Nonpharmacologic Therapy

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VT Surgery is the primary treatment intervention for ovarian cancer. A total abdominal hysterectomy with BSO (TAHBSO) (Fig. 94-1), omentumectomy, and lymphonectomy (or lymph node dissection) is the standard initial surgical treatment of

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ovarian cancer. ' 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.

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 pa-

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tient. ' '- ' ' 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. De-bulking 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. 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. 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..38-4 Patients with limited disease will have observation alone after surgery (Fig. 94-3). Most often, paclit-axel 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).

Figo Staging Ovarian Cancer
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 improve-

ment in overall survival that brought its use to the forefront in the first-line setting. 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, neuro-toxicity, and catheter-related infections.

Ewr Staaten
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/m IV infused over 3 hours + carboplatin AUC = IV infused over 1 hour. Regimen is given once every 21 days x 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

22 Day 1: paclitaxel 135 mg/m IV infused over 24 hours + day 2: cisplatin 100 mg/m IP infused over 1

hour + day 8: paclitaxel 60 mg/m2 IP infused over 1 hour. Regimen is given once every 21 days x 6

cycles

Alternative first-line regimen: Substitution of cisplatin in place of carboplatin. Consider for patients experiencing difficulty with maintaining platelet counts:

22 Paclitaxel 135 mg/m IV infused over 24 hours + day 2: cisplatin 75 mg/m IV infused over 4 hours.

Regimen is given once every 21 days x 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/m IV infused over 1 hour + carboplatin AUC = 5 IV infused over 1 hour. Regimen is given once every 21 days x 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 tax-ane 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

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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. Typically three cycles of the standard combination tax-ane/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 depolymer-

ization of tubulin causing cell cycle arrest in the M-phase. The two most common re-

gimens used in ovarian cancer is a 3-hour infusion of 175 mg/m 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 a-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/m 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/m when administered via IV route or 100 mg/m 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 prehydra-tion thus allowing for outpatient administration. Myelosuppression, primarily thrombocytopenia, is the DLT of carboplatin. Additional common adverse effects can be found in Table 94-2.

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