Treatment
of Metastatic
Breast Cancer
Charles L. Vogel
N 1985, I PRESENTED my views on adjuvant therapy of breast cancer.’ I believe we may have the potential to “cure” more people with the aggressiveuseof adjuvant cytotoxic chemotherapy when tumor bulk has been reducedto a micrometastatic burden. In contrast to my philosophy in the adjuvant situation, my philosophy in the management of metastatic breast cancer in 1990 is very different and highly conservative. To date, we have been unable to break the cure barrier in metastatic breast cancer.* Thus, even the patient with a small subcutaneousrecurrenceon the chest wall has at least 70% to 80% chance of relapsing and ultimately dying.3 The only recurrent diseasesituation that is different is the problem of breast relapse in a patient treated primarily with lumpectomy and radiation. In such patients, mastectomy or, in somecases,even relumpectomy can result in long-term disease-freesurvival and possible cure.4 Aside from that clinical situation, relapse of any sort in breast cancer connotes a dire prognosis. However, even if we cannot cure, long-term survival with remissions and disease exacerbations are possible using conservativetreatmentstrategies and often sequential hormonal manipulations. Although the median survival from first relapse is only 2Y2years5 approximately 25% of patients are alive for 5 years, and a finite percentageof people live 10 or more years even with metastaticdisease. Siegel6 has termed patients who defy the statistics as E-CAPs-+xceptional cancer patients-and nowhere is this more true than in the managementof metastaticbreast cancer. All medical oncologists care for patients with indolent breastcancer who are alive and doing reasonably well 10, 12, and 14 years later. Thus, metastatic breast cancer is by no meansan imme-
I
From the South Florida Comprehensive Cancer Centers, Inc; and the School of Medicine, University of Miami, Miami, FL. Charles L. Vogel, MD, FACP: Medical Director, South Florida Comprehensive Cancer Centers, Inc; Clinical Professor, University of Miami School of Medicine. Address reprint requests to Charles L. Vogel, MD, AMI Kendall Cancer Center, I1 750 Bird Rd, Miami, FL 33175. Copyright 0 1991 by W.B. Saunders Company 0749-2081/91/0703-0007$5.OOlO
194
diate deathsentenceand should not be viewed with an air of pessimism. At the time of first relapse, I have been dismayed when family physicians or internists tell a person that they have “terminal” breast cancer; in reality, the patient may live for many years and be barely inconvenienced by her metastaticproblem. The major determinant of longevity is whether or not the patient has a hormonally sensitive tumor. It should be intuitively obvious that if a patient has a hormonally sensitive tumor (which is largely defined by the estrogen and progesterone receptor assay result), then she will live longer than patients who have a hormonally independent tumor. For the latter group of patients, the only systemicmodality of treatmentavailable is chemotherapy, but with hormonally dependent tumors, we have at least six different hormonal manipulations that can be usedsequentially to try to achieve remissions. LOCOREGIONAL RELAPSE
At the time of any relapse, the patient should be totally restagedincluding a bone scan, chest x-ray, computed axial tomography (CAT) scan of the liver, carcinoembryonic antigen (CEA), CA 15-3, liver function tests, and a hemogram. If a patient’s disease is localized to the chest wall or regional lymph node-bearing areas, my philosophy is to treat with comprehensiveradiation therapy to sterilize the area. Radiation therapy should encompass chestwall, supraclavicular area, and internal mammary areaas well. At this juncture, however, therapeutic options become very complicated. Approximately 15% of these people may have prolonged disease-freesurvival beyond 10 years with no additional therapy.3 The majority of these patients will ultimately relapse and die of metastatic breast cancer. Therefore, three other strategies might be considered and discussed with the patient depending on her age and general physiologic status. If the patient is elderly and receptorpositive, postradiation hormonal therapy should be considered.If younger, the M.D. Anderson Group has published lo-year results in a seriesof patients where, after locoregional therapy has been completed, chemotherapywith doxorubicin-containing Seminars
in Oncology
Nursing,
Vol 7, No 3 (August),
1991:
pp 194-199
TREATMENT
OF METASTATIC
BREAST
CANCER
regimens is administered. In their initial studies, 2 years of therapy were given with a lo-year diseasefree survival rate of 33%, which is the best published anywhere in the world.’ Thus, if a patient does not feel comfortable with a potentially palliative approach such as locoregional therapy alone, a more aggressive adjuvant chemotherapy approach after locoregional therapy might be accepted. Another option is high-dose chemotherapy with rescue by autologous bone marrow reinfusion. This is an investigational approach with the major transplant centers recording mortality rates of 5% to 20% secondary to treatment. At present, all centers treating patients at first relapse are reporting 20% 2- to 4-year disease-free survivals.8’9 One can only hope that these remissions will prove durable and that this toxic therapy will “break the cure barrier” in metastatic breast cancer. For now, I lean in the direction of locoregional therapy alone or followed by 6 months of doxorubicin-based chemotherapy, unless the patient wishes to embark on a more aggressive course of action. HORMONAL THERAPY
Hormonal therapy is the mainstay of metastatic breast cancer treatment for those patients who have positive estrogen or progesterone receptors. Obviously, if the patient has rapidly progressive liver metastases or lymphangitic lung disease, medical oncologists tend to treat with chemotherapy in spite of receptor assay results because one does not have the luxury of waiting for the slow response usually seen with hormonal manipulation. The average breast cancer patient who is receptor-positive can be started on hormonal treatment with an anticipated 60% chance of disease regression. For premenopausal patients, bilateral salpingo-oophorectomy (BSO) remains my standard first-line hormonal manipulation, although many oncologists use tamoxifen. Controlled randomized trials between tamoxifen and oophorectomy have indicated no significant differences. In spite of that fact, tamoxifen may induce hyperestrogenism in premenopausal patients if they have intact ovaries. Since response rates to BSO and tamoxifen appear identical, tamoxifen may soon replace BSO as first line therapy. Alternatively, another potential agent for use in the premenopausal patient is the drug goserelin acetate, a luteinizing hormone-releasing
195
hormone (LHRH) antagonist. This has proved effective in premenopausal patients with breast cancer by acting as a medical oophorectomy. For postmenopausal patients, first-line hormonal therapy should be tamoxifen. Currently, there is a national clinical trial randomizing patients to tamoxifen or toremifene, a new antiestrogen. The latter could prove to have advantages as it does not appear to cause stimulation of the uterus, and uterine cancer has emerged in one study lo as a side effect of long-term tamoxifen therapy. Assuming that premenopausal patients are treated with oophorectomy at first relapse, tamoxifen would be a very good second-line drug. Second-line therapy for postmenopausal patients or third-line therapy for premenopausal patients after oophorectomy and tamoxifen would be either megestrol acetate or aminoglutethimide and hydrocortisone. The major disadvantage to megestrol is excessive weight gain; this may be a detrimental factor for many breast cancer patients who tend to be overweight to start with at disease onset. Thus, outside of the context of a clinical trial, 1 prefer aminoglutethimide and hydrocortisone. Aminoglutethimide was initially designed as a medical adrenalectomy, and, thus, hydrocortisone had to be added to prevent pituitary stimulation of the adrenal gland, which could override the adrenal blockade by aminoglutethimide. We have learned, however, that the major effect of aminoglutethimide is as an aromatase inhibitor. Aromatase is the enzyme in fatty tissue that converts androgens produced by the adrenal gland to estrogens. Since this is the primary mode of action, it may not be absolutely necessary to use hydrocortisone with aminoglutethimide, but there are some studies where hydrocortisone seemed to add something to the regimen compared with aminoglutethimide alone. Another factor in aminoglutethimide therapy is dose. The drug was initially designed as a soporific and so the major side effect was drowsiness. It is not necessary to treat with the initially recommended doses of 1 g/d, and doses of 500 mg and possibly even less are adequate to induce remissions in breast cancer. ” My standard regimen for the use of this drug is to give aminoglutethimide, 250 mg twice a day with 20 mg twice a day of hydrocortisone. Major side effects of this combination include a rash in 10% of patients which may be severe and require discontinuation of therapy. Very rarely, patients may develop agranulocytosis,
196
CHARLES
but there have been very few casesreported. Fever and a flulike syndromeoften occur with the rash or may occur alone. If none of these side effects occur, the patient usually is able to tolerate this medication quite well without as much weight gain as with megestrol acetate. Currently, new studies are available for patients failing tamoxifen, either in the adjuvant situation or metastatic disease. These studies randomize megestrol acetate (most current second-line therapy) against a new aromataseinhibitor (Fadrazole; Ciba-Geigy, Summit, NJ) that has none of the side effects of aminoglutethimide and hydrocortisone. This new compound does not need additional hydrocortisone and appearsto be as well tolerated as tamoxifen. Other hormonal manipulations that might be considered include the male hormone fluoxymesterone and diethylstilbesterol (DES), an estrogen. No one really knows why high dosesof DES cause remissions in breast cancer. It used to be the firstline therapy, but has been replaced by tamoxifen because of the latter’s better tolerability. Some people are unable to tolerate DES becauseof nausea and vomiting, and hypercalcemic flares are more common with DES than with tamoxifen. Fluoxymesterone is usually relegated to last place in our hormonal armamentarium becauseof its tendency to virilize. Regardless, some patients have had extraordinary responsesto this androgen and the virilization can be minimized through good cosmetic treatments. Finally, LHRH antagonists and even somatostatin analogs are being tested in metastatic breast cancer. Thus, we have a broad spectrum of hormonal agentsthat can be used sequentially to induce and maintain remissions in metastatic breast cancer. There is seldom a role today for the older, surgical ablative regimens of adrenalectomy or hypophysectomy. CYTOTOXIC CHEMOTHERAPY
Chemotherapy is a highly effective form of treatment for metastaticbreast cancer, but regardless of effectiveness,it is still more toxic than hormonal therapy. Becauseoutside of the context of clinical trials, our therapeutic goal in the management of metastatic breast cancer is palliation and not cure, hormonal therapy should be used first, except for patients with aggressivediseasepresen-
L. VOGEL
tations or for those patients who clearly have hormonally independent tumors. It should be noted that just becausean estrogen and progesteroneassay report is negative, the patient may not necessarily have a hormonally independent tumor. There are many things that can cause a falsenegative receptor assay, therefore, clinical judgment must be used to determine which patients who are said to be hormonally independent might actually benefit from trials of hormonal manipulation because of a high likelihood that the receptor assayswere spuriously negative.12Regardless,for patients whose tumors are refractory to hormonal therapy or truly have hormonally independent tumors, standardcytotoxic chemotherapyis effective 60% of the time in inducing responses.Given new, excellent antiemetics, the previously frightening side effects of chemotherapy can often be minimized. Standarddrugs usually usedin combination are cyclophosphamide, methotrexate, 5fluorouracil (5-l%), vincristine, prednisone, and doxorubicin. Widely used acronyms include combinations such as CMF, CAF, or CMFVP. Although responserates are good, remission durations are short, with a median remission duration of 8 months. On relapse, alternative chemotherapeutic agentscan be used, usually consisting of the drugs omitted from first-line therapy as mentioned above. Third- and fourth-line therapies include other drugs such as mitoxantrone, thiotepa, mitomycin C, vinblastine, and alternative ways of giving 5-FU. Administered by continuous infusion, 5-FU can even be successfulin people who have failed 5-FU previously. l3 Furthermore, 5-FU plus high-dose leucovorin may be as promising a regimen in breast cancer as it has proved valuable in colon cancer.l4 Cisplatin is highly toxic and generally ineffective in patients with far advanceddisease. However, it does appear to be much more effective when administered as part of first-line chemotherapy.l5 This needsfurther exploration in expandedclinical trials. Currently, our investigational program consists of first-line treatment with cyclophosphamide, doxorubicin, and 5-FU with or without the new drug Adr529, a cardioprotector. Alternatively, we have testedthe drug pirarubicin, which seemsto be as effective as doxorubicin as a single agent, but with much less subjective toxicity.16 Finally, as second- or third-line therapy, we are looking at a combination of mitoxantrone plus 5-FU and high-
TREATMENT
OF METASTATIC
BREAST
CANCER
dose leucovorin, which is very well tolerated subjectively by the patient. This combination is still in early phasesof testing to determine its overall ability to induce antitumor responses;however, the Vanderbilt group has presented encouraging results using this combination, albeit in a different schedule.” IMPROVING CHEMOTHERAPY
FOR THE 1990s
In addition to the more or less standardchemotherapy discussedso far, a number of strategiesare being investigated in an effort to improve on the responserate and responsedurations of cytotoxic chemotherapy in metastatic disease. One such strategy is the use of estrogenpriming. Studies are being done to look at whether stimulation of tumor growth by the use of estrogensjust before chemotherapy is a viable strategy. Preliminary reports indicate that estrogen can increasethe growth rate of tumors, and, after a short course of estrogens, chemotherapy may be more effective because it acts best against rapidly dividing cells.18 Another strategy is the use of verapamil or other agents, such as the phenothiazinesor even tamoxifen, to potentiate the action of chemotherapy.The MDRl gene codes for multiple drug resistance, and one such mechanisminvolves rapid doxorubitin efflux from tumor cells. Drugs like verapamil, phenothiazines, and tamoxifen prevent such efflux and may, in that way, potentiate chemotherapy. The use of chemohormonal therapy using tamoxifen is another strategy. As previously mentioned, there is a trend away from using the two modalities together becausehormones slow tumor growth, and chemotherapy acts best against rapidly dividing cells. There are someelegant data in vitro from Kitten and Osborne” suggestingsynergism between tamoxifen and doxorubicin but antagonism with other chemotherapeuticregimens. A fourth strategy is the use of alternating noncrossresistantcombinations. While it makes sense to try to alternatedifferent combinations to prevent the emergenceof drug resistance,moststudiesdo not indicatethat this strategyprovidessignificant benefit. The concept of increasing dose intensity is one that is under intensive investigation. Dosescan be increased using the new investigational growth factor granulocyte-macrophagecolony-stimulating factor (GM-CSF) to rapidly reconstitute the granulocytes and prevent fatal infection. Another such
197
strategy involves using potentially lethal dosesof chemotherapy followed by antologous bone marrow rescue. This latter strategy has been studied in breast cancer patients by investigators at Duke University (Durham, NC), The M.D. Anderson Cancer Center (Houston, TX), and others, but results must still be viewed as preliminary.R39Patients with far advanced disease do very poorly, and none are cured; there is a high mortality rate from the treatment itself. This has led to the selection of patients with very good risk metastaticpresentations for study. Most of these programs use standard induction chemotherapy to induce good antitumor responsesin patients with minimal metastatic breast cancer and then consolidation using high-dose chemotherapy with autologous bone marrow reinfusion. It is true that approximately 20% of such patients are in long-term, unmaintained complete remission, but this has been only for 2 to 4 years and, given the heterogeneity of metastaticbreast cancer, longer follow-up will be needed to assessthe role of this strategy. Duke University has taken this procedure one step further by treating patients with 10 or more positive axillary lymph nodes and no definite evidence of metastaticdiseaseelsewhereat the time of primary diagnosis with high-dose chemotherapyand autologousbone marrow reinfusion. Someinvestigators arejust escalatingdosesto very high levels without bonemarrow support or GM-CSF, while others are investigating peripheral stem cell reinfusion. This type of approach should only be done within the context of a clinical trial. Finally, the use of chemotherapyin conjunction with the new generation of biologic responsemodifiers is only now beginning. There is little information available on such combination therapy, making only a brief discussionof the current status of biotherapy in metastaticbreast cancer possible. BIOLOGIC THERAPIES
In the 197Os,attempts were made to stimulate the immune response of breast cancer patients through the use of bacille Calmette-Guerin (BCG), levamisole hydrochloride, and Corynebacterium parvum. Whether used alone or in conjunction with chemotherapy, these agents were unsuccessful in altering the natural history of primary or metastatic breast cancer. Currently, a whole new wave of biologic therapiesthat could alter the pic-
198
CHARLES
ture of breast cancer treatment in the decade to come are under investigation. Unfortunately, none of these therapies have matured to the point of human clinical trials, much less to routine use. Although preliminary studies with interferon alpha looked encouraging,” subsequent studies were totally negative.21 The latter studies were done largely with commercially available, recombinant alpha interferons while the initial studies were done with natural interferon alpha. Perhaps renewed interest might be generated for clinical trials of interferon alpha. Combinations of interferon with tamoxifen or cytotoxic chemotherapy are in their infancy. Interleukin-2 (IL-2) either with or without lymphokine-activated killer (LAK) cells22 is another interesting strategy that appearsto hold promise in other diseaseentities, such as renal cell carcinoma and malignant melanoma. To date, very few patients with breast cancer have been treated with this strategy, and few results are available. Rosenberget a122at the National Cancer Institute are now studying more potent activated killer cells (tumor infiltrating lymphocytes) in conjunction with IL-2. These studies are also quite early and are not focused on breast cancer.23 Monoclonal antibodies are an exciting new advance. They can be raised and directed against antigens on tumor cells and, hopefully, could lead
L. VOGEL
to destruction of tumor cells. It is possible to link monoclonal antibodies with plant toxins such as ricin or to chemotherapy or radioactive sources, with the monoclonal antibody delivering these toxic substancesdirectly to tumor cells with less host toxicity. These studies also are in their infancy.24 We are learning more about breastcancer tumor cell growth, for example, that certain growth factors, including insulin-derived growth factor and transforming growth factors alpha and beta, are elaboratedby tumor cells. It may even be that tamoxifen acts by altering growth factors rather than by serving as a competitive inhibitor of endogenous estrogens through the estrogen receptor. Strategiesare being developed to stimulate transforming growth factor beta or to suppresstransforming growth factor alpha either through monoclonal antibody therapy or the use of antisense genes.25 Although our therapiesin 1990remain palliative in nature, the horizon looks encouraging as we continue to explore exciting new therapies in an attempt to “break the cure barrierT2 in metastatic breast cancer. ACKNOWLEDGMENT The author thanks Joy Dabbs and Wendy Oelerich for superb secretarial support.
REFERENCES 1. Vogel CL: Systemic therapy of breast cancer-1985. Semin Oncol Nurs 1:189-194, 1985 2. Holland JF: Breaking the cure barrier. J Clin Oncol 1:7.590, 1983 3. Toonkel L, Fix I, Jacobson LH, et al: The significance of local recurrence of carcinoma of the breast. Int J Radiat Biol Phys 9:33-39, 1982 4. Kurtz J, Amahic R, Brandone H, et al: Results of wide excision for mammary recurrence after breast conserving therapy. Cancer 61:1969-1972, 1988 5. Clark JM, Sledge GW, Osborne CK, et al: Survival from first recurrence: relative importance of prognostic factors in 1015 breast cancer patients. J Clin Oncol 5:55-61, 1987 6. Seigel BS: Love, Medicine and Miracles. New York, NY, Harper and Row, 1988 7. Holmes FA, Buzdar AU, Kau SE, et al: Isolated visceral recurrences of breast cancer: 10 year results of a combined modality approach, in Salmon SE (ed): Adjuvant Therapy of Cancer VI. Philadelphia, PA, Saunders, 1991, pp 262-266 8. Peters WP, Schpall El, Jones RB, et al: High dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer. J Clin Oncol 6:13681376, 1988
9. Dunphy F, Spitzer G, Buzdar AU, et al: Treatment of estrogen receptor negative or hormonally refractory breast cancer with double high-dose chemotherapy intensification and bone marrow support. J Clin Oncol 8:1207-1216, 1990 10. Fomander T, Rutqvist LE, Cedermark B, et al: Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. Lancet 1:112-120, 1989 11. Upright C, Ragaz J, Basco V, et al: Double blind randomized trial of conventional versus low dose arninoglutethimide and hydrocortisone in patients with metastatic hormone responsive breast cancer. Proc ASCO 9:45, 1990 (abstr) 12. Vogel CL, East DR, Wang G, et al: Response to Nolvadex in estrogen receptor “poor” metastatic breast cancer. Cancer 60:1184-l 189, 1987 13. Jabboury K, Holmes FA, Hortobagyi G: 5-Fluorouracil rechallenge by protracted infusion in refractory breast cancer. Cancer 64:793-797, 1989 14. Loprinzi CL: 5-Fluorouracil with leucovorin in breast cancer. Cancer 63:1045-1047, 1989 15. Sledge JW Jr, Roth BJ: Cisplatin in the management of breast cancer. Semin Oncol 16:110-l 15, 1989 (suppl 6) 16. Waldman S, Sridhar KS, Richman S, et al: Phase II trial
TREATMENT
OF METASTATIC
BREAST
CANCER
of pirarubicin in advanced breast cancer. Proc ASCO 950, 1990 1’7. Andrews MB, Greco FA, Johnson DH, et al: Mitoxantrone, 5 FU and high dose leucovorin: An effective, well tolerated regimen for refractory breast cancer. Proc ASCO 9:35, 1990 (abstr) 18. Hung SSJ, East D, Vogel CL, et al: Estrogen priming before progestin therapy in advanced breast cancer. Breast Dis 3:87-94, 1990 19. Kitten L, Osborne K: Antiestrogens antagonize melphalan but not cyclophosphamide cytotoxicity in human breast cancer cells by estrogen receptor independent mechanisms. Proc ASCO 7:9, 1988 (abstr) 20. Gutterman IU, Blumenschein GR, Alexanian R, et al: Leucocyte interferon-induced tumor regression in human metastatic breast cancer, multiple myeloma and malignant melanoma. Ann Intern Med 93:399-406, 1980
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21. Kirkwood JM, Emstoff MS: Interferons in the treatment of human cancer. J Clin Oncol 2:336-352, 1984 22. Rosenberg SA, Lotze MT, Muul LM, et al: Observations on the systemic administration of autologous lymphokine activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313:1485-1492. 1985 23. Fisher B, Packard BS, Read El, et al: Tumor localization of adoptively transferred Indium-III labelled tumor infiltrating lymphocytes in patients with metastatic melanoma. J Clin Oncol 7:250-261, 1989 24. Scheinberg DA, Houghton AN: Current status of antitumor therapy with monoclonal antibodies. Oncology I:3 l-40, 1987 25. Dickson RB, Lippman ME: Control of human breast cancer by estrogen, growth factors and oncogenes. Cancer Treat Rep 40:119-165, 1988
of Metastatic
Breast Cancer
Charles L. Vogel
N 1985, I PRESENTED my views on adjuvant therapy of breast cancer.’ I believe we may have the potential to “cure” more people with the aggressiveuseof adjuvant cytotoxic chemotherapy when tumor bulk has been reducedto a micrometastatic burden. In contrast to my philosophy in the adjuvant situation, my philosophy in the management of metastatic breast cancer in 1990 is very different and highly conservative. To date, we have been unable to break the cure barrier in metastatic breast cancer.* Thus, even the patient with a small subcutaneousrecurrenceon the chest wall has at least 70% to 80% chance of relapsing and ultimately dying.3 The only recurrent diseasesituation that is different is the problem of breast relapse in a patient treated primarily with lumpectomy and radiation. In such patients, mastectomy or, in somecases,even relumpectomy can result in long-term disease-freesurvival and possible cure.4 Aside from that clinical situation, relapse of any sort in breast cancer connotes a dire prognosis. However, even if we cannot cure, long-term survival with remissions and disease exacerbations are possible using conservativetreatmentstrategies and often sequential hormonal manipulations. Although the median survival from first relapse is only 2Y2years5 approximately 25% of patients are alive for 5 years, and a finite percentageof people live 10 or more years even with metastaticdisease. Siegel6 has termed patients who defy the statistics as E-CAPs-+xceptional cancer patients-and nowhere is this more true than in the managementof metastaticbreast cancer. All medical oncologists care for patients with indolent breastcancer who are alive and doing reasonably well 10, 12, and 14 years later. Thus, metastatic breast cancer is by no meansan imme-
I
From the South Florida Comprehensive Cancer Centers, Inc; and the School of Medicine, University of Miami, Miami, FL. Charles L. Vogel, MD, FACP: Medical Director, South Florida Comprehensive Cancer Centers, Inc; Clinical Professor, University of Miami School of Medicine. Address reprint requests to Charles L. Vogel, MD, AMI Kendall Cancer Center, I1 750 Bird Rd, Miami, FL 33175. Copyright 0 1991 by W.B. Saunders Company 0749-2081/91/0703-0007$5.OOlO
194
diate deathsentenceand should not be viewed with an air of pessimism. At the time of first relapse, I have been dismayed when family physicians or internists tell a person that they have “terminal” breast cancer; in reality, the patient may live for many years and be barely inconvenienced by her metastaticproblem. The major determinant of longevity is whether or not the patient has a hormonally sensitive tumor. It should be intuitively obvious that if a patient has a hormonally sensitive tumor (which is largely defined by the estrogen and progesterone receptor assay result), then she will live longer than patients who have a hormonally independent tumor. For the latter group of patients, the only systemicmodality of treatmentavailable is chemotherapy, but with hormonally dependent tumors, we have at least six different hormonal manipulations that can be usedsequentially to try to achieve remissions. LOCOREGIONAL RELAPSE
At the time of any relapse, the patient should be totally restagedincluding a bone scan, chest x-ray, computed axial tomography (CAT) scan of the liver, carcinoembryonic antigen (CEA), CA 15-3, liver function tests, and a hemogram. If a patient’s disease is localized to the chest wall or regional lymph node-bearing areas, my philosophy is to treat with comprehensiveradiation therapy to sterilize the area. Radiation therapy should encompass chestwall, supraclavicular area, and internal mammary areaas well. At this juncture, however, therapeutic options become very complicated. Approximately 15% of these people may have prolonged disease-freesurvival beyond 10 years with no additional therapy.3 The majority of these patients will ultimately relapse and die of metastatic breast cancer. Therefore, three other strategies might be considered and discussed with the patient depending on her age and general physiologic status. If the patient is elderly and receptorpositive, postradiation hormonal therapy should be considered.If younger, the M.D. Anderson Group has published lo-year results in a seriesof patients where, after locoregional therapy has been completed, chemotherapywith doxorubicin-containing Seminars
in Oncology
Nursing,
Vol 7, No 3 (August),
1991:
pp 194-199
TREATMENT
OF METASTATIC
BREAST
CANCER
regimens is administered. In their initial studies, 2 years of therapy were given with a lo-year diseasefree survival rate of 33%, which is the best published anywhere in the world.’ Thus, if a patient does not feel comfortable with a potentially palliative approach such as locoregional therapy alone, a more aggressive adjuvant chemotherapy approach after locoregional therapy might be accepted. Another option is high-dose chemotherapy with rescue by autologous bone marrow reinfusion. This is an investigational approach with the major transplant centers recording mortality rates of 5% to 20% secondary to treatment. At present, all centers treating patients at first relapse are reporting 20% 2- to 4-year disease-free survivals.8’9 One can only hope that these remissions will prove durable and that this toxic therapy will “break the cure barrier” in metastatic breast cancer. For now, I lean in the direction of locoregional therapy alone or followed by 6 months of doxorubicin-based chemotherapy, unless the patient wishes to embark on a more aggressive course of action. HORMONAL THERAPY
Hormonal therapy is the mainstay of metastatic breast cancer treatment for those patients who have positive estrogen or progesterone receptors. Obviously, if the patient has rapidly progressive liver metastases or lymphangitic lung disease, medical oncologists tend to treat with chemotherapy in spite of receptor assay results because one does not have the luxury of waiting for the slow response usually seen with hormonal manipulation. The average breast cancer patient who is receptor-positive can be started on hormonal treatment with an anticipated 60% chance of disease regression. For premenopausal patients, bilateral salpingo-oophorectomy (BSO) remains my standard first-line hormonal manipulation, although many oncologists use tamoxifen. Controlled randomized trials between tamoxifen and oophorectomy have indicated no significant differences. In spite of that fact, tamoxifen may induce hyperestrogenism in premenopausal patients if they have intact ovaries. Since response rates to BSO and tamoxifen appear identical, tamoxifen may soon replace BSO as first line therapy. Alternatively, another potential agent for use in the premenopausal patient is the drug goserelin acetate, a luteinizing hormone-releasing
195
hormone (LHRH) antagonist. This has proved effective in premenopausal patients with breast cancer by acting as a medical oophorectomy. For postmenopausal patients, first-line hormonal therapy should be tamoxifen. Currently, there is a national clinical trial randomizing patients to tamoxifen or toremifene, a new antiestrogen. The latter could prove to have advantages as it does not appear to cause stimulation of the uterus, and uterine cancer has emerged in one study lo as a side effect of long-term tamoxifen therapy. Assuming that premenopausal patients are treated with oophorectomy at first relapse, tamoxifen would be a very good second-line drug. Second-line therapy for postmenopausal patients or third-line therapy for premenopausal patients after oophorectomy and tamoxifen would be either megestrol acetate or aminoglutethimide and hydrocortisone. The major disadvantage to megestrol is excessive weight gain; this may be a detrimental factor for many breast cancer patients who tend to be overweight to start with at disease onset. Thus, outside of the context of a clinical trial, 1 prefer aminoglutethimide and hydrocortisone. Aminoglutethimide was initially designed as a medical adrenalectomy, and, thus, hydrocortisone had to be added to prevent pituitary stimulation of the adrenal gland, which could override the adrenal blockade by aminoglutethimide. We have learned, however, that the major effect of aminoglutethimide is as an aromatase inhibitor. Aromatase is the enzyme in fatty tissue that converts androgens produced by the adrenal gland to estrogens. Since this is the primary mode of action, it may not be absolutely necessary to use hydrocortisone with aminoglutethimide, but there are some studies where hydrocortisone seemed to add something to the regimen compared with aminoglutethimide alone. Another factor in aminoglutethimide therapy is dose. The drug was initially designed as a soporific and so the major side effect was drowsiness. It is not necessary to treat with the initially recommended doses of 1 g/d, and doses of 500 mg and possibly even less are adequate to induce remissions in breast cancer. ” My standard regimen for the use of this drug is to give aminoglutethimide, 250 mg twice a day with 20 mg twice a day of hydrocortisone. Major side effects of this combination include a rash in 10% of patients which may be severe and require discontinuation of therapy. Very rarely, patients may develop agranulocytosis,
196
CHARLES
but there have been very few casesreported. Fever and a flulike syndromeoften occur with the rash or may occur alone. If none of these side effects occur, the patient usually is able to tolerate this medication quite well without as much weight gain as with megestrol acetate. Currently, new studies are available for patients failing tamoxifen, either in the adjuvant situation or metastatic disease. These studies randomize megestrol acetate (most current second-line therapy) against a new aromataseinhibitor (Fadrazole; Ciba-Geigy, Summit, NJ) that has none of the side effects of aminoglutethimide and hydrocortisone. This new compound does not need additional hydrocortisone and appearsto be as well tolerated as tamoxifen. Other hormonal manipulations that might be considered include the male hormone fluoxymesterone and diethylstilbesterol (DES), an estrogen. No one really knows why high dosesof DES cause remissions in breast cancer. It used to be the firstline therapy, but has been replaced by tamoxifen because of the latter’s better tolerability. Some people are unable to tolerate DES becauseof nausea and vomiting, and hypercalcemic flares are more common with DES than with tamoxifen. Fluoxymesterone is usually relegated to last place in our hormonal armamentarium becauseof its tendency to virilize. Regardless, some patients have had extraordinary responsesto this androgen and the virilization can be minimized through good cosmetic treatments. Finally, LHRH antagonists and even somatostatin analogs are being tested in metastatic breast cancer. Thus, we have a broad spectrum of hormonal agentsthat can be used sequentially to induce and maintain remissions in metastatic breast cancer. There is seldom a role today for the older, surgical ablative regimens of adrenalectomy or hypophysectomy. CYTOTOXIC CHEMOTHERAPY
Chemotherapy is a highly effective form of treatment for metastaticbreast cancer, but regardless of effectiveness,it is still more toxic than hormonal therapy. Becauseoutside of the context of clinical trials, our therapeutic goal in the management of metastatic breast cancer is palliation and not cure, hormonal therapy should be used first, except for patients with aggressivediseasepresen-
L. VOGEL
tations or for those patients who clearly have hormonally independent tumors. It should be noted that just becausean estrogen and progesteroneassay report is negative, the patient may not necessarily have a hormonally independent tumor. There are many things that can cause a falsenegative receptor assay, therefore, clinical judgment must be used to determine which patients who are said to be hormonally independent might actually benefit from trials of hormonal manipulation because of a high likelihood that the receptor assayswere spuriously negative.12Regardless,for patients whose tumors are refractory to hormonal therapy or truly have hormonally independent tumors, standardcytotoxic chemotherapyis effective 60% of the time in inducing responses.Given new, excellent antiemetics, the previously frightening side effects of chemotherapy can often be minimized. Standarddrugs usually usedin combination are cyclophosphamide, methotrexate, 5fluorouracil (5-l%), vincristine, prednisone, and doxorubicin. Widely used acronyms include combinations such as CMF, CAF, or CMFVP. Although responserates are good, remission durations are short, with a median remission duration of 8 months. On relapse, alternative chemotherapeutic agentscan be used, usually consisting of the drugs omitted from first-line therapy as mentioned above. Third- and fourth-line therapies include other drugs such as mitoxantrone, thiotepa, mitomycin C, vinblastine, and alternative ways of giving 5-FU. Administered by continuous infusion, 5-FU can even be successfulin people who have failed 5-FU previously. l3 Furthermore, 5-FU plus high-dose leucovorin may be as promising a regimen in breast cancer as it has proved valuable in colon cancer.l4 Cisplatin is highly toxic and generally ineffective in patients with far advanceddisease. However, it does appear to be much more effective when administered as part of first-line chemotherapy.l5 This needsfurther exploration in expandedclinical trials. Currently, our investigational program consists of first-line treatment with cyclophosphamide, doxorubicin, and 5-FU with or without the new drug Adr529, a cardioprotector. Alternatively, we have testedthe drug pirarubicin, which seemsto be as effective as doxorubicin as a single agent, but with much less subjective toxicity.16 Finally, as second- or third-line therapy, we are looking at a combination of mitoxantrone plus 5-FU and high-
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dose leucovorin, which is very well tolerated subjectively by the patient. This combination is still in early phasesof testing to determine its overall ability to induce antitumor responses;however, the Vanderbilt group has presented encouraging results using this combination, albeit in a different schedule.” IMPROVING CHEMOTHERAPY
FOR THE 1990s
In addition to the more or less standardchemotherapy discussedso far, a number of strategiesare being investigated in an effort to improve on the responserate and responsedurations of cytotoxic chemotherapy in metastatic disease. One such strategy is the use of estrogenpriming. Studies are being done to look at whether stimulation of tumor growth by the use of estrogensjust before chemotherapy is a viable strategy. Preliminary reports indicate that estrogen can increasethe growth rate of tumors, and, after a short course of estrogens, chemotherapy may be more effective because it acts best against rapidly dividing cells.18 Another strategy is the use of verapamil or other agents, such as the phenothiazinesor even tamoxifen, to potentiate the action of chemotherapy.The MDRl gene codes for multiple drug resistance, and one such mechanisminvolves rapid doxorubitin efflux from tumor cells. Drugs like verapamil, phenothiazines, and tamoxifen prevent such efflux and may, in that way, potentiate chemotherapy. The use of chemohormonal therapy using tamoxifen is another strategy. As previously mentioned, there is a trend away from using the two modalities together becausehormones slow tumor growth, and chemotherapy acts best against rapidly dividing cells. There are someelegant data in vitro from Kitten and Osborne” suggestingsynergism between tamoxifen and doxorubicin but antagonism with other chemotherapeuticregimens. A fourth strategy is the use of alternating noncrossresistantcombinations. While it makes sense to try to alternatedifferent combinations to prevent the emergenceof drug resistance,moststudiesdo not indicatethat this strategyprovidessignificant benefit. The concept of increasing dose intensity is one that is under intensive investigation. Dosescan be increased using the new investigational growth factor granulocyte-macrophagecolony-stimulating factor (GM-CSF) to rapidly reconstitute the granulocytes and prevent fatal infection. Another such
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strategy involves using potentially lethal dosesof chemotherapy followed by antologous bone marrow rescue. This latter strategy has been studied in breast cancer patients by investigators at Duke University (Durham, NC), The M.D. Anderson Cancer Center (Houston, TX), and others, but results must still be viewed as preliminary.R39Patients with far advanced disease do very poorly, and none are cured; there is a high mortality rate from the treatment itself. This has led to the selection of patients with very good risk metastaticpresentations for study. Most of these programs use standard induction chemotherapy to induce good antitumor responsesin patients with minimal metastatic breast cancer and then consolidation using high-dose chemotherapy with autologous bone marrow reinfusion. It is true that approximately 20% of such patients are in long-term, unmaintained complete remission, but this has been only for 2 to 4 years and, given the heterogeneity of metastaticbreast cancer, longer follow-up will be needed to assessthe role of this strategy. Duke University has taken this procedure one step further by treating patients with 10 or more positive axillary lymph nodes and no definite evidence of metastaticdiseaseelsewhereat the time of primary diagnosis with high-dose chemotherapyand autologousbone marrow reinfusion. Someinvestigators arejust escalatingdosesto very high levels without bonemarrow support or GM-CSF, while others are investigating peripheral stem cell reinfusion. This type of approach should only be done within the context of a clinical trial. Finally, the use of chemotherapyin conjunction with the new generation of biologic responsemodifiers is only now beginning. There is little information available on such combination therapy, making only a brief discussionof the current status of biotherapy in metastaticbreast cancer possible. BIOLOGIC THERAPIES
In the 197Os,attempts were made to stimulate the immune response of breast cancer patients through the use of bacille Calmette-Guerin (BCG), levamisole hydrochloride, and Corynebacterium parvum. Whether used alone or in conjunction with chemotherapy, these agents were unsuccessful in altering the natural history of primary or metastatic breast cancer. Currently, a whole new wave of biologic therapiesthat could alter the pic-
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ture of breast cancer treatment in the decade to come are under investigation. Unfortunately, none of these therapies have matured to the point of human clinical trials, much less to routine use. Although preliminary studies with interferon alpha looked encouraging,” subsequent studies were totally negative.21 The latter studies were done largely with commercially available, recombinant alpha interferons while the initial studies were done with natural interferon alpha. Perhaps renewed interest might be generated for clinical trials of interferon alpha. Combinations of interferon with tamoxifen or cytotoxic chemotherapy are in their infancy. Interleukin-2 (IL-2) either with or without lymphokine-activated killer (LAK) cells22 is another interesting strategy that appearsto hold promise in other diseaseentities, such as renal cell carcinoma and malignant melanoma. To date, very few patients with breast cancer have been treated with this strategy, and few results are available. Rosenberget a122at the National Cancer Institute are now studying more potent activated killer cells (tumor infiltrating lymphocytes) in conjunction with IL-2. These studies are also quite early and are not focused on breast cancer.23 Monoclonal antibodies are an exciting new advance. They can be raised and directed against antigens on tumor cells and, hopefully, could lead
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to destruction of tumor cells. It is possible to link monoclonal antibodies with plant toxins such as ricin or to chemotherapy or radioactive sources, with the monoclonal antibody delivering these toxic substancesdirectly to tumor cells with less host toxicity. These studies also are in their infancy.24 We are learning more about breastcancer tumor cell growth, for example, that certain growth factors, including insulin-derived growth factor and transforming growth factors alpha and beta, are elaboratedby tumor cells. It may even be that tamoxifen acts by altering growth factors rather than by serving as a competitive inhibitor of endogenous estrogens through the estrogen receptor. Strategiesare being developed to stimulate transforming growth factor beta or to suppresstransforming growth factor alpha either through monoclonal antibody therapy or the use of antisense genes.25 Although our therapiesin 1990remain palliative in nature, the horizon looks encouraging as we continue to explore exciting new therapies in an attempt to “break the cure barrierT2 in metastatic breast cancer. ACKNOWLEDGMENT The author thanks Joy Dabbs and Wendy Oelerich for superb secretarial support.
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of pirarubicin in advanced breast cancer. Proc ASCO 950, 1990 1’7. Andrews MB, Greco FA, Johnson DH, et al: Mitoxantrone, 5 FU and high dose leucovorin: An effective, well tolerated regimen for refractory breast cancer. Proc ASCO 9:35, 1990 (abstr) 18. Hung SSJ, East D, Vogel CL, et al: Estrogen priming before progestin therapy in advanced breast cancer. Breast Dis 3:87-94, 1990 19. Kitten L, Osborne K: Antiestrogens antagonize melphalan but not cyclophosphamide cytotoxicity in human breast cancer cells by estrogen receptor independent mechanisms. Proc ASCO 7:9, 1988 (abstr) 20. Gutterman IU, Blumenschein GR, Alexanian R, et al: Leucocyte interferon-induced tumor regression in human metastatic breast cancer, multiple myeloma and malignant melanoma. Ann Intern Med 93:399-406, 1980
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21. Kirkwood JM, Emstoff MS: Interferons in the treatment of human cancer. J Clin Oncol 2:336-352, 1984 22. Rosenberg SA, Lotze MT, Muul LM, et al: Observations on the systemic administration of autologous lymphokine activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313:1485-1492. 1985 23. Fisher B, Packard BS, Read El, et al: Tumor localization of adoptively transferred Indium-III labelled tumor infiltrating lymphocytes in patients with metastatic melanoma. J Clin Oncol 7:250-261, 1989 24. Scheinberg DA, Houghton AN: Current status of antitumor therapy with monoclonal antibodies. Oncology I:3 l-40, 1987 25. Dickson RB, Lippman ME: Control of human breast cancer by estrogen, growth factors and oncogenes. Cancer Treat Rep 40:119-165, 1988
