- Email: [email protected]
Chemotherapy of Ovarian Cancer
Symposium on Gynecologic Cancer
Chemotherapy of Ovarian Cancer Richard I. Fisher, M.D.,* and Robert C. Young, M.D.t
Ovarian cancer now causes 6 per cent of all deaths from cancer in women. It is the fourth most common cause of female death from cancer and the most common fatal gynecologic malignant process. Itis estimated that during 1978 there will be 17,000 new cases and 10,800 deaths from ovarian cancer. In the United States one out of every 100 women will eventually die of ovarian cancer.7 Surgery and radiotherapy are the primary modalities of therapy used in the management of patients with ovarian cancer. Surgery as a single procedure ordinarily provides the initial diagnosis, reasonably accurate staging, and initial therapy. Radiotherapy has traditionally been utilized as an adjuvant to initial therapy in localized disease. Unfortunately, because of the vague presenting signs and symptoms of this disease, approximately 60 per cent ofthe patients initially present with advanced disease (FIGO Stages III and IV) outside the confines of the true pelvis, and such patients require more generalized or systemic therapy. In addition, some 20 to 50 per cent of women, having received surgery with or without additional radiotherapy for localized disease (FIGO Stages I and II), will relapse and require additional therapy. 1 As a consequence of the inability to control ovarian cancer in most instances with surgery and radiotherapy alone, chemotherapy is being increasingly employed in the treatment of this illness. In the past chemotherapy had been used only for patients with advanced stages of ovarian cancer who had failed to respond to prior radiotherapy or were unsuitable for radiotherapy. Retrospective analysis revealed that several classes of chemotherapeutic agents were active in these previously treated patients. Data are now available from several prospective controlled clinical trials that utilized chemotherapy as the initial treatment for all patients with advanced stages of ovarian cancer. These studies have confirmed that there is a broad spectrum of active chemotherapeutic drugs with varying mechanisms of action for the treatment of ovarian cancer. A recent randomized study has demonstrated that combination chemotherapy can achieve higher overall
"Senior Investigator and Attending Physician, Medicine Branch, National Cancer Institute, Bethesda, Maryland. tChief, Medicine Branch, National Cancer Institute, Bethesda, Maryland. Surgical Clinics of North America-Vol. 58, No.1, February 1978
143
144
RICHARD
I.
FISHER AND ROBERT
C.
YOUNG
response rates, more complete remissions, and improved survival when compared with single agent chemotherapy. This review represents an attempt to assemble the available information on the use of single agents and combination chemotherapy in ovarian carcinoma and to review the ongoing chemotherapy studies of interest. Such a review may serve to put chemotherapy in perspective with the other existing modalities of therapy available for the management of ovarian carcinoma.
ALKYLATING AGENTS Alkylating agents have been used more extensively in patients with advanced ovarian cancer than any other class of chemotherapeutic agents. The literature contains reports of over 1,000 patients treated with these agents. Table 1 summarizes the response rates for a number of the most extensive trials in which alkylating agents were employed. 20 The initial response rates cluster around 35 to 65 per cent with 5 to 15 per cent of all treated patients continuing to respond two years after the initiation of therapy. The considerable variation in the overall response rate in many studies relates to the criteria for determining the response, which varied from report to report and in some instances was not stated. In addition, many published studies employing alkylating agents include both untreated patients and those who had previous radiotherapy, and this may also contribute to the variable response rate. Patients with ovarian carcinoma who have received previous therapy will be less responsive to subsequent treatment with alkylating agents. In large series in which cyclophosphamide was used, there was a 75 per cent response rate in previously untreated patients, but only a 42 per cent response rate in those relapsing after, or refractory to, radiotherapy (p<0.01).3 Available information does not suggest particular advantages for one alkylating agent over another, and all appear to have approximately equal Table 1. Alkylating Agents Used in the Treatment of Ovarian Carcinoma NUMBER OF DRUG
PATIENTS
SCHEDULE
RESPONSE
Melphalan
494
Chlorambucil Thiotepa
280 144
47% (20% complete) 50% 64%
Cyclophosphamide
126 104
Mechlorethamine
81
0.2 mg/kg/day for 5 days Orally every 3-5 weeks 0.2 mg/kg/day orally 10 mg/day intravenously for 15 days 50 to 150 mg/day orally 400 mg/day for 4 days intravenously then 50 to 150 mg/day orally 0.2 mg/kg/day for 2 days intravenously then chlorambucil 8 to 14 mg/day orally
49% 37%
35%
CHEMOTHERAPY OF OVARIAN CANCER
145
activity. Furthermore, no particular dose or schedule has been shown to be superior, as similar response rates have been achieved with daily oral doses, oral loading doses, and intermittent intravenous doses. 2o In almost all series, daily or intermittent maintenance alkylating agents were given until relapse because of the several studies suggesting that prompt relapse followed cessation of chemotherapy.2, 11 The alkylating agent melphalan has been accepted by many observers as the standard chemotherapeutic agent to which new drugs or regimens should be compared. The intraperitoneal administration of alkylating agents bas been frequently advocated, although there is little evidence that it is effective or even equivalent to the effect ofthe same agent administered systemically. Generally the intraperitoneal use of alkylating agents has been reported to be less effective than the intravenous use of the same drug and dosage. Green,s studying hemisulphur mustard and comparing its intravenous with its intraperitoneal use in ovarian cancer, indicated that the intraperitoneal administration produced less reduction of ascites, more chemical peritonitis, and in no instance produced a regression of abdominal masses. In contrast, 53 per cent of those patients treated with the same drug used intravenously experienced a reduction in the size of abdominal masses. There would seem to be little indication at present for the intraperitoneal use of alkylating agents in the primary treatment of advanced stages of ovarian cancer. The median survival time of patients with advanced stages of ovarian cancer treated with alkylating agents was 13 to 14 months in two ofthe largest series. 1;), 17 The median survival of those patients responding to chemotherapy was 17 to 20 months, and for those failing to respond the survival time was 6 to 13 months. Little information is available on the survival times of patients left untreated, but one double blind randomized study of placebo versus chlorambucil therapy was performed in 75 patients with advanced ovarian cancer. The median survival of those untreated was 9.3 months, compared to 33.5 months for those treated with chlorambucil. 12 The five-year survival rate of patients with advanced ovarian cancer treated with chemotherapy alone is reported to be 0 to 9 per cent (mean 7 per cent).20
NONALKYLATING AGENTS In the past, response rates to other classes of antitumor agents have generally been lower than those seen after the use of alkylating agents. This finding in part results from the fact that these agents had been used only in advanced stages of ovarian cancer following the failure of alkylating agents or radiotherapy. In that setting one might expect patients to respond poorly to subsequent chemotherapy. This circumstance has resulted in a lack of interest in nonalkylating agents and has necessitated a systematic study of them in carefully designed prospective trials. A summary ofnonalkylating chemotherapeutic agents that have had significant trials in evaluable series of patients with Stage III and IV ovarian car-
146
RICHARD
I.
FISHER AND ROBERT
C.
YOUNG
Table 2. Nonalkylating Agent Therapy in Ovarian Carcinoma NUMBER OF DRUG
PATIENTS
5-Fluorouracil
81
Methotrexate
21 16
Hexamethylmelamine Adriamycin
53 18 33
Cis-Platinum (II) Diammine Dichloride
34
SCHEDULE
RESPONSE
15 mg/kg/day for 5 days then 7.5 32% mgikg every other day for 3 to 4 (18 to 80%) weeks 15 mg/kg per week intravenously 33% 5 mg/day for 5 to 10 days orally 25% or intravenously every 3 to 4 weeks 8 mgikg/day orally 41% 30 mg/M 2/day for 3 days intra28% venously 75 mg/M2 intravenously every 3 36% weeks 30 mg/M 2 daily intravenously for 26% 3 days every 28 days
cinomas is shown in Table 2.20 The responses listed for each drug are in some instances compilations of several studies. With some agents, the dose schedule varied from the listed schedule, but the schedule listed was felt to be a standard one. Whenever possible, responses were included only when the patient demonstrated an objective, complete, or partial regression of disease. Transient or subjective responses are not included. The antitumor antimetabolite 5-fluorouracil has been the most extensively studied of the nonalkylating agents and, regardless of schedule, appears to have a response rate of approximately 32 per cent. Because of the extensive prior chemotherapy or radiotherapy that many of the patients received, a direct comparison of the activity of 5-fluorouracil to the activity of the alkylating agents is not possible from the retrospective data. The only other antimetabolite having had significant study has been methotrexate, and most of the available information relates to its use in combination with alkylating agents. The single study in which it was used as a single agent in 16 patients indicated a response rate of25 per cent. 16 The overall activity of the nitrosoureas and vinca alkaloids appears low. 19 In recent years, three new antitumor agents have shown significant activity in ovarian cancer. Hexamethylmelamine, whose mechanism of antitumor action has not been totally defined, produced objective responses in 41 per cent of the 53 evaluable patients. 20 Furthermore, it is now clear that the drug is active in patients with ovarian carcinoma who have become refractory to conventional alkylating agents. Five of 13 such patients treated at the Medicine Branch of the National Cancer Institute responded to treatment with hexamethylmelamine. Again, the extensive prior therapy of many patients receiving hexamethylmelamine has made the relative activity of the agent difficult to assess. In January, 1973, a prospective randomized clinical trial began at the M.D. Anderson Hospital. Hi Its purpose was to compare the objective response rates of me laphal an, 5-fluorouracil, and hexamethylmelamine in
CHEMOTHERAPY OF OVARIAN CANCER
147
previously untreated patients with Stage III or IV ovarian cancer. One hundred consecutive patients were entered in the study. An objective response was defined as a greater than 50 per cent reduction in the sum of the tumor diameter of all palpable tumors for three months or longer. Objective response rates were as follows: melphalan 36 per cent, 5-fluorouracil 12 per cent, and hexamethylmelamirte 39 per cent. If the high response rate to hexamethylmelamine is confirmed in other trials and if the durations of such responses are equivalent to those achieved with alkylating agents, hexamethylmelamine will be one of the most active single agents in the treatment of ovarian carcinoma. Adriamycin, an antitumor antibiotic, has an overall reported response rate of 33 per cent. De Palo and co-workers 6 randomized 39 previously untreated patients with advanced ovarian cancer to treatment with either melphalan or Adriamycin. Objective responses were seen in 4 of20 (25 per cent) patients treated with melphalan and 8 of 19 (42 per cent) patients taking Adriamycin. The difference in the response rates for the two regimens was not statistically significant. In addition, three of five patients who were crossed over to Adriamycin after failure to respond with melphalan responded, as did four of 12 patients who failed to respond to Adriamycin and were crossed over to melphalan therapy. However, the median duration of response was shorter for Adriamycin (three months) than for melphalan (six months), and more alopecia, gastrointestinal toxicity, and stomatitis were seen with Adriamycin. A second prospective randomized trial at the M.D. Anderson Hospital compared melphalan, hexamethylmelamine, Adriamycin, and a combination of hexamethylmelamine and Cytoxan. Objective responses were seen in 32 per cent of the patients treated with melphalan, 30 per cent of those treated with hexamethylmelamine, 30 per cent of those receiving Adriamycin, and 50 per cent of the patients treated with the combination. Of interest is the fact that there were twice the number of complete responses with the combination compared with any of the single agents. Follow-up is too short to determine the median duration of objective responses. A platinum compound, cis-platinum (II) diammine dichloride, is currently undergoing extensive investigation. Wiltshaw 18 at the Royal Marsden Hospital has treated patients with advanced ovarian cancer who were resistant to one or more cytotoxic drugs with cis-dichlorodiammineplatinum (II). She reported a 26.5 per cent objective response rate with a six month median duration or response. Bruckner et al. 4 from the Mount Sinai School of Medicine, New York, have reported preliminary results of a prospective trial of chemotherapy in advanced ovarian cancer. Responses were determined clinically without biopsy confirmation. Fortyone per cent of the patients treated with cis-platinum had objective responses, and 18 per cent showed a complete response. Responses have been observed in patients who had failed to respond to prior treatment with alkylating agents or even combination chemotherapy. When Adriamycin was combined with platinum, the overall response rate and complete response rates were 66 per cent and 33 per cent respectively.
148
RICHARD
I.
FISHER AND ROBERT
C.
YOUNG
COMBINA TION CHEMOTHERAPY Few studies of combination chemotherapy have been published in which more than a small number of patients with ovarian carcinoma have been included. The largest reported series was that of Smith and Rutledge 13 in which 47 patients refractory to melphalan were treated with a three drug combination including cyclophosphamide, actinomycin D and 5-fiuorouracil. The overall response rate in this group was 38 per cent with 9 per cent complete remissions. Nevertheless, in a subsequent randomized prospective trial comparing the three drug combination with melphalan, the overall response rate to the combination was 45 per cent compared with 42 per cent for the patients treated with melphalan alone, and the toxicity of the combination was greater than that of melphalan alone. Obviously no significant advantage for the combination chemotherapy regimen over melphalan was demonstrated. 14 Studies at the Medicine Branch of the National Cancer Institute have randomized patients with previously untreated Stage III and IV ovarian carcinoma to treatment between melphalan and a regimen termed Hexa-CAF. This combination consists ofhexamethylmelamine, Cytoxan, methotrexate, and 5-fiuorouracil. A recent update of this study revealed that 50 patients had been receiving treatment for more than six months and were evaluable for response data. 21 The overall response to melphalan was61 per cent with 19percent complete remissions. The response rate to Hexa-CAF was 79 per cent with 33 per cent complete responses. The total response rate, complete remission rate, and survival rate were all significantly better in the group receiving combination chemotherapy.
COMBINATION RADIOTHERAPY AND CHEMOTHERAPY Radiotherapy and chemotherapy have been frequently combined in the management of patients with advanced disease. Unfortunately, the patients in many such studies have represented a bewildering assortment of differing stages, histologic types, grades, and previously treated patients who received chemotherapy before, after, or during radiotherapy either in sequence or because of failure of primary radiotherapeutic management. In some studies, patients failing to respond to radiotherapy were dropped from the study before receiving chemotherapy, and in others five-year survivals of radiotherapy alone were calculated without consideration of whether subsequent chemotherapy had been administered. It is difficult, if not impossible, to evaluate such studies and assess the true contribution of the combined modality approach to the management of advanced ovarian carcinoma. Only prospective studies of well staged patients systematically given simultaneous or closely sequential radiotherapy and chemotherapy would demonstrate synergistic effects of the two modalities if such a synergy exists.
CHEMOTHERAPY OF OVARIAN CANCER
149
In contrast to the large number of "collected experience" studies, there are relatively few studies that are prospective and controlled enough to enable the reader to assess the worth ofthe combined therapies. In two such studies, patients with Stage III disease were prospectively randomized to total abdominal radiotherapy with or without alkylating agent chemotherapy (in one instance thiotepa lO and in the other cyclophosphamide5 ). Median survival times of 13 and 14 months were found for patients receiving combined therapy, compared with seven and eight months for those treated with radiotherapy alone (although patients who relapsed after radiotherapy alone subsequently received chemotherapy). Johnson et al.,9 in a randomized prospective trial of patients with previously untreated Stage III disease, compared cyclophosphamide alone with cyclophosphamide and total abdominal radiotherapy and found a median duration survival time of 10.5 and 14 months, respectively. The difference in median survival time was not significant in their study. These and other less well controlled trials have been unable to demonstrate a dramatic benefit to the use of the two modalities in combination. Nevertheless, most of the trials suggest that chemotherapy is either equivalent to or adds some therapeutic benefit to radiotherapy.
CONCLUSION Follow a thorough staging evaluation, the majority of patients with ovarian cancer are found to have advanced stages of disease at their initial presentation. These patients require treatment with systemic chemotherapy. Fortunately, there are numerous single chemotherapeutic agents capable of producing objective tumor responses in ovarian cancer. Alkylating agents can produce approximately 50 per cent objective responses and improved survival rates for the responding patients. Unfortunately only 10 to 15 per cent of these patients will achieve a complete remission and therefore may enjoy long term survival. The results of therapy with alkylating agents have become the standard with which all new chemotherapeutic programs must be compared. Recently several new drugs (cis-platinum, hexamethylmelamine, and Adriamycin) have also demonstrated significant activity. Combination chemotherapy with these agents is now being vigorously pursued. Recent evidence from the Medicine Branch of the National Cancer Institute suggests that such therapy may significantly improve the overall response rate, complete response rate, and ultimate survival of these patients. Future efforts must be directed toward the development of additional active chemotherapeutic agents as well as new effective combination chemotherapy regimens. In the latter case, prospective randomized trials are essential to establish the benefit obtained from these modes of therapy. Sufficient data now exist concerning the effectiveness of chemotherapy in advanced stages of ovarian cancer that randomized trials of adjuvant chemotherapy have been initiated in patients with Stage I or II ovarian cancer.
150
RICHARD
I.
FISHER AND ROBERT
C.
YOUNG
REFERENCES 1. Bagley, C. M., Young, R. C., Canellos, G. P., et al.: Treatment of ovarian carcinoma: possibilities for progress. New Engl. J. Med., 287:856-862, 1972. 2. Barr, W., Cowell, M. A. C., and Chatfield, W. R.: The management of ovarian carcinomaa review of 420 cases. Scot. Med. J., 15:250-256, 1970. 3. Beck, R. E., and Boyes, D. A.: Treatment of 126 cases of advanced ovarian carcinoma with cyclophosphamide. Can. Med. Assoc. J., 98:539-541, 1968. 4. Brucker, H. W., Cohen, C. J., Gusberg, S. B., et al.: Chemotherapy of ovarian cancer with Adriamycin and cis-platinum (DDP). Proc. Am. Soc. Clin. Oncol., 17:287, 1976. 5. Decker, D. G., Mussey, E., Malkasian, G. D., et al.: Adjuvant therapy for advanced ovarian malignancy. Am. J. Obstet. Gynec., 97:171-180,1967. 6. de Palo, G. M., De Lena, M., Di Re, F., et al.: Melphalan versus Adriamycin in the treatment of advanced carcinoma of the ovary. Surg. Gynecol. Obstet., 141 :899-902, 1975. 7. Fisher, R. I., and Young, R. C.: Advances in the staging and treatment of ovarian cancer. Cancer, 39:967-972, 1977. 8. Green, T. H., Jr. : Hemisulfur mustard in the palliation of patients with metastatic ovarian cancer. Obstet. Gynecol., 13:383-393, 1959. 9. Johnson, C. E., Decker, D. G., Van Herik, M., et al.: Advanced ovarian cancer: therapy with radiation and cyclophosphamide in a random series. Am. J. Roentgen. Radium Ther. Nucl. Med., 114:136-141, 1972. 10. Kottmeier, H. L.: Treatment of ovarian carcinomas with thiotepa. Clin. Obstet. Gynecol., 11 :428-438, 1968. 11. Masterson, J. G., and Nelson, J. H., Jr.: The role of chemotherapy in the treatment of gynecologic malignancy. Am. J. Obstet. Gynecol., 93:1102-1111, 1965. 12. Masterson, J. G.: Discussion of Burns, B. C., Jr., Rutledge, F. N., Smith, J. P., et al.: Management of ovarian carcinoma: surgery, irradiation, and chemotherapy. Am. J. Obstet. Gynecol., 98:374-386,1967. 13. Smith, J. P., and Rutledge. F.: Chemotherapy in the treatment of cancer of the ovary. Am. J. Obstet. Gynecol., 107:691-703,1970. 14. Smith, J. P., Rutledge, F., and Wharton, J. T.: Chemotherapy of ovarian cancer: new approaches to treatment. Cancer, 30:1565-1571, 1972. 15. Smith, J. P.: Report of the Ovarian Cancer Contract. National Cancer Institute. Jan. 1, 1976. 16. Sullivan, R. D., Miller, E., Zurek, W. Z., et al.: Re-evaluation of methotrexate as an anticancer drug. Surg. Gynecol. Obstet., 125:819-824, 1967. 17. Wallach, R. C., Kabakow, B., Blinick, G., et al.: Thio-tepa chemotherapy for ovarian carcinoma: influence of remission and toxicity on survival. Obstet, Gynecol., 25:475-478, 1965. 18. Wiltshaw, E. and Kroner, T.: Phase II study of cis-dichlorodiammineplatinum (II) in advanced adenocarcinoma of the ovary. Cancer Treat. Rep., 60:55-60, 1976. 19. Young, R. C., Hubbard, S. H., and DeVita, V. T.: The chemotherapy of ovarian carcinoma. Cancer Treat. Rev., 1 :99-110, 1974. 20. Young, R. C.: Chemotherapy of ovarian cancer: past and present. Semin. Oncol., 2:267276,1975. 21. Young, R. C., DeVita, V. T., and Chabner, B. A.: A prospective trial of melphalan and combination chemotherapy in advanced ovarian cancer. Proc. Am. Soc. Clin. Oncol., 17:279,1976.
Medicine Branch National Cancer Institute Bethesda, Maryland 20014
Chemotherapy of Ovarian Cancer Richard I. Fisher, M.D.,* and Robert C. Young, M.D.t
Ovarian cancer now causes 6 per cent of all deaths from cancer in women. It is the fourth most common cause of female death from cancer and the most common fatal gynecologic malignant process. Itis estimated that during 1978 there will be 17,000 new cases and 10,800 deaths from ovarian cancer. In the United States one out of every 100 women will eventually die of ovarian cancer.7 Surgery and radiotherapy are the primary modalities of therapy used in the management of patients with ovarian cancer. Surgery as a single procedure ordinarily provides the initial diagnosis, reasonably accurate staging, and initial therapy. Radiotherapy has traditionally been utilized as an adjuvant to initial therapy in localized disease. Unfortunately, because of the vague presenting signs and symptoms of this disease, approximately 60 per cent ofthe patients initially present with advanced disease (FIGO Stages III and IV) outside the confines of the true pelvis, and such patients require more generalized or systemic therapy. In addition, some 20 to 50 per cent of women, having received surgery with or without additional radiotherapy for localized disease (FIGO Stages I and II), will relapse and require additional therapy. 1 As a consequence of the inability to control ovarian cancer in most instances with surgery and radiotherapy alone, chemotherapy is being increasingly employed in the treatment of this illness. In the past chemotherapy had been used only for patients with advanced stages of ovarian cancer who had failed to respond to prior radiotherapy or were unsuitable for radiotherapy. Retrospective analysis revealed that several classes of chemotherapeutic agents were active in these previously treated patients. Data are now available from several prospective controlled clinical trials that utilized chemotherapy as the initial treatment for all patients with advanced stages of ovarian cancer. These studies have confirmed that there is a broad spectrum of active chemotherapeutic drugs with varying mechanisms of action for the treatment of ovarian cancer. A recent randomized study has demonstrated that combination chemotherapy can achieve higher overall
"Senior Investigator and Attending Physician, Medicine Branch, National Cancer Institute, Bethesda, Maryland. tChief, Medicine Branch, National Cancer Institute, Bethesda, Maryland. Surgical Clinics of North America-Vol. 58, No.1, February 1978
143
144
RICHARD
I.
FISHER AND ROBERT
C.
YOUNG
response rates, more complete remissions, and improved survival when compared with single agent chemotherapy. This review represents an attempt to assemble the available information on the use of single agents and combination chemotherapy in ovarian carcinoma and to review the ongoing chemotherapy studies of interest. Such a review may serve to put chemotherapy in perspective with the other existing modalities of therapy available for the management of ovarian carcinoma.
ALKYLATING AGENTS Alkylating agents have been used more extensively in patients with advanced ovarian cancer than any other class of chemotherapeutic agents. The literature contains reports of over 1,000 patients treated with these agents. Table 1 summarizes the response rates for a number of the most extensive trials in which alkylating agents were employed. 20 The initial response rates cluster around 35 to 65 per cent with 5 to 15 per cent of all treated patients continuing to respond two years after the initiation of therapy. The considerable variation in the overall response rate in many studies relates to the criteria for determining the response, which varied from report to report and in some instances was not stated. In addition, many published studies employing alkylating agents include both untreated patients and those who had previous radiotherapy, and this may also contribute to the variable response rate. Patients with ovarian carcinoma who have received previous therapy will be less responsive to subsequent treatment with alkylating agents. In large series in which cyclophosphamide was used, there was a 75 per cent response rate in previously untreated patients, but only a 42 per cent response rate in those relapsing after, or refractory to, radiotherapy (p<0.01).3 Available information does not suggest particular advantages for one alkylating agent over another, and all appear to have approximately equal Table 1. Alkylating Agents Used in the Treatment of Ovarian Carcinoma NUMBER OF DRUG
PATIENTS
SCHEDULE
RESPONSE
Melphalan
494
Chlorambucil Thiotepa
280 144
47% (20% complete) 50% 64%
Cyclophosphamide
126 104
Mechlorethamine
81
0.2 mg/kg/day for 5 days Orally every 3-5 weeks 0.2 mg/kg/day orally 10 mg/day intravenously for 15 days 50 to 150 mg/day orally 400 mg/day for 4 days intravenously then 50 to 150 mg/day orally 0.2 mg/kg/day for 2 days intravenously then chlorambucil 8 to 14 mg/day orally
49% 37%
35%
CHEMOTHERAPY OF OVARIAN CANCER
145
activity. Furthermore, no particular dose or schedule has been shown to be superior, as similar response rates have been achieved with daily oral doses, oral loading doses, and intermittent intravenous doses. 2o In almost all series, daily or intermittent maintenance alkylating agents were given until relapse because of the several studies suggesting that prompt relapse followed cessation of chemotherapy.2, 11 The alkylating agent melphalan has been accepted by many observers as the standard chemotherapeutic agent to which new drugs or regimens should be compared. The intraperitoneal administration of alkylating agents bas been frequently advocated, although there is little evidence that it is effective or even equivalent to the effect ofthe same agent administered systemically. Generally the intraperitoneal use of alkylating agents has been reported to be less effective than the intravenous use of the same drug and dosage. Green,s studying hemisulphur mustard and comparing its intravenous with its intraperitoneal use in ovarian cancer, indicated that the intraperitoneal administration produced less reduction of ascites, more chemical peritonitis, and in no instance produced a regression of abdominal masses. In contrast, 53 per cent of those patients treated with the same drug used intravenously experienced a reduction in the size of abdominal masses. There would seem to be little indication at present for the intraperitoneal use of alkylating agents in the primary treatment of advanced stages of ovarian cancer. The median survival time of patients with advanced stages of ovarian cancer treated with alkylating agents was 13 to 14 months in two ofthe largest series. 1;), 17 The median survival of those patients responding to chemotherapy was 17 to 20 months, and for those failing to respond the survival time was 6 to 13 months. Little information is available on the survival times of patients left untreated, but one double blind randomized study of placebo versus chlorambucil therapy was performed in 75 patients with advanced ovarian cancer. The median survival of those untreated was 9.3 months, compared to 33.5 months for those treated with chlorambucil. 12 The five-year survival rate of patients with advanced ovarian cancer treated with chemotherapy alone is reported to be 0 to 9 per cent (mean 7 per cent).20
NONALKYLATING AGENTS In the past, response rates to other classes of antitumor agents have generally been lower than those seen after the use of alkylating agents. This finding in part results from the fact that these agents had been used only in advanced stages of ovarian cancer following the failure of alkylating agents or radiotherapy. In that setting one might expect patients to respond poorly to subsequent chemotherapy. This circumstance has resulted in a lack of interest in nonalkylating agents and has necessitated a systematic study of them in carefully designed prospective trials. A summary ofnonalkylating chemotherapeutic agents that have had significant trials in evaluable series of patients with Stage III and IV ovarian car-
146
RICHARD
I.
FISHER AND ROBERT
C.
YOUNG
Table 2. Nonalkylating Agent Therapy in Ovarian Carcinoma NUMBER OF DRUG
PATIENTS
5-Fluorouracil
81
Methotrexate
21 16
Hexamethylmelamine Adriamycin
53 18 33
Cis-Platinum (II) Diammine Dichloride
34
SCHEDULE
RESPONSE
15 mg/kg/day for 5 days then 7.5 32% mgikg every other day for 3 to 4 (18 to 80%) weeks 15 mg/kg per week intravenously 33% 5 mg/day for 5 to 10 days orally 25% or intravenously every 3 to 4 weeks 8 mgikg/day orally 41% 30 mg/M 2/day for 3 days intra28% venously 75 mg/M2 intravenously every 3 36% weeks 30 mg/M 2 daily intravenously for 26% 3 days every 28 days
cinomas is shown in Table 2.20 The responses listed for each drug are in some instances compilations of several studies. With some agents, the dose schedule varied from the listed schedule, but the schedule listed was felt to be a standard one. Whenever possible, responses were included only when the patient demonstrated an objective, complete, or partial regression of disease. Transient or subjective responses are not included. The antitumor antimetabolite 5-fluorouracil has been the most extensively studied of the nonalkylating agents and, regardless of schedule, appears to have a response rate of approximately 32 per cent. Because of the extensive prior chemotherapy or radiotherapy that many of the patients received, a direct comparison of the activity of 5-fluorouracil to the activity of the alkylating agents is not possible from the retrospective data. The only other antimetabolite having had significant study has been methotrexate, and most of the available information relates to its use in combination with alkylating agents. The single study in which it was used as a single agent in 16 patients indicated a response rate of25 per cent. 16 The overall activity of the nitrosoureas and vinca alkaloids appears low. 19 In recent years, three new antitumor agents have shown significant activity in ovarian cancer. Hexamethylmelamine, whose mechanism of antitumor action has not been totally defined, produced objective responses in 41 per cent of the 53 evaluable patients. 20 Furthermore, it is now clear that the drug is active in patients with ovarian carcinoma who have become refractory to conventional alkylating agents. Five of 13 such patients treated at the Medicine Branch of the National Cancer Institute responded to treatment with hexamethylmelamine. Again, the extensive prior therapy of many patients receiving hexamethylmelamine has made the relative activity of the agent difficult to assess. In January, 1973, a prospective randomized clinical trial began at the M.D. Anderson Hospital. Hi Its purpose was to compare the objective response rates of me laphal an, 5-fluorouracil, and hexamethylmelamine in
CHEMOTHERAPY OF OVARIAN CANCER
147
previously untreated patients with Stage III or IV ovarian cancer. One hundred consecutive patients were entered in the study. An objective response was defined as a greater than 50 per cent reduction in the sum of the tumor diameter of all palpable tumors for three months or longer. Objective response rates were as follows: melphalan 36 per cent, 5-fluorouracil 12 per cent, and hexamethylmelamirte 39 per cent. If the high response rate to hexamethylmelamine is confirmed in other trials and if the durations of such responses are equivalent to those achieved with alkylating agents, hexamethylmelamine will be one of the most active single agents in the treatment of ovarian carcinoma. Adriamycin, an antitumor antibiotic, has an overall reported response rate of 33 per cent. De Palo and co-workers 6 randomized 39 previously untreated patients with advanced ovarian cancer to treatment with either melphalan or Adriamycin. Objective responses were seen in 4 of20 (25 per cent) patients treated with melphalan and 8 of 19 (42 per cent) patients taking Adriamycin. The difference in the response rates for the two regimens was not statistically significant. In addition, three of five patients who were crossed over to Adriamycin after failure to respond with melphalan responded, as did four of 12 patients who failed to respond to Adriamycin and were crossed over to melphalan therapy. However, the median duration of response was shorter for Adriamycin (three months) than for melphalan (six months), and more alopecia, gastrointestinal toxicity, and stomatitis were seen with Adriamycin. A second prospective randomized trial at the M.D. Anderson Hospital compared melphalan, hexamethylmelamine, Adriamycin, and a combination of hexamethylmelamine and Cytoxan. Objective responses were seen in 32 per cent of the patients treated with melphalan, 30 per cent of those treated with hexamethylmelamine, 30 per cent of those receiving Adriamycin, and 50 per cent of the patients treated with the combination. Of interest is the fact that there were twice the number of complete responses with the combination compared with any of the single agents. Follow-up is too short to determine the median duration of objective responses. A platinum compound, cis-platinum (II) diammine dichloride, is currently undergoing extensive investigation. Wiltshaw 18 at the Royal Marsden Hospital has treated patients with advanced ovarian cancer who were resistant to one or more cytotoxic drugs with cis-dichlorodiammineplatinum (II). She reported a 26.5 per cent objective response rate with a six month median duration or response. Bruckner et al. 4 from the Mount Sinai School of Medicine, New York, have reported preliminary results of a prospective trial of chemotherapy in advanced ovarian cancer. Responses were determined clinically without biopsy confirmation. Fortyone per cent of the patients treated with cis-platinum had objective responses, and 18 per cent showed a complete response. Responses have been observed in patients who had failed to respond to prior treatment with alkylating agents or even combination chemotherapy. When Adriamycin was combined with platinum, the overall response rate and complete response rates were 66 per cent and 33 per cent respectively.
148
RICHARD
I.
FISHER AND ROBERT
C.
YOUNG
COMBINA TION CHEMOTHERAPY Few studies of combination chemotherapy have been published in which more than a small number of patients with ovarian carcinoma have been included. The largest reported series was that of Smith and Rutledge 13 in which 47 patients refractory to melphalan were treated with a three drug combination including cyclophosphamide, actinomycin D and 5-fiuorouracil. The overall response rate in this group was 38 per cent with 9 per cent complete remissions. Nevertheless, in a subsequent randomized prospective trial comparing the three drug combination with melphalan, the overall response rate to the combination was 45 per cent compared with 42 per cent for the patients treated with melphalan alone, and the toxicity of the combination was greater than that of melphalan alone. Obviously no significant advantage for the combination chemotherapy regimen over melphalan was demonstrated. 14 Studies at the Medicine Branch of the National Cancer Institute have randomized patients with previously untreated Stage III and IV ovarian carcinoma to treatment between melphalan and a regimen termed Hexa-CAF. This combination consists ofhexamethylmelamine, Cytoxan, methotrexate, and 5-fiuorouracil. A recent update of this study revealed that 50 patients had been receiving treatment for more than six months and were evaluable for response data. 21 The overall response to melphalan was61 per cent with 19percent complete remissions. The response rate to Hexa-CAF was 79 per cent with 33 per cent complete responses. The total response rate, complete remission rate, and survival rate were all significantly better in the group receiving combination chemotherapy.
COMBINATION RADIOTHERAPY AND CHEMOTHERAPY Radiotherapy and chemotherapy have been frequently combined in the management of patients with advanced disease. Unfortunately, the patients in many such studies have represented a bewildering assortment of differing stages, histologic types, grades, and previously treated patients who received chemotherapy before, after, or during radiotherapy either in sequence or because of failure of primary radiotherapeutic management. In some studies, patients failing to respond to radiotherapy were dropped from the study before receiving chemotherapy, and in others five-year survivals of radiotherapy alone were calculated without consideration of whether subsequent chemotherapy had been administered. It is difficult, if not impossible, to evaluate such studies and assess the true contribution of the combined modality approach to the management of advanced ovarian carcinoma. Only prospective studies of well staged patients systematically given simultaneous or closely sequential radiotherapy and chemotherapy would demonstrate synergistic effects of the two modalities if such a synergy exists.
CHEMOTHERAPY OF OVARIAN CANCER
149
In contrast to the large number of "collected experience" studies, there are relatively few studies that are prospective and controlled enough to enable the reader to assess the worth ofthe combined therapies. In two such studies, patients with Stage III disease were prospectively randomized to total abdominal radiotherapy with or without alkylating agent chemotherapy (in one instance thiotepa lO and in the other cyclophosphamide5 ). Median survival times of 13 and 14 months were found for patients receiving combined therapy, compared with seven and eight months for those treated with radiotherapy alone (although patients who relapsed after radiotherapy alone subsequently received chemotherapy). Johnson et al.,9 in a randomized prospective trial of patients with previously untreated Stage III disease, compared cyclophosphamide alone with cyclophosphamide and total abdominal radiotherapy and found a median duration survival time of 10.5 and 14 months, respectively. The difference in median survival time was not significant in their study. These and other less well controlled trials have been unable to demonstrate a dramatic benefit to the use of the two modalities in combination. Nevertheless, most of the trials suggest that chemotherapy is either equivalent to or adds some therapeutic benefit to radiotherapy.
CONCLUSION Follow a thorough staging evaluation, the majority of patients with ovarian cancer are found to have advanced stages of disease at their initial presentation. These patients require treatment with systemic chemotherapy. Fortunately, there are numerous single chemotherapeutic agents capable of producing objective tumor responses in ovarian cancer. Alkylating agents can produce approximately 50 per cent objective responses and improved survival rates for the responding patients. Unfortunately only 10 to 15 per cent of these patients will achieve a complete remission and therefore may enjoy long term survival. The results of therapy with alkylating agents have become the standard with which all new chemotherapeutic programs must be compared. Recently several new drugs (cis-platinum, hexamethylmelamine, and Adriamycin) have also demonstrated significant activity. Combination chemotherapy with these agents is now being vigorously pursued. Recent evidence from the Medicine Branch of the National Cancer Institute suggests that such therapy may significantly improve the overall response rate, complete response rate, and ultimate survival of these patients. Future efforts must be directed toward the development of additional active chemotherapeutic agents as well as new effective combination chemotherapy regimens. In the latter case, prospective randomized trials are essential to establish the benefit obtained from these modes of therapy. Sufficient data now exist concerning the effectiveness of chemotherapy in advanced stages of ovarian cancer that randomized trials of adjuvant chemotherapy have been initiated in patients with Stage I or II ovarian cancer.
150
RICHARD
I.
FISHER AND ROBERT
C.
YOUNG
REFERENCES 1. Bagley, C. M., Young, R. C., Canellos, G. P., et al.: Treatment of ovarian carcinoma: possibilities for progress. New Engl. J. Med., 287:856-862, 1972. 2. Barr, W., Cowell, M. A. C., and Chatfield, W. R.: The management of ovarian carcinomaa review of 420 cases. Scot. Med. J., 15:250-256, 1970. 3. Beck, R. E., and Boyes, D. A.: Treatment of 126 cases of advanced ovarian carcinoma with cyclophosphamide. Can. Med. Assoc. J., 98:539-541, 1968. 4. Brucker, H. W., Cohen, C. J., Gusberg, S. B., et al.: Chemotherapy of ovarian cancer with Adriamycin and cis-platinum (DDP). Proc. Am. Soc. Clin. Oncol., 17:287, 1976. 5. Decker, D. G., Mussey, E., Malkasian, G. D., et al.: Adjuvant therapy for advanced ovarian malignancy. Am. J. Obstet. Gynec., 97:171-180,1967. 6. de Palo, G. M., De Lena, M., Di Re, F., et al.: Melphalan versus Adriamycin in the treatment of advanced carcinoma of the ovary. Surg. Gynecol. Obstet., 141 :899-902, 1975. 7. Fisher, R. I., and Young, R. C.: Advances in the staging and treatment of ovarian cancer. Cancer, 39:967-972, 1977. 8. Green, T. H., Jr. : Hemisulfur mustard in the palliation of patients with metastatic ovarian cancer. Obstet. Gynecol., 13:383-393, 1959. 9. Johnson, C. E., Decker, D. G., Van Herik, M., et al.: Advanced ovarian cancer: therapy with radiation and cyclophosphamide in a random series. Am. J. Roentgen. Radium Ther. Nucl. Med., 114:136-141, 1972. 10. Kottmeier, H. L.: Treatment of ovarian carcinomas with thiotepa. Clin. Obstet. Gynecol., 11 :428-438, 1968. 11. Masterson, J. G., and Nelson, J. H., Jr.: The role of chemotherapy in the treatment of gynecologic malignancy. Am. J. Obstet. Gynecol., 93:1102-1111, 1965. 12. Masterson, J. G.: Discussion of Burns, B. C., Jr., Rutledge, F. N., Smith, J. P., et al.: Management of ovarian carcinoma: surgery, irradiation, and chemotherapy. Am. J. Obstet. Gynecol., 98:374-386,1967. 13. Smith, J. P., and Rutledge. F.: Chemotherapy in the treatment of cancer of the ovary. Am. J. Obstet. Gynecol., 107:691-703,1970. 14. Smith, J. P., Rutledge, F., and Wharton, J. T.: Chemotherapy of ovarian cancer: new approaches to treatment. Cancer, 30:1565-1571, 1972. 15. Smith, J. P.: Report of the Ovarian Cancer Contract. National Cancer Institute. Jan. 1, 1976. 16. Sullivan, R. D., Miller, E., Zurek, W. Z., et al.: Re-evaluation of methotrexate as an anticancer drug. Surg. Gynecol. Obstet., 125:819-824, 1967. 17. Wallach, R. C., Kabakow, B., Blinick, G., et al.: Thio-tepa chemotherapy for ovarian carcinoma: influence of remission and toxicity on survival. Obstet, Gynecol., 25:475-478, 1965. 18. Wiltshaw, E. and Kroner, T.: Phase II study of cis-dichlorodiammineplatinum (II) in advanced adenocarcinoma of the ovary. Cancer Treat. Rep., 60:55-60, 1976. 19. Young, R. C., Hubbard, S. H., and DeVita, V. T.: The chemotherapy of ovarian carcinoma. Cancer Treat. Rev., 1 :99-110, 1974. 20. Young, R. C.: Chemotherapy of ovarian cancer: past and present. Semin. Oncol., 2:267276,1975. 21. Young, R. C., DeVita, V. T., and Chabner, B. A.: A prospective trial of melphalan and combination chemotherapy in advanced ovarian cancer. Proc. Am. Soc. Clin. Oncol., 17:279,1976.
Medicine Branch National Cancer Institute Bethesda, Maryland 20014