Treatmentrelated morbidity in gynaecological ... - Wiley Online Library

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10.1576/toag.12.2.079.27572 http://onlinetog.org

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Review Treatment-related morbidity in gynaecological cancers Authors Richard Hadwin / Gemma Petts / Adeola Olaitan

Key content: • The National Cancer Survivorship Initiative recognises that all treatment modalities in cancer have potential long-term physical and psychosocial implications for patients. • Prediction and early recognition can prevent or minimise treatment-related morbidity in gynaecological cancer.

Learning objectives: • To introduce the concept of survivorship as an essential component of gynaecological oncology care. • To understand the range of problems that women encounter following cancer treatment and the need for a multidisciplinary approach.

Ethical issues: • Informed counselling prior to treatment includes a description of potential long-term morbidity, which may contribute to decision making. Keywords cervical carcinoma / neuropathy / psychological symptoms /sexual function / survivorship / vulval carcinoma Please cite this article as: Hadwin R, Petts G, Olaitan A. Treatment-related morbidity in gynaecological cancers. The Obstetrician & Gynaecologist 2010;12:79–86.

Author details Richard Hadwin MRCOG Subspecialty Trainee in Gynaecology Oncology University College London Hospital Gynaecological Cancer Centre, 2nd Floor North Wing, 250 Euston Road, London NW1 2PG, UK Email: [email protected] (corresponding author)

Gemma Petts MBBS Specialty Trainee Year 2 in Obstetrics and Gynaecology University College London Hospital Gynaecological Cancer Centre, London, UK

© 2010 Royal College of Obstetricians and Gynaecologists

Adeola Olaitan MD FRCOG Consultant Gynaecological Oncologist and Honorary Senior Lecturer Department of Gynaecological Oncology, University College Hospital, London, UK

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Introduction

With 2 million people in the UK living with or beyond cancer, in 2007 the Cancer Reform Strategy1 committed the National Health Service to improving patients’ experiences of cancer care. Consequently, Macmillan Cancer Support and the Department of Health jointly produced the National Cancer Survivorship Initiative. A cancer survivor is defined as ‘one who has completed initial cancer treatment, is living with progressive disease before the terminal stages of illness, or one who has had cancer treatment in the past’.2 A multidisciplinary think-tank event was undertaken in March 2008 with contributions from consumers, psychologists, and hospital and community-based clinicians and nurses, to identify the physical, psychological, social, spiritual, financial and information needs of cancer survivors, carers and families. Seven workstreams were identified, with

Box 1

Seven workstreams of the National Cancer Survivorship Initiative2

1. Assessment, care planning and immediate posttreatment approaches to care Activities include: •

treatment record framework

•

risk stratification framework/tool

•

cancer survivorship assessment tool

•

survivorship care plan

2. Managing active, progressive and recurrent disease Activities include: •

interventions and services required to support cancer survivors and effectively manage the continuing physical, psychological and social effects associated with active or progressive disease

3. Late effects of treatment Activities include: •

comprehensive identification and mapping of late treatment effects per cancer site and/or treatment regimen to support detection and effective intervention

•

establishment of a national late effect notification and recording system

•

development of patient-reported outcome measures

4. Survivors of childhood and young people cancers Devoted to issues encountered by young patients including: •

identification, location and range of services required

•

re-entry into the education system

•

career advice and support to attain first employment

5. Work and finance Activities include: •

working through cancer initiatives

•

financial information and support

6. Expert patient programme/self-management Activities include: •

review and development of self-management programmes

7. Research Cross-cutting themes The workstreams will all result in a need to:

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•

develop new or revised patient, carer and healthcare professional information

•

provide healthcare professionals, carers, patients and volunteers with education and training to manage this stage of the cancer survivor’s journey

•

develop tools/information to support commissioners in the implementation of cancer survivorship services


three cross-cutting themes (Box 1). Future improvements in cancer care will be directed towards and measured against these. Most gynaecological cancers are curable if they present early. Age-standardised 5-year survival rates for cervical and endometrial cancer are 66% and 77%, respectively.3 While disease-free survival is limited in epithelial ovarian cancer, extended periods of progression-free survival are now expected. In the North London Cancer Network at University College London Hospitals, a review of women under the age of 60 who underwent treatment for cervical carcinoma found that 27% experienced major complications of treatment, including vaginal stenosis, bowel fistulae and lymphoedema.4 In older women and/or those with multiple comorbidities the adverse effects of treatment may be significantly increased. When treatment-related effects occur, a multidisciplinary approach, with algorithms of care targeting women to an extended team of professionals with special interests in cancer care, is essential. In addition, in the majority of cases treatment-related morbidity is predictable and where not preventable may guide treatment decisions. (See Box 2 for a summary of potential adverse effects of treatment.)

The gastrointestinal system Bowel-related morbidity is common during and after treatment for gynaecological cancer. There is a high risk of bowel injury during oncology surgery and bowel resection may also be electively undertaken as part of optimal tumour debulking. As a consequence, a working knowledge of bowel surgery techniques is essential for gynaecological oncology surgeons. The bowel is at risk from pelvic radiotherapy; adverse long-term effects on quality of life have been reported in 50% of women treated for gynaecological malignancies.5 This increases where fields extend beyond the pelvis and where the bowel is fixed in the field by adhesions. The ileum, caecum and rectosigmoid are fixed anatomically in the radiation field and are at particular risk. Late effects present up to 5 years after treatment and include diarrhoea, rectal bleeding, obstruction and fistula formation. The cause of chronic diarrhoea following radiotherapy has variously been ascribed to changes in small bowel motility, bile salt malabsorption and bacterial overgrowth. Management is symptomatic with opiate agonists, anticholinergics and bulking agents. Rectal bleeding requires endoscopic assessment and may be treated conservatively or with laser coagulation.6 Management requires the contribution of a gastroenterologist with a special interest in the field; in the North London Cancer Network there is a named gastroenterology lead in the management of bowel injury following radiation. © 2010 Royal College of Obstetricians and Gynaecologists

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Potential effects

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Specific causes

Gastrointestinal Bowel injury

High risk during oncological surgery; resection may be planned as part of debulking procedure

Chronic diarrhoea

Pelvic radiotherapy

Rectal bleeding

Pelvic radiotherapy

Diarrhoea, rectal bleeding, obstruction and fistula formation

Late effects presenting up to 5 years after pelvic radiotherapy

Bowel obstruction

Radiotherapy for cervical carcinoma

Bowel fistulae

Single or combined-modality treatment for cervical carcinoma

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Box 2

Summary of potential adverse effects of gynaecological cancer treatment

Urinary tract injury Intraoperative ureteric injury

Radical hysterectomy without prior radiotherapy

Ureteric fibrosis, leading to obstruction

Radiotherapy

Radiation cystitis

Radiotherapy

Bladder atony

Radical hysterectomy for cervical carcinoma

Ureterovaginal or vesicovaginal fistulae

Radical hysterectomy

Reproductive tract Anovulation or early menopause

Radiotherapy, surgically induced menopause

Sexual Damage to structures important to sexual function

Vulvectomy for vulval carcinoma; vaginectomy for vaginal carcinoma; pelvic exenterative procedures

Shortening and stenosis of the vagina, leading to dyspareunia

Radiotherapy for cervical carcinoma

Psychological effects, e.g. aversion, impact on arousal, orgasm and satisfaction Nervous system Neuropathy

Chemotherapy, e.g. taxanes, platinum compounds

Lymph system Lymphoedema

Lymph node dissection, commonly associated with groin node dissection for vulval cancer treatment

Psychosocial complications and quality of life Anxiety Sexual dysfunction Major depressive disorders Post-traumatic stress disorder

Bowel obstruction is uncommon following gynaecological surgery, but may occur in up to 14.5% of women following radiotherapy for cervical carcinoma.7 Partial bowel obstruction may resolve with conservative management. Total obstruction, perforation and fistulae require intervention. Imaging with computed tomography and follow-through contrast studies should be undertaken to identify the site, number and length of obstructions and to exclude recurrent disease (Figure 1). Endoscopic stent placement may be considered for large and proximal small bowel obstruction. A review of colonic stent placement at University College London Hospital showed good results in 33 patients, including five with ovarian cancer.8 In other cases, surgical resection is recommended. With the blood supply often being impaired in previously irradiated tissues, it is the authors’ practice to defunction the bowel proximal to anastamoses to allow rest and healing. Bowel fistulae in the irradiated woman present a significant challenge. They occur in up to 8% of women undergoing single or combined-modality treatment for cervical carcinoma.9 Because of the avascular nature of the tissue, simple closure is © 2010 Royal College of Obstetricians and Gynaecologists

ineffective. Initial management should include a defunctioning stoma and consideration of referral for reconstructive surgery involving transposition of a new vascular supply, such as a folded colon patch, as described by Bricker.10

Urinary tract injury The urinary tract is similarly vulnerable to injury during and following gynaecological cancer treatment. Intraoperative ureteric injury is, fortunately, uncommon and is recognised in 1% of women undergoing radical hysterectomy without prior radiotherapy.11 Similar rates of ureteric fibrosis causing obstruction are reported as a consequence of radiotherapy.10 The options for ureteric injury identified during surgery are summarised in Box 3. Similar techniques can be used in the management of symptomatic radiotherapy injury and injury identified postoperatively, but a trial of ureteric stenting is often undertaken before surgery is considered. The bladder is at risk during and after radiation and surgical treatment. Radiation cystitis characterised by urgency, dysuria, haematuria and bladder spasms is reported in 26% of women surviving 81

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Figure 1

CT showing radiation bowel injury. Single arrow oedematous bowel loops. Double arrow narrowing of terminal ileum

beyond 5 years following radiotherapy.12 Characteristic changes are seen at cystoscopy, with reduced bladder capacity on urodynamic testing. Biopsy of ulcers should be avoided unless there is significant concern of malignancy because of the risk of fistula formation. Management includes screening for and promptly treating infections,

Box 3

•

Remove the cause

Management of surgical ureteric injury9

•

Mobilise the ureter

•

Assess vascular integrity and excise avascular tissue

•

Small injury – suture over J–J stent

•

Larger injuries – insert J–J stent, then: – above the pelvic brim – ureteroneocystostomy with or without psoas hitch – below the pelvic brim – options include: – transuretero-ureteral anastomosis – Boari flap – ileal interposition

•

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Reassess and remove stents at 6 weeks

which markedly worsen symptoms. There is no clear evidence guiding further treatment, but techniques employed include bladder irrigation and hydrodistension, oral/parenteral/intravesical agents, hyperbaric oxygen therapy, urinary diversion and cystectomy.13 Bladder atony is common following radical hysterectomy for cervical carcinoma, with 2–3% of women experiencing long-term voiding difficulties requiring intermittent self-catheterisation.11 There is emerging evidence that attempts to preserve pelvic splanchnic nerves during hysterectomy may reduce the incidence of postoperative bladder dysfunction.14 Fistulae between the vagina and ureter (ureterovaginal) or bladder (vesicovaginal) occur in 2% of women following radical hysterectomy, with increased rates expected where tissues have previously been irradiated.11 They usually present between 5 and 14 days postoperatively. © 2010 Royal College of Obstetricians and Gynaecologists

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Investigations include cystoscopy, intravenous pyelography and retrograde vesicography/pyelography. Coexistent infections should be identified and treated. Where there has been no prior radiotherapy, up to half of fistulae can be expected to heal with conservative management, including retrograde/antegrade stents in ureterovaginal fistulae and extended duration urethral catheterisation for vesicovaginal fistulae. Where conservative management fails, and in most fistulae associated with radiotherapy, surgery is required. This may be a simple vaginal repair or neovascularisation may be required by transposition of tissue, such as a bulbocavernosus (Martius) flap. If primary repair cannot be achieved, a urinary diversion such as an ileal conduit may be undertaken.

The reproductive tract Ovarian function and fertility In the North London Cancer Network, 28% of women with gynaecological cancer are of reproductive age and in this group pretreatment discussions regarding effects on ovarian and fertility function are essential. For the majority, ovarian preservation may be considered and for a more limited number fertility preservation may be considered. Modified surgical techniques include radical trachelectomy or radical hysterectomy with ovarian preservation for cervical carcinoma; and preservation of the uterus and contralateral ovary in early epithelial and germ cell ovarian cancer. In general, gynaecological malignancy does not involve the classically gonadotoxic regimens of protracted alkylating agents, such as cyclophosphamide, methotrexate and fluorouracil for breast cancer. The ovary, however, is exquisitely sensitive to radiotherapy and this increases with age. Doses as low as 5 Gy may result in permanent anovulation and doses above 10 Gy risk inducing the menopause, particularly in women 35 years of age. Attempts to reduce the sensitivity of the ovary to radiotherapy with gonadotrophin-releasing hormone downregulation have yielded largely disappointing results, with full suppression requiring lengths of therapy that would interfere with the optimal timing of cancer treatment.15 Transposition of the ovaries, either within the peritoneal cavity or into another area of the body, prevents radiotherapy-induced menopause. In the North London Cancer Network we have undertaken ovarian transposition in seven women prior to radical pelvic radiotherapy since 2005; only one of these women has subsequently experienced menopausal symptoms. Most advances in fertility preservation have been made in the use of assisted reproductive techniques. Where the woman is in a stable relationship at © 2010 Royal College of Obstetricians and Gynaecologists

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diagnosis, in vitro fertilisation with embryo cryopreservation is well established as safe and has been used extensively prior to cancer therapy. Improved techniques of ovarian tissue cryopreservation have resulted in an increasing number of reports of successful pregnancy.15 Hormone replacement therapy is widely and safely used following radiotherapy and surgically induced menopause. However, for those unsuitable for, or wary of, conventional hormone replacement therapy treatment, the North London Cancer Network has close links with the Royal London Homoeopathic Hospital for consideration of alternative therapy techniques such as acupuncture and herbal remedies. Sexual function Surgery for a number of gynaecological cancers requires damage to structures that are important in sexual function. Vulval carcinoma may necessitate vulvectomy, resulting in damage to the vaginal introitus, and/or removal of the clitoris; vaginal carcinoma may be treated with vaginectomy; and pelvic exenterative procedures may all result in significant anatomical sexual morbidity. However, the advantages in sexual function of radical hysterectomy over radiation therapy are often used to recommend this treatment in the sexually active woman with early-stage disease.16 The vaginal epithelium is exquisitely sensitive to radiation injury, with shortening and stenosis commonly reported following brachytherapy for cervical carcinoma. Dyspareunia is reported by 55% of women following radiotherapy for cervical carcinoma.17 All women undergoing pelvic radiation at the North London Cancer Network are given information regarding the importance of regular intercourse or are trained in dilator use. There are also significant psychological effects of gynaecological cancer treatment on sexual function, with aversion and impact on arousal, orgasm and satisfaction commonly reported. Information regarding sexual function is often not volunteered and routine enquiry should be undertaken. The psychological contribution of the partner should be appreciated and where the woman discloses difficulties every effort should be made to review the couple together for further assessment. Assessment of the couple may be undertaken using the structure shown in Box 4. Management is based around education and counselling, the use of vaginal lubricants and instruction in dilator use where regular intercourse is not taking place. Some women will require additional support and may require behavioural therapies such as sensate focus. The North London Cancer Network has dedicated 83

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Box 4

•

Marital status/availability of sexual partner

Components of a sexual assessment in oncology15

•

Body image concerns

•

Frequency of activity

•

Components of female sexual dysfunction

•

¶

desire/aversion

¶

excitement

¶

orgasm

¶

resolution – discontentment

Components of male sexual dysfunction ¶

desire

¶

erectile difficulties

¶

orgasm

¶

resolution

clinical nurse specialist sessions for dilator training and support and an in-house clinical psychology team that provides a range of cognitive behavioural therapies. Reconstructive vulvovaginal procedures are generally integrated into primary surgery for vulval and vaginal carcinoma or used for anatomical difficulties not responding to conservative measures. Total restoration of completely normal form and function is generally not possible with surgery; careful patient selection, imaging and counselling is essential. In this context, satisfaction levels from surgery are gratifyingly high. The development of techniques preserving endogenous graft blood supply has dramatically improved results and includes V–Y advancement flaps for vulval defects and bowel flaps for vaginal defects.18 The North London Cancer Network has extensive experience of and success with creating neovaginas because of close liaison with experienced colleagues in paediatric gynaecology.19

Figure 2

Lymphoedema following inguinofemoral lymph node resection


Neuropathy Neurotoxicity caused by chemotherapy can be sensory or sensorimotor and is often associated with dysaesthetic pain. It is mostly dependent on length of treatment and may be dose limiting. Taxanes can cause distal sensory loss and pain in the lower limbs and, uncommonly, affect motor function and reflexes. The effects are dose related and improvements are expected following cessation of therapy. Platinum compounds, commonly used in chemotherapy regimens for gynaecological malignancy, are unique in causing a sensory ganglionopathy with sensory paraesthesia in the distal extremities. Platinum agents can lead to ‘coasting’, where neuropathy progresses for several months following treatment and recovery may be incomplete. As a consequence, it is essential that the drug is discontinued as soon as symptoms present. Attempts at prophylactic prevention of chemotherapy-induced neuropathy with a number of agents have not been successful.20 As a result, where neuropathy is likely to be catastrophic to quality of life, elements may be omitted after informed consultation, for example; a professional pianist was recently treated at the North London Cancer Network at University College London Hospital for ovarian carcinoma and elected not to have taxanes.

Lymphatic obstruction Lymphoedema is the accumulation of interstitial fluid, occurring where the normal function of the lymphatic system is impaired. Untreated, a chronic inflammatory reaction develops, leading to fibrosis. Clinically soft, pitting oedema progresses to fixed induration. Lymphoedema can occur distal to any extensive lymph node dissection, but is commonly associated with groin node dissection for vulval cancer treatment. Prophylactic advice should be given to all women at risk of lymphoedema, including advice on skin care, exercise and support hosiery. Avoiding extensive groin surgery by sentinel lymph node mapping and biopsy should reduce the risk of lymphoedema following treatment for vulval malignancy. The omission of lymph node dissection, with or without sentinel lymph node sampling, in the treatment of cervical and endometrial carcinoma remains controversial. Once soft oedema develops, decongestive lymphatic therapy can be used to prevent further deterioration and fibrosis. This ranges from support hosiery for mild degrees of oedema to compression bandaging, exercise and physiotherapy, positional drainage and massage for more severe disease (Figure 2 and Figure 3). Surgery may be considered for carefully selected patients where conservative treatment has failed and involves resection of the subcutaneous tissues and/or circumferential liposuction.21

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Psychosocial complications and quality of life Cancer survivors may experience psychological symptoms related to treatment; these are a major contributor to morbidity. Symptoms range from anxiety and sexual dysfunction to major depressive disorders and post-traumatic stress disorder. The incidence rates of psychological maladaption may continually increase from the time of treatment and there is a need for continued awareness.22 Psychological support for all women with cancer requires emotional support and information, provided by a named, easily-contactable clinical nurse specialist to encourage self-management. There is also a wide range of specialist peer support groups available. There is evidence that a brief psychosocial intervention may be of benefit for all gynaecological cancer care survivors.23 A smaller group of women may require more extended and formal psychological or psychiatric interventions. The North London Cancer Network has supportive clinical nurse specialists and an embedded psychology team that offers a range of cognitive behavioural therapies. The clinical nurse specialist is central to assessment of needs and to offering support and, where appropriate, co-ordinating targeted interventions. We have successfully implemented the Distress Thermometer scoring system in outpatient clinics, as developed by the National Comprehensive Cancer Network.24 All follow-up patients arriving at the clinic are given a screening tool for reporting practical, family, emotional, spiritual and physical concerns, combined with a pictorial tool for demonstrating overall distress. The clinical nurse specialists review the completed Distress Thermometer with the woman, directing her to management within the extended team, or beyond to social services and pastoral care. High levels of satisfaction have been expressed with the system and improvements in quality of life documented by subsequent Distress Thermometer analysis.

Conclusion The majority of survivors can look forward to a good quality of life, supportive relationships and positive aspects of ‘existential well-being’.25 As practitioners we now have the tools and the opportunity to advance gynaecological oncology into a modern holistic service with targeted specialist interventions. The most significant factor in care improvement will undoubtedly arise from empowering women to request and access information and services, and for services to evolve while remaining responsive to their needs. With implementation of the National Cancer Survivorship Initiative it is hoped that the majority © 2010 Royal College of Obstetricians and Gynaecologists

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Figure 3

The same patient following 5 weeks of intensive physiotherapy

of women will look forward to high levels of satisfaction with care and future life. References 1 Department of Health. Cancer Reform Strategy. London: Department of Health; 2007 [www.dh.gov.uk/en/Publicationsandstatistics/Publications/ PublicationsPolicyAndGuidance/dh_081006]. 2 Department of Health. National Cancer Survivorship Initiative Newsletter: Autumn 2008, Issue 1. London: Department of Health; 2008 [www.dh.gov.uk/en/Publicationsandstatistics/Publications/ PublicationsPolicyAndGuidance/DH_088879]. 3 Cancer Research UK. Cancer survival statistics: cervical cancer and endometrial cancer. [http://info.cancerresearchuk.org/cancerstats]. 4 Hawin R, Huq F, Olaitan A. Morbidity in the North London Cancer Network patient cohort. Institute for Women’s Health Meeting, London 2008. 5 Olopade FA, Norman A, Blake P, Dearnaley DP, Harrington KJ, Khoo V, et al. A modified Inflammatory Bowel Disease questionnaire and the Vaizey Incontinence questionnaire are simple ways to identify patients with significant gastrointestinal symptoms after pelvic radiotherapy. Br J Cancer 2005;92:1663–70. doi:10.1038/sj.bjc.6602552 6 Andreyev HJ. Gastrointestinal problems after pelvic radiotherapy: the past, the present and the future. Clin Oncol (R Coll Radiol) 2007;19:790–9. doi:10.1016/j.clon.2007.08.011 7 Eifel PJ, Levenback C, Wharton JT, Oswald MJ. Time course and incidence of late complications in patients treated with radiation therapy for FIGO stage IB carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1995;32:1289–300. doi:10.1016/0360-3016(95)00118-I 8 Johnson GJ, Gak N, Obichere M, Olaitan A, Obichere A, Pereira SP, et al. Single centre experience of self-expanding metal stents for malignant colonic obstruction: A two year experience. [Unpublished data, referenced with the permission of the authors.] 9 Kasibhatla M, Clough RW, Montana GS, Oleson JR, Light K, Steffey BA, et al. Predictors of severe gastrointestinal toxicity after external beam radiotherapy and interstitial brachytherapy for advanced or recurrent gynecologic malignancies. Int J Radiat Oncol Biol Phys 2006;65:398–403. doi:10.1016/j.ijrobp.2005.12.008 10 Bricker EM, Johnston WD. Repair of postirradiation rectovaginal fistula and stricture. Surg Gynecol Obstet 1979;148:499–506. 11 Mutch DG, Grigsby PW, Markman M, Rubin SC. Management of late effects of gynecologic cancer treatment. In: Hoskins WJ, Perez CA, Young RC, Barakat R, Markman M, Randall M. Principles and Practice of Gynecologic Oncology. Philadelphia PA: Lippincott Williams & Wilkins; 2004. p.1193–214. 12 Parkin DE, Davis JA, Symonds RP. Long-term bladder symptomatology following radiotherapy for cervical carcinoma. Radiother Oncol 1987;9:195–9. doi:10.1016/S0167-8140(87)80230-X 13 Crew JP, Jephcott CR, Reynard JM. Radiation-induced haemorrhagic cystitis. Eur Urol 2001;40:111–23. doi:10.1159/000049760 14 Sakamoto S, Takizawa K. An improved radical hysterectomy with fewer urological complications and with no loss of therapeutic results for invasive cervical cancer. Ballieres Clin Obstet Gynecol 1988;2:953–62. doi:10.1016/S0950-3552(98)80022-9 15 Maltaris T, Boehm D, Dittrich R, Seufert R, Koelbl H. Reproduction beyond cancer: a message of hope for young women. Gynecol Oncol 2006;103:1109–21. doi:10.1016/j.ygyno.2006.08.003

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