Volume 103, Issue 3, Pages 232-236 (December 2008)

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Effectiveness, safety, and acceptability of cryotherapy by midwives for cervical intraepithelial neoplasia in Maharashtra, India

Received 27 May 2008; received in revised form 23 July 2008; accepted 25 July 2008. published online 26 September 2008.

Abstract

Objective

To evaluate the effectiveness, safety, and acceptability of cryotherapy for cervical intraepithelial neoplasia (CIN) when provided by trained midwives in rural India.

Method

Women with colposcopic findings of CIN lesions suitable for ablative treatment received cryotherapy from trained midwives before the biopsy results were known. Cure rates, adverse effects, and complications were assessed and factors influencing cure rates were evaluated by tests. Cure was defined as no clinical or histologic evidence of CIN lesions 6 or more months after treatment.

Results

Of 1068 women treated with cryotherapy, 728 had histologically proven CIN in their pretreatment biopsy specimens; of the 574 reporting for follow-up, 538 (93.7%) were cured (95% confidence interval [CI], 92.1%–96.3%). Cure rates were 96.4% (95% CI, 94.6%–98.1%) for CIN 1 and 82.1% (95% CI, 74.7%–89.4%) for CIN 2 and CIN 3 lesions combined. Minor adverse effects were documented in 5.2% of the women.

Conclusion

Cryotherapy provided by midwives was found to be safe, effective, and acceptable by the women.

Keywords: Cervical cancer, Cervical intraepithelial neoplasia, Cryotherapy, Screening, Safety

Article Outline

• Abstract

• 1. Introduction

• 2. Materials and methods

• 3. Results

• 4. Discussion

• Acknowledgment

• References

• Copyright

1. Introduction

The evidence from published studies, carried out almost exclusively in low-income countries, indicates that cryotherapy provided by physicians is a safe and effective method for the outpatient treatment of cervical intraepithelial neoplasia (CIN), with cure rates exceeding 86% for CIN confined to the visible part of the cervix [1], [2], [3]. Although results from a large study conducted in Southern India were recently published [4], there is still limited information on the effectiveness of cryotherapy in low-income countries.

We are reporting on a substudy within a large trial carried out by the Nargis Dutt Memorial Cancer Hospital (NDMCH), Barshi, India, the Tata Memorial Centre (TMC), Mumbai, India, and the International Agency for Research on Cancer (IARC), Lyon, France, after approval from the institutional scientific and ethical review committees.

This collaborative research project involved 142000 women from 52 village clusters. The women (age, 30–59 years) were randomized to 4 arms (visual inspection with 4% acetic acid (VIA), cytologic testing, human papillomavirus [HPV] testing, or no screening) to evaluate the effectiveness of a single round of screening by trained nurse-midwives in reducing cervical cancer incidence and mortality in Osmanabad district, Western India [5], [6]. The women who screened positive underwent colposcopy, a biopsy, and treatment at NDMCH. Those found to have a CIN lesion were treated with cryotherapy or the loop electrosurgical excision procedure.

In the present article we report on the safety, effectiveness, and acceptability of double-freeze cryotherapy by trained midwives.

2. Materials and methods

Women aged between 30 and 59 years, with an intact uterus and no history of CIN, were identified from listings of households in clusters of villages and randomized to VIA, cytologic testing, or HPV testing by the hybrid capture 2 assay, or to act as controls and receive no screening [5]. Female health workers explained the risk factors, prevention, early detection, and treatment of cervical cancer and the purpose of the study to the eligible women. The health workers then read out and explained a printed consent form and obtained the signature (or left thumb impression) of the women accepting to participate.

Nine auxiliary nurse-midwives with 2 years of nursing education were trained in an intensive 3-week course using manuals prepared by the IARC [3], [7]. The training included lectures, discussions, review of photographs of normal and abnormal cervices; learning how to collect samples for cytologic and HPV testing and how to perform VIA and cryotherapy; and observing colposcopy and colposcopy-guided biopsy procedures [5]. This training also allowed the nurse-midwives to develop skills in taking gynecologic history, visualizing the cervix, recognizing the squamocolumnar junction (SCJ) and the transformation zone, discussing results and management plans with the women, and counseling them on follow-up care. The nurse-midwives were supervised and their performance was regularly reviewed by physicians. Refresher courses were conducted every 3 months to maintain competency.

The women were invited for screening in field clinics organized in the villages' primary health centers, municipal offices, or schools. A physician (a gynecologist, clinical oncologist, or general practitioner) supervised the functioning of the field clinics. In the VIA group the women testing positive underwent colposcopy and, on the basis of the colposcopic impression, directed biopsy in the same session. They were then referred to the NDMCH for cryotherapy. In the cytologic testing and HPV testing groups, the women found positive were referred to the NDMCH for colposcopy, colposcopy-guided biopsy, and cryotherapy.

Colposcopy was carried out by trained doctors with a binocular colposcope using 6–12 magnification, following the IARC manual on colposcopy [3]. If the SCJ was not visible in its entirety, colposcopy was considered unsatisfactory and the women underwent a diagnostic large loop excision of the transformation zone. In women with a fully visible SCJ, the colposcopic impression was based on the aspect of the acetowhite lesions, if any, their color, margins, and surface characteristics; vascular features such as punctation, mosaic, atypical vessels, and atypical vessels growth; and appearance following the application of Lugol's iodine [3]. The impression was then classified as normal; benign abnormalities (in the presence of an ectropion, a polyp, cervicitis, or atrophy); low-grade lesion; high-grade lesion; or invasive cancer. Punch biopsies were obtained from the abnormal areas using a Tischler punch biopsy forceps under colposcopic guidance.

Women with colposcopic features of precancerous lesions were advised to undergo cryotherapy immediately after a colposcopy-guided biopsy, and thus before the biopsy results were known, when all the following criteria were met: the lesion was visible in its entirety, it involved 3 quadrants of the cervix or less, it did not involve the endocervical canal or vaginal wall, it could be covered by the cryoprobe, and there was no suspicion of invasive cancer. Women with lesions not suitable for cryotherapy were advised to undergo surgical excision at the NDMCH.

The midwives explained the colposcopic findings and the potential benefits, adverse effects, and complications of the cryotherapy procedure, and encouraged the eligible women to accept immediate treatment. Without local anesthesia, sedation, or analgesics, they then performed the procedure with a 20- or 24-mm ectocervical cryoprobe using nitrous oxide refrigerant.

The cryoprobe tip was washed in a saline solution and then firmly applied to the cervix to ensure good contact. A double-freeze technique involving a 3-minute freeze, a 5-minute thaw, and a second 3-minute freeze was used [3], and care was taken to prevent the tip from touching the vagina. Time was allowed for thawing before removing the probe from the cervix following the second 3-minute freeze. The cervix and vagina were then examined for bleeding (particularly from the biopsy site) or for any accidental vaginal freezing.

The women were given home care instructions and were provided with a supply of sanitary pads to protect their clothes. They were advised that they could experience mild cramping or a clear or slightly bloody watery discharge for up to 4 to 6 weeks, and to avoid vaginal douching or tampons, or sexual intercourse, for 4 weeks. They were also advised to report to the clinic if they experienced any of the following for more than 2 days during the 4 weeks following treatment: fever, severe lower abdominal pain, a foul-smelling greenish or yellow discharge, or bleeding with clots. All treated women received presumptive antibiotic treatment with ciprofloxacin hydrochloride and tinidozole for 5 days.

The biopsy results were reported by NDMCH pathologists, with TMC pathologists providing quality assurance. As part of quality assurance, the processing of specimens in the laboratory, the laboratory manuals, and the reporting procedures were periodically reviewed, and the technicians and pathologists periodically retrained [5]. Slide samples were reviewed for reproducibility by pathologists from TMC and the University of Lyon, France [5].

Treated women were requested to report for follow-up 3 months and 1 year after treatment. At 3 months, their well-being was assessed and an inspection of the cervix was performed to determine whether the wound had healed and whether gross abnormalities were present. At 1 year, they were examined for CIN lesions. The women who did not report for a follow-up visit within 6 months of treatment were considered lost to follow-up.

The women who reported for follow-up underwent VIA, cytologic testing, HPV testing, or colposcopy, and colposcopy-guided biopsies were taken from areas appearing abnormal on colposcopy. Those with confirmed CIN were treated with repeated cryotherapy or excision, depending on lesion characteristics. The outcome of the evaluation was classified as cure if no CIN was established histologically or, in women who did not have a biopsy, if there were no colposcopic features of CIN.

Expected adverse effects and indicators of acceptability were mild pain, cramps, fainting, and flushing during or after treatment; mild bleeding or spotting immediately after treatment; or a malodorous, excessive discharge following treatment [1]. Vasovagal reactions during the procedure, severe pain; severe cramping or severe bleeding during or after the procedure and requiring further treatment; severe cervical infections; unintended surgical intervention within 4 weeks of the procedure; pelvic inflammatory disease; and functional cervical stenosis were considered treatment complications and were the items of the safety index [1]. 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 the statistic.

3. Results

Colposcopic impression and biopsy results for 1068 women treated with cryotherapy before the results were known are given in Table 1 and Fig. 1. There were 728 women (68.2%) with histologically proven CIN lesions (590 had CIN 1 and 138 had CIN 2 or CIN 3 lesions). One woman with subclinical invasive cancer was referred for cancer treatment.

Table 1.

Colposcopic and histologic findings in 1068 women treated with cryotherapy for suspected cervical neoplasiaa


Biopsy results	Colposcopic impression at enrollment		Total
	Low-grade lesion (n=912)	High-grade lesion (n=156)
No evidence of CIN	313 (34.3)	26 (16.7)	339 (31.8)
CIN 1	511 (56.0)	79 (50.6)	590 (55.2)
CIN 2	61 (6.7)	30 (19.2)	91 (8.5)
CIN 3	26 (2.9)	21 (13.5)	47 (4.4)
Invasive cancer	1 (0.1)	0	1 (0.1)

Abbreviation: CIN, cervical intraepithelial neoplasia.

Values are given as number (percentage); cryotherapy was performed before the biopsy results were known.

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Figure 1. Flow chart of study procedures and results. NED indicates no evidence of disease (ie, the lesions were cured).

Of the 728 women with histologically proven CIN, 154 (21.2%) did not report for follow-up within 6 months of treatment and were considered lost to follow-up. The 574 women (78.8%) included in the analyses of adverse effects, complications, and cure rates (Fig. 1) were followed up for a mean of 30 months. The last follow-up visit was between 8 and 12 months for 20 women (3.5%); between 12 and 24 months for 109 women (19.0%); between 24 and 36 months for 174 women (29.6%); and more than 36 months for 275 women (47.9%). The 574 women who reported for follow-up and the 154 women lost to follow-up were similar regarding age, lesion size, and CIN grade (Table 2).

Table 2.

Characteristics of the fully participating women and those lost to follow-upa


Characteristic	Lost to follow-up (n=154)	Fully participating women (n=574)	P value
Age of participant, y
30–39	116 (75.3)	450 (78.4)	0.42
≥40	38 (24.7)	124 (21.6)
Cervical involvementb
<25%	61 (58.6)	218 (58.1)	0.97
≥25%	43 (41.4)	157 (41.9)
Lesion grade
CIN 1	122 (79.2)	468 (81.5)	0.52
CIN 2 or CIN 3	32 (20.8)	106 (18.5)

Abbreviation: CIN, cervical intraepithelial neoplasia.

Values are given as percentage unless otherwise indicated.

The information was missing in 199 cases.

The follow-up status of the 115 women (20.0%) treated on the basis of their histologic finding and of the 459 women (80.0%) treated on the basis of the colposcopic impression is given in Table 3. There was no evidence of CIN in 538 women (93.7%) who were then considered cured (95% confidence interval [CI], 92.1%–96.3%); the cure rate was 96.4% (95% CI, 94.6%–98.1%) for women with CIN 1 lesions and 82.1% (95% CI, 74.7–89.4%) for women with CIN 2 or CIN 3 lesions (P<0.001).

Table 3.

Final follow-up status for the women who fully participateda


Histologic status at baseline before cryotherapy	No. of women evaluated	Status at the last follow-up visit
Histologic status at baseline before cryotherapy	No. of women evaluated	No evidence of disease (lesion cured)	CIN 1	CIN 2	CIN 3	Invasive cancer
CIN 1	468	451 (96.4)	13 (2.8)	3 (0.6)	1 (0.2)	0
CIN 2	67	55 (82.1)	3 (4.5)	2 (3.0)	3 (4.5)	4 (6.0)
CIN 3	39	32 (82.1)	2 (5.1)	3 (7.7)	2 (5.1)	0
Total	574	538 (93.7)	18 (3.1)	8 (1.4)	6 (1.1)	4 (0.7)

Abbreviation: CIN, cervical intraepithelial neoplasia.

values are given as number or number (percentage). The mean follow-up time was 30 months (range, 8–44 months).

Cure rates (with their 95% confidence intervals) of CIN according to age, lesion size, and CIN grade are given in Table 4. Women with CIN 2 or CIN 3 had a significantly lower cure rate than those with CIN 1 (P<0.001). Neither age nor lesion size affected cure rates.

Table 4.

Cure rates at the final follow-up visit according to the characteristics at screening


Characteristic	No. of lesions cured	Cure rate, % (95% confidence interval)	P valuea
Age of participant
30–39 (n=450)	424	94.2 (92.1–96.4)	0.35
40–59 (n=124)	114	91.9 (87.1–96.8)
Cervical involvementb
<25% (n=218)	203	93.1 (89.7–96.5)	0.33
≥25% (n=157)	150	95.5 (92.3–98.8)
Lesion grade
CIN 1 (n=468)	451	96.4 (96.7–98.1)	<0.001
CIN 2 or CIN 3 (n=106)	87	82.1 (74.7–89.6)

By the independence test.

The information was missing in 199 cases.

The adverse effects recorded following treatment were mild perioperative pain or cramps in 6 women (1.0%), mild bleeding in 9 (1.9%), excessive malodorous vaginal discharge in 5 (1.0%), and fever in 2 (0.4%). The complications recorded were local cervical infection in 8 women (1.4%), cervical tenderness in 5 (0.9%), severe pelvic cramps and lower abdominal pain requiring parenteral medication in 4 (0.7%), and vaginal burns from accidental vaginal freezing in 1 (0.2%). There were no instances of vasovagal reactions, severe bleeding requiring suturing or blood transfusion, unintended surgical intervention, pelvic inflammatory disease requiring hospitalization, or functional cervical stenosis.

4. Discussion

The prevention of cervical cancer cannot occur without successful cervical screening and effective CIN treatment. The dearth of individuals trained to perform colposcopic evaluations and CIN treatment is a major constraint in many low-income countries [8], where screening programs have not resulted in reducing the burden of cervical cancer, in part because of the insufficient number of women treated [8], [9]. There is sufficient evidence that cryotherapy, traditionally provided by physicians, is an effective and safe treatment method for CIN [1], [2], but there is little information on its effectiveness when provided by nonphysicians in field conditions in low-income countries.

Although the evidence of the effectiveness of cryotherapy in curing CIN mostly comes from nonrandomized studies, with their inherent selection bias and their operators of varying skills, its success rate seems to be around 90% [1], [2]. Pooled results from 7 randomized trials indicate that cryotherapy and laser ablation eradicate CIN lesions of all grades with similar success [2], and results from a relatively small number of randomized trials indicate that success rates in curing CIN are similar for radical diathermy ablation, cold coagulation, and cryotherapy [2]. The cure rate of CIN with cryotherapy in the present study is similar to those reported from high-income countries, although such comparisons are fraught with limitations due to variable patient selection, treatment techniques, outcome assessment, and follow-up criteria. The success rates of cryotherapy are clearly lower for high-grade than for low-grade disease in both our and other studies [1], [2], [4]. Although one-fifth of the treated women were lost to follow-up in our study, and could not be assessed for cure, the characteristics of those women were similar to those of the women who were assessed. More than three-fourths of the latter women had more than 2 years of follow-up, and given the difficulties in tracing women in low-income countries, our follow-up rates are considered satisfactory.

In a southern Indian study involving 1026 women treated with cryotherapy by nurses in field conditions, the overall cure rate was 80.3% (81.4% for CIN 1, 71.4% for CIN 2, and 68.0% for CIN 3 lesions) [4]. Minor adverse effects and complications were recorded in less than 3% of the women. In Thailand, nurses provided cryotherapy for VIA-positive women in a study evaluating the single-visit approach [10]. In Cape Town, South Africa, in the context of a randomized trial to evaluate screen-and-treat approaches following VIA or HPV screening, trained nurses treated 949 women with double-freeze cryotherapy. There was only 1 serious adverse event (severe cervical bleeding 2 weeks after treatment), and there were no differences in HIV seroconversion rates between treated and untreated women in that study [11]. The low frequency of adverse effects and complications associated with cryotherapy in our study and others indicate that it is a highly safe treatment with good acceptability [1], [2], [4], [10], [11].

In summary, one-third of the treated women in our study did not have histologically diagnosed CIN, and it was the same in the southern Indian study [4]. Taking a colposcopy-guided biopsy just before cryotherapy proved to be doubly effective — the biopsy in ensuring that no microinvasive cervical cancer would be missed, and cryotherapy in treating CIN lesions on the spot. Cure rates were significantly lower for women with high-grade CIN lesions in our study, but 9 in 10 women with CIN lesions were cured. From a public health perspective, allowing adequately trained and monitored nurses, midwives, or primary health workers to perform cryotherapy should improve the results of cervical screening programs in low-and medium-resource settings.

Acknowledgements

The authors gratefully acknowledge the generous support of the Bill & Melinda Gates Foundation through the Alliance for Cervical Cancer Prevention.

References

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a Nargis Dutt Memorial Cancer Hospital, Tata Memorial Centre Rural Cancer Extension Project, Barshi, Solapur District, Maharashtra, India

b Tata Memorial Centre, Mumbai, Maharashtra, India

c Screening Group, International Agency for Research on Cancer, Lyon, France

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.

PII: S0020-7292(08)00344-5

doi:10.1016/j.ijgo.2008.07.016

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