Judith A. Smith
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Demonstrate understanding the etiology and risk factors associated with the development of ovarian cancer.
2. Justify the risk and benefits of the surgical and chemoprevention options available for decreasing the potential risk of developing ovarian cancer.
3. Interpret and understand the utility of the screening tests and serological markers for diagnosing ovarian cancer.
4. Distinguish the nonspecific physical signs and symptoms of ovarian cancer.
5. Recommend the appropriate surgical and chemotherapy treatment options for newly diagnosed and relapsed ovarian cancer patients.
6. Compare and contrast chemotherapy options for women with recurrent platinum-resistant ovarian cancer.
7. Compare and contrast the treatment options for management of hot flushes in ovarian cancer patients.
8. Devise a plan for the management of common complications associated with advanced and recurrent ovarian cancer.
KEY CONCEPTS
Ovarian cancer is a sporadic disease, less than 10% of ovarian cancers can be attributed to heredity.
Because CA-125 is a nonspecific marker, there is no standard recommendation for routine screening for prevention of ovarian cancer.
Ovarian cancer is denoted “the silent killer” because of the nonspecific signs and symptoms.
Surgery is the primary treatment intervention for ovarian cancer.
Ovarian cancer is staged surgically using the International Federation of Gynecology and Obstetrics (FIGO) staging algorithm.
After initial surgery, the gold standard of care is six cycles of a taxane/platinum-containing regimen.
Although majority of patients will initially achieve a complete response (CR), more than 50% will recur within the first 2 years.
Because the efficacy of the agents is similar, the selection of agent for treatment of recurrent platinum-resistant ovarian cancer is dependent upon residual toxicities, physician preference, and patient convenience.
Precaution should be used in removal of ascites because of the potential complications associated with rapid fluid shifts.
In ovarian cancer patients, small bowel obstruction (SBO) is a common complication of progressive disease (PD). In general, laxatives should not be used in patients with SBOs.
INTRODUCTION
Ovarian cancer is relatively uncommon but the most fatal gynecologic cancer. The primary reason for the high mortality associated with ovarian cancer is the nonspecific symptoms and difficulty for early detection or screening that result in patients presenting with advanced disease. Majority of ovarian cancers are of epithelial origin. Each time ovulation occurs, the epithelium of the ovary is broken followed by occurrence of cell repair. The incessant ovulation hypothesis proposes that the increasing number of times the ovary epithelium undergoes cell repair is associated with the increasing risk of mutations and ultimately ovarian cancer. Ovarian cancer is often denoted as the “silent killer” because although the majority of patients will achieve a complete response (CR) to primary surgery and chemotherapy, over 50% will recur in the first year. Ovarian cancers will often cause metastasis via the lymphatic and blood systems to the liver and/or lungs. Common complications of advanced and progressive ovarian cancer include ascites and small bowel obstruction (SBO), which often are associated with the end of life.
Patient Encounter 1, Part 1
A 67-year-old female with history of coronary artery disease, diabetes, and GI reflux presents to your clinic complaining of persistent flatulence, bloating, and feels she is “getting fat.” After discussing the symptoms with her, you learn that her reflux symptoms are recent onset and her proton pump inhibitor is “working.” However, for the past 3 or 4 months, she also has irregular bleeding and occasional “cramping,” which has been frustrating for her because she thought that ended years ago when she went through menopause. She reports her menses began when she was 9 and lasted all way until she was 61. She has two sisters in good health and a brother with diabetes. She has been married for 25 years with no children. The physician orders a CA-125 and CT scan that both come back positive and suggestive of ovarian cancer.
What symptoms could be associated with ovarian cancer? Does she have any known risk factors?
What are your treatment options for this patient after surgery?
EPIDEMIOLOGY AND ETIOLOGY
In 2009, there were an estimated 21,550 new cases of ovarian cancer diagnosed with an associated 14,600 deaths.1 Ovarian cancer remains the number one gynecologic killer and the fifth leading cause of cancer-related death in women. Despite great efforts and extensive research, there has been little change in the mortality rate associated with ovarian cancer over the past three decades. The high mortality associated with ovarian cancer can be attributed to its insidious onset of nonspecific symptoms resulting in the majority of patients not presenting until the cancer has progressed to stage III–IV disease.
As with many other disease states, a significant risk factor associated with ovarian cancer is aging. A woman’s risk increases as her age advances from 40 to 79 years, with the mean age at diagnosis being 63, majority of women being diagnosed between 55 and 64 years.2
Ovarian cancer is a sporadic disease, less than 10% of ovarian cancers can be attributed to heredity. Majority of the cases of ovarian cancer occur sporadically, thus making it difficult to screen and prevent. Although hereditary accounts for less than 10% of all ovarian cancer cases, when there is a family history it appears to be an important risk factor in the development of ovarian cancer in some patients.3 If one family member has a diagnosis of ovarian cancer, the associated risk is about 9%, but this risk increases to greater than 50% if there are two or more first-degree relatives, that is, mother and sister, with a diagnosis of ovarian cancer or multiple cases of ovarian and breast cancer.3 Both breast cancer activator gene 1 (BRCA1) and breast cancer activator gene 2 (BRCA2) mutations have been associated with ovarian cancer. However, BRCA1 is more prevalent, being associated with 90% of hereditary and 10% of sporadic cases of ovarian cancer.3 Hereditary breast and ovarian cancer (HBOC) syndrome is one of the two different forms of hereditary ovarian cancer and is associated with germ-line mutations in BRCA1and BRCA2.3,4 The hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is a familial syndrome with germ-line mutations causing defects in enzymes involved in DNA mismatch repair (MMR), which has been associated with up to 12% of hereditary ovarian cancer cases.4
Although it is not clearly defined, hormones and reproductive history are associated with the risk of developing ovarian cancer. Nulliparity, infertility, early menarche, or late menopause is associated with an increased risk of ovarian cancer.5,6
Ovarian cancer is associated with certain dietary and environmental factors as well. A diet that is high in galactose and animal fat and meat increases the risk of ovarian cancer, whereas a vegetable-rich diet is suggested to decrease the risk.4,7 Although controversial, exogenous factors such as asbestos and talcum powder use on the perineal area have also been suggested to increase the risk of ovarian cancer.4,7
Screening and Prevention
Screening
Currently there is no standard effective screening tool that is adequately predictive or sensitive for early detection.
Pelvic examinations are effective for detecting obvious tumors present with a sensitivity of 67% for detecting all tumors; however, minimal or microscopic disease cannot be detected on physical examination.8Pelvic examinations are noninvasive and well accepted, but it does not usually detect ovarian cancer until it is in advanced stage. Therefore, routine pelvic examinations will not improve earlier diagnosis or help decrease overall mortality.8
Serum cancer antigen-125 (CA-125) is the most extensively evaluated tumor marker for ovarian cancer. Unfortunately, the CA-125 is nonspecific and elevated levels can be associated with a number of other gynecologic and GI related diseases. CA-125 levels in a woman without ovarian cancer are static or tend to decrease over time, while levels associated with malignancy will continue to rise.9 Because CA-125 is a nonspecific marker, there is no standard recommendation for routine screening for prevention of ovarian cancer.
Patient Encounter 2
A 36-year-old female who has been in good health presents to your clinic complaining of constipation and abdominal pain. She explains to you that she has been feeling stressed lately because her 40-year-old sister is undergoing chemotherapy for breast cancer and they just lost their mother to ovarian cancer a few years ago.
Does she have a hereditary risk factor?
What screening tools could be used to monitor this patient?
Identify the treatment options for prevention of ovarian cancer available to this patient?
Transvaginal ultrasound (TVUS) is a component of current screening practices. Typically, it is used in combination with CA-125 or could be used as a single modality. TVUS releases sonic sound waves that create an image of the ovary to evaluated the size, shape, and detect the presence of cystic or solid masses. Limitations of this technique are lack of specificity and an inability to detect peritoneal cancer or cancer in normal size ovaries.2,9 Most prevention clinics use this multimodality approach to screen high-risk women and recommend yearly ultrasound in combination with CA-125 blood test every 6 months.
Prevention
Ovulation is considered a hostile event to the ovarian epithelium, making it more susceptible to damage and cancer. Interventions or conditions that limit the number of ovulations in a woman’s reproductive history, including multiparity, will have a protective effect.
Chemoprevention Investigational chemoprevention strategies used for ovarian cancer include oral contraceptives (OCs), aspirin and nonsteroidal anti-inflammatory agents, and retinoids, although none of these is currently accepted as standard treatment for the prevention of ovarian cancer. The theory that OCs reduce the number of ovulatory events is a basic explanation of its protective effect. Recent studies have suggested that progestin-induced apoptosis of the ovarian epithelium is responsible for the chemopreventive effect of OCs. The theory is that cells that have genetic damage, but are not yet neoplastic, have an increased chance of undergoing apoptosis.10 OCs decrease the relative risk to less than 0.4% in women that use OCs for greater than 10 years.11 However, the maximum protective effect of OC use in women with BRCA mutations has been reported to be between 3 and 5 years.12 However, at the same time, OC use has been associated with an increased risk of breast cancer.11,12 Thus, women with a family history of breast cancer would not be ideal candidates for this preventative measure.
Nonsteroidal anti-inflammatory agents, aspirin, and acetaminophen have been suggested for use in the prevention of different cancers, especially hereditary nonpolyposis colon cancer.13 While there have been observational studies linked to a reduction of ovarian carcinoma risk, evidence is still lacking. Potential mechanisms include effects on normal ovulation shed and inhibition of ovulation.13,14 Other pharmacologic interventions that have been suggested but are still being evaluated include vitamin A, lutein, and other carotenoids.15–17 The protective effect of these agents is associated with inhibition of cell growth as well as promotion of cellular differentiation.16
Prophylactic Surgery Surgical strategies are also used in the prevention of ovarian cancer. The goal is to remove healthy, at-risk organs and ultimately reduce the risk of developing cancer. These surgeries include prophylactic bilateral salpingo-oophorectomy (BSO) or tubal ligation.
Prophylactic oophorectomy should be considered in any woman with a high risk of developing ovarian cancer.18 The criteria for defining high risk includes any woman with two or more first-degree relatives with epithelial ovarian carcinoma, a family history of multiple occurrences of nonpolyposis colon cancer, endometrial cancer, and ovarian cancer, and a family history of multiple cases of breast and ovarian cancer.18 Patients undergoing prophylactic oophorectomy need to be made aware that complete protection is not guaranteed.11,19 Although a 67% reduction in risk has been shown, a potential 2% to 5% risk of peritoneal carcinomatosis remains.18,20
Tubal ligation is another procedure that has shown potential for risk reduction. However, it is not recommended as a sole procedure in prophylaxis. Protective effect may be due to the limiting exposure of the ovary to environmental carcinogens. A case-control study conducted by Narod and colleagues found that a history of tubal ligation in BRCA-positive women was associated with a statistically significant 63% reduction in risk.21
Genetic Screening Genetic screening is another option available for high-risk patients. Patients can be screened for genes such as BRCA1, BRCA2, or other genes such as those associated with HNPCC or the HBOC syndrome.3,21–23Patient/family counseling and genetic counseling should be available for the patient/family to prepare and deal with the health and psychosocial implications of the genetic test results. Prior to this decision, the potential preventative options should be discussed, such as prophylactic BSO and/or total hysterectomy. Patients specifically positive for BRCA1 or BRCA2 may also consider a mastectomy.24 Cancer risk and patient’s health need to be balanced, but typically surgery can be held off until after the childbearing years.25–27
PATHOPHYSIOLOGY
The three current theories are the incessant ovulation hypothesis, the pituitary gonadotropin hypothesis, and the chronic inflammatory processes hypothesis.2 The incessant ovulation hypothesis proposes that the pathogenesis of ovarian cancer is connected to continual ovulation. Ovulation is considered a “hostile” event to the ovary perhaps with not enough time for adequate repair. Each time ovulation occurs, the ovary epithelium is disrupted and cell damage occurs. Thus, repeated ovulations may lead to a greater number of repairs of the ovarian epithelium and increase the possibility of aberrant repairs, mutation, and carcinogenesis.28–30 The pituitary gonadotropin hypothesis associates the disease with elevations in gonadotropin and estrogen levels.2 This leads to an increase in the number of follicles and therefore an increased risk of malignant changes. Finally, the chronic inflammatory processes may be involved with various environmental carcinogens to cause cancer.2,12
The three major pathologic categories of ovarian tumors include sex-cord stromal, germ cell, and epithelial. About 85% to 90% of ovarian cancers are of epithelial origin. Epithelial ovarian tumors are composed of cells that cover the surface of the ovary such as serous, mucinous, endometrioid, clear cell, and poorly differentiated adenocarcinomas. Germ cell tumors involve the precursors of ova with the most common type being dysgerminoma, which are most commonly diagnosed in women under the age of 40 and generally have a better prognosis.2 Sex-cord stromal tumors are indolent tumors that produce excess estrogen and androgens but also have a better overall prognosis.2Although the histologic type of the tumor is not a significant prognostic factor, it is important to know the histopathologic grade. Undifferentiated tumors are associated with a poorer prognosis than those lesions that are considered to be well or moderately differentiated.
Clinical Presentation and Diagnosis of Ovarian Cancer
General
Ovarian cancer has often been denoted as the “silent killer” because of the nonspecific signs and symptoms. By the time symptoms become unrelenting and bothersome, patients most likely have advanced stage disease.
Symptoms
Patients may experience episodes or persistent symptoms such as abdominal pain, constipation or diarrhea, flatulence, urinary frequency, or incontinence.
Signs
The degree of abdominal swelling secondary to fluid accumulation may present like “pregnant abdomen” and irregular vaginal bleeding.
Laboratory Test
• Cancer antigen-125 (CA-125). The normal level is less than 35 units/mL (35 kilounits/L). Note: this test is associated with a lack of specificity. CA-125 can be elevated in a number of other states such as different phases of the menstrual cycle, endometriosis, and nongynecologic cancers.
• NOTE: It is important to rule out other cancers associated with the abdominal cavity.
• Carcinoembryonic antigen (CEA). CEA is marker for colon cancer. Normal value is less than 3 ng/mL (3 mcg/L).
• CA-19–9 is a marker for many GI tumors such as cholangiocarcinomas.
Chemistries With Liver Function Tests (LFTs)
• LFTs and serum creatinine might be suggestive of extent of disease. Majority of this information is needed to determine if patient is a surgical candidate. Laboratories should be within normal limits.
CBC
• Abnormalities in CBC are not associated with ovarian cancer; however, this information is needed to determine if patient is a surgical candidate. Laboratories should be within normal limits.
Other Diagnostic Tests
To characterize local disease, one or both of the following are completed:
• Transvaginal ultrasound
• Abdominal ultrasound
To evaluate extent of disease, only one of the following is completed:
• CT scan
• MRI
• Positron emission tomography (PET) scan
Chest x-ray is also often done as part of clearance for surgery.
Ovarian cancer is usually confined to the abdominal cavity, but spread can occur to the lung, liver, and less commonly, to bone or brain. Disease is spread by direct extension, peritoneal seeding, lymphatic dissemination, or by blood-born metastasis. Lymphatic seeding is the most common pathway and frequently causes ascites.
Mechanisms of Resistance
The common mechanisms of drug resistance in ovarian cancer include: (a) alteration of drug inactivation by agents such as glutathione S-transferase (GST), (b) enhanced DNA repair, (c) dysregulation of apoptotic pathways through activation of oncogenes or the loss of tumor suppressor gene functions, (d) p-glycoprotein (Pgp) multidrug resistance that leads to decreased drug accumulation, and (e) steroid xenobiotic receptor (SXR) that leads to enhanced drug metabolism. At this time, our understanding about the mechanism of drug resistance in ovarian cancer is incomplete and limited mostly to in vitro studies. Ongoing improvements in current technology have allowed development of in vivo studies to evaluate mechanisms of drug resistance in ovarian cancer. MDR has been one of the major limitations and is one of the ongoing challenges for the successful therapeutic treatment on recurrent and persistent ovarian cancer.
TREATMENT
Desired Outcomes
Health care providers use a multimodality approach including surgery and chemotherapy in initial treatment of ovarian cancer with a curative intent, or restoring a normal life span. Although majority of patients will initially achieve a CR, more than 50% will recur within the first 2 years.2,31 CR to treatment is defined as no evidence of disease can be detected by physical examination or diagnostic tests and patient has a normalized CA-125.
The stage of disease at the time of diagnosis is the most important prognostic factor affecting overall survival in ovarian cancer patients.32 The estimated 5-year survival rate of patients with localized, regional, distant, and unstaged ovarian cancer is 92.7%, 71.1%, 30.6%, and 26%, respectively.32 The histology of the disease is another predominant prognostic factor influencing treatment outcomes. Clear cell and undifferentiated tumors do not respond as well to chemotherapy.2 The extent of residual disease and tumor grade are also predictive of response to chemotherapy and overall survival.2 There are other prognostic factors that may predict how well a patient will respond to adjuvant chemotherapy.
Generally, younger patients with a better performance status tolerate chemotherapy better compared to elderly patients. Caucasian women tend to have a worse prognosis and response to therapy compared to other ethnic backgrounds.2,4,5
The treatment goals shift when a patient presents with recurrent ovarian cancer. The desired outcomes focus on relief of symptoms such as pain or discomfort from ascites, slowing disease progression, and prevention of serious complications such as SBO. When a patient relapses, the prognostic factors are similar as post initial surgery except the amount of time that has lapsed since the completion of chemotherapy should be considered to determine if drug resistance is emerging in the tumor. Recurrent platinum-sensitive ovarian cancer patients generally have a better prognosis than platinum-resistant patients.
Nonpharmacologic Therapy
Surgery is the primary treatment intervention for ovarian cancer.33–37 A total abdominal hysterectomy with BSO (TAHBSO) (Fig. 94–1), omentumectomy, and lymphonectomy (or lymph node dissection) is the standard initial surgical treatment of ovarian cancer.33,35 The objective of the surgery is to debulk the patient to less than 1 cm of residual disease remains. Residual disease less than 1 cm correlates with better CR rates to chemotherapy and better overall survival compared to patients with bulky residual disease (greater than 1 cm).36,37 Indeed, the size of residual tumor masses after primary surgery is found to be another important prognostic factor in patients with advanced ovarian cancer.37
FIGURE 94–1. Diagram of female reproductive tract (uterus, fallopian tubes, ovaries, vagina). Dash-line box outlines what is removed during the total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH/BSO).
A thorough exploratory laparotomy is essential for the accurate staging of the patient.33–35 Ovarian cancer is staged surgically using the International Federation of Gynecology and Obstetrics (FIGO) staging algorithm (Fig. 94–2). For certain patients with limited stage disease, surgery may be curative.
Other surgical procedures have been evaluated to improve overall survival. Debulking surgery is intended to relieve symptoms associated with complications such as SBO and help improve the patient’s quality of life but does not have a curative intent. Interval debulking that is completed after two to three cycles of chemotherapy has not translated to an improved survival benefit. Often debated, the benefit of the “second-look laparotomy” to evaluate residual disease after completing chemotherapy remains controversial because it has been difficult to establish any impact on patient overall survival. It has questionable benefit because, although approximately 40% of patients with advanced disease will have a negative second look, 50% still relapse.2 The role of laparoscopic surgery is somewhat controversial for initial surgery but is more often considered in debulking of recurrent or advanced disease when the intent is palliative rather than curative.36
Pharmacologic Therapy
First-Line Chemotherapy
After initial surgery, the gold standard of care is six cycles of taxane/platinum-containing regimen for patients with advanced ovarian cancer.38–40 Patients with limited disease will have observation alone after surgery (Fig. 94–3). Most often, paclitaxel is the taxane agent used in combination with carboplatin as the preferred platinum agent.38–40 Depending upon patients’ pre-existing comorbidities and how well they tolerate chemotherapy regimens, substitution with docetaxel or cisplatin might be considered. The route of administration should also be discussed. Most often IV administration will be used; however, in some patients intraperitoneal (IP) administration may have an advantage to improve overall survival41 (Table 94–1). Close monitoring of organ function, nausea/vomiting, myelosuppression, and neuropathies is necessary for all taxane/platinum regimens (Table 94–2).
FIGURE 94–2. International Federation of Gynecology and Obstetrics (FIGO) staging algorithm for ovarian cancer.
IP Chemotherapy
For over three decades, numerous investigators have evaluated the IP route for administration of chemotherapy; however, it was not until the third report of an improvement in overall survival that brought its use to the forefront in the first-line setting.42 The principal theory supporting IP administration is to increase drug concentration in the site of disease, specifically the abdominal cavity. Patient characteristics greatly influence response and tolerability of IP chemotherapy. To be selected to receive IP chemotherapy for first-line treatment of ovarian cancer, the patient should have tumor optimally debulked and no bowel resection with primary surgery, normal renal and liver function, younger age, and no significant comorbidities.
If IP therapy is going to be considered, the placement of an IP port should occur at the time of surgery unless otherwise contraindicated. During IP administration, chemotherapy is delivered to the peritoneal space in one liter of normal saline (NS) that has been warmed followed by another liter of NS to enhance drug distribution as tolerated.43,44 In addition, it is recommend to alternate the position of patient every 15 minutes for the first hour after drug IP administration to ensure proper distribution.43,44 The current standard IP regimen includes the administration of paclitaxel IV on day 1 followed by cisplatin IP on day 2 and then paclitaxel IP on day 8 given on a 21-day cycle for a total of six cycles (Table 94–2). The most common toxicities associated with IP administration include abdominal pain, myelosuppression, neurotoxicity, and catheter-related infections.
FIGURE 94–3. Summary of chemotherapy treatment algorithm for epithelial ovarian cancer. (CR, complete response; PR, partial response; PD, progressive disease.)
Table 94–1 Summary of First-Line Chemotherapy Regimens for Advanced Ovarian Cancer
Gold standard first-line chemotherapy after initial surgery for treatment of ovarian cancer:
Paclitaxel 175 mg/m2 IV infused over 3 hours + carboplatin AUC = IV infused over 1 hour. Regimen is given once every 21 days × 6 cycles
Alternative first-line regimen: Paclitaxel IV with substitution of carboplatin IV with cisplatin IP and addition of paclitaxel IP therapy:
Patient selection is critical: must have optimally debulked disease (less than 1 cm), no significant comorbidities, younger patients tolerate better
Day 1: paclitaxel 135 mg/m2 IV infused over 24 hours + day 2: cisplatin 100 mg/m2 IP infused over 1 hour + day 8: paclitaxel 60 mg/m2 IP infused over 1 hour. Regimen is given once every 21 days × 6 cycles
Alternative first-line regimen: Substitution of cisplatin in place of carboplatin. Consider for patients experiencing difficulty with maintaining platelet counts:
Paclitaxel 135 mg/m2 IV infused over 24 hours + day 2: cisplatin 75 mg/m2 IV infused over 4 hours. Regimen is given once every 21 days × 6 cycles
Alternative first-line regimen: Substitution of docetaxel in place of paclitaxel. Consider for patients with pre-existing or increased risk of neuropathies:
Docetaxel 75 mg/m2 IV infused over 1 hour + carboplatin AUC = 5 IV infused over 1 hour. Regimen is given once every 21 days × 6 cycles
Neoadjuvant Chemotherapy
Neoadjuvant chemotherapy is first-line treatment for patients who are poor surgical candidates or patients with bulky or significant tumor burden.31 For patients who are poor surgical candidates because of significant comorbidities, a combination of taxane with platinum agent is administered every 3 to 4 weeks as tolerated with intent to relieve symptoms and slow progression of disease. In some cases, especially elderly patients, single-agent carboplatin is used as palliative treatment instead. Chemotherapy alone has not been curative for patients with advanced ovarian cancer.31
Table 94–2 Summary of Chemotherapy Agents Used for First-Line Treatment of Advanced Ovarian Cancer
In patients with bulky disease or significant tumor burden, neoadjuvant chemotherapy can be used to decrease tumor burden to increase the likelihood of optimal tumor debulking during surgery.31 Typically three cycles of the standard combination taxane/platinum regimen is administered once every 3 weeks. After surgery, patient will receive another three to six cycles depending upon response to chemotherapy.
Consolidation Chemotherapy
Consolidation chemotherapy is the addition of cycles of the taxane/platinum regimen or the addition of single-agent platinum or single taxane after completion of first-line chemotherapy.45 If the tumor has a partial response (PR) to first-line chemotherapy evident by a significant decline in CA-125 by greater than 50% presurgery level and/or tumor regression/decrease in size, then cancer is still considered taxane/platinum sensitive. Additional cycles of chemotherapy are given until CR is achieved (see Fig. 94–3).
Agents Used in First-Line and Consolidation Chemotherapy of Ovarian Cancer
Taxanes
Paclitaxel. Paclitaxel is a taxane that is naturally derived from the bark of the yew tree. Paclitaxel is cytotoxic to cells by stabilizing microtubules to prevent depolymerization of tubulin causing cell cycle arrest in the M-phase. The two most common regimens used in ovarian cancer is a 3-hour infusion of 175 mg/m2 or a 24-hour infusion of 135 mg/m2.
Paclitaxel is a water-insoluble drug so alcohol-based diluent, cremophor, is used in the formulation and is associated with increase hypersensitivity reactions. Patients are pretreated with an H2 blocker, diphenhydramine, and steroids. The dose-limiting toxicity (DLT) of paclitaxel is infusion dependent. For shorter infusion, for example, 3 hours, the DLT is neuropathy and for longer infusions the DLT is myelosuppression. Additional common adverse effects can be found in Table 94–2.
Docetaxel. Docetaxel is another agent in the class of taxanes with a similar mechanism of action as paclitaxel but with differences in affinity for α-tubulin-binding sites, hence more potent.
Because the experience with docetaxel in the treatment of ovarian cancer is limited, it is often considered as a second-line option. However, there are clinical trials ongoing comparing the efficacy and toxicity of docetaxel to paclitaxel in the combination with platinum agents for first-line treatment of ovarian cancer.46 The dose of docetaxel typically used is 75 mg/m2 given every 21 days and is reasonably well tolerated. To avoid severe fluid retention or hypersensitivity reactions, patients are premedicated with corticosteroids. The DLT associated with docetaxel primarily is neutropenia. Additional common adverse effects can be found in Table 94–2.
Platinum Analogues
Cisplatin. Cisplatin forms Pt-DNA adducts that intercalate the DNA interrupting DNA synthesis.
The typical dose of cisplatin used for the treatment of ovarian cancer is 75 mg/m2 when administered via IV route or 100 mg/m2 if administered via IP route. Because cisplatin is nephrotoxic, regardless of route of administration, prehydration with 1 to 3 L of NS is required, which often requires an inpatient stay. The DLT of cisplatin is neurotoxicity that is nonreversible in many patients. Cisplatin is highly emetogenic but can be minimized with 5HT3-antagonists. Additional common adverse effects can be found in Table 94–2.
Carboplatin. Carboplatin has a similar mechanism of action as cisplatin forming PLT-DNA adducts that intercalate the DNA interrupting DNA synthesis to ultimately cause cell death.
Carboplatin dose is determined using the Calvert formula: carboplatin dose (mg) = target AUC * (CrCl + 25). The Calvert formula uses the calculated glomerular filtration rate (GFR) for the estimated creatinine clearance (CrCl) in this equation to individualize the dose and minimize dose-related toxicity. For the first-line treatment of ovarian cancer, the target area under the curve (AUC) is five to seven. Individualized dosing has decreased the incidence and degree of nephrotoxicity associated with carboplatin compared to cisplatin, eliminating the need for intensive prehydration thus allowing for outpatient administration. Myelosuppression, primarily thrombocytopenia, is the DLT of carboplatin. Additional common adverse effects can be found in Table 94–2.
Recurrent Chemotherapy
In the recurrent setting, platinum sensitivity of the tumor is assessed first. If recurrence occurs in less than 6 months or disease progresses while receiving a platinum-based regimen, the cancer is considered to be platinum resistant (see Fig. 94–3). These parameters are also used to determine taxane sensitive or resistant. However, patients resistant to paclitaxel may still respond to docetaxel.47 If the treatment goal is palliative care, then often single therapy will be used, while curative care typically is an aggressive combination regimen (see Fig. 94–3). Often an investigational study may have more likelihood or achieving a response as well or better than the current agents used for the treatment of recurrent ovarian cancer.
Platinum Sensitive
In patients who experienced a CR to first-line chemotherapy and have had greater than a 6-month platinum-free interval, retreatment with a platinum containing regimen is appropriate. Current National Comprehensive Cancer Network (NCCN) guidelines recommend the combination of carboplatin with either gemcitabine or paclitaxel for the treatment of platinum-sensitive recurrent ovarian cancer with a curative intent.41 However, in patients who are unable to tolerate additional combination chemotherapy regimens, carboplatin alone or any one of the second-line agents would be appropriate48 (see Table 94–2).
Platinum Resistant
Recurrent or persistent ovarian cancer after platinum-based regimens has a discouraging prognosis. Second-line agents have not been successful to date, but any active agent that has not been used during initial treatment is available to use. Single-agent chemotherapy is standard practice for recurrent platinum-resistant ovarian cancer. Active agents include altretamine (formerly hexamethylmelamine), anastrozole, capecitabine (5-fluorouracil), cyclophosphamide, docetaxel, gemcitabine, liposomal doxorubicin, oral etoposide, vinorelbine, topotecan, or investigational agents. There are numerous ongoing investigational studies evaluating the benefit of addition of biologically targeted agents such as bevacizumab to cytotoxic agent regimens to improve outcomes in the recurrent ovarian cancer setting (see Fig. 94–3). Since the efficacy of the agents is similar, the selection of agent for treatment of recurrent platinum-resistant ovarian cancer is dependent upon residual toxicities, physician preference, and patient convenience.Table 94–3 gives a short summary of the adverse effects and monitoring parameters for chemotherapy agents commonly used for the treatment of recurrent ovarian cancer.
Patient Encounter 1, Part 2: 1 Year After Initial Diagnosis
This patient was optimally debulked and completed six cycles of paclitaxel/carboplatin after her surgery. Her CA-125 normalized (12 units/mL [12 kilounits/L]) upon completion of her chemotherapy treatment and her CT scan was negative. This patient returns to your clinic for her first 3-month follow-up appointment. Her CA-125 is 45 units/mL (45 kilounits/L) and she reports some mild bloating. CT scan report states mild fluid accumulation in the pelvic cavity.
List the possible chemotherapy treatment options for this patient?
Discuss the side effect profile and administration schedule of each agent and how this information would help in selection of her next chemotherapy regimen?
What is the goal of treatment for this patient?
Table 94–3 Summary of Chemotherapy Agents Used for Second-Line Treatment of Progressive and Recurrent Platinum-Resistant Ovarian Cancer
OUTCOME EVALUATION
Overall survival is impacted by success of initial surgery to debulk tumor to less than 1 cm of disease and response to first-line chemotherapy. The CA-125 level should be monitored with each cycle and at least a 50% reduction in CA-125 after four cycles of taxane/platinum chemotherapy is related to an improved prognosis. Patients who achieve CR should have follow examinations once every 3 months, including CA-125, physical examination, and pelvic examination, and appropriate diagnostic scans (i.e., CT scan, MRI, or PET scan) should be evaluated for the detection of disease. Side effects while evaluating patient for resolution of any residual chemotherapy include neuropathies, nephrotoxicity, ototoxicity, myelosuppression, or nausea/vomiting. In younger patients with an active menstrual cycle prior to surgery will encounter “surgical menopause” and often experience intense hot flushes. Since there are concerns about potential of hormones in the pathogenesis of ovarian cancer, the use of hormone replacement therapy is controversial. The use of phytoestrogen supplements, such as black cohosh or soy, is also controversial. An effective alternative has been the use of the class of serotonin reuptake inhibitors such as venlafaxine controlled released once daily.
In the PD or recurrent setting, CA-125 levels should still be monitored with each cycle, but no change in therapy is recommended until after minimum of three cycles of chemotherapy. In addition, appropriate diagnostic scans (i.e., CT scan, MRI, or PET scan) should be evaluated once every three cycles. Patients should also have routine physical examinations with each cycle of chemotherapy to evaluate for any physical toxicity associated with chemotherapy such as neuropathies, fluid retention, palmar-plantar erythrodysesthesia (PPE), myelosuppression, or nausea/vomiting.
Unfortunately, if patients will eventually progress through all chemotherapy options, then supportive care measures should be provided to maintain patient comfort and quality of life. Common complications while developing a plan for treatment of advanced/progressive ovarian cancer include ascites, uncontrollable pain, and SBO. Precaution should be used in removal of ascites because of the potential complications associated with rapid fluid shifts.Liberal use of opioids to control pain is appropriate as ovarian cancer patients cope with PD and approaching end of life. Appropriate bowel regimens with laxatives and stool softeners should be used to prevent constipation. However, when a patient with a well-controlled bowel regimen presents with new onset of constipation, additional workup is required prior to altering bowel regimen. In ovarian cancer patients, small bowel obstruction is a common complication of progressive disease. In general, laxatives should not be used in patients with SBOs. Prior to treating constipation, patients should have a physical examination and abdominal x-ray to rule out SBO. Often, palliative surgery is required to correct SBO and alleviate patient pain. Patients should not eat any solid or liquids until resolution of SBO. If inoperable SBO exists, then parenteral nutrition can be considered but weighed against ultimate treatment objectives. Overall, providing any measures needed to maintain patient comfort is the priority for patients with progressive ovarian cancer.
Patient Care and Monitoring
1. Assess patient history of nonspecific symptoms to determine if patient should be evaluated by gynecologist.
2. Determine if patient is at high risk for development of ovarian cancer and make appropriate recommendations for screening and prevention.
3. Evaluate patient comorbidities and medications to determine if additional workup is necessary prior to tumor debulking surgery. Do any medications need to be stopped or changed prior to surgery (i.e., aspirin, warfarin, nonsteroidal anti-inflammatory agents)?.
4. Develop a plan for preventing and treatment of nausea and vomiting for patient receiving emetogenic chemotherapy.
5. Monitor patient for signs of hypersensitivity reactions to taxane or platinum chemotherapy regimens.
6. Monitor appropriate laboratories to determine
a. Changes in organ function—adjust chemotherapy doses as indicated
b. Electrolyte wasting—replace and supplement electrolytes IV or oral as indicated.
7. Provide appropriate patient education on respective chemotherapy agents that will be given for treatment of recurrent ovarian cancer.
a. What is chemotherapy and how this agent works?
i. Explain plan for monitoring response to treatment.
b. What side effects to expect during chemotherapy?
i. Precautions to take to prevent infection when neutropenic.
ii. Monitor for signs/symptoms of infection.
c. When to contact physician/clinic between cycles of chemotherapy?
d. Drug or food interactions with chemotherapy to avoid.
Abbreviations Introduced in This Chapter
|
AUC |
Area under the curve |
|
BRCA1 |
Breast cancer activator gene 1 |
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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