Management of carcinoma of the uterus, including carcinosarcoma, varies considerably with stage as well as grade.
Endometroid Adenocarcinoma
Suspected local disease (IIIA or less)
Primary Surgery
The best primary treatment is surgery. The extent of surgery is controversial; American groups (including FIGO, the Gynaecological Oncology Group (GOG) and the American College of Obstetricians and Gynecologists (ACOG)) recommend total hysterectomy, bilateral salpingo-oophrectomy and excision of lymphatic tissue from the inferior mesenteric artery into the pelvis (including external / internal iliac nodes). If there is evidence of cervical involvement, then a radical hysterectomy is performed instead of total hysterectomy.
Outside the USA, lymphadenectomy is controversial. Some gynaecological oncologists perform lymph node sampling instead of dissection if there is evidence of low risk disease (stage IA, grade 1 or 2, endometriod); some clinicians perform no lymph node sampling or dissection. The extent of sampling and dissection should be pelvic and para-aortic nodes, as para-aortic nodal metastases can occur without pelvic lymphadenopathy (eg. through ovarian lymphatics).
The ASTEC study found no survival benefit in women who received lymph node dissection vs no dissection in stage I patients. In general, full dissection is performed more frequently when there is stage IB disease or high risk disease (serous/papillary types).
Avoidance of Surgery
Fertility Preservation
Fertility is impossible after standard surgery. Patients with stage IA Grade 1 endometrioid adenocarcinoma may be treated with high dose progestin therapy. Patients undergoing this therapy require 3 monthly endometrial sampling (D&C). There is a complete response in 78% of patients at 6 months but 25% of patients will progress within 2 years. About 25% of patients will be able to carry a pregnancy.
Primary Radiotherapy
In patients who are inoperable due to medical comorbidities, radiotherapy to the uterus can be considered. This usually combines external beam and brachytherapy.
Adjuvant Therapy
Adjuvant therapy depends significantly on stage and risk.
- Low risk
- Low intermediate risk
- High intermediate risk
- High Risk
Early Stage, Low Grade (Stage IA, Grade 1, No adverse features)
This group requires observation only.
Early Stage, High Grade (Stage IB or Grade 2+ or Adverse features)
This is a controversial group. There is evidence that radiotherapy improves local control but has limited effect on disease specific or overall survival. The presence of other adverse risk factors can help to decide - lymphovascular invasion, patient age and tumour size.
In general:
- Vaginal vault brachytherapy has similar outcomes to pelvic radiotherapy.
- Pelvic radiotherapy is not normally recommended
- Systemic therapy is not normally recommended
- The notable exception is Stage IB Grade 3 disease where some departments offer pelvic RT - this is due to the PORTEC 1 study which demonstrated that a high recurrence risk and poor overall survival rate (58%); this group is also targeted with adjuvant chemotherapy.
Chemotherapy
There are few randomised trials, although PORTEC 3 and GOG 249 are pending
Three randomised trials:
Italian study and Japanese study using old chemotherapy techniques showed radiotherapy and chemotherapy had equivalent survival when used alone
GOG 122 included patients with stage III or IV disease, 14% with macroscopic disease remaining. Patients received whole abdominal radiotherapy + boost vs systemic therapy. This trial led to the reduction in the use of radiotherapy for advanced stage endometrial cancer.
- Toxicity was greater with chemotherapy
- Systemic treatment (doxorubicin + cisplatin) not effective for serous carcinoma
Sequential chemotherapy and radiotherapy
Four randomised studies demonstrate no benefit in survival with addition of sequential chemotherapy. These studies did not include taxane therapy and had poor accrual with non-significant results. Pooled analysis of more recent studies (still mostly lacking taxane therapy) demonstrated a trend towards improved outcomes with systemic therapy.
GOG 184 is evaluated the benefit of doxorubicin + cisplatin (AP) vs doxorubicin, cisplatin and a taxane (TAP). Toxicity was significantly greater in the combined arm.
GOG 249 is evaluating whole pelvic RT vs vaginal vault brachytherpay + chemotherapy.
PORTEC-3 is accruing patients to compare concurrent chemoRT + adjuvant RT in high risk patients with localised disease.
Stage II disease
Stage II disease includes patients with involvement of the cervix. These patients are at risk of vaginal and nodal recurrence. An appropriate strategy would be pelvic radiotherapy with vaginal vault boost (34 Gy / 8.5 Gy fractions). Grade 3 disease also warrants consideration of systemic therapy.
Stage IIIA
Invasion into the adenxal structures requires whole pelvic radiotherapy. Adjuvant systemic therapy is also routine regardless of stage.
Advanced Stages
Occasionally the tumour may be more advanced than predicted by imaging. If surgery has taken place, further management depends on the actual stage:
Systemic chemotherapy is indicated in almost all cases of Stage IIIB+ disease.
Stage IIIB disease - If there is involvement of vagina then whole pelvic radiotherapy with brachytherapy boost is indicated.
Stage IIIC disease should have maximal lymphadenectomy followed by radiotherapy to nodal regions.
Stage IVA disease, with invasion of adjacent pelvic organs, should be maximally debulked and radiotherapy delivered to the pelvis.
Suspected Locally Advanced Disease (IIIB, IIIC, IVA)
Patients who present with clinical involvement of regional nodes, the bladder or bowel have a very poor prognosis. Radiotherapy alone results in poor control (90% of patients have pelvic relapse) and poor survival. The best outcomes are seen in patients who receive combined surgical exenteration or debulking and post-operative radiotherapy although large series are lacking.
Metastatic Disease (IVB)
Patients with metastatic disease may still consider a palliative hysterectomy/oophrectomy to reduce symptoms and oestrogen levels. If unoperable, radiotherapy (either external beam or brachtherapy) can significantly reduce symptoms of bleeding and odour. Systemic therapy remains the only possibility to slow progression of disease. Paclitaxel has been evaluated combined with cisplatin compared to paclitaxel, doxorubicin and cisplatin and may be the new standard of care.
Clear Cell or Serous Adenocarcinoma (Type II)
These patients have a poor outcome with surgery alone and adjuvant therapy is normally used. Surgical management is identical to endometriod adenocarcinoma. Regardless of stage, radiotherapy to the pelvis is normally used, with vaginal vault brachytherapy boost. Systemic chemotherapy generally follows, usually with doxorubicin and cisplatin.
Carcinosarcoma
Management of this high risk disease mirrors that of Clear Cell or Serous Adenocarcinomas, with the exception of systemic chemotherapy choices. Ifosfamide and paclitaxel have been shown to perform better in the treatment of carcinosarcoma.
