Chemotherapy in Gynecologic Cancer

Symposium on Gynecologic Cancer

Chemotherapy in Gynecologic Cancer Julian P. Smith, M.D.*

Although progress in the chemotherapeutic treatment of patients with solid tumors has been slow, it is possible that such treatment may afford some benefit to patients with most types of recurrent or disseminated gynecologic cancer that cannot be helped with either irradiation or surgery. Chemotherapy under these circumstances may be helpful in one of three ways: it may prolong survival, it may be palliative, or, rarely, it may be curative. The several malignant tumors arising in the female genital tract respond to chemotherapy in widely varying degrees. Trophoblastic disease is the most responsive of all human neoplasms, whereas epidermoid carcinoma ofthe lower genital tract is one of the least sensitive. Between these two extremes are ovarian cancer, endometrial cancer, pelvic sarcoma, and carcinoma of the fallopian tube.

OVARIAN CANCER Irradiation was considered the preferred postoperative treatment of patients with ovarian cancer in the past. The use of postoperative irradiation therapy for the epithelial cancers of the ovary has been discontinued at the M.D. Anderson Hospital as a result of a random study comparing melphalan and whole abdominal irradiation. In this study of 149 patients with minimal cancer of the ovary, the treatment results were similar (Fig. 1).21 The cost and complications of the two treatment programs, however, were quite different. Patients treated with chemotherapy required only a monthly blood count and a clinic visit for supervision of their chemotherapy. The 79 patients treated with radiation therapy required eight to 10 weeks of treatment. Several patients required hospitalization because of radiation enteritis, 14 patients lost more than 10 lbs of weight during treatment, and seven patients had a bowel injury that required corrective surgery. The epithelial cancers of the ovary are among the most responsive of all solid tumors to a single chemotherapeutic agent. Approximately 50 per *Professor, Department of Gynecology and Obstetrics; Director, Division of Gynecologic Oncology, Wayne State University School of Medicine, Detroit, Michigan

Surgical Clinics of North America-Vol. 58, No.1, February 1978

201

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Cancer of the Ovary The M D. Anderson Hospital Randomized SIudy 1969 -1974 Accumulative Percentage NED Chema vs. XRT by SIage 100r--_~

Siage I-Chemo(N~28/

80

Figure 1. Ovarian cancer. Number of patients without evidence of disease in a random study of melphalan vs. radiation therapy.

c o

z 40
SlageJI[ 8 N--6"eroo (N~ 22/

20

°0L---~----~--~----~3----~4----~--

Years

cent of the patients with this type of tumor respond to treatment with an alkylating agent. Several ofthese agents, including chlorambucil (Leukeran), triethylenethiophosphoramide (Thiotepa), cyclophosphamide (Cytoxan), and melphalan (Alkeran), seem to be equally effective. The choice of the drug should be based upon the physician's experience with each, and the ease of its administration. At the M.D. Anderson Hospital and Tumor Institute in Houston, melphalan has been the preferred postoperative drug for patients with epithelial cancer of the ovary. IS In evaluating patients treated with chemotherapy on the gynecologic service at the M.D. Anderson Hospital, a complete response is defined as the disappearance of all evidence of cancer for three months or longer, and a partial response is determined as a 50 per cent decrease in the sum of the tumor diameters for three months or longer. If one of several tumors decreases by 50 per cent or more while other tumors do not, this condition is considered "no change." In the treatment with melphalan, melphalan is given for five days, .2 mg per kg per day in divided doses. The five day cycles of the drug are repeated every four weeks if the white blood count rises above 3,000/mm3 and the platelet count is above 100,000/mm3 • If the blood counts fall below these levels, the interval between the cycles of treatment is increased, though the dosage remains unchanged. Approximately 20 per cent of the patients with an epithelial cancer of the ovary have a complete response to melphalan for three months or longer. Approximately 27 per cent of the patients have a partial response for three months or longer; the tumors of 14 per cent exhibit no change, and 38 per cent have increasing cancer (Table 1). The duration of a response to melphalan depends upon the histology of the tumor and whether it completely or partially disappears. A complete response continues longer than a partial response. Since the mucinous tumors seem to be the most differentiated ofthe epithelial cancers of the ovary, patients with this type obtain the longest response to

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Table 1. Ovarian Cancer: Results of Chemotherapy with Melphalan (494 Patients) COMPLETE

PARTIAL RESPONSE

NO CHANGE

INCREASING

RESPONSE HISTOLOGY

PERCENT

PERCENT

PERCENT

PER CENT

Serous Mucinous Undifferentiated adenocarcinomas Total

22 22

27 22

16 20

35 36

13 20

29 27

10 14

48 38

CANCER

chemotherapy. Those with undifferentiated tumors, which tend to be the most virulent, have the shortest responses (Table 2). Forty-two per cent of the responders were alive two years after beginning chemotherapy; only 10 per cent of the nonresponders were alive this long. Sixteen per cent of the responders to chemotherapy were alive at five years; none of the nonresponders survived that long. In the treatment with other chemotherapeutic agents, patients who do not respond to melphalan, or those whose cancer enlarges after an initial response, seldom respond to another drug or combinations of drugs. In a review of 347 patients who were treated with second line chemotherapy after failure of their initial chemotherapy, only 23 patients (6 per cent) had a response to the second trial. 23 Eight patients had a complete response and 13 patients had a partial response. The different drugs used included a combination of actinomycin D, 5-fluorouracil, and cyclophosphamide-145 patients; melphalan-71 patients; 5-fluorouracil-46 patients; Adriamycin-27 patients; hexamethylmelamine-12 patients; and several other drugs and drug combinations. Several new chemotherapeutic agents have elicited some activity in ovarian cancer and may prove beneficial in the treatment ofthis disease. All these drugs have serious toxicities, but they may be valuable when used in drug combination at reduced doses. Three of these drugs investigated at the M.D. Anderson Hospital are hexamethylmelamine, Adriamycin, and cis-diamminedichloroplatinum. In a random study conducted at the M.D. Anderson Hospital, hexamethylmelamine and melphalan were Table 2. Ovarian Cancer: Duration of Response to Melphalan PARTIAL RESPONSE

Mucinous Serous Undifferentiated adenocarcinomas Complete response Mucinous Serous Undifferentiated adenocarcinomas

MEAN DURATION

MEDIAN DURATION

MONTHS

MONTHS

11.6

10

10.4

8.1

9 6

46.4 28.9 22.9

46.5 20.0 16.5

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found to be equally effective. Hexamethylmelamine causes progressive peripheral neuropathy: this side effect is dose related and is largely eliminated if the patient received pyridoxine, 100 mg three times a day, while taking the drug. 20 Adriamycin, as reported in an unpublished study, was as effective as melphalan also. Adriamycin produces accumulative cardiac toxicity, which limits the total dose of the drug and, consequently, the length of time it may be given. Cis-diamminedichloroplatinum, presently under investigation in a random trial, appears to be at least as effective as the other three drugs in the treatment of ovarian cancer. It causes a dose related peripheral neuropathy, and may produce renal tubular damage with prolonged use. It does not cause as much myelosuppression as most other cytotoxic drugs and should be well tolerated when used in combination with other myelosuppressive agents. In a recently completed clinical trial, a combination of cyclophosphamide and hexamethylmelamine appears to be more effective than any of these drugs used alone. In a random study of 132 patients comparing Adriamycin, melphalan, and hexamethylmelamine, the combination of hexamethylmelamine and cyclophosphamide produced more complete responses and more total responses than the other three drugs (Table 3). Second look operations have become an established part of the planned treatment for patients with ovarian cancer who are treated with chemotherapy. This surgery is necessary to determine the success of chemotherapy so that treatment can be modified if necessary or discontinued ifno cancer is found. In an occasional patient it may be possible to resect a previously unresectable tumor mass after an interval of chemotherapy. Only patients who have had a complete response to their treatment are benefited by this type of surgery, and about one in eight patients have been treated in this manner. If it was possible to remove all or almost all of the tumor present, the patients have shown an improvement in the duration of survival. As a result of experience, second look operations are performed after 12 cycles of chemotherapy. In a group of 103 patients who had a second look operation after receiving chemotherapy, only 12 per cent of the patients with less than four cycles survived for five years; those who had five to 10 cycles had a 32 per cent five year survival rate, and for those with 10 or more cycles, the five year survival rate was 80 per cent.

Table 3. Ovarian Cancer: Results of Random Study DRUG

Hexamethylmelamine Adriamycin Melphalan Hexamethylmelamine and cyclophosphamide

COMPLETE

PARTIAL

NO

INCREASING

RESPONSE

RESPONSE

CHANGE

CANCER

TOTAL

4 (13%) 4 (12%) 4 (11%)

5 (16%) 5 (15%) 5 (14%)

12 (39%) 14 (41%) 14 (40%)

10 (32%) 11 (32%) 12 (34%)

31 34 35

11 (34%)

2 (6%)

10 (31%)

9 (28%)

32

CHEMOTHERAPY IN GYNECOLOGIC CANCER

205

MALIGNANT TROPHOBLASTIC TUMORS Malignant trophoblastic disease is quite rare; in the United States approximately 400 new cases are observed each year. Few physicians other than those in special centers have the opportunity to treat more than one or two patients. Of all the malignant diseases for which chemotherapy is given, possibly none requires more expertise in administration. Unfortunately, the reported high success rate and the apparent good health and young age of patients with malignant trophoblastic tumors tempts the inexperienced physician to undertake their treatment despite his meager experience. Brewer" reported that 21 per cent of 65 patients with metastatic trophoblastic disease who were followed by human chorionic gonadotropin titers at the Northwestern Trophoblastic Disease Center but were treated by doctors outside the center died of their disease, and 34 per cent were referred to the center after failing to respond to treatment. Of a group of 116 patients followed at the Southwestern Trophoblastic Disease Center by human chorionic gonadotropin titers (but not treated by physicians in the center), 28 percent died of their disease while under chemotherapy. This high failure rate is inexcusable, and although this experience represents only a fraction of the new cases treated each year, it emphasizes the necessity for strict adherence to protocols for the evaluation and management of this disease. Those physicians who do not have full knowledge of the disease and its treatment, and who do not have the facilities for monitoring the effects of treatment, are well advised to refer patients with metastatic trophoblastic disease to appropriate centers. The several chemotherapeutic drugs used for the treatment of patients with metastatic trophoblastic tumors include methotrexate, actinomycin D (Cosmegen), 6 mecaptopurine (Purinethol), and vinblastine (Velban). In the United States, methotrexate is the drug of choice. It is given intramuscularly in a dose of20 to 30 mg daily for five days, these five day cycles being repeated as soon as the toxicity from the previous course of treatment has subsided. Methotrexate will produce complete remission in approximately 50 per cent of the patients with metastatic tumors. It is contraindicated for those with decreased renal function or significant impairment of hepatic function. Actinomycin D is the second drug of choice for patients with metastatic trophoblastic disease. It is effective in those who are resistant to methotrexate, and it may be safely given to those patients whose renal or hepatic function is impaired. The usual dose of actinomycin D is 10 to 12 p.,g per kg of body weight intravenously, every day for five days. These five day cycles of treatment are repeated as soon as the toxicity from the previous cycles has subsided. Actinomycin D will produce a complete remission in 40 to 50 per cent of the patients with metastatic trophoblastic disease. At the M.D. Anderson Hospital all patients with malignant trophoblastic tumors are given alternate courses of methotrexate and actinomycin D. Initially they receive 25 mg of methotrexate intravenously every day for five days. Approximately three to five days after this course is

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completed, if the patient does not have stomatitis, the white blood count is above 3,0001mm3 and the platelet count is above 100,000Imm3 , she is given.5 mg of actinomycin D daily for five days. Seven to 10 days after the course of actinomycin D is completed she is given a second cycle of methotrexate, provided the white count remain above 3000lmm3 and the platelet count is above 100,0001mm3 and no oral ulcerations have appeared. In subsequent cycles, the dose of both these drugs may be altered according to the response to treatment and the toxicity of the patient. These two drugs are given alternately until the human chorionic gonadotropin titers become normal. The patient then receives one additional cycle of either actinomycin D or' methotrexate. This alternate treatment is well tolerated, and the sensitivity of the tumor to both agents permits a maximum amount of medication to be given in a minimum amount of time, usually before resistance to the drug develops. This alternate therapy also takes advantage of the different mechanisms of action of the two drugs and their slightly different toxicity. During the treatment of every patient with a malignant trophoblastic tumor, a radioimmune assay for human chorionic gonadotropin or its beta subunit should be performed weekly. The patient is considered to be in remission when three successive weekly titers are at or below normal pituitary gonadotropin levels. Thereafter, further titers are obtained monthly for one year. Combination birth control pills are prescribed for all patients throughout the first year after completion of chemotherapy, for the purpose of suppressing the pituitary production of gonadotropins and preventing pregnancy. An accurate assay for human chorionic gonadotropin is an absolute necessity for the proper diagnosis and treatment of patients with malignant trophoblastic disease. The presence of chorionic gonadotropins has been called a "tumor specific index."2 The assay accurately reflects the number of growing and proliferating trophoblasts and serves as a guide to the effectiveness and duration oftreatment. Currently, radioimmune asTable 4. Metastatic Trophoblastic Tumors: Results of Treatment by Human Chorionic Gonadotropin Titer and Interval from Pregnancy to Treatment

Human chorionic gonadotropin more than 100 IVlml of serum Human chorionic gonadotropin less than 100 IVlml of serum More than 4 months from pregnancy to treatment Less than 4 months from pregnancy to treatment Total

NUMBER OF

PERCENT IN

PATIENTS

REMISSION

23

91

21

90

16

81

28

96

44

91

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CHEMOTHERAPY IN GYNECOLOGIC CANCER

Table 5. Non-metastatic Trophoblastic Disease: Results of Treatment NUMBER OF

PER CENT IN

mSTOLOGIC DIAGNOSIS

PATIENTS

REMISSION

Persistent hydatidiform mole Invasive mole Choriocarcinoma

22 7 2

100 100 100

Total

31

100

says of human chorionic gonadotropin in serum are the most widely used assays for monitoring the effects of treatment in the trophoblastic disease centers in the United States. Surgical treatment of patients with metastatic trophoblastic disease is reserved for complications, such as uncontrollable bleeding or infection. An occasional patient requires a hysterectomy for a small focus of non-responsive tumor in the myometrium, though only if this is the only focus of tumor remaining after successful treatment for metastatic lesions. Patients with non-metastatic trophoblastic disease require treatment if an elevated human chorionic gonadotropin titer persists eight or more weeks after a mole is expelled, or if a histologic diagnosis ofinvasive mole or choriocarcinoma is reported. If the patient has completed her family and does not desire any more children, she should have a hysterectomy. Younger patients may be successfully treated by chemotherapy. Forty-four patients with metastatic trophoblastic disease were treated at the M.D. Anderson Hospital from January 1, 1961 to January 1, 1974. Currently, 40 of these patients are in remission and are no longer receiving chemotherapy, representing a complete remission rate of91 per cent. Four patients have died of their disease (Table 4). The average patient required 3.6 cycles oftreatment over 5.7 weeks before the gonadotropin titers were normal. Prior to the alternate use of methotrexate and actinomycin D, the mean number of cycles before the human chorionic gonadotropin titers became normal was 5.2. For the average patient, this required a mean of nine weeks of treatment. Thirty-one patients with non-metastatic trophoblastic tumors were treated between January 1, 1961 and January 1, 1974 (Table 5). At present, all these patients are in complete remission and their treatment has been discontinued. They required an average of 2.8 cycles of treatment over an average period of four weeks before their gonadotropin titers became normal.

ADENOCARCINOMA OF THE ENDOMETRIUM Adenocarcinoma of the endometrium is probably the most curable of all internal cancers. Nevertheless, it was estimated that approximately 3,300 women with this diagnosis would die in 1977. 17 An occasional pa-

208

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tient with recurrent adenocarcinoma in the vagina who has not received irradiation to the vagina with her initial treatment can be successfully treated with local radium or external irradiation to the area of recurrence. Patients with a solitary pulmonary metastasis two or more years after their initial treatment may be cured by resecting the pulmonary metastasis. More often, chemotherapy in the form ofprogestins is necessary, the disease being unamenable to surgical measures. The results of chemotherapy for endometrial cancer with cytotoxic agents have been disappointing. 9 Only a small number of patients at the M.D. Anderson Hospital have obtained a response, and these for only a short period of time. Muggia reported a 62 per cent response rate in eight patients with metastatic endometrial cancer treated with Adriamycin and cyclophosphamide. 14 Only one out of 14 patients treated with this combination at the M.D. Anderson Hospital had a response to treatment. Cohen reported six of seven patients who benefited from treatment with melphalan, 5-fluorouracil, and medroxyprogesterone acetate (Provera). 6 A considerable number of patients with disseminated endometrial cancer respond to treatment with a progestin. Reifenstein,16 who collected results from many investigators following their use of hydroxyprogesterone caproate for recurrent or disseminated adenocarcinoma of the endometrium, reported that approximately 37 per cent of the patients obtained an objective response to this treatment. In 30 per cent of the patients, regression of the tumors was observed, and in 6.8 per cent the disease was arrested. The duration of the response was not recorded in his report. At the M.D. Anderson Hospital, 116 patients with endometrial cancer have received either medroxyprogesterone acetate (Provera), or medrogestone (Colprone). Those treated with medroxyprogesterone acetate were given from 100mgto2.7gmperweek, the majority receiving 250mg per week as an intramuscular injection in a depo vehicle. For patients treated with medrogestone, the dosage was from 50 mg to 2 gm per day orally, the majority being given 200 mg daily. The amount of progestin each patient received did not seem to influence the response rate. Doubling or quadrupling the dose of medication of patients who were not responding to treatment produced an occasional partial response for only a short period of time. Reifenstein found this was also true of hydroxyprogesterone caproate. Table 6. Metastatic or Recurrent Adenocarcinoma of the Endometrium: Results of Treatment with a Progestin DRUG

Medroxyprogesterone acetate Medrogestone Total

COMPLETE

PARTIAL

NO

PROGRESSIVE

TOTAL NUMBER

RESPONSE

RESPONSE

CHANGE

CANCER

OF PATIENTS

6 (11%) 6 (10%)

12 (22%) 15 (25%)

6 2

31 39

55 61

12 (10%)

27 (23%)

8

70

116

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CHEMOTHERAPY IN GYNECOLOGIC CANCER

\

\

\

c

60

\

u

v CL

\

\ \. .... \ """'"Responders \ .... -....

40

\ Recurrent Cone';; .... · - .... \Untreated Non ............ _ Responders - - _

20

o

6

ffi

12

.

... _.-.-.--._._. __ ._.-.

-------~

~

~

M

Q

~

W

~

Survival In Months

Figure 2. Adenocarcinoma of the endometrium. Survival of responders and nonresponders to chemotherapy with a progestin.

Table 7. Metastatic or Recurrent Adenocarcinoma of the Endometrium: Response to Treatment by Site of Tumor SITE OF TUMOR

Pelvis Lungs Abdomen Vagina Lymph nodes Effusion Bone Skin

NUMBER OF

NUMBER OF

PER CENT

PATIENTS

RESPONSES

RESPO~SE

64 43 33 30 25 14 5 3

21 14 8 8 8 2 0 0

33 33 24 27 32 14 0 0

Table 8. Metastatic or Recurrent Adenocarcinoma of the Endometrium: Results of Treatment by Histology of Tumor PER CENT OF PATIENTS

NUMBER OF

RESPONDING TO

PATIENTS

TREATMENT

TREATED

54 25

18 24 4

HISTOLOGY

Squamous metaplasia Papillary adenocarcinoma Undifferentiated adenocarcinoma

o

Table 9. Metastatic or Recurrent Adenocarcinoma of the Endometrium: Subjective Response to Progestin Treatment SURJECTIVE RESPONSE

Free of symptoms Improved No change or worse Total

MEDROXYPROGESTERONEACETATE

MEDROGESTONE

(PER CENT OF PATIENTS)

(PER CENT OF PATIENTS)

38 33 29

24 25 51

100

100

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Thirty-nine of 116 patients given either medroxyprogesterone acetate or medrogestone obtained a complete or partial response for three months or longer (Table 6). Five of 39 responders are living five years or longer, and one of these patients is living at more than 10 years (Fig. 2). Ten per cent of the patients had a complete response, and 23 per cent had a partial response. The site of metastasis did not seem to influence the response to treatment (Table 7), although the length of time from the original treatment to the time of diagnosis of recurrent cancer did seem to have some effect. Among the patients in whom a recurrence or metastasis developed more than three years after their initial treatment, 48 per cent responded to medication with a progestin. The histologic features of the cancer were an important consideration in the attempt to predict whether the patient would respond to treatment. Those tumors exhibiting squamous metaplasia frequently regressed after the patient was given a progestin (Table 8). Patients with undifferentiated tumors or tumors with papillary growth patterns obtained little response to this type of drug. The progestins were well tolerated. During this administration, a subjective improvement was experienced by almost twice as many patients as an objective response (Table 9). Several patients with obviously growing cancer reported that they felt stronger and had a better appetite. Only patients with proven metastases or recurrent adenocarcinoma of the endometrium should be treated with progestins. Once the treatment is started the hormone should be continued for life or until the cancer begins to grow again.

PELVIC SARCOMAS Pelvic sarcomas are usually fatal. In the presence of advanced or recurrent tumors after treatment, patients are seldom benefited by additional irradiation or surgical procedures, or both. During the past several years, a number of authors have reported that combination chemotherapy consisting of either vincristine (Oncovin), actinomycin D (Cosmegen), and cyclophosphamide (Cytoxan), or Adriamycin and dimethyl triazeno Table 10. Pelvic Sarcomas: Site of Origin ORIGIN

Uterus Ovary Vagina

Cervix Rettoperitoneum Perineum Bladder· Fallopian tube Total

NUMBER OF PATIENTS

24 4 3 1 3 1 1 1

38

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CHEMOTHERAPY IN GYNECOLOGIC CANCER

Table 11. Pelvic Sarcomas: Results of Treatment by Histology HISTOLOGY

Mixed mesodermal Leiomyosarcoma Embryonal rhabdomyosarcoma Endometrial stromal sarcoma Alveolar rhabdomyosarcoma Sarcoma botryoides Other sarcomas Total

NUMBER OF

NUMBER

MONTHS

PATIENTS

NED

NED

18 8

4 7

3 3 2 1 3

2 0 0 0 1

38

14

26,34,48,56 10,26,29,33, 34,40 60,72

65

imidazole carboxamide is of value as a treatment for primary sarcomas in other sites in the bodyY' 13 Since January 1, 1965, 38 patients with advan(,'3d, recurrent, or metastatic sarcomas arising in the pelvis have been given concomitant radiation and chemotherapy in the Gynecology Department at the M.D. Anderson Hospital. The site of origin of the several sarcomas is shown in Table 10, and their histologic features are shown in Table 11. The treatment of each patient was individualized according to her needs. Patients with virulent tumors such as embryonal rhabdomyosarcomas or mixed mesodermal sarcomas, received radiotherapy combined with vincristine and actinomycin D. The vincristine was administered intravenously in a dosage of 1.5 mg per m 2 of body surface, once a week for 10 to 12 weeks; actinomycin D was given in a dosage of .5mg per day for five days, every four weeks. After completion of the radiotherapy, cyclophosphamide was added to the treatment and patients received a"combination of vincristine, actinomycin D, and cyclophosphamide (VAC) for two years (Table 12). Patients with less aggressive tumors such as endometrial stromal sarcomas or leiomyosarcomas received radiation combined only with vincristine. The latter was given intravenously in a dose of 1.5 mg per m 2 of body surface, at weekly intervals for 10 to 12 weeks. When the irradiation was completed, the patients received VAC for two years. The amount of radiation given each patient depended upon the location of the tumor. Patients with intraperitoneal metastases received a total dose of 2600 to 2800 rads to the entire abdomen by the moving strip technique, the kidneys and liver being partially shielded, followed by 2000 rads to the pelvis. Most patients with sarcomas confined to the pelvis, or Table 12. Treatment of Pelvic Sarcomas by VAC Vincristine Actinomycin D Cyclophosphamide

1. 5 mg/M2 body surface area every week x 10-12 weeks intravenously .5 mg/day x 5 days every 4 weeks intravenously 5-7 mg/kg/day x 5 days every 4 weeks intravenously

Treatment repeated every 4 weeks, as tolerated, for 2 years.

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Table 13. Pelvic Sarcomas: Complications of Treatment COMPLICATIONS

NUMBER OF PATIENTS

Death Rectal bleeding Hematuria Severe peripheral neuropathy Severe hematologic toxicity Respiratory weakness Ileus requiring hospitalization Bowel injury requiring surgery

5 8 2 9 5 5 2

2

those with pelvic tumors and distant metastases, received 5000 rads to the pelvis through 15 x 15 cm parallel opposed anterior and posterior portals. Four of 18 patients with mixed mesodermal sarcomas were free of disease at 26 to 56 months after the combined treatment. Of eight patients with leiomyosarcomas of the pelvis, seven were alive and without evidence of disease at 10 to 40 months (Table 13). Two patients with embryonal rhabdomyosarcomas were alive and without evidence of recurrent tumor at five and six years. One patient with a neuroblastoma was alive and without evidence of disease at 65 months after treatment. The complications of chemotherapy for pelvic sarcomas have been severe (Table 13). Five patients have died of respiratory failure, probably incident to vincristine toxicity. Eight patients have had rectal bleeding related to radiotherapy; two have required corrective surgery because of intestinal injuries secondary to irradiation. A smaller dosage of vincristine would probably have prevented the respiratory-related deaths, and a smaller amount of radiotherapy might have reduced the number ofintestinal injuries from this combined treatment. Few of these patients, however, could have been expected to live following either chemotherapy or irradiation alone.

ADENOCARCINOMA OF THE FALLOPIAN TUBE Since adenocarcinoma of the fallopian tube is seldom observed, there are few reports of chemotherapy for this type of cancer. 7 Responses to treatment for this tumor with an aklylating agent have been disappointing. A small number of patients has obtained a brief and usually minimal benefit from such drugs. The epithelium of the fallopian tube is derived from the miillerian epithelium and is similar to the epithelium found in serous carcinoma of the ovary and adenocarcinoma of the endometrium. Because of this histologic similarity, since 1965 combination chemotherapy with drugs that have been found effective in ovarian cancer and endometrial cancer has been administered at the M.D. Anderson Hospital. Melphalan in doses outlined for cancer of the ovary has been given, together with a progestin in oral doses, as employed for carcinoma of the endometrium.

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CHEMOTHERAPY IN GYNECOLOGIC CANCER

Table 14. Adenocarcinoma of the Fallopian Tube: Response to Chemotherapy TREATMENT

Thiotepa Melphalan Melphalan and a progestin Total

COMPLETE

PARTIAL

PROGRESSIVE

NUMBER OF

RESPONSE

RESPONSE

CANCER

PATIENTS TREATED

1

0 2

0

2

3

3

2 0

11

5

8

16

22

3

Three of eight patients who received a progestin and melphalan had either a complete or partial response to this treatment (Table 14). Two patients have obtained prolonged responses; one of the two has survived with residual disease for more than five years.

EPIDERMOID CARCINOMA OF THE LOWER GENITAL TRACT Several authors have reported very encouraging results in the chemotherapy of advanced or recurrent squamous cell carcinoma of the cervix, vagina, and vulva. 1, 3, 4,10,12,15 These are all isolated reports, and none of the reported drug regimens has been widely used, nor have they been substantiated by other publications. Patients with epidermoid carcinoma arising in the lower genital tract have seldom benefited from chemotherapy at the M.D. Anderson Hospital. However, numerous agents have been tried, including cyclophosphamide (Cytoxan), melphalan (Alkeran), 5-fluorouracil, vincristine (Oncovin), methotrexate, hydroxyurea (Hydrea), porfiromycin, Adriamycin, and bleomycin (Blenoxane), as well as a combination of vincristine, methotrexate, and hydroxyurea, and a seven drug combination of bleomycin , actinomycin D, methotrexate, cytosine arabinoside, cyclophosphamide, vincristine and 5-fluorouracil,11 and a combination of Adriamycin and methyl CCNU. On the whole, the results of such treatment have not been favorable. Moreover, the toxicity of the drug combinations is often severe, and the cost is excessive. None of the treatments has proven to be superior to either cyclophosphamide or 5-fluorouracil alone. Our choice of these two drugs has been cyclophosphamide. Cyclophosphamide is given intravenously in a dose of 8 mglkg of body weight, daily for five days. These five cycles are repeated every six weeks, provided the white blood count remains above 3,000 and the platelet count above 100,000. Twenty-four of 118 patients (20 per cent) given cyclophosphamide obtained a partial objective response for three months or longer (Table 15), though only a few had responses lasting more than six months. Approximately 40 per cent of these patients who experience pain or other symptoms such as bleeding, vaginal discharge, or a swollen leg reported a subjective improvement for three months or longer.

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Table 15. Epidermoid Carcinoma: Results of Chemotherapy DRUG

Cyclophosphamide Melphalan Thiotepa

NUMBER OF

NUMBER OF

PATIENTS RESPONDING

PATIENTS TREATED

24 (20%) 5 (24%) 1 (17%)

118

21 6

Since epidermoid cancer recurs locally in the pelvis, local treatment with intra-arterial infusions has been explored at this hospital. The drugs employed were methotrexate, 5-fluorouracil, bleomycin, and a combination of methotrexate, hydroxyurea and actinomycin D. The catheters were placed in the lower aorta for infusions of the lower half of the body and legs, and in the hypogastric arteries for infusions of the pelvis. Many of the patients treated with infusions exhibited a short response. Unfortunately, the tumors recurred rapidly. The treatment is expensive, and the results are probably not superior to those obtained with systemic cyclophosphamide or 5-fluorouracil.

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Department of Gynecology and Obstetrics Wayne State University School of Medicine Detroit, Michigan 48201