ORIGINAL STUDY
Quality of Life, Urogynecological Morbidity, and Lymphedema After Radical Vaginal Trachelectomy for Early-Stage Cervical Cancer Ligita Paskeviciute Frøding, MD,* Christian Ottosen, MD,* Berit Jul Mosgaard, MD, PhD,* and Pernille Tine Jensen, MD, PhDÞ
Objective: Radical vaginal trachelectomy (RVT) offers a possibility for future childbearing for young women with early-stage cervical cancer. However, the literature on quality of life and self-reported morbidity in patients undergoing RVT is scarce. The aim of this study was to prospectively assess quality of life after RVT with focus on urogynecological morbidity and lymphedema. Furthermore, the aim of this study was to compare results with those in women treated with radical abdominal hysterectomy (RAH) and with age-matched control women from the general population. Methods and Materials: Eighteen patients with early-stage cervical cancer operated with RVT were prospectively included and assessed preoperatively, 3, 6, and 12 months postoperatively using validated questionnaires. Thirty-two patients treated with RAH were included consecutively and assessed once at 12 months postsurgery, whereas an agematched control group of 30 healthy women was assessed once. Results: Fifty percent of the RVT group and 41% of the RAH reported any grade of incomplete bladder emptying problems at 1 year postsurgery assessment. Eleven percent of the RVT patients and 12.5% of the RAH patients reported severe lymphedema of the legs as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Cervical Cancer Module. The Global Health Status scores of the RVT patients improved over time but were significantly lower than in the healthy controls during the entire observation time (P = 0.029). Conclusions: Patients treated with RVT for early-stage cervical cancer had persistent bladder emptying problems and lymphedema comparable to those experienced by patients treated with RAH and significantly higher than those reported by healthy control women. Key Words: Cervical cancer, Radical trachelectomy, Radical hysterectomy, Quality of life Received October 22, 2014, and in revised form December 20, 2014. Accepted for publication December 21, 2014. (Int J Gynecol Cancer 2015;25: 699Y706)
*Department of Gynecology and Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen; and †Department of Gynecology and Obstetrics, Odense University Hospital, Odense, Denmark. Address correspondence and reprint requests to Ligita Paskeviciute Frøding, MD, Department of Gynecology and Obstetrics, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. E-mail: [email protected]. The authors declare no conflicts of interest. Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000395 International Journal of Gynecological Cancer
cancer is the most common gynecological cancer C ervical affecting women aged younger than 40 years. According 1
to the National Cancer Institute, cervical cancer rates are highest in women aged 35 to 44 years in the United States.2 A significant proportion of these women may have an interest to preserve fertility. Radical vaginal trachelectomy (RVT) with radical pelvic lymph node dissection (PLND) has therefore been used as a safe alternative to conventional radical abdominal hysterectomy (RAH), with similar survival and recurrence rates for tumors smaller than 2 cm.3,4 In countries with systematic cervical cancer screening, 54% of patients are
& Volume 25, Number 4, May 2015
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
699
Frøding et al
International Journal of Gynecological Cancer
diagnosed with stage I disease, with an expected 5-year survival rate of more than 90%.5 Patients treated with RVT are expected to be long-term survivors and must therefore deal with the consequences of surgery for many years. Several studies describe quality of life (QOL) and sexual dysfunction after RAH including PLND.6Y9 Only a few prospective studies on short-term and long-term self-reported morbidity and QOL after RVT have been published.10Y12 We have previously reported our results on sexual functioning and vaginal changes after RVT compared with RAH and QOL impact in early-stage cervical cancer patients.11 Our study showed significant sexual dysfunction and impaired QOL after RVT throughout the first year compared with healthy women. Furthermore, RVT patients had more vaginal changes than the RAH patients, probably caused by more cervical/ vaginal scarring. Although trachelectomy has been an accepted treatment modality over the past 2 decades, the data on surgery-induced morbidity are scarce and derive mainly from retrospective studies. The most common adverse effects reported are lower urinary tract dysfunction and lymph drainage problems.3,13Y15 To our knowledge, there are no data available including prospective longitudinal self-reported assessment of these symptoms in patients after RVT. In the present study, we assessed QOL with focus on short-term and long-term urogynecological morbidity and lymphedema in patients with early-stage cervical cancer treated with RVT and RAH compared with healthy age-matched control group.
MATERIALS AND METHODS Patients Patients with cervical cancer stage IA2 to IB1 treated with RVTwere eligible for the prospective study. Patients with stage IA1 to IB2 treated with RAH at the Department of Gynecology, Copenhagen University Hospital Rigshospitalet and Herlev were eligible as control group. The criteria for offering RVT have been almost unchanged for more than 10 years16: stage IA2 to IB1 cervical cancer, with a tumor smaller than 2 cm, and with a realistic prognosis to preserve fertility. Patients who do not fulfill these criteria are not offered RVT but instead recommended RAH.
Staging All patients were staged by a gynecologist and an oncologist in general anesthesia. A positron emission tomography and computed tomography was conducted in all patients to exclude distant metastases.
Treatment The procedure of RVT has been described earlier.17 To evaluate lymph node status, laparoscopic PLND was performed. A class II to III RAH according to the European Organization for Research and Treatment of Cancer (EORTC) classification and PLND was performed as an open procedure in patients who did not have a desire to preserve fertility.18
700
& Volume 25, Number 4, May 2015
Control Group Nurses and students from both departments of gynecology were asked to participate as a control group. Premenopausal women older than 18 years, without prior cancer disease and with no previous hysterectomy, were eligible. All study participants, cases and control group, were given oral and written information about the study, after which they provided their written informed consent.
Main Outcome Measures The EORTC Quality of Life Core Questionnaire (QLQC30) contains 30 items covering 5 functional scales (physical, role, emotional, social, and cognitive functioning), 3 symptom scales (fatigue, pain, nausea/vomiting), and 6 single items assessing dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties.19 All scale and item scores were transformed to a 0 to 100 scale. For the 5 functional scales and the global QOL scale, a higher score represents a better level of functioning. The EORTC QOL Questionnaire Cervical Cancer Module (QLQ-CX24) contains 24 items about disease and treatment-specific effects after treatment of cervical cancer, and supplements the EORTC QLQ-C30. All scale and item scores were transformed to a 0 to 100 scale.20 In the present study, only scores on bladder functioning and lymphedema are included. The Urogynecological Morbidity Questionnaire (UGQ) contains 18 items on urologic, vaginal, and menopausal changes, and pain. All scale and item scores were transformed to a 0 to 100 scale.21 For the symptom scales and items, a higher score corresponds to worse or more symptoms in all 3 questionnaires.19Y21 Radical vaginal trachelectomy patients were assessed preoperatively, and 3, 6, and 12 months postoperatively. Radical abdominal hysterectomy patients were assessed once, 12 months postoperatively, using the same questionnaires. Healthy women were assessed once at the time of inclusion.
Statistical Analysis Differences in demographic and clinical characteristics between the study groups were compared with a t test for independent samples.
Patients Versus Control Group Patient and control group scores were compared using the Mann-Whitney U test at each assessment (RAH vs control, RVT vs RAH, RVT vs control). For univariate comparison of outcome measures between the treatment groups with the control group, the Kruskal-Wallis H test was conducted. Multivariate analyses were performed to assess the independent association of variables with the end points as urine incontinence, incomplete bladder emptying, bladder sensibility, lymphedema, and the global health status (GHS). For these 5 end points, univariate analyses were performed for the following independent variables: age, menopause, partner and children status, smoking, and study group (RVT, RAH, and control). Backward elimination (P G 0.10 on univariate analysis to be considered in the model) was used to identify * 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 4, May 2015
independent variables to be associated with these 5 end points when comparing the 3 groups at the 12 months assessment.
Precancer Versus Postcancer Comparison of Scores Within Patients The Wilcoxon signed rank test was used for paired comparison within RVT patients of retrospective precancer scores obtained before surgery versus 12 months after surgery to assess the long-term effect of treatment. Data imputing of missing data in the RVT group was performed using the last value carried forward method,22 and thereafter, all statistical analysis were repeated on the complete data set. Statistical differences were indicated if P is less than 0.05. Differences in scale scores of 10 points or more were considered clinically significant.23 All data were analyzed using SPSS 11.5 (SPSS Inc, Chicago, IL).
RESULTS Eighteen RVT patients, 32 RAH patients, and 30 healthy women were included in the study. Sociodemographic and
Quality of Life After RVT
clinical characteristics are given in Table 1. In postmenopausal RAH patients, the ovaries were removed, whereas ovaries were saved in premenopausal women. Nine RAH patients were postmenopausal, and one achieved surgery-induced menopause because the ovaries were removed due to highrisk histology of the cervical cancer (clear cell carcinoma). There was no statistical difference between the groups according to body mass index and partner status, whereas significantly more RVT patients were smokers. Significantly, more RAH patients had children, were older, and were postmenopausal. There was no statistical difference regarding stage and histology in the 2 patient groups. In 1 patient in stage IA1, RAH was performed because of multifocal disease. None of the patients had lymph node metastasis or recurrence during the 12-month follow-up. One RVT and 1 RAH patient had bladder injury during the operation. In the RAH group, 3 ureteral injuries were seen. Postoperatively, 5 RAH patients had urinary tract infection, and 1 patient was admitted with urosepsis. One RVT and 1 RAH patient developed intra-abdominal abscess, and 1 RAH patient had bowel obstruction; all 3 patients needed surgical intervention.
TABLE 1. Sociodemographic and clinical characteristic of study participants Sociodemographic Characteristics n Age, median (range) BMI, median (range) Has a partner Postmenopausal Has children Education Nonacademic Academic Unknown Smoking FIGO tumor stage IA1 IA2 IB1 IB2 Histology Squamous Adenocarcinoma Adenosquamous Clear cell Nodes removed, median (range) Blood loss, median (range), mL
Controls, n (%)
RVT, n (%)
30 28.5 (24Y41)
18 29.0 (23Y42) 23.3 (18.5Y33.7) 13 (72) 0 3 (17)
24 (80) 0 7 (23) 15 (50) 15 (50) 0 3 (10)
13 4 1 9
(72.2) (22.2) (5.6) (50)
P* 0.914 0.545 0.591 0.079 0.079 0.001
RAH, n (%)
P†
32 42.0 (30Y63) 23.2 (19.3Y37.4) 28 (88) 9 (28) 31 (97)
G0.001 0.815 0.184 0.004 G0.001
26 (81.2) 2 (6.3) 4 (12.5) 5 (16)
0 1 17 (94) 0
1 1 29 (91) 1
13 (72) 5 (28) 0 0 20 (16Y36) 150
19 (59) 11 (34) 1 1 24 (7Y41) 500
0.122 0.122 0.003
0.641
0.374 0.639
0.160 G0.001
P G 0.05 is presented in bold numerals. *RVT versus control. †RVT versus RAH. BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics.
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
701
International Journal of Gynecological Cancer
Frøding et al
& Volume 25, Number 4, May 2015
Compliance
Lymphedema
The compliance rates for questionnaire completion of the RVT patients was 100% at baseline and 3 months and 88.9% at the 6-month assessment. The lowest compliance rate was obtained at 1 year postsurgery due to patients’ noncompliance (72.2%). The participation rate in the RAH and the control group was 100% and 64%, respectively.
Lymphedema of the legs (LL) in the RVT group appeared significantly more at 3 months postsurgery assessment versus preoperatively (P = 0.007) and did not seem to improve over time compared at 3 and 12 months (P = 0.314) (Table 2). There were no group differences between the RVT and RAH groups at 12 months postsurgery assessment (P = 0.646). Totally, 39% of the RVT patients and 41% of the RAH patients reported any grade of LL at 12 months postsurgery assessment, whereas only 7% of healthy control women did (P = 0.005). After adjusting for age, menopausal status, and children status in multivariate analysis, RVT patients still had significant more LL compared with healthy women (P = 0.031), whereas this difference disappeared in the RAH group (P = 0.253).
Urogynecological Morbidity Urinary incontinence and incomplete bladder emptying problems were present in the RVT group at 3 months assessment and persisted through 1 year postsurgery with no indication of improvement (Table 2). After dichotomization of scores on incomplete bladder emptying problems to none versus any grade, 50% in the RVT group, 41% in the RAH group, and only 10% in the control group had incomplete bladder emptying problems of any grade 1 year postsurgery (EORTC QLQ-CX24 and UGQ). After adjusting for age, menopausal, and children status in multivariate analysis, both patient groups had significantly more urine incontinence than the control group (P = 0.002 and P = 0.048 for RVT and RAH groups, respectively); the RVT group had significantly more bladder emptying problems (P = 0.002), and the RAH group had more bladder sensitivity problems (P = 0.014) than healthy control women 1 year postsurgery.
Quality of Life Baseline functional scale scores (role, emotional, cognitive, and social functioning) were significantly lower in the RVT group compared with the healthy control women (Table 3). Scores of role and emotional functioning in the RVT group remained significantly lower than those of healthy control women up to 6 months postsurgery, but improved at 12 months postsurgery (Table 3). Cognitive and social function scores as well as GHS scores persisted to be significantly lower in the RVT group compared with healthy women at each assessment (Table 3). After adjusting for age
TABLE 2. Urogynecological symptoms and lymphedema in patients after RVT and RAH compared with healthy control women Months Baseline C n 30 EORTC QLQ-CX24 Frequent voiding 10.0 Pain or burning feeling when urinating 3.3 Urine incontinence 0 Difficult emptying bladder 3.3 Lymphedema 2.2 UGQ Frequent voiding 12.2 Burning sensation or pain when urinating 3.3 Urine incontinence 0 Difficult to tell when need to urinate 1.1 Incomplete bladder emptying 3.3 Bloody urine 0
RVT
3 P*
18
RVT
6 P*
18 25.9 16.7 11.1 21.6 22.2
RVT
12 P*
18 0.071 0.006 0.008 0.003 0.002
20.4 7.4 11.1 18.5 20.4
P*
RVT 18
0.313 0.250 0.008 0.015 0.002
RAH
P†
32
20.4 16.7 0 9.3 1.9
0.176 0.034 1.000 0.469 0.879
18.5 9.6 13.0 22.2 16.7
0.319 0.113 0.003 0.002 0.005
29.0 12.2 15.0 17.2 20.4
1.00 0.237 0.002 0.004 0.004
19.6 11.8 0 0 12.5 3.9
0.479 24.1 0.413 22.2 0.487 18.5 0.577 0.018 16.7 0.003 7.4 0.138 7.4 0.138 1.000 9.3 0.022 9.3 0.022 16.6 G0.001 0.452 3.7 0.286 0 0.439 3.7 0.286 0.165 18.5 0.015 20.4 0.015 22.2 0.002 0.058 2.0 0.184 0 1.000 2.0 0.184
20.8 5.2 11.5 14.6 14.6 1.0
0.696 0.333 0.002 0.018 0.006 0.454
Scores are transformed to 0Y100 scale, and values represent mean scores. P G 0.05 is presented in bold numerals. *Difference between RVT and control group (Mann-Whitney U test). †Difference between all groups (Kruskal-Wallis test). C, control group.
702
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 4, May 2015
Quality of Life After RVT
TABLE 3. EORTC QLQ-C30 scores in RVT and RAH patients compared with healthy control women Months Baseline
n Functional scales Physical Role Emotional Cognitive Social GHS Symptom scales Fatigue Nausea and emesis Pain Single item scales Dyspnea Insomnia Appetite Loss Constipation Diarrhea Financial difficulties
C
RVT
30
18
99 97 86 96 100 87
95 81 62 78 86 66
3 P*
RVT
6 P*
18 0.941 0.032 G0.001 0.002 G0.001 G0.001
89 81 75 82 82 63
RVT
12 P*
18 0.001 0.002 0.210 0.013 G0.001 G0.001
89 81 68 85 84 68
RVT
P*
18 0.022 0.013 0.014 0.039 G0.001 0.007
93 89 80 84 85 69
RAH
P†
32 0.062 0.218 0.496 0.034 G0.001 0.005
91 86 80 85 90 75
0.005 0.066 0.766 0.018 0.002 0.011
11 2.8 6.1
21 6.5 10
0.073 0.419 0.367
30.0 8.3 19
0.001 0.241 0.032
27 6.5 21
0.015 0.664 0.042
27 8.3 19
0.050 0.582 0.019
23.3 2.6 14.6
0.071 0.660 0.073
1.1 13.3 2.2 6.6 2.2 0
7.4 22.2 11.8 11.1 3.7 13.7
0.275 0.537 0.034 0.484 0.594 0.002
11.1 18.5 9.2 18.5 13.0 11.1
0.038 0.899 0.534 0.117 0.044 0.003
6.2 6.2 2.2 12.5 6.2 8.3
0.038 0.200 1.000 0.203 0.215 0.005
0 10.2 5.1 5.1 5.1 5.1
0.510 0.468 0.372 0.724 0.372 0.030
9.3 21.9 6.2 18.7 8.3 4.2
0.049 0.297 0.630 0.186 0.148 0.021
Scores are transformed to 0Y100 scale, and values represent mean scores. P G 0.05 is presented in bold numerals. *Difference between RVT and control group (Mann-Whitney U test). †Difference between all groups (Kruskal-Wallis test). C, control group.
and menopause status, no difference in GHS was observed between the RAH group and healthy controls (P = 0.174). In multivariate analyses, at 1 year postsurgery, the RVT patients had significantly lower GHS than both healthy control women and the RAH patients after adjusting for age, partner, menopausal and children status, and smoking (P = 0.017). Women in the RVT group had more financial difficulties at each assessment compared with healthy women. There were no significant differences between the patient groups (RVT vs RAH) 1 year postsurgery in any EORTC QLQ-C30 scores.
DISCUSSION Although RVT has been adopted as a safe treatment option for patients with early-stage cervical cancer (tumor size G2 cm) who wish to preserve fertility, studies on RVT has mostly focused on surgical technique and oncological and obstetric outcome rather than postoperative late effects and QOL. To our knowledge, this is the first prospective longitudinal study on patient-reported outcomes with focus on urogynecological morbidity and lymphedema comparing RVT and RAH patients and an age-matched healthy control group.
The current study demonstrates a significant risk of bladder dysfunction, persistent lymphedema, and impaired QOL throughout the first year postsurgery after RVT for early-stage cervical cancer. The most dominating urogynecological symptom was incomplete bladder emptying persistently reported with both questionnaires applied. Dysfunction of the lower urinary tract is well documented and ranges from 8% to 80% after radical hysterectomy for cervical cancer.24Y27 Postoperative loss of bladder sensation, voiding dysfunction, and urinary incontinence might be attributable to autonomic nerve damage during radical hysterectomy.28Y31 We expected less affection of the autonomic pelvic nerves with RVT compared with open access surgery due to the vaginal access. However, no significant difference was observed between the 2 surgical modalities. Only a few studies have included patient-reported outcomes on urogynecological morbidity in patients treated with RVT, and to our knowledge, there are no longitudinal data available for direct comparison. In 1 retrospective and 1 cross-sectional study, bladder hypotonia was reported in 4% to 16% after RVT3,13 and was significantly lower compared with 31% in the RAH group (P G 0.004).13 Lanowska et al32 reported bladder function disorder in 6% of the RVT patients,
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
703
Frøding et al
International Journal of Gynecological Cancer
but neither definition of disorder nor assessment method was described. In a case-control study of Beiner et al33 comparing RVT versus RAH, the median time to normal urine residuals (not defined further in the study) was significantly shorter in the RVT group (1 vs 6 days, P G 0.001). In our study, patients’ self-reported incomplete bladder emptying was reported as quite a bit to very much in 11% in the RVT group, whereas 50% of the RVT and 41% of the RAH patients reported any grade of bladder emptying problems 1 year postsurgery. Our results may indicate a comparatively high prevalence of bladder emptying problems. However, due to different assessment methods and imprecise definition of bladder function disorder, results are not comparable. Furthermore, results on surgical-induced late effects are very often underestimated in retrospective studies due to underreporting bias in the patient’s file.32 The incidence of LL postsurgery for cervical cancer varies substantially in the literature (range, 1.6%Y41%) and has been reported to be significantly higher than in the general population.28,34Y38 LL usually presents within 12 months and once developed often becomes chronic. It results in decreased mobility and inability to perform daily activities and has proved to have a negative effect on psychological and social well-being.35Y37 Some of the variation in LL incidence in literature can be attributed to differences in definition and assessment method.34Y37 In our study, LL was reported persistently during the observation time of 1 year postsurgery in the RVT group with no indication of improvement. Although most of those patients reporting any grade of LL (38.9%) had only ‘‘a little of LL’’ (27.8%) and 11.1% of the patients reported ‘‘quite a bit’’ of LL in the RVT group 12 months postsurgery, it is still a noteworthy finding because this young patient group will live with this effect for the rest of their life. There is only 1 available study on patient’s self-reported lymphedema symptoms after RVT and laparoscopic lymphadenectomy for comparison with our findings. Lanowska et al32 noticed that when women were asked about their wellbeing in general, they denied problems, but when asked specifically about frequent symptoms such as mild leg edema, they reported intermittently appearing lymphedema in 24.1% of the cases.32 In agreement with previous results, the surgical approach (laparoscopy vs laparotomy) did not influence the incidence of LL.37,39,40 To reduce LL after PLND, the sentinel lymph node (SLN) technique is being evaluated in cases of cervical cancer with small tumors. Multicenter studies are running in several countries, and preliminary results have indicated that the use of SLN mapping for cervical cancer is promising.41 We were surprised to observe significant impaired global QOL 1 year postsurgery in both patient groups. Of notice, the difference between the control group and the patients had a mean score difference of more than 10 points on a 0 to 100 scale, which is usually perceived as a significant clinical difference.23 Further notable, the RVT group that was comparable to the control group regarding patient characteristics had very low scores on all QOL dimensions (psychological well-being, cognitive, role, and social functioning) except physical functioning at baseline. These scores were obtained after she was diagnosed with cancer but before
704
& Volume 25, Number 4, May 2015
treatment. This may indicate that the use of baseline scores in cancer patients is problematic as we have discussed earlier.8 Scores obtained by patients who are newly diagnosed with cancer are very likely influenced by the knowledge of having cancer and may not represent true baseline scores.8 We had expected a return to the level of the control group women at 12 months postsurgery in both patient groups. In the study of Brotto et al42 comparing RAH and RVT, significant increase in women’s physical and social functioning, level of energy, and emotional well-being was seen already 6 months postsurgery. However, in our study, both patient groups persisted on scores significantly lower than the control group regarding cognitive and social functioning and global QOL, whereas emotional and role functioning scores returned to those of the control group by 12 months postsurgery. This may indicate that this young patient group does recover psychologically within 1 year after their cancer treatment; they do return to their job or study, but their QOL may still be compromised socially and cognitively by the knowledge of persistent late effects and significant financial difficulties.6,42,43 The strengths of the current study are its longitudinal design, the use of validated questionnaires, and the inclusion of homogenous groups regarding stage of disease and treatment. Furthermore, the inclusion of an age-matched control group allowed comparisons to norms from the general population. The results of the current study provides useful knowledge on urogynecological morbidity and QOL after RVT and RAH for early-stage cervical cancer. Because of less surgical trauma, we expected better QOL and less bladder morbidity for the RVT group compared with the RAH group 1 year postsurgery. However, RVT patients reported persistent bladder dysfunction, LL, and impaired QOL throughout the first year postsurgery. In agreement with our previous findings, it may be concluded that patients treated with RVT are equally affected both regarding urological dysfunction and lymphedema as patients treated with RAH.11 Our present and former study highlights the importance of presurgery and postsurgery information and counseling of the patient.11 The current study demonstrates that radical surgery for early-stage cervical cancer may permanently affect the patient postoperatively. Our results highlight the necessity to critically evaluate the available evidence regarding treatment options for early-stage cervical cancer. A prospective international trial randomizing patients between radical hysterectomy and PLND versus simple hysterectomy and PLND is ongoing.44 A trend toward even more conservative surgery as a large cone biopsy or collum amputation and SLN technique in carefully selected early-stage small (G2 cm) tumors might be the next step, which needs to be further validated. Continued research in these areas including evaluation of QOL will give more treatment options for young women with early-stage cervical cancer and hopefully reduce treatmentrelated short-time and long-time morbidity.
REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11Y30. 2. National Cancer Institute. SEER Data: Surveillance, Epidemiology And End Results. Available at: * 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
3.
4. 5.
6.
7.
8.
9.
10.
11.
12.
13.
14. 15.
16.
17.
18.
19.
20.
& Volume 25, Number 4, May 2015
http://seer.cancer.gov/statfacts/html/cervix.html. Accessed January 25, 2015. Plante M, Gregoire J, Renaud MC, et al. The vaginal radical trachelectomy: an update of a series of 125 cases and 106 pregnancies. Gynecol Oncol. 2011;121:290Y297. Shepherd JH. Cervical cancer. Best Pract Res Clin Obstet Gynaecol. 2012;26:293Y309. Danish Gynecological Cancer Group. Danish Gynecological Cancer Database. Annual Report 2012. Available at: http://www.dgcg.dk/images/DGCD_%C3%85 rsrapport_2012_v2.pdf. Accessed January 25, 2015. Bjelic-Radisic V, Jensen PT, Vlasic KK, et al. Quality of life characteristics inpatients with cervical cancer. Eur J Cancer. 2012;48:3009Y3018. Frumovitz M, Sun CC, Schover LR, et al. Quality of life and sexual functioning in cervical cancer survivors. J Clin Oncol. 2005;23:7428Y7436. Jensen PT, Groenvold M, Klee MC, et al. Early-stage cervical carcinoma, radical hysterectomy, and sexual function. A longitudinal study. Cancer. 2004;100:97Y106. Korfage IJ, Essink-Bot ML, Mols F, et al. Health-related quality of life in cervical cancer survivors: a population-based survey. Int J Radiat Oncol Biol Phys. 2009;73:1501Y1509. Carter J, Sonoda Y, Baser RE, et al. A 2-year prospective study assessing the emotional, sexual, and quality of life concerns of women undergoing radical trachelectomy versus radical hysterectomy for treatment of early-stage cervical cancer. Gynecol Oncol. 2010;119:358Y365. Froeding LP, Ottosen C, Rung-Hansen H, et al. Sexual functioning and vaginal changes after radical vaginal trachelectomy in early stage cervical cancer patients: a longitudinal study. J Sex Med. 2014;11:595Y604. Song T, Choi CH, Lee YY, et al. Sexual function after surgery for early-stage cervical cancer: is there a difference in it according to the extent of surgical radicality? J Sex Med. 2012;9:1697Y1704. Alexander-Sefre F, Chee N, Spencer C, et al. Surgical morbidity associated with radical trachelectomy and radical hysterectomy. Gynecol Oncol. 2006;101:450Y454. Gien LT, Covens A. Fertility-sparing options for early stage cervical cancer. Gynecol Oncol. 2010;117:350Y357. Schneider A, Erdemoglu E, Chiantera V, et al. Clinical recommendation radical trachelectomy for fertility preservation in patients with early-stage cervical cancer. Int J Gynecol Cancer. 2012;22:659Y666. Roy M, Plante M. Pregnancies after radical vaginal trachelectomy for early-stage cervical cancer. Am J Obstet Gynecol. 1998;179(6 Pt 1):1491Y1496. Ottosen C. Trachelectomy for cancer of the cervix: dargent’s operation. Vaginal hysterectomy for early cancer of the cervix stage IA1 and CIN III. Best Pract Res Clin Obstet Gynaecol. 2011;25:217Y225. Mota F, Vergote I, Trimbos JB, et al. Classification of radical hysterectomy adopted by the Gynecological Cancer Group of the European Organization for Research and Treatment of Cancer. Int J Gynecol Cancer. 2008;18:1136Y1138. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365Y376. Greimel ER, Kuljanic VK, Waldenstrom AC, et al. The European Organization for Research and Treatment of Cancer
21.
22.
23.
24. 25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
Quality of Life After RVT
(EORTC) Quality-of-Life questionnaire cervical cancer module: EORTC QLQ-CX24. Cancer. 2006;107:1812Y1822. Jensen PT, Klee MC, Groenvold M. Validation of a questionnaire for self-rating of urological and gynaecological morbidity after treatment of gynaecological cancer. Radiother Oncol. 2002;65:29Y38. Fayers PM, Machin D. Missing data. In Quality of Life. The Assessment, Analysis and Interpretation of Patient-Reported Outcomes. 2nd ed. West Sussex, UK: John Wiley & Sons Ltd; 2007:355Y384. Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol. 1998;16:139Y144. Forney JP. The effect of radical hysterectomy on bladder physiology. Am J Obstet Gynecol. 1980;138:374Y382. Low JA, Mauger GM, Carmichael JA. The effect of Wertheim hysterectomy upon bladder and urethral function. Am J Obstet Gynecol. 1981;139:826Y834. Ralph G, Winter R, Michelitsch L, et al. Radicality of parametrial resection and dysfunction of the lower urinary tract after radical hysterectomy. Eur J Gynaecol Oncol. 1991;12:27Y30. Scotti RJ, Bergman A, Bhatia NN, et al. Urodynamic changes in urethrovesical function after radical hysterectomy. Obstet Gynecol. 1986;68:111Y120. Bergmark K, Avall-Lundqvist E, Dickman PW, et al. Lymphedema and bladder-emptying difficulties after radical hysterectomy for early cervical cancer and among population controls. Int J Gynecol Cancer. 2006;16:1130Y1139. Laterza RM, Sievert KD, de RD, et al. Bladder function after radical hysterectomy for cervical cancer. Neurourol Urodyn. February 12, 2014. doi: 10.1002/nau.22570. [Epub ahead of print]. Pieterse QD, Kenter GG, Maas CP, et al. Self-reported sexual, bowel and bladder function in cervical cancer patients following different treatment modalities: longitudinal prospective cohort study. Int J Gynecol Cancer. 2013;23:1717Y1725. Zullo MA, Manci N, Angioli R, et al. Vesical dysfunctions after radical hysterectomy for cervical cancer: a critical review. Crit Rev Oncol Hematol. 2003;48:287Y293. Lanowska M, Mangler M, Spek A, et al. Radical vaginal trachelectomy (RVT) combined with laparoscopic lymphadenectomy: prospective study of 225 patients with early-stage cervical cancer. Int J Gynecol Cancer. 2011;21:1458Y1464. Beiner ME, Hauspy J, Rosen B, et al. Radical vaginal trachelectomy vs. radical hysterectomy for small early stage cervical cancer: a matched case-control study. Gynecol Oncol. 2008;110:168Y171. Werngren-Elgstrom M, Lidman D. Lymphoedema of the lower extremities after surgery and radiotherapy for cancer of the cervix. Scand J Plast Reconstr Surg Hand Surg. 1994;28:289Y293. Ryan M, Stainton MC, Jaconelli C, et al. The experience of lower limb lymphedema for women after treatment for gynecologic cancer. Oncol Nurs Forum. 2003;30:417Y423. Beesley V, Janda M, Eakin E, et al. Lymphedema after gynecological cancer treatment: prevalence, correlates, and supportive care needs. Cancer. 2007;109:2607Y2614. Achouri A, Huchon C, Bats AS, et al. Complications of lymphadenectomy for gynecologic cancer. Eur J Surg Oncol. 2013;39:81Y86.
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
705
Frøding et al
International Journal of Gynecological Cancer
38. Abu-Rustum NR, Gemignani ML, Moore K, et al. Total laparoscopic radical hysterectomy with pelvic lymphadenectomy using the argon-beam coagulator: pilot data and comparison to laparotomy. Gynecol Oncol. 2003;91:402Y409. 39. Abu-Rustum NR, Alektiar K, Iasonos A, et al. The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: a 12-year experience at Memorial Sloan-Kettering Cancer Center. Gynecol Oncol. 2006;103:714Y718. 40. Ghezzi F, Uccella S, Cromi A, et al. Lymphoceles, lymphorrhea, and lymphedema after laparoscopic and open endometrial cancer staging. Ann Surg Oncol. 2012;19:259Y267.
706
& Volume 25, Number 4, May 2015
41. Niikura H, Okamoto S, Otsuki T, et al. Prospective study of sentinel lymph node biopsy without further pelvic lymphadenectomy in patients with sentinel lymph node-negative cervical cancer. Int J Gynecol Cancer. 2012;22:1244Y1250. 42. Brotto LA, Smith KB, Breckon E, et al. Pilot study of radical hysterectomy versus radical trachelectomy on sexual distress. J Sex Marital Ther. 2013;39:510Y525. 43. Park SY, Bae DS, Nam JH, et al. Quality of life and sexual problems in disease-free survivors of cervical cancer compared with the general population. Cancer. 2007;110:2716Y2725. 44. Plante M. The SHAPE trial. http://www.gcig.igcs.org/Spring2012/ 2012_june_shape_trial.pdf. Accessed January 25, 2015.
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
Quality of Life, Urogynecological Morbidity, and Lymphedema After Radical Vaginal Trachelectomy for Early-Stage Cervical Cancer Ligita Paskeviciute Frøding, MD,* Christian Ottosen, MD,* Berit Jul Mosgaard, MD, PhD,* and Pernille Tine Jensen, MD, PhDÞ
Objective: Radical vaginal trachelectomy (RVT) offers a possibility for future childbearing for young women with early-stage cervical cancer. However, the literature on quality of life and self-reported morbidity in patients undergoing RVT is scarce. The aim of this study was to prospectively assess quality of life after RVT with focus on urogynecological morbidity and lymphedema. Furthermore, the aim of this study was to compare results with those in women treated with radical abdominal hysterectomy (RAH) and with age-matched control women from the general population. Methods and Materials: Eighteen patients with early-stage cervical cancer operated with RVT were prospectively included and assessed preoperatively, 3, 6, and 12 months postoperatively using validated questionnaires. Thirty-two patients treated with RAH were included consecutively and assessed once at 12 months postsurgery, whereas an agematched control group of 30 healthy women was assessed once. Results: Fifty percent of the RVT group and 41% of the RAH reported any grade of incomplete bladder emptying problems at 1 year postsurgery assessment. Eleven percent of the RVT patients and 12.5% of the RAH patients reported severe lymphedema of the legs as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Cervical Cancer Module. The Global Health Status scores of the RVT patients improved over time but were significantly lower than in the healthy controls during the entire observation time (P = 0.029). Conclusions: Patients treated with RVT for early-stage cervical cancer had persistent bladder emptying problems and lymphedema comparable to those experienced by patients treated with RAH and significantly higher than those reported by healthy control women. Key Words: Cervical cancer, Radical trachelectomy, Radical hysterectomy, Quality of life Received October 22, 2014, and in revised form December 20, 2014. Accepted for publication December 21, 2014. (Int J Gynecol Cancer 2015;25: 699Y706)
*Department of Gynecology and Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen; and †Department of Gynecology and Obstetrics, Odense University Hospital, Odense, Denmark. Address correspondence and reprint requests to Ligita Paskeviciute Frøding, MD, Department of Gynecology and Obstetrics, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. E-mail: [email protected]. The authors declare no conflicts of interest. Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000395 International Journal of Gynecological Cancer
cancer is the most common gynecological cancer C ervical affecting women aged younger than 40 years. According 1
to the National Cancer Institute, cervical cancer rates are highest in women aged 35 to 44 years in the United States.2 A significant proportion of these women may have an interest to preserve fertility. Radical vaginal trachelectomy (RVT) with radical pelvic lymph node dissection (PLND) has therefore been used as a safe alternative to conventional radical abdominal hysterectomy (RAH), with similar survival and recurrence rates for tumors smaller than 2 cm.3,4 In countries with systematic cervical cancer screening, 54% of patients are
& Volume 25, Number 4, May 2015
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
699
Frøding et al
International Journal of Gynecological Cancer
diagnosed with stage I disease, with an expected 5-year survival rate of more than 90%.5 Patients treated with RVT are expected to be long-term survivors and must therefore deal with the consequences of surgery for many years. Several studies describe quality of life (QOL) and sexual dysfunction after RAH including PLND.6Y9 Only a few prospective studies on short-term and long-term self-reported morbidity and QOL after RVT have been published.10Y12 We have previously reported our results on sexual functioning and vaginal changes after RVT compared with RAH and QOL impact in early-stage cervical cancer patients.11 Our study showed significant sexual dysfunction and impaired QOL after RVT throughout the first year compared with healthy women. Furthermore, RVT patients had more vaginal changes than the RAH patients, probably caused by more cervical/ vaginal scarring. Although trachelectomy has been an accepted treatment modality over the past 2 decades, the data on surgery-induced morbidity are scarce and derive mainly from retrospective studies. The most common adverse effects reported are lower urinary tract dysfunction and lymph drainage problems.3,13Y15 To our knowledge, there are no data available including prospective longitudinal self-reported assessment of these symptoms in patients after RVT. In the present study, we assessed QOL with focus on short-term and long-term urogynecological morbidity and lymphedema in patients with early-stage cervical cancer treated with RVT and RAH compared with healthy age-matched control group.
MATERIALS AND METHODS Patients Patients with cervical cancer stage IA2 to IB1 treated with RVTwere eligible for the prospective study. Patients with stage IA1 to IB2 treated with RAH at the Department of Gynecology, Copenhagen University Hospital Rigshospitalet and Herlev were eligible as control group. The criteria for offering RVT have been almost unchanged for more than 10 years16: stage IA2 to IB1 cervical cancer, with a tumor smaller than 2 cm, and with a realistic prognosis to preserve fertility. Patients who do not fulfill these criteria are not offered RVT but instead recommended RAH.
Staging All patients were staged by a gynecologist and an oncologist in general anesthesia. A positron emission tomography and computed tomography was conducted in all patients to exclude distant metastases.
Treatment The procedure of RVT has been described earlier.17 To evaluate lymph node status, laparoscopic PLND was performed. A class II to III RAH according to the European Organization for Research and Treatment of Cancer (EORTC) classification and PLND was performed as an open procedure in patients who did not have a desire to preserve fertility.18
700
& Volume 25, Number 4, May 2015
Control Group Nurses and students from both departments of gynecology were asked to participate as a control group. Premenopausal women older than 18 years, without prior cancer disease and with no previous hysterectomy, were eligible. All study participants, cases and control group, were given oral and written information about the study, after which they provided their written informed consent.
Main Outcome Measures The EORTC Quality of Life Core Questionnaire (QLQC30) contains 30 items covering 5 functional scales (physical, role, emotional, social, and cognitive functioning), 3 symptom scales (fatigue, pain, nausea/vomiting), and 6 single items assessing dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties.19 All scale and item scores were transformed to a 0 to 100 scale. For the 5 functional scales and the global QOL scale, a higher score represents a better level of functioning. The EORTC QOL Questionnaire Cervical Cancer Module (QLQ-CX24) contains 24 items about disease and treatment-specific effects after treatment of cervical cancer, and supplements the EORTC QLQ-C30. All scale and item scores were transformed to a 0 to 100 scale.20 In the present study, only scores on bladder functioning and lymphedema are included. The Urogynecological Morbidity Questionnaire (UGQ) contains 18 items on urologic, vaginal, and menopausal changes, and pain. All scale and item scores were transformed to a 0 to 100 scale.21 For the symptom scales and items, a higher score corresponds to worse or more symptoms in all 3 questionnaires.19Y21 Radical vaginal trachelectomy patients were assessed preoperatively, and 3, 6, and 12 months postoperatively. Radical abdominal hysterectomy patients were assessed once, 12 months postoperatively, using the same questionnaires. Healthy women were assessed once at the time of inclusion.
Statistical Analysis Differences in demographic and clinical characteristics between the study groups were compared with a t test for independent samples.
Patients Versus Control Group Patient and control group scores were compared using the Mann-Whitney U test at each assessment (RAH vs control, RVT vs RAH, RVT vs control). For univariate comparison of outcome measures between the treatment groups with the control group, the Kruskal-Wallis H test was conducted. Multivariate analyses were performed to assess the independent association of variables with the end points as urine incontinence, incomplete bladder emptying, bladder sensibility, lymphedema, and the global health status (GHS). For these 5 end points, univariate analyses were performed for the following independent variables: age, menopause, partner and children status, smoking, and study group (RVT, RAH, and control). Backward elimination (P G 0.10 on univariate analysis to be considered in the model) was used to identify * 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 4, May 2015
independent variables to be associated with these 5 end points when comparing the 3 groups at the 12 months assessment.
Precancer Versus Postcancer Comparison of Scores Within Patients The Wilcoxon signed rank test was used for paired comparison within RVT patients of retrospective precancer scores obtained before surgery versus 12 months after surgery to assess the long-term effect of treatment. Data imputing of missing data in the RVT group was performed using the last value carried forward method,22 and thereafter, all statistical analysis were repeated on the complete data set. Statistical differences were indicated if P is less than 0.05. Differences in scale scores of 10 points or more were considered clinically significant.23 All data were analyzed using SPSS 11.5 (SPSS Inc, Chicago, IL).
RESULTS Eighteen RVT patients, 32 RAH patients, and 30 healthy women were included in the study. Sociodemographic and
Quality of Life After RVT
clinical characteristics are given in Table 1. In postmenopausal RAH patients, the ovaries were removed, whereas ovaries were saved in premenopausal women. Nine RAH patients were postmenopausal, and one achieved surgery-induced menopause because the ovaries were removed due to highrisk histology of the cervical cancer (clear cell carcinoma). There was no statistical difference between the groups according to body mass index and partner status, whereas significantly more RVT patients were smokers. Significantly, more RAH patients had children, were older, and were postmenopausal. There was no statistical difference regarding stage and histology in the 2 patient groups. In 1 patient in stage IA1, RAH was performed because of multifocal disease. None of the patients had lymph node metastasis or recurrence during the 12-month follow-up. One RVT and 1 RAH patient had bladder injury during the operation. In the RAH group, 3 ureteral injuries were seen. Postoperatively, 5 RAH patients had urinary tract infection, and 1 patient was admitted with urosepsis. One RVT and 1 RAH patient developed intra-abdominal abscess, and 1 RAH patient had bowel obstruction; all 3 patients needed surgical intervention.
TABLE 1. Sociodemographic and clinical characteristic of study participants Sociodemographic Characteristics n Age, median (range) BMI, median (range) Has a partner Postmenopausal Has children Education Nonacademic Academic Unknown Smoking FIGO tumor stage IA1 IA2 IB1 IB2 Histology Squamous Adenocarcinoma Adenosquamous Clear cell Nodes removed, median (range) Blood loss, median (range), mL
Controls, n (%)
RVT, n (%)
30 28.5 (24Y41)
18 29.0 (23Y42) 23.3 (18.5Y33.7) 13 (72) 0 3 (17)
24 (80) 0 7 (23) 15 (50) 15 (50) 0 3 (10)
13 4 1 9
(72.2) (22.2) (5.6) (50)
P* 0.914 0.545 0.591 0.079 0.079 0.001
RAH, n (%)
P†
32 42.0 (30Y63) 23.2 (19.3Y37.4) 28 (88) 9 (28) 31 (97)
G0.001 0.815 0.184 0.004 G0.001
26 (81.2) 2 (6.3) 4 (12.5) 5 (16)
0 1 17 (94) 0
1 1 29 (91) 1
13 (72) 5 (28) 0 0 20 (16Y36) 150
19 (59) 11 (34) 1 1 24 (7Y41) 500
0.122 0.122 0.003
0.641
0.374 0.639
0.160 G0.001
P G 0.05 is presented in bold numerals. *RVT versus control. †RVT versus RAH. BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics.
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
701
International Journal of Gynecological Cancer
Frøding et al
& Volume 25, Number 4, May 2015
Compliance
Lymphedema
The compliance rates for questionnaire completion of the RVT patients was 100% at baseline and 3 months and 88.9% at the 6-month assessment. The lowest compliance rate was obtained at 1 year postsurgery due to patients’ noncompliance (72.2%). The participation rate in the RAH and the control group was 100% and 64%, respectively.
Lymphedema of the legs (LL) in the RVT group appeared significantly more at 3 months postsurgery assessment versus preoperatively (P = 0.007) and did not seem to improve over time compared at 3 and 12 months (P = 0.314) (Table 2). There were no group differences between the RVT and RAH groups at 12 months postsurgery assessment (P = 0.646). Totally, 39% of the RVT patients and 41% of the RAH patients reported any grade of LL at 12 months postsurgery assessment, whereas only 7% of healthy control women did (P = 0.005). After adjusting for age, menopausal status, and children status in multivariate analysis, RVT patients still had significant more LL compared with healthy women (P = 0.031), whereas this difference disappeared in the RAH group (P = 0.253).
Urogynecological Morbidity Urinary incontinence and incomplete bladder emptying problems were present in the RVT group at 3 months assessment and persisted through 1 year postsurgery with no indication of improvement (Table 2). After dichotomization of scores on incomplete bladder emptying problems to none versus any grade, 50% in the RVT group, 41% in the RAH group, and only 10% in the control group had incomplete bladder emptying problems of any grade 1 year postsurgery (EORTC QLQ-CX24 and UGQ). After adjusting for age, menopausal, and children status in multivariate analysis, both patient groups had significantly more urine incontinence than the control group (P = 0.002 and P = 0.048 for RVT and RAH groups, respectively); the RVT group had significantly more bladder emptying problems (P = 0.002), and the RAH group had more bladder sensitivity problems (P = 0.014) than healthy control women 1 year postsurgery.
Quality of Life Baseline functional scale scores (role, emotional, cognitive, and social functioning) were significantly lower in the RVT group compared with the healthy control women (Table 3). Scores of role and emotional functioning in the RVT group remained significantly lower than those of healthy control women up to 6 months postsurgery, but improved at 12 months postsurgery (Table 3). Cognitive and social function scores as well as GHS scores persisted to be significantly lower in the RVT group compared with healthy women at each assessment (Table 3). After adjusting for age
TABLE 2. Urogynecological symptoms and lymphedema in patients after RVT and RAH compared with healthy control women Months Baseline C n 30 EORTC QLQ-CX24 Frequent voiding 10.0 Pain or burning feeling when urinating 3.3 Urine incontinence 0 Difficult emptying bladder 3.3 Lymphedema 2.2 UGQ Frequent voiding 12.2 Burning sensation or pain when urinating 3.3 Urine incontinence 0 Difficult to tell when need to urinate 1.1 Incomplete bladder emptying 3.3 Bloody urine 0
RVT
3 P*
18
RVT
6 P*
18 25.9 16.7 11.1 21.6 22.2
RVT
12 P*
18 0.071 0.006 0.008 0.003 0.002
20.4 7.4 11.1 18.5 20.4
P*
RVT 18
0.313 0.250 0.008 0.015 0.002
RAH
P†
32
20.4 16.7 0 9.3 1.9
0.176 0.034 1.000 0.469 0.879
18.5 9.6 13.0 22.2 16.7
0.319 0.113 0.003 0.002 0.005
29.0 12.2 15.0 17.2 20.4
1.00 0.237 0.002 0.004 0.004
19.6 11.8 0 0 12.5 3.9
0.479 24.1 0.413 22.2 0.487 18.5 0.577 0.018 16.7 0.003 7.4 0.138 7.4 0.138 1.000 9.3 0.022 9.3 0.022 16.6 G0.001 0.452 3.7 0.286 0 0.439 3.7 0.286 0.165 18.5 0.015 20.4 0.015 22.2 0.002 0.058 2.0 0.184 0 1.000 2.0 0.184
20.8 5.2 11.5 14.6 14.6 1.0
0.696 0.333 0.002 0.018 0.006 0.454
Scores are transformed to 0Y100 scale, and values represent mean scores. P G 0.05 is presented in bold numerals. *Difference between RVT and control group (Mann-Whitney U test). †Difference between all groups (Kruskal-Wallis test). C, control group.
702
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 4, May 2015
Quality of Life After RVT
TABLE 3. EORTC QLQ-C30 scores in RVT and RAH patients compared with healthy control women Months Baseline
n Functional scales Physical Role Emotional Cognitive Social GHS Symptom scales Fatigue Nausea and emesis Pain Single item scales Dyspnea Insomnia Appetite Loss Constipation Diarrhea Financial difficulties
C
RVT
30
18
99 97 86 96 100 87
95 81 62 78 86 66
3 P*
RVT
6 P*
18 0.941 0.032 G0.001 0.002 G0.001 G0.001
89 81 75 82 82 63
RVT
12 P*
18 0.001 0.002 0.210 0.013 G0.001 G0.001
89 81 68 85 84 68
RVT
P*
18 0.022 0.013 0.014 0.039 G0.001 0.007
93 89 80 84 85 69
RAH
P†
32 0.062 0.218 0.496 0.034 G0.001 0.005
91 86 80 85 90 75
0.005 0.066 0.766 0.018 0.002 0.011
11 2.8 6.1
21 6.5 10
0.073 0.419 0.367
30.0 8.3 19
0.001 0.241 0.032
27 6.5 21
0.015 0.664 0.042
27 8.3 19
0.050 0.582 0.019
23.3 2.6 14.6
0.071 0.660 0.073
1.1 13.3 2.2 6.6 2.2 0
7.4 22.2 11.8 11.1 3.7 13.7
0.275 0.537 0.034 0.484 0.594 0.002
11.1 18.5 9.2 18.5 13.0 11.1
0.038 0.899 0.534 0.117 0.044 0.003
6.2 6.2 2.2 12.5 6.2 8.3
0.038 0.200 1.000 0.203 0.215 0.005
0 10.2 5.1 5.1 5.1 5.1
0.510 0.468 0.372 0.724 0.372 0.030
9.3 21.9 6.2 18.7 8.3 4.2
0.049 0.297 0.630 0.186 0.148 0.021
Scores are transformed to 0Y100 scale, and values represent mean scores. P G 0.05 is presented in bold numerals. *Difference between RVT and control group (Mann-Whitney U test). †Difference between all groups (Kruskal-Wallis test). C, control group.
and menopause status, no difference in GHS was observed between the RAH group and healthy controls (P = 0.174). In multivariate analyses, at 1 year postsurgery, the RVT patients had significantly lower GHS than both healthy control women and the RAH patients after adjusting for age, partner, menopausal and children status, and smoking (P = 0.017). Women in the RVT group had more financial difficulties at each assessment compared with healthy women. There were no significant differences between the patient groups (RVT vs RAH) 1 year postsurgery in any EORTC QLQ-C30 scores.
DISCUSSION Although RVT has been adopted as a safe treatment option for patients with early-stage cervical cancer (tumor size G2 cm) who wish to preserve fertility, studies on RVT has mostly focused on surgical technique and oncological and obstetric outcome rather than postoperative late effects and QOL. To our knowledge, this is the first prospective longitudinal study on patient-reported outcomes with focus on urogynecological morbidity and lymphedema comparing RVT and RAH patients and an age-matched healthy control group.
The current study demonstrates a significant risk of bladder dysfunction, persistent lymphedema, and impaired QOL throughout the first year postsurgery after RVT for early-stage cervical cancer. The most dominating urogynecological symptom was incomplete bladder emptying persistently reported with both questionnaires applied. Dysfunction of the lower urinary tract is well documented and ranges from 8% to 80% after radical hysterectomy for cervical cancer.24Y27 Postoperative loss of bladder sensation, voiding dysfunction, and urinary incontinence might be attributable to autonomic nerve damage during radical hysterectomy.28Y31 We expected less affection of the autonomic pelvic nerves with RVT compared with open access surgery due to the vaginal access. However, no significant difference was observed between the 2 surgical modalities. Only a few studies have included patient-reported outcomes on urogynecological morbidity in patients treated with RVT, and to our knowledge, there are no longitudinal data available for direct comparison. In 1 retrospective and 1 cross-sectional study, bladder hypotonia was reported in 4% to 16% after RVT3,13 and was significantly lower compared with 31% in the RAH group (P G 0.004).13 Lanowska et al32 reported bladder function disorder in 6% of the RVT patients,
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
703
Frøding et al
International Journal of Gynecological Cancer
but neither definition of disorder nor assessment method was described. In a case-control study of Beiner et al33 comparing RVT versus RAH, the median time to normal urine residuals (not defined further in the study) was significantly shorter in the RVT group (1 vs 6 days, P G 0.001). In our study, patients’ self-reported incomplete bladder emptying was reported as quite a bit to very much in 11% in the RVT group, whereas 50% of the RVT and 41% of the RAH patients reported any grade of bladder emptying problems 1 year postsurgery. Our results may indicate a comparatively high prevalence of bladder emptying problems. However, due to different assessment methods and imprecise definition of bladder function disorder, results are not comparable. Furthermore, results on surgical-induced late effects are very often underestimated in retrospective studies due to underreporting bias in the patient’s file.32 The incidence of LL postsurgery for cervical cancer varies substantially in the literature (range, 1.6%Y41%) and has been reported to be significantly higher than in the general population.28,34Y38 LL usually presents within 12 months and once developed often becomes chronic. It results in decreased mobility and inability to perform daily activities and has proved to have a negative effect on psychological and social well-being.35Y37 Some of the variation in LL incidence in literature can be attributed to differences in definition and assessment method.34Y37 In our study, LL was reported persistently during the observation time of 1 year postsurgery in the RVT group with no indication of improvement. Although most of those patients reporting any grade of LL (38.9%) had only ‘‘a little of LL’’ (27.8%) and 11.1% of the patients reported ‘‘quite a bit’’ of LL in the RVT group 12 months postsurgery, it is still a noteworthy finding because this young patient group will live with this effect for the rest of their life. There is only 1 available study on patient’s self-reported lymphedema symptoms after RVT and laparoscopic lymphadenectomy for comparison with our findings. Lanowska et al32 noticed that when women were asked about their wellbeing in general, they denied problems, but when asked specifically about frequent symptoms such as mild leg edema, they reported intermittently appearing lymphedema in 24.1% of the cases.32 In agreement with previous results, the surgical approach (laparoscopy vs laparotomy) did not influence the incidence of LL.37,39,40 To reduce LL after PLND, the sentinel lymph node (SLN) technique is being evaluated in cases of cervical cancer with small tumors. Multicenter studies are running in several countries, and preliminary results have indicated that the use of SLN mapping for cervical cancer is promising.41 We were surprised to observe significant impaired global QOL 1 year postsurgery in both patient groups. Of notice, the difference between the control group and the patients had a mean score difference of more than 10 points on a 0 to 100 scale, which is usually perceived as a significant clinical difference.23 Further notable, the RVT group that was comparable to the control group regarding patient characteristics had very low scores on all QOL dimensions (psychological well-being, cognitive, role, and social functioning) except physical functioning at baseline. These scores were obtained after she was diagnosed with cancer but before
704
& Volume 25, Number 4, May 2015
treatment. This may indicate that the use of baseline scores in cancer patients is problematic as we have discussed earlier.8 Scores obtained by patients who are newly diagnosed with cancer are very likely influenced by the knowledge of having cancer and may not represent true baseline scores.8 We had expected a return to the level of the control group women at 12 months postsurgery in both patient groups. In the study of Brotto et al42 comparing RAH and RVT, significant increase in women’s physical and social functioning, level of energy, and emotional well-being was seen already 6 months postsurgery. However, in our study, both patient groups persisted on scores significantly lower than the control group regarding cognitive and social functioning and global QOL, whereas emotional and role functioning scores returned to those of the control group by 12 months postsurgery. This may indicate that this young patient group does recover psychologically within 1 year after their cancer treatment; they do return to their job or study, but their QOL may still be compromised socially and cognitively by the knowledge of persistent late effects and significant financial difficulties.6,42,43 The strengths of the current study are its longitudinal design, the use of validated questionnaires, and the inclusion of homogenous groups regarding stage of disease and treatment. Furthermore, the inclusion of an age-matched control group allowed comparisons to norms from the general population. The results of the current study provides useful knowledge on urogynecological morbidity and QOL after RVT and RAH for early-stage cervical cancer. Because of less surgical trauma, we expected better QOL and less bladder morbidity for the RVT group compared with the RAH group 1 year postsurgery. However, RVT patients reported persistent bladder dysfunction, LL, and impaired QOL throughout the first year postsurgery. In agreement with our previous findings, it may be concluded that patients treated with RVT are equally affected both regarding urological dysfunction and lymphedema as patients treated with RAH.11 Our present and former study highlights the importance of presurgery and postsurgery information and counseling of the patient.11 The current study demonstrates that radical surgery for early-stage cervical cancer may permanently affect the patient postoperatively. Our results highlight the necessity to critically evaluate the available evidence regarding treatment options for early-stage cervical cancer. A prospective international trial randomizing patients between radical hysterectomy and PLND versus simple hysterectomy and PLND is ongoing.44 A trend toward even more conservative surgery as a large cone biopsy or collum amputation and SLN technique in carefully selected early-stage small (G2 cm) tumors might be the next step, which needs to be further validated. Continued research in these areas including evaluation of QOL will give more treatment options for young women with early-stage cervical cancer and hopefully reduce treatmentrelated short-time and long-time morbidity.
REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11Y30. 2. National Cancer Institute. SEER Data: Surveillance, Epidemiology And End Results. Available at: * 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
3.
4. 5.
6.
7.
8.
9.
10.
11.
12.
13.
14. 15.
16.
17.
18.
19.
20.
& Volume 25, Number 4, May 2015
http://seer.cancer.gov/statfacts/html/cervix.html. Accessed January 25, 2015. Plante M, Gregoire J, Renaud MC, et al. The vaginal radical trachelectomy: an update of a series of 125 cases and 106 pregnancies. Gynecol Oncol. 2011;121:290Y297. Shepherd JH. Cervical cancer. Best Pract Res Clin Obstet Gynaecol. 2012;26:293Y309. Danish Gynecological Cancer Group. Danish Gynecological Cancer Database. Annual Report 2012. Available at: http://www.dgcg.dk/images/DGCD_%C3%85 rsrapport_2012_v2.pdf. Accessed January 25, 2015. Bjelic-Radisic V, Jensen PT, Vlasic KK, et al. Quality of life characteristics inpatients with cervical cancer. Eur J Cancer. 2012;48:3009Y3018. Frumovitz M, Sun CC, Schover LR, et al. Quality of life and sexual functioning in cervical cancer survivors. J Clin Oncol. 2005;23:7428Y7436. Jensen PT, Groenvold M, Klee MC, et al. Early-stage cervical carcinoma, radical hysterectomy, and sexual function. A longitudinal study. Cancer. 2004;100:97Y106. Korfage IJ, Essink-Bot ML, Mols F, et al. Health-related quality of life in cervical cancer survivors: a population-based survey. Int J Radiat Oncol Biol Phys. 2009;73:1501Y1509. Carter J, Sonoda Y, Baser RE, et al. A 2-year prospective study assessing the emotional, sexual, and quality of life concerns of women undergoing radical trachelectomy versus radical hysterectomy for treatment of early-stage cervical cancer. Gynecol Oncol. 2010;119:358Y365. Froeding LP, Ottosen C, Rung-Hansen H, et al. Sexual functioning and vaginal changes after radical vaginal trachelectomy in early stage cervical cancer patients: a longitudinal study. J Sex Med. 2014;11:595Y604. Song T, Choi CH, Lee YY, et al. Sexual function after surgery for early-stage cervical cancer: is there a difference in it according to the extent of surgical radicality? J Sex Med. 2012;9:1697Y1704. Alexander-Sefre F, Chee N, Spencer C, et al. Surgical morbidity associated with radical trachelectomy and radical hysterectomy. Gynecol Oncol. 2006;101:450Y454. Gien LT, Covens A. Fertility-sparing options for early stage cervical cancer. Gynecol Oncol. 2010;117:350Y357. Schneider A, Erdemoglu E, Chiantera V, et al. Clinical recommendation radical trachelectomy for fertility preservation in patients with early-stage cervical cancer. Int J Gynecol Cancer. 2012;22:659Y666. Roy M, Plante M. Pregnancies after radical vaginal trachelectomy for early-stage cervical cancer. Am J Obstet Gynecol. 1998;179(6 Pt 1):1491Y1496. Ottosen C. Trachelectomy for cancer of the cervix: dargent’s operation. Vaginal hysterectomy for early cancer of the cervix stage IA1 and CIN III. Best Pract Res Clin Obstet Gynaecol. 2011;25:217Y225. Mota F, Vergote I, Trimbos JB, et al. Classification of radical hysterectomy adopted by the Gynecological Cancer Group of the European Organization for Research and Treatment of Cancer. Int J Gynecol Cancer. 2008;18:1136Y1138. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365Y376. Greimel ER, Kuljanic VK, Waldenstrom AC, et al. The European Organization for Research and Treatment of Cancer
21.
22.
23.
24. 25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
Quality of Life After RVT
(EORTC) Quality-of-Life questionnaire cervical cancer module: EORTC QLQ-CX24. Cancer. 2006;107:1812Y1822. Jensen PT, Klee MC, Groenvold M. Validation of a questionnaire for self-rating of urological and gynaecological morbidity after treatment of gynaecological cancer. Radiother Oncol. 2002;65:29Y38. Fayers PM, Machin D. Missing data. In Quality of Life. The Assessment, Analysis and Interpretation of Patient-Reported Outcomes. 2nd ed. West Sussex, UK: John Wiley & Sons Ltd; 2007:355Y384. Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol. 1998;16:139Y144. Forney JP. The effect of radical hysterectomy on bladder physiology. Am J Obstet Gynecol. 1980;138:374Y382. Low JA, Mauger GM, Carmichael JA. The effect of Wertheim hysterectomy upon bladder and urethral function. Am J Obstet Gynecol. 1981;139:826Y834. Ralph G, Winter R, Michelitsch L, et al. Radicality of parametrial resection and dysfunction of the lower urinary tract after radical hysterectomy. Eur J Gynaecol Oncol. 1991;12:27Y30. Scotti RJ, Bergman A, Bhatia NN, et al. Urodynamic changes in urethrovesical function after radical hysterectomy. Obstet Gynecol. 1986;68:111Y120. Bergmark K, Avall-Lundqvist E, Dickman PW, et al. Lymphedema and bladder-emptying difficulties after radical hysterectomy for early cervical cancer and among population controls. Int J Gynecol Cancer. 2006;16:1130Y1139. Laterza RM, Sievert KD, de RD, et al. Bladder function after radical hysterectomy for cervical cancer. Neurourol Urodyn. February 12, 2014. doi: 10.1002/nau.22570. [Epub ahead of print]. Pieterse QD, Kenter GG, Maas CP, et al. Self-reported sexual, bowel and bladder function in cervical cancer patients following different treatment modalities: longitudinal prospective cohort study. Int J Gynecol Cancer. 2013;23:1717Y1725. Zullo MA, Manci N, Angioli R, et al. Vesical dysfunctions after radical hysterectomy for cervical cancer: a critical review. Crit Rev Oncol Hematol. 2003;48:287Y293. Lanowska M, Mangler M, Spek A, et al. Radical vaginal trachelectomy (RVT) combined with laparoscopic lymphadenectomy: prospective study of 225 patients with early-stage cervical cancer. Int J Gynecol Cancer. 2011;21:1458Y1464. Beiner ME, Hauspy J, Rosen B, et al. Radical vaginal trachelectomy vs. radical hysterectomy for small early stage cervical cancer: a matched case-control study. Gynecol Oncol. 2008;110:168Y171. Werngren-Elgstrom M, Lidman D. Lymphoedema of the lower extremities after surgery and radiotherapy for cancer of the cervix. Scand J Plast Reconstr Surg Hand Surg. 1994;28:289Y293. Ryan M, Stainton MC, Jaconelli C, et al. The experience of lower limb lymphedema for women after treatment for gynecologic cancer. Oncol Nurs Forum. 2003;30:417Y423. Beesley V, Janda M, Eakin E, et al. Lymphedema after gynecological cancer treatment: prevalence, correlates, and supportive care needs. Cancer. 2007;109:2607Y2614. Achouri A, Huchon C, Bats AS, et al. Complications of lymphadenectomy for gynecologic cancer. Eur J Surg Oncol. 2013;39:81Y86.
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
705
Frøding et al
International Journal of Gynecological Cancer
38. Abu-Rustum NR, Gemignani ML, Moore K, et al. Total laparoscopic radical hysterectomy with pelvic lymphadenectomy using the argon-beam coagulator: pilot data and comparison to laparotomy. Gynecol Oncol. 2003;91:402Y409. 39. Abu-Rustum NR, Alektiar K, Iasonos A, et al. The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: a 12-year experience at Memorial Sloan-Kettering Cancer Center. Gynecol Oncol. 2006;103:714Y718. 40. Ghezzi F, Uccella S, Cromi A, et al. Lymphoceles, lymphorrhea, and lymphedema after laparoscopic and open endometrial cancer staging. Ann Surg Oncol. 2012;19:259Y267.
706
& Volume 25, Number 4, May 2015
41. Niikura H, Okamoto S, Otsuki T, et al. Prospective study of sentinel lymph node biopsy without further pelvic lymphadenectomy in patients with sentinel lymph node-negative cervical cancer. Int J Gynecol Cancer. 2012;22:1244Y1250. 42. Brotto LA, Smith KB, Breckon E, et al. Pilot study of radical hysterectomy versus radical trachelectomy on sexual distress. J Sex Marital Ther. 2013;39:510Y525. 43. Park SY, Bae DS, Nam JH, et al. Quality of life and sexual problems in disease-free survivors of cervical cancer compared with the general population. Cancer. 2007;110:2716Y2725. 44. Plante M. The SHAPE trial. http://www.gcig.igcs.org/Spring2012/ 2012_june_shape_trial.pdf. Accessed January 25, 2015.
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
