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Outcome of High-Risk Stage IC, Grade 3, Compared With Stage I Endometrial Carcinoma Patients: The Postoperative Radiation Therapy in Endometrial Carcinoma Trial

From the Departments of Radiation Oncology, Biostatistics, Gynecologic Oncology, and Pathology, Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam; Department of Radiation Oncology, University Medical Center, Utrecht; Department of Radiation Oncology, University Hospital, Groningen; Dr Bernard Verbeeten Institute, Tilburg; Department of Radiation Oncology, Catharina Hospital, Eindhoven; Radiotherapy Institute Friesland, Leeuwarden; Maastricht Radiation Oncology Clinic, Maastricht; and Radiotherapy Institute Stedendriehoek cn Omstreken, Deventer, the Netherlands.

Address reprint requests to Carien L. Creutzberg, MD, Department of Clinical Oncology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands; e-mail: c.l.creutzberg{at}lumc.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
PURPOSE: Stage IC, grade 3 endometrial cancer is regarded as a high-risk category. Stage IC, grade 3 patients were not eligible for the randomized Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial, but were registered and received postoperative radiotherapy.

PATIENTS AND METHODS: The PORTEC trial included 715 patients with stage IC, grade 1 or 2, and stage IB, grade 2 or 3 endometrial cancer. Patients were randomly assigned after surgery to receive pelvic radiotherapy (RT) or no further treatment. A total of 104 patients with stage IC, grade 3 endometrial cancer were registered, of whom 99 could be evaluated. Patterns of relapse and survival were compared with PORTEC patients receiving RT. Median follow-up was 83 months.

RESULTS: The actuarial 5-year rates of locoregional relapse were 1% to 3% for PORTEC patients who received RT, compared with 14% for stage IC, grade 3 patients. Five-year distant metastases rates were 3% to 8% for grade 1 and 2 tumors; 20% for stage IB, grade 3 tumors; and 31% for stage IC, grade 3 tumors. Overall survival rates were 83% to 85% for grades 1 and 2; 74% for stage IB, grade 3; and 58% for stage IC, grade 3 patients (P < .001). In multivariate analysis grade 3 was the most important adverse prognostic factor for relapse and death as a result of endometrial cancer (hazard ratios, 5.4 and 5.5; P < .0001).

CONCLUSION: Patients with stage IC, grade 3 endometrial carcinoma are at high risk of early distant spread and endometrial carcinoma-related death. Novel strategies for adjuvant therapy should be explored to improve survival for this patient group.

	INTRODUCTION

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Patients with stage I endometrial carcinoma, treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) and postoperative radiotherapy (RT) tailored to prognostic factors, have 5-year overall survival rates of 80% to 90%, 5-year cancer-specific survival of 90% to 95%, and locoregional recurrence rates of 4% to 8%.^1–8 However, the subgroup of patients with grade 3 tumors with deep (50% or more) myometrial invasion (stage IC, grade 3) has been reported to have a considerably higher risk of both locoregional and distant relapse. Meerwaldt et al² reported a locoregional relapse rate of 20% for the subgroup of patients with stage IC, grade 3 endometrial carcinoma, in contrast with 4% for the other stage I patients. The Gynecological Oncology Group (GOG) staging study⁹ showed the risk of microscopic pelvic node metastases for patients with clinical stage I endometrial carcinoma to be below 10%, except for those with outer 33% myometrial invasion, for whom the risk amounted to 18%. However, among the patients with surgical stage I disease (excluding the patients with intraperitoneal metastasis, gross breakthrough of the uterine serosa, and gross adnexal metastases), only grade 3 tumors with outer 33% invasion had a more than 10% risk of pelvic node metastases. In the randomized trial reported by Aalders et al,¹ in which 540 women with stage I endometrial carcinoma were randomly assigned after TAH-BSO and postoperative vaginal brachytherapy to additional external-beam pelvic RT or observation, pelvic RT was found to reduce vaginal and pelvic recurrence rates, although survival was not improved (5-year survival, 89% v 91%). However, for the subgroup with grade 3 tumors with deep (outer 50%) myometrial invasion, a survival benefit with additional pelvic RT was suggested (18% cancer deaths, as compared with 27% in the brachytherapy-only group).

When designing the multicenter randomized Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial for stage I endometrial carcinoma,¹⁰ it was decided to exclude the subgroup of patients with grade 3 tumors with outer 50% myometrial invasion from random assignment in view of the reported higher relapse rates and because a survival benefit with pelvic RT had been suggested.¹ It was believed that pelvic RT could not be omitted for the stage IC, grade 3 category. However, it was decided to register these patients to enable evaluation of their outcome and comparison with that of the patients randomly assigned to treatment.

The results of the randomized PORTEC trial have been reported previously.¹⁰ This analysis was done to determine the rates of relapse and survival for the registered patients with stage IC, grade 3 disease and focuses on the comparison of their outcome with that of the patients randomly assigned to treatment in the PORTEC trial.

	PATIENTS AND METHODS

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Patient Selection and Treatment
Patients were eligible for the PORTEC trial if they were diagnosed with stage I endometrial carcinoma, either grade 1 or 2 with deep (50% or more) myometrial invasion (stage IC), or grade 2 or 3 with superficial (less than 50%) myometrial invasion (stage IB). Surgery consisted of TAH-BSO without lymphadenectomy. Peritoneal cytology was recommended, but not required for the trial. After surgery, patients were randomly assigned to receive postoperative pelvic RT or no additional treatment. The RT was administered to the pelvic region according to a standardized protocol.¹⁰ The target volume consisted of the previous site of the uterus and adnexa, the parametria, the proximal two thirds of the vagina, and the lymphatic drainage regions along the iliac vessels up to the promontory. The superior field border was specified at the L5-S1 disk. The total dose to be delivered to this volume was 46 Gy using 2-Gy daily fractions.

The PORTEC trial was open to patient entry from June 1990 to December 1997. Patients who had stage I, grade 3 endometrial carcinoma with deep myometrial invasion were not eligible for random assignment. However, these patients were registered in a separate database. They all received postoperative RT and were observed according to a similar schedule as that of the patients randomly assigned to treatment.

Statistical Methods
Patterns of failure were recorded by the sites of failure (ie, vaginal, pelvic, distant, or both). Locoregional failures were defined as vaginal or pelvic recurrences, or both. Combined vaginal and pelvic recurrences were scored as pelvic, and if both distant and locoregional recurrences were detected, the failure type was distant metastases. Competing risk analysis was applied to calculate competing risks of first failure split by site of failure (locoregional relapse, distant relapse, or death without relapse), and risk of death split by cause of death. If the cause of death was unknown, but occurred after relapse, or if there was any doubt about a possible recurrence, the cause of death was considered to be endometrial carcinoma.

The Kaplan-Meier method, log-rank test, and Cox regression analyses were used for time-to-event analyses with the following end points: locoregional recurrence from random assignment or registration, with censoring at the date of last contact or death in case of no locoregional recurrence; relapse from random assignment or registration, with time of failure at the first date of relapse and censoring at the date of last contact or death in case of no relapse; overall survival from random assignment or registration, with failure defined as death irrespective of the cause and censoring at the date of last contact for patients still alive. All reported P values are based on two-sided tests, with P < .05 taken to be significant.

	RESULTS

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A total of 715 patients with stage I endometrial carcinoma were randomly assigned in the PORTEC trial between June 1990 and December 1997; 354 patients were randomly assigned to receive postoperative pelvic RT, and 361 were randomly assigned to receive no additional treatment. Because of patient refusal (12 patients), death (two patients), and major wound problems (one patient), 15 patients who were assigned to RT did not receive it. In the control arm, six patients requested to receive RT.¹⁰ Thus, 345 randomly assigned patients who received RT were included in this analysis. Seven patients (2%) did not complete the RT course as planned, with discontinuation of RT because of (perceived) acute toxicity after doses of 10 to 44 Gy.¹⁰

A total of 104 patients with stage IC, grade 3 endometrial carcinoma who were treated during the study period were registered. Five patients had to be excluded because of insufficient information on their treatment and outcome, and 99 patients could be evaluated. They all received postoperative RT (range, 40 to 50.4 Gy; median, 46.0 Gy; mean, 44.6 Gy; the 16 patients treated to 40 Gy received a brachytherapy boost) and were observed according to a similar schedule as that of the randomly assigned patients. In the registered group, three patients discontinued RT after doses of 26, 28, and 32 Gy.

Table 1 lists the patient characteristics, separated by prognostic group (grade and depth of invasion). The groups were well balanced with regard to patient and treatment characteristics, although the mean age of the patient group with grade 2 and superficial invasion was slightly lower than that of the groups with deep invasion and/or grade 3 disease. Vascular space invasion was observed more frequently in association with deep invasion (8% and 9% for grades 1 and 2 with deep invasion, compared with 2% and 3% for grades 2 and 3 with superficial invasion), but was increased particularly in the stage IC, grade 3 category (17%; P < .001). The subgroups each contained approximately 100 patients, except for the stage IB, grade 3 category, which included only 35 patients. Given that grade 3 tumors show an increased proliferation rate and early infiltration, they are seldom diagnosed with less than 50% myometrial invasion. Peritoneal cytology analysis had been done in 144 patients (39%), of which six showed atypia, two were suspect for malignancy, and three were positive (two of these were in the stage IC, grade 3 group). The number of patients with positive cytology was too low for further analysis.

Outcome
Table 2 shows the actuarial 5-year probabilities of survival, relapse, and causes of death by prognostic group. The 5-year rates of locoregional (vaginal and/or pelvic) relapse were low (1% to 3%) for the randomly assigned patients who received RT, compared with 14% for the stage IC, grade 3 category. The stage IC, grade 3 group had relatively more pelvic relapses (six pelvic, one both vaginal and pelvic, and five vaginal relapses among 99 patients) compared with the randomly assigned patients (one pelvic, one vaginal and pelvic, and six vaginal relapses among 345 patients). The rates of distant metastases were increased in both subgroups with grade 3 tumors: 20% for grade 3 with superficial invasion and 31% for grade 3 with deep myometrial invasion, compared with 3% to 8% for grades 1 and 2 disease, respectively. This increased risk of distant relapse for grade 3 tumors is reflected both in the overall death rate (Fig 1) and in the endometrial carcinoma–related death rate (Table 2). Overall survival at 5 years was 58% for the stage IC, grade 3 patients, compared with 74% for those with stage IB, grade 3 tumors and 83% to 85% for grades 1 to 2 disease (P < .001).

View larger version (17K): [in this window] [in a new window]   Fig 1. Probability of death (all causes) according to grade and myometrial invasion. N, number; O, observed.

Prognostic Factors
Analyses of overall death and relapse rates showed the strong influence of grade 3 histology. As depicted in Figures 2 and 3, grade 3 was a much stronger adverse prognostic factor than depth of myometrial invasion. This was also shown in the multivariate analyses for both of the end points any relapse and endometrial carcinoma–related death (Table 3). Grade 3 was the most important adverse prognostic factor, with hazard ratios (HRs) for relapse and endometrial carcinoma–related death of 5.4 (P = .0001) and 5.5 (P = .0004), respectively.

View larger version (9K): [in this window] [in a new window]   Fig 2. Probability of relapse (A) according to myometrial invasion and (B) according to grade. N, number; O, observed.

View larger version (16K): [in this window] [in a new window]   Fig 3. Probability of relapse according to prognostic group (grade and myometrial invasion combined). N, number; O, observed.

The prognostic significance of vascular space invasion was analyzed in the patient groups with outer 50% myometrial invasion, given that the incidence of vascular space invasion in the group with superficial invasion was low. As shown in Figure 4, the presence of vascular space invasion was associated with a significantly increased risk of relapse (P < .001, univariate analysis). This increased risk was found for distant relapse (32% compared with 8% in first failure analyses), but there was no difference in the rate of locoregional relapse (0% and 3.5%, respectively). Survival rates at 5 years with and without vascular space invasion were 57% and 82%, respectively (P = .03). In the multivariate analysis, vascular space invasion did not reach statistical significance (P = .08 for relapse and P = .2 for survival; Table 3).

View larger version (10K): [in this window] [in a new window]   Fig 4. Probability of relapse for cases with deep myometrial invasion according to the presence (yes) or absence (no) of vascular space invasion. N, number; O, observed.

	DISCUSSION

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The outcome of the stage IC, grade 3 patients in our study was comparable to reported relapse and survival rates for similar patients,¹² and grade 3 was clearly shown to be the most important prognostic factor for relapse and survival. Grigsby et al³ reported 5-year progression-free survival rates for grade 3 tumors with superficial and deep myometrial invasion of 69% and 42%, respectively, compared with 70% to 95% for the other stage I subgroups, and found histologic grade to be the most important prognostic factor. Series reporting the outcome of surgically staged patients confirm the prognostic impact of tumor grade, even in the absence of lymph node metastases. In their surgically staged series of 232 patients, Konski et al¹³ found tumor grade to be strongly predictive of survival, with 78% disease-specific survival for grade 3 disease compared with 88% and 100% for grades 2 and 1, and suggested that disease-free survival (DFS) of stage IC, grade 3 cancers might improve by the addition of RT. Morrow et al¹⁴ reported on the relationship between surgical-pathologic risk factors and outcome in clinical stage I and II endometrial carcinoma. In multivariate analysis among patients without nodal or adnexal metastases, those with grade 3 adenocarcinomas had a relative recurrence risk of 15 (P < .0001). They concluded that patients with surgical-pathologic staging negative for adverse factors other than histologic grade and deep myometrial invasion remained at risk for recurrence even after pelvic irradiation, whereas RT reduced the risk of locoregional recurrence. Kasamatsu et al,¹⁵ reporting on the absence of prognostic impact of peritoneal cytology in their series of 280 surgical stage I to II endometrial carcinoma patients, found in multivariate analysis histologic grade 3 to be the only significant independent prognostic factor both for survival (HR, 11; P = .0003) and DFS (HR, 3.46; P = .02), whereas age older than 60 years was of borderline significance (HR, 2; P = .06). Alektiar et al¹⁶ found no difference in outcome for grade 3 endometrial carcinoma compared with papillary serous and clear-cell cancers, which are generally considered high-risk tumors. The presence of vascular space invasion decreased both pelvic control and DFS.

Vascular space invasion has been reported to have significant prognostic impact. In our study, vascular space invasion correlated significantly with distant relapse and survival, but not with vaginal or pelvic relapse, which may be the result of the use of external-beam pelvic RT in all patients. However, in multivariate analysis, vascular space invasion lost its prognostic significance, reflecting the significant correlation of vascular space invasion with grade and invasion. On the other hand, given that the HR for vascular space invasion was 1.7 after adjustment for grade, age, and depth of invasion, vascular space invasion might have reached significance in the multivariate analysis if the numbers in our study had been larger. Cohn et al¹⁷ reported on the influence of vascular space invasion on the risk of lymph node metastases in 366 surgically staged patients. In multivariate analysis both vascular space invasion and depth of invasion were significant predictive factors for pelvic lymph node metastases, and the authors recommended pelvic RT or lymphadenectomy for deeply invasive vascular space invasion–positive cancers.

Our analysis of 99 stage IC, grade 3 endometrial cancer patients is one of the largest published series and provides clear outcome data. The predominant type of relapse for stage IC, grade 3 patients after adjuvant radiation is distant metastases, and although pelvic RT improves local control, the frequency of metastatic disease is not decreased. In the randomized Norwegian trial,¹ only the stage IC, grade 3 patients seemed to experience a potential survival benefit from the additional pelvic RT. However, the numbers were too small to draw conclusions. In the GOG 99 trial, which until now has been published only as an abstract,¹⁸ patients with stage I to II endometrial cancer were randomly assigned after TAH-BSO with lymphadenectomy to receive pelvic RT or no further treatment. Interestingly, the results are strikingly similar to those obtained in the PORTEC study: 88% 2-year relapse-free survival in the control group (17 locoregional recurrences in 200 patients) and 96% 2-year relapse-free survival in the RT group (three recurrences in 190 patients), with mainly vaginal recurrences in the control group. It should be noted that the lymph node dissections did not prevent the locoregional relapses in the control group, and given that the trial still has not been published as a manuscript, one can only speculate that the grade 3 tumors presumably had the highest locoregional recurrence rates despite the lymphadenectomy. The role of lymphadenectomy other than for staging purposes remains unclear until the results of randomized trials such as GOG 99 and the currently ongoing Medical Research Council-ASTEC study in the United Kingdom are available. Published retrospective studies have been flawed by patient selection (good surgical risk and young patients), stage migration, insufficient numbers, and lack of uniform treatment.^19-21

What can be considered the best treatment for the stage IC, grade 3 category? Whether or not surgical staging has been performed, pelvic RT is generally recommended for grade 3 tumors with deep myometrial invasion.^22–25 In their review of radiation therapy for endometrial cancer, Koh et al²³ strongly recommend pelvic RT for surgically staged IC, grade 3 cancer, and suggest that RT be considered for grade 2 with outer 33% myometrial invasion. In a survey performed after the first results of GOG 99 had been reported, it was found that most GOG members (79%) would still recommended pelvic RT for stage IC, grade 3 disease.²² Straughn et al²⁶ analyzed the outcome of 220 stage IC endometrial cancer patients who had surgical staging including pelvic and para-aortic lymphadenectomy, comparing 99 patients (45%) treated with RT (20% pelvic RT and 25% brachytherapy alone) with 121 patients (55%) who did not receive RT. The selection criteria for RT were unclear. Five-year DFS rates were significantly lower in the observation group (75% v 93%), whereas overall survival rates were similar (90% v 92%). Among the 47 patients with stage IC, grade 3 disease, 5-year DFS rates were 90% after RT and 59% in the observation group.

The majority of stage I endometrial cancer patients have an excellent long-term outcome, and overtreatment by using lymphadenectomy or pelvic RT should be avoided. Patients with stage IB, grade 1 and 2 disease should be observed after TAH-BSO. For patients aged 60 or older with stage IC, grade 1 to 2 or stage IB, grade 3 disease, recent data suggest that vaginal brachytherapy can be used instead of external-beam RT to optimize local control with fewer occurrences and less severe side effects and better quality of life,^27,28 which is the rationale of the currently ongoing randomized PORTEC-2 trial. The challenge is to select effectively the high-risk patients who would benefit from more extensive treatment.

The disease-free and overall survival rates of stage IC, grade 3 endometrial cancer are strongly influenced by the increased distant relapse rates. This raises the question whether adjuvant chemotherapy would lower the risk of distant metastases and thus improve survival. Several groups are conducting randomized phase III trials comparing RT and chemotherapy with RT alone in high-risk endometrial cancer (stage IC, grade 3; stage II to III; and/or papillary serous or clear-cell histology) to investigate the effect of adjuvant chemotherapy. Problems encountered when considering the use of adjuvant chemotherapy, however, are the elderly age and concurrent morbidities of the endometrial cancer population, causing selection of the younger patients for phase II trials. Given that age older than 60 years is a strong adverse prognostic factor in endometrial cancer,^1,10,14,24 this would lead to inclusion of relatively favorable patients in chemotherapy trials, and one should be aware of this potential selection bias when considering the results of phase II studies. In metastatic disease, multiagent chemotherapy has been shown to have superior response rates and duration compared with single-agent therapy.²⁹ Several schemes have been investigated (doxorubicin and cisplatin, and paclitaxel and cisplatin or carboplatin) and have produced response rates of 35% to 75% and time to progression of 4 to 6 months.

Two randomized trials have been published that evaluated the efficacy of chemotherapy in the adjuvant setting. The first trial, using single-agent doxorubicin, did not show any benefit of adjuvant chemotherapy.³⁰ The first results of GOG 122, a randomized trial comparing whole-abdominal RT with combination doxorubicin plus cisplatin chemotherapy in advanced (stages III to IV) endometrial carcinoma, have been presented recently.³¹ Combination chemotherapy was shown to improve both progression-free survival and overall survival rates (13% and 11% at 2 years, respectively) compared with whole-abdominal RT. However, recurrences were frequent (55%), predominantly in the pelvis and abdomen in both arms, and adverse effects were more common in the doxorubicin plus cisplatin chemotherapy arm.

Controversy exists about whether high-risk patients receiving adjuvant chemotherapy should receive pelvic RT or vault brachytherapy alone. The omission of pelvic RT was reported to leave the patients at substantial risk of pelvic failure. Mundt et al³² reported increased pelvic relapse rates when using adjuvant chemotherapy alone in patients with high-risk or advanced-stage endometrial carcinoma. Of the 67% who experienced relapse, 40% had pelvic recurrence and 56% had distant relapse. The 3-year pelvic failure rate was 47%, and in 31% the pelvis was the first or only site of recurrence. Given that these data support the use of pelvic RT in high-risk patients undergoing adjuvant chemotherapy, future trials should explore the optimal sequencing of therapy and the use of concurrent RT and chemotherapy.

In conclusion, our results show the stage IC, grade 3 category to be at a significantly increased risk of distant relapse and endometrial carcinoma–related death. This group should be analyzed and treated separately from the other, more favorable stage I patients. Novel strategies should be investigated to increase the survival rates for patients with stage IC, grade 3 endometrial carcinoma.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The following radiation oncology institutions participated in the PORTEC trial: Erasmus MC Rotterdam/Daniel den Hoed Cancer Center (C.L. Creutzberg, P.C.M. Koper; W.L.J. van Putten, statistician; R. Dercksen, data manager; M. van Lent, gynecologic oncologist; H. Beerman, pathologist); Catharina Hospital, Eindhoven (M.L.M. Lybeert); Medisch Spectrum Twente, Enschede (J.J. Jobsen, J.H. Meerwaldt); University Medical Center, Utrecht (C.C. Wárlám–Rodenhuis); Dr B. Verbeeten Institute, Tilburg (K.A.J. De Winter); MAASTRO Clinic, Maastricht (L.C.H.W. Lutgens); University Hospital, Groningen (A.C.M. van den Bergh); Radiotherapy Institute, Arnhem (E.M. v.d. Steen-Banasik); Radiotherapy Institute, Deventer (M.C. Stenfert Kroese); University Medical Center Radboud, Nijmegen (L.A.M. Pop); University Medical Center, Amsterdam (L. Uitterhoeve); Leiden University Medical Center (A.A. Snijders-Keilholz); Netherlands Cancer Institute, Amsterdam (B.N.F.M. van Bunningen); Westeinde Hospital, The Hague (J.H. Biesta); Leyenburg Hospital, The Hague (F.M. Gescher); R. de Graaf Hospital, Delft (J. Pomp); VU Medical Center, Amsterdam (O.W.M. Meijer); Radiotherapy Institute, Vlissingen (J.H. Tabak); and Radiotherapy Institute, Leeuwarden (A. Slot).

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank the radiation oncologists, the gynecologists, and the data managers at the participating centers, and Renée Dercksen, central data manager at the Daniel Den Hoed Cancer Center Trial Office, for her indispensable assistance in data collection.

	NOTES

 
Support for the PORTEC trial provided by the Dutch Cancer Society (grant CKVO 90-01).

Presented in part at the 21st Annual Meeting of the European Society for Therapeutic Radiology and Oncology (ESTRO), Prague, Czech Republic, September 17–21, 2002.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted August 22, 2003; accepted January 23, 2004.

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