Annals of Oncology Advance Access originally published online on March 9, 2007
Annals of Oncology 2007 18(5):917-924; doi:10.1093/annonc/mdm062
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© 2007 European Society for Medical Oncology
urogenital tumors |
Refining the optimal chemotherapy regimen for good-risk metastatic nonseminomatous germ-cell tumors: a randomized trial of the Genito-Urinary Group of the French Federation of Cancer Centers (GETUG T93BP)
1 CRLC Val d'Aurelle, Montpellier
2 Centre Eugène Marquis, Rennes
3 Institut Gustave Roussy, Villejuif
4 Institut Claudius Régaud, Toulouse
5 Centre Alexis Vautrin, Nancy
6 Institut Bergonié, Bordeaux
7 Centre François Baclesse, Caen
8 Centre Oscar Lambret, Lille
9 Centre Eugène Papin, Angers
10 Centre Léon Bérard, Lyon, France
* Correspondence to: Dr S. Culine, Department of Medical Oncology, CRLC Val d'Aurelle, Parc Euromédecine, 34298 Montpellier Cedex 5, France. Tel: +33-467613152; Fax: +33-467613022; E-mail: stculine{at}valdorel.fnclcc.fr
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Abstract |
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Background: High cure rates are expected in good-risk metastatic nonseminomatous germ-cell tumor (NSGCT) patients with bleomycin, etoposide and cisplatin.
Patients and methods: Patients received either three cycles of BE500P or four cycles of E500P every 3 weeks. Disease was defined according to the Institut Gustave Roussy prognostic model. Patients were retrospectively assigned into the International Germ Cell Cancer Collaborative Group (IGCCCG) classification. A sample size of 250 patients was necessary for an expected favorable response rate (primary end point) of 90% and not more than a 10% difference between the two arms.
Results: Among 257 assessable patients, 124 and 122 patients achieved a favorable response in the 3BE500P and 4E500P arms, respectively (P = 0.34). Median follow-up was 53 months. The 4-year event-free survival rates were 91% and 86%, respectively (P = 0.135). The 4-year overall survival rates were not significantly different [five deaths versus 12 deaths, respectively (P = 0.096)]. Similar nonsignificant trends were observed in good IGCCCG prognosis patients.
Conclusions: Both regimens produced similar results in terms of favorable response rates. As the trial was underpowered for survival analyses, conclusive data would require a larger randomized trial. Unless such a study is done, 3BE500P is the treatment of choice for metastatic NSGCT patients.
Key words: chemotherapy, good-risk, testis cancer, germ cell cancer
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionappendixAcknowledgementsReferences |
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The use of cisplatin-based combination chemotherapy has led to a dramatic improvement in the cure rates of patients with metastatic nonseminomatous germ-cell tumors (NSGCT) [1–3]. In patients with good-risk characteristics, the 5-year overall survival (OS) rate was 92% from a pooled analysis of 5202 patients which were used for defining the consensus classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) [4]. During the last 20 years, a series of clinical trials have been conducted to refine the optimal chemotherapy regimen by reducing short- and long-term toxic effects without compromising cure rates. As a result of its better toxicity profile and equivalent efficacy, etoposide (100 mg/m2/d >5 days or E500) has replaced vinblastine in front-line regimens [5]. At the Memorial Sloan Kettering Cancer Center (MSKCC), four cycles of etoposide and cisplatine (E500P) were shown to be equivalent but less toxic as compared with three cycles of a regimen combining vinblastine, dactinomycin, bleomycin, cyclophosphamide and cisplatin (VAB-6) [6]. From then on, the E500P regimen (four cycles) became the gold standard in this institution. Mature data with 289 patients who received four cycles of E500P were recently reported. Nine (6%) patients died as a result of disease [7]. Concomitantly investigators at the Indiana University demonstrated that three cycles of bleomycin, etoposide and cisplatin (BE500P) were less toxic and equivalent in terms of efficacy as compared with four cycles of BE500P [8, 9]. Thus, three cycles of BE500P were considered as another standard treatment. A European trial recently confirmed the effectiveness of three cycles when using the BE500P regimen [10].
In 1993, the Genito-Urinary Group of the French Federation of Cancer Centers (GETUG) designed a randomized trial to compare the efficacy and toxicity of three cycles of BE500P or four cycles of E500P in patients with good-risk NSGCT. We are reporting the mature results of this study.
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patients and methods |
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patients
Eligible patients had a histologically confirmed NSGCT with the following features: testicular or retroperitoneal primary, no previous chemotherapy, metastatic disease evidenced by radiographic assessment or raised serum tumor markers, good-risk disease according to the Institut Gustave Roussy prognostic model based on serum
-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) levels [11], and adequate hematological, renal and hepatic functions. Exclusion criteria included female sex, pure seminoma, no proof of metastatic disease, second primary tumor and poor prognostic features based on serum AFP and hCG levels or primary mediastinal tumor. Entry to study required confirmation of the histopathology, a computed tomographic scan of the abdomen and thorax, serum AFP, hCG and lactate dehydrogenase (LDH) levels as well as blood tests for bone marrow, renal and hepatic functions. All patients were required to sign written, informed consent before randomization and treatment according to French legal procedures.
treatment plan
Treatment after randomization consisted of either three cycles of BE500P i.e. bleomycin (Sanofi-Aventis, France) (30 IU on days 1, 8 and 15), etoposide (Merck, France) (100 mg/m2 on days 1–5) and cisplatin (Merck, France) (20 mg/m2 on days 1–5) or four cycles of E500P i.e. the same regimen without bleomycin. Each cycle of BE500P or E500P was repeated every 3 weeks. At the end of chemotherapy, the surgical resection of all residual supracentrimetric masses was recommended in both arms as well as the delivery of two additional cycles of chemotherapy with vinblastine, ifosfamide and cisplatin if viable cancer cells were found. Treatment toxicity was graded according to standard World Health Organization criteria [12]. Chemotherapy cycles were to be delayed until recovery if the neutrophil count was <1.0 x 109/l or the platelet count was <100 x 109/l by day 21 of the previous cycle. In the event of febrile neutropenia, the use of hematopoietic growth factors (HGF) was mandatory for subsequent cycles. Other indications for HGF were at the discretion of investigators. No erythropoietin support was used. Bleomycin was to be stopped if there was clinical evidence of pulmonary toxicity. Cisplatin had to be stopped if creatinine clearance fell <0.8 ml/s. Ototoxicity was assessed clinically by asking about tinnitus and/or decreased hearing. The occurrence of a grade 
2 renal toxicity led to stop cisplatin. No other dose attenuation was allowed.
assessment of efficacy
Favorable responses included any of the following situations: clinical complete responses (normal levels of serum tumor markers, no clinical or radiological evidence of residual disease), pathological complete responses (normal levels of serum tumor markers and complete resection of residual masses with pathologic analysis revealing necrotic debris, fibrosis or mature or immature teratoma), surgical complete responses (normal levels of serum tumor markers and complete resection of residual masses with pathologic analysis revealing persistent viable cancer cells) or partial responses (PRs) (normal levels of serum tumor markers and infracentrimetric residual masses). Any other situation was judged as an incomplete response. Relapses were defined as recurrences of the disease observed after favorable responses and requiring second-line chemotherapy (with or without surgery). Pure teratoma relapses requiring surgery only as therapy were not considered as relapses. Incomplete responses, relapses from favorable responses or deaths as first events during follow-up were used for the definition of event-free survival (EFS) analyses.
biostatistical considerations
A sample size of 250 patients was necessary for an equivalence formulation with an expected favorable response rate of 90% and not more than a 10% difference between the two arms using a two-sided type I error = 0.10 and a type II error = 0.20. The results in terms of response were presented with a 90% confidence interval (CI) for the difference on the eligible patient population. Equivalence in terms of favorable response rates was determined from the upper and lower limits of the true treatment difference. Patient characteristics were compared with a chi-squared test for categorical variables and with the Wilcoxon nonparametric test for continuous variables. All survival times were calculated from the date of randomization. Survival estimates were obtained from the Kaplan–Meier method and comparisons between treatment groups were evaluated with the log-rank test on the intention-to-treat population (ITT). OS time was calculated until death or to last known follow-up for patients still alive. EFS times were calculated until incomplete response, relapse or death or last known follow-up for patients still alive. Survival estimates at 4 years are presented with a 95% CI. Median follow-up was estimated from the Kaplan–Meier method, using death as a censoring indicator.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionappendixAcknowledgementsReferences |
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A total of 270 male patients from 28 centers from GETUG were randomized from October 1993 to May 1999 (Figure 1). The median follow-up was 52.7 months (range 7.5 months–9.4 years).
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patient population
Eight (3%) randomized patients (three in the 3BE500P arm and five in the 4E500P arm) did not receive treatment: four patients were nonmetastastic, one patient had a pure seminomatous tumor, one patient had a second primary and one patient had poor prognostic features and entered another clinical trial. One additional patient refused further therapy after randomization and was lost to follow-up. These patients were not analyzed for response, toxicity or survival since no data were collected. The 262 remaining patients, 132 in the 3BE500P arm and 130 in the 4E500P arm, were analyzed for toxicity and survival and comprised the ITT population (Figure 1). Baseline patient characteristics were well balanced (Table 1). The retrospective assignment of patients into the IGCCCG classification identified six patients (four in 3BE500P arm, two in the 4E500P arm) with poor-risk characteristics due to extrapulmonary visceral metastases and elevated (>10 N) LDH levels.
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chemotherapy delivery
The analysis of treatment delivery is shown in Table 2.
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Concerning bleomycin administration, a total of 19 (14%) patients did not receive the full dose planned in the protocol. Four patients were underdosed at the first cycle and received 30 mg (one patient) and 60 mg (three patients), but increased to the scheduled 90 mg for subsequent cycles. Three patients discontinued bleomycin after the second cycle of chemotherapy after having experienced clinical bleomycin-related pulmonary toxicity, two were treated with one additional cycle of E500P and one patient received two further cycles of E500P. Decreased doses of bleomycin were observed for six patients at the second cycle and for five patients at the third cycle. Finally one patient in the 3BE500P arm received a full four cycles.
Thirty-three (12.6%) patients received <97% of total dose of cisplatin, ranging from 232 to 290 mg in the 3BE500P arm (15 patients) and from 300 to 385 mg in the 4E500P arm (18 patients). However, only three and four patients received <95% of total cisplatin dose in the 3BE500P and 4E500P arm, respectively. Nine (3.4%) patients received <97% of total dose of etoposide, ranging from 1102 to 1430 mg in the 3BE500P arm (four patients) and from 1900 to 1940 mg in the 4E500P arm (five patients). All 126 patients in the E500P arm received four cycles.
The analysis of the delivered doses of chemotherapy revealed no significant difference between the two arms as far as either the median dose intensities or the median relative dose intensities of etoposide and cisplatin are concerned. Cycle delays were similarly distributed between the two treatment groups with total treatment time delayed by >2 weeks for 4% and 8% of patients in each treatment arm (P = 0.17). Using strict criteria for protocol adherence (at least 97% of full cisplatin dose, at least 97% of full etoposide dose, full bleomycin dose in 3BE500P arm and not >2 weeks overall delay), there were 73% and 78% of patients who received full treatment protocol according to these definitions in the 3BE500P arm and in the 4E500P arm, respectively.
surgery
Surgical resection of residual masses at the end of chemotherapy was carried out for 51% and 52% of patients in the 3BE500P and the 4E500P arms, respectively, after a median 8 weeks after the end of chemotherapy; 48% and 46% had abdominal surgery (retroperitoneal lymph node dissection), 7% and 13% had thoracic surgery (mediastinal lymph node dissection and/or wedge resection of lung metastases), respectively, and 5% of patients had both types of surgery. Resection was reported by investigators as complete in 92% and 88% (P = 0.45) of patients undergoing abdominal surgery and in 89% and 75% (P = 0.41) of patients undergoing thoracic surgery in the 3BE500P and the 4E500P arms, respectively.
toxicity
No toxic deaths occurred. Grades 3–4 neutropenia was more frequently observed in the 4E500P arm, but no significant difference was detected regarding febrile neutropenia rates (Table 3). HGF were used in 24% and 19% of cycles among 36% and 29% of patients in the 3BE500P and 4E500P arms, respectively. Conversely, grades 1–3 neurotoxicity were more frequently observed in the 3BE500P arm (19 grade 1 and two grade 2) as compared with the 4E500P arm (five grade 1 and one grade 2 and one grade 3 at cycle 4) (P < 0.006), as well as grades 1–3 dermatitis (including Raynaud's phenomenon), which was more frequently observed in the 3BE500P arm (25 grade 1, 11 grade 2 and two grade 3) as compared with the 4E500P arm (seven grade 1 and four grade 2) (P < 0.0001). Pulmonary toxicity occurred in 12 patients (seven grade 1, four grade 2 and one grade 3) and eight patients (five grade 1 and three grade 2) in the 3BE500P and 4E500P arms, respectively, but the difference was not significant.
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responses
A favorable response after chemotherapy alone or postchemotherapy surgery was observed in 124 patients allocated to three cycles of 3BE500P (94.7%, 90%CI 91.4% to 97.9%) and 122 patients allocated to four cycles of 4E500P (96.8%, 90%CI 94.2% to 99.4%) (Table 4). The estimated difference in the favorable response rates is –2.2% (90%CI –5.15% to 0.07%). Forty percent of PR patients underwent surgery for residual masses: 12 among 27 patients treated with 4E500P and six among 16 patients treated with 3BE500P.
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relapses
Clinical characteristics and outcome of 20 patients who relapsed after obtaining a favorable response are reported in Table 5. Six and 14 patients had been treated with 3BE500P and 4E500P, respectively. Six relapses occurred among the 18 PR patients who had undergone previous surgery: four in the 4E500P arm and two in the 3BE500P arm. Among the 25 PR patients who did not undergo surgery, two relapses occurred in the 4E500P arm. Second-line therapy included chemotherapy (based on a combination of vinblastine, ifosfamide and cisplatin in most patients) with surgical resection of residual masses when indicated.
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EFS and OS
The 4-year EFS rates in the ITT population were 91% (95% CI 84.5% to 94.7%) in the 3BE500P arm and 86% (95% CI 78.3% to 90.8%) and in the 4E500P arm, respectively (Figure 2, log-rank, hazard ratio = 0.58 95% CI 0.29–1.19, P = 0.135). For the 198 patients receiving full treatment, 4-year EFS rates were 94% and 87% in the 3BE500P and 4E500P arms, respectively (P = 0.08). For the 64 patients not receiving full treatment, the 4-year EFS rates were 83% and 82% in the 3BE500P and 4E500P arms, respectively. All six patients with poor-risk characteristics according to the ICCCG classification had favorable responses, but four patients relapsed within 1 year, and the other two were alive without disease at 29 and 41 months. Considering only the 256 patients classified as good IGCCCG prognosis, the results are similar in favor of the 3BE500P with a hazard ratio = 0.46 (Figure 3b, log-rank, 95% CI 0.21–1.03, P = 0.052) and estimated 4-year EFS rates of 93% (95% CI 87% to 96%) and 86% (95% CI 79% to 91%) in the 3BE500P and 4EP arms, respectively (Figure 3).
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A total of 245 (94% of patients) were still alive at the time of analysis and 17 deaths (five in the 3BE500P arm, 12 in the 4E500P arm) occurred. All of them were related to disease progression. The 4-year OS rates in the ITT population were 96% (95% CI 91.0% to 98.4%) and 92% (95% CI 85.1% to 95.8%) in the 3BE500P and 4E500P treatment arms, respectively (Figure 4, log-rank, hazard ratio = 0.42 (95% CI 0.15–1.20, P = 0.096). Considering only the 256 patients classified as good IGCCCG prognosis, estimated 4-year OS rates were 97% (95% CI 92% to 99%) and 93% (95% CI 86% to 99%) in the 3BE500P (4 deaths) and 4EP (11 deaths) arms, respectively (Figure 5). Given the low number of deaths, it was judged unreasonable to undertake multivariate analyses to adjust treatment comparisons.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionappendixAcknowledgementsReferences |
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Given an anticipated cure rate in excess of 90% of patients with good-risk metastatic NSGCT, the optimal chemotherapy regimen should combine maximal efficacy with minimal toxicity. In Table 6 are reported the results of selected randomized trials which studied the reduction of the number of cycles of treatment or the elimination of bleomycin. Three trials clearly demonstrated that bleomycin could not be deleted without compromising the efficacy of chemotherapy in the following situations: the protocol was limited to three cycles [13], the total dose of etoposide was reduced to 360 mg/m2/cycle (E360) [14] or the vinblastine was used instead of etoposide [15]. An additional trial demonstrated that four cycles of BE360P (with 30 mg bleomycin on day 1 only) led to inferior results as compared with three cycles of BE500P [16]. The interpretation of this trial is difficult because the regimens differed by three parameters: the number of cycles and the total dose and dose intensities of bleomycin and etoposide. Therefore, the importance of the contribution of bleomycin in maintaining the efficacy when three cycles of treatment are given was clearly highlighted. Consequently, only two options are considered as optimal ones from the literature review: three cycles BE500P or three cycles of E500P. However, it should be kept in mind when assessing the results reported in the above studies that different prognostic assessment models were used to select good-risk patients. Additionally, all but two trials considered patients with seminomatous tumors and nonseminomatous tumors as well. These characteristics may generate potential difficulties in drawing firm conclusions about the optimal regimen to be recommended.
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The results of the present study are of importance since the two optimal regimens mentioned above had never been compared in a randomized trial so far. When retrospectively analyzing the Institut Gustave Roussy experience in patients with good-risk metastatic NSGCT, a trend was observed indicating that inferior results could be associated with four cycles of E500P as compared with three cycles of BE500P [17]. Therefore, the GETUG group embarked on a randomized trial comparing the efficacy and toxicity of these two regimens in good-risk metastatic patients, excluding pure seminoma. Given the design of the study, which was on the basis of an equivalence hypothesis concerning the favorable response rates as primary end point, the results clearly demonstrate that both regimens produce similar effectiveness with slightly divergent toxicity profiles. The 95% and 97% favorable response rates, respectively, observed in the BE500P arm and in the E500P arm are quite similar to those previously reported at the Indiana University with three cycles of BE500P (97% and 94% in two successive trials with 96 and 86 patients, respectively) [8, 13] or at the MSKCC with four cycles of E500P (98% among 289 patients) [7]. Considering acute toxic effects, the results regarding grades 3–4 neutropenia (more frequently observed in the E500P arm) as well as grades 1–2 neurological and dermatological toxic effects (more frequently observed in the BE500P arm) are also in accordance with previous reports [6–10, 13, 18]. More surprisingly no major difference was detected between the two arms regarding pulmonary toxicity. Indeed previous studies in germ-cell tumor patients treated with bleomycin-based chemotherapy regimens have shown a significant decrease of pulmonary function tests, although clinically significant symptoms have been reported in <20% of patients [19]. A possible explanation could be the clinical rather than laboratory assessment of the pulmonary toxicity in our study. Another surprising, counterintuitive but unexplained result was the superior neurotoxicity rate observed in the 3BE500P arm since neurotoxicity is related to the cumulative dose of cisplatin.
EFS and OS were secondary end points of the study. A nonsignificant trend towards more relapses (12 versus 20) and deaths (five versus 12) was observed in the E500P arm and this observation (nine versus 18 and four versus 9) was retained when considering patients with good-risk characteristics according to the IGCCCG classification. A similar nonsignificant trend has been reported in the European Organization for Research and Treatment of Cancer trial comparing 4BE360P (seven deaths) to 4E360P (12 deaths) [14]. However, as the design of the present study was underpowered for survival analyses, it does not allow to exclude that these results have occurred by the play of chance alone. Had we used EFS as primary end point, twice as many patients would have been necessary to detect a 5% difference between the two arms. Other explanations could be related to the delivery of chemotherapy or to the optimal template of surgery for residual masses. In this setting, it is important to remember that the present study was a multicenter trial whereas the majority of evidence for the E500P regimen has been described by a single expert center. Considering chemotherapy, no statistical difference in the percent of patients who received full treatment protocol was observed between the two arms. The other interfering factor could be related to the extent of surgery following chemotherapy but the complete resection rates were not statistically different between the two arms. However, the question whether some patients with PR status at the end of treatment had suboptimal resection of residual masses remains open.
It can be concluded from the present study that the 3BE500P and 4E500P chemotherapy regimens, followed by optimal resection of residual disease, produced similar results in terms of favorable response rates with slightly divergent toxicity profiles. As the trial was underpowered for EFS and OS, conclusive data would require a larger randomized trial. Unless such a study is done, considering that the objective of medical management is to offer a therapy minimizing the risks of failure, 3BE500P (followed by the optimal surgical resection of residual masses) is the treatment of choice for patients with good-risk metastatic NSGCT and 4E500P should only be used if there is a contraindication for bleomycin.
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appendix |
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TopAbstractintroductionpatients and methodsresultsdiscussionappendixAcknowledgementsReferences |
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The following clinicians contributed patients to the trial: Dr P. Beuzeboc (Paris); Dr C. Beaumont-Raymond (Troyes); Dr M. Fabbro (Montpellier); Dr T. Facchini (Metz); Dr P. Fargeot (Dijon); Dr F. Fruge (Poitiers); Dr A. Goupil (Saint-Cloud); Dr Z. Haddad (Chalon-sur-Saone); Dr D. Hauteville (Saint-Mandé); Dr F. Khoser (Colmar); Dr C. Linassier (Tours); Dr J.P. Malhaire (Brest); Dr C. Martin (Annecy); Dr Y. Merrouche (Besançon); Dr N. Mottet (Nîmes); Dr M. Mousseau (Grenoble); Dr C. Platini (Thionville); Dr F. Rolland (Nantes); Dr A. Thyss (Centre A Lacassagne, Nice).
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Acknowledgements |
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Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, USA 2003.
Received for publication October 28, 2006. Revision received January 18, 2007. Accepted for publication January 23, 2007.
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References |
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