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Treatment of cervical dysplasia with electrocautery and tetracycline suppositories
Treatment of cervical dysplasia with electrocautery GEORGE
D.
WILLIAM ROY
WILBANKS,
T.
LOUISE
A. T.
and tetracycline
CREASMAN,
F.A.C:.C).G.++
M.D.,
KAUFMANN,
PARKER,
Durham, North
M.D.,
suppositories
F.A.C.O.G.
B.S.
M.D.,
F.A.C.O.G.
Carolina
The efficacy of electrocautery and tetracycline in causing regression of dysplasia of the cervix were evaluated and compared to a control group. It would appear from the analysis of this material that electrocautery can destroy cervical dysplasia. Tetracycline does not appear to alter appreciably the course of dysplasia of the cervix in comparison to the control group.
C L A s s I c D I A G N o s I s and treatment of early neoplasia of the cervix with biopsy, cold-knife conization, and hysterectomy are time-consuming, costly, and potentially hazardous. There is no generally accepted treatment for dysplasia. Some physicians treat dysplasia as carcinoma in situ, and others simply follow the patient without definitive therapy.l-” Electrocautery and recent cryosurgery have been used to treat dysplasia ; however, electrocautery has not been accepted as a standard mode of therapy, and cryosurgery is still under study. Isolated reports indicated that the use of
From the Department Gynecology, Division University Medical Supported Grant No.
of Obstetrics of Oncology,
Center.
by American 402T.
F;;;ived
for
Accepted
March
and Duke
Cancer
publication
January
Society 16,
15, 1973.
Reprint requests: William T. Creasman, M.D., Department of Obstetrics and Gynecology, P.O. Box 3079, Duke University Medical Center, Durham, North Carolina 27710. *Present address: Rush Medical College, Rush-Presbyterian-St. Luke’s Medical Center, I753 W. Congress Parkway, Chicago, Illinois 60612.
tetracycline suppositories resulted in the disappearance of intraepithelial neoplasms of the cervix. ‘-‘, The project described in this report was designed as a controlled study of the effects of electrocautery and tetracycline suppositories on dysplasia of the cervix. Material
and
methods
All patients in the Duke University Medical Center with abnormal genital cytology and no visible lesion of the cervix, vagina, or vulva are referred to the Abnormal Cervix Clinic as part of an ongoing study of the in vivo behavior of early cervical neoplasia. Each patient has a detailed epidemiologic and medical history, including all events possibly related to cervical neoplasia, as age at first pregnancy, contraception, number of pregnancies, and change in coital partners. These data are stored in a computer and are ready for analysis in each component study. At each visit, usually at 3 month intervals, the patient has \-aginal and cervical Papanicolaou smears, colposcopy, and toluidine blue, XXI Schiller stains. Selected patients also have colpomicroscopy, vaginal cultures for trichomonads and fungi, vaginal fluid for hanging drop and Gram’s stain. and blood for viral antibody studies.
Volume Numbel
117 4
Patients with two consecutive smears indicating mild or moderate dysplasia taken at least one month apart and confirmed with colposcopy were admitted to this study protocol. Patients were randomly assigned by the sealed envelope technique to three groups: ( 1) electrocautery ; (2) tetracycline suppository ; or (3) placebo suppository. Randomization was in groups of 9, so that the members would be reasonably equal during the project. Patients selected for electrocautery were treated according to the technique of Younge’ and Kichart and Sciarra.& With a large ball-tipped electrode (I .O cm. diameter), all cervical lesions visible by the colpomicroscope, and abnormal areas by colposcopy were thoroughly cauterized. If no lesions were visible, the area 2 cm. on the squamous side of the squamocolumnar junction and the entire visible mucous epithelium were destroyed using a Cameron elect.+ocautery unit. Patients were advised not to douche and not to have coitus for 2 weeks and then to resume usual activities. No other medications or instructions were given. Patients in the tetracycline suppository group and in the placebo suppository group were given a numbered bottle containing 20 suppositories, and instructed to insert one suppository high into the vagina twice daily. They were asked to return the bottle at the next visit. All bottles and suppositories were identical. Bottles were randomly numbered so that the examiner was not aware which bottle contained tetracycline or which bottle contained placebo. Patients vvere scheduled to return in 6 weeks, and at 3 month intervals thereafter. Examinations as described above were performed at each posttreatment visit. Regression was determined when the patient had at least two negative smears and examinations over a one year period. Progression was interpreted to be a more advanced lesion cytologically, and in addition, severe dysplasia or carcinoma in situ was present in biopsy study. Patients whose lesions progressed cytologically or colposcopically were studied and treated by cold-knife conization. All pa-
Treatment
of cervical
Table I. Results in therapy
dysplasia
461
of early cervical
neoplasia Therapy patients
Patients regressed
of
Controls Tetracycline Cautery
19 17 19
Total
55
Patients unchanged
4 8* 16 28
Patients progressed
4 4 0 8
11 il 19
“In
4 of the 8 patients regression did not take place until 7, 12. 18. and 21 months. respectively, post therapy, which probably meant that tetracycline therapy did not cause re,g~rssion.
Table II. Time Therapy batients
of
to progression Time interval Cmos. J
ControIs 1I Tetracycline 5 Cautery - 3 Total 19
Table III. Therapy batients
6-46 9-54 8-26
Time
to regression
of
Time
Controls 4 Tetracycline 8 Cautery -16 Total 28
interval Imos. J
Average
time
(mos. J 24 28 17
Average time Cmos. J
26-58 l-11 l-9
tients in this report were followed minimum of one year. Continued follow-up is planned indefinitely.
39 7 2.6
for a patient
Results
Table I shows the results of the 55 patients in the study. The control group had the greatest progression rate, while the cautery group had the greatest regression rate. With three chi square test on the interrelated data progression is statistically significant at the 0.03 level between the control and cautery patients. Progression at the 0.06 level is of significance between the tetracycline suppository therapy and cautery. There was no difference between the control versus tetracycline patients. In Table II the progression time to severe dysplasia or carcinoma in situ (pathologically diagnosed) is depicted in months, Table III notes the regression time (cytologically
462
Wilbanks
et al.
normal smears I of the three groups. ‘I‘hct .17 patients denoted in Tables II and III we1.c followed from 18 to 66 months with the a\.erage being 38 months from the time the? cantered the study. Comment Dysplasia has been defined as an atypical microscopic change in which characteristic undifferentiated malignant cells are present in the epithelium but do not involve the entire thickness of the epithelium. Careful study of esfoliated cytology permits the detection of cervical dysplasia of microscopic size and the identification of the type of epithelium present with accuracy.‘* !’ Colpomicroscopy has been accurate in localizing dysplasia and intraepithelial carcinoma in 70 to 85 per cent of patients with abnormal smears.l”. I1 Diagnostic accuracy is important in the study of the behavior of cervical dysplasia, whether undisturbed or when using various modalities of treatment. A biopsy may completely remove a small area of dysplasia, or the biology may be disturbed by the inflammatory and healing processes after incomplete removal, resulting in regression.” The fate of undisturbed dysplasia is unknown. Stern and Neelyl” followed 130 patients with dysplasia by cytology and biopsy, from 6 months to 9 years, and calculated the rate of progression of dysplasia to carcinoma in situ at 6.4 per cent per year. Koss and associates” in a similar study using biopsy technique found that 46 per cent of lesions progressed to carcinoma in situ, 15 per cent persisted unchanged, and 30 per cent disappeared during a 7 year follow-up. Fox1 followed cytologically 411 patients with dysplasia, or carcinoma in situ. In the 278 patients with mild and moderate dysplasia, 60 per cent progressed, 9 per cent remained stable, and 31 per cent regressed during and up to 90 months of observation. Kichart and Rarron:’ state that once established a dysplastic lesion rarely spontaneously reverts to normal. Kichart and Rarron’s statement was based on observed and predicted results of a
prospecti\~c :>tudy of ,557 patients folio\\ cd without biopsy , utilizing 01i1>. cyto1og.v ;1n<1 colpomicroscopy. From the liter ;ltllrc IX‘ports noted, it can 1~ assumed that approximately one third of dysplastic lesions can be altered by biopsy alone. ‘I’hercforc, 1)xtients in this report were studied and treatt,d Without lJiO[JSy. A simplified method of office treatment of dysplasia is needed because of prevalence, cost of medical care. and feasibility of cure by local therapy. Younge: and Richart and Sciarra,’ have shown electrocautery to bc effective in treating early cervical lesions. Cryosurgery is currently being tested.” None of these studies used control patients. This study with control patients and a random srlective rncthod shows that electrocautery can cause regression of dysplasia in 16 of 19 patients (84 per cent). Of the 3 cautery patients who progressed to carcinoma in situ , 2 had normal cytology after cautery only to have abnormal cytology reappear at 6 and 9 months later, respectively. The third patient progressed without any intervenin,? normal cytology. The regression rate in the 16 patients was rather rapid with an avtxlge of 2.6 months. Two patients did not return until 6 and 9 months post treatment hut had normal cytology on their first postcautery visit. Koss and associates” and Ayrc’ observed regression of cervical intraepithelial neoplasia following the use of antibiotic suppositories; however, these patients had been biopsied. This study was designed to evaluate the role of an antibiotic vaginal suppository only in the treatment of dysplasia of the cervix uteri. It would appear initially that the use of tetracycline may be helpful in altering the environment and therefore change the character of the dysplastic lesion since 8 of 17 (47 per cent) patients showed regression, while 9 patients who received the tetracycline had IJrogression or remained unchanged. The time to progression in this group of patients was not appreciably different from the control group. The tetracycline used by the right patients who had
Treatment
regression of the lesion may not have been the critical factor in their regression. In four patients the regression did not take place until 7, 12, 18, and 21 months post therapy with multiple abnormal cytologic examinations between treatment and regression. To say that the tetracycline caused regression at these time intervals probably would not be valid. Regression that could have been caused by the tetracycline occurred in only 4 patients which was less than the cautery group. These 4 patients did regress timewise comparably with the cauterization patients. Time of follow up in this type of study is critical. The patients who were treated by cauterization of the cervix without benefit either had cytology remain abnormal, or returned to abnormal within a short period of time (O-9 months). To date none of the
REFERENCES
7.
al.: Cancer 16: 1160, Younge, P. A.: The of Carcinoma in Situ Cancer Conference 682-692.
1963. Conservative
Treatment
of the Cervix, National Proceedings, 1956, pp.
dysplasia
463
cautery patients who regressed and remained normal for over one year has had recurrence of abnormal smears. In contrast to the patients who regressed on cautery, the patients in the other two groups had several years pass before progression was noted (4 of the 16 patients did not progress until 4 years after entry to the study). One of the patients in this study had varying degrees of dysplastic changes cytologically for 10 years only to clear spontaneously and remain clear for 5 years. During the subsequent 6 years, the case progressed to severe dysplasia. Because of the unusual behavior of this lesion in a significant number of patients, controls and long-term follow-up are needed before definitive statements can be made concerning the efficacy of a specific therapy.
8.
1. Fox, C. H.: A~I. J. OBSTET. GYNECOL. 99: 960, 1967. 2. Parker, R. T., Cuyler, W. K., Kaufmann, L. A., et al.: AM. J. OBSTET. GYNECOL. 80: 693, 1960. 3. Richart, R. M., and Barron, B. A.: AM. J. OBSTET. GYNECOL. 105: 386, 1969. 4. Ayre, J. E.: South. Med. J. 45: 915, 1952. 5. Jordan, M. J., Bader, G. M., and Day, E.: AM. J. OBSTET. GYNECOL. 89: 160, 1964. 6. Koss, L. G., Steart, F. W., Foote, F. W., et
of cervical
9.
Richart,
R.
OBSTET.
GYNECOL.
12.
and
Sciarra,
in McManus,
J.
J.:
AM.
J.
101: 200, 1968.
Cuyler, W. K.: The Recognition in Situ of the Cervix by
Method, 10. 11.
M.,
of Carcinoma Papanicolaou’s
J. F. A., editor:
Prog-
ress in Fundamental Medicine, Philadelphia, 1952. Lea & Febieer. DR. 261-276. Rich&, R. M.: can;& 18: 950, 1965. Okagaki, T., Austin, J. H., and Younge, P. A.: Acta Cytol. 6: 403, 1962.
Richart, 64,
R. M.: Bull. Sloane Hosp. Worn. 10:
1964.
13. Stern, E., and Neely, P. W.: Cancer 17: 508, 1964. 14.
Townsend, D. E., and Ostergard, Reprod. Med. 6: 171, 1971.
D.
R.:
J.
D.
WILLIAM ROY
WILBANKS,
T.
LOUISE
A. T.
and tetracycline
CREASMAN,
F.A.C:.C).G.++
M.D.,
KAUFMANN,
PARKER,
Durham, North
M.D.,
suppositories
F.A.C.O.G.
B.S.
M.D.,
F.A.C.O.G.
Carolina
The efficacy of electrocautery and tetracycline in causing regression of dysplasia of the cervix were evaluated and compared to a control group. It would appear from the analysis of this material that electrocautery can destroy cervical dysplasia. Tetracycline does not appear to alter appreciably the course of dysplasia of the cervix in comparison to the control group.
C L A s s I c D I A G N o s I s and treatment of early neoplasia of the cervix with biopsy, cold-knife conization, and hysterectomy are time-consuming, costly, and potentially hazardous. There is no generally accepted treatment for dysplasia. Some physicians treat dysplasia as carcinoma in situ, and others simply follow the patient without definitive therapy.l-” Electrocautery and recent cryosurgery have been used to treat dysplasia ; however, electrocautery has not been accepted as a standard mode of therapy, and cryosurgery is still under study. Isolated reports indicated that the use of
From the Department Gynecology, Division University Medical Supported Grant No.
of Obstetrics of Oncology,
Center.
by American 402T.
F;;;ived
for
Accepted
March
and Duke
Cancer
publication
January
Society 16,
15, 1973.
Reprint requests: William T. Creasman, M.D., Department of Obstetrics and Gynecology, P.O. Box 3079, Duke University Medical Center, Durham, North Carolina 27710. *Present address: Rush Medical College, Rush-Presbyterian-St. Luke’s Medical Center, I753 W. Congress Parkway, Chicago, Illinois 60612.
tetracycline suppositories resulted in the disappearance of intraepithelial neoplasms of the cervix. ‘-‘, The project described in this report was designed as a controlled study of the effects of electrocautery and tetracycline suppositories on dysplasia of the cervix. Material
and
methods
All patients in the Duke University Medical Center with abnormal genital cytology and no visible lesion of the cervix, vagina, or vulva are referred to the Abnormal Cervix Clinic as part of an ongoing study of the in vivo behavior of early cervical neoplasia. Each patient has a detailed epidemiologic and medical history, including all events possibly related to cervical neoplasia, as age at first pregnancy, contraception, number of pregnancies, and change in coital partners. These data are stored in a computer and are ready for analysis in each component study. At each visit, usually at 3 month intervals, the patient has \-aginal and cervical Papanicolaou smears, colposcopy, and toluidine blue, XXI Schiller stains. Selected patients also have colpomicroscopy, vaginal cultures for trichomonads and fungi, vaginal fluid for hanging drop and Gram’s stain. and blood for viral antibody studies.
Volume Numbel
117 4
Patients with two consecutive smears indicating mild or moderate dysplasia taken at least one month apart and confirmed with colposcopy were admitted to this study protocol. Patients were randomly assigned by the sealed envelope technique to three groups: ( 1) electrocautery ; (2) tetracycline suppository ; or (3) placebo suppository. Randomization was in groups of 9, so that the members would be reasonably equal during the project. Patients selected for electrocautery were treated according to the technique of Younge’ and Kichart and Sciarra.& With a large ball-tipped electrode (I .O cm. diameter), all cervical lesions visible by the colpomicroscope, and abnormal areas by colposcopy were thoroughly cauterized. If no lesions were visible, the area 2 cm. on the squamous side of the squamocolumnar junction and the entire visible mucous epithelium were destroyed using a Cameron elect.+ocautery unit. Patients were advised not to douche and not to have coitus for 2 weeks and then to resume usual activities. No other medications or instructions were given. Patients in the tetracycline suppository group and in the placebo suppository group were given a numbered bottle containing 20 suppositories, and instructed to insert one suppository high into the vagina twice daily. They were asked to return the bottle at the next visit. All bottles and suppositories were identical. Bottles were randomly numbered so that the examiner was not aware which bottle contained tetracycline or which bottle contained placebo. Patients vvere scheduled to return in 6 weeks, and at 3 month intervals thereafter. Examinations as described above were performed at each posttreatment visit. Regression was determined when the patient had at least two negative smears and examinations over a one year period. Progression was interpreted to be a more advanced lesion cytologically, and in addition, severe dysplasia or carcinoma in situ was present in biopsy study. Patients whose lesions progressed cytologically or colposcopically were studied and treated by cold-knife conization. All pa-
Treatment
of cervical
Table I. Results in therapy
dysplasia
461
of early cervical
neoplasia Therapy patients
Patients regressed
of
Controls Tetracycline Cautery
19 17 19
Total
55
Patients unchanged
4 8* 16 28
Patients progressed
4 4 0 8
11 il 19
“In
4 of the 8 patients regression did not take place until 7, 12. 18. and 21 months. respectively, post therapy, which probably meant that tetracycline therapy did not cause re,g~rssion.
Table II. Time Therapy batients
of
to progression Time interval Cmos. J
ControIs 1I Tetracycline 5 Cautery - 3 Total 19
Table III. Therapy batients
6-46 9-54 8-26
Time
to regression
of
Time
Controls 4 Tetracycline 8 Cautery -16 Total 28
interval Imos. J
Average
time
(mos. J 24 28 17
Average time Cmos. J
26-58 l-11 l-9
tients in this report were followed minimum of one year. Continued follow-up is planned indefinitely.
39 7 2.6
for a patient
Results
Table I shows the results of the 55 patients in the study. The control group had the greatest progression rate, while the cautery group had the greatest regression rate. With three chi square test on the interrelated data progression is statistically significant at the 0.03 level between the control and cautery patients. Progression at the 0.06 level is of significance between the tetracycline suppository therapy and cautery. There was no difference between the control versus tetracycline patients. In Table II the progression time to severe dysplasia or carcinoma in situ (pathologically diagnosed) is depicted in months, Table III notes the regression time (cytologically
462
Wilbanks
et al.
normal smears I of the three groups. ‘I‘hct .17 patients denoted in Tables II and III we1.c followed from 18 to 66 months with the a\.erage being 38 months from the time the? cantered the study. Comment Dysplasia has been defined as an atypical microscopic change in which characteristic undifferentiated malignant cells are present in the epithelium but do not involve the entire thickness of the epithelium. Careful study of esfoliated cytology permits the detection of cervical dysplasia of microscopic size and the identification of the type of epithelium present with accuracy.‘* !’ Colpomicroscopy has been accurate in localizing dysplasia and intraepithelial carcinoma in 70 to 85 per cent of patients with abnormal smears.l”. I1 Diagnostic accuracy is important in the study of the behavior of cervical dysplasia, whether undisturbed or when using various modalities of treatment. A biopsy may completely remove a small area of dysplasia, or the biology may be disturbed by the inflammatory and healing processes after incomplete removal, resulting in regression.” The fate of undisturbed dysplasia is unknown. Stern and Neelyl” followed 130 patients with dysplasia by cytology and biopsy, from 6 months to 9 years, and calculated the rate of progression of dysplasia to carcinoma in situ at 6.4 per cent per year. Koss and associates” in a similar study using biopsy technique found that 46 per cent of lesions progressed to carcinoma in situ, 15 per cent persisted unchanged, and 30 per cent disappeared during a 7 year follow-up. Fox1 followed cytologically 411 patients with dysplasia, or carcinoma in situ. In the 278 patients with mild and moderate dysplasia, 60 per cent progressed, 9 per cent remained stable, and 31 per cent regressed during and up to 90 months of observation. Kichart and Rarron:’ state that once established a dysplastic lesion rarely spontaneously reverts to normal. Kichart and Rarron’s statement was based on observed and predicted results of a
prospecti\~c :>tudy of ,557 patients folio\\ cd without biopsy , utilizing 01i1>. cyto1og.v ;1n<1 colpomicroscopy. From the liter ;ltllrc IX‘ports noted, it can 1~ assumed that approximately one third of dysplastic lesions can be altered by biopsy alone. ‘I’hercforc, 1)xtients in this report were studied and treatt,d Without lJiO[JSy. A simplified method of office treatment of dysplasia is needed because of prevalence, cost of medical care. and feasibility of cure by local therapy. Younge: and Richart and Sciarra,’ have shown electrocautery to bc effective in treating early cervical lesions. Cryosurgery is currently being tested.” None of these studies used control patients. This study with control patients and a random srlective rncthod shows that electrocautery can cause regression of dysplasia in 16 of 19 patients (84 per cent). Of the 3 cautery patients who progressed to carcinoma in situ , 2 had normal cytology after cautery only to have abnormal cytology reappear at 6 and 9 months later, respectively. The third patient progressed without any intervenin,? normal cytology. The regression rate in the 16 patients was rather rapid with an avtxlge of 2.6 months. Two patients did not return until 6 and 9 months post treatment hut had normal cytology on their first postcautery visit. Koss and associates” and Ayrc’ observed regression of cervical intraepithelial neoplasia following the use of antibiotic suppositories; however, these patients had been biopsied. This study was designed to evaluate the role of an antibiotic vaginal suppository only in the treatment of dysplasia of the cervix uteri. It would appear initially that the use of tetracycline may be helpful in altering the environment and therefore change the character of the dysplastic lesion since 8 of 17 (47 per cent) patients showed regression, while 9 patients who received the tetracycline had IJrogression or remained unchanged. The time to progression in this group of patients was not appreciably different from the control group. The tetracycline used by the right patients who had
Treatment
regression of the lesion may not have been the critical factor in their regression. In four patients the regression did not take place until 7, 12, 18, and 21 months post therapy with multiple abnormal cytologic examinations between treatment and regression. To say that the tetracycline caused regression at these time intervals probably would not be valid. Regression that could have been caused by the tetracycline occurred in only 4 patients which was less than the cautery group. These 4 patients did regress timewise comparably with the cauterization patients. Time of follow up in this type of study is critical. The patients who were treated by cauterization of the cervix without benefit either had cytology remain abnormal, or returned to abnormal within a short period of time (O-9 months). To date none of the
REFERENCES
7.
al.: Cancer 16: 1160, Younge, P. A.: The of Carcinoma in Situ Cancer Conference 682-692.
1963. Conservative
Treatment
of the Cervix, National Proceedings, 1956, pp.
dysplasia
463
cautery patients who regressed and remained normal for over one year has had recurrence of abnormal smears. In contrast to the patients who regressed on cautery, the patients in the other two groups had several years pass before progression was noted (4 of the 16 patients did not progress until 4 years after entry to the study). One of the patients in this study had varying degrees of dysplastic changes cytologically for 10 years only to clear spontaneously and remain clear for 5 years. During the subsequent 6 years, the case progressed to severe dysplasia. Because of the unusual behavior of this lesion in a significant number of patients, controls and long-term follow-up are needed before definitive statements can be made concerning the efficacy of a specific therapy.
8.
1. Fox, C. H.: A~I. J. OBSTET. GYNECOL. 99: 960, 1967. 2. Parker, R. T., Cuyler, W. K., Kaufmann, L. A., et al.: AM. J. OBSTET. GYNECOL. 80: 693, 1960. 3. Richart, R. M., and Barron, B. A.: AM. J. OBSTET. GYNECOL. 105: 386, 1969. 4. Ayre, J. E.: South. Med. J. 45: 915, 1952. 5. Jordan, M. J., Bader, G. M., and Day, E.: AM. J. OBSTET. GYNECOL. 89: 160, 1964. 6. Koss, L. G., Steart, F. W., Foote, F. W., et
of cervical
9.
Richart,
R.
OBSTET.
GYNECOL.
12.
and
Sciarra,
in McManus,
J.
J.:
AM.
J.
101: 200, 1968.
Cuyler, W. K.: The Recognition in Situ of the Cervix by
Method, 10. 11.
M.,
of Carcinoma Papanicolaou’s
J. F. A., editor:
Prog-
ress in Fundamental Medicine, Philadelphia, 1952. Lea & Febieer. DR. 261-276. Rich&, R. M.: can;& 18: 950, 1965. Okagaki, T., Austin, J. H., and Younge, P. A.: Acta Cytol. 6: 403, 1962.
Richart, 64,
R. M.: Bull. Sloane Hosp. Worn. 10:
1964.
13. Stern, E., and Neely, P. W.: Cancer 17: 508, 1964. 14.
Townsend, D. E., and Ostergard, Reprod. Med. 6: 171, 1971.
D.
R.:
J.