Ovarian cancer

Ovarian Cancer

JoAnn H. Eriksson and Janet Ruth Walczak

I T IS ESTIMATED that in 1990 there will be 20,500 new cases of ovarian cancer and

12,400 deaths from ovarian cancer in the United States. The virulent behavior of ovarian cancer is demonstrated by the fact that it is the leading cause of death due to gynecologic cancer (47%) while accounting for only 23% of all gynecologic malignancies . It is the fifth leading cause of cancer death among women in the United States’ and a leading cause of death in women in all industrialized countries except Japan. One out of every 71 women in the United States will develop ovarian cancer.’

Malignant neoplasms of the ovary can occur at any age. Throughout childhood and adolescence, germ cell tumors of the ovary are a leading cause of cancer death. Epithelial ovarian cancer occurs most commonly in women more than 50 years of age, with the peak incidence between the ages of 55 and 59 years.3

Despite advances in the staging and treatment of ovarian cancer, most women will not be cured by initial standard therapy. A woman with progressive ovarian cancer will have repeated episodes of intestinal obstruction as the tumor spreads throughout the abdominal cavity and over the surface of the bowel, resulting in inanition, malnutrition, and death. The inability to determine the cause of the disease, to detect the disease early, to reduce mor- tality rates through effective therapy, and to elim- inate suffering from advanced disease makes ovarian cancer a major challenge to all health professionals.

A majority of ovarian cancers are epithelial in origin, yet the nonepithelial cancers, particularly

From the Rush Presbyterian, St Lukes Medical Center and Rush University, Chicago, IL; and The Johns Hopkins Oncol- ogy Center, Baltimore, MD.

JoAnn H. Eriksson, RN, MS: Clinical Nurse Specialist, Gy- necologic Oncology, Rush Presbyterian, St Lukes Medical Cen- ter, and Assistant Professor, College of Nursing, Rush Univer- sity, Chicago, IL; Janet Ruth Walczak, RN, MSN: Clinical Nurse Specialist, Gynecologic Oncology, The Johns Hopkins Oncology Center, Baltimore, MD.

Address reprint requests to Janet Ruth Walczak, RN, MSN, The Johns Hopkins Oncology Center, Room 163, 600 N Wolfe St, Baltimore, MD 21205.

0 1990 W.B. Saunders Company. 0749-2081/90l0403-0006$05.00i0

germ cell and stromal tumors, comprise a distinct and important group in terms of origin, incidence, and treatment. This article discusses epithelial ovarian cancer, the nonepithelial germ cell and stromal tumors, and the overall nursing management of patients with ovarian cancer.

EPITHELIAL OVARIAN CANCER

Epidemiology

Epithelial ovarian cancers account for 85% to 90% of all ovarian cancers seen in the United States. Epidemiologic studies to evaluate risk factors for epithelial ovarian cancer indicate that nulliparous and low parity women have a higher incidence of ovarian cancer.4 The risk of ovarian cancer correlates with the time in a woman’s life when ovulation is not suppressed by pregnancy, lactation, or oral contraceptives.5 These observa- tions support the theory that the ovarian epithelial surface may be sensitive to the chronic irritation of “incessant ovulation. ’ ‘6 When ovulation is suppressed by pregnancy and the use of oral contraceptives, gonadotropin levels are low. Gonadotro- pin levels are high during the postmenopausal years and may account for the increased incidence of ovarian cancer in women over 45 years of age.7

Environmental factors are suspected as risk factors since the highest incidence of ovarian cancer occurs in industrialized countries with the exception of Japan. Japanese immigrants to the United States have an increased rate of ovarian cancer that approaches the rate for white women by the second generation.* Women with higher education, which is correlated with higher income and differences in childbearing practices and dietary habits, have a higher incidence of ovarian cancer.3Y5

Studies regarding dietary fat as a risk factor in ovarian cancer report contradictory findings. The consumption of animal fat as a risk factor has been reported by some investigators, but not by others. 8,9 Consumption of cigarettes, alcohol, and/ or coffee have not been associated with an increased risk of ovarian cancer.8*9

The migration of industrial by-products, such as talc, from the vagina via retrograde flow through the reproductive tract to the peritoneal cavity may account for the exposure of the ovaries to carcino-

214 .%minars in Oncology Nursing, Vol 6, No 3 (August), 1990: pp 214-227

OVARIAN CANCER 215

genie agents. However, investigations of talc exposure revealed no significant correlation with disease. lo

Genetic and familial predisposition are factors in only a small proportion of women with ovarian cancer.6 In families in which ovarian cancer is ev- ident in two or more first-degree relatives, the first-degree relative has a threefold increase in risk. Hereditary ovarian cancer refers to a pattern of autosomal dominant segregation of ovarian cancer in which other cancers, such as breast, endo- metrial, and colon cancer, are associated with ovarian cancer. ‘i Patients in the type A blood group also have a higher incidence of ovarian cancer. I2

Viruses have been suspected as a factor in the development of ovarian cancer. The mumps pa- rotitis virus causing asymptomatic mumps has been investigated as an etiologic agent. However, no evidence exists to incriminate this or any par- ticular virus. *

Despite the many factors associated with ovarian cancer, no etiology has been identified. This failure to determine the cause of ovarian cancer has frustrated efforts in primary prevention and early detection of the disease.

Pathophysiology and Natural History

The epithelial cancers of the ovary are classified histologically as serous, mutinous, endometrioid, mesonephroid (clear cell), Brenner, and undifferentiated types. The histologic types of epithelial ovarian cancer have similar presentation and dis- semination patterns. Histologic type alone has little prognostic significance with the exception of clear cell carcinoma, which is much more aggressive in nature.13

Ovarian cancer originates in the ovary, grows locally, and then invades the capsule and mesova- rium. After invading the capsule, cells most commonly exfoliate into the peritoneal cavity, where they are carried in the peritoneal fluid via the pos- terior gutters to the subdiaphragmatic surfaces. All peritoneal surfaces are potential sites for tumor implants. Cells may implant on the diaphragm, liver, bowels, bladder, or omentum. Cells may also enter the pleural cavities via the diaphragm and implant on the pleural surfaces. When tumor cells obstruct lymphatic channels, malignant ascites may accu- mulate. Tumor cells may also invade the uterus, fallopian tubes, and other pelvic structures by di-

rect extension or through lymphatic channels. Para-aortic lymph node involvement is common, although hematogenous spread is not. Although ovarian cancer usually remains confined to the peritoneal cavity, it may metastasize to other organs, such as liver, lung, and pleura.194*‘3

Ovarian cancer has been described in women whose ovaries have been previously removed.‘4,15 The explanation for such an occurrence is not clear, but it has been suggested that the coelomic epithelium may undergo neoplastic transforma- tion.

Signs and Symptoms

Ovarian cancer is a disease with no specific early symptoms. Frequently, there will be months of delay in detecting the disease because the vague symptoms of dyspepsia, abdominal discomfort, pelvic pressure, urinary frequency, and other di- gestive symptoms are dismissed as insignificant and related to personal stresses or midlife changes. Attention to these abdominal complaints as possible early symptoms of ovarian cancer, especially in the nulliparous woman over 40 years of age with a negative gastrointestinal (GI) workup, may facilitate earlier detection. Detection occurs primarily when the tumor is large enough to be palpable, or when ascites and abdominal distention develop. Other presenting symptoms include pain, dyspnea, and weight 10~s.‘~

Early Detection and Diagnosis

The pelvic examination remains an important means for detecting early ovarian cancer. A palpable ovary in a woman 3 or more years after menopause should suggest an ovarian neoplasm. However, only one ovarian cancer in 10,000 asymptomatic women will be detected by pelvic examination.* Currently, there is interest in eval- uating pelvic ultrasound for screening in the asymptomatic woman. ”

Diagnosis of early ovarian cancer with specific tumor-associated antigens has been investigated. Antigens such as CA-125 and NB/70K have been identified. These antigens have been found to cor- relate with the stage and amount of residual disease. However, serum levels are often undetect- able in the presence of minimal residual disease. The antigens are useful in monitoring progression or recurrence of disease, but are not useful as a screening tool. ’ 8-20 Other types of immunologic

216

markers are being investigated. These include monoclonal antibodies and radiolabeled antibodies to detect metastasis, and tumor-associated antigens that act as targets for antibody-directed treatment.

Routine diagnostic tests are not particularly useful in the evaluation of ovarian cancer, except to rule out possible sites of origin of a pelvic mass. Ultrasound and computed tomography (CT) scans are useful in detecting a pelvic mass, but cannot differentiate between a benign and a malignant process. When pelvic masses are known to exist, these tests may help determine extent of disease, but they do not replace the need for exploratory surgery for diagnosis and staging.2*21

Paracentesis to obtain fluid for cell block and cytologic smear is not done if surgery is planned. Paracentesis could result in the puncture of a self- contained malignant cyst and cause tumor seeding along the needle tract, which would increase the stage of disease and decrease survival2

Barium enema may be performed to rule out a primary colorectal tumor with metastases to the ovary. Proctosigmoidoscopy and a GI series may be indicated in women with intestinal tract symptoms. Chest x-ray is done to assess for pleural effusion and parenchymal metastases. Intravenous pyelogram is helpful in identifying the relationship of the ureters to the tumor and other pelvic structures. 2

Although these studies are helpful in the evaluation of a pelvic mass, they cannot provide a definitive diagnosis. Definitive diagnosis of ovarian cancer requires histologic examination of tumor tissue obtained at the time of laparotomy.

Surgery

Surgical staging and cytoreductive surgery. Surgical staging and cytoreductive surgery provide the basis for treatment of ovarian cancer. The In- ternational Federation of Gynecology and Obstet- rics (FIGO) staging system, which was revised in 1985, is the currently accepted staging system (Ta- ble 1). The staging laparotomy is performed to diagnose the malignancy and to accurately determine the extent of disease (Table 2). This procedure consists of a systematic exploration of all peritoneal surfaces within the abdominal cavity to determine volume and distribution of the ovarian tumor. This is accomplished via a vertical midline incision from the pubis symphysis to above the

ERIKSSON AND WALCZAK

Table 1. FIG0 Shahs for Ovarian Cancer

Stage I IA

IB

IC

II

IIA

IIB IIC

Ill

IIIA

IIIB

IIIC

IV

Growth limited to the ovaries. Growth limited to one ovary; no ascites. No

tumor on the external surface; capsule intact. Growth limited to both ovaries; no ascites. No

tumor on the external surfaces; capsules intact. Tumor either stage IA or IB, but with tumor on

surface of one or both ovaries, with capsule ruptured, with ascites present containing malignant cells, or with positive peritoneal washings.

Growth involving one or both ovaries with pelvic extension.

Extension and/or metastases to the uterus and/or tubes.

Extension to other pelvic tissues. Tumor either stage IIA or IIB, but with tumor on

the surface of one or both ovaries, with capsule(s) ruptured, with ascites present containing malignant cells, or with positive peritoneal washings.

Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastasis equals stage Ill.

Tumor grossly limited to the true pelvis with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces.

Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Nodes are negative.

Abdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes.

Growth involving one or both ovaries with distant metastases. If pleural effusion is present, there must be positive cytology to allot a case to stage IV. Parenchymal liver metastasis equals stage IV.

umbilicus. Once the peritoneal cavity is entered, the presence of ascites is noted and fluid is obtained for cytopathology . If no fluid is present, peritoneal washings are obtained and sent for cytopathology. All peritoneal surfaces are then care- fully examined to determine presence of disease. Attention is paid to the diaphragm, pericolic gutters, serosa of the bowels, pelvic sidewalls, cul- de-sac, and omentum. Multiple, selective biopsy specimens are obtained. The ovaries, if identifi- able, are inspected to determine the presence of bilaterality, tumor excrescences on the capsule, rupture, and adhesions.

A total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), omentectomy, selective pelvic and para-aortic lymph node sampling, and cytoreductive surgery is performed. The

OVARIAN CANCER 217

Table 2. Staging Laparotomy Procedure for Patients With

Ovarian Cancer

Vertical midline incision from the pubis symphysis to

above the umbilicus

Peritoneal cytology (ascitic fluid or washings) from pelvic

paracolic gutters, infradiaphragmatic area

Examination and palpation of all peritoneal surfaces

Omentectomy

Abdominal hysterectomy and bilateral salpingo-

oophorectomy

Multiple selective biopsy specimens taken from cul-de-sac,

pelvic sidewalls, paracolic gutters, and diaphragm

Selective pelvic and para-aortic lymph node sampling

Cytoreductive surgery

Assessment for residual disease

goal of cytoreductive surgery is to remove all tumor masses greater than 1 cm in size without un- due surgical morbidity. This debulking may include extensive dissection of tumor masses and the formation of a colostomy to prevent obstruction. Occasionally, in the case of a young woman who wishes to maintain fertility and has a stage IA, well-differentiated tumor or a tumor of low malignant potential, only the involved ovary is removed. The contralateral ovary is sampled and a complete exploration of the abdominal cavity is accomplished. Five-year survival in this select population is comparable to that of patients in whom all reproductive organs are removed.22

Second-look laparotomy. A “second-look” laparotomy, which is a second operation for exploratory purposes, is performed in patients who have had a complete clinical response to primary therapy. A negative CT scan or ultrasound and a negative CA-125 are useful in deciding who should proceed to a second-look procedure. The purposes of this procedure are to evaluate the effectiveness of treatment, to determine disease sta- tus and the need for further treatment, and to de- bulk any residual tumor identified. The surgical procedure is similar to the initial staging laparotomy in that it consists of peritoneal washings or sampling of peritoneal fluid, a systematic evaluation of all peritoneal surfaces, and selective, multiple biopsy procedures. The impact of second- look laparotomy and secondary cytoreductive surgery on survival remains controversial. l3

Exploratory surgery may also be performed when complications develop. The most common complication is a bowel obstruction that may require ostomy formation or bypass surgery.23

Prognostic Factors Important prognostic factors for women with

ovarian cancer are the stage of the disease, the amount of residual disease following initial debulking surgery, and the histologic grade of the tumor. Survival is associated with stage, and var- ies from 60% to 70% for stage I disease to less than 5% for stage IV disease (Table 3).2,4

The most important prognostic indicator in patients with advanced ovarian cancer is the volume of residual tumor following primary surgery. An increased response to chemotherapy and significantly higher survival rates are noted in patients who are optimally resected.4

Histologic grade is another factor in determining prognosis. Patients with well-differentiated (grade 1) or moderately well-differentiated (grade 2) tumors have significantly higher 5-year survival rates than those with poorly differentiated (grade 3) tumors .4,7

There is a group of ovarian tumors classified as “low malignant potential.” These tumors account for approximately 15% of all ovarian tumors, tend to occur in women less than 40 years of age, and have a favorable prognosis regardless of the stage of disease.4

Treatment

The multimodality approach is essential for the treatment of epithelial ovarian cancer. After initial cytoreductive surgery, treatment is based on stage, grade, and amount of residual disease (Table 4). Stage IA or IB requires no further adjunctive therapy. Stage IA and IB high-grade tumors, stage IC, and stage II tumors with minimal residual disease require treatment with single-agent chemotherapy, intraperitoneal chromic phosphate (P32), or combination chemotherapy. Stage II ovarian cancer with gross residual disease following cytoreductive surgery is treated with a cisplatin-based regimen of combination chemotherapy. Optimally resected stage III residual disease is also treated with cisplatin combination chemotherapy.

Table 3. 5-Year Survival Ratus for Epithelial Ovarian Cancer

stage Survival (%I

I 60-70 II 25-45 III 12-13 IV o-4

-

218 ERIKSSON AND WALCZAK

Table 4. Treatment for Ovarian Cancer

Stage

IA or IB, grade 1

IA, IB, grade 2,3

IC

II, gross residual disease

II, Ill G 2 cm residual disease

Treatment

No further treatment

Single-agent chemotherapy

P32 or combination chemotherapy

Combination chemotherapy including cisplatin

Combination chemotherapy including cisplatin or whole abdominal pelvic radiation

Ill > 2 cm residual disease; IV

Combination chemotherapy including cisplatin

Refractory disease Chemotherapy, immunotherapy, intraperitoneal therapy, hormonal therapy

Whole abdominal and pelvic radiation therapy has been advocated for patients who are optimally resected. Survival rates for radiation therapy equal those for single agent chemotherapy; however, morbidity is significantly increased.’

Stage III with bulky residual disease and stage IV are treated with cisplatin-based multiagent chemotherapy. Hormonal manipulation is usually re- served for salvage therapy.*

Chemotherapy. Single-agent chemotherapy was considered standard treatment for epithelial ovarian cancer prior to 1976. Alkylating agents such as melphalan, cyclophosphamide, and chlo- rambucil were the first drugs used effectively against ovarian cancer. Overall response rates of 40% to 60% and survival rates of 21 to 35 months were reported.* Hexamethylmelamine, doxorubi- tin, 5-fluorouracil(5FU), and cisplatin have been found to be effective as single agents, with response rates ranging from 12% to 61%.*l In 1976, cisplatin was reported to have a response rate of 26% in pretreated patients.24 Today, cisplatin is considered the single most active drug available for the treatment of ovarian cancer. Overall response rates for platinum-based combination therapy are as high as 90%, with complete response rates of 40% to 50%.*

Since single-agent therapy has been of limited success in the treatment of ovarian cancer, combination drug regimens have been used to treat advanced disease. Act-FuCy (dactinomycin, 5-FU, and cyclophosphamide) and Hexa-CAF (hexame-

thylmelamine , cyclophosphamide , methotrexate , and 5-FU) were compared with melphalan, with statistically significant increased response and survival.* With the introduction of cisplatin into combination chemotherapeutic regimens, response rates improved significantly.25*26

Controversy exists over the effectiveness of other drugs in cisplatin-based combination regimens. Cyclophosphamide and cisplatin (CP), or cyclophosphamide, cisplatin with doxorubicin (CAP), are the most effective combinations pres- ently used. The Gynecologic Oncology Group (GOG) reported similar response, disease-free in- terval, and survival rates with CP and CAP in optimally debulked, stage III patients.27 Several researchers**“’ found that CAP had a higher complete response rate (62%) than CP (39%). How- ever, survival rates were not significantly differ- ent.

Most women with ovarian cancer develop recurrence after an initial response to chemotherapy; therefore, additional therapy is given. Second-line chemotherapy, used after failure of initial chemotherapy, produces limited effects. Although many single agents and combination regimens, such as 5-FU, etoposide, high-dose cisplatin, hexamethylmelamine, cisplatin, CAP, and CHAP (cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin) have been used, the highest response rates are achieved when cisplatin is used alone or in combination with other agents. Response rates range from 22% to 72%. However, most were par- tial responses of short duration (4 to 6 months).7

Carboplatin, a cisplatin analogue, is as active as cisplatin in patients with advanced epithelial ovarian cancer3’ and germ cell tumors.32 Carboplatin as well as cisplatin is associated with a significant dose response; that is, the response rate is propor- tional to the dose of drug administered. It is also the most effective agent for patients previously re- sponsive to cisplatin, but who are unable to toler- ate cisplatin due to neurotoxicity or nephrotoxic- ity. Carboplatin is gaining recognition as an important drug in the treatment of ovarian cancer. 31,33

A new investigational drug, taxol , is a diterpene plant product and antineoplastic agent which has a mechanism of action that is unique in that it is unlike other antimicrotubule agents. Tax01 has demonstrated an overall response rate of 30% in pretreated patients. Further evaluation of this drug,

OVARIAN CANCER 219

particularly in combination with cisplatin, is under way.34

Probably the newest and most experimental therapy for advanced ovarian cancer is that of high-dose chemotherapy with autologous bone marrow transplantation. A variety of drugs, including cyclophosphamide, melphalan, carboplatin, and etoposide, have been used in limited pop- ulations of both epithelial and germ cell cancers of the ovary. Although preliminary data is promising, further investigation is needed.35”7

Zntruperifoneaf chemotherapy. Intraperitoneal chemotherapy offers an alternative to intravenous second-line therapy in patients who have minimal residual disease following second-look laparotomy. Intraperitoneal administration of chemotherapeutic agents directly into the abdominal cavity has four advantages over intravenous chemotherapy in this select population: (1) a higher concentration of the drugs in the peritoneal cavity is obtained with intraperitoneal rather than systemic exposure, (2) drugs can be administered directly to the tumor sites, (3) systemic toxicity from the drug is mini- mized, and (4) immunoresponse in the abdominal cavity is enhanced.38,39

Administration of chemotherapeutic agents into the peritoneal cavity requires the use of a catheter. Semipermanent catheters, such as the Tenckhoff dialysis catheter or a peritoneal catheter with an implanted port, are used for multiple administra- tions. Both types have advantages and disadvan- tages. The major problem with both types of catheters is the formation of a fibrin sheath, causing obstruction of the outflow. Occasionally, the infu- sion of drugs may not be possible.40,41 A large intercooperative group study comparing intraperitoneal versus intravenous administration of cisplatin in combination with intravenous cyclophosphamide as first-line treatment is under way for optimal stage IIl disease.42

Immunotherapy. Immunotherapeutic agents have been used in combination with chemotherapy to treat ovarian cancer. Increasing tumor cell kill by nonspecific cellular activation and increased recognition and response to specific tumor antigens have been tested. Initially, it was thought that Corynebacterium parvum and bacillis Calmette- Guerin (BCG) in combination with chemotherapy would show a higher response rate than treatment with chemotherapy alone. However, additional randomized trials were not able to produce the

results.43*44 Intraperitoneal administration of inter- ferons and interleukin-II have also shown promise in initial studies .45*46

Radiation therapy. Radioisotopes, P32 and ra- dioactive gold, have been widely used to treat ovarian cancer. Radioisotopes are effective in treating patients with early stage disease, with reported survival rates of 67% to 95% for stage I disease and 25% to 67% for stage II disease. The radioisotopes are administered into the peritoneal cavity.*

Chromic phosphate is preferred because of its longer half-life and lack of gamma irradiation. The radiation from P32 penetrates to a maximum depth of 4 to 5 mm so it is only used with microscopic disease.* Chromic phosphate is usually infused postoperatively in 500 ml normal saline into the peritoneal cavity through a catheter. The patient’s position is changed every 10 to 15 minutes to promote adequate distribution of the isotope.

External beam radiotherapy is given to the whole abdomen and pelvis in selected patients with minimal residual disease. The kidney and the right lobe of the liver are shielded, usually after the maximum tolerated dose of 2,000 to 2,500 cGy and a pelvic boost of approximately 2,000 to 3,000 cGy are given. Nausea and vomiting as well as significant myelosuppression frequently interrupt and sometimes prevent completion of the full course of therapy. These effects are compounded because many of the patients have received previ- ous myelosuppressive therapy .47

Endocrine therapy. Ovarian cancer may be viewed as an endocrine-related tumor because the ovaries are a primary source of estrogen and progesterone as well as a target organ for these and other hormones. Endocrine therapy consisting of progestins, antiestrogens, and other hormones has been tested.

Progestins, such as medoxyprogesterone acetate (MPA) and megestrol acetate, have only a 10% to 15% objective response rate, and most responses were seen in patients with serous and endometrioid tumors.6 Progestins have been tested in combination with chemotherapy, with high response rates of 76% to 85% in initial studies, but these were not replicated in prospective controlled randomized tSidS.7

Response rates of 14% to 18% were achieved with the combination of MPA and ethynylestra- diol. An increase in response was reported when


estrogens and progestins were administered in a simultaneous and sequential fashion.48 An objective response rate of 4% was seen with tamoxifen therapy alone. However, stabilization of disease occurred in 8% to 80% of the patients. The lutein- izing hormone-releasing hormone agonist, D- Trp-6-LHRH (decapaptyl), has been used in the treatment of ovarian cancer; stabilization of disease and a decrease in tumor size was noted in 50% of cases.49 It is believed that decreasing gonado- tropins may minimize the steroid output of ovarian cancer.

In studies with ovarian cancer, estrogen receptors are seen in 63% of patients, progesterone receptors in 48%, and androgen receptors in 69% of tumors. Both estrogen and progesterone receptors are found in 36% of ovarian cancers. The presence of estrogen and progesterone receptors is a good predictor of response in endometrioid tumors.50 Other studies are needed to further define the correlation between hormonal receptors and response to treatment.

1-antitrypsin, and transferrin. Alpha-fetoprotein (AFP) is a protein produced by the fetal liver and GI tract. It is replaced by albumin as the fetus matures. Alpha-fetoprotein and alpha-4-antitrypsin reappear as certain types of germ cell tumors grow and spread. These tumors include embryonal carcinoma and endodermal sinus tumors (yolk sac carcinoma).53 Syncytiotrophoblastic cells of the human placenta produce human chorionic gonadotropin (HCG), a polypeptide, which disappears from fetal circulation after birth; however, HCG can be identified in syncytiotrophoblastic giant cells in germ cell tumors and can be found in the circulation as the tumor grows and spreads.52,54

The dysgerminoma is a primitive malignant germ cell tumor distinct from embryonal carcinoma. It has not differentiated to form embryonic or extraembryonic structures. It is the female coun- terpart of testicular seminoma. Dysgerminomas often contain elements of other malignant germ cells.54

NONEPITHELIAL TUMORS

Nonepithelial ovarian tumors represent only 10% to 15% of all ovarian cancers and are the most common gynecologic tumors in childhood and adolescence. Staging of these tumors is accomplished in the same manner as for epithelial tumors, using the FIG0 system (Table 1). The majority of these tumors consist of germ cell tumors and stromal tumors of the ovary.

Kurman et al54 proposed a classification of germ cell tumors into germinomas and embryonal carci- nomas based on their relationship with AFP and HCG (Fig 1). Embryonal carcinoma, a tumor com- posed of undifferentiated cells, is the progenitor of embryonic and extraembryonic tumors, and syn-

PRIMORDIeL GERM CELL

Germ Cell Tumors

The understanding of germ cell tumors as a group of neoplasms arising from the gonads has evolved over the last four decades. Primordial germ cells originate from cells differentiating in the caudal region of the yolk sac. They then mi- grate along the dorsal mesentery of the developing embryo into the newly forming gonads and are incorporated into the sex cords, where they develop into oogonia in women.51 Cells arrested during the process of migration may give rise to both benign and malignant tumors in midline sites such as the retroperitoneal and sacrococcygeal regions. However, most germ cell tumors arise from undifferentiated germ cells within the o~ary.~~

GERMINOMA Seminoma or Dysgerminoma

AFP (-) HCG (-)

EMBRYONAL CARCINOMA Aw (+I HCG (+)

Extraembryomc Differentiation

Embryonic Differentiation

Trophoblast Yolk Sac

f

t Immature

AFP (-) Choriocarcinoma Endodermal

AFP (-) Sinus Tumor

HGC (+) AFP (+) HGC (-)

HCG (-)

t Mature Teratoma AFP (-) HCG (-)

The human fetal yolk sac synthesizes several proteins, including albumin, prealbumin, alpha-

Fig 1. Histogenic and immunohistogenic classification of germ call tumors. AFP, alpha-fetoprotein; HCG, human chorionic gonadotropin. (Reprinted with permission.‘9

OVARIAN CANCER 221

thesizes both AFP and HCG, while the dysgerminoma synthesizes neither in a majority of cases.54

The presenting symptoms in descending order of frequency include acute and chronic abdominal pain, asymptomatic mass, abnormal vaginal bleeding, amenorrhea, and abdominal distention.55 Ovarian germ cell tumors are usually rapidly growing tumors and cause a significant amount of pain. The pain can become severe as a result of rupture or torsion of the mass. A hemoperitoneum from rupture of the capsule of the rapidly growing mass is a classic initial sign of dysgerminoma55 (Ta- ble 5).

Dysgerminoma. Dysgerminoma is the most common malignant germ cell tumor of the ovary, accounting for 3.5% of ovarian malignancies. It may occur at any age; however, the majority ap-

pear in adolescence and early adulthood (between 10 to 30 years of age). Dysgerminoma can be associated with gonadal dysgenesis and a gonadoblastoma, and is the only germ cell tumor in which bilateral ovarian involvement may exist. Dysger- minomas have a predilection for lymphatic spread, although metastasis may also occur through extension through the capsule and by peritoneal and vascular spread. Mediastinal and supraclavicular lymph node involvement, bone metastasis, and brain, liver, or lung involvement are late manifes- tations of the disease. About 25% of the patients will have metastatic disease at the time of exploratory surgery. 52

A young patient with stage IA disease who wants to preserve fertility should have a unilateral salpingo-oophorectomy combined with aggressive

Table 5. Germ Cell Tumors of the Ovafl”

Type Description Tumor Markers Treatment

Dysgerminoma

Endodermal sinus tumor

Embryonal carcinoma

Chorocarcinoma

Teratoma, immature

3.5% of ovarian malignancies; highest incidence, lo-30 years of age; bilaterality can occur; spread via lymphatics, vascular channels, direct extension, and peritoneal flow; 25% metastatic at diagnosis

Second most common germ cell tumor of ovary; highest incidence in adolescents and young adults (mean age, 18 years); presenting symptom: abdominal pain in 77% of patients; characterized by rapid growth and intra-abdominal spread; survival with surgery and chemotherapy approaches 70%

4% of malignant germ cell tumors; mean age of incidence, 15 years; survival rates, 39% to 50%

Two groups: gestational and nongestational; arises as a germ cell differentiating toward trophoblastic structures; usually occurs primarily in prepubescent children but also in young women; precocious puberty in prepubescent girls; adults have signs of ectopic pregnancy

Tumor with immature or embryonal tissue arising from ectodermal, mesodermal, and endodermal germ layers; contains neuroepithelial elements; third most common germ cell tumor; usually occurs in the first two decades of life; usually unilateral

AFP - HCG -

Usually HCG - Usually AFP +

AFP + HCG +

HCG +

HCG - AFP-

Unilateral salpingo-oophorectomy if fertility desired in stage IA; TAH and BSO if tumor > 10 cm, tumor adherent to other organs, ascites present, or evidence of metastasis

If patient is pregnant, maintain pregnancy if encapsulated; TAH and BSO if tumor not encapsulated or if tumor > 10 cm

Adjuvant chemotherapy: VAC, VBP, BEP Radiation to whole abdomen and pelvis is

an option unless fertility is desired Surgical debulking followed by

combination chemotherapy: VAC, MAC, and BEP being tested; radiation not useful

Unilaterial salpingo-oophorectomy with combination chemotherapy: VAC and BEP; not radiosensitive

Surgical removal followed by combination chemotherapy MAC

Unilateral salpingo-oophorectomy; adjuvant combination chemotherapy if tumor is grade 2 or 3, ascites present, tumor ruptures, disease persistent, or recurrent; VAC, MAC, and PVB; radiation is of little value

Abbreviations: HCG, human chorionic gonadotropin; AFP, alpha-fetoprotein; VAC, vincristine, dadnomycin, and cyclophosphamide; VBP, vinblastine, cisplatin, and bleomycin; BEP, bleomycin, etoposide, and cisplatin; MAC, methotrexate, dactinomycin, and cyclophosphamide; t, positive serum tumor markers; -, negative serum tumor markers.

222 ERIKSSON AN0 WALCZAK

staging. A TAH and BSO are performed when tumor is greater than 10 cm in diameter or attached to other organs, ascites is present, or there is evidence of metastasis. A pregnancy is left uninter- rupted if an encapsulated tumor can be removed intact. If not, TAH and BSO are recommended.52

Dysgerminomas are highly radiosensitive and whole abdominal and pelvic radiation have been used. However, conservative treatment with pres- ervation of fertility is a major consideration for the majority of patients who are young. Surgery alone for stage I disease and combination chemotherapy for higher stage disease have also produced good results. Regimens used in the treatment of dysgerminoma consist of vincristine, dactinomycin, and cyclophosphamide (VAC); vinblastine, bleomy- tin, and cisplatin (VBP); and bleomycin, etoposide, and cisplatin (BEP).3,52*56”58

Dysgerminomas may occur in combination with gonadoblastoma, a tumor that always occurs with dysgenic gonads. Treatment in this situation requires bilateral oophorectomy because of the frequency of bilateral tumors and absence of normal ovarian function. The uterus is left intact for possible future in vitro fertilization. Genotype and karyotype studies of patients are recommended, especially in patients with developmental abnor- malities or a history of virilization.3

Endodermal sinus tumor. Endodermal sinus tumor (EST) is the second most common form of malignant germ cell tumor of the ovary. It is characterized by rapid growth and extensive intraabdominal spread. The presenting symptom is abdominal pain in approximately 77% of patients.52 Patients are usually seen within 2 weeks of developing symptoms. Endodermal sinus tumor is seen primarily in girls and young women with a median age of 18 years. 52 Human chorionic gonadotropin is usually negative. Since the AFP is frequently elevated, it serves as a good tumor marker.

The FIG0 staging system is not an accurate predictor of response to treatment or survival. The GOG has categorized EST into two categories: all gross tumor resected and unresectable disease or incompletely resected disease. As expected, those with all tumor resected have a more favorable prognosis. 52

Treatment consists of cytoreductive surgery followed by multiple-agent chemotherapy. Until re- cently, the majority of patients with EST died within 2 years of diagnosis. In 1975, Smith and

Rutledge59 reported VAC chemotherapy as effective treatment for advanced EST. Creasman and Soper@ found comparable results using the combination of methotrexate, dactinomycin, and cyclophosphamide (MAC). The BEP regimen is currently being tested in EST. Survival with surgery and chemotherapy approaches 70%.52 Radiother- apy has not been found to be effective with this disease despite some initial responses.55

Embryonal carcinoma. Embryonal carcinoma accounts for only 4% of the malignant ovarian germ cell tumors. It is one of the most malignant cancers of the ovary. Initial presentation is by abdominal or pelvic mass. A large percentage of patients also have signs and symptoms of hormonal stimulation, including precocious pseudopuberty, amenorrhea, irregular uterine bleeding, or hirsut- ism. The mean age of occurrence is 15 years.55 Embryonal carcinoma arises from primordial germ cells that have begun to differentiate, but have not differentiated into embryonic or extraembryonic tissue. The tumors contain AFP, HCG, and syn- cytiotrophoblast-like cells. Alpha-fetoprotein and HCG are useful markers to monitor this disease. Survival is reported as 50% for stage I tumors, with a 39% actuarial survival rate for all stages.61

Treatment consists of unilateral salpingo- oophorectomy and combination chemotherapy. The VAC regimen is active in treating embryonal carcinoma, but not as active as VBP in advanced cases. The BEP regimen is currently being evaluated. Radiation therapy is not an effective treatment modality for this disease.52

Choriocarcinoma. Choriocarcinoma of the ovary is divided into two groups: gestational choriocarcinoma, which is discussed elsewhere in this issue, and nongestational choriocarcinoma. Nongestational choriocarcinoma of the ovary arises as a germ cell differentiating toward trophoblastic structures and secretes HCG. In the majority of tumors, choriocarcinoma is mixed with other neoplastic germ cell elements.

Choriocarcinoma arises primarily in prepubescent children and young adults. Sexual precocious puberty with growth of pubic and axillary hair, breast development, and uterine bleeding is especially noticeable in prepubescent children. Adult women have signs of ectopic pregnancy. Serum and urinary HCG levels are useful diagnostic tests. Unlike gestational choriocarcinoma, nongestational choriocarcinoma is not as sensitive to che-

223

motherapy. Treatments have included MAC and other combination chemotherapeutic regimens. 52

Terutoma. There are two types of teratoma, the immature teratoma and the mature teratoma. A tumor with immature or embryonal tissue arising from the ectodermal, mesodermal, and endodermal germ layers is defined as an immature teratoma. The immature teratoma accounts for less than 1% of ovarian teratomas. It usually occurs in the first two decades of life. An immature teratoma contains immature neuroepithelial elements by definition. The metastatic potential is generally correlated with the grade of the primary tumor.62 In general, the grade of metastasis reflects the grade of the primary lesion and is the best predictor of survival.

Presenting signs and symptoms include pelvic mass with or without pain, abnormal bleeding, and capsule rupture. Signs of abnormal hormonal stimulation are not observed. Immature teratoma is usually unilateral. Treatment consists of unilateral salpingo-oophorectomy. Combination chemotherapy is added for patients with grades 2 and 3 tumors and for all patients with malignant ascites, ruptured tumors, and persistent or recurrent disease. The VAC and MAC treatment regimens have proven to be effective for ovarian teratomas.55’63 However, postoperative chemotherapy has not improved survival for patients with grade 1 lesions. Radiotherapy is of little value in treating immature teratomas.52

Mature cystic teratoma, also called a dermoid cyst, accounts for more than 95% of all ovarian teratomas. Mature cystic teratomas are the most common ovarian tumors in the 20- to 30-year-old age group. They account for 22% to 40% of ovarian tumors in pregnancy.52 The majority of these benign cystic tumors contain mature tissue from the three germ layers. The most frequently observed elements are from the ectodermal layer and may include hair, skin, sweat glands, bone carti- lage, and teeth. When only tissue from the ectodermal layer is found, the tumor is considered a true dermoid cyst. Often, the multicystic lesions contain a mixture of mature tissue. The tumor is usually slow growing. Presenting symptoms are related to its size, compression of surrounding structures, torsion, or a chemical peritonitis secondary to intraabdominal rupture. Torsion is the most frequently observed complication. Treatment consists of removal of the lesion.55,52,60

Mixed germ cell tumors. Malignant mixed

germ cell tumors contain at least two malignant germ cell elements. Dysgerminoma is the most frequently occurring element, followed by endoder- ma1 sinus tumor, immature teratoma, choriocarcinoma, and embryonal carcinoma.64 Prognosis is determined by the size and composition of tumor: prognosis is poor when the tumor is more than 10 cm and when more than one third of the tumor contains endodermal sinus tumor, choriocarcinoma, or grade 3 immature teratoma elements. Surgery alone or followed by radiotherapy has been found to be ineffective.55 Chemotherapy with the VAC and MAC regimens has been used, but the BEP and VBP regimens are being evaluated in the treatment of malignant mixed germ cell tumors of the o~ary.~*

Strom& Tumors

Malignant sex cord stromal tumors account for approximately 1% to 3% of all ovarian tumors.52 They include collagen-producing stromal cells, granulosa cells, theta cells, sertoli cells, and Ley- dig cells. Most of these tumors are hormonally active and capable of producing estrogens, andro- gens, progestins, and certain corticosteroids (Ta- ble 6).

Granulosa cell tumors occur primarily in postmenopausal women. Only 5% occur before puberty. The most common presenting symptom is a palpable abdominal or pelvic mass. Abdominal distention, pain, vague GI complaints, and acute abdominal pain secondary to hemoperitoneum are other presenting symptoms.65 Approximately 70% of women experience abnormal uterine bleeding as a result of hormonal stimulation. Granulosa cell tumors are usually unilateral. They are generally considered low-grade malignancies, with survival rates of 75% to 90% reported for all stages.55 Treatment consists of unilateral salpingo-oophorectomy in women wishing to retain fertility, or TAH and BSO for perimenopausal and postmenopausal patients. 52

Androblastoma and arrhenoblastoma are used synonymously with Sertoli-Leydig cell tumors; the cells resemble testis cells and may cause virilization. These tumors account for less than 0.5% of all ovarian neoplasms . Most Sertoli-Leydig tumors occur in women between 20 to 40 years of age. The majority of Sertoli-Leydig tumors are hormonally active (88%) and cause progressive masculinization.6G68 Sertoli-Leydig cell tumors tend


Table 6. Stromal Tumors of the Ova#‘*aMd)-”

TVP~ Description Signs/Symptoms Treatment

Granulosa cell tumors

1% to 3% of all ovarian tumors; highest incidence in postmenopausal women; 5% occur before puberty; low- grade malignancies; 75% to 90% survival

Sertoli-Leydig cell tumors

Androblastoma or arrhenoblastoma; cells resemble testes; ~0.5% of all ovarian tumors; most occur at 20 to 40 years of age; hormonally active, causing progressive masculinization; remain confined to pelvis; 70% to 90% survival

Palpable abdominal or pelvic mass; abdominal distension, GI complaints; acute abdominal pain due to hemoperitoneum; abnormal uterine bleeding due to hormonal stimulation in 70% of patients

Palpable abdominal or pelvic mass; masculinization

Unilateral salpingo- oophorectomy; TAH and SSO for perimenopausal and postmenopausal patients

Unilateral salpingo- oophorectomy

to remain confined to the pelvis and have a 5-year survival rate of 70% to 90%. Treatment consists of unilateral salpingo-oophorectomy in young women desirous of childbearing.52Y66*67

NURSING MANAGEMENT OF OVARIAN CANCER PATIENTS

Nursing management of the woman with ovarian cancer is multifaceted and focuses on support- ive and rehabilitative efforts to promote optimal quality of life. The care required is dependent on the treatment and stage of disease. At time of diagnosis and staging laparotomy, the woman is faced with a life-threatening disease and potentially extensive cytoreductive surgery. Aggressive preoperative teaching and postoperative care include monitoring and promoting respiratory function; assisting in early, progressive ambulation; monitoring intake and output, electrolytes, vital signs, and GI and renal function; and providing the patient and her family with ongoing emotional support. The nurse can facilitate verbalization of fears and concerns, clarify misconceptions, and initiate planning for adjuvant therapy and the patient’s re- turn home. Since most women with epithelial ovarian cancer are diagnosed with stages III and IV disease, combination chemotherapy will be given and is often initiated during the postoperative pe- riod. Often with all types of ovarian cancer, the woman and her family will not only have to adjust to the diagnosis and surgery, but also to the chemotherapy regimen and its side effects, such as nausea, vomiting, diarrhea, bone marrow depres-

sion, alopecia, neurotoxicity, liver and kidney damage, regular blood counts, and treatments every 3 to 4 weeks.

Because ovarian cancer can occur at any age, issues of fertility, sexuality, femininity, and roles and relationships within the family must be as- sessed and the need for additional support and referrals determined. Referrals may range from the informal opportunity to talk with other cancer patients to referrals to support groups and counselors. The major goals of these interventions would be to facilitate coping with the disease and treatment and to enable the woman and her family to optimize and maintain positive aspects of life.

Maintaining adequate nutrition is a major challenge in the care of the woman with ovarian cancer. Extensive abdominal surgery with prolonged postoperative bowel dysfunction and combination chemotherapy with the associated nausea, vomiting, and anorexia may necessitate enteral and parenteral supplements as well as extensive dietary counseling.

If the tumor progresses or resistance to treatment develops, maintenance of adequate nutrition be- comes more difficult. The disease may cause repeated incidents of bowel obstruction, carcinomatosis ileus, anorexia, cachexia, and ascites. Although patients may be maintained indefinitely on parenteral supplements, the potential benefits of such therapy are questionable in the face of tumor progression. Nursing efforts must focus on providing physical and emotional comfort. Helping patients and their families to understand the goals of nutritional intervention is important since the inability to eat is often a tremendous source of frus-

OVARIAN CANCER 225

Table 7. Nursing Care of the Patient With Malignant As&es

Symptomfrreatment Assessment Intervention

Abdominal distension

Respiratory compromise

Gastrointestinal distress

Fluid and electrolyte imbalance

Paracentesis

Peritoneovenous shunting

Bulging abdomen and flanks; everted umbilicus; shiny skin

Dyspnea; shortness of breath; tachypnea; use of accessory muscles

Anorexia, nausea, vomiting; dyspepsia; cachexia; bowel movements

Signs and symptoms of dehydration; lymphedema of lower extremities; signs of hypokalemia, hyponatremia, hypomagnesia

Puncture site for signs of infection, pain, leakage of ascites, skin breakdown; reaccumulation of ascites

Pain; infection; bleeding; skin integrity at operative site; DIC, tumor embolus

Daily abdominal girths, weights; palpate for fluid wave; percuss for sounds of shifting dullness

Elevate head of bed; provide rest periods; restrict activities as tolerated; oxygen as needed; analgesia as ordered

Antiemetics, antacids, laxatives as ordered; small, frequent feedings, bland diet; food supplements; diversional therapy; daily weights, caloric counts

Monitor serum protein, albumin, electrolytes; albumin, electrolytes, fluid replacements as ordered; daily weights, abdominal girth; monitor input and output, vital signs; high- protein diet; minimize sodium and fluid intake; diuretics as ordered; compression stockings, boots; assist patient in maintaining mobility

Teach patient and family about procedure and expected results; maintain asepsis; monitor drainage of fluid; alter patient’s position as necessary to promote fluid drainage; monitor fluid and electrolytes

Teaching patient and family about surgical procedure, operating room routine, methods of maintaining patency of shunt; provide shunt care; monitor fluid, electrolytes, and coagulation profile.

-

tration. Encouraging small, frequent meals or fo- cusing on comfort measures other than eating may help relieve the tension that patients and families often feel.

Management of ascites from ovarian cancer var- ies from symptom relief and treatment of the cancer to symptomatic relief by drainage of ascites and maintaining systemic fluid and electrolyte bal- ance. As the ascites increases, severe respiratory and gastrointestinal compromise develop. Associ- ated lymphatic obstruction may cause progressive debilitating lymphedema. Nursing care focuses on comfort measures and symptom control for a patient in great distress (Table 7).

Often critical organs such as the kidney or liver are not involved with tumor to permit a timely death. Instead, ovarian cancer progressively causes lymphatic obstruction with resultant lymphedema, anasarca, massive ascites, and pleural effusion while the woman remains mentally alert2 Nurses can provide psychological and physical comfort by assisting the patient to remain active

and independent as long as possible and by making necessary referrals for home and hospice care.

SUMMARY

Prevention, early detection, morbidity, and survival issues continue to challenge health professionals involved in the care of women with ovarian cancer. While advances in diagnosis, staging, and treatment have been made, survival rates remain grim. Continuing research in the areas of screening, diagnosis, and treatment is the key to improved survival. The hope of new drug therapy, such as cisplatin-taxol regimens, intraperitoneal therapy, immunotherapy, and bone marrow transplantation, needs further investigation to become reality. As new and potentially more toxic regimens are developed, the nurse must be knowledge- able about the therapies and adverse effects, and maintain a high level of clinical expertise in order to teach the patient, reinforce information, clarify misconceptions, and provide the patient with sup- portive physical and emotional care.

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