patterns of disease monitoring and treatment among patients with tuberous sclerosis complex related angiomyolipomas

Abstract OBJECTIVE: To use the tuberous sclerosis complex TSC Natural History Database to describe monitoring and treatment patterns among patients with TSC-related angiomyolipomas AML

Accepted Manuscript

Title: Patterns of Disease Monitoring and Treatment among Patients with

Tuberous Sclerosis Complex-Related Angiomyolipomas

Author: Elyse Swallow, Sarah King, Jinlin Song, Miranda Peeples, James E

Signorovitch, Zhimei Liu, Judith Prestifilippo, Michael Frost, Michael

Kohrman, Bruce Korf, Darcy Krueger, Steven Sparagana

Please cite this article as: Elyse Swallow, Sarah King, Jinlin Song, Miranda Peeples, James E

Signorovitch, Zhimei Liu, Judith Prestifilippo, Michael Frost, Michael Kohrman, Bruce Korf,

Darcy Krueger, Steven Sparagana, Patterns of Disease Monitoring and Treatment among Patients

with Tuberous Sclerosis Complex-Related Angiomyolipomas, Urology (2017),

http://dx.doi.org/doi: 10.1016/j.urology.2017.02.036

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Patterns of disease monitoring and treatment among

patients with tuberous sclerosis complex-related

angiomyolipomas

Elyse Swallow, MPP1; Sarah King, BA1; Jinlin Song, PhD1; Miranda Peeples, BA1; James E

Signorovitch, PhD1; Zhimei Liu, PhD2; Judith Prestifilippo, MD2; Michael Frost, MD3; Michael

Kohrman, MD4; Bruce Korf, MD, PhD5; Darcy Krueger, MD6; Steven Sparagana, MD7

1 Analysis Group, Inc.; 2 Novartis Pharmaceuticals Corporation; 3 Minnesota Epilepsy Group;

4 University of Chicago; 5 University of Alabama at Birmingham; 6 Cincinnati Children's

Hospital Medical Center; 7 Texas Scottish Rite Hospital for Children

Source of Funding

This work was funded by Novartis

Author Contributions

All authors participated in the design of the study and contributed to the manuscript

development Statistical analyses were conducted by ES, SK, JS, MP, and JES and were

interpreted in collaboration with ZL, JP, MF, MK, BK, DK, and SS All the authors vouch for

the accuracy and completeness of the data reported and the adherence of the study to the

protocol, and all the authors made the decision to submit the manuscript for publication

Disclosures:

ZL and JP are employees of Novartis and own stock/stock options MF, MK, BK, DK, and SS are

independent consultants who received consultancy fees from Novartis ES, JS, MP, and JES are

employees of Analysis Group Inc., which has received consultancy fees from Novartis for the

analysis described in this manuscript; SK was an employee of Analysis Group Inc at the time of

the study

Abstract

OBJECTIVE: To use the tuberous sclerosis complex (TSC) Natural History Database to describe

monitoring and treatment patterns among patients with TSC-related angiomyolipomas (AMLs)

MATERIALS AND METHODS: This study used the TSC Natural History Database, which contains

demographics, affected areas, diagnosis, and treatments for over 1,300 TSC patients enrolled in 16

participating clinics during 2006-2013 Patient characteristics, AML monitoring tests, and AML

treatments were assessed

RESULTS: Among the 621 patients with TSC-related AMLs, 54% were female; 77% were Caucasian

Median age at TSC diagnosis was <1 year, while median age at AML diagnosis was 9.8 years Most

patients (84%) had at least one monitoring test following AML diagnosis The most commonly used tests

were MRI (65% of patients), ultrasound (62%), and CT (41%) Between 2000 and 2012, MRI made up an

increasingly large proportion of the total number of monitoring tests Once diagnosed, 155 (25%) of

patients received treatment for AML The median time from diagnosis to first treatment was 3.8 years

The most common treatments were embolization (10%), everolimus (9%), sirolimus (6%), and

nephrectomy (6%) The rate of nephrectomies declined over time, with none conducted during 2011 and

2012 No subsequent surgeries were reported among the 71 patients who received mTOR inhibitor as

first-line therapy

CONCLUSION: The use of MRIs increased between 2000 and 2012 among patients with TSC-AML

The majority of TSC-AML patients did not receive treatment for angiomyolipoma Use of nephrectomy

decreased over the study period and was particularly rare in patients who initiated an mTOR inhibitor

INTRODUCTION

Tuberous Sclerosis Complex (TSC) is a rare autosomal dominant disease that affects 25,000 to

40,000 people in the United States and one to two million people worldwide.1 This multi-system

disorder is caused by mutations in the hamartin gene, TSC1, or the tuberin gene, TSC2, leading to

pervasive benign tumors in organ systems throughout the body, including the brain, heart, liver,

lungs, skin, and kidneys.2

A majority of TSC patients (70-80%) develop angiomyolipomas, kidney lesions that can increase

in size over time and may cause acute hemorrhage and other renal complications.3,4 TSC-related

angiomyolipomas (TSC-AMLs) are typically identified and monitored for growth using imaging

procedures such as ultrasound, computed tomography (CT), and magnetic resonance imaging

(MRI) Guidelines published following the 1999 Tuberous Sclerosis Consensus Conference

recommended renal ultrasonography every 1-3 years for monitoring existing angiomyolipomas.5

In 2013, these guidelines were updated to specifically recommend MRI over ultrasound or CT,6

due to its more precise assessment when angiomyolipomas are fat-poor.7

Monitoring can inform the selection of appropriate strategies for treating angiomyolipomas

Large angiomyolipomas, which present a risk of hemorrhage, have historically been treated with

renal arterial embolization or nephrectomy Invasive procedures may not be deemed appropriate

for smaller, asymptomatic angiomyolipomas; in these cases, monitoring is a key component of a

‘watch-and-wait’ strategy Recently available drug therapies offer additional treatment options

In 2012, an mTOR inhibitor, everolimus, was approved by the FDA for the treatment of

TSC-AMLs that do not require immediate surgery.8 Another mTOR inhibitor, sirolimus, has been

shown to be associated with decreased volume of renal angiomyolipomas in TSC-AML

patients.9 In light of these recent changes in preferred imaging methods and the recent

availability of mTOR inhibitor therapies, this study aimed to describe patterns in monitoring and

treatment for TSC-AML

METHODS

Data Source

Data for this study were obtained from the TSC Natural History Database Project The database

was launched in 2006 by the Tuberous Sclerosis Alliance, in partnership with a network of TSC

clinics, for the study of TSC and its clinical features, treatments, and long-term outcomes

Patients included in the database have a diagnosis of TSC based on genetic criteria (an identified

mutation in the TSC1 or TSC2 gene) or clinical criteria (the presence of major and/or minor

clinical features).6 Participating TSC clinics with Institutional Review Board (IRB) approval to

conduct the project are located in sixteen cities: Birmingham, Boston, Brussels, Chicago,

Cleveland, Dallas, Denver, Fairfax, Houston, Loma Linda, Los Angeles, Miami, New York,

Oakland, Philadelphia, and St Paul

The data, which are entered at periodic clinic visits, include information about TSC-related care

received at the clinics, as well as retrospectively-captured information regarding TSC-related

care received outside of the clinics The data are de-identified and HIPAA compliant and do not

require the reporting of adverse events At the time of the analysis, the database housed

information regarding demographics, genotypes, clinical features, diagnostic and follow-up test

results, and treatments for over 1,300 TSC patients

Study Design

This study assessed the characteristics of patients with TSC-AML, patterns in monitoring and

treatment following TSC-AML diagnosis, and trends over time in the monitoring and treatment

of TSC-AML All analyses were conducted using SAS software version 9.3 (SAS Institute, Cary,

NC)

Patient characteristics

Age at TSC and angiomyolipoma diagnoses, age at most recent data update, gender, and race

were summarized for all patients The twenty most commonly diagnosed clinical features were

also reported

Angiomyolipoma-related monitoring tests

Procedures conducted following angiomyolipoma diagnosis were included in the analysis of

monitoring tests These procedures were grouped into the following imaging categories:

ultrasound, MRI, CT, x-ray, angiography, positron emission tomography (PET), nuclear study,

and intravenous pyelogram Additionally, two non-imaging test categories, biopsy and pathology

testing, were included

In order to capture the most recent trends in angiomyolipoma monitoring procedures, the

frequency of tests for each calendar year was assessed from 2000 through 2012 Additionally, to

assess compliance with guideline recommended monitoring frequency, this study assessed

monitoring patterns in the three years following angiomyolipoma diagnosis The monitoring

patterns analysis was limited to patients diagnosed with angiomyolipoma in 2006 or later who

had at least 3 complete years of data following diagnosis to capture the most recent monitoring

trends

Angiomyolipoma-related treatments

Angiomyolipoma-related treatments consisted of mTOR inhibitors, everolimus and sirolimus,

and the following renal procedures: embolization, nephrectomy, renal enucleation, ablation,

resection, dialysis, and transplant For the purposes of the analysis, renal enucleation, ablation,

and resection were grouped together with nephrectomy Treatments initiated before a patient’s

first angiomyolipoma diagnosis were excluded, except in cases where physician comments

specifically indicated that the treatment was related to angiomyolipoma

To assess trends in the treatment of TSC-AML, the frequency of treatments was assessed for

each year from 2000 through 2012 For drug therapies, only treatment initiations were included

(i.e., if a patient’s drug therapy continued from one calendar year into the next, it was included in

the year of initiation only) Flow charts were created to depict all treatment sequences observed

in the sample The charts showed the number and percentage of patients switching to each

subsequent treatment and the median time in years between treatments

RESULTS

Patient characteristics

At the time of this analysis, the TSC Natural History database included 621 patients diagnosed

with angiomyolipoma, approximately half of TSC patients in the database Over half of patients

were diagnosed with TSC prior to age 1; 9% were diagnosed with TSC at age >18 years (Table

1) A majority of patients (72%) were diagnosed with angiomyolipoma before age 18

Approximately 50% of patients were 19 years of age or older as of their most recently recorded

clinic encounter More than half of the patients (54%) were female The majority were white

(77%); 13% were Hispanic, 7% were African-American, 3% were Asian, <1% were American

Indian, <1% were Pacific Islander, and 3% were another race/ethnicity The most common

clinical features diagnosed at any time in a patient’s history were brain tubers (diagnosed in 90%

of patients), subependymal nodules (89%), epilepsy (87%), angiofibromas (77%), and

hypomelanotic or hypopigmented macules (73%) (Table S1) Epilepsy was the most common

first-diagnosed clinical feature (47% of patients)

Angiomyolipoma-related monitoring tests

Of the 621 patients with TSC-AML, 521 (84%) received at least one monitoring test following

angiomyolipoma diagnosis Among these patients, the most common monitoring tests received at

any point after diagnosis were MRI (65% of patients), ultrasound (62%), and CT (41%)

Between 2000 and 2012, the use of MRI increased from 5% of all monitoring tests in 2000 to

56% in 2012, while over the same time period the use of ultrasound decreased from 81% to 30%

(Figure 1)

Among the 521 patients who received at least one monitoring test following TSC-AML

diagnosis, 236 (45%) were diagnosed with angiomyolipoma in 2006 or later; of these patients,

179 (76%) had at least three complete years of observable data following diagnosis Nearly all of

these 179 patients (92%) received an imaging test in at least one of the first three years following

diagnosis (Figure S1) Roughly half (51%) received an MRI in at least one of the first three years

of follow-up (Figure S2)

Angiomyolipoma-related treatments

Of the 621 patients with TSC-AML, 155 (25%) received at least one angiomyolipoma-related

treatment following angiomyolipoma diagnosis The median time from diagnosis to first

treatment was 3.8 years The most common treatments ever received were embolization (10% of

patients), everolimus (9%), sirolimus (6%), and nephrectomy (6%) (Table S2) Few patients

(<1%) underwent dialysis or a renal transplant

mTOR inhibitor therapy was first used in 2005; the rate of initiations increased sharply in 2010,

following the approval of everolimus for renal cell carcinoma (RCC) and TSC-related

subependymal giant cell astrocytomas (TSC-SEGA) (Figure 2).10,11 Nephrectomies declined in

frequency over time, with none conducted during 2011 and 2012

Of the 52 patients who received an embolization as first-line treatment, 54% received no

additional treatment, 25% received at least one subsequent embolization, and 13% received a

nephrectomy (Figure S3) Among the 42 patients who received everolimus as first-line therapy,

no subsequent treatments were reported Among the 29 patients who received sirolimus as

first-line therapy, two (7%) received a subsequent treatment; for both, this treatment was everolimus

DISCUSSION

This study was the first to assess monitoring and treatment patterns of TSC-AMLs using data

from a large-scale patient registry of TSC patients in the United States It showed that most

recently diagnosed TSC-AML patients have been monitored at the frequency recommended by

existing guidelines In addition, MRI was increasingly used to monitor angiomyolipomas in

TSC-AML patients in recent years, replacing ultrasound as the predominant imaging modality It

has also been found that few TSC-AML patients received nephrectomies in recent years

Recently-available mTOR inhibitors have been increasingly used among TSC-AML patients,

though many patients did not receive any treatment after diagnosis

Angiomyolipoma-related monitoring procedures

A majority of patients in the present study received monitoring consistent with TSC-AML

guidelines that recommend at least one renal imagining procedure every three years.5,6 MRI was

increasingly used over the study period This increase reflects national trends in general imaging

practice, as MRI became more widely used in the United States over this period.12 However,

only half of the patients assessed in this study received an MRI in the first three years of

follow-up This may be due to the higher cost of MRI compared to other imaging modalities.12 The large

proportion of young patients in the database may have also contributed to the low percentage of

MRI use in the first three years of follow-up, as MRIs can be challenging to conduct in pediatric

patients due to the long duration of time for which patients need to remain still, usually

necessitating general anesthesia Additionally, pediatric patients may be more likely to have

small angiomyolipomas that are stable or slow-growing; for these patients, monitoring with

ultrasound may be sufficient Future analyses could ascertain whether the recently updated