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Terça-feira, 21.07.15

Postoperative Radiation Therapy for Endometrial Cancer

 

Postoperative Radiation Therapy for Endometrial Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Guideline

  1. Larissa A. Meyer,
  2. Kari Bohlke,
  3. Matthew A. Powell,
  4. Amanda N. Fader,
  5. Gregg E. Franklin,
  6. Larissa J. Lee,
  7. Daniela Matei,
  8. Lourie Coallier and
  9. Alexi A. Wright

+Author Affiliations

  1. Larissa A. Meyer, University of Texas MD Anderson Cancer Center, Houston, TX; Kari Bohlke, American Society of Clinical Oncology, Alexandria, VA; Matthew A. Powell, Washington University School of Medicine, St Louis, MO; Amanda N. Fader, Kelly Gynecologic Oncology Service, Johns Hopkins Hospital, Baltimore, MD; Gregg E. Franklin, New Mexico Cancer Center, Albuquerque, NM; Larissa J. Lee, Brigham and Women's Hospital, Dana-Farber Cancer Institute; Alexi A. Wright, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA; Daniela Matei, Indiana University School of Medicine, Indianapolis, IN; and Lourie Coallier, patient representative, Stanford, CA.
  1. Corresponding author: American Society of Clinical Oncology, 2318 Mill Rd, Suite 800, Alexandria, VA 22314; e-mail: guidelines@asco.org

Abstract

Purpose To provide guidance on the role of adjuvant radiation therapy in the treatment of endometrial cancer.

Methods “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline” by Klopp et al, published in 2014 in Practical Radiation Oncology, was reviewed for developmental rigor by methodologists. The American Society for Radiation Oncology (ASTRO) guideline content and recommendations were further reviewed by the American Society of Clinical Oncology (ASCO) Endorsement Panel.

Results The ASCO Endorsement Panel determined that the recommendations from the ASTRO guideline are clear, thorough, and based on the most relevant scientific evidence. ASCO endorsed the ASTRO guideline with several qualifying statements.

Recommendations Surveillance without adjuvant radiation therapy is a reasonable option for women without residual disease in the hysterectomy specimen and for women with grade 1 or 2 cancer and < 50% myometrial invasion, especially when no other high-risk features are present. For women with grade 1 or 2 cancer and ≥ 50% myometrial invasion or grade 3 cancer and < 50% myometrial invasion, vaginal brachytherapy is as effective as pelvic radiation therapy at preventing vaginal recurrence and is preferred. Patients with grade 3 cancer and ≥ 50% myometrial invasion or cervical stroma invasion may benefit from pelvic radiation to prevent pelvic recurrence. For women with high-risk early-stage disease and advanced disease, the ASCO Endorsement Panel added qualifying statements to the ASTRO recommendations to provide stronger statements in favor of chemotherapy (with or without radiation therapy).

INTRODUCTION

Endometrial cancer is the most common gynecologic cancer among women in the United States, with roughly 54,000 new cases expected in 2015.1 Worldwide, endometrial cancer is the second most common gynecologic cancer (after cervical cancer) and the sixth most common cancer overall among women.2

Surgery is the primary treatment for endometrial cancer, and many women with early-stage endometrial cancer and a low risk of cancer recurrence require no additional treatment.3,4 Adjuvant treatment for women with an intermediate or high risk of recurrence continues to evolve, and options include radiation therapy, chemotherapy, or a combination of these modalities. To provide guidance on the use of postoperative radiation therapy for endometrial cancer, the American Society for Radiation Oncology (ASTRO) published evidence-based recommendations inPractical Radiation Oncology in 2014.5

The purpose of this American Society of Clinical Oncology (ASCO) guideline is to critically appraise and endorse the ASTRO guideline on postoperative radiation therapy for endometrial cancer. This endorsement reinforces the recommendations provided in the ASTRO guideline and acknowledges the effort put forth by ASTRO to produce an evidence-based guideline informing practitioners who care for women with endometrial cancer. The ASTRO recommendations are listed in the Bottom Line Box, with qualifying statements from the ASCO Endorsement Panel. The full ASTRO guideline is available at www.practicalradonc.org/article/S1879-8500(14)00005-8/fulltext, with supplemental material available at www.practicalradonc.org/cms/attachment/2014676400/2036188629/mmc1.pdf.

THE BOTTOM LINE

The American Society of Clinical Oncology (ASCO) endorses “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline,” With Qualifying Statements

Guideline Questions

After surgery for endometrioid endometrial cancer, which women require no additional therapy? Which women should receive vaginal cuff brachytherapy, external-beam radiation therapy, or multimodality treatment?

Target Population
  • Women who have had surgery for endometrial cancer

Target Audience
  • Medical oncologists, gynecologic oncologists, radiation oncologists, and surgical oncologists

Methods

An ASCO Endorsement Panel was convened to consider endorsing “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline.” The American Society for Radiation Oncology (ASTRO) guideline was based on a systematic review of the medical literature. The ASCO Endorsement Panel considered the methodology employed in the ASTRO guideline and carefully reviewed the ASTRO guideline content to determine appropriateness for ASCO endorsement.

Recommendations

ASTRO recommendations are listed here, with qualifying statements added by the ASCO panel listed in bold italics.*

Which patients with endometrioid endometrial cancer require no additional therapy after hysterectomy?

  • Following total abdominal hysterectomy with or without node dissection, no radiation therapy is a reasonable option for patients without residual disease in the hysterectomy specimen, despite positive biopsy (despite a positive prehysterectomy biopsy of any grade).

  • Following total abdominal hysterectomy with or without node dissection, no radiation therapy is a reasonable option for patients with grade 1 or 2 cancers with either no invasion or < 50% myometrial invasion.

  • Vaginal cuff brachytherapy may be considered in patients with negative node dissection with grade 3 tumor without myometrial invasion.

  • Vaginal cuff brachytherapy may be considered in patients with negative node dissection with grade 1 or 2 tumors with < 50% myometrial invasion and higher-risk features, such as age > 60 and/or LVSI [lymphovascular space invasion].

Which patients with endometrioid endometrial cancer should receive vaginal cuff irradiation?

  • Vaginal cuff brachytherapy is as effective as pelvic radiation at preventing vaginal recurrence for patients with: (1) grade 1 or 2 tumors with 50% myometrial invasion or (2) grade 3 tumors with < 50% myometrial invasion.

  • Vaginal cuff brachytherapy is preferred to pelvic radiation in patients with the above risk factors, particularly in patients who have had comprehensive nodal assessment.

Which women should receive postoperative external beam radiation?

  • Patients with grade 3 cancer with ≥ 50% myometrial invasion or cervical stroma invasion (of any grade; personal communication, A. Klopp, February 2015) may benefit from pelvic radiation to reduce the risk of pelvic recurrence.

  • Patients with grade 1 or 2 tumors with ≥ 50% myometrial invasion may also benefit from pelvic radiation to reduce pelvic recurrence if other risk factors are present, such as age > 60 years and/or LVSI.Vaginal brachytherapy may be a better option for patients with these features, especially if surgical staging was adequate, and nodes were negative.

  • The best available evidence at this time suggests that reasonable options for adjuvant treatment of patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum include external beam radiation therapy, as well as adjuvant chemotherapy. The best evidence for this population supports the use of chemotherapy, but consideration of external beam radiation therapy is reasonable.

  • Chemotherapy without external beam radiation may be considered for some patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum based on pathologic risk factors for pelvic recurrence.

  • Radiation therapy without chemotherapy may be considered for some patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum based on pathologic risk factors for pelvic recurrence. Patients receiving chemotherapy seem to have improved survival compared with radiation therapy alone.

When should brachytherapy be used in addition to external beam radiation?

  • Prospective data are lacking to validate the use of vaginal brachytherapy after pelvic radiation, and most retrospective studies show no evidence of a benefit, albeit with small patient numbers. Use of vaginal brachytherapy in patients also undergoing pelvic external beam radiation is not generally warranted, unless risk factors for vaginal recurrence are present.

How should radiation therapy and chemotherapy be integrated in the management of stage I to III endometrioid endometrial cancer?

  • The best available evidence suggests that concurrent chemoradiation followed by adjuvant chemotherapy is indicated for patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum. Evidence regarding concurrent chemoradiation is limited at this time, and this recommendation is based on expert opinion; we anticipate level-one evidence from upcoming prospective randomized clinical trials (GOG 0258 and PORTEC-3). Chemotherapy may also be considered in certain patients with high-risk early-stage endometrial cancer, and clinical trials addressing this question are under way.

  • Alternative sequencing strategies with external beam radiation and chemotherapy are also acceptable. Prospective trials have examined sequential radiation therapy and chemotherapy. Evidence supporting sandwich-type therapy is currentlylimited.

Additional Resources

More information, including a Methodology Supplement, is available atwww.asco.org/endorsements/endometrial. Patient information is available atwww.cancer.net. Full text of “The Role of Postoperative Radiation Therapy for Endometrial Cancer: Executive Summary of an American Society for Radiation Oncology Evidence-Based Guideline” is available atwww.practicalradonc.org/article/S1879-8500(14)00005-8/fulltext, with supplemental material available atwww.practicalradonc.org/cms/attachment/2014676400/2036188629/mmc1.pdf. These publications include information about the strength of each recommendation and the quality of the evidence.

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have the opportunity to participate.

* Recommendations reprinted from Klopp A et al, Practical Radiation Oncology, 4:137-144, 2014, with permission from Elsevier.

OVERVIEW OF THE ASCO GUIDELINE ENDORSEMENT PROCESS

ASCO has policies and procedures for endorsing practice guidelines that have been developed by other professional organizations. The goal of guideline endorsement is to increase the number of high-quality, ASCO-vetted guidelines available to the ASCO membership. The ASCO endorsement process involves an assessment by ASCO staff of candidate guidelines for methodologic quality using the Rigour of Development subscale of the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. (Methodology Supplement provides more detail.)

Disclaimer

The clinical practice guideline and other guidance published herein are provided by ASCO to assist providers in clinical decision making. The information herein should not be relied on as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified herein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Furthermore, the information is not intended to substitute for the independent professional judgment of the treating provider, because the information does not account for individual variation among patients. Recommendations reflect high, moderate, or low confidence that the recommendation reflects the net effect of a given course of action. The use of words like “must,” “must not,” “should,” and “should not” indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an as-is basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.

Guideline and Conflicts of Interest

The ASCO Endorsement Panel (Appendix Table A1, online only) was assembled in accordance with the ASCO Conflicts of Interest Management Procedures for Clinical Practice Guidelines (summarized at http://www.asco.org/rwc). Members of the panel completed the ASCO disclosure form, which requires disclosure of financial and other interests that are relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include Employment; Leadership; Stock or Other Ownership; Honoraria, Consulting or Advisory Role; Speaker's Bureau; Research Funding; Patents, Royalties, Other Intellectual Property; Expert Testimony; Travel, Accommodations, Expenses; and Other Relationships. In accordance with these procedures, the majority of the members of the panel did not disclose any such relationships.

CLINICAL QUESTIONS AND TARGET POPULATION

The ASTRO guideline addressed five key questions: (1) Which patients with endometrioid endometrial cancer require no additional therapy after hysterectomy? (2) Which patients with endometrioid endometrial cancer should receive vaginal cuff radiation? (3) Which women with early-stage endometrial cancer should receive postoperative external beam radiation therapy (EBRT), and which women with stage III to IVA endometrial cancer should receive postoperative EBRT? (4) When should brachytherapy be used in addition to EBRT? (5) How should radiation therapy and chemotherapy be integrated in the management of endometrial cancer? The clinical questions and corresponding recommendations are provided in the Bottom Line Box.

The target population for the ASTRO guideline is women with stage I to IV endometrial cancer of any histologic grade.

SUMMARY OF THE ASTRO GUIDELINE DEVELOPMENT METHODOLOGY

The ASTRO guideline was developed by an expert panel that included radiation oncologists, gynecologic oncologists, and radiation physicists in both academic and private practice settings. The literature search of MEDLINE PubMed, EMBASE, and the Specialized Register of the Cochrane Gynaecological Cancer Review Group spanned the period from 1980 through 2011. Details of the search strategies and the study inclusion criteria and outcomes of interest are available atwww.practicalradonc.org/cms/attachment/2014676400/2036188629/mmc1.pdf. The search identified 330 studies that were fully extracted to provide supportive evidence for the guideline recommendations.

Guideline statements were developed based on the body of evidence categorized by the American College of Physicians strength-of-evidence rating. The level of consensus among the panelists was evaluated using a modified Delphi approach. An initial draft of the guideline was reviewed by three expert reviewers, and a revised draft was made available for public comment.

RESULTS OF THE ASCO METHODOLOGY REVIEW

The methodology review of the ASTRO guideline was completed independently by two ASCO guideline staff members using the Rigour of Development subscale from the AGREE II instrument. Detailed results of the scoring for this guideline are available in the Methodology Supplement. Overall, the ASTRO guideline scored 68%. Scores were generally high, with the exception of those for procedures for updating. The preliminary ASCO content reviewers of the ASTRO guideline, as well as the ASCO Endorsement Panel, found the recommendations well supported in the original guideline. Each section was clear and well referenced from the systematic review.

This is the most recent information as of the publication date. For updates, the most recent information, and to submit new evidence, please visitwww.asco.org/endorsements/endometrial and the ASCO Guidelines Wiki (http://www.asco.org/guidelineswiki).

METHODS AND RESULTS OF THE ASCO UPDATED LITERATURE REVIEW

ASCO guidelines staff conducted an updated literature search. MEDLINE was searched for entries dating from September 1, 2011, to September 10, 2014 (inclusive). The search was restricted to articles published in English and to systematic reviews, meta-analyses, and randomized controlled trials.

The updated search yielded 68 records. A review of these results by the ASCO Endorsement Panel revealed no new evidence that would warrant substantive modification of the ASTRO recommendations. To help inform the discussion and qualifying statements, eight publications from the ASTRO systematic review,613 four publications from the updated literature search,1417 and two additional publications identified by the ASCO Endorsement Panel and reviewers18,19 are discussed.

RESULTS OF THE ASCO CONTENT REVIEW

The ASCO Endorsement Panel reviewed the ASTRO guideline and concurs that the recommendations are clear, thorough, based on the most relevant scientific evidence in this content area, and present options that will be acceptable to patients. Overall, the ASCO Endorsement Panel agrees with the recommendations as stated in the guideline, with several qualifications discussed in the next section.

DISCUSSION

The ASCO Endorsement Panel emphasized a few points regarding postoperative therapy for endometrial cancer:

Lack of a survival benefit with EBRT in early-stage disease.

In a 2012 Cochrane review of adjuvant radiotherapy for stage I endometrial cancer, EBRT reduced the risk of locoregional recurrence (hazard ratio [HR], 0.36; 95% CI, 0.25 to 0.52) but did not have a statistically significant effect on overall survival (HR, 0.99; 95% CI, 0.82 to 1.20) or endometrial cancer–specific survival (HR, 0.96; 95% CI, 0.72 to 1.28).16 The lack of a survival benefit was observed among women in each risk group (low, intermediate, or high). Although the possibility of a benefit among high-risk women could not be excluded, EBRT increased morbidity and reduced quality of life.

Choosing vaginal brachytherapy over EBRT in high-intermediate-risk disease for locoregional control.

The preference of the ASCO Endorsement Panel for vaginal brachytherapy over EBRT for patients with endometrioid histology, grade 1 or 2 tumors, and ≥ 50% myometrial invasion was based primarily on results from the GOG-99 (Gynecologic Oncology Group), PORTEC-1 (Post Operative Radiation Therapy in Endometrial Carcinoma), and PORTEC-2 trials. In GOG-99, EBRT reduced the risk of locoregional recurrence, particularly among women with high-intermediate-risk disease.8 In women randomly assigned to no additional therapy, a majority of the locoregional recurrences occurred in the vagina. EBRT also reduced the risk of locoregional recurrence in the PORTEC-1 trial, but it increased the risk of treatment-related toxicities, including bowel and bladder complications.6,18 The PORTEC-2 trial built on these findings by comparing EBRT with vaginal brachytherapy among women with high-intermediate-risk disease. The two approaches resulted in similar rates of disease-free and overall survival, but vaginal brachytherapy was associated with lower rates of acute GI toxicity.11 The risk of second malignancy after adjuvant radiation therapy was not significantly increased in the PORTEC patient population,14,19although higher rates of secondary cancers have been reported in younger women with longer follow-up.17

Chemotherapy in women with high-risk early-stage or advanced disease.

The ASCO Endorsement Panel emphasized the potential benefits of chemotherapy for women with high-risk early-stage or advanced disease. The GOG-122 trial compared whole-abdominal radiation therapy with doxorubicin and cisplatin chemotherapy in women with stage III or IV endometrial cancer and ≤ 2 cm of postoperative residual disease. Stage-adjusted results suggested that chemotherapy was associated with higher progression-free and overall survival, but also higher rates of acute toxicity.12 In the JGOG 2033 (Japanese Gynecologic Oncology Group) trial, women with stage IC to IIIC endometrial cancer were randomly assigned to pelvic radiotherapy or cyclophosphamide, doxorubicin, and cisplatin chemotherapy. The overall results demonstrated no statistically significant difference between study arms in progression-free or overall survival, suggesting that either treatment approach is reasonable.13 However, in a higher-risk subgroup, defined as either patients age > 70 years with stage IC or grade 3 endometrioid cancer or patients with stage II to IIIA (positive cytology) disease with > 50% myometrial invasion, there was an improvement in overall survival associated with chemotherapy (89.7% v 73.6%; P = .006). In another trial of women with high-risk endometrial cancer by Maggi et al,10no statistically significant differences in outcome among women treated with external radiotherapy or cisplatin, doxorubicin, and cyclophosphamide chemotherapy were reported. However, in a pooled analysis of GOG-122 and the Maggi et al trial, chemotherapy resulted in better overall and progression-free survival than radiotherapy among women with stage III or IV disease (overall survival: HR, 0.75; 95% CI, 0.57 to 0.99; progression-free survival: HR, 0.74; 95% CI, 0.59 to 0.92).15

The effect of adding chemotherapy to radiotherapy was evaluated in a pooled analysis of two randomized trials. Among women with stage I to III endometrial cancer and high-risk features, sequential adjuvant chemotherapy and radiotherapy resulted in better progression-free survival than radiotherapy alone (HR, 0.63; 95% CI, 0.44 to 0.89).7 However, the addition of chemotherapy did not improve progression-free or overall survival in another trial of sequential therapy versus radiotherapy.9

Women with early-stage high-risk disease, including those with deep myometrial invasion and grade 3 tumors, were excluded from the PORTEC trials and under-represented in GOG-99 and the other studies discussed. Given the high rate of distant metastasis in this setting, the role of chemotherapy is being evaluated for patients with early-stage high-risk disease in the GOG-0249 and PORTEC-3 trials. Combinations of chemotherapy and radiation therapy are also being evaluated for patients with advanced-stage disease in the GOG-0258 trial, as well as in the PORTEC-3 study.

The importance of clinical trials.

Given the questions that remain about the optimal postoperative treatment of endometrial cancer, particularly for women with high-risk disease, participation in clinical trials must be encouraged.

Consideration of fertility and quality of life.

When considering the postoperative treatment options available to women with endometrial cancer, discussions with patients must include the impact of treatment options on both short- and longer-term quality of life. Furthermore, management of premenopausal women with endometrial cancer should include a discussion of the effect of treatment on fertility and options available for preservation of ovarian function. ASCO recommendations regarding fertility preservation in patients with cancer are available at www.asco.org/guidelines/fertility.

ENDORSEMENT RECOMMENDATION

ASCO endorses “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline” by Klopp et al, published in 2014 inPractical Radiation Oncology, with qualifying statements.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at www.jco.org.

AUTHOR CONTRIBUTIONS

Manuscript writing: All authors

Final approval of manuscript: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Postoperative Radiation Therapy for Endometrial Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Guideline

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc orjco.ascopubs.org/site/ifc.

Larissa A. Meyer

Travel, Accommodations, Expenses: AstraZeneca

Kari Bohlke

No relationship to disclose

Matthew A. Powell

Honoraria: Roche/Genetech

Consulting or Advisory Role: Roche/Genentech, Arno Therapeutics, Eisai

Speakers' Bureau: Genentech/Roche

Amanda N. Fader

Speakers' Bureau: Ethicon Endosurgery

Travel, Accommodations, Expenses: Intuitive Surgical

Gregg E. Franklin

Employment: New Mexico Cancer Center

Stock or Other Ownership: New Mexico Cancer Center, RainTree

Consulting or Advisory Role: Varian Medical Systems

Speakers' Bureau: Bayer Healthcare

Larissa J. Lee

Travel, Accommodations, Expenses: Intuitive Surgical (I)

Daniela Matei

Honoraria: AstraZenecca

Consulting or Advisory Role: AstraZeneca

Travel, Accommodations, Expenses: AstraZeneca

Lourie Coallier

No relationship to disclose

Alexi A. Wright

No relationship to disclose

Acknowledgment

We thank Gunter von Minckwitz, Jeffrey M. Clarke, and the Clinical Practice Guidelines Committee for their thoughtful reviews and insightful comments on this guideline endorsement.

Appendix

Table A1.

Endorsement Panel Members

 

Footnotes

  • Clinical Practice Guideline Committee approval: January 30, 2015.

  • Editor's note: This American Society of Clinical Oncology (ASCO) clinical practice guideline endorsement provides recommendations based on the review and analyses of the relevant literature in “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline” by Klopp et al, published in 2014 in Practical Radiation Oncology. Additional information, which may include a Methodology Supplement, Data Supplements, slide sets, patient versions, frequently asked questions, and other clinical tools and resources, is available at www.asco.org/endorsements/endometrial.

  • Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

 

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