Epidemiology:
Endometrical cancer is the most common gynecological malignany and the fourth most common cancer in women. The incident rate is about 25 cases per 100,000 women in the United States. The United states has the highest incident rate in the world. Europe has an incident rate of approximately 15 to 20 cases per 100,000 women. Endometrial cancer is typically a cancer of postmenopausal women ( about 75% of all cases 1) between the age of 55 to 85 years old. Less than 5% of the patients are younger than 40 years old. 2
Etiology:
-The cause of endometrial cancers is related to exposure of the endometrium to unopposed estrogens. Early menarche, late menopause, obesity, nulliparity, infertility, and estrogen inducing ovarian tumors are associated with the development of endometrial cancers. 2
-Hypertension and diabetes have been associated with endometrial cancers but it is not clear if they are independant risk factors or associated with obesity.2
-The use of tamoxifen for the prevention and treatment of breast cancer statistically increases the risk of endometrial cancer.2
-Patients with endometrial biopsies confirming hyperplasia with atypia have a 30 to 40% risk of later developing endometrial cancer.
2
-There is an increased risk associated with family history of the disease, especially in women younger than 50 years old. Only 1% of all endometrial cancers have been attributed to familial and genetic factors. 2
-"Women with mutations on the MHL1 and MLH2 genes are at an increased risk for developing endometrial cancer.
2 "
-"Women with Lynch syndrome II have a 20% risk of developing endometrial cancer before age 50, which increases to 60% by age 60.
2"
Signs & Symptoms:
-The most common presenting symptom is vaginal bleeding, which is reported by 70% to 80% of patients.
-Back pain and pressure symptoms caused by the enlarged uterus on bowel and bladder may occur.
-Physical finding are usually minimal; blood in the vagina emanating from the cervical os is the most common finding. 1

Diagnostic Procedures:
- No satisfactory screening method is available for detecting endometrial carcinoma in symptomatic patients.
- The papanicolaou smear detects only approximately 40% of endometrial tumors.
- Endometrial biopsy or aspiration curettage is indicated in postmenopausal women with vaginal bleeding or perimenopausal women with menstrual abnormalities, and obviates in most cases the need for dilation and curettage.
- Fractional dilation and curettage and cervical biopsy are indicated when there is a high degree of suspicion of cancer and diagnosis cannot be made by endometrial biopsy or aspiration curettage.
-Diagnostic studies routinely used in the clinical staging of patients with endometrial cancer vary with stage.
- Computed tomography of the pelvis and abdomen is recommended for all patients with high-grade tumors or with stage II or higher disease to detect possible nodal or extrauterine spread of cancer.
- MRI is not helpful in detecting nodal or peritoneal spread; however, it is useful in demonstrating the depth of myometrial invasion, with an accuracy of approximately 80%.

Diagnostic workup for endometrial cancer

ALL STAGES
Histroy
Physical examination, including pelvic examination
Endometrial biopsy or aspiration curettage
Fractional dilation and curettage (if biopsy or aspiration does not reveal cancer)
Chest radiograph
Cervical biopsy
Urinary imaging study in all patients before surgery (IVP, ultrasound, CT)
Complete blood cell count, urinalysis, blood chemistry

ADVANCED DISEASE OR IF SYSTEMS WARRANT
Cystoscopy
Sigmoidoscopy
CT scan or MRI
IVP
Barium enema 1

Histology:
Endometrioid adenocarinomas are the most common form and make up about 75% to 80% of all cases. This type can be further broken down in to papillary, secretory, ciliated, and adenocarcinoma with squamous differentiation. Secretory carcinomas account for only about 2% of endometrial carcinomas and are most commonly well differentiated and have a good clinical outcome. Ciliated carcinomas are uncommon as well and also have a good prognosis. They are often associated with prior estrogen use. "The most aggressive cancers arising from the endometrial lining include serous carcinomas, clear cell carcinomas, and pure squamous carcinomas. Serous and clear cell tumors tend to occur in older women. Serous carcinomas represent less than 10% of endometrial carcinomas, and clear cell tumors account for less than 4%. Serous tumors are frequently associated with peritoneal spread at the time of initial diagnosis."5

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Figure 2. Tumor classification for endometrium proposed by the International Society of Gynecologic Pathologists.5
Lymph Node Drainage:
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Figure 3. Lymph node drainage of the pelvis.
4

"Lymphatic drainage includes the inguinal lymph nodes (external and internal), pelvic nodes (the internal iliac chain, which originates approximately with the obturator node, and external iliac chain), and peri-aortic nodes. The deep inguinals drain into the external iliac chain, and the internal and external iliac chains join and then drain into the peri-aortics."
4
Metastatic Spread:
Endometrial tumors commonly spready into contiguous areas. Direct extension may include the cervix, vagina, parametrial tissue, bladder, or rectum. The ovaries may become involved by transtubal seeding or vascular metastasis. Peritoneal seeding is more common with endometrial cancer than with cervical cancer because endometral tumors can penetrate the uterine wall or seed transtubally. This is most common with papillary serous or clear cell histologies. "Uterine sarcomas metastasize frequently by hematogenous routes; metastases to the lung develop in 50% to 80% at some time during the clinical course. The incidence of pelvic lympn node involvement is also high, with estimates ranging from 25% to 50% at time of presentation."5
Grading:
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Table provided by American Cancer Society. 7
Staging:
The International Federation of Gynecology and Obstetrics staging system is used for carcinoma of endometrial cancer see figure 1.1 . FIGO staging system is based on surgical-pathologic findings ( see figure 1.2 below). 3

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Figure 1.1 Staging of carcinoma of endometrial cancer 3

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Figure 1.2 Anatomic staging for endometrial carcinoma 3

Radiation Side Effects:
Diarrhea , bleeding, urgency and pain are acute symptoms that can occur at 30 -40 Gy. A dose of 4-5 Gy to the ovary, produces a permanent cessation of menses in most young women and 100% of women older than 50. 4 If the whole bladder is treated , acute cystitis can occur at doses of 30Gy. Acute erythema and desquamation can occur in the vulva and perineum areas at doses above 40 Gy. The uterus and cervix can tolerate high doses of radiation therapy. Brachytherapy can deliver extremely high doses without necrosis. Late complications include: chronic cystitis( 6 mths post tx at doses above 50-60Gy), Contracture/ hemorrhagic cystitis( dose above 65Gy), and bowel obstruction ( at doses above 45Gy). 4
Prognosis:
-"Comprehensive retrospective analyses and prospective, randomized studies have established major prognostic factors for survival and relapse to be: Stage, Patient age, Histological cell type, Tumor grade, Depth of myometrial invasion, and prescence of lymphvascular space invasion. 2"
-The age at diagnosis is an important factor. Older patients have a higher chance of myometrial involvement, advance stage and a lower 5 year survival.
1
-"The most significant prognostic factor is clinical or pathologic stage. 1"
-In most studies, depth of myometrial invasion had a less strong prognostic value than tumor grade.
2
-Depth of invasion into the outer third of the myometrial wall has been associated with an increased risk of relapse.2
-Lymphovascular invasion is a major prognostic factor that significantly and independantly increases the risk of relapse ( especially distant relapse). 2
Treatments:
Operable Stage I Endometrial Carcinoma

  • Total abdominal hysterectomy and bilateral salpingo-oophorectomy is the basic treatment for all patients with stage I endometrial carcinoma.
  • In all but grade I lesions, it is recommended that pelvic and periaortic lymph node sampling be performed at the time of surgical exploration. The incidence of nodal involvement in stage I patients with grade I histology is too low to make routine sampling of lymph nodes worthwhile.
  • Peritoneal washings are recommended for all patients at time of surgery.
  • In the US, surgery is done on most patients with stage I disease, regardless of tumor grade, to adequately assess the extent of diesease and allow radiation therapy to be tailored to the pathologic findings.
  • In stage I patients with grade I tumors and less than 50% myometrial invasion, no further therapy is recommended because the prognosis is good.
  • In patients with stage I, grade II disease and less than 50% but more than 25% myometrial invasion, it is debatable whether vaginal cuff radiation is indicated. Although this adjuvant therapy is the subject of debate, it may be justifiable in patients with stage I, grade III disease who have from 25% to less than 50% myometrial invasion.
  • Post-op radiation is recommended in patients with stage I, grade I or II disease with more than 50% myometrial involvement, and in patients with grade III disease regardless of depth of myometrial invovlement.
  • Vaginal cuff radiation is delivered with colpostats or vaginal cylinders. The dose with low-dose-rate (LDR) brachytherapy is 60-70 Gy to the vaginal mucosa in one or two insertions. With high-dose-rate (HDR) brachytherapy, the prescription is 6-7 Gy per fraction at 0.5-cm depth; 3 fractions given 1-2 weeks apart.
  • High-risk patients are sometime treated with a combination of external-beam radiation and vaginal cuff insertion.

Inoperable Stage I Endometrial Carcinoma

  • Two brachytherapy insertions for 7,000- 8,000 mgRaEq-h (LDR) and external-beam radiation to the pelvis to a total dose of 50.4 Gy with a midline block at 20Gy is recommended for patients who are medically inoperable.

Stage II Endometrial Carcinoma

  • Patients with stage II endometrial carcinoma are subdivided into those with endocervical glandular involvement and those with cervical stromal invasion.
  • The gynecologic oncologic community favors surgery followed by post-op radiation, based on histologic findings.
  • The incidence of pelvic lymph node involvement varies from 20%- 50% in patients with stromal involvement. This necessitates adequate treatment of nodal areas and parametrial tissues with external pelvic radiation.
  • Survival for patients with stage II disease ranges from 50%- 85%. Patients with endocervical glandular involvement only (stage IIA) have a much better 5-year survival rate than those with cervical stromal invasion.

Stage III Endometrial Carcinoma

  • Treatments for stage III disease must be individualized.
  • In the US the trend has been to do surgery first on patients without extensive parametrial or vaginal extension to assess the extent of the disease and debulk the tumor.
  • All stage III patients are candidates for post-op radiation after surgical staging and debulking of the tumor.
  • Radiation fields are defined by the histologic extent of the tumor.
  • Patients with periaortic nodal involvment should be treated with extended-field radiation encompassing the periaortic lymph nodes. The recommended dose for the periaortic lymph nodes is 45 Gy, and the pelvic dose to 50.4 Gy.
  • For inoperable patients, whole-pelvis radiation (20-40 Gy) and additional boost to the lateral pelvic wall to 50-60 Gy after placement of a midline block (depending on clinical evidence of parametrial invasion), combined with 2 LDR intracavitary implantations for a total of 5,000- 8,000mgRaEq-h, is the treatment of choice.

Stage IV Endometrial Carcinoma

  • Medically inoperable patients with bladder or rectal wall involvement without pelvic wall fixation may be considered for pelvic exenteration.
  • Patients with stage IVB disease may be treated with whole-pelvic radiation for control of local symptoms of bleeding, discharge, and pelvic pain.

Radioactive Phosphorus

  • Intraperitoneal 32P is effective in decreasing recurrences in selected patients with subclinical intraperitoneal disease. The usual dose is 15 mCi.
  • It is strongly recommended not to combine this treatment with external-beam radiation to the pelvis because of excessive bowel toxicity.

Chemotherapy


  • Doxorubicin (Adriamycin) is the principal theraputic agent used to treat patients with metastatic endometrial cancer.

Recurrent Endometrial Carcinoma


  • Optimal treatment for recurrent endometrial cancer depends on the size of the recurrent tumor, spread of tumor beyond the confines of the true pelvis, and type of therapy delivered after initial diagnosis.
  • It is recommended that patients with recurrent cancer in the pelvis who have not received previous radiation, to administer external-beam radiation to the whole pelvis (45-50 Gy in 5-6 weeks).
  • An additional boost of 10-15 Gy to the tumor bulk can be delivered with external-beam radiation when the tumor involves the central pelvis or the pelvic side wall.
  • Vaginal recurrences can receive boost radiation with intracavitary or interstitial radiation therapy to bring the total tumor dose to 80 Gy.
  • Patients with disseminated tumors are treated with progestational agents, which may be given alone or combined with chemotherapy, depending on the status of estrogen or progesterone receptors.
  • Radiation therapy in indicated for palliation.

Radiation Therapy Techniques

  • The external-beam field should extend superiorly to cover the common iliac lymph nodes and inferiorly to encompass the upper half of the vagina.
  • The lateral border of the treatment field should extend 1.5- 2-cm beyond the border of the bony pelvis to include the pelvic lymph nodes.
  • Treatment can be delivered using a 4-field box technique to provide a homogeneous dose distribution.
  • If external-beam therapy alone is to be used post-op, a dose of 45-50 Gy is indicated.
  • If external-beam radiation is combined with brachytherapy, a dose of 20-30 Gy, with an additional prametrial boost (with midline block) to deliver 50 Gy to the pelvic lymph nodes, is used.
  • For pre-op intracavitary insertions, the vaginal wall should be irradiated.
  • If there is tumor extension into the vagina, the entire length of the organ should be treated iwth a cylinder, Delclos applicator, or Syed interstitial implant because of the propensity of advanced endometrial tumors to metastasize to this site.
  • In patients with recurrent tumors, the choice of intracavitary device depends on tumor bulk and location. The entire vagina should be treated. The uninvolved mucosa should receive doses of 50-60 Gy, depending on the external-beam dose to the whole pelvis. A total dose of approximately 75-80 Gy should be used.
  • Medically inoperable patients can be treated with radiation alone. Two intracavitary insertions to deliver 60 Gy to the vaginal surface are combined with external-beam radiation with an additional 20-40 Gy to the whole pelvis and subsequent boosting of the lateral pelvic wall to ta total dose of 50 Gy. A midline pelvic shield protects the bladder and bowel. Additional boost radiation is indicated if there is residual tumor. 1


4-field Box Technique

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AP/PA and Lateral Treatment Field DRR's

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RF Treatment Plan w/ Midline Block

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RF AP/PA and Lateral DRR's w/ Midline Block

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HDR Brachytherapy Treatment Plan

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HDR Brachytherapy Source Verification DRR's
AP and L Lateral


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All treatment plan snapshots and field photos provided by Central Mississippi Medical Center in Jackson, MS.
TD5/5:
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Table provided by Wikibooks. 6
References:
1. Chao KS, Perez CA, Brady LW. Radiation Oncology Management Decisions. 2nd edition. Philadelphia, PA: Lippincott Williams & Wilkins. 2002. 511-514, 511-512, 514-518.
2.
Gunderson, LL & Tepper, JE. (Eds.) Clinical Radiation Oncology. 2nd edition. Philadelphia, PA: Elsevier, Churchill & Livingstone. 2007: 1360-1363.
3. Rubin, P. Clinical Oncology A Multidisciplinary Approach for Physicians and Students. 8th Edition. Philadelphia, Pennsylvania: W.B. Saunders Company. 2001; 480-481.
4. Washington CM, Leaver D. Principles and Practice of Radiation Therapy. Second Edition. St. Louis, Missouri: Mosby, Inc : 2004; 781-782.
5. Perez CA, Brady LW, Halperin EC, Schmidt-Ullrich RK. Principles and Practice of Radiation Oncology. 4th edition. Philadelphia, PA: Lippincott Williams & Wilkins. 2004: 1919-1920.
6. Radiation Oncology/Toxicity/Emami. Wikibooks. Available at: http://en.wikibooks.org/wiki/Radiation_Oncology/Toxicity/Emami. Accessed: January 5, 2010.
7. Lenhard RE, Osteen RT, Gansler T. The American Cancer Society's Clinical Oncology. 1st ed. Atlanta, GA: ACS, Inc. 2001: 423.