Sentinel lymph node (SLN) mapping is a less invasive and more accurate nodal staging technique that may replace radical pelvic lymphadenectomy (PL) in women with early-stage cervical cancer. However, evidence regarding the accuracy of SLN mapping in women with tumors >20 mm remains scarce. Further, there is limited evidence regarding the potential reduction of lymphedema and its effects on quality of life (QoL). The overall aim of this PhD thesis was to investigate the clinical aspects of the SLN mapping procedure, including the technique, accuracy, and patient-reported lymphedema in women with early-stage cervical cancer.
To achieve this objective, we conducted a multicenter pilot study (Paper 1) and a national multicenter prospective cohort study (SENTIREC CERVIX) (Papers 2, 3, and 4).
In Paper 1, we facilitated structured surgical training in national centers that undertake the surgical treatment of cervical and endometrial cancer in Denmark to ensure surgeon proficiency of the SLN mapping technique. Each center performed a minimum of 30 surgical procedures due to the previously documented learning curve when implementing SLN mapping. The four centers performed a total of 140 (range 30-46) procedures following a protocolled introduction to SLN mapping. The total SLN detection rate was 91.3%, with 68.8% bilateral mapping. The cumulative SLN detection rate was above the pre-set criterion of 80% from the beginning of inclusion at three centers, while one center reached the criterion after 20 procedures.
In Paper 2, we evaluated SLN mapping in women with early-stage cervical cancer and investigated the accuracy of SLN mapping and fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in women with tumors >20 mm. We included women with cervical cancer in a national prospective cohort study from March 2017 – January 2021 to undergo SLN mapping in addition to their standard operation. Women with tumors ≤20 mm underwent SLN only. Women with tumors >20 mm underwent completion PL and removal of FDG-PET/CT positive nodes. We determined the SLN detection rate and the incidence of nodal disease in all women. Further, the sensitivity and negative predictive value (NPV) of SLN mapping and the sensitivity, specificity, NPV, and positive predictive value (PPV) of FDG-PET/CT were assessed in women with tumors >20 mm. We included 245 women, in whom 38 (15.5%) had nodal metastasis. The SLN detection rate was 96.3%, with 82.0% bilateral detection. Nodal metastatic disease was detected in 5.4% of 130 women with tumors ≤20 mm and in 27.0% of 115 women with tumors >20 mm. In a stratified analysis of 103 women with tumors >20 mm, 27 (26.2%) had nodal metastases. The sensitivity of SLN mapping adhering to the algorithm was 96.3% (95% confidence interval (CI) 81.0-99.9%), and the NPV was 98.7% (95% CI 93.0-100%). For FDG-PET/CT imaging the sensitivity was 14.8% (95% CI 4.2-33.7%), the specificity 85.5% (95% CI 75.6-92.5%), the NPV 73.9% (95% CI 63.4-82.7%), and the PPV 26.7% (95% CI 7.8-55.1%).
In Paper 3, we evaluated if the revised International Federation of Gynecology and Obstetrics (FIGO) 2018 staging in women with early-stage cervical cancer correctly predicted the risk for nodal metastases. We reallocated women from FIGO-2009 to FIGO-2018 stages and used regression models to investigate the risk ratio (RR) of FIGO-2018 stages and tumor characteristics associated with nodal metastases. Stage migration occurred in 54.7%; due to tumor size or depth of invasion in 71.6%, and due to nodal metastases in 28.4%. In multivariate analysis, risk factors significantly associated with nodal metastases were FIGO-2018 ≥ IB2 (RR 5.0, 95% CI 2.3-10.9, p < 0.001), proportionate depth of invasion > 2/3 (RR 1.9, 95% CI 1.1-3.4, p = 0.03), and lymphovascular space invasion (RR 5.6, 95% CI 2.9-10.6, p < 0.001).
In Paper 4, we assessed patient-reported incidence and severity of lymphedema and its impact on QoL in women with early-stage cervical cancer who underwent SLN mapping only or SLN+PL as part of their primary surgery. A total of 200 women completed validated patient-reported outcome measures before surgery and three months postoperative. The incidence of early lymphedema was 5.6% (95% CI 2.1-11.8%) in women who underwent SLN mapping only and 32.3% (95% CI 22.9-42.7%) in women who underwent SLN mapping and PL. Lymphedema symptoms did not impair physical performance (p = 0.09) and appearance (p = 0.2) in women who underwent SLN mapping only. In women who underwent SLN+PL, lymphedema symptoms were severe with impairment of physical performance (p = 0.001) and appearance (p = 0.007). Reporting lymphedema was significantly associated with impaired body image (p = 0.002), physical- (p = 0.008), role- (p = 0.04), and social functioning (p = 0.007), and a higher level of fatigue (p = 0.01) and pain (p = 0.04).
The results of this thesis contribute with high-quality data regarding clinical and patient-related aspects of the SLN mapping procedure in women with early-stage cervical cancer. Our study has high external validity since all national cancer centers participated with a high participation rate. We show that SLN mapping seems to be an adequate staging procedure in early-stage cervical cancer tumors ≤20 mm. In tumors >20 mm, SLN mapping is highly sensitive but demands full adherence to the SLN algorithm. The contribution of FDG-PET/CT in nodal staging of women with FIGO I stages with tumors <40 mm seems limited, and we suggest reserving it for women with locally advanced disease. The revised FIGO-2018 staging system with attention on depth of invasion rather than horizontal width seems to correctly reflect the risk of metastases since women with depth of invasion ≤5 mm have a low risk of lymph node metastases independent of tumor size. Further, we show that women who undergo SLN mapping only rarely develop early lymphedema. In contrast, women who undergo completion PL have a high incidence of lymphedema, impairing physical performance and appearance. Finally, we demonstrate a considerable deterioration of QoL in women reporting lymphedema, involving several areas of psychological well-being and physical functioning
Implementing research into the clinical everyday setting is crucial. With this project, SLN mapping was introduced to women with early-stage cervical cancer in Denmark. These studies contributed to changing the Danish national guidelines for nodal staging of women with early-stage cervical cancer. The more accurate and less invasive SLN mapping technique is now implemented as standard procedure, replacing PL in women with tumors ≤20 mm. In women with tumors >20 mm, we suggest that SLN mapping is an accurate method for nodal staging, which may replace PL due to the high sensitivity and increased detection of nodal metastases allowing for improved allocation to adjuvant therapy. However, due to the explorative nature of this study and the awaited recurrence and survival data from larger studies, we cannot yet finally conclude on the accuracy and the oncological safety of SLN mapping in women with tumors >20 mm. Until the oncological safety is established, we recommend SLN mapping combined with PL in women with tumors >20 mm. This recommendation has now been adopted in the Danish national guidelines.
Our results on the association between lymph node metastases and stages of the revised FIGO-2018 system have contributed to supporting the Danish recommendations of treatment decisions in the adaptation to FIGO-2018. We confirm that women with FIGO-2018 ≥ IB2, proportionate depth of invasion > 2/3, and lymphovascular space invasion have a significantly higher risk of nodal metastases. However, we note that a large number of women with these intermediate-risk factors do not have lymph node metastases and may not need adjuvant therapy. The implementation of SLN mapping with ultrastaging has improved the identification of women with a higher risk of recurrence due to the increased detection of nodal metastases. However, if no lymph node metastases are identified, it could be considered to omit routine adjuvant therapy in women with intermediate-risk factors. We comprehensively mapped patient-reported lymphedema and contribute new evidence regarding patient-related effects of SLN only and of SLN with completion PL. Our study provides new knowledge for patient information, communication, and shared-decision making regarding future standard staging procedures in which information on accuracy, oncological safety, along with advantages and possible disadvantages of the procedure, should be taken into account. Future updated long-term results of the SENTIREC CERVIX study will provide oncological safety data in women with tumors ≤20 mm besides longitudinal patient-reported outcome assessment of lymphedema and its impact on QoL after SLN only and SLN with completion PL.