Gynecologic Malignancies: Detection, Prevention, and Therapeutics

Gynecologic Malignancies: Detection, Prevention, and Therapeutics Part 1. Ovarian Cancer By Janelle Perkins, PharmD Introduction

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n 1986, 73,000 new cases of invasive gynecologic cancers and 22,400 deaths from these cancers were reported by the American Cancer Society. Endometrial cancer is the most common of the malignancies but ovarian cancer is the most fatal (Table 1). Early diagnosis plays a major role in the curability of these diseases. Ovarian cancer, which is observable in early stages in less than 35% of patients, remains the fourth leading cause of cancer death in women. In contrast, with the development of the Papanicolaou (Pap) smear affording early detection of cervical cancer, death rates from that neoplasm have fallen by more than 65%. The female reproductive tract includes the ovaries, Fallopian tubes, uterus, vagina, and, externally, the vulva. The uterus conJanelle Perkins, PharmD, is clinical pharmacist, H. Lee Moffitt Cancer Center and Research Institute at the University ofSouth Florida, Tampa, 33682. American Pharmacy~ cancer screening series' guest editor is Celeste Lindley, PharmD, ofthe University ofNorth Carolina School of Pharmacy.

Table 1. Relative Frequency and Fatality of Gynecologic Malignancies

Cancer

Endometrial Ovarian Cervical Other

40

% of All Malignancies in Women

Deaths! Years (est.)

13 6 6 2-3

3,000 11 ,500 700 1,000

sists of the endometrium (the inner layer of the uterine wall), the myometrium (the muscular wall of the uterus), and the cervix (the neck of the uterus that extends into the vagina). The myometrium and endometrium make up the corpus (body) of the uterus (Figure 1). Neoplastic disease may arise from any of these tissues and will differ in its diagnosis, natural history, staging, and management depending on its site of origin. This cancer screening series discusses the most common gynecological tumors: cancers of the ovary, cervix, and endometrium. Part 1 discusses ovarian cancer. (Part 2, to be published in December, will discuss cervical and endometrial cancers.)

Epidemiology

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ne in 70 women will develop ovarian cancer. Rarely seen before menarche, the age-specific incidence for ovarian cancer rises with the peak incidence in women aged 40 to 70 years old. The greatest number of cases occur in the sixth decade of life. Ovarian germ cell tumors are more common in children and adolescents and therefore are an exception. Ovarian cancer is seen more frequently in industrialized countries (excluding Japan). In this country, ovarian cancer is more common in white women than in black women. A higher incidence is seen in women with a low number or no pregnancies, and those with a history of difficulty in conception. Oral contraceptives have been reported to have a protective effect. Compared to women without breast cancer, those with breast cancer have twice the risk of developing ovarian cancer and those with ovarian cancer have three to four times the risk of being diagnosed with

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breast cancer. These facts suggest a hormonal influence on the development of the disease. However, no clear-cut effect has been ascertained.

Fallopian Tubes

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Pathogenesis and Natural History

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umors of the ovary can arise from different histologic (cell or tissue) types normally found in the ovary. Epithelial neoplasms account for 90% of ovarian cancers with the remainder classified as stromal tumors and germ cell tumors. Each of these tumor types carries a different prognostic value and treatment strategy. An even more important prognostic factor than histologic type is histologic grade of the tumor cell. Grade is based on how well differentiated (or how much the tumor cell resembles the cell of origin) the tumor is when evaluated by a pathologist. Well differentiated (mature) tumors carry a better prognosis generally than poorly differentiated (immature) tumor cells. Epithelial tumors are classified as "benign, malignant" (invasive), or "low malignant potential" (borderline). Approximately 15% of patients less than 30 years of age with ovarian tumors will have borderline neoplasms on pathology. These tumors progress and metastasize slowly with 10-year survival rates of 90% (compared to 30% 10-year survival overall for malignant ovarian tumors). Treatment for these borderline tumors consists of surgery for early stages and, for advanced stages, more aggressive therapy similar to that used for invasive tumors. Stromal tumors are associated with precocious puberty and feminizing effects secondary to tumor secretion of estrogen. Surgery is the treatment of choice. Certain types of germ cell tumors correspond to seminoma of the testis in males with regard to natural history and treatment. These tumors are managed with surgery and radiation therapy. Five-year survival with treatment is 80% to 90%. Other types of germ cell tumors are more aggressive, metastasize through the bloodstream (hematogenously), and are treated with chemotherapy. Epithelial tumors, the most common type of ovarian neoplasms, are the focus of this discussion. Unlike many cancers, epithelial ovarian tumors spread either through surface implantation or lymph system, as opposed to through the bloodstream. The earliest spread is usually to the other ovary as well as uterus and Fallopian tubes. The tumor then commonly extends to the peritoneum, omentum, bowel surfaces, and retroperi toneal lymph nodes. In very ad-

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vanced stages, the tumor may be found in the liver, lung, kidney, bone, bladder, and spleen.

Diagnosis and Staging t present, no screening test exists that A is sufficiently specific or sensitive for early detection of ovarian cancer. Symptoms (pain, abdominal distention, and vaginal bleeding) usually are not manifested until the disease is advanced. Early symptoms are vague and nonspecific and include nausea, dyspepsia, and lower abdominal discomfort. Most early stage disease is found serendipitously during a routine pelvic examination. During reproductive years ovarian enlargement is most likely due to a dysfunctional ovarian cyst. In women less than 30 years old, 90% of ovarian tumors are benign. Ovarian cysts will usually regress over the course of one or two menstrual cycles. In a perimenopausal woman, however, greater than 30% of ovarian masses are malignant. When an ovarian mass is detected, ultrasound is performed to determine the consistency of the mass. Evidence of solid elements and involvement of surrounding tissue suggests malignancy. Further pretreatment evaluation includes a complete physical examination and medical history, abdominal CT scan, and surgery (exploratory laparotomy). Surgery is important in evaluating the extent of disease in ovarian cancer and should be performed by a surgeon who is well acquainted with the natural history and patterns of spread for ov~rian cancer. Staging - and therefore prognosis and treatment - is based on the findings from

American Pharmacy, Vol. NS28, No. 11 November 19881719

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Tumor Markers is an antigen found on the surface C of ovarian cancer cells that can be measured by a blood test. Eighty percent to 90% A 125

Stage

Extent of Disease Growth limited to ovaries

la

One ovary, capsule intact, no tumor on ovarian surface

Ib

Both ovaries, capsule intact, no tumor on ovarian surface

Ic

One or both ovaries with any of the following: capsule ruptured, tumor on ovarian surface, malignant ascites or peritoneal washings positive for tumor

II

Growth involving one or both ovaries with pelvic extension

lIa

Extension and/or implants to uterus and/or Fallopian tubes

lib

Extension to other pelvic tissues

IIc

Pelvic extension with malignant ascites or peritoneal washings positive for tumor

III

Growth involving one or both ovaries with microscopically confirmed intraperitoneal metastasis outside the pelvis or + regional lymph nodes

Treatment

Ilia

Microscopic peritoneal metastases beyond pelvis

Ilib

Macroscopic peritoneal metastases beyond the pelvis 2 cm or less in greatest dimension

IIIc

Macroscopic peritoneal metastases beyond the pelvis> 2 cm in greater dimension and/or regional lymph node metastases

IV

Growth involving one or both ovaries with distant metastases; if pleural effusion is present, must have + cytology

~=-~~

III IV

'igurell. the above procedures. The International Federation of Obstetrics and Gynecology (FIGO) has described a staging system that, combined with histologic grade, is used to determine treatment (Table 2 and Figure 2). 42

of patients with ovarian cancer will have tumor cells that express CA 125. However, because of a high rate of false positivity (percentage of women who do not have ovarian cancer but who have elevated titers of the antigen), CA 125 is not used as a screening test. Antigen levels are usually measured when a patient is diagnosed and then followed throughout the disease course. Increasing and decreasing levels correlate with disease activity in 93% of patients, thus it can be usef"Q-I as a sign of progression or regression of disease.

Stage I: Treatment of choice for these patients is total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO) with removal of as much grossly visible disease as is resectable. Less radical surgery may be performed in patients who wish to have children if their tumor is stage IA and well differentiated. Prognosis and recurrence rate in stage I ovarian carcinoma are determined by amount of residual disease following initial surgery and histologic grade of tumor. Patients who have residual tumor greater than 1.5-2 cm in diameter have a much poorer prognosis than those with minimal «1.5-2 cm) or no residual disease. The degree of residual disease becomes more important in more advanced stages. Patients with stage I disease whose tumors are poorly differentiated are subject to high rates of recurrence and are therefore considered candidates for postoperative therapy. Treatment may consist of radiation therapy, oral chemotherapy (melphalan 0.2 mg/kg/ day by mouth for 5 days every 4-6 weeks), or intraperitoneal instillation of radioactive phosphorus (P32)' Intraperitoneal chemotherapy with cisplatin or doxorubicin is currently under investigation in this group. Stage I patients with well differentiated tumors require no further therapy but close follow-up is well advised. Reports of fiveyear survival rates for stage I patients range from 60% to 80% depending on degree of differentiation and extent of disease following surgery. Stage II: Treatment of patients with stage II disease is similar to that described for stage I. If no bulky disease remains after surgery and the tumor is well differentiated, no additional therapy is warranted. If the

American Pharmacy, Vol. NS28, No. 11 November 19881720

stage II disease is poorly differentiated and minimal or no residual is left at surgery, the patient may be treated with melphalan or combination chemotherapy, radiation therapy, or intraperitoneal instillation of P 32 or chemotherapy. The choice between these options usually depends on side effeet profile and/or patient tolerance since neither has been shown to be superior in tenus of survival. Melphalan's major toxicity, bone marrow suppression, is usually not severe; however, the drug has been associated with development of acute leukemia at a rate greater than expected in the normal population. The risk of leukemia is highest in patients who received melphalan for longer than 2 years, had concurrent radiation therapy, and experienced prolonged periods of pancytopenia, secondary to melphalan therapy. Melphalan should therefore not be given concomitantly with radiation therapy or on a long-term basis. Complications of radiation therapy to the pelvic area include enteritis (diarrhea, nausea and vomiting, and' weight loss), reversible depression of peripheral blood counts, hepatitis, and nephritis. If bulky disease persists, radiation therapy or systemic chemotherapy is required. Reports of five-year survival rates in patients treated with radiation therapy range from 13% to, 70% in stage II patients with the-lower end probably representing failure to control disease outside the radi~tion field. Stage IIIIIV: Patients with stage III disease who have minimal or no residual tumor after surgery may be treated as stage IIII with radiation therapy or single-agent chemotherapy. However, for most patients with stage III or IV disease, the mainstay of therapy is systemic combination chemotherapy. As much tumor is removed at initial surgery as possible. Tumor debulking at initial surgery has been shown to increase response rates to chemotherapy. Chemotherapeutic agents that are used include cyclophosphamide, doxorubicin, cisplatin, and. hexamethylmelamine. Combination chemotherapy has been shown to be more beneficial than single agents; for instance, median survival improves from 17 months with melphalan alone to 29 months with combination chemotherapy. Cisplatin-based regimens seem to be the most active and widely used. Combination regimens used to' treat advanced stage or recurrent disease are seen in Table 3. Complete response (disappearance of all disease observed clinically without surgery) occurs in 30% to 40% of patients

Drug

Dose

AP

Adriamycin Cisplatin (Platinol)

50:--60 mg/m 2 50 mg/m2

q21d

CP

Cyclophosphamide Cisplatin (Platinol)

1000 mg/m2 50 mg/m2

q21d

CAP (PAC)

Cyclophosphamide Adriamycin Cisplatin (Platino!)

q21d

CHAP (CHAD)

Cyclophosphamide Hexamethylmelamine Adriamycin Cisplatin (Platino!)

500 mg/m2 50 mg/m2 50 mg/m2 300-500 mg/m2 150 mg/m2 po x 7d 30--50 mg/m2 50 mg/m2

q28d

treated initially with combination chemotherapy. Rates have been higher for those with minimal residual disease. Second-Look Operations: Surgery following therapy may be done ,to assess the need for continuation of therapy. Controversy lies in the decision of what should be done with residual disease iffound at "second look." Combination chemotherapy regimens have not been found to be as effective when used as second-line therapy following cisplatin-based regimens. The benefits of radiation therapy for residual disease found following. primary surgery and chemotherapyare under investigation.

Suggested Readings R. C. Young et aI., Cancer of the Ovary, in Cancer: Principles and Practice of Oncology, vol 1, V. T., DeVita.et aI., eds., J. B.. Lippincott Co., Philadelphia, 1985, p. 1083. J. B. Beecham et aI., Tumors of the Female Reproductive Organs, in Clinical Oncology: A Multidisciplinary Approach, P. Rubin, ed., American Cancer Society, New York, 1983" p. 428. O. H. Beahrs et aI., Gynecologic Sites, in Manual for Staging of Cancer, J. B. Lippincott Co., Philadelphia, 1988, p. 151. M. S. Piver, Ovarian Carcinoma: A Decade of Progress, Cancer, 54, 2706 (1984). T. Thigpen et aI., Chemotherapy for Advanced or Recurrent Gynecologic Cancer, Cancer, 60, 2104 (1987). L. W. Brady et aI., Treatment of Advanced and Recurrent Gynecologic Cancer, Cancer, 60, 2081 (1987). R. C. Young, Initial Therapy for Early Ovarian Carcinoma,. Cancer, 60, 2042 (1987). ®

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