Abstract

INTRODUCTION

Cancer of the cervix is the second most common cancer among women worldwide, with an estimated 493,000 new cases and 274,000 deaths (¹1. Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55: 74-108.). Being the most common gynaecological cancer in the developing world, it accounts for two-thirds of cases and continues to be a serious health problem (¹1. Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55: 74-108.). The introduction of screening programs has resulted in the earlier detection of the disease (²2. Jackson KS, Naik R: Pelvic floor dysfunction and radical hysterectomy. Int J Gynecol Cancer. 2006; 16: 354-63.) leading to the majority of cervical carcinoma patients diagnosed at a relatively young age. Most of them live for many years with sequelae of the disease and its treatment (³3. Park SY, Bae DS, Nam JH, Park CT, Cho CH, Lee JM, et al.: Quality of life and sexual problems in disease-free survivors of cervical cancer compared with the general population. Cancer. 2007; 110: 2716-25.).

The primary treatment for patients with cervical cancer depends on a variety of factors, including staging, tumor characteristics, comorbid medical conditions, and patient and provider preference (⁴4. Frumovitz M, Sun CC, Schover LR, Munsell MF, Jhingran A, Wharton JT, et al.: Quality of life and sexual functioning in cervical cancer survivors. Oncol. 2005; 23: 7428-36.). Radical hysterectomy (RH) and radiotherapy (RT) are effective treatment options for patients with cervical cancer (⁵5. Greimel ER, Winter R, Kapp KS, Haas J: Quality of life and sexual functioning after cervical cancer treatment: a long-term follow-up study. Psychooncology. 2009; 18: 476-82.). The addition of chemotherapy to radiotherapy (chemoradiation - CT/RT) results in an absolute improvement in overall survival and a significant reduction in local recurrence for all stages of disease (⁶6. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and metaanalysis of individual patient data from 18 randomized trials. J Clin Oncol. 2008; 26: 5802-12.

7. Green J, Kirwan J, Tierney J, Vale C, Symonds P, Fresco L, et al.: Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev. 2005; 3:CD002225.-⁸8. Kirwan JM, Symonds P, Green JA, Tierney J, Collingwood M, Williams CJ: A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol. 2003; 68: 217-26.).

Traditionally, oncologists have focused their efforts on maximizing the overall survival rate of their patients (⁴4. Frumovitz M, Sun CC, Schover LR, Munsell MF, Jhingran A, Wharton JT, et al.: Quality of life and sexual functioning in cervical cancer survivors. Oncol. 2005; 23: 7428-36.). However, when different treatment options result in equivalent clinical outcomes, quality of life (QoL) considerations become particularly important (⁴4. Frumovitz M, Sun CC, Schover LR, Munsell MF, Jhingran A, Wharton JT, et al.: Quality of life and sexual functioning in cervical cancer survivors. Oncol. 2005; 23: 7428-36.). In the management of cervical cancer, attention has turned to reducing morbidity, especially those related to the pelvic organs (²2. Jackson KS, Naik R: Pelvic floor dysfunction and radical hysterectomy. Int J Gynecol Cancer. 2006; 16: 354-63.). Pelvic floor dysfunction describes a range of impairments to one or more of the pelvic floor compartments, i.e., the urinary, anorectal, and genital systems as well as to the pelvic floor muscles (²2. Jackson KS, Naik R: Pelvic floor dysfunction and radical hysterectomy. Int J Gynecol Cancer. 2006; 16: 354-63.). Autonomic nerve damage during surgery is thought to play a crucial role in the etiology of the pelvic floor dysfunctions that can be seen after RH (⁹9. Pieterse QD, Maas CP, ter Kuile MM, Lowik M, van Eijkeren MA, Trimbos JB, et al.: An observational longitudinal study to evaluate miction, defecation, and sexual function after radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer. Int J Gynecol Cancer. 2006; 16: 1119-29.). RT is associated to fibroelastic and muscle alterations (¹⁰10. Da Silva GM, Berho M, Wexner SD, Efron J, Weiss EG, Nogueras JJ, et al.: Histologic analysis of the irradiated anal sphincter. Dis Colon Rectum. 2003; 46: 1492-7.

11. Reis ED, Vine AJ, Heimann T: Radiation damage to the rectum and anus: pathophysiology, clinical features and surgical implications. Colorectal Dis. 2002; 4: 2-12.-¹²12. Kim GE, Lim JJ, Park W, Park HC, Chung EJ, Seong J, et al.: Sensory and motor dysfunction assessed by anorectal manometry in uterine cervical carcinoma patients with radiation-induced late rectal complication. Int J Radiat Oncol Biol Phys. 1998; 41: 835-41.). Moreover, RT and CT can cause ovary failure and early menopause, leading to a decrease in vaginal lubrication and elasticity as well as on the strength of the pelvic floor muscles (¹³13. Bruner DW, Nolte SA, Shahin MS, Huang HQ, Sobel E, Gallup D, et al.: Measurement of vaginal length: Reliability of the vaginal sound--a Gynecologic Oncology Group study. Int J Gynecol Cancer. 2006; 16: 1749-55.). Although CT/RT treatments increase the chances of some serious acute toxicity, particularly hematologic and gastrointestinal, few trials measured late toxicity, and reported QoL outcomes (⁶6. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and metaanalysis of individual patient data from 18 randomized trials. J Clin Oncol. 2008; 26: 5802-12.,¹⁴14. Paul Abrams LC, Saad Khory, Alan Wein: 4th International Consultation on Incontinence. 4th International Consultation on Incontinence. Paris: © Health Publication Ltd. 2009: pp. 1-1821.). The investigation of the impact of different types of treatment for cervical cancer on the pelvic floor function and QoL of women, might offer relevant information to support oncologists' decision about the best intervention for the patient in question. Therefore, a prospective study was designed to describe the occurrence of pelvic floor dysfunction in women treated for cervical cancer as well as to investigate the impact of the type of treatment on the occurrence of pelvic floor dysfunctions in women who survived cervical cancer.

MATERIALS AND METHODS

Cancer of the cervix is the second most common cancer among women worldwide, with an estimated 493,000 new cases and 274,000 deaths (¹1. Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55: 74-108.). Being the most common gynaecological cancer in the developing world, it accounts for two-thirds of cases and continues to be a serious health problem (¹1. Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55: 74-108.). The introduction of screening programs has resulted in the earlier detection of the disease (²2. Jackson KS, Naik R: Pelvic floor dysfunction and radical hysterectomy. Int J Gynecol Cancer. 2006; 16: 354-63.) leading to the majority of cervical carcinoma patients diagnosed at a relatively young age. Most of them live for many years with sequelae of the disease and its treatment (³3. Park SY, Bae DS, Nam JH, Park CT, Cho CH, Lee JM, et al.: Quality of life and sexual problems in disease-free survivors of cervical cancer compared with the general population. Cancer. 2007; 110: 2716-25.).

The primary treatment for patients with cervical cancer depends on a variety of factors, including staging, tumor characteristics, comorbid medical conditions, and patient and provider preference (⁴4. Frumovitz M, Sun CC, Schover LR, Munsell MF, Jhingran A, Wharton JT, et al.: Quality of life and sexual functioning in cervical cancer survivors. Oncol. 2005; 23: 7428-36.). Radical hysterectomy (RH) and radiotherapy (RT) are effective treatment options for patients with cervical cancer (⁵5. Greimel ER, Winter R, Kapp KS, Haas J: Quality of life and sexual functioning after cervical cancer treatment: a long-term follow-up study. Psychooncology. 2009; 18: 476-82.). The addition of chemotherapy to radiotherapy (chemoradiation - CT/RT) results in an absolute improvement in overall survival and a significant reduction in local recurrence for all stages of disease (⁶6. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and metaanalysis of individual patient data from 18 randomized trials. J Clin Oncol. 2008; 26: 5802-12.

7. Green J, Kirwan J, Tierney J, Vale C, Symonds P, Fresco L, et al.: Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev. 2005; 3:CD002225.-⁸8. Kirwan JM, Symonds P, Green JA, Tierney J, Collingwood M, Williams CJ: A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol. 2003; 68: 217-26.).

Traditionally, oncologists have focused their efforts on maximizing the overall survival rate of their patients (⁴4. Frumovitz M, Sun CC, Schover LR, Munsell MF, Jhingran A, Wharton JT, et al.: Quality of life and sexual functioning in cervical cancer survivors. Oncol. 2005; 23: 7428-36.). However, when different treatment options result in equivalent clinical outcomes, quality of life (QoL) considerations become particularly important (⁴4. Frumovitz M, Sun CC, Schover LR, Munsell MF, Jhingran A, Wharton JT, et al.: Quality of life and sexual functioning in cervical cancer survivors. Oncol. 2005; 23: 7428-36.). In the management of cervical cancer, attention has turned to reducing morbidity, especially those related to the pelvic organs (²2. Jackson KS, Naik R: Pelvic floor dysfunction and radical hysterectomy. Int J Gynecol Cancer. 2006; 16: 354-63.). Pelvic floor dysfunction describes a range of impairments to one or more of the pelvic floor compartments, i.e., the urinary, anorectal, and genital systems as well as to the pelvic floor muscles (²2. Jackson KS, Naik R: Pelvic floor dysfunction and radical hysterectomy. Int J Gynecol Cancer. 2006; 16: 354-63.). Autonomic nerve damage during surgery is thought to play a crucial role in the etiology of the pelvic floor dysfunctions that can be seen after RH (⁹9. Pieterse QD, Maas CP, ter Kuile MM, Lowik M, van Eijkeren MA, Trimbos JB, et al.: An observational longitudinal study to evaluate miction, defecation, and sexual function after radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer. Int J Gynecol Cancer. 2006; 16: 1119-29.). RT is associated to fibroelastic and muscle alterations (¹⁰10. Da Silva GM, Berho M, Wexner SD, Efron J, Weiss EG, Nogueras JJ, et al.: Histologic analysis of the irradiated anal sphincter. Dis Colon Rectum. 2003; 46: 1492-7.

11. Reis ED, Vine AJ, Heimann T: Radiation damage to the rectum and anus: pathophysiology, clinical features and surgical implications. Colorectal Dis. 2002; 4: 2-12.-¹²12. Kim GE, Lim JJ, Park W, Park HC, Chung EJ, Seong J, et al.: Sensory and motor dysfunction assessed by anorectal manometry in uterine cervical carcinoma patients with radiation-induced late rectal complication. Int J Radiat Oncol Biol Phys. 1998; 41: 835-41.). Moreover, RT and CT can cause ovary failure and early menopause, leading to a decrease in vaginal lubrication and elasticity as well as on the strength of the pelvic floor muscles (¹³13. Bruner DW, Nolte SA, Shahin MS, Huang HQ, Sobel E, Gallup D, et al.: Measurement of vaginal length: Reliability of the vaginal sound--a Gynecologic Oncology Group study. Int J Gynecol Cancer. 2006; 16: 1749-55.). Although CT/RT treatments increase the chances of some serious acute toxicity, particularly hematologic and gastrointestinal, few trials measured late toxicity, and reported QoL outcomes (⁶6. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and metaanalysis of individual patient data from 18 randomized trials. J Clin Oncol. 2008; 26: 5802-12.,¹⁴14. Paul Abrams LC, Saad Khory, Alan Wein: 4th International Consultation on Incontinence. 4th International Consultation on Incontinence. Paris: © Health Publication Ltd. 2009: pp. 1-1821.). The investigation of the impact of different types of treatment for cervical cancer on the pelvic floor function and QoL of women, might offer relevant information to support oncologists' decision about the best intervention for the patient in question. Therefore, a prospective study was designed to describe the occurrence of pelvic floor dysfunction in women treated for cervical cancer as well as to investigate the impact of the type of treatment on the occurrence of pelvic floor dysfunctions in women who survived cervical cancer.

Statistical analysis

The data was prospectively collected, digitalized and saved in the SPSS program for Windows version 16.0 (SPSS Inc., Chicago, IL, USA). Comparisons between groups were performed using the Kruskal-Wallis and the Chi-square tests. Post hoc analysis was performed using the Tukey test. The level of significance was set at p < 0.05. The sample size of 20 participants per group was defined as sufficient to avoid a difference superior to 40% among the proportions, and to distinguish the standard deviations from the differences in the means among the groups, with a statistical power of 80% and a confidence level of 95%.

RESULTS

The clinical stage of the tumor was I in 25 cases (41.7%), II in 12 (20%), III in 22 (36.7%) and IV in one case (1.7%). The predominant histological type of carcinoma was squamous cell carcinoma (88.3%), followed by adenocarcinoma (8.3%), adenosquamous (1.7%) and others (1.7%). There was no difference between groups regarding age, number of pregnancies, menopause status, body mass index and histological type of the tumor. There were differences among groups regarding the tumor clinical stage (p < 0.001), (Table-1).

The occurrence of stress urinary incontinency (p = 0.563), mictional urgency (p = 0.449), urge incontinency (p = 0.549), mictional frequency (p = 0.256), vesical pain (p = 0.61), recurrent urinary infection (p = 0.549) and nocturia (p = 0.535) was similar between groups (Table-2). There was also no difference regarding pre- and post-treatment subjective perception of the urinary function (p = 0.308) (Figure-1A).

There were significant differences between the treatment types regarding the number of daily evacuations (p = 0.001) and diarrhea episodes (p = 0.025). CT/RT treatment was positively correlated to frequency of evacuations and diarrhea episodes compared to others groups of treatments. Diarrhea was also significantly more frequent in the RT group when compared to RH and CT/RT (Table-3). There was no differences among groups concerning the sensation of incomplete bladder emptying (p = 0.766), evacuation urgency (p = 0.122) and soiling (p = 0.435), also in pre- and post- treatment subjective perception of the intestinal function (p = 0.124) (Figure-1B).

Active sex life was more frequent among women submitted to RH (90%) than in women submitted to RT (50%) and CT/RT (50%) (p = 0.01). Additionally, a lower dyspareunia rate was observed in the RH group in comparison to the other two groups (p = 0.021) (Table-4). No differences were found among groups regarding a pleasant feeling during sexual intercourse, excitement, orgasm, passion, satisfaction, or number of weekly sexual relations. There was no difference between groups in pre- and post-treatment subjective evaluation of the sexual function (p = 0.308) (Figure-1C).

The vaginal length was shorter in patients submitted to CT/RT (5.3 ± 1.5 cm) or RT (5.5 ± 1.9 cm) when compared to the RH group (7.4 ± 1.1 cm) (p < 0.001) (Figure-2).

No differences were observed regarding the contraction capacity of the pelvic floor muscles between RH (2.9 ± 1.2), RT (2.2 ± 1.6) or CT/RT (2.5 ± 1.6) (p = 0.302) patients (Figure-3).

DISCUSSION

The effects of different types of treatment for cervical carcinoma on the women's pelvic floor functions have recently received some attention. However studies are still scarce and heterogeneous regarding research questions and methods. Despite the trends towards multimodal treatment regimes, to our knowledge, there are no clinical studies that compare the side effects on the pelvic floor functions between patients treated with RH, RT or CT/RT for cervical cancer. The present study prospectively evaluated cervical cancer survivors and identified association between types of treatment and pelvic floor dysfunctions. The impact on the pelvic floor functions seems to depend more on the type of treatment than on the stage of the tumor.

In conjunction, the occurrence of urinary dysfunction in the investigated sample was not different from women who did not undergo treatment for cervical cancer. The International Continence Society reports prevalence between 25% and 45%, indicating that the treatment types investigated in the present study did not contribute to the increase of occurrence of symptoms of urinary dysfunctions (¹⁴14. Paul Abrams LC, Saad Khory, Alan Wein: 4th International Consultation on Incontinence. 4th International Consultation on Incontinence. Paris: © Health Publication Ltd. 2009: pp. 1-1821.). The type of treatment did also not influence urinary function. These results are similar to those reported by Lin et al., 1998 who also did not find any differences in detrusor instability or bladder compliance in women submitted to the RH and/or RT, evaluated by urodynamics (¹⁹19. Lin HH, Sheu BC, Lo MC, Huang SC: Abnormal urodynamic findings after radical hysterectomy or pelvic irradiation for cervical cancer. Int J Gynaecol Obstet. 1998; 63: 169-74.). Further studies involving similar participants should be developed to corroborate these findings.

Abnormal anorectal function occurs frequently following pelvic irradiation for gynecological malignant diseases. In the present study, RT and CT/RT were associated with high rates of diarrhea and frequent evacuations. These results are corroborated by others who have also documented the side effects of pelvic radiation on defecation (²⁰20. Iwamoto T, Nakahara S, Mibu R, Hotokezaka M, Nakano H, Tanaka M: Effect of radiotherapy on anorectal function in patients with cervical cancer. Dis Colon Rectum. 1997; 40: 693-7. Erratum in: Dis Colon Rectum 1997; 40: 1298.,²¹21. Hsu WC, Chung NN, Chen YC, Ting LL, Wang PM, Hsieh PC, et al.: Comparison of surgery or radiotherapy on complications and quality of life in patients with the stage IB and IIA uterine cervical cancer. Gynecol Oncol. 2009; 115: 41-5.). This is relevant because some data suggest that acute toxicity and diarrhea during radiation therapy of cervical carcinoma significantly increased the risk of severe late toxicity, therefore, affecting patient's quality of life (²²22. Wang CJ, Leung SW, Chen HC, Sun LM, Fang FM, Huang EY, et al.: The correlation of acute toxicity and late rectal injury in radiotherapy for cervical carcinoma: evidence suggestive of consequential late effect (CQLE). Int J Radiat Oncol Biol Phys. 1998; 40: 85-91.). Bile acid malabsorption and bacterial overgrowth are frequently found in patients with chronic or intermittent diarrhea (²³23. Danielsson A, Nyhlin H, Persson H, Stendahl U, Stenling R, Suhr O: Chronic diarrhoea after radiotherapy for gynaecological cancer: occurrence and aetiology. Gut. 1991; 32: 1180-7.). The reduced rectal reservoir capacity and impaired sensory functions were crucial factors for functional disorder in such patients (¹²12. Kim GE, Lim JJ, Park W, Park HC, Chung EJ, Seong J, et al.: Sensory and motor dysfunction assessed by anorectal manometry in uterine cervical carcinoma patients with radiation-induced late rectal complication. Int J Radiat Oncol Biol Phys. 1998; 41: 835-41.,²⁴24. Yeoh E, Sun WM, Russo A, Ibanez L, Horowitz M: A retrospective study of the effects of pelvic irradiation for gynecological cancer on anorectal function. Int J Radiat Oncol Biol Phys. 1996; 35: 1003-10.). In addition, radiation damage to the external anal sphincter muscle was considered to be an important cause of motor dysfunction (¹²12. Kim GE, Lim JJ, Park W, Park HC, Chung EJ, Seong J, et al.: Sensory and motor dysfunction assessed by anorectal manometry in uterine cervical carcinoma patients with radiation-induced late rectal complication. Int J Radiat Oncol Biol Phys. 1998; 41: 835-41.,²⁴24. Yeoh E, Sun WM, Russo A, Ibanez L, Horowitz M: A retrospective study of the effects of pelvic irradiation for gynecological cancer on anorectal function. Int J Radiat Oncol Biol Phys. 1996; 35: 1003-10.).

Most of the literature concerning sexual functioning among cervical cancer patients has focused on those with early stage disease. Our finding that women who received RT or CT/RT had increased levels of dyspareunia is consistent with earlier studies (³3. Park SY, Bae DS, Nam JH, Park CT, Cho CH, Lee JM, et al.: Quality of life and sexual problems in disease-free survivors of cervical cancer compared with the general population. Cancer. 2007; 110: 2716-25.,²⁵25. Schover LR, Fife M, Gershenson DM: Sexual dysfunction and treatment for early stage cervical cancer. Cancer. 1989; 63: 204-12.,²⁶26. Jensen PT, Groenvold M, Klee MC, Thranov I, Petersen MA, Machin D: Longitudinal study of sexual function and vaginal changes after radiotherapy for cervical cancer. Int J Radiat Oncol Biol Phys. 2003; 56: 937-49. Erratum in: Int J Radiat Oncol Biol Phys. 2004; 58: 1321.). The decrease in vaginal length may explain in part the increased dyspareunia. Vaginal shortening can occur during the course of intracavity and external irradiation (²⁷27. Katz A, Njuguna E, Rakowsky E, Sulkes A, Sulkes J, Fenig E: Early development of vaginal shortening during radiation therapy for endometrial or cervical cancer. Int J Gynecol Cancer. 2001; 11: 234-5.

28. Brand AH, Bull CA, Cakir B: Vaginal stenosis in patients treated with radiotherapy for carcinoma of the cervix. Int J Gynecol Cancer. 2006; 16: 288-93.-²⁹29. Bruner DW, Lanciano R, Keegan M, Corn B, Martin E, Hanks GE: Vaginal stenosis and sexual function following intracavitary radiation for the treatment of cervical and endometrial carcinoma. Int J Radiat Oncol Biol Phys. 1993; 27: 825-30.). In the present study the vaginal length was smaller in patients submitted to CT/RT or RT when compared to the RH group. Although the sexual activity rate is lower in RT and CT/RT groups, they are able to enjoy sexual intercourse similar to patients after surgery. The low sexual activity in cancer patients is a limitation regarding the interpretation of sexual function in this study. However, the results are consistent with those previously reported (⁵5. Greimel ER, Winter R, Kapp KS, Haas J: Quality of life and sexual functioning after cervical cancer treatment: a long-term follow-up study. Psychooncology. 2009; 18: 476-82.).

Pelvic floor muscles dysfunction is correlated with urinary, sexual, or gastroenterological complaints and pelvic organ prolapse (³⁰30. Voorham-van der Zalm PJ, Lycklama A Nijeholt GA, Elzevier HW, Putter H, Pelger RC: “Diagnostic investigation of the pelvic floor”: a helpful tool in the approach in patients with complaints of micturition, defecation, and/or sexual dysfunction. J Sex Med. 2008; 5: 864-71.,³¹31. Ghetti C, Gregory WT, Edwards SR, Otto LN, Clark AL: Severity of pelvic organ prolapse associated with measurements of pelvic floor function. Int Urogynecol J Pelvic Floor Dysfunct. 2005; 16: 432-6.). However, in the present study, no differences were observed regarding the capacity of pelvic floor muscle contraction evaluated through bidigital palpation. This result might be due to the good capacity of the pelvic floor muscles contraction in the sample investigated, since most women presented degrees of contraction higher than or equal to 2 (weak) on the modified Oxford scale.

There was no difference regarding pre-and post-treatment subjective perception of the urinary, intestinal and sexual functions. The relief resulting from the completion of potentially curative treatment may also have contributed to this result despite changes in pelvic functions.

CONCLUSIONS

Our data suggest that RT and CT/RH are associated to more sexual dysfunctions, as less active sexual life and dyspareunia, and more intestinal dysfunctions, as constipation and also diarrhea, after treatment for invasive cervical carcinoma. Further studies are needed to develop techniques that will minimize the development of sexual and intestinal dysfunction following RT and CT/RT and to improve clinicians' awareness of the prevalence and impact of these symptoms on their patients' functional status and quality of life.

REFERENCES

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