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Bleomycin, vincristine, and methotrexate with citrovorum factor rescue in the treatment of advanced squamous cell carcinoma of the cervix
GYNECOLOGIC
ONCOLOGY
19, 57-59 (1984)
Bleomycin, Vincristine, and Methotrexate with Citrovorum Factor Rescue in the Treatment of Advanced Squamous Cell Carcinoma of the Cervix EDWARD Division
V. HANNIGAN, M.D. ,l E. ARCHER DILLARD, JR., M.D., AND TUNG VAN DINH, M.D.
of Gynecologic
Oncology, Department of Obstetrics and Gynecology, Medical Branch, Galveston, Texas 77550
University
of Texas
Fourteen patients with advanced or locally recurrent squamous cell carcinoma of the uterine cervix were treated with bleomycin, vincristine, and moderately high dose methotrexate with citrovorum rescue. Two patients (14%) had a partial response; no patient had a complete response. Two patients were felt to have signihcant bleomycin associated pulmonary toxicity. This chemotherapy regimen is not felt to be clinically useful in our patient population.
Bleomycin containing combination chemotherapy regimens have been widely used for advanced or locally recurrent squamous cell carcinoma of the uterine cervix. Results obtained with these regimens vary widely [l-6]. Behnam et al. [7] utilizing a regimen of bleomycin, vincristine, and methotrexate recently reported a response rate of 53% in 17patients (1 complete responder and 8 partial responders). They felt a significant dose limiting factor in therapy was methotrexate associated myelosuppression which prevented administration of the regimen at regular intervals, and suggested this toxicity might be reduced by the concomitant use of citrovorum factor with high dose methotrexate. This paper reports our experience at the University of Texas Medical Branch at Galveston with the use of bleomycin, vincristine, and methotrexate with citrovorum factor rescue in patients with advanced squamous cell carcinoma of the uterine cervix. MATERIALS AND METHODS Between July 1981and December 1982 14 patients were treated with combination bleomycin, vincristine, and methotrexate with citrovorum factor rescue. To be eligible for inclusion in the study a patient was required to have easily measurable recurrent or advanced histologically proven squamous cell carcinoma of the cervix, to have had no prior cytotoxic chemotherapy, to have a Karnofsky performance status of 60 or greater, and to have no impairment of kidney and/ or liver and/or pulmonary function. The median age of the treated patients was ’ To whom correspondence should be addressed. 57 0090-8258184$1.50 Copyright 0 1984 by Academic Press, Inc. All rights of reproduction in any form reserved.
58
HANNIGAN,
DILLARD,
AND
DINH
53 with a range from 33 to 75 years. Ten patients had been previously treated with pelvic irradiation; 4 had received no prior irradiation therapy. The initial stage was IB in 3 patients, IIA in 5 patients, IIB in 1 patient, IIIB in 3 patients, and IVB in 2 patients. The site of the measurable lesion was in the pelvis in 10 patients and in the lung in 4 patients. For the 10 patients who had previously been treated with potentially curative irradiation therapy, the median time from initial diagnosis to the evidence of recurrent disease was 11 months with a range of 5 to 91 months. The patients were treated every 28 days. Bleomycin was given as a 60-hr intravenous infusion with a total dose of 60 mg per course. Vincristine was given intravenously, 1.5 mg/i’@, with the total dose not to exceed 2.5 mg. Following the vincristine, methotrexate (150 mg/M*) was given intravenously. After 12 hr citrovorum factor was administered at a rate of 12 mg every 6 hr for 8 doses. This regimen was repeated every 28 days until there was evidence of growing tumor. A patient was said to have a complete response to chemotherapy if all known carcinoma disappeared for at least 2 months, and a partial response if there was at least a 50% decrease in the sum of the two greatest diameters of all measurable lesions lasting for 2 months. During this period of partial response there could be no growth of cancer at any other site. RESULTS Fourteen patients received a total of 40 courses of combination chemotherapy. No patient had a complete response. Two patients met the criteria for a partial response for a rate of 14%. Both partial responses lasted 2 months. The measurable lesion in both patients was located in the pelvis and had previously received high doses of pelvic irradiation. One patient had a 6 x 7-cm mass located in the pelvis, visible in the vagina, which decreased to a small linear streak at the apex of the vagina. The second patient had an irregularly shaped 6 x 6-cm mass fixed to the right pelvic wall in the area of the common iliac vessels. This mass, which was easily palpable on physical examination and easily imagable with CT scanning of the pelvis, decreased in size to 2 X 3 cm for a 2-month period before beginning to grow. In addition, there were two patients with pulmonary metastases that decreased in size. These decreases, however, were not of sufficient size to meet the criteria for partial responses. Both patients had progression of their disease after 1 month. The two responders lived 6 and 7 months, respectively, from the onset of chemotherapy. Two patients remain alive with growing disease 4 and 7 months after beginning chemotherapy. The remaining 10 patients expired with a median survival of 9 months. The most significant toxicity associated with the combination was pulmonary impairment, with 2 patients developing significant pulmonary compromise. One patient was noted to have a marked decrease in her pulmonary function as measured by the forced expiratory volume at 1 set (FEV 1). After receiving 125 mg of bleomycin, her FEV 1 decreased to 67% of previous pretreatment measurements. In addition, she developed a visible pulmonary infiltrate and dyspnea. Chemotherapy was discontinued because of presumed bleomycin-associated pul-
BLEOMYCIN,
VINCRISTINE,
AND
METHOTREXATE
59
monary fibrosis. A second patient, who had childhood asthma quiescent for over 35 years, developed the acute onset of expiratory wheezing during her second intravenous infusion of bleomycin. This progressed rapidly into the syndrome of adult respiratory distress and the patient expired of pulmonary insufficiency. Fever greater than 38°C developed during 24 of the 40 administered courses of therapy. One patient developed numbness and a tingling sensation in the fingertips after receiving four courses of therapy. The combination regimen was discontinued at that time because of evidence of growing disease. Myelosuppression was not a problem. No patient had either a dose reduction or delay in therapy because of myelosuppression. DISCUSSION Of the 14 evaluable patients treated with this combination for advanced cervical cancer there was a response rate of 14% with no complete responders. The median duration of survival for the responders was not significantly different from nonresponders. Two of the 14 patients were felt to have developed significant bleomycin associated pulmonary toxicity. Although the use of moderately high dose of methotrexate with citrovorum rescue apparently did reduce the incidence of dose limiting myelosuppression reported by others utilizing combination bleomycin, vincristine, and methotrexate, the response rate in this group of patients is considerably lower. It is concluded that both the response rate and duration of survival are too low to warrant the use of this combination chemotherapy in women with squamous cell carcinoma of the cervix. REFERENCES 1. Alberts, D. S., Martimbeau, P. W., Surwit, E. A., and Oishi, N. Mitomycin-C, bleomycin, vincristine, and cis-platinum in the treatment of advanced, recurrent squamous cell carcinoma of the cervix, Cancer C/in. Trials 4, 313-316 (1981). 2. Baker, L. H., Opipari, M. K., Wilson, H., Bottomley, R., and Coltman, C. A. Mitomycin-C, vincristine, and bleomycin therapy for advanced cervical cancer, Obstet. Gynecol. 52, 146-150 (1978). 3. Boice, C. R., Freedman, R. S., Herson, J., Wharton, J. T., and Rutledge, F. N. Bleomycin and mitomycin-C (BLM-M) in recurrent squamous uterine cervical carcinoma, Cancer 49, 22422245 (1982). 4. Greenberg, B. R., Hannigan, J., Gerretson, L., Turbow, M. M., Friedman, M. A., Hendrickson, C. A,, Glassberg, A., and Carter, S. K. Sequential combination of bleomycin and mitomycin in advanced cervical cancer-An American experience: A northern California Oncology Group study, Cancer Treat. Rep. 66, 163-165 (1982). 5. Miyamoto, T., Takabe, Y., Watanabe, M., and Terasima, T. Effectiveness of a sequential combination of bleomycin and mitomycin-C on an advanced cervical cancer, Cancer 41, 403-413 (1978). 6. Swenerton, K. D., Evers, J. A., White, G. W., and Boyes, D. A. Intermittent pelvic infusion with vincristine, bleomycin, and mitomycin-C for advanced recurrent carcinoma of the cervix, Cancer Treat. Rep. 63 1379-1381 (1979). 7. Behnam, K., Lewis, G. C., Lee, J. H., and Looka, M. H. Treatment of cervical carcinoma with methotrexate, bleomycin and vincristine, Cancer Clin. Trials 4, 75-79 (1981).
ONCOLOGY
19, 57-59 (1984)
Bleomycin, Vincristine, and Methotrexate with Citrovorum Factor Rescue in the Treatment of Advanced Squamous Cell Carcinoma of the Cervix EDWARD Division
V. HANNIGAN, M.D. ,l E. ARCHER DILLARD, JR., M.D., AND TUNG VAN DINH, M.D.
of Gynecologic
Oncology, Department of Obstetrics and Gynecology, Medical Branch, Galveston, Texas 77550
University
of Texas
Fourteen patients with advanced or locally recurrent squamous cell carcinoma of the uterine cervix were treated with bleomycin, vincristine, and moderately high dose methotrexate with citrovorum rescue. Two patients (14%) had a partial response; no patient had a complete response. Two patients were felt to have signihcant bleomycin associated pulmonary toxicity. This chemotherapy regimen is not felt to be clinically useful in our patient population.
Bleomycin containing combination chemotherapy regimens have been widely used for advanced or locally recurrent squamous cell carcinoma of the uterine cervix. Results obtained with these regimens vary widely [l-6]. Behnam et al. [7] utilizing a regimen of bleomycin, vincristine, and methotrexate recently reported a response rate of 53% in 17patients (1 complete responder and 8 partial responders). They felt a significant dose limiting factor in therapy was methotrexate associated myelosuppression which prevented administration of the regimen at regular intervals, and suggested this toxicity might be reduced by the concomitant use of citrovorum factor with high dose methotrexate. This paper reports our experience at the University of Texas Medical Branch at Galveston with the use of bleomycin, vincristine, and methotrexate with citrovorum factor rescue in patients with advanced squamous cell carcinoma of the uterine cervix. MATERIALS AND METHODS Between July 1981and December 1982 14 patients were treated with combination bleomycin, vincristine, and methotrexate with citrovorum factor rescue. To be eligible for inclusion in the study a patient was required to have easily measurable recurrent or advanced histologically proven squamous cell carcinoma of the cervix, to have had no prior cytotoxic chemotherapy, to have a Karnofsky performance status of 60 or greater, and to have no impairment of kidney and/ or liver and/or pulmonary function. The median age of the treated patients was ’ To whom correspondence should be addressed. 57 0090-8258184$1.50 Copyright 0 1984 by Academic Press, Inc. All rights of reproduction in any form reserved.
58
HANNIGAN,
DILLARD,
AND
DINH
53 with a range from 33 to 75 years. Ten patients had been previously treated with pelvic irradiation; 4 had received no prior irradiation therapy. The initial stage was IB in 3 patients, IIA in 5 patients, IIB in 1 patient, IIIB in 3 patients, and IVB in 2 patients. The site of the measurable lesion was in the pelvis in 10 patients and in the lung in 4 patients. For the 10 patients who had previously been treated with potentially curative irradiation therapy, the median time from initial diagnosis to the evidence of recurrent disease was 11 months with a range of 5 to 91 months. The patients were treated every 28 days. Bleomycin was given as a 60-hr intravenous infusion with a total dose of 60 mg per course. Vincristine was given intravenously, 1.5 mg/i’@, with the total dose not to exceed 2.5 mg. Following the vincristine, methotrexate (150 mg/M*) was given intravenously. After 12 hr citrovorum factor was administered at a rate of 12 mg every 6 hr for 8 doses. This regimen was repeated every 28 days until there was evidence of growing tumor. A patient was said to have a complete response to chemotherapy if all known carcinoma disappeared for at least 2 months, and a partial response if there was at least a 50% decrease in the sum of the two greatest diameters of all measurable lesions lasting for 2 months. During this period of partial response there could be no growth of cancer at any other site. RESULTS Fourteen patients received a total of 40 courses of combination chemotherapy. No patient had a complete response. Two patients met the criteria for a partial response for a rate of 14%. Both partial responses lasted 2 months. The measurable lesion in both patients was located in the pelvis and had previously received high doses of pelvic irradiation. One patient had a 6 x 7-cm mass located in the pelvis, visible in the vagina, which decreased to a small linear streak at the apex of the vagina. The second patient had an irregularly shaped 6 x 6-cm mass fixed to the right pelvic wall in the area of the common iliac vessels. This mass, which was easily palpable on physical examination and easily imagable with CT scanning of the pelvis, decreased in size to 2 X 3 cm for a 2-month period before beginning to grow. In addition, there were two patients with pulmonary metastases that decreased in size. These decreases, however, were not of sufficient size to meet the criteria for partial responses. Both patients had progression of their disease after 1 month. The two responders lived 6 and 7 months, respectively, from the onset of chemotherapy. Two patients remain alive with growing disease 4 and 7 months after beginning chemotherapy. The remaining 10 patients expired with a median survival of 9 months. The most significant toxicity associated with the combination was pulmonary impairment, with 2 patients developing significant pulmonary compromise. One patient was noted to have a marked decrease in her pulmonary function as measured by the forced expiratory volume at 1 set (FEV 1). After receiving 125 mg of bleomycin, her FEV 1 decreased to 67% of previous pretreatment measurements. In addition, she developed a visible pulmonary infiltrate and dyspnea. Chemotherapy was discontinued because of presumed bleomycin-associated pul-
BLEOMYCIN,
VINCRISTINE,
AND
METHOTREXATE
59
monary fibrosis. A second patient, who had childhood asthma quiescent for over 35 years, developed the acute onset of expiratory wheezing during her second intravenous infusion of bleomycin. This progressed rapidly into the syndrome of adult respiratory distress and the patient expired of pulmonary insufficiency. Fever greater than 38°C developed during 24 of the 40 administered courses of therapy. One patient developed numbness and a tingling sensation in the fingertips after receiving four courses of therapy. The combination regimen was discontinued at that time because of evidence of growing disease. Myelosuppression was not a problem. No patient had either a dose reduction or delay in therapy because of myelosuppression. DISCUSSION Of the 14 evaluable patients treated with this combination for advanced cervical cancer there was a response rate of 14% with no complete responders. The median duration of survival for the responders was not significantly different from nonresponders. Two of the 14 patients were felt to have developed significant bleomycin associated pulmonary toxicity. Although the use of moderately high dose of methotrexate with citrovorum rescue apparently did reduce the incidence of dose limiting myelosuppression reported by others utilizing combination bleomycin, vincristine, and methotrexate, the response rate in this group of patients is considerably lower. It is concluded that both the response rate and duration of survival are too low to warrant the use of this combination chemotherapy in women with squamous cell carcinoma of the cervix. REFERENCES 1. Alberts, D. S., Martimbeau, P. W., Surwit, E. A., and Oishi, N. Mitomycin-C, bleomycin, vincristine, and cis-platinum in the treatment of advanced, recurrent squamous cell carcinoma of the cervix, Cancer C/in. Trials 4, 313-316 (1981). 2. Baker, L. H., Opipari, M. K., Wilson, H., Bottomley, R., and Coltman, C. A. Mitomycin-C, vincristine, and bleomycin therapy for advanced cervical cancer, Obstet. Gynecol. 52, 146-150 (1978). 3. Boice, C. R., Freedman, R. S., Herson, J., Wharton, J. T., and Rutledge, F. N. Bleomycin and mitomycin-C (BLM-M) in recurrent squamous uterine cervical carcinoma, Cancer 49, 22422245 (1982). 4. Greenberg, B. R., Hannigan, J., Gerretson, L., Turbow, M. M., Friedman, M. A., Hendrickson, C. A,, Glassberg, A., and Carter, S. K. Sequential combination of bleomycin and mitomycin in advanced cervical cancer-An American experience: A northern California Oncology Group study, Cancer Treat. Rep. 66, 163-165 (1982). 5. Miyamoto, T., Takabe, Y., Watanabe, M., and Terasima, T. Effectiveness of a sequential combination of bleomycin and mitomycin-C on an advanced cervical cancer, Cancer 41, 403-413 (1978). 6. Swenerton, K. D., Evers, J. A., White, G. W., and Boyes, D. A. Intermittent pelvic infusion with vincristine, bleomycin, and mitomycin-C for advanced recurrent carcinoma of the cervix, Cancer Treat. Rep. 63 1379-1381 (1979). 7. Behnam, K., Lewis, G. C., Lee, J. H., and Looka, M. H. Treatment of cervical carcinoma with methotrexate, bleomycin and vincristine, Cancer Clin. Trials 4, 75-79 (1981).