Clinical outcomes comparison on the addition of adjuvant radiotherapy to minimally invasive surgery versus adjuvant radiotherapy to open radical hysterectomy in women with cervical cancer: a systematic review

Introduction

Background

Minimally invasive surgery (MIS) is increasingly utilized in the treatment of cervical cancer due to several benefits, including reduced operative blood loss, shorter hospital stays, and a lower incidence of postoperative complications compared to open radical hysterectomy (ORH). Over the past decade, minimal access techniques for radical hysterectomy in the treatment of cervical cancer have gained significant popularity and are now widely implemented across Europe and the Americas. This shift has been facilitated by the use of advanced imaging technologies to identify patients suitable for initial chemoradiotherapy, offering less extensive surgical interventions for early-stage disease, providing fertility-sparing surgery for selected individuals, incorporating sentinel lymph node dissections, and adopting minimally invasive surgical approaches, including conventional laparoscopy and robotic-assisted techniques (1).

However, multiple meta-analyses and the prospective randomized controlled trial called Laparoscopic Approach to Carcinoma of the Cervix (LACC) trial have demonstrated inferior long-term oncological outcomes with MIS, leading to significant changes in clinical practice guidelines for cervical cancer treatment (1). These studies indicate that MIS is associated with higher recurrence rates, lower overall survival (OS), and decreased disease-free survival (DFS) compared to ORH, particularly in patients with early-stage cervical cancer. Furthermore, MIS was found to be a poor prognostic factor in patients with final pathological tumor size of ≤2 cm and in low-risk patients with a tumor size of less than 2 cm without adjuvant treatment (2,3).

The incorporation of radiotherapy or chemoradiotherapy following MIS has been demonstrated to increase the efficacy of MIS by decreasing the risk of recurrence and enhancing local control in women with early-stage cervical cancer. Adjuvant radiotherapy may theoretically counteract MIS disadvantage by targeting residual microscopic disease that could remain in the pelvis following MIS. By delivering localized cytotoxic treatment to areas at risk of harboring undetected tumor cells, including parametrial tissues, the vaginal cuff, and regional lymphatic pathways (4), adjuvant radiotherapy may improve local control by eradicating residual microscopic disease.

Therefore, radiotherapy may reduce the likelihood of recurrence.

Although the indications for postoperative adjuvant therapy are still under investigation, a complete consensus has not yet been reached, with regional variations in clinical practice. The Japan Society of Gynecologic Oncology (JSGO) guidelines suggest that patients with one or more intermediate risk factors may benefit from radiotherapy (5). In contrast, the European Society of Medical Oncology (ESMO) recommends against adjuvant treatment for patients with intermediate risk factors following surgery for early-stage cervical cancer, based on evidence level 2B (6).

A recent systematic review and meta-analysis by da Silva et al. (7) evaluated outcomes of adjuvant radiotherapy compared with observation alone in patients with early-stage cervical cancer classified as intermediate risk after surgery. Their findings indicated that the effectiveness of adjuvant radiotherapy in this subgroup remains uncertain, highlighting ongoing debate regarding its true clinical benefit. In addition, advances in surgical techniques, particularly the widespread adoption of minimally invasive approaches for radical hysterectomy over the past decade underscore the need for updated evidence. Therefore, our study aims to assess and compare the impact of adjuvant radiotherapy following MIS versus MIS alone, as well as adjuvant radiotherapy after ORH versus ORH alone. This disparity highlights the need for consensus to establish clearer, more unified recommendations.

Rationale and knowledge gap

The oncological safety of MIS in combination with radiotherapy remains uncertain, particularly in its ability to manage residual microscopic disease and reduce the risk of cervical cancer recurrence. Establishing the comparative effectiveness of adjuvant radiotherapy or chemoradiotherapy in the context of MIS versus ORH is crucial for optimizing treatment protocols and improving survival outcomes. However, no randomized controlled trials have yet provided robust evidence on the benefits of radiotherapy when combined with MIS. Additionally, more precise criteria are needed to determine which patients would derive the greatest benefit from MIS compared to ORH in conjunction with radiotherapy.

Objective

A comprehensive literature search was performed across multiple electronic databases using predefined inclusion criteria, to evaluate and compare the clinical outcomes of adjuvant radiotherapy following MIS versus adjuvant radiotherapy following ORH in women with early-stage cervical cancer. We present this article in accordance with the PRISMA reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-25-24/rc).

Methods

This study was registered at the International Prospective Register of Systematic Reviews (PROSPERO) on 17 January 2025 with registration number CRD42025632524.

Information sources and search strategy

In this systematic review, all searches were completed in PubMed, Scopus, EuropePMC, and Springer with a timeline restriction from inception until November 9, 2025. Search structures, Medical Subject Headings (MeSH) and keywords were tailored in accordance to each database by a medical research librarian (B.A.T., C.A.S., N.D.W.) with previous experience in conducting systematic reviews. Searches were limited to interventional or observational study, and no restriction on the year of publication. Reference lists of the included articles were then searched manually. The complete search strings are listed in Table S1, and the detailed search terms for MEDLINE, EuropePMC, Springer, and Scopus are shown in Table S2.

Study selection process

Following the initial search, each reviewer (B.A.T., C.A.S., N.D.W.) independently screened the titles and abstracts to identify potentially relevant studies. Full-text articles deemed relevant were then independently assessed for inclusion and exclusion criteria by two reviewers (N.D.W., C.A.S.). Grey literature and any related sources were excluded in the selection process of this study. Any discrepancies were resolved through consensus with the involvement of experienced researchers in the corresponding field (G.G., D.A.W.).

Eligibility criteria

This systematic review was conducted in accordance with the PRISMA 2020 checklist and flow diagram (Table S1). Each retrieved study was independently evaluated by the reviewers, with any discrepancies resolved through consensus.

The inclusion criteria were as follows:

• Adult women aged 18 years or older;
• Biopsy-confirmed cervical cancer [International Federation of Gynecology and Obstetrics (FIGO) stage IA–IIB] without evidence of metastases;
• Recipient of adjuvant radiotherapy or chemoradiotherapy;
• Undergoing either MIS or open hysterectomy (ORH);
• Inclusion of all prognostic risk factors;
• Availability of primary clinical outcomes, including OS, DFS, progression-free survival (PFS), and locoregional recurrence, with treatment-related complications or adverse effects as secondary outcomes;
• A Newcastle-Ottawa Scale (NOS) score of ≥7, indicating high methodological quality.

Studies were excluded if they were case reports, case series, conference abstracts, book sections, or commentaries/editorials. Additionally, studies with duplicate populations from other included studies were excluded.

Population

Studies involving adult patients (>18 years) diagnosed with cervical cancer (FIGO stage I–IIB) were included, regardless of tumor size or histopathological presentation. However, studies involving patients with systemic disease (M1) or a prior history of irradiation were excluded. MIS was defined as a laparoscopic or robotic surgical approach performed with adjuvant chemoradiotherapy or external beam radiotherapy (EBRT), irrespective of radiotherapy dose or chemotherapy type/dose.

Outcomes

The primary outcomes of interest included disease-specific survival (DSS), defined as the time to death due to cervical cancer; OS, defined as the time to death from any cause; and recurrence-free survival (RFS), defined as the time to cancer recurrence. Safety endpoints were also included and were defined as treatment-related adverse events.

Risk of bias and data collection

The risk of bias for observational studies was assessed using the modified NOS, with a minimum score of 7 required to indicate high methodological quality. For the randomized controlled trial by Rotman et al. (8), risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, which evaluates bias across domains including randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results. Data extracted from the included studies included author, year, and country of origin, study design and duration, population, disease subgroup, treatment arms, regiments, and procedures (N), median follow-up (months), measured outcomes, and safety endpoints and therapy-related side-effects. Additionally, intraoperative and postoperative complications among patients undergoing MIS hysterectomy with adjuvant radiotherapy versus ORH with adjuvant radiotherapy were analyzed.

Certainty of evidence assessment using Grading of Recommendations Assessment Development and Evaluation (GRADE)

The certainty of evidence for each primary outcome was assessed using the GRADE approach. Observational studies were initially rated as low certainty and randomized controlled trials as high certainty. Certainty ratings were then downgraded or upgraded based on predefined domains including risk of bias, inconsistency, indirectness, imprecision, and publication bias. Upgrading was considered for large magnitude of effect or evidence of dose response. Each outcome was classified as high, moderate, low, or very low certainty.

Results

Study selection

As illustrated in Figure 1, a flowchart was constructed to present the process of study selection and the associated outcomes. The initial search, conducted across four independent databases including Scopus, PubMed, EuropePMC, and Springer Link, identified a total of 1,825 potentially relevant studies. After removing 411 duplicate records, 1,414 studies remained for title and abstract screening, which narrowed the selection to 23 studies. Full-text evaluation of these 23 studies resulted in the exclusion of 17 that did not meet the eligibility criteria. Specifically, two studies had insufficient follow-up duration, four involved neoadjuvant therapy, and eleven reported outcomes that were not appropriate for inclusion. As a result, six studies were incorporated into the systematic review.

Figure 1 PRISMA 2020 flow diagram of study selection.

Characteristics of the included studies

A total of 1,346 patients were included across the six studies summarized in (Table 1). All studies utilized a retrospective cohort design, with median follow-up periods ranging from 40.4 months in the study by Kim et al. (11) to 120 months in the study by Rotman et al. (8). Five of the six studies stratified patients according to the International Federation of Gynecology and Obstetrics (FIGO) staging system, with the exception of Rotman et al. (8). Based on this classification, Stage IB was the most frequently reported stage, except in the study conducted by Gruen et al. (12), which identified Stage IIB as the most common.

Rotman et al. (8) reported that more than 75 percent of their patient population, totaling 218 individuals, were diagnosed with squamous cell carcinoma. Four studies, namely Zhang et al. (9), Burgess et al. (10), Gruen et al. (12), and Kim et al. (11), administered concomitant post-operative chemotherapy. Cisplatin, used as a single agent, was the most frequently employed chemotherapeutic drug. The most commonly used pelvic radiation technique was intensity-modulated radiation therapy (IMRT), typically delivered in total doses of 45–50 Gy over 5 weeks. Other external beam techniques included extended-field radiation therapy (EFRT), three-dimensional conformal radiation therapy (3DCRT), and EBRT combined with para-aortic irradiation. In addition, several studies used brachytherapy or EBRT in combination with brachytherapy, including intracavitary approaches.

Qualitative synthesis of study findings by outcome

Across the six included studies, clinical outcomes were reported heterogeneously but could be qualitatively synthesized according to oncologic efficacy and safety endpoints. The primary outcomes evaluated included OS, DSS, RFS, PFS, and locoregional recurrence.

Survival outcomes

OS was reported in Kim et al. (11), Zhang et al. (9), Burgess et al. (10), and Rotman et al. (8), while disease specific survival was reported in Gruen et al. (12). In general, the addition of adjuvant radiotherapy after radical hysterectomy was associated with improved survival related outcomes compared with surgery alone, although effect estimates varied across studies. Kim et al. (11) demonstrated improved OS and RFS among intermediate risk patients receiving adjuvant radiotherapy, particularly within the MIS subgroup. Gan et al. (4) reported improved local RFS and distant metastasis-free survival (DMFS) among patients undergoing laparoscopic hysterectomy followed by postoperative radiotherapy. Burgess et al. (10) reported OS and PFS outcomes, with benefit observed primarily among higher risk subgroups receiving adjuvant therapy. In contrast, Rotman et al. (8), a randomized controlled trial, demonstrated a statistically significant improvement in RFS and PFS with postoperative pelvic radiotherapy in intermediate risk stage IB disease.

Recurrence and local control outcomes

Locoregional recurrence and recurrence related survival outcomes were reported in Gan et al. (4), Zhang et al. (9), Burgess et al. (10), Kim et al. (11), and Rotman et al. (8). Five studies (4,8-11) observed lower recurrence rates among patients receiving adjuvant radiotherapy compared with surgery alone. This effect was particularly evident after MIS in Gan et al. (4) and Kim et al. (11), where postoperative radiotherapy reduced local recurrence risk. Burgess et al. (10) reported recurrence reduction primarily in higher risk pathological subgroups, whereas Zhang et al. (9) observed disease free survival improvement following adjuvant radiotherapy regardless of surgical approach.

Safety and toxicity outcomes

Safety outcomes were reported in Gan et al. (4), Zhang et al. (9), Burgess et al. (10), Kim et al. (11), Gruen et al. (12), and Rotman et al. (8), although the depth of reporting varied substantially. Gan et al. (4), Zhang et al. (9), Kim et al. (11), and Gruen et al. (12) described acceptable acute gastrointestinal and genitourinary toxicity profiles with modern radiotherapy techniques, particularly intensity modulated radiation therapy. Rotman et al. (8) reported higher rates of acute grade three toxicity in the radiotherapy arm compared with observation, but severe grade four events were uncommon. Late toxicity and quality of life outcomes were sparsely and inconsistently reported across studies.

Sources of heterogeneity

Observed heterogeneity across studies may be attributed to differences in surgical technique, patient risk stratification, radiotherapy modality and dose, use of concurrent chemotherapy, and retrospective study design. Additionally, preferential allocation of higher risk patients to adjuvant radiotherapy in observational studies may have introduced confounding by indication.

Risk of bias of each included studies

The risk of bias for the five observational cohort studies was evaluated using the modified NOS, with all studies achieving seven or more stars, indicating good methodological quality. The randomized controlled trial by Rotman et al. (8) was assessed using the Cochrane RoB 2 tool and was judged to have overall low risk of bias across domains, including randomization process, outcome measurement, and reporting, although some concerns related to performance bias were noted due to the nature of radiotherapy intervention. The results are shown within Tables 2,3. Consensus to settle any disagreements was used.

Certainty of evidence assessment

Using the GRADE framework, the overall certainty of evidence for survival and recurrence outcomes was rated as low to moderate. Most outcomes were derived from retrospective observational studies and were downgraded for risk of bias and inconsistency. Survival outcomes including OS and DSS were rated as low certainty due to heterogeneity in effect estimates and potential confounding by indication. Recurrence related outcomes were rated as moderate certainty, supported by consistent direction of effect across multiple studies, particularly for reduced locoregional recurrence following adjuvant radiotherapy after MIS. Certainty for safety outcomes was rated as very low due to inconsistent reporting, limited follow up, and imprecision.

Discussion

Adjuvant radiotherapy has long been integrated into the management of early-stage cervical cancer with intermediate-risk features, following the evidence established by the GOG-92 (Sedlis) trial, which demonstrated reduced recurrence after radical hysterectomy in patients meeting specific pathological criteria (13-16). Although these criteria continue to guide clinical decision-making, variation across international guidelines persists. The National Comprehensive Cancer Network (NCCN) recommends adjuvant RT only when Sedlis criteria are met, whereas the JSGO advocates for RT in the presence of any intermediate-risk factor, and ESMO adopts a more conservative approach (4,17). These inconsistencies reflect the ongoing debate regarding which patients derive the greatest benefit from postoperative RT.

At the same time, the surgical landscape has changed substantially. The LACC trial highlighted inferior oncologic outcomes with MIS compared with ORH, prompting renewed interest in whether adjuvant RT can mitigate the increased recurrence risk associated with MIS (18). We also found two observational studies that have reported that adjuvant RT may improve local control after MIS, whereas its added benefit after ORH appears more modest (8,11). These findings emphasize the importance of understanding interactions between surgical modality and postoperative treatment.

An important aspect that needs further consideration is the potential interaction between surgical technique and the effectiveness of adjuvant radiotherapy. MIS has been hypothesized to increase local recurrence risk through mechanisms such as tumor exposure during intracorporeal colpotomy, CO₂ pneumoperitoneum–related tumor dissemination, and the use of uterine manipulators. In this context, adjuvant radiotherapy may serve as a compensatory strategy by sterilizing microscopic residual disease in the pelvis and vaginal cuff. The observation that MIS combined with radiotherapy achieved oncologic outcomes comparable to or exceeding those of ORH in several included studies supports this biological rationale, although causality cannot be confirmed (4). Several individual studies support these observations. Gan et al. (4) and Kim et al. (11) both reported improved local control and reduced recurrence among patients receiving adjuvant RT, particularly after MIS. Rotman et al. (8) further demonstrated that postoperative pelvic RT reduces recurrence and prolongs PFS in stage IB disease, especially in adenocarcinoma and adenosquamous histologies. Collectively, these studies reinforce the principle that adjuvant RT offers measurable oncologic benefit in selected intermediate-risk patients, although its magnitude varies depending on surgical approach.

Variability in pathological risk profiles and adjuvant regimens across studies, together with retrospective designs, raises the possibility of selection bias. For example, preferential allocation of patients with more advanced or unfavorable disease to combination therapy may have introduced selection bias. In addition, adverse events and late toxicity were inconsistently reported, limiting the ability to weigh oncologic benefit against treatment-related harm. Differences in the application of Sedlis criteria, four-factor models, and institutional practices likely contributed to variation in outcomes and may have influenced treatment allocation. This variability mirrors the lack of consensus among international guidelines regarding the optimal use of adjuvant radiotherapy in intermediate-risk disease. Our findings suggest that surgical approach should be considered alongside pathological risk factors when making adjuvant treatment decisions, rather than being viewed in isolation. Taken together, these factors reinforce that the current evidence base does not permit strong causal conclusions and that our findings should be viewed as exploratory.

Advances in radiotherapy technology, such as IMRT, image-guided brachytherapy, and MRI-based target delineation offer improved precision and potentially better outcomes, yet adoption across centers remains inconsistent. Ongoing randomized trials, including GOG-263, are expected to clarify the benefit of concurrent chemoradiation in intermediate-risk disease and provide more definitive guidance regarding optimal sequencing and combination of surgery and adjuvant therapy. Larger prospective data are needed to validate whether MIS patients require distinct postoperative treatment algorithms.

Safety outcomes were not reported consistently across the included studies, which limited meaningful comparisons of treatment-related toxicity between surgical approaches. While most studies described acceptable toxicity profiles with modern radiotherapy techniques, particularly IMRT, the lack of standardized adverse event reporting precludes definitive conclusions regarding long-term morbidity. Given that adjuvant radiotherapy may be preferentially considered to offset oncologic disadvantages of MIS, careful evaluation of treatment-related toxicity is essential to ensure that potential survival benefits are not outweighed by increased late complications. Future studies should incorporate standardized safety endpoints and longer follow-up to better define the risk–benefit balance of adjuvant radiotherapy in this setting.

Strength and limitations of the study

As of writing, this study offered a comprehensive overview of adjuvant radiotherapy across both surgical approaches of radical hysterectomy. However, the number of eligible studies remained small, with only one randomized trial and the rest being retrospective cohorts. This limited evidence base contributes to substantial heterogeneity in patient characteristics, treatment protocols, and reporting quality.

Future directions

Future research using quantitative approaches such as meta-analysis or network meta-analysis would be valuable to strengthen the statistical evidence comparing clinical outcomes between adjuvant radiotherapy following MIS and adjuvant radiotherapy after ORH in women with cervical cancer. In addition, well-designed studies are needed to better define the magnitude of benefit and to clarify which clinical or pathological characteristics may help identify patients undergoing MIS who are most likely to benefit from adjuvant radiotherapy.

Conclusions

This systematic review suggests that the addition of adjuvant radiotherapy may play a meaningful role in improving oncologic outcomes among women with FIGO stage IA–IIB cervical cancer undergoing radical hysterectomy, regardless of surgical approach. Across the included studies, adjuvant radiotherapy was consistently associated with improved local control and recurrence-related outcomes, with a potentially greater relative benefit observed in patients treated with MIS. These findings support the hypothesis that adjuvant radiotherapy may partially mitigate the increased risk of local recurrence historically associated with minimally invasive approaches.

Nevertheless, the current evidence base remains limited and is largely derived from retrospective observational studies with heterogeneous patient populations, treatment protocols, and outcome reporting. As a result, definitive conclusions regarding the magnitude of survival benefit, particularly for OS and distant metastasis outcomes, cannot yet be established. Future well-designed prospective studies are required to clarify the role of adjuvant radiotherapy in the context of MIS and to refine patient selection criteria that can guide individualized postoperative treatment strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-25-24/rc

Peer Review File: Available at https://tro.amegroups.com/article/view/10.21037/tro-25-24/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-25-24/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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