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Cyclophosphamide, adriamycin, and platinum chemotherapy in treatment of advanced and recurrent cervical carcinoma
GYNECOLOGIC
ONCOLOGY
16, 15-18 (1983)
Cyclophosphamide, Adriamycin, and Platinum Chemotherapy in Treatment of Advanced and Recurrent Cervical Carcinoma
Department
SHASHIKANT
B. LELE, M.D., M. STEVEN PIVER, M.D., AND JOSEPH J. BARLOW, M.D.
of Gynecologic
Oncology,
Roswell Park Memorial New York 14263
Institute,
666 Elm Street, Buffalo,
Received January 7, 1982 The chemotherapeutic combination of cyclophosphamide, doxorubicin (Adriamycin), and cis-dichlorodiammineplatinum was used in the treatment of women with metastatic or recurrent cervical carcinomas not amenable to surgery or radiotherapy. A total of 20 patients with evaluable parameters were treated. Three partial remissions and one complete remission were obtained, giving an overall response rate of 20%.
Surgery or radiotherapy continue to be the primary modalities of treatment in cervical cancer. How to treat patients with either initially advanced metastatic cervical carcinoma or relapse after radiotherapy or surgery, and not amenable to these therapeutic modalities, continues to be a problem. Various single and combination chemotherapeutic agents have been utilized with varied success and short-lasting responses [3]. The duration of survival of responders, compared to nonresponders, has not been statistically significant in most of the studies. The problem of distinguishing pelvic cancer from surrounding radiation fibrosis poses a problem in evaluating the tumor response. Initially, we tried Adriamycin alone in the treatment of carcinomas of the cervix and vagina with a response rate of 25% [ 11.The addition of cyclophosphamide and 5fluorouracil to Adriamycin given on a single day once every 3 weeks yielded a 12.5% response rate. This combination of cyclophosphamide, Adriamycin, and 5-FU (CAF) given daily over a period of 5 days at 4-week intervals gave a response rate of 16.5% [2]. cis-Dichlorodiammineplatinum (c&platinum) as a single agent or in combination has been found to be effective in the treatment of cervical cancer [3-51. In a phase II trial of cis-platinum by the Gynecologic Oncology Group a 50% response rate was reported in 22 patients with no prior chemotherapy (three complete and eight partial responses) [3]. We have substituted cis-platinum for 5-FU in the CAF combination. Twenty patients with evaluable metastatic or recurrent cervical cancer treated with this new combination of cyclophosphamide, Adriamycin, and cis-platinum (CAP) are the subject of this report. 15 0090-8258183 $1.50 Copyright 0 1983 by Academic Press. Inc. All rights of reproduction in any form reserved.
16
LELE,
PIVER,
MATERIALS
AND
BARLOW
AND METHODS
Twenty patients referred to Roswell Park Memorial Institute (RPMI) with metastatic and/or recurrent cancer were entered in the study. Sixteen patients had prior radiotherapy, two patients had prior surgery only, and two patients had no prior therapy. All patients had measurable disease prior to initiating chemotherapy. The treatment regimen consisted of cyclophosphamide 400 mg/m’ and Adriamycin 40 mg/m2 as iv boluses and cis-dichlorodiammineplatinum (cis-DDP) 40 mg/m2 in 5% dextrose with 0.5% normal saline as an iv infusion over a 6-hr period. The dose of platinum used in this combination was lower (40 mg vs 50 mg/m2) as most of the patients had prior radiation therapy and cis-DDP was used with Adriamycin and Cytoxan. This cycle was repeated every 3 weeks provided white blood cell (WBC) and platelet counts were adequate. (WBC greater than 3000/ mm3 and platelet greater than 100,000/mm3).Also required was an electrocardiogram showing no evidence of cardiac toxicity and in some instances normal (>50%) ventricular-ejection fraction as per radionuclide studies, and a urine creatinine clearance of greater than 60 ml per min. Complete response was defined as complete disappearance of all measurable disease, and a partial response was defined as greater than 50% reduction in the product of tumor diameters for 1 month or longer. Stationary disease was defined as absence of growth of measurable disease. Progression was defined as 25% or more increase in the measurable disease and/or appearance of new lesions. RESULTS Histology
of Tumor
There were 15 squamous cell carcinomas, 2 adenocarcinomas, 1 adenosquamous carcinoma, and 2 poorly differentiated carcinomas of the cervix. Sites of Recurrence Central recurrence. Eleven patients had central recurrence. However, five of these patients had distant metastasis also. Seven patients developed pelvic nodal recurrence and four of these patients had recurrence at other distant sites. Five patients had disease in the upper abdomen; however, they also had disease at other sites. Six patients developed pulmonary metastasis, but five of these patients had recurrence at other sites. There were four patients with metastasis to sites not mentioned above; however, they also had disease at one of the sites mentioned. Response to Therapy
There was one complete and three partial responses giving an overall response rate of 20% (4/20) to CAP chemotherapy (Table 1). The patient who achieved a complete response had a pelvic recurrence only, whereas the three patients who achieved a partial response had multiple metastatic sites as shown in Table 2. Twelve patients had stationary disease with a duration of response lasting 2-6 months. Four patients had progressive disease following their first course of therapy. Progression was noted in the first patient by virtue of increase in iliac
CERVICAL
CARCINOMA
TABLE
17
CHEMOTHERAPY
1
RESPONSE
Complete Partial Stationary disease Progression
1 3 12 4
lymph node mass causing complete obstruction of external iliac artery and gangrene of her leg. Three other patients who progressed had pulmonary lesions as one of the parameters which showed progressive disease. The four responding patients had squamous cell carcinoma of the cervix with no responses in other histologic variants. Performance Status All patients were evaluated for performance according to Karnofsky scale starting with 0 for those at full activity and symptom free to a scale of 4 when 100% bedridden due to symptoms. The distribution according to performance was O-l, 1-7, 2-6, 3-4, and 4-2. Toxicity (1) Hematologic toxicity. Three patients developed WBC nadir counts below 1000/mm3 (500, 700, and SOO),and two of these patients also developed platelet counts below 100,000/mm3 (80,000 and 90,000). Another patient developed a platelet count of 70,000 with a WBC count of 1400. Two patients developed sepsis requiring intravenous antibiotics and hospitalization. There were no deaths related to chemotherapeutic toxicity. Seven patients developed anemia (Hb < 10 g%) requiring multiple transfusions. (2) Cardiac toxicity. Four patients developed cardiac toxicity based on EKG changes (low voltage, premature ventricular contractions) and radionuclide studies showed a reduced ventricular ejection fraction (less than 50%). None of these patients had clinical signs of cardiac failure. Adriamycin was discontinued after the first course in one patient, after the fourth course in two patients, and after TABLE 2 DURATION OF RESFONSEAND METASTATIC SITES
Duration (months)
Performance (Karnofsky scale)
4 8
3 2
3. Partial
10
1
4. Partial
10+
2
Response 1. Complete 2. Partial
Sites of metastasis (before starting chemotherapy) Pelvis Pelvis and pulmonary Liver, supraclavicular Node, and lung Para-aortic nodes and lung
18
LELE,
PIVER,
AND
BARLOW
the thirteenth course in the last patient because of cardiac toxicity. One of the patients continued to respond for another 6 months on cis-platinum and cyclophosphamide therapy only after discontinuation of Adriamycin after the fourth course of CAP therapy. (3) Ototoxicity. Two patients developed ototoxicity with severe ringing in the ear and one of these patients had loss of high-frequency hcaiing by audiogram. (4) Nephrotoxicity. One patient developed a creatinine clc:lr.ance of 30 cc per minute from a previous normal clearance. Her serum creatinine also rose to I .7 mg% and platinum was omitted from the combination. This patient progressed and died from metastatic disease. DISCUSSION
In a continuing effort to find new and effective chemotherapeutic regimens for the treatment of carcinoma of the cervix, we initially treated eight patients with carcinoma of the cervix with Adriamycin alone with a response rate of 25%. The addition of cyclophosphamide and Sfluorouracil to Adriamycin (CAF) given every 3 weeks as a single injection gave a 12.5% response rate. In 36 patients, when the CAF combination was used over a S-day period, a 16.5% response was obtained. &-Platinum has since been found to be effective as a single agent in this disease and in this study was added to cyclophosphamide and Adriamycin. The combination CAP given every 3 weeks to patients with no prior chemotherapy gave a 20% response rate. The response rate of 20% with this therapy compared to 50% cited for single agent is difficult to explain. In our past experience when we added cis-DDP to our methotrexate and Cytoxan combination a lower response rate was observed in treatment of ovarian carcinoma [6]. Thus, CAP did not prove to be any more effective than single-agent Adriamycin or platinum in patients with carcinomas of the cervix. REFERENCES I. Barlow, J. J., Piver. M. S., Chuang, J. T., et al. Adriamycin and bleomycin, alone and in combination, in gynecologic cancers, Cancer 32, 4. 735-743 (9173). 2. Piver, M. S., Barlow. J. J., and Dunbar, J. Doxorubicin, cyclophosphamide, and S-fluorouracil in patients with carcinoma of the cervix or vagina. Cancer Treut. Rep. 64, 4-5, 549-551 (1980). 3. Thigpen, T., Vance, R. B., Balducci, L., and Blessing, J. Chemotherapy in the management of advanced or recurrent cervical and endometrial carcinoma, Cancer 48, 2, 658-665 (1981). 4. Rosenthal, C. J.. Platica, 0.. Boyce, J., et (11. Effective combination chemotherapy (CT) in advanced squamous cell carcinoma (SQ CA), ASCO Abstr.. C-330 (1979). 5. Vogl, W. E., Moukhtar, M., Calanog, A., Greenwald, E. H., and Kaplan, B. H. Chemotherapy for advanced cervical cancer with bleomycin, vincristine, mitomycin C, and cis-diamminedichloroplatinum (II) (BOMP), Cancer Treut. Rep. 64, 1005-1007 (1980). 6. Lele, S. B., Piver, M. S., and Barlow, J. J. High-dose methotrexate with cyclophosphamide and &-platinum in treatment of advanced ovarian carcinoma. Gvnecol. Oncol. 8, 74-77 (1979).
ONCOLOGY
16, 15-18 (1983)
Cyclophosphamide, Adriamycin, and Platinum Chemotherapy in Treatment of Advanced and Recurrent Cervical Carcinoma
Department
SHASHIKANT
B. LELE, M.D., M. STEVEN PIVER, M.D., AND JOSEPH J. BARLOW, M.D.
of Gynecologic
Oncology,
Roswell Park Memorial New York 14263
Institute,
666 Elm Street, Buffalo,
Received January 7, 1982 The chemotherapeutic combination of cyclophosphamide, doxorubicin (Adriamycin), and cis-dichlorodiammineplatinum was used in the treatment of women with metastatic or recurrent cervical carcinomas not amenable to surgery or radiotherapy. A total of 20 patients with evaluable parameters were treated. Three partial remissions and one complete remission were obtained, giving an overall response rate of 20%.
Surgery or radiotherapy continue to be the primary modalities of treatment in cervical cancer. How to treat patients with either initially advanced metastatic cervical carcinoma or relapse after radiotherapy or surgery, and not amenable to these therapeutic modalities, continues to be a problem. Various single and combination chemotherapeutic agents have been utilized with varied success and short-lasting responses [3]. The duration of survival of responders, compared to nonresponders, has not been statistically significant in most of the studies. The problem of distinguishing pelvic cancer from surrounding radiation fibrosis poses a problem in evaluating the tumor response. Initially, we tried Adriamycin alone in the treatment of carcinomas of the cervix and vagina with a response rate of 25% [ 11.The addition of cyclophosphamide and 5fluorouracil to Adriamycin given on a single day once every 3 weeks yielded a 12.5% response rate. This combination of cyclophosphamide, Adriamycin, and 5-FU (CAF) given daily over a period of 5 days at 4-week intervals gave a response rate of 16.5% [2]. cis-Dichlorodiammineplatinum (c&platinum) as a single agent or in combination has been found to be effective in the treatment of cervical cancer [3-51. In a phase II trial of cis-platinum by the Gynecologic Oncology Group a 50% response rate was reported in 22 patients with no prior chemotherapy (three complete and eight partial responses) [3]. We have substituted cis-platinum for 5-FU in the CAF combination. Twenty patients with evaluable metastatic or recurrent cervical cancer treated with this new combination of cyclophosphamide, Adriamycin, and cis-platinum (CAP) are the subject of this report. 15 0090-8258183 $1.50 Copyright 0 1983 by Academic Press. Inc. All rights of reproduction in any form reserved.
16
LELE,
PIVER,
MATERIALS
AND
BARLOW
AND METHODS
Twenty patients referred to Roswell Park Memorial Institute (RPMI) with metastatic and/or recurrent cancer were entered in the study. Sixteen patients had prior radiotherapy, two patients had prior surgery only, and two patients had no prior therapy. All patients had measurable disease prior to initiating chemotherapy. The treatment regimen consisted of cyclophosphamide 400 mg/m’ and Adriamycin 40 mg/m2 as iv boluses and cis-dichlorodiammineplatinum (cis-DDP) 40 mg/m2 in 5% dextrose with 0.5% normal saline as an iv infusion over a 6-hr period. The dose of platinum used in this combination was lower (40 mg vs 50 mg/m2) as most of the patients had prior radiation therapy and cis-DDP was used with Adriamycin and Cytoxan. This cycle was repeated every 3 weeks provided white blood cell (WBC) and platelet counts were adequate. (WBC greater than 3000/ mm3 and platelet greater than 100,000/mm3).Also required was an electrocardiogram showing no evidence of cardiac toxicity and in some instances normal (>50%) ventricular-ejection fraction as per radionuclide studies, and a urine creatinine clearance of greater than 60 ml per min. Complete response was defined as complete disappearance of all measurable disease, and a partial response was defined as greater than 50% reduction in the product of tumor diameters for 1 month or longer. Stationary disease was defined as absence of growth of measurable disease. Progression was defined as 25% or more increase in the measurable disease and/or appearance of new lesions. RESULTS Histology
of Tumor
There were 15 squamous cell carcinomas, 2 adenocarcinomas, 1 adenosquamous carcinoma, and 2 poorly differentiated carcinomas of the cervix. Sites of Recurrence Central recurrence. Eleven patients had central recurrence. However, five of these patients had distant metastasis also. Seven patients developed pelvic nodal recurrence and four of these patients had recurrence at other distant sites. Five patients had disease in the upper abdomen; however, they also had disease at other sites. Six patients developed pulmonary metastasis, but five of these patients had recurrence at other sites. There were four patients with metastasis to sites not mentioned above; however, they also had disease at one of the sites mentioned. Response to Therapy
There was one complete and three partial responses giving an overall response rate of 20% (4/20) to CAP chemotherapy (Table 1). The patient who achieved a complete response had a pelvic recurrence only, whereas the three patients who achieved a partial response had multiple metastatic sites as shown in Table 2. Twelve patients had stationary disease with a duration of response lasting 2-6 months. Four patients had progressive disease following their first course of therapy. Progression was noted in the first patient by virtue of increase in iliac
CERVICAL
CARCINOMA
TABLE
17
CHEMOTHERAPY
1
RESPONSE
Complete Partial Stationary disease Progression
1 3 12 4
lymph node mass causing complete obstruction of external iliac artery and gangrene of her leg. Three other patients who progressed had pulmonary lesions as one of the parameters which showed progressive disease. The four responding patients had squamous cell carcinoma of the cervix with no responses in other histologic variants. Performance Status All patients were evaluated for performance according to Karnofsky scale starting with 0 for those at full activity and symptom free to a scale of 4 when 100% bedridden due to symptoms. The distribution according to performance was O-l, 1-7, 2-6, 3-4, and 4-2. Toxicity (1) Hematologic toxicity. Three patients developed WBC nadir counts below 1000/mm3 (500, 700, and SOO),and two of these patients also developed platelet counts below 100,000/mm3 (80,000 and 90,000). Another patient developed a platelet count of 70,000 with a WBC count of 1400. Two patients developed sepsis requiring intravenous antibiotics and hospitalization. There were no deaths related to chemotherapeutic toxicity. Seven patients developed anemia (Hb < 10 g%) requiring multiple transfusions. (2) Cardiac toxicity. Four patients developed cardiac toxicity based on EKG changes (low voltage, premature ventricular contractions) and radionuclide studies showed a reduced ventricular ejection fraction (less than 50%). None of these patients had clinical signs of cardiac failure. Adriamycin was discontinued after the first course in one patient, after the fourth course in two patients, and after TABLE 2 DURATION OF RESFONSEAND METASTATIC SITES
Duration (months)
Performance (Karnofsky scale)
4 8
3 2
3. Partial
10
1
4. Partial
10+
2
Response 1. Complete 2. Partial
Sites of metastasis (before starting chemotherapy) Pelvis Pelvis and pulmonary Liver, supraclavicular Node, and lung Para-aortic nodes and lung
18
LELE,
PIVER,
AND
BARLOW
the thirteenth course in the last patient because of cardiac toxicity. One of the patients continued to respond for another 6 months on cis-platinum and cyclophosphamide therapy only after discontinuation of Adriamycin after the fourth course of CAP therapy. (3) Ototoxicity. Two patients developed ototoxicity with severe ringing in the ear and one of these patients had loss of high-frequency hcaiing by audiogram. (4) Nephrotoxicity. One patient developed a creatinine clc:lr.ance of 30 cc per minute from a previous normal clearance. Her serum creatinine also rose to I .7 mg% and platinum was omitted from the combination. This patient progressed and died from metastatic disease. DISCUSSION
In a continuing effort to find new and effective chemotherapeutic regimens for the treatment of carcinoma of the cervix, we initially treated eight patients with carcinoma of the cervix with Adriamycin alone with a response rate of 25%. The addition of cyclophosphamide and Sfluorouracil to Adriamycin (CAF) given every 3 weeks as a single injection gave a 12.5% response rate. In 36 patients, when the CAF combination was used over a S-day period, a 16.5% response was obtained. &-Platinum has since been found to be effective as a single agent in this disease and in this study was added to cyclophosphamide and Adriamycin. The combination CAP given every 3 weeks to patients with no prior chemotherapy gave a 20% response rate. The response rate of 20% with this therapy compared to 50% cited for single agent is difficult to explain. In our past experience when we added cis-DDP to our methotrexate and Cytoxan combination a lower response rate was observed in treatment of ovarian carcinoma [6]. Thus, CAP did not prove to be any more effective than single-agent Adriamycin or platinum in patients with carcinomas of the cervix. REFERENCES I. Barlow, J. J., Piver. M. S., Chuang, J. T., et al. Adriamycin and bleomycin, alone and in combination, in gynecologic cancers, Cancer 32, 4. 735-743 (9173). 2. Piver, M. S., Barlow. J. J., and Dunbar, J. Doxorubicin, cyclophosphamide, and S-fluorouracil in patients with carcinoma of the cervix or vagina. Cancer Treut. Rep. 64, 4-5, 549-551 (1980). 3. Thigpen, T., Vance, R. B., Balducci, L., and Blessing, J. Chemotherapy in the management of advanced or recurrent cervical and endometrial carcinoma, Cancer 48, 2, 658-665 (1981). 4. Rosenthal, C. J.. Platica, 0.. Boyce, J., et (11. Effective combination chemotherapy (CT) in advanced squamous cell carcinoma (SQ CA), ASCO Abstr.. C-330 (1979). 5. Vogl, W. E., Moukhtar, M., Calanog, A., Greenwald, E. H., and Kaplan, B. H. Chemotherapy for advanced cervical cancer with bleomycin, vincristine, mitomycin C, and cis-diamminedichloroplatinum (II) (BOMP), Cancer Treut. Rep. 64, 1005-1007 (1980). 6. Lele, S. B., Piver, M. S., and Barlow, J. J. High-dose methotrexate with cyclophosphamide and &-platinum in treatment of advanced ovarian carcinoma. Gvnecol. Oncol. 8, 74-77 (1979).