Intrapleural Cisplatin and Cytarabine in the Management of Malignant Pleural Effusions: A Lung Cancer Study Group Trial By Valerie W. Rusch, Robert Figlin, David Godwin, and Steven Piontadosi Malignant pleural effusions are a common and significant problem in patients with advanced malignancies. Pleurodesis with tetracycline or other sclerosing agents is the usual treatment for malignant pleural effusions. In contrast to this approach, intrapleural chemotherapy has the potential advantage of treating the underlying malignancy in addition to controlling the effusion. Intracavitary cisplatin-based chemotherapy, which is cytotoxic rather than sclerosing, has proven safe and effective via the intraperitoneal route in ovarian cancer and malignant mesothelioma. There has been little previous experience, however, with intrapleural cisplatin-based chemotherapy. As part of a planned series of trials in malignant mesothelioma, the Lung Cancer Study Group first evaluated intrapleural cisplatin and cytorabine in patients with malignant pleural effusions from a variety of solid tumors. From April 1986 to November 1987, 46 patients with cytologically proven, symptomatic, and previously untreated malignant pleural effusions were entered on study. A
MALIGNANT
pleural effusions occur frequently in patients who have locally advanced or disseminated cancer. They are associated with a short life expectancy and may cause considerable morbidity.' The most common therapy for malignant pleural effusions is a tube thoracostomy and the intrapleural instillation of a sclerosing agent to obliterate the pleural space and prevent reaccumulation of the effusion. Many different sclerosing agents have been advocated, however, testifying to the fact that no single one is uniformly satisfactory."3 Tetracycline pleurodesis has become the standard treatment for malignant pleural effusions because it can be performed at the bedside, is inexpensive, and prevents reaccumulation of the effusion in up to 75% of patients.v However, tetracycline has the disadvantages of causing severe pain, of not controlling the effusion in a substantial number of patients, and of not treating the underlying malignancy. There has been a recurring interest in using intrapleural chemotherapy for malignant pleural effusions because of its potential ability to treat the underlying malignancy in addition to providing local control of the effusion. Some of the chemotherapeutic agents that have been administered in
single dose of cisplatin 100 mg/m' plus cytarabine 1,200 mg was instilled into the pleural space via a chest tube, which was then immediately removed. Patients were evaluated for toxicity and response at 24 hours; 1, 2, and 3 weeks; and then monthly. No recurrence of the effusion was considered a complete response (CR). Partial response (PR) was defined as a 75% or greater decrease in the amount of the effusion on serial chest radiographs. One patient experienced reversible grade 4 renal toxicity, four patients had grade 3 hematologic toxicity, and five patients had grade 3 cardiopulmonary toxicity. The overall response rate (CR plus PR) at 3 weeks was 49% (18 of 37 patients). The median length of response was 9 months for a CR and 5.1 months for a PR. The outcome of this trial was sufficiently encouraging that this regimen has been incorporated into subsequent trials for malignant pleural mesothelioma. J Clin Oncol 9:313-319. o 1991 by American Society of ClinicalOncology.
the past include nitrogen mustard (mechlorethamine), doxorubicin, and bleomycin." Mechlorethamine and doxorubicin are no longer used because of the severe toxicity they cause.'0 Bleomycin has few side effects, may be more effective overall than tetracycline, but is expensive and has little chemotherapeutic activity in some of the cancers that commonly cause effusions.11'12 Re-
cently, cisplatin has been used as an agent for intracavitary chemotherapy and has been shown to be safe and effective. Unlike mechlorethamine or
doxorubicin, intracavitary cisplatin acts by direct
From the Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, NY; Division of Medical Oncology, Department of Medicine, University of California School of Medicine, Los Angeles, CA; Department of Radiology, University of Washington, Seattle, WA; and Johns Hopkins Oncology Center, Baltimore, MD. Submitted May 14, 1990; acceptedAugust 2, 1990. Supported by PublicHealth Service grant CA-36045from the NationalCancerInstitute, NationalInstitutes of Health, Department of Health and Human Services. Address reprintrequests to Valerie W Rusch, MD, Memorial Sloan-Kettering CancerCenter, 1275 York Ave, New York, NY 10021. © 1991 by American Society of Clinical Oncology. 0732-183X/91/0902-0019$3.00/0
Journal of Clinical Oncology, Vol 9, No 2 (February), 1991: pp 313-319
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cytotoxicity rather than by sclerosis.'" Cisplatin has been studied mainly as an intraperitoneal agent in the management of ovarian cancer where it has been found to provide local control of intraabdominal disease and potentially to prolong overall survival.'3- The experience with intrapleural cisplatin-based chemotherapy has been relatively '
small.'"
The Lung Cancer Study Group (LCSG) was interested in incorporating intrapleural chemotherapy into treatment regimens for patients with malignant mesothelioma or locally advanced nonsmall-cell lung cancer. Cisplatin was chosen because of the experience with intraperitoneal chemotherapy, and because of the known activity of cisplatin in both non-small-cell lung cancer and malignant mesothelioma. The LCSG felt, however, that additional phase II experience with intrapleural cisplatin in the setting of advanced disease was necessary before adding it to treatment regimens for earlier-stage disease. A decision was made to add cytarabine to cisplatin because in vitro studies suggested that these two drugs were synergistic and because preliminary clinical trials indicated that they could be administered safely together.""' The doses of cisplatin and cytarabine used were based on those used by Markman et al"' in phase I and II studies of intracavitary chemotherapy. The LCSG initiated this trial (LCSG 861) as the first of a planned series of studies, primarily in the management of malignant mesothelioma. MATERIALS AND METHODS Patients were eligible for this study if they had symptomatic, cytologically proven and previously untreated malignant pleural effusions that were refractory to standard systemic therapy. Patients who had an obligatory pleural space because of a "trapped lung" were excluded. Systemic chemotherapy was not given for 2 weeks before and 3 weeks after intrapleural chemotherapy unless the effusion had developed in the face of the systemic chemotherapy regimen, and continued systemic treatment was mandatory for other reasons. Radiation therapy to the lung, mediastinum, and pleura was also withheld during this time period. Renal, hematologic, neurologic, and cardiac function sufficient to permit the administration of cisplatin and cytarabine were required for entry on study. The parameters used for this were (1) creatinine clearance greater than 60 mLlmin; (2) WBC greater than 3,000 cells per cubic centimeter, platelet count greater than 100,0(X) cells per cubic centimeter; and (3) lack of clinically evident auditory loss or peripheral neuropathy. A life expectancy of 2 months or greater and a
performance status of greater than 30 by the Karnofsky scale were required. This trial was approved by the Institutional Review Board at each of the participating institutions, and informed consent was obtained from all patients before entry on study. Patients were admitted to the hospital and were given hydration, diuretics, and antiemetic medication as if they were receiving systemic cisplatin. At a minimum, this included pretreatment hydration with 1,000 mL of normal saline infused over 6 to 12 hours followed by another 1,000 mL of normal saline infused over 6 to 12 hours after the administration of the chemotherapy. Furosemide 20 mg and/or mannitol 12.5 g were given intravenously at the time of and 4 hours after the instillation of the chemotherapy. Additional hydration and diuresis could be given as necessary by the treating physician. A baseline posteroanterior (PA) and lateral chest radiograph was obtained. A small caliber chest tube or thoracentesis catheter was inserted into the pleural space and the effusion drained for no longer than 12 hours before administering the chemotherapy. A second PA and lateral chest radiograph was obtained after insertion of the chest tube to make certain that the lung expanded fully. Cisplatin 100 mg/m2 and cytarabine 1,200 mg mixed together in 250 mL of normal saline were then instilled via the chest tube or catheter and left in the pleural space for 4 hours. The patient was asked to change position every 15 to 20 minutes during that time in order to assure good dispersion of the drugs throughout the pleural space. The tube or catheter was then unclamped, allowed to drain for no more than 2 hours, and removed. Patients were evaluated for toxicity and response at 24 hours, and 1, 2, and 3 weeks after intrapleural chemotherapy. Thereafter, patients were evaluated monthly for 6 months, then every 3 months for 1 year. Patients experiencing a complete response (CR) or partial response (PR) or progression at 3 weeks posttreatment did not receive any additional intrapleural chemotherapy. Patients who experienced stabilization of the effusion were to receive a second dose of intrapleural chemotherapy identical to the first and were then placed on follow-up. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria. Response was assessed by serial PA and lateral chest radiographs and compared with the baseline chest radiograph taken before insertion of the chest tube. The response criteria used were (1) CR, total disappearance of pleural fluid or residual pleural fluid too minimal to be approachable by thoracentesis; (2) PR, 75% or greater reduction of pleural effusion compared to baseline pretreatment chest radiograph; (3) stabilization (S) less than a 75% reduction and not greater than 25% increase in the amount of pleural fluid compared to baseline chest radiograph; and (4) progression (P), greater than 25% increase of pleural fluid compared to baseline chest radiograph. Response was initially evaluated by the investigator and a radiologist at the participating institution. After closure of the study, a reference radiologist (D.G.) performed a blinded review of the chest radiographs without knowledge of response rates previously recorded at the participating institution. In cases where there was disagreement between the response recorded at the participating institution and that recorded by
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INTRAPLEURAL CISPLATIN, MALIGNANT PLEURAL EFFUSION Table 1. Primary Tumor Sites in the 46 Patients Entered on LCSG Trial 861 Primary Tumor Site
No. of Patients
Lung Breast Ovary Pleura Esophagus Pancreas Stomach Unknown
24 8 5 2 1 1 1 4
the reference radiologist, the assessment of the reference radiologist was used for the purposes of this analysis. The primary statistical end point of this study was the estimation of CR and PR rates, and the proportion of patients with defined toxicities. Secondary end points included response rates among survivors. The proportion of responders was estimated in all patients placed on study. Similarly, all patients were assessable for toxicity. Confidence limits for proportions were determined using exact binomial methods. For response duration and survival, the product-limit method"9 was used to estimate the median event time.
RESULTS From April 1986 to November 1987, 46 patients were entered on study (LCSG protocol 861). There were 20 men and 26 women. The average age was 63 years (range, 39 to 88 years). Primary tumor sites are shown in Table 1. The majority of patients had non-small-cell lung cancer. Adenocarcinoma was the most common cell type and was seen in 39 patients. Two patients had malignant mesothelioma and two had small-cell lung cancer. Three patients had poorly differentiated carcinoma that could not be further characterized. Forty-three of the 46 patients were assessable for toxicity. The three other patients died unexpectedly after being registered on study but before they received treatment. The major toxicities are shown in Table 2. The only life-threatening toxicity was an episode of renal failure requiring short-term dialysis in an elderly patient who did not receive adequate hydration before chemother-
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apy. Pretreatment serum creatinine in this patient was 1.1 mg/dL. Four patients (9%) experienced grade 3 hematologic toxicity characterized by leukopenia and/or thrombocytopenia that resolved without sequelae of infection or bleeding. Five patients (11%) manifested grade 3 cardiopulmonary symptoms thought to be related to fluid overload. Grade 1 to 2 nausea and vomiting occurred in 38 patients (88%). Thirty-three patients (77%) complained of grade 1 to 2 pain, but this was not clearly related to the cisplatin and may have been secondary to the chest tube. The intrapleural chemotherapy did not affect performance status. Average values for Karnofsky performance scores at registration, 24 hours, 1 week, 2 weeks, and 3 weeks were 60.8, 60.4, 60.5, 60.6, and 70.0, respectively. Thirty-seven of the 46 patients were assessable for response at 3 weeks. The remaining nine patients died of progressive disease during the first 3 weeks after entry on study. These early deaths did not seem to be related to the intrapleural chemotherapy. Six patients had a CR and 12 patients had a PR at 3 weeks for an overall initial objective response rate of 39% (18 of 46; 95% confidence interval, 25% to 55%). Among the 37 patients assessable at 3 weeks, this represents a response rate of 49% (95% confidence interval, 32% to 66%). Only four patients received a second course of intrapleural chemotherapy. None experienced an objective response. The median length of response for the six patients with a CR was 9 months. For the 12 patients experiencing a PR, it was 5.1 months. At last follow-up, 14 months after closure of the study, 40 of the 46 patients had died. This translates to a death rate of 1.195 per person year. The median survival was 5.7 months. DISCUSSION Malignant pleural effusions are recognized as a problem of significant magnitude in cancer pa-
Table 2. Toxicity in the 43 Assessable Patients on LCSG Trial 861 Type of Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Total Patients With Toxicity
Cardiopulmonary Gastrointestinal Hematologic Renal
14 12 16 13
8 26 5 2
5 1 4 1
0 0 0 1
27 39 25 17
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tients. Lung cancer is the leading cause of malignant effusions. It is estimated that 15% of lung cancer patients have an effusion at diagnosis and that 50% develop an effusion in the course of their disease.' 8 Metastatic breast cancer is the second most common cause, and effusions are seen in approximately 48% of patients with disseminated disease. Lymphomas are the third most common cause, but these effusions are usually caused by lymphatic obstruction and resolve with the systemic chemotherapy or radiation administered for the primary tumor. A variety of solid tumors are responsible for the remainder of malignant effusions. Thus the patients participating in our study are typical of this patient population as a whole. 20 There are two issues with regard to the management of malignant pleural effusions: (1) the control of the effusion for the palliation of symptoms, and (2) the impact of the treatment of the effusion on the overall course of the disease. The second issue assumes more importance if the tumor is primarily intrathoracic and extrathoracic disease is absent or indolent. Malignant mesothelioma and some locally advanced non-small-cell lung cancers are examples of such situations. The traditional management of malignant pleural effusions has emphasized the control of the effusion for the palliation of symptoms. The number of treatment regimens used for this purpose is legion. They include the intrapleural administra23 2 1 22 tion of talc, , radioisotopes,'
6
quinacrine, '
Corynebacterium parvum, 24'25mechlorethamine,7 '8 doxorubicin, 7 and tetracycline." 6 The feature common to all of these agents is that they produce an inflammatory response in the pleura that in turn leads to pleurodesis. Tetracycline has emerged as the agent of choice because it is at least as effective as all of the others, and is practical, easily available, and inexpensive. The side effect of severe pleuritic pain associated with the administration of intrapleural tetracycline remains a significant unsolved problem. Intrapleural chemotherapy has waxed and waned in popularity over the past 40 years. The initial chemotherapeutic agents used, such as mechlorethamine, doxorubicin, fluorouracil, and thiotepa, were administered primarily with the intent to produce sclerosis and without much thought as to whether they contributed to overall cancer treatment."', More recently, there has been
a renewed interest in using drugs that are thought to act primarily by cytotoxicity rather than by sclerosis.26 This approach to intracavitary chemotherapy evolved away from empiric treatment when a mathematical model of the pharmocokinetics of intraperitoneal chemotherapy was proposed by Dedrick et al in 1978.27 According to this model, the patient can be divided into two compartments: the peritoneal cavity and the remainder of the body. The concentration of a drug present in the peritoneal cavity is inversely proportional to its rate of clearance from both compartments. In general, the clearance rates are determined by (1) the characteristics of the cavity, (2) the characteristics of the drug itself (eg, the molecular weight, the lipid-water coefficient, and the association constant), (3) the concentration of the drug delivered, (4) the route of egress into the plasma, (5) the sites of metabolism, and (6) the mode of excretion. Depending on all of these factors, the intracavitary levels of a chemotherapeutic agent administered into the peritoneum or pleural space can be many fold higher than the systemic levels. Indeed, intraperitoneal levels 21-fold higher than serum levels have been reported after the intraperitoneal administration of cisplatin. In theory, such an approach could maximize the chemotherapeutic treatment of local disease while minimizing 26 29 systemic toxicity. ,28,
Intracavitary chemotherapy has several limitations, though. It requires good dispersion throughout the space being treated in order to be effective, and it penetrates tumor to a distance of only a few millimeters.13,26 Patients who have bulky tumors or intrapleural or peritoneal adhesions are unlikely to benefit by this treatment modality." Much remains unknown about the pharmocokinetics of intracavitary chemotherapy. The activity and pharmocokinetics of intrapleural chemotherapy are thought to parallel those of intraperitoneal chemotherapy,26 but thus far, there is little data in this regard. A case report detailing the pharmacokinetics of intrapleurally instilled etoposide indicates that the pleural cavity exposure to etoposide was 46 times greater, and systemic exposure 50% less than if a similar dose had been given intravenously.3 0 Similar pharmacokinetic studies have not been carried for intrapleural cisplatin or cytarabine. Both cisplatin and bleomycin are thought to be
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INTRAPLEURAL CISPLATIN, MALIGNANT PLEURAL EFFUSION
primarily cytotoxic drugs when administered into the pleural space or peritoneum. In the case of cisplatin, this is substantiated by the absence of adhesions in patients undergoing second-look laparotomy after intraperitoneal cisplatin; and by the fact that patients can show a treatment response whether or not the cavity was completely evacuated of fluid before the cisplatin was instilled. 5 '30 The LCSG was interested in the possibility of incorporating intrapleural cisplatin into an overall treatment regimen for some intrathoracic malignancies, especially early-stage malignant mesothelioma. Little information was available about the safety and potential efficacy of intrapleural cisplatin, however. We felt that it was important to evaluate this modality first in the setting of advanced disease. We chose to add cytarabine to the cisplatin because of in vitro data from a solid tumor cell line suggesting that these two agents were synergistic.1 38,'13 233 , The doses chosen for these drugs were based on the best information then available from phase I and II trials by Piver et al and Markman et al using a combination of cispla5 16 1 8 tin and cytarabine., ' ' The toxicities seen in this study are similar to those reported on cisplatin and cytarabine when these agents are administered systemically, intraperitoneally,1s"3 or intrapleurally in previous smaller studies. 16' 18 The incidence of cardiopulmonary toxicity in this trial may be falsely elevated because it is particularly difficult to quantify this in patients with advanced disease who have many reasons to be dyspneic. It is of note, though, that there was no significant change in the patients' performance status during the course of the study. The occurrence of bone marrow suppression and of renal toxicity, albeit limited, suggests that a significant amount of these drugs is ultimately absorbed systemically. Unfortunately, measurement of intrapleural and serum cisplatin levels was not possible in this multiinstitutional study. Overall, the toxicity was acceptable, particularly considering that the patients treated were frequently terminally ill. In keeping with the presumption that the combination of cisplatin and cytarabine is not a sclerosant, the chest tube or thoracentesis catheter was left in place a minimal length of time---only as long as was necessary from the practical standpoint of administering the drug. Therefore, it is unlikely
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that the responses seen in this study are related to instrumentation of the pleural space. The overall response rate, and the median length of CRs and PRs, suggest that intrapleural cisplatin-based chemotherapy has significant activity in the solid tumors treated in this study. This is impressive considering that almost all patients received only one dose of cisplatin, that some patients had bulky disease, and that most of the patients had previously received systemic chemotherapy. The response rates and response durations are not superior to those historically reported for intrapleural tetracycline. 4 6 However, this comparison is difficult because the criteria for response and the length of follow-up in studies evaluating tetracycline are variable and sometimes poorly defined. In contrast, we felt that we could only confidently measure a 75% or greater decrease in the amount of fluid, ie, near total resolution of the pleural effusion. Therefore, we have not reported minor responses. While clinicians may prefer to use tetracycline when the goal is simply to palliate a patient's symptoms, intrapleural cisplatin and cytarabine are safe and may play a role in treating the underlying malignancy as well as controlling the effusion. One disease in which intrapleural cisplatinbased chemotherapy could play such a role is malignant mesothelioma. Conceivably, repeated administration of intrapleural cisplatin-based chemotherapy might be effective in the few patients who have very early disease with minimal pleural thickening and large pleural effusions. Intrapleural chemotherapy would not be feasible or effective as the sole treatment in mesothelioma patients with bulky disease. However, it could be used in conjunction with surgical debulking of pleural tumor and systemic chemotherapy. Encouraging results have been seen in small phase II trials using such an approach in peritoneal mesothelioma.34-3 9 Subsequent to the study reported here, the LCSG initiated a trial designed to evaluate this combined modality approach. Patients with potentially resectable pleural mesothelioma underwent pleurectomy and decortication. Intrapleural cisplatin and cytarabine in the same doses used in this study were administered at the completion of thoracotomy. Systemic cisplatin and mitomycin were then given postoperatively. The results of this trial are currently under evaluation.
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RUSCH ET AL APPENDIX
This study was conducted by the Lung Cancer Study Group (LCSG). The following institutions, principal and co-principal investigators participated in this study: Albany Medical College, Albany, NY: John C. Ruckdeschel, MD, Martin McKneally, MD, PhD; Fred Hutchinson Cancer Center, Seattle, WA: Lucius Hill, MD, Nevin Murray, MD, Bill Nelems, MD, Valerie W. Rusch, MD; Hopital Laval, Quebec, Que, Canada: Jean Deslauriers, MD; Illinois Cancer Council: Paul Thomas, MD; Johns Hopkins Oncology Center, Baltimore, MD: Steven Piantadosi, MD, PhD*; University of California, Los Angeles, Los Angeles, CA: E. Carmack Holmes, MD,t Robert Figlin, MD; University of Colorado, Denver, CO: Michael Johnston, MD, Paul Bunn, MD; The University of Texas, San Antonio, TX: Frederick L. Grover, MD; University of Toronto, Toronto, Ontario, Canada: Ronald Feld, MD, Robert Ginsberg, MD; *Group Statistician, tGroup Chairman. Data management for this study was performed by: Information Management Services, Inc, Rockville, MD: William H. Lake, Jr, Sherrill Long, Barbara Harrington.
REFERENCES 1. Memon AN, Zawadzki GA: Pleural effusions. Cur Prob Cancer 5:3-30, 1981 2. Greenwald DW, Phillips C, Bennett JM: Management of malignant pleural effusion. J Surg Oncol 10:361-368, 1978 3. Ruckdeschel JC: Management of malignant pleural effusion: An overview. Semin Oncol 15:24-28, 1988 4. Wallach HW: Intrapleural tetracycline for malignant pleural effusions. Chest 68:510-512, 1975 5. Zaloznik AJ, Oswald SG, Langin M: Intrapleural tetracycline in malignant pleural effusions. A randomized study. Cancer 51:752-755, 1983 6. Bayley TC, Kisner DL, Sybert A, et al: Tetracycline and quinacrine in the control of malignant pleural effusions. A randomized trial. Cancer 41:1188-1192, 1978 7. Tattersall MHN: Intracavitary Adriamycin nitrogen mustard and tetracycline in the control of malignant effusions. A randomized study. Med J Aust 2:447-448, 1980 8. Anderson CB, Philpott GW, Ferguson TB: The treatment of malignant pleural effusions. Cancer 33:916-922, 1974 9. Paladine W, Cunningham TJ, Sponzo R, et al: Intracavitary bleomycin in the management of malignant effusions. Cancer 38:1903-1908, 1976 10. Hausheer FH, Yarbro JW: Diagnosis and treatment of malignant pleural effusion. Semin Oncol 12:54-75, 1985 11. Ostrowski MJ: An assessment of the long-term results of controlling the reaccumulation of malignant effusions using intracavity bleomycin. Cancer 57:721-727, 1986 12. Ruckdeschel J, Moores D, Lee J, et al: Management of malignant pleural effusions (MPE): A randomized comparison of tetracycline (tetra) and belomycin (bleo). Proc Am Soc Clin Oncol J Clin Oncol 9:323, 1990 (abstr) 13. Reichman B, Markman M, Hakes T, et al: Intraperitoneal cisplatin and etoposide in the treatment of refractory/ recurrent ovarian carcinoma. J Clin Oncol 7:1327-1332, 1989 14. Markman M, Cleary S, Lucas W, et al: Ip chemotherapy employing a regimen of cisplatin, cytarabine, and bleomycin. Cancer Treat Rep 70:755-760, 1986 15. Piver SM, Lele SB, Marchetti DL, et al: Surgically documented response to intraperitoneal cisplatin, cytarabine, and bleomycin after intravenous cisplatin-based chemotherapy in advanced ovarian adenocarcinoma. J Clin Oncol 6:1679-1684, 1988 16. Markman M, Howell S, Green MR: Combination intracavitary chemotherapy for malignant pleural disease. Cancer Drug Deliv 1:333-336, 1984
17. Bergerat JP, Drewinko B, Corry P, et al: Synergistic lethal effect of cis-cichlorodiammineplatinum and 1-beta-Darabinofuranosylcytosine. Cancer Res 41:25-30, 1981 18. Markman M, Cleary S, King ME, et al: Cisplatin and cytarabine administered intrapleurally as treatment of malignant pleural effusions. Med Pediatr Oncol 13:191-193, 1985 19. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 20. Johnston WW: The malignant pleural effusion. A review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer 56:905-909, 1985 21. Harley HRS: Malignant pleural effusions and their treatment by intercostal talc pleurodesis. Br J Dis Chest 73:173-177, 1979 22. Adler RH, Sayek I: Treatment of malignant pleural effusion: A method using tube thoracostomy and talc. Ann Thorac Surg 22:8-14, 1976 23. Taylor SA, Hooton NS, MacArthur AM: Quinacrine in the management of malignant pleural effusion. Br J Surg 64:52-53, 1977 24. Casali A, Gionfra T, Rinaldi M, et al: Treatment of malignant pleural effusions with intracavitary corynebacterium parvum. Cancer 62:806-811, 1988 25. Leahy BC, Honeybourne DC, Brear SG, et al: Treatment of malignant pleural effusions with intrapleural corynebacterium parvum or tetracycline. Eur J Respir Dis 66:5054, 1985 26. Markman M: Intracavitary chemotherapy. Cur Prob Cancer 10:402-437, 1986 27. Dedrick RL, Myers CE, Bungay PM, et al: Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep 62:1-10, 1978 28. Howell SB, Pfeifle CE, Wung WE, et al: Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection. Cancer Res 43:1426-1431, 1983 29. Howell SB, Pfeifle CL, Wung WE, et al: Intraperitoneal cisplatin with systemic thiosulfate protection. Ann Intern Med 97:845-851, 1982 30. Jones JM, Olman EA, Egorin MJ, et al: A case report and description of the pharmacokinetic behavior of intrapleurally instilled etoposide. Cancer Chemother Pharmacol 14:172-174, 1985 31. Piccart MJ, Abrams J, Dodion PF, et al: Intraperitoneal chemotherapy with cisplatin and melphalan. JNCI 80:1118-1124, 1988
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INTRAPLEURAL CISPLATIN, MALIGNANT PLEURAL EFFUSION 32. Kingston R, Ramos R, Sevin BI, et al: Synergistic effects of cis-platinum (CP) and cytosine arabinoside (ara-C) on ovarian carcinoma cell lines demonstrated by dual parameter flow cytometry (FCM). 18th Ann Meet Soc Gyn Oncol, 1987 (abstr 24) 33. Kern DH, Hidebrand-Zanki S: In vitro pharmacokinetics of cytosine arabinoside. 19th Interntl Cancer Congress, 1986 (abstr) 34. Markman M, Cleary S, Pfeifle CE, et al: High-dose intracavitary cisplatin with intravenous thiosulfate. Cancer 56:2363-2368, 1985 35. Markman M, Cleary S, Pfeifle C, et al: Cisplatin administered by the intracavitary route as treatment for malignant mesothelioma. Cancer 58:18-21, 1986
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36. Pfeifle CE, Howell SB, Markman M: Intracavitary cisplatin chemotherapy for mesothelioma. Cancer Treat Rep 69:205-207, 1985 37. Lederman GS, Recht A, Herman T, et al: Long-term survival in peritoneal mesothelioma. The role of radiotherapy and combined modality treatment. Cancer 59:18821886, 1987 38. Pfeifle CE, Howell SB, Markman M: Intracavitary cisplatin chemotherapy for mesothelioma. Cancer Treat Rep 69:205-207, 1985 39. Markman M, Kelsen D: Intraperitoneal cisplatin and mitomycin as treatment for malignant peritoneal mesothelioma. Cancer Treat Rep 2:49-53, 1989
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MALIGNANT
pleural effusions occur frequently in patients who have locally advanced or disseminated cancer. They are associated with a short life expectancy and may cause considerable morbidity.' The most common therapy for malignant pleural effusions is a tube thoracostomy and the intrapleural instillation of a sclerosing agent to obliterate the pleural space and prevent reaccumulation of the effusion. Many different sclerosing agents have been advocated, however, testifying to the fact that no single one is uniformly satisfactory."3 Tetracycline pleurodesis has become the standard treatment for malignant pleural effusions because it can be performed at the bedside, is inexpensive, and prevents reaccumulation of the effusion in up to 75% of patients.v However, tetracycline has the disadvantages of causing severe pain, of not controlling the effusion in a substantial number of patients, and of not treating the underlying malignancy. There has been a recurring interest in using intrapleural chemotherapy for malignant pleural effusions because of its potential ability to treat the underlying malignancy in addition to providing local control of the effusion. Some of the chemotherapeutic agents that have been administered in
single dose of cisplatin 100 mg/m' plus cytarabine 1,200 mg was instilled into the pleural space via a chest tube, which was then immediately removed. Patients were evaluated for toxicity and response at 24 hours; 1, 2, and 3 weeks; and then monthly. No recurrence of the effusion was considered a complete response (CR). Partial response (PR) was defined as a 75% or greater decrease in the amount of the effusion on serial chest radiographs. One patient experienced reversible grade 4 renal toxicity, four patients had grade 3 hematologic toxicity, and five patients had grade 3 cardiopulmonary toxicity. The overall response rate (CR plus PR) at 3 weeks was 49% (18 of 37 patients). The median length of response was 9 months for a CR and 5.1 months for a PR. The outcome of this trial was sufficiently encouraging that this regimen has been incorporated into subsequent trials for malignant pleural mesothelioma. J Clin Oncol 9:313-319. o 1991 by American Society of ClinicalOncology.
the past include nitrogen mustard (mechlorethamine), doxorubicin, and bleomycin." Mechlorethamine and doxorubicin are no longer used because of the severe toxicity they cause.'0 Bleomycin has few side effects, may be more effective overall than tetracycline, but is expensive and has little chemotherapeutic activity in some of the cancers that commonly cause effusions.11'12 Re-
cently, cisplatin has been used as an agent for intracavitary chemotherapy and has been shown to be safe and effective. Unlike mechlorethamine or
doxorubicin, intracavitary cisplatin acts by direct
From the Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, NY; Division of Medical Oncology, Department of Medicine, University of California School of Medicine, Los Angeles, CA; Department of Radiology, University of Washington, Seattle, WA; and Johns Hopkins Oncology Center, Baltimore, MD. Submitted May 14, 1990; acceptedAugust 2, 1990. Supported by PublicHealth Service grant CA-36045from the NationalCancerInstitute, NationalInstitutes of Health, Department of Health and Human Services. Address reprintrequests to Valerie W Rusch, MD, Memorial Sloan-Kettering CancerCenter, 1275 York Ave, New York, NY 10021. © 1991 by American Society of Clinical Oncology. 0732-183X/91/0902-0019$3.00/0
Journal of Clinical Oncology, Vol 9, No 2 (February), 1991: pp 313-319
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cytotoxicity rather than by sclerosis.'" Cisplatin has been studied mainly as an intraperitoneal agent in the management of ovarian cancer where it has been found to provide local control of intraabdominal disease and potentially to prolong overall survival.'3- The experience with intrapleural cisplatin-based chemotherapy has been relatively '
small.'"
The Lung Cancer Study Group (LCSG) was interested in incorporating intrapleural chemotherapy into treatment regimens for patients with malignant mesothelioma or locally advanced nonsmall-cell lung cancer. Cisplatin was chosen because of the experience with intraperitoneal chemotherapy, and because of the known activity of cisplatin in both non-small-cell lung cancer and malignant mesothelioma. The LCSG felt, however, that additional phase II experience with intrapleural cisplatin in the setting of advanced disease was necessary before adding it to treatment regimens for earlier-stage disease. A decision was made to add cytarabine to cisplatin because in vitro studies suggested that these two drugs were synergistic and because preliminary clinical trials indicated that they could be administered safely together.""' The doses of cisplatin and cytarabine used were based on those used by Markman et al"' in phase I and II studies of intracavitary chemotherapy. The LCSG initiated this trial (LCSG 861) as the first of a planned series of studies, primarily in the management of malignant mesothelioma. MATERIALS AND METHODS Patients were eligible for this study if they had symptomatic, cytologically proven and previously untreated malignant pleural effusions that were refractory to standard systemic therapy. Patients who had an obligatory pleural space because of a "trapped lung" were excluded. Systemic chemotherapy was not given for 2 weeks before and 3 weeks after intrapleural chemotherapy unless the effusion had developed in the face of the systemic chemotherapy regimen, and continued systemic treatment was mandatory for other reasons. Radiation therapy to the lung, mediastinum, and pleura was also withheld during this time period. Renal, hematologic, neurologic, and cardiac function sufficient to permit the administration of cisplatin and cytarabine were required for entry on study. The parameters used for this were (1) creatinine clearance greater than 60 mLlmin; (2) WBC greater than 3,000 cells per cubic centimeter, platelet count greater than 100,0(X) cells per cubic centimeter; and (3) lack of clinically evident auditory loss or peripheral neuropathy. A life expectancy of 2 months or greater and a
performance status of greater than 30 by the Karnofsky scale were required. This trial was approved by the Institutional Review Board at each of the participating institutions, and informed consent was obtained from all patients before entry on study. Patients were admitted to the hospital and were given hydration, diuretics, and antiemetic medication as if they were receiving systemic cisplatin. At a minimum, this included pretreatment hydration with 1,000 mL of normal saline infused over 6 to 12 hours followed by another 1,000 mL of normal saline infused over 6 to 12 hours after the administration of the chemotherapy. Furosemide 20 mg and/or mannitol 12.5 g were given intravenously at the time of and 4 hours after the instillation of the chemotherapy. Additional hydration and diuresis could be given as necessary by the treating physician. A baseline posteroanterior (PA) and lateral chest radiograph was obtained. A small caliber chest tube or thoracentesis catheter was inserted into the pleural space and the effusion drained for no longer than 12 hours before administering the chemotherapy. A second PA and lateral chest radiograph was obtained after insertion of the chest tube to make certain that the lung expanded fully. Cisplatin 100 mg/m2 and cytarabine 1,200 mg mixed together in 250 mL of normal saline were then instilled via the chest tube or catheter and left in the pleural space for 4 hours. The patient was asked to change position every 15 to 20 minutes during that time in order to assure good dispersion of the drugs throughout the pleural space. The tube or catheter was then unclamped, allowed to drain for no more than 2 hours, and removed. Patients were evaluated for toxicity and response at 24 hours, and 1, 2, and 3 weeks after intrapleural chemotherapy. Thereafter, patients were evaluated monthly for 6 months, then every 3 months for 1 year. Patients experiencing a complete response (CR) or partial response (PR) or progression at 3 weeks posttreatment did not receive any additional intrapleural chemotherapy. Patients who experienced stabilization of the effusion were to receive a second dose of intrapleural chemotherapy identical to the first and were then placed on follow-up. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria. Response was assessed by serial PA and lateral chest radiographs and compared with the baseline chest radiograph taken before insertion of the chest tube. The response criteria used were (1) CR, total disappearance of pleural fluid or residual pleural fluid too minimal to be approachable by thoracentesis; (2) PR, 75% or greater reduction of pleural effusion compared to baseline pretreatment chest radiograph; (3) stabilization (S) less than a 75% reduction and not greater than 25% increase in the amount of pleural fluid compared to baseline chest radiograph; and (4) progression (P), greater than 25% increase of pleural fluid compared to baseline chest radiograph. Response was initially evaluated by the investigator and a radiologist at the participating institution. After closure of the study, a reference radiologist (D.G.) performed a blinded review of the chest radiographs without knowledge of response rates previously recorded at the participating institution. In cases where there was disagreement between the response recorded at the participating institution and that recorded by
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INTRAPLEURAL CISPLATIN, MALIGNANT PLEURAL EFFUSION Table 1. Primary Tumor Sites in the 46 Patients Entered on LCSG Trial 861 Primary Tumor Site
No. of Patients
Lung Breast Ovary Pleura Esophagus Pancreas Stomach Unknown
24 8 5 2 1 1 1 4
the reference radiologist, the assessment of the reference radiologist was used for the purposes of this analysis. The primary statistical end point of this study was the estimation of CR and PR rates, and the proportion of patients with defined toxicities. Secondary end points included response rates among survivors. The proportion of responders was estimated in all patients placed on study. Similarly, all patients were assessable for toxicity. Confidence limits for proportions were determined using exact binomial methods. For response duration and survival, the product-limit method"9 was used to estimate the median event time.
RESULTS From April 1986 to November 1987, 46 patients were entered on study (LCSG protocol 861). There were 20 men and 26 women. The average age was 63 years (range, 39 to 88 years). Primary tumor sites are shown in Table 1. The majority of patients had non-small-cell lung cancer. Adenocarcinoma was the most common cell type and was seen in 39 patients. Two patients had malignant mesothelioma and two had small-cell lung cancer. Three patients had poorly differentiated carcinoma that could not be further characterized. Forty-three of the 46 patients were assessable for toxicity. The three other patients died unexpectedly after being registered on study but before they received treatment. The major toxicities are shown in Table 2. The only life-threatening toxicity was an episode of renal failure requiring short-term dialysis in an elderly patient who did not receive adequate hydration before chemother-
315
apy. Pretreatment serum creatinine in this patient was 1.1 mg/dL. Four patients (9%) experienced grade 3 hematologic toxicity characterized by leukopenia and/or thrombocytopenia that resolved without sequelae of infection or bleeding. Five patients (11%) manifested grade 3 cardiopulmonary symptoms thought to be related to fluid overload. Grade 1 to 2 nausea and vomiting occurred in 38 patients (88%). Thirty-three patients (77%) complained of grade 1 to 2 pain, but this was not clearly related to the cisplatin and may have been secondary to the chest tube. The intrapleural chemotherapy did not affect performance status. Average values for Karnofsky performance scores at registration, 24 hours, 1 week, 2 weeks, and 3 weeks were 60.8, 60.4, 60.5, 60.6, and 70.0, respectively. Thirty-seven of the 46 patients were assessable for response at 3 weeks. The remaining nine patients died of progressive disease during the first 3 weeks after entry on study. These early deaths did not seem to be related to the intrapleural chemotherapy. Six patients had a CR and 12 patients had a PR at 3 weeks for an overall initial objective response rate of 39% (18 of 46; 95% confidence interval, 25% to 55%). Among the 37 patients assessable at 3 weeks, this represents a response rate of 49% (95% confidence interval, 32% to 66%). Only four patients received a second course of intrapleural chemotherapy. None experienced an objective response. The median length of response for the six patients with a CR was 9 months. For the 12 patients experiencing a PR, it was 5.1 months. At last follow-up, 14 months after closure of the study, 40 of the 46 patients had died. This translates to a death rate of 1.195 per person year. The median survival was 5.7 months. DISCUSSION Malignant pleural effusions are recognized as a problem of significant magnitude in cancer pa-
Table 2. Toxicity in the 43 Assessable Patients on LCSG Trial 861 Type of Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Total Patients With Toxicity
Cardiopulmonary Gastrointestinal Hematologic Renal
14 12 16 13
8 26 5 2
5 1 4 1
0 0 0 1
27 39 25 17
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tients. Lung cancer is the leading cause of malignant effusions. It is estimated that 15% of lung cancer patients have an effusion at diagnosis and that 50% develop an effusion in the course of their disease.' 8 Metastatic breast cancer is the second most common cause, and effusions are seen in approximately 48% of patients with disseminated disease. Lymphomas are the third most common cause, but these effusions are usually caused by lymphatic obstruction and resolve with the systemic chemotherapy or radiation administered for the primary tumor. A variety of solid tumors are responsible for the remainder of malignant effusions. Thus the patients participating in our study are typical of this patient population as a whole. 20 There are two issues with regard to the management of malignant pleural effusions: (1) the control of the effusion for the palliation of symptoms, and (2) the impact of the treatment of the effusion on the overall course of the disease. The second issue assumes more importance if the tumor is primarily intrathoracic and extrathoracic disease is absent or indolent. Malignant mesothelioma and some locally advanced non-small-cell lung cancers are examples of such situations. The traditional management of malignant pleural effusions has emphasized the control of the effusion for the palliation of symptoms. The number of treatment regimens used for this purpose is legion. They include the intrapleural administra23 2 1 22 tion of talc, , radioisotopes,'
6
quinacrine, '
Corynebacterium parvum, 24'25mechlorethamine,7 '8 doxorubicin, 7 and tetracycline." 6 The feature common to all of these agents is that they produce an inflammatory response in the pleura that in turn leads to pleurodesis. Tetracycline has emerged as the agent of choice because it is at least as effective as all of the others, and is practical, easily available, and inexpensive. The side effect of severe pleuritic pain associated with the administration of intrapleural tetracycline remains a significant unsolved problem. Intrapleural chemotherapy has waxed and waned in popularity over the past 40 years. The initial chemotherapeutic agents used, such as mechlorethamine, doxorubicin, fluorouracil, and thiotepa, were administered primarily with the intent to produce sclerosis and without much thought as to whether they contributed to overall cancer treatment."', More recently, there has been
a renewed interest in using drugs that are thought to act primarily by cytotoxicity rather than by sclerosis.26 This approach to intracavitary chemotherapy evolved away from empiric treatment when a mathematical model of the pharmocokinetics of intraperitoneal chemotherapy was proposed by Dedrick et al in 1978.27 According to this model, the patient can be divided into two compartments: the peritoneal cavity and the remainder of the body. The concentration of a drug present in the peritoneal cavity is inversely proportional to its rate of clearance from both compartments. In general, the clearance rates are determined by (1) the characteristics of the cavity, (2) the characteristics of the drug itself (eg, the molecular weight, the lipid-water coefficient, and the association constant), (3) the concentration of the drug delivered, (4) the route of egress into the plasma, (5) the sites of metabolism, and (6) the mode of excretion. Depending on all of these factors, the intracavitary levels of a chemotherapeutic agent administered into the peritoneum or pleural space can be many fold higher than the systemic levels. Indeed, intraperitoneal levels 21-fold higher than serum levels have been reported after the intraperitoneal administration of cisplatin. In theory, such an approach could maximize the chemotherapeutic treatment of local disease while minimizing 26 29 systemic toxicity. ,28,
Intracavitary chemotherapy has several limitations, though. It requires good dispersion throughout the space being treated in order to be effective, and it penetrates tumor to a distance of only a few millimeters.13,26 Patients who have bulky tumors or intrapleural or peritoneal adhesions are unlikely to benefit by this treatment modality." Much remains unknown about the pharmocokinetics of intracavitary chemotherapy. The activity and pharmocokinetics of intrapleural chemotherapy are thought to parallel those of intraperitoneal chemotherapy,26 but thus far, there is little data in this regard. A case report detailing the pharmacokinetics of intrapleurally instilled etoposide indicates that the pleural cavity exposure to etoposide was 46 times greater, and systemic exposure 50% less than if a similar dose had been given intravenously.3 0 Similar pharmacokinetic studies have not been carried for intrapleural cisplatin or cytarabine. Both cisplatin and bleomycin are thought to be
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INTRAPLEURAL CISPLATIN, MALIGNANT PLEURAL EFFUSION
primarily cytotoxic drugs when administered into the pleural space or peritoneum. In the case of cisplatin, this is substantiated by the absence of adhesions in patients undergoing second-look laparotomy after intraperitoneal cisplatin; and by the fact that patients can show a treatment response whether or not the cavity was completely evacuated of fluid before the cisplatin was instilled. 5 '30 The LCSG was interested in the possibility of incorporating intrapleural cisplatin into an overall treatment regimen for some intrathoracic malignancies, especially early-stage malignant mesothelioma. Little information was available about the safety and potential efficacy of intrapleural cisplatin, however. We felt that it was important to evaluate this modality first in the setting of advanced disease. We chose to add cytarabine to the cisplatin because of in vitro data from a solid tumor cell line suggesting that these two agents were synergistic.1 38,'13 233 , The doses chosen for these drugs were based on the best information then available from phase I and II trials by Piver et al and Markman et al using a combination of cispla5 16 1 8 tin and cytarabine., ' ' The toxicities seen in this study are similar to those reported on cisplatin and cytarabine when these agents are administered systemically, intraperitoneally,1s"3 or intrapleurally in previous smaller studies. 16' 18 The incidence of cardiopulmonary toxicity in this trial may be falsely elevated because it is particularly difficult to quantify this in patients with advanced disease who have many reasons to be dyspneic. It is of note, though, that there was no significant change in the patients' performance status during the course of the study. The occurrence of bone marrow suppression and of renal toxicity, albeit limited, suggests that a significant amount of these drugs is ultimately absorbed systemically. Unfortunately, measurement of intrapleural and serum cisplatin levels was not possible in this multiinstitutional study. Overall, the toxicity was acceptable, particularly considering that the patients treated were frequently terminally ill. In keeping with the presumption that the combination of cisplatin and cytarabine is not a sclerosant, the chest tube or thoracentesis catheter was left in place a minimal length of time---only as long as was necessary from the practical standpoint of administering the drug. Therefore, it is unlikely
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that the responses seen in this study are related to instrumentation of the pleural space. The overall response rate, and the median length of CRs and PRs, suggest that intrapleural cisplatin-based chemotherapy has significant activity in the solid tumors treated in this study. This is impressive considering that almost all patients received only one dose of cisplatin, that some patients had bulky disease, and that most of the patients had previously received systemic chemotherapy. The response rates and response durations are not superior to those historically reported for intrapleural tetracycline. 4 6 However, this comparison is difficult because the criteria for response and the length of follow-up in studies evaluating tetracycline are variable and sometimes poorly defined. In contrast, we felt that we could only confidently measure a 75% or greater decrease in the amount of fluid, ie, near total resolution of the pleural effusion. Therefore, we have not reported minor responses. While clinicians may prefer to use tetracycline when the goal is simply to palliate a patient's symptoms, intrapleural cisplatin and cytarabine are safe and may play a role in treating the underlying malignancy as well as controlling the effusion. One disease in which intrapleural cisplatinbased chemotherapy could play such a role is malignant mesothelioma. Conceivably, repeated administration of intrapleural cisplatin-based chemotherapy might be effective in the few patients who have very early disease with minimal pleural thickening and large pleural effusions. Intrapleural chemotherapy would not be feasible or effective as the sole treatment in mesothelioma patients with bulky disease. However, it could be used in conjunction with surgical debulking of pleural tumor and systemic chemotherapy. Encouraging results have been seen in small phase II trials using such an approach in peritoneal mesothelioma.34-3 9 Subsequent to the study reported here, the LCSG initiated a trial designed to evaluate this combined modality approach. Patients with potentially resectable pleural mesothelioma underwent pleurectomy and decortication. Intrapleural cisplatin and cytarabine in the same doses used in this study were administered at the completion of thoracotomy. Systemic cisplatin and mitomycin were then given postoperatively. The results of this trial are currently under evaluation.
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RUSCH ET AL APPENDIX
This study was conducted by the Lung Cancer Study Group (LCSG). The following institutions, principal and co-principal investigators participated in this study: Albany Medical College, Albany, NY: John C. Ruckdeschel, MD, Martin McKneally, MD, PhD; Fred Hutchinson Cancer Center, Seattle, WA: Lucius Hill, MD, Nevin Murray, MD, Bill Nelems, MD, Valerie W. Rusch, MD; Hopital Laval, Quebec, Que, Canada: Jean Deslauriers, MD; Illinois Cancer Council: Paul Thomas, MD; Johns Hopkins Oncology Center, Baltimore, MD: Steven Piantadosi, MD, PhD*; University of California, Los Angeles, Los Angeles, CA: E. Carmack Holmes, MD,t Robert Figlin, MD; University of Colorado, Denver, CO: Michael Johnston, MD, Paul Bunn, MD; The University of Texas, San Antonio, TX: Frederick L. Grover, MD; University of Toronto, Toronto, Ontario, Canada: Ronald Feld, MD, Robert Ginsberg, MD; *Group Statistician, tGroup Chairman. Data management for this study was performed by: Information Management Services, Inc, Rockville, MD: William H. Lake, Jr, Sherrill Long, Barbara Harrington.
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