Article Text
Abstract
Background There is limited information about the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent platinum-based chemotherapy on sexuality in patients with advanced ovarian cancer.
Objective To evaluate the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent platinum-based chemotherapy on sexuality in patients with advanced ovarian cancer as a sub-protocol of the prospectively randomized LION trial.
Methods The Sexual Activity Questionnaire was applied to assess sexual function according to its sub-scales activity, pleasure, and discomfort. The 'orgasm' sub-scale from the Female Sexual Function Index was also added. The questionnaire was administered in combination with the EORTC QLQ-C30 questionnaire at baseline prior surgery, after 6, 12, and 24 months. The primary endpoint was changes in sexual function.
Results Overall, 495 patients received the questionnaires. 254 (51%) responded at baseline. Of these, 55 (22%) patients were sexually active, 182 (72%) were sexually inactive, and for 17 (7%) patients' data were not available. There was a total of 55/495 (11%) patients at 6 months, 139 (28%) patients at 12 months, and 81 (16%) patients at 24 months. Median age was 60.5 years (range 21.4–75.8). At baseline, sexually active responders were significantly younger (median age 51.5 years,) than sexually inactive responders (median age 61.8 years) and tended to have a better performance status. Discomfort evaluated as dryness of the vagina and pain during sexual intercourse was significantly worse at 12 months than at baseline (p<0.001); however, the surgical variable, lymphadenectomy, did not have any impact on this. The orgasm sub-scale showed diverging results with a deterioration from baseline to 12 months in the lymphadenectomy group compared with the no-lymphadenectomy group (p=0.02).
Conclusion The majority of patients were sexually inactive; however, in those who were sexually active, pain during intercourse was worse at 12 months. In addition, the orgasm sub-scale demonstrated worse results in patients who underwent complete lymphadenectomy. The study suggests that surgery in the retroperitoneal space may influence sexual function.
- gynecologic surgical procedures
- ovarian cancer
- quality of life (PRO)/palliative care
- SLN and lympadenectomy
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- gynecologic surgical procedures
- ovarian cancer
- quality of life (PRO)/palliative care
- SLN and lympadenectomy
HIGHLIGHTS
After cytoreductive surgery for ovarian cancer sexual discomfort was significantly worse at 12 months than at baseline.
Systematic pelvic and para-aortic lymphadenectomy lead to impaired sexual function, particularly difficulty in having an orgasm.
Undergoing a lymphadenectomy did not have any impact on sexual discomfort.
INTRODUCTION
There is very limited information on sexual activity in patients with advanced ovarian cancer and the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent chemotherapy on sexuality. Many cancer survivors are older women and it may be a misconception that sexual health issues are less important in this age group. However, in a European cohort of healthy post-menopausal women aged between 56 and 69 years, engagement in sexual activity during the last month was reported in approximately 47% of patients.1 2
Sexual activity and functioning are important factors influencing quality of life. Immediately after diagnosis of cancer, most patients focus on anti-cancer treatment and its challenges and sexuality becomes less important.3 In this scenario the primary objective of treatment is to cure the disease or prolong life and maintain quality of life. Since survival rates and life expectancy after treatment for cancer are increasing due to more effective therapies and the implementation of screening programs, quality-of-life concerns and the underlying factors are more in focus.
Despite a high prevalence of sexual dysfunction in patients with gynecologic cancers, awareness of healthcare providers about this problem is limited. The majority of patients with ovarian cancer present with advanced stage disease.4 Primary treatment consists of a sequence of surgery and chemotherapy in combination with maintenance therapy of anti-angiogenic drugs or poly (ADP-ribose) polymerase inhibitors.2 After surgery, pre-menopausal patients are likely to have premature onset of menopause, whereas post-menopausal patients may have a loss of libido. The stromal and the hilar interstitial cells in the ovaries are essential for the synthesis of androgens (testosterone and androstenedione), which, among other factors, preserve a woman’s libido after menopause.5 6 Davison et al showed that serum testosterone levels did not vary as a consequence of natural menopause, but were significantly lower in women aged 55 years or older after bilateral salpingo-oophorectomy than in women of the same age group without surgery.7 Therefore, bilateral salpingo-oophorectomy can affect all age groups.
As a consequence of diagnosis and treatment patients may have vaginal dryness, dyspareunia, decreased libido, hot flashes, decreased sexual desire, decreased ability to achieve orgasm, loss of sensation in the genital area, depression, anxiety, changes in self- and body-image, and inter-personal relationship changes with their partner.8
In a cross-sectional study of 189 survivors of ovarian cancer and 287 age-adjusted healthy controls, patients with cancer were less sexually active (47%) than controls (53%).9 Sexually active patients with ovarian cancer reported lower levels of sexual pleasure (p<0.001) and higher levels of discomfort (p<0.001) than controls. Lack of interest and physical problems were significantly more common in sexually inactive patients with cancer than in controls.9
The aim of this study was to evaluate the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent platinum-based chemotherapy on sexuality in patients with advanced ovarian cancer.
METHODS
In the prospectively randomized LION trial (NCT00712218), patients with newly diagnosed advanced ovarian cancer who had undergone macroscopically complete resection and had normal lymph nodes both before and during surgery were randomly assigned to either undergo or not undergo lymphadenectomy.10 Comparing both groups, which differed only in the performance of a lymphadenectomy, we prospectively evaluated the role of radical surgery in the retroperitoneal space on sexual function (sub-study LION-PAW). In the LION trial there were no requirements for nerve-sparing surgical techniques.
The Sexual Activity Questionnaire was used to assess sexual function according to its sub-scales habit, pleasure, and discomfort.11 The questionnaire is divided in three sections. In section 1, patients are asked about their sexual relationship and whether they are sexually active or not. Those who are not sexually active go on to complete section 2 and omit section 3. In section 2, seven possible reasons for sexual inactivity are listed and patients choose those that apply to them. Additional space for any personal reasons is provided. Section 3 consists of 10 questions assessing those aspects of sexual functioning that may be influenced by hormonal status, such as desire, frequency, satisfaction, dryness of the vagina, and penetration pain.11 For all three sub-scales habit (range 0–3), pleasure (range 0–18), and discomfort (range 0–6), higher values indicate more agreeable outcomes. Discomfort was evaluated as dryness of the vagina and pain during sexual intercourse.
Additional to the Sexual Activity Questionnaire the ‘orgasm’ sub-scale from the Female Sexual Function Index was added with the three items—frequency, difficulty, and satisfaction, and a score range from 0 to 5 for each item.12 Patients who were not sexually active were excluded from the analysis. The questionnaires were administered together with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) questionnaire at baseline before surgery, and after 6, 12, and 24 months. Because of a low response rate (11%) questionnaires at 6 months were not evaluated. Therefore, our primary endpoint was the evaluation at 12 months.
The primary objective was to assess the influence of systematic pelvic and para-aortic lymphadenectomy and optimal tumor debulking surgery on sexual function in patients with advanced ovarian cancer. The secondary objective was to assess the psychometric properties and acceptance of the Sexual Activity Questionnaire in patients with advanced ovarian cancer.
Statistical Methods
Proportions were compared using chi-square tests. Continuous variables, such as the scores resulting from questionnaires at given time points, were compared using Wilcoxon U-test. For longitudinal analyses of scores, mixed models with restricted maximum likelihood estimation were applied, with repeated measurements within patients and a treatment variable (lymphadenectomy yes/no) and its interaction with time as factors. Only available assessments were used, no imputation was performed for missing assessments. P values less than 0.05 were considered as statistically significant. No adjustment for multiplicity was applied.
RESULTS
Overall, 495 patients received the questionnaires. A total of 254 patients (51%) responded at baseline. Of these, 55 (22%) were sexually active, 182 (72%) were sexually inactive, and 17 patients (7%) did not answer the question about sexual activity. At 6 months 55 patients (11%) completed the questionnaires and at 12 months 139 patients (28%). Of the latter, 42 patients were sexually active, 89 patients were sexually inactive, and for eight patients data were not available. At 24 months, 81 (16%) patients still responded, and of these, 22 were sexually active, 56 were sexually inactive, and for three patients data were not available (Figure 1).
The median age of responders was 60.5 years (range 21.4–75.8). Sexually active patients had a median age of 51.5 years (range 21–74), sexually inactive patients a median age of 61.8 (range 29–75). Thus, sexually active responders at baseline were significantly younger than sexually inactive women (p<0.0001) and tended to have a better performance status (ECOG 0 vs ECOG 1) (p=0.052) (Table 1). At baseline, ‘no current partner’ was the main reason for sexual inactivity in both groups, followed by ‘no interest in sex’, ‘physical problems’, and ‘too tired’ (Table 2). There were no significant differences between responders and non-responders in age, ECOG performance status, histology, International Federation of Gynecology and Obstetrics (FIGO) stage, and lymphadenectomy or no lymphadenectomy. When comparing sexual activity for each assessment time point between patients with and without recurrence at the given time point, we observed no difference in the proportion of patients reporting sexual activity.
Mean discomfort with intercourse at baseline was 5.2 (SD 0.9) in the lymphadenectomy group and 4.5 (SD 1.3) in the no-lymphadenectomy group. After 12 months, it dropped to 3.8 (SD 2.0) and 4.1 (SD 1.9), respectively. Therefore, discomfort was significantly worse at 12 months than at baseline (p<0.001); however, the surgical variable lymphadenectomy did not show any impact on this variable (Figure 2).
In contrast, the orgasm sub-scale showed diverging results with deterioration from baseline to 12 months in the lymphadenectomy group, but slightly improving in the no-lymphadenectomy group, excluding patients who were not not sexually active from the analysis. Baseline orgasm scores were 5.1 (SD 0.9) in the lymphadenectomy group and 4.6 (SD 1.6) in the no-lymphadenectomy group. After 12 months, the score dropped to 3.8 (SD 1.6) in the lymphadenectomy group and reached 5.1 (SD 1.3) in the no-lymphadenectomy group. This difference was significant at 12 months (p=0.02) (Figure 3) but not at 24 months. Neither of the sub-scales ‘pleasure’ or ‘habit’ showed significant differences between the arms at any time point.
DISCUSSION
In the LION study, pelvic and para-aortic lymphadenectomy in patients with advanced ovarian cancer who had undergone intra-abdominal macroscopically complete resection and had normal lymph nodes both before and during surgery had not been associated with longer overall or progression-free survival than no lymphadenectomy.10 In the LION-PAW study, discomfort during sexual activity was significantly worse at 12 months than at baseline (p<0.001). Lymphadenectomy was associated with a higher incidence of post-operative complications, including a significant change of the orgasm score from baseline to 12 months in sexually active patients. These findings may be a result of several factors. One may be the hormonal ablation after bilateral salpingo-oophorectomy,8 13 the extent of surgery, or the impact of subsequent chemotherapy. One might also consider that there might be damage during the lymphadenectomy to the sympathetic or parasympathetic nerves in the retroperitoneum.
In our study, in spite of all complications and side effects, there were no clinical meaningful differences in global health status and sub-domains of quality of life found between the lymphadenectomy or no-lymphadenectomy group or at least these were not regarded as clinically relevant.10 Larger trials in younger oncological patient populations may shed light on the effect of pelvic and para-aortic lymphadenectomy on the autonomic nerves and its associated impairment of sexual function. In these studies, urinary tract and colorectal function, as well as hormonal replacement therapy, should be evaluated simultaneously.
In the LION-PAW study, the median age of responders was 60.5 years (range 21.4–75.8). Of these, only 22% were sexually active. A representative German survey assessing intimate relationship with someone in the past year showed that almost 75% of women aged 61 to 70 years reported having been sexually active.14 In contrast to this report, the rate of sexually active women of this age group in the LION-PAW study was 12%. Lindau et al also investigated sexual activity in this group and found that the majority of older adults engaged in intimate relationship and regarded sexuality as an important part of life.15 The low rate of sexual activity in patients with ovarian cancer as in the LION PAW study was confirmed by Matulonis et al, who evaluated the sexual functioning of 58 survivors of early stage ovarian cancer and found that less than 10% of survivors had either an interest in sex or were sexually active.16
Sexual function after treatment for ovarian cancer was also investigated by Taylor et al in 232 women, of whom 47% were still receiving therapy. Fifty percent of the patients reported sexual activity during the last month. Of those, 80% had problems with vaginal dryness and 62% complained about pain or discomfort during sexual intercourse. Seventy-five percent of women reported problems reaching orgasm, 50% to more than 90% of time.17
In a survey of 200 participants, 60% of patients with a history of ovarian cancer and a minimum of 2 years post-treatment reported that their sex lives had been negatively influenced by their disease and 75% characterized their sex lives as ‘adequate to poor’.18 Within the study ‘Carolin meets Hanna’ the overall sexuality score for long-term survivors of ovarian cancer was much lower, with a score of 5.2, than for healthy women of the control group, with a score of 28.2 (score range 2.0–36.0 of the Female Sexual Function Index).19 The studies mentioned above show the high prevalence of sexual dysfunction in patients after therapy for ovarian cancer.
Communication about sexual function and especially sexual problems still seems to be difficult for healthcare providers and for patients even in an anonymous setting. In the LION-PAW study this was shown by the low percentage of completed questionnaires (254 of 495 patients, 51.3%) at baseline, which dropped to 16.4% (n=81) after 24 months. In a retrospective multicenter study evaluating sexual function after cancer therapy, 396 patients with breast cancer and 93 patients with ovarian cancer, between the ages of 18 and 70 years, were interviewed at least 24 months after cancer diagnosis and compared with 60 healthy women; the response rate was comparably low with 42.4% responders. Besides ‘other reasons’, the most frequently given reason for non-participation was ‘questions are too intimate’.20
Patients are looking for more information about the effects of cancer and of treatment side effects on their sexuality. In a study by Stead et al, although most healthcare professionals knew that the majority of patients with ovarian cancer would have a sexual problem, only a quarter of doctors and a fifth of nurses discussed sexual issues with their patients.21 Reasons for not dealing with sexual issues were not feeling responsible, embarrassment in this sensitive and personal area, lack of knowledge and experience, and lack of resources to provide support.21 In a trial evaluating sexual health as part of gynecologic cancer care, 57% of the patients reported never discussing sexuality.22
LION-PAW suggests that potential long-term consequences, such as discomfort and reduced quality of orgasm, of oncologic therapies on sexual function and quality of life have to be considered and discussed with each patient prior to surgery.
In a group of patients with ovarian cancer, sexual health education and rehabilitation training, relaxation, and cognitive training led to significant improvements in overall sexual functioning and psychological distress.23 Patients need to understand that sexual dysfunction does not imply a failure on their part in the recovery process. Physicians and psycho-oncologists have a role-model function regarding the discussion of sexuality as an essential element of quality of life. This includes three main steps: knowledge, diagnosis, and sexual counseling.24 The potential impact that cancer therapies like surgery or systemic therapy can have on sexual function need to be discussed prior to treatment, including preventive options. Many patients also appreciate it, if their partner is included in the communication and informed about the possible side effects of cancer and therapy on sexuality and relationship.25
The majority of patients in the LION-PAW study were sexually inactive and furthermore, the compliance to respond to the sexuality questionnaire was limited, therefore our study is only hypothesis generating in so far that surgery in the retroperitoneal space may influence sexual function. The value of our study is to raise the question, whether radical lymphadenectomy in the retroperitoneal space may influence sexuality in women and whether patients with ovarian cancer of all age groups should be offered prospective counseling to cope with sexual dysfunction caused by disease and/or therapy.
References
Footnotes
Contributors All authors: substantial contributions to the conception of the work, acquisition, and interpretation of data. Drafting the work or revising it critically for important intellectual content. Final approval of the version published. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The LION trial was supported by the Deutsche Forschungsgemeinschaft (project WA 740/4) and the Austrian Science Fund (project KLI 176-B00).
Competing interests AH reports personal fees from Astra Zeneca, personal fees from MedConcept, personal fees from MedUpdate, personal fees from Pfizer, personal fees from Roche, personal fees from Streamedup!GmbH, personal fees from Pharma Mar, personal fees from Tesaro, outside the submitted work; BS reports grants and personal fees from Roche, grants and personal fees from AstraZeneca, grants and personal fees from Tesaro, personal fees from Clovis, personal fees from MSD, personal fees from Ethicon, outside the submitted work; SM reports personal fees from AbbVie, grants and personal fees from AstraZeneca, personal fees from Clovis, personal fees from GSK, grants and personal fees from Medac, personal fees from MSD, personal fees from Novartis, personal fees from OLYMPUS Europa, grants and personal fees from PharmaMar, grants and personal fees from Roche, personal fees from Sensor Kinesis, grants and personal fees from Tesaro, personal fees from Teva, outside the submitted work; AdB reports personal fees from Roche, personal fees from Clovis, personal fees from Astra Zeneca/MSD, personal fees from GSK/Tesaro, personal fees from BIOCAD, personal fees from Genmab/seattle genetics, personal fees from Pfizer, outside the submitted work; PH reports grants and personal fees from Astra Zeneca, grants and personal fees from Roche, personal fees from Sotio, grants and personal fees from Tesaro, personal fees from Stryker, personal fees from Zai Lab, personal fees from MSD, grants and personal fees from public funding (ASCO, DKH, DFG), personal fees from Clovis, personal fees from Immunogen, grants from GSK, grants from Boehringer Ingelheim, grants from Medac, grants from Genmab, outside the submitted work.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data are available fromannette.hasenburg@unimedizin-mainz.de.