lntraperitoneal Chemotherapy in the Management of Ovarian Cancer

Transcription

1 1565 lntraperitoneal Chemotherapy in the Management of Ovarian Cancer Maurie Markman, M.D.,* Bonnie Reichman, M.D.,* Thomas Hakes, M.D.,* John Curtin, M.D.,t Walter Jones, M.D.,t John L. Lewis, Jr., M.D.,t Richard Barakaf, M.D.,t Stephen Rubin, M.D.,t Boys Mychalczak, M.D.,$ Pafricia Saigo, M.D.,tj Lois Almadrones, R.N.,t and William Hoskins, M.D.t During the past decade, intraperitoneal therapy of ovarian cancer has evolved from a pharmacologic model into an established treatment technique for women with this malignancy. Approximately 40% of patients with smallvolume residual ovarian cancer (microscopic disease or macroscopic tumor, cm in maximum tumor diameter), after an objective response to initial organoplatinum-based systemic chemotherapy, may have a surgically documented complete response to platinum-based intraperitoneal chemotherapy. Patients who have not responded to systemic platinum administration rarely will respond to the drug given intraperitoneally, despite the presence of only small-volume residual disease when this regional treatment strategy is used. Other agents with antineoplastic activity after intraperitoneal administration in women with ovarian cancer include mitoxantrone, taxol, alpha-interferon and gamma-interferon, and interleukin-2. Although intraperitoneal therapy currently is being examined as a component of the initial chemotherapeutic program for patients with ovarian cancer, a precise role for regional drug delivery in this clinical setting remains to be defined. Cancer 1993; 71: Key words: intraperitoneal chemotherapy, cancer chemotherapy, ovarian cancer, cisplatin. Presented at the National Conference on Gynecologic Cancers, Orlando, Florida, April 2-4, From the *Breast/Gynecology Service, tdivision of Solid Tumor Oncology, Department of Medicine, the Gynecology Service, $Department of Surgery, the Department of Radiation Oncology, and of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. Supported in part by the Avon Program in Ovarian Cancer, Memorial Sloan-Kettering Cancer Center (New York, New York) and National Cancer Institute grant CA (Bethesda, Maryland). Address for reprints: Maurie Markman, M.D., Department of Hematology/Oncology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH Accepted for publication September 2, In 1978, a group at the National Cancer Institute published an article in which it was suggested that the intraperitoneal administration of certain antineoplastic agents could result in significantly increased exposure of tumor present in the peritoneal cavity of patients with ovarian cancer compared with that of systemic administration.' This hypothesis, which was based on known characteristics of specific cytotoxic agents and previously reported features of the cavity itself, was found to describe accurately the pharmacokinetics of these drugs when they are administered directly into the peritoneal cavity (Table 1). During the past decade, much has been learned of both the advantages and limitations of intraperitoneal drug delivery in the treatment of ovarian cancer. In this review, the current state of intraperitoneal therapy in ovarian cancer will be outlined, followed by a discussion of the instances in which this therapeutic strategy might be considered an appropriate option outside the study setting and the direction in which future research efforts using regional drug delivery will need to be directed. Limitations of lntraperitoneal Therapy in the Management of Ovarian Cancer As Table 1 shows, the peritoneal cavity can be exposed to fold higher concentrations of certain cytotoxic agents after intraperitoneal drug delivery than would be measured in the systemic circulation. Because the antineoplastic activity of various drugs active in ovarian cancer is concentration dependent in experimental systems, these two findings suggest that intraperitoneal drug administration may result in greater tumor cell kill than can be achieved after systemic drug delivery.* Unfortunately, several factors seriously limit the potential clinical application of this innovative treat-

2 1566 CANCER Supplement February 25, 2993, Volume 71, No. 4 Table 1. Pharmacokinetic Advantage Associated With Intraperitoneal Antineoplastic Drug Delivery Agent Cisplatin Carboplatin Doxorubicin Mitoxantrone Mitomycin C 5-Fluorouracil Methotrexate Peak peritoneal cavity-to-plasma concentration ratio ment strategy. First, because any added advantage from the high concentrations achieved in the peritoneal cavity after regional delivery requires that the agent be in direct contact with the tumor, it is critical that all regions of the peritoneal cavity are bathed with the drug-containing fluid. In patients who have undergone one or more laparotomies, adhesion formation is common. In addition, both the tumor itself and the cytotoxic agents can elicit an inflammatory response leading to the formation of adhesions and interference with intraperitoneal drug distribution. Several trials have shown that large treatment volumes (22 1) can achieve reasonably good drug distribution (all regions of the cavitv bathed by drug-containing fluid) in most patients treated by this r~ute.~,~ However, many patients who would otherwise be excellent candidates for this form of treatment are unable to accept the necessary treatment volume (e.g., pain with fluid administration and excessively slow flow into the cavity) and should be treated with alternative strategies. The major factor defining the patient population that might be considered appropriate for an intraperitoneal treatment regimen is the demonstrated limited ability of cytotoxic agents to penetrate directly into either normal or tumor tissue. Several experimental systems have shown that the depth of penetration is limited to less than 1-2 mm from the surface of the peritoneal lining5-' Perhaps even more important than the actual depth of penetration of drugs into tumors after intraperitoneal delivery is the concentration of the agent achieved in the tissue with regional instillation compared with what is obtained after systemic drug administration. This point has been addressed directly for cisplatin in a rat model.5 Tissue concentrations of the drug were examined at various depths from the peritoneal surface after either systemic or intraperitoneal administration. Although cisplatin was present at depths of more than 2 mm after either intraperitoneal or systemic drug delivery, the increased concentration (the advantage for re- gional administration) was limited to a depth of 1 mm or less. As will be discussed later in this review, these experimental observations have been supported strongly by clinical data showing that the patients with ovarian cancer who reasonably might be expected to respond to an intraperitoneal approach will be those with only microscopic disease or small tumor nodules that are present when the regional therapeutic approach is initiated. One additional point should be addressed before discussing the results of clinical trials of intraperitoneal therapy. The data presented in Table 1 show that the peritoneal cavity can be exposed to significantly higher concentrations of cytotoxic drugs after intraperitoneal delivery than will be present in the systemic compartment. However, although these high concentrations might be associated with increased cytotoxicity, we should reasonably question whether any reduction in the amount of drug reaching the systemic compartment might result in a decrease in the overall efficacy of the therapeutic program, secondary to less drug delivery to the tumor by capillary flow. Various drugs, including cisplatin and carboplatin, produce limited local toxicity when administered directly into the peritoneal ca~ity.~*'-'' For these drugs, the dose-limiting toxicity will be their systemic effects. Thus, under conditions in which patients receive such agents at the maximally tolerated dose, the concentrations of the drugs reaching the systemic compartment, and subsequently the tumor by capillary flow, should be equivalent to that achieved by their systemic administration. By contrast, for drugs whose doses are limited by local toxic effects, such as doxorubicin," mit~mycin,'~ or mit~xantrone,'~,'~ the systemic exposure will be reduced compared with their intravenous administration. It is important to recognize this potential limitation of certain drugs, although such agents ultimately may produce considerable cytotoxicity secondary to their high local concentrations in direct contact with the tumor confined to the cavity. Cisplatin-Based lntraperitoneal Chemotherapy in Persistent or Recurrent Ovarian Cancer As a result of its central role in the management of ovarian cancer, cisplatin has been the agent most extensively studied for intraperitoneal administration in this disease. Several Phase I trials have confirmed both the safety and pharmacokinetic advantage associated with the intraperitoneal administration of this agent (Table 1). A number of Phase I1 studies in patients with persistent or recurrent ovarian cancer after initial cisplatin-

3 Intraperitoneal Chemotherapy in Ovarian Cancer/Markman et al based systemic therapy have shown that approximately 25-35% of patients can achieve a surgically documented complete response after treatment with either single-agent or cisplatin-based combination intraperitoneal Recently, we retrospectively evaluated patients treated in two second-line Phase I1 cisplatin-based combination intraperitoneal chemotherapeutic trials at the Memorial Sloan-Kettering Cancer Center in an attempt to define more critically those patient characteristics that would predict a response to this therapeutic strategy." The details of the two studies have been reported previo~sly.'~~~~ Overall, 32% of 50 patients whose largest tumor mass measured less than 1 cm had a surgically defined complete response to therapy compared with a 5% surgical complete response rate (2 of 39 patients) if the largest residual nodule was more than 1 cm. In addition, in the 36 patients with small-volume residual disease (< 1 cm) who previously had responded to a systemically administered organoplatinum compound, the surgically defined complete response rate was 42% compared with only 7% in the 14 patients with similar disease who had not responded to intravenous platinum (P < 0.025). These data provide support for the concept that any advantage associated with the regional route of drug delivery will be relative rather than absolute. Thus, the 1 O-20-fold increased concentration of cisplatin present in the peritoneal cavity after intraperitoneal administration may be effective in killing a sensitive tumor. By contrast, tumors that inherently are resistant to the organoplatinum compounds are unlikely to be killed with the moderately increased concentrations of cisplatin that can be obtained in the peritoneal cavity after regional drug delivery. However, it is possible that cytotoxic agents associated with a significantly greater regional pharmacokinetic advantage (e.g., > 2 logarithms) may have important antineoplastic activity against ovarian cancers that are resistant to the organoplatinum drugs. The search for such agents should be an important research goal of future experimental and clinical efforts focused on intraperitoneal therapy of ovarian cancer. Other Antineoplastic Agents Examined for lntraperitoneal Delivery in the Management of Ovarian Cancer Several reported trials have explored a possible role for intraperitoneal carboplatin in the management of ovarian cancer.lo*" This drug produces minimal local toxic- ity after regional delivery and is associated with a pharmacokinetic advantage similar to cisplatin. The objective response rate to intraperitoneal carboplatin used as salvage therapy in ovarian cancer appears to approximate that of cisplatin. However, because the dose-limiting toxicity of intraperitoneal carboplatin is bone marrow suppression, particularly thrombocytopenia, the amount of drug that can be administered as second-line treatment of ovarian cancer is limited. In addition, investigators in the Netherlands who used the same experimental system to examine the depth of penetration of carboplatin as was used to evaluate cisplatin found that the cavity tissue concentrations of carboplatin were lower than those observed with an equitoxic dose of cisplatin.20 Although the clinical implications of this experimental observation remain to be determined, it would be inappropriate currently to conclude that carboplatin and cisplatin are equivalent drugs for intraperitoneal administration. Mitoxantrone is an extremely interesting drug for intraperitoneal drug delivery. In vitro, this agent has an extremely steep dose-response curve for ovarian cancer cells, with more than 90% of all tested human ovarian tumors being sensitive at concentrations achievable after regional drug administration.2 A more than 3 logarithmic pharmacokinetic advantage has been demonstrated for peritoneal cavity exposure after intraperitoneal administration.21 As previously noted, there is limited systemic exposure to mitoxantrone when the drug is delivered by the intraperitoneal route because the dose-limiting toxicity is significant abdominal pain, adhesion formation, and bowel obstr~ction.'~*'~ However, despite the potential for significant local side effects, objective antineoplastic activity, including surgically defined complete responses, have been observed in patients with ovarian cancer whose tumors previously were resistant to cisplatin the rap^.'^,'^ Current research efforts using intraperitoneal mitoxantrone have focused on reducing the local toxicity (by administering a lower dose), increasing the dose intensity (by more frequent treatments), and maximizing the intraabdominal drug distribution (by using larger treatment volumes) after regional delivery. Taxol, a unique antineoplastic agent that produces its cytotoxic effect by stabilizing microtubules, is active in platinum-resistant ovarian cancer.22 In a recently reported Phase I trial, this drug was associated with a major pharmacokinetic advantage (2 3 logarithms) after intraperitoneal admini~tration.~~ In addition, extremely high levels of taxol persisted in the cavity for more than 48 hours after a single intraperitoneal treatment. The dose-limiting toxicity of regionally delivered

4 1568 CANCER Supplement February 25, 2993, Volume 71, No. 4 taxol was abdominal pain. However, even at intraperitoneal doses that were not associated with significant abdominal discomfort, pharmacokinetic analysis revealed systemic concentrations of the agent previously demonstrated to be associated with major cytotoxic activity in experimental systems.24 Finally, objective antitumor responses (e.g., disappearance of malignant ascites and significant decreases in CA 125 levels) were observed in patients previously documented to have tumors resistant to ~isplatin.'~ Additional exploration of a potential role for this unique antineoplastic agent after intraperitoneal drug delivery is indicated. It also should be noted that several biologic agents, including recombinant alpha-interferon and gammainterferon and recombinant interleukin-2, have been associated with a pharmacokinetic advantage when administered by the intraperitoneal ro~te.~~-~' In addition, surgically defined complete responses have been documented in patients with small-volume residual dis- ease. 25,2829 A unique feature associated with the regional administration of biologic agents is the potential opportunity to activate local immunoregulatory mechanisms that may be important in tumor cytotoxicity. However, it is uncertain currently whether if the clinical responses observed after regional administration of biologic agents are secondary to an indirect stimulation of local immunoreactive cells or are the result of a direct cytotoxic effect of these agents. Current Status of lntraperitoneal Therapy in the Management of Ovarian Cancer and Future Directions The available experimental and clinical data regarding intraperitoneal therapy of ovarian cancer lead us to the conclusion that there are several clinical situations in which an intraperitoneal regimen might be considered to be a reasonable therapeutic option in the management of the disease (Table 2). As previously noted, patients with small-volume residual ovarian cancer after systemically delivered platinum-based therapy who have had an objective response to their initial treatment regimen are appropriate candidates for a second-line platinum-based intraperitoneal chemotherapeutic program. On the basis of current experience regarding this therapeutic approach, it is reasonable to suggest that this strategy might be considered an acceptable patient management option outside a study setting. Although there is only limited data available to suggest that second-line platinum-based intraperitoneal therapy has an impact on ultimate patient s~rvival,~' the surgically documented complete response rate we discussed were Table 2. Clinical Situations in Which Intraperitoneal Therapy May be Considered a Therapeutic Option in the Management of Ovarian Cancer Salvage tberapy of patients with small-volume (microscopic, tumor nodules I 0.5 cm in maximum diameter) residual disease after systemic chemotherapy Demonstrated platinum sensitivity Demonstrated platinum resistance Consolidafioti therapy of patients with high-grade tumors who achieve a surgically documented complete response after systemic chemotherapy (ultimate relapse rate approaches 50-60%) ltiitial therapy of patients with high-grade tumors with Stage 1-11 disease liiitial tberapy of patients with advanced disease with all or some of the drugs administered by the intraperitoneal route Local ititeiisificatioii therapy after a limited number of courses of systemic chemotherapy to "debulk chemically" the tumor to small-volume residual disease equivalent or superior to reported alternative treatment programs in this clinical setting. Patients with small-volume residual disease who have not responded to systemic platinum-based therapy have a limited likelihood of responding to intraperitoneal platinum and probably should be considered for alternative treatment strategies, including the intraperitoneal drug delivery of a nonplatinum-containing regimen. Although a specific alternative regimen cannot be recommended currently, the activity of intraperitoneal mitoxantrone in platinum-resistant small-volume residual disease is highly noteworthy, and this treatment strategy might be considered an appropriate therapeutic approach outside a study setting. Although intraperitoneal antineoplastic drug administration has theoretic appeal in other settings in patients with ovarian cancer (Table 2), the currently available clinical data are insufficient to define a precise role for this therapeutic strategy in the standard clinical management of this malignancy. Future research efforts in intraperitoneal therapy of ovarian cancer should be directed toward finding new agents whose activity might be improved at the higher drug concentrations possible within the peritoneal cavity after direct intraperitoneal drug delivery. In this regard, taxol is an exciting candidate. In addition, if it were possible to decrease the chemotherapy-induced adhesion formation significantly (e.g., using nonsteroidal antiinflammatory agents), intraperitoneal drug distribution probably would be improved and the local toxicity associated with the regional administration of certain antineoplastic drugs might be reduced. Investigators have begun to evaluate the use of intraperitoneal therapy as initial management in ovarian

5 Intraperitoneal Chemotherapy in Ovarian Cancer/Markman et al cancer.31 The Southwest and the Gynecologic Oncology Groups are nearing completion of a randomized trial in patients receiving initial chemotherapy to compare intraperitoneal and intravenous cisplatin, with all patients also receiving systemic cyclophosphamide. The preliminary results of this trial, which are awaited with great interest, should be available within the next year. Finally, it will be important to examine various methods of combining intraperitoneal drug delivery with standard systemic chemotherapeutic administration in an effort to improve the results of therapy for patients with ovarian cancer. For example, it may be reasonable to administer several courses of a high-dose systemic chemotherapeutic regimen to "chemically debulk" the tumor, followed by intraperitoneal chemotherapy at a time when the remaining tumor may be reduced significantly in volume, allowing the regional treatment strategy to exert its maximal influence on the course of the di~ease.~' Ultimately, however, if intraperitoneal therapy is to play a role in the standard initial management of patients with advanced ovarian cancer its benefits will need to be demonstrated in well-designed randomized clinical trials. References Dedrick RL, Myers CE, Bungay PM, DeVita, VT Jr. Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep 1978; Alberts DS, Young L, Mason N, Salmon SE. In vitro evaluation of anticancer drugs against ovarian cancer at concentrations achievable by intraperitoneal administration. Semin Oncol 1985; lz(supp1 4): Dunnick NR, Jones RB, Doppmen JL, Speyer J, Myers CE. Intraperitoneal contrast infusion for assessment of intraperitoneal fluid dynamics. AIR Am I Roentgenol 1979; Howell SB, Pfeifle CE, Wung WE, Olshen RA, Lucas WE, Yon JL, et al. lntraperitoneal cisplatin with systemic thiosulfate protection. Ann Intern Med 1982; 97: Los G, Mutsaers PHA, van der Vijgh WJF, Baldew GS, de Graaf PW, McVie JG. Direct diffusion of cis-diamminedichloroplatinum(i1) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy. Cancer Res 1989; 49: Ozols RF, Locker GY, Doroshow JG, Grotzinger KR, Myers CE, Young RC. Pharmacokinetics of Adriamycin and tissue penetration in murine ovarian cancer. Cancer Res 1979; 39: West GW, Weichselbau R, Little JB. Limited penetration of methotrexate into human osteosarcoma spheroids as a proposed model for solid tumor resistance to adjuvant chemotherapy. Cancer Res 1980; 40: Hacker NF, Berek JS, Pretorius RG, Zuckerman J, Eisenkop S, Lagasse LD. Intraperitoneal cis-platinum as salvage therapy for refractory epithelial ovarian cancer. Obstet Gynecol 1987; 70: Markman M, Cleary S, Howell SB, Lucas WE. Complications of extensive adhesion formation following intraperitoneal chemotherapy. Surg Gynecol Obstet 1986; Speyer JL, Beller U, Colombo N, Sorich 1, Wernz JC, Hochster H, et al. Intraperitoneal carboplatin: favorable results in women with minimal residual ovarian cancer after cisplatin therapy. I Clin Oncol 1990; 8: Pfeiffer P, Bennedaek 0, Bertelsen K. Intraperitoneal carboplatin in the treatment of minimal residual ovarian cancer. Gynecol oncor 1990; 36:306-i Ozols RF, Young RC, Speyer JL, Sugarbaker PH, Green R, Jenkins J, et al. Phase 1 and pharmacological studies of Adriamycin administered intraperitoneally to patients with ovarian cancer. Cancer Res 1982; Gyves J. Pharmacology of intraperitoneal infusion 5-fluorouracil and mitomycin-c. Semin Oncol 1985; 12(Suppl 4): Markman M, Reichman B, Ianotti N, Hakes T, Hoskins W, Rubin S. Phase 2 trial of intraperitoneal mitoxantrone in the management of refractory ovarian carcinoma. J Clin Oncol 1990; 8: Markman M, Hakes T, Reichman B, Lewis JL Jr., Rubin S, Jones W, et al. Phase 2 trial of weekly or biweekly intraperitoneal mitoxantrone in epithelial ovarian cancer. I Clin Oncol 1991; 9: Reichman B, Markman M, Hakes T, Hoskins W, Rubin S, Jones W, et al. lntraperitoneal cisplatin and etoposide in the treatment of refractory/recurrent ovarian carcinoma. Clin Oncol 1989; 7~ Markman M, Hakes T, Reichman B, Hoskins W, Rubin S, Almadrones L, et al. Intraperitoneal cisplatin and cytarabine in the treatment of refractory ovarian carcinoma. Clin Oncol 1991; 9~ Piver MS, Lele SB, Marchetti DL, Baker TR, Emrich LJ, Hartman AB. Surgically documented response to intraperitoneal cisplatin, cytarabine, and bleomycin after intravenous cisplatin-based chemotherapy in advanced ovarian adenocarcinoma. I Clin Oncol 1988; 6~ Markman M, Reichman B, Hakes T, Jones W, Lewis JL Jr., Rubin S, et al. Responses to second-line cisplatin-based intraperitoneal therapy in ovarian cancer: influence of a prior response to intravenous cisplatin. 1 Clin Oncol 1991; 9: Los G, Verdegaal EME, Mutsaers PHA, McVie JG. Penetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy. Cancer Chemother Pharma- Cor 1991; 2m Alberts DS, Sunvit EA, Peng Y-M, McCloskey T, Rivest R, Graham V, et al. Phase 1 clinical and pharmacokinetic study of mitoxantrone given to patients by intraperitoneal administration. Cancer Res 1988; 48: McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC, Ettinger DS, Armstrong DK, et al. 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6 1570 CANCER Supplement February 25, 2993, Volume 71, No D Acquisto R, Markman M, Hakes T, Rubin S, Hoskins W, Lewis JL Jr., et al. A phase 1 trial of intraperitoneal recombinantgamma interferon in advanced ovarian carcinoma. ] Clin Oncol 1988; 6~ Chapman PB, Kolitz JE, Hakes T, Gabrilove JL, Kolitz JE, Welte K, et al. A phase 1 pilot study of intraperitoneal recombinant interleukin 2 in patients with ovarian carcinoma. Invest New Drugs 1988; 6: Pujade-Lauraine E, Colombo N, Namer N, Fumoleau P, Monnier A, Nooy MA, et al. Intraperitoneal human r-inf gamma in patients with residual ovarian carcinoma at second look laparotomy [abstract]. Proc Ani Soc Cliri Oncol 1990; 9: Lembersky B, Baldisseri M, Kunschner A, Seski J, Zook D, Hammond R, et al. Phase 1-11 study of intraperitoneal low dose inter- leukin-2 in refractory stage 111 ovarian cancer [abstract]. Proc Am Soc Cliti Oticol 1989; 8~ Howell SB, Zimm S, Markman M, Abramson IS, Cleary S, Lucas WE, et al. Long term survival of advanced refractory ovarian carcinoma patients with small-volume disease treated with intraperitoneal chemotherapy. ] Clin Oncol 1987; 5: Howell SB, Kirmani S, Lucas WE, Zimm S, Goel R, Kim S, et al. A phase 11 trial of intraperitoneal cisplatin and etoposide for primary treatment of ovarian epithelial cancer. Chi Oticol 1990; 8~ Hakes T, Markman M, Reichman 8, Hoskins W, Jones W, Rubin S, et al. High intensity intravenous cyclophosphamide/cisplatin and intraperitoneal cisplatin for advanced ovarian cancer [abstract]. Proc Am Soc Cliri Oncol 1989; 8:152.