11 - Gynecologic Cancer | Handbook of Cancer Chemotherapy

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 11 - Gynecologic Cancer

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Chapter 11

Gynecologic Cancer

Stephen Andrews

In 2006, there were an estimated 77,250 new female genital tract cancers in the United States and more than 28,000 deaths. The history of gynecologic cancer treatment in the United States has witnessed many successes such as the widespread acceptance of routine screening for cervical cancer with the Papanicolaou (Pap) smear. The Pap smear is creditedwith dramatic reduction in both the incidence rate and the death rate of cervical cancer over the past 40 years. More recent success includes the use of combined chemoradiotherapy to increase survival in the treatment of advanced cervical cancer and the increased survival realized with combined use of both intraperitoneal and intravenous chemotherapy for advanced ovarian cancer. The elucidation of the human papilloma virus (HPV) as the causative agent for cervical cancer worldwide has opened new techniques for cervical cancer screening. The use of HPV DNA detection on a cervical cytology specimen can identify those women who are at increased risk for developing cervical dysplasia and cervical cancer. The research on HPV has allowed the introduction of an HPV vaccine that will hopefully decrease further, if not eliminate, cervical cancer. In addition, there is now evidence that the involvement of a gynecologic oncologist in the treatment of a woman with a gynecologic cancer will enhance the outcome of treatment.

Despite many advances, there are still challenges ahead. Ovarian cancer is responsible for the overwhelmingmajority of deaths from gynecologic cancers because of the advanced stage at time of diagnosis and the lack of an effective screening test for this dreaded disease. Although the Pap smear is an effective screening test for cervical cancer, most women who develop invasive cervical cancer come from an unscreened or an under-screened population. Quality of life (QOL), the ramifications of sexual dysfunction after treatment for a gynecologic cancer, and fertility preservation for younger women with a gynecologic malignancy are all important issues that are now moved to the forefront of clinical research.

Women diagnosed with a gynecologic malignancy are best treated with a team approach. Review of all pertinent data at a prospective, multidisciplinary tumor board is recommended for optimal care. The oncologist should discuss treatment options based upon evidence-based research with the patient in a quiet, supportive setting with adequate time to address all her concerns. An open dialogue combined with an empathetic clinical support staff who understand and are committed to the care of women with gynecologic cancers will optimize the patient's treatment and QOL.

I. Carcinoma of the cervix

In 2006, there were approximately 9,710 new cases of invasive cervical cancer and 3,700

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deaths from the disease in the United States. In developed countries with cervical cancer screening programs by Pap smears the incidence and death rate of invasive cervical cancer have decreased dramatically. However, cervical cancer is the second most common malignancy the world over, especially in nondeveloped countries that lack Pap smear screening programs. The relation between HPV infection and invasive cervical cancer is well established, especially HPV types 16 and 18 that account for 70% of all cervical cancers worldwide. Other risk factors for cervical cancer include early onset of coitus, multiple sex partners, high parity, tobacco use, human immunodeficiency virus and the high-risk male. This is a man who has had multiple sex partners, has frequented prostitutes or is positive for high-risk HPV types.

A. Pathology and patterns of spread

Histology. Approximately 80% of cervical cancers are squamous cell carcinomas, both keratinizing and nonkeratinizing. The other 20% are adenocarcinomas. Squamous cell carcinomas typically arise from the squamo columnar junction, an active zone of squamous metaplasia on the ectocervix. Adenocarcinomas arise from the endocervical canal. Both are associated with HPV, although squamous cells are more likely to be HPV-16 positive and adenocarcinomas HPV-18 positive. Adenosquamous carcinomas and adenoid cystic carcinomas, both of which have a worse prognosis stage for stage, are less commonly seen. A particularly virulent, and fortunately rare, type is small cell carcinoma of neuroendocrine origin. The most common metastatic lesions to the cervix are from other gynecologic cancers, especially endometrial.
The continuum of neoplasia. The dramatic decrease in the incidence of invasive cervical cancer in the United States is due to the detection of cervical dysplasia through Pap smear screening. This allows preclinical disease to be diagnosed and treated. In 1988, the Bethesda system for reporting Pap smears was established and has undergone three revisions. The most recent American Cancer Society (ACS) guidelines for Pap smear screening recommends initiation of Pap smears 3 years after the onset of vaginal coitus, or by the age of 21. Dysplasias are divided into high-grade squamous intraepithelial lesions (HGSILs) and low-grade squamous intraepithelial lesions (LGSILs). The goal of Pap smear screening is to identify HGSIL (moderate dysplasia, severe dysplasia, and carcinoma in situ). Since most (91% over 36 months) of LGSILs (mild dysplasia and HPV changes) resolve spontaneously, observation alone is warranted and recommended. Biopsy-proved HGSIL changes can be treated conservatively with loop electrosurgical excision, cryotherapy, or CO2 laser ablation.

Glandular dysplasias are more difficult to detect and diagnose. Any glandular abnormality of a Pap smear requires immediate evaluation with colposcopy, directed biopsies, endocervical curettings, and possibly endometrial sampling. A cervical biopsy showing glandular dysplasia requires further sampling with cervical conization. There does not appear to be a spectrum of dysplastic changes in glandular epithelium akin to cervical epithelium. In
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addition, the histologic boundarywithin the cervical stroma makes delineation ofmargins more difficult for the pathologist. Therefore, after a diagnosis of adenocarcinoma in situ, even with clear margins, simple hysterectomy is recommended if the patient's childbearing is complete.
Spread patterns. The most common spread pattern is by direct extension through the cervical stroma and into the parametrial tissues (cardinal ligaments) and/or directly onto the vaginal wall. Pelvic spread is typically lateral rather than anterior or posterior into the bladder or rectum due to the investing fascia of the cardinal ligaments. Lymphatic metastasis is not uncommon because of the rich lymphatic drainage of the cervix with a typical orderly spread pattern from the pelvic nodes (obturator, internal iliac, external iliac, and common iliac) to the para-aortic nodes. Hematogenous metastasis is found in approximately 10% of patients, with the most common site being lung or bone.

B. Diagnosis and staging

Clinical manifestations. The classic symptom of cervical cancer is abnormal vaginal bleeding, typically postcoital bleeding, although intramenstrual bleeding and sudden vaginal hemorrhage are not uncommon. An abnormal vaginal discharge is also common. Pain, typically sciatic, lumbosacral, or flank pain is usually a sign of locally advanced disease.
Diagnosis. Biopsy of a cervical lesion is the only way to diagnose cervical cancer. Any suspicious or gross lesion of the cervix should be biopsied. A Pap smear should only be performed on a clinically normal cervix.
Staging (Table 11.1). Cervical cancer is staged clinically on the basis of international standards. Procedures allowed include examination under anesthesia, cystoscopy, proctoscopy, chest x-ray and an intravenous pyelogram (IVP). However, in the United States, there is a tendency to perform a computed tomography (CT) of the abdomen or pelvis to evaluate the retroperitoneum for lymphadenopathy. Positron emission tomography (PET) imaging has also been used to evaluate cervical cancer spread. Although CT and PET may be used in treatment planning, they cannot be used to change the clinical stage. Surgical staging with either laparoscopic or retroperitoneal lymphadenectomy (LND) has been promoted by some; however, the sensitivity of PET scanning may allow for nonsurgical staging.

C. Treatment

Early clinical disease

Microinvasive. The definition of a microinvasive cervical cancer adopted by the Society of Gynecologic Oncologists (SGO) states that invasion must be less than or equal to 3 mm below the basement membrane, with absence of lymphatic or vascular invasion and negative margins on a conization specimen. The SGO definition closely corresponds to International Federation of Gynecology and Obstetrics (FIGO) stage IA1 and represents a lesion with essentially a zero chance of lymph node metastasis. This stage of disease can be treated with

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simple hysterectomy, or if the patient desires further childbearing, conization alone.

Table 11.1. 1995 International Federation of Gynecology and Obstetrics Staging (Montreal) for carcinoma of the cervix uteri

Stage Grouping	Definition
I	The carcinoma is strictly confined to the cervix (extension to the corpus should be disregarded)
IA	Invasive cancer identified only microscopically. All gross lesions even with superficial invasion are stage IB cancers. Invasion is limited to measured stromal invasion with maximum depth of 5 mm and no wider than 7 mm
IA-1	Measured invasion of stroma no greater than 3 mm in depth and no wider than 7 mm
IA-2	Measured invasion of stroma >3 mm, no greater than 5 mm, and no wider than 7 mm. The depth of invasion should not be more than 5 mm, taken from the base of the epithelium, either surface or glandular, from which it originates. Preformed space involvement (vascular or lymphatic) should not alter the staging but should be specifically recorded to determine whether it should affect treatment decisions in the future
IB	Clinical lesions confined to the cervix or preclinical lesions greater than those of stage IA
IB-1	Clinical lesions no greater than 4 cm in size
IB-2	Clinical lesions >4 cm in size
II	The carcinoma extends beyond the cervix but has not extended to the pelvic wall. The carcinoma involves the vagina but does not extend as far as the lower third
IIA	No obvious parametrial involvement
IIB	Obvious parametrial involvement
III	The carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the vagina. All cases with hydronephrosis or nonfunctioning kidney are included unless they are known to be due to other causes
IIIA	No extension to the pelvic wall
IIIB	Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney
IV	The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum. (Bullous edema does not permit a case to be allotted to stage IV)
IVA	Spread of the growth to adjacent organs
IVB	Spread to distant organs

Stage IA2, IB1. Patients with a gross lesion on the cervix less than or equal to 4.0 cm or a microinvasive lesion with greater than 3 mm of invasion require more aggressive therapy. The incidence of pelvic lymph node metastasis with microinvasion between 3.1 and 5.0 mm is reported at 7%.
- Patients in this category require radical hysterectomy with pelvic LND. For patients thought to be poor surgical candidates the use of radiation therapy (RT) offers similar cure rates. However, surgical therapy offers the advantages of ovarian preservation, less long-term morbidity and better posttreatment sexual function. Risk stratification for recurrence after surgical treatment is based upon clinicopathologic criteria.
Patients at the highest risk for recurrence include those with positive pelvic lymph nodes, positive margins, or disease in the parametrial tissue. Patients with one or more of these poor prognostic factors do better with chemotherapy plus radiation versus RT alone as shown by 4-year disease-free (80% vs. 63%) and overall survival (81% vs. 71%). Recommended treatment is
- 4,930 cGy external beam pelvic RT and
- Cisplatin 70 mg/m² IV and a 96-hour continuous infusion of fluoruracil, 1,000 mg/m²/day 4 days, given every 3 weeks for a total of 4 cycles.
- The first two cycles are administered concurrently with RT.
Patients with intermediate-risk factors based upon tumor size, depth of invasion and presence of lymphvascular space involvements appear to benefit from postoperative pelvic RT although at the cost of increased morbidity.
Stage IB2 (bulky). The optimal treatment of bulky stage I tumors (>4.0 cm) is controversial. Survival rates for these bulky cancers are substantially worse than those for smaller IB cancers.
- RT with cisplatin at 40 mg/m² IV weekly 6 (maximum dose 70 mg) has been shown in a Gynecologic Oncology Group (GOG) study to offer a survival advantage over RT alone.
  
  The role of the postradiation hysterectomy is debated as it most likely only benefits those with residual cancer in the cervix postchemoradiotherapy.
Advanced disease
- Stage IIA. Very early stage IIA disease with only minimal involvement of the upper vagina (classically seen in the postmenopausal women because of atrophy of the cervix) can be adequately treated with radical hysterectomy with upper vaginectomy and pelvic LND. However, bulky stage IIA is best treated with RT and radiosensitizing chemotherapy as detailed in the preceding text.
- Stage IIB to IVA. These locally advanced cancers are best treated with RT, teletherapy and brachytherapy, along with radiosensitizing chemotherapy.
  - RT doses usually include 5,000 cGy to the whole pelvis initially to shrink the tumor, followed by 3,000 cGy delivered by high-dose rate brachytherapy.
  - Cisplatin 40 mg/m² (maximum 70 mg) infused IV at a rate of 1 mg/minute is given weekly for 6 weeks as radiosensitizing drug. On the day of infusion, chemotherapy should precede the RT fraction.
- Stage IVB. These patients should have the treatment individualized as they are not considered curable. RT to alleviate bleeding and chemotherapy (see Section 2.d.(3) below) in the palliative setting is acceptable.
- Recurrent disease
  - Surgical therapy. The only accepted role for surgical excision in recurrent cervical cancer is in the patientwho presents with a central pelvic recurrence. These patients can be offered pelvic exenteration with an expected 5-year survival of 50% to 60%. The use of continent urinary diversion, low rectal reanastomosis and neovaginal reconstruction allows for a better QOL for these women.
  - Chemotherapy. Patients with recurrent or persistent (failed radiochemotherapy) cervical cancers represent the largest group referred for systemic chemotherapy. Unfortunately, these women who are not exenteration candidates are not considered curable. The response rates to chemotherapy are significantly lower for patients with disease in a previously irradiated area or those who have received prior chemotherapy. Responses are generally short lived and do not affect progression-free and overall survival to a great extent.
  - Chemotherapy options. The standard treatment for recurrent or metastatic disease for the past 25 years is single-agent cisplatin 50mg/m² IV every 3 weeks.
    
    This has an expected overall response rate of 38%. Subsequent studies have reported on cisplatin combined with several other agents, such as ifosfamide, dibromodulcitol, mitomycin C, bleomycin, and paclitaxel. Most of these studies showed increased response rate with multiagent chemotherapy (up to 69% with bleomycin, ifosfamide and cisplatin) but with no significant change in overall survival versus single agent cisplatin, and at the cost of increased toxicity. The exception is a combination of
    - Cisplatin 50 mg/m² on day 1 plus
    - Topotecan 0.75 mg/m² IV on days 1 to 3.
    - Repeat every 21 days.
    This regimen has shown a significant increased survival advantage of 2.9 months as compared to patients treated with cisplatin alone. In addition,
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    the QOL scores were similar between these two regimens. Interestingly, those patients who had received cisplatin as a radiosensitizing agent had poorer response rates overall. In addition, the time to recurrence was a powerful prognostic predictor of response, similar to the platinum-free interval in epithelial ovarian cancer (EOC).
    
    Other active single agents include paclitaxel, ifosfamide, vinorelbine, fluorouracil, and mitomycin.
  - Future developments. For patients with recurrent disease, combinations of cytotoxic agents (e.g., cisplatin combined with paclitaxel, gemcitabine, vinorelbine or topotecan) and molecularly targeted agents should offer further insight into the optimal treatment of these patients.

II. Endometrial cancer

Endometrial cancer is the most common of gynecologic malignancies. In 2006, it is estimated there were approximately 41,200 new cases and 7,350 deaths from endometrial cancer in the United States. Risk factor for developing endometrial cancer include advancing age, nulliparity, chronic anovulation, obesity, and unopposed estrogen and tamoxifen use. Of these, obesity carries the highest relative risk, especially for those women who are more than 100 pounds overweight. These patients typically present with postmenopausal bleeding, or dysfunctional uterine bleeding for those not yet postmenopausal. The diagnosis can often be made in the office with an endometrial biopsy or by a dilatation and curettage (D & C) in the operating room. A transvaginal sonogram of the uterus for the endometrial stripe can be performed on those women who may be difficult to biopsy because of a stenotic cervix. A stripe greater than 5 mm in a postmenopausal woman is considered abnormal and would require surgical sampling to rule out endometrial cancer.

A. Pathology and patterns of spread

Histology. The classic endometrial cancer is an endometrioid adenocarcinoma, accounting for approximately 90% of all uterine cancers. Grading is a function of the amount of solid areas in the tumor specimen. The presence of squamous metaplasia, adenocanthoma, does not harbor a worse prognosis. However, the presence of malignant squamous elements, adenosquamous carcinoma, typically portends a poorer prognosis, as they are usually poorly differentiated tumors. Approximately 5% of uterine cancers will be adenocarcinoma subtypes such as papillary serous or clear carcinoma, both of which are poor-prognosis cell types. The remaining 5% of uterine cancers will be the uterine sarcomas, comprising carcinosarcoma (mixed mullerian tumors [MMTs]), leiomyosarcoma (LMS) and endometrial stromal sarcomas (ESSs).
Patterns of spread. Endometrioid adenocarcinoma begins in the endometrial lining and then invades into the underlying myometrium where it can then invade lymph and vascular spaces. The pelvic and para-aortic lymph nodes are the most common sites of lymphatic metastasis. Spread to the vagina or cervix is not uncommon. Another pattern of spread can be into the abdominal cavity, either by direct extension through the uterine serosa or by
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exfoliation through the fallopian tubes. Distant spread to the liver, lungs, and brain are usually late events. However, extrauterine spread into the abdominal cavity is not uncommon with the uterine sarcomas and the papillary serous and clear cell adenocarcinomas.

B. Pretreatment evaluation

Diagnostic tests. In clinically early endometrial cancer, extensive imaging and testing are not necessary. A complete physical examination looking for evidence of vaginal or lymphatic spread is performed. A chest radiograph is obtained to rule out pulmonary metastasis. If the clinical examination or history suggests advanced disease, then CT imaging, cystoscopy, or proctoscopy may be useful. If intraabdominal spread is suspected, a preoperative CA125 level may be useful as a tumor marker.
Staging. By international convention, endometrial cancer is staged surgically (Table 11.2) requiring hysterectomy, bilateral salpingo-oophorectomy (BSO), peritoneal washings, and pelvic and para-aortic lymph node sampling. In addition, any suspected intra-abdominal metastasis should be biopsied and resected. Owing to early symptoms, most endometrial cancers (80%) are found in stage I.

C. Management

Surgery. The classic therapy for endometrial cancer or uterine sarcoma is surgical with extrafascial hysterectomy and BSO. To complete the surgical staging, pelvic and para-aortic lymph node sampling and peritoneal washings should be obtained. In addition to staging, selective pelvic

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and para-aortic lymph node sampling may also have a therapeutic effect. Patients undergoing lymph node sampling seem to have a survival advantage across all risk groups. In the event of intra-abdominal spread, complete surgical excision is beneficial.

Table 11.2. International Federation of Gynecology and Obstetrics Staging for carcinoma of the corpus uteri

Stage	Definition
I	Tumor confined to the uterine fundus
IA	Tumor limited to the endometrium
IB	Invasion to less than one-half of the myometrium
IC	Invasion to more than one-half of the myometrium
II	Tumor extends to the cervix
IIA	Endocervical glandular involvement only
IIB	Cervical stromal invasion
III	Regional tumor spread
IIIA	Tumor invades the serosa and/or adnexa and/or has positive peritoneal cytology
IIIB	Vaginal metastases
IIIC	Metastases to pelvic and/or periaortic lymph nodes
IV	Bulky pelvic disease or distant spread
IVA	Tumor invasion of the bladder and/or bowel mucosa
IVB	Distant metastases, including intra-abdominal and/or inguinal lymph nodes

Special cases. Patients who present with gross cervical involvement that is not deemed surgically resectable may be offered preoperative radiation therapy to shrink the tumor. This may then allow a postradiation hysterectomy. For patients who are poor surgical candidates, radiation therapy (both teletherapy and brachytherapy) is the best option; however, the cure rate is inferior to surgical therapy. Rarely, endometrial cancer will develop in a young woman who still desires fertility. This usually occurs in a woman with long-standing anovulatory cycles (polycystic ovarian disease). There are reports of these young women being treated successfully with uterine curettage followed by high-dose progestins. After reversal of the cancer, documented by repeat uterine curettage, ovulation induction is often necessary for conception.
Postoperative management
- Risk stratification. After surgical staging, patients can generally be placed in one of three categories: (1) those with a low incidence of recurrence (low risk); (2) those who have an increased rate of recurrence who may or may not benefit from additional therapy (intermediate risk); and (3) those at high risk for recurrence without some type of additional therapy (high risk). Risk factors for recurrence in stage I disease (confined to the uterine corpus) include increasing grade, increasing depth of invasion (especially invasion of the outer third), lymph-vascular space invasion, older age, and depth of myometrial invasion.
- Adjuvant treatment. Patients in the low-risk group are those with stage IA or IB disease with grade 1 or 2 tumors. These patients are adequately treated with surgery alone. Adjuvant therapy for the intermediaterisk group is not well established. This group includes patients with deep myometrial invasion of any grade (IC), patients with grade 3 tumors, and those with cervical involvement (IIA and IIB). Studies in both staged and unstaged patients have shown adjuvant pelvic RT to decrease the risk of locoregional recurrence, but without a significant increase in survival. A study of unstaged patients showed a locoregional relapse rate of 14% in the observation group versus 4% in those treated with pelvic RT. Arandomized study in staged patients showed a 2-year recurrence rate of 12% in the observation arm versus 3% in the pelvic RT arm. The role of vaginal brachytherapy alone in the adjuvant setting for this group is also not clear. Those at high risk for recurrence include patients with disease outside of the uterus such as adnexal involvement, nodal disease, intraperitoneal spread, or distant metastasis (stage III and IV). These patients require additional therapy after surgical staging.
- Advanced disease treatment
  - Radiotherapy (RT). Patients with evidence of retroperitoneal (nodal) disease only (stage IIIC) are typically treated with tailored RT. Those who are found to have intra-abdominal disease can be offered systemic chemotherapy or whole abdominal radiotherapy (WART). However, a recent randomized phase III trial in more than 400 women with stage III and IV disease receiving WART with a pelvic boost versus eight cycles of doxorubicin 60 mg/m² and cisplatin 50 mg/m² every 3 weeks showed a significant improvement in both progression-free and overall survival in the chemotherapy arm. WART appears to be most effective in patients with maximally resected disease. A study of 180 evaluable patients with stage III and IV disease showed survival rates of 35% with WART, although no patient with gross residual disease after surgical staging survived. The trend in those patients with intraperitoneal disease is for systemic treatment with chemotherapy.
  - Systemic therapy. Patients with intraabdominal spread are candidates for chemotherapy after maximal surgical reduction. Active agents include cisplatin, the anthracyclines, and the taxanes:
    - TAP, a three-drug regimen of
      - Cisplatin (Platinol) 50 mg/m² IV and
      - Doxorubicin (Adriamycin) 45 mg/m² IV day 1 followed by
      - Paclitaxel (Taxol)160 mg/m² day 2 with filgrastim support
      repeated every 21 days, improves response rate (57% vs. 34%), progression-free survival (median, 8.3 vs. 5.3 months) and overall survival (median, 15.3 vs. 12.3 months), compared with cisplatin and doxorubicin alone, but with increased toxicity, especially neuropathy.
    - The doublet of carboplatin an area under the curve (AUC) of 6 and paclitaxel at 175 mg/m² every 3 weeks has also been reported with 60% to 70% response rates in phase II trials.
  - Recurrent disease. Patients who present with isolated vaginal cuff recurrences who have not been irradiated represent the only clinical situation where cure rates of 50%to 60%are reported. Surgical restaging with possible upper vaginectomy may be considered to help rule out intra-abdominal spread and to completely resect the tumor. Patients who present with distant metastasis present difficult clinical situations. These patients are often elderly, obese and harbor other medical comorbidities that complicate aggressive chemotherapy. In the chemonaive patient, treatment with TAP or carboplatin and taxol may be considered. Patients who have failed primary therapy have few good options. Liposomal doxorubicin, topotecan, ifosfamide and etoposide all have response
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    rates in the range of 15% to 30%. The use of systemic progestins is best reserved with patients with late, asymptomatic recurrences that are well-differentiated tumors. The response rate of progestins varies inversely with the grade of the tumor. However, for tumors with positive progesterone receptors, a response rate of 37% was reported by the GOG. Risks of progestins includeweight gain and thrombosis. Drugs include megestrol acetate at 160 mg/day or medroxyprogesterone acetate at 200 mg/day.
Special cases. A variety of less common uterine neoplasms can occur. These need to be treated according to the unique biology.
- Uterine papillary serous carcinoma (UPSC) and clear cell carcinoma. These histologies have a predilection for early intra-abdominal spread and distant recurrences. At the time of presentation, approximately 70% of patients with UPSC will have disease outside of the uterus. Patients diagnosed with UPSC or clear cell endometrial cancer should be referred to a gynecologic oncologist for complete surgical staging to include total abdominal hysterectomy (TAH/BSO), pelvic and para-aortic lymph node sampling, peritoneal washings, omentectomy and careful assessment of the entire peritoneal cavity. Overall, patients with stage I disease have recurrence rates of 40% to 50%. Recommendations for adjuvant therapy for stage I UPSC and clear cell carcinomas have varied considerably and a clear consensus is lacking.
  - Stage IA patients with no residual disease in the hysterectomy specimen can be observed.
  - Patients with stage I disease with residual disease in the hysterectomy specimen should be treated with adjuvant chemotherapy with carboplatin AUC 5 and paclitaxel 175 mg/m² every 3 weeks and vaginal cuff brachytherapy.
  - Patients with advanced-stage UPSC and clear cell carcinoma require platinum-based chemotherapy after maximal tumor reduction.
- Uterine sarcomas. Approximately 5% of uterine neoplasms will be sarcomas. The carcinosarcoma or MMT is the most common of the uterine sarcomas. As with most sarcomas, early systemic spread with distant recurrence is common. Unlike endometrial adenocarcinomas, patients with stage I uterine sarcomas have 5-year survival rates of 40% to 60%. Recurrences are approximately evenly divided between local (pelvic) and distant sites.
  - For stage I uterine sarcomas, adjuvant pelvic RT has been shown to decrease the local recurrence rate, but not change overall survival, principally because of distant disease. However, adjuvant chemotherapy does not appear to be of benefit.
  - Patients with advanced or recurrent MMT are best treated with ifosfamide 1.2 to 1.5 g/m²/day IV on days
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    1 to 4 with mesna protection along with cisplatin 20 mg/m²/day IV for 4 days.
  Several phase II trials have also shown carboplatin with an AUC of 5 to 6 and paclitaxel 135 to 175 mg/m² to be effective.
  
  The secondmost common uterine sarcoma is the LMS. These patients tend to be younger than those with MMT and the disease is rarely diagnosed preoperatively. Adjuvant RT to the pelvis for stage I and II disease will decrease local recurrence rate but not affect overall survival. The role of adjuvant chemotherapy is unclear. Patients with advanced-stage or recurrent LMS are best treated with an adriamycin-based regimen such as adriamycin and cisplatin. Recently, the combination gemcitabine 900 mg/m² IV on days 1 and 8 with docetaxel 100 mg/m² on day 8 with filgrastim support showed a 53% overall response rate. Single-agent etoposide also has activity with LMS.
  
  Patients with advanced-stage low-grade ESSs are best treated with progestins as they are typically rich in progesterone receptors.

III. Fallopian tube cancer

Fallopian tube cancer is rarely suspected preoperatively and accounts for less than 1% of all gynecologic malignancies. Patients usually undergo surgery for a complex pelvic mass or may present in a manner similar to advanced ovarian cancer with ascites and evidence of intraabdominal spread. Preoperative symptoms that are unique to fallopian tube cancer include a watery vaginal discharge associated with a colicky pelvic pain. Rarely, a Pap smear showing serous adenocarcinoma or psammoma bodies lead to the diagnosis. Fallopian tube cancer is staged and managed surgically in a manner identical to ovarian cancer.

IV. Ovarian cancer

Ovarian cancer is the leading killer among gynecologic malignancies accounting for more deaths than all the other gynecologic cancers combined. In 2006, there were approximately 20,180 new cases and 15,310 deaths. The ovary is formed from three embryologic tissues; germ cells, stroma, and epithelium. Each of these groups gives rise to a distinct neoplasm that is biologically diverse and is treated differently.

A. Histologic types and treatment of germ cell and stromal tumors

Germ cell ovarian cancers. Germ cell tumors (GCTs) of the ovary account for approximately 5% of all ovarian malignancies. They are found in a young age group and are curable. GCTs are typically fast-growing neoplasms and often present with the sudden onset of abdominal or pelvic pain. Surgical therapy for GCT is conservative with removal of the affected ovary and comprehensive staging. Even in the event of advanced disease, preservation of the contralateral ovary and uterus is recommended because of the sensitivity of GCT to chemotherapy. For chemotherapy purposes, GCTs are usually divided into dysgerminomas and nondysgerminomas.

All nondysgerminoma GCTs, except for stage IA grade 1 immature teratoma, will require chemotherapy. Patients with completely resected nondysgerminoma GCT require

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three courses of adjuvant bleomycin, etoposide, and cisplatin (BEP, Table 11.3). With adjuvant therapy, relapse rates should be less than 5%, but without adjuvant BEP, the rates are 40% to 80%. Those with incompletely resected nondysgerminoma GCT require four courses.

Table 11.3. Multiagent chemotherapy in germ cell cancers of the ovary

BEP:	Bleomycin 20 units/m² IV (maximum 30 units) weekly Etoposide 100 mg/m² IV daily x 5 days q3 week Cisplatin 20 mg/m²I V daily x 5 days q3 week
VAC:	Vincristine 1.5 mg/m² IV (maximum 2 mg) q2 week Actinomycin-D 350 g/m² IV daily x 5 days q4 week Cyclophosphamide 150 mg/m² IV daily x 5 days q4 week

Patients with a completely staged IA dysgerminoma do not require chemotherapy and may be observed. The recurrence rate in this group will be approximately 20%; however, they can be successfully treated with BEP. All other stages of dysgerminoma require BEP similar to nondysgerminomas.

Most patients with a dysgerminoma will not be completely staged. Few of these patients are managed surgically by a gynecologic oncologist and the diagnosis is most often made postoperatively. Careful surveillance is recommended in this group of patients to allow early detection of recurrence and chemotherapy with BEP.

Patients with GCT who relapse or cannot receive BEP as primary therapy, should receive a combination of vincristine, actinomycin-D, and cyclophosphamide (VAC) (Table 11.3).

Stromal tumors. Stromal tumors represent the least common of the ovarian neoplasms. They are derived from the sex cords and the ovarian stroma of the ovary and are usually divided into those tumors that represent the female cells (granulosa and theca cells) and the male cells (Sertoli and Leydig cells). Occasionally, they are characterized by their hormonal production, especially in the rare juvenile granulosa cell tumor where estrogen production will cause precocious pseudopuberty. Stromal tumors of the ovary are usually found at stage I and allow for conservative surgery consisting of a unilateral salpingo-oophorectomy in those patients who still desire childbearing. Typically, they are slow-growing, indolent neoplasms that are managed surgically. Chemotherapy is reserved for advanced stage or for recurrent disease. Options for chemotherapy include BEP (see Table 11.3) or a platinum and a taxane, as with EOC.
Epithelial ovarian cancer (EOC). The overwhelming majority of ovarian malignancies belong to the epithelial group (e.g., serous, mucinous, endometrioid, clear cell). In contrast to GCT, EOC generally occurs after menopause, is advanced at the time of diagnosis, and is rarely curable. The remainder of this section deals with the diagnosis and management of this common variety of ovarian cancer.

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B. Diagnosis and screening of EOC

Diagnosis. The diagnosis of early-staged EOC is difficult because of the lack of early signs or symptoms. In the United States, 70% to 80% of ovarian cancers are diagnosed at an advanced stage when cure is difficult. Rarely, an asymptomatic pelvic mass will be felt on pelvic examination. Symptoms of early EOC are often pelvic or lower abdominal pressure, pain or discomfort. Imaging studies, such as a pelvic CT or ultrasound (USD)will reveal a pelvicmass. Radiologic characteristics of an ovarian malignancy include the presence of solid areas within the mass ( complex ), ascites, bilaterality, and irregularity in the shape of themass. Most benign pelvic or ovarian masses will be completely cystic and rounded on imaging studies. As the age of the patient increases, the chance of a pelvic mass being malignant increases as well. Patients with advanced EOC will often have as a presenting symptom a sudden increase in abdominal girth due to ascites. These women will often have vague abdominal complaints such as pelvic or abdominal fullness, urinary frequency, early satiety, or pelvic discomfort for several months preceding the diagnosis. Imaging studies will often reveal widespread ascites, omental caking, peritoneal implants, and pleural effusions. Preoperative diagnostic tests such as needle biopsies and paracenteses are generally meddlesome, carry the risk of disseminating disease, and do not alter the ultimate need for surgery. The diagnosis will be made by surgical exploration, preferably by a fellowship-trained gynecologic oncologist. In the case of early-staged EOC, a frozen section should be obtained during surgical exploration to make the diagnosis and allow for complete surgical staging in the case of malignancy.
Screening. The overall 5-year survival for stage I or II EOC is 80% to 90%; however, the overall 5-year survival for stage III or IV EOC is 30% to 35%. The potential value for earlier diagnosis is unequivocal, but neither the use of transvaginal ultrasound (TVS) with or without Doppler flow studies nor serum screening for CA125 has the necessary sensitivity and specificity to accurately predict early-stage EOC, and these are therefore not good screening tools in the average risk woman.

This is in distinction to the observation that two classes of serum tumor markers, monoclonal antibodies (e.g., CA125 with EOCs) and peptide markers (e.g., -fetoprotein with endodermal sinus tumors, m llerian-inhibiting factor, and inhibin with granulosa cell tumors) have proved useful in monitoring the treatment of ovarian cancer. Additionally, preoperative evaluation of tumor markers and pelvic USD may be useful in estimating risk of malignancy and aid in appropriate preoperative patient triage.

Overall lifetime risk of developing EOC is 1 in 70 or approximately 1.4%. The strongest risk factor for developing EOC is a positive family history. Unfortunately, only 10% of new patients with EOC will have a suggestive family history. Factors that decrease a woman's risk include pregnancy, lactation, oral contraceptive use, tubal ligation, and hysterectomy. Women with a family history suggestive of
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familial ovarian cancer or any woman of Ashkenazi Jewish descent who develops breast or ovarian cancer should be referred for genetic counseling and possible genetic studies for the BRCA1 and BRCA2 gene mutations. The breast and ovarian cancer syndrome, associated with germline BRCA1 and BRCA2 mutations that function as tumor suppressor genes, is inherited in an autosomal dominant manner. Female carriers of a mutation in the BRCA1 or BRCA2 gene have a 15% to 60% risk of developing EOC by the age of 70, with the risk being lower for BRCA2 than for BRCA1. Approximately 5% to 10% of ovarian cancer cases are likely attributable to such mutations. Women at high risk for developing EOC and those who harbor a BRCA1 or BRCA2 germline mutation should consider prophylactic oophorectomy after childbearing. This procedure will decrease dramatically the patient's chance of developing an ovarian cancer and also decrease her risk of developing a breast cancer. Women in this high-risk group who decide to retain their ovaries should consider surveillance with TVS twice yearly. Increased surveillance in the form of CA125 levels can also be valuable, especially in the postmenopausal setting. An increased risk of ovarian cancer is also associated with hereditary nonpolyposis colon cancer (HNPCC), with mutations documented in the mismatch repair genes MSH2, MLH1, PMS1, and PMS2.

C. Management

Surgery. Ovarian cancer is staged surgically (Table 11.4). Any woman with a suspicious ovarian or pelvic mass requires surgical exploration. Surgery allows for accurate diagnosis, thorough staging of disease, and, in advanced disease, valuable tumor debulking.

Early disease and surgical staging. At surgical exploration, the ovarian mass is resected intact if possible (i.e., without rupture), and diagnosis is established on the basis of frozen-section evaluation. During surgery, 20% of EOCs appear visually or grossly confined to the ovary (i.e., stage I), but 30% to 50% of these patients will have extraovarian microscopic disease. A thorough surgical staging will identify those patients with more advanced-stage disease and allow for selection of appropriate chemotherapy.

Advanced disease. Eighty percent of women have advanced disease (stage III or IV) at diagnosis. Most of the women have disease disseminating throughout the abdominal cavity with ascites. The finding of advanced EOC often portrays a seemingly insurmountable picture of unresectable peritoneal and bulky pelvic and abdominal tumor. Fortunately, with the proper surgical approach, maximal tumor resection is possible in 80% of patients. The benefit of optimal debulking has been recognized in several retrospective reviews. A recent meta-analysis of patients with advanced ovarian cancer treated postoperatively with platinum-based chemotherapy showed that each 10% increase in maximal cytoreduction was associated with a 5.5% increase

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in median survival time. Another multi-institutional review reported a median survival of 38.4 months in those patients optimally debulked versus only 10.3 months in the nonoptimally debulked patients. Therefore, initial therapy for advanced EOC is optimal surgical debulking. The value of a focused expertise in managing EOC has been directly recognized by the National Cancer Institute (NCI) in their recommendation that where the potential for such cases exists, they be managed by fellowship-trained gynecologic oncologists.

Table 11.4. International Federation of Gynecology and Obstetrics staging system for ovarian cancer

Stage	Definition
I	Growth limited to the ovaries
IA	Growth limited to one ovary; no ascites; no tumor on the external surfaces; capsule intact
IB	Growth limited to both ovaries; no ascites; no tumor on the external surfaces; capsule intact
IC	Tumor either stage IA or IB but with tumor on the surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells or with positive peritoneal washings
II	Growth involving one or both ovaries with pelvic extension
IIA	Extension and/or metastases to the uterus and/or tubes
IIB	Extension to other pelvic tissues
IIC	Tumor either stage IIA or IIB but with tumor on the surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells or with positive peritoneal washings
III	Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes; surface liver metastasis equals stage III; tumor is limited to the true pelvis but with histologically verified malignant extension to small bowel, large bowel, or omentum
IIIA	Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces
IIIB	Tumor of one or both ovaries; histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes negative
IIIC	Abdominal implants >2 cm in diameter and/or positive retroperitoneal or inguinal nodes
IV	Growth involving one or both ovaries with distant metastases; if pleural effusion is present, there must be positive cytologic test results to allot a case to stage IV; parenchymal liver metastases equals stage IV

Systemic chemotherapy. The need and route of administration for postsurgery chemotherapy is determined
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in the context of histology, grade, stage, and amount of residual tumor. Patients with ovarian tumors of low malignant potential (or borderline ovarian tumors) are treated with surgical resection alone and do not require chemotherapy.
- Early stage, low risk. Patients with a thoroughly staged IA or IB, grade 1 or 2 EOC are considered at low risk for recurrence, have an expected 5-year survival rate of greater than 90%, and do not require chemotherapy.
- Early stage, high risk. Patients with early-stage EOC who are considered at high risk for relapse include all patients with stage IA/IB with grade 3 or clear cell histologies, stage IC and stage II disease. Adjuvant platinum-based chemotherapy has proved to prolong disease-free survival and possibly survival itself. The standard treatment for patients with high-risk, stage I or II EOC is three courses of carboplatin and paclitaxel.
  - Carboplatin AUC of 7.5 IV and
  - Paclitaxel 175 mg/m² IV every 21 days.
- Stage III and IV, advanced disease. Patients with more advanced disease are currently treated with a platin and paclitaxel regimen after debulking surgery. For patients with optimally debulked stage III EOC, a combination of IP and IV chemotherapy has been shown to be superior to standard IV chemotherapy (see Section IV.C.3). For patients with suboptimally debulked EOC, appropriate intravenous regimens include the following:
  - Carboplatin AUC of 5 to 7. 5 IV plus paclitaxel 175 mg/m² IV over 3 hours or
  - Cisplatin 50 mg/m² IV plus paclitaxel 135 mg/m² IV over 24 hours (high neurotoxicity otherwise) or
  - Carboplatin AUC of 5 to 7. 5 IV plus docetaxel 60 to 80 mg/m² IV.
  Each of these regimens is repeated every 21 days for a total of 6 to 8 courses.
  
  Recent data suggest that docetaxel, when substituted for paclitaxel in combination with carboplatin, has a similar overall efficacy for initial treatment of EOC with a more favorable neurotoxicity profile. Therefore, this regimen is an alternative for patients at high risk for, or with preexisting neuropathy. Several prospective, randomized studies have shown carboplatin to be similar in efficacy to cisplatin with a toxicity profile favoring carboplatin. This, in addition to the ease of administration in an outpatient setting, favors carboplatin over cisplatin.
  
  Overall, the response rate to paclitaxel and carboplatin as first-line treatment of EOC (complete response plus partial response) is 70% to 80%, of which 50% are complete clinical responses and 30% complete pathologic responses. Patients are carefully monitored during chemotherapy to determine treatment efficacy. Before receiving each cycle, they should undergo physical examination, CA125 determination, and other studies as indicated to assess disease response.
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  If any parameter suggests treatment failure (i.e., progression of disease), the regimen is immediately curtailed, and strategic options that remain are presented to the patient. Patients who progress during initial platinum-based chemotherapy generally do not respond well to second-line agents. Patients opting for secondline treatment, on or off protocol, should do so realistically and with a great concern for maintaining the best possible QOL under difficult circumstances.
Intraperitoneal (IP) chemotherapy. A recent prospective study on patientswith stage III optimally debulked EOC or primary peritoneal cancer, defined as no residual mass greater than 1.0 cm, was reported. This showed that when IP was added to IV therapy, there was an increase in the median duration of progression-free survival to 23.8 months in the IP/IV arm versus 18.3 months in the IV arm.

Themedian duration of overall survival was 65.6 months in the IP/IV arm and 49.7 months in the IV arm. The regimen recommended is
- Paclitaxel 135 mg/m² IV over 24 hours followed by
- Cisplatin 100 mg/m² IP on day 2 and
- Paclitaxel 60 mg/m² IP on day 8. The cycle is repeated every 21 days for 6 courses.
Only 42% of the patients in the IP/IV arm completed all six courses. A QOL index was significantly worse in the IP/IV group before cycle four and 3 to 6 weeks after treatment, but was not different 1 year after treatment. Although the IP mode of therapy is more difficult for the patient to tolerate, a clear survival advantage was seen and changed the standard of care for patients with optimally debulked stage III EOC and primary peritoneal cancer.
Maintenance therapy. As noted earlier, even with advanced EOC, it is expected that approximately 60% to 70% of patients will achieve a clinical remission after initial platinum-based chemotherapy. However, most of these women are destined to recur with eventual death from their disease. Therefore, the concept of maintenance chemotherapy to extend survival is attractive. Studies have shown that extending combined carboplatin and paclitaxel beyond six courses does not prolong survival. A recent trial looking at four additional courses of topotecan after initial platinum-based therapy also showed no survival advantage. However, one trial studied women with advanced EOC who achieved a complete clinical remission after carboplatin and taxol. They were then randomized to an additional 3 or 12 cycles of paclitaxel alone at 175 mg/m² every 28 days. A statistically significant progression-free survival of 28 versus 21 months in the arm with 12 additional courses of paclitaxel was seen. To date, this has been the only trial showing an advantage with extended or maintenance chemotherapy.
Second-look laparotomy. Once a part of standard ovarian cancer treatment, second-look laparotomy is rarely performed currently. Recent data has not shown any survival advantage to routine second-look surgery at the end of
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primary treatment and should not be offered outside of an approved clinical trial. Even after a pathologically negative second-look laparotomy, more than 50% of patients will eventually have a recurrence and die of their disease.

D. Follow-up

After six courses of a platinum-based chemotherapy, patients in complete clinical remission can be offered entry into a clinical trial of consolidation or maintenance therapy, maintenance therapy with an additional 12 courses of paclitaxel on a monthly basis, or close observation with reinitiating chemotherapy for documented recurrence. Observation usually entails monitoring of the CA125 level, physical examination, and directed radiologic studies such as CT or PET scan on a scheduled basis.

E. Recurrent and persistent disease

Patients with recurrent EOC are generally grouped based upon their duration of response from initial platinum-based therapy. Patients who have a recurrence within 6 months of their last dose of platinum-based therapy are termed platinum resistant and are best treated with a non cross-resistant drug or placed on a research protocol. Patients who have a disease-free interval of greater than 6 months are termed platinum sensitive. The length of this disease-free interval directly corresponds to the anticipated response rate of retreatment with platinum. Patients who have a long disease-free interval from their initial platinum regimen (12 or more months) are probably best retreated with their initial regimen of a platinum drug and a taxane.

Many patients will demonstrate marker-only relapse (elevated CA125) without symptoms and without evidence of recurrence by examination or CT scan. The decision to treat on the basis of tumor marker elevation only is often difficult for the patient and for the physician. These women may be enjoying a good QOL, and introduction of chemotherapy for an asymptomatic disease will reduce this quality. A frank and honest discussion with the patient is warranted. The patient may be a good candidate for observation or enrollment in a clinical trial. However, most gynecologic oncologists, as well as most patients, elect to treat with chemotherapy on the basis of the belief that retreatment with low tumor volume may enhance the possibility of a second remission. Once the decision to utilize chemotherapy is made, the choice of agent is based upon the patient's platinum-free interval, as discussed in the preceding text.

Several agents are available for those who are platinum resistant. The selection of a drug is based upon balancing anticipated toxicities with scheduling, as second-line chemotherapy regimens have yielded similar responses. Generally, singleagent therapy is used, unless the patient is on protocol. Taxanes (paclitaxel and docetaxel) can be given if they are not used up front or if the patient has received a taxane up front but is not considered taxane resistant. Various schedules of taxanes and other agents with reported activity include the following (used as single agents, not in combinations):

Paclitaxel 135 to 175 mg/m² IV over 3 hours every 21 days
Paclitaxel 50 to 80 mg/m² IV over 1 hour on days 1, 8, and 15 every 28 days

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Docetaxel 60 to 80 mg/m² IV every 21 days
Docetaxel 25 to 35 mg/m² IV days on 1, 8, and 15 every 28 days
Liposomal doxorubicin (Doxil) 40 to 50 mg/m² IV every 3 weeks
Topotecan 1.0 to 1.5 mg/m² IV on days 1 to 5 every 3 weeks or Topotecan 3 to 4 mg/m² days 1, 8 and 15 every 28 days
Oral etoposide 50 mg/m² (30 mg/m² for prior RT) on days 1 to 21 every 28 days
Gemcitabine 800 to 1,000 mg/m² IV on days 1, 8, and 15 every 28 days
Vinorelbine 30 mg/m² IV on days 1, 8, and 15 every 28 days
Tamoxifen 20 mg PO b.i.d.
Oral altretamine (hexamethylmelamine, Hexalen) 260 mg/m²

Responses with second-line treatment range from 20% to 40%. Most are short, but responses can occasionally exceed 1 to 2 years, justifying the concept of second-line chemotherapy for the informed patient who still wishes to try. High-dose therapy including peripheral blood stem cell transplant has not been found to improve survival in EOC. In the setting of a relapse, patients should be encouraged to participate in clinical trials.

The addition of gemcitabine to cisplatin has been shown in vitro in an ovarian cancer cell line to demonstrate synergetic activity. In an attempt to reverse platin resistance, a trial in platin- and paclitaxel-resistant patients using gemcitabine 750 mg/m² IV over 30 minutes followed by cisplatin 30 mg/m² on days 1 and 8 every 21 days was reported. An overall response rate of 43% with a median response duration of 11 months was seen in this refractory group of patients.

The use of targeted therapeutics has been reported in recurrent disease. A monoclonal antibody directed against vascular endothelial growth factor (VEGF), bevacizumab, was used in combination with oral cytoxan in a group of heavily pretreated patients with recurrent, refractory EOC, and primary peritoneal cancer. Patients were treated with bevacizumab 10 mg/kg IV on days 1, 8 and 15, then every 2 weeks along with oral cyclophosphamide 50 mg PO daily until the disease progresses. Toxicities were minimal and this combination showed a 21% partial response, 59% stable disease, and a progression-free survival of 5.8 months.

V. Gestational trophoblastic neoplasm (GTN)

GTN comprises a spectrumof neoplastic growth ranging fromhydatidiform mole (HM), invasive molar disease, choriocarcinoma and the rare placental site trophoblastic tumor (PSTT). All of these represent abnormal proliferation of trophoblastic tissue. The terminology and classification systems used for these disorders can be confusing. GTN is now considered the more appropriate term to encompass the variety of clinical situations encountered. The evaluation and management of GTN has been standardized to make it one of themost curable gynecologicmalignancies. Reasons for the high cure rate include the presence of a sensitive tumor marker, -human chorionic gonadotropin ( -hCG), that is directly related to the extent of disease, the extreme sensitivity of GTN to a variety of chemotherapeutic agents, the identification of highrisk factors to allow for individualization of treatment, and the

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aggressive use of multiagent chemotherapy combined with other modalities such as surgery and radiation for recalcitrant cases.

A. Hydatidiform mole (HM)

The most common form of GTN is the HM, with the complete HM being found more frequently than the partial HM. A complete HM is the result of fertilization of an anucleate ovum by a sperm. Cytogenetic studies have shown that all genetic material in a complete HM is paternal. They are always diploid (> 90% 46 XX) and are devoid of any fetal tissue. The partial HM, in contrast, is associated with triploidy (usually 69 XXY) and fetal tissue. Risk factors for developing an HM include being at the extremes of the reproductive age, prior history of GTN, and being of Asian descent. The most common symptom is first trimester vaginal bleeding or the passage of vesicular tissue from the vagina. Although a high -hCG is often associated with GTN, there is no single level that is diagnostic of GTN. The development of preeclampsia before the 20th week of gestation is pathognomonic of GTN. Diagnosis is made by an USD of the uterus, showing the classic snowstorm appearance with multiple small vesicles in the case of a complete GTN, and of a large hydropic placenta with a fetus in the event of a partial HM.

Management. Once the diagnosis of an HM is made by USD, the patient should be scheduled for uterine evacuation in the operating room expeditiously. Preoperative evaluation includes a baseline -hCG, complete blood count (CBC), chest x-ray, and a careful physical examination to rule out evidence of genital metastasis (especially vaginal) and for any signs of hyperthyroidism or pre-eclampsia. Liver and thyroid function tests may be considered, based on the physical findings. If the USD shows evidence of theca luetin cysts (they can be quite large) they should be followed expectantly, as they will resolve after evacuation of the HM. The optimal method of evacuation for a complete HM is by suction curettage. Prostaglandin induction should not be performed. In the event of an extremely large uterus, larger than 16 weeks size, intraoperative USD guidance to avoid uterine perforation and insure complete evacuation of all molar tissue is recommended. Evacuation of an incomplete HM usually involves a combination of prostaglandin induction and suction curettage.
Monitoring. After evacuation of an HM, serum -hCG levels are monitored weekly until three consecutive normal values (<5 mIU/mL) are obtained. Monthly titers are then drawn for 6 months. An effective form of contraception should be used to avoid pregnancy. Approximately 15% to 20% of complete HMand 3% to 5% of partial HMwill recur. Risk factors for persistence or metastasis include patients with paraneoplastic disorders such as hyperthyroidism or pre-eclampsia, uterus being greater than 16-weeks size at diagnosis, extremely high baseline -hCG levels, and the presence of theca luetin cysts. During the follow-up, if there is a plateau or a rise in the -hCG level, than prompt evaluation and staging are imperative. Referral of these women to a trophoblastic disease center or to a gynecologic oncologist is highly recommended to optimize outcome.

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B. Persistent GTN

During follow-up for an HM, a plateau or a rise in the -hCG level mandates prompt staging and treatment. At the minimum, a complete physical and pelvic examination, chest x-ray, liver function tests, and CBC are necessary. If residual disease is suspected in the uterus, a pelvic sonography can be performed. The only indication for repeat curettage is in the setting of residual disease in the uterus. If any evidence of metastatic disease is found on these preliminary studies or suspected on physical examination, then a CT of the abdomen and pelvis and head is necessary. There are several staging systems for GTN. The most clinically relevant is the American College of Obstetricians and Gynecologists (ACOG) staging (Table 11.5). The FIGO staging system and the World Health Organization (WHO) classification are also used but are more cumbersome (Table 11.6). All patients with persistent GTN require treatment with chemotherapy. The key treatment monitor for persistent GTN is the serum -hCG level. Using the ACOG classification system, patients can be divided into three separate groups based upon the presence of absence of metastatic disease.

Table 11.5. International Federation of Gynecology and Obstetrics staging for gestational trophoblastic neoplasia

Stage	Definition
I	Strictly confined to uterine corpus
II	Extends outside uterus but limited to genital structures
III	Extends to lungs with or without genital tract involvement
IV	All other metastatic sites
Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging handbook, 6th ed. Springer-Verlag, 2002.

Nonmetastatic GTN. By definition, patients with nonmetastatic GTN are 100% curable since all the disease is still contained in the uterus. Treatment involves singleagent chemotherapy with either methotrexate (MTX) or dactinomycin (Actinomycin-D, Act-D). Cure rates are similar between the two drugs. Recommended dosages and schedule for Act-D include 10 to 13 g/m² IV daily for 5 days every 14 days. However, Act-D 1.25 mg/m² IV every 2 weeks is often preferred as it is logistically easier for the patient. Schedules acceptable for MTX include 0.5 mg/kg IM daily for 5 days every 2 weeks; 1 mg/kg on days 1, 3, 5, and 7 followed by leucovorin 0.1 mg/kg on days 2, 4, 6, and 8 every 15 to 18 days; and MTX 30 to 50 mg/m² IM weekly. The latter regimen has increased in popularity because of its ease of administration. Treatment is continued until the -hCG level normalizes. Fortunately, few patients with nonmetastatic GTN fail primary therapy. Those who do can be switched to the alternative single-agent therapy. In the event of resistance to both Act-D and MTX, patients should be switched to multiagent therapy with EMA-CO or EMAEP (see Table 11.7). Patients with nonmetastatic GTN who

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no longer desire fertility can be considered for hysterectomy as primary therapy. The use of hysterectomy will decrease the number of cycles of chemotherapy necessary for remission. Additionally, patients with refractory nonmetastatic disease can also be considered for hysterectomy in the salvage setting. If a nodule of GTN deep in the myometrium is present on imaging studies, successful remission with resection of the lesion or intrapelvic chemotherapy infusion and preservation of the uterus has been reported.

Table 11.6. Modified American College of Obstetricians and Gynecologists classification of gestational trophoblastic neoplasm

Nonmalignant GTN
1. Hydatidiform mole
  1. Complete
  2. Incomplete
Malignant GTN
1. Nonmetastatic GTN: no evidence of disease outside of uterus, not assigned to prognostic category
2. Metastatic GTN: any metastases
  1. Good-prognosis metastatic GTN
    Short duration (<4 months)
    Low -hCG level (<40,000 mIU/mL serum -hCG)
    No metastases to brain or liver
    No antecedent term pregnancy
    No prior chemotherapy
  2. Poor-prognosis metastatic GTN: any high-risk factor
    Long duration (>4 months since last pregnancy)
    High pretreatment -hCG level (>40, 000 mIU/mL serum -hCG)
    Brain or liver metastases
    Antecedent term pregnancy
    Prior chemotherapy

GTN, gestational trophoblastic neoplasm; -hCG, -human chorionic gonadotropin.

Low-risk metastatic GTN. Patients in this group are treated in a manner similar to those with nonmetastatic GTN with single agent ACT-D or MTX. Therapy is continued for at least one course past a normal -hCG titer. Patients who fail single-agent therapy are candidates for multiagent chemotherapy with EMA-CO.

High-risk metastatic GTN. This group of patients represents a significant challenge to the clinician. They have often developed drug resistance, as well as toxicity, and depleted bone marrow reserves from prior therapy. The current treatment of choice is the use of multiagent chemotherapy with EMA-CO every 2 weeks (see Table 11.7) with expected cure rates of 70% to 90%. Treatment is continued until three consecutive weekly normal -hCG levels have been obtained and at least two to four cycles of therapy have been delivered after normalization of the -hCG.

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Patients who fail EMA-CO have been salvaged with replacement of the cyclophosphamide and vincristine on day 8 with etoposide 100 mg/m² IV and cisplatin 80 mg/m² IV (EMA-EP). Alternative regimens for the refractory patient, although less effective than EMA-EP include platinum, vinblastine and bleomycin (PVB), and bleomycin, etoposide, and cisplatin (BEP), or single-agent paclitaxel, topotecan, gemcitabine, irinotecan, and oxaliplatin.

Table 11.7. Multiagent chemotherapy regimens for gestational trophoblastic disease

Regimen	Schedule and Doses	Regimen	Repeated
EMA-CO	Etoposide	100 mg/m² IV day 1 2	Every 2 week
	Actinomycin	0.5 mg IV push day 1 2
	Methotrexate	100 mg/m² IV push, then 200 mg/m² IV over 12 h day 1
	Leucovorin	15 mg IM or PO q12 h x 4 24 h after MTX
	Vincristine	1 mg/m² IV push day 8
	Cyclophosphamide	600 mg/m² IV push day 8
EMA-EP	Etoposide^a	100 mg/m² IV push day 8
EMA-EP	Cisplatina	80 mg/m² IV day 8
^aSame as EMA-CO, except substitute etoposide/cisplatin for vincristine cyclophosphamide.

Special situations. Owing to the usually young age of these patients and of the potential for salvage, aggressive multimodality therapy and aggressive support should be considered for those patients with resistant or refractory disease. Patients with refractory disease should undergo investigation for solitary lesions that may be surgically resectable such as an isolated pulmonary, hepatic or cerebral metastasis. Additionally, intrathecal chemotherapy with MTX or whole brain irradiation may be considered for central nervous system (CNS) disease. Patients with hepatic lesions may be candidates for whole-liver radiation in conjunction with chemotherapy to help reduce the risk of hepatic hemorrhage.
Placental site trophoblastic tumors (PSTT). Treatment guidelines for patients with PSTT are less well established owing to their rarity. These rare tumors arise from the intermediate trophoblastic cell and are usually
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slow-growing, indolent neoplasms. Diagnosis of PSTT several years after pregnancy is not unusual. They produce low levels of -hCG, and human placental lactogen has been used as a reliable tumor marker. Hysterectomy is considered the treatment of choice. For patients with metastatic or recurrent disease, treatment with EMA-CO or EMAEP is recommended. However, owing to their low growth fraction, chemotherapy is rarely successful.

VI. Vulvar cancer

Primary malignancy of the vulva is rare, accounting for 4% to 5% of all gynecologic malignancies. This is usually a disease of elderly women with most cases diagnosed in the seventh or eighth decade of life. Recently there has been an increased incidence of invasive vulvar cancer in younger women. These younger women will very often have a long history of HPV infection, multifocal vulvar dysplasia and tobacco abuse. Symptoms of vulvar cancer include vulvar pruritus, vulvar pain, vulvar bleeding, or a noticeable lump or mass.

A. Pathology

Squamous cell cancers represent 90% of all vulvar cancers followed in decreasing frequency by melanoma, adenocarcinoma (usually of the Bartholin's gland), and sarcomas.

B. Diagnosis and evaluation

Diagnosis is by biopsy of the lesion. Vulvar cancers can spread by lymphatic dissemination first to the groin/inguinal lymph nodes, then to pelvic and para-aortic nodes, or by direct spread to the vagina, urethra, or anus. Evaluation of a woman with invasive vulvar cancer includes chest x-ray, routine laboratory studies, and careful physical examination of the vulvar and inguinal area to assess the clinical extent of the disease. CT imaging of the pelvis and abdomen may be considered if suspicious adenopathy is found in the inguinal nodes to rule out spread to the pelvic or para-aortic nodes.

C. Treatment

Surgery. Vulvar cancer is treated primarily with surgery. In select cases preoperative chemotherapy (Section VI.C.3) and radiation is warranted. Surgical treatment involves a radical wide local resection of the primary lesion with a 1-cmgross margin combined with an inguinal lymph node dissection. An ipsilateral inguinal node dissection can be performed through a separate incision. Bilateral inguinal node dissection should be performed if the ipsilateral inguinal nodes are positive or if the primary lesion involves midline structures (clitoris, urethra, vagina, perineum or anus). A lesion less than 2 cm in diameter with less than 1 mm of invasion (stage IA) can be safely treated with wide resection alone. All lesions with more than 1.0 mm of invasion require an inguinal node dissection. The use of lymphatic mapping and sentinel lymph node biopsy is still considered investigational. Often, for large vulvar lesions, reconstruction with a skin or myocutaneous flap may be necessary.

Staging, risk stratification (Table 11.8). Vulvar cancer is surgically staged on the basis of the size of the primary lesion, direct extension to the vagina, anus or urethra, and by the pathologic status of the inguinal lymph

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nodes. Clinical staging is often used to direct primary therapy. However, clinical evaluation of normal inguinal lymph nodes is historically inaccurate with disease in up to 20% of patients with palpably normal inguinal nodes. The impact of spread to the inguinal lymph nodes is prognostically significant. A patient with a T1 lesion and negative inguinal lymph nodes (stage IB) will have a 5-year survival of more than 90%. Pathologic spread to the inguinal nodes with the same size of primary lesion (stage III) will portend a 5-year survival of approximately 60%. After surgical staging, patients with negative inguinal lymph nodes and negative surgical margins are in a low-risk group and are generally observed. Patients with evidence of pathologic spread to the inguinal nodes are offered adjuvant RT to the affected groin and pelvis.

Table 11.8. 1995 International Federation of Gynecology and Obstetrics staging for carcinoma of the vulva

Stage	Definition
0	Carcinoma in situ; intraepithelial carcinoma (Tis)
I	Tumor confined to the vulva and/or perineum, 2 cm in greatest dimension; nodes are negative (T1, N0, M0)
IA	Lesions 2 cm in size confined to the vulva or perineum with stromal invasion no greater than 1 mm No nodal metastases. The depth of invasion is defined as the measurement of the tumor from the epithelial stromal junction of the adjacent most superficial derma papilla to the deepest point of invasion
IB	Lesions 2 cm in size confined to the vulva or perineum with stromal invasion >1 mm; no nodal metastases
II	Tumor confined to the vulva and/or perineum, >2 cm in greatest dimension; nodes are negative (T2, N0, M0)
III	Tumor of any size with (a) adjacent spread to the lower urethra and/or the vagina or to the anus; and/or (b) unilateral regional lymph node metastasis (T3, N0, M0; T3, N1, M0; T1, N1, M0; T2, N1, M0)
IVA	Tumor invades any of the following: upper urethra, bladder mucosa, rectal mucosa, pelvic bone; and/or bilateral regional node metastasis (T1, N2, M0; T2, N2, M0; T3, N2, M0; T4, any N, M0)
IVB	Any distant metastasis, including pelvic lymph nodes (any T, any N, M1)
TNM classification
Primary tumor
Tis	Preinvasive carcinoma (carcinoma in situ)
T1	Tumor confined to the vulva and/or perineum <2 cm in greatest dimension
T2	Tumor confined to the vulva and/or perineum >2 cm in greatest dimension
T3	Tumor of any size with adjacent spread to the urethra and/or vagina and/or to the anus
T4	Tumor of any size infiltrating the bladder mucosa and/or the rectal mucosa, including the upper part of the urethral mucosa and/or fixed to the bone
Regional lymph nodes
N0	No lymph node metastasis
N1	Unilateral regional lymph node metastasis
N2	Bilateral regional lymph node metastasis
Distant metastasis
M0	No clinical metastasis
M1	Distant metastasis (including pelvic lymph node metastasis)

Candidates for chemotherapy. Patients with distant disease are candidates for chemotherapy. Clinical data on the optimal choice of chemotherapy for these patients are lacking owing to the rarity of the disease. Most agents that are effective against squamous cell cancers occurring at other sites are deemed effective in the treatment of distant metastasis from vulvar cancer. Cisplatin, bleomycin, topotecan, flurouracil, methotrexate, mitomycin, and doxorubicin all have reported activity. However, response of distant disease to chemotherapy is usually brief.

Patients who initially present with locally advanced disease (T3 or T4) that would require exenterative type radical resection are also candidates for combined chemotherapy and RT. This includes patients presenting with fixed or ulcerative (N3 or N4) inguinal nodes. A prospective clinical trial treated 73 patients with locally advanced disease with local irradiation and concurrent chemotherapy; cisplatin 50 mg/m² IV on day 1 plus flurouracil 1,000 mg/m² as a continuous IV infusion on days 1 to 4 every 3 weeks during radiation gave a 46% complete response rate and only three patients required interruption of the gastrointestinal or genitourinary system. Chemoradiation appears to be the treatment of choice for those patients who present with locally advanced vulvar or inguinal disease. However, a recent trial involved 14 patients with locally advanced vulvar cancer involving the anal sphincter and/or urethra who were treated with neoadjuvant chemotherapy alone consisting of cisplatin and flurouracil followed by radical vulvectomy. A response rate of 100% with preservation of the urethra and anal sphincter in all patients was observed.