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Randomized Phase III Trial of High–Dose-Intensity Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (MVAC) Chemotherapy and Recombinant Human Granulocyte Colony-Stimulating Factor Versus Classic MVAC in Advanced Urothelial Tract Tumors: European Organization for Research and Treatment of Cancer Protocol No. 30924

From the Vincenzo Pansadoro Foundation, Rome, Italy.

Address reprint requests to Cora N. Sternberg, MD, FACP, Clinic Pio XI, Via Aurelia 559, Rome, Italy 00165; email: cstern{at}mclink.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: This randomized trial evaluated antitumor activity of and survival asociated with high–dose-intensity chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) plus granulocyte colony-stimulating factor (HD-MVAC) versus MVAC in patients with advanced transitional-cell carcinoma (TCC).

PATIENTS AND METHODS: A total of 263 patients with metastatic or advanced TCC who had no prior chemotherapy were randomized to HD-MVAC (2-week cycles) or MVAC (4-week cycles).

RESULTS: Using an intent-to-treat analysis, at a median follow-up of 38 months, on the HD-MVAC arm there were 28 complete responses (CRs) (21%) and 55 partial responses (PRs) (41%), for an overall response of 62% (95% confidence interval [CI], 54% to 70%). On the MVAC arm, there were 12 CRs (9%) and 53 PRs (41%), for an overall response of 50% (95% CI, 42% to 59%). The P value for the difference in CR rate was .009; and for the overall response, it was .06. There was no statistically significant difference in survival (P = .122) or time to progression (P = .114). Progression-free survival was significantly better with HD-MVAC (P=.037; hazard ratio .75; 95% CI .58 to .98). The median progression-free survival time was 9.1 months on the HD-MVAC arm versus 8.2 months on the MVAC arm. The 2-year progression-free survival rate was 24.7% for HD-MVAC (95% CI, 17.1% to 32.3%) versus 11.6% for MVAC (95% CI, 5.9% to 17.4%).

CONCLUSION: With HD-MVAC, it was possible to deliver twice the doses of cisplatin and doxorubicin in half the time, with fewer dose delays and less toxicity. Although a 50% difference in median overall survival was not detected, a benefit was observed in progression-free survival, CR rates, and overall response rates with HD-MVAC.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ADJUSTED (world standard population) rates of mortality due to bladder cancer range between five and eight persons per 100,000 in Europe, and rates are even higher in Denmark, Hungary, and Italy. Bladder cancer mortality has begun to decrease in Europe, approximately 10 years later than in the United States, most likely because of the delay in controlling major risk factors for bladder cancer such as tobacco and occupational exposure to carcinogens.¹

Currently, systemic combination chemotherapy is the only treatment that may result in long-term survival in some patients with advanced metastatic disease. Although antitumor activity has been demonstrated with several single agents, the median duration of survival associated with single-agent therapy has generally varied between 4 and 6 months. The median survival time for combination regimens such as methotrexate plus vinblastine or doxorubicin plus cisplatin has been 8 months.²

The development of cisplatin-based combination chemotherapy regimens for advanced urothelial cancer began in the 1980s. In addition, during this period more reproducible and accurate assessments of efficacy were developed. The combinations of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); cisplatin, methotrexate, and vinblastine; cisplatin and methotrexate; and cyclophosphamide, doxorubicin, and cisplatin (CISCA or CAP) were considered some of the most active regimens.^3-5

That era was highlighted by the development of the MVAC regimen at Memorial Sloan-Kettering Cancer Center (MSKCC).⁶ In 121 cases of bidimensionally measurable disease, the response rate (complete response [CR] plus partial response [PR]) was 72%. Thirty-six percent of patients attained a CR. Long-term survival was achieved by patients with a CR. Patients with a CR to chemotherapy plus surgery survived twice as long as patients who had a PR.³ The overall survival time for the whole group was 13.1 months. Chemotherapy was shown to be more effective against nodal disease than against visceral metastases.^3,7

Two prospective randomized trials established the value of MVAC.^7,8 In a multicenter, international trial involving 239 assessable patients, response was noted in 11% of patients treated with single-agent cisplatin therapy and in 36% treated with MVAC chemotherapy. The median survival time associated with MVAC was 13.5 months, compared with 8.2 months among patients treated with cisplatin (P = .04).

At the M.D. Anderson Cancer Center, MVAC was also found to be superior to CISCA. The median survival time was 11.2 months after treatment with MVAC, compared with 8.4 months after CISCA chemotherapy. The response rate (CR + PR) was 65% with MVAC and 46% with CISCA (P < .05).⁷

Pretreatment patient characteristics, particularly performance status and sites of disease, may have an impact on both response rates and survival among patients with advanced urothelial disease treated with MVAC.^8-10 In a study by Bajorin et al¹⁰ at MSKCC, risk factors for worsened survival included a baseline performance status score of less than 80% and the presence of visceral metastases.

The MVAC data were updated by the MSKCC group, who reported results in 203 patients treated with different MVAC regimens. At a median follow-up of 47 months, 46 patients had attained a CR with chemotherapy alone. The 5-year survival rate was 40%. Among 30 patients who had a CR with chemotherapy plus surgery, the 5-year survival rate was 33% at a median follow-up of 37 months. Postchemotherapy resection of viable tumor resulted in long-term survival in selected patients.¹⁰

The use of cisplatin-based combination chemotherapy has been associated with significant toxicity and resulted in long-term survival in approximately 15% to 20% of patients in the MSKCC series.¹⁰ The median survival time was only 13 months, and long-term survival was achieved in approximately 15% of patients with metastases in visceral sites and 30% of those with nodal disease. In the long-term follow-up of the intergroup study, only 3.2% of patients with metastatic lesions treated with MVAC were alive and free of disease.¹¹

For this reason, other therapeutic options are clearly needed. One strategy for enhancing the CR rate is to increase the dose of chemotherapy with hematologic growth factor support. In an early study, MVAC was given with granulocyte colony-stimulating factor (G-CSF), and both mucositis and myelosuppression were ameliorated.¹² After initial favorable reports of responses in heavily pretreated patients with escalated MVAC and growth factor therapy,¹³ several groups began phase II trials of escalated chemotherapy.^14-16 In the United States, this approach has been largely abandoned because of excessive toxicity.

In Europe, a novel treatment involving escalated doses of MVAC and granulocyte macrophage colony-stimulating factor given in 2-week cycles was evaluated in previously untreated patients.¹⁴ The study’s 70% response rate was encouraging. On the basis of the results of this preliminary trial, the Genitourinary Tract Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer began a randomized trial in which the dose-intensities of cisplatin and doxorubicin were increased. This study was initiated to determine whether increasing the dose-intensity of MVAC by adding G-CSF could lead to an improvement in overall survival. This cooperative trial is the only study that has addressed the issue of dose-intensity in a randomized fashion involving standard MVAC.¹⁷

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The trial was initiated in June 1993 as a randomized phase II trial and became a randomized phase III trial in April 1996. The main objective was to evaluate antitumor activity (phase II) of and overall survival (phase III) associated with high–dose-intensity MVAC plus recombinant methionyl human G-CSF, given in 2-week cycles, versus classic MVAC in patients with advanced urothelial tract cancer.

Eligibility criteria included the presence of transitional-cell carcinoma (TCC) of the urinary tract (bladder, ureter, urethra, or renal pelvis) and bidimensionally measurable metastatic or locally advanced decease, no prior systemic cytotoxic or biologic treatment, and a World Health Organization (WHO) performance status of 0, 1, or 2. Adequate renal (creatinine level < 150 µmol/L, measured creatinine clearance > 60 mL/min) and liver (bilirubin level < 20 µmol/L) functions were required.

Bidimensionally measurable metastases (M1, stage IV) included lung metastases not adjacent to any other structure, superficial lymph node metastases, skin and subcutaneous metastases, and metastases in lymph nodes in the mediastinum and in the retroperitoneal region that could be measured by computed tomography (CT). The initial diameters of such nodes had to be greater than 2.5 cm, to allow reliable measurements during follow-up. Liver metastases were only acceptable if measurable by sonography, CT, or magnetic resonance imaging. The initial diameters had to be greater than 2.5 cm.

Unresectable primary bladder cancer (T3-T4) was considered an indicator lesion only if the tumor could be measured bidimensionally by magnetic resonance imaging or CT. To ensure reproducibility of subsequent CT scans, detailed anatomic landmarks were given in the reports and the applied technique was performed according to a detailed protocol, which specified the interval between serial cuts, preferably a maximum of 1 cm. Lesions occurring in tissues that had been irradiated previously were assessable only if radiation treatment had been completed at least 3 months earlier and if the lesions had since progressed or were new.

The protocol was conducted according to the guidelines of the Helsinki Declaration. Written informed consent was obtained from patients according to the rules and regulations of the individual participating institutions.

Chemotherapy
On the classic MVAC arm, the target doses were delivered in 4-week cycles. On the HD-MVAC arm, cycles lasted 14 days. The protocol treatment schedules are shown in Fig 1. Over a similar period of 8 weeks, patients on the classic MVAC arm received two cycles and patients on the HD-MVAC arm received four cycles.

View larger version (16K): [in this window] [in a new window]   Fig 1. MVAC and HD-MVAC regimens. ADM, doxorubicin; CDDP, cisplatin; MTX, methotrexate; VLB, vinblastine.

Treatment Duration
At least two courses were given. Patients were evaluated on days 28 and 56 and every two cycles thereafter. To confirm response, a repeat evaluation was performed after 1 month, per good clinical practice. Patients with an objective response or no change and with stable performance status continued treatment until there was objective evidence of disease progression or until significant toxicity occurred.

Criteria for Evaluation
Patients were not normally considered assessable for response if they had not received at least two treatment cycles. However, patients whose disease rapidly progressed after one course were deemed assessable for response (as having progressive disease) and were included in the analyses of response rate.

Patients were evaluated according to WHO criteria. A CR was defined as complete disappearance of all objective parameters (determined by two observations not less than 4 weeks apart) and no development of new lesions. A PR was defined as a 50% reduction in the sum of the products of the two largest perpendicular diameters of all measurable lesions (determined by two observations not less than 4 weeks apart) and no development of new lesions. A reduction of less than 50% or an increase of less than 25% in the sum of the products of the two largest perpendicular diameters of one or more lesions was considered stable disease. Independent review of responses was not undertaken. Progressive disease was defined as the appearance of new lesions or an increase greater than 25% of the product of the two largest perpendicular diameters of one or more measurable lesions. Response duration was defined as the time from the start of treatment to the date on which progressive disease was first noted. The time to first progression was considered the time from entry onto the study until the first event of progression. Patients without evidence of disease were censored at the time of most recent follow-up. Progression free-survival duration was defined as the interval between entry onto the study and either death due to any cause or progression (whichever occurred first). Patients alive without evidence of disease were censored at the time of most recent follow-up. Survival time was the interval between study entry and death, and patients were censored at the time of most recent follow-up.

Statistical Design
Patients were randomized to classic MVAC or HD-MVAC. Stratification was according to the treating institution and WHO performance status. The main end point of the phase III trial was overall survival. Secondary end points included progression-free survival, time to progression, response rate, and toxicity. The objective of the trial was to detect a relative difference of 50% in median overall survival time between the two arms from 12 months to 18 months (hazards ratio [HR], 1.5). This corresponds to an absolute difference of 13% at the time of the median. With a two-sided log-rank test at the 5% significance level and 80% power, this objective required 192 events (deaths).

Statistical Analysis
All analyses were carried out according to the intent-to-treat principle, and statistical significance was set at the .05 level. Time-to-event comparisons were performed using the log-rank test. Estimation of survival curves was by the Kaplan-Meier technique. Comparison of distribution of binary and nonordered categorical variables was performed using the ² test, and comparison of continuous variables was performed using the Wilcoxon rank sum test. Comparison of ordered categorical variables was performed using a ² test for linear trend.

Dose-intensities were computed by dividing the actual total dose of the drug by the overall duration of the treatment and by the body surface area of the patient. Dose-intensities were expressed in milligrams per meter squared per week.

Listed in Table 1 are the intended dose-intensities and the dose-intensity ratios (ratios of dose-intensities on the HD-MVAC arm to dose-intensities on the MVAC arm). With HD-MVAC, the dose-intensities of doxorubicin and cisplatin were doubled, but only approximately 70% of the vinblastine and methotrexate doses were intentionally given compared with MVAC. A ratio of less than 1 indicated reduced dose-intensity on the HD-MVAC arm compared with MVAC, and a ratio of more than 1 indicated increased dose-intensity on the HD-MVAC arm compared with MVAC.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between June 1993 and November 1998, 263 patients from 21 European centers in eight countries (see Appendix) were randomized to classic MVAC (n = 129) or HD-MVAC (n = 134). The median follow-up was 38 months (maximum, 74 months).

The two groups were well balanced in terms of patient characteristics ( Table 2). The median WHO performance status was 1. Twenty percent of patients on the MVAC arm and 15% on the HD-MVAC arm had had prior radiotherapy, and 73% who received MVAC and 75% who received HD-MVAC had had prior surgery. In 82% of patients on the MVAC arm and 88% of patients on the HD-MVAC arm, the primary tumor had originated in the bladder. The renal pelvis was the initial site of disease in 12% of patients receiving MVAC and 8% receiving HD-MVAC. Other patients had tumors that had originated in the ureter, urethra, or prostatic ducts (Table 2). Visceral metastases were present in 47 patients (36%) on the MVAC arm and in 37 (28%) on the HD-MVAC arm. In other words, there were no lung, liver, or bone metastases in 82 patients (64%) receiving MVAC and 97 (72%) receiving HD-MVAC (P = .125).

With regard to HD-MVAC, the median number of cycles was six (range, one to 12) and the treatment duration was 12 weeks (range, 4 to 40 weeks), compared with four cycles (range, one to eight) and 21 weeks (range, 2 to 28 weeks) for MVAC. The median cycle duration for HD-MVAC was 15 days (range, 13 to 27 days), compared with 31 days (range, 24 to 47 days) for MVAC.

The median relative dose-intensity of methotrexate was 71% on the MVAC arm, compared with 91% on the HD-MVAC arm; median relative dose-intensities of vinblastine resembled those of methotrexate: 71% (MVAC) and 90% (HD-MVAC). The median relative dose-intensity of doxorubicin was 88% on the MVAC arm, compared with 91% on the HD-MVAC arm. Eighty-eight percent of the cisplatin was delivered in the MVAC regimen, v 90% in the HD-MVAC regimen.

The median total dose of methotrexate delivered in the MVAC regimen was 349 mg/m², compared with 157 mg/m² in the HD-MVAC regimen. The median vinblastine dose in the MVAC regimen was also double that in the HD-MVAC regimen (34 mg/m² v 16 mg/m²). The median doxorubicin dose was 162 mg/m² on the HD-MVAC arm, compared with 133 mg/m² on the MVAC arm; median cisplatin doses were 382 mg/m² and 286 mg/m², respectively.

An intent-to-treat analysis (all patients entered onto the study) revealed that there were 12 CRs (9% of patients; 95% confidence interval [CI], 5% to 16%) and 53 PRs (41%; 95% CI, 33% to 50%) on the MVAC arm, for an overall response rate of 50% (95% CI, 42% to 59%). On the HD-MVAC arm, there were 28 CRs (21% of patients; 95% CI, 14% to 28%) and 55 PRs (41%; 95% CI, 33% to 49%), for an overall response rate of 62% (95% CI, 54% to 70%). The P value for the difference in CR rate was .009 and for the difference in overall response rate (CR + PR) was .06.

One hundred twenty-one patients on the MVAC arm and 127 on the HD-MVAC arm had bidimensionally measurable TCC and were also eligible for response assessment. In these patients with bidimensionally measurable disease, the overall response rate for HD-MVAC was 72% (95% CI, 65% to 81%), compared with 58% (95% CI, 48% to 67%) for MVAC. The CR rate was 25% (95% CI, 17% to 33%) for HD-MVAC, compared with 11% (95% CI, 5% to 16%) for MVAC. The P value for the difference in CR rate was .006, and the P value for the difference in overall response rate (CR + PR) was .016.

Responses according to disease site are listed in Table 5. Complete remissions were most often reported in lymph nodes; however, responses were noted at all disease sites.

View larger version (13K): [in this window] [in a new window]   Fig 2. Overall survival. HR, hazards ratio; N, number of patients treated; O, number of observed events.

View larger version (13K): [in this window] [in a new window]   Fig 3. Time to first progression. N, number of patients treated; O, number of observed events.

View larger version (13K): [in this window] [in a new window]   Fig 4. Progression-free survival. N, number of patients treated; O, number of observed events.

Toxicity
Toxicities encountered during chemotherapy are listed in Table 7. There was a trend toward more WBC toxicity on the MVAC arm than on the HD-MVAC arm, probably because of the G-CSF (P < .001). On the HD-MVAC arm, only 20% of patients had grade 3 to 4 WBC toxicity. In terms of thrombocytopenia, more than 70% on the MVAC arm and more than 60% in the HD-MVAC arm did not have grade 2 to 4 toxicity at any time during their courses. Neutropenic fever was significantly less frequent on the HD-MVAC arm (10%) than on the MVAC arm (26%; P < .001). G-CSF was given infrequently to patients on the MVAC arm in this study. Only 19% received G-CSF, as opposed to 94% on the HD-MVAC arm. Mucositis was more frequent with MVAC than with HD-MVAC. The toxic death rate was 3% on the HD-MVAC arm and 4% on the MVAC arm. MVAC chemotherapy may have been the cause of death in six cases (4%). One of these patients had a hemorrhage and ischemic colitis, two patients had gastrointestinal bleeding, two patients had pulmonary infection, and one had granulocytopenic fever resulting in candida septicemia 1 month after chemotherapy. On the HD-MVAC arm, there were four deaths (3%) that may have been due to chemotherapy. Two patients had septic shock, one had neutropenia and pneumonia, and one stopped therapy after two cycles because of urosepsis but died 5 months later because of infection. There was no differences in creatinine toxicity between the two arms, despite the schedule of administration every 2 weeks (P = .815). Grade 2 to 3 toxicity occurred in 5% (MVAC) and 6% (HD-MVAC).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this trial, the dose-intensities of the individual drugs in the MVAC regimen were increased and this new regimen was compared with classic MVAC. A statistically significant difference in terms of CR rate and progression-free survival in favor of HD-MVAC was noted in this patient population, in which risk factors were well balanced. Although the survival curves seem to diverge in favor of the HD-MVAC arm, there are small numbers of patients in the tails of the curves. There is, however, the potential for a cohort of long-term survivors in this study. Survival is the key end point, and response rates may not be a good surrogate end point in this disease.¹⁸ Survival was the most important end point in this trial, and no statistically significant difference in overall survival was demonstrated.

The dose-intensities of cisplatin (205%) and doxorubicin (201%) in the high-dose regimen were twice those in the classic MVAC regimen. The dose-intensities of methotrexate (86%) and vinblastine (81%) were lower on the HD-MVAC arm.

On the HD-MVAC arm, the total doses of doxorubicin and cisplatin were higher. The total doses of methotrexate and vinblastine were higher, however, on the MVAC arm. The total duration of treatment was also longer on the MVAC arm. The HD-MVAC regimen is therefore a more dose-dense regimen in terms of doxorubicin and cisplatin. It must be emphasized that this study may demonstrate the benefit of administering G-CSF in conjunction with MVAC rather than the benefit of dose-intensification.

In this study, HD-MVAC had a more favorable toxicity profile than MVAC. It was possible to give more cycles in a shorter period on the HD-MVAC arm than on the MVAC arm. This was probably because there was less WBC toxicity and mucositis, owing to the inclusion of G-CSF in the regimen, and because less total methotrexate was administered to the former group. The toxic death rates of 3% with HD-MVAC and 4% with MVAC are comparable to those reported in the literature. In a concurrent multicenter study, the toxic death rate with MVAC was 3%.¹⁹ The use of growth factors such as G-CSF has considerably improved the toxicity profile. It is unfortunate that G-CSF was given to only 19% of patients on the MVAC arm in this study.

In an industry-sponsored study, MVAC was compared with gemcitabine and cisplatin (GC).¹⁹ GC was evaluated in patients with locally advanced or metastatic TCC (but not necessarily bidimensionally measurable disease). Overall survival was similar on both arms, as were time to progression, time to treatment failure, and response rates. The GC regimen was not associated with improved survival but may be tolerated better than classic MVAC. This regimen has never been compared with HD-MVAC.

Other regimens that have become increasingly popular for treating patients with metastatic transitional-cell tumors include combinations of paclitaxel and carboplatin. In most studies, response rates have been high, with median survival times of 8 to 9 months.^18,20,21 An ongoing Eastern Cooperative Oncology Group phase III trial is comparing the combination of paclitaxel and carboplatin with MVAC.

For patients who tolerate cisplatin-based therapy, other new and interesting regimens that include cisplatin, paclitaxel, ifosfamide, and/or gemcitabine are possibilities.^22,23 None of these new regimens have been compared with MVAC in a phase III study.

In conclusion, both regimens were relatively safe in this multicenter international trial. HD-MVAC permitted delivery of higher doses in a shorter time. A significant difference in terms of CR rate and overall response rate was noted. A benefit in terms of progression-free survival in favor of HD-MVAC was noted as well. No difference in overall survival, the main end point of the study, was found.

With HD-MVAC, in which MVAC plus G-CSF is given in 2-week cycles, it is possible to deliver twice the doses of cisplatin and doxorubicin in half the time, with fewer dose delays and less toxicity. This decrease in toxicity compared with standard MVAC is most likely attributable to the G-CSF. The shorter time needed for administration may make the newer regimen attractive for use in both neoadjuvant and adjuvant settings.

Research in the last 10 years has established the chemosensitivity of urothelial tumors, and the MVAC regimen has been the gold standard for treatment of such tumors. Whether the gold standard may be shifting is a matter of debate. In 1989, the median survival time with MVAC was approximately 1 year. Recent reports of survival times of less than 9 months, along with high response rates, with novel, less toxic combination regimens should be viewed with skepticism.^18,20,21 Patient selection, early diagnosis, and stage migration may be responsible for the shift in more recent trials toward a median survival time of 18 to 20 months.^24,22 Only randomized, controlled phase III trials with an end point of improved survival can definitively change the gold standard.

Participating centers include the following: San Raffaele, Rome; Centro Di Riferimento Oncologico, Aviano; Ospedale di Circolo e Fundazione Macchi, Varese; and University of Palermo, Palmero, Italy; University Medical Centre, Nijmegen; Antoni van Leeuwenhoekhuis; Academisch Ziekenhuis der Vrije Universiteit; Academisch Medisch Centrum, Amsterdam; Universitaire Ziekenhuis, Antwerpen; Erasmus Hospital, Rotterdam; and Bosch Medicentrum, The Netherlands; Institut Gustave Roussy, Villejuif; Hospices Civils de Strasbourg; and Hopital Leon Berard, Lyon, France; Klinikum Nurnberg; and Medizinische Fakultät der RWTH, Aachen, Germany; Radium Hospital, Oslo, Norway; Freeman Hospital, Newcastle, England; and Hospital Nuestra Senora del Pino, Las Palmas, Spain.

	ACKNOWLEDGMENTS

 
Supported by grant nos. 5U10-CA11488-22 through 5U10-CA11488-30 from the National Cancer Institute, Bethesda, MD.

	NOTES

 
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted November 27, 2000; accepted February 8, 2001.

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