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© 2003 American Society for Clinical Oncology Role of Intraperitoneal Chemotherapy in the Front-Line SettingFrom the Cleveland Clinic Taussig Cancer Center and the Department of Hematology/Medical Oncology, The Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Maurie Markman, MD, Department of Hematology/Medical Oncology (R-35), The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; email: markmam{at}ccf.org.
During the last several decades, clinical investigators have confirmed the safety and pharmacokinetic advantage associated with the intraperitoneal delivery of a number of antineoplastic agents with known activity in ovarian cancer. Phase II experience has revealed that objective responses, including surgically documented complete remissions, can occur when regional drug delivery is used as second-line treatment of this malignancy. Three randomized trials have shown that when cisplatin-based intraperitoneal treatment is used in the front-line setting, it results in superior progression-free and overall survival compared with intravenous cisplatin. Despite these facts, an ultimate role for regional drug delivery as initial treatment of ovarian cancer will require additional trials to define how to optimize the use of this unique therapeutic strategy.
THE CONCEPT of regional drug delivery in the treatment of ovarian cancer has been investigated for more than four decades.1 Multiple phase I and II trials have revealed the safety, pharmacokinetic advantage, and opportunity for intraperitoneal drug delivery to be associated with a favorable clinical outcome.2,3 Surgically defined responses, including complete remissions, have been noted when ovarian cancer patients are treated with a variety of second-line (mostly cisplatin-based) regional treatment regimens.3–6 In addition, several centers have documented the potential for long-term survival (> 3 to 5 years) after the use of cisplatin-based intraperitoneal therapy in this clinical setting.7–10 Unfortunately, until recently, this area of clinical investigation has been characterized by the striking absence of phase III randomized trials that directly compare systemic with regional drug delivery. The critical questions to be asked are as follows: Can the higher concentrations of cytotoxic drugs and longer durations of exposure achievable within the peritoneal cavity after intraperitoneal treatment be translated into an improved clinical outcome (eg, longer survival and less toxicity)? Will the additional cost, time, and effort, as well as the unique side effects (eg, abdominal pain and infections), associated with regional therapy negate any benefits documented in well-designed and well-conducted randomized trials? Both experimental data and phase II clinical trial experience have demonstrated a major limitation in the potential patient populations to be considered for entry onto such trials. Despite the high concentrations of drugs measurable within the peritoneal cavity after regional treatment, several model systems revealed that the actual depth of penetration of the agents directly into tumor (or healthy) tissue was extremely limited (ie, several cell layers to < 1 mm from the surface).11–13 Furthermore, in phase II trials of second-line intraperitoneal chemotherapy, patients whose largest tumor mass was estimated to be more than 1 cm in diameter rarely exhibited an objective response; the greatest opportunity for surgically documented biologic activity was seen in women with microscopic or small-volume macroscopic residual cancer (eg, largest tumor mass < 0.5 cm in maximum diameter).4 As a result of this experience, when randomized intraperitoneal chemotherapy trials were initiated in front-line treatment of ovarian cancer, the eligible patient population was restricted to those individuals with relatively small-volume residual disease after an attempt at maximal surgical cytoreduction.
A landmark study, conducted by the Southwest Oncology Group and the Gynecologic Oncology Group (GOG), initiated in the mid 1980s and published in 1996, compared a regional cisplatin-based approach with one of the standard intravenous chemotherapy regimens used during this period.14 The trial used intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide as initial treatment of small-volume residual advanced ovarian cancer. The size of the largest residual tumor nodule permitted after initial cytoreductive surgery was 2 cm. The doses of intravenous and intraperitoneal cisplatin delivered in the trial were identical (100 mg/m2), as was the amount of intravenous cyclophosphamide (600 mg/m2). Patients received a maximum of six treatment courses delivered once every 3 weeks. Overall, there were limited differences in the degree of toxic effects experienced by women treated with regional or systemic drug delivery. However, the intraperitoneal treatment program was associated with a statistically significant reduction in the incidence of neutropenia and tinnitus. Not surprisingly, this method of drug delivery was found to produce more abdominal discomfort. However, the pain was generally only mild or modest in severity, was self-limited, and rarely interfered with the continuation of treatment. Of greatest interest, patients treated with intraperitoneal cisplatin experienced a statistically significant improvement in overall survival (median, 49 v 41 months; P = .02). The risk hazard ratio was 0.76, indicating a 24% reduction in the risk of death, in favor of the regional treatment program. In addition, although it is difficult to directly compare the results of treatment for different diseases in determining the relative value of a particular treatment approach, the level of risk reduction documented in this intraperitoneal chemotherapy trial approximates that observed when tamoxifen is administered as adjuvant treatment of breast cancer.15 Despite the highly favorable outcome of the previously discussed trial, the results were largely ignored by the oncology community because the trial (which was initiated in the 1980s) did not include paclitaxel.16 Some argued that if all patients had received paclitaxel (in addition to cisplatin), any benefit associated with regional drug administration would have disappeared. Thus, it became important to perform a second randomized trial comparing intraperitoneal with intravenous cisplatin, with all patients also receiving paclitaxel by the systemic route.17 This trial used moderately high-dose carboplatin followed by intraperitoneal cisplatin plus intravenous paclitaxel versus intravenous cisplatin plus intravenous paclitaxel. In this new study, the size of the largest residual tumor mass after surgical resection had to be less than 1 cm in maximum diameter. This trial, conducted by the GOG, the Southwest Oncology Group, and the Eastern Cooperative Oncology Group, added another concept to the simple substitution of regional delivery for systemic delivery of cisplatin.17 As noted previously, preclinical and clinical data had strongly indicated that the optimal patient to take advantage of the extremely high concentrations of cytotoxic drug within the peritoneal cavity after intraperitoneal therapy would be one with the smallest amount of gross residual disease present when this management approach was initiated. Thus, it was argued, if several cycles of moderately dose-intensive systemic chemotherapy were delivered before intraperitoneal treatment to cytoreduce the residual volume of disease chemically, regional therapy could prove to be more effective.18 Therefore, in this trial, patients in the experimental arm received two courses of single-agent intravenous carboplatin (area under the curve, 9) before intraperitoneal cisplatin (100 mg/m2) and intravenous paclitaxel (135 mg/m2 for 24 hours) were initiated. Individuals randomly assigned to the control study arm received intravenous cisplatin (75 mg/m2) plus intravenous paclitaxel (135 mg/m2 for 24 hours). Unfortunately, the initial two systemic chemotherapy courses proved to produce excessive bone marrow suppression, particularly thrombocytopenia, such that 18% of patients randomly assigned to the regional delivery arm actually received two or fewer treatment cycles delivered by this route. This was not because of any direct toxic effects of intraperitoneal treatment, but rather because of persistent bone marrow suppression. Despite this fact, patients randomly assigned to the regional program experienced a statistically significant improvement in both progression-free survival (28 v 22 months; P = .01) and overall survival (63 v 52 months; P = .05). Of note, the risk hazard ratio in this trial was 0.78 for progression-free survival and 0.81 for overall survival, both in favor of regional therapy. The striking similarity of this outcome to the previously noted front-line intraperitoneal cisplatin study14 provides strong support for the validity of these results. The second randomized intraperitoneal chemotherapy trial, although confirming the clinical utility of regional drug delivery as initial treatment of ovarian cancer, could not be considered a new standard of care because of its unfavorable systemic toxicity profile. In addition, emerging data indicated that it was also important to consider the use of intraperitoneal paclitaxel (along with intraperitoneal cisplatin), on the basis of the known activity of the drug in ovarian cancer and its safety and pharmacokinetic advantage (eg, 1,000-fold increased exposure to the cavity compared with the systemic compartment) after regional delivery.19–21 Thus, a third randomized front-line chemotherapy trial examining intraperitoneal delivery in ovarian cancer was initiated.22 In this study, conducted by the GOG, patients in the experimental arm were treated with intravenous paclitaxel (135 mg/m2 for 24 hours day 1) plus intraperitoneal cisplatin (100 mg/m2 day 2) and intraperitoneal paclitaxel (60 mg/m2 day 8). Treatment was repeated on an every-21-day cycle. The control study arm received intravenous cisplatin (75 mg/m2) plus paclitaxel (135 mg/m2 for 24 hours) on an every-21-day cycle. The preliminary results of this trial were presented at the 2002 Annual Meeting of the American Society of Clinical Oncology (Orlando, FL, May 18–21, 2002).22 Although the combined intraperitoneal/intravenous approach was associated with greater toxicity, an observed improvement in progression-free survival (relative risk of recurrence, 0.73) was again associated with this management approach compared with systemic drug delivery alone. An update on this trial, particularly information regarding the effect of treatment on ultimate survival, is awaited with great interest.
On the basis of the available data, it is difficult (if not impossible) to continue to ignore the use of the intraperitoneal route of drug delivery as a viable management option for initial treatment of small-volume residual advanced ovarian cancer. All three reported randomized trials that examined this issue have shown an improvement in the end points of progression-free survival, overall survival, or both. Although it is appropriate to argue that an optimal management strategy using the intraperitoneal route of drug delivery has not been defined, this fact and the previously described survival data should stimulate greater research efforts in this area. One logical approach would be to attempt to substitute carboplatin for cisplatin in an effort to reduce the significant systemic toxicity associated with the older platinum compound.23,24 Carboplatin has been examined for intraperitoneal use and has a documented pharmacokinetic advantage for cavity exposure similar to that of cisplatin.25,26 Regional delivery of carboplatin causes minimal local effects, and the dose-limiting toxic effects are (as with cisplatin) systemic (eg, bone marrow suppression). In addition, objective responses, including surgically documented complete responses, have been noted when intraperitoneal carboplatin is administered in the second-line setting to patients with ovarian cancer.27,28 Two minor caveats should be noted regarding the regional delivery of carboplatin. First, one preclinical system that modeled the use of intraperitoneal therapy found that the concentration of platinum within tumor cells was greater when cisplatin, rather than carboplatin, was used.29 Second, in a retrospective review of several nonrandomized, second-line intraperitoneal chemotherapy trials for ovarian cancer conducted at a major cancer center, it was suggested that patients with any residual macroscopic tumor at the initiation of treatment had a greater chance of achieving a surgically documented complete response when treated with cisplatin than with carboplatin.30 In contrast, patients who began therapy with only microscopic disease had the same objective response rate, regardless of which platinum agent was used. One hypothesis to explain this observation is that cisplatin is able to penetrate deeper into tumor tissue than carboplatin. However, only the conduct of a well-designed randomized trial (comparing intraperitoneal carboplatin with intraperitoneal cisplatin) will permit an appropriate evaluation of the clinical relevance of these observations. Such a study is urgently needed. In conclusion, despite the substantial delay in the initiation of definitive trials that examine a role for intraperitoneal therapy as front-line treatment of ovarian cancer, the verdict finally seems to be in. The concept is clinically valid, and intraperitoneal drug delivery should be considered a rational, noninvestigative, front-line therapeutic option in this clinical setting. Unfortunately, it is currently not possible to define an optimal front-line intraperitoneal drug regimen for the management of small-volume residual advanced ovarian cancer. Although the use of intraperitoneal cisplatin is reasonable, when delivered with systemic paclitaxel, this therapy produces significant systemic toxic effects. It would be rational to consider using a lower dose of cisplatin (eg, 75 mg/m2 rather than 100 mg/m2), which would certainly result in a more favorable treatment-related side-effect profile. This would also seem to be an appropriate strategy considering extensive randomized trial data that refute the clinical relevance of platinum dose-intensity in the initial management of ovarian cancer.31–36 As noted herein, substituting intraperitoneal carboplatin for intraperitoneal cisplatin would be another alternative, but randomized trial data using this agent by the regional route of drug delivery are currently lacking. The answer to this clinical dilemma, however, is clear. There is a critical need for the conduct of additional high-quality randomized trials that explore intraperitoneal therapy in the front-line management of ovarian cancer.
DR. CANNISTRA: Is there any concern that detection of relapse within the peritoneum after intraperitoneal therapy is compromised compared to systemic treatment? Are you inducing more fibrosis or are you inducing other changes on the CT that lead to an inability to detect relapse as early? DR. MARKMAN: I don't know of any data to that effect. DR. CANNISTRA: In Dr. Markman's most recent randomized IP trial, there was a modest trend towards improved overall survival in favor of the IP arm [J Clin Oncol 19:1001-1007, 2001]. However, this difference was of borderline statistical significance with a one-tail t test. Many statisticians have argued that the best way to analyze these randomized data is with a two-tailed t test, especially since toxicity may be increased in your experimental arm to the point where it could have been deleterious. So if you do that, the P value becomes nonsignificant, and the effect of IP therapy on overall survival is not clearly demonstrated. DR. MARKMAN: Statisticians do not like using P values in this setting. They want to look at the risk hazard ratios, because if we had doubled the number of patients and we had the same outcome, the P value would have looked a lot better. The risk hazard ratio would not have changed. DR. VASEY: I wonder if the recurring theme is the systemic delivery of platinum, because if you look at the second study where you get the AUC of 9 delivered, and there's an advantage there, these patients get more platinum. DR. MARKMAN: I agree it's delivering more platinum, but I don't think it's systemically. It is delivery of therapy, but it's got to also have something to do with regional delivery. DR. VASEY: But the IP arms are significantly more toxic systemically [Proc Am Soc Clin Oncol 21:201A, 2003]. Therefore, it's a systemic effect. DR. MARKMAN: In the first study, it was 100 mg/m2 versus 100 mg/m2, IV and IP. DR. McGUIRE: The IV was more toxic. DR. CANNISTRA: The most important issue is that we now have a long heritage of randomized trials asking the dose intensity question using systemically administered platinum, and the majority of these trials are negative [Classic Papers series, J Clin Oncol 7:1-4, 2002]. It's not a strong testimony to the rationale of providing increased dose intensity through the IP route. DR. MARKMAN: What improvement would you have to see to alter the standard of care and the treatment? DR. CANNISTRA: A convincing difference in overall survival and/or quality of life, compared to our current standard of care (intravenous paclitaxel and carboplatin). DR. MARKMAN: So is 20% enough? DR. CANNISTRA: Yes, if a statistically significant improvement can be demonstrated in overall survival with an acceptable toxicity profile. If only disease-free survival was improved in the absence of an overall survival benefit, then I would at least need to see a convincing improvement in quality of life. DR. MARKMAN: This gets into issues of consolidation therapy and quality of life. I would argue that the issue of toxicity would be secondary in a setting where we are talking about a true impact on survival and the issues of quality of life. Obviously, if you say to a patient, you're going to experience significant toxicity but you're going to live longer, I think that the patient will say that's okay. But if you say you're going to experience significant toxicity, and all we're going to do is prolong the time before you develop symptoms and you're going to live the same amount of time, then that's an entirely different question. DR. BEREK: Most of the chemotherapists where I reside simply don't want to be troubled with putting in catheters and they certainly don't want to give platinum in any form other than carboplatin. I think it becomes a moot point, unless one shows an absolute survival advantage. DR. MARKMAN: That's why I asked how much of an advantage do you have to show to make it worth it. DR. BEREK: I think for most people in the community, they want at least 20% percent and they want it to be meaningful and durable. DR. McGUIRE: There are also two issues in terms of the theory behind IP therapy. First, the fact that you can show 1 to 3 log changes in peritoneal to plasma ratios doesn't say anything about what the tumor cell receives. There are studies with carbon 14-labeled carboplatin that show penetration is minuscule [Cancer Chemother Pharmacol 28:159-195, 1991]. Second, we know in stage III disease that at least 40% of those patients have retroperitoneal disease [Gynecol Oncol 65:467-472, 1997; Gynecol Oncol 51:150-154, 1993]. So I still fail to understand how intraperitoneal therapy is more effective in treating retroperitoneal disease than intravenous therapy. DR. MARKMAN: It isn't. DR. BAST: I guess along the same lines, you might predict that you could change the pattern of recurrence if you're really being more effective against intraperitoneal disease. Is there any evidence from the three major studies that have been done that you've changed the pattern of recurrence for extraperitoneal disease? [J Clin Oncol 10:706-717, 1992; Proc Am Soc Clin Oncol 21:201a, 2002; J Clin Oncol 19:1001-1007, 2001]. DR. MARKMAN: No, but when you give a drug like platinum that gets into the systemic compartment, there should be no disadvantage to the retroperitoneum. There certainly would be no advantage of doing it, but there shouldn't be any disadvantage. DR. BOOKMAN: I wanted to return to the issue of the biology of the peritoneal cavity. We know that it's a different milieu in terms of cytokines, growth factors, angiogenesis, and a variety of other biologic parameters that no doubt are related to why this disease grows and behaves the way it does. Approaching that with intraperitoneal platinum and paclitaxel is like using a sledgehammer with no rhyme or reason. It's far more likely that you're changing the biology of the peritoneum rather than having direct cytotoxic effects for all the reasons that have been mentioned. In addition, we know that there are adhesions, loculations, and areas where even in an ideal peritoneal cavity you're not going to get 100% tumor exposure for these approaches, particularly several months after their initial laparotomy. Clearly, there's a change in the peritoneal cavity after this type of therapy. It's not a cytotoxic effect. It's a question of biology.
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17. Markman M, Bundy BN, Alberts DS, et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: An intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19:1001–1007, 2001 18. Shapiro F, Schneider J, Markman M, et al: High-intensity intravenous cyclophosphamide and cisplatin, interim surgical debulking, and intraperitoneal cisplatin in advanced ovarian carcinoma: A pilot trial with ten-year follow-up. Gynecol Oncol 67:39–45, 1997[CrossRef][Medline]
19. Markman M, Rowinsky E, Hakes T, et al: Phase I trial of intraperitoneal taxol: A Gynecologic Oncology Group study. J Clin Oncol 10:1485–1491, 1992 20. Francis P, Rowinsky E, Schneider J, et al: Phase I feasibility and pharmacologic study of weekly intraperitoneal paclitaxel: A Gynecologic Oncology Group pilot study. J Clin Oncol 13:2961–2967, 1995[Abstract] 21. Markman M, Brady MF, Spirtos NM, et al: Phase II trial of intraperitoneal paclitaxel in carcinoma of the ovary, tube, and peritoneum: A Gynecologic Oncology Group study. J Clin Oncol 16:2620–2624, 1998[Abstract] 22. Armstrong DK, Bundy BN, Baergen R, et al: Randomized phase III study of intravenous paclitaxel and cisplatin versus intravenous paclitaxel, intraperitoneal cisplatin and intraperitoneal paclitaxel in optimal stage II epithelial ovarian cancer: A Gynecologic Oncology Group trial (GOG 172). Proc Am Soc Clin Oncol 21:201a, 2002 (abstr)
23. Alberts DS, Green S, Hannigan EV, et al: Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: Final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 10:706–717, 1992
24. Swenerton K, Jeffrey J, Stuart G, et al: Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: A randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 10:718–726, 1992 25. DeGregorio MW, Lum BL, Holleran WM, et al: Preliminary observations of intraperitoneal carboplatin pharmacokinetics during a phase I study of the Northern California Oncology Group. Cancer Chemother Pharmacol 18:235–238, 1986[Medline] 26. Elferink F, van der Vijgh WJF, Klein I, et al: Pharmacokinetics of carboplatin after intraperitoneal administration. Cancer Chemother Pharmacol 21:57–60, 1988[Medline] 27. Speyer JL, Beller U, Colombo N, et al: Intraperitoneal carboplatin: Favorable results in women with minimal residual ovarian cancer after cisplatin therapy. J Clin Oncol 8:1335–1341, 1990[Abstract] 28. Pfeiffer P, Bennedbaek O, Bertelsen K: Intraperitoneal carboplatin in the treatment of minimal residual ovarian cancer. Gynecol Oncol 36:306–311, 1990[CrossRef][Medline] 29. Los G, Verdegaal EME, Mutsaers PHA, et al: Penetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy. Cancer Chemother Pharmacol 28:159–165, 1991[CrossRef][Medline] 30. Markman M, Reichman B, Hakes T, et al: Evidence supporting the superiority of intraperitoneal cisplatin compared to intraperitoneal carboplatin for salvage therapy of small volume residual ovarian cancer. Gynecol Oncol 50:100–104, 1993[CrossRef][Medline] 31. Gore M, Mainwaring P, A’Hern R, et al: Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer: London Gynaecological Oncology Group. J Clin Oncol 16:2426–2434, 1998[Abstract]
32. Wrigley E, Weaver A, Jayson G, et al: A randomised trial investigating the dose intensity of primary chemotherapy in patients with ovarian carcinoma: A comparison of chemotherapy given every four weeks with the same chemotherapy given at three week intervals. Ann Oncol 7:705–711, 1996
33. McGuire WP, Hoskins WJ, Brady MF, et al: Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 13:1589–1599, 1995
34. Jakobsen A, Bertelsen K, Andersen JE, et al: Dose-effect study of carboplatin in ovarian cancer: A Danish Ovarian Cancer Group study. J Clin Oncol 15:193–198, 1997
35. Conte PF, Bruzzone M, Carnino F, et al: High-dose versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin in suboptimal ovarian cancer: A randomized study of the Gruppo Oncologico Nord-Ovest. J Clin Oncol 14:351–356, 1996 36. Repetto L, Pace M, Mammoliti S, et al: The impact of received dose intensity on the outcome of advanced ovarian cancer. Eur J Cancer 29A:181–184, 1993[CrossRef] Submitted January 10, 2003; accepted February 28, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
