GYNECOLOGIC
ONCOLOGY
5,
109-120 (1977)
Chemotherapy GEORGE
of Carcinoma
D. MALKASIAN,
JR., M.D., DAVID EDWARD 0. JORGENSEN,
of the Cervix G. DECKER, M.D.
M.D.,
AND
Department of Obstetrics and Gynecology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901 Received September 29, 1976 At the Mayo Clinic, 18.7% of 208 patients with carcinoma of the cervix who were treated with 5-fluorouracil (5-FU) showed an objective response or stabilization of their tumors. In 24 additional patients, 5-FU was used with local radiation, and 8.3% showed a similar response. Of 40 patients treated with cyclophosphamide alone, 17.5% had tumor control.
After two decades of drug use, metastatic and recurrent carcinomas of the cervix (either squamous cell epithelioma or adenocarcinoma) form a group of gynecologic tumors for which the use of chemotherapeutic agents must still be considered on a clinical trial basis. These tumors have better response rates to conventional therapeutic modalities, that is, surgery or radiation therapy or both. Only when these latter modalities have been utilized and their usefulness exhausted should chemotherapy be considered. Certain treatment criteria must be met if useful information is to be obtained from clinical trials of drugs at known drug-tolerance dose levels: The patient (i) must have a life expectancy of at least 4 months, (ii) must have manifestations of tumor pronounced enough so that response to the drug can be measured, and (iii) must be aware of the diagnosis. We believe that the third criterion is necessary in order to obtain full cooperation from the patient and her family and to justify the risks involved in chemotherapy. Despite the ready availability of chemotherapeutic agents for more than 15 years, experience with any one agent or with a large series of carcinomas of the cervix remains relatively uncommon. Squamous cell carcinoma of the cervix, unlike squamous cell carcinoma primary in the head and neck, has not adapted itself well to evaluation of chemotherapeutic agents. The difference lies in (i) the difficulty in accomplishing pelvic infusion and perfusion techniques as opposed to similar techniques used in head and neck tumor therapy, (ii) the exhaustion of radiation therapy in cervical carcinomas before the use of chemotherapeutic agents, and (iii) the frequently impaired renal function associated with widespread cervical carcinoma. The clinical course of carcinoma of the cervix is well documented. The initial recurrence usually is lymphatic spread to regional lymph nodes or is locally at the site of the primary lesion. These recurrences are treated by conventional surgical or radiologic techniques or both. The adequacy of standard methods of treating primary carcinomas of the cervix and the commonest initial identifiable localized pelvic recurrences are evidenced by the increasing numbers of patients who have 109 Copyright @ I!277 by Academic Press, Inc. All rights of reproduction in any form reserved.
110
MALKASIAN,
DECKER,
AND
JORGENSEN
little or no evidence of pelvic disease but who have pulmonary or other distant metastases. During the early 1960s there was significant emphasis on regional chemotherapy by either perfusion or infusion techniques [l]. The hope had been that the response of tumors would be increased by increasing the dose of the drug. Experience with regional chemotherapy developed infusion and perfusion techniques that were useful; however, no drug was successful enough to warrant pursuing this course further; therefore, the evaluation of systemic agents was expanded. The literature through 1973 on systemic chemotherapy for carcinoma of the cervix, recurrent and metastatic, is summarized in Table 1. If, in this summary, only drugs other than hormones are considered, 47 (14%) of 336 patients had tumor response. No compounds or category of compounds was found to be significantly superior. Side effects included stomatitis, nausea, vomiting, diarrhea, dermatitis, leukopenia, anemia, and thrombocytopenia. In many cases, there was the additional problem of alopecia. MAYO CLINIC
EXPERIENCE
The experience involves 318 patients with carcinoma of the cervix, in whom the tumors were progressing despite maximal use of conventional forms of surgical or radiation therapy or both. In 46 of the 318 patients, previous chemotherapy had been employed. Selection ofpatients. To be considered for chemotherapy, a patient had to have had reasonable (though not necessarily normal) hepatic and renal function, a leukocyte count of greater than 4000/mm3, a platelet count of greater than 100,000/mm3, and a hemoglobin concentration of more than 10 g/dl. The desired hemoglobin concentration was at times attained by transfusion of packed erythrocytes. No patient was considered for treatment with cytotoxic agents if she was unaware of the diagnosis or of the fact that the disease was spreading. Each patient was informed of the possible side effects and potential dangers of the drugs and, accordingly, some patients declined their use. Initially, all patients, regardless of age, were accepted; however, we later treated no patient older than 70 years because of the apparent lower drug tolerance in the elderly. Of the 318 patients in the series, 232 were treated with 5fluorouracil (5-FU), 40 were treated with cyclophosphamide, and 46 were treated with other drugs or combinations of drugs. In the group of 46 patients, 9 received 5-FU plus 6,17-dimethyl-6dehydroprogesterone, with no objective responses; 8 received cyclophosphamide plus 6,17-dimethyl-6-dehydroprogesterone, with one objective response; and 9 received cyclophosphamide and methotrexate, with no objective response. There were also 5 patients who were treated with methotrexate, 2 with vincristine, 4 with vinblastine, 1 with actinomycin D, and 4 with phenylalanine mustard; none of these had objective responses. Four patients were treated with hexamethylmelamine, and 1 had an objective response. This group of 46 patients will not be discussed further in the present report. Our experience with chemotherapeutic agents suggests that tumor sensitivity
CARCINOMA
OF
THE
CERVIX
111
and, therefore, tumor response is drug specific rather than dose specific. Thus, we have extended our studies with systemic chemotherapy and, should we identify an agent that can provide good objective tumor response, further studies with regional chemotherapy could be undertaken. Evaluation of data. An objective response was defined as one in which there was (i) a decrease of 25% in the size of measurable lesions, as measured by use of a ruler in each of two perpendicular diameters or (ii) a decrease of 50% in each of two diameters in a palpable lesion. The lesions in the former group were primarily metastatic lesions of the skin, superficial metastatic lesions of the lymph nodes, and pulmonary lesions measured on standard stereoscopic chest films or pulmonary tomograms. The lesions in the latter group were mainly pelvic recurrences or upper abdominal masses. These changes were not accepted as valid if they (i) lasted less than 3 months or (ii) occurred in the presence of an obviously progressing tumor elsewhere in the body. An equivocal response was defined as one in which the tumor mass did not regress but progression did not occur for at least 3 months. A subjective response was defined as one in which the patient could abandon the use of narcotics for pain, the cough secondary to metastatic pulmonary involvement disappeared, or the foul discharge from ulcerated lesions disappeared. To be considered valid, response must be present for 3 months or longer. Incidentally, subjective responses may be influenced by the patient’s knowledge that a therapeutic attempt is being made and that she is not being completely abandoned. Of the 318 patients, 272 were assigned to three treatment groups: A, B, and C. These groups received primary chemotherapy. The patient was assigned to group A (24 patients) if there was a single, identifiable (by ruler or palpably) measurable lesion that had had no previous radiation therapy, was not amenable to surgery, and was located where radiation therapy could be given in cancerocidal doses. The patient was assigned to group B (208 patients) or C (40 patients) when the involved areas were too widespread to be treated with radiation or surgery. The other 46 patients had failed on previous therapy and were given combination-drug therapy or single-drug therapy other than that stated for groups A, B, and C. Drug administration. Patients in the group designated as cervix group A received 5-FU in a daily amount of 15 mg/kg of body weight, but the total course was limited to 3 days and irradiation to tolerance was given to a localized measurable lesion. This treatment regimen was chosen on the basis of reports on the capacity of 5-FU to potentiate the effect of radiation [4,28-301. Patients in cervix group B received therapy that consisted of 5-FU given intravenously in a dose of 15 mg/kg of ideal body weight daily for up to 5 days and, occasionally, if more could be tolerated, 7.5 mg/kg every other day, for a maximum of four additional doses. If the patient was underweight, the actual body weight was used for calculation of the dose. The course of therapy was terminated whenever toxic symptoms were observed; generally, the earliest symptoms to appear were severe nausea, vomiting, diarrhea, or stomatitis. The next course of treatment @ias instituted 4 weeks after the conclusion of the previous one, if the patient’s marrow status permitted. If there was an objective or a subjective
1962 1962
Hreshcyhyshyn and Holland [5] Richardson er a/. [6]
1968 1969 1969 1970
I%8
1964 1964 1965 1965 1966 1968 1968 1968 1968
1960 1962
Varga and Henriksen [7] Bateman [8] Frick et al. [9] Kaplan et al. [lo] Solidoro er al. [ 111 Weiss et al. [12] Moore et al. [ 131 Moore et al. [14] Moore et al. [153 Moore et al. [16] Moore et al. [173 Smith [18] Save1 and Burns [19] Kato et al. [20]
2 21
1960
Colsky et al. [2] Brennan and Vaitkevicius [33 Ansfield et al. [4]
13 12 3 1 39 6 15 18 26 9 18 91 1 8
18 10 8 2
2
Year
Author [reference]
Total patients
0 3 0 0 6 0 5 0 7 0 0 18 0 1
2 0 0 0
1 4
0
Objective regression P,
Hydroxyprogesterone Azetepa Many compounds Methotrexate Cyclophosphamide Azotomycin 5-FU 6Methylprednisolone Chlorambucil Meturedepa Mitomycin Cyclophosphamide Cytosine arabinoside Bleomycin
Many compounds Uracil mustard Cyclophosphamide A-139
5-FU S-FU
Actinomycin
Dw
TABLE 1 SUMMARY OF LITERATURE ON SYSTEMIC CHEMOTHERAPY FOR CARCINOMA OF CERVIX Treatment
% 5 z Ii
F
w E im Oral iv iv and oral iv iv Oral Oral iv iv Not stated SC iv
*% -
SC $ : z iv and oral iv iv
iv iv
iv
Route
..-
Year
1972
1972 1972
1972 1972 1973 1973
Author [reference]
Ota et al. [21]
Izbicki et al. [22] Ohnuma et al. [23]
Kogler et a/. [24] Wampler et al. [25] Bergevin et a/. [26] Tormey et a/. [27]
15 1
2
Total patients
TABLE
5 0
1
Objective regression
1 (Continued)
Mitomycin, S-FU plus cytosine arabinoside Porfiromycin Bleomycin, dibromodulcitol Carbestrol Hexamethylmelamine Hexamethylmelamine Adriamycin plus bleomycin
Dw
Treatment
Oral Oral Oral iv
iv iv
iv
Route
i2 7 5?
3
g
!
P z 5
114
MALKASIAN,
DECKER,
AND
JORGENSEN
response after two or more courses, the patient was maintained on a weekly intravenous dose of I.5 mg/kg of ideal or actual weight (whichever was less). The treatment was stopped if the patient could no longer tolerate the drug, if the tumor was growing despite therapy, or if there was a return of subjective symptoms previously controlled by the chemotherapy. Patients in cervix group C received therapy that consisted of 500 mg of cyclophosphamide intravenously per day for 3 days and repeated monthly. After 3 to 4 months, this regimen was switched to one involving 50 to 100 mg of oral cyclophosphamide per day. Therapy was discontinued under the same circumstances as with 5-FU. Ciinical~eutu~es. The ranges and means of the ages of the patients when they received their chemotherapy are shown in Table 2. The mean age for patients with TABLE AGE
-___
OF PATIENTS
Group Aa Bb CC
LI SFluorouracil plus irradiation * 5-Fluorouracil alone. c Cyclophosphamide.
AT Tlhw
2
OF CHEMOTHERAPY
-____
Number of patients 24 208 40 of a limited
FOR CARCINOMA
OF CERVIX
Age (years)
Range
Mean
38-65 15-74 19-70
48.7 48.7 51.1
lesion.
these carcinomas is about what might be expected from other reports in the literature. Study of the distribution of patients according to stage of the original lesion revealed that 20 patients (83.3%) in group A, 148 patients (71.1%) in group B, and 28 patients (70.0%) in group C had known early (Stage I or II) lesions when cancer was first diagnosed and treated by conventional means (Table 3). This may indicate a need for more careful initial staging, more vigorous initial therapy, or more meticulous follow-up. Side effects. The side effects of the drugs included nausea, vomiting, diarrhea, stomatitis, alopecia, dermatitis (photosensitivity, dry scaling, and increased pigmentation), and bone marrow depression. These were temporary and subsided from 1 to 3 weeks after cessation of drug therapy. A late side effect seen with cyclophosphamide was hemorrhagic cystitis. Because the effective dosage of these drugs is close to one that is severely toxic, the adjustment of dosage can be a problem. The major concern is delayed thrombocytopenia and leukopenia, which occasionally have been profound enough to warrant hospitalization, antibiotic therapy, and transfusion with fresh whole blood. Even these procedures are sometimes insufficient to maintain the patient until her own marrow can function, and death ensues secondary to overwhelming infection, frequently pneumonia, against which the patient is defenseless. Most patients in our series had decreased
CARCINOMA
TABLE DISTRIBUTION
OF PATIENTS AND
WITH
3
CARCINOMA
STAGE
OF CERVIX,
OF ORIGINAL
TO SITE
Number of patients
Group A I II 111 IV Unknown Group B I II III IV Unknown Stump
24
69 79 26 16 12 6
Group C 1 II 111 IV Unknown Stump
12 16 5 2 4 1
13 7 1 1 2 208
40
Total a International
ACCORDING
LESIONS
Stagen
---__
115
OF THE CERVIX
212
classification of cancer of the cervix
function of bone marrow secondary to prior pelvic irradiation, and they frequently exhibited significant leukopenia and thrombocytopenia. Tumor responses. Objective responses were seen in 2 of 24 patients in group A (8.3%), 20 of 208 in group B (9.6%), and 2 of 40 in group C (5.0%) (Table 4). In cervix group A, because of the nature of the group, the recurrences were localized and the patient responding had lesions in the pelvis and abdomen. In TABLE ORIGINAL
TREATMENT PATIENTS
Group
X Ray only
A B C
Oil” O/S -
Radium and x ray 2112 151154 0122
RELATED WITH
4 TO OBJECTIVE
CARCINOMA
OF CERVIX
Surgery only
Surgery and irradiation
016 3123 1112
O/5 2125 015
RESPONSE
IN
Drug as only treatment
Total
O/I l/l
2124 201208 2140
u Numerator is number of patients with objective tumor response; denominator category.
is total number in
116
MALKASIAN,
DECKER,
AND
JORGENSEN
cervix group B, responses occurred in nodal, vaginal, pelvic, pulmonary, and osseous lesions. No one region showed a higher incidence of response. In cervix group C, no objective response was seen in patients with pulmonary or osseous lesions. Besides objective responses, equivocal responses were noted in 0 of 20 patients in group A, 19 of 208 (9.1%) in group B, and 5 of 40 (12.5%) in group C. These data, added to the percentages of objective responses, make a total of 8.3% in group A, 18.7% in group B, and 17.5% in group C whose tumors either decreased in size or were stabilized by the drugs used in the program. Table 4 further delineates the form of initial therapy showing that no one initial therapeutic modality either hindered or enhanced the chemotherapeutic efforts. The respective subjective response rates for the three groups were 33.3, 12.0, and 0%. In an effort to determine whether or not there is a time after the initial therapy when one would expect a better drug response, we compared objective tumor response with elapsed time from original treatment to start of chemotherapy (Table 5). No such optimal time after original treatment was found. The relationships of objective response to the histologic cell type and the pathologic grade (Broders, [31]) classification of the tumors are shown in Table 6. No one histologic cell type or grade within a cell type was particularly sensitive to chemotherapy with 5-FU. Two lesions responded to cyclophosphamide therapy: a grade 1 squamous cell epithelioma and a grade 2 adenocarcinoma. The durations of objective, equivocal, and subjective responses in each group are given in Table 7. In proportion to the risks involved, the responses are distressingly ephemeral. Although the responses were brief, many of these patients pursued normal lives while under chemotherapy, whereas they were unable to do so before. Prior to the availability of percutaneous tractotomy, chemotherapy afforded a number of patients permanent relief of pain. Approximately half of the subjective responses involved the permanent relief of pain. When percutaneous tractotomy is not available, systemic chemotherapy should be considered for attempted pain relief. A perplexing problem involves the maintenance of the hematopoietic system during prolonged drug treatment so that if one drug fails another compound may be employed; this is of further importance with compounds that have a fixed total dose such as adriamycin. To date we have had no success with the use of iron, multiple-specific vitamins, testosterone, or steroids. None of our patients who TABLE ELAPSED
TIME
FROM
TREATMENT
IN PATIENTS
Group A B C a Numerator category.
tl
Year 0170 4167 l/l6 is number
l-2
Years
WITH
of patients
TO CHEMOTHERAPY
OF CERVIX
3-4
4-5
o/4 3134 O/6 with
LESION
CARCINOMA
2-3 Years
o/4 10146 l/6
5
OF ORIGINAL
objective
Years l/3 2/l 1 o/4
tumor
Years
>5 Years
Total
l/5 l/34 O/5
2124 201208 2140
O/l O/16 o/3 response;
denominator
is total
number
in
II3
C
o/3
Ollb 2117
2
ill7 151135 O/l2
3
o/7
O/6 2139
4
I
o/2
II2
RELATED
TABLE
6 IN PATIENTS
Number of patients
2 20 2
Group
A B C
Range (months) ~~ 9-12 3-40 5-6
Objective
10.5 10.4 -
TABLE
7
I9 5
O/I
8.0 5.6
4-16 3-10
RESPONSES
Mean (months)
SUBJECTIVE OF CERVIX
Range (months)
Equivocal
EQUIVOCAL, AND WITH CARCINOMA
Number of patients
OF OBJECTIVE, IN PATIENTS
Mean (months)
DURATION
-
I
CARCINOMA
-
8 26 0
Number of patients
o/2 O/I
2 o/2 -
3
Adenocanthoma, grade”
OF CERVIX
is total number in category.
o/3 -
o/4 o/3
4
-
3
WITH
o/3 II8
2
Adenocarcinoma, gradeD
TO RESPONSE
’ Broders’ classification [3l]. b Numerator is number of patients with objective tumor response; denominator
-
I
A B
Group
OF LESION
Squamous-cell enithelioma, grade”
GRADING
3-12 3-11 -
Range (months)
Subjective
O/I -
-
4
7.5 6.8 -
Mean (months)
201208 2140
2124
Total
E 4
MALKASIAN,
118
DECKER, TABLE
SURVIVAL
FROM
START
OF CHEMOTHERAPY
AND JORGENSEN 8 TO DEATH
IN CARCINOMA
Patients with objective response
OF CERVIX
Patients with no response
Group
Number
Mean (months)
Number
Mean (months)
A B
2 20 2
20.5 21.9 14.0
22 188 38
7.1 8.35 7.35
C
obtained objective regression of tumor growth tolerated any other cytotoxic compound when the initial drug was no longer effective. Patients whose tumors responded objectively survived two to three times longer than did patients whose tumors did not (Table 8). In this group of 232 patients treated with 5-FU there were 20 deaths attributable to the drug. One of the deaths was due to a coronary occlusion, and the rest were secondary to pancytopenia. COMMENT AND SUMMARY To date, antitumor compounds have been credited with no cures when used to treat recurrent and metastatic carcinomas of the cervix. However, they have been responsible for inducing some objective tumor regression, for halting tumor growth, and for relieving many of the disabling symptoms that plague patients with metastatic or recurrent lesions ‘or both. Our initial experience with 5-FU suggested that it was more effective against adenocarcinoma of the cervix than against squamous cell lesions [32,33]. This has been shown to be untrue as our experience expanded. The present series suggests that 5-FU is more useful than cyclophosphamide for the treatment of recurrence of these lesions and that 5-FU as an adjuvant to radiation therapy is of no value in increasing the response rate. At present, no compounds appear to be effective enough against recurrent and metastatic carcinoma of the cervix to warrant their consideration as an integral part of the initial treatment of this lesion. The primary therapy is still surgery or radiation, or both, and these two modalities are still the treatment of choice for recurrent disease. Currently, we believe that chemotherapy for carcinoma of the cervix can be considered only in patients with locally recurrent or metastatic disease, after all other modalities have been utilized and have failed. There is no compound specifically effective against these lesions. REFERENCES I. Cromer, J. K., Bateman, J. C., Berry, G. N., Kennelly. J. M., Klopp, C. T., and Platt, L. I. Use of intra-arterial nitrogen mustard therapy in the treatment of cervical and vaginal cancer,Amer. J. Obstet.
Gynecol.
63, 538-548
(1952).
CARCINOMA
OF THE CERVIX
119
2. Colsky, J., Franzino, A., Majima, H., and Jones, R., Jr. Human pharmacologic studies with actinomycin P2 (PA 126-P,), Cancer Chemother. Rep. 8, 27-32 (1960). 3. Brennan, M. J., and Vaitkevicius, V. K. 5-Fluorouracil in clinical cancer experience with I55 patients, Cancer Chemorher. Rep. 6, S-l 1 (1960). 4. Ansfield, F. J., Gollin, F. F., Schroeder, J. M., Curreri, A. R., and Vermund, H. Five years clinical experience with 5-fluorouracil, J. Amer. Med. Assoc. 181, 295-299 (1962). 5. Hreshcyhyshyn, M. M., and Holland, J. F. Chemotherapy in patients with gynecologic cancer, Amer. J. Obstet. Gynecol. 83, 468-489 (1962). 6. Richardson, G. S., Hall, T. C., Green, T. H., and Ulfelder, H. Chemotherapy of cervical carcinoma, Arm. N.Y. Acad. SC;. 97, 841-869 (1962). 7. Varga, A., and Henriksen, E. Effect of l7-alpha-hydroxyprogesterone 17-n-caproate on various pelvic malignancies, Obstet. Gynecol. 23, 51-62 (1964). 8. Bateman, J. C. Clinical studies with azetepa in the treatment of advanced cancer, Acru Unio fnr. Contra Cancrum 20, 345-35 I (1964). 9. Frick, H. C., II, Atchoo, N., Adamsons, K., Jr., and Taylor, H. C., Jr. The efficacy of chemotherapeutic agents in the management of disseminated gynecologic cancer: Review of 206 cases, Amer. J. Obsret. Gynecol. 93, 1112-l I21 (1965). IO. Kaplan, A. L., Wall, J. A., and Hudgins, P. T. Management of persistent carcinoma of the cervix, Tex. State J. Med. 61, 607-612 (1965). II. Solidoro, A. S., Esteves, L., Castellano. C., Valdivia, E., and Barriga, 0. Chemotherapy of advanced cancer of the cervix: Experience in 55 cases treated with cyclophosphamide,Amer. J. Obsret. Gynecol. 94, 208-213 (1966). 12. Weiss, A. J., Ramirez, G., Grage, T., Strawitz, J., Goldman, L., and Downing, V. Phase II study of azotomycin (NSC-56654), Cancer Chemorher. Rep. 52, 61 l-614 (1968). 13. Moore, G. E., Bross, 1. D. J., Ausman, R., Nadler, S., Jones, R., Jr., Slack, N., and Rimm, A. A. Effects of 5-fluorouracil (NSC-19893) in 389 patients with cancer, Cancer Chemother. Rep. 52, 641-653 (1968). 14. Moore, G. E., Bross, 1. D. J., Ausman, R., Nadler, S., Jones, R., Jr., Slack, N., and Rimm, A. A. Effects of 6-mercaptopurine (NSC-755) in 290 patients with advanced cancer, Cancer Chemorher. Rep. 52, 655-660 (1968). IS. Moore, G. E., Bross, 1. D. J., Ausman, R., Nadler, S., Jones, R., Jr., Slack, N., and Rimm, A. A. Effects of chlorambucil (NSC-3088) in 374 patients with advanced cancer, Cancer Chemother. Rep. 52, 661-666 (1968). 16. Moore, G. E., Bross, 1. D. J., Ausman, R., Nadler, S., Jones, R., Jr., Slack, N., and Rimm, A, A. Effects of meturedepa (NSC-51325) in 233 patients with advanced cancer, Cancer Chemother. Rep. 52, 667-673 (1968). 17. Moore, G. E., Bross, I. D. J., Ausman, R., Nadler, S., Jones, R., Jr., Slack, N., and Rimm, A. A. Effects of mitomycin C (NSC-26980) in 346 patients with advanced cancer, Cancer Chemother. Rep.
52, 675-684
(1968).
IS. Smith, J. P. Discussion, in Cancer oj’rhe areras and o\zury (A collection of papers presented at the Eleventh Annual Clinical Conference on Cancer, 1966, at the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas), Year Book Medical Publishers, Chicago, pp. 345-346 (1969). 19. Savel, H., and Burns, S. L. Cytosine arabinoside (NSC-63878) given subcutaneously to patients with cancer, Cancer Chemother. Rep. 53, 153-156 (1969). 20. Kato, T., Abe, H., Yamagami, T., and Uchino, M. Therapeutic effects of bleomycin, an anticarcinogenic agent, on cancers occurred in the female genital organs, Kurume Med. J. 17, 75-95 (1970). 21. Ota, K., Kurita, S., Nishimura, M., Ogawa, M., Kamei, Y., Imai, K., Ariyoshi, Y., Kataoka, K., Murakami, M., Oyama, A., Hoshino, A., Amo, H., and Kato, T. Combination therapy with mitomycin C (NSC-26980), 5-fluorouracil (NSC-19893), and cytosine arabinoside (NSC-63878) for advanced cancer in man, Cancer Chemorher. Rep. 56, 373-385 (1972). 22. Izbicki, R., Al-Sarraf, M., Reed, M. L., Vaughn, C. B., and Vaitkevicius, V. K. Further clinical trials with pofiromycin (NSC-56410) (large intermittent doses), Cancer Chemorher. Rep. 56, 615-624 (1972).
120
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DECKER,
AND JORGENSEN
23. Ohnuma, T., Holland, J. F., Sako, K., and Shedd, D. P. Effects of combination therapy with bleomycin (NSC-125066) and dibromodulcitol (NSC-104800) on squamous cell carcinoma in man, Cancer Chemother. Rep. 56, 625-633 (1972). 24. Kogler, J., Hill, G., Sedransk, N., Cole, D. R., Weiss, A. J., and Wilson, W. Phase II study of carbestrol (NSC-19962) in patients with solid tumors, Cancer Chemother. Rep. 56, 641-647 (1972). 25. Wampler, G. L., Mellette, S. J., Kupermine, M., and Regelson, W. Hexamethylmelamine (NSC13875) in the treatment of advanced cancer, Cancer Chemorher. Rep. 56,. 505-514 (1972). 26. Bergevin, P. R., Tormey, D. C., and Blom, J. Clinical evaluation of hexamethylmelamine (NSC13875), Cancer Chemother. Rep. 57, 51-58 (1973). 27. Tormey, D. C., Bergevin, P., Blom, J., and Petty, W. Preliminary trials with a combination of adriamycin (NSC-123127) and bleomycin (NSC-125066) in adult malignancies, Cancer Chemother. Rep. 57, 413-418 (1973). 28. Ansfield, F. J., Gollin, F. F., Schroeder, J. M., Curreri, A. R., and Vermund, H. A clinical study of combined chemo- and radiotherapy in primary bronchogenic carcinoma (abstract), Proc. Amer. Assoc. Cancer Res. 3, 300 (1962). 29. Foye, L. V., Jr., Willett, F. M., Hall, B., and Roth, M. The potentiation of radiation effects with 5-fluorouracil, Cancer Chemother. Rep. 6, 12-15 (1960). 30. Hall, B. E., Foye, L. V., Jr., Roth, M., Willett, F. M., Hales, D. R., Ward, J. H., Jr., Butler, H. T., and Godfrey, M. H. Treatment of inoperable cancer with 5-fluorouracil and irradiation (Letter to the Editor), Lancer 1, 115-116 (1960). 31. Broders, A. C. Carcinoma: grading and practical application, Arch. Pathol. 2, 376-381 (1926). 32. Malkasian, G. D., Jr., Decker, D. G., Mussey, E., and Johnson, C. E. Preliminary observations on carcinoma of the cervix treated with 5-fluorouracil, Amer. J. O&et. Gyecol. 88, 82-85 (1964). 33. Malkasian, G. D., Jr., Decker, D. G., Mussey, E., and Johnson, D. E. Observations on gYnecologic malignancy treated with 5-fluorouracil, Amer. J. Obsrer. Gynecol. 180, 1012-1017 (1968).
ONCOLOGY
5,
109-120 (1977)
Chemotherapy GEORGE
of Carcinoma
D. MALKASIAN,
JR., M.D., DAVID EDWARD 0. JORGENSEN,
of the Cervix G. DECKER, M.D.
M.D.,
AND
Department of Obstetrics and Gynecology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901 Received September 29, 1976 At the Mayo Clinic, 18.7% of 208 patients with carcinoma of the cervix who were treated with 5-fluorouracil (5-FU) showed an objective response or stabilization of their tumors. In 24 additional patients, 5-FU was used with local radiation, and 8.3% showed a similar response. Of 40 patients treated with cyclophosphamide alone, 17.5% had tumor control.
After two decades of drug use, metastatic and recurrent carcinomas of the cervix (either squamous cell epithelioma or adenocarcinoma) form a group of gynecologic tumors for which the use of chemotherapeutic agents must still be considered on a clinical trial basis. These tumors have better response rates to conventional therapeutic modalities, that is, surgery or radiation therapy or both. Only when these latter modalities have been utilized and their usefulness exhausted should chemotherapy be considered. Certain treatment criteria must be met if useful information is to be obtained from clinical trials of drugs at known drug-tolerance dose levels: The patient (i) must have a life expectancy of at least 4 months, (ii) must have manifestations of tumor pronounced enough so that response to the drug can be measured, and (iii) must be aware of the diagnosis. We believe that the third criterion is necessary in order to obtain full cooperation from the patient and her family and to justify the risks involved in chemotherapy. Despite the ready availability of chemotherapeutic agents for more than 15 years, experience with any one agent or with a large series of carcinomas of the cervix remains relatively uncommon. Squamous cell carcinoma of the cervix, unlike squamous cell carcinoma primary in the head and neck, has not adapted itself well to evaluation of chemotherapeutic agents. The difference lies in (i) the difficulty in accomplishing pelvic infusion and perfusion techniques as opposed to similar techniques used in head and neck tumor therapy, (ii) the exhaustion of radiation therapy in cervical carcinomas before the use of chemotherapeutic agents, and (iii) the frequently impaired renal function associated with widespread cervical carcinoma. The clinical course of carcinoma of the cervix is well documented. The initial recurrence usually is lymphatic spread to regional lymph nodes or is locally at the site of the primary lesion. These recurrences are treated by conventional surgical or radiologic techniques or both. The adequacy of standard methods of treating primary carcinomas of the cervix and the commonest initial identifiable localized pelvic recurrences are evidenced by the increasing numbers of patients who have 109 Copyright @ I!277 by Academic Press, Inc. All rights of reproduction in any form reserved.
110
MALKASIAN,
DECKER,
AND
JORGENSEN
little or no evidence of pelvic disease but who have pulmonary or other distant metastases. During the early 1960s there was significant emphasis on regional chemotherapy by either perfusion or infusion techniques [l]. The hope had been that the response of tumors would be increased by increasing the dose of the drug. Experience with regional chemotherapy developed infusion and perfusion techniques that were useful; however, no drug was successful enough to warrant pursuing this course further; therefore, the evaluation of systemic agents was expanded. The literature through 1973 on systemic chemotherapy for carcinoma of the cervix, recurrent and metastatic, is summarized in Table 1. If, in this summary, only drugs other than hormones are considered, 47 (14%) of 336 patients had tumor response. No compounds or category of compounds was found to be significantly superior. Side effects included stomatitis, nausea, vomiting, diarrhea, dermatitis, leukopenia, anemia, and thrombocytopenia. In many cases, there was the additional problem of alopecia. MAYO CLINIC
EXPERIENCE
The experience involves 318 patients with carcinoma of the cervix, in whom the tumors were progressing despite maximal use of conventional forms of surgical or radiation therapy or both. In 46 of the 318 patients, previous chemotherapy had been employed. Selection ofpatients. To be considered for chemotherapy, a patient had to have had reasonable (though not necessarily normal) hepatic and renal function, a leukocyte count of greater than 4000/mm3, a platelet count of greater than 100,000/mm3, and a hemoglobin concentration of more than 10 g/dl. The desired hemoglobin concentration was at times attained by transfusion of packed erythrocytes. No patient was considered for treatment with cytotoxic agents if she was unaware of the diagnosis or of the fact that the disease was spreading. Each patient was informed of the possible side effects and potential dangers of the drugs and, accordingly, some patients declined their use. Initially, all patients, regardless of age, were accepted; however, we later treated no patient older than 70 years because of the apparent lower drug tolerance in the elderly. Of the 318 patients in the series, 232 were treated with 5fluorouracil (5-FU), 40 were treated with cyclophosphamide, and 46 were treated with other drugs or combinations of drugs. In the group of 46 patients, 9 received 5-FU plus 6,17-dimethyl-6dehydroprogesterone, with no objective responses; 8 received cyclophosphamide plus 6,17-dimethyl-6-dehydroprogesterone, with one objective response; and 9 received cyclophosphamide and methotrexate, with no objective response. There were also 5 patients who were treated with methotrexate, 2 with vincristine, 4 with vinblastine, 1 with actinomycin D, and 4 with phenylalanine mustard; none of these had objective responses. Four patients were treated with hexamethylmelamine, and 1 had an objective response. This group of 46 patients will not be discussed further in the present report. Our experience with chemotherapeutic agents suggests that tumor sensitivity
CARCINOMA
OF
THE
CERVIX
111
and, therefore, tumor response is drug specific rather than dose specific. Thus, we have extended our studies with systemic chemotherapy and, should we identify an agent that can provide good objective tumor response, further studies with regional chemotherapy could be undertaken. Evaluation of data. An objective response was defined as one in which there was (i) a decrease of 25% in the size of measurable lesions, as measured by use of a ruler in each of two perpendicular diameters or (ii) a decrease of 50% in each of two diameters in a palpable lesion. The lesions in the former group were primarily metastatic lesions of the skin, superficial metastatic lesions of the lymph nodes, and pulmonary lesions measured on standard stereoscopic chest films or pulmonary tomograms. The lesions in the latter group were mainly pelvic recurrences or upper abdominal masses. These changes were not accepted as valid if they (i) lasted less than 3 months or (ii) occurred in the presence of an obviously progressing tumor elsewhere in the body. An equivocal response was defined as one in which the tumor mass did not regress but progression did not occur for at least 3 months. A subjective response was defined as one in which the patient could abandon the use of narcotics for pain, the cough secondary to metastatic pulmonary involvement disappeared, or the foul discharge from ulcerated lesions disappeared. To be considered valid, response must be present for 3 months or longer. Incidentally, subjective responses may be influenced by the patient’s knowledge that a therapeutic attempt is being made and that she is not being completely abandoned. Of the 318 patients, 272 were assigned to three treatment groups: A, B, and C. These groups received primary chemotherapy. The patient was assigned to group A (24 patients) if there was a single, identifiable (by ruler or palpably) measurable lesion that had had no previous radiation therapy, was not amenable to surgery, and was located where radiation therapy could be given in cancerocidal doses. The patient was assigned to group B (208 patients) or C (40 patients) when the involved areas were too widespread to be treated with radiation or surgery. The other 46 patients had failed on previous therapy and were given combination-drug therapy or single-drug therapy other than that stated for groups A, B, and C. Drug administration. Patients in the group designated as cervix group A received 5-FU in a daily amount of 15 mg/kg of body weight, but the total course was limited to 3 days and irradiation to tolerance was given to a localized measurable lesion. This treatment regimen was chosen on the basis of reports on the capacity of 5-FU to potentiate the effect of radiation [4,28-301. Patients in cervix group B received therapy that consisted of 5-FU given intravenously in a dose of 15 mg/kg of ideal body weight daily for up to 5 days and, occasionally, if more could be tolerated, 7.5 mg/kg every other day, for a maximum of four additional doses. If the patient was underweight, the actual body weight was used for calculation of the dose. The course of therapy was terminated whenever toxic symptoms were observed; generally, the earliest symptoms to appear were severe nausea, vomiting, diarrhea, or stomatitis. The next course of treatment @ias instituted 4 weeks after the conclusion of the previous one, if the patient’s marrow status permitted. If there was an objective or a subjective
1962 1962
Hreshcyhyshyn and Holland [5] Richardson er a/. [6]
1968 1969 1969 1970
I%8
1964 1964 1965 1965 1966 1968 1968 1968 1968
1960 1962
Varga and Henriksen [7] Bateman [8] Frick et al. [9] Kaplan et al. [lo] Solidoro er al. [ 111 Weiss et al. [12] Moore et al. [ 131 Moore et al. [14] Moore et al. [153 Moore et al. [16] Moore et al. [173 Smith [18] Save1 and Burns [19] Kato et al. [20]
2 21
1960
Colsky et al. [2] Brennan and Vaitkevicius [33 Ansfield et al. [4]
13 12 3 1 39 6 15 18 26 9 18 91 1 8
18 10 8 2
2
Year
Author [reference]
Total patients
0 3 0 0 6 0 5 0 7 0 0 18 0 1
2 0 0 0
1 4
0
Objective regression P,
Hydroxyprogesterone Azetepa Many compounds Methotrexate Cyclophosphamide Azotomycin 5-FU 6Methylprednisolone Chlorambucil Meturedepa Mitomycin Cyclophosphamide Cytosine arabinoside Bleomycin
Many compounds Uracil mustard Cyclophosphamide A-139
5-FU S-FU
Actinomycin
Dw
TABLE 1 SUMMARY OF LITERATURE ON SYSTEMIC CHEMOTHERAPY FOR CARCINOMA OF CERVIX Treatment
% 5 z Ii
F
w E im Oral iv iv and oral iv iv Oral Oral iv iv Not stated SC iv
*% -
SC $ : z iv and oral iv iv
iv iv
iv
Route
..-
Year
1972
1972 1972
1972 1972 1973 1973
Author [reference]
Ota et al. [21]
Izbicki et al. [22] Ohnuma et al. [23]
Kogler et a/. [24] Wampler et al. [25] Bergevin et a/. [26] Tormey et a/. [27]
15 1
2
Total patients
TABLE
5 0
1
Objective regression
1 (Continued)
Mitomycin, S-FU plus cytosine arabinoside Porfiromycin Bleomycin, dibromodulcitol Carbestrol Hexamethylmelamine Hexamethylmelamine Adriamycin plus bleomycin
Dw
Treatment
Oral Oral Oral iv
iv iv
iv
Route
i2 7 5?
3
g
!
P z 5
114
MALKASIAN,
DECKER,
AND
JORGENSEN
response after two or more courses, the patient was maintained on a weekly intravenous dose of I.5 mg/kg of ideal or actual weight (whichever was less). The treatment was stopped if the patient could no longer tolerate the drug, if the tumor was growing despite therapy, or if there was a return of subjective symptoms previously controlled by the chemotherapy. Patients in cervix group C received therapy that consisted of 500 mg of cyclophosphamide intravenously per day for 3 days and repeated monthly. After 3 to 4 months, this regimen was switched to one involving 50 to 100 mg of oral cyclophosphamide per day. Therapy was discontinued under the same circumstances as with 5-FU. Ciinical~eutu~es. The ranges and means of the ages of the patients when they received their chemotherapy are shown in Table 2. The mean age for patients with TABLE AGE
-___
OF PATIENTS
Group Aa Bb CC
LI SFluorouracil plus irradiation * 5-Fluorouracil alone. c Cyclophosphamide.
AT Tlhw
2
OF CHEMOTHERAPY
-____
Number of patients 24 208 40 of a limited
FOR CARCINOMA
OF CERVIX
Age (years)
Range
Mean
38-65 15-74 19-70
48.7 48.7 51.1
lesion.
these carcinomas is about what might be expected from other reports in the literature. Study of the distribution of patients according to stage of the original lesion revealed that 20 patients (83.3%) in group A, 148 patients (71.1%) in group B, and 28 patients (70.0%) in group C had known early (Stage I or II) lesions when cancer was first diagnosed and treated by conventional means (Table 3). This may indicate a need for more careful initial staging, more vigorous initial therapy, or more meticulous follow-up. Side effects. The side effects of the drugs included nausea, vomiting, diarrhea, stomatitis, alopecia, dermatitis (photosensitivity, dry scaling, and increased pigmentation), and bone marrow depression. These were temporary and subsided from 1 to 3 weeks after cessation of drug therapy. A late side effect seen with cyclophosphamide was hemorrhagic cystitis. Because the effective dosage of these drugs is close to one that is severely toxic, the adjustment of dosage can be a problem. The major concern is delayed thrombocytopenia and leukopenia, which occasionally have been profound enough to warrant hospitalization, antibiotic therapy, and transfusion with fresh whole blood. Even these procedures are sometimes insufficient to maintain the patient until her own marrow can function, and death ensues secondary to overwhelming infection, frequently pneumonia, against which the patient is defenseless. Most patients in our series had decreased
CARCINOMA
TABLE DISTRIBUTION
OF PATIENTS AND
WITH
3
CARCINOMA
STAGE
OF CERVIX,
OF ORIGINAL
TO SITE
Number of patients
Group A I II 111 IV Unknown Group B I II III IV Unknown Stump
24
69 79 26 16 12 6
Group C 1 II 111 IV Unknown Stump
12 16 5 2 4 1
13 7 1 1 2 208
40
Total a International
ACCORDING
LESIONS
Stagen
---__
115
OF THE CERVIX
212
classification of cancer of the cervix
function of bone marrow secondary to prior pelvic irradiation, and they frequently exhibited significant leukopenia and thrombocytopenia. Tumor responses. Objective responses were seen in 2 of 24 patients in group A (8.3%), 20 of 208 in group B (9.6%), and 2 of 40 in group C (5.0%) (Table 4). In cervix group A, because of the nature of the group, the recurrences were localized and the patient responding had lesions in the pelvis and abdomen. In TABLE ORIGINAL
TREATMENT PATIENTS
Group
X Ray only
A B C
Oil” O/S -
Radium and x ray 2112 151154 0122
RELATED WITH
4 TO OBJECTIVE
CARCINOMA
OF CERVIX
Surgery only
Surgery and irradiation
016 3123 1112
O/5 2125 015
RESPONSE
IN
Drug as only treatment
Total
O/I l/l
2124 201208 2140
u Numerator is number of patients with objective tumor response; denominator category.
is total number in
116
MALKASIAN,
DECKER,
AND
JORGENSEN
cervix group B, responses occurred in nodal, vaginal, pelvic, pulmonary, and osseous lesions. No one region showed a higher incidence of response. In cervix group C, no objective response was seen in patients with pulmonary or osseous lesions. Besides objective responses, equivocal responses were noted in 0 of 20 patients in group A, 19 of 208 (9.1%) in group B, and 5 of 40 (12.5%) in group C. These data, added to the percentages of objective responses, make a total of 8.3% in group A, 18.7% in group B, and 17.5% in group C whose tumors either decreased in size or were stabilized by the drugs used in the program. Table 4 further delineates the form of initial therapy showing that no one initial therapeutic modality either hindered or enhanced the chemotherapeutic efforts. The respective subjective response rates for the three groups were 33.3, 12.0, and 0%. In an effort to determine whether or not there is a time after the initial therapy when one would expect a better drug response, we compared objective tumor response with elapsed time from original treatment to start of chemotherapy (Table 5). No such optimal time after original treatment was found. The relationships of objective response to the histologic cell type and the pathologic grade (Broders, [31]) classification of the tumors are shown in Table 6. No one histologic cell type or grade within a cell type was particularly sensitive to chemotherapy with 5-FU. Two lesions responded to cyclophosphamide therapy: a grade 1 squamous cell epithelioma and a grade 2 adenocarcinoma. The durations of objective, equivocal, and subjective responses in each group are given in Table 7. In proportion to the risks involved, the responses are distressingly ephemeral. Although the responses were brief, many of these patients pursued normal lives while under chemotherapy, whereas they were unable to do so before. Prior to the availability of percutaneous tractotomy, chemotherapy afforded a number of patients permanent relief of pain. Approximately half of the subjective responses involved the permanent relief of pain. When percutaneous tractotomy is not available, systemic chemotherapy should be considered for attempted pain relief. A perplexing problem involves the maintenance of the hematopoietic system during prolonged drug treatment so that if one drug fails another compound may be employed; this is of further importance with compounds that have a fixed total dose such as adriamycin. To date we have had no success with the use of iron, multiple-specific vitamins, testosterone, or steroids. None of our patients who TABLE ELAPSED
TIME
FROM
TREATMENT
IN PATIENTS
Group A B C a Numerator category.
tl
Year 0170 4167 l/l6 is number
l-2
Years
WITH
of patients
TO CHEMOTHERAPY
OF CERVIX
3-4
4-5
o/4 3134 O/6 with
LESION
CARCINOMA
2-3 Years
o/4 10146 l/6
5
OF ORIGINAL
objective
Years l/3 2/l 1 o/4
tumor
Years
>5 Years
Total
l/5 l/34 O/5
2124 201208 2140
O/l O/16 o/3 response;
denominator
is total
number
in
II3
C
o/3
Ollb 2117
2
ill7 151135 O/l2
3
o/7
O/6 2139
4
I
o/2
II2
RELATED
TABLE
6 IN PATIENTS
Number of patients
2 20 2
Group
A B C
Range (months) ~~ 9-12 3-40 5-6
Objective
10.5 10.4 -
TABLE
7
I9 5
O/I
8.0 5.6
4-16 3-10
RESPONSES
Mean (months)
SUBJECTIVE OF CERVIX
Range (months)
Equivocal
EQUIVOCAL, AND WITH CARCINOMA
Number of patients
OF OBJECTIVE, IN PATIENTS
Mean (months)
DURATION
-
I
CARCINOMA
-
8 26 0
Number of patients
o/2 O/I
2 o/2 -
3
Adenocanthoma, grade”
OF CERVIX
is total number in category.
o/3 -
o/4 o/3
4
-
3
WITH
o/3 II8
2
Adenocarcinoma, gradeD
TO RESPONSE
’ Broders’ classification [3l]. b Numerator is number of patients with objective tumor response; denominator
-
I
A B
Group
OF LESION
Squamous-cell enithelioma, grade”
GRADING
3-12 3-11 -
Range (months)
Subjective
O/I -
-
4
7.5 6.8 -
Mean (months)
201208 2140
2124
Total
E 4
MALKASIAN,
118
DECKER, TABLE
SURVIVAL
FROM
START
OF CHEMOTHERAPY
AND JORGENSEN 8 TO DEATH
IN CARCINOMA
Patients with objective response
OF CERVIX
Patients with no response
Group
Number
Mean (months)
Number
Mean (months)
A B
2 20 2
20.5 21.9 14.0
22 188 38
7.1 8.35 7.35
C
obtained objective regression of tumor growth tolerated any other cytotoxic compound when the initial drug was no longer effective. Patients whose tumors responded objectively survived two to three times longer than did patients whose tumors did not (Table 8). In this group of 232 patients treated with 5-FU there were 20 deaths attributable to the drug. One of the deaths was due to a coronary occlusion, and the rest were secondary to pancytopenia. COMMENT AND SUMMARY To date, antitumor compounds have been credited with no cures when used to treat recurrent and metastatic carcinomas of the cervix. However, they have been responsible for inducing some objective tumor regression, for halting tumor growth, and for relieving many of the disabling symptoms that plague patients with metastatic or recurrent lesions ‘or both. Our initial experience with 5-FU suggested that it was more effective against adenocarcinoma of the cervix than against squamous cell lesions [32,33]. This has been shown to be untrue as our experience expanded. The present series suggests that 5-FU is more useful than cyclophosphamide for the treatment of recurrence of these lesions and that 5-FU as an adjuvant to radiation therapy is of no value in increasing the response rate. At present, no compounds appear to be effective enough against recurrent and metastatic carcinoma of the cervix to warrant their consideration as an integral part of the initial treatment of this lesion. The primary therapy is still surgery or radiation, or both, and these two modalities are still the treatment of choice for recurrent disease. Currently, we believe that chemotherapy for carcinoma of the cervix can be considered only in patients with locally recurrent or metastatic disease, after all other modalities have been utilized and have failed. There is no compound specifically effective against these lesions. REFERENCES I. Cromer, J. K., Bateman, J. C., Berry, G. N., Kennelly. J. M., Klopp, C. T., and Platt, L. I. Use of intra-arterial nitrogen mustard therapy in the treatment of cervical and vaginal cancer,Amer. J. Obstet.
Gynecol.
63, 538-548
(1952).
CARCINOMA
OF THE CERVIX
119
2. Colsky, J., Franzino, A., Majima, H., and Jones, R., Jr. Human pharmacologic studies with actinomycin P2 (PA 126-P,), Cancer Chemother. Rep. 8, 27-32 (1960). 3. Brennan, M. J., and Vaitkevicius, V. K. 5-Fluorouracil in clinical cancer experience with I55 patients, Cancer Chemorher. Rep. 6, S-l 1 (1960). 4. Ansfield, F. J., Gollin, F. F., Schroeder, J. M., Curreri, A. R., and Vermund, H. Five years clinical experience with 5-fluorouracil, J. Amer. Med. Assoc. 181, 295-299 (1962). 5. Hreshcyhyshyn, M. M., and Holland, J. F. Chemotherapy in patients with gynecologic cancer, Amer. J. Obstet. Gynecol. 83, 468-489 (1962). 6. Richardson, G. S., Hall, T. C., Green, T. H., and Ulfelder, H. Chemotherapy of cervical carcinoma, Arm. N.Y. Acad. SC;. 97, 841-869 (1962). 7. Varga, A., and Henriksen, E. Effect of l7-alpha-hydroxyprogesterone 17-n-caproate on various pelvic malignancies, Obstet. Gynecol. 23, 51-62 (1964). 8. Bateman, J. C. Clinical studies with azetepa in the treatment of advanced cancer, Acru Unio fnr. Contra Cancrum 20, 345-35 I (1964). 9. Frick, H. C., II, Atchoo, N., Adamsons, K., Jr., and Taylor, H. C., Jr. The efficacy of chemotherapeutic agents in the management of disseminated gynecologic cancer: Review of 206 cases, Amer. J. Obsret. Gynecol. 93, 1112-l I21 (1965). IO. Kaplan, A. L., Wall, J. A., and Hudgins, P. T. Management of persistent carcinoma of the cervix, Tex. State J. Med. 61, 607-612 (1965). II. Solidoro, A. S., Esteves, L., Castellano. C., Valdivia, E., and Barriga, 0. Chemotherapy of advanced cancer of the cervix: Experience in 55 cases treated with cyclophosphamide,Amer. J. Obsret. Gynecol. 94, 208-213 (1966). 12. Weiss, A. J., Ramirez, G., Grage, T., Strawitz, J., Goldman, L., and Downing, V. Phase II study of azotomycin (NSC-56654), Cancer Chemorher. Rep. 52, 61 l-614 (1968). 13. Moore, G. E., Bross, 1. D. J., Ausman, R., Nadler, S., Jones, R., Jr., Slack, N., and Rimm, A. A. Effects of 5-fluorouracil (NSC-19893) in 389 patients with cancer, Cancer Chemother. Rep. 52, 641-653 (1968). 14. Moore, G. E., Bross, 1. D. J., Ausman, R., Nadler, S., Jones, R., Jr., Slack, N., and Rimm, A. A. Effects of 6-mercaptopurine (NSC-755) in 290 patients with advanced cancer, Cancer Chemorher. Rep. 52, 655-660 (1968). IS. Moore, G. E., Bross, 1. D. J., Ausman, R., Nadler, S., Jones, R., Jr., Slack, N., and Rimm, A. A. Effects of chlorambucil (NSC-3088) in 374 patients with advanced cancer, Cancer Chemother. Rep. 52, 661-666 (1968). 16. Moore, G. E., Bross, 1. D. J., Ausman, R., Nadler, S., Jones, R., Jr., Slack, N., and Rimm, A, A. Effects of meturedepa (NSC-51325) in 233 patients with advanced cancer, Cancer Chemother. Rep. 52, 667-673 (1968). 17. Moore, G. E., Bross, I. D. J., Ausman, R., Nadler, S., Jones, R., Jr., Slack, N., and Rimm, A. A. Effects of mitomycin C (NSC-26980) in 346 patients with advanced cancer, Cancer Chemother. Rep.
52, 675-684
(1968).
IS. Smith, J. P. Discussion, in Cancer oj’rhe areras and o\zury (A collection of papers presented at the Eleventh Annual Clinical Conference on Cancer, 1966, at the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas), Year Book Medical Publishers, Chicago, pp. 345-346 (1969). 19. Savel, H., and Burns, S. L. Cytosine arabinoside (NSC-63878) given subcutaneously to patients with cancer, Cancer Chemother. Rep. 53, 153-156 (1969). 20. Kato, T., Abe, H., Yamagami, T., and Uchino, M. Therapeutic effects of bleomycin, an anticarcinogenic agent, on cancers occurred in the female genital organs, Kurume Med. J. 17, 75-95 (1970). 21. Ota, K., Kurita, S., Nishimura, M., Ogawa, M., Kamei, Y., Imai, K., Ariyoshi, Y., Kataoka, K., Murakami, M., Oyama, A., Hoshino, A., Amo, H., and Kato, T. Combination therapy with mitomycin C (NSC-26980), 5-fluorouracil (NSC-19893), and cytosine arabinoside (NSC-63878) for advanced cancer in man, Cancer Chemorher. Rep. 56, 373-385 (1972). 22. Izbicki, R., Al-Sarraf, M., Reed, M. L., Vaughn, C. B., and Vaitkevicius, V. K. Further clinical trials with pofiromycin (NSC-56410) (large intermittent doses), Cancer Chemorher. Rep. 56, 615-624 (1972).
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AND JORGENSEN
23. Ohnuma, T., Holland, J. F., Sako, K., and Shedd, D. P. Effects of combination therapy with bleomycin (NSC-125066) and dibromodulcitol (NSC-104800) on squamous cell carcinoma in man, Cancer Chemother. Rep. 56, 625-633 (1972). 24. Kogler, J., Hill, G., Sedransk, N., Cole, D. R., Weiss, A. J., and Wilson, W. Phase II study of carbestrol (NSC-19962) in patients with solid tumors, Cancer Chemother. Rep. 56, 641-647 (1972). 25. Wampler, G. L., Mellette, S. J., Kupermine, M., and Regelson, W. Hexamethylmelamine (NSC13875) in the treatment of advanced cancer, Cancer Chemorher. Rep. 56,. 505-514 (1972). 26. Bergevin, P. R., Tormey, D. C., and Blom, J. Clinical evaluation of hexamethylmelamine (NSC13875), Cancer Chemother. Rep. 57, 51-58 (1973). 27. Tormey, D. C., Bergevin, P., Blom, J., and Petty, W. Preliminary trials with a combination of adriamycin (NSC-123127) and bleomycin (NSC-125066) in adult malignancies, Cancer Chemother. Rep. 57, 413-418 (1973). 28. Ansfield, F. J., Gollin, F. F., Schroeder, J. M., Curreri, A. R., and Vermund, H. A clinical study of combined chemo- and radiotherapy in primary bronchogenic carcinoma (abstract), Proc. Amer. Assoc. Cancer Res. 3, 300 (1962). 29. Foye, L. V., Jr., Willett, F. M., Hall, B., and Roth, M. The potentiation of radiation effects with 5-fluorouracil, Cancer Chemother. Rep. 6, 12-15 (1960). 30. Hall, B. E., Foye, L. V., Jr., Roth, M., Willett, F. M., Hales, D. R., Ward, J. H., Jr., Butler, H. T., and Godfrey, M. H. Treatment of inoperable cancer with 5-fluorouracil and irradiation (Letter to the Editor), Lancer 1, 115-116 (1960). 31. Broders, A. C. Carcinoma: grading and practical application, Arch. Pathol. 2, 376-381 (1926). 32. Malkasian, G. D., Jr., Decker, D. G., Mussey, E., and Johnson, C. E. Preliminary observations on carcinoma of the cervix treated with 5-fluorouracil, Amer. J. O&et. Gyecol. 88, 82-85 (1964). 33. Malkasian, G. D., Jr., Decker, D. G., Mussey, E., and Johnson, D. E. Observations on gYnecologic malignancy treated with 5-fluorouracil, Amer. J. Obsrer. Gynecol. 180, 1012-1017 (1968).
