Lymphoedema of the leg is a potential major morbidity after a complete inguinal-femoral lymph node dissection (CLN removal of all superficial and deep inguinal nodes located between the superficial and deep fascia over the femoral triangle, and the femoral lymph nodes medial to the femoral vein) for the treatment of vulvar cancer. A study from our institution1 showed that 59% of women who had CLN for the treatment of vulvar cancer reported leg lymphoedema, similar to the 63.5% incidence in the Gynecologic Oncology Group study.2 Janda et al3 showed that the most frequent symptom influencing the quality of life (QoL) in these women was lymphoedema. Rates of lymphoedema are significantly lower after the sentinel lymph node biopsy (SLN removal of only the first lymph node(s) receiving drainage from the vulvar cancer after identification with blue dye and radioactive tracer) compared with those of the CLN,4 but questions remain about the effect of lymphoedema on the global QoL since Oonk et al5 showed no difference in the QoL between a group of patients who underwent SLN and those who had CLN.
The SLN procedure is becoming the preferred method for staging in women with stage IB and stage II (<4 cm) vulvar cancer. Approximately 20% will have metastases to inguinal-femoral lymph nodes, which means that approximately 80% could be spared the morbidity of CLN. However, the omission of a lymphadenectomy when a squamous cell carcinoma is present in the nodes is the single most important factor affecting survival.6,7 The SLN procedure must therefore have a false-negative rate that is acceptable to the patient, given that survival is poor after recurrence in an undissected groin.8
Van der Zee et al4 reported 6 groin recurrences (2.3%) in 259 women after SLN. More recently, the Gynecologic Oncology Group 1739 multi-institutional study reported 11 false-negative sentinel nodes (8.3%) in 132 women with lymph node metastasis and unifocal tumors of less than 6 cm, giving a false-negative predictive value (1 - negative predictive value) of 3.7% in 418 women with early-stage vulval cancer. The false-negative predictive value for tumors less than 4 cm was 2.0%. However, a single-institution study in Poland showed 7 false-negative sentinel nodes in 56 women, a higher false-negative rate of 27%.10 It is recognized that the false-negative rate of the SLN procedure is dependent on the expertise of the surgeon. Because vulvar cancer is uncommon, most surgeons will treat small numbers, thus limiting their experience with the procedure.
Two studies have addressed the preferences of women for SLN versus CLN in the treatment of vulvar cancer. De Hullu et al11 asked women who had CLN whether they would prefer SLN or CLN if the false-negative rate was 5%, and 66% preferred CLN. Oonk et al5 compared the acceptance of SLN in 2 groups of women in the GROINNS (Gronigen International Study on Sentinel nodes in Vulvar Cancer) study. The 2 groups consisted of 35 women who had SLN and whose node was found to be negative as well as 27 women who had SLN with a positive node, who then underwent CLN. When the false-negative rate was stated as 1%, 97% of the women who had the SLN procedure would recommend it, whereas 62% of the women who required the CLN would recommend it. (P = 0.001). When the false-negative rate was stated as 10%, 84% of the SLN group recommended the SLN procedure, but only 48% of the CLN group advised it (P = 0.005). Acceptance of the SLN in this study depended on the false-negative rate and the presence of positive lymph nodes. There are other decision-related factors that may be important, such as concern about the adverse effects of CLN and willingness of women with cancer to risk survival.
The first aim of this study was to determine the relationship between lymphoedema and QoL in a cohort of women treated for early-stage vulvar cancer with CLN. The second aim of the study was to determine what risk of missing a positive lymph node would be acceptable to this same group of women to avoid the adverse effects of lymphoedema. A better understanding of this “acceptable false-negative rate” is needed before SLN becomes standard care.
MATERIALS AND METHODS
The study group included women diagnosed with the 1988 International Federation of Gynecology and Obstetrics stage IB, II, and III squamous cell carcinoma of the vulva without clinically detectable lymph node metastases treated at the Royal Hospital for Women in Sydney between 1989 and 2007. All women had a unilateral or bilateral inguinal-femoral lymphadenectomy. The SLN procedure was not offered to women.
After obtaining ethics approval, 10 pilot questionnaires were sent to the women treated for other gynecological cancers to ensure that the questions were understood. Sixty-three women meeting the inclusion criteria were then contacted before receiving the questionnaire and followed up in person or by telephone before returning the questionnaire.
The women were questioned about the severity of leg swelling, pain, and infection. Leg swelling and pain were defined as mild, moderate, or severe. Mild cellulitis was defined as 1 to 2 infections per year not requiring hospital admission, moderate cellulitis as 3 to 5 infections per year requiring antibiotics but not admission, and severe cellulitis as more than 5 infections per year requiring antibiotics or admission to hospital in the previous 12 months.
The women were asked to mark between −1 (very bad effect) and +1 (very good effect) on a linear graph the effect the removal of lymph nodes had made on their overall QoL. They indicated on a standard 20-cm visual analogue scale a rating for their current health state. The Utility-Based Questionnaire-Cancer, a validated cancer-specific QoL questionnaire,12 was used to measure QoL in terms of global health, physical function, social activities, self-care, and levels of emotional distress. Using these data, forest plots were constructed to illustrate the mean differences (95% confidence interval) in QoL scores between women with positive lymph nodes, lymphoedema, or leg pain and women without these variables, after the CLN (Fig. 1).
The women were shown a pictorial representation of the advantages and disadvantages of SLN using a “scales of justice” diagram (Supplemental Digital Content 1, available at http://links.lww.com/IGC/A212). A false-negative rate of 5% for the SLN procedure was used, meaning that in 5% of cases where cancer cells are present in lymph nodes, they would falsely be reported as being cancer free. Because 20% of women with early-stage vulvar cancer have cancer in lymph nodes, there would be a 1 in 100 risk for each woman of missing positive nodes. It was made clear that missing the diagnosis would usually mean death from cancer. On the other side of the scale, it was stated that SLN could avoid the adverse effects of lymphoedema, which would occur in 60% of women. The women were then asked if they would choose SLN or CLN dissection had they been given a choice at the time of diagnosis. The conditional binomial exact test13 was used to calculate the strength of evidence for the association of this choice with the degree of lymphoedema, leg pain, or diagnosis of positive lymph nodes in these women after a CLN.
A standard-gamble question was used to quantify the woman’s choice between SLN and CLN. The standard-gamble is a utility measurement that measures the trade-off between QoL and survival duration.14 In this study, the trade-off was the risk of missing cancer in lymph nodes when the sentinel node was negative (with the SLN procedure) versus always finding the cancer but with a 60% chance of a lymphoedema (with the CLN). A total of 10 choices were given, with the chance of missing cancer in lymph nodes stated as 1 in 2, 1 in 5, 1 in 10, 1 in 20, 1 in 50, 1 in 100, 1 in 200, 1 in 500, 1 in 1000, and 1 in a million (Supplemental Digital Content 2, available at http://links.lww.com/IGC/A212).
Sixty-three women, having undergone CLN for early-stage vulvar cancer, were sent the QoL questionnaire, and sixty women (95%) responded. The mean age was 63 years (range, 31–89 years). Most women (55/60, 92%) had their operation more than 18 months ago. Twelve women (20%) had positive lymph nodes, and 10 (17%) received an adjuvant radiotherapy. Sixteen women (27%) had a recurrence of the cancer; 15 had the recurrence at the vulva and 1 in the contralateral (undissected) groin. The patients’ characteristics are shown in Table 1.
Responses showed leg swelling in 44 (73%), rated as mild in 18 (30%), moderate in 19 (31%), and severe in 7 (12%). Of the 10 women, 8 (80%) who received a radiotherapy reported lymphoedema, which was severe in 2 women (20%). Leg pain was experienced by 32 (53%), mild in 17 (28%), moderate in 11 (18%), and severe in 4 (7%). Lower limb cellulitis was reported by 14 (23%), mild in 9 (15%), moderate in 3 (5%), and severe in 2 (3%). (Supplemental Digital Content 3, available at http://links.lww.com/IGC/A212) shows the reported adverse effects.
When women were asked to mark on a line of −1 (negative), 0 (no effect), and +1 (positive) the effect the removal of groin nodes had on their overall QoL, 22 (37%) reported a negative effect, 29 (48%) reported a no effect, and 10 (17%) reported a positive effect. The effect was scored in terms of the current ability to enjoy life compared with enjoyment before the removal of groin nodes. Supplemental Digital Content 4, available at http://links.lww.com/IGC/A212 shows the distribution of results. The average current health state was rated on a visual analogue scale as 74% of full health. Women without lymphoedema rated their current health 80%, whereas those with lymphoedema rated it 72%.
The QoL scores using the Utility-Based Questionnaire-Cancer identified that the activity most affected in all women was physical function, especially the ability to perform vigorous activities such as running and climbing stairs. Social life and self-care activities were least affected. Thirty-six women (60%) identified themselves as being sexually active. Of these women, 18 (50%) reported that their health did not affect their sex life, whereas the same number of women reported that it did.
When comparing those who reported lymphoedema or leg pain with those who did not experience these symptoms, QoL scores were significantly lower in the symptomatic group (Fig. 1). In women reporting lymphoedema, the greatest negative effects were on sex life, physical function, and social activities. The women who experienced leg pain had, in addition, higher levels of emotional distress and loss of ability to perform self-care activities. The women with positive lymph nodes did not show a significant difference in any QoL score compared with women with negative nodes, but the number of women with positive nodes was small (12/60, 20%). Of these 12 women, 9 had received a radiotherapy.
When the women were asked to make a choice between CLN and SLN, 48 (80%) chose CLN, 9 (15%) chose SLN, and 3 (5%) were unable to make a decision. Of the 9 women who chose SLN, 3 had positive lymph nodes. Those women who chose SLN rather than CLN were younger (mean age, 58 vs 64 years). There was an association between the choice of CLN or SLN and the severity of lymphoedema. Of the 48 women choosing CLN, 4 reported moderate or severe lymphoedema, whereas of the 9 women choosing SLN, 3 reported moderate or severe lymphoedema (P = 0.04). There was no evidence for an association between the choice for CLN or SLN and leg pain (P = 0.20) or positive lymph nodes (P = 0.27) (Table 2).
When asked what level of risk each woman would take of missing the diagnosis of cancer in lymph nodes to avoid lymphoedema, 38 (63%) would take essentially no risk (0 or 1 in a million chance) (Fig. 2, group D). However, 19 (32%) would take some quantity of risk (Fig. 2, groups A–C). Within this group (C) are 10 (17%) of the 48 women who initially chose CLN if the risk of missing cancer in the lymph node was 1 in a 100 (false-negative rate, 5%). These 10 women would then change their choice to SLN if the risk fell between 1 in 200 and 1 in 1000. The 9 women who would always choose SLN would take a risk of missing a positive node of between 1 in 2 and 1 in 100.
The 60 women with early-stage vulvar cancer in this study are similar to those in the literature for age, stage, and recurrence rate. Overall, 73% of the women reported leg lymphoedema after a CLN, which is higher than in previous studies.1,4,15 The presence of either lymphoedema or leg pain was associated with worse physical function, social activity, and sex life. Leg pain was also associated with significant emotional distress. Similar effects have previously been reported.3,16 Interestingly, in our study, it was not the presence of positive lymph nodes that was most closely associated with the negative effect on QoL but the presence of lymphoedema.
As shown in the forest plots (Fig. 2) and results for scales of health, global health scores were significantly lower in women with lymphoedema and leg pain after the CLN than those without these symptoms. The findings differ from those of Oonk et al5 who did not show significant differences in global health status after CLN. This difference may be because our study had greater power because a larger number of women had CLN (60 compared with 27). Our study also had longer follow-up (79 months), demonstrating the chronicity of symptoms and the need for long-term management.
Twenty percent (12/60) of the women in our study had positive lymph nodes. This concurs with other studies and allows us to assume that, with a false-negative rate of 5%, 1 in 100 women would have lymph node metastases missed with SLN. When informed of this risk, 80% of study participants would choose CLN, which is higher than the 66% reported by De Hullu et al.11 Similar to findings of previous studies,5,11 as the stated risk of missing a positive lymph node decreased, more women preferred SLN.
This study was the first to use the standard-gamble table to define the levels of risk women would take with the SLN procedure. Of the 48 women who chose CLN, 38 (68%) would essentially take no risk of missing a positive lymph node. As one 75-year-old woman stated, “I was never one to play Russian roulette.” On the other hand, of the 9 women who chose SLN and who experienced severe lymphoedema, 1 stated that she would take a 1 in 2 chances of missing a positive lymph node. She stated, “I can’t do anything meaningful that I once enjoyed. I can’t work as an archeologist, play tennis, or buy shoes that fit ever again.”
Of interest are the 10 women (17%) who, if the risk of missing a positive lymph node was lower than 1 in 100, would switch to the SLN procedure. Together with the 9 women who would always choose SLN, a total of 19 (32%) of the 60 women would choose SLN if the risk of missing a positive lymph node was low enough to be acceptable to them.
It is important to recognize that the false-negative rate for SLN varies depending on the surgeon’s experience with the technique and the accuracy of associated procedures of lymphoscintigraphy and histopathology. Similarly, the risk of harboring a positive lymph node will vary depending on the tumor characteristics such as size and depth of invasion. Therefore, each woman will have a different risk of finding (or missing) a positive lymph node. In the situation of a woman with a small, minimally invasive tumor, treated by an experienced surgeon/unit with a low false-negative rate, the chance of missing a positive node may be low and, with informed consent, that woman may prefer SLN. In other types of cancers involving the sentinel node procedure (eg, breast, melanoma), logistic regression modeling is being used to develop nomograms for predicting positive sentinel nodes.17,18 Although a similar tool is possible in vulvar cancer, the rarity of the disease makes it difficult to validate. Moreover, unlike breast cancer, in which most women receive adjuvant therapy even when the SLN is negative, the decision to administer adjuvant treatment of vulvar cancer relies heavily on the detection of metastases in the inguinal-femoral lymph nodes. A false-negative result may lead to a death from cancer, which must be made clear to the patient.
An interesting finding from this study was the heterogeneity in the treatment-related decisions that was not fully explained by the predictive factors such as risk of disease (positive nodes) and adverse effects of treatment (lymphoedema and leg pain). For example, 3 women with positive lymph nodes identified by CLN would still prefer SLN if it had been offered, even with the knowledge of a 5% false-negative rate. Although all the 3 women had lymphoedema, there may be underlying behavioral factors influencing this decision that require further study.
Our study demonstrates that the majority of the women were able to make an informed choice about the treatment when presented with the risks and benefits in a way they could understand. Recent studies in breast19,20 and ovarian21 cancers have shown that patients’ perceived involvement in the decision making about cancer treatment is associated with a better QoL. Good communication is paramount to this process.
There are some limitations to this study. Overall, the women reported an average QoL scores despite significantly lower scores in specific areas such as physical functioning and sex life. The long follow-up period introduces the possibility of adaptation22 because women have had many years to adjust to the adverse effects of treatment (eg, by wearing stockings for lymphoedema) and to concentrate on areas of their lives that give them pleasure. The retrospective nature of asking women to choose a treatment after already having received a treatment is problematic because of the possibility of cognitive dissonance, where women are more likely to choose the treatment they have already had to avoid psychological conflict. In addition, it must be discussed with the patient that there is a small risk of groin node recurrence of approximately 0.5% to 1% after complete lymphadenectomy7,23–25 and similarly a small risk of lymphoedema of approximately 2% after sentinel node biopsy.
In conclusion, almost three quarters of the women in our study reported lymphoedema after the CLN for early vulvar cancer and these women had reduced QoL. Most women were not willing to sacrifice survival by choosing SLN. However, there is a group of women who will prefer SLN after an accurate counseling with regard to the risks and benefits of the procedure. Furthermore, studies are needed to understand how women interpret information regarding the risk and the psychological characteristics that influence decisions about the treatment of early-stage vulvar cancer.
Rhana Pike assisted with article editing. Ellen Barlow provided assistance in collecting questionnaires. The authors are grateful to all patients whose participation made this study possible.
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