- Academic Editors
Background: The World Health Organization (WHO) has recently endorsed thermal coagulation as an alternative to cryotherapy for cervical precancerous lesions. However, the comparative efficacy and safety of these two treatments lack robust support from large-sample data. This systematic review and meta-analysis aim to evaluate the effectiveness and safety of thermocoagulation compared to cryotherapy in the treatment of cervical precancerous lesions. Methods: A comprehensive search of PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov was conducted from inception. Additional trials were identified through the reference lists of published reviews. Inclusion criteria encompassed original data studies with colposcopically, biopsied, cytologically, or visually inspected (VIA/VILI) identified patients. Studies were required to have a follow-up duration of at least 6 months, a sample size exceeding 20 patients, a follow-up attendance rate exceeding 50%, and involve cryotherapy or thermocoagulation treatments. Results: Inclusive of all patients, thermocoagulation demonstrated a significantly higher pooled cure proportion compared to cryotherapy (85% vs. 81%, z = 2.245, p = 0.025). However, for VIA-positive patients alone, the difference was not statistically significant (80.0% vs. 79%, z = 1.932, p = 0.053). The incidence of pain was comparable between the two treatment arms, while both exhibited a high incidence of vaginal discharge. Thermocoagulation displayed a lower complication rate for intraoperative pain and postoperative vaginal discharge than cryotherapy, providing a higher level of patient comfort. Conclusions: Thermal coagulation proves to be more effective for patients with cervical precancerous lesions, but the effectiveness of the two regimens is similar if only for VIA-positive patients. In terms of complications, thermocoagulation exhibits a similar rate of intraoperative pain and a lower rate of postoperative vaginal discharge than cryotherapy, enhancing patient comfort.
Cervical cancer ranks as the fourth most common cancer globally, both in terms of incidence and mortality among women, and ranks the eighth most common cancer among all cancers. In the Global Cancer Data Statistics 2020, the number of new cases of cervical cancer was 604,127 and the number of new deaths was 341,831. Cervical cancer is the most commonly diagnosed cancer in 23 countries and the leading cause of cancer deaths in 36 countries [1]. Although the incidence of cancer is gradually decreasing in developed Western countries, the incidence of many cancers (e.g., cervical cancer) is still on the rise in low-and middle-income countries (LMICs). In resource-constrained settings, the World Health Organization (WHO) has recommended the implementation of “see-and-treat” screening programs, and cryotherapy has been suggested as an alternative ablation technique for cervical precancerous lesions, but the implementation of cryotherapy in LMICs has been limited by a number of factors, and the WHO has recently recommended the use of thermal ablation as an alternative to cryotherapy [2], the comparative efficacy and safety of these two treatments lack robust support from large-sample data.
This study systematically reviews and meta-analyzes the efficacy and safety of thermocoagulation compared to cryotherapy in the treatment of cervical precancerous lesions.
A thorough search of PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), ICTRP, and ClinicalTrials.gov from inception to 1 May 2023, was conducted. Inclusion criteria encompassed original data studies with colposcopically, biopsied, cytologically, or visually inspected (VIA/VILI) identified patients, a follow-up duration of at least 6 months, a sample size exceeding 20 patients, and a follow-up attendance rate exceeding 50%. Studies involved cryotherapy or thermocoagulation treatments. The risk of bias was assessed using the Newcastle-Ottawa Scale for retrospective studies and Cochrane Handbook guidelines for randomized controlled trials (RCTs).
This study was previously registered with PROSPERO (CRD42023485006) and followed PRISMA guidelines.
For all relevant papers identified for inclusion, the following items were collected separately using a data extraction form: author information, publication year, patient age, case definition, human immunodeficiency virus (HIV) status, treatment procedures, number of patients treated, attendance, follow-up, cured patients, follow-up duration, cure definition, and complications.
STATA/SE 16.0 (Stata Corp, College Station, TX, USA) will be used for
meta-analysis. Whenever appropriate, we will calculate odds ratios (OR), risk
ratios (RR), or effect label together with 95%
confidence intervals (95% CIs). p
values of
Following an exhaustive search across various platforms, a total of 307 articles were identified. Subsequent screening based on titles, abstracts, etc., led to the exclusion of 285 articles. The remaining 22 underwent detailed review, with 5 articles excluded due to a lack of original data, 6 for having a sample size below 20 patients, 3 for attendance below 50%, and 3 for insufficient data to calculate cure rates. Ultimately, 5 articles were included in this review (Fig. 1). And Table 1 (Ref. [3, 4, 5, 6, 7]) provides the details of the included papers.
Fig. 1.Study flow diagram.
| Study | Study type | Case definition | Treatment providers | Cure definition | Cryotherapy | TA | ||||||||
| N | Age | Cure rates | Satisfaction | HIV (N) | N | Age | Cure rates | Satisfaction | HIV (N) | |||||
| Banerjee 2020 [3] | RCT | VIA/HPV positive | Trained female health workers | No CIN | 150 | 36.1 | 74.10% | 98% | / | 136 | 36.7 | 81% | 99.30% | / |
| Chigbu 2020 [5] | RCT | VIA positive | Trained medical personnel | VIA negative | 512 | 47.3 | 85.50% | 80.5 | / | 511 | 47.1 | 89.20% | 93.20% | / |
| Duan 2021 [4] | RCT | CIN2/3 | Staff gynecologic colposcopy specialist | HPV and cytology negative, CIN2– | 71 | 31.2 | 92.30% | / | 0 | 74 | 31.5 | 98.50% | / | 0 |
| Pinder 2020 [7] | RCT | VIA positive | Trained nurses at the clinic | HPV negative (positive for the same HPV type at baseline), negative VIA (baseline HPV negative) | 250 | 25–49 | 60% | 100% | 40% | 250 | 25–49 | 64% | 100% | 45% |
| Verma 2022 [6] | RCT | VIA positive | Not mentioned | VIA negative | 34 | 34.35 | 90.32% | / | / | 34 | 36.82 | 93.54% | / | / |
RCT, randomized controlled trial; VIA, visual inspection with acetic acid; HPV, human papillomavirus; CIN, cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; TA, thermocoagulation.
Addressing the question of treatment effectiveness between cryotherapy and
thermo-coagulation for patients with precancerous cervical lesions, a
meta-analysis was conducted on the five included papers. “Cure rate” served as
the outcome indicator, revealing a combined sample size of 1663 cases. The pooled
cure proportion for cryotherapy was 81% (Fig. 2, Ref. [3, 4, 5, 6, 7]), while for
thermo-coagulation, it was 85% (Fig. 3, Ref. [3, 4, 5, 6, 7]). Statistical heterogeneity
was minimal (I
Fig. 2.The pooled cure proportions of cryotherapy. 95% CI, 95% confidence interval.
Fig. 3.The pooled cure proportions of TA.
Fig. 4.Cure rates of TA arm and cryotherapy arm of all patients in the included studies.
In the subset analysis of VIA-positive patients, three papers were considered,
revealing pooled cure proportions of 80.0% (thermocoagulation (TA) arm)
vs. 79% (cryotherapy arm), demonstrating mild statistical heterogeneity
(p = 0.830, I
Additionally, Banerjee et al.’s study [3] focused on women with
cervical intraepithelial neoplasia (CIN) 1 or worse lesions, reporting cure rates
of 74.1% (cryotherapy arm) and 81% (TA arm) (p = 0.57). Meanwhile,
Duan et al.’s study [4] included patients with CIN grades 2–3, with
cure rates of 92.3% (cryotherapy arm) and 98.5% (TA arm), respectively
(p
A total of five papers in this study [3, 4, 5, 6, 7] focusing on the occurrence of pain
during treatment, results from the analysis of pain levels across these studies
revealed that the incidence of moderate or higher pain during cryotherapy ranged
from 2.4% to 17.6%, whereas for thermal coagulation, it ranged from 1.6% to
5.9%. Meta-analysis of four of these papers, utilizing a random-effects model,
demonstrated a similar level of pain between the two treatment arms (test for
heterogeneity: I
Fig. 5.Moderate or higher pain of TA arm and cryotherapy arm of all patients in the included studies.
Studies have confirmed that cervical cancer is considered to be almost entirely
preventable if highly effective primary (human papillomavirus (HPV) vaccine) and
secondary (screening) preventive measures are taken; however, these measures have
not been equitably implemented between and within countries, and as of May 2020,
According to the findings of this review, both thermal coagulation and cryotherapy are effective methods for treating precancerous cervical lesions in terms of cure rates, and in the combined analysis of CIN and VIA-positive patients, the cure rate was higher in the thermal coagulation group, whereas the cure rates of the two arms were similar in the inclusion of VIA-positive patients only. Already in 2014, in a Meta-analysis by Dolman et al. [9] it was suggested that thermocoagulation was comparable to other therapies (freezing, excision, etc.) in terms of effectiveness for the treatment of CIN; additionally, de Fouw et al. [10] in a review published in 2019 included eleven papers on cryotherapy and seven on thermocoagulation and showed that, both cryotherapy and thermal coagulation were effective treatments for CIN lesions, with cure rates ranging from 90.1%–92.8% for VIA-positive lesions, 91.4%–93.8% for CIN1, and 82.6%–91.6% for CIN2/3, the difference in cure rates between the two regimens in VIA-positive patients and CIN1 grade was not statistically significant, the difference between the treatment effectiveness for CIN2/3 lesions was statistically significant, but when comparing the effectiveness of both treatment modalities in LMICs only, the proportion of cure was similar. Notably, our study’s focus on LMICs revealed similar cure proportions for both treatment modalities, with lower overall pooled cure rates, possibly influenced by the inclusion of middle/low-income countries and a significant number of HIV-positive patients in certain studies. These results align with previous research, emphasizing the need for targeted interventions in LMICs.
Regarding intraoperative pain levels, both regimens demonstrated low incidence rates of moderate and higher pain levels, with high patient satisfaction and willingness to recommend the treatment. A randomized non-inferiority clinical trial by Soler et al. [11] supported the safety and acceptability of both ablative treatments. In addition, the incidence of postoperative vaginal fluid was high in both arms, but more studies have concluded that the rate of postoperative vaginal fluid is lower with thermal coagulation than with cryotherapy.
In addition, only Pinder et al.’s study [7] in the review counted the HIV status of the patients, and in that study, the HIV-positive rate of the patients in both arms was high (49% in the TA arm and 54% in cryotherapy arm). Importantly, despite lower cure rates for HIV-positive patients, the regimens proved safe and equally effective. However, due to the small sample size, further research is warranted to explore the efficacy and safety of thermal coagulation in HIV-positive patients.
While our study adhered to a review protocol, several limitations need acknowledgment. The small number and size of included studies, along with heterogeneity in sample sizes, follow-up duration, inclusion criteria, and “cure rate” definition, necessitate cautious interpretation. On the other hand, the treatment providers in the studies were professionally trained physicians or clinical nurses, and the institutions ranged from rural clinics to teaching hospitals, the experience of treatment providers and the medical level of each institution may have a certain impact on the research results. Future research, incorporating more extensive studies and larger sample sizes, is vital to validate our conclusions.
In summary, thermal coagulation proves to be more effective for patients with cervical precancerous lesions, with comparable effectiveness to cryotherapy in the subset of VIA-positive patients. In terms of complications, thermocoagulation exhibits a similar rate of intraoperative pain and a lower rate of postoperative vaginal discharge than cryotherapy, enhancing patient comfort. Moreover, the cost-effectiveness of transportation and storage further positions thermal coagulation as a promising solution. This study underscores the potential suitability and merits of thermal coagulation in the management of cervical precancer, particularly in middle/low-income countries. Its attributes advocate for further promotion and integration into clinical applications.
All data points generated or analyzed during this study are included in this article and there are no further underlying data necessary to reproduce the results.
JL and XP designed the research study. JL, XP and HC performed the research. JL and XP analyzed the data. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
Not applicable.
We would like to express our gratitude to all those who helped us during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.
This research received no external funding.
The authors declare no conflict of interest.
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