CUBAN MEDICAL RESEARCH

Chemotherapy in Breast Cancer in Cuba
Dr. Ana Victoria de la Torre Santos, Second Degree Specialist in Oncology

Breast cancer is the most frequent malignant neoplasia in Cuba’s female population. It also tops the list of cancer mortality in women and, without doubt, is a health problem for our population. (1)

Important efforts have been made in the field of early diagnosis by means of the National Breast Cancer Control Program, which is based on complete coverage of our population by the family doctor and nurse. Active screening is achieved through physical examination and mammography, along with training to perform breast self-examination. This program also considers surgical, clinical and radiant treatment, as well as rehabilitation and palliative care for breast cancer patients.

The development of Public Health Care in our country, and accessibility of medical services everywhere on the Island, have led to the proliferation of assistance groups for breast cancer patients. It was necessary for the National Institute of Oncology and the National Group to produce guidebooks on unified treatment criteria for all multidisciplinary groups working in the country. The first guidebooks were published in 1978, and were entitled Technological Therapeutic Models. Later, in 1987, the Therapeutic Oncology Norms (TON) (2) were published, and from then on Cuban Oncology Guidebooks (3) have been compiled as a result of joint meetings of experts from the main hospitals involved in Cancer care.

In spite of the effects caused by the blockade upon our health care system, a lot has been done to improve technology necessary for pre-clinical diagnosis, and new drugs have been incorporated to our therapeutic arsenal, along with the introduction of new radiotherapy equipment.

To insure that the entire population has access to all these advances, it was necessary to create referential centers to assist patients by geographical regions. These centers are nothing more than hospitals equipped with human and material resources specialized in the treatment of cancer which receive patients seeking more specific treatment. For example, the “Celestino Hernandez Robau” Hospital in Santa Clara, Province of Villa Clara, admits oncology patients from the three central provinces for radiotherapy and certain clinical treatment with the latest cytostatic drugs, hormone management, and active and passive immunotherapy. The latter is performed through Clinical Trials. This allows each and every Cuban citizen, regardless of where they live, access to all resources that contribute to adequate medical care with the required treatment, free of charge.

Breast cancer continues to be one of the diseases most studied and discussed due to its high incidence and mortality, and to the traumatic effect both surgical and chemotherapeutic treatment cause in women’s looks. It is, without doubt, one of the neoplasias in which more has been achieved in terms of therapy, early diagnosis, and knowledge of cellular biology.

It was surgery that started the development of breast cancer treatment with Halsted´s operation in 1894, based on the local-regional concept of the disease. (4)

It was not until the 1960`s that Fisher and his collaborators put forward their theory based on better knowledge of breast cancer biology. They argue that there is micro-metastasis at the moment of diagnosis in most women with breast cancer, and for that reason it is not possible to get rid of it just by applying local-regional treatment with surgery and radiotherapy. (5)

Adjuvant chemotherapy in breast cancer started in the 1970`s. Between 1972 and 1980, Veronesi and his collaborators initiated a clinical trial by comparing Halsted’s radical mastectomy with quadrantectomy plus radiotherapy in women with tumors smaller than 2 cm and clinically negative ganglia. Adjuvant chemotherapy with CMF was applied on women with metastatic axillary ganglia as adjuvant treatment. This trial reported identical survival for both groups. Between 1985 and 1988 trials (Milan II and III) were continued to compare quadrantectomy with lumpectomy, both with axillary removal and radiotherapy; and the Milan III trial to compare quadrantectomy plus axillary removal with and without radiotherapy. Results were published in 1992 with an increase in recurrence for the group without radiotherapy, showing no differences with Halsted´s radical surgery after a 19-year follow-up. (6)

The appearance of anthracyclins in 1980 caused an important turn in cytostatic treatment. A decade later, the development of taxanes (paclitaxel and docetaxel) has created new hope in treating metastatic diseases as neo-adjuvant, and presently as adjuvant treatment. The first stage-II trials were conducted as unique agents in metastasic disease with response rates ranging from 25 to 60%, depending on the dosage. The effect was higher in those patients who had used anthracyclins when the taxanes were compared with the CMF plan as treatment for metastatic disease. (7,8)

Some other drugs have joined taxanes to increase response rates. Such is the case of docetaxel plus capacitabine for metastasic disease, or docetaxel plus adriamycin and cyclophfosphamide (TAC) as adjuvants, resulting in higher response rates.

Immunotherapy with monoclonals as trastuzumab in women with HER-2/neo-positive, alone or together with chemotherapy and new drugs for hormone management, has opened new horizons in breast cancer treatment. Hormone therapy is applied on women with positive estrogen receptors. Tamoxifen is unquestionably the most commonly used and best studied drug (9,10). New hormone treatments have been developed with the use of aromatasa and LH-RH agonist inhibitor. First results which are now being published do not demonstrate its superiority. A panel of experts recommended at ASCO 2003 to keep on using tamoxifen as standard treatment for positive estrogen receptor post-menopause women, and to use anastrozole only in case of intolerance or contraindication. (11,12)

Chemotherapy is used in several breast cancer situations:

Adjuvant treatment: after surgery, so as to eliminate possible micro-metastasis in women with a risk of relapse.
Neo-adjuvant treatment: on patients with locally advanced tumors so as to reduce tumor size for later surgery with a chance of conservation.
Treatment for metastasic disease.

Adjuvant treatment:

It was in the 1970´s that the first data were published with adjuvant treatment results by:

The National Surgical Adjuvant Breast and Borrel Project (NSABP): They wanted to determine the efficacy of Chemotherapy with Melfalan in breast cancer for two years.

The Milan Cancer Institute: They chose the use of múltiple agents, applying the CMF poly-chemotherapy (Cyclophosphamide, Methotrexate and 5 Fluorouracil) during 12 cycles (5)

Both studies were applied on women with positive ganglia, and even though their results were very controversial, they launched chemotherapy as adjuvant treatment in breast cancer. Bonadonna presents in 1975 the first report on the efficacy of CMF adjuvant treatment in breast cancer. Later, in 1995, he publishes the results of a 20-year follow-up, indicating an improvement both in terms of the disease-free period and global survival, which persists along the 20 years of follow-up (13,14). Determining which group of women would benefit from adjuvant therapy is one field that has been worked on. Definitions have been made of subpopulations of women with localized breast cancer in which chemotherapy has proven to cause substantial improvement during the disease-free period and in global survival. (15)

A panel of experts meeting at the Consensus Development Conference in November, 2000, made several recommendations: poly-chemotherapy administration (two or more drugs) is better than only one drug; four to six treatment courses (3 to 6 months) are enough. Additional administration would increase toxicity; the use of anthracyclins in poly-chemotherapy plans causes slight but significant survival improvement compared to other plans not using this drug. Different studies that have been carried out have not shown that high doses (with bone marrow or peripheral stem cell transplants) are better than standard chemotherapy programs. Chemotherapy is recommended only in women under 70 years old and a tumor larger than 1 cm. Adjuvant chemotherapy can be used regardless of the state of axillary ganglia, and the women’s menopausal and estrogenic status. (16,17)

A large number of the research papers presented at the 38 th Annual Meeting of the American Society of Clinical Oncology in May this year focused on breast cancer. One of the novelties was the application of docetaxel. Nabholtz and his collaborators at the Breast Cancer International Research Group (BCIRG) reported preliminary results for this trial in which six standard cycles of CAF (cyclophosphamide and 5 fluorouracil at 500 mg/m 2 and adriamycin at 50 mg/m 2) were compared to the TAC plan (docetaxel at 75 mg/m 2, adriamycin at 50 mg/m 2 and cyclophosphamide at 500 mg/m 2) every 21 days. The study included 1491 patients with positive ganglia, 69% of which were estrogenic receptor (ER) and/or progestogenic positive (PR) receptors, and 20% were HER2/neo-positive. All of the positive ER and/or PR patients also received tamoxifen orally for 5 years. The follow-up median was 33 months. The group that received the TAC plan showed a lower number of recurrences and better global survival. The group of positive ER women benefited more in terms of the disease-free period, as well as the group of patients with one to three metastatic ganglia. The TAC plan, however, is associated with more episodes of febrile neutropenia (24% vs. 2%) and degree 3 and 4 sepsis (2.8% vs. 1.3%). No deaths were reported due to sepsis in either arm. This study proved the effectiveness of docetaxel as a component of adjuvant or neo-adjuvant treatment in high-risk patients at stage II or with locally advanced cancer. High percentages of febrile neutropenia episodes (24%) were reported, and no benefit was shown in patients with more than three metastatic ganglia. Two previous studies had failed in trying to demonstrate the benefit of using paclitaxel sequentially after cyclophosphamide plus adriamycin (trials C9344 and B30), though the first one showed some benefit in the disease-free period for negative estrogenic receptor women. (18)

It is true that in the past decade high doses of chemotherapy in women with 10 or more positive ganglia seemed to anticipate hope for a group of women whereas adjuvant therapy had not been successful. But this therapy was seriously questioned when Bezwoda’s study (19) was shown to be based on false data. High doses are presently re-evaluated in several trials both in metastasic disease and adjuvant therapy. Two of the most important trials are the CALGB-Intergroup with 783 patients, and the Dutch study of Rodenhuis with 885 patients, with a follow-up median of more than three years. Rodenhuis compares 4 FEC cycles with 5 cycles of FEC plus CTCb (carboplatin, tiotepa and cyclophosphamide) with the support of hematopoietic cells, followed by surgery, radiotherapy and tamoxifen. A preliminary analysis indicated that the disease-free interval and global survival were higher for the group of women who received high doses. (20,21)

The Cuban guidebooks consider the following prognostic and predictive factors for the selection of adjuvant treatment: age, tumor size, axillary ganglia status, histological type, status of the (RH) estrogen receptor, and the HER-2 (3) as well. They follow the risk levels for negative ganglia in accordance with the Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer held in Gallen, Switzerland, in February, 2001. (17)

Risk levels (Chemotherapy will be applied on patients with negative post-surgical ganglia pNo):

A negative ganglion is considered high risk in the following cases: Tumor size larger than 1cm, nuclear degree II-III, negative estrogenic receptor, and age under 35 years.

A negative ganglion is considered low risk in the following cases: tumor size 1cm or smaller, nuclear degree 1, positive estrogenic receptor, and older than 35 years.

Chemotherapy instructions in Cuban treatment guidebooks.

T1N0M0 and T2N0M0 for high risk:

T1N0M0:T1, tumor size 2cm or smaller in its larger dimension,. N0 (no metastasis in the ipsolateral axillary lymphatic ganglia), M0 (absence of distance metastasis).

T2N0M0 : T2 (tumor is larger than 2cm, but smaller than 5cm in its larger dimension).

For pre-menopause patients:

4 cycles of adriamycin plus cyclophosphamide (AC) preferably, or 6 cycles of cyclophosphamide, methotrexate and 5 fluorouracil (CMF).

In the presence of positive estrogenic receptor (ER), continue treatment with tamoxifen 20mg for five years.

For post-menopause patients:

6 cycles of CMF.

In the presence of positive estrogenic receptor (ER), tamoxifen 20mg a day for five years.

Pre and post menopause low-risk patients

No chemotherapy.

Use of chemotherapy for positive ganglia:

Chemotherapy should be started within the three weeks after surgery.

T2N1M0 : T2N1M0 : T2 (tumor is larger than 2cm, but smaller than 5cm in its larger dimension), N1: metastasis to mobile ipsolateral lymphatic ganglion or ganglia.

If there is 1 to 3 metastasic ganglia, four cycles of adjuvant chemotherapy with AC plus three cycles with CMF.

If there are four or more ganglia, 4 cycles of AC plus 6 cycles of CMF will be administered.

Neo-adjuvant chemotherapy:

Locally advanced cancer, stage III a -b - c and T3N0M0 (stage II b).

Stage lll a: T0N2M0; T1N2M0; T2N2M0; T3N1M0; T3N2M0.

Stage lll b: T4N0M0; T4N1M0, T4N2M0

Stage IIIC: any T, N3M0

Treatment:

4 cycles of AC, if there is tumor reduction (less than 5cm) surgery is indicated.

Chemotherapy after surgery, 6 cycles of CMF.

If anthracyclins are contraindicated, 4 cycles of induction CMF and 4 cycles after surgery.

Patients not responding to the third chemotherapy cycle go through treatment with paclitaxel. Post-surgery chemotherapy should be started 5 weeks after the last cycle.

Metastasic disease:

Disseminated breast cancer has been traditionally considered an incurable disease. This is the harsh truth in most cases, although much has been advanced in its treatment. (23,24). Patients with metastasic disease are candidates for chemotherapy from the beginning or after hormone treatment failure. The decision of what treatment to use depends on the gravity of the disease, previous treatment, specific biological characteristics of the tumor, and patient preferences. The choice of using hormone treatment as a first option is limited to positive ER patients with dermal, ganglionar or osseous relapse, preferably without previous hormone treatment. Most patients are therefore very likely to use chemotherapy as long as it is not contraindicated. The chosen plan also depends on the drugs that were previously used and the seriousness of the disease. Plans containing anthracyclins get the best degree of response (51% vs. 45%) and better survival. Chemotherapy should be used early. Its administration from the beginning renders better survival than when hormone treatment is used first. (25). There is also argument that the number of cycles should be increased to modestly increase survival. (26)

Chemotherapy is still the initial choice for treatment, mainly on high-risk patients with short-term life risk, or on those who relapse shortly after primary treatment, or those patients with negative estrogenic receptor. (14). One of the problems the doctor is faced with is what drugs to use. New drugs have been incorporated to the therapeutic arsenal: liposomal adriamycin, anti-metabolites (Capecitabine, Edetrexate Gencitabine, Tomudex), topoisomerase inhibitors (Irinotecan and Topotecan), poisons (taxanes and vinorelbine), among others. Paclitaxel in mono-chemotherapy produces response rates of 32% - 56% for 6 to 9 months. When the patients have used previous chemotherapeutic treatment, these rates go down. (27). Docetaxel produces 54% - 67% responses in women who were not treated, and between 35% and 60% in treated patients. It should be noted that 25% of the paclitaxel-resistant patients responded to docetaxel. Using this drug in combination with others like adriamycin, gencitabine and capecitabine, has rendered amazing responses. The docetaxel – capecitabine combination in locally advanced breast cancer showed higher responses (41.6%) than when only docetaxel was used (29.7%).

Chemotherapy is the treatment to use on patients with metastasic disease who are older than 70 with negative estrogenic receptor. This is a controversial issue. Some authors recommend applying it with anthracyclins. This determination, without a doubt, depends upon the state of health of the patients, more than on their age (28).

The development of immunotherapy with monoclonal antibodies and vaccine preparations has also rendered good results. (14). Monoclonal antibody trastuzumab or herceptin has been used above all on metastasic disease, alone or in combination with multiple cytotastics on patients with over-expression of HER-2, and the best results have been achieved. They are very costly though, which prevents many third world women from being able to benefit from them. (29,30,31,32)

Treatment protocols for metastasic breast cancer are conducted in reference centers in Cuba with such products as Herceptin, Capecitabine, Zoladex, and Docetaxel, (33,34). Patients who meet inclusion requisites are treated in these centers, given that control over these drugs is necessary to provide them only to those patients who really need them, as they are very costly. It is also necessary to evaluate patient response to treatment.

A number of clinical trials are being conducted in Cuba with active immunotherapy by means of vaccine preparations for metastasic breast cancer. They are locally produced and are under assessment (35). Several decades of education and development of the health care system in our country have led us to achieve first class levels of cancer care, which can only be attained in a third world country thanks to our social system where human beings are the first priority.

REFERENCES:

Incidencia del Cáncer en Cuba.1999. Registro Nacional del Cáncer. Instituto Nacional de Oncología y Radiobiología. Registro Nacional del Cáncer. La Habana: MINSAP; 2003.
Normas Oncológicas Terapéuticas (NOT). La Habana: Instituto Nacional de Oncología y Radiobiología: MINSAP;1987.
Guías Cubanas de tratamiento del Cáncer. La Habana: MINSAP; 2001(en prensa).
Da Silva C. La mujer de riesgo: en Hernández Muñoz G. Tratamiento Conservador en Cáncer de mama. Bogotá: Mc Gran Hill; 2002. P.3-6.
Gianni L, Valagussa P, Zambetti. Adjuvant and Neoadjuvant Treatment of Breast Cancer. Seminars Oncol. 2001; 28(1): 13-29.
Laviña Risso R. Indicaciones del tratamiento Conservador del Cáncer de mama. Bogotá: Mc Graw Hill; 2002.p. 41-53.
Alba E. Quimioterapia de segunda línea en el cáncer de mama metastásico. Rev. Cáncer (Madrid) 2002;16: 94-95.
Vogel C. Adjuvant Taxanes. Education Book.38 th Annual Meeting of the American Society of Clinical Oncology.2003.;1092-9118 .58-64.
Blum J, Dieras V, lo Russo P, Horton J, Rutman O, et al. Multicenter, Phase II Study of Capacitabine in Taxane-Pretreated Metastasic Breast Carcinoma Patients. J.Clin Oncol 2003 ; 21(11) :2101-2109.
Llombart A. Presente y futuro del cáncer de mama. Cáncer (Madrid) 2002; 16(1):105-107.
Pérez Manga G. Hormonoterapia. Cáncer (Madrid) 2002; 16(1):96-98.
Mouridsen H, Gershanovich M, Sun Y, et al. Phase III Study of Letrozole Versus Tamoxifen as First-Line Therapy of Advanced Breast Cancer in Postmenopausal Woman: Analysis of Survival and Update of Efficacy From the International Letrozole Breast Cancer Group. J Clin Oncol 2003 ;21 (11) :2101-2109.
Bonadonna G, Brusamolino E, Valagussa P. Combination chemotherapy as an adjuvante treatment in operable breast cancer. N. Engl J Med 1976 ; 294: 405-410.
Bonadonna G, Vaagussa P, Moliterni A, Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil in node positive Breast Cancer N Engl J . Med 1995 ; 332 : 901-906.
Horton R. Scientific misconduct: exaggerated fear but real and requiring a proportionate response. Lancet 1999; 354:7-8.
Adjuvant Therapy for Breast Cancer. Nov 2000.NIH Consensus Statement 114 Adjuvant Therapy for Breast Cancer . (en línea) 1999,July 8(fecha de acceso 25 Enero 2003)vrl disponible en: http// odp.od.nih.gov/consensus/114/114-statement.htm.
Goldhhisch A ,Glick J, Gelber D. Meeting Highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Clin. Oncol. 2001; 18 :( 3817-3827).
Weiss RB, Rifkin RM, Stewart FM .High Chemotherapy for high-risk primary breast cancer: an on-site review of the Wezwoda study. Lancet 2000; 355: 999-1003.
Sparano J. Adjuvant Therapy of Breast Cancer .Medscape coverage of: 38 th Annual Meeting of the American Society of Clincal Oncology. Breast Cancer. en línea ( fecha de abceso 20-07-03 disponible en Medscape File: // E: Mama /breastcancer.htm 1 –9.
Lluch A. Tratamiento sistemático adyuvante del cáncer de mama. Cáncer (Madrid).2002;16(4): 154-162.
Rodenhuis S. Richal DJ, Van der Wall E, et al. Radomized trial of high-dose chemotherapy and haemopoictic progenitor-cell support in operable breast cancer with extensive axilary lymph node involvement. Lancet.1998; 352: 515- 521.
Albanell J. Gallardo E, Baselga J.M, Cáncer de Mama(l). Generalidades. Cap 19 Oncología Clínica. González Varón. 2da edición pág. 2552-68; 1998.
Martín M Cáncer de mama (III): Tratamiento de la enfermedad diseminada. Oncología Clínica. González Varón. 2da edición cap. 21 pag 287-298; 1998.
Balducci L, Extermann M, Carreca I. Management of Breast Cancer in the older woman. Cancer Control 2001; 8 (5):431-441.
Perez - Manga G, Criado P, Cañon E. Tratamiento con quimioterapia del cáncer de mama metastásico. Cancer (Madrid) 2002 ; 16(4): 172-184.
Stockeler M, Wilcken NRC, Gherse D, et al. Systematic reviews of chemotherapy and endocrine therapy in metastatic breast Cancer. Cancer treatment Reviews 200; 26: 151-168.
Valero V, Jones SE, Von Hoff DD, et al. A phase II study od docetaxel in patients with paclitaxel-resistant metastatic breast cancer. J. Clin Oncol. 1998; 16: 3362.
Diaz N. -. Laboratory Testing for Her2_neu in Breast Carcinoma: An Evolving Strategy to Predict Response to Targeted Therapy. Cancer Control 2001;8(5):414-418
Vorobiof D.A., Kleeberg U.R, Pérez Carrion R. A Randomized open,parallel-group trial to compare the endocrine effects of oral anastrozole (Arimidex) wiht intramuscular formestane in postmenopausal women with advanced breast cancer. Ann Oncol 1999; 10:1219-1225.
Esteva F, Velero V, Boosar D. Phase II Study of Weekly Docetaxel and Trastuzumad for Patients With HER-2 Overexpressing Metastatic Breast Cancer J Clin Oncol. 2002;20(7):1800-1808.
Goss P. Anti- aromatase Agents in the Treatment and Prevention of Breast Cancer. Cancer Control 2002; 9 (2):2-8.
Slamon D, Leyland-Jones B, Shak S. Use of Chemotherapy plus a monoclonal antibody against Her2 for metastatic Breast Cancer That Overexpesses Her2.N Engl J Med. 2001;334(11): 783-792.
Burstein H, Kuter I ,Campos S. Clinical Activity of Trastuzumab and Vinorelbine in Woman with HER2-Overexpressing Metastatic Breast Cancer. J Clin Oncol 2001;19(10): 2722-2730.
Ravdin P. Should HER2 Status Be Routinely Measured for all Breast Cancer Patients? S Oncol. 1999;26(4): 117-123.
Carr Adriana, Rodriguez E. Inmumotherapý of Advanced Breast Cancer With a Heterophilic Ganglioside ( NeuGcGM39 Cancer Vaccine. J Clin Oncol. 2003;21(6):1015-1021