Abstract
Objective:
To compare the prevalence of patient-reported lower extremity lymphedema and evaluate patient-reported quality of life after sentinel lymph node mapping versus comprehensive lymphadenectomy with or without sentinel lymph node mapping for the surgical management of early-stage cervical cancer.
Methods:
In July 2022, we mailed a survey that included a validated 13-item lower extremity lymphedema screening questionnaire to patients who underwent lymph node evaluation at time of primary surgery for 2018 FIGO stage IA1 to IIB cervical cancer between January 1, 2006, and January 31, 2019. We excluded patients diagnosed with lower extremity lymphedema prior to surgery and those who answered ≤6 survey items, and we carried out two group comparisons: sentinel lymph node mapping versus lymphadenectomy with or without sentinel lymph node mapping, and patients with lower extremity lymphedema versus not.
Results:
Of 459 potential participants, 90 (20%) responded to the survey, all of which were evaluable (37 sentinel lymph node; 53 lymphadenectomy ± sentinel lymph node). Self-reported lower extremity lymphedema prevalence was 10.8% (4/37) in the sentinel lymph node mapping group and 43.4% (23/53) in the lymphadenectomy with or without sentinel lymph node mapping group (odds ratio [OR], 6.32; 95% confidence interval [CI], 2.14 to 23.5; p=0.002). Histologic subtype and number of lymph nodes removed were associated with increased prevalence of lower extremity lymphedema. After adjusting for histology subtype, lymphadenectomy retained independent association with an increased prevalence of lower extremity lymphedema over sentinel lymph node mapping (OR, 4.96; 95% CI, 1.61 to 18.8; p=0.009). Patients with self-reported lower extremity lymphedema had significantly worse quality of life compared to those without self-reported lower extremity lymphedema.
Conclusion:
We found sentinel lymph node mapping to be independently associated with a significantly decreased prevalence of patient-reported lower extremity lymphedema and with improved quality of life in patients undergoing surgical management of early-stage cervical cancer.
Keywords: cervical cancer, sentinel lymph node, lymphadenectomy, lymphedema, patient-reported outcomes
Introduction
Lymph node assessment is integral for managing early-stage cervical cancer, as the presence of nodal metastases guides decisions around adjuvant therapy. Thus, pelvic lymphadenectomy with radical hysterectomy or trachelectomy has long been the surgical standard of care to evaluate patients with stage IA1 (with lymphovascular space invasion) to stage IIB tumors. However, because the incidence of nodal involvement in this composite cohort is about 15% to 20% (varies based on increasing tumor size), lymphadenectomy can lead to unnecessary surgical risk and morbidity.(1–3)
One potential complication of pelvic lymphadenectomy is lower extremity lymphedema. If left untreated, this can increase patients’ risk of cellulitic infections, functional decline, and impaired wound healing,(4–6) eventually leading to severe lifelong morbidity and diminished quality of life (QoL).(7, 8) Although early recognition is key to treatment and prevention of worsening symptoms, avoidance of predisposing factors such as lymphadenectomy is crucial.
Sentinel lymph node biopsy represents a potential alternative to lymphadenectomy. The procedure is based on two principles: that lymphatic drainage follows a predictable pattern, and that the sentinel lymph node represents the filter where cancer, if present, should first be detected. This technique has been studied and deemed safe and effective in breast cancer and melanoma,(9, 10) and its wide adoption in breast cancer surgery has dramatically reduced rates of upper extremity lymphedema.
Sentinel lymph node mapping has also been proven safe and effective in cervical cancer, with confirmed high sensitivity and low false-negative rates for detecting pelvic nodal disease.(11–13) Thus, national guidelines now recommend this procedure in addition to lymphadenectomy in early-stage cervical cancer.(14) The therapeutic superiority of lymphadenectomy over sentinel lymph node mapping alone for cervical cancer, especially in high-risk cases and those with sentinel lymph node metastasis, is an area of debate, and two ongoing prospective studies (SENTIX [NCT02494063] and SENTICOL III [NCT03386734]) aim to evaluate oncologic outcomes following sentinel lymph node biopsy in cervical cancer.
In addition, limited data exist regarding lower extremity lymphedema after sentinel lymph node biopsy. In general, the incidence of surgery-related lower extremity lymphedema in gynecologic malignancies is about 25% but may be as high as 70% in some populations.(15–17) Lack of standardized measurements and variations in timing of postoperative assessment impact the wide range of reported incidence and limit the interpretation of these values.
Currently, researchers have developed two validated lower extremity lymphedema patient-reported outcome questionnaires, with one 13-item version validated by investigators at the Mayo Clinic.(18) The researchers used this tool in a population of patients with endometrial cancer and observed a 23% attributable risk of lower extremity lymphedema, which was associated with a significant negative effect on QoL, in those who underwent a comprehensive pelvic and para-aortic lymphadenectomy.(19) Recently, Leitao et al demonstrated a significantly lower prevalence of self-reported lower extremity lymphedema in patients that underwent sentinel lymph node mapping versus lymphadenectomy for endometrial carcinoma; however, this has not been objectively assessed using validated methods in patients undergoing surgery for cervical cancer.(20)
Here, we report the results of an institutional review board–approved protocol with the primary aim of determining the prevalence of self-reported lower extremity lymphedema among patients who underwent either sentinel lymph node mapping or lymphadenectomy during surgery for newly diagnosed early-stage cervical cancer at our institution. We used a validated lower extremity lymphedema patient-reported outcome tool to assess the prevalence of lower extremity lymphedema, and our secondary aim was to determine whether patient-reported lower extremity lymphedema was associated with worse QoL.
Methods
Following Memorial Sloan Kettering Cancer Center institutional review board approval (22–002) for this cohort study, we identified all patients who had undergone primary surgery for newly diagnosed cervical cancer at our institution between January 1, 2006, and January 31, 2019. We used the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system; therefore, all stage II cases were based on final pathologic findings. We excluded patients that had died at the time of study initiation, did not speak English, or had a “do not contact” notation in their electronic medical record. We mailed a questionnaire to the included patients, which consisted of a validated 13-item lower extremity lymphedema screening survey and validated QoL assessment tools (online supplemental text) in July 2022—a minimum of 36 months after surgery.
The 13-item survey (items 9 to 21 in the online supplemental text) is indicative of the presence of lower extremity lymphedema if the score exceeds 5 (range, 0 to 52). Validated by the Mayo Clinic, the survey has high sensitivity (95.5%) and specificity (86.5%) for predicting lower extremity lymphedema in all patients (with 94.8% and 76.5%, respectively, in obese patients).(18) Our mailed questionnaire also included two validated QoL assessment tools: European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (QLQ-C30) (items 22 to 49 in the online supplemental text) and EORTC QLQ-CX24 (items 50 to 75 in the online supplemental text).(21–23) Item 8 identified patients who reported a diagnosis of lower extremity lymphedema prior to surgery.
To contact patients, we utilized a two-phase mail-first recruitment design,(24, 25) which involved distributing a second mailing to nonrespondents a month after the first mailing. After another month, we used an institutional review board–approved phone script to call the remaining nonrespondents no more than two times and remind them to complete the questionnaire. We used the electronic medical record to abstract clinicopathologic data and entered questionnaire responses into the web-based Research Electronic Data Capture platform. Those who reported preoperative lower extremity lymphedema (item 8) or answered ≤6 of the 13 survey items were excluded.
The primary endpoint was patient-reported lower extremity lymphedema prevalence among the two cohorts: the sentinel lymph node group, which included patients who had only sentinel lymph nodes excised and mapped, with at least one identified both clinically and pathologically, plus patients who had a unilateral, side-specific lymphadenectomy of an unmapped hemipelvis; and the lymphadenectomy group, which included patients who had a lymphadenectomy alone or following sentinel lymph node mapping at their initial surgical management, plus those for whom bilateral sentinel lymph node mapping had failed.
The statistical design of this protocol assumed a two-sided type I error of 5% and power of 90%, with an expected sample size of 94 patients per arm to detect a difference of lower extremity lymphedema rates from 35% (lymphadenectomy arm) to 15% (sentinel lymph node arm). We assumed binomial distribution to estimate the rate of lower extremity lymphedema and 95% confidence interval (CI) in each cohort. To compare prevalence between the two groups, we used a two-sample binomial proportions test. In addition, we performed a sensitivity analysis considering time to development of lower extremity lymphedema as a time-to-event variable starting from surgery date to questionnaire date using interval censoring methodology(26) (27) (the exact lower extremity lymphedema date was not known but was before the questionnaire date). To compare lower extremity lymphedema incidence between the cohorts, we applied a type I interval censoring method.(28)
We have provided descriptive statistics for all baseline variables for the entire cohort and the sentinel lymph node and lymphadenectomy subgroups (Table 1). We used the Fisher exact test and Wilcoxon rank sum test to compare the distribution of covariates between the groups and univariate logistic regression to investigate the effect of baseline covariates on the presence of patient-reported lower extremity lymphedema. In the logistic regression, we applied logarithm transformation to the number of total lymph nodes removed because the data were skewed. In the univariate setting, we built a multivariate logistic model based on significant variables (p<0.05).
Table 1.
Select clinicopathologic characteristics.
| Characteristic | Whole cohort | SLN | LND | p value for SLN vs LND only |
|---|---|---|---|---|
| N | 90 | 37 | 53 | |
|
| ||||
| Age at surgery (years) | 0.2 | |||
| Median | 39 | 41 | 38 | |
| Range | 15–78 | 15–78 | 21–65 | |
|
| ||||
| BMI (kg/m 2 ) | 0.6 | |||
| Median | 23.9 | 24.1 | 23.7 | |
| Range | 17.9–37.6 | 18.2–35.2 | 17.9–37.6 | |
|
| ||||
| FIGO stage | 0.02 | |||
| IA | 19 (21.1) | 13 (35.1) | 6 (35.8) | |
| IB | 65 (72.2) | 23 (62.2) | 42 (79.2) | |
| II | 6 (6.7) | 1 (2.7) | 5 (9.4) | |
|
| ||||
| FIGO tumor grade | 0.06 | |||
| 1 | 16 (17.8) | 10 (27.0) | 6 (11.3) | |
| 2 | 45 (50.0) | 13 (35.1) | 32 (60.4) | |
| 3 | 21 (23.3) | 9 (24.3) | 12 (22.6) | |
| Missing | 8 (8.9) | 5 (13.5) | 3 (5.7) | |
|
| ||||
| Histology | 0.03 | |||
| Squamous | 27 (30.0) | 16 (43.2) | 11 (20.7) | |
| Adenocarcinoma | 54 (60.0) | 20 (54.1) | 34 (64.1) | |
| Other* | 9 (10) | 1 (2.7) | 8 (15.1) | |
|
| ||||
| Surgical procedure | <0.001 | |||
| Radical hysterectomy | 59 (65.6) | 25 (67.5) | 34 (64.2) | |
| Simple hysterectomy | 4 (4.4) | 3 (8.1) | 1 (1.9) | |
| Trachelectomy | 19 (21.1) | 2 (5.4) | 17 (32.1) | |
| CKC/LEEP | 8 (9.9) | 7 (18.9) | 1 (1.9) | |
|
| ||||
| Hypertension | 0.7 | |||
| No | 79 (87.8) | 33 (89.2) | 46 (86.8) | |
| Yes | 11 (12.2) | 4 (10.8) | 7 (13.2) | |
|
| ||||
| Diabetes | 0.2 | |||
| No | 88 (97.8) | 37 (100.0) | 51 (96.2) | |
| Yes | 2 (2.2) | 0 (0.0) | 2 (3.8) | |
|
| ||||
| Previous pelvic surgery | 0.3 | |||
| No | 62 (68.9) | 23 (62.2) | 39 (73.6) | |
| Yes | 28 (31.1) | 14 (37.8) | 14 (26.4) | |
|
| ||||
| Smoking history | 0.6 | |||
| No | 59 (65.6) | 23 (62.2) | 36 (67.9) | |
| Yes | 31 (34.4) | 14 (37.8) | 17 (32.1) | |
|
| ||||
| Adjuvant therapy | 1.0 | |||
| No | 61 (67.8) | 25 (67.6) | 36 (67.9) | |
| Yes | 29 (32.2) | 12 (32.4) | 17 (32.1) | |
|
| ||||
| Total LNs removed | <0.001 | |||
| Median | 11 | 4 | 18 | |
| Range | 1–67 | 1–14 | 5–67 | |
Values are number (%) unless otherwise indicated. Bold p values indicate statistical significance.
BMI, body mass index; CKC, cold knife cone; FIGO, International Federation of Gynecology and Obstetrics; LEEP, loop electrosurgical excision procedure; LN, lymph node; LND, lymphadenectomy cohort; SLN, sentinel lymph node mapping cohort.
Other histologies include adenosquamous carcinoma, sarcoma, and lymphoepithelioma.
For the QoL questionnaire, we calculated the score according to the EORTC QLQ-C30 and EORTC QLQ-CX24 manuals.(23, 29) The QLQ-C30 summary score is calculated from the mean of 13 of the 15 questionnaire scales,(22) and we applied the Wilcoxon rank sum test to compare the score distribution between patients who developed lower extremity lymphedema and those who did not. We also applied Bonferroni correction for multiple comparisons adjustment to the QoL analysis.
In accordance with the journal’s guidelines, we will provide our data for independent analysis by a selected team by the Editorial Team for the purposes of additional data analysis or for the reproducibility of this study in other centers if such is requested.
Results
Of 459 potential participants, 90 (20%) responded to the survey, which was a lower response rate than anticipated for our study design. We included all respondents as no patient answered ≤6 of the 13 survey items and no respondents had preexisting lower extremity lymphedema, for a total of 90 evaluable patients (37 sentinel lymph node; 53 lymphadenectomy) (Figure 1). Patient surgery dates ranged from March 10, 2006, to January 30, 2019, and the median time from date of surgery to date of questionnaire completion was 67.0 months (range, 43.3 to 162.0) in the sentinel lymph node cohort and 150.6 months (range, 64.7 to 199.8) in the lymphadenectomy cohort (p<0.001 for both).
Figure 1.
Study recruitment flow. LND, lymphadenectomy; SLN, sentinel lymph node.
We have provided clinicopathologic characteristics for the entire cohort and each subcohort in Table 1. The sentinel lymph node and lymphadenectomy cohorts were similar in age, body mass index, tumor grade, histology, medical comorbidities, and receipt of adjuvant therapy. However, we noted differences in the surgical procedures performed between the two groups, with more frequent excisional biopsies in the sentinel lymph node group and more trachelectomies in the lymphadenectomy group (p<0.001). More total lymph nodes were removed in the lymphadenectomy versus the sentinel lymph node group (median, 18 [range, 5 to 67] vs 4 [range, 1 to 14]; p<0.001).
Overall, based on the 13-item lower extremity lymphedema patient-reported outcome questionnaire, we noted that 27 of 90 patients (30%) had the condition. In the sentinel lymph node cohort, 4 of 37 patients (10.8%; 95% CI, 3.0% to 25.4%) screened positive for self-reported lower extremity lymphedema versus 23 of 53 patients (43.4%; 95% CI, 29.8% to 40.6%) in the lymphadenectomy cohort (p=0.001 for both using two-sample binomial proportion test), representing an absolute difference of approximately 32.6% (95% CI, 15.9% to 49.3%) between the groups. When we considered a time-to-event analysis for time to lower extremity lymphedema development, the two groups showed no difference (two-sided p=0.46). Although our study enrolled fewer patients than anticipated based on our a priori analysis, we still detected a significant difference in the rate of lower extremity lymphedema (>20%) between the two groups (two-sided type I error=0.05).
Table 2 presents results from the univariate logistic regression of patient-reported lower extremity lymphedema with various factors such as body mass index, surgical approach, and use of adjuvant therapy. The total number of lymph nodes removed was associated with the risk of lower extremity lymphedema on univariate logistic regression (p=0.002). Because of high correlation between the total number of lymph nodes removed and the group assignment (sentinel lymph node vs lymphadenectomy ± sentinel lymph node), we chose to include the sentinel lymph node versus lymphadenectomy ± sentinel lymph node groups but exclude the lower extremity lymphedema versus none groups in the final multivariate model to avoid multicollinearity. Lymphadenectomy retained an independent association with patient-reported lower extremity lymphedema compared to sentinel lymph node mapping after adjusting for histology and number of lymph nodes resected (Table 3). Total and global QoL scores were significantly worse in patients who reported lower extremity lymphedema, and these patients had worse scores on all subscales (Table 4).
Table 2.
Univariate analysis of various clinicopathologic characteristics’ association with patient-reported lower extremity lymphedema.
| Characteristic | No patient-reported LEL | Patient-reported LEL | OR* | 95% CI | p value |
|---|---|---|---|---|---|
| Surgery cohort | |||||
| LND | 30 (56.6) | 23 (43.4) | 6.32 | 2.14–23.5 | 0.002 |
| SLN | 33 (89.2) | 4 (10.8) | 1.00 | ||
|
| |||||
| BMI >30 (kg/m 2 ) | |||||
| No | 52 (58.4) | 20 (22.5) | 1.00 | ||
| Yes | 11 (12.4) | 6 (6.7) | 1.42 | 0.44–4.27 | 0.54 |
|
| |||||
| Histology | |||||
| Squamous | 23 (36.5) | 4 (14.8) | 1.00 | ||
| Adenocarcinoma | 37 (58.7) | 17 (63.0) | 2.64 | 0.85–10.1 | 0.023 |
| Other‡ | 3 (4.8) | 6 (2.2) | 11.5 | 2.18–76.9 | |
|
| |||||
| Primary surgery | |||||
| Hysterectomy | 44 (69.8) | 19 (70.4) | 1.00 | ||
| Trachelectomy | 12 (19.1) | 7 (25.9) | 1.35 | 0.44–3.92 | 0.48 |
| CKC/LEEP | 7 (11.1) | 1 (3.7) | 0.33 | 0.02–2.05 | |
|
| |||||
| Surgical approach | |||||
| MIS | 36 (57.1) | 10 (37.0) | 1.00 | 0.084 | |
| Open | 27 (42.9) | 17 (63.0) | 2.27 | 0.91–5.89 | |
|
| |||||
| Adjuvant therapy | |||||
| Yes | 18 (28.6) | 11 (40.7) | 2.02 | 0.77–5.27 | 0.15 |
| No | 45 (71.4) | 16 (59.3) | 1.00 | ||
|
| |||||
| Number LNs removed | |||||
| Total LNs | - | - | 1.06 | 1.02–1.11 | 0.008 |
| Log (total LNs)§ | - | - | 2.64 | 1.48–5.19 | 0.002 |
Values are number (%). Percentage is for total in the row. Bold p values indicate statistical significance.
BMI, body mass index; CI, confidence interval; CKC, cold knife cone; LEEP, loop electrosurgical excision procedure; LEL, lower extremity lymphedema; LN, lymph node; LND, lymphadenectomy cohort; MIS, minimally invasive surgery; OR, odds ratio; SLN, sentinel lymph node mapping cohort.
OR for developing LEL.
Other histologies include adenosquamous carcinoma, sarcoma, and lymphoepithelioma.
Log transformation also shown because the distribution of lymph nodes removed was skewed.
Table 3.
Multivariate model assessing independent association with patient-reported lower extremity lymphedema.
| Characteristic | OR* | 95% CI | p value |
|---|---|---|---|
| SLN or LND | 0.009 | ||
| SLN only | 1.00 | - | |
| LND±SLN | 4.96 | 1.61–18.8 | |
| Histology | 0.12 | ||
| Squamous | 1.00 | - | |
| Adenocarcinoma | 2.04 | 0.61–8.11 | |
| Other‡ | 6.75 | 1.17–48.2 |
Total number of cases included in the model is 27.
CI, confidence interval; LND, lymphadenectomy; OR, odds ratio; SLN, sentinel lymph node mapping.
OR for developing lower extremity lymphedema.
Other histologies include adenosquamous carcinoma, sarcoma, and lymphoepithelioma.
Table 4.
EORTC QLQ-C30 and -CX24 scores between patients with and without self-reported lower extremity lymphedema.
| No patient-reported LEL | Patient-reported LEL | p value* | |
|---|---|---|---|
| EORTC QLQ-C30 | |||
| Overall score | |||
| QLQ Total Score | 94.2/92.9 (52.4–100) | 82.5/74.3 (26.8–100.0) | <0.001 |
| Global QoL | 83.3/84.3 (41.7–100) | 75.0/69.8 (16.7–91.7) | 0.009 |
| Functional scales | |||
| Physical functioning | 100/96.8 (40–100) | 86.7/80 (20–100) | <0.001 |
| Role functioning | 100/95 (16.7–100) | 100/75.3 (0–100) | 0.006 |
| Emotional functioning | 91.7/85.3 (25–100) | 75/68.5 (0–100) | 0.058 |
| Cognitive functioning | 100/87 (16.7–100) | 66.7/70.4 (0–100) | 0.026 |
| Social functioning | 100/94.4 (50–100) | 83.3/74.7 (0–100) | 0.015 |
| Symptom scales | |||
| Fatigue | 22.2/31.3 (0–100) | 11.2/12.2 (0–66.7) | 0.001 |
| Nausea and vomiting | 0/12.3 (0–66.7) | 0/1.3 (0–16.7) | 0.002 |
| Dyspnea | 0/21.0 (0–100) | 0/2.6 (0–33.3) | <0.001 |
| Insomnia | 33.3/46.9 (0–100) | 0/13.8 (0–100) | <0.001 |
| Appetite loss | 0/13.6 (0–100) | 0/1.1 (0–33.3) | 0.014 |
| Constipation‡ | 33.3/28.4 (0–100) | 0/5.9 (0–66.7) | <0.001 |
| Diarrhea‡ | 0/19.8 (0–66.7) | 0/6.5 (0–66.7) | 0.17 |
| Financial difficulties‡ | 0/20.5 (0–100) | 0/2.6 (0–66.7) | 0.002 |
| EORTC QLQ-CX24 | |||
| Functional scales | |||
| Sexual activity§ | 66.7/63.9 (8.3–100) | 16.7/25.4 (0–100) | 0.001 |
| Sexual enjoyment§ | 66.7/63.9 (8.3–100) | 16.7/25.4 (0–100) | 0.001 |
| Symptom scales | |||
| Lymphedema | 16.7/25.4 (0–100) | 66.7/63.9 (8.3–100) | 0.001 |
| Peripheral neuropathy | 0/10.1 (0–66.7) | 33.3/29.6 (0–100) | 0.073 |
| Menopausal symptoms | 0/15.9 (0–100) | 33.3/25.9 (0–100) | >0.99 |
| Poor body image | 11.1/17.1 (0–77.8) | 33.3/42.0 (0–100) | <0.001 |
| Sexual/vaginal problems§ | 16.7/25.4 (0–100) | 66.7/63.9 (8.3–100) | 0.001 |
| Sexual worry | 16.7/25.4 (0–100) | 66.7/63.9 (8.3–100) | 0.001 |
Data are reported as median/mean (range).
EORTC, European Organisation for Research and Treatment of Cancer; LEL, lower extremity lymphedema; QLQ, Quality of Life Questionnaire; QoL, quality of life.
p value obtained using Wilcoxon rank sum test, and all except “sexual enjoyment” and “sexual activity” remained significant using Bonferroni correction for multiple comparisons adjustment.
Data missing from 1 for constipation, diarrhea, and financial difficulties.
Data missing from 35 for sexual activity items.
DISCUSSION
Summary of Main Results
To our knowledge, this is the first published report of a protocol using a validated lower extremity lymphedema patient-reported outcome tool to compare the prevalence of lower extremity lymphedema between sentinel lymph node mapping and lymphadenectomy in cervical cancer. Based on patient-reported symptoms in our cohort, we observed a lower extremity lymphedema prevalence of 10.8% (4 of 37) (sentinel lymph node mapping) and 43.4% (23 of 53) (lymphadenectomy).
Results in the Context of Published Literature
Our findings demonstrate that compared with lymphadenectomy, sentinel lymph node biopsy carries a lower but still nonzero risk of patient-reported lower extremity lymphedema, which is in contrast to prior small retrospective studies in cervical cancer that reported a 0% rate of lymphedema in patients that underwent the procedure.(30, 31) However, the limitations of these retrospective studies make direct data comparisons difficult. Because humans will develop lymphedema “symptoms” for various reasons as they age, a 0% rate of patient-reported lower extremity lymphedema is unlikely, and it can also be difficult to assess how much of the lymphedema is attributable to sentinel lymph node mapping or lymphadenectomy. However, the important finding is the difference we noted between the cohorts using a validated tool.
Currently, investigators have performed two landmark prospective studies to assess lower extremity lymphedema development in cervical cancer. SENTICOL II randomized patients to sentinel lymph node mapping or sentinel lymph node mapping with pelvic lymphadenectomy with a primary endpoint of morbidity and a secondary endpoint of 3-year recurrence rate.(32) While SENTICOL II reported higher rates of lower extremity lymphedema than those observed in our study (31% for sentinel lymph node mapping and 51.5% for lymphadenectomy with sentinel lymph node mapping), the follow-up time of 6 months likely overestimated patients who may have had transient lower extremity lymphedema.(32) Moreover, measurements were missing in 27% of patients, limiting this interpretation, and they did not utilize a validated patient-reported outcome tool.
SENTIX, a single-arm prospective study of 150 patients with cervical cancer who underwent sentinel lymph node mapping, evaluated a primary endpoint of lower extremity lymphedema incidence.(33) Investigators reported a 26.5% rate of lower extremity lymphedema in this cohort, with a median development time of 9 months, and they observed transient edema in 22%. They utilized an unvalidated questionnaire to evaluate patient-reported symptoms; interestingly, the subjective lower extremity lymphedema rate was only 10.7%—a number close to what we observed. In contrast to our study, the investigators did not observe a correlation between number of lymph nodes removed and lower extremity lymphedema; however, the median number removed was only 3, and there was no comparator arm.
Strengths and Weaknesses
Recall bias is a concern in all studies of this design. In addition, the low questionnaire response rate (20%) may impact the generalizability of our findings. We could only assess prevalence rates at the time patients received the questionnaires and thus could not establish incidence rates over time. However, we tried to address this with our sensitivity analysis. We also recognize that the median time since surgery was different between the sentinel lymph node and lymphadenectomy cohorts, which may impact the rate of patient-reported lower extremity lymphedema, especially as patients continue to age. However, the minimum time from surgery was 43 months in both cohorts, which is a reasonable amount of time to assess the possible development of surgery-related, patient-reported lower extremity lymphedema. Stage distribution was slightly different between the two cohorts, but the rate of adjuvant therapy use was exactly the same, so the stage difference is not important. There was also a difference in the type of surgical procedures. On univariate analysis, type of procedure was not associated with patient-reported lower extremity lymphedema, but the number of cases is small and may have led to our finding of nonsignificance, especially for those who had an excisional procedure alone.
Several factors likely impacted the response rate. Importantly, the median age of the total cohort was 39 years old, an age reflective of typical cervical cancer demographics but associated with life transition; we had 84 packets returned as undelivered because of change in address. While our protocol accounted for this possibility and thus permitted contact through the electronic patient portal, many of these patients underwent their procedures prior to development of the portal and had no established account. In addition, we were unable to reach 230 patients via follow-up phone call, with 26 phone numbers out of service. Even so, we noted no difference between those who responded to the questionnaire and those who did not in terms of age, adjuvant therapy, or type of nodal assessment (p>0.05).
Implications for Practice and Future Research
The benefit of sentinel lymph node mapping over comprehensive lymphadenectomy likely lies in the reduction of lymphatic morbidity and subsequent improvement in QoL. Currently, there are no agreed upon standard guidelines for the diagnosis of lower extremity lymphedema, and the use of patient-reported outcome instruments in this setting is lacking.
The 20-item Gynecologic Cancer Lymphedema Questionnaire is another lower extremity lymphedema patient-reported outcome tool, which was modified from the Lymphedema Breast Cancer Questionnaire, and it has acceptable reported sensitivity (85.7%) and specificity (90%).(34) It has been previously studied in a cohort of patients with cervical cancer who underwent radical surgery and lymphadenectomy,(35) and it would be interesting to use it in a cohort similar to ours and compare results.
CONCLUSIONS
Our results demonstrate that when compared to lymphadenectomy, sentinel lymph node mapping is independently associated with a significantly lower prevalence of self-reported lower extremity lymphedema in patients who have undergone surgery for early-stage cervical cancer. Sentinel lymph node mapping has been proven to provide accurate surgical staging and decreased morbidity, and our data support use of this procedure in women with cervical cancer.
Supplementary Material
Key Messages.
What is already known on this topic:
Pelvic lymphadenectomy is part of the standard surgical evaluation for patients with 2018 FIGO stage IA1 to stage IIB cervical cancer. However, one common complication of this procedure is lower extremity lymphedema, which can cause severe lifelong morbidity that affects patients’ quality of life. Because only 15% to 20% of patients have nodal involvement in their cancer, this standard of care can be considered an unnecessary surgical risk.
What this study adds:
This protocol compares the prevalence of patient-reported lower extremity lymphedema in patients who underwent sentinel lymph node mapping versus lymphadenectomy for newly diagnosed early-stage cervical cancer and whether it was associated with poorer quality of life. We found that sentinel lymph node mapping was associated with a significantly lower prevalence of patient-reported lower extremity lymphedema.
How this study might affect research, practice or policy:
These data provide additional support for using sentinel lymph node mapping in women with cervical cancer and highlight the benefits of using validated patient-reported outcome tools in this patient population.
Funding
This research was funded in part by the NIH/NCI Cancer Center Support Grant P30 CA008748.
Footnotes
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Patient consent for publication Not applicable.
Ethics approval This study involves human participants and was approved by our institutional review board (22–002) before initiating the trial.
Competing interests KMM: none declared. CL: none declared. QZ: None declared. AI: None declared. RB: None declared. BR: None declared. YS: None declared. JJM: None declared. VB: None declared. NRA-R: Grants or contract fees paid to the institution: GRAIL. MML Jr: Consulting fees: Medtronic. Ad-hoc speaker fees: Intuitive Surgical, Inc. Advisory Board: Johnson and Johnson/Ethicon, Immunogen.
Declaration of interests
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Nadeem Abu-Rustum reports a relationship with Grail Inc. that includes: funding grants. Mario Leitao reports a relationship with Medtronic that includes: consulting or advisory. Mario Leitao reports a relationship with Intuitive Surgical Inc that includes: speaking and lecture fees. Mario Leitao reports a relationship with Johnson and Johnson that includes: board membership. Mario Leitao reports a relationship with ImmunoGen Inc that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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