In the United States, the American Cancer Society (ACS) estimates approximately 12,000 women are diagnosed with cervical cancer each year and 4,000 die of disease. Among the gynecologic cancers it is the third most common diagnosis, but among women 20 to 39 years it is the second leading cause of death. As many as 300,000 women die globally each year as a result of cervical cancer. Historically a common disease, cervical cancer has become relatively rare in the developed world, thanks to successful screening with the Papanicolaou (Pap) test, which has allowed for early detection and therefore drastically reduced mortality rates. In developing countries, however, where access to effective and regular screening is not always available, the incidence of disease is much higher.

The vast majority of cervical cancers are caused by human papillomavirus (HPV) infection. The development of an effective HPV vaccine has made the disease all the more preventable, and the mortality associated with cervical cancer in developed countries should decrease further in the coming decades. Still, global rates will remain high until both the vaccine and screening test are readily and consistently available in both resource-poor and developed countries.

Cervical cancer is classified as squamous cell carcinoma (keratinizing, nonkeratinizing, verrucous): 80% to 85%; endometrioid and adenocarcinoma: 15%; and adenosquamous: 3% to 5%.

For asymptomatic women, preinvasive lesions are found only after abnormal routine screening Pap smear of the ecto-/endocervix (transformation zone) junction. Cervical cancer mortality has decreased in the United States by more than 70% since the Pap test was introduced in 1941.

The Pap test is simple, safe, inexpensive, and well validated. Conventional cytology screening is reported to be 60% (30% to 87%) sensitive for dysplasia. Newer techniques using an ethanol medium (Sure-Path, BD Diagnostics, Franklin Lakes, NJ; Thin-Prep, Hologic, Bedford, MA; MonoPrep, MonoGen, Lincolnshire, IL) are as effective as conventional methods, are easier to read, and allow for sexually transmitted infection and HPV testing.

Approximately 3.5 million women have an abnormal Pap smear every year in the United States. The American Congress of
Obstetricians and Gynecologists (ACOG) and ACS recommend that if a patient is exposed to diethylstilbestrol or is immunosuppressed (e.g., due to human immunodeficiency virus [HIV] infection), screening should be indefinite. In addition, HIV-positive women should be provided cervical cytology screening twice (every 6 months) within the first year after initial HIV diagnosis and, if both tests are normal, annual screening can be resumed thereafter.

The older terminology (mild, moderate, severe dysplasia) was replaced with cervical intraepithelial neoplasia I to III, based on the replacement of each third of the epithelium. This has since been replaced by the present system of “abnormal squamous cells of unknown significance” (ASCUS), which represents two-thirds of all abnormal Pap smears, and squamous intraepithelial lesions (SILs), which can be further classified as low-grade SIL or highgrade SIL.

An ASCUS Pap should trigger HPV testing. If positive, the patient should be referred for colposcopy. Women older than 40 years with normal endometrial cells on Pap smear require endometrial biopsy (EMB), although the yield of endometrial neoplasia is low. There is a clear correlation between cytologic diagnosis and histologic diagnosis at colposcopy in approximately half of patients.

In the United States, both the United States Preventive Services Task Force (USPSTF) and the ACS recommend against routine yearly testing. Instead, the guidelines recommend testing every 3 years for women ages 21 to 65; routine cervical cancer screening for women below 21 and above 65 is no longer recommended. The two groups also introduced the option of a lengthened, 5-year screening interval for women ages 30 to 65 when screened with a combination of Pap testing and HPV testing.¹

Cervical cancer in the absence of demonstrable HPV infection is extremely rare. Beyond the Pap test, HPV testing appears to be more sensitive and superior to standard Pap screening.²

The most common symptoms of invasive cervical cancer are abnormal vaginal bleeding, either postcoital or intramenstrual, and vaginal discharge. Larger tumors may also interfere with urination and defecation and may be accompanied by pelvic pain. Locoregional disease can manifest as unilateral lower extremity swelling, back pain, neuropathic pain, and/or postobstructive renal failure. It should be noted that many women with cervical cancer do not present with any symptoms, but rather with disease detected during pelvic examination or screening procedures.

The most common clinical sign of cervical cancer is an abnormal lesion on the cervix, usually detected by a physician
during a pelvic exam. The exophytic lesion often presents as necrotic and friable. Involvement of surrounding tissues should be assessed, including the parametria, sidewalls, and uterosacral ligaments, as well as the superficial groin and femoral lymph nodes and the supraclavicular region. Infiltration of surrounding tissues is the most common reason to consider chemoradiation therapy over surgery.

Once an abnormal cervical lesion has been assessed by a physician, a tissue biopsy should be performed to either confirm or rule out malignancy. The physician should make sure the biopsy is deep enough so as to include non-necrotic tissue, thus ensuring a diagnostically relevant sample.

Stage, histologic grade and type, tumor size, depth of stromal invasion, involvement of parametrium, and lymphovascular space invasion (LVSI) all influence prognosis. Pelvic lymph node metastasis significantly decreases the survival rate of patients.

In a report of whole-exome sequencing analysis of 115 cervical carcinoma normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumor-normal pairs was performed. Novel somatic mutations in 79 primary squamous cell carcinomas included recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%), and ERBB2 (6%). The authors also observed somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. In this study, squamous cell carcinomas had higher frequencies of somatic mutations in the Tp*C dinucleotide context than adenocarcinomas. Gene expression levels at HPV integration sites were significantly higher in tumors with HPV integration compared with expression of the same genes in tumors without viral integration at the same site.³

Cervical cancer is staged clinically and includes palpation, colposcopy, cystoscopy, endocervical curettage, proctoscopy, hysteroscopy, intravenous (IV) urography, and radiograph. Many centers also use magnetic resonance imaging (MRI) to define the local extent of disease and positron emission tomography (PET)/computed tomography (CT) to determine if there is any metastatic spread. Postoperatively, pathologic staging does not change clinical International Federation of Gynecology and Obstetrics (FIGO) staging.⁴

Over the last decades, the management of cervical preinvasive and invasive disease has changed significantly. Colposcopy is being used with increasing frequency to treat preinvasive disease,
surgery is preferred to radiation therapy for early-stage invasive disease, and adoption of chemoradiation therapy over radiation as primary or adjuvant therapy.

Options for treatment include cervical conization (loop diathermy or cold knife) or hysterectomy. Lymphadenectomy is not required if stage IA-1 disease is demonstrated, as risk of metastases is very small (1%). If margins are positive, completion of hysterectomy might be required. For patients with positive excisional margins, reexcision is recommended before offering hysterectomy for definitive treatment in order to rule out a more deeply invasive tumor that would require radical hysterectomy over simple or extrafascial hysterectomy. In patients with negative conization margins, careful follow-up is adequate.

Early-stage disease can be treated with either chemoradiation or surgery. Surgery generally results in definitive treatment, an improvement in survival over primary radiotherapy (RT), and may provide a better quality of life. Retrospective data from case-control and nonrandomized studies showed that stage IB/IIA cancer of the cervix can be treated equally well with radical surgery and radical radiation therapy. A randomized controlled trial (RCT) of 343 patients with stage IB/IIA carcinoma cervix showed that these two modalities were equally effective in controlling the disease judged by the disease-free and total survival as well as by the relapse rates. This trial also conclusively showed that surgery has a survival advantage over radiation therapy for patients with adenocarcinoma cervix. However, surgery was associated with more serious adverse events (28% vs. 12%), and 64% of the surgical patients required postoperative radiation, likely associated with increased morbidity.⁵ Surgery should be considered in premenopausal women where ovarian function can be preserved, in patients with an undiagnosed pelvic mass, in patients with more risk of bowel toxicity from RT (adhesions because of pelvic inflammatory disease, endometriosis, inflammatory bowel disease, or in very thin women), or when compliance with the RT schedule may be difficult (with socially disadvantaged patients, for example).

An important goal is to identify patients who would likely need RT and then avoid surgery; most clinicians now use PET/CT scans to screen for metastatic disease and MRI to evaluate the extent of local disease. This allows patients with more advanced disease to be triaged and treated with chemoradiation.

Morbidly obese patients are typically not considered for standard surgery because of high surgical risk, though robotically assisted surgery may prove safer. Age does not appear to be a significant contraindication to radical hysterectomy.
Treatment should be appropriately tailored in unusual circumstances such as pregnancy or patients with HIV.

Lymphadenectomy is a standard part of surgical management of any early-stage disease being treated with radical hysterectomy. Sentinel node biopsy is still investigational. Retrospective analysis of lymph node debulking of palpable nodes prior to RT suggests a survival advantage in the prechemoradiation era, but is now more controversial with modern imaging (MRI and PET/CT) and chemoradiation.

Based on a prospective study, the Gynecologic Oncology Group (GOG) defined an intermediate-risk group using various combinations of three factors (LVSI, deep stromal invasion, and tumor size). This approach resulted in the following “GOG criteria”: (a) positive capillary-LSVI, deep and middle third penetration, and clinical tumor size of 2 cm; (b) superficial third penetration and clinical tumor size of 5 cm; and (c) negative capillary-lymphatic space involvement with middle or deep third penetration and clinical tumor size of 4 cm. In an RCT, in women with intermediate risk factors, adjuvant pelvic radiation following radical hysterectomy reduced the number of recurrences among women with stage IB cervical cancer.⁶ The role of chemoradiation in this population is currently being investigated.

In contrast, adjuvant chemoradiation is necessary for women who have high-risk features after radical hysterectomy (positive lymph nodes, margins, or parametrium). A Southwest Oncology Group RCT in 243 women revealed that chemoradiation with cisplatin and 5-fluorouracil (5-FU) was significantly superior to RT alone (overall survival [OS] at 4 years of 81% with chemoradiation vs. 71% with RT), though it had more toxicity.⁷

If fertility preservation is desired, radical trachelectomy (removal of only the cervix and parametria) with concomitant lymphadenectomy for small (less than 2 cm) tumors may be considered. This procedure appears to be associated with retention of fertility (with up to 50% of patients becoming pregnant after radical trachelectomy) along with acceptable risk of recurrence in carefully selected patients. Tumor size is the single most important criterion in considering fertility-preserving surgery, but other criteria, including grade, canal involvement, and LVSI, may be important.⁸ Patients being evaluated for radical trachelectomy should have pretreatment imaging studies including pelvic MRI and PET/CT to exclude extracervical disease.

In 1999, the National Cancer Institute (NCI) released a clinical alert highlighting the survival advantage documented in five NCI-sponsored clinical trials evaluating the use of concurrent chemoradiation. A systematic review of 18 randomized trials revealed absolute benefit in progression-free survival (PFS) and
OS of 16% (95% confidence interval 13% to 19%) and 12% (8% to 16%), respectively, but with twice the gastrointestinal (GI) toxicity. Late toxicity is anticipated to be less with concurrent chemotherapy because of the total lower dose of RT.

Weekly cisplatin 40 mg/m² during RT has been adopted as the preferred strategy because of its more favorable toxicity profile when compared with cisplatin and 5-FU. There has not been a direct comparison of cisplatin versus cisplatin and 5-FU, though many extrapolate their equivalence from GOG-120, which compared RT with cisplatin versus the combination of cisplatin, 5-FU, and hydroxyurea versus hydroxyurea alone in 526 patients with stages IIB, III, IVA cancer. In both groups who received radiation and cisplatin, the 3-year survival rate was 65% compared with 47% for women receiving radiation and hydroxyurea.⁹

Combining cisplatin with another agent improves response at the expense of considerably worse toxicity. In an international RCT of women with stages IIB and III cervical cancer, the investigators compared standard concurrent weekly cisplatin and pelvic radiation with intensification of pelvic treatment with the addition of potentially radiosensitizing concurrent weekly gemcitabine and two further courses of adjuvant gemcitabine/cisplatin, a doublet with some independent systemic activity. Patients in the combination arm had a 9% improvement in PFS at the fixed time point of 3 years of follow-up.¹⁰ In addition, the International Gynecologic Cancer Intergroup is currently comparing standard therapy with concurrent weekly cisplatin and radiation with that same therapy followed by three additional courses of systemic adjuvant carboplatin and paclitaxel (OUTBACK trial).

Adenocarcinoma is associated with a worse prognosis, although we do not stratify treatment based on histology. Therefore, these patients are typically the same as that for squamous cell carcinomas.

Primary chemotherapy (neoadjuvant) with combination platinum-based chemotherapy (cisplatin, vincristine, bleomycin) can have a very high response rate (90% in stage IB2) with consolidative adjuvant radiation.¹¹ In parts of the world where access to radiotherapy is limited, neoadjuvant chemotherapy before surgical treatment is administered for locally advanced cervical cancer. However, there are no data that this approach is equally or more effective than primary chemoradiation.

Three contemporary RCTs (GOG-204, GOG-240, and Japanese Clinical Oncology Group 0505 [JCOG-0505]) have investigated the optimal chemotherapy regimen in advanced and recurrent cervical cancer. GOG-204 was conducted to reconcile the
relatively high overall response rate of 36% observed using the cisplatin-paclitaxel doublet in an earlier trial and the 2.9-month OS benefit attributed to the US Food and Drug Administration (FDA)-approved cisplatin-topotecan doublet. In GOG-204, a final definitive comparison of four cisplatin-based chemotherapy doublets was undertaken: cisplatin plus paclitaxel (standard arm), cisplatin plus vinorelbine, cisplatin plus gemcitabine, and cisplatin plus topotecan. Despite hope for progress with newer agents, no regimen outperformed the standard cisplatin-paclitaxel arm, in which a trend for improved response and survival rates was observed.¹²

The Japanese GOG reported that the more convenient and better-tolerated regimen of paclitaxel 175 mg/m² over 3 hours with carboplatin at area under the serum concentration-time curve 5 every 21 days was not inferior to cisplatin plus paclitaxel. Thus, both the cisplatin and carboplatin combinations are acceptable with cisplatin having more renal, nerve, and intestinal toxicities but carboplatin having more marrow-related adverse events, especially thrombocytopenia.

Finally, GOG-240 study used a 2 × 2 factorial design; patients were assigned to either of two chemotherapy regimens involving cisplatin plus paclitaxel or topotecan and paclitaxel, and then randomly assigned to receive 15 mg/kg of bevacizumab or not. Treatment cycles were repeated every 21 days until disease progression, unacceptable toxicity, or complete response. More than 70% of patients in both groups had received prior platinum-based therapy. Importantly, in this trial the incorporation of bevacizumab showed a significantly improvement in the median OS as compared with chemotherapy alone (17.0 vs. 13.3 months). These data have led to the FDA approval of bevacizumab plus chemotherapy for these patients (Table 11.1).¹³

There is a desperate need for more effective therapy for recurrent cervical cancer. Agents that target the vascular endothelial growth factor, epidermal growth factor, and HER2/neu receptors are currently in clinical trial and look promising. However, there are no targeted treatments (beyond bevacizumab) that have a role in the current treatment of cervical cancer.

Supportive care, which addresses physical, psychological, social, and spiritual issues, is an essential part of the holistic care of patients as they approach the end of their life. Common medical problems include pain, nausea and vomiting, lymphedema, obstruction (genitourinary and GI), and fistulas, and require multiprofessional care.

In the United States, endometrial cancer is the most common gynecologic malignancy. The ACS estimates that approximately 49,500 women are diagnosed with endometrial cancer every year in the United States, and 8,000 deaths attributable to the disease. The cancer typically presents at an early stage with vaginal bleeding in postmenopausal women. Because it usually presents while still confined to the uterus, it is often cured with surgery alone. Tamoxifen use is a significant risk factor for developing endometrial cancer. Given the continued and expanding use of tamoxifen in the prevention and treatment of breast cancer, a growing number of women have an increased risk of developing endometrial cancer.

Endometrial cancer includes epithelial endometrial carcinomas (95%) and mesenchymal tumors (5%). Two broad histologic categories of epithelial endometrial cancer have been described, termed types I and II carcinomas. They appear to have different patterns of molecular alterations that underlie their pathogenesis and clinical outcomes. Type I endometrial cancers are associated with unopposed estrogen exposure and are often preceded by premalignant disease. They are usually early stage at diagnosis, low-grade tumors (predominantly of endometrioid histology), and carry a favorable prognosis. Obesity and family history remain two of the strongest risk factors for this type of endometrial cancer.¹⁴

In contrast, type II endometrial cancers represent estrogen-independent tumors and are associated with a more aggressive clinical course. Unlike type I tumors, there is no readily observed premalignant phase. Both clear cell and serous carcinoma and perhaps grade 3 endometrioid tumors comprise these histologic phenotypes. Some experts also classify uterine carcinosarcomas as a representative of type II histology.

Mesenchymal tumors are composed of uterine sarcomas (leiomyosarcomas [LMS] and endometrial stromal sarcoma) and mixed epithelial/stromal tumors (carcinosarcomas and adenosarcomas).

Screening is not necessary for endometrial cancer as the disease typically presents early with postmenopausal vaginal bleeding and has a good prognosis. Although screening patients by ultrasound
for thickened endometrial stripe has been evaluated, specifically for patients who are on tamoxifen, there is no clear survival advantage over clinical surveillance. By contrast, patients at higher-than-average risk of endometrial cancer because of a family history of colorectal cancer (Lynch II syndrome or hereditary nonpolyposis colorectal cancer syndrome) should undergo screening ultrasound and in-office EMB starting at age 30 to 35 years or prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO) if fertility is no longer desirable.¹⁵ Lynch-associated endometrial cancer survivors should also undergo colorectal cancer screening.

Family members who have not yet been diagnosed with any cancers should undergo screening for both endometrial cancer and colorectal cancer. Colorectal surveillance is the only surveillance protocol in Lynch syndrome proved to be effective. Regular colonoscopy every 3 years leads to a reduction of colon cancer-related mortality and also to a significant reduction of overall mortality in contrast with colon cancer screening in the general population. Women with Cowden syndrome, an autosomal-dominant syndrome, are also associated with a 13% to 28% increased lifetime risk of developing endometrial cancer. Although there are no specific guidelines for endometrial screening in these patients, most advocate the same strategy used for women with Lynch II syndrome.

The most common symptoms of endometrial cancer are abnormal vaginal bleeding and discharge. Because such bleeding can be caused by disorders other than cancer, special attention should be paid to women with abnormal bleeding who are either postmenopausal or women who are at high risk for endometrial cancer and are above the age of 35 years. Metastatic intraperitoneal (IP) disease may also cause symptoms similar to those seen in advanced-stage ovarian cancer, including abdominal distention, pelvic pressure, and pelvic pain. In women with postmenopausal bleeding, a thickened endometrium on pelvic ultrasound is a sign of possible endometrial cancer and should be followed up with endometrial sampling.

Definitive endometrial cancer diagnosis requires tissue sampling, which can be procured either via EMB or fractional dilation and curettage (D&C). EMB is the preferred method of evaluating abnormal uterine bleeding. It should be noted that EMB has proven more effective in postmenopausal, rather than premenopausal, women and is better at confirming the presence of cancer rather than its absence. In cases where outpatient EMB is not possible, or if abnormal bleeding persists despite negative biopsy, fractional D&C should be performed.

The 5-year survival rate for endometrial cancer is 83%, and tumor-related prognostic factors at diagnosis include histologic subtype, stage, grade, depth of myometrial invasion, and LVSI. The prognosis of type I carcinomas is more favorable than that of type II.

The presence of certain molecular abnormalities also contributes to poor prognosis. One such abnormality is the overexpression of the epidermal growth factor receptor (EGFR). In endometrioid adenocarcinomas, overexpression of EGFR decreases the overall 5-year survival rate from 89% to 69%; in serous and clear cell, the presence of EGFR overexpression decreases the survival rate from 86% to 27%.

Recently the results from The Cancer Genome Atlas’ (TCGA) analysis of 373 endometrial tumor samples utilizing array- and sequencing-based technologies have classified the disease into groups with differing prognoses. According to the study, some endometrial tumors with similar histologic features actually differ in their molecular profile and might benefit from different treatments. Uterine serous tumors and approximately 25% of high-grade endometrioid tumors had extensive copy number alterations, few DNA methylation changes, low estrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumors had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS and novel mutations in the SWI/SNF chromatin remodeling complex gene ARID5B. A subset of endometrioid tumors that were identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. With these results the authors classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high. The POLE group, with 17 tumors, or less than 10% of the cohort, was associated with the best prognosis in the study, while those in the high-copy number alterations had the worst outcomes.¹⁶

Endometrial cancer is surgically staged.⁴

Although historically this procedure has been carried out by laparotomy, laparoscopic management has increasingly been integrated into the forefront of surgical staging. The GOG performed a large prospective trial from 1996 to 2005 that included more than 2,600 women with clinically early-stage endometrial cancer. Women were randomized in a 2:1 ratio to laparoscopic versus open hysterectomy, BSO, and pelvic and aortic lymph node sampling. The first report from the study (Laparoscopic Surgery or Standard Surgery in Treating Patients with Endometrial Cancer or Cancer of the Uterus [LAP2]) confirmed the presumed short-term advantages of laparoscopy, including shorter hospital stays, fewer perioperative complications, reduced blood loss, and improved body
image. Recurrence rates at 3 years after surgery were 11.39% in the laparoscopy group and 10.24% in the open surgery group (hazard ratio [HR] for laparoscopy 1.14; 95% CI, 0.92 to 1.46). Although the difference in 3-year survival was small, the trial was deemed inconclusive because laparoscopy could not be demonstrated with 95% confidence to have a HR below the predetermined threshold of 1.4 for noninferiority.¹⁷

As per FIGO recommendation, surgery for endometrial cancer includes, at the minimum, examination of the omentum, liver, adnexal surfaces, peritoneal cul-de-sac, and enlarged aortic and pelvic nodes, and total extrafascial hysterectomy with BSO. To complete the surgical staging of endometrial cancer, the removal of bilateral pelvic and paraaortic lymph nodes is also required. Many gynecologic oncologists have moved toward performing comprehensive surgical staging for nearly all patients with endometrial cancer. The rationale for uniform staging includes the lack of a patient population for whom nodal disease is so low that nodes should be omitted, the inaccuracy of preoperative or intraoperative assessments predicting the risk for nodal disease, the potential for therapeutic benefit in node-positive and -negative patients, and the lack of significant morbidity associated with the procedure. Postoperative adjuvant decisions are best made with the most complete information. If nodal assessment is the predominant factor by which to categorize patients into risk groups, routine nodal dissection is the best method by which to determine which few patients will require adjuvant therapy.

It should be noted, however, that the role of complete lymphadenectomy is controversial after the publication of two negative randomized studies.

A Study in the Treatment of Endometrial Cancer (ASTEC) randomized patients with endometrial cancer treated with hysterectomy to pelvic lymphadenectomy or not. Following surgery, patients with stages I and IIA diseases were then randomized again to observation or pelvic radiation therapy if they had grade 3, serous, or clear cell histology, more than 50% myometrial invasion, or endocervical glandular invasion (stage IIA). Treatment centers were also permitted to use vaginal cuff brachytherapy regardless of pelvic radiation assignment. The results show no evidence of benefit in terms of overall or recurrence-free survival for pelvic lymphadenectomy in women with early endometrial cancer.¹⁸

A similar study was performed by Italian investigators (CONSORT trial). In this trial, 514 patients were assigned to hysterectomy with or without pelvic lymphadenectomy. Patients were required to have myometrial invasion, and patients with grade 1 tumors and less than 50% invasion were excluded. In the no-lymph no-dissection (LND) group, 22% of patients had nodal dissections due to clinical suspicion with 14% of these cases, or 3% of the entire
no-LND arm, having node-positive disease. In the LND group, the median number of nodes removed was 26. Paraaortic dissection could be performed at the surgeon’s discretion and was done in 26% of cases. In the LND group, 13% were found to have positive nodes. Postoperative therapy was not protocol prescribed, but the use of radiation therapy was more common in the no-LND group (25% vs. 17%). The 5-year disease-free survival was 81% in both groups, and 5-year survival was 90% in the no-LND group versus 86% in the LND group (HR 1.2, p = 0.5). The authors concluded that pelvic lymphadenectomy could not be recommended as a routine procedure for therapeutic purposes.¹⁹

Although the new FIGO staging continues to require the collection of peritoneal cytology, positive pelvic washings are no longer formally considered part of the staging system, and consequently, do not alter staging. Positive cytology alone is generally not deemed to be a high-risk tumor criterion in the formulation of adjuvant treatment planning of patients with endometrial cancer. Treatment decisions in women with endometrial cancer should be based on extent of disease, as determined by staging, and final pathologic tumor features.⁴

Surgical resection alone can be curative in many patients with endometrial cancer. ACOG recommends at least a total hysterectomy and BSO. The role of concomitant assessment of lymph nodes in all patients with endometrial cancer remains controversial. For patients with high-grade histologic subtypes of endometrial cancer, lymph node dissection at the time of hysterectomy and BSO is appropriate. For patients with low-grade tumors (grade 1 to 2) of endometrioid histology, lymphadenectomy should be based on other tumor risk factors, such as size of primary lesion, depth of myometrial invasion, and cervical stromal involvement. Laparoscopic surgery is associated with significantly shorter hospital stays and better quality of life. The use of robotically assisted laparoscopic hysterectomy has increased dramatically, especially in the obese patient population, and has resulted in significantly lower perioperative complications compared with abdominal surgery. However, whether robotic surgery is cost-effective has yet to be seen.

Prophylactic total hysterectomy and BSO have been reported to prevent 100% of uterine cancers of women undergoing risk-reducing surgery for Lynch II syndrome or hereditary nonpolyposis colon cancer.

Radiation is given adjuvantly to reduce the risk of local recurrence (brachytherapy to the vaginal vault postoperatively) to reduce the risk of a local recurrence, although a benefit in OS has
not been shown. External-beam RT is indicated for completely resected, node-positive disease (stage IIIC) and is also considered for higher-risk patients (poor grade, or adverse histology, deep invasion, advanced age) with early-stage disease. In addition, brachytherapy is a reasonable and less toxic treatment. More extensive RT (extended field) may be indicated in carefully selected patients with small-volume residual disease, but the benefit has to be weighed against the risk of late complications.²⁰

Two prospective randomized trials compared surgery alone to surgery and postoperative external-beam radiation in early-stage endometrial cancer. The first trial was conducted by the GOG (GOG 99) where 390 patients with stages IB and IIB endometrial cancers who underwent a total abdominal hysterectomy and BSO and pelvic/paraaortic lymph nodes sampling were randomized to observation (n = 202) or postoperative pelvic radiation (n = 190). With a median follow-up of 69 months, the 4-year survival rate was 92% in the irradiation arm, compared with 86% in the observation arm (p = 0.6). The 2-year estimated PFS rate was 97% versus 88% in favor of the irradiation arm (p = 0.007), with the greatest decrease seen in vaginal/pelvic recurrences.²¹ The second trial was the PORTEC study where 714 patients with stage IB grades 2, 3 and stage IC grades 1, 2 were randomized after total abdominal hysterectomy and BSO and no lymph nodes sampling to observation (n = 360) or pelvic radiation (n = 354). With a median follow-up of 52 months, the 5-year vaginal/pelvic recurrence rate was 4% in the radiation arm compared with 14% in the observation arm (p < 0.001). The corresponding 5-year survival rates were 81% and 85%, respectively (p = 0.37).²²

In a follow-up study including 427 patients with higher-risk disease (age >60 years plus either grade 1 to 2 and outer 50% invasion, or grade 3 with inner 50% invasion, or stage IIA [1988 FIGO] disease), the PORTEC 2 study compared pelvic radiation therapy with vaginal brachytherapy. None of the patients underwent nodal assessment, and 5-year PFS (78% to 83%) and survival (80% to 85%) suggested that in this population vaginal brachytherapy was equivalent to pelvic radiation.²³

Medically infirmed patients can be treated with primary RT with good clinical benefit, and radiation is very good palliation of symptomatic metastases (brain or bone metastases, pelvic pain, or bleeding).

Endocrine therapy has been used for patients with endometrial cancer, although it is limited to the treatment of metastatic or advanced disease.²⁴ While it is most often administered to patients with a low- or intermediate-grade cancer, the predictive impact of hormone receptor status is not clear. For example, in one GOG trial that evaluated megestrol acetate alternating with
tamoxifen in 56 women, the overall response rate was 27% and OS was 14 months.²⁵ Interestingly, patients with a grade 3 tumor had a 22% response rate. Progestins and tamoxifen as single agents are reasonable options as well; although data are far more limited, the aromatase inhibitors appear to have little activity in this disease with response rates less than 10% in two small trials.

4. Chemotherapy (Table 11.2)

Increasingly, systemic therapy is being used earlier for patients with endometrial cancer. Adjuvant chemotherapy has been reported to increase 5-year survival rates (from 78% to 88%, HR 0.51, p = 0.02) in high-risk early-stage disease and is commonly recommended for deep-penetrative, node-positive, high-grade tumors. The data to support chemotherapy come from the GOG-122 trial, which included 396 patients with stage III and optimally debulked stage IV disease that were randomly assigned to treatment with whole abdomen radiation or to doxorubicin-cisplatin (AP) chemotherapy. There was significant improvement in both PFS (50% vs. 38%; p = 0.007) as well as OS (55% vs. 42%; p = 0.004), respectively, in favor of chemotherapy.²⁶

The GOG conducted a randomized trial (GOG-163) for patients with primary stages III and IV or recurrent endometrial cancer with measurable disease comparing doxorubicin and cisplatin to doxorubicin with 24-hour paclitaxel and granulocyte colony-stimulating factor (G-CSF). There were no significant differences in response rate, PFS, or OS. The disadvantage of GOG-163 was the lack of platinum in the taxane-containing arm, however. The addition of a taxane was subsequently studied in GOG-177 evaluating doxorubicin with cisplatin as the standard
arm versus paclitaxel, doxorubicin, and cisplatin (TAP regimen) and G-CSF as the investigational regimen. Overall, TAP chemotherapy increased 12-month survival to 59% compared with 50% with doxorubicin and cisplatin with a HR of 0.75 (0.56 to 0.99). Although the TAP regimen produced an improvement in response rate and PFS, survival was minimally increased, and was associated with greater toxicity.²⁷

On the basis of GOG 209, carboplatin and paclitaxel are now the more routinely administered regimen. In this trial, almost 1,300 women with recurrent or advanced endometrial cancer (including stage III disease) were randomly assigned to TAP or carboplatin plus paclitaxel. As presented at the 2012 Society of Gynecologic Oncologists Annual Meeting, women who were treated with carboplatin and paclitaxel had a similar overall response rate to those treated with TAP (51% in both arms). In addition, survival results were no different (PFS, 13 months in each arm; OS 37 vs. 40 months, respectively). However, carboplatin and paclitaxel were significantly more tolerable.

Recurrent disease (especially ER/PR-negative disease) is often treated with further palliative chemotherapy. However, response rates are very low and benefit is rarely durable.²⁸

All uterine papillary serous carcinomas are typically treated with chemotherapy after initial surgery, although patients with a serous carcinoma limited to a uterine polyp may not require adjuvant chemotherapy.

Multiple molecular pathways of cellular proliferation have been identified, and several targets within these pathways have been explored. A growing understanding of the underlying molecular biology of endometrial cancer has established the mammalian target of rapamycin, angiogenesis, and the EGFR family as relevant therapeutic targets. In addition, a subgroup of tumors have overexpression or amplification of HER2/neu; however, the role of HER2-directed therapies remains unclear and use of these drugs should be considered investigational.

The limited efficacy of systemic therapy for patients with advanced or recurrent disease has led to the initiation of several clinical trials that have tested targeted approaches against the key drivers of these pathways. Unfortunately, even though there is an initial response with these therapies, some epithelial tumors have intrinsic mutations that make them primarily resistant or eventually resistant during the course of the treatment. The mutations give the tumor the ability to bypass the blockage of one pathway and, since most pathways are redundant, tumors are still able to grow.

GOG-122 (doxorubicin-cisplatin vs. whole-abdominal irradiation) changed the landscape of endometrial cancer treatment with proof that chemotherapy improved survival compared with radiation alone for stages III and IV disease. These patients need tailored multimodality therapy; however, the sequence and schedule are not optimally defined. Therapy most commonly consists of surgery, followed by chemotherapy and tailored RT.

Surveillance requires a pelvic exam every 3 months in the first 2 years to detect a potentially curable local recurrence, and supportive care should address functional, psychological, social, and spiritual issues.

Endometrial stromal sarcomas (ESSs) and undifferentiated endometrial sarcomas are rare forms of uterine sarcomas. ESSs, whose cells resemble endometrial stromal cells, are of low grade. Other uterine sarcomas include LMS.

Uterine LMS are rare aggressive tumors, with high recurrence rates, even when confined to the uterine corpus at the time of diagnosis. These tumors are large myometrial masses, which typically spread hematogenously. Patients present with vague symptoms similar to those of patients with leiomyomas. Most patients are diagnosed with LMS postoperatively.