Although surgical therapy and surgicopathologic staging is the mainstay of treatment for the majority of endometrial cancers and uterine sarcomas, nonsurgical therapies, such as radiation therapy, chemotherapy, and hormonal therapy, play a role in the treatment of uterine cancers. However, most of these therapies are used as adjuvant/adjunctive therapy or in the treatment of recurrences or metastatic disease.
Of these therapies, only radiotherapy has any place in primary therapy for early endometrial cancer and uterine sarcomas. Primary radiotherapy (total dose to tumor of up to 80 Gy) is the treatment of choice for those patients who are poor surgical candidates. Although the survival rate with primary radiation alone is 15-20% less than with surgery, the morbidity and mortality from surgical therapy in some patients may outweigh the benefits gained in terms of survival and recurrence.
The other instance in which primary radiation is recommended is with stage III disease based on vaginal and/or parametrial extension, where complete resection of the tumor with primary surgery is unlikely. Even in this case, adjuvant hysterectomy and adnexectomy are performed 6 weeks after radiation is completed, when feasible. Treatment of clinical stage IV disease is individualized based on the disease sites. In addition to surgical therapy to control bleeding, radiation therapy is usually administered for symptomatic bone and CNS metastases, as well as for local tumor control if the tumor extends to the bladder or rectum. Primary hormone therapy and chemotherapy may be indicated with distant disease. Primary radiation for uterine sarcomas is usually limited to those patients who are medically inoperable.
Surgical therapy: Exploratory surgery with staging is the treatment of choice in stage I and early stage II disease. The type of surgery performed is dependent on the preoperative examination findings, as well as the intraoperative findings. In the past, patients with well-differentiated endometrioid adenocarcinomas of the endometrium without adverse risk factors (eg, deep myometrial invasion and tumor size <2 cm) were treated by simple total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO). The problem was that lymph node metastasis risks based on myometrial invasion, extracorporeal metastases, or local extension to the cervix had been determined primarily by looking at the final pathology. The accuracy of frozen section analysis looking for microscopic deep invasion or higher grade carcinoma that would necessitate staging is controversial. Based on recent evidence, most recommend that the primary surgery be completed by a gynecologic oncologist who is trained to perform extensive staging procedures.
One recent study found that almost 20% of grade 1 patients who underwent routine staging, avoided whole-pelvic radiation based on pathologic findings. Also, a small percentage of grade 1 patients required whole-pelvic radiation that they would not have received based on uterine and adnexal pathology. High-risk factors for extrauterine spread include clinical cervical extension, atypical histology (eg, papillary serous, clear cell), FIGO grade 2 or 3 tumors, elevated CA-125 level, and patients who are thin and elderly.
Staging
Clinical stage I and occult stage II (grossly limited to the uterine corpus)
Most patients with endometrial cancer are in this category. Preoperative workup and risk assessment is completed. The patient then undergoes a TAH/BSO and pelvic washings or laparoscopically assisted vaginal hysterectomy/BSO. Removing a vaginal cuff margin does not decrease the incidence of local recurrences. If the patient had preoperative risk factors for more advanced disease, such as clear cell or papillary serous histology, grade 2 or 3 endometrioid adenocarcinoma, or elevated CA-125 level, the surgeon should proceed with bilateral pelvic and selective para-aortic lymphadenectomy (BPPLND) via an open or laparoscopic approach. Omental and peritoneal biopsies are performed as indicated. Whether the hysterectomy specimen is immediately examined for gross pathology and frozen section histologic analysis is truly controversial and surgeon dependent. Surgeons who stage all patients typically do not use frozen pathology.
Surgeons who do not routinely stage all endometrial cancers, including grade 1, should proceed to staging if any of the following exist: a grade 2 or 3 tumor, greater than 50% invasion of the myometrium, adnexal metastases, cervical extension, elements of papillary serous or clear cell histology, lymphvascular space involvement, or more than half (or >2 cm tumor size) of the endometrial cavity is involved. Of course, extended staging should be performed if suspicious lymphadenopathy or extrapelvic disease is present even in the absence of the aforementioned adverse risk factors.
Morbidity with extended staging when performed by surgeons trained in these techniques is not dramatically increased. Again, many gynecologic oncologists suggest performing at least limited staging for all patients with endometrial cancer because a significant upgrade or deeper microscopic myoinvasion (15% in some series) may be missed on frozen section and gross examination. However, some patients, specifically elderly patients or those with significant comorbidities, are better served by extrafascial hysterectomy and bilateral adnexectomy alone, followed by radiation as indicated by histologic factors, even in light of adverse risk factors.
Adjuvant hysterectomy and bilateral adnexectomy following preoperative radiotherapy with external beam with one brachytherapy application (total dose of 65-75 Gy) is occasionally performed. However, most surgeons choose primary surgical therapy followed by postoperative radiation, given that postoperative radiotherapy is no different from preoperative radiotherapy in terms of decreasing the incidence of local recurrences.
Vaginal hysterectomy may be used in the morbidly obese or medically infirm patient who may tolerate the vaginal approach better than the abdominal or laparoscopic approach. Recent studies demonstrate similar survival rates for clinical stage I disease. Tumor differentiation, depth of myometrial invasion, and patient age are significantly associated with recurrence and survival rates.
Clinical stage II (gross cervical involvement)
Endometrial cancer with overt clinical involvement of the cervix can be treated by several approaches. In some cases, complete surgical resection is the therapy of choice. The traditional procedure is a Wertheim radical hysterectomy with BPPLND followed by postoperative radiation (vaginal brachytherapy or whole-pelvic radiotherapy based on pathologic results). TAH/BSO and BPPLND followed by whole-pelvic postoperative radiation based on pathologic results have been suggested to be adequate for clinical stage II disease. Another option is whole-pelvic radiotherapy (40-50 Gy), usually with one application of brachytherapy (total dose 65-75 Gy) followed by adjuvant TAH/BSO 6 weeks after completion of radiation.
Clinical stage III (vaginal extension, adnexal mass, and/or suspicious retroperitoneal lymphadenopathy)
Surgical treatment of stage III endometrial cancer depends upon the specific clinical findings. As discussed, bulky vaginal extension (stage IIIB) or involvement of the parametria by local extension, although technically not part of the FIGO staging, is an indication for primary radiation therapy. This may be followed with TAH/BSO if the residual tumor is resectable. Radical upper vaginectomy, in combination with standard surgical staging, may be used with localized upper vaginal metastases in select patients. Clinical stage III disease based on the presence of an adnexal mass should be treated with laparotomy TAH/BSO, pelvic washings, and BPPLND. This approach offers the advantage of surgicopathologic staging and definitive diagnosis of the adnexal mass. This is important because the differential diagnosis of the adnexal mass includes metastatic endometrial cancer, malignant ovarian/tubal neoplasm, benign ovarian/tubal pathology, or metastatic disease from another primary tumor site.
The prognosis differs greatly for a benign ovarian neoplasm as compared to metastatic endometrial cancer to the adnexa. Stage IIIA disease based solely on positive findings on peritoneal cytology, in which the disease is otherwise limited to the uterus, is typically diagnosed postoperatively.
Clinical stage IV (gross bladder and bowel invasion and distant metastases)
Treatment of clinical stage IV disease is determined by whether local extension into the bladder or rectum (stage IVA) or distant/extrapelvic metastases (IVB) is present. Primary radiation for stage IVA disease is discussed in Medical therapy. The role of surgery in stage IVB disease may involve tumor reduction or palliative chemotherapy or radiation. Tumor reductive surgery is typically followed with adjuvant/adjunctive chemotherapy, hormonal therapy, and/or radiation therapy.
Surgery with staging is also the primary treatment of choice for uterine sarcomas. Patients with an LMS, MMT, or HGESS benefit from total abdominal hysterectomy and bilateral salpingo-oophorectomy through a vertical midline incision, with pelvic washings, omental biopsy, and selective pelvic and para-aortic lymphadenectomy. Lymphadenectomy for LGESS is of limited value because the incidence of lymph node metastases is low. The difficulty with LMS and LGESS is that the diagnosis is usually made intraoperatively or postoperatively. HGESS and MMT are typically diagnosed preoperatively. Subsequently, surgical therapy for patients with LMS and LGESS is often incomplete unless surgeons comfortable with extensive staging are available. The management dilemma is dealt with in the postoperative period.
Preoperative details: After diagnosis of endometrial cancer or uterine sarcoma is made, preoperative workup should include complete blood cell count, electrolytes, CA-125 (if indicated by atypical presentation or histology), chest radiographs, and any of the above-noted tests, as indicated. Also, the patient should be in compliance with routine health maintenance screening (ie, mammography, Pap smear, sigmoidoscopy/colonoscopy as indicated by patient age or symptoms).
If the patient has specific symptoms such as neurologic abnormalities, bone pain, or respiratory symptoms, a directed metastatic workup should be performed preoperatively (eg, head CT scan/MRI, bone scan).
Other tests that are occasionally used are barium enemas, intravenous pyelogram, proctosigmoidoscopy, and cystoscopy. These are more important in the patient who is medically inoperable. Nonsurgical treatment can then be individualized for these patients. Again, the adverse risk factors discovered preoperatively should prompt a referral to a gynecologic oncologist because the probability that extensive staging is required is increased.
Postoperative details: In order to determine the need for postoperative adjuvant therapy, patients are stratified according to risk. Pathologic features, such as depth of myometrial invasion, lymphvascular space involvement, atypical histology, cervical extension, and nuclear grade, are important in determining risk for recurrence and, subsequently, the need for adjuvant therapy. With endometrial cancer that is clinically confined to the uterus, 3 separate categories for recurrence risk exist:
- Low risk (<4-5%) is defined as grade 1 or 2 endometrioid/adenosquamous tumors with only inner one third myometrial invasion, no cervical extension, no lymphvascular space involvement, and negative findings on cytology and grade 3 with no myometrial invasion. These patients need no adjuvant therapy, although some gynecologic oncologists administer adjuvant therapy to all patients with grade 3 tumors.
- Moderate risk (5-10%) is defined as grade 1 or 2 endometrioid tumors with outer two-thirds myometrial invasion, grade 1 or 2 endometrioid tumors with less than 10% myometrial invasion and extension to the cervix, negative findings on cytology, and no lymphvascular involvement. These patients may have some small benefit from postoperative vaginal brachytherapy.
- High risk (>10%) is defined as grade 1 or 2 endometrioid/adenosquamous tumors with greater than or equal to 50% myometrial invasion, grade 2 endometrioid/adenosquamous tumors with greater than one-third myometrial invasion and extension to the cervix, grade 3 tumors with any myometrial invasion, and lymphvascular space involvement. These patients benefit from adjuvant therapy. While some recommend whole-pelvic radiation therapy, others advocate only vaginal brachytherapy if the tumor is fully staged without evidence of extracorporeal spread. The results of a recent Gynecologic Oncology Group study demonstrated that, while adjuvant whole-pelvic radiation therapy for high-risk early-stage patients reduced the risk of pelvic recurrence by 50%, overall survival was not improved.
No proven benefit of adjuvant chemotherapy and/or hormonal therapy exists in early-stage endometrial cancer.
After tumor reductive surgery for extrapelvic/advanced disease at the time of laparotomy, adjuvant/adjunctive therapy is individualized. Localized radiation therapy is administered for CNS and bone metastases. Adjuvant whole-abdominal radiation therapy is reserved for those who have no macroscopic extrapelvic disease secondary to its high morbidity; however, this is controversial. Otherwise, these patients are treated with chemotherapy and/or progestin or antiestrogen therapy. Medroxyprogesterone acetate and megestrol therapy is efficacious for those low-grade tumors that are estrogen and/or progesterone receptor–positive.
Tamoxifen is an effective alternative when progestin therapy is contraindicated (eg, coronary artery disease, breast cancer). A 75-80% objective response occurs with estrogen and/or progesterone receptor–positive tumors compared to less than 5% in the absence of estrogen and/or progesterone receptor–positive tumors. Unfortunately, the tumors that tend to have intra-abdominal metastases are high grade and are less likely to be estrogen and/or progesterone receptor–positive tumors (15-41%). In cases of advanced disease, sending tissue, specifically from metastatic sites, for receptor analysis is useful. Metastases are receptor positive in 25% of metastatic tumors compared to 60% of primary tumors.
If advanced disease is not amenable to localized/whole-abdominal radiotherapy or hormonal therapy, chemotherapy is initiated. Doxorubicin and cisplatin are the most effective agents used. Combination of the 2 agents increases the progression-free interval, with a complete remission in about 10-15% of cases and a partial response in 25%. More recently, the addition of paclitaxel with growth factor support appears to improve response and survival.
Whole-pelvic radiotherapy and, sometimes, systemic chemotherapy is recommended for clear cell carcinoma and papillary serous carcinoma with negative surgical staging, negative lymphvascular space involvement, and minimal myometrial invasion. If UPSC is more advanced, patients may receive chemotherapy with paclitaxel, carboplatin, and doxorubicin. Studies have not demonstrated a consistent response to chemotherapy. UPSC does not respond as well to platinum-based chemotherapy as does its ovarian epithelial counterpart.
The major curative treatment of uterine sarcomas is TAH/BSO with surgical staging. However, a significant number of these tumors are diagnosed intraoperatively and postoperatively. Subsequently, postoperative therapy usually is necessary, although disagreement generally exists regarding its efficacy in terms of survival. At times, reoperation for removal of remaining gynecologic organs with surgical staging may be necessary. In terms of adjuvant therapy, whole-pelvic radiation or progestin therapy is recommended for LGESS only with extrauterine disease or lymphvascular space involvement. Whole-pelvic radiation improves local control for HGESS, especially stage I disease.
However, if advanced disease is present, progestin therapy and doxorubicin-based chemotherapy have a role. Because of the increased tendency for LMS to hematogenously spread and recur at distant/extrapelvic sites, whole-pelvic radiotherapy is relatively ineffective. Chemotherapy with doxorubicin, ifosfamide, etoposide, and/or cisplatin may be used with LMS. Recently, gemcitabine and taxotere combination therapy has shown promise in unresectable LMSs of different sites. Patients with MMT that is limited to the pelvis benefit from whole-pelvic radiation with respect to local control. Those patients with evidence of extrapelvic disease may respond to additional postoperative therapy with doxorubicin, cisplatin, and/or ifosfamide. These cytotoxic therapies have demonstrated up to a 20% complete response rate in patients with advanced or recurrent disease.
In conclusion, radiation therapy provides local tumor control but no consistent improvement in survival rates. Chemotherapy and hormonal therapy are better suited for evidence of extrapelvic spread but yield somewhat inconsistent results. For these reasons, postoperative therapy for uterine sarcomas is quite variable.
Follow-up care: Routine surveillance intervals are typically every 3-4 months for the first 2 years, since 85% of recurrences occur in the first 2 years after diagnosis. Intervals are every 6 months for the next 3 years and annually thereafter. Each visit should include a pelvic examination, a Pap smear, and a lymph node survey. Chest radiographs may be taken annually or if symptoms arise. CA-125 levels are helpful if they were elevated preoperatively. Most recurrences are discovered during evaluation of symptomatic patients. The majority of recurrences in early-stage disease are at the vaginal cuff and pelvis.
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center and Women's Health Center. Also, see eMedicine's patient education articles Cervical Cancer and Vaginal Bleeding.
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