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Effectiveness and safety of loop electrosurgical excision procedure for cervical neoplasia in rural India
International Journal of Gynecology and Obstetrics 104 (2009) 95–99
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Effectiveness and safety of loop electrosurgical excision procedure for cervical neoplasia in rural India Rengaswamy Sankaranarayanan a,⁎, Vijay Keshkar b, Ashok Kothari b, Shubhada Kane c, Jean-Marie Fayette a, Surendra Shastri c a b c
Screening Group, International Agency for Research on Cancer, Lyon, France Nargis Dutt Memorial Cancer Hospital, Tata Memorial Centre Rural Cancer Extension Project, Barshi, Solapur District, Maharashtra, India Tata Memorial Centre, Parel, Mumbai, India
a r t i c l e
i n f o
Article history: Received 14 August 2008 Received in revised form 5 September 2008 Accepted 8 September 2008 Keywords: Cervical cancer Cervical intraepithelial neoplasia Cure Loop electrosurgical excision procedure Safety See-and-treat
a b s t r a c t Objective: To evaluate the effectiveness and safety of loop electrosurgical excision procedure (LEEP) to treat cervical intraepithelial neoplasia (CIN) in rural India. Method: Women with CIN colposcopic features unsuitable for cryotherapy were treated with LEEP using a “see-and-treat” approach. Women with unsatisfactory colposcopy had diagnostic LEEP. Cure was defined as no clinical or histologic evidence of CIN at 1-year follow-up. Factors influencing cure rates were evaluated by χ2 tests. Results: Of the 1141 women who underwent LEEP (569 see-and-treat; 572 unsatisfactory colposcopy), 634 had histologically proven CIN. Of those, 489 reported for follow-up and 459 (93.9%) had no evidence of disease. Cure rates were 98.1% for women with CIN 1, 93.6% for CIN 2, and 85.0% for CIN 3. Patients with CIN 2–3 had significantly lower cure rates. Conclusion: Cure rates for LEEP provided by newly trained doctors in rural India were similar to those reported in the gynecological literature. © 2008 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Loop electrosurgical excision procedure (LEEP), or large loop excision of the transformation zone (LLETZ), is the most widely used surgical treatment modality for cervical intraepithelial neoplasia (CIN) and has virtually replaced cold knife conization. Among CIN excision treatment modalities, LEEP is certainly the easiest to learn and the equipment required is less expensive than for laser. LEEP provides an excised tissue specimen for histology. Evidence from published studies from high-income countries [1–8] indicates that LEEP is associated with cure rates exceeding 90% [8]. However, it is not clear whether similar cure rates could be achieved for LEEP in lower-income countries. LEEP is increasingly used in a “see-andtreat” approach to diagnose and treat CIN thereby avoiding multiple visits and reducing noncompliance [9]. There has been very limited evaluation of the see-and-treat approach in lower-income countries [7]. We adapted the see-and-treat principles to achieve maximum compliance of women who screened positive for treatment of CIN in a randomized controlled screening trial in western India, which was designed to evaluate the impact of a single round of screening with
⁎ Corresponding author. Screening Group, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372, Lyon cedex 08, France. Tel.: +33 472 73 85 99; fax: +33 472 73 85 18. E-mail address: [email protected] (R. Sankaranarayanan).
conventional cytology, visual inspection with acetic acid (VIA), or human papillomavirus (HPV) testing (using the HC2 test) on cervical cancer incidence and mortality. The screening trial, a collaborative research project of Nargis Dutt Memorial Cancer Hospital (NDMCH), Barshi, India, Tata Memorial Centre (TMC), Mumbai, India, and the International Agency for Research on Cancer (IARC), Lyon, France, was reviewed and approved by the institutional ethical committees and the design and methodology have been published elsewhere [10,11]. The present study describes the results of the effectiveness and safety of LEEP in the treatment of CIN in the context of the population-based study described above. 2. Materials and methods Women who appeared healthy, were aged between 30 and 59 years, and with an intact uterus and no past history of cervical neoplasia were considered eligible to participate. Female health workers explained the study, risk factors, prevention, early detection, and treatment of cervical cancer to eligible women and obtained informed consent from all participants. Patients with positive test results on VIA, cytology or HPV testing were referred to the NDMCH for colposcopy and further management. Colposcopy and LEEP had never been widely practiced at the NDMCH—or anywhere else in Maharashtra State—before this screening trial study due to the lack of a cervical screening program and colposcopy services in the state. Hence, 5 doctors at NDMCH were trained in colposcopy and LEEP before initiation of this study using the
0020-7292/$ – see front matter © 2008 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2008.09.009
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R. Sankaranarayanan et al. / International Journal of Gynecology and Obstetrics 104 (2009) 95–99
IARC colposcopy manual [12]. The training allowed the doctors to develop skills in colposcopy, identifying and assessing the transformation zone (TZ) after application of acetic acid and Lugol's iodine, directing punch biopsies, discussing the results and management plans with the patient, performing LEEP, and follow-up care and follow-up evaluation of women post treatment. Colposcopy was carried out with a binocular colposcope using 6– 12 magnification, according to the IARC colposcopy manual [12]. In women whose squamocolumnar junction (SCJ) was fully visible after application of 4%–5% acetic acid, the colposcopic impression was based on the color tone, margins and surface characteristics of the acetowhite lesions, vascular features and growth, if any, and appearance after applying Lugol's iodine. The impression was then classified as normal, benign abnormalities, low- or high-grade CIN, or invasive cancer. LEEP was indicated for women with large ectocervical lesions involving more than 75% of the TZ, lesions that could not be covered adequately by a cryoprobe or lesions extending into the endocervical canal. In some women, punch biopsies were obtained before the LEEP. If the SCJ was not visible in its entirety, colposcopy was termed unsatisfactory and those women were further investigated with diagnostic LEEP. Before treatment the doctors explained the colposcopy results and the LEEP procedure, the potential benefits, adverse effects and complications, and encouraged each woman to accept immediate treatment. A detailed medical history was taken to exclude uncontrolled hypertension, diabetes mellitus, bleeding disorders, tendency for allergic reactions, exposure to diethylstilbestrol, and pregnancy.
After counseling, LEEP was performed under local anesthesia under colposcopic guidance as a day care procedure [12]. The cervix was exposed using an insulated vaginal speculum and was assessed after application of 4% acetic acid, followed by Lugol's iodine to delineate the distal limits of the lesion. Local anesthesia was applied by submucosal infiltration of 3–5 mL of 2% xylocaine with 1:100 000 epinephrine. The lesion and entire TZ were excised under colposcopic observation. Single, multiple, or 2-layer excisions were carried out depending on the clinical extent of the lesion. Hemostasis was obtained by fulgurating bleeding points using a 3- or 5-mm ball electrode. The rim of the wound was then fulgurated circumferentially and Monsel's paste was applied to the base of the wound. No routine postoperative intravaginal preparation or packing was used. The specimen was dispatched for histopathologic examination. Women were given home care instructions and informed that they could experience mild cramping or blood-stained discharge. They were advised to avoid vaginal douching or tampons, or sexual intercourse, for 1 month. They were also advised to return to the clinic immediately if they experienced any of the following for more than 2 days during the 4 weeks after treatment: fever, severe lower abdominal pain, foul-smelling greenish or yellow discharge, or bleeding with clots. All women were prescribed nonsteriodal antiinflammatory drugs for pain, and a routine course of presumptive antibiotic treatment with ciprofloxacin hydrochloride and tinidazole. The women were advised to attend for clinical follow-up 12 months after treatment to assess the cervix and to rule out cervical neoplasia. LEEP tissue specimens were processed by the pathologists at the NDMCH and pathologists from TMC provided quality assurance. As
Fig. 1. Flow chart of study procedures and results. Abbreviation: NED, no evidence of disease (cured).
R. Sankaranarayanan et al. / International Journal of Gynecology and Obstetrics 104 (2009) 95–99 Table 1 Colposcopy and LEEP specimen histology results for 1141 women treated with LEEP
Table 3 Final diagnosis in 1141 women treated with LEEP
Colposcopy impression LEEP resection specimen histology at enrolment Normal CIN 1 CIN 2 CIN 3 Cancer Inconclusive Total
Colposcopy impression at enrolment
Unsatisfactory colposcopy CIN 1 CIN 2–3 Cancer Total
Unsatisfactory CIN 1 CIN 2–3 Cancer Total
331 127 84 7 549
114 80 55 9 258
44 21 39 5 109
37
0
29 51 19 136
46
3 3 3 9
13 15 6 80
572 273 247 49 1141
part of quality assurance, processing of specimens in the laboratory, laboratory manuals, and reporting procedures were reviewed periodically, and technicians and pathologists were reoriented on a regular basis [10]. All those who did not report, or who reported less than 6 months after treatment but did not return afterwards, were considered lost to follow-up. At the follow-up clinics the women were assessed with cytology, HPV testing, VIA, and colposcopy; biopsies were taken from colposcopically abnormal areas. Women with confirmed disease at follow-up were treated depending on the characteristics of the lesion. The outcome of the evaluation was defined as cure if no CIN lesion was established histologically or if no colposcopic features of CIN were demonstrated. Cure rates were assessed among women reporting for follow-up. Mild pain or mild cramps during or after treatment, vasomotor symptoms of fainting and flushing during or immediately after treatment, mild bleeding or spotting immediately after treatment, a malodorous excessive discharge, menorrhagia, and fever/chills following treatment were all assumed to be adverse effects and indicators of acceptability [13]. Vasovagal reactions during treatment; vaginal burns, severe pain, cramps or bleeding during or after LEEP requiring further treatment; severe local cervical infections; unintended surgery within 4 weeks; pelvic inflammatory disease (PID); and functional cervical stenosis were assumed to be complications of treatment and an indicator of its safety [13]. Cure rates, adverse effects, and complications were reported as frequency percentages. Cure rates categorized by age, area of lesion, and grade of CIN were compared using χ2 tests. 3. Results A total of 1141 women received LEEP in this study during 2000– 2003. The study profile is shown in Fig. 1. LEEP was carried out within 2 weeks from the date of screening in 152 (13.3%) women, within 2– 4 weeks in 506 (44.4%), and after 1 month in 483 (42.3%). The distribution of colposcopy findings and histopathology results, based on LEEP resection specimens, are given in Table 1. The histologic results could not be assessed in 27 cases due to charring of specimens, and thus interpretation remained inconclusive. Punch biopsies were taken in 433 women with satisfactory colposcopy before LEEP
Table 2 Histologic agreement between punch biopsy and LEEP resection specimens in 433 women Punch biopsy histology
LEEP specimen histology Normal
CIN 1
CIN 2
CIN 3
Cancer
Inconclusive
Total
Normal CIN 1 CIN 2 CIN 3 Cancer Inconclusive Total
65 56 21 11 0 27 180
13 67 17 8 1 12 118
4 19 13 12 1 3 52
0 6 19 41 0 6 72
0 0 2 4 0 0 6
0 1 0 2 0 2 5
82 149 72 78 2 50 433
Agreement = 43.4; k = 0.27.
97
Final diagnosis based on histology of LEEP specimen or punch biopsy Normal
CIN 1
CIN 2
CIN 3
Cancer
Total
343 94 51 7 495
131 113 65 6 315
51 32 54 5 142
47 31 71 28 177
0 3 6 3 12
572 273 247 49 1141
resection. The agreement between punch biopsy and LEEP specimen histology in those 433 women is given in Table 2. The colposcopic impressions and final diagnoses among the 1141 women are given in Table 3. The final diagnosis was based on LEEP specimen histology when this was the only specimen available; when the LEEP specimen was inconclusive, punch biopsy was accepted for final diagnosis; and when both were available, the higher grade reported on either specimen was taken as the final diagnosis. The final diagnoses for the 572 women who had unsatisfactory colposcopy were: no evidence of CIN in 343 (60.0%), CIN 1 in 131 (22.9%), and CIN 2–3 in 98 (17.1%). Among the 569 women with a colposcopic diagnosis of low- or high-grade precancerous lesions, no evidence of CIN was found in 152 (26.7%), CIN 1 in 184 (32.3%), CIN 2–3 in 221 (38.8%), and occult invasive cancer in 12 (2.1%) (Table 3). The women with subclinical invasive cancer were referred for further investigations and treatment. Of the 634 women with a final diagnosis of CIN who had LEEP, 145 (22.9%) did not report for follow-up; the 489 (77.1%) who did, between 9 and 48 months after treatment, were included in the analysis of cure rates for LEEP (Fig. 1). The characteristics of those who were included (n = 489) and excluded (n = 145) in terms of age, menopausal status, lesion size, and grade were similar. The mean follow-up duration was 25 months. The disease status at follow-up was based on histology in 70 (14.3%) women and on colposcopy in 419 (85.7%). The distribution of follow-up status is given in Table 4: 459 (93.9%) women had no evidence of CIN; 98.1% (253/258) with CIN 1 were cured compared with 89.2% (206/231) of those with CIN 2–3 (P b 0.001). Cure rates for CIN according to age, area of cervix involved, menopausal status, and grade of lesion are given in Table 5. Women with CIN 2–3 had significantly lower cure rates (89.2%) compared with CIN 1 (98.1%, P b 0.001). Age, menopausal status, and area of lesion did not affect cure rates. The adverse effects observed were mild pain or cramps during or after treatment in 40 women (3.5%), mild bleeding in 18 (1.6%), malodorous excessive vaginal discharge following treatment in 6 (0.5%), menorrhagia in 3 (0.3%), and fever in 4 (0.4%). The complications recorded were severe postoperative bleeding requiring hysterectomy in 1 woman (0.09%), vaginal burns in 5 (0.4%), cervical inflammation in 5 (0.4%), and severe pelvic cramps and lower abdominal pain requiring parenteral medication in 2 (0.2%). There
Table 4 Follow-up status based on histology or colposcopy (range 9–48 months, mean followup 25 months) Follow-up status No. of women evaluated No evidence of disease (cured %) CIN 1 (%) CIN 2 (%) CIN 3 (%) Invasive cancer (%)
Baseline histology CIN 1
CIN 2
CIN 3
Total
258 253 (98.1) 4 (1.6) 0 (0.0) 1 (0.4) 0 (0.0)
110 103 6 0 1 0
121 103 9 1 7 1
489 459 (93.8) 19 (3.8) 1 (0.2) 9 (1.8) 1 (0.2)
(93.6) (5.5) (0.0) (0.9) (0.0)
(85.1) (7.5) (0.8) (5.8) (0.8)
98
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Table 5 Cure rates at follow-up according to characteristics of women at screening Characteristics
Cure rate, %
Age, y 30–39 40–59
94.2 (244/259) 93.5 (215/230)
0.74
Menopausal status Premenopause Postmenopause
93.8 (317/338) 94.0 (142/151)
0.91
Area of involvement of cervix by the lesiona b 25% 98.4 (60/61) ≥ 25% 92.3 (172/186) Grade if CINb CIN 1 CIN 2–3
98.1 (253/258) 89.2 (206/231)
P value for χ2 independent test
0.1
b0.001
were no instances of vasovagal reactions, severe bleeding requiring suturing or blood transfusion, PID requiring hospitalization, or functional cervical stenosis. 4. Discussion Successful cervical cancer screening programs and effective treatment are essential for the prevention of cervical cancer. Existing screening programs in lower-income countries have been less successful at reducing the burden of cervical cancer, in part caused by inadequate treatment coverage for women with CIN [14,15]. Considerable attention has been devoted to discussing the quality and limitations of screening tests and screening coverage, while practically no attention has been given to the important aspects of facilities, resources, coverage, and quality of CIN treatment when discussing the failure of existing cervical screening programs. The compromised and inadequate treatment coverage of detected lesions is often underemphasized and lack or inadequacy of well-trained staff to perform colposcopy and treatment is a major resource constraint. Important evidence has emerged that successful linkage of screening, diagnosis, and treatment of CIN can substantially reduce cervical cancer mortality in low-income country settings [16]. Our findings have important implications for the provision of LEEP in low-income countries. In 2.4% of our cases, LEEP specimens were charred and inadequate for histologic evaluation, which reflects the learning curve in providing satisfactory LEEP resection because most of these events occurred in the initial months. Although a quarter of the women who were treated could not be evaluated for cure given the difficulties in tracing women in low-income countries, our followup rates are satisfactory. Our results confirm that a see-and-treat approach combining colposcopy and LEEP in the same session by newly-trained doctors is acceptable to women and has been proven safe by the low frequency of adverse effects and complications. A quarter of women with a colposcopic impression of CIN had normal histologic results (ie, 1 out of 4 women were treated unnecessarily). At the same time, occult cancer was diagnosed in 2%. That 71% of women with a colposcopic impression of a precancerous lesion had a histologically confirmed CIN in the LEEP resection specimens indicates that competent colposcopy was provided. It was our policy to treat low-grade disease because our intervention is a once in a lifetime treatment owing to the difficulties in ensuring follow-up. Our results reflect treatment and safety outcomes that are similar to experiences reported from high-income countries, and cure rates for those with high-grade CIN were significantly lower than those for low-grade lesions. Our overall cure rate of 94% compares favorably with the 90%–95% from nonrandomized studies [1–6,8]. Adverse effects and complications were observed in a negligible proportion of women and none were major
or life threatening, which is similar to those reported in other studies [1–8,17–19]. Discordance between colposcopically directed biopsy and LEEP histology has been reported widely and the agreement between cervical biopsies and LEEP specimens in our study is in the lower range of agreement (46%–90%) reported in other studies [6,20–23]. Removal of small lesions by punch biopsy and the inflammatory reaction followed by application of Monsel's paste may be partly responsible for this discrepancy. Our findings, in addition to the results from other low-income countries [7,17,18], reinforce that LEEP can be performed effectively in low-resource settings with a low frequency of complications and high rates of disease control. The widespread use of LEEP for CIN, particularly in a see-and-treat setting, should be an important integral component of screening programs in low-income countries. Although affordable electrosurgical instruments are widely manufactured and marketed in many low-income countries, loop electrodes are still expensive. The possibility of making loop electrodes more affordable, the widespread training of doctors during their medical or in-service training, possibly providing nurses with experience of colposcopy, and increasing the skills and capacities of pathologists and pathology laboratories are important in the context of improving treatment coverage using the see-and-treat LEEP technique. From a public health perspective our results provide important evidence that adequately trained doctors in low-income countries can be trained to deliver see-and-treat services using LEEP in cervical screening programs. However, the quality of their inputs and outcomes should be closely and continuously monitored to ensure good quality services. Acknowledgments The authors gratefully acknowledge the generous support of the Bill & Melinda Gates Foundation, through the Alliance for Cervical Cancer Prevention.
References [1] Prendiville W, Cullimore J, Norman S. Large loop excision of the transformation zone (LLETZ). A new method of management for women with cervical intraepithelial neoplasia. Br J Obstet Gynaecol 1989;96(9):1054–60. [2] Bigrigg MA, Codling BW, Pearson P, Read MD, Swingler GR. Colposcopic diagnosis and treatment of cervical dysplasia at a single clinic visit. Experience of lowvoltage diathermy loop in 1000 patients. Lancet 1990;336(8709):229–31. [3] Luesley DM, Cullimore J, Redman CW, Lawton FG, Emens JM, Rollason TP, et al. Loop diathermy excision of the cervical transformation zone in patients with abnormal cervical smears. BMJ 1990;300(6741):1690–3. [4] Whiteley PF, Oláh KS. Treatment of cervical intraepithelial neoplasia: experience with the low-voltage diathermy loop. Am J Obstet Gynecol 1990;162(5):1272–7. [5] Wright Jr TC, Gagnon S, Richart RM, Ferenczy A. Treatment of cervical intraepithelial neoplasia using the loop electrosurgical excision procedure. Obstet Gynecol 1992;79(2):173–8. [6] Ferris DG, Hainer BL, Pfenninger JL, Zuber TJ, DeWitt DE, Line RL. Electrosurgical loop excision of the cervical transformation zone: the experience of family physicians. J Fam Pract 1995;41(4):337–44. [7] Santos C, Galdos R, Alvarez M, Valarde C, Barriga O, Dyer R, et al. One-session management of cervical intraepithelial neoplasia: a solution for developing countries. A prospective, randomized trial of LEEP versus laser excisional conization. Gynecol Oncol 1996;61(1):11–5. [8] Martin-Hirsch PL, Paraskevaidis E, Kitchener H. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev 2002(2):CD001318. [9] Ferris DG, Hainer BL, Pfenninger JL, Zuber TJ. ‘See and treat’ electrosurgical loop excision of the cervical transformation zone. J Fam Pract 1996;42(3):253–7. [10] Sankaranarayanan R, Nene BM, Dinshaw KA, Mahe C, Jayant K, Shastri SS, et al. A cluster randomized controlled trial of visual, cytology and human papillomavirus screening for cancer of the cervix in rural India. Int J Cancer 2005;116(4):617–23. [11] Nene B, Jayant K, Arrossi S, Shastri S, Budukh A, Hingmire S, et al. Determinants of women's participation in cervical cancer screening trial in the state of Maharashtra, India. Bull World Health Organ 2007;85:264–72. [12] Sellors J, Sankaranarayanan R, editors. Colposcopy and treatment of cervical intraepithelial neoplasia: A beginners' manual. Lyon: IARC Press; 2003. [13] Castro W, Gage J, Gaffikin L, Ferreccio C, Sellors J, Sherris J, et al. Effectiveness, safety, and acceptability of cryotherapy: a systematic literature review. Cervical
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Cancer Prevention Issues in Depth, vol. 1. Alliance for Cervical Cancer Prevention; 2003. Available at: http://www.path.org/publications/details.php?i=687. Sankaranarayanan R, Budukh AM, Rajkumar R. Effective screening programmes for cervical cancer in low- and middle-income developing countries. Bull World Health Organ 2001;79(10):954–62. International Agency for Research on Cancer (IARC). Cervix cancer screening. IARC handbooks on cancer prevention, vol 10. Lyon: IARC Press; 2004. Sankaranarayanan R, Esmy PO, Rajkumar R, Muwonge R, Swaminathan R, Shanthakumari S, et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomised trial. Lancet 2007;370 (9585):398–406. Lee KE, Koh CF, Watt WF. Outpatient procedures for cervical dysplasia: a 3 year review of laser vaporisation and LEEP. Med J Malays 1999;54(1):47–51. Kietpeerakool C, Srisomboon J, Khobjai A, Chandacham A, Tucksinsook U. Complications of loop electrosurgical excision procedure for cervical neoplasia: a prospective study. J Med Assoc Thai 2006;89(5):583–7.
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[19] Kietpeerakool C, Srisomboon J, Suprasert P, Phongnarisorn C, Charoenkwan K, Cheewakriangkrai C, et al. Outcomes of loop electrosurgical excision procedure for cervical neoplasia in human immunodeficiency virus-infected women. Int J Gynecol Cancer 2006;16(3):1082–8. [20] Buxton EJ, Luesley DM, Shafi MI, Rollason M. Colposcopically directed punch biopsy: a potentially misleading investigation. Br J Obstet Gynaecol 1991;98(12): 1273–6. [21] Howe DT, Vincenti AC. Is large loop excision of the transformation zone (LLETZ) more accurate than colposcopically directed punch biopsy in the diagnosis of cervical intraepithelial neoplasia? Br J Obstet Gynaecol 1991;98(6):588–91. [22] Bonardi R, Cecchini S, Grazzini G, Ciatto S. Loop electrosurgical excision procedure of the transformation zone and colposcopically directed punch biopsy in the diagnosis of cervical lesions. Obstet Gynecol 1992;80(6):1020–2. [23] Lee KE, Koh CF, Watt WF. Comparison of the grade of CIN in colposcopically directed biopsies with that in outpatient loop electrosurgical excision procedure (LEEP) specimens – a retrospective review. Singap Med J 1999;40(11):694–6.
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Effectiveness and safety of loop electrosurgical excision procedure for cervical neoplasia in rural India Rengaswamy Sankaranarayanan a,⁎, Vijay Keshkar b, Ashok Kothari b, Shubhada Kane c, Jean-Marie Fayette a, Surendra Shastri c a b c
Screening Group, International Agency for Research on Cancer, Lyon, France Nargis Dutt Memorial Cancer Hospital, Tata Memorial Centre Rural Cancer Extension Project, Barshi, Solapur District, Maharashtra, India Tata Memorial Centre, Parel, Mumbai, India
a r t i c l e
i n f o
Article history: Received 14 August 2008 Received in revised form 5 September 2008 Accepted 8 September 2008 Keywords: Cervical cancer Cervical intraepithelial neoplasia Cure Loop electrosurgical excision procedure Safety See-and-treat
a b s t r a c t Objective: To evaluate the effectiveness and safety of loop electrosurgical excision procedure (LEEP) to treat cervical intraepithelial neoplasia (CIN) in rural India. Method: Women with CIN colposcopic features unsuitable for cryotherapy were treated with LEEP using a “see-and-treat” approach. Women with unsatisfactory colposcopy had diagnostic LEEP. Cure was defined as no clinical or histologic evidence of CIN at 1-year follow-up. Factors influencing cure rates were evaluated by χ2 tests. Results: Of the 1141 women who underwent LEEP (569 see-and-treat; 572 unsatisfactory colposcopy), 634 had histologically proven CIN. Of those, 489 reported for follow-up and 459 (93.9%) had no evidence of disease. Cure rates were 98.1% for women with CIN 1, 93.6% for CIN 2, and 85.0% for CIN 3. Patients with CIN 2–3 had significantly lower cure rates. Conclusion: Cure rates for LEEP provided by newly trained doctors in rural India were similar to those reported in the gynecological literature. © 2008 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Loop electrosurgical excision procedure (LEEP), or large loop excision of the transformation zone (LLETZ), is the most widely used surgical treatment modality for cervical intraepithelial neoplasia (CIN) and has virtually replaced cold knife conization. Among CIN excision treatment modalities, LEEP is certainly the easiest to learn and the equipment required is less expensive than for laser. LEEP provides an excised tissue specimen for histology. Evidence from published studies from high-income countries [1–8] indicates that LEEP is associated with cure rates exceeding 90% [8]. However, it is not clear whether similar cure rates could be achieved for LEEP in lower-income countries. LEEP is increasingly used in a “see-andtreat” approach to diagnose and treat CIN thereby avoiding multiple visits and reducing noncompliance [9]. There has been very limited evaluation of the see-and-treat approach in lower-income countries [7]. We adapted the see-and-treat principles to achieve maximum compliance of women who screened positive for treatment of CIN in a randomized controlled screening trial in western India, which was designed to evaluate the impact of a single round of screening with
⁎ Corresponding author. Screening Group, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372, Lyon cedex 08, France. Tel.: +33 472 73 85 99; fax: +33 472 73 85 18. E-mail address: [email protected] (R. Sankaranarayanan).
conventional cytology, visual inspection with acetic acid (VIA), or human papillomavirus (HPV) testing (using the HC2 test) on cervical cancer incidence and mortality. The screening trial, a collaborative research project of Nargis Dutt Memorial Cancer Hospital (NDMCH), Barshi, India, Tata Memorial Centre (TMC), Mumbai, India, and the International Agency for Research on Cancer (IARC), Lyon, France, was reviewed and approved by the institutional ethical committees and the design and methodology have been published elsewhere [10,11]. The present study describes the results of the effectiveness and safety of LEEP in the treatment of CIN in the context of the population-based study described above. 2. Materials and methods Women who appeared healthy, were aged between 30 and 59 years, and with an intact uterus and no past history of cervical neoplasia were considered eligible to participate. Female health workers explained the study, risk factors, prevention, early detection, and treatment of cervical cancer to eligible women and obtained informed consent from all participants. Patients with positive test results on VIA, cytology or HPV testing were referred to the NDMCH for colposcopy and further management. Colposcopy and LEEP had never been widely practiced at the NDMCH—or anywhere else in Maharashtra State—before this screening trial study due to the lack of a cervical screening program and colposcopy services in the state. Hence, 5 doctors at NDMCH were trained in colposcopy and LEEP before initiation of this study using the
0020-7292/$ – see front matter © 2008 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2008.09.009
96
R. Sankaranarayanan et al. / International Journal of Gynecology and Obstetrics 104 (2009) 95–99
IARC colposcopy manual [12]. The training allowed the doctors to develop skills in colposcopy, identifying and assessing the transformation zone (TZ) after application of acetic acid and Lugol's iodine, directing punch biopsies, discussing the results and management plans with the patient, performing LEEP, and follow-up care and follow-up evaluation of women post treatment. Colposcopy was carried out with a binocular colposcope using 6– 12 magnification, according to the IARC colposcopy manual [12]. In women whose squamocolumnar junction (SCJ) was fully visible after application of 4%–5% acetic acid, the colposcopic impression was based on the color tone, margins and surface characteristics of the acetowhite lesions, vascular features and growth, if any, and appearance after applying Lugol's iodine. The impression was then classified as normal, benign abnormalities, low- or high-grade CIN, or invasive cancer. LEEP was indicated for women with large ectocervical lesions involving more than 75% of the TZ, lesions that could not be covered adequately by a cryoprobe or lesions extending into the endocervical canal. In some women, punch biopsies were obtained before the LEEP. If the SCJ was not visible in its entirety, colposcopy was termed unsatisfactory and those women were further investigated with diagnostic LEEP. Before treatment the doctors explained the colposcopy results and the LEEP procedure, the potential benefits, adverse effects and complications, and encouraged each woman to accept immediate treatment. A detailed medical history was taken to exclude uncontrolled hypertension, diabetes mellitus, bleeding disorders, tendency for allergic reactions, exposure to diethylstilbestrol, and pregnancy.
After counseling, LEEP was performed under local anesthesia under colposcopic guidance as a day care procedure [12]. The cervix was exposed using an insulated vaginal speculum and was assessed after application of 4% acetic acid, followed by Lugol's iodine to delineate the distal limits of the lesion. Local anesthesia was applied by submucosal infiltration of 3–5 mL of 2% xylocaine with 1:100 000 epinephrine. The lesion and entire TZ were excised under colposcopic observation. Single, multiple, or 2-layer excisions were carried out depending on the clinical extent of the lesion. Hemostasis was obtained by fulgurating bleeding points using a 3- or 5-mm ball electrode. The rim of the wound was then fulgurated circumferentially and Monsel's paste was applied to the base of the wound. No routine postoperative intravaginal preparation or packing was used. The specimen was dispatched for histopathologic examination. Women were given home care instructions and informed that they could experience mild cramping or blood-stained discharge. They were advised to avoid vaginal douching or tampons, or sexual intercourse, for 1 month. They were also advised to return to the clinic immediately if they experienced any of the following for more than 2 days during the 4 weeks after treatment: fever, severe lower abdominal pain, foul-smelling greenish or yellow discharge, or bleeding with clots. All women were prescribed nonsteriodal antiinflammatory drugs for pain, and a routine course of presumptive antibiotic treatment with ciprofloxacin hydrochloride and tinidazole. The women were advised to attend for clinical follow-up 12 months after treatment to assess the cervix and to rule out cervical neoplasia. LEEP tissue specimens were processed by the pathologists at the NDMCH and pathologists from TMC provided quality assurance. As
Fig. 1. Flow chart of study procedures and results. Abbreviation: NED, no evidence of disease (cured).
R. Sankaranarayanan et al. / International Journal of Gynecology and Obstetrics 104 (2009) 95–99 Table 1 Colposcopy and LEEP specimen histology results for 1141 women treated with LEEP
Table 3 Final diagnosis in 1141 women treated with LEEP
Colposcopy impression LEEP resection specimen histology at enrolment Normal CIN 1 CIN 2 CIN 3 Cancer Inconclusive Total
Colposcopy impression at enrolment
Unsatisfactory colposcopy CIN 1 CIN 2–3 Cancer Total
Unsatisfactory CIN 1 CIN 2–3 Cancer Total
331 127 84 7 549
114 80 55 9 258
44 21 39 5 109
37
0
29 51 19 136
46
3 3 3 9
13 15 6 80
572 273 247 49 1141
part of quality assurance, processing of specimens in the laboratory, laboratory manuals, and reporting procedures were reviewed periodically, and technicians and pathologists were reoriented on a regular basis [10]. All those who did not report, or who reported less than 6 months after treatment but did not return afterwards, were considered lost to follow-up. At the follow-up clinics the women were assessed with cytology, HPV testing, VIA, and colposcopy; biopsies were taken from colposcopically abnormal areas. Women with confirmed disease at follow-up were treated depending on the characteristics of the lesion. The outcome of the evaluation was defined as cure if no CIN lesion was established histologically or if no colposcopic features of CIN were demonstrated. Cure rates were assessed among women reporting for follow-up. Mild pain or mild cramps during or after treatment, vasomotor symptoms of fainting and flushing during or immediately after treatment, mild bleeding or spotting immediately after treatment, a malodorous excessive discharge, menorrhagia, and fever/chills following treatment were all assumed to be adverse effects and indicators of acceptability [13]. Vasovagal reactions during treatment; vaginal burns, severe pain, cramps or bleeding during or after LEEP requiring further treatment; severe local cervical infections; unintended surgery within 4 weeks; pelvic inflammatory disease (PID); and functional cervical stenosis were assumed to be complications of treatment and an indicator of its safety [13]. Cure rates, adverse effects, and complications were reported as frequency percentages. Cure rates categorized by age, area of lesion, and grade of CIN were compared using χ2 tests. 3. Results A total of 1141 women received LEEP in this study during 2000– 2003. The study profile is shown in Fig. 1. LEEP was carried out within 2 weeks from the date of screening in 152 (13.3%) women, within 2– 4 weeks in 506 (44.4%), and after 1 month in 483 (42.3%). The distribution of colposcopy findings and histopathology results, based on LEEP resection specimens, are given in Table 1. The histologic results could not be assessed in 27 cases due to charring of specimens, and thus interpretation remained inconclusive. Punch biopsies were taken in 433 women with satisfactory colposcopy before LEEP
Table 2 Histologic agreement between punch biopsy and LEEP resection specimens in 433 women Punch biopsy histology
LEEP specimen histology Normal
CIN 1
CIN 2
CIN 3
Cancer
Inconclusive
Total
Normal CIN 1 CIN 2 CIN 3 Cancer Inconclusive Total
65 56 21 11 0 27 180
13 67 17 8 1 12 118
4 19 13 12 1 3 52
0 6 19 41 0 6 72
0 0 2 4 0 0 6
0 1 0 2 0 2 5
82 149 72 78 2 50 433
Agreement = 43.4; k = 0.27.
97
Final diagnosis based on histology of LEEP specimen or punch biopsy Normal
CIN 1
CIN 2
CIN 3
Cancer
Total
343 94 51 7 495
131 113 65 6 315
51 32 54 5 142
47 31 71 28 177
0 3 6 3 12
572 273 247 49 1141
resection. The agreement between punch biopsy and LEEP specimen histology in those 433 women is given in Table 2. The colposcopic impressions and final diagnoses among the 1141 women are given in Table 3. The final diagnosis was based on LEEP specimen histology when this was the only specimen available; when the LEEP specimen was inconclusive, punch biopsy was accepted for final diagnosis; and when both were available, the higher grade reported on either specimen was taken as the final diagnosis. The final diagnoses for the 572 women who had unsatisfactory colposcopy were: no evidence of CIN in 343 (60.0%), CIN 1 in 131 (22.9%), and CIN 2–3 in 98 (17.1%). Among the 569 women with a colposcopic diagnosis of low- or high-grade precancerous lesions, no evidence of CIN was found in 152 (26.7%), CIN 1 in 184 (32.3%), CIN 2–3 in 221 (38.8%), and occult invasive cancer in 12 (2.1%) (Table 3). The women with subclinical invasive cancer were referred for further investigations and treatment. Of the 634 women with a final diagnosis of CIN who had LEEP, 145 (22.9%) did not report for follow-up; the 489 (77.1%) who did, between 9 and 48 months after treatment, were included in the analysis of cure rates for LEEP (Fig. 1). The characteristics of those who were included (n = 489) and excluded (n = 145) in terms of age, menopausal status, lesion size, and grade were similar. The mean follow-up duration was 25 months. The disease status at follow-up was based on histology in 70 (14.3%) women and on colposcopy in 419 (85.7%). The distribution of follow-up status is given in Table 4: 459 (93.9%) women had no evidence of CIN; 98.1% (253/258) with CIN 1 were cured compared with 89.2% (206/231) of those with CIN 2–3 (P b 0.001). Cure rates for CIN according to age, area of cervix involved, menopausal status, and grade of lesion are given in Table 5. Women with CIN 2–3 had significantly lower cure rates (89.2%) compared with CIN 1 (98.1%, P b 0.001). Age, menopausal status, and area of lesion did not affect cure rates. The adverse effects observed were mild pain or cramps during or after treatment in 40 women (3.5%), mild bleeding in 18 (1.6%), malodorous excessive vaginal discharge following treatment in 6 (0.5%), menorrhagia in 3 (0.3%), and fever in 4 (0.4%). The complications recorded were severe postoperative bleeding requiring hysterectomy in 1 woman (0.09%), vaginal burns in 5 (0.4%), cervical inflammation in 5 (0.4%), and severe pelvic cramps and lower abdominal pain requiring parenteral medication in 2 (0.2%). There
Table 4 Follow-up status based on histology or colposcopy (range 9–48 months, mean followup 25 months) Follow-up status No. of women evaluated No evidence of disease (cured %) CIN 1 (%) CIN 2 (%) CIN 3 (%) Invasive cancer (%)
Baseline histology CIN 1
CIN 2
CIN 3
Total
258 253 (98.1) 4 (1.6) 0 (0.0) 1 (0.4) 0 (0.0)
110 103 6 0 1 0
121 103 9 1 7 1
489 459 (93.8) 19 (3.8) 1 (0.2) 9 (1.8) 1 (0.2)
(93.6) (5.5) (0.0) (0.9) (0.0)
(85.1) (7.5) (0.8) (5.8) (0.8)
98
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Table 5 Cure rates at follow-up according to characteristics of women at screening Characteristics
Cure rate, %
Age, y 30–39 40–59
94.2 (244/259) 93.5 (215/230)
0.74
Menopausal status Premenopause Postmenopause
93.8 (317/338) 94.0 (142/151)
0.91
Area of involvement of cervix by the lesiona b 25% 98.4 (60/61) ≥ 25% 92.3 (172/186) Grade if CINb CIN 1 CIN 2–3
98.1 (253/258) 89.2 (206/231)
P value for χ2 independent test
0.1
b0.001
were no instances of vasovagal reactions, severe bleeding requiring suturing or blood transfusion, PID requiring hospitalization, or functional cervical stenosis. 4. Discussion Successful cervical cancer screening programs and effective treatment are essential for the prevention of cervical cancer. Existing screening programs in lower-income countries have been less successful at reducing the burden of cervical cancer, in part caused by inadequate treatment coverage for women with CIN [14,15]. Considerable attention has been devoted to discussing the quality and limitations of screening tests and screening coverage, while practically no attention has been given to the important aspects of facilities, resources, coverage, and quality of CIN treatment when discussing the failure of existing cervical screening programs. The compromised and inadequate treatment coverage of detected lesions is often underemphasized and lack or inadequacy of well-trained staff to perform colposcopy and treatment is a major resource constraint. Important evidence has emerged that successful linkage of screening, diagnosis, and treatment of CIN can substantially reduce cervical cancer mortality in low-income country settings [16]. Our findings have important implications for the provision of LEEP in low-income countries. In 2.4% of our cases, LEEP specimens were charred and inadequate for histologic evaluation, which reflects the learning curve in providing satisfactory LEEP resection because most of these events occurred in the initial months. Although a quarter of the women who were treated could not be evaluated for cure given the difficulties in tracing women in low-income countries, our followup rates are satisfactory. Our results confirm that a see-and-treat approach combining colposcopy and LEEP in the same session by newly-trained doctors is acceptable to women and has been proven safe by the low frequency of adverse effects and complications. A quarter of women with a colposcopic impression of CIN had normal histologic results (ie, 1 out of 4 women were treated unnecessarily). At the same time, occult cancer was diagnosed in 2%. That 71% of women with a colposcopic impression of a precancerous lesion had a histologically confirmed CIN in the LEEP resection specimens indicates that competent colposcopy was provided. It was our policy to treat low-grade disease because our intervention is a once in a lifetime treatment owing to the difficulties in ensuring follow-up. Our results reflect treatment and safety outcomes that are similar to experiences reported from high-income countries, and cure rates for those with high-grade CIN were significantly lower than those for low-grade lesions. Our overall cure rate of 94% compares favorably with the 90%–95% from nonrandomized studies [1–6,8]. Adverse effects and complications were observed in a negligible proportion of women and none were major
or life threatening, which is similar to those reported in other studies [1–8,17–19]. Discordance between colposcopically directed biopsy and LEEP histology has been reported widely and the agreement between cervical biopsies and LEEP specimens in our study is in the lower range of agreement (46%–90%) reported in other studies [6,20–23]. Removal of small lesions by punch biopsy and the inflammatory reaction followed by application of Monsel's paste may be partly responsible for this discrepancy. Our findings, in addition to the results from other low-income countries [7,17,18], reinforce that LEEP can be performed effectively in low-resource settings with a low frequency of complications and high rates of disease control. The widespread use of LEEP for CIN, particularly in a see-and-treat setting, should be an important integral component of screening programs in low-income countries. Although affordable electrosurgical instruments are widely manufactured and marketed in many low-income countries, loop electrodes are still expensive. The possibility of making loop electrodes more affordable, the widespread training of doctors during their medical or in-service training, possibly providing nurses with experience of colposcopy, and increasing the skills and capacities of pathologists and pathology laboratories are important in the context of improving treatment coverage using the see-and-treat LEEP technique. From a public health perspective our results provide important evidence that adequately trained doctors in low-income countries can be trained to deliver see-and-treat services using LEEP in cervical screening programs. However, the quality of their inputs and outcomes should be closely and continuously monitored to ensure good quality services. Acknowledgments The authors gratefully acknowledge the generous support of the Bill & Melinda Gates Foundation, through the Alliance for Cervical Cancer Prevention.
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