Final survival analysis from the LACC trial defines the current standard of care in surgical treatment of cervical cancer, however does not mark the final say
Editorial Commentary

Final survival analysis from the LACC trial defines the current standard of care in surgical treatment of cervical cancer, however does not mark the final say

Sahar Salehi1,2 ORCID logo, Henrik Falconer1,2

1Department of Women’s and Children’s Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden; 2Department of Pelvic Cancer, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden

Correspondence to: Dr. Sahar Salehi, MD. Department of Women’s and Children’s Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden; Department of Pelvic Cancer, Theme Cancer, Karolinska University Hospital, Eugeniavägen 3, A5:01, 171 76 Stockholm, Sweden. Email: sahar.salehi@regionstockholm.se; sahar.salehi@ki.se.

Comment on: Ramirez PT, Robledo KP, Frumovitz M, et al. LACC Trial: Final Analysis on Overall Survival Comparing Open Versus Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer. J Clin Oncol 2024;42:2741-6.

Keywords: Procedural phase III trials; minimally invasive surgery; oncologic outcome; cervical cancer

Received: 07 October 2024; Accepted: 29 November 2024; Published online: 23 February 2025.

doi: 10.21037/actr-24-208

Introduction

The final results from the Laparoscopic Approach to Cervical Cancer (LACC) trial was recently published in the Journal of Clinical Oncology (1). As expected, the outcomes remain more or less unchanged compared to the initial publication in 2018, and the authors conclude that the open approach should be standard of care for surgical treatment of early-stage cervical cancer (2). The unexpected results from the LACC-trial call for a wider discussion on the limitations and pitfalls of randomized trials in surgery including a background on the development of minimally invasive surgery.

Surgical trials differ substantially from pharmaceutical trials and provide their own sets of challenges and pitfalls discussed herein, with special focus on minimally invasive surgical oncology.

The phase III trial in the context of surgical development

While drug therapy typically does not necessitate specific expertise to deliver new treatments, the outcomes of surgical/interventional procedures are profoundly influenced by the surgeon’s/operator’s proficiency (and experience). As a result, new surgical procedures or techniques must involve surgeons that have reached an adequate level of competence with the new technique before the start of a phase III trial. At the same time, the new procedure/technique must not yet be considered standard of care by surgeons and patients. Moreover, the surgical expertise/proficiency in the gold standard/control method must remain. Accordingly, considerable difficulties in timing of a surgical phase III trial exists. Albeit surgical proficiency is inherently a subjective variable that may never objectively be defined within the boundaries of science, in the setting of clinical trials, surgical proficiency has to be standardized/defined to some extent.

The cornerstones to consider in all studies are internal validity/systematic error (bias, confounding), precision/random error, causality and external validity.

The main advantage of the phase III trial is the reduction in risk of uneven confounding and bias by randomization. Therefore, the phase III trial is considered the ultimate methodology to determine standard of care. For this aim to be met, the study design, power and sample size, the total study time and feasibility must also be carefully considered. To mitigate risk of uneven confounding/bias (systematic error) the sample size must be large enough, and the surgical proficiency must be equally sufficient for the experimental technique/procedure and the gold standard/control. However, in trials involving procedural interventions, there are particular challenges:

  • There is a probability that the new technique is introduced by either less experienced (“younger”) surgeons that do not master the old/gold standard procedure or the more experienced (“older”) surgeons that already master the old/gold standard procedure. Either way this poses risk of an uneven level of proficiency by randomization arm.
  • There is a risk that some patients are eager to receive the novel procedure/technique and decline participation, reducing the intended sample size needed to sufficiently ascertain the certainty of the results. In order to mitigate selection bias, the experimental procedure should therefore not be offered outside the clinical trial, especially within participating centers within a trial.
  • The accrual target must be feasible/manageable to avoid exhaustion among recruiting health care professionals. Including multiple centers may increase the likelihood of achieving the intended sample size, however, may result in decreased internal validity as surgical proficiency becomes more difficult to control.

The generalizability is critical when considering the implementation of the results of a phase III trial. To increase the external validity, the inclusion and exclusion criteria should be pragmatic to represent the actual population/clinical practice. In addition, participation of multiple institutions, especially from different countries/regions, increase the generalizability.

  • Nevertheless, an increased external validity may decrease the internal validity by reducing the control of the level of surgical proficiency. The internal validity is in turn also a prerequisite for external validity. Moreover, patient selection is key for successful outcome, why the inclusion and exclusion criteria must be carefully considered.

A phase III trial may be designed in different ways to determine: (I) if a new or different surgical procedure/technique is better (superiority design); (II) if a new/different surgical procedure/technique is equally efficient as the standard however with other advantages, e.g., fewer side-effects, easier to perform (equality design); (III) if a new surgical procedure/technique is at least not worse than the standard treatment, however with the advantage of superior outcomes in other ways, e.g., health economics, complications, quality of life (non-inferiority design) (3-5). A negative trial with a superiority design may not conclude that the intervention is equal to the control. Albeit there is a possibility of an inconclusive result that may not lead to any definitive conclusion, the equivalence and non-inferiority trial designs enable researchers to determine both superiority and/or inferiority of novel interventions. As the non-inferiority trial is one sided, the sample size needed to reject or retain the null hypothesis is smaller than in the two-sided equivalence trial. For this reason and since minimally invasive surgery per se (given that the surgical procedure remains the same) has not generally been considered to improve oncologic outcome, the non-inferiority design is prevalent in trials investigating the oncologic safety of minimally invasive surgery. However, the non-inferiority design is in essence a test of secondary outcomes of interest that must be motivated, carefully considered and disclosed. Moreover, the chosen margin of inferiority that is accepted in the intervention, the non-inferiority margin, may always be debated and even be considered unethical to accept altogether when investigating oncologic outcome. Theoretically, the non-inferiority design could lead to the acceptance of gradually worse survival outcomes, especially if large non-inferiority margins are applied. In addition, it is important to consider the chosen hazard ratio (HR) for the non-inferiority margin. Even if the actual absolute percentage of the non-inferiority margin is fixed, the chosen HR for the non-inferiority margin may substantially increase or decrease the sample size and the number of events needed to reject or retain the null hypothesis. A larger HR for the non-inferiority margin furthermore reduces the precision of the estimate and overall reliability of the results.

Oncologic safety of minimally invasive surgery

The role of minimally invasive surgery in pelvic cancers was investigated in the new millennium. The results of phase III trials to determine the oncologic safety of minimally invasive surgery as compared to laparotomy established the non-inferiority of minimally invasive surgery in cancer of the urinary bladder, the rectum and the endometrium (6-9). Nevertheless, despite their non-inferiority design, no other obvious convincing patient or health care benefit was reported from these trials.

Considering the long learning curve and the level of proficiency needed to perform more advanced procedures by traditional laparoscopy, the uptake of the minimally invasive approach in gynecologic oncology increased dramatically only after the introduction of robot assisted laparoscopic surgery in 2005, when the United States Food and Drug Administration (U.S. FDA) approved its use in gynecologic surgery (10).

Surgical treatment of cervical cancer

Surgical treatment of early stage cervical cancer includes the resection of the uterus and uterine cervix including the adjacent tissues and the upper vagina in combination with a pelvic lymphadenectomy. In contrast to malignancies in the endometrium, urinary bladder and rectum, cervical cancer is not confined or enclosed within the organ per se. When resecting the cervix from the vagina, there is risk for exposure of tumour. The first phase III trial to investigate the oncologic safety of minimally invasive surgery in cervical cancer was prematurely closed with results that demonstrated a detrimental effect of minimally invasive surgery on oncologic outcome (2).

The LACC trial

The international LACC trial was a multi-center phase III trial to determine the oncologic safety of minimally invasive surgery as compared to laparotomy for the treatment of early stage cervical cancer. The primary outcome was disease-free survival (DFS) at 4.5 years after randomization (2). The trial was initially set up as a two-tailed equivalence trial, accepting a 7% margin of equivalence and power of 80% when assuming a 90% DFS in the control group, for rejection of the null hypothesis. The corresponding HR or number of events needed for declaring equivalence is not clear and was not disclosed. These assumptions rendered a sample size of 740 women with a total study time of 9 years equally divided by accrual and follow-up. The study was finally analyzed and reported as a non-inferiority trial.

Women with International Federation of Gynecology and Obstetrics (FIGO) [2009] stages IA1 (with lymph vascular invasion), IA2, or IB1 were included and the randomization procedure, by equal allocation (1:1), was stratified by participating center, age and stage. The trial attempted to control for proficiency in the experimental approach and participating surgeons were required to have performed at least 10 procedures independently to be accredited including providing two recorded videos of the procedure, reviewed by members of the Trial Steering Committee.

The LACC trial was initiated during 2008, however the accrual was much slower than expected and still ongoing after 9 years. At this time, it was prematurely closed in 2017 after concerning safety signals from the trial’s Data Safety Monitoring Committee, before reaching the planned sample size, due to imbalances in deaths by randomization arm. The final study population comprised 631 women randomized to either open radical hysterectomy (n=312) or minimally invasive surgery (n=319). In the minimally invasive surgery group, the majority of women were operated using conventional laparoscopy (84%) and 16% by robot assisted laparoscopic surgery. There were no differences in tumor size, histology, adjuvant treatment or patient characteristics. After a median follow-up of 30 months, minimally invasive surgery was inferior to laparotomy with an HR of 3.7 [95% confidence interval (CI): 1.63–8.58] for DFS and 6.0 (95% CI: 1.77–20.3) for overall survival. These estimates were based on 34 recurrences (27 in the minimally invasive surgery group and 7 in the open surgery group) and 22 deaths (19 in the minimally invasive surgery group and 3 in the open surgery group).

The results after complete follow-up, matching the preplanned 4.5 years, was recently published (1). In this final data follow-up paper, the previous results were corroborated, with a better precision and substantially decreased estimate for death. The HR for DFS in the minimally invasive surgery group was 3.91 (95% CI: 2.02–7.58), based on in total 48 recurrences (37 in the minimally invasive group and 11 in the open surgery group) and the HR for death 2.71 (95% CI: 1.32–5.59) based on 38 deaths (28 in the minimally invasive surgery group and 10 in the open surgery group).

Discussion

To date, the LACC trial has delivered the highest level of evidence for the effect of minimally invasive surgery in early stage cervical cancer. Moreover, the secondary outcomes that motivated the trial including its design were also negative, as there was no difference in perioperative complications and adverse events within 6 months after surgery and no difference in health-related quality of life (11,12).

The trial was appropriately designed to answer the intended research question with obvious efforts made to ascertain internal validity and generalizability to be able to conclude causality. For this reason, the results must constitute the basis for current standard. At the same time, the study protocol lacks information on the definitive study design (equivalence or non-inferiority) albeit reported as a non-inferiority trial. Moreover, data on the HR for the non-inferiority margin and number of events needed to reject or retain the null hypothesis is not stated. These variables affect the precision of the estimate as well as the overall ability to assess the soundness of the statistical assumption that lays the foundation of any phase III trial. Several explanations behind the potentially harmful effects of minimally invasive surgery have been suggested following the LACC trial. In particular, surgical proficiency/learning curve and the impact of intrauterine manipulation and risk of intraoperative tumor spillage that could lead to a varied pattern of recurrence have been debated. However, these remain mainly theoretical suggestions without supporting evidence (13).

As most well conducted phase III trial, the LACC trial also has weaknesses. The method of ascertaining surgical proficiency may be criticized for its subjective nature and was only attempted for the intervention and not the control. The trial recruited participants from 33 centers worldwide. Albeit this strengthens the generalizability, it also weakens the internal validity, represented by the skewness of the concentration of all primary outcome events (recurrences) to only 14 of the participating centers (in the first publication) (2). In addition, the accrual period was two times longer than planned at time of premature closure. During this time robot assisted surgery developed to the preferred modality for minimally invasive surgery in gynecologic oncology and even standard of care at many international centers.

The number of events behind the practice changing results of the LACC trials also leaves a demur to digest. Discarding an established surgical technique based on 48 recurrences, unchallenged, may not be considered reasonable. Computerization will certainly lead to continuous refinement of robotic-assisted laparoscopy, and it would be unwise to discard the technology based on such few events. In response, three phase III trials are currently recruiting participants to investigate the oncologic safety of minimally invasive surgery in comparison to laparotomy in early stage cervical cancer (14-16). The ongoing three trials will together, if their intended plan is reached, contribute with an additional 552 events to determine the effect of minimally invasive surgery on oncologic outcome. Details of the three trials including a head-to-head comparison to the LACC trial is provided in Table 1.

Table 1

Original study design of the four phase III trials investigating oncologic outcome after minimally invasive surgery in operable cervical cancer

Variables LACC trial Different surgical approaches in patients of early-stage cervical cancer RACC trial ROCC trial
Phase III design Equivalence Non-inferiority Non-inferiority Non-inferiority
Recruitment area World-wide China Europe (open for all) North America
Inclusion IA1*–IB1 (FIGO 2009) IA1*, IA2, IB1 (FIGO 2009) 1B1–IIA1** (FIGO 2018) 1A2–1B2 (FIGO 2018)
Intervention Minimally invasive surgery*** Minimally invasive surgery*** Robot-assisted laparoscopy Robot-assisted laparoscopy
Control Laparotomy Laparotomy Laparotomy Laparotomy
Primary outcome DFS at 4.5 years DFS at 5 years RFS at 5 years DFS at 3 years
Planned accrual/follow-up time/total study time, years 4.5/4.5/9 2/4/6 5/3/8 NA
Non-inferiority margin, % 71 8 7.5 7
Expected DFS/RFS in the control arm, % 90 85 85 92
HR for the non-inferiority margin NA 1.60 1.57 NA
Number of events NA 336 127 89
Power, % (1 − β) 80 80 80 90
α 0.05 (two-sided) 0.05 (two-sided) 0.05 (one-sided) 0.05 (one-sided)
Estimated ample size****, n 740 1,158 768 840
Intrauterine manipulator Allowed Allowed Not allowed Not allowed
Attempt to control institutional proficiency No NA Yes2 NA
Attempt to control surgical proficiency in intervention arm Yes3 Yes4 Yes5 NA
Attempt to control surgical proficiency in the control arm No Yes4 Yes2,5 NA

*, with lymph-vascular space invasion; **, 1B3 excluded; ***, laparoscopy and robot assisted laparoscopy; ****, not including estimated drop-outs. 1, equivalence margin. 2, established robotic surgery unit for at least 3 years. At least 10 radical hysterectomies for early-stage cervical cancer per year in the unit. Minimum of 20 radical upfront/interval debulking surgeries per year for advanced ovarian cancer. Intensive care unit available. Review of 20 surgical (advanced open procedures and radical hysterectomies) and pathology reports including 30-day complications, peroperative bleeding and operation time. 3, 10 documented cases of minimally invasive radical hysterectomies as main surgeon, or providing a videorecording of one MIS radical hysterectomy, reviewed and accepted by the Trial Management Committee. 4, for surgeon to qualify: “the skills and learning curves of these surgeons, at least 100 unselected, consecutive radical hysterectomy cases for early-stage cervical cancer in their past decade of practice will be retrospectively collected for the analysis of surgical and survival outcomes”. 5, all included surgeons must be approved by the coordination investigators ensuring adherence to protocol. In the site identification and quality assessment form the participating surgeons experience and annual case-load will be reported for review. LACC, Laparoscopic Approach to Cervical Cancer; RACC, Robot-assisted Approach to Cervical Cancer; ROCC, Robotic Versus Open Hysterectomy Surgery in Cervix Cancer; FIGO, International Federation of Gynecology and Obstetrics; DFS, disease-free survival; RFS, recurrence-free survival; HR, hazard ratio; NA, information not publicly available.

In conclusion, the results of the LACC trial demonstrates the importance of clinical equipoise and of conducting well-designed phase III trials despite favorable results from multiple observational studies, recommendations of consensus groups and expert opinion (17-19). Nevertheless, standard of care cannot be determined on a limited number of events, especially when assessing surgical innovations/procedures. It is for this reason important to test the reproducibility of the LACC-trial results in a controlled fashion with informed patient consent within additional phase III trials. Accordingly, the final analysis on oncologic outcome from the LACC trial defines current standard of care, however, does not mark the final say.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-208/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-208/coif). H.F. reports payments from Surgical Science and is a board member of Surgical Science. The other author has 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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doi: 10.21037/actr-24-208
Cite this article as: Salehi S, Falconer H. Final survival analysis from the LACC trial defines the current standard of care in surgical treatment of cervical cancer, however does not mark the final say. AME Clin Trials Rev 2025;3:8.

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