Mersey and Cheshire Regional Guidelines August 2016: Review August 2018 MANAGEMENT OF UTERINE CANCERS

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1 Mersey and Cheshire Regional Guidelines August 2016: Review August 2018 MANAGEMENT OF UTERINE CANCERS These guidelines have been developed by members of the Gynaecological Oncology Guidelines Group, for approval by the Merseyside and Cheshire Gynaecological Cancer Network Group. 1. Background 2 2. Diagnosis 2 3. Referral to Gynae Oncology Team 3 4. Staging 3 5. Prognostic Factors 4 6. Pre-operative assessment 5 7. Surgery 6 8. Radiotherapy 7 9. Hormonal Therapy Chemotherapy Palliative Care and Nursing Follow Up Hormone Replacement Therapy Clinical Trials Appendix P age

2 1. Background Endometrial cancer is now the most common gynaecological malignancy in the UK. Over 7,500cases are registered annually with a lifetime risk of just over 1%. Eighty percent occur in post-menopausal women with a median age at diagnosis of 60yrs. Less than 5% occur in women aged <45yrs. Presentation is predominantly with post-menopausal bleeding although up to 25% of endometrial cancers are detected in pre-menopausal women. 75% of patients present with early stage disease which commonly represents a good prognosis, though this does depend on the histological type. Endometrioid adenocarcinoma is the most common form comprising approximately 75% of the total with other variants including mucinous, serous, clear cell and squamous carcinomas, mixed mesodermal tumours, endometrial sarcomas and undifferentiated tumours. 2. Diagnosis The majority of women with endometrial cancer present with post menopausal bleeding, though intermenstrual bleeding, post coital bleeding, menorrhagia and abnormal smears can be the presenting feature. As the majority of cases present with a number of well recognised symptoms, prompt referral as outlined in the NHS Cancer Plan and Department of Health waiting time targets is feasible. The referral criteria were updated in 2015 by NICE (NG 12). 1. Refer women using a suspected cancer pathway referral (for an appointment within 2 weeks) for endometrial cancer if they are aged 55 and over with post menopausal bleeding (unexplained vaginal bleeding more than 12 months after menstruation has stopped because of the menopause). 2. Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for endometrial cancer in women aged under 55 with post menopausal bleeding. 2 P age

3 3. Consider a direct access ultrasound scan to assess for endometrial cancer in women aged 55 and over with: - unexplained symptoms of vaginal discharge who: are presenting with these symptoms for the first time or have thrombocytosis or report haematuria, or - visible haematuria and: low haemoglobin levels or thrombocytosis or high blood glucose levels. Diagnosis is on the basis of History Examination Transvaginal ultrasound Symptomatic women (women with post menopausal bleeding) require a transvaginal ultrasound for assessment. Varying endometrial thicknesess requiring further investigation have been published (Wong AS, 2016) (Ciatto S, 2002) (Smith-Bindman R, 2004). A consensus agreement from the Mersey and Cheshire CNG agreed that women not on HRT with post menopausal bleeding and an endometrial thickness of 4m or more should be advised to have an endometrial biospy. Endometrial biopsy (pipelle or hysteroscopy) It is worth noting that a sampling diagnosis of complex atypica hyperplasia carries significant risk of an underliying cancer (up to 50% in recent regional audits), so all cases of complex atypical hyperplasia should be regarded as a endometrial cancer in terms of planning treatment. Please refer to the RCOG Green top Guidelines on Endometrial Hyperplasia. (RCOG, 2016) 3. Referral to the Gynaecological Oncology Team In keeping with the Department of Health, Improving Outcomes Guidance (1999) referrals to the Gynaecology Oncology Centre include: all Grade 3 tumours 3 P age

4 Type 2 cancers (clear cell and UPSC) Stage 2 or above Specific concerns on an individual patient basis should be discussed with the Gynae MDT or its members 4. Staging The method of staging favoured in this country is that introduced by FIGO in 1989 which is outlined below. This has been updated in 2015, and includes uterine carcinosarcomas. Equivalent TNM classification is available. 5. Prognostic Factors Poor prognostic factors in early stage include: depth of myometrial invasion, histological grade, lymphovascular invasion and histological cell type such as serous cell and clear cell carcinoma. The risk of recurrence in early stage endometrial cancer therefore can vary from less than 10% to as high as 50% depending upon the presence of number of risk factors. It is divided into 3 main groups. Low Risk: Myometrial invasion less than 50%, Grade 1-2, No LVI Intermediate Risk: Myometrial invasion more than 50%, Grade 1 and 2, No LVI. Myometrial invasion less than 50%, Grade 3 High Risk: Myometrial invasion more than 50%, Grade 3 +/- LVI. Clear cell / Serous cell with Myometrial invasion 4 P age

5 6. Pre-operative assessment Given the usual age of presentation and the association of endometrial cancer with obesity, patients presenting with an endometrial cancer commonly have significant comorbidities. Obesity, cardiovascular disease, diabetes and musculoskeletal disorders can all impact on a patient s fitness for surgery. Routine assessment includes Blood tests - FBC - U+Es - LFTs - Group and Save ECG Chest x ray Preop review of current medication and illnesses Additional tests that may be relevant on an individual basis include Pulmonary function tests Echocardiogram Patients should be assessed for their fitness for laparoscopic surgery in view of the reduced post operative morbidty associated with the laparoscopic approach. Preoperative Imaging For patients with high grade disease (Grade 3 adenocarcinoma or Type 2 cancers; clear cell or papillary serous), a preoperative CT of abdomen and pelvis is required. A chest CT should also be included for patients with a known carcinosarcoma. 5 P age

6 Treatment Initial Rx based on clinical assessment (mobility of tumor, patient fitness). Most cancers are treated surgically if feasible. Adjuvant treatment is dependent of the final histology. 7. Surgery Laparoscopic hysterectomy and oophorectomy is now the treatment of choice for Type 1 early stage endometrial cancer. The laparoscopic approach fits with the NHS focus on Enhanced Recovery, allowing earlier mobilisation, reduced analgesic requirements, earlier discharge and quicker return to health than the traditional open surgery. Extensive previous abdominal surgery, morbid obesity, and anaesthetic concerns of cardiac or respiratory comprimise are all concerns for any surgical approach, and can be an issue during the required head down position for surgery and the increased intra-abdominal pressure for laparoscopic insufflation. Management of the medically unfit patients needs to be individualised, with discussion between the Gynaecologist and Anaesthetiist. The traditional approach for uterine cancer has been an open technique, via a low transverse or vertical midline incision, as indicated individually by considerations of build and access to the pelvis. Cardio-respiratory co-morbidity in these patients suggests that the low transverse incision is employed wherever possible, aided by apronectomy to facilitate access to the pelvis in the patient with a pendulous, obese abdomen. In unfit patients where there are concerns that general anaesthesia, open or laparoscopic surgery may significantly increase the risk of serious complications, vaginal hysterectomy alone under regional anaethesia is a reasonable alternative with acceptable results (Chan JK, 2001) 7.1 Surgery and stage 1 6 P age

7 Surgery is the preferred treatment modality for Stage 1 disease and should include the following: a) thorough assessment of the abdominal cavity b) selective pelvic and para-aortic lymph node sampling may be appropriate c) total hysterectomy and bilateral salpingo-oophorectomy (open or laparoscopic) d) Omentectomy in papillary serous cancer only The incidence of lymph node involvement in stage one disease is approximately 10%, but the results of the ASTEC trial demonstrated no survival benefit from a routine systematic lymphadenectomy in early stage endometrial cancer. Removal of clinically suspicious nodes is recommended, though a routine systematic pelvic or para aortic lymphadenectomy is not recommended except as part of a randomised controlled trial 7.2 Surgery and stage 2 If pre-operative diagnosis is Stage 2 surgery is the preferred treatment option., though it is recognised that the majority of Stage 2 are diagnosed post-operatively. Surgery if undertaken for patients with clinical involvement of the cervix should include: a) laparotomy via midline incision, or laparoscopic approach used for a laparoscopic radical hysterectomy for cervical cancer b) peritoneal washings for cytology c) radical extended hysterectomy and bilateral salpingo-oophorectomy d) Omentectomy for papillary serous cancer e) Consideration should be given to pelvic and para-aortic lymphadenectomy. (In these cases the risk of spread to pelvic lymph nodes may be as high as 30%) In patients not suitable for surgery with clinical stage 2 disease, radiotherapy is an option. 7.3 Surgery and stage 3 or 4 These are a heterogenous group of patients who must be managed on an individual basis. Recommended treatments include surgery, surgery followed by radiation, radiotherapy, hormonal treatment or chemotherapy. 7 P age

8 With respect to surgery debulking surgery similar to that undertaken for ovarian cancer has been advocated in advanced disease. Goff et al reported a study of 47 patients which included 20 who preoperatively were considered to have disease confined to the uterus (Goff, 1994). Debulking was carried out in 29 patients with stage 4 disease with a peri-operative mortality of 7%. Multivariate analysis showed that surgical cytoreduction was the only significant prognostic factor for survival and although median survival was only 12 months this was extended to 21 months in those patients who were optimally debulked and had chemotherapy. 7.4 Surgery and recurrent disease The role for surgery in recurrent disease is limited; more commonly hormones, radiotherapy or palliative chemotherapy are the more appropriate options. Occasional isolated recurrences (eg vulval) can be excised locally, and there is a potential role for extenterative surgery in patients with - long time interval between the initial treatment and the recurrence (usually more than 2 years) - central local recurrence at vaginal vault - no distant disease on CT or PET-CT scanning - patient willingness and fitness to consider anterior/ complete exenteration 8. Radiotherapy Adjuvant external beam radiotherapy reduces the risk of local recurrence but does not improve survival. There are number of randomised studies postoperatively in adjuvant endometrial cancer (Mallipeddi, 1992) (Chum, 1999) (De Palo G, 1971) and recently published pooled analaysis of ASTEC and Candian study EN.5. Neither found survival benefit, although local recurrence was reduced (Blake P, 2009). 8.1 Stage I disease 8 P age

9 8.1.1 Low risk patients Patients in this group do not receive radiotherapy Moderate and High Risk Patients The beneifits and side effects of adjuvant radiotherapy are discussed in these group of patients and offered PORTEC 3 trail (see entry criteria NCRN Gynaecological Trials) to eligible patients. Selected patients are offered Brachtherapy only if morbidity to radiotherapy is significantly high such as obesity. 8.2 Stage II Disease There is less data for stage II disease compared with stage I. In general, most patients are offered postoperative radiotherapy and considered for PORTEC 3 trial. If there is only focal involvement of the cervix and otherwise the patient falls into a low risk, Brachtherapy only to vaginal vault is considered. 8.3 Stage III disease Stage three disease is an uncommon and heterogenous disease including patients with tumour spread beyond the uterus to involve the serosa, adnexae, peritoneal fluid, vagina, pelvic ± para-aortic nodes. Treatments recommended have included postoperative radiotherapy to the pelvis, systemic chemotherapy followed by consolidation radiotherapy to pelvis if disease confined to pelvis only or systemic chemotherapy only if disease is spread outside pelvis. 8.4 Stage IV disease Treatment is individualised for these patients using combinations of surgery/radiotherapy/ hormones and chemotherapy. The aim is to control disease and maintain quality of life. 9 P age

10 8.4.1 Stage IVa Treatment is generally palliative. Occasional patients may be suitable for radical approach either in the form of radiotherapy or surgery Stage IVb disease Palliative radiotherapy can be used for patients who are symptomatic with local pelvic symptoms. Hormonal treatment and/or chemotherapy can be considered for those presenting with metastatic disease. 8.5 Treatment of patients with unfavourable histology Both uterine papillary serous (UPSC) and clear cell histology are associated with a poor prognosis. The pattern of intraperitoneal spread resembles ovarian cancer. 5-year survival rates are of the order of 30 40% 1, (Goff, 1994) (Greven, 1993) Uterine papillary serous carcinoma (UPSC), and clear cell carcinoma. These tumours tend to be deeply myoinvasive and frequently have vascular space invasion. Most surgically staged patients have unsuspected extrauterine disease (Goff, 1994) Of patients who recur 50% appear to do so in the upper abdomen (Eifel, 1983)The treatment of UPSC should probably include ovarian style debulking surgery and staging, including omenectomy. The exact type of adjuvant treatment is unclear. There is data to support no adjuvant treatment in those patients with stage 1a disease who have been staged appropriately. There is phase 2 data to support adjuvant chemo-radiotherapy in stage 1 or II disease. Up to recently it has been felt that unlike serous carcinomas of the ovary response rates to platinum containing regimes are low. GOG 122 included 21.3% of patients with serous papillary tumours and although numbers were small response rates were similar in these patients with Cisplatin/Doxorubicin (Randall, 2006) 10 P age

11 Treatment options include Observation for 1a disease following TAH/BSO Pelvic radiotherapy for stages 1 and II disease. Chemotherapy considered in selected cases. Platinum based chemotherapy for patients with Stages 3 & 4 disease who have been surgically debulked with radiotherapy afterwrards. Randomisation to Portec-3 in due course. 8.6 Treatment of endometrial carcinoma with radiotherapy alone Patients who are morbidly obese or are deemed unfit for surgery should be reviewed by one of the Gynaecological Oncologists at the Centre. If they are then felt unfit for surgery they can be can be considered for Radical Radiotherapy. With Radical Radiotherapy the local control rates are high in patients with stage 1 and 2 disease and 5 year disease specific survival rates are similarly good. Audit of patients treated at CCC showed 5 year disease specific survival to be 70% in patients with stage I/II disease and 33% in stage III/IV disease (Chum, 1999). However 5 year overall survival rates in these patients are generally only 30 50% as a consequence of their medical problems. 8.7 Treatment of recurrent disease Recurrent endometrial cancer is confined to the pelvis in half of patients and of these approx 50% are confined to the vagina. Salvage of these cases is more usual when disease involves the vagina. Treatment options depend on previous radiotherapy (1) If no previous radiotherapy: Radical radiotherapy with external beam and brachytherapy. 11 P age

12 (2)If previously irradiated treatment is generally palliative. There may be scope for further external beam or Brachytherapy. 8.8 Adjuvant Vault Brachytherapy At CCC, adjuvant vault brachytherapy is given to all suitable patients at the end of external beam radiotherapy. This consists of a single vault treatment. PORTEC- 2 trial has demonstrated that vaginal vault brachtherapy only is effective in preventing vaginal vault recurrence. However, significantly increased pelvic failure rate (Nout RA, 2009). Selective intermediate risk patients patients may be offered vault brachytherapy alone, which consists of 3 treatments over a period of 2 to 3 weeks. 9. Hormonal therapy On the basis of the available published evidence the routine use of adjuvant progestogen therapy cannot be recommended after initial treatment of early stage disease. De Palo in a multi-centre randomised trial (De Palo G, 1971) suggested that hormonal treatment does not improve survival whilst Quirm found a 5-6% survival advantage in higher risk groups based on differentiation, tumour type and myometrial invasion (M Q., 1995). Meta-analysis of published trials demonstrated that overall survival may be adversely affected (Martin- Hirsch P, 1996). Initial analysis of the large COSA-NZ-UK trial did not show any significant survival advantage for adjuvant progestogen therapy although a second analysis did show a small survival benefit (COSA-W-UK ECSG, 1998). In advanced or recurrent disease however, up to 30% of patients may respond to hormonal therapy (Lentz S, 1996). Higher response rates are noted in patients with grade 1 disease, positive progesterone receptors, and a longer disease free interval. Retrospective ER-PR status may be helpful in determining management. Although there are no randomised controlled trials of the use of hormonal therapy in this setting, its use is often of palliative 12 P age

13 benefit and may possibly enhance survival. The particular agent used does not affect the response rates. We recommend Provera (medroxyprogesterone acetate) 200mg BD or 300mg OD or Megace (megestrol acetate) 160mg od. 10. Chemotherapy Adjuvant The role of adjuvant chemotherapy is not clearly established and is currently tested in clinical trial setting (PORTEC 3 Trial). Selected patient with high risk recurrent disease who are not willing to consider clinical trial, adjuvant cisplatinum based chemotherapy can be offered (Thigpen LT, 1994) (Fleming, 2007). Advanced disease In patients with advanced or recurrent endometrial cancer survival is greatly diminished. Hormonal therapy and chemotherapy play a major role in the management of advanced or recurrent endometrial cancer. The combination of cisplatin plus doxorubicin is the most commonly used regime, but carboplatin plus paclitaxel represents an efficacious, low toxicity regimen in advanced or recurrent endometrial cancer. The addition of paclitaxel to cisplatin plus doxorubicin appears to improve response rates, progression-free survival and overall survival, but to worsen toxicity profile. 11. Palliative Care and Nursing care Palliative care input is appropriate to consider at all stages of the patient s cancer journey. Please refer to the separate nursing and palliative care guidelines for detailed advice. All women with a diagnosis of a Gynaecological cancer should be offered the support of and have access to a Clinical Nurse Specialist (CNS) in order to facilitate the woman s needs throughout the cancer journey, including those of her partner and family. This CNS will be the keyworker for the patient and family. The skills of the CNS as a consultant, practitioner and educator can be drawn upon at all stages throughout their illness from pre-diagnosis to the terminal stage-incorporating the 13 P age

14 Specialist Palliative care services provided in the hospital and the community setting. Bereavement support will also be available, if appropriate. The specifics of the role will include: All women will be offered information about their disease including psychosocial and psychosexual issues that: Is available at the time they want it Includes the amount of detail that they want and are able to deal with Is in a suitable format, including written information Ensure that the information is available about: The stage of the disease, treatment options and prognosis How to manage the side effects of both the disease and its treatments Sexuality including fertility and hormone treatment Symptoms and signs of disease recurrence Genetics referrals if appropriate Self help strategies to optimise independence and coping Where to go for support including local and national support groups How to deal with emotions Financial and social impacts and where to go for help with these issues All patients are to be offered a Holistic needs assessment (HNA) at the milestones indicated in the Merseyside and Cheshire HNA and keyworker guidance. The CNS will undertake a number of key responsibilities including; Linking with other professionals who can help the patients throughout the system A resource for information and support to the patient and carer and other HCP s Liaison point for HCP s in primary and secondary care Teacher and educator Be involved in research, audit, standards and guidelines Coordinate and develop care services 12. Follow-up Atypical hyperplasia is cured by hysterectomy, and hence may be discharged with open appointment in the event of new symptoms or concerns. Patients with Stage 1A with no myometrial invasion (Grade 1 or 2) may be discharged on an individual basis. 14 P age

15 For the remainder, standard follow-up is recommended: Four monthly for years 1 and 2, six monthly to 3 years. Discharge with open access to CNS in the event of new symptoms or concerns. CNS holistic assessment is carried out 6 weeks after the completion of primary treatment. 13. Hormone Replacement The question as to whether hormone replacement therapy may be prescribed is a matter of some debate. Type 1 endometrial cancer is an oestrogen-dependent cancer and traditional thinking has been that oestrogen replacement therapy is contraindicated. Recent opinion is suggesting that continuous combined oestrogen/progesterone therapy may be considered after a diagnosis of endometrial cancer. However, there is a lack of prospective randomised trial data to determine safety. There is some data from 5 case controlled studies which showed no increase in the risk of recurrence. The Map of Medicine guidance and RCOG suggests to consider oestrogen replacement therapy for patients who are at low risk of tumour recurrence. A period of 12 months is allowed between the diagnosis of endometrial cancer and initiation of HRT. Therefore, HRT can be given on an individual patient basis if the prognostic indicators are favourable and the patient is willing to accept HRT without evidence based data. Consideration can be given to relieve menopausal symptoms by the use of phytopreparations or an SSRI such as venlafaxine. 14. Clinical Trials The centre is commited to recrutining to national trials. For information on the current trials, please go to the MCCRN website. 15 P age

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17 Appendix 1 Radiotherapy for Endometrial carcinoma 1. Adjuvant radiotherapy A 3 or 4 field technique is used to treat the pelvis. The patient lies in the supine position and is planned using the CT simulator. There is no routine need to use a vaginal marker when planning with a virtual simulation technique. The dose schedule is external beam radiotherapy 45Gy in 25# over 5 weeks followed by a single brachytherapy treatment to the vaginal vault, giving a dose of 6Gy at 5mm from the applicator surface, treating the top 2 to 4cm of the vagina using HDR. See radiotherapy protocol book for field definitions. 2. Radical radiotherapy A. A 3 or 4 field technique is used to treat the pelvis. The dose is 45Gy in 25# over 5 weeks external beam treatment followed by HDR brachytherapy, 7Gy in 2#. B. For obese patients with early stage disease, can be treated with brachytherapy alone, dose 7Gy in 5#. 3. Whole abdominal radiotherapy This treatment is not used at the Clatterbridge Cancer Centre. 4. Treatment of pelvic recurrence 17 P age

18 In patients previously treated by surgery alone who develop a central pelvic recurrence, salvage can be achieved with pelvic radiotherapy. A CT scan of the abdomen and pelvis should be performed before radiotherapy is given. The schedule is 45Gy in 25# external beam radiotherapy to the pelvis followed by 2 brachytherapy treatments to the vaginal vault, each of 6 or 7Gy ensuring all the vaginal disease is covered. 5. Palliative radiotherapy A, Pelvic Disease A smaller pelvic field can be used to encompass gross disease, to achieve symptom control and minimise toxicity. Acceptable dose fractionations include: 20Gy in 5# 30Gy in 10# 40Gy in 15# A single treatment of 8 to 10Gy may be suitable for frail patients. B, Metastatic Disease Bone mets can be treated either with a single 8Gy treatment or 20Gy in 5# Brain mets can be treated with 12Gy in 2# or 20Gy in 5# Selected patients with high risk disease can be treated with chemoradiotherapy followed by a further 4 cycles of chemotherapy. 18 P age

19 References Abeler. (1992). Carcinoma of the endometrium in Norway: a histopathological and prognositc survey of a total population. Int J Gynec Cancer(2), Barret RJ, B. L. (1993). Doxorubicin cisplatin chemotherapy for advanced endometrial cancer: a phase 2 study of the Gynecologic Oncology Group. Am J Clinic Oncol, 16, 494. Blake P, S. A.-A. (2009). Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN5 radndomised trial); pooled trial results, systematic review and meta analysis. Lancet, 146, 373. Chan JK, L. Y. (2001). Vaginal hysterectomy as primary treatment of endometrial cancer in medically compromised women. Obstet Gynecol, 97, Chum. (1999). Primary radiotherapy for carcinoma of the endometrium using external beam radiotherapy and single line source brachytherapy. Clinical Oncology(11), Ciatto S, C. S. (2002, Nov). Association of endometrial thickness assessed at trans-vaginal ultrasonography to endometrial cancer in postmenopausal women asymptomatic or with abnormal uterine bleeding. Radiol Med, 104(5), COSA-W-UK ECSG. (1998). Adjuvant medroxyprogresterone acetate in high risk endometrial cancer. Int J Gynecol Cancer, 8, De Palo G, M. C. (1971). Stage 1 endometrial carcinoma with intensive surgery, radiotherapy and hormonotherapy according to pathological prognostic groups. Long term results of a randomised multicentre study. Eur J Cancer, Eifel. (1983). Adenocarcinoma of the endometrium. Analysis of 256 cases with disease limted to the uterine corpus. Cancer (52), Fleming. (2007). Systemic chemotherapy for uterine carcinoma. metastatic and adjuvant. J Clin Oncol, Goff. (1994). Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecol Oncol(54), Greven. (1993). Pathologic stage 3 endometrial carcinoma. Prognostic factors and paterns of recurrence. Cancer(71), Lentz S, B. M. (1996). High dose megestrol acetate in advanced or recurrent endometrial cancer: A Gynecologic Oncology Group study. J Clin Oncol, 14, M, Q. (1995). Adjuvant medroxyprogesterone acetate in high risk endometrial cancer. Int J Gynecol Cancer(5), 2. M, Q. (1995). Adjuvant medroxyprogesterone acetate in high risk endometrial cancer. Int J Gynecolo Cancer(5), 2. Mallipeddi. (1992). Long term survival with adjuvant whole abdominopelvic irradiation for uterine papillary serous carcinoma. Cancer(71), Martin-Hirsch P, L. R. (1996). Adjuvant progestogen therapy for the treatment of endometrial cancer: review and meta-analyses of the published randomised controlled trials. Eur J Obstet Gynae & Reprod Biol, 65, P age

20 Nout RA, P. H. (2009). Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the randomised PORTEC 2 trial. J Clin Oncol, 27(21), Randall, M. F. (2006). Randomised Phase III trail of whole abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma; a Gynecological Oncology group study. J Clin Oncol, RCOG. (2016). Endometrial Hyperplasia. Green Top Guidelines, 67. Smith-Bindman R, W. E. (2004, Oct). How thick is too thick? When endometrial thickness should prompt biopsy in postmenopausal women without vaginal bleeding. Ultrasound Obstet Gynecol, 24(5), Thigpen LT, B. L. (1994). A randomised comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma - a GOG study. J Clin Oncol, 12, Wong AS, L. T. (2016, Feb). Reappraisal of endometrial thickness for the detection of endometrial cancer in postmenopausal bleeding: a retrospective cohort study. BJOG, 123(3), P age