What Drugs Should One Use?
The underlying principles for effective IP therapy have been most clearly articulated by Dedrick and coworkers when introducing it into clinical use,[35] and by Howell in molding its current clinical application. The following factors are taken into account.
Peritoneum Features
The peritoneal membrane has been used for many years for peritoneal dialysis, as a semipermeable membrane allowing exchange between the peritoneal cavity and the mesenteric blood vessels. Depending on the molecular weight, size, and the water solubility, larger-molecular-weight drugs stay longer within the peritoneal cavity while smaller molecules may penetrate the outer cell layers of a tumor more easily, albeit diffusing outside the peritoneum faster. When IP chemotherapy is delivered, however, the drug reaches the tumor both by diffusion via the free tumor surface in the peritoneal cavity, and by capillary flow via the systemic circulation.
Pharmacologic Features
The pharmacological advantage of IP therapy relates to high intraperitoneal concentrations delivered to the tumor, with less systemic toxicity compared with IV administration, often expressed as the ratio between the AUC in the peritoneum and the AUC in plasma. The efficacy of IP therapy depends on the peritoneal/plasma concentration ratio (pharmacokinetics) of the different drugs, their systemic absorption, and the penetration into tumor tissue (limited to a depth of few millimeters [2-9 mm], under the tumor surface). Based on the phase III trials reviewed, the cytotoxic drugs widely used are cisplatin(Drug information on cisplatin), carboplatin(Drug information on carboplatin), and paclitaxel(Drug information on paclitaxel).
Cisplatin is rapidly and well absorbed systemically following IP administration, resulting in 50%–100% of systemic exposure compared with IV administration when comparable doses are given. Otherwise, peak IP concentrations are 10- to 20-fold compared with IV administration and provide very high IP concentrations for locoregional disease within a broad range of clinically effective systemic cisplatin dose-schedules (50–100 mg/m2) for disease outside the abdomen. Dose-limiting toxicity from IP administration is directly related to the systemic effects of cisplatin (myelosuppression, neurotoxicity).
Carboplatin is absorbed following IP administration 2–4 hours after infusion. Miyagi et al compared the pharmacokinetics of carboplatin in IP and IV spaces after IP or IV administration of carboplatin.[36] They demonstrated that 24-h platinum AUC in the serum was exactly the same regardless of IP of IV administration of carboplatin. However, the 24-h platinum AUC in the peritoneal cavity was approximately 17 times higher when carboplatin was administered by the IP route. They suggested that IP carboplatin was feasible as regional therapy and also as systemic chemotherapy. The GOG 158 trial (designed as a noninferiority study) demonstrated that the IV combination of carboplatin AUC 7.5 mg/mL/min plus paclitaxel 175 mg/m2 in a 3-hour infusion was not inferior to the IV combination of cisplatin 75 mg/m2 plus paclitaxel 135 mg/m2 in a 24-hour continuous infusion in terms of PFS and OS in patients with stage III EOC.[37] Because of these results IV carboplatin replaced IV cisplatin, but IP carboplatin has not been compared against cisplatin in the IP setting. One preclinical and one clinical study originally supported the superiority of IP cisplatin over IP carboplatin. The first was an animal model (rats with colon carcinoma) that showed cisplatin was more effective than carboplatin at penetrating into tumor nodules (10-fold more carboplatin than cisplatin was required to obtain comparable intratumoral platinum concentrations).[38] The second was an outdated retrospective study of 65 patients that showed a higher response rate in patients who received IP cisplatin at 100 mg/m2 than those who received IP carboplatin at 200–300 mg/m2.[39] A later retrospective analysis by Fujiwara et al on 165 EOC patients treated with IP carboplatin at doses of < 400 mg/m2 or ≥ 400 mg/m2 alone or in combination with cyclophosphamide(Drug information on cyclophosphamide) or paclitaxel emphasized the importance of IP carboplatin dose-intensity on outcome.[40] The survival time was 24.5 months when the dose of carboplatin was < 400 mg/m2 and 51 months when the dose was ≥ 400 mg/m2. More recently another animal-model study compared the ability of IP cisplatin and IP carboplatin to penetrate into tumor nodules (2–9 mm) of nu/nu mice. Animals were treated with IP cisplatin at 10 mg/kg or equimolar dose of IP carboplatin at 12.4 mg/kg or an equitoxic dose of carboplatin at 85 mg/kg. The platinum tumor concentration was 3.4-fold higher in mice receiving cisplatin than in those receiving the equimolar dose of carboplatin; however, when cisplatin and carboplatin were given at equitoxic doses, the platinum tumor concentration was similar (and even nonsignificantly higher for carboplatin).[41] Based on these data, further clinical trials are reasonable to evaluate IP carboplatin efficacy.
Paclitaxel was deemed an attractive agent for IP administration in ovarian cancer based on the studies performed by the GOG. It has a high molecular weight and bulky structure, resulting in slow clearance from the peritoneal compartment, thus increasing the exposure of tumor in the peritoneal cavity. On the other hand, little is known about penetrance into tumors, and its tendency to form micelles may diminish its availability to tumor cell surfaces. It is metabolized in the liver, which increases the peritoneal/plasma concentration ratio. After IP paclitaxel infusion, the peak peritoneum/plasma concentration ratio is approximately 1,000, and this is maintained for 24–48 hours. Abdominal pain is the dose-limiting toxicity of IP paclitaxel at doses of more than 125 mg/m2.[42-44]
In the preceding section, clinical trials data supporting the use of IP therapy, and specifically IP cisplatin, were reviewed. From the standpoint of toxicity considerations, as well as the added complexity of treatment and the absence of validation beyond a single phase III trial, the case for using IP paclitaxel is less persuasive. The pragmatic approach of one of the authors (FM) in adopting GOG 114 (IV drug administration first, and no IP paclitaxel) as his guiding strategy is reflected in the following clinical vignette:
Clinical vignette 1—In June 2004, the patient, a 61-year-old woman, noted abdominal distension and underwent a workup, including computerized tomography (CT), that confirmed ascites and perihepatic as well as pelvic masses. The CA125 level was 185 U/mL on June 23. On July 20, TAH/BSO (total abdominal hysterectomy/bilateral salpingo-oophorectomy) appendectomy, pelvic lymph node dissection, and debulking were performed. The mass appeared to arise from the right fallopian tube; a cul-de-sac nodule, and tumor involving the surfaces of the diaphragm around the right lobe of the liver, were noted and resected. The right-diaphragm tumor measured 8 × 5.5 × 3.5 cm. The patient was optimally cytoreduced but did not have IP catheter placement. The recommendation in August 2004 was: “off protocol, I prefer early reassessment (at cycle 4) and then insertion of an IP catheter as long as the patient has a clinical complete response. The findings of a negative or positive reassessment then determine the number of cycles to be given as consolidation. She will consider this option in the next few days.” After 4 cycles with excellent tolerance, she underwent laparoscopic placement of an IP catheter. With negative findings, 2 cycles of IP cisplatin 60 mg/m2 were given. Subsequently, she tested positive for BRCA1 mutation. She is well 6 years later.
Therefore, in response to the question “What regimen should one use?,” one of us (FM) would answer the following: if an IP port has been placed and the patient fulfills other criteria for proceeding with IP therapy (no prior treatment, normal renal function), the patient should receive IV paclitaxel at 175 mg/m2 on day 1, followed by IP cisplatin at 75 mg/m2 on day 2. These treatments should be repeated every 21 days and continued for as many as 6 cycles (with appropriate dose adjustment for cisplatin-related nonhematologic toxicities) as long as neuropathy does not exceed grade 1. With grade 2 neuropathy, the paclitaxel should be discontinued. If an IP port has not been placed, my policy would be to administer IV carboplatin plus paclitaxel, and then proceed as indicated in the clinical vignette. Lack of clinical trials (level 1) evidence in such a recommendation is troubling; even more troubling, however, is the inability to formulate an adequate treatment plan for a patient who does not fit into a clinical-trial algorithm. Further thoughts on additional situations in which IP therapy should be considered are explored in the next section.
When Should We Consider IP Drug Administration?
The weight of the evidence supports a favorable effect on outcome with the administration of IP cisplatin. In phase III trials, a favorable outcome has been demonstrated in stage III ovarian cancer that has been cytoreduced to < 2 cm residuum in one trial and < 1 cm in two trials. All utilized IP cisplatin at 100 mg/m2 per cycle to be given over 6 cycles, but completion rates and platinum dose intensity were considerably less in these three trials—nevertheless, they achieved superior results! Toxicity considerations and trials by the IV route suggest that even a reduced dose of IP cisplatin at 50 mg/m2 achieves results comparable to higher doses given to similar total cumulative amounts.[45] Currently, an IP cisplatin dose of 75 mg/m2 could be used in patients who meet the criteria of the previously described debulking characteristics and in whom an IP catheter has been inserted, with the expectation of achieving results similar to those of GOG172.
Suboptimally debulked patients and patients in whom an IP port has not been placed should also be considered for IP therapy after documentation of complete regression by imaging and CA125 after 4 cycles of IV carboplatin plus paclitaxel. A reassessment no later than cycle 4 (and before 6 cycles are administered) may be vastly more satisfactory for consolidating with IP cisplatin, for the following reasons: 1) any advantage from extending IV doublet treatment or even crossing over to other IV drugs beyond 4 cycles has not been proven; 2) all evidence supporting IP treatment suggests it is effective before occurrence of platinum resistance; and 3) if residual peritoneal disease is documented at such reassessment, at least four more cycles of IP therapy could be desirable and for toxicity reasons, very challenging to administer after 6 cycles of IV therapy (and even worse if the patient has received 8 IV cycles, as given by some without any evidence favoring such lengthy treatments).
Should IP therapy be contemplated as consolidation now that IV bevacizumab(Drug information on bevacizumab) maintenance therapy shows an improved PFS after first-line therapy? There is a good preclinical rationale for antiangiogenic agents to potentiate IP drug administration, both for cisplatin and for topotecan(Drug information on topotecan),[46] but there are not enough tolerance studies at present for the safety of this treatment, and one must await the results of GOG252.[45]
Another scenario in which IP therapy might be considered is in the recurrence setting, when the recurrence is peritoneal and is either low-volume disease or can be easily debulked. The initial case series by King et al[47] and several phase II studies point to considering such an intervention under these circumstances. Below we add clinical vignette numbers 2 and 3. Clinical vignette number 2 also shows how drugs that are not effective by the IV route may have activity against peritoneal disease.
Clinical vignette 2—A 68-year-old woman originally diagnosed in 1979 was referred in 1981 to Dr. Stephen Howell, to enroll in an IP cytarabine(Drug information on cytarabine) (ARA-C, Cytosar) protocol.[47] She had just suffered here second recurrence of cytology-positive ascites after a few months in remission following cisplatin-containing regimens. She received 6 cycles of cytarabine, and remained in documented clinical complete remission prior to her death 9 years later from pneumonia complicating Alzheimer’s disease during her last 2 years.
Clinical vignette 3—This woman, mother of two daughters, is now 70 years old. Her initial diagnosis was made in 1992, as stage IIIB high-grade papillary serous cancer following optimal cytoreductive surgery upon demonstration of an elevated CA125 (obtained by her gynecologist at the patient’s request). One year following completion of 6 cycles of caboplatin + cyclophosphamide, she experienced a symptomatic pelvic recurrence with presence of a cul-de-sac mass and pelvic ascites. She underwent surgical resection and insertion of an IP catheter, and entered a phase I study of IP platinums combined with floxuridine.[27] She received 6 cycles of IP cisplatin plus floxuridine and remains well, with no recurrence 16 years after cisplatin plus FUDR.
Finally, patients with synchronous ovarian and uterine primaries and those with uterine papillary serous cancer may also potentially benefit from IP approaches, as illustrated by clinical vignette 4.
Conclusion
The place of IP chemotherapy in the treatment of ovarian cancer continues to be broadly discussed, but few appreciate the many nuances of this wide-ranging debate. For precisely this reason, it is important to emphasize the key role and rationale for IP administration of cisplatin, which may be lost amongst the many concerns about IP drug delivery and its toxicity. Our major premise within this debate is that this successful treatment strategy should be kept simple, to ensure safety while retaining the positive signal coming from the trials reviewed (ie, based on IP cisplatin at doses ranging from 60–75 mg/m2, depending on clinical circumstances and prior exposure to platinum drugs). Of interest, a meta-analysis of treatments for ovarian cancer points to IP therapy as leading to yet another incremental advance.[48,49]
Ongoing clinical trials by the GOG and others will undoubtedly clarify these issues that have been raised, and they hold promise for enhancement in efficacy (eg, by adding bevacizumab) or reductions in toxicity (eg, based on findings with IP carboplatin). The results of these trials are eagerly awaited. In the meantime, IP therapy should be considered on an individual basis in patients who do not qualify for clinical trials. A strategy utilizing IP cisplatin administration is already applicable to many patients, based on the weight of the evidence to date.
Financial Disclosure: The authors have no significant interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
