36 weeks in the 3-weekly arms) was more convenient for patients with no loss in survival gain.

Dr Larry Norton, Head of Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, USA, a pioneer in investigating the importance of dose-density and scheduling, is interested in how the patient may benefit from these results. "Breast cancer is a common disease and adjuvant chemotherapy has already demonstrated a positive impact on reducing recurrences and saving lives. In my view these data strongly suggest that the use of dose-dense chemotherapy with standard agents including paclitaxel may significantly improve the life-saving impact of treatment. In addition, the dose-dense treatment is less toxic and completed in one- third less time, which should have a positive effect on the quality of life during therapy. This is a major step forward toward the total control of this potentially devastating disease."

The Cancer and Leukemia Group B is an NCI-sponsored cooperative group of 250 institutions and more than 3000 oncology specialists that conducts cancer clinical trials in breast cancer, lung cancer, GI cancer, GU cancer, leukemia, lymphoma and melanoma. About 3500 patients are enrolled each year on 100 active protocols that address novel cancer treatment strategies, assess health-related quality of life and examine relationships between the molecular feature of tumors and treatment outcomes.
-end-
Richard L. Schilsky, M.D. Chairman

For further information, or to interview a range of clinicians please contact: Dr Marc Citron or Dr Larry Norton on: 773-702-9171

Visit the CALGB website at: http://www.calgb.org/

Editor's notes
  • Taxol® (paclitaxel) in Europe is indicated for the treatment of ovarian, breast, and non-small cell lung cancer. In the US Taxol® is indicated for the adjuvant treatment of breast cancer with doxorubicin and cyclophosphamide.
  • Produced by recombinant DNA technology, Neupogen® (Filgrastim) is a protein that stimulates neutrophil production in the bone marrow and accelerates the recovery of neutrophil counts following chemotherapy. Neupogen is prescribed to reduce the risk of infection (initially marked by fever) in patients with some tumors receiving chemotherapy that may decrease the number of infection-fighting white blood cells. Neupogen has been shown to reduce the risk of hospitalization due to infection, the days of intravenous antibiotic treatment, and the episodes of fever.
  • According to the World Health Organisation more than 1.2 million women will be diagnosed with breast cancer this year worldwide. In Europe 236,000 women will be diagnosed with breast cancer and nearly 100,000 will die from the disease, the majority from metastatic spread of the disease. The earlier it is detected the better the prognosis for survival, but unfortunately only 16% of women with MBC usually survive longer than 5 years .
  • The Importance of Dose-Dense Scheduling on Targeting Cell Death
    The majority of chemotherapy agents target a certain phase of a cell's cycle and eventually the rate of cell death reaches a plateau. More frequent exposure to chemotherapy could result in a delay in tumor regrowth between cycles and limit proliferation of tumor cells that are resistant to chemotherapy.
  • The advantage to the patient is that dose-dense adjuvant treatment can be given over a shorter period of time, there is improved convenience due to the ease of administration as an outpatient, good tolerance and reduced toxicity.

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