Update on the Chemotherapeutic

Management of Endometrial Cancer

Amy Bregar, MD, Katina Robison, MD, and Don S. Dizon, MD

Dr Bregar is a fourth-year resident in Abstract: Endometrial cancer is the most common gynecologic
obstetrics and gynecology at Women & cancer in the United States and the fourth most common cancer
Infants Hospital/Warren Alpert Medical in women. Although endometrial cancer most often presents at
School of Brown University in Providence,
an early stage, when surgical treatment is effective, chemotherapy
Rhode Island. Dr Robison is a gynecologic
oncologist at Women & Infants Hospital has become a critical component in the treatment of advanced
and an assistant professor at the Warren or recurrent endometrial cancer. The use of chemotherapy has
Alpert Medical School of Brown University evolved and is now often administered to women with early-stage
in Providence, Rhode Island. Dr Dizon is disease in the presence of high-risk features (eg, clear cell or serous
a medical oncologist at the Massachusetts histology), or in the adjuvant setting for women with advanced
General Hospital Cancer Center and
disease that has been surgically cytoreduced. There are no agents
Harvard Medical School in Boston,
Massachusetts. approved by the US Food and Drug Administration for second-
line or later use in the setting of endometrial cancer. Options for
Address correspondence to: women whose disease progresses after adjuvant chemotherapy
Don S. Dizon, MD have varying success. Therapies that target specific molecular
55 Fruit Street pathways have emerged as promising treatments for endometrial
Boston, MA 02114
cancer. Given the poor response rates for systemic chemotherapy
Tel: 617-724-4800
Fax: 888-922-8041 in patients with advanced or recurrent disease, these novel agents
E-mail: [email protected] have great potential to influence our care for women with endo-
Twitter: @drdonsdizon metrial cancer. In this article, we review the role of chemotherapy
in the treatment of endometrial cancer, with an emphasis on first-
and second-line treatment and novel agents in clinical trials.

Introduction

Endometrial cancer is the most common gynecologic cancer in the

United States and the fourth most common cancer in women, sur-
passed only by breast, lung, and colon cancer. The American Cancer
Society estimates that in 2014, there will be approximately 52,630
new cases of uterine cancer and 8590 women will die of their dis-
ease.1 The median age of diagnosis is 61 years, with the majority
of endometrial cancers presenting between ages 50 and 60 years.2
Incidence varies by race. Although the incidence of uterine cancer
has stabilized in white women, it has increased by approximately 2%
per year since 2004 for African American women.3 African Ameri-
Keywords
Chemotherapy, endometrial cancer, epothilones, can women also are more likely to die of their disease compared with
mTOR inhibitors, tyrosine kinase inhibitors white women, independent of risk factors.4

Clinical Advances in Hematology & Oncology Volume 12, Issue 10 October 2014  659
 BREGAR ET AL

Table 1. Characteristics of Type 1 and Type 2 Endometrial Cancer

Prognosis depends on many factors including stage,
grade, histologic type, depth of myometrial invasion, Type 1 Type 2
lymphovascular space invasion, and the presence of dis- Histology Endometrioid Serous or clear cell
tant disease.5-8 Although endometrial cancer is most often
Grade Low High
diagnosed at an early stage owing to symptoms such as
vaginal bleeding and bloating,2 some women present with Precursor Hyperplasia Atrophy
advanced or metastatic disease. In aggregate, patients who Distribution 85% 15%
present with early-stage, localized disease have 5-year sur- Hormonal Estrogen dependent Estrogen
vival rates approaching 90%, whereas patients with dis- impact independent
tant disease at the time of diagnosis have a dismal 5-year Body habitus Obese Thin
survival rate of approximately 16%.3
Age Perimenopausal Postmenopausal
Endometrial cancer is surgically staged according to
the 2009 Federation of Gynecologists and Obstetricians Risk factors Diabetes, PCOS, nulli­ None
(FIGO) staging system.9 Most endometrial cancers are parity, late menopause
adenocarcinomas and can be classified into 2 types based Genetic PTEN inactivation, P53 mutation,
on clinical, pathologic, and molecular data (Table 1).10 mutations KRAS mutation, P16 mutation,
Grade 3 endometrioid adenocarcinomas tend to behave microsatellite instability HER2
overexpression
similarly to more aggressive type 2 tumors, raising ques-
tions about the appropriateness of their classification as Prognosis Better prognosis More aggressive,
type 1 tumors.11 generally higher
In this report we provide an overview of the role of mortality
chemotherapy in this disease, with an emphasis on the HER2, human epidermal growth factor receptor 2; PCOS, polycystic ovary
syndrome; PTEN, phosphatase and tensin homolog.
first- and second-line treatment and novel agents in clini-
Data from Lewin SN. Clin Obstet Gynecol. 2011;54(2):215-218.9
cal trials. Owing to space limitations, adjuvant treatment
for early-stage, high-risk endometrial carcinoma and the
role of endocrine therapy for this disease are not covered. that paclitaxel was not associated with a survival advan-
tage and that it caused an increase in toxicity.14
First-line Chemotherapy in Endometrial Given the toxicities associated with TAP, a subsequent
Cancer randomized trial evaluated the efficacy of carboplatin and
paclitaxel, which is a more common and less toxic regimen.
The use of chemotherapy has evolved and chemotherapy In GOG 209, over 1300 women were randomly assigned
is now often administered to women with early-stage to receive either carboplatin plus paclitaxel or TAP. Pre-
disease in the presence of high-risk features (clear cell or liminary results, which were presented at the 2012 Society
serous histologies) or in the adjuvant setting for women of Gynecologic Oncology Annual Meeting on Women’s
with advanced disease that has been surgically cytore- Cancer, showed that carboplatin plus paclitaxel resulted in
duced. This precedent was initially established from equivalent PFS compared with TAP (median, 14 months
trials, including Gynecologic Oncology Group (GOG) in both arms; HR, 1.03) and similar overall survival
122, which randomly assigned 396 women with surgi- (median, 32 months vs 38 months; HR, 1.01).15
cally cytoreduced stage III and IV endometrial cancer to
whole abdominal radiation therapy (RT) or doxorubicin Second-line Chemotherapy Options for
and cisplatin (AP) chemotherapy.12 Compared with Endometrial Cancer
whole abdominal RT, AP improved progression-free
survival (PFS) (hazard ratio [HR] for progression, 0.71 There are no US Food and Drug Administration–approved
[95% CI, 0.55-0.91]) and overall survival (stage-adjusted agents for second-line or later treatment of endometrial
death HR, 0.68 [95% CI, 0.52-0.89]). The most com- cancer. Options for women whose disease progresses after
mon grade 3 and 4 toxicities were hematologic (RT vs receiving adjuvant chemotherapy have varying success
AP: leukopenia, 4% vs 6%; neutropenia, <1% vs 85%; (Table 2). Limited data suggest that a better response
thrombocytopenia, 3% vs 21%) and gastrointestinal to initial chemotherapy portends a better outcome with
(RT vs AP: 13% vs 20%).12 Results of the subsequent additional chemotherapy. A retrospective pooled analy-
GOG 177 trial suggested that the addition of paclitaxel sis of 5 phase 3 GOG protocols demonstrated that the
(taxane, anthracycline, and platinum; TAP) might pro- progression-free interval (PFI; the time between the
duce a greater benefit when administered with AP13; a end of initial adjuvant chemotherapy and the diagnosis
subsequent phase 3 trial of TAP vs AP, GOG 184, found of relapse) was the most significant factor predictive of

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 U P D AT E O N T H E C H E M O T H E R A P E U T I C M A N A G E M E N T O F E N D O M E T R I A L C A N C E R

Table 2. GOG Phase 2 Trials of Single-Agent Chemotherapy

Novel Agents for Endometrial Cancer
in Second-line Treatment of Advanced or Recurrent
Endometrial Cancer
Therapies targeting specific molecular pathways have
GOG Protocol N Drug RR, % emerged as promising treatments for endometrial cancer.
86-I 33 Ifosfamide 24.3 Given the poor response rates with systemic chemotherapy
Sutton et al, 199638 in patients with advanced or recurrent disease, these novel
86-M 52 Liposomal 11.4 agents have great potential to influence our care for women
Homesley, 200539 doxorubicin with endometrial cancer. Completed studies have evaluated
a novel microtubule-stabilizing agent (ixabepilone [Ixem-
129-C 44a,b Paclitaxel 27.3
Lincoln et al, 200340 pra, Bristol-Myers Squibb]), agents that inhibit mamma-
lian target of rapamycin (mTOR; temsirolimus [Torisel,
129-E 25a Dactinomycin 12
Wyeth], everolimus [Afinitor, Novartis], ridaforolimus),
Moore et al, 199941
agents that target epidermal growth factor receptor (erlo-
129-H 42a Liposomal 9.5 tinib [Tarceva, Genentech/Astellas], gefitinib, cetuximab
Muggia et al, 200242 doxorubicin
[Erbitux, Bristol-Myers Squibb/Lilly), an agent that targets
129-J 28a Topotecan 9 human epidermal growth factor receptor 2 (trastuzumab
Miller et al, 200243 [Herceptin, Genentech]), and antiangiogenesis agents
129-K 52a Oxaliplatin 13.5 (bevacizumab [Avastin, Genentech], ziv-aflibercept [Zal-
Fracasso et al, 200644 trap, Sanofi/Regeneron], brivanib).
129-N 26a Docetaxel 7.7
Garcia et al, 200845 (weekly) Epothilones
129-P 50 a
Ixabepilone 12 The epothilones are a novel class of microtubule-stabiliz-
Dizon et al, 200920 ing agents with a mechanism of action similar to that of
GOG, Gynecologic Oncology Group; RR, response rate. the taxanes. While epothilones and taxanes bind to the
a
Prior chemotherapy.
same site on β-tubulin, epothilones bind in a different
manner. The benefit of epothilones is that they appear
b
Paclitaxel-naive.
to retain activity in taxane-resistant tumors, theoretically
survival after second-line chemotherapy. Compared with owing to their differing binding technique. In addition,
an initial PFI of less than 6 months, a PFI of greater than they act synergistically in combination with other agents,
6 months resulted in a 30% reduction in the risk of death including bevacizumab and sunitinib (Sutent, Pfizer),
(HR, 0.70 [95% CI, 0.59-0.84]) and an improvement in based on preclinical activity in breast, lung, and colon
median overall survival (10 months vs 5 months) after cell lines.18,19 Ixabepilone, a semisynthetic epothilone,
second-line chemotherapy.16 has been approved for the treatment of metastatic breast
These results are in line with data from a Japanese cancer and is now being investigated in the treatment of
study that evaluated the platinum-free interval among advanced and recurrent endometrial cancer.
women treated with a platinum-based combination In GOG trial 129-P, 50 patients with persistent or
as second-line therapy after prior receipt of first-line recurrent endometrial cancer who had received prior
platinum-based treatment (n=56) and a separate cohort taxane chemotherapy were administered ixabepilone
receiving first-line platinum-based chemotherapy for (40 mg/m2 over 3 hours on day 1 of a 21-day cycle) until
advanced or recurrent disease (n=21).17 Among those disease progression or intolerable toxicity occurred.20
receiving platinum-based treatment in the second-line Patients received a total of 224 cycles and a median of
setting, a platinum-free interval of greater than 12 4 cycles. The overall response rate was 12%; 1 patient
months was associated with an improvement in both experienced a complete response (2%) and 5 patients
response and overall survival. For those being treated demonstrated a partial response (10%). Stable disease
with first-line platinum-based treatment, a platinum-free for 8 weeks was noted in 30 patients (60%). The major
interval of less than 3 months was associated with worse toxicities (grades 3 to 4) were neutropenia (52%), leuko-
outcomes. These data require prospective validation, penia (48%), gastrointestinal toxicity (24%), neurologic
but for women who are chemotherapy-naive or have a toxicity (18%), infection (16%), and anemia (14%).20
long platinum-free interval at the time of recurrence or Unfortunately, a phase 3 trial comparing ixabepilone
metastatic disease, treatment with carboplatin and pacli- to a community standard (paclitaxel or doxorubicin)
taxel would be a reasonable option. However, given the as second-line therapy for advanced and metastatic
limited data available, we advocate for participation in endometrial cancer showed no benefit with the use of
well-designed clinical trials. ixabepilone.21 Compared with the use of paclitaxel or

Clinical Advances in Hematology & Oncology Volume 12, Issue 10 October 2014  661
 BREGAR ET AL

doxorubicin, ixabepilone resulted in shorter overall Table 3. Recent Phase 2 Trials of Targeted Therapies
survival (10.9 months vs 12.3 months; HR, 1.3 [95% in Second-line Treatment of Advanced or Recurrent
CI, 1.0-1.7]) and similar PFS (3.4 months vs 4 months; Endometrial Cancer
HR, 1.0 [95% CI, 0.8-1.3]). There was also no differ- Reference Na Drug RR, %
ence in the overall response rate (15% in both groups).21
mTOR inhibitors
The role of ixabepilone in the treatment of endo-
metrial cancer remains undefined. However, it is being Slomovitz et al, 201046 28b Everolimus 21
evaluated as part of a randomized phase 2 trial conducted (CBR)
by the GOG. In GOG 86-P (NCT00977574), patients Oza et al, 201127 29(25b) Temsirolimus 14(4)
were randomly assigned to treatment in 1 of 3 arms: (1) Angiogenesis inhibitors
carboplatin, paclitaxel, and bevacizumab; (2) carboplatin, Correa et al, 201034 20(12b) Sunitinib 15
paclitaxel, and temsirolimus; or (3) carboplatin, ixabepi-
Nimeiri et al, 2010 35
40 a
Sorafenib 5
lone, and bevacizumab. This study has completed accrual
and results are eagerly anticipated.22 Aghajanian et al, 2011 31
52 a
Bevacizumab 13.5
Coleman et al, 201232 44a Aflibercept 6.7
mTOR Inhibitors Powell et al, 2012 33
43 a
Brivanib 18.6
Mammalian target of rapamycin (mTOR) is an intracel- Dizon et al,36 2014 32 Nintedanib 9.4
lular serine-threonine kinase that has a role in the regula-
EGFR inhibitors
tion of cell growth, proliferation, and survival.23 A muta-
tion of PTEN, a tumor-suppressor gene, is common in Oza et al, 200847 32 Erlotinib 12.5
endometrial cancer and results in increased activation of Slomovitz et al, 201048 23a Cetuximab 5
the phosphoinositide 3-kinase/Akt pathway. Downstream Fleming et al, 2010 49
33(25 ) b
Trastuzumab 0
effects include upregulation of mTOR and, accordingly, Leslie et al, 2012 50
30 b
Lapatinib 3
decreased regulation of cell cycle control.
Leslie et al, 201351 26b Gefitinib 4
The first-generation mTOR inhibitors include
everolimus (Afinitor, Novartis), temsirolimus, and ridafo- Combined therapies
rolimus (AP23573 or MK-8669). Early phase 2 trials of Alvarez et al, 201328 49b Temsirolimus + 24.5
these mTOR inhibitors demonstrated promising results bevacizumab
and established the basis for their continued investigation Fleming et al, 201429 20b/50b Temsirolimus 14/22
in the treatment of endometrial cancer.24-26 It remains +/− megestrol
unclear, however, which patients are most likely to benefit acetate/tamoxifen
from treatment. As an example, in one trial temsirolimus CBR, clinical benefit response: confirmed complete response, partial response, or
was administered to women who had previously received stable disease at 20 months; EGFR, epidermal growth factor receptor; mTOR,
mammalian target of rapamycin; RR, response rate.
chemotherapy (n=25) and a separate cohort of women
who were chemotherapy-naive (n=29). The response rates
a
Slashes differentiate between groups and parentheses represent a subset.

were 4% and 14%, respectively, with stable disease in b

Prior chemotherapy exposure.
48% and 69%. In addition, median overall survival was
longer when temsirolimus was administered to women 2 patients experienced intestinal perforations, 1 patient
who were chemotherapy-naive than to those who were had a grade 3 hemorrhage while receiving warfarin, and
previously treated (9.7 months vs 5.1 months).27 1 patient experienced a grade 4 thrombotic event. Three
Recent phase 2 studies have utilized mTOR inhibi- possible treatment-related deaths were also noted.28 GOG
tors in combination with other agents with the goal of 248 randomly assigned patients to temsirolimus (25 mg
achieving better response rates. GOG 229-G combined IV weekly) vs the combination of weekly temsirolimus
temsirolimus (25  mg intravenously [IV] weekly) with with a regimen of megestrol acetate 80  mg twice a day
bevacizumab, a monoclonal vascular endothelial growth for 3 weeks, alternating with tamoxifen 20  mg twice a
factor (VEGF) inhibitor (10  mg/kg given every other day for 3 weeks, in women with recurrent or metastatic
week), in women with persistent or recurrent disease endometrial carcinoma. The combination arm was closed
after 1 or 2 prior cytotoxic chemotherapies. Twelve early owing to an excess of venous thrombosis (5 deep
of 49 evaluable patients achieved a clinical response, venous thromboses and 2 pulmonary emboli); however,
for a response rate of 24.5%, and 23 patients (46.9%) a response rate of 14% was noted in the 21 patients who
survived progression-free for at least 6 months. Despite received combination treatment. A total of 50 evalu-
these promising results, significant toxicities occurred: able patients were treated in the single-agent arm and a
2 patients experienced gastrointestinal-vaginal fistulas, response rate of 22% was noted.29

662  Clinical Advances in Hematology & Oncology Volume 12, Issue 10 October 2014
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In summary, while mTOR inhibitors hold promise (18%/0%). Two treatment-related deaths also were noted,
for the treatment of endometrial cancer, the results from 1 caused by gastrointestinal perforation and 1 caused by
trials have been fairly disappointing. Subsequent studies arterial rupture. While afliberept achieved pretrial activity
should concentrate on identifying patients who are most parameters, significant toxicity at the prescribed dose and
likely to benefit from therapy. Unfortunately, alterations schedule is likely prohibitive and more research is needed.32
in PTEN or PIK3CA appear to be unreliable biomarkers We await the results of GOG 86P to define the activity of
for drug activity, though the presence of a KRAS mutation bevacizumab when combined with chemotherapy (carbo-
might predict inactivity of these agents. In addition, data platin with either paclitaxel or ixabepilone) as a first-line
reviewed by Myers suggest that not all alterations result in treatment for endometrial cancer.
a similar cellular impact, which suggests that future work
should specify the mutational features associated with Multitargeted Receptor Tyrosine Kinase Inhibitors
potential drug activity.30 As noted above, the role of temsi- Another class of agents is receptor tyrosine kinase
rolimus in the first-line treatment of endometrial cancer is inhibitors that target multiple pathways, and several have
being investigated in the recently completed GOG 86-P undergone evaluation in uterine carcinoma. Brivanib
trial and results are anticipated. (BMS-582664) is a dual tyrosine kinase inhibitor of
VEGF receptors (VEGFR2 and VEGFR3) and fibroblast
Angiogenesis Inhibitors growth factor receptors (FGFR1, FGFR2, and FGFR3).
Angiogenesis is an essential component of tumor growth, Brivanib was investigated in GOG 229-I, which demon-
proliferation, and metastasis and its inhibition is an attrac- strated a response rate of 19% in women with recurrent
tive anticancer strategy that has been widely employed in or advanced endometrial cancer; 30% of patients were
cancer treatment. Angiogenesis has been inhibited pri- progression-free at 6 months.33
marily in 2 fashions: either by targeting the growth factors Sunitinib is a tyrosine kinase inhibitor against mul-
or by targeting the growth factor receptors. tiple VEGF receptors that was investigated in a phase
Bevacizumab is a monoclonal antibody against 2 trial of 34 patients with recurrent or advanced endo-
VEGF-A. VEGF is essential for normal angiogenesis and metrial cancer. Women received 50 mg of oral sunitinib
its expression is upregulated in cancer cells. GOG 229E daily for 4 consecutive weeks followed by 2 weeks without
investigated the activity of single-agent bevacizumab treatment. Of the 20 patients evaluable for response, 3
(15 mg/kg IV every 3 weeks until progression or toxicity) patients (15%) achieved a partial response. Five patients
in 52 women with persistent or recurrent endometrial had a best response of stable disease, 4 of them remaining
cancer treated with up to 2 prior cytotoxic chemothera- progression-free for greater than 6 months.34 Sorafenib is
peutic regimens. The overall response rate with bevaci- a multitargeting drug that also has a role in the inhibi-
zumab was 13.5% and included 1 complete response and tion of VEGF receptors. A multicenter phase 2 study that
6 partial responses. The 6-month PFS rate was 40.4%. No included 40 patients with recurrent or advanced endo-
gastrointestinal perforations or fistulae were seen, and the metrial carcinoma demonstrated a partial response rate of
primary grade 3 and 4 toxicities were hypertension (4), only 5% and a stable disease rate of 42.5%.35
pain (4), musculoskeletal (3), hemorrhage (2), throm- Finally, nintedanib, a potent oral tyrosine kinase
bosis/embolism (2), proteinuria (2), and constitutional inhibitor against platelet-derived growth factor receptors,
(2). Only 6% of women discontinued therapy prior to FGF receptors, and VEGF receptors was evaluated in
progression.31 These results suggest that single-agent beva- GOG 229-K. Of 32 eligible patients, 3 partial respond-
cizumab may have a promising role in the treatment of ers were recorded (overall response rate, 9.4%) and the
recurrent endometrial cancer. event-free survival rate at 6 months was 22%.36 Although
Aflibercept is a protein that binds to VEGF-A, VEGF- this study closed after the first stage of accrual owing to a
B, and placental growth factor, thus exhibiting a unique lack of activity, preclinical data suggest that endometrial
method of antiangiogenesis. A phase 2 trial of aflibercept cancers with a loss of function mutation of P53 may be
(4 mg/kg IV every 14 days in 28-day cycles) in 24 patients highly susceptible to nintedanib when combined with
with recurrent endometrial cancer demonstrated a response paclitaxel.37 These data lend support to a potential phase
rate of 6.7% (0 complete responses and 3 partial responses) 2 randomized trial, stratified by P53 status. Such a trial
and 18 patients (41%) had PFS of 6 months. However, is under consideration in the cooperative group system.
8 of the 18 patients had to discontinue therapy owing to
toxicity and began receiving another therapy before reach- Conclusion
ing 6 months. Significant grade 3 and 4 toxicities included
cardiovascular (23%/5%), constitutional (7%/0%), Despite endometrial cancer being the most common
hemorrhagic (2%/5%), metabolic (7%/2%), and pain gynecologic malignancy, increasing evidence suggests that

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 BREGAR ET AL

14. Homesley HD, Filiaci V, Gibbons SK, et al. A randomized phase III trial
endometrial cancer is a heterogeneous disease, divisible in advanced endometrial carcinoma of surgery and volume directed radiation
into categories based on not only histology and stage but followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic
Oncology Group study. Gynecol Oncol. 2009;112(3):543-552.
also grade, prior treatment efforts, genetic mutations, and
15. Miller D, Filiaci V, Fleming G, et al. Randomized phase III noninferiority trial of first
alterations in molecular pathways. Although our arma- line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic
mentarium of chemotherapeutic and biologic agents con- Oncology Group study [SGO abstract LBA-1]. Gynecol Oncol. 2012;125(3):771-773.
16. Moore KN, Tian C, McMeekin DS, Thigpen JT, Randall ME, Gallion HH.
tinues to grow, we have yet to achieve significant improve-
Does the progression-free interval after primary chemotherapy predict survival after
ment in meaningful clinical outcomes such as improved salvage chemotherapy in advanced and recurrent endometrial cancer?: a Gynecologic
survival or disease stability in patients with recurrent or Oncology Group ancillary data analysis. Cancer. 2010;116(23):5407-5414.
17. Matoda M, Omatsu K, Yamamoto A, et al. Importance of platinum-free inter-
persistent disease. Cytotoxic chemotherapy remains the
val in second-line chemotherapy for advanced or recurrent endometrial cancer. Eur
primary treatment in patients with advanced or meta- J Gynaecol Oncol. 2014;35(3):224-229.
static disease, and carboplatin plus paclitaxel is the regi- 18. Lee FY, Covello KL, Castaneda S, et al. Synergistic antitumor activity of ixa-
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20. Dizon DS, Blessing JA, McMeekin DS, Sharma SK, DiSilvestro P, Alvarez RD.
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