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The Oncologist, Vol. 13, No. 4, 403-409, April 2008; doi:10.1634/theoncologist.2007-0058
© 2008 AlphaMed Press
Intraperitoneal Chemotherapy for Women with Epithelial Ovarian Cancer
Edward L. Trimblea,b,
Sharon Thompsonb,
Michaele C. Christiana,
Lori Minasiana
aNational Cancer Institute, Bethesda, Maryland, USA;
bJohns Hopkins Hospital, Baltimore, Maryland, USA
Correspondence: Edward L. Trimble, M.D., M.P.H., Division of Cancer Treatment and Diagnosis, National Cancer Institute, 6130 Executive Boulevard, Suite 7025, MSC 7436, Bethesda, Maryland 20892-7436, USA. Telephone: 301-496-2522; Fax: 301-402-0557; e-mail: trimblet{at}ctep.nci.nih.gov
Received March 23, 2007;
accepted for publication January 4, 2008.
Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.
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Learning Objectives
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After completing this course, the reader will be able to:- Assess the rationale behind using i.p. chemotherapy for epithelial ovarian cancer patients and critically evauate the data supporting its use.
- Interpret the argument that i.p. chemotherapy cannot be accepted as standard of care for first-line systemic treatment of advanced ovarian carcinoma.
- Determine which epithelial ovarian cancer patients may be appropriate for i.p. chemotherapy.
- Avoid and/or manage the toxicities observed with i.p. chemotherapy.
Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com
The CME activity for this article consists of material from both "Intraperitoneal Chemotherapy for Women with Epithelial Ovarian Cancer" (Trimble et al.) and "Intraperitoneal Chemotherapy in Patients with Advanced Ovarian Cancer: The Con View" (Vergote et al.).
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ABSTRACT
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In 2006, i.p. chemotherapy re-emerged as a controversial topic in debates about the optimal treatment for women with advanced epithelial ovarian cancer. In this paper, we address the rationale behind i.p. chemotherapy, the data supporting its use, the selection of appropriate patients for i.p. chemotherapy, how best to avoid and manage the toxicities observed with i.p. chemotherapy, and directions for future research.
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RATIONALE FOR I.P. CHEMOTHERAPY
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Epithelial ovarian cancer appears to arise from the epithelial surface of the ovary. Spread of the disease may include local extension, intra-abdominal dissemination to other sites within the peritoneal cavity, and lymphatic spread to pelvic and para-aortic nodes in the retroperitoneum. The recommended treatment includes primary surgery for diagnosis, staging, and cytoreduction, followed by chemotherapy. Unlike many other solid tumors, effective cytoreduction ("debulking") conveys a survival benefit among women with ovarian carcinoma [1]. The goal of primary surgical cytoreduction is to reduce the burden of ovarian cancer to no or minimal residual disease. The recommended initial chemotherapy has been a platinum and taxane combination given by i.v. infusion every 3 weeks for six courses [2].
Because residual ovarian cancer after surgery and initial recurrences are primarily confined to the abdomen, the i.p. administration of chemotherapy was first proposed several decades ago [3]. Certain chemotherapeutic agents, including cisplatin, and more recently, paclitaxel, were found to have distinct pharmacokinetic advantages when given via an i.p. route [4–6]. These include a high i.p. concentration of the drug as well as a longer half-life of the drug in the peritoneal cavity, compared with that observed with i.v. administration. For cisplatin, there was a 10- to 20-fold greater exposure in the peritoneal cavity over what is achieved with the i.v. route [7]. In addition, i.p. administration resulted in longer systemic exposure to the chemotherapeutic agents.
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DATA SUPPORTING THE USE OF I.P. CHEMOTHERAPY IN OVARIAN CANCER
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Over the past 20 years, seven phase III trials have compared chemotherapy given via an i.v. route with chemotherapy given via a combined i.v.–i.p. route as part of primary therapy among women with ovarian cancer [8–14]. The design of those seven trials is shown in Table 1. An eighth trial comparing i.p. consolidation therapy with no further treatment among women with no evidence of disease after primary surgery and adjuvant chemotherapy has also been reported [15] (Table 2). The combined data from the initial seven trials demonstrated a 9-month longer median overall survival time associated with the combined i.v.–i.p. approach, with significantly lower hazard ratios for both recurrence and death (Figs. 1 and 2), albeit with a clear increase in both hematologic and other systemic toxicities. On average, i.p. therapy was associated with a 21.6% lower risk for death (hazard ratio, 0.79; 95% confidence interval, 0.70–0.89). Because the expected median duration of survival for women with optimally debulked ovarian cancer receiving standard treatment is approximately 4 years, this size reduction in the overall death rate is expected to translate into about a 12-month longer median overall survival time. In the most recently reported trial, Gynecologic Oncology Group (GOG) 172, women who received combined i.v.–i.p. chemotherapy experienced a 15-month longer median overall survival time than those who received i.v. chemotherapy only. Three recent meta-analyses have confirmed the benefits of i.p. chemotherapy for appropriate patients with epithelial ovarian cancer as well as the importance of chemotherapy combining platinums and taxanes in improving survival [16–18]. According to Kyrgiou et al. [17], for example, "Monte Carlo simulations showed a 92% probability that the regimen which best prolonged survival is a platinum and taxane combination with intraperitoneal administration."
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Table 1. Randomized trials comparing i.v. chemotherapy with i.p. chemotherapy or combined i.v.–i.p. chemotherapy for the first-line treatment of ovarian cancer
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Figure 1. Treatment hazard ratios (HR) for progression-free survival (PFS) for i.p. versus i.v. therapy.  2 heterogeneity (3 d.f.) = 0.629; p = .89. The red diamond shows the pooled estimate of the treatment HR for PFS: 0.79 (95% confidence interval, 0.70–0.90). PFS HRs are not available from the published report on SWOG 8501/GOG 114 or the studies of Kirmani et al. [8], Polyzos et al. [10], and Yen et al. [13]. The PFS HR is not reported for the study of Gadducci et al. [11] but it is calculated from the available data reported.
Abbreviations: d.f., degrees of freedom; EORTC, European Organization for Research and Treatment of Cancer; GOG, Gynecologic Oncology Group; GONO, Gruppo Oncologico Nord-Ovest; SWOG, Southwest Oncology Group.
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Figure 2. Treatment hazard ratios (HRs) for overall survival for i.p. versus i.v. therapy. 2 heterogeneity (5 d.f.) = 2.70; p = .75. The red diamond shows the pooled estimate of the treatment HR for survival: 0.79 (95% confidence interval, 0.70–0.89). The HR was not reported for the study of Gadducci et al. [11], but it is calculated from the available data reported. The HR is not available from the studies of Kirmani et al. [8] and Polyzos et al. [10].
Abbreviations: d.f., degrees of freedom; EORTC, European Organization for Research and Treatment of Cancer; GOG, Gynecologic Oncology Group; GONO, Gruppo Oncologico Nord-Ovest; SWOG, Southwest Oncology Group.
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TOXICITIES ASSOCIATED WITH I.P. CHEMOTHERAPY
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The toxicities associated with i.p. chemotherapy may be divided into three categories: those resulting from the presence of an i.p. catheter, such as infection and adhesions; those resulting from the administration of fluid and chemotherapy into the abdominal cavity, such as temporary abdominal pain, discomfort, and nausea; and those resulting from the relatively high doses of chemotherapeutic agents infused into the peritoneum, including acute and chronic metabolic imbalances and neurotoxicity. A summary of the toxicities reported in phase III clinical trials of i.p. chemotherapy is shown in Table 3. Women and their families should be counseled about these potential risks as they decide with their physicians on a chemotherapeutic regimen for ovarian cancer. In addition, physicians and nurses should take appropriate steps, as outlined below, to avoid and ameliorate such toxicities.
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SELECTION OF PATIENTS FOR I.P. CHEMOTHERAPY
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The ideal patient for i.p. chemotherapy is a woman with stage III epithelial ovarian cancer who has no or minimal residual disease after primary surgery and who can tolerate the greater toxicity associated with the combined i.v.–i.p. approach. If a woman has had a bowel resection and reanastomosis at the time of primary surgery, most experts would recommend giving her one course of i.v. chemotherapy before beginning combined i.v.–i.p. chemotherapy to reduce the risk for postoperative complications. Women who are not good candidates for i.p. chemotherapy include those found to have extensive intra-abdominal adhesions, those with stage IV disease on the basis of parenchymal liver disease, and those with major comorbidities. We do not know whether a woman with stage IV disease on the basis of metastatic disease found in pleural effusions who has otherwise undergone optimal surgical debulking is appropriate for i.p. chemotherapy.
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PLACEMENT OF PORTS FOR I.P. CHEMOTHERAPY
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An i.p. port may be placed at the time of primary staging and surgical cytoreduction, or afterwards, via laparoscopy, minilaparotomy, or interventional radiology. As noted above, most centers with expertise in placing i.p. ports and giving i.p. chemotherapy recommend interval placement if primary surgery includes bowel resection and reanastomosis. Centers with expertise in delivering i.p. chemotherapy recommend that the type and location of the i.p. port be standardized throughout the institution, because this benefits the nursing staff responsible for maintaining port access and troubleshooting port flow issues. Occasionally, the presence of an i.p. port will result in superficial cellulitis, which should be treated with appropriate i.v. or oral antibiotics. Rarely, patients may develop bacterial peritonitis, which should be treated with the appropriate i.v. antibiotics and, in many cases, removal of the port. The presence of an i.p. catheter may also cause intestinal adhesions. Rarely, the i.p. catheter may migrate into the lumen of the bowel or the vagina.
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SUPPORTIVE CARE MEASURES DURING AND AFTER I.P. CHEMOTHERAPY
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Women should receive aggressive i.v. hydration before i.p. chemotherapy to decrease the risk for renal toxicity resulting from the administration of cisplatin. Many women also benefit from i.v. hydration after chemotherapy to prevent dehydration resulting from the greater gastrointestinal toxicity associated with i.p. chemotherapy. Contemporary antiemetics, such as serotonin receptor antagonists, neurokinin receptor antagonists, and steroids, are necessary to prevent both acute and delayed nausea and vomiting. Careful monitoring and replacement of serum electrolytes is necessary to prevent and treat metabolic disturbances associated with both drug-related and i.p. route–related toxicities. Standard premedications for taxanes should be given before both i.v. and i.p. administration of taxanes to prevent allergic reactions. To minimize discomfort during i.p. port access, topical analgesics should be applied to the port site before access. Both non-narcotic and narcotic analgesics may be necessary to treat the discomfort associated with the i.p. fluid volume given with chemotherapy. Physicians should also be alert to the need for dose reduction of cisplatin or paclitaxel based on toxicity. Early dose reduction of cisplatin for any degree of neurotoxicity is particularly important. G-CSF may be required to prevent neutropenia associated with therapy, as well as erythropoietins or blood transfusions for the prevention and treatment of chemotherapy-associated anemia.
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OPTIMAL NUMBER OF COURSES OF I.P. CHEMOTHERAPY
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In the Southwest Oncology Group (SWOG) 8501, GOG 114, and GOG 172 trials, the number of i.p. treatments was often limited because of toxicity. The number of women completing the planned six courses of i.p. chemotherapy ranged from 71% (GOG 114) to 58% (SWOG 8501) to 42% (GOG 172). Most of the patients who stopped i.p. chemotherapy because of toxicity were able to tolerate additional i.v. chemotherapy. Analysis of outcome data from GOG 172, however, showed that even women who only received one course of i.p. chemotherapy experienced significantly better survival than those who only received i.v. chemotherapy. No phase III trial has compared a shorter with a longer regimen of i.p. chemotherapy treatments. Most cancer centers that are using the combined i.v.–i.p. approach today try to give six courses of i.v.–i.p. chemotherapy.
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HEALTH-RELATED QUALITY OF LIFE
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Health-related quality of life (HRQOL) data are available from GOG 172 [19]. Abdominal discomfort improved from baseline to chemotherapy cycle 4 for women in both the i.v. and i.v.–i.p. chemotherapy arms, although the improvement was greater among women in the i.v. arm. The authors observed better HRQOL among women in the i.v. arm than among women randomized to the combined i.v.–i.p. arm during and immediately after treatment. These differences disappeared over time, however, so that at 1 year, HRQOL and pain scores were similar between the two arms except for paresthesias, which were more likely to persist at moderate levels among the patients in the i.v.–i.p. arm. These findings suggest that the additional toxicity, with the exception of paresthesias, that may be observed with i.p. delivery is generally transient and not a long-term issue for most patients.
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LEARNING HOW TO GIVE I.P. CHEMOTHERAPY
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As i.p. chemotherapy for ovarian cancer has not been the standard of care in the past, many doctors and nurses have never given i.p. chemotherapy or have not given it off protocol for several decades. Explicit recommendations about how to give i.p. chemotherapy are included in the 2006 National Cancer Institute (NCI) clinical announcement regarding i.p. chemotherapy for ovarian cancer [20]. Additional educational materials for doctors, nurses, and patients are available on the GOG website [21]. Three recent review articles provide excellent summaries of the literature surrounding the use of i.p. chemotherapy for women with ovarian cancer [22–24]. The NCI maintains a registry of cancer centers, hospitals, and practices with expertise in the multidisciplinary care of ovarian cancer, including the administration of i.p. chemotherapy [20]. In general, these practices have been happy to share their experiences in giving i.p. chemotherapy. The Society of Gynecologic Oncologists maintains a speakers' bureau including many lecturers with expertise in i.p. chemotherapy. A DVD focused on teaching nurses about the administration of i.p. chemotherapy has recently become available [25]. Centers with expertise in giving i.p. chemotherapy identify consistency in orders, port placement, chemotherapy delivery, and management of toxicities as the most important factors in the success of i.p. chemotherapy programs.
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OBSTACLES TO DIFFUSION OF I.P. CHEMOTHERAPY
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Delivery of i.p. chemotherapy requires the presence of a multidisciplinary treatment team. This should include a gynecologic oncologist with experience in optimal cytoreductive surgery for women with ovarian cancer as well as placement of i.p. ports, either a gynecologic oncologist or medical oncologist with experience in prescribing i.p. chemotherapy and managing toxicities, and oncology nurses with experience in administering i.p. chemotherapy. In addition, patients receiving combined i.v.–i.p. chemotherapy require more time and resources than a similar patient receiving only i.v. chemotherapy. In the outpatient setting, for example, a woman receiving i.p. chemotherapy needs to recline on a bed or stretcher, rather than sitting in a chair. The i.p. infusion also lasts longer than a comparable i.v. infusion. Both of these requirements may affect both staffing and equipment needs. If the 24-hour infusion of paclitaxel is conducted in the hospital, rather than in the outpatient setting, then additional in-patient beds need to be reserved for that purpose. There has also been concern among many physicians that the reimbursement rates for giving i.p. chemotherapy compared with those for giving i.v. chemotherapy do not reflect the additional time required for a more complicated regimen with greater risks for toxicity. The greater risks for toxicity themselves also may deter both patients and physicians, who both prefer the ease and toxicity profile of standard i.v. chemotherapy. Finally, i.p. chemotherapy is an old idea, and thus less attractive than more novel chemotherapeutic regimens both to patients and physicians.
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FUTURE RESEARCH
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We need to know how best to modify the existing regimens, such as those used in the experimental arm of GOG 172, to decrease toxicity and preserve efficacy. Will substitution of i.p. carboplatin for i.p. cisplatin, for example, reduce metabolic and neurotoxicities while retaining efficacy? Is i.p. chemotherapy appropriate for patients with lymph node metastases as the only or primary extraovarian sites of disease? Is there a role for i.p. chemotherapy after neoadjuvant chemotherapy, after interval surgical cytoreduction, as consolidation therapy, or at the time of recurrence? Can we integrate a combined i.v.–i.p. approach with newer biologic agents, such as bevacizumab [26]? Is there a minimum number of courses of i.p. chemotherapy needed to improve survival? Is there a maximum number of courses of i.p. chemotherapy after which the risk for greater toxicity outweighs the potential survival benefits? What changes in port and catheter design might reduce the risk for infection, adhesive disease, or malfunction?
Finally, what factors influence the adoption of i.p. chemotherapy into community practice?
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OPTIMIZING OUTCOMES FOR WOMEN WITH OVARIAN CANCER
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The importance of a multidisciplinary team to care for women with ovarian cancer must be underscored. The first step in ovarian cancer treatment is generally effective surgical staging and cytoreduction. This should be followed by the appropriate chemotherapy based on a platinum–taxane combination. Women with optimally debulked stage III disease who are able to tolerate greater toxicity should be offered a combined i.v.–i.p. approach. During both active treatment and surveillance, women will benefit from effective management of symptoms and side effects of treatment. Finally, women should be encouraged to consider enrollment into prospective clinical trials for which they meet the eligibility criteria.
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AUTHOR CONTRIBUTIONS
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Manuscript writing: Edward L. Trimble, Sharon Thompson, Michaele C. Christian, Lori Minasian
Final approval of manuscript: Edward L. Trimble, Sharon Thompson, Michaele C. Christian, Lori Minasian
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REFERENCES
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Learning Objectives
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