The Role of Intraperitoneal Therapy in Advanced Ovarian Cancer

Intraperitoneal (IP) chemotherapy is a preferred treatment option that should be offered to all women for front-line treatment of stage III optimally debulked ovarian cancer. Patients should be provided with information on the survival and toxicity for both IP and intravenous (IV) therapies, as well as practical information about the administration of each regimen, so that they may play an active role in the decision-making process. When making a decision between IP and IV therapeutic options, the experience and preference of the oncologist are critical factors in determining appropriate therapy for each woman.

In January 2006, the Gynecologic Oncology Group (GOG) published findings from GOG-172, the third phase III randomized trial of intraperitoneal (IP) cisplatin for the treatment of newly diagnosed, stage III ovarian cancer.[1] The study compared an IP regimen (intravenous [IV] paclitaxel at 135 mg/m² over 24 hours on day 1 + cisplatin at 100 mg/m² IP on day 2 + paclitaxel at 60 mg/m² IP on day 8) to an IV regimen (paclitaxel at 135 mg/m² over 24 hours IV on day 1 + cisplatin at 75 mg/m² IV on day 2) administered every 3 weeks for six cycles. The results of GOG-172 demonstrated a median 65.6-month overall survival associated with intraperitoneal chemotherapy, compared to 49.7 months associated with intravenous therapy (P = .03). These results were consistent with the previous two GOG randomized trials,[2,3] which also demonstrated significantly improved survival associated with intraperitoneal cisplatin-containing treatment regimens.

Concurrent with the publication of GOG-172, the National Cancer Institute issued a clinical announcement[4]-a document that is published only when an intervention that is available to the general public has been found to "substantially improve the survival outcome for a significant number of people with reasonable certainty."[5] Furthermore, this announcement emphasized that the discussion about this procedure should begin with the surgeon prior to debulking surgery, as women should be aware of how surgery may be tailored for subsequent IP therapy.

Following the publication of the GOG-172 trial and the NCI clinical announcement, the oncology and scientific communities have been highly prolific in terms of editorials and commentaries on IP therapy.[6-16] Associated with the publication of GOG-172 were two additional studies related to quality of life and catheter outcomes in that trial.[17,18]

On January 19, 2006, the GOG sponsored a workshop[5] in which the results from the three GOG randomized trials that demonstrated improved survival among patients treated with IP cisplatin (Southwest Oncology Group [SWOG]-8501/GOG-104,[2] GOG-114,[3] and GOG-172[1]) were discussed in detail. Information was also presented on practical issues, such as toxicity management, patient quality of life, controversies about IP therapy, surgical and administrative guidelines, catheter placement, and nursing issues. The GOG website contains the workshop recording, surgical training videos, and other educational materials to facilitate the implementation of IP therapy.[19]

Similarly, the SWOG issued a press release[20] and sponsored a training workshop during their October semiannual meeting to further educate the oncology community about IP therapy. The reports of these workshops provide further details about the history, rationale for, and implementation of IP therapy.[5,21] The details of this body of knowledge will not be repeated here, but readers are encouraged to refer to the GOG and SWOG training and workshop materials.

Overall, these resources demonstrate the following key points: The scientific evidence supports the use of IP therapy, and opportunities for education and training are available to ensure its safe administration. IP therapy has been evaluated since the 1970s, and it has reached a point in its development where there is sufficient scientific evidence for it to be safely offered.

Despite the data demonstrating improved survival outcomes and a manageable toxicity profile, IP therapy is not routinely offered as a treatment option to all patients for the front-line treatment of optimally debulked stage III ovarian cancer. Although institutions and providers develop practice patterns and favored treatment regimens for a variety of reasons, substantial evidence supports two primary reasons why IP therapy is a treatment regimen that must be offered to all patients with optimally debulked, stage III disease: the data demonstrating improved survival and the patient's right to informed choice. These should be balanced by providing patients with the toxicity profile and practical considerations of IP therapy.

Improved Survival

The GOG-172 IP regimen demonstrated the longest median survival-65.6 months, compared to 49.7 months in the IV control group-of any randomized study of primary chemotherapy for advanced ovarian cancer to date.[1] The relative risk of death was 0.75 (95% confidence interval [CI] = 0.58-0.97, P = .03) for IP therapy compared to those treated with IV paclitaxel (135 mg/m² over 24 hours) plus IV cisplatin (75 mg/m²), which translates to a 25% reduction in the risk of death among those treated via IP administration in this study. This 16-month improvement in survival is impressive, particularly considering the fact that only 42% of patients enrolled in the IP treatment arm received all six courses of planned IP therapy. Progression-free survival was 18.3 months in the IV treatment group and 23.8 months in the IP treatment group (P = .05).

The magnitude of the improvement in survival has been surrounded by controversy, primarily related to the fact that the GOG-172 IP regimen was not directly compared with the current standard IV carboplatin-plus-paclitaxel regimen. However, GOG-158 demonstrated nonsignificant differences in survival between IV carboplatin plus paclitaxel and IV cisplatin plus paclitaxel.[22] Compared to the GOG-158 IV carboplatin-plus-paclitaxel regimen, the GOG-172 IP regimen demonstrated approximately a 9-month median survival improvement (or a 19% improvement in the risk of death).[6] Although such cross-comparisons with historical controls lack the validity of a prospective trial,[6] these do represent the two viable front-line treatment options that should be presented to stage III ovarian cancer patients. Furthermore, GOG-158 and GOG-172 were contemporary trials, conducted among similar populations and with similar study designs through the GOG.

Toxicity of IP vs IV Therapy

The significant improvement in overall survival associated with IP therapy is not without cost. Although patient-reported quality of life was equivalent among patients treated with IV vs IP therapy 1 year following completion of treatment,[18] the GOG-172 IP regimen does produce a short-term impact on quality of life and a greater chance that the patient will experience toxicity. Specifically, patients randomized to receive IP therapy experienced greater grade 3/4 pain (11% vs 1%), fatigue (18% vs 4%), leukopenia (76% vs 64%), infection (16% vs 6%), and platelet (12% vs 4%), gastrointestinal (46% vs 24%), metabolic (27% vs 7%), and neurologic toxicities (19% vs 9%) than those randomized to IV therapy. However, the study showed no differences in treatment-related deaths between groups-four deaths occurred in the IV group and five in the IP group, all of which were related to infection.[1] However, a recent meta-analysis demonstrated that across IP cisplatin trials, only fever and gastrointestinal toxicity were significantly higher among those treated IP, whereas ototoxicity was significantly higher among those treated IV.[23]

IP therapy also produces a different toxicity profile than the current IV carboplatin-plus-paclitaxel regimen (Table 1). Each of these toxicities is manageable and short-term in nature. Current and planned research is largely focused on reducing the toxicities associated with the GOG-172 IP treatment regimen to improve acceptability and to increase the proportion of patients who are able to complete the full course of treatment.[21]

It is now standard practice to reduce the 24-hour infusion of paclitaxel to 3 hours to reduce the myelosuppressive activity of the agent[21,24] and to allow for administration in an outpatient setting. The rationale for reducing the IV paclitaxel infusion time is based on the regimen used in GOG-158,[22] which tested a 24-hour infusion of paclitaxel (plus carboplatin), but which is now used in practice as a 3-hour infusion of paclitaxel (plus carboplatin), with no evidence of an impact on outcome.

Practical Considerations

For a variety of practical reasons, IP cisplatin therapy may not be appropriate for every patient. Foremost among these considerations are travel requirements, as the GOG-172 regimen necessitates patient visits to the infusion room on days 1, 2, and 8 of every 21-day treatment cycle, as opposed to a single infusion room visit with IV carboplatin and paclitaxel therapy in the same 21-day cycle. Delivery of IP therapy does require additional training, but this can be gained through available training modules and by having experienced physicians provide guidance to gynecologic oncology fellows and physicians new to the therapy. Physicians who have not been trained in IP therapy are nevertheless obliged to discuss this option with patients and, should a patient prefer this modality, to refer her to experienced colleagues.

As stated earlier, more than half of the patients were unable to complete the prescribed six cycles of IP therapy in GOG-172; the mean number of IP cycles completed was 3.7, compared with a mean of 5.4 among those treated with IV therapy.[24] Of the 205 eligible patients randomized to IP therapy, 20% discontinued treatment due to catheter complications; 9% refused IP therapy; 8% discontinued therapy due to nausea, vomiting, or dehydration; and 7% stopped due to renal/metabolic toxicity.[17] The primary catheter complications included infection (n = 21), blockage (n = 10), leakage (n = 3), and port access problems (n = 5). Of note, seven patients who had catheter-related problems were able to have the device replaced, and four of these seven were then able to successfully complete IP therapy.[17] The timing of catheter placement was not associated with completion of IP therapy; 37% of patients who had catheters placed during surgery and 41% of patients who had delayed catheter placement were able to complete all six cycles of IP therapy. (Data regarding timing of catheter placement were not available for 23 patients.)[17]

These considerations must be discussed with patients considering IP therapy. Moreover, such findings demonstrate the need for improvements in catheter placement. A video presentation illustrating appropriate intraperitoneal catheter placement is available at the GOG website.[19] Since the discontinuation of peritoneal catheters (ie, those with outlet holes along the length of the catheter) over the past 15 years, the catheter complication rate has largely disappeared. Consideration should be given to the placement of the IV catheter into the intraperitoneal space to avoid fibroblast proliferation and sheath formation that occurs along the length of standard IP catheters.

Informed Choice

A growing body of scientific evidence demonstrates improved outcomes, patient-provider relationships, and satisfaction associated with the patient's ability to make an informed choice.[25-29] Certainly, ovarian cancer patients are offered clinical trials and are provided with information about treatment alternatives if research protocols are available. This same informed choice should be available for these women to choose IV or IP therapy; patient choice should not be limited to experimental therapies.

There are two extremes to decision-making, neither of which are recommended. The first is the directive model of the past, in which the physician makes decisions for the patient who is expected to comply. In the alternative situation, the physician provides information on alternatives and leaves the decision to the patient.[30] On the one extreme, the patient has no voice in her care, but on the other, the patient has full responsibility for care in the absence of the expertise of the physician-a situation that has been termed "abandonment."[31]

A study of more than 200 cancer patients found that patients who have a role in decision-making were the most satisfied with their care, whereas those in situations in which either the physician or patient made health-care decisions exclusively were the least satisfied with their care.[32] Evidence across medical conditions confirms that patient involvement in care decisions is associated with higher satisfaction.[26,29] In addition, patients with chronic illnesses who have an active role in decisions about their care have demonstrated improved outcomes.[26] Increasing participation in the decision-making process may improve hope for a favorable outcome among cancer patients,[25] as demonstrated by improved psychosocial outcomes and adjustment during cancer care.[27,28] Although a patient's selection of IV or IP therapy may not always agree with physician recommendations, the importance of including patients in decisions about their care cannot be understated.

What Should Be Offered and to Whom

It is important to note that the large phase III trials demonstrating significant improvement in survival were trials of IP cisplatin; the most recent study, GOG-172, added IP paclitaxel to the regimen. The regimens used in the large phase III trials (SWOG-8501/GOG-104, GOG-114, and GOG-172) were developed over many years with a sequential series of carefully planned preclinical, pharmacokinetic, phase I and II trials to evaluate safety and efficacy data prior to being evaluated in the phase III trial setting.[33-39]

IP therapy, while theoretically having a sound foundation for clinical efficacy,[37] has not been demonstrated for the wide range of available antineoplastic drugs. Not every drug is a suitable candidate for IP delivery. The pharmacokinetic and pharmacodynamic properties of drugs differ, and the findings of previous randomized trials do not directly translate to the intraperitoneal use of other drugs or regimens. Investigation of the IP administration of other chemotherapeutics, such as mitoxantrone and doxorubicin, has revealed excessive toxicity and insufficient response to justify additional research.[38,40-43]

In the IV setting, carboplatin and cisplatin have demonstrated similar survival outcomes when combined with paclitaxel,[22] but their equivalency has not been demonstrated with IP administration to date. The pharmacokinetics of IP carboplatin are not identical to those of IP cisplatin.[44-48] Early-phase trials have suggested the safety and efficacy of IP carboplatin,[49-51] and research is ongoing to assess the potential future use of this agent by the intraperitoneal route. Sufficient prospective, randomized phase III randomized trial survival data must be available before agents other than cisplatin plus paclitaxel can be recommended for intraperitoneal delivery outside of a clinical trial.

Additionally, all clinical research is plagued with the efficacy vs effectiveness dilemma. Clinical trials are designed to demonstrate efficacy, or whether a treatment can work. Despite the best efforts to provide diversity, patients who participate in clinical trials tend to be a highly selected and homogeneous population. Therefore, the information obtained in clinical trials may not be applicable to individuals who vary from the study population. Effectiveness, on the other hand, is demonstrated by results in the general population outside of a clinical trial. Trials of intraperitoneal therapy for ovarian cancer are no exception to this dilemma. SWOG-8501/GOG-104,[2] GOG-114,[3] and GOG-172[1] tested IP therapy in relatively homogeneous populations. The eligibility criteria for GOG-172 are presented in Table 2. As the IP strategy is used to treat patients who significantly deviate from these requirements, the effectiveness of such therapy may be compromised.

One of the key considerations in the selection of patients who should be offered IP therapy is the amount of residual disease following surgery. The proposed mechanism of IP therapy is the destruction of cancer cells, layer by layer, with each subsequent infusion. Patients with more than 1 cm of residual disease have not been shown to benefit from IP therapy, as six cycles of treatment cannot penetrate bulky disease or be adequately dispersed in the abdominal cavity with the presence of intra-abdominal adhesions.[53-56] In addition, the use of IP therapy has not demonstrated significant improvement in survival among patients being treated for recurrent disease.[56,57] Thus, current research can only recommend IP cisplatin-based therapy for the front-line treatment of patients with optimally debulked disease.

Conclusions

IP cisplatin-based therapy is a preferred treatment option for the front-line treatment of optimally debulked, stage III ovarian cancer patients. IP therapy may not be the right treatment for all patients, but for patients in this particular situation, physicians have the obligation to offer IP therapy as a viable treatment choice and to allow patients to make informed decisions about their care. Providing patients with the option of IP therapy and unbiased information on the survival and toxicity differences between IP vs IV therapy, while still providing one's opinion and preference for care, is essential to empowering patients to make an informed choice.

Disclosures:

This work was supported in part by grant CA-23074 from the National Cancer Institute and the Better Than Ever Research Fund at the Arizona Cancer Center. The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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