April 2007, Volume 11, Number 2

 

Feature Article

Evidence-Based Research  for Intraperitoneal Chemotherapy in Epithelial Ovarian Cancer

 

 

Lois Almadrones, RN, MS, FNP, MPA

 

 

 

Intraperitoneal (IP) therapy is the administration of chemotherapy or biologic agents directly into the peritoneal cavity. A recent Gynecologic Oncology Group trial showed a survival advantage for women with advanced ovarian cancer and small residual disease after initial surgical staging and debulking who received IP therapy when compared to the standard IV regimen. The results prompted a National Cancer Institute announcement recommending the use of IP therapy in women who meet the criteria. This article describes the rationale for and underlying principles of IP therapy and summarizes the results of the three main clinical trials that led to the recommendation for incorporation of IP therapy into initial treatment of epithelial ovarian cancer.

 

At A Glance

 

·          Intraperitoneal (IP) therapy is the delivery of chemotherapy or biologic agents directly into the peritoneal cavity through a port and catheter.

·          Results of a series of cooperative group clinical trials demonstrated improved survival for women who received IP therapy versus those who received only IV therapy.

·          Basic principles of IP therapy must be adhered to for patient outcomes to be successful.

 

In 2007, an estimated 22,430 women in the United States will be diagnosed with epithelial ovarian cancer and 15,280 will die of the disease (Jemal et al., 2007). Ovarian cancer is the leading cause of death in women with gynecologic malignancies. Since 1996 (McGuire et al.), the standard treatment for advanced-stage ovarian cancer has been surgical debulking, followed by six cycles of IV paclitaxel and carboplatin administered every 21 days. Despite the aggressive treatment and some improvement in five-year survival, the median survival for patients with the disease remains about 40 months. Because of the less-than-optimal results, treatments using novel drug combinations or high-intensity chemotherapy have been researched, but neither has produced evidence of clinical benefit or improved survival. Hence, when the results of a Gynecologic Oncology Group trial using intraperitoneal (IP) and IV chemotherapy agents known to be active in ovarian cancer confirmed a definite survival advantage in the IP arm when compared to the IV standard, the National Cancer Institute issued a clinical announcement that strongly suggested a change in standard practice for the initial chemotherapy regimen for the disease.

 

Although IP therapy is not a new method of drug delivery, it has been done principally as part of investigational research trials in cooperative groups’ participating institutions or comprehensive cancer centers. Therefore, many clinicians and nurses outside of the research clinical trial setting are not familiar with IP therapy rationale and basic principles and guidelines for its administration in patients with ovarian cancer. This article will review the rationale, principles, and evidence-based research for the use of IP therapy in this population.

Use of Intraperitoneal Chemotherapy

Rationale

IP therapy is the delivery of chemotherapy or biologic agents directly into the peritoneal cavity. It has been studied in investigational research trials in tumors confined to the peritoneal cavity since the late 1970s. The therapeutic advantage is thought to be the ability to deliver a higher concentration of drug and a longer exposure of active drug that, over time, penetrates directly into small tumor tissue in the peritoneal cavity. In addition, the active chemotherapy, after first-pass metabolism in the liver, has a systemic cytotoxic effect through capillary flow into the tumor bed.

 

Dedrick, Myers, Bungay, and DeVita (1978) described the pharmacokinetic rationale of IP therapy using a mathematical model that suggests evidence about how chemicals move across the peritoneal membrane and are cleared from the systemic plasma. Dedrick et al.’s model demonstrated that, on average, the concentration of methotrexate or cytosine arabinoside (ara-C) in the peritoneal cavity was one to three logs greater than its concentration in the blood. Since that initial research, many other chemotherapeutic agents have demonstrated a peritoneal-plasma ratio that exceeds a 20-fold concentration difference. In particular, Howell et al. (1982) demonstrated that cisplatin peritoneal concentrations were 12–15 times greater than in the plasma; subsequently, Markman et al. (1992) reported a 1,000-fold difference in paclitaxel peritoneal-plasma concentrations. Many other chemotherapeutic and biologic agents also have been studied, and many show a similar pharmacokinetic advantage when administered through the IP route (Markman et al., 1989).

 

The peritoneal cavity can be thought of as a compartment that has dynamic properties of permeability and absorption of the body’s naturally occurring electrolytes, chemicals, proteins, and fluids. Compartment, or local, drug therapy is not a new concept. It is the basic underlying rationale for intrathecal therapy that is used successfully in leukemia. Intrathecal therapy also takes advantage of the restricted transfer of drugs from cerebrospinal fluid (CSF) and has shown a twofold higher difference in CSF compared to plasma concentrations (Bleyer & Dedrick, 1977; Shapiro, Young, & Mehta, 1975). Applying the same rationale for the use of IP therapy also will exploit the peritoneal-plasma ratio to benefit tumor types such as ovarian cancer that remain principally confined to the peritoneum for their natural lives in the majority of women with cancer.

Principles

 

The basic principles of IP therapy are listed in Figure 1 and must be adhered to for successful outcomes to occur (e.g., response, increased survival).

 

Principle 1: The IP agent must have slow peritoneal clearance to maximize its direct exposure to the tumor. In contrast, when the agent reaches the systemic circulation, rapid clearance is necessary to minimize the toxicity of high-dose therapy (Dedrick, 1985; Dedrick et al., 1978; Markman et al., 1989; Markman & Walker, 2006). In the peritoneal cavity and the systemic circulation, the agent must maintain its anticancer properties.

 

Principle 2: The agent administered preferably is metabolized during the first pass through the liver into nontoxic metabolites. Most metabolism of peritoneal agents enters systemic circulation through the portal circulation (Kraft, Tompkins, & Jesseh, 1968). To minimize systemic toxicity, nontoxic metabolites need to enter the circulation. Similarly, drugs that compete for hepatic or renal clearance with the anticancer agents should not be coadministered to lessen the potential for more severe systemic toxicity (Dedrick et al., 1978). Women with severely compromised renal or hepatic function may have more severe toxicity, and adequate preventive measures need to be employed prior to IP therapy.

Principle 3: The individual tumor size must be small (Alberts et al., 1996; Dedrick et al., 1978; Howell et al., 1982). The IP agent is limited and dependent on direct tumor diffusion in the peritoneal cavity and blood perfusion through capillary flow once the agent enters the systemic circulation. If the tumor size is larger than a few millimeters in greatest dimension, the diffusibilty of the agent is limited and a less-than-desirable response can be anticipated. A recent debulking laparotomy, preferably performed by a gynecologic oncologist, leaving either no gross residual or visible tumor greater than 0.5 cm in dimension prior to IP therapy, offers the best opportunity for an optimal response. However, the current IP standard is based on the Armstrong et al. (2006) trial, where eligibility was no tumor greater than 1 cm in dimension prior to IP.

 

Principle 4: Sufficient volume of distillate with the antitumor agent must be instilled to ensure exposure of the agent and optimize the drug distribution to the entire peritoneal cavity (Alberts et al., 1996; Armstrong et al., 2006; Dedrick et al., 1978; Markman et al., 1989, 1992, 2001). All clinical trials that have demonstrated better response with IP versus IV therapy have used a volume of 2 L of normal saline solution in the peritoneal cavity. Although the principle is probably responsible for most of the toxicities related to IP therapy (i.e., abdominal bloating, pain, and temporary shortness of breath), it is important and cannot be modified without the possibility of compromising maximum tumor response.

 

Principle 5: IP therapy should be administered through a port connected to a catheter that floats freely in the peritoneal cavity. The access system has evolved over time from a single-use percutaneous catheter placed and removed at each treatment to a transcutaneous, semipermanent catheter system and, finally, to the current subcutaneously placed, semipermanent port and catheter system. More research is needed to determine which type of catheter provides the best delivery and fewest catheter-related problems. Currently, studies recommend either a single-lumen polyurethane IV catheter or a fenestrated semipermanent catheter. Additional research may determine whether one of the catheters is superior. Complications related to the catheter and access system will be discussed in the article on pp. 221–225.

Evidence-Based Research

 

Data from phase I and II trials in the literature during the 1980s and early 1990s describe the potential response benefit of IP therapy when administered to women who meet the criteria for optimum response (e.g., small-volume disease confined to the peritoneal cavity with the potential for good peritoneal distribution of the anticancer agent) and have not demonstrated resistance to the particular chemotherapeutic agent. However, cooperative groups enlisted patients in phase III clinical trials that studied other experimental IV regimens that incorporated either high-dose chemotherapy or multiple sequential agents using the known standard active agents. Results of intergroup trials (Southwest Oncology Group, Eastern Cooperative Oncology Group, and Gynecologic Oncology Group) by Alberts et al. in 1996 and Markman et al. in 2001, however, generated provocative results that initiated a third trial in the Gynecologic Oncology Group alone, recently published by Armstrong et al. (2006). Following are brief summaries of each of the major phase III IP trials.

IV Cisplatin and Cyclophosphamide Versus IP Cisplatin and IV Cyclophosphamide

Conducted from June 1986–July 1992, this trial enrolled 654 women (546 eligible for evaluation) with pathologically confirmed stage III epithelial ovarian cancer who, after surgical debulking, had no tumor nodules greater than 2 cm in dimension (see Figure 2). Each woman was stratified by size of the largest tumor after debulking surgery (< 0.5 cm versus > 0.5–2 cm) and then randomized to receive either standard IV cisplatin and cyclophosphamide or the investigational arm of IP cisplatin and IV cyclophosphamide. Each regimen was given at three-week intervals for six cycles. Results confirmed a modest survival advantage in the IP group (41 versus 47 months, respectively; p = 0.02). Covariates that determined survival included absence of gross disease at enrollment (p < 0.001), younger age (p < 0.001), tumor type other than clear cell or mucinous carcinoma (p < 0.001), and enrollment after surgery (p < 0.001) (Alberts et al., 1996). Conclusions of this trial demonstrated that a modest overall survival advantage was achieved in the IP group. However, another Gynecologic Oncology Group trial done during the same time period as the IP trial compared standard IV cisplatin and cyclophosphamide versus IV paclitaxel and cisplatin. Results of that trial suggested a significant survival time in the IV paclitaxel and cisplatin arm (McGuire et al., 1996). Therefore, the IV regimen became the new gold standard, and the researchers advised that IP therapy needed further study.

IV Paclitaxel and Cisplatin Versus Moderately High-Dose Carboplatin and IV Paclitaxel and IP Cisplatin

Conducted from August 1992–April 1995, this trial enrolled 523 women (462 eligible for evaluation) with pathologically confirmed stage III epithelial ovarian cancer and largest residual tumor < 1 cm in diameter after surgical debulking (see Figure 3). The original trial had three arms. One arm included standard cisplatin and cyclophosphamide, but after the results of the paclitaxel and cisplatin trial became known, the arm was discontinued. The other two arms included the new standard IV paclitaxel and cisplatin versus IV carboplatin for two cycles followed by IP cisplatin and IV paclitaxel for six cycles. Results showed modest improvement in progression-free (p = 0.01, one-tailed) and overall (p = 0.05, one-tailed) survival in the experimental group, but the improvement likely was explained by the two extra cycles given to women in the experimental arm of the trial rather than the IP route administration (Markman et al., 2001). However, further exploration with IP therapy was initiated by the Gynecologic Oncology Group.

24-Hour IV Paclitaxel and Cisplatin on Day 2 Versus 24-Hour IV Paclitaxel and IP Cisplatin on Day 2 and IP Paclitaxel on Day 8

Conducted from March 1998–January 2001, this Gynecologic Oncology Group trial enrolled 429 women (415 eligible for evaluation) with pathologically confirmed epithelial ovarian or primary peritoneal cancer with no residual disease mass greater than 1 cm after surgical debulking (see Figure 4). The trial randomized one group to the standard IV paclitaxel and cisplatin and a second group to IV paclitaxel and IP cisplatin and then IP paclitaxel on day eight of the 21-day regimen for each arm for six cycles. Results showed that the experimental arm had a progression-free survival advantage of 18.3 versus 23.8 months (p = 0.05 by the log-rank test) and an overall survival advantage of 49.5 months versus 66.9 months (p = 0.03 by the log-rank test). The trial reported the longest survival in women with advanced ovarian cancer, and the advantage was in women in the IP arm of the trial (Armstrong et al., 2006).

 

Although the trial’s results support further use of IP therapy in advanced ovarian cancer, the toxicity profile for this mode of therapy was higher than in the standard arm, and quality-of-life during treatment also was reduced. IP catheter complications were the major reason for discontinuation of therapy.

Conclusion

 

With the introduction of any new treatment regimen or mode of administration such as IP therapy, a learning curve is expected for all health professionals involved in the care of patients receiving such therapy. Understanding the rationale and principles that underlie the basic premises of IP therapy is the first step needed in the educational process to ensure successful treatment and avoid, or at least lessen, the complications that are associated with IP therapy. As nurses become more familiar with how to access the IP port and the correct way to administer therapy directly into the peritoneal cavity, the same or better survival benefit may be observed without increasing toxicity or having to sacrifice quality of life during treatment. The articles on pp. 201–207 and pp. 221–225 review the recommended nursing performance competency checklist for IP therapy and related patient education. See Appendix for a patient guide to IP therapy.

 

References

 

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Lois Almadrones, RN, MS, FNP, MPA, is a clinical nurse specialist in the gynecology service at Memorial Sloan-Kettering Cancer Center in New York, NY. No financial relationships to disclose. (Submitted March 2006. Accepted for publication June 4, 2006.)

 

Author Contact: Lois Almadrones, RN, MS, FNP, MPA, can be reached at almadrol@mskcc.org, with copy to editor at

CJONEditor@ons.org.

 

Digital Object Identifier: 10.1188/07.CJON.211-216