Medical and Pediatric Oncology 2:55-60 (1976)
MlTOMYClN C IN LARGE INFREQUENT DOSES IN BREAST CANCER Gregory R. Wise, M. D., lrvin N. Kuhn, M. D., and Thomas E. Godfrey, M. D. Department of Medicine, Section of Oncology, Lorna Linda University, Lorna Linda, California
Seventy-one women with far-advanced breast cancer resistant t o standard chemotherapeutic agents were administered mitomycin C using an intermittent high dose schedule. One group consisted of 54 patients with measurable metastatic tumor; a second group consisted of 18 patients with nonmeasurable osseous metastases. Objective response rate in group 1 was 26% for an average duration of 2% months. Subjective response rate in group 2 was 44% for an average duration of 3 months. Response and toxicity data were similar t o those of studies employing the less convenient protracted low-dose schedule. Prior treatment with other alkylating agents did not adversely affect response. Further investigation into the role of mitomycin in combination chemotherapy programs is recommended. Key words: mitomycin C, breast cancer
Mitomycin C is an antibiotic isolated from the broth 0.f Streptomyces caespitosus. Also possessing antineoplastic activity, this deep blue-violet compound is thought to have a mechanism of action similar to that of the alkylating agents (1-4). For the past 15 years extensive research has documented its effectiveness in several types of human cancer. Recently the drug has been released by the Food and Drug Administration and is now marketed in this country as Mutamycin (Bristol Laboratories, Syracuse). The drug monograph lists its primary indications as adenocarcinomas of the stomach, pancreas and colon. Breast cancer is a secondary indication for mitomycin C in those patients with advanced disease after appropriate surgical, radiotherapeutic, hormonal and other chemotherapeutic modalities have failed. The Eastern Clinical Drug Evaluation Program in a Phase 11 screening study found an objective response rate of 36% in patients with breast cancer and recommended that more detailed investigation be undertaken (5). A brief review of the literature lists tumor response rates for breast cancer patients treated with mitomycin C ranging from 0 to 67% with an average of 40% (5-12).
Address reprint requests t o Dr. T. E. Godfrey, Lorna Linda University Medical Center, Lorna Linda, California 92354.
55
0 1976 Alan R. Liss, Inc., 150 Fifth Avenue, New York, N.Y. 10011
56
Wise, Kuhn, and Godfrey
The dosage administration schedule for mitomycin has been far from uniform in the literature, but the most commonly used regimen has been 0.05 mg/kg/daily for 6 days and then every other day until signs of toxicity appear or until a total of SO mg is attained (10, 12, 13). Sullivan compared the efficacy and toxicity of prolonged daily continuous infusions compared t o single daily injections and found no significant therapeutic differences (1 4). However, other early investigational work suggested that an intermittent dosage schedule might be less toxic as well as more efficacious in producing tumor response (15-20). A prior study done at this institution investigated the administration of mitomycin C in large infrequent doses t o 106 patients with various types of tumor including breast (21). That study demonstrated that toxicity and therapeutic effect did not differ significantly from studies using small daily doses but that the time saved and the greater convenience to both patient and physician were considerable by using the large infrequent dosage schedule. The present paper is a retrospective study investigating the toxicity and turn01 response of mitomycin C administered in large infrequent doses t o patients with far-advanced breast cancer. MATERIALS A N D METHODS
A total of 7 5 patients received mitomycin C o n an intermittent high-dose schedule. Three patients were excluded from the study; 2 were lost to follow-up, and 1 patient had a subjective response while receiving concurrent radiation and hormonal treatment. The average age of the remaining 7 2 patients was 56 years, with a range from 3 1 t o 8 2 . All patients were women with distant metastatic breast carcinoma who had received and had become resistant to appropriate radiation therapy, hormonal manipulation, and prior treatment with the standard alkylating and antimetabolite chemotherapeutic agents. Of the 7 2 evaluable patients, only 4 had not received prior alkylator therapy. Four other patients had not received prior antimetabolite therapy. Sixty-three patients had received both alkylator and antimetabolite therapy, and many patients had received additional chemotherapeutic agents such as CCNU, Adriamycin, vincristine, vinblastine, and prednisone. Only 2 patients were not either naturally or surgically postmenopausal; both of these patients had extensive hepatic metastases which generally d o not respond favorably to hormonal manipulation. The drug was supplied in vials containing 5 mg of mitomycin C in lyophilized powder form. After reconstitution with 10 cc of sterile water for injection, the drug was injected over 5-10 min through the tubing of an intravenous set containing normal saline. Care was exercised to avoid extravasation which would result in tissue slough. Most patients received an initial 20-30 mg of the drug followed in 1 week by an additional 10-20 mg dose. Responsive patients then received subsequent doses of 10-20 mg at 4-6 week intervals. Determination of dose and frequency was modified according to response, toxicity, and patient weight. Patients were divided into 2 groups depending upon accessibility of metastatic tumor t o objective measurement. Group 1 consisted of those patients with directly measurable tumor bulk, such as pulmonary and skin metastases. Only in these patients could objective tumor response be evaluated confidently. Complete objective response was defined as total disappearance of all metastatic tumor. Partial objective response was defined as a 50% reduction in tumor mass for a minimum of 1 month. For those lesions with only 2-dimensional measurements possible, response was equated with a 50% decrease in the sum of the products of the
57
Mitomycin C in Breast Cancer
perpendicular diameters of the lesions. Those patients in whom tumor bulk during therapy either remained the same or increased were regarded as treatment failures and were classified as nonresponders. Group 2 consisted of those patients whose tumor was confined solely to osseous metastases. Unfortunately there are no reliable methods currently available to quantify objective response to treatment of bone metastases. Recalcification of osteolytic lesions was rejected as a criterion of objective response because the average duration of response to mitomycin is too short to allow for the 3 or more months that is often necessary for recalcification of malignant bone lesions to become evident radiographically. Consequently these patients could not be evaluated in regard to objective response. Relief of bone pain was used as an admittedly poor but nonetheless important indication of tumor response. Subjective response was defined as a significant reduction of bone pain, as determined by the patient, for a minimum of 1 month. RESULTS
Table I summarizes our results of tumor response in regard to duration of response, prior chemotherapeutic agents, and principal site of metastasis. The 72 evaluable patients were separated into 2 groups. Group 1 consisted of 54 patients who had measurable tumor and who were evaluated for objective response. Group 2 consisted of 18 patients who had solely bone metastases and who were evaluated for subjective response. Fourteen patients (26%) of those with measurable tumor fulfilled the criteria for objective response. Of these 1 4 , 2 patients received a complete objective response with disappearance of all metastatic lesions. The average and median duration of response for the patients in Group 1 was 2.5 months, with a range from 1 to 8 months. When response TABLE I. Objective and Subjective Tumor Response in Relation to Patient Age, Duration of Response, Prior Chemotherapy and F’rincioal Site of Metastasis ~
~~~~
Number of patients Age in years range mean Duration of response Pr~ortreatment with alkylators Prior treatment with 5-FU Prior treatment with MTX Responders principal site of metastases liver lung skin-cutaneous remaining breast nodal peritoneal bone Totals
~
~
Group I Patients with measurable tumor
Group 2. Patients without medsurdble tumor @one metastases)
54
18
31 -82 55 2%mo (1-8)
40-77 58 3 mo (1% - 6 )
51 (94%) 49 (91%) 11 (20%)
16 (89%) 18 (100%) 2 (1 1%)
211 1 2/14 611 8
3/ I 112 011 ~
14/54 (26%)
~
~
~
~
-
8118 8/18 (44%)
58
Wise, Kuhn, and Godfrey
rates were broken down in respect to principal site of metastatic involvement, certain points became clear. As a group, 35% of the women with skin, subcutaneous, nodal, and opposite breast metastases responded to the drug; whereas only 2 out of 11 patients with hepatic metastases and only 2 out of 14 patients with pulmonary metastases responded to mitomycin. Group 2 consisted of 18 patients with osseous metastases as their sole site of tumor involvement. All 18 of these patients had subjective complaints of bone pain in areas documented to be involved by tumor. Eight (44%) of these patients had what was to them a significant reduction in bone pain for an average of 3 months, and they were classified as subjective responders. The subjective response in 3 of these patients was also supported by a marked improvement in the %Tc bone scan. Those patients receiving subjective responses characteristically noted significant decrease in bone pain occurring within the first week of treatment. TOXIC IT Y
Sixty-eight patients were evaluable for liematological toxicity. Table 11 gives our results in regard to leukopenia and thrombocytopenia. Only 13% developed severe leukopenia defined as a leukocyte count below 2,000/mm3. Only 14%developed severe thrombocytopenia defined as a platelet count below 50,000/mm3. Responding patients did not experience greater toxicity than nonresponders. N o patient developed severe hemorrhage or sepsis as a result of hematological toxicity. Other types of toxicity such as gastrointestinal side effects were difficult to evaluate in a retrospective study. We did not feel, however, that nausea, vomiting, or diarrhea were encountered any more commonly in this study than in those using a protracted lowdose schedule. A somewhat surprising finding was that 4 patients out of 72 (including one responder) developed localized herpes zoster infection while on mitomycin chemotherapy. Their clinical course did not differ from the usual infection that occasionally develops in cancer patients. Renal toxicity has been associated with mitomycin administration (22). Although serum creatinine and blood urea nitrogen determinations were not routinely preformed on our patients, only one developed significant azotemia. She had preexistent mild azotemia and hypertension prior to mitomycin therapy, and the deterioration of her renal function could have been explained solely on a renovascular basis. She did not come to necropsy. DISCUSSION
Our response rate of 26% may appear somewhat lower than that quoted by other investigators using a protracted low-dose program (6, 8 , 9 , 10, 12). Moore et al. (10) in a series of 42 patients report a response rate of 36%, with a 95% confidence limit of 225276, and our results would fall within this range. It should be noted that many of these studies have used criteria for objective response which have been much more liberal than ours. Furthermore, all of our patients, in contrast to those in other studies, had already become resistant to prior chemotherapeutic agents. If mitomycin had been used as the initial therapy, our response rate might have been higher. Most reports in the literature do not distinguish between breast cancer and other tumor types in relation to mitomycin toxicity. Moore et al. (10) studied toxicity in 292 patients with various types of cancer treated with mitomycin on a low protracted dosage program. They found 71% of treated patients with leukopenia below 4,000/mm3 and 65% with thrombocytopenia below 100,000/mm3.Our data give somewhat lower values of 64% and 49%,respectively. Comparing data between breast cancer patients and those with
Mitomycin C in Breast Cancer
59
TABLE II. Hematolomcal Toxicitv ~
WBC (/rnm3) ‘Total no. of patients (%) Objective responders (“/u)
Platelets (/rnm3)
4,000
100,000
19 (28) 211 4
55 (51) 11/14
(14)
(791
other types of solid tumors is subject to certain modifying considerations. Breast cancer has a well known predilection to spread to bone marrow with an inevitable effect on hematopoiesis. In addition, all of our patients had received prior chemotherapy and many had undergone extensive bone irradiation, both of which are known marrow suppressants. Had patients been treated with mitomycin earlier, their marrow reserve might have been less compromised and the drug’s effects on platelets and white cells less severe. In contrast to other reports using the protracted low-dose schedule, our study failed to identify a positive correlation between toxicity and tumor response (6, 10). Schimpff et al. (23) have reported a 1.8% frequency of herpes zoster in patients with solid tumors. A frequency of 3.5% has been reported in patients with breast carcinoma undergoing radiation (24). The occurrence of herpes zoster in our study may be reflecting an immunosuppressive effect that Sakauchi and DeWitt ( 2 5 ) have demonstrated for mitomycin. Although our data support the studies done by others which suggest a reduced toxicity in patients treated on an intermittent high-dose schedule, we do not believe that this reduction is necessarily a significant one. We do conclude that while the large infrequent dosage schedule may not differ in toxicity or response from the low protracted dosage schedule, the greater convenience and superior patient compliability of the former warrant its more general acceptance into clinical chemotherapy. Allowing for some variation in the amount of mitomycin we have been using, a safe intermittent high-dose schedule appears to be 0.5 mg of the drug per kilogram body weight (actual or ideal, whichever is less), given initially as a rapid intravenous infusion. An additional 0.2 mg/kg of the drug can be administered at monthly intervals, providing that WBC is above 4,000 and the platelet count is above 150,000. If the WBC is between 3,0004,000 and/or the platelet count is between 100,000-1 50,000, the dose should be reduced to 0.1 mg/kg. If the WBC or platelet count is below these levels withhold the dose until safe values return. The mechanism of action of mitomycin has been thought to be principally alkylation. This is partially supported by demonstration of cross-resistance between mitomycinresistant tumors and the use of other alkylating agents (3). However, this observation is not borne out in our study since 13 of 14 objective responders had already proven resistant to prior alkylator therapy. Consequently the clinician should not be hesitant to use mitomycin in the face of tumor resistance to other alkylating agents. Although combination chemotherapy has been used as treatment for advanced breast carcinoma since 1963, it remained for Cooper to popularize this approach in 1969 (26). He observed a significant increase in response when combination chemotherapy was utilized. More recently, Irwin et al. (27) have documented an increase in duration of response and survival when combination chemotherapy is utilized over single agents given sequentially. Since mitomycin has been particularly effective in breast cancer patients resistant to the standard chemotherapeutic agents, a logical extension of its use might be in its addition to a combination chemotherapy program.
60
Wise, Kuhn, and Godfrey
REFERENCES 1 . CLirter, S. K., Mitornycin C (NSC-26980) - clinical brochure. Cancer Chemother. Rep. 1:99-114, 1968. 2. Carter, S. K., Single and combination nonhormonal chemotherapy in breast cancer. Cancer 30: 1543-1555,1972. 3. Cheng, C. C., and Zee-Cheng, K., Some antineoplastic antibiotics. J . Pharm. Sci. 61:485-499, 1972. 4. Livingston, R., and Carter, S., Single agents in cancer chemotherapy. New York: Plenum Press, 1970. 5. Colsky, J., Escher, G . C., Evans, A,, Mitus, A., Li, M. C., Roath, S., Sullivan, R. D., Sykes, M. P., and Tan, C. T. C., Preliminary clinical pharmacology of mitomycin C. Proc. Am. Assoc. Cancer Res. 3:13, 1959 (abstr.). 6. Frank, W., and Osterberg, A. E., Mitomycin C (NSC-26980) - an evaluation of the Japanese reports. Cancer Chemother. Rep. 9:114-119, 1960. 7. Gary-Bobo, J., La mitomycinc seule e t an association thkrapeutiquc dans le traitement palliatif des tumeurs solides. J. Radiol. Electrol. Med. Nucl. 52:858-862, 1971. 8. Jones, R., Jr., Mitomycin C: A preliminary report of studies of human pharmacology and initial therapeutic trial. Cancer Chemother. Rep. 2:3-7, 1959. 9. Manheimer, L., and Vital, I., Mitomycin C in the therapy of far-advanced malignant tumors. Cancer 1 9 : 2 0 7 - 212, 1966. 10. Moore, G. E., Bross,I. D. J., Ausman, R., Nadler, S., Jones, R., Jr., Slack, N., and Rimm, A. A,, Effects of mitomycin C (NSC-26980) in 346 patients with advanced cancer. Cancer Chemother. Rep. 52:675-684, 1968. 11. Saba, Z., Hall, T. C., and Griffiths, C. T., Cancer chemotherapy following adrenalectomy in breast cancer patients. Cancer 23:1122-1125, 1969. 12. Shingleton, W. W., Sedransk, N., and Johnson, R. O., Systemic chemotherapy of mammary carcinoma. Ann. Surg. 173:913-918, 1971. 13. Watne, A. L., Moore, D., and Gorgun, B . , Solid tumor chemotherapy with mitomycin C. Arch. Surg. 95:175-178, 1967. 14. Sullivan, R. D., Clinical effects of the continuous and prolonged infusion of antibiotics in cancer Chemotherapy. Antimicrobial Agents and Chemotherapy. 4:540-544, 1964. 15. Comis, R. L., and Carter, S., A review of chemotherapy in gastric cancer. Cancer 34:1576-1586, 1974. 16. Hata, T., Hossenlopp, C., and Takita, H., Studies o n mitomycin C, especially method of administration. Cancer Chemother. Rep. 13:67-77, 1961. 17. Kenis, Y . , and Stryckmans, P., Action de la mitomycin C sur l'h6matopoiese dans le cancer en phase avancke. Nouv. Rev. Fr. Hematol. 4:15-30, 1964. 18. Kenis, Y., and Stryckmans, P., Letter to Editor. Intermittent dose schedule of mitomycin C (NSC-26980) in solid tumors. Cancer Chemother. Rep. 56-151, 1972. 19. Matsunaga, F., Shimoyama, T., Mikawa, K., and Ishiwata, J., Comparative study of methods of administering mitomycin C. Cancer 20:805-808, 1967. 20. Sokoloff, B., Nakabayashi, K., Enomoto, K., Miller, T., Bicknell, A., Bird, L., Trauner, W., Niswonger, J., and Renninger, G., Experimental studies o n mitomycin C. Growth 23: 109-1 35, 1959. 21. Godfrey, T. E., and Wilbur, D. W., Clinical experience with mitomycin C in large infrequent doses. Cancer 29:1647-1652, 1972. 22. Liu, K., Mittelman, A,, Sproul, E. E., and Elias, E. G., Renal toxicity in man treated with mitomycin C. Cancer 28:1314-1320, 1971. 23. Schimpff, S., Serpick, A,, Stoler, B., Rumack, B., Mellin, H., Joseph, J. M., and Block, J., Varicella-zoster infection in patients with cancer. Ann. Int. Med. 76:241-254, 1972. 24. Pendergrass, E. P., and Kirsh, D., The role of irradiation in the management of carcinoma of the breast. Radiology 51 :767-778, 1948. 25. Sakauchi, G., and DeWitt, C. W., Immunosuppressive activity of mitomycin C. Transplantation 5:248-255, 1967. 26. Cooper, R., Combination chemotherapy in hormone resistant breast cancer. Proc. Am. Assoc. Cancer Res. 10:15, 1969. 27. Irwin, L. E., Pugh, R., Sadoff, L., Hestorff, R., and Weiner, J., The influence on survival of combination chemotherapy vs. sequential single drug chemotherapy in patients with breast cancer. In Abstracts of the 11 th International Cancer Congress. 1974, p. 597 (abstr.).
MlTOMYClN C IN LARGE INFREQUENT DOSES IN BREAST CANCER Gregory R. Wise, M. D., lrvin N. Kuhn, M. D., and Thomas E. Godfrey, M. D. Department of Medicine, Section of Oncology, Lorna Linda University, Lorna Linda, California
Seventy-one women with far-advanced breast cancer resistant t o standard chemotherapeutic agents were administered mitomycin C using an intermittent high dose schedule. One group consisted of 54 patients with measurable metastatic tumor; a second group consisted of 18 patients with nonmeasurable osseous metastases. Objective response rate in group 1 was 26% for an average duration of 2% months. Subjective response rate in group 2 was 44% for an average duration of 3 months. Response and toxicity data were similar t o those of studies employing the less convenient protracted low-dose schedule. Prior treatment with other alkylating agents did not adversely affect response. Further investigation into the role of mitomycin in combination chemotherapy programs is recommended. Key words: mitomycin C, breast cancer
Mitomycin C is an antibiotic isolated from the broth 0.f Streptomyces caespitosus. Also possessing antineoplastic activity, this deep blue-violet compound is thought to have a mechanism of action similar to that of the alkylating agents (1-4). For the past 15 years extensive research has documented its effectiveness in several types of human cancer. Recently the drug has been released by the Food and Drug Administration and is now marketed in this country as Mutamycin (Bristol Laboratories, Syracuse). The drug monograph lists its primary indications as adenocarcinomas of the stomach, pancreas and colon. Breast cancer is a secondary indication for mitomycin C in those patients with advanced disease after appropriate surgical, radiotherapeutic, hormonal and other chemotherapeutic modalities have failed. The Eastern Clinical Drug Evaluation Program in a Phase 11 screening study found an objective response rate of 36% in patients with breast cancer and recommended that more detailed investigation be undertaken (5). A brief review of the literature lists tumor response rates for breast cancer patients treated with mitomycin C ranging from 0 to 67% with an average of 40% (5-12).
Address reprint requests t o Dr. T. E. Godfrey, Lorna Linda University Medical Center, Lorna Linda, California 92354.
55
0 1976 Alan R. Liss, Inc., 150 Fifth Avenue, New York, N.Y. 10011
56
Wise, Kuhn, and Godfrey
The dosage administration schedule for mitomycin has been far from uniform in the literature, but the most commonly used regimen has been 0.05 mg/kg/daily for 6 days and then every other day until signs of toxicity appear or until a total of SO mg is attained (10, 12, 13). Sullivan compared the efficacy and toxicity of prolonged daily continuous infusions compared t o single daily injections and found no significant therapeutic differences (1 4). However, other early investigational work suggested that an intermittent dosage schedule might be less toxic as well as more efficacious in producing tumor response (15-20). A prior study done at this institution investigated the administration of mitomycin C in large infrequent doses t o 106 patients with various types of tumor including breast (21). That study demonstrated that toxicity and therapeutic effect did not differ significantly from studies using small daily doses but that the time saved and the greater convenience to both patient and physician were considerable by using the large infrequent dosage schedule. The present paper is a retrospective study investigating the toxicity and turn01 response of mitomycin C administered in large infrequent doses t o patients with far-advanced breast cancer. MATERIALS A N D METHODS
A total of 7 5 patients received mitomycin C o n an intermittent high-dose schedule. Three patients were excluded from the study; 2 were lost to follow-up, and 1 patient had a subjective response while receiving concurrent radiation and hormonal treatment. The average age of the remaining 7 2 patients was 56 years, with a range from 3 1 t o 8 2 . All patients were women with distant metastatic breast carcinoma who had received and had become resistant to appropriate radiation therapy, hormonal manipulation, and prior treatment with the standard alkylating and antimetabolite chemotherapeutic agents. Of the 7 2 evaluable patients, only 4 had not received prior alkylator therapy. Four other patients had not received prior antimetabolite therapy. Sixty-three patients had received both alkylator and antimetabolite therapy, and many patients had received additional chemotherapeutic agents such as CCNU, Adriamycin, vincristine, vinblastine, and prednisone. Only 2 patients were not either naturally or surgically postmenopausal; both of these patients had extensive hepatic metastases which generally d o not respond favorably to hormonal manipulation. The drug was supplied in vials containing 5 mg of mitomycin C in lyophilized powder form. After reconstitution with 10 cc of sterile water for injection, the drug was injected over 5-10 min through the tubing of an intravenous set containing normal saline. Care was exercised to avoid extravasation which would result in tissue slough. Most patients received an initial 20-30 mg of the drug followed in 1 week by an additional 10-20 mg dose. Responsive patients then received subsequent doses of 10-20 mg at 4-6 week intervals. Determination of dose and frequency was modified according to response, toxicity, and patient weight. Patients were divided into 2 groups depending upon accessibility of metastatic tumor t o objective measurement. Group 1 consisted of those patients with directly measurable tumor bulk, such as pulmonary and skin metastases. Only in these patients could objective tumor response be evaluated confidently. Complete objective response was defined as total disappearance of all metastatic tumor. Partial objective response was defined as a 50% reduction in tumor mass for a minimum of 1 month. For those lesions with only 2-dimensional measurements possible, response was equated with a 50% decrease in the sum of the products of the
57
Mitomycin C in Breast Cancer
perpendicular diameters of the lesions. Those patients in whom tumor bulk during therapy either remained the same or increased were regarded as treatment failures and were classified as nonresponders. Group 2 consisted of those patients whose tumor was confined solely to osseous metastases. Unfortunately there are no reliable methods currently available to quantify objective response to treatment of bone metastases. Recalcification of osteolytic lesions was rejected as a criterion of objective response because the average duration of response to mitomycin is too short to allow for the 3 or more months that is often necessary for recalcification of malignant bone lesions to become evident radiographically. Consequently these patients could not be evaluated in regard to objective response. Relief of bone pain was used as an admittedly poor but nonetheless important indication of tumor response. Subjective response was defined as a significant reduction of bone pain, as determined by the patient, for a minimum of 1 month. RESULTS
Table I summarizes our results of tumor response in regard to duration of response, prior chemotherapeutic agents, and principal site of metastasis. The 72 evaluable patients were separated into 2 groups. Group 1 consisted of 54 patients who had measurable tumor and who were evaluated for objective response. Group 2 consisted of 18 patients who had solely bone metastases and who were evaluated for subjective response. Fourteen patients (26%) of those with measurable tumor fulfilled the criteria for objective response. Of these 1 4 , 2 patients received a complete objective response with disappearance of all metastatic lesions. The average and median duration of response for the patients in Group 1 was 2.5 months, with a range from 1 to 8 months. When response TABLE I. Objective and Subjective Tumor Response in Relation to Patient Age, Duration of Response, Prior Chemotherapy and F’rincioal Site of Metastasis ~
~~~~
Number of patients Age in years range mean Duration of response Pr~ortreatment with alkylators Prior treatment with 5-FU Prior treatment with MTX Responders principal site of metastases liver lung skin-cutaneous remaining breast nodal peritoneal bone Totals
~
~
Group I Patients with measurable tumor
Group 2. Patients without medsurdble tumor @one metastases)
54
18
31 -82 55 2%mo (1-8)
40-77 58 3 mo (1% - 6 )
51 (94%) 49 (91%) 11 (20%)
16 (89%) 18 (100%) 2 (1 1%)
211 1 2/14 611 8
3/ I 112 011 ~
14/54 (26%)
~
~
~
~
-
8118 8/18 (44%)
58
Wise, Kuhn, and Godfrey
rates were broken down in respect to principal site of metastatic involvement, certain points became clear. As a group, 35% of the women with skin, subcutaneous, nodal, and opposite breast metastases responded to the drug; whereas only 2 out of 11 patients with hepatic metastases and only 2 out of 14 patients with pulmonary metastases responded to mitomycin. Group 2 consisted of 18 patients with osseous metastases as their sole site of tumor involvement. All 18 of these patients had subjective complaints of bone pain in areas documented to be involved by tumor. Eight (44%) of these patients had what was to them a significant reduction in bone pain for an average of 3 months, and they were classified as subjective responders. The subjective response in 3 of these patients was also supported by a marked improvement in the %Tc bone scan. Those patients receiving subjective responses characteristically noted significant decrease in bone pain occurring within the first week of treatment. TOXIC IT Y
Sixty-eight patients were evaluable for liematological toxicity. Table 11 gives our results in regard to leukopenia and thrombocytopenia. Only 13% developed severe leukopenia defined as a leukocyte count below 2,000/mm3. Only 14%developed severe thrombocytopenia defined as a platelet count below 50,000/mm3. Responding patients did not experience greater toxicity than nonresponders. N o patient developed severe hemorrhage or sepsis as a result of hematological toxicity. Other types of toxicity such as gastrointestinal side effects were difficult to evaluate in a retrospective study. We did not feel, however, that nausea, vomiting, or diarrhea were encountered any more commonly in this study than in those using a protracted lowdose schedule. A somewhat surprising finding was that 4 patients out of 72 (including one responder) developed localized herpes zoster infection while on mitomycin chemotherapy. Their clinical course did not differ from the usual infection that occasionally develops in cancer patients. Renal toxicity has been associated with mitomycin administration (22). Although serum creatinine and blood urea nitrogen determinations were not routinely preformed on our patients, only one developed significant azotemia. She had preexistent mild azotemia and hypertension prior to mitomycin therapy, and the deterioration of her renal function could have been explained solely on a renovascular basis. She did not come to necropsy. DISCUSSION
Our response rate of 26% may appear somewhat lower than that quoted by other investigators using a protracted low-dose program (6, 8 , 9 , 10, 12). Moore et al. (10) in a series of 42 patients report a response rate of 36%, with a 95% confidence limit of 225276, and our results would fall within this range. It should be noted that many of these studies have used criteria for objective response which have been much more liberal than ours. Furthermore, all of our patients, in contrast to those in other studies, had already become resistant to prior chemotherapeutic agents. If mitomycin had been used as the initial therapy, our response rate might have been higher. Most reports in the literature do not distinguish between breast cancer and other tumor types in relation to mitomycin toxicity. Moore et al. (10) studied toxicity in 292 patients with various types of cancer treated with mitomycin on a low protracted dosage program. They found 71% of treated patients with leukopenia below 4,000/mm3 and 65% with thrombocytopenia below 100,000/mm3.Our data give somewhat lower values of 64% and 49%,respectively. Comparing data between breast cancer patients and those with
Mitomycin C in Breast Cancer
59
TABLE II. Hematolomcal Toxicitv ~
WBC (/rnm3) ‘Total no. of patients (%) Objective responders (“/u)
Platelets (/rnm3)
4,000
100,000
19 (28) 211 4
55 (51) 11/14
(14)
(791
other types of solid tumors is subject to certain modifying considerations. Breast cancer has a well known predilection to spread to bone marrow with an inevitable effect on hematopoiesis. In addition, all of our patients had received prior chemotherapy and many had undergone extensive bone irradiation, both of which are known marrow suppressants. Had patients been treated with mitomycin earlier, their marrow reserve might have been less compromised and the drug’s effects on platelets and white cells less severe. In contrast to other reports using the protracted low-dose schedule, our study failed to identify a positive correlation between toxicity and tumor response (6, 10). Schimpff et al. (23) have reported a 1.8% frequency of herpes zoster in patients with solid tumors. A frequency of 3.5% has been reported in patients with breast carcinoma undergoing radiation (24). The occurrence of herpes zoster in our study may be reflecting an immunosuppressive effect that Sakauchi and DeWitt ( 2 5 ) have demonstrated for mitomycin. Although our data support the studies done by others which suggest a reduced toxicity in patients treated on an intermittent high-dose schedule, we do not believe that this reduction is necessarily a significant one. We do conclude that while the large infrequent dosage schedule may not differ in toxicity or response from the low protracted dosage schedule, the greater convenience and superior patient compliability of the former warrant its more general acceptance into clinical chemotherapy. Allowing for some variation in the amount of mitomycin we have been using, a safe intermittent high-dose schedule appears to be 0.5 mg of the drug per kilogram body weight (actual or ideal, whichever is less), given initially as a rapid intravenous infusion. An additional 0.2 mg/kg of the drug can be administered at monthly intervals, providing that WBC is above 4,000 and the platelet count is above 150,000. If the WBC is between 3,0004,000 and/or the platelet count is between 100,000-1 50,000, the dose should be reduced to 0.1 mg/kg. If the WBC or platelet count is below these levels withhold the dose until safe values return. The mechanism of action of mitomycin has been thought to be principally alkylation. This is partially supported by demonstration of cross-resistance between mitomycinresistant tumors and the use of other alkylating agents (3). However, this observation is not borne out in our study since 13 of 14 objective responders had already proven resistant to prior alkylator therapy. Consequently the clinician should not be hesitant to use mitomycin in the face of tumor resistance to other alkylating agents. Although combination chemotherapy has been used as treatment for advanced breast carcinoma since 1963, it remained for Cooper to popularize this approach in 1969 (26). He observed a significant increase in response when combination chemotherapy was utilized. More recently, Irwin et al. (27) have documented an increase in duration of response and survival when combination chemotherapy is utilized over single agents given sequentially. Since mitomycin has been particularly effective in breast cancer patients resistant to the standard chemotherapeutic agents, a logical extension of its use might be in its addition to a combination chemotherapy program.
60
Wise, Kuhn, and Godfrey
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