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Journal of Clinical Oncology, Vol 20, Issue 13 (July), 2002: 2965-2970
© 2002 American Society for Clinical Oncology

Cisplatin, Gemcitabine, and Ifosfamide As Weekly Therapy: A Feasibility and Phase II Study of Salvage Treatment for Advanced Transitional-Cell Carcinoma

By Lance C. Pagliaro, Randall E. Millikan, Shi-Ming Tu, Dallas Williams, Danai Daliani, Christos N. Papandreou, Christopher J. Logothetis

From the Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Lance C. Pagliaro, MD, Department of Genitourinary Medical Oncology, Box 427, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; email: lpagliar{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: We investigated the feasibility, safety, and antitumor activity of weekly gemcitabine given in combination with low doses of cisplatin and ifosfamide in previously treated patients with advanced transitional-cell carcinoma (TCC) of the urothelium.

PATIENTS AND METHODS: Patients with measurable, metastatic or unresectable TCC who had received one or two prior chemotherapy regimens were eligible. On a 28-day course, doses of cisplatin 30 mg/m2, gemcitabine 800 mg/m2, and ifosfamide 1 g/m2 were given on day 1 and then repeated on day 8 and day 15 unless there was dose-limiting hematologic toxicity.

RESULTS: Fifty-one patients were registered; 10 patients participated in a pilot study, after which 41 patients were registered onto the phase II protocol. Forty-eight patients (94.1%) had dose-limiting hematologic toxicity on day 8 or day 15. Nonhematologic toxicity of grade 3 or greater consisted mainly of nausea and vomiting (seven patients, 13.7%) and infection (seven patients, 13.7%). Responses could be assessed in 49 of 51 eligible patients; two complete responses (4.1%) and 18 partial responses (36.7%) were observed for an overall response rate of 40.8% (exact 95% confidence interval, 27% to 56%).

CONCLUSION: This regimen of cisplatin, gemcitabine, and ifosfamide is not feasible for weekly administration because of hematologic toxicity. Nevertheless, there was promising activity with only two doses per 28-day cycle. On the basis of these results, we have initiated a phase II trial of this combination given as a single dose every 14 days in patients with untreated, metastatic urothelial carcinoma.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
CHEMOTHERAPY IS the principal treatment modality for advanced urothelial carcinoma.1,2 The optimal use of an increasing number of available drugs in untreated patients with metastatic urothelial carcinoma continues to be the focus of large, multi-institutional phase III clinical trials.3,4 Combinations such as methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) or gemcitabine and cisplatin have been validated for use as first-line therapy, but the overall response rate and survival have not improved significantly in 20 years.1-4 On the other hand, the increasing diversity in drugs and highly effective regimens has allowed progress in the development of neoadjuvant, adjuvant, and salvage treatments, as well as strategies for achieving similar response rates with less toxicity and improved quality of life.5-8

Ifosfamide is an alkylating agent with significant activity in advanced urothelial carcinoma, and as a single agent, it has an overall response rate of 20% in previously treated patients.6 Ifosfamide, like other DNA-damaging agents, may be more effective when given in combination with gemcitabine because it is likely that the incorporation of gemcitabine into the damaged DNA inhibits DNA repair.9,10 Results of a phase I trial combining low-modulatory doses of gemcitabine (90 to 200 mg/m2 day 2 and day 4) with ifosfamide (2 g/m2 for 4 days) and doxorubicin (20 mg/m2 for 3 days) supported the hypothesis of a mechanistic interaction between these drugs because both considerable toxicity and an antitumor effect were seen.11 The combined toxicity of doxorubicin/ifosfamide/gemcitabine required a dosing interval of 21 days.

Another dosing strategy is to give weekly gemcitabine at higher, cytotoxic doses in combination with one or more DNA-damaging agents. The doublet of gemcitabine and cisplatin has been used in patients with urothelial carcinoma, with cisplatin given either as a single dose on day 1 or 24,12 or weekly at a low dose of 30 mg/m2 together with gemcitabine.13 The combination of weekly gemcitabine (1,000 mg/m2 days 1 and 8) with single doses of ifosfamide (2.5 g/m2) and cisplatin (75 mg/m2) per 21-day course has been described in patients with non–small-cell lung cancer,14 as have other triplet combinations with gemcitabine,15 but the myelosuppression caused by three drugs at standard doses generally prohibits administering combinations such as these on a weekly schedule.

The optimal combination of gemcitabine with DNA-damaging agents should allow their maximum interaction for an antitumor effect while keeping their combined toxic effects within acceptable limits. With that objective, we sought to determine the feasibility of giving weekly gemcitabine together with low doses of cisplatin and ifosfamide. We investigated the safety and efficacy of salvage chemotherapy using three weekly doses of cisplatin, gemcitabine, and ifosfamide (CGI) in patients with advanced transitional-cell carcinoma (TCC) of the urothelium.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Eligibility
Patients with pathologically documented metastatic or unresectable TCC of the urothelium (renal pelvis, ureter, bladder, or urethra) were eligible for the study. The following entry criteria were required: (1) Zubrod performance status <= 3; (2) measurable or assessable lesion; (3) at least one but not more than two previous cytotoxic treatments; (4) absolute granulocyte count more than 2,000/µL; platelet count more than 100,000/µL, AST less than three times normal, ALT less than three times normal, bilirubin level <= 2.0 mg/dL, and creatinine clearance more than 40 mL/min; (5) no previous pelvic radiation; (6) no previous gemcitabine or ifosfamide; and (7) written informed consent. Those patients with a history of significant heart disease (symptoms of congestive heart failure or left ventricular ejection fraction <= 40%), presence of brain metastases, or persistent toxicity (grade 1 or greater) from previous cisplatin were not eligible.

Treatment Plan
Patients did not require hospitalization for the treatment. On day 1, chemotherapy was administered sequentially starting with ifosfamide 1 g/m2 (1-hour infusion), followed by gemcitabine 800 mg/m2 (30-minute infusion), and subsequently cisplatin 30 mg/m2 (in 250 mL of normal saline containing mannitol 10 g infused intravenously for 1 hour). Sodium mercaptoethanesulfonate (mesna, 800 mg/m2) was given intravenously just before ifosfamide. Patients received 1 L of intravenous fluids with mannitol and supplemental potassium and magnesium for 5 hours, after which a second dose of mesna 500 mg was given orally. The entire treatment was administered again on day 8 and day 15 provided there was no dose-limiting toxicity. Treatment was repeated every 28 days.

Toxicity Criteria and Dose Modification
Toxic effects were graded according to the National Cancer Institute common toxicity criteria (version 1.0). Dose-limiting toxicity was defined as any grade 4 toxicity or persistent toxicity greater than grade 2. For the pilot study, treatment was given on days 1, 8, and 15 and was repeated every 28 days provided the absolute granulocyte count was >= 500/µL (granulocytopenia < grade 4) and platelet count was >= 50,000/µL (thrombocytopenia < grade 3). After the pilot study was completed and one patient had developed prolonged thrombocytopenia (grade 4) during course 5, the parameters were amended for safety reasons to an absolute granulocyte count >= 1,000/µL and platelet count >= 100,000/µL. These criteria were used for day 8 and day 15 treatment of all patients on the phase II component of the study.

Dose reductions of cisplatin were defined for nephrotoxicity. On day 1 of therapy, any patient with serum creatinine >= 2.0 mg/dL had the cisplatin dose reduced by 25%, and all therapy was discontinued in any patient with an estimated creatinine clearance of less than 30 mL/min.

Definition of Response
Response was assessed in all patients who received at least one complete cycle of treatment, with dose reductions when necessary. A complete response (CR) was defined as the disappearance of all evidence of the tumor for at least 2 months. Partial response (PR) was defined as a 50% decrease in tumor size (recorded as the product of the longest perpendicular diameters of measurable lesions) persisting for 2 months. Progressive disease was defined as an increase of at least 25% in the size of measurable lesions or the appearance of new lesions.

Statistical Methods
The two-stage accrual design described by Simon16 was chosen to define the total number of patients required for the phase II study; this design also ensured that the number of patients exposed to this therapy was minimized should the therapy prove ineffective. We set an overall response rate of 50% as the target level and chose 30% as the lowest overall response rate of interest, with a planned sample size of 46 patients (type I error, 0.10; type II error, 0.10). Overall survival was defined as the interval between the start of chemotherapy to death or last follow-up visit. Median overall survival was estimated using the Kaplan-Meier analysis method.17


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Patient characteristics are listed in Table 1. From April 1997 to January 2000, 51 patients were enrolled onto the pilot study (10 patients) or the phase II trial (41 patients). The accrual target for the phase II component was 46 patients, but we decided to terminate the study after 41 patients because it was clear that the response rate of interest would be exceeded and that the schedule would need to be modified. Patients in the pilot study and the phase II trial received identical treatment and are considered together. There were 34 men and 17 women; median age was 65 years (range, 31 to 81 years). Four patients (7.8%) were in the poor prognostic category associated with visceral metastasis and compromised performance status.18 One patient had a bladder cancer with mixed TCC and adenocarcinoma histology, and one patient had a poorly differentiated carcinoma of the bladder that, on clinical grounds, was determined to be TCC of urachal origin. All other patients had pathologically confirmed pure TCC. There were nine patients with tumors at the primary site, of whom six (11.8%) had primary tumors with metastases, two (3.9%) had a bladder primary tumor only, and one (2.0%) had an unresectable bladder wall recurrence after a partial cystectomy.


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  		Table 1. Table 1. Patient Characteristics
 
All patients had received previous chemotherapy, the majority within the preceding 12 months (43 patients, 84.3%). Thirty-three patients (64.7%) had received at least one previous chemotherapy regimen for the treatment of metastatic disease, and 10 patients (19.6%) had received one regimen of adjuvant chemotherapy only. The remaining eight patients had received chemotherapy as neoadjuvant (two patients, 3.9%) or for treatment of locally advanced or recurrent disease (six patients, 11.8%). Fifty patients had received M-VAC (32 patients, 62.7%) or another platinum-based regimen (18 patients, 35.3%). Seventeen patients had received two previous regimens.

Response to treatment could be assessed in 49 patients. Two patients received less than one cycle of therapy: one withdrew consent and sought alternative treatment, and the other died of sepsis before the first cycle was completed. Toxicity could be assessed in all registered patients.

Toxicity
Forty-eight patients (94.1%) experienced dose-limiting hematologic toxicity as defined by the study. As a result, the intended schedule of weekly doses given three times per cycle was not deliverable. A 100% dose omission on either day 8 or day 15 occurred in virtually every course that was given, all due to granulocytopenia, thrombocytopenia, or both. During the pilot study, one patient developed grade 4 thrombocytopenia during the fifth course, which improved to grade 1 after 102 days. Subsequent patients were treated only if the platelet count was >= 100,000/µL; all other hematologic toxicity was readily reversible. Eleven patients (21.6%) received granulocyte colony-stimulating factor while on the study.

Two patients (3.9%) experienced febrile neutropenia. One patient developed sepsis related to a central venous catheter and died 1 week after receiving the first dose of chemotherapy. No other deaths occurred while patients were on the study.

Nonhematologic toxicities are listed in Table 2. A total of 135 courses were administered (median, two courses; range, zero to six courses). Nonhematologic toxicity of grade 3 or greater consisted mainly of nausea and vomiting (seven patients, 13.7%) and infection (seven patients, 13.7%). Grade 1 or 2 fatigue was reported by four patients (7.8%) and grade 3 fatigue by one patient (2.0%). Nephrotoxicity and neurotoxicity were minimal, occurring in 2.2% and 5.2%, respectively, of courses delivered. Grade 1 or 2 paresthesias were reported in three patients (5.9%). One patient experienced proximal muscle weakness of undetermined etiology, and one patient experienced mental status changes that were possibly related to ifosfamide. There were no reports of hemorrhagic cystitis.


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  		Table 2. Table 2. Nonhematologic Toxicity
 
Dose reductions beyond the omission of day 8 or day 15 were infrequent, and the majority of patients tolerated this regimen at full dose-intensity when given twice per month. One patient did complete two courses without any omission or modification. Eight patients (15.7%) received gemcitabine at the reduced dose of 600 mg/m2 because of hematologic toxicity, of which one required further dose reduction to 500 mg/m2. Three of these patients also required dose reductions of cisplatin to 25 mg/m2, ifosfamide to 800 mg/m2, or both cisplatin and ifosfamide to 20 mg/m2 and 800 mg/m2, respectively, for hematologic toxicity. Cisplatin was omitted during one course because of nephrotoxicity.

Tumor Response and Survival
Response could be assessed in 49 of 51 registered patients. Two CRs (4.1%) and 18 PRs (36.7%) were observed for an overall response rate of 40.8% (exact 95% confidence interval, 27% to 56%). The two patients who achieved a CR had previous cystectomies and tumor confined to the lymph nodes. Both patients subsequently underwent lymph node dissection, at which time microscopic residual disease was detected (response duration to time of surgery, 3 and 4 months). The response rate was 47.8% (11 of 23 patients) for patients with tumor confined to the lymph nodes, local recurrence, or locally advanced disease and was 34.6% (nine of 26 patients) for those with extranodal metastases at the time of study entry. The response rates by disease site for the entire group are shown in Table 3.


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  		Table 3. Table 3. Response Rate by Tumor Site
 
The median overall survival duration was 9.5 months (Fig 1); the 2-year survival was 18.4% (nine of 49 assessable patients). Five patients were alive with disease at the time of their last follow-up (survival duration, 25+, 27+, 42+, 51+, and 52+ months).



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  		Fig 1. Overall survival from study registration.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We found that giving cisplatin/gemcitabine together with ifosfamide 1 g/m2 weekly for 3 weeks was not feasible because of myelosuppression. Patients on this trial received only two doses of CGI per 28-day cycle (days 1 and 8 or days 1 and 15), as determined by recovery of the peripheral-blood cell counts. Given this way, the CGI regimen produced remarkably little nonhematologic toxicity, which is in contrast to regimens containing more traditional doses of ifosfamide.

Ifosfamide has demonstrated favorable single-agent activity in patients with advanced urothelial carcinoma when given at a dose of 7.5 g/m2 for 2 to 5 days but was associated with dose-limiting renal and CNS toxicities.6 Combination regimens containing standard doses of ifosfamide (4.5 to 7 g/m2 per cycle) have yielded response rates of 67% to 79% in patients with untreated, metastatic urothelial carcinoma but were also poorly tolerated.19,20 Bladder cancer patients are often elderly or have had previous exposure to cisplatin and seem to have a higher risk of nonhematologic toxicity from ifosfamide than is typically observed in the soft tissue sarcoma setting.21 Toxicity is therefore a significant challenge in combining ifosfamide with gemcitabine for the treatment of metastatic bladder cancer.11 In this study, a representative group of patients with advanced TCC tolerated a small dose of ifosfamide combined with a cytotoxic dose of gemcitabine exceptionally well, with myelosuppression that was manageable when treatment was limited to two doses per month.

We observed an overall response rate of 40.8% with a median survival of 9.5 months, which is similar to results of salvage therapy reported with more toxic regimens.5,6 Two CRs were observed, both in patients with disease confined to the lymph nodes, and neither patient had a pathologic CR. PRs were seen in patients with visceral and nonvisceral metastases as well as in patients with locally advanced disease. These results demonstrate that CGI administered twice per month is an active regimen in the treatment of metastatic and unresectable urothelial carcinoma. Activity was seen despite previous treatment with platinum-based chemotherapy. Salvage therapy for metastatic TCC often includes a platinum agent as a component of combination chemotherapy, such as paclitaxel/methotrexate/cisplatin, because combination regimens consistently outperform single-agent therapy.3,5,6 However, with an increasing number of active agents, there are now reports of new combination regimens without platinum such as doxorubicin/ifosfamide/gemcitabine,11 paclitaxel/gemcitabine,8,22 and paclitaxel/ifosfamide.23 The role of cisplatin in the salvage therapy of metastatic TCC will be further defined through prospective study of CGI and these other new regimens.

TCC is a particularly chemosensitive tumor, and response rates of 20% to 60% are not unusual in the salvage setting.5,6,8,22 However, we note that this degree of antitumor activity is unexpected for the drugs given at these small doses, and the result provides further evidence of synergy between gemcitabine and the DNA-damaging drugs cisplatin and ifosfamide. Weekly chemotherapy administration was chosen to sustain the exposure to gemcitabine, but dose-dense schedules, such as CGI, have other potential advantages compared with treatment administered at longer intervals of 3 or 4 weeks. Treatment given every 1 or 2 weeks is often less toxic and less costly and has better patient acceptance.24 The combination of gemcitabine 2,500 to 3,000 mg/m2 and paclitaxel 150 mg/m2 given every 2 weeks for salvage therapy of urothelial carcinoma was recently reported by Sternberg et al8; this was well tolerated and produced responses in 80% of patients whose adjuvant or neoadjuvant chemotherapy failed and 27% of patients whose chemotherapy for metastatic disease failed. In our study, we found that CGI was not practical for weekly administration but was effective and well tolerated when given twice per month, or approximately every 2 weeks.

On the basis of these results, the authors have initiated a phase II trial of this combination given as a single dose every 14 days in patients with untreated, metastatic urothelial carcinoma. We have adjusted the cisplatin and gemcitabine starting doses to 50 mg/m2 and 900 mg/m2, respectively, in anticipation of better hematologic tolerance in untreated patients. The ifosfamide dose has been kept at 1 g/m2 and is well tolerated without the routine administration of mesna.


   ACKNOWLEDGMENTS
 
Supported by Eli Lilly and Company, Indianapolis, IN, and in part by core grant no. CA16672 from the National Cancer Institute, Bethesda, MD.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Sternberg CN, Yagoda A, Scher HI, et al: Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 133: 403-407, 1985[Medline]

2. Scher H, Bahnson R, Cohen S, et al: NCCN urothelial cancer practice guidelines. Oncology 12: 225-271, 1998[Medline]

3. Loehrer PJ, Einhorn LH, Elson PJ, et al: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group trial. J Clin Oncol 10: 1066-1073, 1992[Abstract]

4. von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter phase III study. J Clin Oncol 18: 3068-3077, 2000[Abstract/Free Full Text]

5. Tu SM, Hossan E, Amato R, et al: Paclitaxel, cisplatin, and methotrexate combination chemotherapy is active in the treatment of refractory urothelial malignancy. J Urol 154: 1719-1722, 1995[CrossRef][Medline]

6. Witte RS, Elson P, Bono B, et al: Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol 15: 589-593, 1997[Abstract/Free Full Text]

7. Millikan R, Dinney C, Swanson D, et al: Integrated therapy for locally advanced bladder cancer: Final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 19: 4005-4013, 2001[Abstract/Free Full Text]

8. Sternberg CN, Calabro F, Pizzocaro G, et al: Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy. Cancer 92: 2993-2998, 2001[CrossRef][Medline]

9. Iwasaki H, Huang P, Keating MJ, et al: Differential incorporation of ara-C, gemcitabine, and fludarabine into replicating and repairing DNA in proliferating human leukemia cells. Blood 90: 270-278, 1997[Abstract/Free Full Text]

10. Plunkett W, Huang P, Searcy CE, et al: Gemcitabine: Preclinical pharmacology and mechanisms of action. Semin Oncol 23: 3-15, 1996 (suppl 10)[Medline]

11. Millikan RE, Plunkett WK, Smith TL, et al: Gemcitabine modulation of alkylator therapy: A phase I trial of escalating gemcitabine added to fixed doses of ifosfamide and doxorubicin. Cancer 92: 194-199, 2001[CrossRef][Medline]

12. Kaufman D, Raghavan D, Carducci M, et al: Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J Clin Oncol 18: 1921-1927, 2000[Abstract/Free Full Text]

13. von der Maase H, Anderson L, Crino L, et al: Weekly gemcitabine and cisplatin combination therapy in patients with transitional cell carcinoma of the urothelium: A phase II clinical trial. Ann Oncol 10: 1461-1465, 1999[Abstract/Free Full Text]

14. Marini G, Ferrari VD, Marpicati P, et al: Gemcitabine (GEM) in combination with ifosfamide (IFO) and cisplatin (CDDP) in advanced non-small cell lung cancer (NSCLC): A phase II study. Proc Am Soc Clin Oncol 18: 516a, 1999 (abstr 1989)

15. Bunn PA: Triplet chemotherapy with gemcitabine, a platinum, and a third agent in the treatment of advanced non-small cell lung cancer. Semin Oncol 26: 25-30, 1999 (suppl 4)[Medline]

16. Simon R: How large should a phase II trial be? Cancer Treat Rep 71: 1079-1085, 1987[Medline]

17. Kaplan EL, Meier P: Non parametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef]

18. Bajorin DF, Dodd PM, Mazumdar M, et al: Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 17: 3173-3181, 1999[Abstract/Free Full Text]

19. Einhorn LH, Roth BJ, Ansari R, et al: Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma. J Clin Oncol 12: 2271-2276, 1994[Abstract/Free Full Text]

20. Bajorin DF, McCaffrey JA, Hilton S, et al: Treatment of patients with transitional-cell carcinoma of the urothelial tract with ifosfamide, paclitaxel, and cisplatin: A phase II trial. J Clin Oncol 16: 2722-2727, 1998[Abstract]

21. Antman K, Ryan L, Elias A, et al: Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol 7: 126-131, 1989[Abstract]

22. Meluch AA, Greco FA, Burris HA, et al: Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: A phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 19: 3018-3024, 2001[Abstract/Free Full Text]

23. Sweeney CJ, Williams SD, Finch DE, et al: A phase II study of paclitaxel and ifosfamide for patients with advanced refractory carcinoma of the urothelium. Cancer 86: 514-518, 1999[CrossRef][Medline]

24. Fizazi K, Zelek L: Is ‘one cycle every three or four weeks’ obsolete: A critical review of dose-dense chemotherapy in solid neoplasms. Ann Oncol 11: 133-149, 2000[Abstract/Free Full Text]

Submitted November 21, 2001; accepted March 19, 2002.


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