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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4466-4471 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.3846 Phase III Randomized Trial of Intravenous Cisplatin Plus a 24- or 96-Hour Infusion of Paclitaxel in Epithelial Ovarian Cancer: A Gynecologic Oncology Group Study
From the Division of Solid Tumor Oncology, Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York; Gynecologic Oncology Group Statistical & Data Center, Roswell Park Cancer Institute, Buffalo, NY; Gynecologic Oncology and Pelvic Surgery Associates, Mount Carmel Health Center, Columbus, OH; Division of Gynecologic Oncology, University of North Carolina School of Medicine, Chapel Hill, NC; Department of Clinical Obstetrics & Gynecology, Division of Gynecologic Oncology, University of California-Irvine Medical Center, Orange, CA; Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Gynecologic Oncology, Tacoma General Hospital, Tacoma, WA; and the Department of Pathology, Southeast Georgia Cancer Care Center, Brunswick, GA Address reprint requests to David R. Spriggs, MD, Memorial Sloan-Kettering Cancer Center, Department of Medical Oncology, 1275 York Ave, New York, NY 10021; e-mail: spriggsd{at}mskcc.org
Purpose This study was undertaken to assess if prolonged paclitaxel administration in combination with cisplatin improves overall survival (OS) in epithelial ovarian cancer (EOC). Patients and Methods Eligible patients with suboptimal stage III or IV EOC, fallopian tube, or primary peritoneal cancer were randomly allocated to receive six cycles of cisplatin 75 mg/m2 and either paclitaxel 135 mg/m2 during 24 hours (arm 1) or paclitaxel 120 mg/m2 during 96 hours (arm 2). Results Planned accrual was 324 patients; 293 were enrolled before the study was closed as a result of a scheduled interim futility analysis. There were 13 ineligible patients; thus, 140 patients in each arm were assessable. In arm 1, 80% of patients completed all six cycles compared with 83% of patients in arm 2. Grade 4 granulocytopenia was more common in arm 1 (79% v 54%; P < .001) whereas grade 3 or worse anemia was more severe in arm 2 (6% v 18%; P < .003). The median progression-free survival was 1.03 years for arm 1 versus 1.05 years for arm 2. The median OS was 2.49 and 2.54 years for arms 1 and 2, respectively. There have been 237 reported deaths. The relative death rate was approximately 12% greater in arm 2 (hazard ratio, 1.12; 95% CI, 0.860 to 1.45). Conclusion Patients with advanced EOC have a relatively poor prognosis. The results of treatment with cisplatin and paclitaxel are not significantly improved by prolonging the paclitaxel infusion from 24 to 96 hours.
Publication of Gynecologic Oncology Group (GOG) trial 111 in 1996 made paclitaxel part of ovarian cancer treatment in the United States,1 and subsequently the paclitaxel/platinum combination became the accepted standard of care in much of the world after confirmation by the OV10 trial.1,2 A significant amount of investigative energy has been directed toward defining the best dose and schedule of paclitaxel. The pharmacokinetics of paclitaxel are complex, with both a rapid equilibrium phase and a protracted terminal half-life.3,4 The bifactorial randomized study by the National Cancer Institute of Canada concluded that the effects of 135 and 175 mg/m2 were similar in terms of efficacy.5 A subsequent study of higher dose paclitaxel showed no significant advantage; thus, doses of 135 mg/m2 during 24 hours or 175 mg/m2 during 3 hours became the de facto standards.5,6 During the initial development of paclitaxel, studies of short infusions (1 to 3 hours) were complicated by acute histamine reactions, so that the 24-hour schedule was chosen for its safety and efficacy, whereas longer schedules were disregarded as inconvenient.7-10 However, studies of paclitaxel pharmacodynamics suggested that the myelotoxicity of paclitaxel was best described by a model that used time over a critical threshold of 0.05 µM.3,4 In addition, both 96-hour infusions and short weekly infusions proved able to achieve responses in some patients who were resistant to shorter paclitaxel infusions, perhaps because of prolonged time above the 0.05 µM threshold.11-13 On the basis of these observations, it was important to investigate further the value of extended paclitaxel exposures in the primary treatment of ovarian cancer patients. Pharmacokinetic models suggested that a 96-hour continuous infusion at 30 mg/m2/d would achieve and maintain a paclitaxel concentration around the 0.05 µM target, and pilot data with cisplatin combinations showed an acceptable safety profile.14 On the basis of these results, the GOG elected to investigate the efficacy of continuous infusion paclitaxel 120 mg/m2 during 96 hours combined with cisplatin 75 mg/m2 on day 5 (arm 2). This regimen was repeated every 3 weeks and the results were to be compared with standard paclitaxel 135 mg/m2 during 24 hours followed by cisplatin 75 mg/m2 on day 2 (arm 1). Six cycles of therapy were planned, and limited pharmacokinetic sampling was proposed to document the paclitaxel exposures achieved in each arm. The population was a small group of stage IV epithelial ovarian cancer (EOC) patients and a group of advanced, suboptimally debulked stage III patients who were ineligible (based on organ involvement) for the concurrent GOG study of interval cytoreduction (GOG 152).15 The primary end point for this study was survival.
Eligibility Criteria Patients had histologically confirmed EOC, fallopian tube, or primary peritoneal cancer. All stage IV patients and only those stage III patients with suboptimal disease who were not candidates (because of organ involvement) for interval cytoreductive surgery on GOG 152 were eligible. Measurable disease was not required. Cytologic confirmation of malignant pleural effusion was required if entry onto the study was based on this factor. Enrollment onto the study was to be within 6 weeks of staging surgery. No prior chemotherapy or radiation therapy was allowed. Patients were required to have granulocytes  1,500/µL; platelets 100,000/µL; adequate renal function (creatinine  2.0 mg/dL); and adequate liver function (AST and ALT 3x institutional normal, bilirubin 1.5x institutional normal); and a GOG performance status of 0 to 2. Participating institutions received approval of the protocol by their local institutional review board before enrolling any patient, and written informed consent was provided by all patients before initiating protocol therapy. Patients with a history of malignancy other than basal cell carcinoma of the skin were excluded. Central review to confirm the diagnosis was conducted by the GOG Pathology Committee, and operative reports were reviewed to confirm adequacy of the initial staging surgery. Patients underwent a baseline assessment including physical examination, blood counts, blood chemistries, CA-125 level, and postoperative computed tomography before study entry.
Study Treatment
Study End Points Toxicities were evaluated using the standard GOG toxicity criteria.16 Only the eligible patients who received any of their study treatment are included in the treatment comparisons of toxicities. A complete response (CR) was defined as the disappearance of all clinical evidence of malignant disease for at least 4 weeks; a partial response (PR) was a 50% or greater reduction in the sum of the products obtained from measurement of all measurable lesions for at least 4 weeks. Tumor assessments that did not meet these criteria were classified as exhibiting no response for the intent-to-treat analysis involving the eligible patients with measurable disease. Patients were monitored for response every two cycles by computed tomography scan.
Pharmacology Studies
Statistical Considerations The first planned interim analysis was to occur at the semiannual meeting of the GOG Data Monitoring Committee (DMC) after at least 54 deaths were reported among those patients randomly assigned to the 24-hour paclitaxel infusion regimen (arm 1). The study design included stopping guidelines for extreme efficacy as well as for futility. Stochastic curtailment procedures were to be used to assess futility. Specifically, the conditional probability of rejecting the null hypothesis at the final analysis was to be estimated given the observed data and assuming that future data were consistent with the alternative hypothesis being true. If the conditional probability of rejecting the null hypothesis was less than 10%, then early termination for futility could be considered. An O'Brien and Fleming–like type I error spending function defined the stopping boundary for extreme efficacy.19 For the purposes of this report, the analyses of PFS and OS include all eligible patients regardless of the amount of study treatment received. The cumulative distribution of event times was estimated with the product-limit method.20 The comparison of response by treatment group includes all eligible patients who were reported to have clinically measurable disease at the time they were enrolled onto the study. PFS and probability of clinical response were considered secondary end points.
After 52 months of open recruitment, 293 women were enrolled onto this study; after a centralized review of patient eligibility, 280 were deemed eligible. Reasons for ineligibility are listed in Figure 1. Among the 280 eligible patients, 140 were enrolled onto each treatment arm; patient characteristics are listed in Table 1.
Ninety-eight patients in arm 1 and 83 patients in arm 2 had clinically measurable disease reported when they were enrolled. As illustrated, the treatment arms were reasonably balanced for age, race, performance status, cell type, and disease stage. In each arm, more than 82% of patients had stage IV disease. The number of cycles of study treatment administered is shown in Figure 1. At least 80% of patients in each arm received six cycles of study therapy, and the frequency and reasons for discontinuation were similar between the two arms (Table 2). Although slightly more deaths occurred while patients received treatment in arm 1 than in arm 2 (10 v three), this difference is not statistically significant. However, nine deaths were at least partially attributed to the study regimen, six during treatment in arm 1 and three during treatment in arm 2. Seven of these nine deaths were due to sepsis with or without neutropenia, one was due to pulmonary hemorrhage, and one was due to toxic megacolon without indication of bowel obstruction.
Toxicity A detailed summary of toxicity is listed in Table 3. Overall treatment-related toxicity was similar in both arms. Grade 4 granulocytopenia was statistically more common in arm 1 (109 patients; 79%) than in arm 2 (75 patients; 54%; P < .001). Grade 3 or worse anemia was more common in arm 2 (25 patients; 18%) than in arm 1 (nine patients; 6%; P = .003). However, neither of these results was of clinical significance. There was no appreciable difference between arms in the frequency of infection (neutropenic fever). Other toxicities occurred similarly between the two regimens. Of interest, the frequency of peripheral neuropathy was not significantly reduced by extending the infusion duration from 24 to 96 hours, with 19 patients (14%) in arm 1 and 21 patients (15%) in arm 2 experiencing grade 2 or grade 3 neuropathy. Similarly, the severity of GI toxicity, allergic reaction, or alopecia was not altered by changing the duration of the paclitaxel infusion. Grade 3 or 4 GI toxicity was seen in 28 patients (20%) in arm 1 compared with 35 patients (27%) in arm 2.
Response to Therapy The majority of patients enrolled onto the study had measurable disease and it was from this group that clinical response was assessed. As illustrated in Table 4, in arm 1, of 98 eligible patients with clinically measurable disease at study enrollment, 33 patients (34%) attained a CR and 28 patients (28%) achieved a PR. In the 96-hour paclitaxel infusion arm, among 83 eligible patients with measurable disease, 35 patients (42%) achieved a CR and 23 patients (28%) attained a PR. The overall percentage of response (PR + CR) is 62% and 70% in arms 1 and 2, respectively. The difference in the proportion of patients responding between the two treatment arms was not statistically significant.
Efficacy of Treatment At the time of the first scheduled interim analysis, 54 deaths were reported in arm 1 and 59 were reported in arm 2; these data were presented to the DMC. The futility analysis indicated it was very unlikely that this study would demonstrate that arm 2 was superior to arm 1 (conditional probability of rejecting the null hypothesis = 7.5%). The DMC voted to stop accrual, but continue to observe the patients already enrolled. Both PFS and OS were assessed in this trial. Figure 2A depicts median PFS, with similar results between treatment arms (1.03 years for arm 1 year v 1.05 years for arm 2). Adjusted for initial measurable disease status (present v absent), performance status (0 v 1 v 2), histology (clear cell or mucinous adenocarcinoma v other cell types), and stage of disease (III v IV), the PFS relative hazard ratio (HR) was 1.00 (95% CI, 0.784 to 1.28). Figure 2B also shows that median OS for the two groups is similar (arm 1, 2.49 years; arm 2, 2.54 years). After adjusting for measurable disease status as specified in the study design, the death rate was 12% greater in the 96-hour paclitaxel infusion arm relative to arm 1 (HR, 1.12; 95% CI, 0.860 to 1.45). When we adjusted for additional important prognostic factors including initial performance status, histology, and stage of disease, the death rate is approximately 17% greater among patients randomly assigned to arm 2 (HR, 1.17; 95% CI, 0.899 to 1.52). This difference was not statistically significant.
Pharmacology Results The number of patient plasma samples acquired as part of this study (101 full data sets) was insufficient to provide a useful model of paclitaxel pharmacology. However, we can report that the 96-hour paclitaxel infusion did achieve and maintain the 0.05 µM concentrations required to test the hypothesis. The data are presented in Appendix 2 and Figure A1 (online only). This study population includes a large proportion (80%) of women with stage IV disease compared with previous GOG study samples consisting of 15% to 20% stage IV patients. To provide a benchmark for planning future studies enrolling only stage IV patients, it is noted that the median PFS and median OS for stage IV patients in this study are 1.2 and 2.3 years, respectively (Fig 3).
The results of the current study are notable for several reasons. First, both chemotherapy regimens produced a familiar toxicity profile, and overall toxicity was not changed substantially when the paclitaxel infusion was extended to 96 hours. There was a statistically higher incidence of grade 4 granulocytopenia in arm 1, but in terms of clinical management, the difference in myelotoxicity between the two arms was unremarkable. Similarly, nonhematologic toxicity was also unchanged by extending the paclitaxel infusion to 96 hours, and this schedule produced no advantage in the incidence of neurotoxicity or GI toxicity. Completion of planned therapy was similar in both arms despite its obvious inconvenience. Given that these patients received identical doses of cisplatin, common platinum toxicities such as nephrotoxicity, nausea, and vomiting were balanced in the two arms. We cannot rule out the possibility that single-agent therapy with 24- and 96-hour paclitaxel infusions might have different toxicity profiles in this patient population; however, it is likely that cisplatin-related toxicity blunted the ability to differentiate toxicity attributable to 24- v 96-hour paclitaxel infusions. Similar studies of 96-hour infusions have been studied in lung cancer and breast cancer, without evidence of a substantial advantage.21,22 Second, regarding the principal objective to ascertain the antineoplastic effect of a 96-hour paclitaxel infusion in combination with cisplatin on OS for EOC patients, efficacy was remarkably similar in the two arms (rate of CR, 34% in arm 1 v 42% in arm 2). There also were no appreciable differences in median PFS (1.03 years for arm I v 1.05 years for arm 2) or median OS (2.49 years for arm 1 v 2.54 years for 2). The evidence from this study supports the hypothesis that the combination of cisplatin and 96-hour paclitaxel infusion is not superior to cisplatin and 24-hour paclitaxel, and the complexity of a 96-hour infusion cannot be justified by outcome. However, given that GOG 13223 demonstrates that platinum is the most efficacious individual agent in the treatment of ovarian cancer, the relative contribution of paclitaxel may be less apparent.1,2,24 The dominant effect of platinum treatment may obscure modest differences between the tested treatments. Third, it is notable that limited sampling substantiated the study's pharmacologic objective. It is clear that a paclitaxel target value of 0.05 µM is both achievable and sustainable in a 96-hour infusion schedule. Finally, this is by far the largest reported experience with stage IV patients with paclitaxel/platinum. The outcome among stage IV patients in this study appears almost identical to that expected for stage III suboptimally debulked patients. In both GOG 132 and GOG 152, median PFS and median OS were consistent with those of the present study.23 This report can serve as a useful benchmark for future studies of stage IV patients.
The following Gynecologic Oncology Group member institutions participated in this study: Duke University Medical Center, Abington Memorial Hospital, Walter Reed Medical Center, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group, PC, University of California at Los Angeles, University of Washington, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University Medical Center, Wake Forest University School of Medicine, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St Luke's Medical Center, SUNY Downstate Medical Center, University of Kentucky, The Cleveland Clinic Foundation, State University of New York at Stony Brook, Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical School, Women's Cancer Center, University of Oklahoma, University of Virginia, University of Chicago, Tacoma General Hospital, Thomas Jefferson University Hospital, Mayo Clinic, Case Western Reserve University, Tampa Bay Cancer Consortium, Brookview Research, Inc, and Ellis Fischel Cancer Center.
Pharmacology results. A total of 101 full sample sets were available for analysis. There was poor overall compliance with the 96-hour sampling schedule, reflecting the difficulty of asking patients to return at the 48- and 96-hour time points. Thus, insufficient data were provided to complete a formal analysis of the population pharmacokinetics of paclitaxel, as originally intended. There was substantial variation in paclitaxel concentrations among the patients. The range and frequency of steady-state (end of infusion) paclitaxel concentrations is shown in Appendix Figure A1. In Figure A1A, the distribution of 24-hour paclitaxel concentrations is shown. Although more than one half of the patients had concentrations of 100 to 200 ng/mL 24 hours, 6% were below 50 ng/mL and more than 20% of patients had paclitaxel concentrations less than 100 ng/mL at 24 hours. A similar distribution was seen in the 96-hour infusion group (Fig A1B). We present the distribution of the two schedules in proportion (that is, the concentrations in the 24-hours concentration groups are 4x the concentrations in the 96-hour concentration groups). In this way, the similarity of paclitaxel disposition can be readily perceived. We conclude that the variability of the paclitaxel concentration was substantial for both the 24- and 96-hour infusions, and population differences of taxane disposition may provide a future area of fruitful research. Nearly one quarter of patients had steady-state concentrations of paclitaxel less than 100 ng/mL, whereas one quarter had paclitaxel concentrations above 200 ng/mL. Unfortunately, the impact of these variations on tumor response cannot be assessed in this limited data set.
The author(s) indicated no potential conflicts of interest.
Conception and design: David R. Spriggs, Mark F. Brady, Daniel L. Clarke-Pearson, Robert A. Burger Administrative support: Mark F. Brady Provision of study materials or patients: Luis Vaccarello, Daniel L. Clarke-Pearson, Robert A. Burger, Robert Mannel, John F. Boggess, Roger B. Lee, Mark Hanly Collection and assembly of data: Mark F. Brady, Luis Vaccarello, Daniel L. Clarke-Pearson, Robert Mannel, Mark Hanly Data analysis and interpretation: David R. Spriggs, Mark F. Brady, Robert A. Burger Manuscript writing: David R. Spriggs, Mark F. Brady, Daniel L. Clarke-Pearson, Robert A. Burger, Robert Mannel Final approval of manuscript: David R. Spriggs, Mark F. Brady, Luis Vaccarello, Daniel L. Clarke-Pearson, Robert A. Burger, Robert Mannel, John F. Boggess Other: Mark Hanly [Pathology consultant]
Supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office (Grant No. CA 27469) and the GOG Statistical Office (Grant No. CA 37517). Presented in abstract form at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996 2. Piccart MJ, Bertelsen K, James K, et al: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J Natl Cancer Inst 92:699-708, 2000 3. Kearns CM, Gianni L, Egorin MJ: Paclitaxel pharmacokinetics and pharmacodynamics. Semin Oncol 22(3 suppl 6):16-23, 1995 4. Gianni L, Kearns CM, Giani A, et al: Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13:180-190, 1995 5. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 12:2654-2666, 1994 6. Omura GA, Brady MF, Look KY, et al: Phase III trial of paclitaxel at two dose levels, the higher dose accompanied by filgrastim at two dose levels in platinum-pretreated epithelial ovarian cancer: An intergroup study. J Clin Oncol 21:2843-2848, 2003 7. Donehower RC, Rowinsky EK, Grochow LB, et al: Phase I trial of Taxol in patients with advanced cancer. Cancer Treat Rep 71:1171-1177, 1987[Medline] 8. Schiller JH, Storer B, Tutsch K, et al: A phase I trial of 3-hour infusions of paclitaxel (Taxol) with or without granulocyte colony-stimulating factor. Semin Oncol 21(5 suppl 8):9-14, 1994 9. McGuire WP, Rowinsky EK, Rosenshein NB, et al: Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111:273-279, 1989[CrossRef][Medline] 10. Spriggs DR, Tondini C: Taxol administered as a 120 hour infusion. Invest New Drugs 10:275-278, 1992[CrossRef][Medline] 11. Fennelly D, Aghajanian C, Shapiro F, et al: Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 15:187-192, 1997 12. Seidman AD, Hochhauser D, Gollub M, et al: Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. J Clin Oncol 14:1877-1884, 1996 13. Abu-Rustum NR, Aghajanian C, Barakat RR, et al: Salvage weekly paclitaxel in recurrent ovarian cancer. Semin Oncol 24(5 suppl 15):S15-62-S15-67, 1997 14. Georgiadis MS, Schuler BS, Brown JE, et al: Paclitaxel by 96-hour continuous infusion in combination with cisplatin: A phase I trial in patients with advanced lung cancer. J Clin Oncol 15:735-743, 1997 15. Rose P, Nerenstone S, Brady M, et al: Secondary surgical cytoreduction in advanced ovarian carcinoma: A Gynecologic Oncology Group study. N Engl J Med 351:2489-2497, 2004 16. Blessing JA: Design, analysis and interpretation of chemotherapy trials in gynecology cancer, in Deppe G (ed): Chemotherapy of Gynecology Cancer (ed 2). New York, NY, Alan R Liss, 1990, pp 63-97 17. Schoenfeld DA: Sample-size formula for the proportional-hazards regression model. Biometrics 39:499-503, 1983[CrossRef][Medline] 18. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc A 35:185-206, 1972 19. O'Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 35:549-556, 1979[CrossRef][Medline] 20. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 21. Wilson WH, Berg SL, Bryant G, et al: Paclitaxel in doxorubicin refractory or mitoxantrone refractory breast cancer: A phase I/II trial of 96 h infusion. J Clin Oncol 12:1621-1629, 1994 22. Breathnach OS, Georgiadis MS, Schuler BS, et al: Phase II trial of paclitaxel by 96-hour continuous infusion in combination with cisplatin for patients with advanced non-small cell lung cancer. Clin Cancer Res 6:2670-2676, 2000 23. Muggia FM, Braly PS, Brady MF, et al: Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 18:106-115, 2000 24. ICON3 Investigators: Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: The ICON3 randomised trial. Lancet 360:505-515, 2002[CrossRef][Medline] Submitted January 25, 2007; accepted July 3, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
