Complete Remissions in Metastatic Breast Cancer Treated with Combination Drug Therapy

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1 Complete Remissions in Metastatic Breast Cancer Treated with Combination Drug Therapy SEWA S. LEGHA, M.D.; AMAN U. BUZDAR, M.D.; TERRY L SMITH, B.S.; GABRIEL N. HORTOBAGYI, M.D.; KENNETH D. SWENERTON, M.D.; GEORGE R. BLUMENSCHEIN, M.D.; EDMUND A. GEHAN, Ph.D.; GERALD P. BODEY, M.D.; and EMIL J FREIREICH, M.D.; Houston, Texas One hundred sixteen patients with metastatic breast cancer who achieved complete remission with combination chemotherapy were analyzed to ascertain the factors that affect the duration of complete remission and the patterns of relapse. The median duration of complete remission was 17 months. Disease recurred in 81 patients (70%) at periods ranging from 3 to 44 months after achievement of complete remission. The duration of complete remission was inversely related to the bulk of metastatic tumor. Twenty-three patients treated with combined oophorectomy and chemotherapy experienced the longest remissions (median duration of 33 months); only eight (35%) of them have relapsed. Seventy-six percent of the relapses occurred in previously known sites of tumor involvement; most of the remainder involved the brain. The short duration of complete remissions and tendency to relapse in sites of initial involvement suggest that patients with metastatic breast cancer who achieved complete remission with combination chemotherapy still had substantial residual tumor. Consolidation treatments, using hormonal therapy and non-cross-resistant chemotherapy along with irradiation to initial sites of metastases, should be investigated to ascertain their usefulness in prolonging the remissions. TREATMENT of various malignant tumors with combination chemotherapy has resulted in substantial palliation, and long-term remissions have been seen in a significant proportion of patients with acute leukemia and lymphomas (1-3). In these diseases the attainment of a complete remission has been the first step toward the achievement of potential cure. With the available cytotoxic agents complete remission can be achieved in 75% of patients with Hodgkin's disease and 90% of children with acute lymphoblastic leukemia. Unfortunately, chemotherapy has not been as effective against the nonhematologic tumors of adults, and complete remissions are distinctly uncommon. Among solid tumors of adults, metastatic breast cancer is one of the most responsive to various chemotherapeutic agents. With the recent development of combination chemotherapy, a number of centers have reported response rates of 60% to 75% in metastatic breast cancer (4-6). Although the majority of such responses are partial, 15% to 20% of the treated patients achieve a complete remission. In general, patients who achieve complete remission have a longer duration of remission and longer survival, and a fraction of them are From the Departments of Developmental Therapeutics, Medicine, and Biomathematics, The University of Texas System Cancer Center M. D. Anderson Hospital and Tumor Institute; Houston, Texas. potentially curable. A careful study of the quality and length of complete remissions in breast cancer is essential in order to estimate the overall impact of chemotherapy on the survival of patients with metastatic breast cancer. We have analyzed our experience with a large group of patients with metastatic breast cancer treated at M.D. Anderson Hospital and Tumor Institute in recent years in order to define the natural history of patients in complete remission and their patterns of relapse. Such information should be valuable in exposing the sources of failure and help in the design of improved therapies. Patients and Methods Between June 1973 and June 1976, 619 patients with metastatic breast cancer were treated with various combination chemotherapy regimens, shown in Table 1. These drug regimens were basically similar and contained an induction phase therapy with FAC 5-fluorouracil, doxorubicin (Adriamycin; Adria Laboratories Inc., Columbus, Ohio), and cyclophosphamide and maintenance therapy with CMF cyclophosphamide, methotrexate, and 5-fluorouracil. Minor variations in induction regimen consisted either of substitution of 5-fluorouracil with an analog (ftorafur) or utilization of an alternating sequence of induction and maintenance therapy agents. Most protocols also used nonspecific immunotherapy with BCG, levamisole, or methanol-extracted residue of BCG (MER). The details of the chemotherapy used and the data on response rates have been reported previously (7). Because of the similarity in induction regimens and resulting response rates, all patients achieving complete remission during this time have been included in this report. The extent of metastatic involvement was carefully evaluated for each patient before initiation of chemotherapy. Bone involvement was diagnosed on the basis of lytic or blastic abnormalities on roentgenogram. Abnormalities detected by bone scan alone were not considered diagnostic unless bone marrow examination revealed tumor cells. Liver involvement was diagnosed by either biopsy or liver scan, or both, showing defects consistent with metastases. Pleural or peritoneal involvement was diagnosed by proof of positive cytologic findings for malignant cells in the effusion fluid. Complete remission was defined as complete disappearance of all clinical evidence of disease, accompanied by normalization of all laboratory variables for a minimum period of 8 weeks. In the case of osseous metastases, the criteria for complete remission included clear evidence of complete bone recalcification accompanied by either normalization of a previously abnormal bone scan or attainment of a near normal architecture of the involved bone lesions. The latter change frequently evolved as a gradual fading of the sclerotic bone lesions. Development of new lesions or reactivation of disease in previous sites of involvement or development of brain metastases constituted loss of remission. Annals of Internal Medicine. 1979;91:

2 Table 1. Characteristics of 116 Patiei nts in Complete Re mission Number Pati ents (Percent) Sites of metastases (one or more) Skin and/or breast 45 (39) Lymph nodes 42 (36) Bone and marrow Lung (34) (28) Pleura 30 (26) Liver 15 (13) Peritoneum 6 (5) Number of sites 1 49 (42) 2 43 (37) (21) Type of chemotherapy* F + A + C V + A + C F + Mf (53) (25) Ft + A + C 25 (22) * F = 5-fluorouracil; A = doxorubicin; C 1 = cyclophosphamide; Ft = ftorafur; V = vincristine; and M = methotrexate, t Alternating cycles of VAC and FM. Remission duration was measured from the time of achievement of complete remission to the time when recurrent disease was detected. Survival was measured from the initiation of chemotherapy to death or last follow-up. Remission duration and survival curves were calculated by the method of Kaplan and Meier (8), and the differences between pairs of curves were tested for statistical significance by a modified Wilcoxon test (9). The risk of recurrence per unit of time (hazard rate) was calculated by an actuarial method (10). Distributions of patient characteristics between groups were compared by Wilcoxon or chisquare test. Results CHARACTERISTICS OF PATIENTS IN COMPLETE REMISSION One hundred sixteen (19%) of the total group of 619 patients with metastatic breast cancer achieved complete remission and are the subject of this analysis. The median age of the group was 50 years, with a range of 27 to 75 years. The proportion of premenopausal and postmenopausal patients was approximately equal. Sixty-two patients previously had received endocrine therapy (oophorectomy, 44; estrogens, 16; androgens, two) and the remainder were previously untreated for their metastatic disease. Although most patients who had endocrine therapy had evidence of progressive disease before the initiation of chemotherapy, in 23 patients oophorectomy was followed by chemotherapy before enough time had elapsed to ascertain the response to oophorectomy (early chemotherapy group). Because estrogen receptor assay was not available, the decision to combine chemotherapy with oophorectomy was more or less empirical. The sites and extent of tumor in patients who achieved complete remission are shown in Table 1. Dominant sites of metastases, as defined traditionally, included visceral disease in 67 patients (58%), soft tissue in 27 (23%), and bone in 22 (19%). When the distribution of metastases was determined purely on the basis of the extent of the disease, the "predominant" sites of metastases included visceral, 57 (49%); soft tissue, 36 (31%); and bone, 23 (20%). Most of the patients who achieved complete remission had a relatively small tumor burden. The median number of metastatic sites was two (range, one to five). Only 21% of the patients had more than two metastatic lesions. Median time to achievement of complete remission was 5 months (range, 1 to 23 months). Median time to complete remission was significantly longer for osseous metastases compared with nonosseous metastases (12 months versus 4 months; P < 0.01). Chemotherapy was discontinued in 47 patients, generally after a patient had been in complete remission for at least 2 years. In some patients therapy was discontinued earlier for lack of accessible peripheral veins or because of poor tolerance to the side-effects of the treatment. DURATION OF COMPLETE REMISSION The median duration of complete remission was 17 months, with 81 (70%) of the 116 patients having relapsed at times ranging from 3 to 44 months after attainment of complete remission. All patients have been followed for more than 24 months from the start of chemotherapy. Figure 1A is a semilog plot of the remission duration curve for the total group. There is an initial slow fall in the curve, attributable in part to the criterion that complete remissions be of at least 2 months' duration, after which the curve is approximately linear. The estimated risk of recurrence after complete remission is achieved (hazard rate) is given in Table 2. The lowest hazard rate, 0.018, occurred in the first 6 months after complete remission. In other words, an estimated 1.8% of the patients at risk relapsed in each of the first 6 months. After this time, the hazard rate rose to approximately 5% recurrences per month. Although the hazard rate diminished somewhat among patients remaining in complete remission longer than 30 months, it is too soon to tell whether this represents a significant decline in risk for these patients. Only four patients have been followed up longer than the time at which the last recurrence was detected; these women have remained free of disease for 45 to 50 months. FACTORS RELATED TO DURATION OF COMPLETE REMISSION Estimated median durations of complete remission are given in Table 3 for subgroups of patients according to pretreatment characteristics and previous therapy. Although patients under age 50 had a somewhat longer median duration of complete remission than older patients (19 months versus 15 months), the difference in overall distributions was not statistically significant. There also was no real evidence that the length of disease-free interval (interval between mastectomy and evidence of metastasis) was related to length of complete remission. There was some indication that the extent of metastatic involvement at start of chemotherapy, as measured by number of involved sites, was related to duration of complete remission. Although there was little difference in duration of complete remission for those with one or two involved sites, patients with metastases at three or more sites had considerably shorter responses, with median 848 December 1979 Annals of Internal Medicine Volume 91 Number 6

3 remission duration of 13 months (Table 3). Response could be ascertained for 30 of the patients who had received hormonal therapy, but numbers were too small to ascertain whether hormone responsiveness affected the duration of response to chemotherapy. However, patients unresponsive to hormonal therapy tended to have shorter remissions than those in the remainder of the group. Remission duration curves are plotted in Figure IB for two groups: patients who underwent oophorectomy followed by chemotherapy in a period of 4 weeks (early chemotherapy group) and those for whom chemotherapy was delayed until progression of disease after oophorectomy (delayed chemotherapy group). The median duration of response for the 23 patients who received early chemotherapy was 33 months compared to 13 months for the 21 patients in whom chemotherapy was delayed. This difference was highly statistically significant. The median time interval between oophorectomy and chemotherapy in the delayed chemotherapy group was 7 months (range, 1 to 29 months). Some characteristics of these two groups of patients at the start of chemotherapy are compared in Table 4. Though there was a somewhat higher prevalence of osseous involvement among patients who received early chemotherapy, differences between the groups were not statistically significant. PREVALENCE OF BRAIN METASTASIS Nineteen patients (24%) developed brain metastases during the period of the study. It was the initial site of failure in 12 patients (15%), whereas the remainder developed brain metastases either simultaneously with (one patient) or subsequent to (six patients) relapse in an extracranial site. Nine patients with brain metastases remained free of systemic disease at the time of death or at their most recent follow-up. Relations of several factors to frequency of brain metastasis are summarized in Table 3. There was no real evidence that prevalence differed by age, length of disease-free interval, or response to hormone therapy. None of the 23 patients who received oophorectomy and early chemotherapy has developed brain metastases, whereas the 21 patients who were treated with oophorectomy and delayed chemotherapy had a 24% prevalence of brain metastasis (P = 0.04). Patients with initial involvement of three or more sites had a somewhat higher prevalence of brain metastasis, although the difference was not statistically significant (P = 0.11). PATTERNS OF RELAPSE Fifty-six (69%) of the 81 relapses occurred in one or more of the initial sites involved by tumor. In six patients, relapses occurred simultaneously in a previously involved site along with new sites of involvement. Nineteen patients had recurrence in sites not previously involved by the tumor. Twelve of the new sites of metastases involved the central nervous system (brain or meninges), and the remainder occurred in extracranial sites. Excluding the patients with brain metastases, relapse in a previously unaffected site was thus very uncommon, Figure 1A. Metastatic breast carcinoma: duration of complete remission with combination chemotherapy. B. Metastatic breast carcinoma: duration of complete remission related to whether chemotherapy was instituted at the time of oophorectomy (early chemotherapy) or delayed until disease progression (delayed chemotherapy) after oophorectomy. affecting only 9% of the patients. There was no significant predilection for relapse in any particular site of previous involvement. However, metas- Legha et al. Breast Cancer Remissions 849

4 Table 2. Rate of Recurrence of Disease After Achievement of Complete Remission in Metastatic Breast Cancer Months from Number Number of Hazard SEM of Start of Entering Recurrences Rate* Hazard Rate Complete Interval Remission There have been 47 deaths in this group of complete remission patients, and the estimated percentage of patients surviving 3 years after start of chemotherapy was 59%. Patients with three or more sites of involvement when chemotherapy was initiated survived for significantly shorter periods than those with lesser number of metastatic sites. Patients treated with oophorectomy and early chemotherapy had significantly longer survival than those for whom chemotherapy was delayed, whether survival was measured from date of oophorectomy or from date of start of chemotherapy > * Risk of recurrence per month. tases involving the chest wall and pleura showed the highest frequency of first relapses; 21 of 45 patients (47%) with chest wall lesions and 13 of 30 (43%) with pleural lesions accounted for the first relapse, either alone or in combination with other sites. Patients with lymph node metastases had the lowest frequency of relapse, eight of 42 (20%). The proportion of relapses in previously known sites of disease in lung, bone, and liver were in the range of 34% to 36%. Seventeen of 47 (36%) patients in whom chemotherapy was discontinued after attainment of a complete remission have relapsed. Except for one patient who relapsed after 42 months off therapy, most relapses occurred within 12 months of discontinuation of therapy. SURVIVAL Discussion Although approximately one fifth of metastatic breast cancer patients treated with chemotherapy achieved a complete remission, these responses were usually of short duration. Only one third of the patients who achieved a complete remission remained in remission beyond 24 months, and although the recurrence rate dropped slightly after 30 months, there was no real evidence that recurrence rate was decreasing significantly with time. The tendency for relapse to occur in previously involved sites and the temporary nature of the complete remissions suggest that the fractional tumor cell kill with currently available chemotherapeutic agents in breast cancer is small and that many patients with complete response still have a substantial subclinical tumor burden. Because most patients relapsed while they were still receiving maintenance chemotherapy, it is obvious that their tumors had developed resistance to the maintenance thera py- The standard chemotherapeutic regimen for the treatment of metastatic breast cancer in our clinic has been the triple drug combination of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). During the past 5 years, we have attempted to introduce new agents into this regimen to improve the response rate, but without success. Another commonly used drug regimen for the treatment of metastatic breast cancer contains a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). The overall response rate and survival Table 3. Factors Affecting the Duration of Complete Remission and Frequency of Brain Metastases Among Patients with Complete Remission Characteristics Number of Number of Median Duration Patients with Brain Patients Recurrences of Complete Metastasis (Percent of Total) Remission Number (Percent) P\ Months P* All patients (16) Age < 50 years 52 (45) (17) 0.36 > 50 years 64 (55) (15) Disease-free interval <2 years 65 (56) (18) 0.41 >2 years 51 (44) (14) Number of involved sites 1,2 90 (78) (13) (22) o.iot 7 (29) Response to hormone therapy Responsive 9 (8) 8 15 Nonresponsive 21 (18) Oophorectomy > chemotherapy Early chemotherapy 23 (20) 8 33 Delayed chemotherapy 21 (18) (ID 8 (38) < (0) 5 (24) > * Two-tailed Wilcoxon test. t Chi-square test. j One-tailed Wilcoxon test, P = December 1979 Annals of Internal Medicine Volume 91 Number 6

5 results with the FAC regimen are superior to those reported with the CMF regimen, although the rate of complete remission is more or less similar (4, 5, 11). Many of our FAC protocols for metastatic breast cancer have used immunotherapy of one type or another; however, our overall results have not been significantly different from those reported by other institutions using similar chemotherapy but without immunotherapy. The question of the duration of maintenance chemotherapy in patients who achieve complete remission is not resolved. We have empirically continued chemotherapy for a total of 2 years in the responding patients. Whether shorter duration of chemotherapy would have given similar results needs to be investigated. Although there are many active antitumor agents for the management of metastatic breast cancer, they are most effective when used as the first-line chemotherapy. Failure of first-line chemotherapy leaves the patient with a very small chance for a second remission. This probably reflects development of nonspecific resistance to the commonly used second-line cytotoxic agents, most of which inherently have a low response rate. This could explain the general failure of the strategy of using alternating non-cross-resistant drug combinations in the treatment of metastatic breast cancer (12, 13). The availability of an effective secondary regimen and its utilization at a time when the patient has received most of the benefit from primary chemotherapy might prevent early relapses in breast cancer patients in complete remission. Development of newer and more potent drugs is the best hope for finding such back-up chemotherapy for consolidation of remissions achieved with the currently available drug regimens. One of the most effective therapies in breast cancer patients failing chemotherapy has been hormonal manipulation (14). This suggests that chemotherapy and endocrine treatments might have different cellular sites of action, which would support their combined use in the treatment of breast cancer. Two recent reports using simultaneous hormonochemotherapy for metastatic breast cancer have reported encouraging results (15, 16). Our observation of significantly longer remissions in patients who were treated with combined oophorectomychemotherapy regimens (the early chemotherapy group) lends further support to this concept. Based on these preliminary leads there there are at present a number of ongoing studies addressing the question of whether a combination hormonochemotherapy approach to the treatment of breast cancer would be superior to the current practice of using endocrine therapy and chemotherapy sequentially. At present simultaneous hormonochemotherapy would not be justified for routine practice until its superiority is conclusively proved in well-controlled studies. Most relapses among the patients in complete remission occurred in sites initially involved by the tumor. At present there are only a limited number of tools available for investigating the potential for improvement in the duration of complete remissions. Because radiotherapy has proven effectiveness against breast cancer, its use to local- Table 4. Characteristics of Patients Treated with Oophorectomy and Early Versus Delayed Chemotherapy Characteristics Early Chemo- Delayed Chemo- P Value therapy Group therapy Group Number of patients Median disease-free interval, months (range, 0 to 64) (range, 0 to 88) Extent of metastatic disease, no. patients (%) 1,2 sites 20 (87) 18 (86) sites 3(13) 3(14) Dominant sites Visceral 10 (43) 11 (52) Osseous 10 (43) 5(24) 0.34 Soft tissue 3(13) 5(24) ly consolidate the remissions achieved with chemotherapy might help prolong the complete remissions achieved with chemotherapy. This would be most suitable for patients whose tumors are localized to areas such as chest wall, lymph nodes, and isolated bone metastases. Because radiotherapy is a local modality of treatment, its use as a consolidation treatment may be most fruitful in conjunction with systemic modalities of treatment such as alternative chemotherapy or endocrine treatment. Consolidation treatment with systemic therapies should be used for the control of tumor in areas that cannot be safely irradiated or for micrometastases that may exist in the unirradiated sites. The late development of central nervous system metastases in patients in complete remission is of serious concern. Although half the central nervous system relapses in this series occurred in patients with progressive disease elsewhere, the other half occurred in patients free of systemic metastases who had the potential of long-term disease-free survival had this complication not occurred. Prophylactic cranial irradiation has been shown to significantly reduce the frequency of brain metastases in carcinoma of the lung (17, 18). Because cranial irradiation has established therapeutic activity against brain metastases from breast cancer, the large number of central nervous system relapses observed in breast cancer patients in remission warrants investigation of the usefulness of cranial irradiation in preventing this complication. We were unable to identify patients at high risk for central nervous system metastases, indicating the need for additional studies to characterize patients who would benefit most from such prophylactic therapy. Since most brain metastases from breast cancer affect the parenchyma rather than the leptomeninges, intrathecal chemotherapy is unlikely to prevent this complication except in the small proportion of patients who have only meningeal involvement (approximately 10% of all central nervous system metastases). In conclusion, our experience with metastatic breast cancer patients who attained complete remission with combination chemotherapy revealed their great propensity to relapse, most often in sites of initial involvement. Nevertheless, a small proportion of patients with widely Legha et al. Breast Cancer Remissions 851

6 metastatic disease did achieve 2 to 4 years of recurrencefree survival. Combined treatment with oophorectomy and chemotherapy resulted in the longest remissions. Brain metastases developed in a significant proportion of patients in complete remission. Combined-modality approaches with proper sequencing of chemotherapy and hormonotherapy, along with local consolidation with radiotherapy to sites of bulky tumor, have the potential of improving the frequency and quality of complete remissions in advanced breast cancer and need to be investigated. ACKNOWLEDGMENTS: Grant support: in part by contract N01-CM , National Institutes of Health; Bethesda, Maryland. Dr. Legha is a recipient of Junior Faculty Clinical Fellowship Award of the American Cancer Society. Requests for reprints should be addressed to Sewa S. Legha, M.D., Department of Developmental Therapeutics, M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Avenue, Houston, TX Received 25 June 1979; revision accepted 16 August References 1. SIMONE JV, AUR JA, HUSTU HO, VERZOSA MS, PINKEL D. Three to ten years after cessation of therapy in children with leukemia. Cancer. 1978;42(suppl): AISENBERG AC. The staging and treatment of Hodgkin's disease. N Engl J Med. 1978;299: FREI E, S ALL AN SE. Acute lymphoblastic leukemia: treatment. Cancer. 1978;42(suppl): CANNELLOS GP, DEVITA VT, GOLD GL, CHABNER BA, SCHEIN PS, YOUNG RC. Combination chemotherapy for advanced breast cancer: response and effect on survival. Ann Intern Med. 1976;84: GUTTERMAN JU, CARDENAS JO, BLUMENSCHEIN GR, et al. Chemoimmunotherapy of advanced breast cancer: prolongation of remission and survival with BCG. Br Med J. 1976;2: JONES SE, DURIE BGM, SALMON SE: Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer. 1975;36: SWENERTON K, LEGHA S, SMITH T, et al. Prognostic factors in metastatic breast cancer treated with combination chemotherapy. Cancer Res. 1979;39: KAPLAN EL, MEIER P. Non-parametric estimation from incomplete observations. J Am Statist Assoc. 1958;53: GEHAN EA. A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika. 1965;52: GEHAN EA. Estimating survival functions from the life table. / Clin Dis. 1969;21: BULL JM, TORMEY DC, Li SH, et al. Randomized comparative trial of Adriamycin versus methotrexate in combination drug therapy. Cancer. 1978;41: BRAMBILLA C, VALAGUSSA P, BONADONNA G. Sequential combination chemotherapy in advanced breast cancer. Cancer Chemother Pharmacol. 1978;1: KENNEALEY GT, BOSTON B, MITCHELL MS, et al. Combination chemotherapy in advanced breast cancer. Cancer. 1978;42: LEGHA SS, BUZDAR AU, HORTOBAYGI GN, et al. Tamoxifen in the treatment of metastatic breast cancer refractory to combination chemotherapy. JAMA. 1979;242: AHMANN DL, O'CONNELL MJ, HAHN RG, BISEL HF, LEE RA, ED MONSON JH. An evaluation of early or delayed adjuvant chemotherapy in premenopausal patients with advanced breast cancer undergoing oophorectomy. N Engl J Med. 1977;297: HOGE AF, BOTTOMLEY RH, SHAW MT, ASAL NR. Adrenalectomy and oophorectomy plus limited-term chemotherapy in the treatment of breast cancer. Cancer Treat Rep. 1976;60: Cox JD, PETROVICH Z, PAIG C, STANLEY K. Prophylactic cranial irradiation in patients with inoperable carcinoma of the lung. Cancer. 1978;42: CHRISTOPHER WJ. Prevention of brain extension in small-cell carcinoma of the bronchus. Med Pediatr Oncol. 1978;4: December 1979 Annals of Internal Medicine Volume 91 Number 6