Endometrial cancer

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1.  Background
Endometrial cancer is now the second most common gynaecological malignancy in the UK. Over 5,000 cases 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. The mortality associated with endometrial cancer is 30%, considerably less than for cervical or ovarian cancers. This simply reflects the early presentation of disease since 75% of patients present with disease that is apparently confined to the uterus (stage 1). Indeed stage related survival figures are, if anything, worse than for the other main gynaecological tumours. 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.

Historically, patients with endometrial carcinoma were treated with radiotherapy and consequently the prognostic factors which might be revealed by histopathological examination were obliterated. This was reflected in the FIGO staging which was used from 1971-1989. This system used factors such as uterine cavity length, tumour grade and spread determined by clinical examination, to determine stage and prognosis. Using this system, 75% of patients were assigned to stage 1 but their 5 year survival varied from 51% -89%.

The appreciation that this system failed to distinguish between women with vastly different prognoses, and that extra‑uterine disease was far commoner than suggested by clinical examination alone, accompanied the increasing use of surgery as a primary therapeutic modality. The FIGO staging system was therefore redesigned in 1989 to account for changes in both understanding of the disease and its treatment.

2.  Diagnosis
As the majority of cases present with a number of well recognised symptoms, prompt referral and an early out‑patient appointment are of importance as outlined in the NHS Cancer Plan and Department of Health waiting time targets.  These symptoms include:
  • Post‑menopausal bleeding                                                      see within 2 weeks
  • Abnormal smear suggestive of endometrial cancer                        see within 2 weeks ideally in                                                                                                         Colposcopy
  • Irregular bleeding on HRT                                                       see within 6 weeks
  • Irregular perimenopausal bleeding                                        see within 6 weeks
  • Post-menopausal discharge                                                    see within 2 weeks
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
  • adverse histological types (clear cell and UPSC)
  • anything more than Stage 1
  • when the Unit lead is unhappy about risk factors it is also appropriate these patients are referred to the Centre
4.  Staging
The method of staging favoured in this country is that introduced by FIGO in 1989 which is outlined below.  Equivalent TNM classification is available.

Stage la                                   Tumour limited to the endometrium
Stage Ib                                   Invasion of < 1/2 myometrium
Stage lc                                   Invasion of > 1/2 myometrium
Stage 2a                                 Endocervical glandular involvement only
Stage 2b                                 Cervical stromal invasion
Stage 3a                                 Tumour invades serosa and/or adnexae and/or positive
                                                 peritoneal washings
Stage 3b                                 Vaginal metastases
Stage 3c                                  Metastases to pelvic and/or para‑aortic lymph nodes
Stage 4a                                 Tumour invasion of bladder or bowel mucosa
Stage 4b                         Distant metastases including intra‑abdominal disease and/or inguinal node metastases
5.  Prognostic Factors
There is a close correlation between different prognostic factors so that it is not uncommon for a patient to have a number of adverse prognostic indicators. Similarly it is possible for a patient to have a mixture of good and bad prognostic factors and hence the allocation of an overall risk factor is not necessarily straightforward. In an attempt to clarify this situation the Gynecologic Oncology Group (GOG) has recently published data on the univariate and multivariate analysis of prognostic factors in 819 patients with clinical stage 1&2 disease[1]. Using the two methods of analysis a proportional hazards model was developed which predicts the relative risk of death from cancer. The results are summarised below and an overall risk factor can be developed for a patient from the product of each individual risk factor. The effect of increasing numbers of adverse risk factors has been confirmed by Kadar et al who showed that five year survival for patients with more than 2 of these risk factors was 17% compared with 66% for those with two and 95% for those with no or only one risk factor[2].
6.  Effect of individual prognostic factors on relative risk to survival
Prognostic factor                                                                Relative risk
Endometrioid histology        Grade 1                                           1.0
                                                 Grade 2                                           1.6
                                                 Grade 3                                           2.6
Serous histology                   Grade 1                                           2.9
                                                 Grade 2                                           4.4
                                                 Grade3                                            6.6
Myometrial penetration        endometrium only                         1.0
                                                 inner 1/3                                          1.2
                                                 inner 2/3                                          1.6
                                                 outer 1/3                                          3.0
Positive washings                                                                          3.0
Age                                          45 years                                          1.0
                                                 65 years                                          3.4
Lymphovascular space involvement                                          1.5
7.  Pre-operative assessment
Since treatment options vary enormously, careful pre‑operative and intra-operative evaluation is necessary in order to correctly determine the appropriate management. Pre-operative information can be gained from the following sources:

7.1)     Histological examination of the specimen obtained for diagnostic purposes.
It should be noted that undue emphasis should not be placed upon this since interpretation of endometrial curettage specimens is notoriously unreliable in the assessment of tumour grade and histological type. It is particularly important to note that a diagnosis of atypical hyperplasia based on a sampling technique may none the less be associated with invasive endometrial cancer in 20% or more of cases.

In some circumstances it may be appropriate to perform fractional currettage in order to assist in distinguishing an endometrial tumour from one of endocervical origin.

7.2)     Pre-operative examination either in the out-patient clinic or possibly as a formal EUA +/- hysteroscopy.
This may provide additional information relating to the site and stage of disease.

7.3)     Imaging studies
We do not consider the routine use of investigations such as MRI or CT justified at present although they may clearly be of use in the assessment of  cases of clinically advanced disease or poor prognosis variants such as uterine papillary serous carcinoma.  

Pre‑operative investigations should include
                         FBC, urea & electrolytes and LFTs
                         Blood group and save
                         Chest X‑ray
8.  Treatment
8.1)     Surgery
Where surgery is indicated as the appropriate treatment and the patient is considered fit for the procedure it should take place 31 days from decision to treat.

8.2)     Choice of Incision
Traditionally, surgery for uterine cancer has been carried out abdominally, using 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 patioent with a pendulous, obese abdomen.

More recently, laparoscopically assisted vaginal hysterectomy and oophorectomy has become increasingly popular on account of more rapid recovery time without compromise of effective surgical staging or tumour excision. It is becoming increasingly regarded as the approach of choice.

In unfit patients where there are concerns that any surgical trauma to the abdominal wall may significantly increase the risk of serious complications, vaginal hysterectomy alone is a reasonable alternative with acceptable results.[3]

8.3)     Stage 1
Surgery is the preferred treatment modality and should include the following: a) thorough assessment of the abdominal cavity b) peritoneal washings for cytology c) selective pelvic and para-aortic lymph node sampling may be appropriate d) total abdominal hysterectomy and bilateral salpingo-oophorectomy.  There are no plans to introduce routine systematic lymphadenectomy unless the final published results of the  ASTEC Trial recommend otherwise.

The incidence of lymph node involvement in stage one disease is approximately 10%. The role of lymph node sampling or lymphadenectomy remains unclear.

8.4)     Stage 2
If pre-operative diagnosis is Stage 2 surgery is the preferred treatment option.  It is recognised that the majority of Stage 2 are diagnosed post-operatively.  See radiotherapy below. 
Surgery if undertaken for patients with clinical involvement of the cervix should include:
a)    laparotomy via midline incision
b)    peritoneal washings for cytology
c)         radical extended hysterectomy and bilateral salpingo-oophorectomy
d)         pelvic +/- 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. 

8.5)     Stage 3 and 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. 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'. 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. This aggressive surgical approach for patients with advanced disease is also supported by the GOG 122 study( reference)[4].
9.  Radiotherapy
There are controversies regarding the management of all stages of endometrial cancer. There are now three randomised studies of post-operative radiotherapy in early endometrial cancer1,2,[5]. The ASTEC study has been published in abstract and Portec-3 is due to be introduced  imminently.

9.1)     Stage I disease
9.1.1   Low risk patients
Patients with a low risk of recurrence do not receive postoperative radiotherapy (XRT). These include those patients who after TAH/BSO have:
        Grade1/grade2 (G1/G2) tumours with less than 50% myometrial invasion (stage 1A or 1B)
 (2)       Grade 3 (G3) tumours limited to the endometrium (stage 1A)

9.1.2   Moderate to High Risk Patients
These include all other patients. Three randomised trials have shown that while radiotherapy reduces the risk of pelvic relapse, it does not significantly affect overall survival1,2,5. In subset analysis of one of these studies (Aalders) there was a survival advantage for radiotherapy in patients with G3 disease and deep myometrial invasion (Stage 1C). In the other two studies (GOG 99 /PORTEC) very few patients with G3/1C disease were included1,2. It may be that radiotherapy offers an advantage to this subgroup of patients.

The options for these higher risk patients are
(1)          postoperative XRT or
(2)       observation with radiotherapy for pelvic relapse

Treatment decisions are made on an individual basis taking patient preferences and comorbid conditions into consideration. Radiotherapy is associated with a small risk of major bowel/bladder morbidity in addition to long term minor toxicity. The rationale for offering observation with radiotherapy for relapse is that vault recurrence can be salvaged with radiotherapy in a high proportion of cases[6].
9.2)     Stage II Disease
There is much less data for stage II disease compared with stage I. These patients have a higher risk of involvement of pelvic nodes and a higher risk for failure[7]Studies tend to be small retrospective series where patients received adjuvant radiotherapy.  Some patients with stage II disease may be overstaged as a result of cervical implantation after currettage.

If there is only focal involvement of the cervix and otherwise the patient falls into a low risk group observation is an option. In general all other patients are offered postoperative radiotherapy.

9.2.1   Trials in progress in stage I and II disease
The PORTEC-3 trial is a randomised phase III trial comparing concurrent chemoradiotherapy and adjuvant chemotherapy with pelvic radiotherapy alone in high risk and advanced stage endometrial cancer following hysterectomy.  It is an international collaboration led by the Dutch Cooperative Gynaecologic Oncology Group and hopes to recruit 500 patients over 5 years.
The primary objective of this study is to establish overall survival and failure-free survival where failure is defined as relapse or death due to endometrial cancer or due to treatment complications.
The secondary objectives are to establish and compare the rates of treatment-related toxicity, quality of life and pelvic and distance recurrence.
Patients randomised  to receive the experimental arm of the trial,  will have cisplatin on day 1 and 22 of radiotherapy and the external radiotherapy dose will be 48.6Gy in 27#.  Then 4 cycles of adjuvant chemotherapy with carboplatin and paclitaxel every 3 weeks.  A brachytherapy boost is given if there is cervical involvement.
9.3)     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, to the pelvis and para-aortic region, whole abdominal radiotherapy (WAR), intraperitoneal P32, progestogens or chemotherapy[8]. The impact of these treatments on outcome is not clear, much of the evidence coming from small single arm studies.

9.3.1   Stage IIIa
Patients with serosal/adnexal involvement generally receive post operative radiotherapy.  The significance of malignant peritoneal cytology is unclear. It is usually associated with other risk factors for recurrence such as deep myoinvasion or G3[9]. If there are no associated high risk factors, observation is an option.

9.3.2   Stage IIIb disease
This is uncommon. Patients generally receive postoperative radiotherapy to the pelvis + vault brachytherapy.

9.3.3   Stage IIIc disease
Postoperative radiotherapy to the pelvis is generally used for patients with involved pelvic nodes.  Extended field radiotherapy treating the para-aortic nodes can be considered for fit patients with:

Common iliac positive pelvic nodes as these have a high risk of paraaortic nodal involvement5Microscopically positive para-aortic nodes.In these groups of patients small series have reported long term survival of approximately 50% with extended field radiotherapy5,[10],[11].

If patient has had a radical hysterectomy, radiotherapy is considered if more than one pelvic node is involved.

The management of patients with bulky nodes is unclear.  General opinion is that if  there is a single bulky node resection + postoperative radiotherapy can be considered. Patients who have multiple bulky nodes have incurable disease and treatment is palliative. In this situation treatment modalities may include radiation/hormones and chemotherapy.

9.4)     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.

9.4.1   Stage IVa 
Treatment is generally palliative. Occasional patients may be suitable for radical approach either in the form of radiotherapy or surgery.

9.4.2   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.

9.5)     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%[12],[13].

9.5.1  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[14]. Of patients who recur 50% appear to do so in the upper abdomen[15].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/Doxarubicin[16].

Treatment options include
        Observation for 1a disease following TAH/BSO
        Pelvic radiotherapy for stages 1 and II disease. Chemotherapy considered in selected cases.
        Cisplatin/Doxarubicin chemotherapy for patients with Stages 3 & 4 disease who       have been surgically debulked with radiotherapy afterwrards.
        Randomisation to Portec-3 in due course.

9.6)     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 CCO showed 5 year disease specific survival to be 70% in patients with stage I/II disease and 33% in stage III/IV disease[17]. However 5 year overall survival rates in these patients are generally only 30 –50% as a consequence of their medical problems.

9.7)     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 vaginaError! Bookmark not defined.,17. Salvage of these cases is more usual when disease involves the vaginaError! Bookmark not defined.,17.

Treatment options depend on previous radiotherapy
(1) If no previous radiotherapy:
Radical radiotherapy with external beam and intracavity treatment

(2) If previously irradiated treatment is generally palliative and dosimetry limited.
There may be scope for further external beam or intracavity treatment.

9.8)     Adjuvant Vault Brachytherapy
At CCO, adjuvant vault brachytherapy is given to all suitable patients at the end of external beam radiotherapy.  This consists of a single vault treatment.
There are no completed randomised trials addressing the role of vault brachytherapy alone in endometrial cancer.  However, the PORTEC-2 trial, which is ongoing, randomises patients with “high-intermediate risk” disease to pelvic radiotherapy and vaginal brachytherapy.
Selective intermediate risk patients patients may be offered vault brachytherapy  alone, which consists of 3 treatments over a period of 2 to 3 weeks.
10.  Hormonal therapy
Available evidence does not show there is a role for the use of hormones in early stage disease.  De Palo in a multi-centre randomised trial[18] suggested that hormonal treatment does not improve survival whilst Quinn found a 5-6% survival advantage in higher risk groups based on differentiation, tumour type and myometrial invasion[19]. Meta-analysis of published trials demonstrated that overall survival may be adversely affected[20]. 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[21],[22]. 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. The situation in advanced or recurrent disease is different however since up to 30% of patients may respond to hormonal therapy22. 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 benefit and may possibly enhance survival. The particular agent used does not affect the response rates.

We recommend         Provera (medroxyprogesterone acetate)  100mg tid.
                                     Megace (megestrol acetate)   160mg od.
                                     There is interest developing in the use of aromatase inhibitors.

11.  Chemotherapy
Adjuvant                    There may be a role for adjuvant chemotherapy in selected                                       patients[23],[24]
Advanced disease   Chemotherapy can be considered in patients with advanced                                                disease
                                    Patients are suitable if creatinine clearance is>50ml/min and                                    performance status 1 or 2.
Agents and doses:                                                   Cisplatin       60mg /m2
                                                                                    Adriamycin    40mg /m2
                                                                                    Cycle time 21--8 days for 4-6 cycles
                                                                                    Delay treatment if ANC = <1.5

Expected response rate = 34%24

Updated data has been published supporting the use of cisplatin and adriamycin[25]. A further randomised comparison has been published by Fleming et al in 2004 comparing Cisplatin, adriamycin and paclitaxel with the standard AC combination[26]. Whilst this shows an 8.3 month survival gain, in view of the grade 3 and 4 myelopsuppression  this 3 drug combination is not recommended as standard. 
12.  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 palliative care guideline 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 or carer.

The skills of the C.N.S. as a consultant, practitioner and educator can be drawn upon at all stages throughout their illness, from the pre-diagnosis to the terminal stage – incorporating the Specialist Palliative Care Services provided in the hospital and the community setting. Bereavement Support will also be available, if appropriate.

Important aspects of the role are to provide advice, support, information and to effectively incorporate appropriate resources. The C.N.S. will be receptive to the social, physical, psychological, cultural, sexual and spiritual needs of the patient. The aim of the patient support is to assist with the improvement in the quality of their lives, allowing them to become more empowered; to help take control and enhance their self esteem.

The C.N.S. works closely with Surgeons, Oncologists, Radiotherapists, Consultants in Palliative Medicine and others (Nurses & P.A.M.s).

They 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 carer and other H.C.P.s
Liaison point for other health care professionals in primary and secondary care
Teacher and Educator
Standards and Audit Co-ordinator
Co-ordinate Care Services
13.  Follow-up
Atypical hyperplasia is cured by hyterectomy, and patients with stage 1a disease have a very low risk of relapse. They may therefore be discharged with open appointment in the event of new symptoms or concerns.

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.
14.  Hormone Replacement
The question as to whether hormone replacement therapy may be prescribed is a matter of some debate. Endometrial cancer is considered to be an oestrogen-dependent cancer and hence traditional thinking has been that oestrogen replacement therapy is contraindicated. However there is no published data to support this argument. On the contrary there are a growing number of reports which suggest that not only is oestrogen replacement therapy' safe [27],[28] in these circumstances but that survival may be enhanced by its prescriptions.
15.  Clinical Trials
The centre is currently planning to participate in the Portec-3 trial, investigating whether adjuvant chemoradiation is superior to radiation alone.

Appendix 1 Radiotherapy for Endometrial carcinoma
  1. 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.
  1. 2.            Radical radiotherapy
  2. 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#.
  1. For obese patients with early stage disease, can be treated with brachytherapy alone, dose 7Gy in 5#.

  1. 3.             Whole abdominal radiotherapy
This treatment is not used at Clatterbridge Centre for Oncology.
  1. 4.             Treatment of pelvic recurrence
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.
  1. 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.
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Posted on กรกฎาคม 3, 2013, in บทความ. Bookmark the permalink. ใส่ความเห็น.


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