3.1 Search method

A systematic literature search was conducted to identify studies evaluating Total Mesometrial Resection (TMMR) for cervical cancer. The search was performed in PubMed and Scopus databases in January 2025. We included all studies published up to the search date, with no restrictions on publication year or country of origin. Only studies entirely published in English were considered for inclusion.

To ensure comprehensive coverage, the search strategy included the following Medical Subject Headings (MeSH) and free-text terms: “Hysterectomy” AND “Uterine Cervical Neoplasms”. The search was adapted to each database according to its specific syntax and indexing system.

3.2 Study selection

Study selection was made independently by GC and MCS. In case of discrepancy, CR decided on inclusion or exclusion. Inclusion criteria were: (1) studies that included patients with Early-stage cervical cancer or stage IB3 or IIB according to FIGO [10]; (2) studies that reported at least one outcome of interest (DFS, OS); (3) peer-reviewed articles published originally. We excluded non-original studies, preclinical trials, animal trials, abstract-only publications, and articles in languages other than English. If possible, the authors of studies that were only published as congress abstracts were contacted via email and asked to provide their data. We mentioned the studies selected and all reasons for exclusion in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart (Fig. 1). We assessed all included studies regarding potential conflicts of interest. A PRISMA checklist is included in Supplementary material.

Fig. 1.PRISMA flow diagram.

3.3 Outcome measures and data extraction

The primary outcome of this systematic review was 3-year disease-free survival (DFS), defined as the percentage of patients free from disease 36 months after undergoing TMMR. The secondary outcome was 3-year overall survival (OS), calculated as the proportion of patients alive at 36 months post-TMMR. Additionally, we assessed the recurrence rate (RR), which is defined as the proportion of patients experiencing disease recurrence during the study’s follow-up period. Recurrence was determined based on clinical and/or imaging findings, as reported in the individual studies included in the systematic review.

Recurrences were categorized as follows: Local recurrence: Tumor recurrence confined to the pelvis; Distant recurrence: Disease spread beyond the pelvis and/or parenchymal metastases.

Patients presenting both local and distant recurrences were counted under each recurrence type but only once in the overall recurrence rate (RR).

For each included study, the following data were extracted: Study design, Number of enrolled patients, Country of study conduction, Patient enrollment period, Follow-up duration expressed in months, FIGO staging, classified according to the 2018 International Federation of Gynecology and Obstetrics (FIGO) criteria for cervical cancer.

Postoperative complications were defined as any adverse event occurring within the first 30 days post-surgery and were classified according to the Clavien-Dindo system [11]. Only complications classified as Grade III or higher were included in the analysis. The number of patients experiencing at least one complication was reported as absolute values and percentages.

3.4 Surgical technique

Radical hysterectomy, as classically defined by the Piver-Rutledge classification (Type II–III) and adopted in most clinical guidelines, involves the en bloc removal of the uterus, upper vaginal cuff, parametria, and uterosacral ligaments, often sacrificing pelvic autonomic nerves. This procedure aims to ensure wide surgical margins and local tumor control. In contrast, TMMR is based on the ontogenetic cancer field theory and focuses on the precise removal of the Müllerian compartment as defined during embryonic development, preserving autonomic nerves and minimizing collateral damage [6]. Key anatomical differences include the boundaries of resection: while radical hysterectomy extends laterally to include parametria, TMMR targets the mesometrial tissue with embryologic precision. Technically, TMMR avoids direct tumor manipulation and aims for complete resection of at-risk compartments with preservation of nerve structures. These differences may account for the variations in recurrence patterns and functional outcomes observed between the two techniques. TMMR was defined in accordance with the technique described initially by Höckel et al. [6] in 2003, which is based on the ontogenetic cancer field theory. This approach involves the en bloc resectioning of the embryologically defined Müllerian compartment while preserving the autonomic pelvic nerves. This systematic review considered both open (laparotomic) TMMR and minimally invasive TMMR (laparoscopic and robotic-assisted approaches).

The procedure consists of the following standardized surgical steps:

1. Identification of the Müllerian compartment: The uterus, mesometria, upper two-thirds of the vagina, and paracervical lymphatic drainage pathways are resected in continuity.

2. Dissection of the vascular mesometrium: The uterine artery is ligated at its origin, and all mesometrial lymphatic structures are removed.

3. Resection of the ligamentous mesometrium: The paracolpium and the sacrouterine and rectovaginal ligaments are dissected to their embryological boundaries.

4. Nerve-sparing approach: The hypogastric plexus and visceral pelvic nerves are carefully preserved.

5. Lymphadenectomy: A systematic pelvic lymph node dissection includes the paravisceral, external iliac, common iliac, and presacral nodes. Para-aortic lymphadenectomy is performed selectively based on tumor staging and intraoperative findings.

For laparoscopic and robotic-assisted TMMR, the exact anatomical principles were applied, with modifications to accommodate minimally invasive instrumentation. The main differences include Pneumoperitoneum establishment and trocar placement for optimal access; Endoscopic suturing techniques for vaginal cuff closure and lymphatic sealing.

This definition of TMMR was consistently applied across the included studies to maintain the comparability of oncological and perioperative outcomes.

3.5 Statistical analysis

Descriptive statistics were used to summarize patient characteristics, surgical variables, and oncological outcomes. Continuous variables (e.g., follow-up duration, age, operative time) were reported as means. Categorical variables (e.g., recurrence type, complication rates) were presented as absolute numbers and percentages.

Pooled estimates were calculated when feasible for the primary outcome, 3-year disease-free survival (DFS), and the secondary outcome, 3-year overall survival (OS). Recurrence rates (local and distant) were analyzed separately. In cases of concurrent recurrences, patients were counted in each respective category but only once in the total recurrence rate.

Additionally, to improve clinical contextualization, a comparative analysis was conducted between the pooled TMMR data and the open surgery arm of the LACC trial (Ramirez et al. [8]), which serves as the current standard of care for early-stage cervical cancer. Hazard ratios for overall recurrence, locoregional recurrence, and overall survival were calculated using Cox proportional hazards regression models, with statistical significance assessed using log-rank tests. A Fisher’s exact test was used for categorical variables when event counts were low.

All statistical analyses were performed using R software (meta-package), following PRISMA guidelines [9]. A p-value < 0.05 was considered statistically significant.

3.6 Quality assessment

The methodological quality of the included studies was evaluated using the Newcastle-Ottawa Scale (NOS) [12]. This tool assesses study quality based on three main domains: selection of study participants, comparability of cohorts, and assessment of outcomes (for cohort studies) or exposure (for case-control studies). The NOS assigns scores ranging from 0 (lowest quality) to 9 (highest quality), with higher scores indicating a lower risk of bias.

Two independent reviewers (CS and MCDD) conducted the quality assessment. In case of discrepancies, consensus was reached through discussion, and if needed, a third reviewer (VC) was consulted to make the final decision.

The detailed Newcastle-Ottawa Scale scoring for each included study is provided in the Supplementary material.

4.1 Studies’ characteristics

Following the database search, 67 articles met the initial search criteria. After removing duplicates, records without full-text availability, and studies with ineligible designs (e.g., reviews, meta-analyses), 14 studies remained for full-text screening. Of these, 7 studies met the inclusion criteria and were included in the systematic review. 6 studies were non-comparative, single-arm investigations evaluating only TMMR, one study compared TMMR to radical hysterectomy. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), as detailed in the Supplementary Table 1. The included studies were published between 1998 and 2024, encompassing patients diagnosed with FIGO 2009 stage IA–IIB cervical cancer who underwent TMMR [13]. 2 studies by Falconer and Hockel, included patients with positive node at the imaging. The mean follow-up period ranged from 18 to 62 months. A summary of the study characteristics, including publication year, study design, FIGO stage, number of participants, and country of origin, is presented in Table 1 (Ref. [14, 15, 16, 17, 18, 19, 20]).

4.2 Outcomes

A total of 1071 patients were included in the review. All the 7 selected studies presented DFS data and OS data.

The main outcome was DFS at 3 years. In the included studies, the series described by Falconer et al. [16] had the lowest DFS (85%), while the highest was published by Chiantera et al. [15] (97.1%). Regarding the 3-year OS, the reported values ranged from 87.9% to 100%. Those results are summarized in Table 2 (Ref. [14, 15, 16, 17, 18, 19, 20]).

The RR ranged from 0.3% to 14.3%, with 2/7 studies having results below 1%. Regarding the recurrence pattern, only the Hockel [17], Falconer [16], and Buderath [14] studies reported extrapelvic (Distant) recurrences. Conversely, all reported studies reported at least 1 pelvic recurrence. These results are summarized in Table 3 (Ref. [14, 15, 16, 17, 18, 19, 20]).

Only 6 studies reported complication rates in the first 30 days post-treatment. Buderath’s study [14] is the only one that reported an event rate above 5% (17.4%). The remaining studies reported case histories between 1 and 4%. The rates of the individual studies are shown in Table 4 (Ref. [14, 15, 17, 18, 19, 20]).

4.3 Comparison with LACC trial

To enhance the clinical relevance of the findings, we reanalyzed the reported cases by comparing them with the open surgery arm of the LACC trial (Ramirez et al. [8]), which currently represents the standard of care for the surgical treatment of early-stage cervical cancer.

4.4 Recurrence analysis

Among patients undergoing TMMR, a total of 122 recurrences out of 1071 patients were reported, compared to 8 recurrences out of 312 patients in the open surgery arm of the LACC trial. This resulted in a Hazard Ratio (HR) of 4.89 (95% CI: 2.42–9.88, p < 0.001) for overall recurrence risk, indicating a statistically significant difference between the two surgical approaches.

For locoregional recurrences, patients treated with TMMR had an HR of 4.65 (95% CI: 1.70–12.69, p = 0.001) compared to those who underwent radical abdominal hysterectomy, suggesting a higher but significant risk of local recurrence.

4.5 Survival analysis

Regarding overall survival (OS), the estimated risk of death among TMMR patients was HR 16.48 (95% CI: 4.08–65.99, p < 0.001) compared to the LACC trial’s open surgery arm, further indicating a statistically significant difference in mortality between the two approaches.

These comparative results are summarized in Table 5.

4.6 Comparison for patients with early-stage cervical cancer

To refine our analysis further, we conducted a pooled subgroup analysis restricted to patients with disease stages below IB3 (447). In this subgroup, the Hazard Ratio (HR) for recurrence associated with TMMR was 1.32 (95% CI: 0.57–3.07, p = 0.57), indicating a no statistically significant difference compared to the control group. Regarding local recurrence, the HR was 2.31 (95% CI: 0.76–7.01, p = 0.14), failing to reach statistical significance. Similarly, for OS, the HR was 0.70 (95% CI: 0.10–4.92, p = 0.72), suggesting no meaningful survival difference between the two groups. These results are summarized in Table 6.

5.1 Interpretation of results

This systematic review evaluates the oncological and safety performance of TMMR in the surgical management of early-stage cervical cancer. The findings indicate high oncological effectiveness, with all studies reporting 3-year DFS and OS above 85%. The safety profile of TMMR also appears acceptable, with a complication rate below 5% in five out of six studies. However, one study (Buderath et al. [14]) deviates from this trend, reporting a threefold higher complication rate than other studies included in this systematic review. Notably, this study is the only multicenter investigation involving 15 different centers. Despite its multicentric design, the study included only 116 patients, suggesting that several centers performed fewer than 10 procedures over 9 years. This low-volume bias may have influenced the observed higher complication rate and lower oncological performance.

A key finding is the higher recurrence risk associated with TMMR compared to the open surgery arm of the LACC trial. Our pooled analysis found a statistically significant increase in overall and locoregional recurrence risk in patients undergoing TMMR. These results suggest that TMMR may be associated with a higher rate of tumor persistence or local failure, potentially due to technical inconsistencies or patient selection bias. However, it is important to note that TMMR was also performed in patients with higher-stage disease (IB3/IIB). In contrast, LACC [8] strictly excluded such cases, possibly overestimating recurrence risk in the TMMR cohort. Furthermore, it is important to acknowledge that the LACC trial itself has been the subject of significant debate in the literature. Since its publication, several studies have raised concerns about methodological limitations, including heterogeneous patient selection, lack of central pathology review, variability in surgical technique across centers, and the limited experience of some participating surgeons with minimally invasive approaches. These flaws may have influenced the trial’s outcomes and limit its utility as a definitive benchmark. As such, while LACC remains a widely cited reference, caution should be exercised when using it as the sole comparator for assessing alternative surgical strategies such as TMMR. Survival outcomes showed an even greater difference, with a 16-fold increased mortality risk in TMMR patients compared to the LACC trial’s open surgery arm [8]. While this finding is statistically significant, it should be interpreted with caution, as differences may influence it in baseline patient characteristics, adjuvant treatment administration, and disease burden. Furthermore, including higher-stage cases in the TMMR studies may have introduced a survival disadvantage that is not directly attributable to the surgical approach itself. For example, the study that showed the worst oncological outcomes is also the study with the highest percentage of locally advanced tumors (38%). In addition, the studies by Falconer [16] and Hockel [17] enrolled patients with diagnosed lymph node positivity, including patients with a loss of local disease control, who would likely benefit from adjuvant treatment. Not surprisingly, these his studies showed the highest reported rate of recurrence and mortality. Therefore, a subanalysis limited to early-stage cervical cancer was conducted. These findings indicate that when excluding higher-stage cases (IB3 or above), TMMR does not appear to confer a higher risk of recurrence or mortality compared to standard radical hysterectomy. However, given the wide confidence intervals and the non-significant p-values, these results should be interpreted with caution and warrant further prospective validation.

Another important consideration is the local recurrence rate. While TMMR is conceptually designed to remove all tissues ontogenetically susceptible to tumor spread, thus theoretically minimizing the risk of locoregional recurrence, this principle should not be interpreted as implying that recurrence risk is null or that adjuvant oncological treatment is unnecessary. Contemporary cancer management emphasizes a multidisciplinary approach, and the decision to omit adjuvant therapy must be based on a rigorous assessment of individual risk factors such as tumor size, lymphovascular space invasion, nodal involvement, and surgical margins. Although TMMR may reduce the need for additional treatment in selected early-stage cases, the benefits of systemic therapy and radiotherapy remain well-established, particularly in higher-risk patients. Therefore, any suggestion that TMMR can fully replace oncological treatment must be approached with caution and supported by prospective validation. While most studies report low local recurrence rates (<1%), complete local control was observed in Höckel’s original study [7], which first described the technique. The presence of locoregional recurrences in other studies suggests that technical execution variability and surgical expertise play a crucial role in determining oncological outcomes. This finding emphasizes the need for standardization and surgeon training to ensure optimal application of TMMR in clinical practice. Furthermore, the worst oncologic results were in the larger series, which also suggested greater variability of surgeons. This observation aligns with one of the major criticisms of the LACC trial, where significant variability in surgeon experience and a lack of standardized credentialing processes were identified as major limitations. Specifically, post-publication commentaries highlighted that participating surgeons had to perform only a minimal number of minimally invasive radical hysterectomies (as few as 10 cases) to be eligible, which may not be sufficient for overcoming the steep learning curve associated with such procedures. These factors may have contributed to the unexpectedly high recurrence rates observed in the minimally invasive arm. Similarly, the wide variability in TMMR outcomes across studies in our review may reflect differences in institutional expertise and the centralization of complex surgery in high-volume centers. This reinforces the necessity of standardizing training pathways and considering volume thresholds for surgeons performing TMMR in future prospective trials. This might testify that the technique requires very high expertise and experience, and single-center series at smaller volumes might have benefited from the performance of a single surgeon.

5.2 Clinical implication

The findings of this systematic review provide valuable insights into the oncological and safety profile of TMMR, reinforcing its potential role in the surgical management of early-stage cervical cancer in highly selected patients and experienced centers. Despite not being widely adopted as a standard approach, TMMR demonstrates a vast difference in DFS and OS rates, with reports comparable to those reported for radical hysterectomy, with the additional advantage of potentially reducing the need for adjuvant therapy. This could be particularly relevant for patients who wish to avoid radiotherapy-related morbidity, preserving quality of life while maintaining effective oncological control. In addition to its theoretical oncological advantages, TMMR may also offer short-term clinical benefits compared to traditional radical hysterectomy. These advantages are likely due to the more anatomically tailored dissection and preservation of autonomic nerves.

However, the variability in local recurrence rates across studies highlights the critical importance of technical standardization. Since TMMR is designed to remove all ontogenetically susceptible tissues, any local recurrence could suggest inconsistencies in surgical execution. This underscores the need for centralized surgical training programs and strict adherence to standardized TMMR protocols to ensure optimal oncological outcomes. This is also evidenced by how only two studies differed significantly from the rates of the other five, raising the possibility that the biases are related to applying the technique.

The comparison with the LACC trial [8] also discourages TMMR as an alternative to open radical hysterectomy. The observed data indicate a higher recurrence risk and death risk. Finally, TMMR represents a conceptually unique surgical approach based on the ontogenetic cancer field theory. If validated through additional research, it could pave the way for a paradigm shift in gynecologic oncology surgery, promoting a more tailored and compartmentalized approach to cervical cancer treatment.

5.3 Comparison with literature

With the publication of the LACC trial [8], huge reevaluations have occurred on the appropriateness of surgical treatment for cervix carcinomas. This may be related to the need to adhere to well-established surgical principles since their description by Shauta in 1908 [21] and Wertheim in 1911 [22]. TMMR should combine the principles of no direct exposure of the tumor with removing all tissue ontogenetically susceptible to disease, adding a level of oncologic safety. The impression is that where surgery adheres to these principles, DFS and OS rates are extremely high regardless of technique.

However, our analysis also highlights discrepancies in recurrence rates across studies, particularly regarding local control. This mirrors observations from studies on laparo-assisted vaginal radical hysterectomy (LAVRH) [23, 24], where differences in local recurrence patterns were attributed to variations in surgical technique and experience levels among operators​. This suggests technical variability, learning curve effects, and deviations from the original technique may account for isolated failures.

A key point of discussion is the role of adjuvant therapy. Unlike the open surgery arm of the LACC trial [8], where adjuvant treatment was administered according to Sedlis criteria [25], TMMR is designed as a standalone surgical approach [7]. This fundamental difference may account for the observed recurrence disparities and highlights the need for long-term follow-up studies directly comparing TMMR with and without adjuvant therapy. An additional consideration is that the TMMR series has included patients with IB3 and IIB cervical cancer, stages that, according to major clinical guidelines, would typically require definitive chemoradiotherapy (CCRT) rather than primary surgery [2, 3]. However, recent studies have suggested that post-neoadjuvant surgery may have a role in the management of these tumors, challenging the traditional paradigm of exclusive CCRT [26]. In contrast, TMMR is based on the opposite principle, proposing surgery as the primary and sole treatment for these patients. Given this conceptual divergence, a subgroup analysis focusing on patients with IB3 and IIB disease is essential to clarify whether TMMR offers comparable or superior oncological outcomes compared to standard multimodal treatment. Although we cannot perform this subanalysis in the reported studies, it should be noted that the worst oncological performance was reported in the study with the highest percentage of locally advanced carcinomas or including lymph node positive patients [16, 17]. This finding would also seem to be supported by the fact that the subanalysis devoted to the early stage cervical cancer groups showed no statistically significant differences with the standard of care, suggesting that adjuvant therapy played a large role in determining cancer outcomes in at-risk patients.

5.4 Strength and limitation

One of the main strengths of this study is the rigorous methodology, following PRISMA guidelines [9], which ensures a transparent and systematic analysis of the available literature. By evaluating DFS, OS, recurrence patterns, and perioperative complications, this review comprehensively assesses TMMR’s clinical impact, addressing its effectiveness, feasibility, and potential risks. A key strength is the comparative evaluation with the LACC trial [8], which serves as the gold standard for open radical hysterectomy. This comparison allows for a clinically relevant contextualization of TMMR outcomes, helping to clarify whether this approach can be considered comparable to standard radical surgery.

Despite these strengths, several limitations must be acknowledged. First, the heterogeneity of the included studies is a major challenge, as they differ in sample size, surgical execution, patient selection criteria, and follow-up duration, making direct comparisons difficult. Additionally, most studies are single-center and retrospective, meaning that results may be influenced by institutional expertise and selection biases, limiting the generalizability of the findings.

A particularly relevant limitation is that all available studies on TMMR have been conducted in only three countries: Italy, Sweden, and Germany. This clearly indicates that TMMR remains a highly niche technique with limited international adoption. The lack of multicentric, multinational trials raises concerns about whether TMMR outcomes are reproducible across different clinical settings or whether its success is highly dependent on a few experienced centers. Another critical issue is the potential learning curve effect. The fact that recurrence rates vary significantly across studies suggests that surgeon experience and case volume play a significant role in oncological success. In particular, the multicentric study by Buderath et al. [14], which included multiple centers with low case volumes, showed higher complication rates and poorer oncological outcomes, reinforcing the idea that TMMR requires significant expertise to achieve optimal results.

Additionally, this review underscores the lack of randomized controlled trials (RCTs) directly comparing TMMR to standard radical hysterectomy. Without such data, it remains difficult to determine whether TMMR truly represents an alternative in terms of long-term oncological control. Finally, an unresolved issue concerns the role of adjuvant therapy in TMMR. While this technique is designed to eliminate the need for additional treatments, no study has directly compared patients undergoing TMMR with and without adjuvant therapy, leaving open questions regarding its optimal application in clinical practice.

One of the significant limitations of the included studies is the lack of analyses assessing the correlation between oncologic outcomes and tumor-intrinsic factors. The significant variability in patient enrollment, particularly regarding tumor size and extracervical dissemination, may obscure the true efficacy of TMMR. This is especially relevant because TMMR has often been applied to very high-risk patients, who would not typically be considered for surgical treatment under current standards of care. Future studies with more rigorous patient selection criteria will be necessary to clarify these uncertainties.