Bethesda Handbook of Clinical Oncology, 2nd Edition

Gynecologic

17

Ovarian Cancer

Eddie Reed*

Ramin Altaha

*Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia

Section of Hematology/Oncology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia

Ovarian cancer is divided into three broad histologic categories: epithelial carcinomas, germ cell tumors, and stromal cell tumors. Approximately 90% of all cases of ovarian cancer are of the epithelial variety. This chapter is devoted to epithelial ovarian carcinoma, except for the section on fallopian tube carcinoma and extraovarian peritoneal carcinoma. The number of estimated new cases of ovarian cancer in 2003 was 25,400 in the United States, the estimated number of deaths from this disease totaled 14,300. Ovarian cancer represents approximately 25% of the total number of cancer cases involving the female genital tract. However, unlike cervical cancer or endometrial cancer, the most ovarian cancer cases present as stage III or stage IV. The overall survival rate had improved from approximately 35% in the 1970s, to more than 50% in the 1990s. This decrease is believed to have resulted from the introduction of platinum-based therapy for management of this disease. Further improvements in survival have been observed with the introduction of paclitaxel and other agents that have been recently approved for use in this disease by the U.S. Food and Drug Administration (FDA). Some reports suggest that the introduction of cisplatin and carboplatin into chemotherapeutic regimens not only resulted in improved survival statistics but may also be associated with emerging patterns of metastatic spread suggestive of more aggressive disease.

TUMOR MARKERS

The best tumor marker for this disease is CA125. CA125 is a high–molecular-weight glycoprotein that is elevated in up to 50% of stage I tumors and elevated in 80% to 90% of stage II, III, or IV tumors. Minor elevations in CA125 levels are not specific for ovarian cancer and can be seen in endometriosis, benign tumors, fibroids, and in pregnant or postpartum women. In addition, moderate elevations in CA125 levels can be seen in other adenocarcinomas such as breast cancer and endometrial cancer. However, CA125 levels greater than 2,000, with the appropriate clinical history, should be considered to represent epithelial ovarian cancer until proved otherwise.

Once the diagnosis of ovarian cancer has been made, CA125 is useful in following the disease. It is a useful surrogate for tumor response but does not predict complete response. A persistently rising CA125 following disease response is representative of tumor recurrence. Some reports suggest that CA125 plus transvaginal ultrasound may be effective in screening for previously undiagnosed disease. Other biochemical entities have been suggested as possible markers for previously undiagnosed ovarian cancer. They include OVX-1, lysophosphatidic acid, and an advanced proteomic analysis method performed on patient plasma.

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SCREENING

The National Cancer Institute (NCI) recommends screening for ovarian cancer in women with known genetic syndromes associated with this disease and for women with a particularly strong family history of the disease regardless of the presence of a recognized genetic syndrome. A recent study randomized 20,000 women without a family history of ovarian cancer to screening and to no screening. CA125 was the first screening test, followed by ultrasound for patients with an elevated CA125. There was no difference between the two groups in the ability to detect early stage disease nor was there any difference in the number of deaths from ovarian cancer. Therefore, routine screening of women without a family history of ovarian cancer is not recommended.

RISK FACTORS AND PREVENTION

Ovarian cancer risk increases with age and with a family history of ovarian cancer. Although most cases of ovarian cancer occur in women without any known risk factors, there are several genetic syndromes that are strongly associated with this disease. These syndromes include the hereditary breast and ovarian cancer syndromes associated with BRCA1 and BRCA2 and with the hereditary nonpolyposis colorectal cancer syndrome (Lynch II syndrome). In each of these genetic syndromes, variable penetrance has been observed.

Recent studies show that prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO), can be effective in reducing the predicted occurrence of ovarian cancer in women with BRCA1 or BRCA2 mutations. In addition, studies suggest that oral contraceptives may have a preventive effect on this disease, which appears to increase with the duration of contraceptive use. It should be noted that the newer, low-estrogen formulations have not yet proved to have the same protective effect. Other maneuvers that are associated with a reduction in the number of ovulations (i.e., pregnancy, nursing after pregnancy, etc.) appear to have protective effects as well.

PATHOLOGY

Epithelial histologies account for about 90% of all ovarian cancers. These include the histologies of serous, mucinous, endometrioid, transitional, and clear cells. Among these cell types, clear cell appears to have a consistently worse prognosis. Tumors of low malignant potential (borderline tumors) may exist within each of the above five histologic types. Mixed Müllerian tumor is probably of epithelial origin and is also associated with clinical resistance to therapy.

Generally, any of the aforementioned tumor histologies may be well differentiated, moderately differentiated, or poorly differentiated. Clinical prognosis worsens with poorly differentiated cells. Rarely, a tumor may clearly be an ovarian cancer but may be sufficiently undifferentiated so that it cannot be assigned to any of the six cell types noted.

The germ cell tumors are classified as dysgerminoma, endodermal sinus tumor, malignant teratoma, embryonal carcinoma, or primary choriocarcinoma. Stromal tumors are mesenchymal in origin and consist of granulosa tumors or Sertoli-Leydig cell tumors.

DIAGNOSIS AND WORKUP

Clinically, the nature of the three broad classes of tumors is directly related to the clinical presenting symptoms of the disease. Tumors of epithelial histology tend to present in the advanced stage (i.e., III or IV) and are associated with abdominal discomfort, low back pain, bloating, and abdominal distension. Germ cell tumors tend to behave clinically in a manner similar to that of germ cell tumors in men. Sertoli-Leydig cell tumors produce virilization in affected individuals. Granulosa cell tumors may cause precocious puberty in premenarchal women, amenorrhea in women of reproductive age, and vaginal bleeding in postmenopausal women.

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A small percentage of women of reproductive age in whom surgery is performed for a pelvic mass will have a malignant tumor, with the likelihood of the malignancy increasing with age. Approximately 50% of the postmenopausal women in whom surgery is performed for a pelvic mass will have a malignant neoplasm. Preoperative workup of a patient suspected to have an ovarian mass may include any or all of the following: blood chemistries, liver function tests (LFTs), renal function tests, complete blood counts (CBCs), ultrasonography, CA125, computerized tomography (CT) scan of the abdomen and pelvis, α-fetoprotein, and β-human chorionic gonadotropin (β-HCG). Additional studies may be performed, as appropriate. A summary of the suggested preoperative workup is given in Table 17.1.

TABLE 17.1. The workup for patients suspected of having an ovarian malignancy

BUN, blood urea nitrogen; LDH, lactate dehydrogenase; CBC, complete blood count; PT, prothrombin time; PTT, partial thromboplastin time; INR, international normalized ratio; AFP, α-fetoprotein; HCG, human chorionic gonadotropin; CT, computerized tomography; CXR, chest x-ray; MRI, magnetic resonance imaging; PET, positron emission tomography.
Consider possible abnormal hormone secretion syndromes.
Consider possible concurrent malignancies from other sites.
Consider possible metastases to the ovary, from other sites (breast, colon, etc.).

Personal and family history and physical examination

Liver function tests, BUN, creatinine, LDH

CBC with platelets, PT, PTT, INR

Tumor markers (CA125, AFP, and β-HCG)

CT scan of abdomen and pelvis, and CXR. CT of chest if CXR is abnormal.

Radiographic tests of unclear utility: MRI of abdomen and pelvis, PET scan

Surgery should be performed by a gynecologic oncologist or a surgical oncologist—preferably the former. The Gynecologic Oncology Group (GOG) has defined the appropriate surgical procedure for ovarian cancer and has insisted that surgical protocol should be followed in every patient undergoing surgery for this disease. The prognostic importance of maximal surgical debulking has been demonstrated in multiple studies over the last 4 decades.

Favorable prognostic factors include younger age at the time of diagnosis (younger than 65 years), good performance status, cell type other than clear cell, stage I or II disease, well-differentiated tumor, diploid tumors, no overexpression of HER2, low vascular endothelial growth factor (VEGF) expression, and optimal tumor debulking during surgery to <1 cm for any single lesion. Patients with germline mutations of BRCA1 may have better survival after chemotherapy. Unfavorable prognostic factors include clear cell histology, high tumor grade, increased VEGF or other markers of increased angiogenesis, elevated postoperative CA125 level, stage III or IV disease, residual tumor masses >3 cm after surgery, and aneuploidy.

STAGING

Ovarian cancer may exist in stage I, II, III, or IV. This determination can be made only after appropriate abdominopelvic surgery. Stage IV disease can sometimes be diagnosed without invasion of the abdominopelvic space. However, recent studies show that tumor debulking favorably affects prognosis, even in stage IV disease. Current Federation Internationale de Gynecogie et d'Obstetrique (FIGO) staging criteria are listed in Table 17.2.

TABLE 17.2. Federation Internationale de Gynecogie et d'Obstetrique (FIGO) staging of ovarian cancer

Stage I

Growth limited to one or both 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; capsule ruptured; ascites present containing malignant cells; or positive peritoneal washings

Stage II

Growth involving one or both ovaries with pelvic extension

IIA

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

IIB

Extension to other pelvic organs

IIIC

Tumor either stage IIA or IIB but with tumor on the surface of one or both ovaries; capsule(s) ruptured; ascites present containing malignant cells; or positive peritoneal washings

Stage III

Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes: metastases to the surface of the liver equals stage III; tumor is limited to the true pelvis but with histologically verified malignant extension to the small 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 >2 cm in diameter; node negative

IIIC

Abdominal implants >2 cm in diameter and/or positive retroperitoneal or inguinal nodes

Stage IV

Growth involving one or both ovaries and with distant metastases; if pleural effusion is present, there must be positive cytologic test results to allot a case to stage IV; parenchymal liver metastasis equals stage IV

Stage I disease is confined to one or both ovaries. Malignant ascites, but no implants, may be present on the abdominopelvic wall. Stage II involves one or both ovaries, with extension to the pelvic viscera. As in the case of stage I disease, there may be malignant ascites, but no implants on the abdominopelvic wall. Stage III disease is associated with implants on the abdominopelvic wall or the serosal surface of the liver or involves the small bowel or omentum.

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Stage IV disease shows metastasis to parenchymal liver, lung, the pleural cavity, or other demonstrated metastases outside the abdominopelvic space.

TREATMENT OF OVARIAN CANCER

Surgery

Upon initial presentation, surgery is the primary tool in the treatment and staging of the disease. When surgeons follow the specific surgical protocol designed by the GOG, the disease can be definitively staged. Stage I disease with favorable prognostic features can be treated by surgery alone. Stage II disease with favorable prognostic features can be treated by surgery followed by a limited course of platinum-based chemotherapy (three to four cycles). For the initial presentation of the disease, all other settings of ovarian cancer of epithelial histology require appropriate surgery followed by at least six cycles of paclitaxel and carboplatin. Currently, there is debate over the potential value of following this regimen with two or more additional cycles of paclitaxel as a single agent.

The primary goal of ovarian cancer surgery is to remove all visible disease, if possible. Retrospective analyses show that patients with no visible disease after surgery, as a group, show significant recovery, followed by patients with visible disease of <1 cm, and then by patients with 2 to 3 cm disease, and finally by patients with bulky residual disease. This underscores the importance of the surgery being performed by a skilled, experienced individual. There are subsets of patients who appear to benefit from “interval debulking,” and patients who benefit from “secondary debulking.” Detailed discussion of these considerations is beyond the scope of this chapter.

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Second-look laparotomy is no longer commonly used in this disease. Second-look laparoscopy is frequently used to assess the success of systemic chemotherapy. The purpose of either procedure is to determine whether the active disease continues to exist in the abdominopelvic space, and, if so, how extensive that disease might be. A second-look procedure should be utilized if clinical decision making will be influenced by this approach. If not, one should question the wisdom of exposing a patient to the surgical risk, however small that risk might be.

In tumors of low malignant potential, surgery may be the only treatment modality used for some individuals. In some cases, the disease may grow very slowly after the initial debulking procedure, thereby necessitating repeat surgery (without intervening chemotherapy) many years later. With use of this approach, a patient can be spared the toxicity of systemic chemotherapy in a setting in which cure is not feasible.

For stromal cell tumors too, surgery can be the only treatment approach for some individuals. However, chemotherapy with etoposide and carboplatin (with or without doxorubicin) may be required for persons with poor prognostic features.

x-Irradiation

There is a strong indication in the literature that external beam radiation therapy is clinically active in ovarian cancer. This is true for all stages of disease. However, this approach is used more extensively in Canada and Europe than in the United States. External beam radiation therapy appears to be potentially curative in early stage disease in some subsets of patients. However, long-term toxicity from x-irradiation tends to limit treatment options in patients who may have disease recurrence later on. Intraperitoneal P 32 was in common use several decades ago but is not routinely used presently.

External beam x-irradiation is useful for several manifestations of this illness. Metastases to the brain, although uncommon, are no longer considered rare. Gamma-knife approaches, IMRT (intensity modulated radiation therapy), and standard whole brain XRT (radiotherapy), are all effective in controlling metastatic disease. The use of any one of the approaches will depend on the clinical setting and the technology available. On occasion, large lesions in the pelvis or metastases to bone (unusual) will respond readily to XRT.

Chemotherapy for the Initial Disease Presentation

The following treatments are the standards of care for stage III or stage IV disease. After appropriate surgery, six cycles of carboplatin should be administered at an area under the exposure-time curve (AUC) of 5 or 6; with paclitaxel at 175 mg per m2 given every 21 days. Current studies are investigating other approaches to the treatment of the initial presentation of advanced stage disease. Those approaches include neoadjuvant chemotherapy with surgical debulking after the first two to three cycles, the addition of two to four cycles of paclitaxel after the initial six chemotherapy treatments, other chemotherapy “doublets” for which there is demonstrated activity in this disease, and three-drug therapy for patients with a particularly poor prognosis (i.e., cisplatin, paclitaxel, and cytoxan). Several published regimens for the initial systemic therapy of this disease are given in Table 17.3.

TABLE 17.3. Chemotherapy regimens for the initial therapy of ovarian cancer

AUC, area under the exposure-time curve; G-CSF, granulocyte colony stimulating factor; WBC, white blood cell.

Carboplatin plus paclitaxel

Standard therapy; should be considered first; Paclitaxel 175 mg/m2/dose; one 3-hr i.v. infusion followed by carboplatin AUC = 5 or 6, one 1-hr i.v. infusion; repeat this regimen q21d for six cycles

Carboplatin plus cyclophosphamide

Should be considered in patients who are hypersensitive to paclitaxel; Carboplatin AUC = 5 or 6; or, carboplatin 400 mg/m2/dose, one 1-hr i.v. infusion; cyclophosphamide 1,000 mg/m2/dose; one 1-hr i.v. infusion; repeat this regimen q21d for six cycles

Doxorubicin plus cyclophosphamide

For consideration in patients who are hypersensitive to paclitaxel and platinum agents;

Doxorubicin 40 mg/m2/dose, one 1-hr i.v. infusion;

Cyclophosphamide 1,000 mg/m2/dose, one 1-hr i.v. infusion;

Repeat this regimen q21d for six cycles

Cisplatin plus paclitaxel plus

For consideration in poor prognosis patients as defined in Kohn EC, Sarosy G, Davis P, et al. Gyn Oncol 1996:62:181–191;

Cyclophosphamide

Cyclophosphamide 750 mg/m2/dose, one 1-hr i.v. infusion;

Paclitaxel 250 mg/m2/dose, one 24-hr i.v. infusion;

Cisplatin 75 mg/m2/dose, one 1-hr i.v. infusion;

G-CSF 10 µg/kg/dose, s.c., daily × 8, starting the day after the cisplatin dose;

Drugs given in this order; repeat q21–28 d depending on WBC recovery

On the basis of the current literature, each patient should be given an initial treatment regimen with platinum (carboplatin or cisplatin) and paclitaxel unless there is a specific medical reason to do otherwise (e.g., hypersensitivity to either drug). Generally, carboplatin is less toxic and better tolerated than cisplatin, and these two drugs show equal efficacy in this disease. Carboplatin dosing should be based on the Calvert formula for calculating AUC; milligram dosage of carboplatin = AUC × (GFR + 25), where GFR is glomerular filtration rate. At our institution, the carboplatin infusion is delivered over 1 hour and the paclitaxel infusion is delivered over 3 hours. Paclitaxel is always delivered first. For carboplatin and cisplatin, toxicity has been loosely correlated with the duration of the infusion, with shorter infusion times being associated with increased toxicities.

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Occasionally, patients will have hypersensitivity to paclitaxel and/or to platinum with the very first treatment doses. Several desensitization regimens have been published, and these generally meet with variable success. A regimen used in the past that might be considered in such patients is doxorubicin (or liposomal doxorubicin) plus cytoxan.

Chemotherapy for Recurrent or Persistent Disease

A number of agents have demonstrated substantial activity in recurrent and/or persistent ovarian cancer of epithelial histology. The more common currently used regimens include liposomal doxorubicin, topotecan, gemcitabine, taxotere, 5-fluorouracil, oral etoposide, weekly paclitaxel, tamoxifen, and hexamethylmelamine. These regimens are detailed in the Table 17.4. This list is not exhaustive. Although single agent therapy is usually recommended in the treatment of recurrent disease, one may chose to utilize any of the several published drug combinations.

TABLE 17.4. Chemotherapy regimens for the therapy of recurrent or persistent ovarian cancer

WBC, white blood cell.

Cisplatin or carboplatin

Use only for platinum-sensitive disease, as discussed in the text;

       

Carboplatin AUC = 5 or 6 or carboplatin 400 mg/m2/dose, one 1-hr i.v. infusion; q28 d

       

Cisplatin 60 mg/m2/dose or 75 mg/m2/dose, one 1-hr i.v. infusion; q21–28d;

       

Vigorous i.v. hydration is important with both drugs, and particularly so with cisplatin

       

5-Fluorouracil plus leucovorin

Leucovorin 500 mg/m2/dose, i.v. over 30 min, followed 1 hr later by 5-FU at 375 mg/m2/dose;

       

i.v. bolus; repeat daily for five consecutive days; repeat this regimen q21–28d depending on WBC recovery; reduce to daily × 4, for grade >3 toxicity

       

Gemcitabine

1,000 mg/m2/dose i.v. over 30 min, on d 1 and d 8;

       

Repeat q21d depending on WBC recovery;

       

Hexamethylmelamine

Several different regimens are commonly used; 260 mg/m2/day, PO, divided into 4 doses, after meals; each day for 14 consecutive d; then 7 or 14 d off; Repeat q21 or 28 d

       

Liposomal doxorubicin

40 mg/m2 or 50 mg/m2/dose, one 1-hr i.v. infusion; repeat q21 d

       

Oral etoposide (VP16)

Several different regimens are commonly used;

       

100 mg/dose, PO, daily, × 14 d, followed by 7 or 14 d off; repeat q21 or 28 d

       

Tamoxifen

20 mg/dose, PO, b.i.d, continuously

       

Taxotere

70 mg/m2 or 80 mg/m2/dose; one 1-hr i.v. infusion; repeat q21d

       

Topotecan

1.5 mg/m2/dose; i.v., daily × 5; do not exceed 7.5 mg/m2 total dose/cycle;

       

Repeat q21d

       

Weekly paclitaxel

70 mg/m2/dose or 80 mg/m2/dose, one 1-hr i.v. infusion, weekly; 3 wk on, 1 wk off;

       

Repeat q28d

       

The first step for patients with recurrent or persistent disease is to determine whether the patient's disease is platinum sensitive or platinum resistant. Generally, if a patient has persistent or progressive disease while receiving cisplatin- or carboplatin-based therapy, the disease should be considered platinum resistant. In addition, if the patient appears to respond but has disease recurrence or progression within 6 months of the most recent dose of platinum, the disease should be considered platinum resistant. If disease recurs more than 1 year after the most recent dose of platinum, the disease may be considered to be platinum sensitive. Data suggest that the likelihood of a second clinical response to retreatment with platinum is more than 70% in patients who have been given their last platinum dose more than 2 years prior to the retreatment. Furthermore, data suggest that this principle may hold true for paclitaxel in this disease.

Recurrent ovarian cancer is now considered a chronic disease by most medical and gynecologic oncologists. This is because this illness will usually respond to a series of different treatment regimens over time, commonly resulting in a 5- to 10-year time frame of disease persistence with

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good quality of life. Accomplishing this, however, requires skillful utilization of currently accepted principles of clinical drug resistance and the treatment approaches used to counter drug resistance.

For example, a patient who receives initial therapy with carboplatin and paclitaxel may experience a clinical complete remission initially and exhibit disease recurrence several years later. In such instances, retreatment with carboplatin and paclitaxel would be appropriate. One can expect a likelihood of more than 70% that the disease will respond again. When the disease becomes platinum resistant, a non–cross-resistant medication such as liposomal doxorubicin must be used for treatment.

Once resistance develops to this new agent, the patient should be treated with an agent that is non–cross-resistant with any of the previous three medications, such as gemcitabine. The next regimen used might be topotecan, probably followed by oral VP16, and so on. With use of this type of approach, the disease can be controlled in some patients for several years, with acceptable toxicity and with good quality of life. For patients with disease recurrence but few or no symptoms, the use of tamoxifen at 20 mg PO b.i.d. should be considered. This can be done for biochemical recurrence of the CA125 only or for radiographic recurrence of disease without physical symptoms.

Common Toxicities from Treatment

Table 17.5 lists a range of toxicities that commonly occur with chemotherapy treatment regimens for ovarian cancer. With the exception of thrombocytopenia, the myelosuppression caused

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by these regimens can be readily treated with currently approved cytokines, such as granulocyte colony stimulating factor (G-CSF) and erythropoietin. Nausea and vomiting should be approached in a preventative manner. Aggressive preventive antinausea therapy should be used for platinum-containing regimens. Once nausea and vomiting are well established in a patient, it is usually very difficult to control.

TABLE 17.5. Common toxicities from the treatment of epithelial ovarian cancer

Myelosuppression

Associated with all the agents listed in this chapter, except tamoxifen

All three lineages affected; persistent thrombocytopenia is associated with the platinum compounds

Nausea and vomiting

Preventive treatment is very important; delayed nausea and vomiting is very common

Steroids, HT3 inhibitor, and substance P inhibitor all are recommended for routine use with platinum-containing regimens

Renal dysfunction

Seen with cisplatin and with carboplatin; usually more clinical significant with cisplatin

Serum creatinine may be normal, in the face of a markedly reduced creatinine clearance; this is important because the use of other renally cleared drugs may be needed (antibiotics, etc.);

Platinum-related renal insufficiency is nonoliguric; vigilance is required

Neurotoxicity

Clinically occurs before detectable changes on EMG/NCTs; stocking-and-glove distribution;

Usually progressive with repeated platinum doses, and can become severe; cisplatin is more likely to cause this problem than carboplatin

Fatigue/weakness

May be related to anemia but is a frequent side effect of several newer agents including gemcitabine, topotecan, irofulven, and others

Altered sexual function

Common side effect; seldom discussed spontaneously by the patient; can be an underlying contributing factor to family disruption, and clinical reactive depression;

Usually is a combined function of surgery, and effect of neuroactive anticancer agent (platinum, etc.)

Clinical depression

Common side effect; many patients will request a medication for this; sometimes a severe problem

Rare toxicities

Acute hypersensitivity to paclitaxel; acute hypersensitivity to cisplatin/carboplatin (usually after six–eight cycles of therapy, when it occurs);

Desensitization is occasionally appropriate and can be successful. On most occasions, switch to another agent right away

Renal dysfunction is frequently underestimated in patients who have received either cisplatin or carboplatin in the past. Substantial reductions in creatinine clearance can coexist with a normal blood urea nitrogen (BUN) and serum creatinine after substantial doses of either agent. Neurotoxicity is common, and mild, when currently accepted doses of carboplatin and/or paclitaxel are used. When severe neurotoxicity develops (grade 3 or greater), this can be very difficult to manage and tends to resolve slowly. Drug-induced fatigue (as opposed to anemia-related fatigue) is a frequently overlooked side effect and should be considered when symptoms develop.

Altered sexual function is a frequent, but not frequently discussed, clinical problem. This may contribute to family discord, and clinical depression, in some situations. This problem is currently understudied. Rare but severe side effects (using current treatment and supportive regimens) include hypersensitivity to paclitaxel and/or platinum compounds and acute leukemia.

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Experimental THERAPY

Generally, patients should be encouraged to participate in controlled clinical trials approved by the NCI and/or the FDA. Cooperative groups such as the GOG routinely conduct phase III trials for individuals who are diagnosed for the first time. It is through carefully performed clinical phase III trials that improvements on current treatment approaches can be made. For all patients beyond their initial diagnosis, efforts should be made to identify phase III or phase II clinical trials that are appropriate. Phase I clinical trials are reasonable treatment options for some patients.

Experimental therapies that are being tested, or have recently been tested, include gene therapy approaches, high-dose chemotherapy with bone marrow transplantation, antiangiogenesis therapies, immunotherapies, efforts to reverse resistance to standard drugs, novel combinations of drugs, and novel small molecules. Generally, high-dose chemotherapy with bone marrow transplantation is not currently recommended in this disease. In addition, intraperitoneal therapy, once considered to have great promise, is currently not in general use.

FALLOPIAN TUBE CARCINOMA AND EXTRAOVARIAN PERITONEAL CARCINOMA

These are two variants of adenocarcinoma that occur in women, which clinically behave and respond to therapy in a manner similar to epithelial ovarian cancer. The staging process is very similar to ovarian cancer for both malignancies, and the treatment approaches are identical, stage for stage.

SUPPORTIVE CARE

Among those clinical situations that may occur as a direct result of uncontrolled disease, bowel obstruction and urinary tract obstruction are the most troublesome. In the setting of the initial presentation of the illness, every effort should be made to surgically relieve this problem and should be immediately followed by systemic therapy. In recurrent or persistent disease, if there is a strong likelihood of clinical drug sensitivity, surgical remedy of either problem should again be attempted immediately.

As stated previously, nausea and vomiting should be treated preventively. Clinical depression can sometimes interfere with a patient's adherence to therapy and should be taken seriously. Participation of the patient in cancer support groups can sometimes be very helpful to the affected individual, and this can be of assistance to the health care provider.

SUGGESTED READINGS

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Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage; prospect of evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:1748–1756.

Cornelison TL, Reed E. Nephrotoxicity and hydration management for cisplatin, carboplatin, and ormaplatin: a review. Gynecol Oncol1993;50:147–158.

Hoskins WJ, McGuire WP, Brady MF, et al. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 1994;170:974–979.

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

Kohn EC, Sarosy G, Davis P, et al. A phase I/II study of dose-intense paclitaxel with cisplatin and cyclophosphamide as initial therapy of poor-prognosis advanced-stage epithelial ovarian cancer. Gynecol Oncol 1996;62:181–191.

Link C, Bicher A, Kohn E, et al. Flexible G-CSF dosing in ovarian cancer patients receiving dose intense taxol therapy. Blood1994;83:1188–1192.

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McGuire WP, Hoskins WJ, Brady MF, et al. Taxol and cisplatin improve outcome in patients with advanced ovarian cancer as compared to cytoxan/cisplatin. N Engl J Med 1996;334:1–6.

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

Ozols RF, Schwartz PE, Eifel PJ. Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer principles and practice of oncology, 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001:1597–1532.

Reed E. Cisplatin and analogs. In: Chabner BA, Longo D, eds. Cancer chemotherapy and biotherapy principles and practice, Chapter 15, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001:447–465.

Reed E, Evans MK. Acute leukemia following cisplatin-based chemotherapy in a patient with ovarian cancer. J Natl Cancer Inst1990;82:431–432.

Reed E, Jacob J. Carboplatin and renal dysfunction. Ann Intern Med 1989;110:409.

Reed E, Zerbe CS, Brawley OW, et al. Analysis of autopsy evaluations of ovarian cancer patients treated at the National Cancer Institute, 1972-1988. Am J Clin Oncol 2000;28:107–116.

Sarosy G, Reed E. Autologous stem cell transplantation in ovarian cancer: is more better? Ann Intern Med 2000;133:555–556.