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Interferon for the therapy of condyloma acuminatum
Delivery after pelvic arteriovenous fistula
Volume 153 Number 2
were well occluded by the coils placed there ang10graphically 2 years prior to delivery. Comment This case report illustrates that pelvic arteriography should be considered when significant unresponsive uterine bleeding occurs at any time during long-term follow-up of a patient who has been cured of trophoblastic disease. Arteriography allowed the selective embolization of vessels feeding the fistula, thus avoiding a surgical approach that would have been difficult and dangerous. Contact hysteroscopy is a procedure that is especially useful in evaluating active uterine bleeding, because plasma itself acts as a contrast medium and gives good resolution. Hysteroscopy was performed on
this young woman for the purpose of specifically identifying the site of the bleeding. Finally, this report shows us a useful and much safer alternative to the once standard surgical approach of hypogastric ligation or hysterectomy in the management of a pelvic arteriovenous fistula. Fertility may be preserved, as evidenced by this patient's successful pregnancy outcome. We wish to acknowledge the assistance of Drs. Michael S. Baggish and Charles B. Hammond. REFERENCES 1. Yu-Zeng F. Chemotherapy and conservative surgery in a pelvic arteriovenous fistula and fertility preservation. Chin Med J (Engl) I 983;96:553. 2. Forssman L. Conservative treatment of uterine arteriovenous fistula. Acta Obstet Gynecol Scand 1982;6 I :85.
Interferon for the therapy of condyloma acuminatum Stanley A. Gall, M.D., Connie E. Hughes, R.N., and Kenneth Trofatter, Ph.D. Durham, North Carolina Lymphoblastoid interferon, Wellferon, was used to treat patients with resistant and persistent condyloma acuminatum at initial doses of 5, 3, and 1 million unit/square meter (Mu/M 2). The objectives of this study were to evaluate the efficacy and toxicity of, and tolerance to, intramuscular and intralesional interferon. Seventeen patients were treated with 5 Mu/M 2 , 14 patients with 1 Mu/M 2 , and 37 patients with 3 Mu/M 2 ; daily administration was followed by three-times-a-week dosing. The complete response rate in patients receiving initial dose of interferon of 5 Mu/M 2 was 69%, that for doses of 1 Mu/M 2 was 43%, and that for doses of 3 Mu/M2 was 57%. All patients given interferon developed initial elevations of temperature of limited duration, whereas all patients given the 5 Mu/M 2 dose had to have the amount reduced because of biologic side effects. However, only five of 37 (14%) of the patients given 3 Mu/M 2 required a reduction in the dosage, and no patient given 1 Mu/M 2 needed to have the dosage reduced. These studies suggest that interferon is efficacious in the treatment of resistant and persistent condyloma acuminatum, and that the biologic side effects were dose-related, well tolerated, and not life-threatening. (AM J OBSTET GYNECOL 1985;153:157-63.)
Key words: Condyloma acuminatum, interferon, dosage side effects Condyloma acuminatum is a fibroepithelial tumor of viral etiology which exhibit a predilection for the genital area. The viral agent of condyloma acuminatum was identified with electron microscopy by several investigators, 1 in 1968, but has not been convincingly cultured. The virus particles observed in condyloma are
From the Department of Obstetrics and Gynecology, Duke University Medical Center. Presented at the Forty-seventh Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, January 27-30, 1985. Reprint requests: Dr. Stanley A. Gall, Department of Obstetrics and Gynecology, University of Illinois College of Medicine, 840 South Wood St., Chicago, II 60612.
members of the Papovaviridae family and share the morphologic characteristics and size of papillomaviruses. Papillomaviruses are found in a variety of human warty lesions, including skin warts, plantar warts, oral and laryngeal papillomas, and lesions of epidermodysplasia verruciformis. Until recently, the prevailing thought was that the lesions were caused by the same virus. However, with the use of DNA hybridization techniques, more than 21 serotypes of human papillomavirus have been described. Hybridization studies have shown that 93% of all genital warts are human papillomavirus type 6, but tissue from cervical, vulvar, and penile carcinomas contain no detectable human 157
158 Gall, Hughes, and Trofatter
papillomavirus type 6.2 Additional studies have identified human papillomavirus type 1 in condyloma tissue, and types 16 and 18 in high-grade cervical intraepithelial neoplasia and invasive cancer.'· 4 The therapy of condyloma acuminatum has not been standardized because of the unpredictable natural course of the lesions and the inability to grow human papillomavirus in tissue culture. At least one third of the patients who have condyloma acuminatum for the first time will experience spontaneous regression within 6 months. Current therapy usually includes the application of caustic or keratolytic agents. 5 Application of 25% podophyllin in benzoin, trichloroacetic acid, or 5fluorouracil for mild or primary lesions is often successful, with recurrent or resistant disease treated with cryotherapy, surgical excision, or laser fulguration. Recurrences are common. 6 Experimental therapies, such as autologous vaccines, 7 colchicine,8 or dinitrochlorobenzene sensitization, 9 have had sporadic use and limited success. Studies have been reported in which topically applied leukocyte interferon 10 and topically or systemically applied fibroblast interferon 11 were used. This study was designed to evaluate the efficacy and toxicity of, and tolerance to, intramuscularly and intralesionally administered Wellferon (human lymphoblastoid interferon, Wellcome) at several dosing and injection schedules.
Material and methods Study population. The clinical trial was conducted at Duke University Medical Center from December, 1982, to July, 1984. All patients were judged to have resistant and/or persistent disease if condyloma acuminatum had been present for at least 6 months, and if ten or more applications of podophyllin or equivalent treatment had been given. Equivalent treatment could have been applications of either trichloroacetic acid or 5-fluorouracil, surgical removal, fulguration, cryotherapy, or laser therapy. Histologic confirmation of condyloma acuminatum was required. An informed consent approved by the institutional review committee was signed by each patient. Patients were excluded for any of the following reasons: (1) immunologic therapy within the previous 3 months or known major immunodeficiencies; (2) concomitant corticosteroids, cytotoxic immunosuppression, or radiotherapy; (3) renal dysfunction manifested by serum creatinine greater than 1.4 mg/di; (4) anemia (hemoglobin less than 10 gm/di), thrombocytopenia (less than 100,000/mm', leukopenia (less than 4000/mm'), clinical or laboratory coagulopathy; (5) hepatic dysfunction; (6) nursing women; (7) pregnancy or inadequate contraceptive practice; (8) malignant degeneration in biopsied tissue. Study design. A schematic diagram of this study is
September 15, 1985 Am J Obstet Gynecol
presented in Figs. 1 and 2. Patients accessed to these studies were admitted to the clinical research unit for 2 days for observation while interferon therapy was initiated. A complete medical history was taken and physical examination was performed on each patient. The genital warts were documented by recording the bidimensional measurements on a divided grid, by taking photographs initially and at each evaluation, and by histologic evaluation. Blood was obtained for complete blood count, including platelets, blood urea nitrogen, creatinine, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and bilirubin. Blood tests were repeated weekly when patients were receiving daily administrations of interferon, and every 2 weeks thereafter. Therapy with the interferon (Wellferon, human lymphoblastoid interferon, Wellcome) was initiated by two different dosing and administration protocols. The first protocol was studied on 17 patients who were given interferon by intramuscular injections at 5 Mu/M 2 daily for 28 days, followed by the same dose three times per week for 2 additional weeks. The second protocol consisted of 51 patients who were given interferon intramuscularly at either 1 or 3 Mu/M 2 daily for 2 weeks, followed by the same dosage for an additional 4 weeks. Wellferon is a highly purified preparation of a-interferons derived from viral induction of the human lymphoblastoid cell line N amalwa. 12 Modifications of dosage were made if patients encountered severe side effects or clinical laboratory toxicities subsequent to administration of interferon. Measurements of condylomatous lesions were made at the time the patients entered the study and every 2 weeks thereafter. Protocol evaluations were made at 43 days and at the end of the study, on the basis of the following disease assessment. Complete response was total disappearance of the condylomas. Partial response was a 50% or greater decrease in the size of the condylomas. No response was any change less than a 50% decrease in the products of the bidimensional measurements. Patients in the first protocol who were judged to have a complete response were observed for 6 months, whereas those who had a partial response after 6 weeks of therapy continued to receive interferon three times per week for an additional 6 weeks. If no response occurred, the patient was offered intralesional therapy at a dose of 1 Mu/M 2 twice weekly for 4 weeks or until the condyloma disappeared. All patients with no response at 6 weeks were offered intralesional therapy. Twenty-eight patients in the second protocol were randomized to receive interferon at initial doses of either 1 or 3 Mu/M 2 • An additional 23 patients were treated with interferon at a dose of 3 Mu/M 2 • The patients were treated with either 1or3 Mu/M 2 daily for 14 days, and
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159
Observe
E
E - - CR
v
v
v
A
A
A
L 5Mu/m2
L 5 Mu/m2 IM~
L - - PR
u
u
5Mu/m2 t. i.w. x 6 wk
u FIRST
6 months
E
~
IM qdx28d
Tiw x 2 wk
Continue Rx
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E - - NR
V -
PROG
Day 0
29
43
E
l
CR
A L -
PR
Intralesional
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CR
I Mu b. i.w. x4
v-"~ A L
NR
Off Study
PROG
Fig. 1. Wellferon condyloma acuminatum study: 5 Mu/M 2 protocol. CR, complete response; PR, partial response; NR, no response.
then with the same dose three times per week for 4 weeks. Patients were evaluated for response at the end of 6 weeks of therapy and judged to have either a complete, partial, or no response by the criteria already mentioned. Patients judged to have a complete response were observed for 6 months, whereas those who had a partial response were continued on the same schedule of administration of interferon for an additional 4 weeks. Those patients who were judged to have no response had the dose of interferon increased (those who were receiving 1 Mu/M 2 three times per week were given an increase to 3 Mu/M 2 three times per week, and those receiving 3 Mu/M 2 three times per week were given 5 Mu/M 2 ). At the conclusion of the additional 4 weeks of therapy, the patients were reevaluated and observed without further therapy for 6 additional months, at the end of which time a final assessment of response was made. Symptomatic side effects, including fever, chills, fatigue, malaise, nausea/vomiting, and headache, were recorded daily by the patients. Clinical laboratory values and side effects were evaluated weekly while the patient was receiving interferon daily and every 2 weeks while the patient was receiving interferon three times per week, with dose modification made on the basis of severity grading.
Results Disease responses. Seventeen patients were entered on the protocol with the initial interferon dose of 5 Mui M2 , 14 patients received 1 Mu/M 2 , and 37 patients re-
ceived 3 Mu/M 2 • The mean age and racial and sex characteristics are presented in Table I. Sixteen of seventeen patients who entered the 5 Mui M2 study were evaluable. The first patient accessed to the study withdrew after eight injections because of nausea and vomiting. After 6 weeks of therapy, four patients (25%) were judged to be complete responders, whereas 11 patients (69%) were partial responders, and one patient (6%) demonstrated no response. Eleven patients received an additional 6 weeks of therapy three times per week, with four patients showing a complete response. Four patients received intralesional therapy, with a complete response in three. Three patients refused intralesional therapy. At the conclusion of the protocol, 11 patients (69%) were completely cured of their condylomas (Table II). Fourteen patients were treated with 1 Mu/M 2 of interferon as initial therapy, with three (21 %) showing a complete response, eight (57%) showing a partial response, and three (21 %) showing no response after 6 weeks of therapy. The eight patients who had a partial response were continued at the same dose, 1 Mu/M 2 , for an additional 4 weeks, whereas the three patients with no response had the dose of interferon increased to 3 Mu/M 2 for 4 weeks. Three patients who originally had a partial response were given additional interferon and then had a complete response. Therefore, at the conclusion of the protocol, six patients (43%) had a complete response, five (36%) had a partial response, and three (21 %) had no response. Upon completion of the protocol, adjuvant surgical excision was performed
160 Gall, Hughes, and Trofatter
September 15, 1985 Am J Obstet Gynecol
CR ~observe 6 months PR ~l Hu/m2 t.i.w.x4wk E 1 Hu/m2/d x 14
SECOND
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-7 observe -4 3
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Fig. 2. Wellferon condyloma acuminatum study: 3 Mu/M 2 versus 1 Mu/M' protocol. CR, complete response; PR, partial response; NR, no response.
Table I. Characteristics of patients in interferon trials Trial by initial dose
N Mean age (yr) Range, age (yr) Female Male White Black
5 Mu!M2
1 Mu/M2
17 31.2 18-48 17 0 14 3
14 28.9 20-58 13
3 Mu/M2
37
10
31.5 8-64 32 5 32
4
5
1
on two patients who had had a partial response. These two patients then had a complete response, which remained for more than 6 months (Table II). Of 37 patients who were treated with an initial dose of interferon of 3 Mu/M2, 30 were evaluable. Seven patients withdrew from the study because of either difficulty in coming to the clinic, other intercurrent disease, or a loss of interest in self-administered intramuscular injections. Thirty patients were evaluable after 6 weeks of therapy and at the end of the protocol. After 6 weeks of therapy, 12 patients (40%) demonstrated a complete response, 15 patients (57%) were judged to have a partial response, and three patients (IO%) had no response. The 15 patients who demonstrated a partial response were given an additional 4
weeks of interferon at 3 Mu/M 2 three times per week, and five patients became complete responders. The three patients who showed no response were given an additional 4 weeks of interferon at 5 Mu/M' three times per week, and none showed a response. At the conclusion of this protocol, 17 patients (57%) were judged to have a complete response, 10 patients (33%) had a partial response, and three patients (10%) had no response. After the conclusion of the protocol, six patients who were partial responders had surgical excision of their lesions, and one patient had cryotherapy, and the seven patients became complete responders. The seven have remained free of condylomas for more than 6 months. Dose alterations. The alterations in dosing schedules for the three initial interferon protocols are presented in Table Ill. All reductions in dosage were due to biologic side effects or laboratory abnormalities of hematologic or hepatic function. Increases in dosage resulted when a lack of response was noted. All reductions occurred after 1 week of therapy, and increases in dosage occurred after 10 weeks of therapy. All patients who received 5 Mu/M' of interferon required reductions in dosage, mainly because of neutropenia-but because of elevated hepatic enzymes in one patient. Reductions in dosage in the 3 Mu/M' group occurred in only five patients and were due to neutropenia, elevated hepatic enzymes, and nausea and vomiting. Increases in dosage occurred when response was judged
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161
Table II. Responses of patients to different doses of interferon 5 Mu/M 2 (N
=
1 Mu/M 2 (N
17)
=
14)
3 Mu/M 2 (N
= 37)
Response at times of treatment
Complete response Partial response No response Evaluated Not evaluated
6 wk
%
End
%
6 wk
%
End
%
*
%
6 wk
%
End
%
*
%
4 II I I6 I
25 69 6
II 4 I I6
69 25 6
3 8 3 I4 0
2I 57 2I
6 5 3 I4 0
43 36 2I
8 3 3 I4 0
57 2I 2I
I2 I5 3 30 7
40 50
I7
57 33
24 3 3 30 7
80
IO
I
3 30 7
IO
IO
IO IO
*With adjuvant surgical procedure or cryotherapy after conclusion of protocol. to be poor or absent. This happened with greatest frequency in the 1 Mu/M 2 group, infrequently in the 3 Mu/M 2 group (19%), and did not occur in the 5 Mu/ M2 group. Biologic side effects. Biologic side effects, including fever, chills, fatigue, nausea/vomiting, malaise, and headaches, were recorded by the patient on each dosing day. All patients in each group demonstrated fever of more than 38° C, to temperatures as high as 40.3° C, accompanied by chills with the initial intramuscular injection of interferon. The fever usually lasted less than 12 hours and did not recur unless there was a dosing lapse of more than 3 days. The most prevalent side effects were those of fatigue and malaise, which were greatest during the daily intramuscular portion of each protocol. All side effects were greatly reduced in incidence and severity when the patient received interferon on a schedule of three times per week. In addition, the side effects were very mild in patients given interferon at the 1 or 3 Mu/M 2 dose, as compared to those in patients given the 5 Mu/M 2 dose. Clinical laboratory results. The principal alterations in laboratory tests were in the total white blood cell count, lymphocytes, granulocytes, platelets, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and hemoglobin levels. In all patients treated with 5 Mu/M 2 for 28 days, there were significant decreases in mean white blood cell counts, lymphocytes, neutrophils, eosinophils, and platelets at all days tested, as determined by the Wilcoxon signed-rank test. Fourteen of 17 patients in this protocol had platelet reductions of at least 50,000/mm 3 , but only one patient had a platelet count of less than 100,000/mm 3 • No patient experienced a bleeding diathesis. Hematologic abnormalities were markedly diminished in the 3 Mu/M 2 group, with only three of 37 patients (8%) requiring a reduction in dosage because of a white blood cell count of <3,000/mm 3 • No severe hematologic aberrations occurred at the 1 Mu/M 2 dosage. All patients in the 5 Mu/M 2 protocol manifested some abnormalities of serum glutamic pyruvic transaminase
Table III. Changes in dosage in patients receiving Wellferon Dosage decreased Dose
5 Mu/M I Mu/M' 3 Mu/M 2 2
N
No.
I7 I4 37
I7 0 5
I
Dosage increased
%
No.
IOO 0
0 9
I4
7
I
% 0
64 I9
and serum glutamic oxaloacetic transaminase, with minimal elevations over normal baseline, whereas three patients had elevations of serum glutamic oxaloacetic transaminase as high as 156 IU/ml on week 7. All hepatic abnormalities returned to baseline when the dosage was reduced. One patient who was receiving 3 Mu/ M2 required a reduction in dosage because of hepatic abnormalities, whereas no patient who was receiving 1 Mu/M 2 showed hepatic abnormalities.
Comment Condyloma acuminatum, recognized for centuries as a nuisance disease, has recently been linked to the development of intraepithelial neoplasia of the cervix, vagina, and vulva. 13• 14 This implies that efficient and adequate therapy should be available to the clinician to control this disease process. Although the natural history of papillomaviral infection in humans is not completely known because of our inability to culture the virus, we do recognize that spontaneous regressions of the disease occur. This spontaneous regression rate can be as high as 33% within 6 months. Therefore, in any study of patients with condyloma acuminatum, there must be a clear statement of whether the patients have resistant and persistent disease or whether they have newly developed lesions. In the present study, all patients had resistant and persistent disease as represented by the presence of disease for more than 6 months and failure of at least 10 applications of podophyllin or equivalent therapy.
162 Gall, Hughes, and Trofatter
Exogenous topical interferon therapy was first reported in 1975, by Ikic et al. 10 Topical application of a Vasoline-lanolin ointment of crude leukocyte interferon resulted in complete disappearance of lesions in 36 or 40 women treated for 4 to 12 weeks. No information was recorded on the length of time the patients' lesions were present prior to therapy. Schonfeld et al. 11 demonstrated that intramuscular injection was the most suitable route of administration for fibroblast interferon (IFN-f3). Two additional groups of patients each were given doses (3 x 106 or 9 x 106 units intramuscularly) of IFN-13 on 2 consecutive days, which resulted in complete disappearance of genital warts. The patients treated by Schonfeld et al. or by Ikic et al. were largely untreated patients, whereas the patients treated in these studies were selected to have resistant and persistent condylomas acuminata. The objectives of our studies were to evaluate the efficacy, biologic side effects, and toxicity of varying dosage schedules of Wellferon (lymphoblastoid interferon). Previous studies in patients with malignant disease to whom increasing doses up to 200 Mu/day were given have shown excessive toxicity at high doses (>20 Mu/M 2 ). 15 · 16 Patients given interferon at all dosages tested will manifest fever to 40.3° C for a period of 12 hours after initial intramuscular injection. Patients given 5 Mu/M 2 daily will manifest some unpleasant side effects, such as fever, malaise, nausea/vomiting, and headache. These side effects decrease as therapy is continued and will diminish substantially when threetimes-per-week dosing is used. The side effects at 3 Mu/M 2 /day are well tolerated, with almost no symptoms when three-times-per-week dosing is reached at this dosage level. The patients who were given interferon at I Mu/M 2 had few side effects, with fatigue as the most common symptom. Hematologic aberrations were the most prominent laboratory abnormalities in response to interferon; however, no serious clinical effects were noted as secondary events to these changes. The hematologic aberrations occurred mainly in patients who were given the 5 Mu/M 2 dose. All patients who were given 5 Mu/ M2 /day demonstrated statistically significant decreases in mean total white blood cell count, lymphocytes, granulocytes, eosinophils, and platelets after I week of therapy, whereas three patients who were given 3 Mu/M 2 and no patients who were given I Mu/M 2 demonstrated these toxicities. No patient in any of the trials experienced abnormal loss of blood, evidence of hemolysis, or infection. These clinical trials with Wellferon at various dosing schedules have demonstrated that this interferon is active as a possible treatment for women with resistant and persistent condylomas acuminata. The side effects
September 15, 1985 Am J Obstet Gynecol
even at the 5 Mu/M 2 level were not life-threatening and were lessened when the dosage was reduced. Importantly, patients treated with 3 Mu/M 2 /day or I Mu/m 2 / day reported fewer side effects, had less hematologic aberration, but demonstrated an efficacy of treatment not different from that found in the 5 Mu/M 2 group. The addition of cryotherapy or surgical excision as an adjuvant treatment to interferon appears to be a promising treatment modality. Increased numbers of patients were cured of their warts, without recurrence, when treated after the conclusion of the interferon protocol. This suggests that combination or sequential therapy of interferon and surgical excision, cryotherapy, or laser therapy may play a prominent role in a lasting treatment program. REFERENCES I. Dunn AEG, Ogilule MM: Intranuclear virus particles in
2.
3.
4.
5. 6. 7. 8. 9.
IO.
11.
12.
I3. 14.
human genital wart tissue: observation on the ultrastructure of the epidermal layer. J Ultrastruct Res I968;22:282-95. Gissman L, De Villiers EM, ZurHausen H. Analysis of human warts (condyloma acuminata) and other genital tumors for human papillomavirus type 6 DNA. lntJ Cancer I982;29:I43-6. Durst M, Gissman L, Ikenburg H, ZurHausen H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci USA I983;80:38I2-5. Gissman L, Wolnik L, Ikenburg H, Koldousky U, Schnurch HG, ZurHausen H. Human papillomavirus types 6 and I I, DNA sequences in genital and laryngeal papillomas and in some cervical cancers. Proc Natl Acad Sci USA I 983;80:560-3. Von Krogh G. Topical treatment of penile condylomata acuminata with podophyllin, podophyllotoxin and colchicine. Acta Derm Venereal (Stockh) 1978;58: 163-8. Rasmussen JE. Warts and what to do about them. Drug Ther 1981; 11 :65-76. Powell LC, Pollard M, Jenkins JL. Treatment of condyloma acuminata by autologous vaccine. South Med J I 970;63:202-5. Von Krogh G, Ruden AK. The treatment of penile condyloma acuminata with colchicine at 48-72 hour intervals. Acta Derm Venereal I 980;60:87-9. Foster DC, Woodruff JD. The use of dinitro chlorobenzene in the treatment of vulvar carcinoma-in-situ. Gynecol Oncol 1981; 11: 330-9. Ikic D, Bosnic N, Smerdel S,Jusci D, Soos E, Delimar N. Double-blind clinical study with human leukocyte interferon in the therapy of condyloma acuminata. Proceedings of symposium on clinical use of interferon. Zagreb, 1975:229-33. Schonfeld A, Nitke S, Schattner A, Wallach D, Crespi M, Hahn T, Levair H, Varden 0, ShohamJ, DoernerT, Revel M. Intramuscular human interferon-J3 injections in treatment of condyloma acuminata. Lancet 1984; I: I 038-42. Finter NB, Fantes KH. The purity and safety of interferons prepared for clinical use: the case for lymphoblastoid interferon. In: Gresser I, ed. Interferon. New York: Academic Press, I981:65-80. (vol 3). Meisels A, Morin C. Human papillomavirus and cancer of the uterine cervix. Gynecol Oncol 1981;12:Slll-23. Crum CP, Ikenburg H, Richart R, Gissman L. Human
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papillomavirus type 16 early cervical neoplasia. N Engl J Med l 984;310:880-3. 15. Rohatiner AZS, Barkwill FR, Griffin DB. A phase I study of human lymphoblastoid interferon administered by continuous intravenous infusion. Cancer Chemother Pharmacol 1982;9:97-102. 16. KnostJA, Sherwin SA, Abrams PG, et al. The treatment of cancer patients with human lymphoblastoid interferon: a comparison of two routes of administration. Cancer Immunol Immunother 1983;15:144-8.
Editors' note: This manuscript was revised after these
discussions were presented.
Discussion DR. R. PINKNEY RANKIN, JR., Charlotte, North Carolina. Dr. Gall et al. have measured the response of genital condylomas to intramuscular lymphoblastoid interferon in 60 healthy immunocompetent patients. Final assessment was made 6 months after completion of treatment. With the use of three different dosage protocols, complete response to systemic interferon alone was achieved in 43% to 57% of patients. The dosage regimen of 3 Mu/M 2 combined a higher response rate with acceptable toxicity. At the inception of the study, all patients had persistent disease, resistant to previous conventional therapy-thus minimizing the risk of spontaneous regression. This is a critical feature of the study, since most other reports on the use of intralesional or systemic interferon have involved a smaller series of untreated patients with disease of indeterminate duration. The authors then extended their study design by treating nine suboptimum responders with adjuvant surgical therapy (either excision or cryosurgery-no laser vaporization). The amount of residual bulk disease was not specified, but response was complete in all patients for at least 6 months. In fact, the 80% complete response in 30 patients who were given 3 Mu/M 2 of interferon was achieved with seven of these patients. Everyone is aware of the early emergence of latent or new lesions after surgical excision, cryotherapy, or laser vaporization. Although the numbers are small, they strongly suggest improved outcome with sequential systemic interferon and adjuvant surgical therapy. Confirmation, however, must await a comparison of se-
163
quential therapy with surgical ablation alone-in patients with comparable disease. Although Dr. Gall et al. reported no serious morbidity in this study, leukopenia, thrombopenia, and hepatic dysfunction are invitations to potential disaster. A reduction in dosage seemed to be prudent in 21 patients. Eight patients dropped out of the study-one for protracted vomiting and seven for a variety of reasons, some of which might have been related to unacceptable symptoms. Treatment with systemic interferon is not innocuous. Hence, the ability to select patients with high-risk precursor lesions is crucial. We know, from the work of Fu et al.,' that dysplastic lesions with abnormal mitoses are aneuploid, with a high risk of progression, whereas diploid and polyploid lesions without abnormal mitoses often regress. This, however, lays too much burden on the microscope and the microscopist! Using DNA hybridization, Crum et al. 2 confirmed a predominance of human papillomavirus 16 in aneuploid lesions and a predominance of human papillomavirus 6 and 11 in diploid lesions. Human papillomavirus 16 is probably a marker for squamous carcinoma and its precursors. We are primarily limited by our inability to grow the human papillomavirus in culture and our inability to identify its subtypes. When we can, we will be able to tailor the treatment (with its inherent toxicity) to the patient's disease potential. I have the following questions. ( 1) What was the incidence of cervicovaginal mucosa! lesions in Dr. Gall et al.'s study group? (2) Did the authors note any differential response between lesions of the mucosa and the lesions of the perinea! skin? (3) Were there any data on associated dysplasia and its therapeutic fate? In summary, I commend Dr. Gall et al. for the quality of this complex but well-designed study.
REFERENCES 1. Fu YS, Reagan JW, Richart RM, Townsend DE. Nuclear
DNA and histologic studies of genital lesions in DES-exposed progeny. I. Intraepithelial squamous abnormalities. Am J Clin Pathol 1979;72:502-14. 2. Crum CP, lbenberg H, Richart RM, Gissman L. Human papilloma virus 16 and early cervical neoplasia. N Engl J Med 1984;310:880-3.
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were well occluded by the coils placed there ang10graphically 2 years prior to delivery. Comment This case report illustrates that pelvic arteriography should be considered when significant unresponsive uterine bleeding occurs at any time during long-term follow-up of a patient who has been cured of trophoblastic disease. Arteriography allowed the selective embolization of vessels feeding the fistula, thus avoiding a surgical approach that would have been difficult and dangerous. Contact hysteroscopy is a procedure that is especially useful in evaluating active uterine bleeding, because plasma itself acts as a contrast medium and gives good resolution. Hysteroscopy was performed on
this young woman for the purpose of specifically identifying the site of the bleeding. Finally, this report shows us a useful and much safer alternative to the once standard surgical approach of hypogastric ligation or hysterectomy in the management of a pelvic arteriovenous fistula. Fertility may be preserved, as evidenced by this patient's successful pregnancy outcome. We wish to acknowledge the assistance of Drs. Michael S. Baggish and Charles B. Hammond. REFERENCES 1. Yu-Zeng F. Chemotherapy and conservative surgery in a pelvic arteriovenous fistula and fertility preservation. Chin Med J (Engl) I 983;96:553. 2. Forssman L. Conservative treatment of uterine arteriovenous fistula. Acta Obstet Gynecol Scand 1982;6 I :85.
Interferon for the therapy of condyloma acuminatum Stanley A. Gall, M.D., Connie E. Hughes, R.N., and Kenneth Trofatter, Ph.D. Durham, North Carolina Lymphoblastoid interferon, Wellferon, was used to treat patients with resistant and persistent condyloma acuminatum at initial doses of 5, 3, and 1 million unit/square meter (Mu/M 2). The objectives of this study were to evaluate the efficacy and toxicity of, and tolerance to, intramuscular and intralesional interferon. Seventeen patients were treated with 5 Mu/M 2 , 14 patients with 1 Mu/M 2 , and 37 patients with 3 Mu/M 2 ; daily administration was followed by three-times-a-week dosing. The complete response rate in patients receiving initial dose of interferon of 5 Mu/M 2 was 69%, that for doses of 1 Mu/M 2 was 43%, and that for doses of 3 Mu/M2 was 57%. All patients given interferon developed initial elevations of temperature of limited duration, whereas all patients given the 5 Mu/M 2 dose had to have the amount reduced because of biologic side effects. However, only five of 37 (14%) of the patients given 3 Mu/M 2 required a reduction in the dosage, and no patient given 1 Mu/M 2 needed to have the dosage reduced. These studies suggest that interferon is efficacious in the treatment of resistant and persistent condyloma acuminatum, and that the biologic side effects were dose-related, well tolerated, and not life-threatening. (AM J OBSTET GYNECOL 1985;153:157-63.)
Key words: Condyloma acuminatum, interferon, dosage side effects Condyloma acuminatum is a fibroepithelial tumor of viral etiology which exhibit a predilection for the genital area. The viral agent of condyloma acuminatum was identified with electron microscopy by several investigators, 1 in 1968, but has not been convincingly cultured. The virus particles observed in condyloma are
From the Department of Obstetrics and Gynecology, Duke University Medical Center. Presented at the Forty-seventh Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, January 27-30, 1985. Reprint requests: Dr. Stanley A. Gall, Department of Obstetrics and Gynecology, University of Illinois College of Medicine, 840 South Wood St., Chicago, II 60612.
members of the Papovaviridae family and share the morphologic characteristics and size of papillomaviruses. Papillomaviruses are found in a variety of human warty lesions, including skin warts, plantar warts, oral and laryngeal papillomas, and lesions of epidermodysplasia verruciformis. Until recently, the prevailing thought was that the lesions were caused by the same virus. However, with the use of DNA hybridization techniques, more than 21 serotypes of human papillomavirus have been described. Hybridization studies have shown that 93% of all genital warts are human papillomavirus type 6, but tissue from cervical, vulvar, and penile carcinomas contain no detectable human 157
158 Gall, Hughes, and Trofatter
papillomavirus type 6.2 Additional studies have identified human papillomavirus type 1 in condyloma tissue, and types 16 and 18 in high-grade cervical intraepithelial neoplasia and invasive cancer.'· 4 The therapy of condyloma acuminatum has not been standardized because of the unpredictable natural course of the lesions and the inability to grow human papillomavirus in tissue culture. At least one third of the patients who have condyloma acuminatum for the first time will experience spontaneous regression within 6 months. Current therapy usually includes the application of caustic or keratolytic agents. 5 Application of 25% podophyllin in benzoin, trichloroacetic acid, or 5fluorouracil for mild or primary lesions is often successful, with recurrent or resistant disease treated with cryotherapy, surgical excision, or laser fulguration. Recurrences are common. 6 Experimental therapies, such as autologous vaccines, 7 colchicine,8 or dinitrochlorobenzene sensitization, 9 have had sporadic use and limited success. Studies have been reported in which topically applied leukocyte interferon 10 and topically or systemically applied fibroblast interferon 11 were used. This study was designed to evaluate the efficacy and toxicity of, and tolerance to, intramuscularly and intralesionally administered Wellferon (human lymphoblastoid interferon, Wellcome) at several dosing and injection schedules.
Material and methods Study population. The clinical trial was conducted at Duke University Medical Center from December, 1982, to July, 1984. All patients were judged to have resistant and/or persistent disease if condyloma acuminatum had been present for at least 6 months, and if ten or more applications of podophyllin or equivalent treatment had been given. Equivalent treatment could have been applications of either trichloroacetic acid or 5-fluorouracil, surgical removal, fulguration, cryotherapy, or laser therapy. Histologic confirmation of condyloma acuminatum was required. An informed consent approved by the institutional review committee was signed by each patient. Patients were excluded for any of the following reasons: (1) immunologic therapy within the previous 3 months or known major immunodeficiencies; (2) concomitant corticosteroids, cytotoxic immunosuppression, or radiotherapy; (3) renal dysfunction manifested by serum creatinine greater than 1.4 mg/di; (4) anemia (hemoglobin less than 10 gm/di), thrombocytopenia (less than 100,000/mm', leukopenia (less than 4000/mm'), clinical or laboratory coagulopathy; (5) hepatic dysfunction; (6) nursing women; (7) pregnancy or inadequate contraceptive practice; (8) malignant degeneration in biopsied tissue. Study design. A schematic diagram of this study is
September 15, 1985 Am J Obstet Gynecol
presented in Figs. 1 and 2. Patients accessed to these studies were admitted to the clinical research unit for 2 days for observation while interferon therapy was initiated. A complete medical history was taken and physical examination was performed on each patient. The genital warts were documented by recording the bidimensional measurements on a divided grid, by taking photographs initially and at each evaluation, and by histologic evaluation. Blood was obtained for complete blood count, including platelets, blood urea nitrogen, creatinine, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and bilirubin. Blood tests were repeated weekly when patients were receiving daily administrations of interferon, and every 2 weeks thereafter. Therapy with the interferon (Wellferon, human lymphoblastoid interferon, Wellcome) was initiated by two different dosing and administration protocols. The first protocol was studied on 17 patients who were given interferon by intramuscular injections at 5 Mu/M 2 daily for 28 days, followed by the same dose three times per week for 2 additional weeks. The second protocol consisted of 51 patients who were given interferon intramuscularly at either 1 or 3 Mu/M 2 daily for 2 weeks, followed by the same dosage for an additional 4 weeks. Wellferon is a highly purified preparation of a-interferons derived from viral induction of the human lymphoblastoid cell line N amalwa. 12 Modifications of dosage were made if patients encountered severe side effects or clinical laboratory toxicities subsequent to administration of interferon. Measurements of condylomatous lesions were made at the time the patients entered the study and every 2 weeks thereafter. Protocol evaluations were made at 43 days and at the end of the study, on the basis of the following disease assessment. Complete response was total disappearance of the condylomas. Partial response was a 50% or greater decrease in the size of the condylomas. No response was any change less than a 50% decrease in the products of the bidimensional measurements. Patients in the first protocol who were judged to have a complete response were observed for 6 months, whereas those who had a partial response after 6 weeks of therapy continued to receive interferon three times per week for an additional 6 weeks. If no response occurred, the patient was offered intralesional therapy at a dose of 1 Mu/M 2 twice weekly for 4 weeks or until the condyloma disappeared. All patients with no response at 6 weeks were offered intralesional therapy. Twenty-eight patients in the second protocol were randomized to receive interferon at initial doses of either 1 or 3 Mu/M 2 • An additional 23 patients were treated with interferon at a dose of 3 Mu/M 2 • The patients were treated with either 1or3 Mu/M 2 daily for 14 days, and
Condyloma acuminatum
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159
Observe
E
E - - CR
v
v
v
A
A
A
L 5Mu/m2
L 5 Mu/m2 IM~
L - - PR
u
u
5Mu/m2 t. i.w. x 6 wk
u FIRST
6 months
E
~
IM qdx28d
Tiw x 2 wk
Continue Rx
A
A
A
T
T
T
E
E
E - - NR
V -
PROG
Day 0
29
43
E
l
CR
A L -
PR
Intralesional
E -
CR
I Mu b. i.w. x4
v-"~ A L
NR
Off Study
PROG
Fig. 1. Wellferon condyloma acuminatum study: 5 Mu/M 2 protocol. CR, complete response; PR, partial response; NR, no response.
then with the same dose three times per week for 4 weeks. Patients were evaluated for response at the end of 6 weeks of therapy and judged to have either a complete, partial, or no response by the criteria already mentioned. Patients judged to have a complete response were observed for 6 months, whereas those who had a partial response were continued on the same schedule of administration of interferon for an additional 4 weeks. Those patients who were judged to have no response had the dose of interferon increased (those who were receiving 1 Mu/M 2 three times per week were given an increase to 3 Mu/M 2 three times per week, and those receiving 3 Mu/M 2 three times per week were given 5 Mu/M 2 ). At the conclusion of the additional 4 weeks of therapy, the patients were reevaluated and observed without further therapy for 6 additional months, at the end of which time a final assessment of response was made. Symptomatic side effects, including fever, chills, fatigue, malaise, nausea/vomiting, and headache, were recorded daily by the patients. Clinical laboratory values and side effects were evaluated weekly while the patient was receiving interferon daily and every 2 weeks while the patient was receiving interferon three times per week, with dose modification made on the basis of severity grading.
Results Disease responses. Seventeen patients were entered on the protocol with the initial interferon dose of 5 Mui M2 , 14 patients received 1 Mu/M 2 , and 37 patients re-
ceived 3 Mu/M 2 • The mean age and racial and sex characteristics are presented in Table I. Sixteen of seventeen patients who entered the 5 Mui M2 study were evaluable. The first patient accessed to the study withdrew after eight injections because of nausea and vomiting. After 6 weeks of therapy, four patients (25%) were judged to be complete responders, whereas 11 patients (69%) were partial responders, and one patient (6%) demonstrated no response. Eleven patients received an additional 6 weeks of therapy three times per week, with four patients showing a complete response. Four patients received intralesional therapy, with a complete response in three. Three patients refused intralesional therapy. At the conclusion of the protocol, 11 patients (69%) were completely cured of their condylomas (Table II). Fourteen patients were treated with 1 Mu/M 2 of interferon as initial therapy, with three (21 %) showing a complete response, eight (57%) showing a partial response, and three (21 %) showing no response after 6 weeks of therapy. The eight patients who had a partial response were continued at the same dose, 1 Mu/M 2 , for an additional 4 weeks, whereas the three patients with no response had the dose of interferon increased to 3 Mu/M 2 for 4 weeks. Three patients who originally had a partial response were given additional interferon and then had a complete response. Therefore, at the conclusion of the protocol, six patients (43%) had a complete response, five (36%) had a partial response, and three (21 %) had no response. Upon completion of the protocol, adjuvant surgical excision was performed
160 Gall, Hughes, and Trofatter
September 15, 1985 Am J Obstet Gynecol
CR ~observe 6 months PR ~l Hu/m2 t.i.w.x4wk E 1 Hu/m2/d x 14
SECOND
l
E 1 Hu/m2 t.i.w.)'
E
v
v
v
v
Observe
A
A
A
A
6 mo.
L
L
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u
u
u
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A
T 3 Hu/m2/d x 14)
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3 Hu/m2 t.i.w.) T
E
E
4 weeks
E
t. i.w.x4wk
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-7 observe -4 3
6 months
Mu/m2 t. i.w. x4wk t. i.w.x4wk
Day 0
15
43
E
E
v
Observe
A
6 mo.
L
Fig. 2. Wellferon condyloma acuminatum study: 3 Mu/M 2 versus 1 Mu/M' protocol. CR, complete response; PR, partial response; NR, no response.
Table I. Characteristics of patients in interferon trials Trial by initial dose
N Mean age (yr) Range, age (yr) Female Male White Black
5 Mu!M2
1 Mu/M2
17 31.2 18-48 17 0 14 3
14 28.9 20-58 13
3 Mu/M2
37
10
31.5 8-64 32 5 32
4
5
1
on two patients who had had a partial response. These two patients then had a complete response, which remained for more than 6 months (Table II). Of 37 patients who were treated with an initial dose of interferon of 3 Mu/M2, 30 were evaluable. Seven patients withdrew from the study because of either difficulty in coming to the clinic, other intercurrent disease, or a loss of interest in self-administered intramuscular injections. Thirty patients were evaluable after 6 weeks of therapy and at the end of the protocol. After 6 weeks of therapy, 12 patients (40%) demonstrated a complete response, 15 patients (57%) were judged to have a partial response, and three patients (IO%) had no response. The 15 patients who demonstrated a partial response were given an additional 4
weeks of interferon at 3 Mu/M 2 three times per week, and five patients became complete responders. The three patients who showed no response were given an additional 4 weeks of interferon at 5 Mu/M' three times per week, and none showed a response. At the conclusion of this protocol, 17 patients (57%) were judged to have a complete response, 10 patients (33%) had a partial response, and three patients (10%) had no response. After the conclusion of the protocol, six patients who were partial responders had surgical excision of their lesions, and one patient had cryotherapy, and the seven patients became complete responders. The seven have remained free of condylomas for more than 6 months. Dose alterations. The alterations in dosing schedules for the three initial interferon protocols are presented in Table Ill. All reductions in dosage were due to biologic side effects or laboratory abnormalities of hematologic or hepatic function. Increases in dosage resulted when a lack of response was noted. All reductions occurred after 1 week of therapy, and increases in dosage occurred after 10 weeks of therapy. All patients who received 5 Mu/M' of interferon required reductions in dosage, mainly because of neutropenia-but because of elevated hepatic enzymes in one patient. Reductions in dosage in the 3 Mu/M' group occurred in only five patients and were due to neutropenia, elevated hepatic enzymes, and nausea and vomiting. Increases in dosage occurred when response was judged
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161
Table II. Responses of patients to different doses of interferon 5 Mu/M 2 (N
=
1 Mu/M 2 (N
17)
=
14)
3 Mu/M 2 (N
= 37)
Response at times of treatment
Complete response Partial response No response Evaluated Not evaluated
6 wk
%
End
%
6 wk
%
End
%
*
%
6 wk
%
End
%
*
%
4 II I I6 I
25 69 6
II 4 I I6
69 25 6
3 8 3 I4 0
2I 57 2I
6 5 3 I4 0
43 36 2I
8 3 3 I4 0
57 2I 2I
I2 I5 3 30 7
40 50
I7
57 33
24 3 3 30 7
80
IO
I
3 30 7
IO
IO
IO IO
*With adjuvant surgical procedure or cryotherapy after conclusion of protocol. to be poor or absent. This happened with greatest frequency in the 1 Mu/M 2 group, infrequently in the 3 Mu/M 2 group (19%), and did not occur in the 5 Mu/ M2 group. Biologic side effects. Biologic side effects, including fever, chills, fatigue, nausea/vomiting, malaise, and headaches, were recorded by the patient on each dosing day. All patients in each group demonstrated fever of more than 38° C, to temperatures as high as 40.3° C, accompanied by chills with the initial intramuscular injection of interferon. The fever usually lasted less than 12 hours and did not recur unless there was a dosing lapse of more than 3 days. The most prevalent side effects were those of fatigue and malaise, which were greatest during the daily intramuscular portion of each protocol. All side effects were greatly reduced in incidence and severity when the patient received interferon on a schedule of three times per week. In addition, the side effects were very mild in patients given interferon at the 1 or 3 Mu/M 2 dose, as compared to those in patients given the 5 Mu/M 2 dose. Clinical laboratory results. The principal alterations in laboratory tests were in the total white blood cell count, lymphocytes, granulocytes, platelets, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and hemoglobin levels. In all patients treated with 5 Mu/M 2 for 28 days, there were significant decreases in mean white blood cell counts, lymphocytes, neutrophils, eosinophils, and platelets at all days tested, as determined by the Wilcoxon signed-rank test. Fourteen of 17 patients in this protocol had platelet reductions of at least 50,000/mm 3 , but only one patient had a platelet count of less than 100,000/mm 3 • No patient experienced a bleeding diathesis. Hematologic abnormalities were markedly diminished in the 3 Mu/M 2 group, with only three of 37 patients (8%) requiring a reduction in dosage because of a white blood cell count of <3,000/mm 3 • No severe hematologic aberrations occurred at the 1 Mu/M 2 dosage. All patients in the 5 Mu/M 2 protocol manifested some abnormalities of serum glutamic pyruvic transaminase
Table III. Changes in dosage in patients receiving Wellferon Dosage decreased Dose
5 Mu/M I Mu/M' 3 Mu/M 2 2
N
No.
I7 I4 37
I7 0 5
I
Dosage increased
%
No.
IOO 0
0 9
I4
7
I
% 0
64 I9
and serum glutamic oxaloacetic transaminase, with minimal elevations over normal baseline, whereas three patients had elevations of serum glutamic oxaloacetic transaminase as high as 156 IU/ml on week 7. All hepatic abnormalities returned to baseline when the dosage was reduced. One patient who was receiving 3 Mu/ M2 required a reduction in dosage because of hepatic abnormalities, whereas no patient who was receiving 1 Mu/M 2 showed hepatic abnormalities.
Comment Condyloma acuminatum, recognized for centuries as a nuisance disease, has recently been linked to the development of intraepithelial neoplasia of the cervix, vagina, and vulva. 13• 14 This implies that efficient and adequate therapy should be available to the clinician to control this disease process. Although the natural history of papillomaviral infection in humans is not completely known because of our inability to culture the virus, we do recognize that spontaneous regressions of the disease occur. This spontaneous regression rate can be as high as 33% within 6 months. Therefore, in any study of patients with condyloma acuminatum, there must be a clear statement of whether the patients have resistant and persistent disease or whether they have newly developed lesions. In the present study, all patients had resistant and persistent disease as represented by the presence of disease for more than 6 months and failure of at least 10 applications of podophyllin or equivalent therapy.
162 Gall, Hughes, and Trofatter
Exogenous topical interferon therapy was first reported in 1975, by Ikic et al. 10 Topical application of a Vasoline-lanolin ointment of crude leukocyte interferon resulted in complete disappearance of lesions in 36 or 40 women treated for 4 to 12 weeks. No information was recorded on the length of time the patients' lesions were present prior to therapy. Schonfeld et al. 11 demonstrated that intramuscular injection was the most suitable route of administration for fibroblast interferon (IFN-f3). Two additional groups of patients each were given doses (3 x 106 or 9 x 106 units intramuscularly) of IFN-13 on 2 consecutive days, which resulted in complete disappearance of genital warts. The patients treated by Schonfeld et al. or by Ikic et al. were largely untreated patients, whereas the patients treated in these studies were selected to have resistant and persistent condylomas acuminata. The objectives of our studies were to evaluate the efficacy, biologic side effects, and toxicity of varying dosage schedules of Wellferon (lymphoblastoid interferon). Previous studies in patients with malignant disease to whom increasing doses up to 200 Mu/day were given have shown excessive toxicity at high doses (>20 Mu/M 2 ). 15 · 16 Patients given interferon at all dosages tested will manifest fever to 40.3° C for a period of 12 hours after initial intramuscular injection. Patients given 5 Mu/M 2 daily will manifest some unpleasant side effects, such as fever, malaise, nausea/vomiting, and headache. These side effects decrease as therapy is continued and will diminish substantially when threetimes-per-week dosing is used. The side effects at 3 Mu/M 2 /day are well tolerated, with almost no symptoms when three-times-per-week dosing is reached at this dosage level. The patients who were given interferon at I Mu/M 2 had few side effects, with fatigue as the most common symptom. Hematologic aberrations were the most prominent laboratory abnormalities in response to interferon; however, no serious clinical effects were noted as secondary events to these changes. The hematologic aberrations occurred mainly in patients who were given the 5 Mu/M 2 dose. All patients who were given 5 Mu/ M2 /day demonstrated statistically significant decreases in mean total white blood cell count, lymphocytes, granulocytes, eosinophils, and platelets after I week of therapy, whereas three patients who were given 3 Mu/M 2 and no patients who were given I Mu/M 2 demonstrated these toxicities. No patient in any of the trials experienced abnormal loss of blood, evidence of hemolysis, or infection. These clinical trials with Wellferon at various dosing schedules have demonstrated that this interferon is active as a possible treatment for women with resistant and persistent condylomas acuminata. The side effects
September 15, 1985 Am J Obstet Gynecol
even at the 5 Mu/M 2 level were not life-threatening and were lessened when the dosage was reduced. Importantly, patients treated with 3 Mu/M 2 /day or I Mu/m 2 / day reported fewer side effects, had less hematologic aberration, but demonstrated an efficacy of treatment not different from that found in the 5 Mu/M 2 group. The addition of cryotherapy or surgical excision as an adjuvant treatment to interferon appears to be a promising treatment modality. Increased numbers of patients were cured of their warts, without recurrence, when treated after the conclusion of the interferon protocol. This suggests that combination or sequential therapy of interferon and surgical excision, cryotherapy, or laser therapy may play a prominent role in a lasting treatment program. REFERENCES I. Dunn AEG, Ogilule MM: Intranuclear virus particles in
2.
3.
4.
5. 6. 7. 8. 9.
IO.
11.
12.
I3. 14.
human genital wart tissue: observation on the ultrastructure of the epidermal layer. J Ultrastruct Res I968;22:282-95. Gissman L, De Villiers EM, ZurHausen H. Analysis of human warts (condyloma acuminata) and other genital tumors for human papillomavirus type 6 DNA. lntJ Cancer I982;29:I43-6. Durst M, Gissman L, Ikenburg H, ZurHausen H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci USA I983;80:38I2-5. Gissman L, Wolnik L, Ikenburg H, Koldousky U, Schnurch HG, ZurHausen H. Human papillomavirus types 6 and I I, DNA sequences in genital and laryngeal papillomas and in some cervical cancers. Proc Natl Acad Sci USA I 983;80:560-3. Von Krogh G. Topical treatment of penile condylomata acuminata with podophyllin, podophyllotoxin and colchicine. Acta Derm Venereal (Stockh) 1978;58: 163-8. Rasmussen JE. Warts and what to do about them. Drug Ther 1981; 11 :65-76. Powell LC, Pollard M, Jenkins JL. Treatment of condyloma acuminata by autologous vaccine. South Med J I 970;63:202-5. Von Krogh G, Ruden AK. The treatment of penile condyloma acuminata with colchicine at 48-72 hour intervals. Acta Derm Venereal I 980;60:87-9. Foster DC, Woodruff JD. The use of dinitro chlorobenzene in the treatment of vulvar carcinoma-in-situ. Gynecol Oncol 1981; 11: 330-9. Ikic D, Bosnic N, Smerdel S,Jusci D, Soos E, Delimar N. Double-blind clinical study with human leukocyte interferon in the therapy of condyloma acuminata. Proceedings of symposium on clinical use of interferon. Zagreb, 1975:229-33. Schonfeld A, Nitke S, Schattner A, Wallach D, Crespi M, Hahn T, Levair H, Varden 0, ShohamJ, DoernerT, Revel M. Intramuscular human interferon-J3 injections in treatment of condyloma acuminata. Lancet 1984; I: I 038-42. Finter NB, Fantes KH. The purity and safety of interferons prepared for clinical use: the case for lymphoblastoid interferon. In: Gresser I, ed. Interferon. New York: Academic Press, I981:65-80. (vol 3). Meisels A, Morin C. Human papillomavirus and cancer of the uterine cervix. Gynecol Oncol 1981;12:Slll-23. Crum CP, Ikenburg H, Richart R, Gissman L. Human
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papillomavirus type 16 early cervical neoplasia. N Engl J Med l 984;310:880-3. 15. Rohatiner AZS, Barkwill FR, Griffin DB. A phase I study of human lymphoblastoid interferon administered by continuous intravenous infusion. Cancer Chemother Pharmacol 1982;9:97-102. 16. KnostJA, Sherwin SA, Abrams PG, et al. The treatment of cancer patients with human lymphoblastoid interferon: a comparison of two routes of administration. Cancer Immunol Immunother 1983;15:144-8.
Editors' note: This manuscript was revised after these
discussions were presented.
Discussion DR. R. PINKNEY RANKIN, JR., Charlotte, North Carolina. Dr. Gall et al. have measured the response of genital condylomas to intramuscular lymphoblastoid interferon in 60 healthy immunocompetent patients. Final assessment was made 6 months after completion of treatment. With the use of three different dosage protocols, complete response to systemic interferon alone was achieved in 43% to 57% of patients. The dosage regimen of 3 Mu/M 2 combined a higher response rate with acceptable toxicity. At the inception of the study, all patients had persistent disease, resistant to previous conventional therapy-thus minimizing the risk of spontaneous regression. This is a critical feature of the study, since most other reports on the use of intralesional or systemic interferon have involved a smaller series of untreated patients with disease of indeterminate duration. The authors then extended their study design by treating nine suboptimum responders with adjuvant surgical therapy (either excision or cryosurgery-no laser vaporization). The amount of residual bulk disease was not specified, but response was complete in all patients for at least 6 months. In fact, the 80% complete response in 30 patients who were given 3 Mu/M 2 of interferon was achieved with seven of these patients. Everyone is aware of the early emergence of latent or new lesions after surgical excision, cryotherapy, or laser vaporization. Although the numbers are small, they strongly suggest improved outcome with sequential systemic interferon and adjuvant surgical therapy. Confirmation, however, must await a comparison of se-
163
quential therapy with surgical ablation alone-in patients with comparable disease. Although Dr. Gall et al. reported no serious morbidity in this study, leukopenia, thrombopenia, and hepatic dysfunction are invitations to potential disaster. A reduction in dosage seemed to be prudent in 21 patients. Eight patients dropped out of the study-one for protracted vomiting and seven for a variety of reasons, some of which might have been related to unacceptable symptoms. Treatment with systemic interferon is not innocuous. Hence, the ability to select patients with high-risk precursor lesions is crucial. We know, from the work of Fu et al.,' that dysplastic lesions with abnormal mitoses are aneuploid, with a high risk of progression, whereas diploid and polyploid lesions without abnormal mitoses often regress. This, however, lays too much burden on the microscope and the microscopist! Using DNA hybridization, Crum et al. 2 confirmed a predominance of human papillomavirus 16 in aneuploid lesions and a predominance of human papillomavirus 6 and 11 in diploid lesions. Human papillomavirus 16 is probably a marker for squamous carcinoma and its precursors. We are primarily limited by our inability to grow the human papillomavirus in culture and our inability to identify its subtypes. When we can, we will be able to tailor the treatment (with its inherent toxicity) to the patient's disease potential. I have the following questions. ( 1) What was the incidence of cervicovaginal mucosa! lesions in Dr. Gall et al.'s study group? (2) Did the authors note any differential response between lesions of the mucosa and the lesions of the perinea! skin? (3) Were there any data on associated dysplasia and its therapeutic fate? In summary, I commend Dr. Gall et al. for the quality of this complex but well-designed study.
REFERENCES 1. Fu YS, Reagan JW, Richart RM, Townsend DE. Nuclear
DNA and histologic studies of genital lesions in DES-exposed progeny. I. Intraepithelial squamous abnormalities. Am J Clin Pathol 1979;72:502-14. 2. Crum CP, lbenberg H, Richart RM, Gissman L. Human papilloma virus 16 and early cervical neoplasia. N Engl J Med 1984;310:880-3.