MATERIALS AND METHODS - Impact of Pelvic Floor Dysfunction on Quality of Life in Cancer Survivo

A. Participants

Women with cervical cancer and endometrial cancer who had radical hysterectomy and pelvic lymph node dissection between July 2009 and December 2009 were recruited among the patients who registered at cancer clinics at Seoul National University Bundang Hospital, Korea. All participants were 20 years or older and were able to give an informed consent and to comply with instructions to use a biofeedback device. We confined study participants to patients who had no infectious disease in the urinary tract and vagina, because PFMT with biofeedback device was not available for them. Among 50 subjects who met the inclusion criteria, 6 refused to participate in the study because of time constraints or unwillingness to visit the clinic. Ten subjects were excluded because they had unstable medical conditions such as fever, anemia at the time of baseline measurement. To assess the prevalence of pelvic floor disorders in gynecologic cancer survivors compared with healthy women who had no history of a gynecologic cancer, women who were >20 years old without a diagnosis of cancer were recruited. We matched for age (maximal difference of 3 years), being nulli- or multiparous, and BMI.

Finally, 34 subjects with gynecological cancer and 16 health women agreed to participate (reference group) and completed Korean version of pelvic floor questionnaire and Korean version of the EORTC QLQ-C30 and QLQ-CX24. All participants provided written informed consent. This study complied with the Declaration of Helsinki, and its protocol was approved by the institutional review board of Seoul National University,

Bundang Hospital.

Participants were randomly allocated to exercise group comprising intensive pelvic floor muscle training incorporated with core exercise or control group by the computerized stratified block randomization procedure allocating participants according to cancer stage and age. The subjects were identified by means of 2 levels of 2 strata:

stratum 1, cancer stage 1, 2 or 3, 4, and stratum 2, age < 50 and  50 years. They were

assigned into two groups so that the number of subjects in each stratum was approximately equal in the 2 groups.

B. Methods

1. Pelvic Floor Rehabilitation Program (PFRP) Protocol

The pelvic floor rehabilitation program (PFRP) was designed with 45-minute duration per session, once per week, for 4 weeks. The standardized intervention given to women in exercise group consisted of six appointments with a specialist and a physiotherapist over a 4-week period (at weeks 0, 1, 2, 3, 4 and 5). At the first visit, the history of cancer treatment was taken, and both subjective pelvic floor dysfunction assessment and objective internal pelvic floor function measurement were carried out. Patients learned anatomy and function of the pelvic floor muscles and how to correctly contract the pelvic floor muscles. The PFRP consisted of biofeedback sessions and core exercise sessions.

After supervised instruction, patients were taught PFM exercise via biofeedback (BioCon-200, mcubetech inc, Seoul, Korea). Biofeedback was performed in lithotomy

position via a vaginal silicon pressure sensor (Pathway™ Vaginal Silicon Pressure Sensor , THE PROMETHEUS GROUP, Dover, USA). A two-channel EMG biofeedback apparatus was used, with all channels for rectus abdominal muscles, and the signal received through surface electrodes

During the initial two to three sessions, a strong emphasis was placed on the specificity of muscle contraction (isolated contraction of the pelvic muscles with the minimum possible activity of the rectus abdominal muscles). Every session lasted 20 min and consisted of 40 cycles with 10s activity followed by 20s of relaxation. After 5 min of resting period, patients received 20-minute intensive core exercise session consisted of strengthening exercises for the pelvic floor muscles and transverse abdominus muscles and of stretching exercises for muscles attached to the pelvic girdle such as gluteus, tensor fascia latae, piriformis muscles and adductors and surrounding ligaments according to Evjenth and Hamberg (Blomberg, Svardsudd et al. 1992) under the supervision by physical therapists. Diaghragmatic breathing techniques were taught as an important part of the core-strengthening program and abdominal hollowing was also performed to activate the transversus abdominis (McGill 2001) One trained evaluator conducted all the evaluation of PFMT.

In once a week visits for 4 weeks, 30 min counseling and an individualized home exercise program were provided after PFRP. Patients were encouraged to perform six sets of exercises daily (one set consisted of up to ten maximum voluntary contractions held

for up to 10 s, with 4 s rest between each contraction and, after a one minute rest, ten or more fast contractions), with the use of an exercise diary. Changes of symptoms, compliance with the advices for lifestyle modification and changes in pelvic floor muscle strength measured by vaginal pressure sensor were recorded at each visit. The content of the home exercise program adjusted to the conditions of the subjects. Eventually, we developed a comprehensive functional program consisting of all components including teaching of pelvic floor exercises, pelvic floor muscle assessment, lifestyle advices and the encouragement of home based exercises. Furthermore, standardized clinical documents, exercise diaries and leaflets were used to ensure systematic approach and consistent outcome.

Patients in control group were taught in detail about the methods of constricting their pelvic muscles, with special emphasis on avoiding constricting the abdominal muscles simultaneously. Verbal guidance and feedback of the contractions were used to instruct the patient how to correctly and selectively contract the anal sphincter while relaxing the abdominal muscles. They were advised to practice for 20 minutes per day five times a week. The exercise session was designed to include short and long duration exercises. In addition, these patients received an informative leaflet with these instructions and a telephone number for further explanations. The leaflet identical to that given to the intervention group was provided. The control group did not see a physiotherapist and had no planned visit of the hospital by the follow-up appointment.

2. Measurements

The outcome measures were (1) pelvic floor dysfunction questionnaire, (2) pelvic floor muscle strength, (3) motor evoked potential of pudendal nerve, and (4) patient-reported HRQOL Quality of life measured by the Korean Version of the European Organization for Research and Treatment of Cancer Quality of Life core questionnaire (EORTC QLQ-C30) and the Korean Version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Cervical Cancer Module (EORTC QLQ-CX-24). All outcomes were measured as changes from completion at the 5 weeks assessment to baseline.

Pelvic floor dysfunction questionnaire

Subjective quotients in pelvic floor dysfunction were assessed from the interview based evaluation. All participants completed the interviewer-administered pelvic floor questionnaire (Baessler, O'Neill et al. 2009) This tool encompassed all aspects of pelvic floor function including condition-specific quality of life issues and bothersome symptoms in a reproducible and valid fashion. The questionnaires contained the questions on bladder, bowel and sexual symptoms and impact on quality of life. To assess frequency, severity of pelvic floor symptoms, a 4-point scoring system was used for most items of the questionnaires except for defecation frequency, bowel consistency, sufficient lubrication, and the reason for sexual abstinence. Answers to above 4 questions did not allow for a graded, interval-scaled scoring system. Cronbach‟s alpha coefficients were

acceptable in all domains: bladder function 0.72, bowel function 0.82 and sexual function 0.81(Baessler, O'Neill et al. 2009) . Kappa coefficients of agreement for test-retest analyses varied from 0.5 to 1.0 (Baessler, O'Neill et al. 2009).

Pelvic floor muscle strength

The PFM strength was measured by perineometry prior to and after 4 weeks treatment. Vaginal pressure was then measured using a vaginal silicon pressure sensor perineometer (sensitivity 0.06 kPa, sensitivity 5 mV, threshold 1.5 V). Perineometer is a dynamometry which is used for the assessment of PFM strength objectively. This perineometer uses cms/H2O. The probe is inserted 3-3.5 cm into the vagina, and the patient is instructed to contract the PFM in the same dorsal position. All measurements were carried out by the same evaluator, who also observed the woman to ensure she wasn‟t „straining‟ the pelvic floor during the procedure.

Motor evoked potential of pudendal nerve

The motor evoked potential (MEP) from pelvic floor was obtained by sacral and transcranial magnetic stimulation (Magstim 200, UK) at baseline and follow-up after 4 weeks treatment. Patients lied in the left lateral decubitus position. Specially designed intra-anal sponge electrode (Dantec, Skovlund, Denmark) was lubricated and gently placed into the anal canal. Monophasic single pulses of magnetic stimuli were delivered by a double cone coil (9902-00, Magstim, UK) at the vertex corresponding to the

primary motor center in the precentral gyrus. Figure-of-8 coil (9762-00, Magstim, UK) was used to stimulate the dorso-laterally over the side sacrum corresponding to the exit of the sacral nerves from the sacral bone (Fig 1). To evaluate the cortical facilitation, we recorded MEPs in two conditions: with the relaxation of the target muscles and with the voluntary contraction moderately to maximally. We measured latency, amplitude and excitability threshold (ET) of MEPs detected from pelvic floor muscles without and with facilitation. The excitability threshold at rest (RET) was defined as the lowest intensity that produced MEP responses of 100 μV or over in at least 3 of 6 applied stimuli while muscle was at rest (Rossini et al., 1994). For optimal facilitation, we measured latency of MEPs with minimal contraction (10% of MVC) with RET intensity and amplitude with a moderate contraction (30% of MVC) with 110% of RET intensity.(Han, Kim et al. 2001)

Fig 1. Site of sacral stimulation A: intra-anal sponge electrode (Dantec, Skovlund, Denmark), B: Figure-of-8 coil (9762-00, Magstim, UK)

Patient-reported HRQOL Quality of life

Generic and condition-specific HRQOL aspects were assessed with the EORTC QLQ-C30 and QLQ-CX24 questionnaire (Yun, Park et al. 2004) (Shin, Ahn et al. 2009). The EORTC QLQ-C30 is a multidimensional questionnaire for cancer patients containing 30 items grouped into one global health status/QOL scale, five functional scales (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, pain and nausea and vomiting) and six single-item scales (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties)(Aaronson, Ahmedzai et al. 1993). The specific cervical cancer module (QLQ-CX24) (Shin, Ahn et al. 2009) consists of 3 multi-item and 6 single-item scales and examines 3 variables that are not sufficiently addressed by the core instrument (i.e. subjects‟ symptom experience, body image and sexuality).

3. Blinding

Blinding of participants was not possible because of the nature of the interventions.

Training sessions and strength measurements were administered by different persons so that knowledge of an individual‟s training progression would not influence the process of measurement and vice versa. Outcome evaluators were also blinded to group allocation of participants.

4. Assessment of Exercise Adherence and Adverse Events

A physical therapist and trained evaluator monitored adherence and adverse effects.

The subjects who experienced aggravation of pelvic floor symptoms and/or had some difficulty in continuing to do the exercise because of some other cause were excluded from the final assessment.

5. Statistical Analyses

Data was presented as mean (SD) or median (25th to 75th percentiles) according distribution. The differences in the baseline data between the groups were analyzed using t-test and the non-parametric Mann-Whitney test for the continuous variables with and without a normal distribution, respectively and chi-square test for the categorical variables.

The EORTC QLQ-C30 and the QLQ-CX24 scores were calculated using the recommended EORTC procedure (Fayers, Aaronson et al. 1999). The means were compared and interpreted following previous findings indicating that the difference of at least 10 points could be considered as a clinically meaningful change (Osoba, Rodrigues et al. 1998). In order to evaluate the impact of pelvic floor dysfunction on HRQOL scales, univariate linear regression analysis was used.

Difference scores (5weeks, baseline) constructed in for all variables were used to assess the changes. The changes of dependent variables between pre-intervention and post-intervention in the exercise and control group were analyzed using an analysis of

variance (ANOVA) with repeated measures. Within-group comparisons were made using paired t-test or Wilcoxon rank sign test. For categorical dichotomous variables the Mac Nemar test was used, while the Marginal Homogeneity test was used for categorical variables with more than two categories.

All analyses were performed using SPSS 17.0 (SPSS Inc.,Chicago, IL, USA).

Ⅲ. RESULTS

A. Pelvic floor dysfunction and its impact on quality of life in gynecological cancer survivors

There were no significant differences between the groups in the baseline characteristics such as age, marital status, multiparous and level of education (Table 1).

Statistically significant difference was noted between the groups in the employment status (p=0.003). Mean age of 34 participants who underwent the initial evaluation and 16 reference group were 51.5 ± 8.3 years (range, 35-67 years) and 51.8 ± 8.3 years (range, 39-61 years). In the gynecological cancer group, 30 women were cervical cancer survivors and 4 women were endometrial cancer survivors. Twenty percent of gynecological cancer survivors had early-stage disease. Median interval between cancer treatment and baseline assessment was 1.2 years (range 1 to 5 years). Two women had been treated with radical hysterectomy and pelvic lymph node dissection only, 10 underwent surgery and adjuvant radiotherapy, 13 underwent surgery and adjuvant chemotherapy and 9 underwent surgery and adjuvant chemoradiotherapy.

Table 1 Demographic and disease-related characteristics of gynecological cancer

Time since treatment (years, range) 1.2 (1-5) Treatment type

1. Comparison of pelvic floor symptom with reference group

Table 2 displays the pelvic floor symptoms in gynecological cancer group and reference group. In the urinary symptoms, gynecological cancer patients showed significantly higher rate of urinary frequency, nocturia and stress incontinence. In bowel symptoms, gynecological cancer group showed significantly higher rate of straining, urgency and incomplete emptying stool than the reference group.

Gynecological cancer survivors were less likely to be sexually active than the reference group (38.2% vs 93.7%). The sexual symptom questions were provided individually to find the difference between the groups; the data are summarized in Table 3. Gynecological cancer survivors reported less sexual desire (libido), less vaginal lubrication during intercourse and more pain with intercourse.

Table 2-1. Pelvic floor dysfunction in gynecological cancer group and reference

Difficulty emptying bladder 12 (35.3) 3 (18.7) 0.068 Bowel function

Table 3. Sexual questionnaire item analysis

How would you describe your level of sexual interest during the past month (libido)?

None 13 2 How often do you have an orgasm?

3 Seldom 1 0.215

Do you have sufficient natural vaginal lubrication during intercourse?

0 Yes 4 13 0.022

1 No 9 2

Do you experience pain with intercourse?

0 Never 2 10 0.008

1 Occasionally 3 5

2 Frequently 5

3 Always 3

Is sexual intercourse enjoyable for you?

3 Not at all 5 3 0.09

2 Occasionally 8 5

1 Frequently 6

0 Always 1

2. Relation of pelvic floor symptoms with pelvic floor muscle strength and MEP Subsequently, we divided the gynecological cancer survivors in two subgroups according to whether the urinary incontinence or not: incontinence group and continence group and compared the pelvic floor strength and MEP. In incontinence group, pelvic floor muscle strength is significantly weaker than that in continence group (4.21 vs 19.53, P = 0.04). We obtained motor evoked responses in only five patients of incontinence group, but in twelve patients of continence gorup with all the stimulations (cord, cortical and sacral plexus, respectively). Two in incontinence group and six in continence group showed motor evoked potential with stimulation on only one side of sacral plexus and the potential could evoked with cortical stimulation at the same cases. The latency with cortical stimulation with facilitation in incontinence group was more delayed compared to that in the continence group, but not significantly (p=0.07) (Table 4). One in incontinence group showed no motor evoked potential by sacral stimulation and cortical stimulation at rest, but by cortical stimulation with facilitation, the potential was evoked (latency 19.60 ms, amplitude 0.50 mV, CET 100%). Interestingly, five of them had lymphedema at the same side where the potentials were not provoked. Other participants we could not evoked motor responses at any stimulation.

Table 4. Comparison of pelvic muscle strength between incontinence and continence group in gynecological cancer survivors

Incontinence group

(n=16)

Continence group

(n=18) P value

Pelvic muscle strength

Peak pressure (cmH2O) 4.21 ± 3.12 19.53 ± 14.32 0.04

Sacral stimulation

Latency 3.80 (2.95-4.35) 3.35 (2.80-3.70) 0.21

Amplitude 0.20 (0.10-0.30) 0.25(0.10-0.35) 0.53

Cortical stimulation at rest

Latency 22.05 (19.80-28.05) 21.20(18.00-24.20) 0.26

Amplitude 0.30 (0.10-0.40) 0.25 (0.10-0.40) 0.52

Threshold 85.00 (65.00-97.00) 80.00 (60.00-95.00) 0.42 Cortical stimulation at facilitation

Latency 20.15 (17.15-25.00) 18.00(16.80-20.25) 0.07

Amplitude 0.55 (0.20-0.75) 0.60 (0.20-0.80) 0.46

Threshold 75.00 (67.00-85.00) 70.00 (65.00-76.00) 0.24

3. Comparison of HRQOL outcomes with reference group

Clinically meaningful differences (10 points) were observed between gynecological

cancer patients and healthy controls in terms of physical functioning (71.7 vs 84.6), social functioning (79.2 vs 95.8) and global health status (52.6 vs 75.7) (Fig 2).

Fig 2. Mean functional scores of patients with gynecological cancer compared with reference group. A higher score represents a higher level of functioning or global health status/QOL. *Differences in health-related quality of life scores between groups were considered clinically relevant if 10 points

Fatigue Nausea/vomitting Pain Dyspnea Insomnia Appetite loss Constipation Diarrhea Financial difficulties As for symptom-related showed remarkably worse outcomes in terms of constipation (38.8 vs 8.3), diarrhea (33.3 vs 18.7) and financial difficulties (24.2 vs 4.2) (fig 3).

Fig 3. Mean symptom scores of patients with gynecological cancer compared with reference group. A higher score represents a higher perception of the symptom. *Differences in health-related quality of life scores between groups were considered clinically relevant if 10 points

4. Impact of pelvic floor dysfunction on cancer generic HRQOL outcomes (EORTC QLQ-C30)

There was a strong association between functional scales and bladder and bowel function-related covariates. Urinary urgency negatively affected physical functioning (p=0.003), role functioning (p=0.005) and social functioning (0=0.007) and urinary incontinence negatively associated with the global health status/QOL (p=0.021) and physical functioning (p=0.024). Difficulty emptying negatively affected the global health status/QOL (p=0.019) and social functioning (p=0.034). Incomplete evacuation was negatively associated with the physical functioning (p=0.007). Sexual inactivity negatively affected the global health status/QOL (p=0.021) (Table 5). No variables were associated with emotional functioning (data no shown).

Table 5. Relationship among generic (EORTC QLQ-C30) HRQOL outcomes and pelvic

EORTC European Organisation for Research and Treatment of Cancer, QOL Quality of life, HRQOL health-related quality of life

*Statistically significant difference (p<0.05)

B. Effectiveness of Pelvic Floor Rehabilitation Program for gynecological cancer survivor

There were no significant differences between exercise and control groups in any of the baseline characteristics (Table 6). No significant difference in the participants‟ ages was found between the intervention and control groups at baseline. The proportions of marriage, education level and employment status were not significantly different between the groups. A diagnosis of stage 1 disease had been made in 20% and 18.1%, and 10%

and 9.1% had undergone surgery without additional treatments respectively. Before beginning the exercise programs, pelvic floor strength measured by perineometer were 12.8 ±16.6 and 11.3 ± 9.9, No differences were found in the baseline latencies and amplitudes of pudendal motor nerve stimulating at cortical area, cord and sacral plexus among groups. We only obtained motor evoked responses in eight patients in exercise group and nine patients in control group at baseline assessment. Other participants we could not evoked motor responses with magnetic stimulation.

Table 6-1. Baseline comparative characteristics between the two groups in gynecological

Table 6-2. Baseline comparative pelvic floor function between the two groups in

Threshold 70.0 (65.0-77.5) 78.0 (71.3-100.0) 0.25

Cranial stimulation with facilitation

Latency 19.2 (18.3-22.2) 20.9 (20.1-24.8) 0.13

Amplitude 0.5 (0.2-0.7) 0.3 (0.1-0.4) 0.32

Threshold 65.0 (35.0-77.5) 70.0 (70.0-80.0) 0.22

Table 6-3. Baseline comparative quality of life between the two groups in gynecological

Emotional functioning 72.22 ± 14.43 65.15 ± 20.69 0.46

Cognitive functioning 79.63 ± 11.11 75.76 ± 15.57 0.71

Social functioning 87.04 ± 16.20 72.73 ± 23.89 0.21

Thirty-four participants who underwent the initial evaluation were randomly allocated into 2 groups: 17 subjects were assigned to the exercise group, and 17 to the control group. Before they began to do exercises, three women from exercise group and three women from control group failed to appear in the program session for personal reasons.

Two patients from the each group were dropped out during the intervention. Finally, 12 and 12 participants in the exercise and control groups, respectively, completed the interventions and the follow-up evaluations (Fig 4).

Gynecological cancer met

Fig 4 Flow chart of participants through the randomized controlled trial of the exercise program and analysis.

1. Changes in frequency of pelvic floor dysfunction

Stress incontinence was decreased from 64.3% to 33.3% after the intervention in the exercise group (p=0.036). Urinary urgency was decreased from 57.1% to 33.3% after the intervention in the exercise group (p=0.042). Flatus incontinence was decreased from 57.1 % at the baseline to 25.0 % after the intervention in the exercise group (p=0.033) and defecation urgency was decreased from 42.9% to 16.7% after the intervention in the exercise group (p=0.027). But these variables revealed no statistically changes between before and after the intervention in control group. The comparison of changes in prevalence of stress incontinence and flatus incontinence revealed significantly difference between the exercise and control group, but the changes of urinary and

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