Adjuvant Docetaxel for High-Risk, Node-Negative Breast Cancer — NEJM

Original Article
Adjuvant Docetaxel for High-Risk, Node-Negative Breast Cancer

Miguel Martín, M.D., Ph.D., Miguel A. Seguí, M.D., Antonio Antón, M.D., Ph.D., Amparo Ruiz, M.D., Manuel Ramos, M.D., Encarna Adrover, M.D., Ignacio Aranda, M.D., Alvaro Rodríguez-Lescure, M.D., Ph.D., Regina Große, M.D., Lourdes Calvo, M.D., Agustí Barnadas, M.D., Ph.D., Dolores Isla, M.D., Ph.D., Purificación Martinez del Prado, M.D., Manuel Ruiz Borrego, M.D., Jerzy Zaluski, M.D., Angels Arcusa, M.D., Montserrat Muñoz, M.D., José M. López Vega, M.D., Ph.D., José R. Mel, M.D., Ph.D., Blanca Munarriz, M.D., Ph.D., Cristina Llorca, M.D., Ph.D., Carlos Jara, M.D., Ph.D., Emilio Alba, M.D., Ph.D., Jesús Florián, M.D., Junfang Li, Ph.D., José A. López García-Asenjo, M.D., Amparo Sáez, M.D., María José Rios, M.D., Sergio Almenar, M.D., Gloria Peiró, M.D., and Ana Lluch, M.D., Ph.D. for the GEICAM 9805 Investigators

N Engl J Med 2010; 363:2200-2210December 2, 2010

The survival benefits of adjuvant chemotherapy for patients with early-stage breast cancer are well established. The 15-year survival results from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG)1 showed that a combined chemotherapy regimen of cyclophosphamide, methotrexate, and fluorouracil (CMF) reduces annual recurrence and death rates, a benefit that is largely independent of tamoxifen use or nonuse, estrogen-receptor status, nodal status, and other tumor characteristics.1 This meta-analysis also showed that anthracycline-based regimens offer an additional advantage over CMF.

More recent studies and several other meta-analyses of randomized trials have shown that adding a taxane to anthracycline-based adjuvant therapy reduces the risk of recurrence and improves survival in patients with node-positive breast cancer.2-8 In the Breast Cancer International Research Group (BCIRG) 001 trial (ClinicalTrials.gov number, NCT00688740), which compared the effects of a regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC) with those of a regimen of fluorouracil, doxorubicin, and cyclophosphamide (FAC), the risk of recurrence for the TAC group was reduced by 28%, and the risk of death by 30%.2

Most taxane trials have focused on patients with axillary-lymph-node–positive breast cancer, although a small number of trials have involved both patients with node-positive disease and those with node-negative disease.9-11 Although some current estimates show that a majority of patients with operable breast cancer have node-negative disease at diagnosis,12 there is little guidance about taxane use in patients with node-negative disease. Consequently, the role of these agents in the treatment of patients with node-negative disease remains undefined.

Adjuvant chemotherapy with anthracyclines improves survival among patients with node-negative, early-stage breast cancer.1 A planned subgroup analysis of patients with node-negative breast cancer from the Spanish Breast Cancer Research Group (GEICAM) trial 8701 showed that adjuvant FAC improves disease-free survival and overall survival as compared with CMF.13 However, more than 25% of node-negative patients treated with FAC had recurrent disease at 10 years. Consequently, in 1998, the GEICAM 9805 trial was initiated to compare the effects of FAC with TAC in patients with high-risk, node-negative breast cancer as defined according to the St. Gallen criteria (for details see the Supplementary Appendix, available with the full text of this article at NEJM.org).14 The results of this trial regarding toxicity and health-related quality of life have been reported previously.15 This report describes disease-free survival, overall survival, and toxicity at a median follow-up of 77 months.

Methods
Study Design and Oversight

This was a phase 3, open-label, randomized study comparing TAC with FAC as adjuvant therapy for patients with high-risk, node-negative breast cancer. The study was performed in accordance with the Declaration of Helsinki and was approved by the ethics committees and health authorities at participating institutions in Spain, Germany, and Poland. All patients provided written informed consent before entering the study.

Details of the study design have been reported previously.15 The primary end point was disease-free survival, defined as the interval from the date of randomization to the date of local, regional, or metastatic relapse; diagnosis of a second primary cancer; or death from any cause, whichever occurred first. A second primary cancer was defined as another type of invasive cancer, as determined on the basis of histopathological findings, including a second invasive primary breast cancer in the ipsilateral or contralateral breast but excluding nonmelanoma skin cancer and in situ carcinoma of the cervix or breast. Secondary end points included overall survival, measured from the date of randomization to the date of death from any cause, and toxic effects. Disease-free survival was also assessed in subgroups defined on the basis of hormone-receptor status and human epidermal growth factor receptor type 2 (HER2) status.

The trial was sponsored by GEICAM and Sanofi-Aventis. The original study protocol was designed by the first author and is available at NEJM.org. Data collection, data maintenance, and statistical analyses were conducted by Sanofi-Aventis and Pivotal, a contract research organization in Madrid. The first author prepared the first draft of the manuscript — with assistance from a medical writer who was funded by Sanofi-Aventis — and made the decision to submit the manuscript for publication. Sanofi-Aventis reviewed an earlier version of the manuscript, but the final content was determined and approved by all authors.
Patients

Eligible women were 18 to 70 years of age, had undergone primary surgery for unilateral operable breast carcinoma (tumor stage T1, T2, or T3), and had negative axillary lymph nodes (≥10 nodes examined). Patients were also required to meet one or more of the high-risk criteria described in the 1998 St. Gallen consensus recommendations for patients with operable node-negative breast cancer (tumor size >2 cm, negative results on tests for expression of estrogen receptor and progesterone receptor, tumor histologic grade 2 or 3, or age <35 years).14 Patients underwent randomization within 60 days after surgery to receive TAC or FAC according to a center-specific randomization block. Randomization was centralized and stratified for the participating institution and for menopausal status. Treatment On day 1 of each of six 21-day treatment cycles, patients received an intravenous infusion of either TAC (75 mg of docetaxel per square meter of body-surface area, 50 mg of doxorubicin per square meter, and 500 mg of cyclophosphamide per square meter) or FAC (500 mg of fluorouracil per square meter, 50 mg of doxorubicin per square meter, and 500 mg of cyclophosphamide per square meter). To prevent edema, patients in the TAC group were given a standard dose of dexamethasone before receiving the study treatment. Primary prophylactic antibiotic therapy (consisting of 500 mg of ciprofloxacin twice daily on days 5 through 14 of each cycle) was mandatory during all cycles for patients receiving TAC. Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was not permitted in the original protocol. Owing to an incidence of neutropenic fever of more than 25% in the TAC group, the protocol was amended after 230 patients had been enrolled to permit primary prophylaxis with G-CSF for all subsequently enrolled patients receiving TAC.15 Any patient in the FAC group who had an episode of febrile neutropenia or infection was given prophylactic antibiotics and G-CSF for all cycles. Hormone-receptor status was assessed for the primary tumor at local laboratories before randomization. After the last cycle of chemotherapy, patients with hormone-receptor–positive tumors received tamoxifen (20 mg daily for 5 years). After completion of chemotherapy, radiation therapy was mandatory for patients who had undergone lumpectomy, and it was allowed for those who had undergone mastectomy, depending on the guidelines at each participating institution for the treatment of patients with large tumors (>5 cm).

Assessments

Baseline assessments (bilateral mammography, chest radiography, electrocardiography, abdominal ultrasonography or computed tomography, bone scanning, and bone radiography in the case of suspicious lesions on the bone scan) were performed a maximum of 12 weeks before enrollment (20 weeks for mammography). Hematologic and biochemical assessments were performed a maximum of 14 days before enrollment, and a pregnancy test (for fertile women) was performed a maximum of 7 days before enrollment.

Toxic effects were assessed before each chemotherapy cycle and were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf) or with the use of the Coding Symbols for a Thesaurus of Adverse Reaction Terms. Follow-up visits took place every 3 months during the first 2 years, every 6 months during years 3 through 5, and annually during years 6 through 10. Chest radiography and mammography were performed yearly during the first 5 years of follow-up.

Paraffin-embedded tumor samples obtained at the time of surgery were processed centrally (for details, see the Supplementary Appendix). Hormone-receptor status was evaluated with the use of immunohistochemical analysis for progesterone and estrogen receptors and the semiquantitative 8-point score developed by Allred et al.16 Tumors were considered to be positive for the expression of hormone receptor if they were positive for either estrogen receptor or progesterone receptor.

HER2 protein expression was scored centrally according to the guidelines for HER2 staining17 (tumors with a score of 0 or 1+ were considered to be negative and those with a score of 3+ were considered to be positive). Fluorescence in situ hybridization for HER2 was performed for all tissue samples with a score of 2+ or higher. Assessment for the expression of HER2 and chromosome 17 was performed, and the ratio of HER2 to chromosome 17 signaling was established for scoring. The American Society of Clinical Oncology–College of American Pathologists (ASCO–CAP) guidelines for HER2 testing in breast cancer were followed, with HER2 amplification defined as a ratio of HER2 to chromosome 17 signaling that was more than 2.2.17 The final score for each tumor sample was the mean score for two cores from each specimen.
Statistical Analysis

The planned primary analysis of survival was performed when at least 5 years of follow-up had been completed for all patients who were alive. The trial was designed to have an overall power of 90% to detect an increase of 7.5 percentage points in disease-free survival at 5 years, from an estimated 80.0% for patients treated with FAC to 87.5% for those treated with TAC. A sample of 1022 patients who could be evaluated (511 per group) was required to detect this difference at the 5% significance level. To account for an anticipated ineligibility rate of 3%, at least 527 patients were to be recruited into each group.

The primary analysis was performed for the intention-to-treat population, whereas the safety analysis was performed for all patients who received one or more infusions of the study treatment. The Kaplan–Meier product-limit method was used to estimate disease-free survival and overall survival, and the unstratified log-rank test was used to compare treatment groups. Confidence intervals were calculated with the use of Greenwood's method. A Cox proportional-hazards model was used to estimate survival, with adjustment for major prognostic factors, including age, menopausal status, type of surgery, histopathological features, hormone-receptor status, HER2 status, and tumor size. The interaction between treatment and major prognostic factors was tested at a significance level of 0.10. Hypothesis testing was two-sided at a significance level of 0.05.


FULL-TEXT:
Adjuvant Docetaxel for High-Risk, Node-Negative Breast Cancer — NEJM

Address reprint requests to Dr. Martín at Servicio de Oncologia Medica, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Dr Esquerdo 46, Madrid 28007, Spain, or at mmartin@geicam.org.



GINECOLOGÍA
Actualidad Ultimas noticias - JANOes
Crean un nuevo estándar de tratamiento para el cáncer de mama en fase inicial
JANO.es · 03 Diciembre 2010 00:04



Una investigación prueba que la quimioterapia con docetaxel reduce en un 32% el riesgo de recaída tras la cirugía en mujeres con un tumor de mama detectado en fase precoz.

La oncología española ha establecido un nuevo estándar de tratamiento para el cáncer de mama en estadios iniciales, gracias a los resultados de un estudio de la Fundación Grupo Español de Investigación en Cáncer de Mama (GEICAM).

Más de 1.000 pacientes y 50 hospitales españoles han participado en este trabajo cuyos resultados se publican en The New England Journal of Medicine. La investigación prueba que la quimioterapia con docetaxel reduce en un 32% el riesgo de recaída tras la cirugía en mujeres con un tumor de mama detectado en fase precoz, cuando el cáncer aún no se ha extendido a los ganglios linfáticos (sin afectación axilar o ganglios negativos).

"Este trabajo marca un hito en la investigación del cáncer de mama en nuestro país y pone de relieve el alto nivel de la oncología española. Por primera vez un estudio español, realizado por un grupo de investigación independiente y con pacientes españolas, ha establecido un nuevo estándar en el tratamiento de este tumor en su estadio más inicial", ha indicado el presidente de la Fundación GEICAM y jefe del Servicio de Oncología del Hospital Gregorio Marañón de Madrid, Dr. Miguel Martín.

A cerca del 70% de las pacientes se les diagnostica la enfermedad en estadio inicial y, según el Dr. Martín, este nuevo tratamiento es efectivo y consigue curar "a más de un 6% adicional de pacientes", lo que, en términos absolutos, son más de 800 mujeres al año adicionales que se curarían con esta nueva terapia.


New England Journal of Medicine 2010;363:2200-2210
Adjuvant Docetaxel for High-Risk, Node-Negative Breast Cancer — NEJM

GEICAM
GEICAM - Grupo Español de Investigación en Cáncer de Mama

Actualidad Ultimas noticias - JANOes - Crean un nuevo estandar de tratamiento para el cancer de mama en fase inicial - JANO.es - ELSEVIER