Original Papers « 1991 S. Karger AG. Basel 0030 2414 91 0484 0265 S 2.75 0
Oncology 1991:48:265-269
Mitoxantrone as Second-Line Single Agent in Metastatic Breast Cancer Moshe Stein, Riva Borovik, Eliezer Robinson Northern Israel Oncology Center, Rambam Medical Center. Technion, Faculty of Medicine. Haifa, Israel
Key Words. Metastatic breast cancer • Second-line treatment • Response • Cardiotoxicity
Introduction Anthracyclines have long been shown to have sig nificant antitumor activity in several experimental and human neoplasms [1-3]. The most active of these compounds, Adriamycin, has been shown to achieve a response rate of 40% in previously untreated patients with advanced breast cancer, falling to 20% in chemotherapy-pretreated patients [4, 5]. Nevertheless, the cardiotoxicity and other side effects associated with Adriamycin have resulted in an unfavorable thera peutic ratio. Mitoxantrone (MIX), a dihydroxy-anthracenedione, has been the subject of many clinical trials in the treatment of metastatic breast cancer and other solid malignancies [6, 7], All these studies indicate that MIX has an activity in advanced breast cancer that is comparable to that of other anthracycline compounds in current use with
diminished cardiotoxicity [8-10]. This finding may be related to the lack of thedaunosamine group which is postulated to be the moiety responsible for anthracyline myocardial damage [11]. MIX has been evaluated in two broad screening phase II studies (South West Oncology Group; Euro pean Organization for Research or Treatment of Can cer) as a single-agent treatment for advanced breast cancer in patients refractory to previous chemothe rapy. The overall response rate in both trials was 11 % [12, 13], It is noteworthy that most patients in both studies had received prior Adriamycin. Those patients who received an initial dose of 13-14 mg/m2 showed a response rate of 31%. Other studies, enrolling pa tients heavily pretreated but with no previous ex posure to Adriamycin, showed a response rate that ranged between 20-25% with relatively modest toxi city [14, 15], Based on these reports, we gave MIX to metastatic
Downloaded by: Washington University 128.252.67.66 - 5/23/2018 1:10:24 PM
Abstract. Mitoxantrone (MIX), a member of the anthraquinone chemical class, was found to be a potential anticancer agent. It has a similar spectrum of activity as Adriamycin in experimental and human tumors. Thirty-five female patients with metastatic breast cancer, refractory to previous chemotherapy, were treated between 1986 and 1987 with MIX (14 mg/m2 i.v. every 3 weeks); patients with diffuse bone metastases or heavily pretreated patients received 10-12 mg/m2 MIX. All patients were evaluable for response and toxicity. Two patients achieved complete response and 4 partial response, giving an overall response rate of 17%. Median time of response was 5.5 months. The drug was well tolerated. Objective response was obtained mostly in patients with a performance status (Karnofsky scale) of more than 70%, and in those who received more than 12 mg/m2 MIX per course. One patient developed cardiomyopathy, another an acute myocardial infarction, and 3 patients had pathological changes on echocardiography or multigated nuclear angiography. Hematologi cal and gastrointestinal toxicity was tolerable. We found MIX to be a potentially effective second-line treatment with mild toxicity in patients with metastatic breast cancer.
Stein Borovik/Robinson
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Materials and Methods Thirty-five female patients who failed adjuvant or therapeutic chemotherapy for metastatic breast cancer entered this protocol between 1986 and 1987. All patients had at least one area of measur able or evaluable disease and a performance status (Karnofsky scale) of minimum 40%. Patients treated with adjuvant radio therapy or hormone therapy were also admitted to the protocol. Pretreatment assessment included height, weight, performance status, physical examination with measurement of lesions. Radio isotope liver and bone scans, skeletal survey and computerized tomography (CT) scans as indicated, chest X-ray, full blood count and biochemical screen. The protocol inclusion criteria demanded pretreatment white blood count of 4 x 10g/l, platelet count 120 x 10 g/1, bilirubin level within the normal range unless abnormality was attributable to proven liver involvement by the tumor. Cardiac function had to be found normal by clinical examina tion. electrocardiogram, nuclear cardioangiography or echocardio graphy. Patients with a prior history of congestive heart failure, myocardial infarction, active ischemic heart disease or uncontrolled hypertension were excluded from the protocol. MIX was administered as an intravenous infusion over 30 min diluted in 100 ml 5% dextrose in water at a dose of 14 mg/m2 every 21 days. Patients with diffuse bone mctastascs or heavily pretreated patients received 10-12 mg/m2 MIX. Treatment was delayed as necessary to permit the recovery of the white blood count to 4 x 10 g/1 and platelet count to 120 x 10 g/1, or to permit the resolution of any significant nonhematological toxicity. Cardiac assessment was performed before starting therapy, after cumulative dose of 60 mg/m2, 100 mg m2 or according to clinical findings. Toxicity was recorded employing World Health Organization criteria, and the criteria of response were those defined by the Union Internationale contrc le Cancer [16]. Concerning cardiac toxicity, we used the criteria originally suggested for Adriamycin by Alexan der ct al. [17], A complete response was defined as the complete disappearance of all signs of active disease, no new lesions and/or remineralization of lytic bone metastases. A partial response required a reduction of more than 50% in the sum of the products of the longest perpen dicular axes of measurable lesions and no development of new lesions. Stabilization was scored if there was no change that could be described as partial response or increasing disease, and pro gression was defined as more than 25% increase in the size of existing measurable lesions or the appearance of new lesions. The pretreatment characteristics arc given in table 1.
Results All 35 patients could be evaluated for response as well as for toxicity. Four patients received only 1
Table 1. Pretreatment characteristics of patients evaluated Patients, n Mean age, years Menopausal status Premenopausal Postmenopausal Median Karnofsky scale Prior therapy Adjuvant CM F CM F for metastatic disease Adriamycin-containing combinations Hormone therapy Radiotherapy
16 15 4 35 23
Predominant site of metastasis Bone Lung Liver Soft-tissue
9 6 12 8
35 54 (range 33-87) 7 28 6 (range 4-9)
CM F = Cyclophosphamide; methotrexate; 5-fluorouracil.
course of treatment, 13 patients between 2 and 4 courses and 18 patients more than 4 courses (the highest number of treatment courses was 9). The overall response rate was 17% and the median time of response was 5.5 months. Two patients with local recurrences (chest wall) showed a complete re gression of their disease. One of them received a total of 9 courses of MIX with a cumulative dose of 122.5 mg/m2. Treatment was stopped because of a marked decrease in the fractional shortening of the left ventricle, as demonstrated by echocardiogram. Four patients demonstrated partial regression of their metastatic disease, stabilization was noted in 11 patients and disease progression in 18 patients. Objec tive responses were mostly obtained in patients with soft-tissue metastasis and in those with a performance status over 70%. All responding patients received 12-14 mg/m2 per course. The survival of the 2 complete responders since the beginning of MIX therapy was 15 and 12 months. Median survival of the partial responders was 9 months, with stable disease 6.5 months and those whose disease progressed during treatment 4.2 months only. Toxicity
Myelosuppression was the most important side ef fect. Nineteen (54%) patients developed leukopenia and 3 patients showed thrombocytopenia below
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breast cancer patients who have been pretreated with chemotherapy in order to prove its effectiveness. This study summarizes the results of our experience.
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267
Table 2. Cardiac events associated with mitoxantrone therapy Patient No.
Age years
Risk factors/previous therapy
1
65
Postoperative adjuvant radiotherapy (left chest wall)
2
50
Adjuvant CMF/VA
112
3
64
None
122.5
4
50
Mitral stenosis (due to rheumatic fever)
144
5
61
Hypercholesterolemia
122.5
Dose received mg/m2 60
Abnormality
Outcome
Pathological ECHO (FS |) cardiomyopathy CHF LVEF | (MUGA); asymptomatic Pathological ECHO (FS j); asymptomatic Minimal pericardial effusion; no change in FS; asymptomatic FS j; dyspnea
Stopped treatment
Stopped treatment Slopped treatment Stopped treatment
Stopped treatment; 10 months later: acute MI (anteroseptal)
ECHO = Echocardiography; CH F = congestive heart failure; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; VA = Velbc. Adriamycin; LVEF = left ventricular ejection fraction; MUGA = multigated angiocardiography; FS = fractional shortening; MI = myocardial infarction; J, = decrease.
ing risk factors such as postoperative radiation thera py, hypercholesterolemia, mitral stenosis and prior therapy with Adriamycin.
Discussion MIX is a representative of a newly developed class of chemical compounds that has antineoplastic activ ity in experimental tumor models and in human can cer [1,3, 18]. MIX, like Adriamycin, has the potential to intercalate with DNA and to inhibit nucleic acid synthesis. This antitumor activity is related to the quinone functional groups [19], In vitro studies have shown that MIX can decrease cell survival, thymidine labeling and colony formation of T-47D human breast cancer cells [1, 19]. These effects depend on the MIX concentration. Using a clonogenic assay technique, Van Hoff et al. [20] demonstrated that surgical biopsies of tumors were also sensitive to MIX. Based on such studies, phase II trials of MIX were initiated in patients with metastatic breast cancer re fractory to other therapy. The response rates ranged
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100,000 with the lowest nadir 54,000. There were 4 episodes of neutropenic infection, 1 of these proved fatal. Fourteen (45%) patients developed mild to moderate nausea and/or vomiting and 9 (26%) pa tients mild alopecia. Other nonhematologic toxic ef fects included severe mucositis in a heavily pretreated patient and another patient a mild conjunctivitis. One patient who received a total cumulative dose of 144 mg/m2 developed transient paresthesia. MIX did not adversly effect renal or hepatic function. Five (14%) patients developed cardiac events asso ciated with MIX therapy (table 2). Only 2 patients (No. 1 and 5) had clinical manifestations of cardiac damage. The other 3 patients developed neither anam nestic nor clinical signs of heart failure. One patient (No. 5) died 10 months after reaching a cumulative dose of 122.5 mg/m2 due to acute myo cardial infarction. She had hypercholesterolemia which can be considered as a risk factor, but the role of MIX in this cardiac event seems more reasonable. No endomyocardial biopsies have been done and no autopsy was permitted by the family. It should be taken into consideration that 4 of the 5 patients with the cardiac events have had predispos
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268
in the presence of the amino sugar daunosamine as well as peroxidation of unsaturated membrane lipids and free-radical formation [26, 27], MIX lacks this amino sugar moeity, does not induce free-radical for mation and, paradoxically, inhibit lipid peroxidation [26, 28], Serial endomyocardial biopsies showed reversible (adaptive) signs simulating cardiomyopathy but with out the pathognomonic irreversible ultrastructure fea tures of myocytolysis, mitochondrial swelling, myofi brillar loss and cytoplasmatic vacuolization, charac teristics for Adriamycin cardiomyopathy [26, 29]. Nevertheless, the incidence of cardiomyopathy in patients receiving MIX as second-line treatment is somewhat higher than in those receiving it as a firstline treatment [9, 21, 30]. This is because the majority of these patients have been treated with prior anthra cycline chemotherapy and/or radiotherapy to the chest wall, making them more susceptible to conges tive heart failure. These facts imply the need for par ticular caution in any patient with previous exposure to anthracyclines or radiotherapy. In most reports, a statistically significant difference in favor of MIX was shown for toxicity parameters such as alopecia, mucositis/stomatitis, nausea and vomiting [24, 30-32]. In contrast, Adriamycin causes severe alopecia which occurs abruptly and has severe psychological effects; mucositis and stomatitis can become a grave problem, causing cessation of therapy. On the basis of our results, we can conclude that MIX is an active agent with tolerable toxicity and, hence, can provide a good quality of life in patients treated for metastatic breast cancer. MIX could well become the preferred drug in patients who are par ticularly prone to develop gastrointestinal toxicity (nausea, vomiting, stomatitis) and in those patients who refuse treatment because of alopecia. Added cau tion is required in patients with known cardiotoxicity risk factors, and careful monitoring of cardiac func tion is needed.
References 1 Durr FC: Biologic and biochemical effects of mitoxantrone. Semin Oncol 1984;11:3-10. 2 Wallace RE, Murdock KC, Angicr BB. et al; Activity of a novel anthraccnedionc l,4-dihydroxy-5.8,-bis (2-((2-hydroxyethyl)amino)-ethyl)amino)-9,10-anthracencdionc dihydrochlo ride. against experimental tumors in mice. Cancer Res 1979;39: 1570-1574.
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from 6 to 27% [14, 15, 21]. Out of a total of 410 patients reported in six studies, 57 (14%) responded with a complete or partial remission and with a mean duration response of 6 months. The response rate was dose dependent [13, 22], It is well known that second-line chemotherapy in metastatic breast cancer results in a lower response rate and shorter response duration. Most patients die within 1 year [23]. Adriamycin was found to be the most active single agent in the treatment of metastatic breast cancer as a first- or second-line treatment. In untreated patients, Adriamycin yields a response rate of 40%, whereas in previously treated patients, the response rate can reach 20% [5], Adriamycin alone or in combination is frequently used to palliate the symptoms of patients with meta static breast cancer who have failed a cyclophos phamide, methotrexate and 5-fluorouracil type regi men. The debilitating gastrointestinal and cardiotoxic side effects are a limit to the regular use of Adriamycin in previously treated metastatic breast cancer patients. On the other hand, randomized and nonrandomized trials showed that the response rate and duration of response to MIX are marginally inferior (but never statistically significant) compared to those achieved by Adriamycin, with much less incidence and severity of nonhematologic side effects [9, 24, 25], Consequently, the quality of life in patients receiving MIX is more acceptable. Since second-line treatment of advanced breast cancer can only be considered palliative, even in the face of good remission, the quality of life must remain the main goal. One of the reasons in selecting MIX for clinical use in previously treated metastatic breast cancer patients was the proven reduced cardiotoxicity compared with Adriamycin. Cardiotoxicity associated with MIX has been reported to be 0.9-4% and with doxorubicin 4.5-12% [8-10], Although the overall incidence of cardiac events has been reported to be low, a cardiotoxicity rate of 13% has been reported in patients previously treated with Adriamycin, after irradiation, prolonged treat ment with MIX or with preexisting cardiovascular damage [8, 21], All these risk factors were present among our patients. Among the suggested mechanisms of anlhracycline-induced cardiomyopathy are myocardial uptake
Mitoxantrone in Metastatic Breast Cancer
19 Murdock KC. Wallace RE, White RJ. ct al: Discovery and preclinical development of Novantrone; in Coltman CA Jr (ed): The Current Status of Novantrone. New York. Wiley, 1985. pp 3-13. 20 Van Hoff DD. Coltman CA, Forscth B: Activity of mitoxantronc in human tumor cloning assay. Cancer Res 1981:41: 1853-1855. 21 Smith IE: Mitoxantrone (Novantrone): A review of experimen tal and early clinical studies. Cancer Treat Rev 1983:10:103 115. 22 Stewart DJ: Development of mitoxantrone in breast cancer: in Salmon SE. Ogawa U (cds): Rational Development of a New Anti-Cancer Agent. Proc 14th Int Congr Chemotherapy. Tokyo. 1986. pp 21 26. 23 George SL, Hoogstraten B: Prognostic factors in the initial response to therapy by patients with advanced breast cancer. J Natl Cancer Inst 1978:60:731 736. 24 Henderson IC, Allegra JC. Woodcock T, et al: Randomized clinical trial comparing mitoxantrone with doxorubicin in pre viously treated patients with metastatic breast cancer. J Clin Oncol 1989:7:560-571. 25 Ncidhart J A. Gochnour D. Roach R, ct al: Comparable efficacy of Novantrone and Adriamycin in breast cancer; in Coltman CA Jr (ed): The Current Status of Novantrone. New York. 1985. pp 39-43. 26 White RJ, Durr FE: Development of mitoxantrone. Invest New' Drugs 1985:3:85-93. 27 Brener H. Brener J: Cancer treatment with anthracyclines. Harcfuah 1983:104:205-206. 28 Kharasch ED. Novak RF: Inhibition of Adriamycin-stimulated microsomal lipid peroxidation by mitoxantrone and ametantrone. two new' anthracenedione antineoplastic agents. Biochcm Biophys Res Commun 1982;108:1346-1352. 29 Sparano BM. Gordon G. Hall C. el al: Safety assessment of a new' anti-cancer compound, mitoxantrone. in beagle dogs. II. Histologic and ultrastructural pathology. Cancer Treat Rep 1982:66:1145-1158. 30 Posner LE. Dukart G. Gcldbcrg J. ct al: Mitoxantrone: An overview of safety and toxicity. Invest New Drugs !985;3: 123-132. 31 Weiss RB: Mitoxantrone: Its development and role in clinical practice. Oncology 1989:3:135-147. 32 Robertson JFR. Williams M R. Todd JH. ct al: Mitoxantrone A useful palliative therapy in advanced breast cancer. Am J Clin Oncol 1989;12:393-397.
Dr. M. Stein Northern Israel Oncology Center Rambam Medical Center Haifa (Israel)
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3 Anderson KC, Cohen G l, Garnick MB: Phase II trial of mit oxantrone. Cancer Treat Rep 1982:66:1929 1931. 4 Nemoto T. Rosner D, Diaz R. et al: Combination chemo therapy for metastatic breast cancer. Cancer 1978;41 : 2073-2077. 5 Ingle JN, Green SJ, Brunk SF. et al: Randomized clinical trials of doxorubicin alone or combined with mitolactol in women with advanced breast cancer and prior chemotherapy exposure. Am J Clin Oncol 1985;8:275-282. 6 Cornbleet MA. Stuart-Harris RC, Smith IF.: Mitoxantrone for the treatment of advanced breast cancer: Single agent therapy in previously untreated patients. Fur J Cancer Clin Oncol 1984;20:1141-1146. 7 Gams RA, Steinberg J. Posner L: Mitoxantrone in malignant lymphoma. Semin Oncol 1984:11:47-49. 8 Benjamin RS, Chawla SP, Ewer MS. ct al: Evaluation of mitoxantrone cardiac toxicity by nuclear angiography and endomyocardial biopsy: An update. Invest New Drugs 1985; 3:117-121. 9 Henderson IC. Wolff SN, Allegra JC. et al: A randomized trial comparing mitoxantrone and doxorubicin in patients with metastatic breast cancer, in Coltman CA Jr (ed): The Current Status of Novantrone. Advances in Cancer Chemotherapy. San Antonio. 1985. pp 45-53. 10 Cowan JD. Osborne CK, Constanzi JJ, et al: Randomized trial of Novantrone (N), bisantrcnc (B) and Adriamycin (A) in ad vanced breast cancer (abstract). Proc Am Soc Clin Oncol 1985; 5:59. 11 Double JC. Brown JR: Evaluation of the binding of some anthraquinones and naphtacenequinones to DNA. J Pharm Pharmacol 1976:28:116 169. 12 Knight WA. Van Hoff D. Tranwin B. et al: Phase II trial of dihydroxyanthracenedione (DHAD. mitoxantrone) in breast cancer. A Southwest Oncology Group (SWOG) study (ab stract). Proc Am Soc Clin Oncol 1982:1:86. 13 De Jagcr R: EORTC phase II clinical trial of mitoxantrone: Results of a broad screening programme (data on file). Lederle Laboratories. 1982. 14 Lenzhofcr R. Rainer H. Schuster R. et al: Mitoxantrone in the primary treatment of metastasizing breast cancer. Wien Med Wochenschr 1984;96:319-326. 15 Osborne CK. Cowan JD, Niedhart JA, et al: The Southwest Oncology Group randomized trial of Novantrone, Adriamycin and Bisantrene in advanced breast cancer; in Coltman CA Jr (ed): The Current Status of Novantrone. New York. Wiley, 1985: pp 55 58. 16 Hayward J L. Rubens RD. Carbone PP: Assessment of response to therapy in advanced breast cancer. Br J Cancer I972;35: 292-298. 17 Alexander J, Dainiak N. Berger HJ. ct al: Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med 1979:300:278-283. 18 Jones SE, Dean IC, Young LA. et al: The human tumor clonogenic assay in human breast cancer. J Clin Oncol 1985;3:92-97.
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Oncology 1991:48:265-269
Mitoxantrone as Second-Line Single Agent in Metastatic Breast Cancer Moshe Stein, Riva Borovik, Eliezer Robinson Northern Israel Oncology Center, Rambam Medical Center. Technion, Faculty of Medicine. Haifa, Israel
Key Words. Metastatic breast cancer • Second-line treatment • Response • Cardiotoxicity
Introduction Anthracyclines have long been shown to have sig nificant antitumor activity in several experimental and human neoplasms [1-3]. The most active of these compounds, Adriamycin, has been shown to achieve a response rate of 40% in previously untreated patients with advanced breast cancer, falling to 20% in chemotherapy-pretreated patients [4, 5]. Nevertheless, the cardiotoxicity and other side effects associated with Adriamycin have resulted in an unfavorable thera peutic ratio. Mitoxantrone (MIX), a dihydroxy-anthracenedione, has been the subject of many clinical trials in the treatment of metastatic breast cancer and other solid malignancies [6, 7], All these studies indicate that MIX has an activity in advanced breast cancer that is comparable to that of other anthracycline compounds in current use with
diminished cardiotoxicity [8-10]. This finding may be related to the lack of thedaunosamine group which is postulated to be the moiety responsible for anthracyline myocardial damage [11]. MIX has been evaluated in two broad screening phase II studies (South West Oncology Group; Euro pean Organization for Research or Treatment of Can cer) as a single-agent treatment for advanced breast cancer in patients refractory to previous chemothe rapy. The overall response rate in both trials was 11 % [12, 13], It is noteworthy that most patients in both studies had received prior Adriamycin. Those patients who received an initial dose of 13-14 mg/m2 showed a response rate of 31%. Other studies, enrolling pa tients heavily pretreated but with no previous ex posure to Adriamycin, showed a response rate that ranged between 20-25% with relatively modest toxi city [14, 15], Based on these reports, we gave MIX to metastatic
Downloaded by: Washington University 128.252.67.66 - 5/23/2018 1:10:24 PM
Abstract. Mitoxantrone (MIX), a member of the anthraquinone chemical class, was found to be a potential anticancer agent. It has a similar spectrum of activity as Adriamycin in experimental and human tumors. Thirty-five female patients with metastatic breast cancer, refractory to previous chemotherapy, were treated between 1986 and 1987 with MIX (14 mg/m2 i.v. every 3 weeks); patients with diffuse bone metastases or heavily pretreated patients received 10-12 mg/m2 MIX. All patients were evaluable for response and toxicity. Two patients achieved complete response and 4 partial response, giving an overall response rate of 17%. Median time of response was 5.5 months. The drug was well tolerated. Objective response was obtained mostly in patients with a performance status (Karnofsky scale) of more than 70%, and in those who received more than 12 mg/m2 MIX per course. One patient developed cardiomyopathy, another an acute myocardial infarction, and 3 patients had pathological changes on echocardiography or multigated nuclear angiography. Hematologi cal and gastrointestinal toxicity was tolerable. We found MIX to be a potentially effective second-line treatment with mild toxicity in patients with metastatic breast cancer.
Stein Borovik/Robinson
266
Materials and Methods Thirty-five female patients who failed adjuvant or therapeutic chemotherapy for metastatic breast cancer entered this protocol between 1986 and 1987. All patients had at least one area of measur able or evaluable disease and a performance status (Karnofsky scale) of minimum 40%. Patients treated with adjuvant radio therapy or hormone therapy were also admitted to the protocol. Pretreatment assessment included height, weight, performance status, physical examination with measurement of lesions. Radio isotope liver and bone scans, skeletal survey and computerized tomography (CT) scans as indicated, chest X-ray, full blood count and biochemical screen. The protocol inclusion criteria demanded pretreatment white blood count of 4 x 10g/l, platelet count 120 x 10 g/1, bilirubin level within the normal range unless abnormality was attributable to proven liver involvement by the tumor. Cardiac function had to be found normal by clinical examina tion. electrocardiogram, nuclear cardioangiography or echocardio graphy. Patients with a prior history of congestive heart failure, myocardial infarction, active ischemic heart disease or uncontrolled hypertension were excluded from the protocol. MIX was administered as an intravenous infusion over 30 min diluted in 100 ml 5% dextrose in water at a dose of 14 mg/m2 every 21 days. Patients with diffuse bone mctastascs or heavily pretreated patients received 10-12 mg/m2 MIX. Treatment was delayed as necessary to permit the recovery of the white blood count to 4 x 10 g/1 and platelet count to 120 x 10 g/1, or to permit the resolution of any significant nonhematological toxicity. Cardiac assessment was performed before starting therapy, after cumulative dose of 60 mg/m2, 100 mg m2 or according to clinical findings. Toxicity was recorded employing World Health Organization criteria, and the criteria of response were those defined by the Union Internationale contrc le Cancer [16]. Concerning cardiac toxicity, we used the criteria originally suggested for Adriamycin by Alexan der ct al. [17], A complete response was defined as the complete disappearance of all signs of active disease, no new lesions and/or remineralization of lytic bone metastases. A partial response required a reduction of more than 50% in the sum of the products of the longest perpen dicular axes of measurable lesions and no development of new lesions. Stabilization was scored if there was no change that could be described as partial response or increasing disease, and pro gression was defined as more than 25% increase in the size of existing measurable lesions or the appearance of new lesions. The pretreatment characteristics arc given in table 1.
Results All 35 patients could be evaluated for response as well as for toxicity. Four patients received only 1
Table 1. Pretreatment characteristics of patients evaluated Patients, n Mean age, years Menopausal status Premenopausal Postmenopausal Median Karnofsky scale Prior therapy Adjuvant CM F CM F for metastatic disease Adriamycin-containing combinations Hormone therapy Radiotherapy
16 15 4 35 23
Predominant site of metastasis Bone Lung Liver Soft-tissue
9 6 12 8
35 54 (range 33-87) 7 28 6 (range 4-9)
CM F = Cyclophosphamide; methotrexate; 5-fluorouracil.
course of treatment, 13 patients between 2 and 4 courses and 18 patients more than 4 courses (the highest number of treatment courses was 9). The overall response rate was 17% and the median time of response was 5.5 months. Two patients with local recurrences (chest wall) showed a complete re gression of their disease. One of them received a total of 9 courses of MIX with a cumulative dose of 122.5 mg/m2. Treatment was stopped because of a marked decrease in the fractional shortening of the left ventricle, as demonstrated by echocardiogram. Four patients demonstrated partial regression of their metastatic disease, stabilization was noted in 11 patients and disease progression in 18 patients. Objec tive responses were mostly obtained in patients with soft-tissue metastasis and in those with a performance status over 70%. All responding patients received 12-14 mg/m2 per course. The survival of the 2 complete responders since the beginning of MIX therapy was 15 and 12 months. Median survival of the partial responders was 9 months, with stable disease 6.5 months and those whose disease progressed during treatment 4.2 months only. Toxicity
Myelosuppression was the most important side ef fect. Nineteen (54%) patients developed leukopenia and 3 patients showed thrombocytopenia below
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breast cancer patients who have been pretreated with chemotherapy in order to prove its effectiveness. This study summarizes the results of our experience.
Mitoxantrone in Metastatic Breast Cancer
267
Table 2. Cardiac events associated with mitoxantrone therapy Patient No.
Age years
Risk factors/previous therapy
1
65
Postoperative adjuvant radiotherapy (left chest wall)
2
50
Adjuvant CMF/VA
112
3
64
None
122.5
4
50
Mitral stenosis (due to rheumatic fever)
144
5
61
Hypercholesterolemia
122.5
Dose received mg/m2 60
Abnormality
Outcome
Pathological ECHO (FS |) cardiomyopathy CHF LVEF | (MUGA); asymptomatic Pathological ECHO (FS j); asymptomatic Minimal pericardial effusion; no change in FS; asymptomatic FS j; dyspnea
Stopped treatment
Stopped treatment Slopped treatment Stopped treatment
Stopped treatment; 10 months later: acute MI (anteroseptal)
ECHO = Echocardiography; CH F = congestive heart failure; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; VA = Velbc. Adriamycin; LVEF = left ventricular ejection fraction; MUGA = multigated angiocardiography; FS = fractional shortening; MI = myocardial infarction; J, = decrease.
ing risk factors such as postoperative radiation thera py, hypercholesterolemia, mitral stenosis and prior therapy with Adriamycin.
Discussion MIX is a representative of a newly developed class of chemical compounds that has antineoplastic activ ity in experimental tumor models and in human can cer [1,3, 18]. MIX, like Adriamycin, has the potential to intercalate with DNA and to inhibit nucleic acid synthesis. This antitumor activity is related to the quinone functional groups [19], In vitro studies have shown that MIX can decrease cell survival, thymidine labeling and colony formation of T-47D human breast cancer cells [1, 19]. These effects depend on the MIX concentration. Using a clonogenic assay technique, Van Hoff et al. [20] demonstrated that surgical biopsies of tumors were also sensitive to MIX. Based on such studies, phase II trials of MIX were initiated in patients with metastatic breast cancer re fractory to other therapy. The response rates ranged
Downloaded by: Washington University 128.252.67.66 - 5/23/2018 1:10:24 PM
100,000 with the lowest nadir 54,000. There were 4 episodes of neutropenic infection, 1 of these proved fatal. Fourteen (45%) patients developed mild to moderate nausea and/or vomiting and 9 (26%) pa tients mild alopecia. Other nonhematologic toxic ef fects included severe mucositis in a heavily pretreated patient and another patient a mild conjunctivitis. One patient who received a total cumulative dose of 144 mg/m2 developed transient paresthesia. MIX did not adversly effect renal or hepatic function. Five (14%) patients developed cardiac events asso ciated with MIX therapy (table 2). Only 2 patients (No. 1 and 5) had clinical manifestations of cardiac damage. The other 3 patients developed neither anam nestic nor clinical signs of heart failure. One patient (No. 5) died 10 months after reaching a cumulative dose of 122.5 mg/m2 due to acute myo cardial infarction. She had hypercholesterolemia which can be considered as a risk factor, but the role of MIX in this cardiac event seems more reasonable. No endomyocardial biopsies have been done and no autopsy was permitted by the family. It should be taken into consideration that 4 of the 5 patients with the cardiac events have had predispos
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in the presence of the amino sugar daunosamine as well as peroxidation of unsaturated membrane lipids and free-radical formation [26, 27], MIX lacks this amino sugar moeity, does not induce free-radical for mation and, paradoxically, inhibit lipid peroxidation [26, 28], Serial endomyocardial biopsies showed reversible (adaptive) signs simulating cardiomyopathy but with out the pathognomonic irreversible ultrastructure fea tures of myocytolysis, mitochondrial swelling, myofi brillar loss and cytoplasmatic vacuolization, charac teristics for Adriamycin cardiomyopathy [26, 29]. Nevertheless, the incidence of cardiomyopathy in patients receiving MIX as second-line treatment is somewhat higher than in those receiving it as a firstline treatment [9, 21, 30]. This is because the majority of these patients have been treated with prior anthra cycline chemotherapy and/or radiotherapy to the chest wall, making them more susceptible to conges tive heart failure. These facts imply the need for par ticular caution in any patient with previous exposure to anthracyclines or radiotherapy. In most reports, a statistically significant difference in favor of MIX was shown for toxicity parameters such as alopecia, mucositis/stomatitis, nausea and vomiting [24, 30-32]. In contrast, Adriamycin causes severe alopecia which occurs abruptly and has severe psychological effects; mucositis and stomatitis can become a grave problem, causing cessation of therapy. On the basis of our results, we can conclude that MIX is an active agent with tolerable toxicity and, hence, can provide a good quality of life in patients treated for metastatic breast cancer. MIX could well become the preferred drug in patients who are par ticularly prone to develop gastrointestinal toxicity (nausea, vomiting, stomatitis) and in those patients who refuse treatment because of alopecia. Added cau tion is required in patients with known cardiotoxicity risk factors, and careful monitoring of cardiac func tion is needed.
References 1 Durr FC: Biologic and biochemical effects of mitoxantrone. Semin Oncol 1984;11:3-10. 2 Wallace RE, Murdock KC, Angicr BB. et al; Activity of a novel anthraccnedionc l,4-dihydroxy-5.8,-bis (2-((2-hydroxyethyl)amino)-ethyl)amino)-9,10-anthracencdionc dihydrochlo ride. against experimental tumors in mice. Cancer Res 1979;39: 1570-1574.
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from 6 to 27% [14, 15, 21]. Out of a total of 410 patients reported in six studies, 57 (14%) responded with a complete or partial remission and with a mean duration response of 6 months. The response rate was dose dependent [13, 22], It is well known that second-line chemotherapy in metastatic breast cancer results in a lower response rate and shorter response duration. Most patients die within 1 year [23]. Adriamycin was found to be the most active single agent in the treatment of metastatic breast cancer as a first- or second-line treatment. In untreated patients, Adriamycin yields a response rate of 40%, whereas in previously treated patients, the response rate can reach 20% [5], Adriamycin alone or in combination is frequently used to palliate the symptoms of patients with meta static breast cancer who have failed a cyclophos phamide, methotrexate and 5-fluorouracil type regi men. The debilitating gastrointestinal and cardiotoxic side effects are a limit to the regular use of Adriamycin in previously treated metastatic breast cancer patients. On the other hand, randomized and nonrandomized trials showed that the response rate and duration of response to MIX are marginally inferior (but never statistically significant) compared to those achieved by Adriamycin, with much less incidence and severity of nonhematologic side effects [9, 24, 25], Consequently, the quality of life in patients receiving MIX is more acceptable. Since second-line treatment of advanced breast cancer can only be considered palliative, even in the face of good remission, the quality of life must remain the main goal. One of the reasons in selecting MIX for clinical use in previously treated metastatic breast cancer patients was the proven reduced cardiotoxicity compared with Adriamycin. Cardiotoxicity associated with MIX has been reported to be 0.9-4% and with doxorubicin 4.5-12% [8-10], Although the overall incidence of cardiac events has been reported to be low, a cardiotoxicity rate of 13% has been reported in patients previously treated with Adriamycin, after irradiation, prolonged treat ment with MIX or with preexisting cardiovascular damage [8, 21], All these risk factors were present among our patients. Among the suggested mechanisms of anlhracycline-induced cardiomyopathy are myocardial uptake
Mitoxantrone in Metastatic Breast Cancer
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Dr. M. Stein Northern Israel Oncology Center Rambam Medical Center Haifa (Israel)
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