Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

10. Gynecologic Cancer

Thomas McNally, Richard T. Penson, Chau Tran, and Michael J. Birrer

I. CERVICAL CANCER

In 2009, the American Cancer Society (ACS) reported an estimated 11,270 new cases of cervical cancer in the United States, with 4,070 deaths attributable to the disease. 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. As many as 300,000 women die globally each year as a result of cervical cancer

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 Pap test are readily and consistently available in both poor and developed countries.

A. Histology

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

B. Screening

Early-stage disease is asymptomatic, and 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 over 70% since the Pap test was introduced in 1941.

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

The Pap test is simple, safe, inexpensive, and well validated. Screening should start within 3 years of initiating sexual intercourse, or from age 21, and be repeated every 1 to 3 years. 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. HPV-negative women over the age of 30 years with normal Pap tests can decrease their screening interval to every 3 years and stop at the age of 70, at which point the risk of having significant dysplasia is about 1 in 1000.

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 high-grade 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. There is a clear correlation between cytologic diagnosis and histologic diagnosis at colposcopy in approximately half of patients.

C. Clinical disease and staging

1. Clinical presentation. 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. Once the disease has metastasized to the regional lymph nodes, unilateral leg swelling, back pain, neuropathic pain, and postobstructive renal failure are also common symptoms. 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 chemotherapy over surgery.

2. Diagnosis. 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.

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

4. Staging (Table 10.1). 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 (MBI) 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.

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D. Treatment

Over the last century, management of cervical cancer has changed significantly: (1) more precancerous disease is managed through colposcopy, (2) there is now a preference for surgery over primary radiation, and (3) there is new evidence in the last 10 years that chemoradiation is significantly superior to radiation as primary or adjuvant therapy.

1. Dysplasia and in situ carcinoma. Options for treatment include conization (loop diathermy or cold knife), loop electrosurgical excision procedure, 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 or chemoradiation is needed. With negative margins, careful follow-up is adequate.

2. Early-stage disease. Early-stage disease can be treated with either chemoradiation or surgery, both of which have similar survival rates but different morbidity. Surgery may better preserve sexual function, although this has not been confirmed in well-controlled studies. Surgery should also 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 radiotherapy (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).

The only randomized controlled trial (RCT) to compare RT with surgery for treatment of stage IB cervical cancers reported equivalent survival (83%) and similar recurrence rates (surgery 25%; RT 26%). However, surgery was associated with more serious adverse events (28% versus 12%), and 64% of the surgical patients required postoperative radiation, likely associated with increased morbidity. 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 primary chemotherapy.

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 radicalhysterectomy. 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 and obsolete with modern imaging (MRI and PET/CT) and chemotherapy.

Adjuvant chemotherapy 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 versus 71% with RT), though it had more toxicity.

If preservation of fertility is desired, vaginal radical trachelectomy (removal of only the cervix) with lymphadenectomy for small (less than 2 cm) tumors appears to be associated with an increased fertility (with up to 50% of patients becoming pregnant postradical 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, lymphovascular space invasion, and MRI, are increasingly considered.

3. Locally advanced disease (stage IIB–IVA). In 1999, the National Cancer Institute (NCI) released a clinical alert about the large survival advantage in five NCI-sponsored clinical trials of the administration of concurrent chemotherapy with RT. 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 become the popular strategy because of its more favorable toxicity profile compared to cisplatin and 5-FU. There has not been a direct comparison of cisplatin versus cisplatin and 5-FU, though many extrapolate their equivalence from Gynecologic Oncology Group (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 to 47% for women receiving radiation and hydroxyurea.

Combining cisplatin with another agent improves response at the expense of considerably worse toxicity, but many clinicians suspect that two drugs are better than one. A provocative RCT presented at the 2009 meeting of the American Society of Clinical Oncology suggested a 32% improvement in OS forcisplatin 40 mg/m2 and gemcitabine 124 mg/m2 (both weekly for 6 weeks) over cisplatin alone 40 mg/m2weekly for 6 weeks as chemotherapy (p = 0.0220). Typically half of the operative specimens from bulky tumors contain residual carcinoma after chemoradiation, and an adjuvant extrafascial hysterectomy is typically recommended.

4. Adenocarcinoma. Adenocarcinoma is associated with a worse prognosis, with no clear data that a more aggressive approach results in a better outcome. Treatment is typically the same as that for squamous cell carcinomas.

5. Neoadjuvant and adjuvant chemotherapy. 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. However, early positive results could not be confirmed and this approach has fallen out of favor.

6. Palliative chemotherapy. For recurrent tumors, the ultimate goals of treatment are palliative, and the most active single agents are cisplatin, ifosfamide, paclitaxel, vinorelbine, and topotecan with response rates of 15% to 23%. Response rates of tumors located within a radiation field are typically halved; in the chemotherapy era, palliative chemotherapy is less effective. Combination platinum-based therapy with ifosfamide, paclitaxel, or topote-can is associated with higher response rates for all three agents, but cisplatin 50 mg/m2 on day 1 with topotecan 0.75 mg/m2 on days 1 to 3 is the only combination associated with an OS advantage (9.4 months versus 6.5 months). Despite this, the standard of care is cisplatin 50 mg/m2 on day 2 and paclitaxel 135 mg/m2 on day 1 as a 3- or 24-hour infusion because of its better toxicity profile. Single-agent, nonplatinum combination or paclitaxel and carboplatin are reasonable options. A newer study (GOG-240) compares cisplatin and paclitaxel with topo-tecan and paclitaxel, with and without bevacizumab, because with cisplatin as the standard in chemotherapy, response rates to platinum combination regimens has fallen.

7. Novel biologics. 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.

8. Palliative care. Supportive care, which addresses physical, psy-chological, 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 fistulae, and require multiprofessional care.

II. ENDOMETRIAL CANCER

Endometrial cancer is the most common gynecologic malignancy. The ACS estimates that there were 42,160 new cases in 2009 in the United States, with 7780 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 readily cured with surgery alone. Prior treatment with tamoxifen is a significant risk factor for developing endometrial cancer. As tamoxifen has been used in the prevention and treatment of all stages of breast cancer, a significant population of women has been exposed to this drug and is therefore at increased risk of developing endometrial cancer.

A. Histology

Endometrial cancer includes endometrial carcinomas (95%) and mesenchymal tumors (5%). Mesenchymal tumors are comprised of uterine sarcomas (leiomyosarcomas and endometrial stromal sarcoma) and mixed epithelial/stromal tumors (carcinosarcomas and adenosarcomas). Histologic subtypes of endometrial carcinomas include endometrioid (75% to 80%), serous (5% to 10%), clear cell (1% to 5%), and other rare carcinomas (less than 2%), such as mucinous, squamous cell, transitional cell, and small-cell cancers. Endometrial carcinomas are also designated as types I and II, with type I being an estrogen-driven, endometrioid tumor occurring in obese women, and type II referring to all other, more aggressive histologic subtypes.

B. Screening

Screening is not necessary for endometrial cancer as the disease typically presents early with postmenopausal vaginal (PMV) bleeding and has a good prognosis with effective treatment (sur-gery). Although screening patients by ultrasound for thickened endometrial stripe has been advocated for patients who are on tamoxifen and are at increased risk of endometrial cancer, there is no clear survival advantage over clinical surveillance for PMV bleeding. Therefore, the role of ultrasound is probably limited to surveillance of pre-existing benign lesions. By contrast, in patients at higher than average risk of endometrial cancer because of a family history of colorectal cancer (Lynch II syndrome), prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO) prevents all (100%) uterine cancers.

C. Clinical disease

1. Clinical presentation. The most common symptoms ofinvasive 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 who are at high risk for endometrial cancer and are over the ageof 40 years. Metastatic intraperitoneal disease may also cause symptoms similar to ovarian cancer, including abdominal dis-tension, pelvic pressure, and pelvic pain. On pelvic ultrasound, a thickened endometrium is a sign of possible endometrial cancer and should be followed up by a gynecologic oncologist.

2. Diagnosis. For a definitive diagnosis of endometrial cancer, a tissue biopsy must be performed, usually through an endometrial biopsy (EMB) or fractional dilation and curettage (D&C). Today, 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. Tissue samples from either diagnostic method allow for pathologic evaluation of the endometrium, which can help determine the cause of the patient's symptoms, even if they are not the result of cancer.

3. Prognostic factors. 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 lymphovascular space invasion. The prognosis of type I carcinomas is more favorable than that of type II because of their lower grade and sensitivity to hormone therapy.

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%.

4. Staging (Table 10.2). Endometrial cancer is surgically staged. As per FIGO recommendation, the surgery is done via an abdominal incision, followed by parametrial washings along with examination and palpation of omentum, liver, adnexal surfaces, peritoneal cul-de-sac, and enlarged aortic and pelvic nodes. Total abdominal hysterectomy (TAH) with BSO and complete lymphadenectomy are also standard in the United States. It should be noted, however, that the benefits of complete lymph-adenectomy have been challenged with two negative randomized studies and are not standard in Europe. Further pathologic examination and frozen section assessment also contribute to accurate staging.

D. Treatment

1. Surgery. Surgery is most commonly all that is needed to cure endometrial cancer. Although ACOG recommends at least aTAH-BSO and node dissection, the role of nodal dissection is increasingly controversial. 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 (4% versus 21%, p = 0.007).

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Debulking involved lymph node metastases (greater than 8 mm) may have an impact on prognosis, but lymphadenectomy for patients with stage I and II disease is not associated with a survival advantage in a recent RCT, and a growing consensus appears to support less aggressive surgical approaches in women with grade 1 or 2 endometrioid tumors with less than 50% myometrial invasion, less than 2 cm in tumor length, and no obvious other macroscopic disease.

Prophylactic TAH-BSO has been reported to prevent 100% of uterine cancers of women undergoing risk-reducing surgery for hereditary nonpolyposis colon cancer.

2. RT. Radiation is given adjuvantly to reduce the risk of local recurrence (brachytherapy to the vaginal vault postoperatively). External-beam RT (EBRT) 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. However, this is increasingly controversial as there is no proven survival advantage. RT in the form of brachytherapy is administered to the vaginal vault for high-risk tumors and tumors involving the lower uterine segment. 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.

Medically unfit patients with serious comorbidities 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).

3. Hormonal therapy. Hormonal therapy is recommended only for patients with recurrent or inoperable tumor that is estrogen receptor (ER)/progesterone receptor (PR) positive. Adjuvant progestin therapy is not recommended because of excess cardiovascular mortality. Clinical responses to progestins (such as medroxyprogesterone acetate 80 mg twice a day) are consistently reported in approximately one-third of patients (15% to 34%), similar to other agents, such as tamoxifen, and probably no better than the highest reported response rate with tamoxifen alternating with a progestin. Aromatase inhibitors and gonadotropin-releasing hormone agonists are reasonable alternatives.

4. Chemotherapy (Table 10.3). The role of systemic therapy for endometrial cancer is changing and controversial. Adjuvant che-motherapy has been reported to increase 5-year survival rates (from 78% to 88%, hazard ratio [HR] 0.51, p = 0.02) in high-risk early-stage disease and is commonly recommended for deep penetrative, node-positive, poor-grade tumors. Although one standard combination is paclitaxel, doxorubicin, and cispla-tin, paclitaxel and carboplatin is the most popular choice because of a better toxicity profile. These are being compared in GOG-209.

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Recurrent disease (especially ER/PR-negative disease) is often treated with further palliative chemotherapy such as weekly paclitaxel, liposomally encapsulated doxorubicin, topo-tecan, low-dose gemcitabine, and cisplatin. However, response rates are very low and benefit is rarely durable.

5. Uterine papillary serous carcinoma. All uterine papillary serous carcinomas, except those limited to a polyp, are typically treated with chemotherapy after initial surgery. Although they more commonly have HER2/neu overexpression or amplification, trastuzumab has no proven role.

6. Novel biologics. The role of mTOR, AKT inhibitors, and PI3 kinase inhibitors looks promising for endometrioid tumors, but remains investigational. One report suggests that with a 16% response rate, bevacizumab is worthy of further study.

7. Multimodality therapy. GOG-122 (doxorubicin-cisplatin versus whole-abdominal irradiation [WAI]) changed the landscape of endometrial cancer treatment with proof that chemotherapy improved survival compared to radiation alone for stage III and IV disease, with 50% compared to 38% of patients alive at 5 years (HR 0.68, p 0.01). 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. Paclitaxel, doxorubicin, and cisplatin (TAP) is thought to be more toxic than the more popular regimen of paclitaxel and carboplatin.

8. Follow-up. Surveillance requires apelvic 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.

III. UTERINE SARCOMAS

A. Histology

Endometrial stromal sarcomas (ESSs) and undifferentiated endo-metrial sarcomas are rare forms of uterine sarcomas. ESSs, whose cells resemble endometrial stromal cells, are low-grade. Other uterine sarcomas include malignant mixed mullerian tumor (MMMT) and leiomyosarcomas.

B. Clinical disease

1. Clinical presentation and diagnosis. ESSs are a specific histologic subtype within the larger group of mesenchymal tumors of the uterine corpus. The most common symptom experienced by women with ESS is abnormal vaginal bleeding. ESS tumors are almost always low-grade and on gross examination usually present as a single mass. They can occur in sites other than the uterus, including the ovary, fallopian tube, cervix, vagina, vulva, pelvis, abdomen, retroperitoneum, placenta, sciatic nerve, or round ligament. ESS can be mistaken for endometrial stromal nodules; two distinguishing characteristics are infiltrating margins with or without angioinvasion, both of which are found in sarcomas but are absent in nodules. A definitive diagnosis of ESS is not possible from endometrial curettage specimens alone, and a full hysterectomy is required.

Undifferentiated endometrial sarcomas are marked by ex-tensive cytologic atypia to the point where they can no longer be recognized as arising from the endometrial stroma. Grossly, these tumors resemble undifferentiated mesenchymal tumors and mimic high-grade sarcomas in behavior.

2. Prognostic factors. Stage and grade for all three types are important when considering a patient's prognosis. ESS has a good prognosis, in part due to its low-grade characteristics, and mostare cured surgically. However, low-grade ESS behaves aggres-sively if the following characteristics are present: high expressionof androgen receptors or low expression of estrogen receptors. The relapse rate for ESS is 62%. Recurrence commonly includespulmonary metastases and responds to hormonal therapy(progestins or aromatase inhibitors). MMMTs, which behave ina manner similar to high-grade sarcomas, are often fatal andhave a relapse rate of 85%.

3. Staging is according to FIGO criteria.

C. Treatment

ESS is typically treated with surgery and possible hormonal therapy, including progestins or aromatase inhibitors. Leiomyosarcoma is treated with surgery, RT, and palliative chemotherapies. These include gemcitabine with docetaxel and occasionally hormonal therapy, as with ESS. MMMT is treated with surgery followed by multimodal therapies, including RT and chemotherapy. Chemotherapy includes carboplatin with paclitaxel or ifosfamide with cisplatin, although the latter combination is much more toxic. Chemotherapy (cisplatin-ifosfamide and mesna) may be superior to other regimens as postsurgical therapy in stage I to IV carcinosarcoma (MMMT) of the uterus (52% versus 58% [WAI], HR 0.789, p = 0.245).

IV. OVARIAN CANCER

Ovarian cancer is a relatively rare disease, with an incidence of about 1 in 70 women. In the United States, there were 21,550 new cases of ovarian cancer and 14,600 deaths attributable to the disease in 2009, according to the ACS. As early-stage ovarian cancer is rarely symptomatic, and due to the fact that there are no effective screeningprotocols, ovarian cancer patients typically present with advanced stage disease (stages II to IV). Although the tumors are very responsive to chemotherapy, thus enabling the majority of patients to live for years with their disease (overall 5-year survival rate is 45.6%), the patients are rarely cured. The cause of epithelial ovarian cancer remains unknown, but theories relate it to incessant ovulation or abnormalities in the fallopian tube fimbria.

A. Histology

Epithelial ovarian carcinomas are classified as serous (70%), endometrioid (20%), clear cell (10%), and more rare types including Brenner and undifferentiated or mixed epithelial tumors. Seventy-five percent of papillary serous carcinomas of the ovary are diagnosed in the advanced stages, while only 40% of mucinous, endometrioid, and clear cell carcinomas are diagnosed in the advanced stages. Gene profiling studies suggest that treatment will be tailored to genotype or histology. However, these studies are only in the planning stages.

B. Screening

Screening for ovarian cancer would be an important benefit because most patients present with advanced, and therefore incurable, disease. Screening tests (ultrasound and cancer antigen [CA]-125) appear sensitive, but there are no data that suggest that screening improves survival. The challenges of developing an effective screening regimen are considerable: (1) there is no clear premalignant precursor, (2) serous carcinoma appears to develop rapidly, and (3) the morbidity from the diagnostic procedure (laparotomy) requires that the screening tests be very specific. The serum marker CA-125 is elevated in only 50% of patients with stage I disease, but is elevated in 90% of stage II to IV ovarian cancers. CA-125 testing typically has a specificity of 97% to 99%, but with a 1 in 70 lifetime risk of ovarian cancer, occult disease is present in only 1 of 2,300 postmenopausal women. As a result, a false positive rate of 1% to 3% is unacceptably high.

The largest CA-125 based screening study reported to date included 21,935 postmenopausal healthy women in the United Kingdom. In the study, a positive CA-125 test was followed by ultrasound, and the death rate was apparently halved by screening (18 of 10,977 versus 9 of 10,958, p = 0.083). The definitive UK Collaborative Trial of Ovarian Cancer Screening in 200,000 post-menopausal normal-risk women is expected to report by 2014. In contrast to previous studies, the CA-125 arm of the trial uses Risk of Ovarian Cancer Algorithm (ROCA), which examines previous CA-125 values from a screened subject to interpret her latest CA-125 test and decide whether to refer for ultrasound. In preliminary data, ROCA resulted in only 100 surgeries to find 41 cancers (positive predictive value [PPV] 41%) compared with 855 surgeriesto find 44 cancers when using ultrasound alone (PPV 5%). The US study (Prostate, Lung, Colorectal, and Ovary Cancer Screening Trial) has enrolled 150,000 subjects: 75,000 women screened for lung, colorectal, and ovarian cancer, and 75,000 men screened for prostate, lung, and colorectal cancer. In the first analysis, 89 cancers were diagnosed, with 60 from screening (PPV 1% to 1.3%), and the surgery-to-cancer ratio was greater than 20:1 with 72% stage III or IV. There continues to be speculation about whether the sensitivity of screening can be improved by the use of other biomarkers. Screening with six monthly CA-125 and transvaginal ultrasound is recommended in high-risk populations (positive family history, BRCA-mutation carrier). However, risk-reducing salpingo-oophorectomy reduces the risk of subsequent cancer by 90% to 95% and is a safer strategy once a woman has finished bearing children.

C. Clinical disease

1. Clinical presentation and diagnosis. The most common symptoms experienced by women with ovarian cancer include persistent bloating, pelvic or abdominal pain, early satiety, and urinary urgency or frequency. While these symptoms are common and not specific to women with cancer, they have been found to be much more common and severe in women with an ovarian malignancy. Other symptoms reported include fatigue, indigestion, back pain, pain during intercourse, constipation, and menstrual irregularities, although these do not appear to be any more common in women with cancer. The most common clinical sign of ovarian cancer is an adnexal mass as found on a pelvic ultrasonography (ultrasound) or through manual palpation during a pelvic exam. Most masses do not prove malignant in premenopausal women. As such, a simple cyst less than 8 cm in diameter in a premenopausal woman can be followed up by the treating physician in 1 to 3 months. Adnexal masses in premenarchal or postmenopausal women, however, are much more concerning for malignancy, especially if they are large and complex. Physical features of an adnexal mass commonly associated with malignancy, as seen on a pelvic ultrasound, include irregular borders, multiple echogenic patterns due to presence of solid elements, multiple irregular septa, and bilateral tumors. A serum CA-125 level greater than 35 U/mL in nonpregnant women should also be cause for concern for ovarian cancer. Typically, a conclusive diagnosis is not possible until after surgery, followed by an assessment of the surgical specimen by a pathologist.

2. Prognostic factors. Prognostic factors for epithelial ovarian cancer include stage, volume of residual disease, grade, and histologic subtype. With respect to stage, the 5-year survival is directly correlated. Stage I disease has a 90% 5-year survival, while stage II disease has an 80% 5-year survival. The percentage decreases dramatically for stage III (15% to 20% 5-year survival) and stage IV (less than 5% 5-year survival). Optimally cytoreduced patients (1 cm) have a higher median survival than suboptimally cytoreduced patients.

Epithelial ovarian cancer subtypes have different overall patient survivals with respect to both histology and stage at diagnosis. Among early stage (I and II) ovarian carcinomas, patients with endometrioid and mucinous tumors have a 10-year survival rate of 85% and 79%, respectively, while those patients with clear cell and high-grade serous tumors have a 10-year survival rate of 70% and 57%, respectively. However, compared to endometrioid and serous tumors, clear cell and mucinous tumors have a dramatically poorer prognosis in late stage (III and IV) disease. The overall 10-year survival rate for all stages is 39%.

Low-grade and low malignant potential (LMP) cancers have better survival rates than high-grade cancers, but are more likely to be refractory for chemotherapy. The grade of the ovarian cancer affects the overall patient survival due to differences in the gene expression of proliferative markers. Late-stage high-grade tumors express high levels of genes involved in cell proliferation and metastasis, such as PDCD4, E2F3, MCM4, CDC20, and PCNA. LMPs and low-grade serous tumors exhibit low expression of proliferation markers such as CDC2, KIF11, TOP2A, CCNB1, and MKI67, as well as activation of wild-type p53.

3. Staging (Table 10.4). Stagingfor ovarian cancer occurs at surgery. Per FIGO, complete exploration of the abdomen and pelvis with resection of all gross disease as well TAH-BSO and pelvic and para-aortic lymphadenectomy are recommended. If desired, fertility-conserving surgery may be performed on patients with low-stage, low-grade lesions.

D. Treatment

1. Cytoreductive surgery. Ovarian cancer is one of the only cancers where resection of metastatic disease is a standard part ofinitial management. Laparotomy is often both the diagnostic procedure and initial therapeutic intervention, and the key to cure.

Griffiths was one of the first to pioneer the concept that successful surgical debulking to a residual tumor size of ≤1.5 cm (now 1 cm) maximum diameter results in superior survival. Surgical cytoreduction (debulking) has several purposes: (1) it removes some or all of the tumor, (2) it improves physiology (GI obstruction and protein loss to ascites), (3) it removes de novo chemotherapy-resistant clones, and (4) it facilitates drug delivery by removing tumor with a compromised blood supply. Patients are stratified into “optimally ”(1 cm residual disease) or “suboptimally” cytoreduced; it is the second most powerful predictor of outcome after stage.

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Primary or “neoadjuvant” chemotherapy has gained popularity with preliminary data from European Organization for the Research and Treatment of Cancer (EORTC) 55971, an RCT of initial chemotherapy or initial surgery in a poorer prognosis group (median PFS 12 months and OS 30 months) of 718 women. There were equivalent outcomes, with a 2% mortality after upfront debulking surgery, suggesting that neoadjuvant chemotherapy may be safer in patients that have disease that is difficult to resect, significant comorbidities, or are older in age, and that it may also get more patients to have an optimal surgi-cal procedure at some point in their clinical course.

Follow-up for patients should include a pelvic examination and CA-125, initially every 3 months, though early detection of recurrence does not appear to improve survival.

2. Early-stage ovarian cancer. Although only 15% of ovarian cancers present as early-stage disease, one-third to one-half of all cured patients are from this group. Formal staging is requiredby a surgeon with subspecialty training with an exploratory laparotomy, TAH-BSO, omentectomy, complete examination of the peritoneal surfaces, multiple biopsies, peritoneal washings, and para-aortic and pelvic lymph node sampling. Patients diagnosed with apparently early-stage ovarian cancer without adequate staging should undergo a second exploratory surgery for definitive staging. Approximately one-quarter will be upstaged by positive nodes.

The 5-year survival of patients with stage I epithelial cancer is ≥90%. Patients with stage IA and IB disease of low-grade do not need adjuvant chemotherapy. All other patients require adjuvant platinum-based chemotherapy based on the joint International Collaboration in Ovarian Neoplasia (ICON I) and EORTC's ACTION study for an 8% improvement in OS.

GOG-157 compared three with six cycles of carboplatin and paclitaxel (TC) in early-stage disease. While more cycles were associated with more toxicity, there is also a significant superior survival outcome (in serous tumors), and most patients receive six cycles of chemotherapy if they can tolerate it.

3. Advanced-stage ovarian cancer. The principles of treatment for patients with advanced ovarian cancer are to (1) surgically cytoreduce, or debulk, tumor with surgery, followed by (2) chemotherapy (Table 10.5). A remission (normal CA-125 and CT scan) only translates into cure for a minority, but 5-year survival rates for patients treated with platinum-based regimens are >40%. Even after a complete response to first-line chemotherapy, only approximately half of patients with negative second-look operations are eventually cured.

4. Platinum-based first-line chemotherapy. Chemotherapy has improved through the last 40 years from single-agent alkylators (melphalan and cyclophosphamide) to anthracycline combinations and finally platinum- and taxane-based therapy. Cisplatin and carboplatin (less GI toxicity but more heme toxicity), nonclassic alkylators, were demonstrated to have a significant survival advantage, and meta-analysis of randomized trials before 1991 concluded that cisplatin combinations were superior to single-agent or noncisplatin therapy, and that cisplatin and carbopla-tin were equally effective. Paclitaxel inhibits microtubule depo-lymerization and demonstrated significant activity in patients with ovarian cancer refractory to platinum chemotherapy, once hypersensitivity reactions to the diluent ethoxylated castor oil in paclitaxel were overcome by dexamethasone premedication. GOG-111 reported a substantial survival advantage replacing cyclophosphamide with paclitaxel in 410 randomly assigned women with suboptimally debulked advanced ovarian cancer. Cisplatin 75 mg/m2 and paclitaxel 135 mg/m2 over 24 hours was associated with more alopecia, neutropenia, fever, and al-lergic reactions, but improved median OS from 24 to 38 months (p0.001). Standard of care was defined in GOG-158, which compared cisplatin and paclitaxel with TC. Six cycles of carboplatin area under the curve (AUC) 7.5 and paclitaxel 175 mg/m2 over 3 hours was a convenient outpatient regimen that produced less GI, renal, and metabolic toxicity, and had a similar degree of peripheral neuropathy with a median OS of 57 months.

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5. Promising strategies. A number of different strategies have been pursued to try and improve survival outcomes, but moderate increases in platinum dose or density, alternate cytotoxics that are active in recurrent disease (such as gemcitabine, pegylated liposomally-encapsulated doxorubicin [PLD], and topotecan-based triplets), have not impacted survival.

Four strategies appear promising but await confirmatory studies: (1) intraperitoneal administration, (2) the addition of bevacizumab, (3) maintenance therapy, and (4) dose-dense paclitaxel. A better appreciation of the biologic mechanisms underpinning the behavior of ovarian cancer is anticipated to herald the rational integration of novel targeted therapeutics, personalized to particular subsets of cancer genotype [such as BRCA-defective serous tumors, poly-(ADP-ribose) polymerase [PARP] inhibitors, or BRAF overexpressing low-grade tumors].

6. Intraperitoneal chemotherapy. Delivering regional chemotherapy with the highest possible concentration of drug at the tumor appears rational. Ovarian cancer invites intraperitoneal (IP) infusion with a high ratio of IP to systemic drug concentration (cisplatin 10×, paclitaxel 1000×). Three randomized studies have suggested a substantial survival advantage. However, unacceptable toxicity has been a barrier to utilization of IP which is not considered standard therapy.

GOG-104 was a randomized trial of IV cyclophosphamide with either IP or IV cisplatin and associated with an 8-month median survival advantage. GOG-114 included IV paclitaxel with IP cisplatin and two initial cycles of moderate dose carboplatin and an 11-month survival advantage. The third study (GOG-172) led to an NCI alert about the potential advantage of IP therapy in patients with optimally debulked ovarian cancer because of an unprecedented 16-month survival advantage. The Armstrong regimen of paclitaxel 135 mg/m2 over a 24-hour period (to reduce neurotoxicity) followed by IP cisplatin 100 mg/m2on day 2 with IP paclitaxel 60 mg/m2 on day 8 given every 3 weeks for six cycles was associated with more fatigue and hematologic, GI, metabolic, and neurologic toxicity, with significantly worse quality of life, but an improvement in median duration of OS from 50 to 66 months (p = 0.03).

The GOG recommends trying to put the IP catheter in at the time of original laparotomy if possible, but if a bowel resection is required, a first cycle of IV chemotherapy followed by a laparoscopically placed IP catheter may reduce complications. BardPort (Bard Access System, Salt Lake City, UT) silicone peritoneal catheter 14.3 Fr with no Dacron cuff (U.S. Food and Drug Administration [FDA]-approved for use in IP therapy) and silicone 9.6 Fr singlelumen IV access devices are most commonly used.

Concerns remain that IP chemotherapy may not reach subperitoneal disease, lymph nodes, or areas walled off by adhesions. However, the biggest concerns are about catheter complications (infection, pain, and blockage), which are serious in a quarter of patients and prevented 58% of patients from completing IP therapy in GOG-172. Technical challenges remain a barrier to its use in some settings, and a further study (GOG-252) will explore IP carboplatin, dose-dense paclitaxel, and the role of bevacizumab.

7. Bevacizumab. GOG-218 investigated the integration of bevacizumab in the upfront treatment of advanced ovarian cancer with TC. A preliminary report suggested that maintenance, not just concurrent bevacizumab, is associated with a statistically significant PFS advantage. Bevacizumab is a particularly promising agent as the response rate is highest in ovarian cancer compared with any other solid tumor. Toxicities in patients with recurrent disease have included hypertension, proteinuria, and arterial thromboses. One study was halted with 5 of 44 patients developing bowel perforations, two of which proved fatal.

8. Maintenance therapy. In patients with suboptimally debulked disease, who are destined to have relapse, maintenance therapy is a rational strategy. GOG-178 compared 1 year of single-agent paclitaxel with only 3 months, and it appeared to delay the time to recurrence by an additional 7 months. Though it is not a standard of care, it provoked GOG-212, which investigates a potentially less neurotoxic agent, polyglutamated paclitaxel (Xyotax).

9. Dose-dense (weekly) paclitaxel. Weekly paclitaxel in the recurrent setting is associated with more peripheral neuropathy but less overall toxicity, both hematologic and nonhematologic, and has become a popular option. A recent RCT of AUC 6 carbopla-tin with either paclitaxel 180 mg/m2 every 21 days or 80 mg/ m2 every 7 days (dose-dense paclitaxel [Taxol] and carboplatin [dd-TC]) in 631 Japanese patients reported better median PFS (28 months versus 17 months), and OS at 2 years (84% versus 78%, p = 0.05). Grade 3 and 4 anemia was reported more frequently in the dd-TC group, and other toxicities were similar in both groups. This strategy is being tested in GOG-262.

10. PARP inhibition. Possibly the most promising area of investigation is the inhibition of PARP.PARP adds nicotinamide adenine dinucleotide polymers to histones and other nuclear proteins, thereby improving cell survival after DNA damage. If this sys-tem is inhibited, PARP-1 activation cannot lead to DNA repair through the base excision repair pathway. If there is no other repair system, such as when a patient carries a BRCA-1 or -2 mutation, or has functional impairment in the repair pathways, which has been reported in up to nearly half of serous ovarian tumors (synthetic lethality), apoptosis results. The oral agent olaparib (AZD-2281) is well tolerated with responses in a third of heavily pretreated patients with BRCA mutations, and the IV PARP inhibitor BSI-201 (iniparib) has improved response rates, PFS, and OS in triple negative breast cancer, which has a similar genotype. Other agents such as ABT-888 (veliparib) are in development.

11. Docetaxel and carboplatin. The SCOTROC studydemonstrated that docetaxel was significantly less neurotoxic than paclitaxel and equally effective in combination with carboplatin, and is a valid but less used alternate to paclitaxel.

12. Recurrent disease. Most patients develop recurrent disease, initially with subsequent remission, then continual treatment, and finally palliation, most commonly of bowel obstruction. Ovarian cancer is sometimes considered a chronic disease, as treatment with palliative chemotherapy allows patients to live for years with their disease and with good quality of life.

Recurrent ovarian cancer is triaged by the predictive factor, platinum-free interval, and divided into potentially platinum sensitive (more than 6 months since prior platinum) with a median survival measured in years and platinum-resistant disease with survival measured in months.

The definition of relapse is important as a rising CA-125 typically has a lead time of 2 to 6 months before symptoms develop. Patients with an asymptomatic rising marker can be managed expectantly, as palliative chemotherapy has toxicities and OV05/55955 clearly demonstrated that treating women with an asymptomatic rising CA-125 adversely affected quality of life and did not impact survival. The study was designed to detect a 10% improvement in 2-year OS and randomized 1,442 patients to (1) immediate chemotherapy if CA-125 levels rose to greater than twice the upper limit of normal (a median of 5 months earlier), or (2) patient and clinician were blinded to the CA-125, and then got treatment at symptomatic progression of disease.

13. Platinum-sensitive disease. Rechallenge with a platinum com-bination is appropriate with a platinum-free interval of at least 6 months and standard combinations include (1) pacli-taxel and carboplatin, (2) gemcitabine and carboplatin, and (3) PLD and carboplatin.

ICON 4 demonstrated an absolute improvement in the 1-year PFS of 10% and 18% reduction in risk of death (p = 0.02) for paclitaxel and carboplatin over conventional platinum-based chemotherapy. The AGO (German) study led to the FDA approval of the combination for platinum-sensitive recurrent ovarian cancer with a 28% improvement in PFS for carboplatin and gemcitabine over carboplatin (p = 0.0031). Lastly, CALYPSO, reported only in abstract form, suggests that PLD carboplatin may be associated with a significant superior PFS (11.3 months versus 9.4 months, p = 0.005), and less alopecia and neurotoxicity.

14. Platinum-resistant disease. When disease becomes resistant to platinum, the goals are maximum time without symptoms from cancer or toxicity from treatment. Chemotherapy is chosen as much on the convenience and side effect profile as potency, and response rates are consistently poor (15% to 20%). Continual, sequential, single-agent palliative chemotherapy has been the mainstay of treatment for recurrent disease. CA-125 may better predict response to treatment and outcome than CT scans. PLD, topotecan, a different taxane schedule (e.g., a weekly paclitaxel), rechallenge with platinum, gemcit-abine, altretamine, pemetrexed, or oral etoposide are all reasonable options. Hormonal therapy, often tamoxifen, can be effective in ER-positive tumors. The role of surgery is controversial. Many patients are appropriate for clinical trials, and an exciting number of agents are being investigated.

15. Palliative care. Obstructive symptoms typically herald the last months of patients' lives and require intense and multiprofes-sional care. Surgery should be limited to patients with chemo-therapy-responsive disease, and for others a gastric venting tube alleviates vomiting. Total parenteral nutrition does not substantially alter the clinical course, and attending to end-of-life issues is an essential part of compassionate care.

V. VULVAR CANCER

Vulvar cancer is rare, representing 4% of all gynecologic malignancies and 0.6% of all cancers in women. The ACS estimates that 3,580 women were diagnosed with vulvar cancer in 2009, with 900 deaths attributable to the disease. Older women are at increased risk, with less than 20% of cases occurring in women under the age of 50, and roughly half occurring in women 70 years and older. Vulvar cancer in younger women tends to be associated with HPV infection. The disease usually presents with symptoms at an early stage, making it a highly treatable disease. However, due to its very personal nature, as well as its relative rarity, symptoms may often go unaddressed for some time, allowing the disease to progress beyond the early stages.

A. Histology

Carcinoma of the vulva is classified as squamous (80% to 90%), melanoma (9%), and Bartholin gland cancer and sarcomas (1% to 11%).

B. Screening

There are no routine screening protocols for the detection of vul-var cancer, and clinical presentation is the earliest detection pointfor the disease. However, patients should be encouraged to be vigilant about their genital health, and clinicians should be proactive in examining and performing biopsies on vulvar abnormalities.

C. Clinical disease

1. Clinical presentation and diagnosis. The majority of women who present with early-stage vulvar cancer have a recognizable lesion on the vulva, along with local symptoms, including soreness and itching. The treating clinician should proceed directly to tissue biopsy in order to avoid delay in diagnosis. The biopsy should include both the cutaneous lesion in question and the underlying stroma in order to determine the depth of invasion, if any. If left untreated for a long period of time, advanced-stage disease may result, and the patient will often present with local pain, bleeding, and surface drainage. Advanced disease can also metastasize to the regional lymph nodes and eventually more distant tissues.

2. Prognostic factors. Age of patient, clinical stage, nuclear grade, depth of tumor invasion, and presence of lymph node metastasis are significant prognostic parameters, with depth of tumor invasion being an independent factor. Patients with metastasis to the inguinal lymph nodes will experience recurrences within 2 years of first-line therapy, and the long-term survival is reduced by 50%. In addition, the overexpression of p53 has been linked to tumor aggressiveness.

3. Staging (Table 10.6). The method of staging vulva cancer is surgery with histologic findings.

D. Treatment

1. Early-stage disease. Vulvar cancer is surgically staged. Early-stage tumors (microinvasive, stage I and II) are treated with surgical approaches. Microinvasive tumors can usually be successfully treated with local resection, but multifocal disease remains a problem. All patients should be carefully followed.

a. Stage IA. Stage I disease is subdivided based on depth of stromal invasion. For stage IA lesions, invading less than 1 mm into the stroma, the treatment of choice is radical local excision without lymph node dissection, as the risk of nodal invasion for these lesions is less than 1%.

b. Stage IB. Stage IB lesions have ≥1 mm stromal invasion. As the risk of inguinofemoral node involvement is ≥8%, it is recommended that patients undergo inguinofemoral lymph node dissection. Whether patients need a unilateral or bilateral lymph node dissection (for midline lesions) depends on the location of the lesion.

c. Stage II. Surgical resection of stage II lesions needs to procure a ≥1 cm circumferential tumor-free margin around the primary lesion. In order to achieve this goal, the excision mayinvolve a radical local excision, a partial radical vulvectomy, an excision using a three-incision technique, or the involvement of plastic surgery and skin flaps.

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In general, given the long-term side effects and morbidity of RT, this treatment modality is avoided in the man-agement of early-stage disease. For patients whose tumors have a positive margin, following initial surgical excision, the recommendation is for surgical re-excision unless this is anatomically not feasible or the patient is not an appropriate surgical candidate for re-excision. Re-excision is favored over RT given the toxicity associated with RT.

RT is usually recommended for patients with two or more microscopically positive groin nodes, one or more mac-roscopically positive lymph nodes, evidence of extracapsular nodal involvement, or in some aggressive cases where only a small number of lymph nodes were retrieved.

2. Advanced-stage disease

a. Stage III and IV. In general, the treatment of advanced-stage disease is individualized. Although many of these lesions can beresected surgically, this treatment modality may significantly impair quality of life. For example, for tumors involving the urethra, anus, bladder, or pelvic bone, surgical resection would require removing vital structures or pelvic exenteration with creation of a urinary conduit and colostomy. Given the morbidity of this surgical procedure, for these patients, the favored treatment modality is chemo-RT. In these cases, chemo-RT can be given preoperatively in order to reduce tumor volume and allow for a less radical surgical resection. For tumors that completely respond to chemo-RT, surgical resection can be omitted. In general, these patients are treated with RT and concurrent cisplatin and 5-FU chemotherapy as radiation sensitizers.

b. Palliative chemotherapy. In patients with advanced-stage disease, those too medically infirm for surgery, or those with inoperable disease, palliative chemotherapy may be appropriate as treatment when curative intent is not feasible. Therapeutic options are limited and agents active in other squamous cancers, such as cisplatin, 5-FU, doxorubicin, methotrexate, mitomycin C, bleomycin, cisplatin, and paclitaxel, are associated with low response rates in vulvar cancer. Novel targeted therapies with promise in the treatment of vulvar cancer include anti-EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and monoclonal antibodies such as cetuximab, either as single-agent therapy or in combination with chemotherapeutic drugs such as cisplatin.

VI. OVARIAN GERM CELL TUMORS

Germ cell tumors represent a rare subset of ovarian cancer. They usually present in a younger age group (median age 30 years) compared with epithelial ovarian cancers. The etiology of these tumors remains unknown. They are highly chemosensitive, and as such, are usually highly curable.

A. Histology

Germ cell tumors account for 2% to 3% of ovarian cases and are comprised of the following subtypes: dysgerminoma, yolk sac tumor, embryonal carcinoma, polyembryoma, nongestational cho-riocarcinoma, mixed germ cell tumor, and teratoma. The majority of patients (50% to 75%) are diagnosed in the early stages (I and II).

B. Screening

Because these tumors are so rare, there is currently no screening strategy. However, diagnosis should be considered preoperatively in the young, and markers should be drawn so that treatment can be planned accordingly (especially for fertility-sparing surgery).

C. Clinical disease

1. Clinical presentation and diagnosis. Malignant ovarian germ cell tumors usually occur in women much younger than withepithelial ovarian cancer, with a median age between 16 and 20 years, depending on the specific histologic type. Common signs and symptoms of the disease include a pelvic mass, usually detected during a pelvic exam, and abdominal pain, often resulting from ovarian rupture, hemorrhage, or torsion. Other symptoms include abdominal distension, fever, and vaginal bleeding, although these are less common. Many germ cell tumors will produce biologic markers, which are useful in the diagnosis and observation of the disease. The two most common are human chorionic gonadotropin (hCG) and a-fetoprotein (AFP). Elevated AFP suggests a teratoma rather than dysgermi-noma, the most common histologic subtype. As with epithelial ovarian cancer, CA-125 may also be elevated in patients with germ cell tumors.

2. Prognostic factors. Patients diagnosedwith germ cell tumors have a relatively good prognosis due to sensitivity to chemotherapy. A combination of complete resection of tumors, proper surgical staging, and effective therapy ensures a high survival rate. Long-term survivorship can be achieved even without complete tumor resection or with advanced tumors at presentation.

3. Staging. Per FIGO recommendation, staging follows the same principles as for epithelial ovarian tumors (see Table 10.4).

D. Treatment

Surgery is the first step in managing malignant ovarian germ cell tumors. Because the patient population is fairly young, it is not un-reasonable to attempt fertility-sparing surgery while attempting to optimally resect the tumor bulk. If only one ovary is involved, then a unilateral salpingo-oophorectomy is performed while the contralateral ovary and uterus is preserved. For management of stages II to IV, dysgerminoma is more commonly bilateral and at least a biopsy is required from the contralateral ovary. However, as chemotherapy is so effective, BSO is often not required. Debulking of advanced disease, however, is important. Second-look surgery may be advantageous for patients whose primary tumor was in-completely resected and contained a teratoma.

Most patients are candidates for platinum-based chemotherapy following surgery, except patients whose tumor was stage IA dysgerminoma or immature, grade I teratoma, in which surveillance is appropriate. Three courses of bleomycin 30 units weekly IV, etoposide 100 mg/m2 on days 1 to 5, and cisplatin, 20 mg/m2 on days 1 to 5 (BEP) is the standard treatment for completely resected disease; four courses of BEP are necessary for residual disease. In the recurrent setting, patients are initially treated with one cycle of standard vinblastine, ifosfamide, and cisplatin (see 11Section III.E) followed by two cycles of high-dose carboplatin and etoposide. Alternate agents include taxanes, gemcitabine, and ifosfamide.

VII. STROMAL OR GRANULOSA CELL TUMORS

Stromal or granulosa cell tumors (GCTs) are very rare, hormone-secreting tumors that can cause precocious puberty in young girls.

A. Histology

GCTs account for 70% of malignant sex-cord stromal tumors but only 5% of malignant ovarian tumors. GCTs are comprised of adult-type (AGCT; 95%) and juvenile-type (JGCT; 5%).

B. Clinical disease

1. Clinical presentation. The most common symptoms ofAGCT are abnormal vaginal bleeding, abdominal distension, and abdominal pain. The pain and distension are due to the usually large size of the tumor at diagnosis. Some patients may have ascites, and premenopausal women may experience menometrorrhagia, oligomenorrhea, or amenorrhea. Because GCTs are estrogen-secreting, breast tenderness, uterine myohypertrophy, and en-dometrial hyperplasia are also common signs and symptoms. In JGCT, prepubertal patients commonly present with isosexual precocious pseudopuberty. Patients will also almost always present with increasing abdominal girth, and a palpable mass will be found during abdominal, pelvic, or rectal exam. Finally, abdominal pain, dysuria, and constipation are common.

2. Prognostic factors. Stage at diagnosis, increasing tumor size, rupture and nuclear grade in stage I patients, nuclear atypia, and increased mitotic activity all contribute to poorer prognosis for patients with AGCTs. For JGCTs, however, surgical stage and mitotic activity are the most significant prognostic factors.

3. Staging. Per FIGO recommendation, the staging system used for GCTs is the same as that used for epithelial ovarian cancer.

C. Treatment

Standard treatment for GCTs includes hysterectomy with BSO fol-lowed by platinum-based chemotherapy along the lines derived from experience with epithelial ovarian tumors. Chemotherapy for GCTs also frequently includes taxanes. Some studies have shown that a conservative surgical approach without hysterectomy may be appropriate for some patients with JGCT. Studies of the use of TKIs, including imatinib, have shown some promise in treating GCTs. Further research, however, is required.

VIII. GESTATIONAL TROPHOBLASTIC NEOPLASM (GTN)

A. Histology

The histologic patterns of GTNs depend on the state of the preceding pregnancy. After molar pregnancy, GTN presents with the histologic pattern of either molar tissue or choriocarcinoma (CCA). Following a miscarriage or term pregnancy, GTN presents with the histologic pattern of CCA. Following ectopic pregnancy, the histologic pattern is either of molar tissue or CCA. Placental-site trophoblastic tumor is a rare form of CCA.

B. Screening

Following either a partial or complete molar pregnancy, patients should have weekly hCG serum level measurements until they are normal for 3 weeks, followed by monthly hCG screening for 6 months. If nondetectable hCG levels are reached, the risk of devel-oping GTN approaches zero.

C. Clinical disease

1. Clinical presentation. The signs and symptoms for GTNs varyde-pending on the extent of disease. Locally invasive disease usually presents with IP bleeding or vaginal hemorrhage resulting from the tumor perforating the myometrium or uterine blood vessels. Metastatic disease is usually found in the lungs, vagina, brain, and liver, and is usually hemorrhagic, causing hemoptysis, IP bleeding, and acute neurologic deficits. GTN can cause various radiologic patterns in the lungs, including pleural effusion, alveolar or snowstorm pattern, discrete rounded densities, or embolic pattern. Vaginal lesions may also be present and are highly hemorrhagic; biopsy of these lesions should be completely avoided. Patients with cerebral metastases have a high rate of fatal hemorrhage during the first week of treatment and may need RT first (standard in United States) or low-dose chemotherapy to “cool off” (standard in the United Kingdom). Finally, patients with liver metastases usually present with jaundice, intra-abdominal pain, or epigastric pain.

2. Diagnosis. During diagnostic workup, all patients should have a base-line hCG taken and hepatic, thyroid, and renal function tests. If chest radiography is negative for metastatic disease, a chest CT scan should also be performed. It is unlikely that asymptomatic patients with normal pelvic exam and negative chest CT scan would have brain or liver metastasis. However, if vaginal or lung metastases are present, a head or abdominal CT should be obtained to rule out brain or liver metastases.

3. Prognostic factors. Site of involvement, tumor volume (hCG level, size and number of metastases), prior chemotherapy, and duration of disease all contribute to poor prognosis. Delayed diagnosis, high levels of hCG, and brain or liver metastases could lead to resistance to single-agent chemotherapy. The development of choriocarcinoma following term pregnancy also has poor prognosis.

4. Staging (Table 10.7). Per FIGO recommendation, an anatomic staging system is used in the case of GTN.

D. Treatment

1. Stage I or low-risk metastatic GTN. For patients with early-stage or low-risk GTN, the choice of treatment plan is based on whether the patient desires to preserve fertility. If the ability to conceive is no longer a concern, management should include hysterectomy with single-agent adjuvant chemotherapy. The chemotherapy is necessary as a precaution against tumorcells spread to locations outside the primary site and to treat occult metastases. If the patient wishes to preserve fertility, single-agent chemotherapy should be administered with methotrexate or actinomycin D (ACT-D). Both treatments are well tolerated, but patients on ACT-D do have a higher instance of side effects. These include nausea (61% versus 50%), emesis (33% versus 14%), and alopecia (26% versus 14%). Currently, the preferred regimen is methotrexate 100 mg/m2 by IV bolus and 200 mg/m2 by TV infusion over 12 hours, followed by folinic acid 15 mg intramuscularly or orally every 12 hours for four doses starting 24 hours after the start of methotrexate. If the patient is resistant to methotrexate, ACT-D should be used. If resistance to single-agent therapy develops, patients should be treated with combination therapy, including methotrexate, ACT-D, and cyclophosphamide or etoposide, methotrexate, ACT-D, cyclo-phosphamide, and vincristine (EMA-CO; Table 10.8).

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Patients with low-risk stage II and III disease can also be treated with single-agent chemotherapy, similar to stage I. If patients have high-risk stage II or III disease, they should be treated with EMA-CO. If resistance occurs, etoposide can be substituted with cisplatin on day 8, and the methotrexate dose can be elevated to 1 g/m2.

Patients with stage IV disease should be treated with rigor-ous combination chemotherapy (EMA-CO) and selective RT and surgery. If the patient has cerebral metastases, the dose of metho-trexate should be increased to 1 g/m2and RT should be applied.

After the first line of chemotherapy, additional treatment is withheld as long as the patient's hCG levels continue to fall. Patients with stage I, II, or III disease should be followed up after treatment with weekly hCG tests until levels reach normal for 3 consecutive weeks, then monthly for 12 months. Patients with stage IV disease should have weekly hCG tests until normal for 3 weeks, followed by monthly tests for 24 months. Risk of recurrence after initial remission varies by stage of disease: 2.9% for stage I disease, 8.3% for stage II, 4.2% for stage III, and 9.1% for stage IV.

Selected Readings

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Endometrial Cancer

Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endome-trial cancer. Lancet. 2005;366:491–505.

Benedet JL, Bender H, Jones H 3rd, Ngan HY, Pecorelli S. FIGO staging classificationsand clinical practice guidelines in the management of gynecologic cancers. Int J Gynaecol Obstet. 2000;70:209–262.

Benedetti-Panici P, Maneschi F, Cutillo G, D'Andrea G, Manci N, Rabitti C. Anatomical and pathological study of retroperitoneal nodes in endometrial cancer. Int J Gyncol Cancer. 1998;8:1837–1842.

ASTEC/EN.5 Study Group, Blake P, Swart AM, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet. 2009;373(9658):137–146.

Carey MS, Gawlik C, Fung-Kee-Fung M, et al. Systematic review of systemic therapy for advanced or recurrent endometrial cancer. Gynecol Oncol. 2006;101:158–167.

Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multi-centre randomised trial. PORTEC Study Group. Post operative radiation therapy in endometrial carcinoma Lancet. 2000;355:1404–1411.

DeNardis SA, Holloway RW, Bigsby GE 4th, Pikaart DP, Ahmad S, Finkler NJ. Roboti-cally assisted laparoscopic hysterectomy versus total abdominal hysterectomy and lymphadenectomy for endometrial cancer. Gynecol Oncol.2008;111(3):412–417.

Dizon DS. Treatment options of advanced endometrial carcinoma. Gynecol Oncol. 2010;117:373–381.

Fiorica JV Brunetto VL, Hanjani P, et al. Phase II trial of alternating courses of meges-trol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol.2004;92:10–14.

Fleming GF, Brunetto VL, Cella D, 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;22:2159–2166.

Hogberg T. Adjuvant chemotherapy in endometrial carcinoma: overview of randomised trials. Clin Oncol. 2008;20(6):463–469.

Khalifa MA, Mannel RS, Haraway SD, Walker J, Min KW. Expression of EGFR, HER-2/ neu, P53, and PCNA in endometrioid, serous papillary, and clear cell endometrial adenocarcinomas. Gynecol Oncol.1994;53:84–92.

Kornblith AB, Huang HQ, Walker JL, Spirtos NM, Rotmensch J, Cella D. Quality of life of patients with endometrial cancer undergoing laparoscopic international federation of gynecology and obstetrics staging compared with laparotomy: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27(32):5337–5342.

Lentz SS. Endocrine therapy of endometrial cancer. Cancer Treat Res. 1998;94:89–106.

Mariani A, Webb M, Galli L, Podratz K. Potential therapeutic role of para-aortic lymph-adenectomy in node-positive endometrial cancer. Gynecol Oncol. 2000;76:348–356.

Mundt AJ, Murphy KT, Rotmensch J, Waggoner SE, Yamada SD, Connell PP. Surgery and postoperative radiation therapy in FIGO Stage IIIC endometrial carcinoma. Int JRadiat Oncol BiolPhys.2001;50:1154–1160.

Neven P, De Muylder X, Van Belle Y, Van Hooff I, Vanderick G. Longitudinal hysteroscopic follow-up during tamoxifen treatment. Lancet. 1998;351:36.

Nout RA, Putter H, Jurgenliemk-Schulz IM, et al. Vaginal brachytherapy versus external beam pelvic radiotherapy for high-intermediate risk endometrial cancer: results of the randomized PORTEC-2 trial. 2008 ASCO Annual Meeting. J Clin Oncol. 2008;26.

Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix and endometrium. Int J Gynaecol Obstet. 2009;105:103–104.

Randall ME, Filiaci VL, Muss H, et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endome-trial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2006;24:36–44.

Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. 2006;354:261–269.

Thigpen JT, Brady MF, Alvarez RD, et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin Oncol.1999;17:1736–1744.

Wolfson AH, Brady MF, Rocereto T, et al. A gynecologic oncology group randomized phase III trial of whole abdominal irradiation (WAI) vs. cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcoma (CS) of the uterus. Gynecol Oncol. 2007;107(2):177–185.

Ovarian Cancer

Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34–43.

Bristow RE, Eisenhauer EL, Santillan A, Chi DS. Delaying the primary surgical effort for advanced ovarian cancer: a systematic review of neoadjuvant chemotherapy and interval cytoreduction. Gynecol Oncol. 2007;104(2):480–490.

Cannistra SA Cancer of the ovary. N Engl J Med. 2004;351:2519–2529.

Cannistra SA, Matulonis U, Penson R, et al. Bevacizumab in patients with advanced platinum-resistant ovarian cancer. J Clin Oncol. 2007;25:5180–5186.

Chan JK, Tian C, Fleming GF, et al. The potential benefit of 6 vs. 3 cycles of chemotherapy in subsets of women with early-stage high-risk epithelial ovarian cancer: an exploratory analysis of a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116(3):301–306.

Colombo N, Guthrie D, Chiari S, et al. International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst.2003;95:125–132.

du Bois A, Quinn M, Thigpen T, et al. 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International Gynecologic Cancer In-tergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol. 2005;16(Suppl 8):viii7–vii12.

Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer. 2007;109:221–227.

Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–134.

Harter PA, Hahmann M, Lueck HJ, et al. Surgery for recurrent ovarian cancer: role of peritoneal carcinomatosis: exploratory analysis of the DESKTOP I trial about risk factors, surgical implications, and prognostic value of peritoneal carcinomatosis. Ann Surg Oncol. 2009;16:1324–1330.

Jacobs IJ, Skates SJ, MacDonald N, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet. 1999;353:1207–1210.

Kaku T, Ogawa S, Kawano Y, et al. Histological classification of ovarian cancer. Med Electron Microsc. 2003;36:9–17.

Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009;17:1331–1338.

Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002;346:1609–1615.

Köbel M, Kalloger S, Santos J, Huntsman DG, Gilks CB, Swenerton KD. Tumor type and substage predict survival in stage I and II ovarian carcinoma: insights and implications. Gynecol Oncol.2010;116(1):50–56.

Markman M, Rothman R, Hakes T, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991;9(3):389–393.

McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334:1–6.

Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet.2003;361:2099–2106.

Partridge E, Kreimer AR, Greenlee RT, et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol. 2009:113(4):775–782.

PfistererJ, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24(29):4699–4707.

Pujade-Lauraine E, Mahner S, Kaern J, et al. A randomized, phase III study of car-boplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in relapsed platinum-sensitive ovarian cancer (OC): CALYPSO study of the Gynecologic Cancer Intergroup (GCIG). J Clin Oncol. 2009;27:18s.

O'Shaughnessy J, Osborne C, Pippen J, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol. 2009;27:18s.

Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21(17):3194–3200.

Rose PG, Nerenstone S, Brady MF, et al. Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med. 2004;351:2489–2497.

Rustin GJ, van der Burg ME, on behalf of MRC and EORTC. A randomized trial in ovarian cancer (OC) of early treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials). J Clin Oncol. 2009;27:18s.

Vasey PA, Jayson GC, Gordon A, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst.2004;96(22):1682–1691.

Vergote I. Randomized trial comparing primary debulking (PDS) with neoadjuvant chemotherapy (NACT) followed by interval debulking (IDS) in stage IIIC-IV ovarian, fallopian tube, and peritoneal cancer. IGCS Bangkok, October 25th 2008.

Visintin I, Feng Z, Longton G, et al. Diagnostic markers for early detection of ovarian cancer. Clin Cancer Res. 2008;14:1065–1072.

Zorn KK, Bonome T, Gangi L, et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005;11(18):6422–6430.

Gestational Trophoblastic Neoplasm

Horowitz NS, Goldstein DP, Berkowitz RS. Management of gestational trophoblastic neoplasia. Semin Oncol. 2009;36:181–189.

Stromal or Granulosa Cell Tumor

Jamieson S, Fuller PJ. Management of granulosa cell tumour of the ovary. Curr Opin Onc. 2008;20:560–564.