Archive for November, 2007.
Surgical removal of epithelial cancer that is confined to the ovary, followed by a full surgical staging procedure, may be adequate therapy. In other early-stage patients, some type of adjunctive treatment may be required. Epithelial ovarian cancer is categorized as early disease (stages I and II with no residual cancer) and advanced disease (stage II with residual cancer and stage III and stage IV cancer).
Table 10 provides a classification system for patients within broad categories. Early ovarian cancer can be divided into low-risk and high-risk disease. For properly staged low-risk epithelial ovarian cancer, survival is approximately 95% and no therapy has been shown to be more effective than surgical removal of the cancer. For patients who wish to continue childbearing, unilateral salpingo-oophorectomy is acceptable providing they had a full surgical staging procedure. Most authorities would recommend removal of the retained ovary when childbearing is complete.
High-risk cancer, however, requires adjuvant treatment with either irradiation or chemotherapy. With adjunctive therapy, survival rates for patients with high-risk cancer are 75-95%. In these patients, the role of conservative surgery is more controversial, although some oncologists will preserve childbearing capability in these women despite the requirement for adjunctive chemotherapy. These patients do not have the option of choosing irradiation as a therapeutic option because such therapy would destroy the retained ovary.
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Primary Cytoreductive Surgery. Reports in the late 1960s indicated improved survival in patients who had extensive surgical resection followed by whole-abdomen radiation. In a 1975 study, the exact residual diameter of tumors was recorded, and size was related to duration of survival. All of the study patients had been treated postoperatively with a single alkylating agent. The study reported a survival time of 39 months for patients with no residual tumors, 29 months for patients with residual tumors smaller than 0.5 cm in diameter, 18 months for patients whose tumors were 0.6-1.5 cm in diameter, and 11 months for patients with residual tumors larger than 1.5 cm. Since that report, many other reports have confirmed that patients whose tumors are reduced to small-volume disease are more likely to have a response to chemotherapy and the frequency of complete responses is greater. Overall response rates were 66.8% in patients with optimal residual disease compared with 53.3% in patients with suboptimal residual disease. The complete response rate was 42.7% in patients with optimal residual disease compared with 24% for patients with suboptimal residual disease.
A group of researchers evaluated 324 patients who had been entered in a Gynecologic Oncology Group study for patients with optimal (<1 cm) disease in an effort to define the benefit of cytoreductive surgery in relation to a variety of other prognostic factors. These investigators found that although cytoreductive surgery was an important factor in determining outcome, it was not the only significant factor. Also important was the age of the patient, the number of residual tumor nodules, and the grade of the tumor.
Treatment
Treatment of ovarian cancer usually involves several types of therapy. Surgical therapy is the initial form of intervention, but it is curative in only a small percentage of cases. Usually, adjunctive chemotherapy, radiation therapy, or both are necessary. Surgical reassessment after adjunctive therapy
is necessary for most patients with advanced disease. In a large percentage of patients, some type of salvage therapy is important. Table 10 outlines current therapies and therapeutic options for epithelial ovarian cancer.
• TABLE 8. Gynecologic and Nongynecologic
Cancers That May Have Serum Elevations of CA 125
Gynecologic Cancers Nongynecologic Cancers
Epithelial ovarian cancer Pancreatic cancer
Some germ cell tumors Lung cancer
Some stromal tumors Breast cancer
Fallopian tube cancer Colon cancer
Endometrial cancer
Endocervical cancer
• TABLE 9. Gynecologic and Nongynecologic Benign Conditions That May Have Serum Elevations of CA 125
Gynecologic Conditions Nongynecologic Conditions
Endometriosis Pancreatitis
Adenomyosis Cirrhosis
Leiomyomata uteri Passive liver congestion
Ectopic pregnancy Peritonitis
Normal pregnancy Peritoneal tuberculosis
Pelvic inflammatory disease Peritoneal sarcoidosis
Menses Recent laparotomy
TABLE 10. Optional Therapy for Epithelial Ovarian Cancer*
Category of Ovarian Cancer Recommended (Standard) Therapy
Early ovarian cancer
Low risk (stages IA & B, grade 1) TAH, BSO, full surgical staging
High risk (stages IA & B, grades 2 & 3, TAH, BSOt, full surgical staging
stages IC, IIA, B & C, no residual} Adjunctive therapy with combination platinum-based chemotherapy
Second look: Not recommended
Alternative: Whole abdominal radiation therapy
Investigational: Paclitaxel in combination with a platinum compound
Advanced ovarian cancer
Optimal§ Maximal surgical cytoreduction
Combination chemotherapy with a platinum compound and paclitaxel
Second look: Recommended
Alternative: Whole abdominal radiation therapy for patients with no gross residual
Investigational: High-dose chemotherapy with stem cell rescue
Suboptimal Maximal surgical cytoreduction
Combination chemotherapy with cisplatin and paclitaxel
Second look: Recommended
Alternative: None
Investigational: High-dose chemotherapy with stem cell rescue
Recurrent or persistent ovarian cancer Investigational therapy or topotecan, ifosfamide, or hexamethylmelamine
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*TAH indicates total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy. Some investigators include grade 2 in the low-risk category. t Unilateral salpingo-oophorectomy permissible in patients who desire further childbearing. §Optimal (stage III, <1 cm residual).
I I Suboptimal (stage III, >1 cm residual, or stage IV).
Staging of ovarian carcinoma is based on findings at clinical examination and by surgical exploration. The histologic findings are to be considered in the staging, as are the cytologic findings as far as effusions are concerned. It is desirable that a biopsy be taken from suspicious areas outside of the pelvis.
Stage I Growth is limited to the ovaries.
Stage IA Growth is limited to one ovary; no ascites present containing malignant cells. There is no tumor on the external surface; capsule is intact.
Stage lB Growth is limited to both ovaries; no ascites present containing malignant cells. There is no tumor on the external surfaces; capsules are intact.
Stage IC* Tumor is classified as either stage IA or lB but with tumor on the surface of one or both ovaries; or with ruptured capsule(s); or with ascites containing malignant cells present or with positive peritoneal washings.
Stage II Growth involves one or both ovaries, with pelvic extension.
Stage IIA There is extension and/or metastases to the uterus and/or tubes.
Stage lIB There is extension to other pelvic tissues.
Stage IIC* Tumor is either stage IIA or lib but with tumor on the surface of one or both ovaries; or with capsule(s) ruptured; or with ascites containing malignant cells present or with positive peritoneal washings.
Stage Ill Tumor involves one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis but with histologically proven malignant extension to small bowel or overturn.
Stage IlIA Tumor is grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces.
Stage IIIB Tumor involves one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative.
Stage IIIC There are abdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes.
Stage IV Growth involves one or both ovaries, with distant metastases. If pleural effusion is present, there must be positive cytologic findings to assign a case to stage IV. Parenchymal liver metastasis equals stage IV.
*To evaluate the impact on prognosis of the different criteria for assigning cases to stage IC or IIC, it would be of value to know whether the rupture of the capsule was spontaneous or caused by the surgeon and if the source of malignant cells detected was peritoneal washings or ascites.
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Unfortunately, most patients with ovarian cancer are diagnosed after the disease has spread beyond the ovary. In these patients, symptoms may be abdominal pain or a bloated feeling, gastrointestinal or urinary tract disturbances, or in many cases, the onset of clinically detectable ascites. Some patients with advanced disease have menstrual irregularity or postmenopausal bleeding, but these symptoms occur infrequently. Occasionally, a patient may present with a palpable inguinal lymph node, tumor in a hernia sac, or pleural effusion. For patients with advanced disease, diagnosis is established by tissue obtained at exploratory laparotomy. In rare instances when a patient cannot undergo surgery because of medical problems, the histologic or cytologic diagnosis is established by needle biopsy.
Early ovarian cancer is diagnosed by the surgical evaluation of an adnexal mass. The decision to subject a patient to surgical exploration is difficult to make. Ultrasonographic evaluation of the adnexal mass has improved the ability to distinguish patients who should have surgical exploration from those who can be observed, but it has also resulted in an increasing number of patients who are found to have an asymptomatic ovarian cyst. This is of particular concern in the postmenopausal woman. Table 7 outlines the diagnostic criteria for surgical exploration of a patient with an adnexal mass. As with any diagnostic or therapeutic schema, the criteria for exploration cannot be absolute. For example, a patient with known endometriosis may meet the criteria for surgical exploration when it is not the best treatment option, or a postmenopausal patient with a 4-cm simple cyst may have risk factors for surgery that make observation a more reasonable option.
Cancer treatment
The use of tumor markers to assist in the evaluation of a patient with an adnexal mass is not inappropriate, but misinformation may result. Serum CA 125 is used most often and is the only serum marker available with the potential accuracy to be beneficial, but even this marker is less than optimal. Approximately half of early-stage ovarian cancer patients do not have elevated serum CA 125 levels. Also, a variety of nonmalignant and nonovarian malignant conditions can result in elevated serum CA 125 levels. These conditions are listed in Tables 8 and 9, page 43. A serum CA 125 elevation above 35 U may be helpful in deciding whether or not to recommend surgery in a postmenopausal patient with an ovarian mass, but a negative value is not helpful. Likewise, a serum CA 125 elevation in women of reproductive age with both an ovarian mass and leiomyomata or endometriosis may not be helpful.
TABLE 7. Management Schema for a Patient with an Adnexal Mass
Observe and Repeat Examination in 4-6 Weeks Surgical Exploration
Reproductive age Premenarchal or postmenopausal*
Mass <8 cm Mass >8 cm
Simple cysts on ultrasonography Complex cysts on ultrasonography
Decreasing size Increase in size or persistence through 2-3 menstrual cycles
Cystic and smooth Solid and irregular
Mobile Fixed
Unilateral Bilateral
Asymptomatic Pain or other symptoms of acute intraabdominal process
No ascites Ascites
*Simple cysts smaller than 3 cm may be followed closely with ultrasonography.
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Staging classification is made on the basis of surgical evaluation, and the removal of as much tumor as possible is the cornerstone of treatment. Despite the importance of surgery, some type of adjunctive treatment is almost always required. The proper surgical procedure and the appropriate choice of adjunctive therapy depend on the findings at initial exploration, the histologic type of the tumor, and the age and reproductive desires of the patient. There are few diseases encountered by the gynecologist that will demand as much knowledge and skill as the therapy of ovarian cancer.
Cancer
Staging
The FIGO staging classification scheme for ovarian cancer is outlined in the box, page 42. The staging of advanced disease (spread throughout the abdomen) may be obvious to most physicians, but it is important for a surgeon to be meticulous in the staging of early ovarian cancer. In one study it was found that one third of patients referred with stage I or stage II disease were actually found to have stage III disease when the appropriate staging operation was performed. Similar results have been reported by other researchers. Buy cheap levitra at Canadian Pharmacy
To perform a staging operation appropriately, the spread patterns of the cancer should be understood. The cancer can spread by direct infiltration of pelvic structures such as the pelvic peritoneum, bladder surface, rectal surface, fallopian tube, broad ligament, or uterus. Lymphatic spread occurs early in ovarian cancer, with nodal metastases occurring in 10-12% of patients with stage I cancer and 2025% of patients with stage II disease. In stage III and stage IV, the incidence of positive lymph nodes is 50-70%. By far, however, the most significant spread of ovarian cancer is exfoliation of clonogenic cells into the peritoneal cavity. These cells are swept up the right abdominal gutter to the diaphragm and omentum by the clockwise flow of peritoneal fluid in the abdomen. The cells implant, form tumor nodules, and in turn exfoliate more cells. The normal daily activities of the patient and normal peristalsis of the intestine result in spread of the disease throughout the abdominal cavity. Proper staging requires a generous lower and upper midline incision and meticulous exploration with multiple peritoneal and nodal biopsies.
In young patients who wish to bear children and have epithelial, germ cell, or stromal tumors confined to one ovary, conservation of the uterus and other ovary and fallopian tube is possible, provided that a full surgical staging procedure is performed. In these patients, it is particularly important to be meticulous in the evaluation of the entire abdomen.
Ovarian tumors are usually categorized by their tissue of origin: epithelial (from the coelomic epithelial cells that line the ovary), sex cord-stromal (from the mesenchymal tissue of the ovary), and germ cell (from the germinal epithelium). Epithelial tumors account for approximately 85% of ovarian cancers, germ cell cancers account for approximately 10%, and the remaining 5% of tumors are sex cord-stromal in origin. The World Health Organization’s classification system for ovarian tumors is shown in the box, pages 40-41.
Of the malignant epithelial ovarian cancers, 40-50% are serous tumors, 15-25% are endometrioid tumors, 6-16% are mucinous tumors, and 5-11% are clear cell tumors. Transitional cell (Brenner), mixed epithelial, and undifferentiated carcinomas are encountered less frequently. Epithelial tumors may be benign, have low malignant potential, or be frankly malignant. Tumors of low malignant potential (borderline tumors) have a much better prognosis than the frankly malignant cancers, but they are nevertheless malignant and can result in death. Malignant tumors are further subdivided by histologic grade either into three grades based on architecture (FIGO classification) or into four grades based on nuclear atypia (Broders’ index).
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The most common germ cell tumor is the mature cystic teratoma, a benign tumor. The most common malignant germ cell tumor is the dysgerminoma, followed in incidence by the endodermal sinus tumor and the immature teratoma. As can be seen in Figure 4, the germ cell tumors are most commonly seen in the first two decades of life.
The sex cord-stromal tumors are usually divided into the female type, characterized by the granulosa cell tumor, and the male type, characterized by the Sertoli-Leydig cell tumor. More than 90% of malignant stromal tumors are granulosa cell tumors. Although these tumors can occur at any age, they are more common before menopause.