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5. Management

5.1 Surgery

A. Primary Surgery (If the cancer appears to be confined to the uterus, i.e., clinical Stage I):

Preoperative Grade 1: Hysterectomy and bilateral salpingo-oophorectomy (HBSO*) by gynecologist

Preoperative Grade 2 or 3:  HBSO, possible lymph node sampling or nodal debulking by gynecologic oncologist

Preoperative Type 2 cancer (high grade serous, clear cell carcinoma, carcinosarcoma): HBSO, lymphadenectomy, omentectomy, peritoneal washings**, tumour debulking by gynecologic oncologist

* HBSO can be accomplished by laparotomy or minimally invasive approach (vaginal, laparoscopic assisted, total laparoscopic, robotic assisted).

** Status of washings is no longer considered part of FIGO staging, nor does it influence adjuvant treatment decisions for Type 1 (endometrioid) cancers.  However, it may still be useful in those with Type 2 cancers, which have atypical patterns of metastases (peritoneal washings may be positive in the absence of metastatic disease).

B. Delayed primary surgery (if surgery upfront is not possible):

Clinical Stage II (bulky cervical involvement)

Clinical Stage IIIC (with bulky/unresectable nodes)

Clinical Stage IV (metastatic disease on preoperative imaging, or bladder/bowel involvement)

These patients will receive chemotherapy +/- radiotherapy first, followed by repeat imaging and assessment by a gynecologic oncologist after the 2nd cycle of chemotherapy to determine response to treatment and suitability for delayed primary surgery.  If there has been a good response to treatment, surgery will usually be considered after the 3rd cycle of chemotherapy.  This will be followed by an additional 3 cycles of chemotherapy, with or without radiotherapy, to be determined by the multidisciplinary team. For details, see the "Adjuvant Therapy" section below.

Indications for referral to a Gynecologic Oncologist:

  1. preoperative grade 2 or 3
  2. preoperative high-risk histology (Type 2 cancers) including papillary serous, clear cell or carcinosarcoma
  3. clinically advanced stage endometrial cancer – clinical stage II and beyond

5.2 Adjuvant Therapy

5.2.1 Endometrioid Carcinomas

Risk Group

Number of Risk Factors*

Stage/grade

Risk of recurrence without adjuvant therapy

Low Risk

0

Stage IA, grade 1 or 2

3-5%

Intermediate Risk

1

Stage IA, grade 3 or Stage 1B, grade 1

10%

High Risk

2

Stage IB, grade 3

25%


high risk features include: deep myometrial invasion, grade 3 histology

Adjuvant pelvic radiation is offered to those whose disease appears to be confined to the pelvis (uterus, cervix, adnexae, pelvic nodes), but remain at risk for pelvic recurrence after surgery. Adjuvant vault radiation is offered to those whose disease appears to be confined to the uterus, but have at least one high-risk uterine factor (deep myometrial invasion, or Grade 3 tumour) that increases their risk for vault recurrence. 

Patients with LVSI (+) and low-risk and intermediate-risk disease are considered at high risk of recurrence and pelvic radiation is recommended.  Most of these recurrences in the absence of adjuvant therapy occur in the pelvis.  There is insufficient evidence that patients with low-risk or intermediate-risk disease with LVSI+ should receive chemotherapy. 

Patients with Stage I high-risk disease (deep myometrial invasion and grade 3 tumour) as well as Stage II disease are at high risk of locoregional as well as distant recurrence, regardless of their lymph node status (negative or unknown)1. They should be referred for consideration of chemotherapy and radiotherapy. For those with Stage I high-risk disease, the standard is 3 cycles of chemotherapy, followed by radiotherapy, and for those with Stage II (with at least one additional risk factor) or III (any) disease, the recommendation is 6 cycles of chemotherapy and radiotherapy in either a “sandwich” or “sequential” protocol3,4. The “sandwich” protocol consists of 3 cycles of chemotherapy, radiotherapy, then 3 more cycles of chemotherapy, and the “sequential” protocol includes 6 cycles of chemotherapy followed by radiotherapy. For those with Stage IIIC disease (node-positive), radiotherapy to the para-aortic nodes will be considered. The multidisciplinary team (medical and radiation oncology) should collectively determine the optimal protocol for each eligible patient.

Stage IVB. With upper abdominal disease present, the likelihood of distant recurrence is very high, in which case chemotherapy alone for 6 cycles is generally recommended. 

Adjuvant chemotherapy

Carboplatin/paclitaxel (GOENDCAT) is the recommended protocol based upon the superiority of taxane-platin containing regimens over platinum-anthracycline regimens and lower toxicity of carboplatin-paclitaxel compared to cisplatin/adriamycin/paclitaxel2. If a patient has intolerance to GOENDCAT, consideration should be given to another taxane-platinum regimen. Carboplatin/liposomal doxorubicin (GOOVPLDC) can be considered if there is a contraindication to all taxanes.

Table 1. Adjuvant therapy guidelines for endometrioid carcinomas:

 

 IA

 IB

 II**

 IIIA /B

IIIC^ IV***

 Grade 1

 O*

 V

 C, P, V C+P C+P C

 Grade 2 

 O*

 V

 C, P, V

 C+P

 C+P C

 Grade 3

 V

C+P

 C, P, V

 C+P

 
 C+P C

O=observation
V=vault brachytherapy
P=pelvic radiation
C=chemotherapy

* For Stage IA or IB recommend pelvic radiotherapy if there is LVSI (any extent).

** For Stage II, recommend chemotherapy if there is at least one additional high-risk uterine factor (deep myometrial invasion, or grade 3 tumour).

^ Pelvic radiotherapy will include extended field to cover para-aortic nodes if positive pelvic or para-aortic nodes.

*** Consider using hormones instead of chemotherapy as first-line therapy for stage IVB grade 1 tumours. Grade 1 tumours have a response rate up to 30% whereas it is around 10% for Grade 3. Treatment options include: Tamoxifen 20 mg po od, Letrozole 2.5 mg po od, Megace 160 mg po od, or Provera 200 mg po od. If hormone therapy fails, the next choice would be standard chemotherapy.


5.2.2 Non-Endometrioid Carcinomas

These cancers have an atypical pattern of metastatic spread.  Unlike endometrioid carcinomas, there can be extrauterine involvement even in the absence of myometrial invasion.  Non-endometrioid carcinomas are all considered high-risk, even when confined to the endometrium.  The only exception is if patients have undergone a complete surgical staging procedure and are proven to have no myometrial invasion.  These patients do not require any adjuvant therapy as their recurrence risk is less than 10%.  

For those who have undergone a full surgical staging procedure and have Stage I disease limited to less than 50% myometrial invasion, vault brachytherapy will suffice for local control, in additional to chemotherapy for distant control.  However, if there is deep myometrial invasion despite negative nodes (Stage IB), these patients are at high risk of pelvic recurrence and should receive pelvic radiotherapy, in addition to chemotherapy.  Although these patients have Stage I disease, they are considered high-risk and should receive 6 cycles of chemotherapy (with radiotherapy as per sandwich or sequential protocol). 

Table 2. Adjuvant therapy guidelines for non-endometrioid carcinomas:

IA M- IS M+ IB, II, III** IV***
Fully staged*ObservationC+VC+PC
Incompletely stagedRestaging, or C+PC+PC+PC

M–: no myometrial invasion; M+: myometrial invasion

* Fully staged includes complete lymphadenectomy, omentectomy, washings 

** Pelvic radiotherapy will include extended field to cover para-aortic nodes if positive pelvic or para-aortic nodes

5.2.3 Special Histologies

1.  Small Cell Carcinomas
     Rare tumour in endometrium. See cervix protocol (SMCC2)

References

  1. Kwon JS et al. Are uterine risk factors more important than nodal status in predicting survival in endometrial cancer? Obstet Gynecol 2009;114(4):736-43. 
  2. Fleming GF et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma:  a Gynecologic Oncology Group study. J Clin Oncol 2004;22(11):2159-66. 
  3. Hoskins PJ et al. Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a Phase II study.  J Clin Oncol 2001;19(20):4048-53. 
  4. Carey MS et al. Systematic review of systemic therapy for advanced or recurrent endometrial cancer. Gyn Oncol 2006;101(1):158-67. 

5.3 Recurrent Endometrial Cancer

Treatment of recurrent endometrial cancer will depend on sites of recurrence and primary treatment.

In the setting of isolated disease in the absence of previous adjuvant therapy, cure may be possible with radiotherapy or surgery for isolated vaginal vault or pelvic disease.  These patients should be referred to BC Cancer.

Radiotherapy is generally reserved for those with localized recurrences, while chemotherapy is offered to those with distant disease. Pelvic exenteration may be considered for those who recur within a radiated field, when the recurrence is localized to the central pelvis and there is no evidence of distant disease based on PET/CT.

5.4 Advanced Endometrial Cancer

In the upfront treatment setting, combination chemotherapy with carboplatin/taxane is recommended for 6 cycles (GOENDCAT or GOENDCAD), or carboplatin alone for patients who are not able to receive combination chemotherapy. In the event that the patient has an ongoing clinical response but not a complete response, treatment may continue to 9 cycles, or with carboplatin alone. 

Second line therapy may include doxorubicin (GOENDD) for 6 cycles.

Grade 1 (and possibly grade 2) histology or significant comorbidities precluding chemotherapy- consider hormonal therapy if tumour is ER or PR positive (GOENDAI or GOENDH).

Early initiation of palliative care/supportive care is recommended with or without chemotherapy. Overall prognosis is poor. Radiation therapy may be considered for symptomatic disease (e.g. pain, bleeding). 

5.5 Mismatch Repair

In the Vancouver Coastal Health Authority Region, all endometrial cancers are currently tested (universal testing) using immunohistochemistry (IHC) for 4 mismatch repair (MMR) proteins as a reflex screening test for Lynch Syndrome. In other health regions, the BC Cancer pathology department will perform MMR immunohistochemical analysis on patients with endometrial cancer as per clinician’s request. Approximately 20-25% of all endometrial cancers have abnormal MMR (deficiency of staining for one of the MMR proteins). Women with abnormal MMR should be referred for genetic counselling and testing through the Hereditary Cancer Program (HCP) at BC Cancer, regardless of age and family history1. Abnormal MMR does not necessarily mean that the patient has a germline mutation in the corresponding gene. However those with abnormal MSH2 or MSH6 on IHC have at least a 50% risk of having a mutation, and therefore having Lynch Syndrome. Those with abnormal MLH1 have about a 10% risk of having a mutation. The remaining 90% of those with abnormal MLH1 have a somatic phenomenon called hypermethylation of the MLH1 promoter, which is not associated with Lynch Syndrome2. Therefore, tumours with abnormal MLH1 should undergo further testing to determine if there is hypermethylation, and if unmethylated, this should prompt referral to HCP. Early data on improved response to immunotherapy (PD-L1 blockade) suggests that patients with MMR deficiency should be considered for enrolment into a clinical trial. The tumour group recommends MMR reflex testing on all endometrial cancers, irrespective of age at diagnosis.

Referral to the Hereditary Cancer Program at BC Cancer for genetic testing is important for these women even though they have already had endometrial cancer because:
  1. they are still at risk for colorectal cancer, and therefore they can undergo more frequent screening to prevent this cancer;
  2. they may have unaffected first degree relatives who could benefit from this information, and undergo risk-reducing interventions to prevent endometrial and colorectal cancers. 
Screening for MMR may become routine for all endometrial cancers in British Columbia in the near future. At the present time, any woman diagnosed with endometrial cancer under the age of 50 in British Columbia is eligible for MMR IHC, but a direct request for testing must be submitted to BC Cancer.

References

  1. Kwon JS et al. Testing women with endometrial cancer to detect Lynch Syndrome. J Clin Oncol 2011;29(16):2247-52.  
  2. Buchanan DD et al. Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing. J Clin Oncol 2014;32(2):90-100.

5.6 Estrogen Replacement Therapy

Endometrial tumours that develop on estrogen replacement therapy tend to be well differentiated and minimally invasive, and therefore these women generally have a good prognosis.  However, the known association between estrogen and endometrial cancer causes concern when women with a history of endometrial carcinoma request hormone replacement. 

Many of these patients are asymptomatic. There is a small proportion of patients (usually premenopausal) who suffer from extreme vasomotor symptoms. Unfortunately, there are limited non-hormonal alternatives to estrogen, such as clonidine or venlafaxine.

For premenopausal women, thorough discussion of the risks and benefits of estrogen replacement is essential. . The absence of hormone replacement therapy in young women who have surgery including bilateral salpingo-oophorectomy before age 50 is known to be associated with an increased risk of death secondary to coronary heart disease, osteoporosis, thromboembolic events, and cancers such as lung and colorectal cancer1. There is no evidence that estrogen replacement therapy use alters the prognosis in women who have had treatment for endometrial cancer2.

References

  1. Parker WH et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol 2013;121(4):709-16.  
  2. Barakat RR et al. Randomized double-blind trial of estrogen replacement therapy versus placebo in Stage I or II endometrial cancer:  A Gynecologic Oncology Group study J Clin Oncol 2006;1;24(4):587-92. 

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