Results of outpatient therapy of cervical intraepithelial neoplasia

GYNECOLOGIC

ONCOLOGY

12, S306-S316 (1981)

Results of Outpatient Therapy of Cervical Intraepithelial Neoplasia WILLIAM

T. CREASMAN, M.D., DANIEL L. CLARKE-PEARSON M.D., AND JOHN C. WEED, JR., M.D.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710 Presented at the Conference on Early Cervical Neoplasia, March 23-25, 1981

The role of total outpatient management (appropriate evaluation, diagnosis, and treatment) in patients with cervical intraepithelial neoplasia (CIN) continues to be debated. Therapy of any kind is contraindicated without proper evaluation. Cytology, colposcopy, colposcopy-directed biopsies, endocervical curettage (ECC), and clinical examination all properly carried out by experienced physicians are the minimal diagnostic procedures required in the outpatient arena. The object of these exercises is to rule out invasive cancer. This has effectively been done when the colposcopically abnormal lesion is limited to the portio of the cervix, the colposcopic findings are indicative of CIN only, the ECC is negative, cytology indicates only an intraepithelial lesion, biopsies suggest only disease limited to the epithelium, and the clinical examination does not raise the suspicion of an invasive lesion. Approximately 8590% of all patients presenting with an abnormal Pap smear indicating CIN and without obvious gross cancer on the cervix can be evaluated adequately on an outpatient basis. If the above criteria have not been met, conization of the cervix is mandatory. The real concern and question being asked is what is the proper therapy for those 85-90% of patients who, in fact, have a intraepithelial lesion limited to the visual part of the cervix. In other words, what is the role of outpatient therapy in the management of a patient with CIN? The face of cervical neoplasia has changed dramatically over the last three decades, and continues to do so. The American Cancer Society’s statistical report estimates that during the decade of the 1970sthe yearly number of invasive cervical cancers dropped from 20,000 in 1971to 16,000in 1980[ 11.The anticipated deaths from this disease have also declined by 1900during the same time interval. Therefore, from 1971 to 1980 there have been 29,000 fewer cervical cancers diagnosed in the United States and 7000 fewer deaths. Only recently has the American Cancer Society attempted to predict the number of patients who might have carcinoma in situ of the cervix. The current figure is 45,000 per year. Using those figures one may estimate that almost 200,000 women in the United States s306 0090-8258/81/05S306-11$01.00/O Copyright All rights

0 t9gt by Academic Press, Inc. of reproduction in any form reserved.

RESULTS

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OF CIN

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this year will be identified as having a cervical intraepithelial lesion. Certainly before the use of the Papanicolaou smear as a screening technique, identification of these patients was somewhat fortuitous. The CIN was usually noted at hysterectomy which had been done for other gynecological reasons. The number of patients with CIN has probably increased over the last several years. Epidemiological studies have definitely established that this disease entity is closely related to the age of early onset of sexual activity and to the number of partners [2]. With “new morality” it has been suggested that the number of these lesions will continue to increase over the years. Not only has there been a change from fewer invasive lesions to a larger number of CIN, but the pattern of intraepithelial lesions also appears to be changing. Navarre [3] has recently stated that in a large number of patients followed in a prepaid Kaiser Foundation Health Plan in Southern California, he is currently seeing earlier CIN lesions compared to just a few years ago. In 1966, 63% of biopsies from new patients with abnormal Pap smears showed moderate dysplasia or worse, but by 1973 this figure had dropped to 36%. This trend has been observed in our own material in that between 1970 and 1975, 27% of our patients with biopsy proven intraepithelial disease had CIN-1. Since 1975, this figure has increased to 46%. Concominantly, there has been a drop in CIN-III diagnoses from 44 to 21% during the same time interval. The size of the lesion on the portio has also changed. From 1970 to 1975, 52% of our patients had disease limited to one quandrant of the cervix, and this increased to 64% post-1975. During that same time interval the large lesions, that is, greater than 50% of the cervix, decreased from 15 to 6%. This is as expected because the size of the lesion generally increases with the severity of the CIN. This change in pattern probably means more and more patients may be eligible for conservative, nonoperative therapy. Considerable experience has been obtained using several different modalities of outpatient therapy. Failures have occurred with all treatment regimens. Considerable concern has been voiced regarding the identification of the patient at risk of failing, the criteria for failure of treatment, and the patient reliability for long-term follow-up in large clinic populations. The following areas are of potential concern regarding the failures of outpatient therapy: 1. Histology. Outpatient therapy was generally restricted to the less severe forms of CIN during its early usage, so that its efficacy could be investigated safely. Once the effectiveness had been proved in CIN-I and II lesions, therapy was extended to CIN-III (severe dysplasia and carcinoma in situ). Many investigators evaluating the various types of outpatient therapy have shown a good response in CIN-III disease. Townsend [4] reviewed a large group of patients treated with cryosurgery and found that the histologic grade is not the determinant factor of successful ablation of a patient’s lesion. Recently Ostergard [5] made the statement condemning cryosurgery as acceptable treatment of severe dysplasia or cervical carcinoma in situ. His experience with 354 patients treated with cryosurgery contained only 46 who fell into the CIN-III category. Twentyeight of these patients were classified as having severe dysplasia; and the failure rate in this group was the same as the failure rate in the CIN-I and II category.

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For the 18 patients who had carcinoma in situ the failure rate was 38.8%. The small number of CIN-III patients may bias his results and conclusion. Most investigators would agree with the conclusions of Townsend and would not hesitate to treat a patient with CIN-III under appropriate conditions. 2. Size of the lesion. Recently in evaluating his cryosurgery failures, Townsend [4] concluded that the size of the lesion, not the histologic grade of the intraepithelial neoplasia, was more important relative to the ability to eradicate a lesion. To a certain degree, the histologic grade and the size of the lesion correlate in that as the lesion advances in grade from CIN-I to III, the size of the lesion also increases. In our material, both size and the histologic grade of the lesions appear to be important in failures of therapy; however, when corrected for lesion size, grade was more important. 3. Location of the lesion. Of paramount importance prior to outpatient therapy for CIN is proper and complete evaluation. All investigators agree that the cervical lesion must be limited to the portio of the cervix and seen in its entirety. A negative ECC gives objective evidence that disease has not extended into the endocervical canal. Outpatient therapy should not be considered unless these prerequisites have been met. Most of those patients who have had invasive cervical carcinoma after cryosurgery were found to have had inadequate pretreatment evaluation [6]. In some instances even a Pap smear had not been obtained. This admonition would appear self-evident; however, if the protocol is not rigidly followed inappropriate therapy can be expected. This occurs more often in the occasional user of these modalities. 4. Depth of destruction. The question that has been raised for several years is the adequacy of outpatient therapy to destroy disease that may be present in the endocervical glands. Recently Anderson and Hartley [7] have presented very important data evaluating the conization specimens of 344 patients with carcinoma in situ. They looked at the depth of the deepest crypt, and at the deepest point of neoplastic involvement. Very seldom was the deepest endocervical crypt involved with the carcinoma in situ. The mean involvement of these crypts extended only 1.24 mm from the surface of the epithelium. If a destructive process penetrates 3.8 mm from the surface of the epithelium, 99.7% of the lesions would be eliminated. As patients increase in age, there was a gradual increase in the depth of crypt involvement. At least a theoretical consideration in the treatment of this disease is whether or not disease can be eradicated on the surface while leaving viable neoplasm in the crypts thereby obscurring residual diser se. Although it is a theoretical consideration, practical evidence is lacking. Our experience in the cryosurgery conization of the cervix study indicated that no patients with endocervical glandular involvement had clearing of the epithelium and persistence in the crypts [8]. Those patients who had disease present in the glands precryosurgery had clearing on the surface as well as in the glands on the conization specimen. The above-mentioned four areas of concern must be addressed when outpatient therapy is contemplated in this group of patients. We shall now consider the data concerning different treatment modalities.

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RESULTS OF OUTPATIENT THERAPY OF CIN

Electrocautery Richart and Sciarra [9] were one of the first to report on the efficacy of electrocautery in the treatment of dysplasias. Their rationale for using this therapy was the suggestion from uncontrolled studies that electrocautery might be used prophylactically to prevent cervical cancer. They reported 182 women with dysplasia who were treated with electrocautery. Only seven of these patients had severe dysplasia, the rest having either mild or moderate dysplasia. No individual had carcinoma in situ. Eighty-nine percent of the patients had their lesion eradicated with one treatment. In addition 1l/13 patients retreated with electrocautery had the lesion destroyed. The authors state that 97% of the patients treated had the lesion removed either with the pretreatment biopsy, endocervical curettage, or by the electrocautery treatment itself. Several subsequent studies have ap,peared in the literature indicating the effectiveness of this treatment (Table 1). Ortiz and associates [lo] treated 148 patients with electrocautery. Sixty of these individuals had CIN-I and II lesions, and all had their lesions eradicated with electrocautery. In the 88 patients who had CIN-III disease, a failure rate of 13.6% was noted. They found that there was no difference in persistent disease if endocervical glands were initially involved with the disease process or not. Hollyock and Chanen [ 1l] reported their experience in 438 patients treated with electrocoagulation diathermy and found an apparent primary cure rate of 93.6%. Eight of their failures had repeat diathermy and were apparently cured. As a result, 95.4% of all patients had destruction of their disease with this modality. There was no difference in the control rate between CIN-I and CIN-III disease, the latter making up 45% of the total patient population. Chanen [12] more recently updated his experience, reporting 812 patients treated with approximately half having CIN-III disease. His cure rate for the entire group was 95%. He stated that the severity of the lesion had no relationship to their ability to eradicate the disease but that the anatomical extent of the lesion was important. Radiothermia of small residual areas of dysplasia or CIN boosted the cure rate by another 1.5%. It should be stressed that the excellent results obtained by Chanen and his co-workers involved a technique which is different from electrocautery as practiced in this country. The patients are treated under general or regional anesthesia, TABLE ELECTR~CAUTERY

AND ELECTROCOAGULATION

1 DIATHERMY

AS TREATMENT

FOR CIN

Failures” Source

Richart and Sciarra [9] Ortiz et al. [lo] Hollyock and Chanen [ill Total

UN-1

CIN-II

CIN-III

14/114 (12.0) O/18 ( 0) 11/130 ( 8)

3151 (6) O/42 (0) 61111 (5)

2/5 (40) 12/88 (14) 11/197 ( 5)

25/262 ( 9)

91204 (4)

25/290 ( 9)

’ Results of one treatment only. Nineteen of the failures were retreated with subsequent clearing of the lesion. Corrected failures, 40/756 (5%). Percentages are shown in parentheses.

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allowing the destruction of the entire transformation zone and obviously cannot be performed on an outpatient basis. Even using a lesser procedure as performed in the United States, one notes a considerable decrease in the popularity of electrocautery, because of pain and discomfort to the patient while the procedure is being performed. In the operating room, cervical dilatation, endocervical and intrauterine curettage are performed as a preliminary procedure. The diathermy technique destroys the whole area of the transformation zone including the deeper tissue where glandular crypts may be involved. Both the needle and ball electrodes are used. The needle electrode is inserted to a depth of approximately 1 4 cm into the cervix and the current applied. This is continued until the mucous from deep in the glands has ceased extruding from the crypt openings, indicating to these investigators that the glands have been destroyed. Multiple punctures are made over the whole of the transformation zone and adjacent areas of columnar epithelium. A ball electrode is then used to coagulate the whole surface of the area which has been subjected to the needle diathermy electrode. This achieves destruction of abnormal tissue both by the process of fulguration and coagulation. Complications have been minimal, and their excellent results attest to the effectiveness of this particular technique. The necessity of hospitalizing these patients and performing the procedure in the operating room detracts from these excellent results by increasing the costs to the patient from this procedure. Cryosurgery During the last decade, experience with cryosurgery in the treatment of patients with CIN has been considerable. Pain, which has been the main problem with electrocautery, is essentially nonexistent with cryosurgery. Considering patient comfort, one would prefer cryosurgery as an ideal outpatient modality. Charles and Savage [13] reviewed this therapy in a report published in 1980. They referenced 16 authors’ experiences. The success rate from these studies ran from 27 to 96%. The wide variation in results was probably due to many factors, including the experience of the operator, the number of patients treated, criteria established to determine a “cure,” as well as freezing techniques, equipment, and refrigerant used. This collected series, however, did represent almost 3000 patients. Table 2 details four recent studies, three of which were not included in the review by Charles and Savage [ 4, 14, 151. Evaluation of the four studies indicates that the failure rates were 6,7, and 14%, respectively, for CIN-I, II, and III lesions in a total of 1910 patients. The total failure rate for the entire group irrespective of the histological grade was 9%. Richart and associates [16] noted that the recurrence rate was less than 1% in almost 3000 patients with CIN treated with cryosurgery and followed for 5 years or longer (Table 3). All of these patients had at least three cytological smears after cryosurgery. Almost half of these recurrences were noted within the first year postcryosurgery, and probably represent persistence not true recurrence. No cases of invasive cancer have developed in these patients during the follow-up period. This recurrence rate is equal to or less than the expected incidence of lesions in these high-risk patients. It would therefore appear that in those patients with CIN which has been treated successfully a true recurrence

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RESULTS OF OUTPATTENT THERAPY OF CIN TABLE 2 CRYOSURGERY ASTREATMENTFORCIN Failures” Source

CIN-I

Popkin er al. [14] Townsendb 141 Kaufman and Irwin [15] Creasman et al. [S] Total

CIN-II

CIN-III

o/57 ( 0) lU250 ( 5) 8/66 (12) 12/134 ( 9)

4176 ( 5) 27/250 (11) 6/142 ( 4) 7/145 ( 5)

5/75 ( 1) 401250(16) 30/187 (16) 331278(12)

32l507 ( 6)

441613( 7)

108/790 (14)

’ Percentages are shown in parentheses. b Approximate numbers.

is rare. The failure rate generally indicates patients failing after one freezing session, although some patients were treated using the single while others the double-freeze technique. Townsend [4] states that all of the failures in the CINI category were retreated successfully with cryosurgery. The failure rate for retreated patients who failed the first treatment lowered the overall failure rate to 3% for CIN-II and 7% for CIN-III disease. Townsend finds his highest failure rate in patients with the extensive lesions irrespective of the histological grade. For lesions less than 1 cm in size his failure was 7%, but for lesions greater than 2 cm his failures increased to 42%. He gives no data concerning the efficacy of refreezing for extensive lesions. Creasman and associates found the histologic grade to be more important than the size of the lesion, and failures were much lower than reported by Townsend when size alone was evaluated. The difference in the finding of these two investigators may be due to the fact that Townsend used a single-freeze technique while the Duke group has been a long advocate of the double-freeze technique. As previously indicated, the concern of many investigators with this technique remains the variability of the freeze, particularly as it relates to destruction of disease in the endocervical crypts. Crisp [17] has stated that using the doublefreeze technique adequate destruction of tissue for a depth of 5-6 mm was noted. This would certainly destroy 99.7% of anticipated endocervical disease as indicated in the pathological study by Anderson and Hartley [7]. Experimental data indicates that the effect of repetitive freeze-thaw cycles is a gradually TABLE 3 CRYOSURGERY RECURRENCE AT 5 YEARS Number of patients CIN-I CIN-II CIN-III

898 977 964

Recurrences 19 (0.41%)

’ Life-table analysis. Total of 22 recurrences in 40,134 total women years.

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increasing volume of frozen tissue, and that with each successive cycle the freezing effect travels through the tissue at a greater rate than the preceding cycle. There is also evidence to indicate that freezing causes a faster rate of temperature descent in malignant versus normal tissue, that there is a lower tissue temperature at the end of the freeze cycle in malignant tissue, there is a plateau-type temperature thaw pattern in malignant tissue, and a longer recovery from the freeze cycle in malignant tissue which may explain why disease within the crypts is destroyed if the endocervical glands remain intact [Ml. Therefore, total destruction of the endocervical crypt system is not sine qua non to effective therapy with this or other modalities. Laser Laser therapy in the management of CIN has been evaluated recently by several investigators. The experience with this modality in a research setting is increasing although most results are limited and represent the initial effort of the investigator. Its effectiveness must be compared with other available modalities, particularly in view of the comparative expense of the equipment. In the five studies noted in Table 4 the failure rate is higher than with either cryosurgery or electrocautery [ 19-231. This difference may in part be due to several factors. It was originally thought that laser therapy could be limited to the exact lesion as delineated colposcopically thereby saving the rest of the cervix from destruction. Experience has shown that the failure rate in patients so treated has been very high, and all authors now advocate complete destruction of the transformation zone. The depth of destruction also appears to be very important, and failure rates were very high when only minimal destruction (1-2 mm) was achieved. As the depth of destruction has increased, the number of failures have decreased. The results of some of the studies noted in Table 4 include patients who were failures after the first therapy but on retreatment had total destruction of their disease. Burke and associates [I91 conclude from their experience that successful treatment was not related to the severity of the histologic grade nor size of the lesion. A continuous beam gave a better result than did an intermittent beam. The depth of destruction was important and must include the lamina propria, and endocervical glandular involvement did not preclude success. TABLE 4 LASERAS TREATMENTFORCIN Failures” Source Burke et al. [19] Carter et al. [20] stall et al. [21] Baggish [22] Bellina and Seto [231 Total

CIN-I 6/21 206 o/9 5/25 2/45

(28) (17) ( 0) (20) ( 4)

lY116 (13)

a Percentages are shown in parentheses.

CIN-II 11/19 l/17 l/14 13/43 4/147

(58) ( 6) ( 7) (30) ( 3)

30/240 (12)

CIN-III 5120 4/16 4123 15/47 3/55

(25) (25) (17) (32) ( 5)

31/109 (28)

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OF CIN

TABLE 5 LASER AS TREATMENT

CIN-I CIN-II CIN-III Total

FOR

CIN

Cure6

Treatment rate

61/63 ( 97) 62/62 (100) 165/174 ( 95)

1.21 1.21 1.35

288/299 ( 96)

1.27

a Jordan and Mylotte [24]. b Percentages are shown in parentheses.

Most recently Jordan and Mylotte [24] from England have reported their experience, the largest to date, regarding the . number of patients treated with laser therapy (Table 5). Many of their patients required retreatment to achieve the success rate as noted. Table 5 also indicates the number of treatments per patient required in each category to obtain their level of success. They do not feel that a patient should be designated a failure when they are retreated successfully with the laser. In Table 6, these authors evaluate their cure rate with a single laser application related to the depth of vaporization obtained by their therapy. It is obvious that destruction of tissue to the 5 to 7-mm depth is required to obtain an acceptable cure rate. The ability to precisely measure the depth of destruction answers the question of the ability of this modality to destroy disease within the endocervical crypts. “Cold”

Coagulator

Recently a new modality has been introduced as a possible alternative for the outpatient treatment of CIN. This apparatus uses a lower temperature than electrocautery, but is still capable of tissue destruction. Staland [25], in 1978, reported 71 patients with CIN II and III disease treated with a “cold” coagulator. There were only 2 patients who failed to have their lesion destroyed. Duncan [26] has reported his experience with this procedure (Table 7). The failure rate with one application was 6% in 213 patients. The author states that it is an ideal outpatient procedure as it is associated with little or no discomfort. It is inexTABLE 6 DEPTH OF LASER VAPORIZATION

IN

CIN

Depth

(mm) l-2 2-4 4-5 5-7

Cureb 8139 (20) 481105 (46) 23130 (77) 192/210 (91)

’ Jordan and Mylotte [24]. ’ All grades of CIN. Percentages are shown in parentheses.

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AND

WEED

TABLE 7 COAGULATOR AS TREATMENT FOR CIN Failures”

UN-1 CIN-II CIN-III Total ’ Percentages

2136 (5) 2133 (6) 81144 (5) 12/213 (6) are shown in parentheses.

pensive, rapid, silent, odorless, and smokeless, and it appears to have no impairment of fertility. The instrument is designed to destroy tissue to a depth of 3-4 mm at the setting used in this study. DISCUSSION The changing patterns of cervical neoplasia are becoming more evident. The identification of a young individual with intraepithelial neoplasia of the cervix is commonplace. Because of the youth of the patient and her desire for future fertility, physicians seek the means to adequately evaluate and treat the patient without operative procedures. By necessity comparison must be made with conization of the cervix, which heretofore has been the method of management for the young patient with an abnormal Pap smear. The data presented would suggest that the failure rate is comparable to that of conization. Three studies evaluating over 3000 patients using conization of the cervix as treatment for carcinoma in situ have indicated that persistence or recurrence of the carcinoma in situ occurred in over 6% of these patients [27-291. These same authors noted 2 1 patients (0.6%) subsequently developed invasive cancer, It should be apparent to even the causal observer that outpatient treatment for cervical intraepithelial neoplasia cannot be performed without appropriate diagnostic evaluation, but this cannot be overemphasized. The large number of reported invasive carcinomas of the cervix after outpatient therapy is due mainly to inappropriate evaluation of the patient before therapy. In some instances a “bad-looking cervix” was treated without even the benefit of a Pap smear. This is inexcusable! In 1973, Andras et al. [30] presented their experience in 148 patients who had the diagnosis of invasive carcinoma made at the time of a simple hysterectomy. The simple hysterectomy in most of these patients was for benign disease, and the carcinoma was a surprise finding. Many other articles in the literature attest to similar findings. The establishment of a diagnosis of invasive cancer on a simple hysterectomy specimen is also inappropriate. This problem is not new and continues to confront us even today. Continued education must be stressed. It would appear that there are alternatives available for the management of the patient with an abnormal Pap smear and a grossly normal cervix. Colposcopy and the directed diagnostic techniques are the diagnostic evaluations of a choice in such an individual, particularly if she is young or pregnant. If these techniques are not available to the physician, serious consideration must be given to referral

RESULTS OF OUTPATIENT THERAPY OF CIN

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of that patient. Outpatient therapy should not be performed without proper evaluation. Jordan and Mylotte [24] have stated that before considering any forms of destructive therapy for CIN it is imperative that the following criteria be met: 1. The patient must be seen and assessed by an expert colposcopist. 2. The colposcopist must be certain that he can see the entire lesion. 3. The colposcopist must be certain that invasive carcinoma is not present. 4, There is adequate cytologic and colposcopic follow-up. The authors could not agree more! REFERENCES 1. Cancer Statistics, 1980, Ca Cancer J. Clin. 30, 23 (1980). 2. Rotkin, I.D. A comparison review of key epidemiological studies in cervical cancer related to current searches for transmissible agents, Cancer Res. 33, 1353 (1973). 3. Navarre, G.L. Trends in colposcopy, J. Reprod. Med. 26, 1 (1981). 4. Townsend, D. E. Cryosurgery for GIN, Obstet. Gynecol. Saw. 34, 838 (1979). 5. Ostergard, D.R. Cryosurgical treatment of cervical intraepithelial neoplasia, Obstet. Gynecoi. 56, 231 (1980). 6. Townsend, D. E., Richart, R. M., Marks, E., and Nielsen, J. Invasive cancer following outpatient evaluation and therapy for cervical disease, Obstet. Gynecol. 57, 145 (1981). 7. Anderson, M. C., and Hartley, R. B. Cervical Crypt involvement by intraepithelial neoplasia, Obstet. Gynecol.

55, 546 (1980).

8. Creasman, W. T., Weed, J. C., Jr., Curry, S. L., et al. Efficacy of cryosurgical treatment of severe cervical intraepithelial neoplasia, Obstet. Gynecol. 41, 501 (1973). 9. Richart, R. M., and Sciarra, J. J. Treatment of cervical dysplasia by outpatient electrocauterization, Amer. J. Obstet. Gynecof. 101, 200 (I%S). 10. Ortiz, R., Newton, M., and Tsai, A. Electrocautery treatment of cervical intraepithelial neoplasia, Obstet. Gynecol.

41, 113 (1973).

11. Hollyock, V. E., and Chanen, W. Electrocoagulation diathermy for treatment of cervical dysplasia and carcinoma-in-situ, Obstet. Gynecol. 47, 196 (1976). 12. Chanen, W. Electrocoagulation diathermy treatment of cervical intraepithelial neoplasia, Obstet. Gynecol.

Surv. 34, 829 (1979).

13. Charles, E. H., and Savage, E. W. Cryosurgical treatment of cervical intraepithelial neoplasia, Obstet. Gynecol.

Surv. 35, 539 (1980).

14. Popkin, D. R., Scali, V., and Ahmed, M. N. Cryosurgery for treatment of cervical intraepithelial neoplasia, Amer. J. Obstet. Gynecol. 130, 551 (1978). 15. Kaufman, R. H., and Irwin, J. F. The cryosurgery therapy of cervical intraepithelial neoplasia Ill: Continuing followup, Amer. J. Obstet. Gynecol. 131, 381 (1978). 16. Richart, R. M., Townsend, D. E., Crisp, W., et al. An analysis of “long-term” followup results in patients with cervical intraepithelial neoplasia treated by cryosurgery, Amer. J. Obstet. Gynecol.

137, 823 (1980).

17. Crisp, W. E., Cryosurgery in the treatment of abnormal cervical lesions: An invitational symposium, J. Peprod. Med. 7, 147 (1971). 18. Hrycak, P.. Levy, M. J., and Witchins, S. A., “Cryosurgery of Lesions Through Contact Freezing and Estimates of Penetration Times,” Amer. Sot. Mech. Eng. Pup. 75WaiBio-11 1975). 19. Burke, H., Lovell, L., and Antoniolo, D. Carbon Dioxide Laser therapy of cervical intraepithelial neoplasia: Factors determining success rate, Lasers Surg, Med. 1, 113 (1980). 20. Carter, R., Krantz, K. E., Hara. G. S., et al. Treatment of Cervical intraepitheliai neoplasia with carbon dioxide laser beam, Amer. J. Obstet. Gynecol. 131, 831 (1978). 21. StatI, A., Wilkinson, E. J., and Mattingly, R. S. Laser Treatment of cervical and vaginal neoplasia, Amer. J. Obstet. Gynecol.

128, 128 (1977).

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22. Baggish, M. S. High-power density carbon dioxide laser therapy for early cervical neoplasia, Amer. J. Obstet. Gynecol. 136, 117 (1980). 23. Bellina, J. H., and Seto, Y. J. Pathological and physical investigations into CO, laser-tissue interactions with specific emphasis on cervical intraepithelial neoplasia, Lasers Surg. Med. 1, 47-60 (1980).

24. Jordan, J. A., and Mylotte, M. J. The treatment of cervical intraepithelial neoplasia by CO, laser vaporization, submitted for publication (1981). 25. Staland, B. Treatment of pre-malignant lesions of the uterine cervix by means of moderate heat thermosurgery using the SEMM coagulator. Ann. Chit-, Gynaecol. 67, 112 (1978). 26. Duncan, I. D. The treatment of cervical intraepithelial neoplasia with the SEMM “cold” coagulator, submitted for publication (1981). 27. Boyes, D. A., Worth, A. J., and Fidler, H. K. The results of treatment of 4389 cases of preclinical cervical squamous carcinoma, J. Obstet. Gynecol. Bit. Commonw. 72, 769 (1970). 28. Bjerre, B., Sjoberg, N., and Soberberg, J. Future Treatment after conization, J. Reprod. Med. 21, 232 (1978).

29. Kolstad, P., and Klen, V. Long-term followup of 1121 cases of carcinoma-in-situ, Obster. Gynecol. 48, 125 (1976). 30. Andras, E. J., Fletcher, G. H., and Rutledge, F. Radiotherapy of Carcinoma of the cervix following simple hysterectomy, Amer. .I. Obstet. Gynecol. 115, 647 (1973).