Leanne M. Sakamoto, Pharm. D.
Clinical Pharmacist, University of Southern California / Kenneth Norris, Jr. Cancer Hospital and Research Institute
Assistant Professor of Clinical Pharmacy, University of southern California School of Pharmacy
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Leanne M. Sakamoto, Pharm. D. |
Ovarian cancer is the fourth leading cause of cancer deaths in women and is the leading cause of gynecological cancer death in the United States. It affects primarily postmenopausal women in their sixth decade. In the United States, it is estimated that approximately 26,700 new cases of ovarian cancer were diagnosed, and an estimated 14,800 deaths were associated with ovarian cancer in 1996.1, 2 Clearly, the social and economic impact of ovarian cancer is enormous.
Ovarian cancer, when diagnosed and treated in its early stage, has a 5-year survival rate of 91%.1 Unfortunately, because ovarian cancer in its early stage is often silent, 60-70% of patients will have advanced disease at the time of diagnosis—a point at which the tumor has spread to the peritoneal surfaces of the upper abdomen. The prognosis for these women is poor because it is difficult to eradicate extensive intra-abdominal disease by surgical debulking, and many patients will have only a partial response to chemotherapy. The 5-year survival rate for advanced disease is only 23%.'
There are three major types of ovarian cancer: epithelial, germ cell, and stromal. Of the three, epithelial ovarian cancer is the most common. Epithelial ovarian tumors account for 80-90% of all cases. This article focuses on epithelial ovarian cancer, its risk factors, diagnosis, screening and treatment, with an emphasis on chemotherapeutic options.
The exact cause of ovarian cancer is unknown; however, risk factors have been identified. Awareness of these risk factors may help provide for timely screening for ovarian cancer (see Table 1).
| Table 1: Risk Factors for Ovarian Cancer |
|---|
| Positive Risk Factors |
| Women > 40 years old |
| Nulliparity or 1st pregnancy after the age of 35 |
| Hereditary conditions (e.g.. Hereditary breast-ovarian cancer syndrome) Negative Risk Factors |
| Oral contraceptives |
| Pregnancy (each pregnancy reduces the risk of ovarian cancer by 10%) |
The risk of ovarian cancer increases with age. Ovarian cancer usually develops in women more than 40 years of age. The peak incidence is in women between the ages of 55 and 59 years. Postmenopausal women are at greater risk.
Never having borne a child (nulliparity), pregnancy after the age of 35, few pregnancies, and late menopause all increase the risk for ovarian cancer. Ovarian cancer is thought to be linked to many years of constant ovulation, which makes malignant transformation of the ovarian epithelium more likely. Each pregnancy reduces the risk of ovarian cancer by 10%. The use of oral contraceptives, which suppress ovulation, has also been shown to decrease the risk of ovarian cancer.
Lately, the study of genes linked to cancer has been widely publicized. Three hereditary syndromes have been identified which carry an increased risk of ovarian cancer: site-specific ovarian cancer, hereditary breast-ovarian cancer syndrome, and Lynch syndrome II. Hereditary breast-ovarian cancer syndrome is the most common. It is associated with mutations of the breast cancer genes (BRCA1 and BRCA2). Women with this condition have a greater than 90% risk of developing breast or ovarian cancer by the age of 70.1
Because ovarian cancer in its early stages has a much better prognosis than late disease, there is a need for early diagnosis. Unfortunately, detecting ovarian cancer early is difficult. There is no one proven screening method which allows for early detection and provides improved survival. Currently, the American Cancer Society recommends that all women over the age of 40 have a cancer-related checkup yearly which includes a pelvic examination to aid in the early detection of ovarian cancer.1
A thorough, annual pelvic exam is an important means of identifying pelvic masses. However, this exam may not be sensitive enough or specific enough to adequately screen for ovarian cancer. Often masses can be missed, and not all masses that are detected are malignant. All women, particularly perimenopausal and postmenopausal women with abdominal or pelvic symptoms, should have a thorough physical and pelvic exam as part of their work-up. The most common symptom of ovarian cancer is vague gastrointestinal discomfort, such as bloating, fullness and early satiety, pelvic pressure and pain. If a mass is detected, further diagnostic tests are warranted. However, a definitive diagnosis of ovarian cancer is usually established by tumor biopsy at the time of an exploratory laparotomy, when staging of the cancer and tumor debulking also take place.
Women who are at high risk for ovarian cancer may benefit from additional screening by transvaginal ultrasound and CA-125 serum tumor marker studies.4 These two methods also can aid in determining if a detected mass requires surgical evaluation. Transvaginal ultrasonography is a useful method for imaging the ovary. It provides information that is predictive of the presence of cancer. However, this method also lacks specificity. In a study of 5,479 women, based on the findings of transvaginal ultrasound, only one case of ovarian cancer was found for every 65 exploratory laparotomies performed.4
The CA-125 antigen is a serum tumor marker that is elevated in 80% of epithelial ovarian cancers. However, because elevated levels are only present in 50% of patients with early-stage ovarian cancer, the risk for false negatives is substantial. In addition, premenopausal women may have nonmalignant conditions, including endometriosis, pregnancy, and benign cysts that can raise CA-125 levels above normal, causing false positive results. Because of this, CA-125 is not an adequate screening test to be used alone, although it an be very useful in monitoring for early recurrence of disease.4
Since benign ovarian masses are indistinguishable from malignant masses by ultrasound and many benign conditions can cause an elevated CA-125 level an exploratory laparotomy is often necessary to diagnose ovarian cancer. If ovarian cancer is confirmed, a surgical resection or debulking of as much ovarian cancer as possible, as well as a total abdominal hysterectomy, a bilateral salpingo-oophorectomy (removal of the ovaries and fallopian tubes), and an omentectomy (removal of the omentectomy; a fold of peritoneum) are usually performed. In addition, biopsies of lymph nodes and other suspected areas are performed, and a sample of fluid from ascites (if present) is checked for malignant cells to aid in the staging and grading of the cancer.
| Table 2: Staging of Ovarian Cancer3 | |
|---|---|
| International Federation of Gynecology and Obstetrics (FIGO) staging of ovarian cancer | |
| Stage I: Disease limited to ovaries | |
| IA: | tumor limited to one ovary tumor capsule intact no tumor on ovarian surface |
| IB: | disease in both ovaries tumor capsule intact no tumor on ovarian surface |
| IC: | tumor limited to one or both ovaries with any of the following: • capsule rupture • tumor on ovarian surface • malignant cells in ascites or peritoneal washings |
| Stage II: Disease involves one or both ovaries with pelvic cavity spread | |
| IIA: | malignancy extending or metastasizing into the uterus or fallopian tubes |
| IIB: | tumor extending into other pelvic tissues |
| IIC: | tumor is either stage IIA or IIB with malignant cells in ascites or peritoneal washings |
| Stage III: Disease found in one or both ovaries with peritoneal metastasis outside the pelvis and/or regional lymph node spread | |
| IIIA: | microscopic peritoneal metastasis beyond pelvis |
| IIIB: | macroscopic peritoneal metastasis beyond pelvis <20 mm in diameter |
| IIIC: | metastasis beyond pelvis >20 mm in diameter and/or regional lymph |
| Stage IV. Tumor involving one or both ovaries with distant metastases or liver metastasis or positive pleural effusion | |
Staging of the cancer is based on the extent and location of disease found at the time of surgery (see Table 2). The prognosis of ovarian cancer depends on the stage and tumor grade at the time of surgery—the higher the stage and grade of the cancer, the poorer the prognosis. The presence of residual disease after initial surgery also influences the prognosis.
Surgery is the primary treatment for ovarian cancer, which allows for accurate staging, diagnosis, and optimal debulking. The stage and grade of the tumor determine the need for chemotherapy after surgery. Following surgery, patients with stage IA tumors and most patients with stage IB tumors (which are well differentiated) do not require chemotherapy.4 These patients have a 5-year disease-free survival of 91-98%, which is not improved by chemotherapy.7 Unfortunately, only 25% of women with newly diagnosed ovarian cancer will have stage I disease at the time of diagnosis. As mentioned earlier, the majority of women will have advanced disease at the time of diagnosis. Despite treatment with platinum-based chemotherapy, the overall survival rate for advanced disease (stage III or IV) is only 10-30%.7
| Table 3: Initial Chemotherapeutic Regimens Commonly Used to Treat Ovarian Cancer | |||
|---|---|---|---|
| Agents | Dose/Schedule | Cycle | Response Rate |
| Cydophosphamide | 750 mg/m2 IV | every 21 days for 6 cycles | Overall response rate 60% median survival 24 months4 |
| Cisplatin | 75 mg/m2 IV | ||
| Cydophosphamide | 600 mg/m2 IV | every 28 days for 6 cycles | Similar to above with less toxidties |
| Carboplatin | 300 mg/m2 IV | ||
| Paclitaxel | 135 mg/m2 IV | every 21 days for 6 cycles | Overall response rate 73% median survival 38 months8 |
| Cisplatin | 75 mg/m2 IV | ||
| Paclitaxel | 135-175 mg/m2 IV | every 21 days for 6 cycles | Similar to above with less toxicities |
| Carboplatin | Dose calculation using Calvert Formula with an AUC of 5-7* | ||
| * Carboplatin dose calculation using Calvert Formula:
Carboplatin total dose (mg) = target AUC X (GFR + 25) target AUC ranges from
5-7 GFR = Patients calculated creatinine clearance |
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The combination of platinum drugs—carboplatin (Paraplatin™) or cis-platin (Platinol™)—with paclitaxel (Taxol™) is considered first-line initial chemotherapy for treatment of advanced disease following surgery (see Table 4).4 Studies have shown that this combination improves the duration of progression-free survival and overall survival in women with advanced stage ovarian cancer when compared to platinum drugs combined with cyclophosphamide (Cytoxan™).4, 7, 8
A study of 410 women with advanced ovarian cancer with residua] masses larger than 1 cm after initial surgery demonstrated that cisplatin with paclitaxel resulted in a 73% response. (By contrast, cisplarin with cyclophosphamide resulted in a 60% response.)
Progression-free survival was also significantly longer in the cisplarin-paclitaxel group than in the cisplatin-cyclophosphamide group; 18 vs. 13 months respectively. Overall survival was also significantly longer in the cisplatin-paclitaxel group than in the cisplatin-cyclophosphamide group.8 Because of results from similar studies, platinum-paclitaxel combinations have replaced platinum-cyclophosphamide as first-line therapy
| Table 4: Initial Chemotherapeutic Regimens Commonly Used to Treat Ovarian Cancer | |||
|---|---|---|---|
| Drug | Dose | Side Effects | Special Considerations |
| Cisplatin (Platinol™) | 50-75 mg/m2 IV every 3 weeks | Highly emetogenic (acute and delayed emesis), nephrotoxidty, ototoxicity, neurotoxidty | Nephrotoxidty reduced with mannitol and pre-hydration. Neurotoxidty can be additive with paclitaxel. Pre-treat with antiemetic HT-3 receptor antagonist (granisetron or ondansetron). |
| Carboplatin (Paraplatin™) | 400-500 mg/m2 IV every 3 weeks | Myleosuppression, dose-limiting
thrombocytopenia, nausea and vomiting Calvert Formula*: target AU X (GFR + 25) = total dose (mg) |
Efficacy equal to dsplatin. Lower emetogenic potential than dsptetin. Pre-hydration not necessary. Platelet nadir occurs 3 weeks post treatment with recovery at 4-5 weeks. |
| Cydophosphamide (Cytoxan™) | 500-1500 mg/m2 IV every 3 weeks | Myleosuppresion, dose-limiting leukopenia, hemorrhagic cystitis, alopeci | Hemorrhagic cystitis can -be reduced with adequate hydration. Leucocyte nadir occurs 8-14 days post treatment with recovery at 18-25 days. |
| Paditaxel (Taxol™) | 135-175 mg/m2 IV every 3 weeks | Myleosuppresion, dose-limiting leukopenia, dose-limiting peripheral neuropathy, cardiotoxidty, alopeda | Pre-treat with dexamethasone, diphenhydramine and cimetidine of ranitidine to p hypersensitivity reactions. Active against platinum-resistant tumors. Leukocyte nadirs occur 10 days after treatment with recovery at 15 days. Prepared paclitaxel for IV infusion should be in glass or non-PVC containers. Non-PVC nitroglycerin tubing should be used for administration with a 0.2 m in-line filter. |
| Topotecan (Hycamtin™) | 1.5 mg/m2 IV daily for 5 days, repeat every 21 days | Myleosuppression. dose-limiting neutropenia, nausea/vomiting, alopeda | Treatment should be held if ANC < 1500 cells/mm3. Neutrophil nadir occurs at 11 days with recovery at 18 days. Antiemetics are not routinely necessary, If G-CSF is necessary it should not be given until day 6 to prevent prolongation of neutropenia. |
| * Calvert Formula calculates Carboplatin dose based on patient's creatinine clearance (GFR). Target AUC of 5-6 is generally used for combination chemotherapy. | |||
Although cisplatin has good activity in advanced ovarian cancer, toxicity can be a problem. Cisplatin causes nausea and vomiting in almost all patients and can cause nephrotoxicity as well as neurotoxicity. When combined with paclitaxel, the neurotoxic effects can be additive. Carboplatin, an analogue of cisplatin, has been shown to have efficacy equal to cisplatin when used in combination with cyclophosphamide and paclitaxel, but with fewer toxici-ties.4, 7, 9 Carboplatin causes less nausea, vomiting and neurotoxicity and is better tolerated than cisplatin. In addition, carboplatin can be considered easier to administer because pre-hydrarion is not necessary. Consequently, many physicians are using carboplatin plus paclitaxel as first-line treatment for ovarian cancer (see Table 3).
Recently, a new medication called amifostine (Ethyol™) was approved by the FDA for use in reducing cumulative renal effects associated with repeated use of cisplatin in patients with advanced ovarian cancer and nonsmall-cell lung cancer. Amifostine, when given prior to cisplatin, reduces the renal toxicities of cisplatin while having no effect on cisplatin's anritumor activity. Amifostine is initiated, 30 minutes prior to the start of chemotherapy, with a dose of 910 mg/m2 IV given over 15 minutes. The most common side effects are hypotension, nausea and vomiting. Patients receiving amifostine should receive pretreatment with an antiemetic, such as granisetron or ondansetron, and 20 mg of dexamethasone IV. The manufacturer of amifostine recommends hydration prior to infusing amifostine and infusing the medication while the patient is lying down to decrease the drug's hypertensive effects.
Although most women with advanced disease respond to first-line treatment, they still have a 40-50% chance of relapse within two years following initial treatment.6 Unfortunately, most patients eventually die of progressive disease that is resistant to available chemotherapeutic agents. Women who relapse after primary chemotherapy with platinum can be divided into two groups based on their interval to relapse. Women who relapse six months after treatment can be successfully retreated with subsequent platinum-containing regimens. Those who relapse earlier, within six months of treatment, have a poor subsequent response to platinum-containing regimens. This group of patients may benefit from paclitaxel, which has a response rate of 35%.4 However, with the increasing use of paclitaxel as a first-line agent and the occurrence of resistance, there is a need for the development of new agents which can be used as second-line therapy for recurrent disease. Recently, several new chemotherapeutic agents were approved by the FDA. These include topotecan (Hycamrin™), gemcitabine (Gemzar™), liposomal doxorubicin (Doxil™), and docetaxol (Taxotere™). Of these, topotecan (Hycamrin™) is the only one approved for second-line or subsequent therapy in women with advanced ovarian cancer.
Topotecan is a topoisomerase I inhibitor. It is an analog of camptothecin, a plant alloloid derived from the oriental tree Camptotheca acuminata. It is FDA approved for the treatment of patients with metastatic ovarian cancer after failure of initial or subsequent chemotherapy. Topotecan's FDA approval was based, in part, on data from an open, randomized comparative study of women who had failed one prior platinum-based chemotherapy regimen and who had no prior paclitaxel treatment. This study compared topotecan with paclitaxel. Patients treated with topotecan had a significantly longer progression-free survival (23 vs. 14 weeks) and higher response rates (20% vs. 13%) when compared to patients who received paclitaxel.10 Additional studies have reported response rates of 4-28% in previously platinum treated patients, including platinum-resistant patients.11 These studies indicate that topotecan is an effective second-line agent in patients who fail platinum and paclitaxel. Topotecan is given as a dose of 1.5 mg/m2 by IV infusion over 30 minutes for 5 consecutive days every 21 days, with treatment for at least four courses. No dosage adjustments are necessary for patients with hepatic impairment; however, patients with moderate renal impairment (Ccr 20-39 ml/min) should receive a reduced dose of 0.75 mg/m2 . The dose-limiting toxicity of topotecan is bone marrow suppression, particularly neutropenia (an abnormally small number of white blood cells). Severe neutropenia (<500 cells/mm3) occurs in 80% of patients with a nadir occurring at day 11. The median duration of neutropenia is about seven days. Severe thrombocytopenia (an abnormally small number of platelets) and anemia can also occur. Topotecan should not be administered until the neutrophil count returns to >1000 cells/mm3 platelets recover to >100,000 cells/mm3 and hemoglobin levels recover to 9 mg/dl. Neutropenia can be managed with granulocyte-colony stimulating factor (G-CSF) therapy, however G-CSF should not be given until 24 hours after the last topotecan dose to avoid prolongation of neutropenia. Studies with high dose topotecan with G-CSF revealed that concurrent therapy with G-CSF and topotecan resulted in severe bone marrow suppression. Administering G-CSF after the fifth day of therapy (day six) did not cause the same effect.12 Topotecan can also cause hair loss and mild nausea and vomiting, usually not requiring serotonin type 3 receptor antagonist antiemetics (e.g., granisetron or ondansetron).
Docetaxel (Taxotere™), a new semisynthetic taxoid, has also been studied for the treatment of advanced ovarian cancer. It is currently approved by the FDA for the treatment of patients with advanced or metastatic breast cancer who have progressed during anthracycline-based therapy or have relapsed during anthracycline-based adjuvant therapy. A study was conducted of patients who received docetaxel for the treatment of advanced epithelial ovarian cancer with disease relapse or progression with platinum-based chemotherapy. Docetaxel was administered at a dose of 100 mg/m2 as a 1 hour infusion every 3 weeks. The overall response rate was 24% with a median progression-free survival of four months. The median overall survival was 8.4 months. Toxicities most commonly associated with docetaxel are neutropenia of <2000 cells/mm3, neurotoxicity, skin reactions, hypersensitivity reactions and fluid retention.13 Pretreatment with oral corticosteroids such as dexamethasone 16 mg/day for five days, starting one day prior to docetaxel administration, reduces the severity and incidence of fluid retention and hypersensitivity reactions. Docetaxel appears to be effective in the treatment of platinum-refractory ovarian cancer patients.13
Other new chemotherapeutic agents which have shown potential for treatment of advanced ovarian cancer include liposomal doxorubicin (Doxil™) and gemcitabine (Gemzar™). Liposomal doxorubicin (Doxil™), an agent approved for the treatment of Kaposi's sarcoma, is being studied for use in advanced ovarian cancer. While the use of nonliposomal doxorubicin has not had a role as a second-line treatment for advanced ovarian cancer, the use of the liposomal doxorubicin has had favorable results. Gemcitabine (Gemzar™) is approved as a first-line treatment for patients with advanced or metastatic pancreatic cancer. Geincitabine has also been studied for the treatment of advanced ovarian cancer. Response rates of 19%, with a median duration of response of 8.1 months and median progression-free survival time of 2.8 months, were demonstrated in previously platinum treated patients with advanced ovarian cancer.14 The use of gemcitabine with platinum drugs is also being investigated for the treatment of advanced ovarian cancer.
In addition to chemotherapy for the treatment of recurrent or persistent disease, patients are sometimes treated with other methods, some of which are palliative therapies (i.e., therapies that relieve symptoms, but do not change the course of the underlying disease). A second debulking surgery is sometimes performed; however, this will only benefit a small, select group of patients.4 Whole-abdomen radiotherapy has not been shown to improve survival in patients who have persistent residual disease after platinum chemotherapy.7 However, radiation therapy can provide palliative therapy for patients with recurrent or metastatic ovarian cancer following first-line and second-line chemotherapy. The instillation of intraperitoneal (IP) chemotherapy is another approach sometimes used in patients with recurrent or persistent disease. The benefits of IP chemotherapy have not been clearly established. A recent study comparing IV cyclophosphamide plus either IV or IP cisplatin showed a significant survival advantage for the IP group, with less toxicity/' Patients with minimal tumors (<1 to 2 cm) after surgery are most likely to benefit from IP chemotherapy. For all treatments, the risks of aggressive treatment, as well as the effect on the patients quality of life. should be considered. Often, for recurrent or persistent ovarian cancer, there is very little chance for a cure.
Because early stage ovarian cancer has a much better prognosis than advanced stage ovarian cancer, there is a great need for early diagnosis. Unfortunately, no effective screening method for the general public is available. The NIH currently recommends that women have an annual pelvic exam. Women at high risk for oval-ran cancer should have a CA-125 test and trans-vaginal ultrasonography in addition to annual pelvic exams. Surgery is the primary treatment for ovarian cancer, with adjuvant chemotherapy, if necessary. Treatment with paclitaxel and platinum compounds is considered first-line therapy. With the newer chemotherapeutic agents becoming available, such as topotecan, there is renewed hope in the battle against ovarian cancer.