endometrial carcinoma - nhs wales · web viewendometrial carcinoma index 1. clinical symptoms and...

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ENDOMETRIAL CARCINOMA

Index

1. Clinical symptoms and signs

2. Screening 2.1 Family history - Lynch type 2 syndrome

3. Ref erral pathway 3.1 For GP3.2 For non-oncological consultants/ firms3.3 For referral from unit to centre

4. Diagnosis

5. Investigations

6. Gynaecological cancer multidisciplinary team 6.1 Information

7. Pathology 7.1 Endometrial carcinoma classification (adapted from WHO classification)7.2 Architectural grading of endometrioid adenocarcinoma (FIGO)7.3 Nuclear grading7.4 Type 1 and type 2 tumours7.4.1 Type 1 carcinoma7.4.2 Type 2 carcinoma7.4.3 Overall outcome for endometrial carcinoma based on pathology 7.5 Pathological reporting of endometrial carcinoma

8. Staging

9. Histopathology minimum dataset

10. Treatment 10.1 Abdominal, vaginal and laparoscopic hysterectomy 10.2 Pelvic lymphadenectomy10.3 Indications for adjuvant radiotherapy for stage I disease 10.4 Further indications for radiotherapy10.5 Management of stage II/III disease 10.6 Chemotherapy / progestogens and HRT10.7 Uterine sarcomas/ carcinosarcomas

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008) 1

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11. Dealing with recurrent disease 11.1 Palliative care

12. Survival 12.1 Cancer dataset/ inventory of active trials

13. Follow up 13.1 Identification and management of late effects of treatment

14. Contact names/ numbers

15. Algorithm for postmenopausal bleeding

16. Algorithm

17. Summary

18. References


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IntroductionCurrently about 3900 new cases are diagnosed annually in England and Wales with 770 deaths. This survival is disappointing considering 75% of patients present with early (stage I) disease, and reflects the need to develop central referral and the application of All Wales Guidelines (CSCG, 2001). In Wales, endometrial carcinoma accounts for nearly 4% of all female cancer registrations (1993-2002) with the highest age-standardised incidence in Anglesey and the lowest in Cardiff. The overall incidence in Wales is 13.5/100,000 women (WCISU, 1991-1999). The one-year relative survival increased from 88% for the period 1990-1994 to 92% for the period 1995-1999. A similar improvement was noted in the five-year relative survival from 75% to 80%.Endometrial carcinoma is a disease of postmenopausal women with only 25% presenting before the menopause. Only 2-5% is diagnosed before the age of 40 years. The mean age is 60 years with a peak incidence between 55 and 70 years. Risk factors include:

obesitynulliparitypolycystic ovary syndromediabetes hypertension family history of endometrial, ovarian or intestinal malignancypast history of breast, ovarian or intestinal malignancy.

1. Clinical symptoms and signs Over 90% of endometrial carcinomas present with postmenopausal bleeding. However only 20% of patients with postmenopausal bleeding will have a malignant origin for their bleeding of which over 50% will be due to endometrial carcinoma. The older the woman the higher the chances are that the bleeding is due to tumour. A small proportion will present with an offensive vaginal discharge due to a draining pyometra. About 1 to 5% of tumours are asymptomatic and detected largely by cervical screening or ultrasonography. It may also be a chance finding at operation for suspected benign disease.There is usually little to find on examination. The uterus may be enlarged in advanced disease and vaginal metastases particularly in the lower third and the suburethral area are the most common sites.

2. Screening There is no screening programme to detect endometrial carcinoma.

2.1 Family history - Lynch type 2 syndromeAsymptomatic women are eligible for review with the Cancer Genetics Service in Wales if there are 3 first degree affected relatives with colonic carcinoma or 2 first degree relatives with colonic carcinoma aged 60 years or less at onset or 1 at 40 years or less at onset with 1 first degree relative with ovarian cancer. Such women may have a 30% lifetime risk of endometrial carcinoma. Contact number:North Wales 01745 534447

3. Referral pathway (see 14. Contact names/ numbers)

3.1 For GPIf endometrial cancer is suspected then referral should be to a general gynaecologist, the lead in the cancer unit or gynaecological oncologist in the cancer centre.


StandardsRapid access to the specialist should be available with the patient seen within 2 weeks of date of receipt of the referral letter/ fax.

Definitive treatment should be commenced no later than 62 days after receipt of the referral letter/ fax.

Definitive treatment should be commenced no later than 31 days after diagnosis for non urgent suspect cancer referrals.

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3.2 For non-oncological consultants/ firmsIf the diagnosis is suspected or confirmed referral to the local unit lead or gynaecological cancer centre should be made.

3.3 For referral from unit to centreThis is appropriate for all cancer cases FIGO Ic and type 2/ poorly differentiated FIGO Ib. All sarcomas and carcinosarcomas should be referred to the centre (see 15. Algorithm for primary management of patients with endometrial cancer).

4. Diagnosis Primary assessment in all cases is with transvaginal ultrasound (Karlsson et al, 1995) and pelvic examination. This strategy also appears to the most cost effective (Clark et al, 2006). All postmenopausal patients with an endometrial thickness >5mm or persistent bleeding despite a normal endometrial thickness should have an endometrial biopsy (NHS Executive, 1999; grade B recommendation). If there is difficulty in obtaining a pelvic scan then an endometrial sample should be attempted in clinic. If the endometrium is difficult to identify then hysteroscopy should also be considered. The value of endometrial thickness in perimenopausal bleeding is questionable as the thickness range is variable. Cervical cytology will detect endometrial carcinoma in only 40% of cases and is far too unreliable.Hysteroscopy can be performed in an outpatient setting. It can enable visualisation of the degree of encroachment of the tumour to the internal os which may then modify the form of treatment offered (see 15. Algorithm for postmenopausal bleeding).

5. Investigations After confirming the diagnosis the objectives of further investigations are to

determine the extent of disease determine suitability for treatment.

Those that penetrate more deeply into the myometrium are more likely to have involved pelvic nodes. The frequency of pelvic and para-aortic node involvement increases to 25 and 17% respectively for deep muscle invasion (Creasman et al, 1987). A chest X-ray is essential. An MR scan will help identify the site and size of the primary tumour, any evident myometrial invasion (Kim et al, 1995; Yamashita et al, 1993), the presence of lymph node metastases and the presence of occult cervical involvement but image resolution of the myometrium can be disturbed by a recently performed uterine curettage. MR scanning should be considered for all patients with endometrial cancer prior to treatment (grade B recommendation). Ultrasound can be used as an alternative but is less accurate than MR. CT scanning is less accurate than both ultrasound and MR for measuring myometrial infiltration but is an alternative method of imaging extra uterine disease if a patient is unsuitable for MR.


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6. Gynaecological cancer multidisciplinary team

Core team Named team member Additional member or Cover (core team only)

Gynae oncologist Mr Leeson / Mr ToonGynae lead cancer surgeon Mr Bickerton/ tbaMedical oncologist Prof Stuart Dr WilliamsClinical Oncologist Dr Al-Sammarie tbaPathologist/ Cytopathologist Dr Lord tbaPalliative care team Dr Williams tbaRadiologist Dr Barwick Dr WenhamMDT co-ordinator Ms Jones tbaCNS Ms HallExtended team

Ultrasonographer tbaJunior doctorsPsychologistGeneticist Ms GrierSocial worker tbaWard Sister Sr WilliamsResearch nurseColorectal/ urological/ plastics as required

6.1 Information

7. Pathology

7.1 Endometrial Carcinoma Classification (adapted from WHO classification).

Endometrioid Villoglandular Secretory Ciliated cell with squamous metaplasia Endometrioid with squamous differentiationSerousClear cellMucinousSquamousMixed types


StandardsAll patients must have access to a gynaecological oncology clinical nurse specialist within 24 hours of the patient being informed of her diagnosis (this should include a daytime contact telephone number for the clinical nurse specialist). Preferably the nurse specialist should be at the consultation when the patient is given her diagnosis.

All referring practitioners and/ or patients GP’s should be informed by letter or secure fax within 24 hours of the patient being informed of her diagnosis.

All patients must be given appropriate literature about the management, treatment and outcome for cervical cancer such as a Cancerbackup leaflet or equivalent.

All these activities must be documented in the patient’s case record.

Core/ extended teams to include members from YGC/ NEWT

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Undifferentiated

7.2 Architectural grading of endometrioid adenocarcinoma (FIGO)Grade I 5% or less of the tumour shows a solid patternGrade II Between 6 and 50% of the tumour exhibits solid growthGrade III More than 50% of the tumour shows a solid growth pattern

It is important to avoid areas with squamous differentiation and evaluate only glandular areas.

7.3 Nuclear gradingGrade 1 Oval/ elongated nuclei, fine chromatin, small nucleoli, few mitosesGrade 2 Features between 1 and 3Grade 3 Enlarged/ pleomorphic nuclei, coarse chromatin, prominent nucleoli, many mitoses

If an endometrioid adenocarcinoma is a FIGO morphological grade I or II tumour it should be raised by one grade if it shows nuclear grade 3 features. Serous carcinoma, clear cell carcinoma, squamous carcinoma and undifferentiated carcinoma are not graded, these tumours are basically highly malignant neoplasms. Serous carcinoma, clear cell carcinoma and undifferentiated carcinoma of large cell type usually exhibit grade 3 nuclear abnormalities.

7.4 Type 1 and type 2 tumoursOver recent years it has become evident that there are two types of endometrial carcinoma. Type 1 is associated with unopposed oestrogenic stimulation and previous endometrial hyperplasia. This is the commonest form of endometrial carcinoma and the endometrioid subtype is the prototypic tumour in this category. Serous carcinoma is the prototypic type 2 carcinoma and these tumours are not related to oestrogenic hyperstimulation and not usually associated with pre-existing hyperplasia. Mucinous, endometrioid with squamous differentiation and ciliated cell carcinomas fall into the type 1 group but clear cell carcinoma is also regarded as a type 2 carcinoma. Recent molecular genetic data support carcinosarcomas also being epithelial tumours with metaplasia to a stromal component and many would now put these tumours into the poorly differentiated carcinoma category. This classification follows the WHO and ISGP histological classification of endometrial carcinomas.

7.4.1 Type 1 carcinomaEndometrioid carcinoma is the most common tumour in this group and the most common form of endometrial carcinoma overall, accounting for ¾ of all cases. By definition such tumours do not contain more than 10% squamous, serous, mucinous, or clear cell differentiation, as if they did they would be regarded as mixed tumours. Most patients with this tumour are peri- or postmenopausal and those rare cases that occur in women under the age of 30 years appear to have a very good prognosis, being low grade and often minimally or non-invasive. Endometrioid carcinomas tend to be well differentiated but the tumours are graded on the basis of a combination of the architecture and nuclear detail. Zones of squamous epithelium are not included as solid areas and the tumour is graded on the glandular component only. Marked discordance between the architectural and nuclear grade is unusual in endometrioid carcinoma and always raises the concern that the tumour may be of type 2. Discordance in grading between curettage and hysterectomy specimens occurs in up to a ¼ cases and also perhaps 40% of curettage specimens diagnosed as atypical hyperplasia will have carcinoma on hysterectomy.

7.4.2 Type 2 carcinomaMost data on type 2 carcinomas relate to serous carcinoma. There appears to be an in-situ phase of this tumour, termed endometrial intraepithelial carcinoma but this is usually only seen, when there is already established serous carcinoma. A papillary pattern typically predominates in serous carcinomas but a papillary pattern of itself may be seen in low grade as well as high grade carcinoma. The cytological features of the tumour cells are varied but marked nuclear atypia is always present and is required for a tumour to qualify as high grade serous carcinoma. A primary feature of this tumour is the discordance between the architecture, which usually appears well differentiated, and the nuclear morphology, which is high grade. The aggressive nature of this tumour can be deduced from the fact that even patients with only endometrial intraepithelial carcinoma, in a completely sampled endometrium can have metastatic disease in the ovaries, peritoneum or omentum, presumably as a result of implantation of tumour. Clear cell carcinomas are generally believed to be similar overall in outcome to serous carcinoma.


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7.4.3 Overall outcome for endometrial carcinoma based on pathology Endometrioid adenocarcinoma spreads by lymphatic and vascular dissemination, direct extension and transperitoneal seeding. Pelvic lymph nodes tend to be involved before para-aortic. In a GOG study of 1180 patients with clinical stage I and occult stage II adenocarcinoma, multivariant analysis showed that advancing age worsens prognosis and cell type, architectural grade, depth of myometrial invasion, vascular space involvement and peritoneal cytology all appear to be independent risk factors for recurrence and death (Morrow et al, 1991). Patients with grade I endometrioid carcinoma and with tumour confined to the endometrium and without vascular invasion, have an approximately 95% or greater 5 years survival disease-free, whereas patients with grade III tumours and involvement to the middle third of the myometrium, together with vessel involvement, have a 5 year disease free survival of approximately 65%. Statistical models to predict survival are the best method of assessing relative risk. In general, as most endometrioid carcinomas tend to be low stage and low grade, survival is high. The outcome for type 2 carcinomas is very different. These patients tend to be considerably older than those with endometrioid carcinoma and are often high stage at the time of presentation. Under-staging clinically is common. Five and 10 year survival rates for all stages are approximately 36% and less than 20%. Some studies even for pathological stage I serous carcinomas have revealed 5 year survival of no more than 40%. With type 2 tumours prognostic factors indicative of shorter survival include increasing age, vessel invasion and greater than half the myometrial depth involved. Even intraendometrial carcinomas have a high risk of metastasis, with 13% of carcinomas confined to the endometrium having para-aortic lymph node metastases and some studies suggest an outcome even for stage Ia tumours of only 57% survival at 5 years. Endometrial carcinomas containing a component of serous carcinoma, making up as little as 25% of the tumour, appear to have the same survival as pure serous carcinomas.

7.5 Pathological reporting of endometrial carcinoma It is firmly recommended that reporting of endometrial carcinoma of any type should follow the national minimum dataset for endometrial carcinoma, given below. Either the protocol sheet should be provided, or the histological report should include all features given in the dataset.

8. Staging

FIGO stages NM categories

primary tumour cannot be assessed TXno evidence of primary tumour T0

Stage 0 carcinoma in situ (preinvasive carcinoma) Tis

Stage I carcinoma confined to the corpus T1a carcinoma confined to the endometrium T1ab < ½ myometrial invasion T1bc > ½ myometrial invasion T1c

Stage II involving cervix but does not extend beyond uterus T2a glandular involvement only T2ab cervical stromal involvement T2b

Stage III local and/ or regional spread as defined in IIIa, b or c T3 and/ or N1a disease involving the adnexae (direct extension or

metastases), serosa or +ve peritoneal cytology(washings or ascites) T3a

b vaginal metastases (direct extension or metastases) T3bc pelvic or para-aortic node metastases N1

Stage IVa bladder* or rectal mucosal involvement T4b extrapelvic metastases including

inguinal lymph nodes M1

*The presence of bullous oedema is not sufficient evidence to classify a tumour as T4.FIGO, 2003

Regional lymph nodes (N) Distant Metastasis (M)

NX regional lymph nodes cannot be assessed MX distant metastasis cannot be assessed


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N0 no regional lymph node metastasis M0 no distant metastasisN1 regional lymph node metastasis M1 distant metastasis


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9. Histopathology minimum dataset

National Minimum DatasetEndometrial Cancer Histopathology Report

Gross descriptionDimensions of uterus: Length ..........mm Transverse .......mm Antero-posterior........mm

Maximum dimensions of tumour: .…......mm

Is there obvious myometrial invasion: Yes ¨ No ¨

HistologyType: Endometrioid ¨ Serous ¨ Clear cell ¨

MMMT ¨ other (please specify) ……………………………………

Grade (FIGO): (only applies to endometrioid carcimona) I II III N/A

Myometrial invasion: None ¨ <50% ¨>50% ¨

Is there microscopic involvement of;

the cervical stroma Yes ¨ No ¨

the appendages Yes ¨ No ¨

the serosa Yes ¨ No ¨

Is there lymphovascular invasion: Yes ¨ No ¨

Is there associated endometrial hyperplasia: No ¨ Yes ¨ Simple ¨ Complex¨ Atypical ¨

Normal: right ovary ¨ left ovary ¨ right tube ¨ left tube ¨

Abnormal: (please specify) ……………………………………………………Pelvic Nodes (including obturator, internal and external iliac)

right left Common Iliac nodes right left

total number of nodes retrieved …….. ……..

total number of nodes retrieved …….. ……..

lymph nodes with tumour deposits …….. ……..

lymph nodes with tumour deposits …….. ……..

Para-aortic nodes: not sampled ¨ positive ¨ negative ¨

Peritoneal washings: not sampled ¨ positive ¨ negative ¨

Comments

SNOMED CodesT82000 Uterus (endometrium) M81403 (Adenocarcinoma) M84413(Serous adenocarcinoma)

M83103 (Clear cell carcinoma) M89503 (Mixed Müllerian tumour)T08000 Lymph node M81406 (Metastatic carcinoma)


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10. Treatment (see 16. Algorithm and 17. Summary) Factors such as tumour stage, medical fitness and wishes of the patient will all influence

management.

10.1 Abdominal, vaginal and laparoscopic hysterectomyStage I disease is treated with surgery. Total abdominal hysterectomy and bilateral salpingo-oophorectomy is routine and appropriate for stage Ia/b well and moderately differentiated tumours (Mariani et al, 2000; grade B recommendation). Peritoneal washings are part of standard surgical assessment but may be misleading in modern practice following hysteroscopy (Leveque et al, 1998). Disease free survival was found to be reduced in a retrospective study of 369 patients with stage I endometrioid adenocarcinoma where 13 patients had positive peritoneal cytology and appeared to be an independent prognostic indicator for disease free status (Obermair et al, 2001). Peritoneal washings should be used in the routine assessment at laparotomy (grade B recommendation) but would not determine adjuvant therapy in early stage disease. Omental biopsy should be considered (Neito et al, 2002; grade C recommendation).Vaginal hysterectomy with or without adnexectomy may be considered in a grossly obese patient with a degree of uterine prolapse and an adequate vaginal capacity. A large episiotomy can be helpful. Laparoscopic assisted hysterectomy with or without laparoscopic lymphadenectomy is a useful technique to reduce morbidity of major surgery in the elderly with equivalent 3 year survival and recurrence rates to abdominal hysterectomy (Magrina et al, 1999). At present laparoscopic assisted vaginal hysterectomy accounts for only a small minority of cases (preliminary ASTEC data).

Patients are to be referred to the Liverpool Womens Hospital if for laparoscopic node dissection.

10.2 Pelvic lymphadenectomyApproximately 10% of patients have occult pelvic lymph node involvement (Creasman et al, 1976).Selective sampling of the para-aortic, common iliac, internal and external iliac and the obturator nodes may indicate which high risk patients are more likely to be upstaged and require adjuvant therapy. Lymph node sampling is unlikely to be therapeutic and its value is questionable as it provides limited assessment of the pelvic nodal status.Bilateral pelvic lymphadenectomy provides a more logical surgical approach for provisionally staged Ic tumours and /or poorly differentiated tumours and other adverse histological sub types (high risk) for patients fit enough to withstand a more prolonged procedure (Podratz et al, 1998; grade C recommendation). This may obviate the need for external beam radiotherapy for node negative high risk patients (Nelson et al, 1999; grade B recommendation). Preliminary data from ASTEC (a prospective RCT of 1408 women assessing the role of lymphadenectomy and radiotherapy for endometrial carcinoma) suggests that there is no survival benefit from bilateral pelvic lymphadenectomy for any group of stage I patients. However until this data has been published and subject to critique, Ic tumours at MR imaging, poorly differentiated or type 2 tumours and sarcomas should be considered for bilateral pelvic lymphadenectomy if a patient is fit enough to have the extensive surgery. A retrospective review of 12,333 patients from the SEER database found an improved survival for stage Ib poorly differentiated and all stage Ic women after multivariate analysis adjusted for confounders including adjuvant radiotherapy (Chan et al, 2006). The management of node positive patients is less clear (see 10.4 and 10.6). A case control study showed improved survival in lymphadenectomised women, but these results could have been influenced by case mix and non surgical treatment (Kilgore et al, 1995). The COSA /NZ /UK Endometrial Cancer Study Groups, 1996 examined the role of pelvic lymphadenectomy in 238 high risk patients as part of a randomised trial of adjuvant hormone therapy. Although this study had a 45% (14/31) recurrence rate in node positive patients as opposed to 14% (29/207) in the node negative group, all but 5% of the node positive recurrences were extrapelvic. Clearly residual disease appears likely in node positive patients and this residual disease may be locoregional at the time of surgery. The role of para-aortic sampling and para-aortic lymphadenectomy is unclear.

10.3 Indications for adjuvant radiotherapy for stage I disease Although the efficacy of adjuvant locoregional radiotherapy appears unproven such treatment appears appropriate for node positive patients until further information becomes available. The role of adjuvant vaginal brachytherapy is unclear (Irwin et al, 1998). It is associated with additional pelvic morbidity and is not incorporated into all treatment protocols (grade B recommendation).For patients having TAH/BSO without pelvic lymphadenectomy, adjuvant radiotherapy is appropriate for patients with myometrial invasion to more than ½ of its thickness, if there is unsuspected cervical involvement, if sampled nodes are involved or if the tumour is infiltrating


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myometrium and poorly differentiated. Stage Ib adenosquamous, clear cell and serous-papillary tumours should have post operative radiation (grade C recommendation). Two RCTs have found that adjuvant radiotherapy reduced the rate of local recurrences, but there was no evidence of a survival advantage (Aalders et al, 1980; Creutzberg et al, 2000). However a recent retrospective non-randomised analysis of over 21,000 women from 1988-2001 has shown that adjuvant radiotherapy after hysterectomy improved overall and relative survival in stage Ic well and poorly differentiated tumours (Lee et al, 2006). The lack of a survival advantage for moderately differentiated tumours may have been due to insufficient size of this cohort of patients.

All cases must be discussed at the gynae cancer MDT to decide further treatment.

10.4 Further indications for radiotherapy

External beam / brachytherapy should be given to all stage II patients unsuspected at laparotomy. Bilateral pelvic lymphadenectomy and radiotherapy may improve local control for node positive women but additional morbidity (particularly small bowel and ureteric obstruction) must be considered (Mariani et al, 2006; grade B recommendation). Radiotherapy should be considered for stage II patients treated with radical hysterectomy if nodes are subsequently found to be involved (re-staged IIIc). Patients with stage III and IV disease should be treated with brachytherapy and external beam therapy. This should be used for stage I and II patients where surgery is contraindicated. Patients with uterine serosal disease (stage IIIa) and positive peritoneal washings may indicate risk of peritoneal carcinomatosis and adjuvant chemotherapy could be considered with or without pelvic radiotherapy.

To refer for radical radiotherapy at YGC. Brachytherapy provided by the Christie Hospital in Manchester.All cases must be discussed at the gynae cancer MDT to decide further treatment.

10.5 Management of stage II/III disease Patients with disease clinically involving the cervix should have a radical hysterectomy with bilateral pelvic lymphadenectomy and removal of a vaginal cuff with dissection of the ureters (Lawton, 1997; Mariani et al, 2001; grade B recommendation). For patients unsuitable for such radical surgery, radiotherapy is appropriate (external beam and additional brachytherapy to the vaginal vault) as primary treatment or preferably as adjuvant following total abdominal hysterectomy and bilateral salpingo-oophorectomy.Stage III disease needs to be considered on an individualised basis but cytoreductive surgery with omentectomy may be an option. A retrospective report of patients with stage IIIc disease found benefit in surgical cytoreduction prior to adjuvant radiotherapy, 45% of patients had palpable nodes (Mariani et al, 2006; grade B recommendation).


10.6 Chemotherapy / progestogens and HRT Combination chemotherapy including a platinum based agent has been shown to have a substantial response rate (up to 60%; Lovecchio et al, 1984) in advanced disease but rarely provides a suitable option as drug combinations are toxic despite a progression free survival of around 15 months as overall survival is not obviously improved (Humber et al, 2007; grade A recommendation). Chemotherapy may have a role for papillary serous tumours and carboplatin and taxol appearing the most active. Anthracyclines such as doxorubicin or epirubicin may be considered as alternatives to taxanes and could precede pelvic radiotherapy or pelvic radiotherapy with para-aortic extension in node positive cases. Progesterone receptors may inhibit the stimulatory effect of oestrogens as mitogens in endometrial carcinoma. Hormonal therapy has a place in the management of recurrent disease particularly where


StandardsRadiotherapy should start 14 days after referral for radical treatment (good practice) although 28 days is acceptable (minimum standard).Radiotherapy should start 28 days after referral for adjuvant treatment (minimum standard).

JCCO/RCR guidance

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vaginal bleeding is distressing. Kelley and Baker (1961) first described a beneficial effect of progestogens in metastatic endometrial carcinoma. Although popular, further trials have not shown endocrine therapy to be effective as adjuvant treatment for primary disease (MacDonald et al, 1988; grade A recommendation). HRT does not appear to alter disease free survival and continuous combined therapy may be theoretically most appropriate for post operative patients with persistent climacteric symptoms using a low dose progestin (grade C recommendation). Cases should be managed on an individual basis and patients deserve a comprehensive explanation balancing any potential risks with benefits.

To refer for radical radiotherapy at YGC. Brachytherapy provided by the Christie Hospital in Manchester. Chemotherapy provided at all 3 North Wales Trusts.All cases must be discussed at the gynae cancer MDT to decide further treatment.

10.7 Uterine sarcomas/ carcinosarcomas Uterine sarcomas and carcinosarcomas (leiomyosarcomas, mixed Mullerian tumours and stromal sarcomas) are not discussed in detail. These are aggressive tumours which frequently metastasise and commonly present at an advanced stage. Low grade sarcomas are occasionally encountered but these generally have a propensity to recur locally. If disease is confined to the uterus then total abdominal hysterectomy and bilateral salpingo-oophorectomy is standard, usually combined with adjuvant pelvic radiotherapy. The role of bilateral pelvic lymphadenectomy is unclear for this group but may be offered to patients able to tolerate the longer surgical procedure. The outlook for these tumours as a whole is poor with an overall 5 year survival of 42% for endometrial stromal sarcomas, 34% for leiomyosarcomas and 33% for carcinosarcomas (Olah et al, 1992).

All cases must be discussed at the gynae cancer MDT to decide further treatment. Case discussion with the Royal Liverpool Hospital MDT should be considered.

11. Dealing with recurrent disease Up to 35% of patients with endometrial cancer will develop recurrent disease within 2 years. Fifty per cent of recurrent disease is local and usually at the vaginal vault. A central isolated post radiation recurrence can be dealt with exenterative surgery. Most of the remaining metastases occur in lung, liver or bone. Radiotherapy for isolated vault recurrence can be considered for patients who had not previously received radiotherapy with a 5 year survival of around 65% (Creutzberg et al, 2003; grade A recommendation). Extrapelvic recurrence must be excluded by CT scan prior to treatment.Medroxyprogesterone or megestrol should be considered although a modest response rate of 11-33% is more marked in well differentiated tumours and those with a prolonged time from treatment to recurrence (grade C recommendation). Goserelin may be an alternative particularly for those patients at risk of the cardiac side effects of high dose progestins. Tamoxifen does not appear to offer improvement in survival or overall quality of life (Quinn and Campbell, 1989). Localised symptomatic distant recurrences in bone or supraclavicular glands should be offered radiotherapy. Chemotherapy may be considered for other sites of recurrent disease in younger patients who are fit to tolerate treatment (grade A recommendation). Remissions are partial and improve survival by about 6 months. Platinum based combination chemotherapy gives a higher response rate than single agents but is more toxic (Aapro et al, 1994; Thigpen et al, 1993).


11.1 Palliative care (see palliative care file) The provision of palliative and supportive care for patients with gynaecological malignancies should be an integral part of service. The NICE guidance Improving Supportive and Palliative Care for Adults with Cancer was published in March 2004 and provides detailed recommendations which complement and inform this guidance (NICE, 2004).There is little robust evidence from the palliative care literature that is specific to patients with advanced gynaecological malignancies, therefore this guidance is based on evidence from studies looking at patients with a broad range of advanced malignancies.


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12. Survival Patients over 59 years of age at diagnosis may have poorer survival than younger patients (Frick et al., 1973) and may partly be explained by the increase of poorly differentiated adenocarcinomas, adenosquamous and clear cell adenocarcinomas in this age group.

Five year survival:

Stage I 77%Stage II 48%Stage III34%Stage IV 7%

Frick et al, (1973); Morrow et al, (1973); Berman et al, (1980); Kauppila et al, (1982); Connelly et al, (1982).Seventy four percent of patients present with stage I disease. Overall 5 year survival varies from66 - 77%.

12.1 Cancer dataset/ inventory of active trialsCaNISC data items to be developed.Active trials – Wales Cancer Bank

13. Follow up The value of clinical follow up is debatable. There is no evidence that an earlier detection of recurrence leads to an improved survival. However careful inspection and palpation of the vaginal vault and palpation for any pelvic masses should be performed 3 monthly for 2 years, 6 monthly for 1 year and then annually. Hospital follow up should be for 5 years. Vaginal vault cytology is not helpful.All patients must be encouraged to report any symptoms suggestive of recurrent disease immediately by contacting their CNS rather than wait until their next outpatient appointment. 13.1 Identification and management of late effects of treatment Pyschosexual, emotional, bowel, genitourinary, neuropraxia other problems may need detailed discussion with the clinical nurse specialist and psychological, lymphoedema, pain, spiritual and other support services.

14. Contact names/ numbers Simon Leeson Obstetrician and Gynaecologist YG (t 01248 384954); CNS Sr Liz Hall (t 01248 385003)Philip Toon Obstetrician and Gynaecologist NEWT (t 01978 725834)Nigel Bickerton Obstetrician and Gynaecologist YGC (t 01745 534655)


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15. Algorithm for postmenopausal bleeding

USC (see within 2 weeks of referral)

<5mm >5mm >5mm

Biopsy normal Biopsy inadequate

Biopsy normal

*other pathology excluded from this algorithm (such as atypical hyperplasia and endometrial polyps).

In the presence of recurrent bleeding hysteroscopy and biopsy is appropriate.


Postmenopausal bleeding

TV USSendometrial

thickness

Hysteroscopy/ Biopsy*

Endometrial Biopsy*

Discharge to GP

Endometrial carcinoma

Other carcinoma

MDTEndometrial carcinoma

algorithm (see 16)

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16. Algorithm Algorithm for management of patients with endometrial cancer

Stage I

<50% myo >50%myo G I/ II all G III/ all type 2

Stage II Diagnosed after surgery Diagnosed pre surgery

or unfit and fit

Stage III/IV

ERT = external beam radiotherapyMyo = myometrial infiltration


Pre-OpBiopsy

HysteroscopyMR scan/ CXR

MDT

Low risk or unfit TAH/BSO/washings/omental biopsy

High risk and fit TAH/BSO/washings/omental biopsy

pelvic lymphadenectomy

ERT ifG I/II >50% myo

G III or Type 2 – Ib or greater

ERT ifNode positive

Adjuvant vaginal brachytherapy/ pelvic ERT or

primary brachytherapy/ ERT

Radical hysterectomy/BSO/washings/omental biopsypelvic lymphadenectomy

ERT if node positive

ERT/ Surgical debulking and chemotherapy decided on case by case basis

Cancer Unit or Centre

Cancer Centre only

Consider laparoscopic or vaginal hysterectomy

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17. Summary

Pre-op assessment TVS - if postmenopausal for endometrial thickness/ assess adnexae Biopsy +/- hysteroscopy - if ET >5mm/ repeat referral Hb, U+E, liver function tests, consider 2 unit cross match chest X-ray MR scan abdomen/ pelvis

Surgery ‘Low risk’ endometrial cancer (stage I; well/ moderately

differentiated adenocarcinoma, <1/2 thickness myometrial invasion and no lymph node metastases on MR scanning) - TAH/BSO/washings/omental biopsy.

‘High risk’ endometrial cancer (stage I; poorly differentiated, adenosquamous, clear cell or serous papillary carcinoma, or well/ moderately differentiated >1/2 thickness myometrial invasion) - TAH/BSO/washings/omental biopsy/pelvic lymphadenectomy if patient suitable for prolonged surgery.

Consider laparoscopic or vaginal hysterectomy. Stage II disease - radical (Wertheim) hysterectomy/pelvic

lymphadenctomy. Post radiation isolated central pelvic recurrence - anterior/ posterior

exenteration. Isolated vaginal recurrence – consider surgical excision/radiotherapy.

Radiotherapy/ hormone therapy/ chemotherapy ERT - if had TAH/BSO: adjunct to well/mod differentiated if post

operative specimen reveals >1/2 myometrial invasion, all Ib tumours with poor differentiation, adenosquamous, clear cell or serous papillary histology. Adjunct to all ‘high risk’ lymph node positive patients. Additional brachytherapy considered on a case by case basis. Adjunct with brachytherapy for post operative stage II for patients not having radical hysterectomy and lymphadenectomy. Adjunct to all radical hysterectomy lymph node positive patients. Primary treatment for surgically unfit patients and stage III-IV disease.

Progestogen therapy - for recurrent disease (megace 160mg. od or provera 150mg. bd).

Chemotherapy – consider for stage III/ recurrent disease (consider carboplatin + taxol/ epirubicin).


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18. References

Aalders J, Abler V, Kolstad P et al. (1980) Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathological study of 540 patients. Obstet Gynecol, 56, 419-27.

Aapro M, Bolis G et al. (1994) An EORTC-GCCG randomised phase II trial of doxorubicin (DOX) versus dox-cisplatin (CDDP) in endometrial carcinoma (abstract). Proc Am Soc Clin Oncol, 13, 275.

Berman ML, Barlow SC, Lagasse LD et al. (1980) Prognosis and treatment of endometrial cancer. Am J Obstet Gynecol, 136, 679.

Chan JK, Cheung MK, Huh WK et al. (2006) Therapeutic role of lymph node resection in endometrioid corpus cancer. Cancer, 107, 1823-30.

Clark TJ, Barton PM, Coomarasamy A et al. (2006) Investigating postmenopausal bleeding for endometrial cancer: cost-effectiveness of initial diagnostic strategies. Br J Obstet Gynaecol, 113, 502-10.

Connelly PJ, Alberhashy RC, Christopherson WM (1982) Carcinoma of the endometrium III. Analysis of 865 cases of adenocarcinoma and adeno-acanthoma. Obstet Gynecol, 59, 569.

COSA-NZ-UK Endometrial cancer study groups. (1996) Pelvic lymphadenectomy in high risk endometrial cancer. Int J Gynecol Cancer, 6, 102-7.

Creasman WT, Boronow RC, Morrow CP et al. (1976) Adenocarcinoma of the endometrium: Its metastatic lymph node potential. Gynecol Oncol, 4, 239

Creasman W, Morrow C, Bundy B et al. (1987) Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group study. Cancer, 60, 2035-41.

Creutzberg CL, van Putten WL, Koper PC et al. (2000) Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Lancet; 35, 1404-11.

Creutzberg CL, van Putten WLJ, Koper PC et al. (2003) Survival after relapse in patients with endometrial cancer: results from a randomised trial. Gynecol Oncol; 89, 201-9.

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Frick HC II, Munnell EW, Richart RM et al. (1973) Carcinoma of the endometrium. Am J Obstet Gynecol, 115, 663.

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Kilgore C, Partridge EE, Alvarez RD et al. (1995) Adenocarcinoma of the endometrium:survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol, 56, 29-33.

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Olah KS, Dunn JA, Gee H. (1992) Leiomyosarcomas have a poorer prognosis than mixed mesodermal tumours when adjusting for known prognostic factors: the result of a retrospective study of 423 cases of uterine sarcoma. Br J Obstet Gynaecol, 99, 590-4.

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Quinn MS, Campbell JJ. (1989) Tamoxifen therapy in advanced/ recurrent endometrial carcinoma. Gynecol Oncol, 32, 1-3.

Thigpen, T, Blessing J et al. (1993) Phase III trial of doxorubicin +/- cisplatin in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group (GOG) study (abstract). Proc Am Soc Clin Oncol, 12, 261.

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Classification of evidence levels

Ia Evidence obtained from meta-analysis of randomised controlled trials

Ib Evidence obtained from at least one randomised controlled trial

IIa Evidence obtained from at least one well designed controlled study without randomisation

IIb Evidence obtained from at least one other type of well designed quasi-experimental study

III Evidence obtained from well designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies

IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities

Lower limit of acceptable evidence base is level IIa.

Grades of recommendation

A Requires at least 1 randomised controlled trial as part of a body ofliterature of overall good quality and consistency addressing the specific recommendation

B Requires the availability of well controlled clinical studies but no randomised clinical trials on the topic of recommendation

C Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality

Lower limit of acceptable grade of recommendation is B.


This guideline has been developed by the North Wales Cancer Centre Guideline Group

Simon Leeson Obstetrician and Gynaecologist (chair)Philip Toon Obstetrician and GynaecologistNigel Bickerton Obstetrician and Gynaecologist

endometrial carcinoma - nhs wales · web viewendometrial carcinoma index 1. clinical symptoms and...

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