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Impact of PET on the Management of Patients with Cancer:

What We Have Learned From NOPR

Barry A. Siegel, M.D.Mallinckrodt Institute of Radiology

Barry A. Siegel, M.D.Disclosures

• Advisory Board– GE Healthcare

• Consulting– ImaginAb– Blue Earth Diagnostics

• Lecture Honoraria– Siemens

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Dissemination of PET into clinical practice has been very slow!

Barriers• Expensive technology• Slow acceptance by clinicians• Reliable supply of radiopharmaceuticals• Regulation of radiopharmaceutical production• Variable and restrictive coverage policies by

government and private payers (reflecting lack of definitive evidence of utility)

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PET Reimbursement in the USA

• Dependent on FDA approval of PET drugs–Unique approach, aided by legislation

• Reimbursable clinical indications –Determined by technology assessment panels

of third-party payers–Process dominated by Centers for Medicare &

Medicaid Services (CMS)

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Medicare Coverage of PET

• Standard for reimbursement is “reasonable and necessary”

• In 1990s, CMS adopted a new evidence-based approach for making coverage determinations– Requires peer-reviewed scientific evidence to

document that new technology leads to changes in patient management and to improved health outcomes for Medicare beneficiaries

• Prompted in part by poor quality of evidence used to support MRI coverage

The MRI BacklashPET Became the “Whipping Boy”

of High Technology Medicine

PET

Payers

MRI

http://www.sportsofboston.com/wordpress/wp-content/uploads/2009/07

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Challenges with Diagnostics

• Determining “value” is a barrier for all diagnostics– Traditional blood assays, genetic profiling, or imaging

• Testing is a single node in a chain of diagnostic and therapeutic interventions

• Can one attribute improvements in health outcomes directly back to any single event in the chain, let alone a diagnostic imaging test?

• Usefulness of a diagnostic is constrained by the (non)availability of good therapies

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Medicare Coverage of Oncologic PET

• CMS elected not to consider oncologic indications for PET broadly

• Rather evaluated the evidence on a cancer-specific and indication-specific basis

• Problematic because the specific evidence typically has not been very robust

• “Catch 22”

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Does PET Improve Health Outcomes in Patients with Cancer?

• This has been very difficult to demonstrate• Vast majority of PET clinical trials

–Single-institution–Pilot phase II–Small patient numbers (<50)

• A major reason for unfavorable technology assessments of PET (and for limited coverage)

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Does PET Improve Health Outcomes in Patients with Cancer?

• Evidence accruing in the last few years• Randomized controlled trials

–All done in countries with highly restricted PET coverage

• Practice-based evidence (e.g., registries)• Change in management largely used as a

“surrogate” for improved outcome (especially avoidance of futile therapies)

RCTs: FDG-PET in Oncology

Cancer(Indication)

No. RCTs Results

NSCLC(preoperative staging)

5 Mixed, but favor reduction in futile thoracotomy

Colorectal cancer(liver metastasis resection)

2 Conflicting results with respect to reduction in futile surgery

Colorectal cancer (recurrence detection)

1 Earlier detection and increased likelihood of complete resection of recurrence

Cervical cancer(Treatment of extrapelvic disease guided by PET)

1 No improvement in OS or DFS

ITT Analyses: no improvements in survival.But should a diagnostic test be expected to improve survival?

No practical way to fund RCTs for each tumor/indication!

Evolving Role of FDG-PET for Response Assessment and Treatment Monitoring

• More reliable than anatomical imaging for determining end-of-treatment response–Now standard of care in Hodgkin and aggressive

non-Hodgkin lymphoma

• Early monitoring during therapy allows for:–Response adaptation in high- and low-risk patients–Discontinuation of ineffective (expensive) therapy–Conflicting results to date of adaptive trials

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Medicare Coverage of Oncologic PET1998 Evaluation of solitary pulmonary nodules and

initial staging of NSCLC

1999 Suspected recurrent colorectal cancer, lymphoma,

2001 Further coverage for 6 prevalent cancers

2002 Individual requests submitted for several other cancers

2004

Unwieldy Approach

Proposed mechanism for expanded coverage

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Coverage with Evidence Development (CED)

• An option for coverage of promising drugs, biologics, devices, diagnostics, and procedures that would not otherwise meet Medicare’s evidentiary standards for being “reasonable and necessary”

• CED links coverage to requirement that patients participate in a registry or clinical trial

• Goal of longitudinal data collection to improve understanding of the new technology

• First applied to biologic therapies for colon cancer, implantable cardiac defibrillators, and oncologic PET

National Oncologic PET Registry: A Nationwide Collaborative Program

Sponsored by

Managed by

Advisor

Endorsed by

• Chair, Bruce Hillner, MD, Virginia Commonwealth University• Co-chair, Barry A. Siegel, MD, Washington University• Co-chair, R. Edward Coleman, MD, Duke University• Co-chair, Anthony Shields, MD, PhD Wayne State University• Statisticians: Dawei Liu, PhD, Fenghai Duan, PhD, Ilana Gareen,

PhD, , Lucy Hanna, MS, Brown University

Objective• Assess the effect of PET on referring physicians’

plans of intended patient management – across a wide spectrum of cancer indications

for PET not currently covered by Medicare

Hypothesis• PET will lead to change of patient management

as often for non-covered as reported for covered cancers

Goals

• Provide access to the service (PET)

• Minimize the burden to patients, PET facilities, and referring physicians

• Generate evidence of reasonable quality to help CMS decide whether to expand coverage of PET

• Registry to be financially self-supporting

Referring MD requests PETReferring MD requests PET

Pre-PET Form

Pre-PET Form

PETdonePETdone

PET interpreted& reported

PET interpreted& reported

Post-PETForm sent,

including question for referring MD consent

Post-PETForm sent,

including question for referring MD consent

Post-PET Form completed.

Claim submitted

Post-PET Form completed.

Claim submitted

Ongoingpatient

management

Ongoingpatient

management

NOPR Workflow

Ask patient for consent

Ask patient for consent

Pre-PET Form: Intended Patient Management

Observation (with close follow-up) Additional imaging (CT, MRI) or other non-invasive diagnostic tests Tissue biopsy (surgical, percutaneous, or endoscopic). Treatment (if treatment is selected, then also complete the following)

Treatment Goal: (check one) Curative Palliative

Type(s): (check all that apply)– Surgical Chemotherapy (including biologic modifiers)– Radiation Other Supportive care

If PET were not available, your current management strategy would be (select one)?

Intended management, given PET findings, asked on post-PET form

Key NOPR Results (Before 2009 NCD)Overall Impact on Patient Management

– Diagnosis, Staging, Restaging, Recurrence– Data on 22,975 scans from May 8, 2006 – May 7, 2007– J Clin Oncol 2008; 26:2155-61

Impact on Patient Management by Cancer Type– Confirmed Cancers– Staging, Restaging, Recurrence– Data on 40,863 scans from May 8, 2006 – May 7, 2008– J Nucl Med 2008; 49:1928-35

Treatment Monitoring– Data on 10,447 scans from May 8, 2006 – Dec 31, 2007– Cancer 2009:115:410-18

Cohort Profile• First year of NOPR

(5/8/06 to 5/7/07)• 22,975 “consented”

cases from 1,519 facilities

• Technology profile – 84% PET/CT– 71% non-hospital– 76% fixed sites

Hillner et al., J Clin Oncol 2008

PET Changed Intended Management in 36.5% of Cases

Non-Treat Treat 23.2 31.6 28.6 29.2 28.3

Treat Non-Treat 7.9 7.9 7.5 9.7 8.2

Patients with change post-PET (%) 31.1 39.5 36.1 39.0 36.5

Hillner et al., J Clin Oncol 2008; 26:2155, Hillner et al., J Nucl Med 2008; 49:1928

Clinical Indication for PET Study (Percent)

Pre-Pet Plan

Post-PET Plan

Dxn=5,616

Staging n=6,464

Restaging n=5,607

Recurrence n=5,388

Alln=22,975

Treat Same 16.0 46.5 15.8 20.4 25.5

Non-Treat Same 52.9 14.0 48.0 40.7 37.9

Essentially uniform across different cancer types

Imaging-adjusted Change in Management

• Inclusion of cases where the pre-PET plan was alternative imaging (CT or MRI) may overestimate the impact of PET– i.e., outcome might be the same if CT or MRI had been

done instead of PET• As a lower boundary of the impact of PET on intended

management, we re-analyzed the data assuming no benefit from the information provided by PET in cases with a pre-PET imaging plan (all such cases were included in the denominator)

• 14.7% vs. 38.0% overall

Hillner et al., J Nucl Med 2008; 49:1928

Impact of PET Used for Treatment Monitoring• Chemotherapy 82%, chemoRT 12%, RT 6%

• Ovarian, pancreas, NSCLC, SCLC most frequent

• Metastatic disease in 54%

• PET findings led to:

– Switch to another therapy in 26%

– Adjust dose or duration of therapy in 17%

– Switch from therapy to observation/supportive care in 6%

• Management change more often if post-PET prognosis worse rather than improved/unchanged (70% vs. 40%)

Hillner et al., Cancer 2009; 115:410

2006 National Oncologic PET Registry (NOPR) begins data collection

2008 Initial NOPR results published and expanded coverage requested

2009 National Coverage Determination (NCD)– Expands coverage for initial treatment strategy of most

cancers and for subsequent treatment strategy of several cancers

– Data collection continued for other cancers

Medicare CED and Oncologic PET

• Over 90% of US PET facilities participated• Complete data for nearly 133,000 scans

NOPR-2009

• Data collection continued for subsequent treatment strategy of remaining cancers (with minor CRF modifications)

• 155,540 scans with complete data submission

• Primary analysis: comparison of NOPR-2006 and NOPR-2009 cohorts (J Nucl Med 2012; 53:831-7)

– Restaging, recurrence or treatment monitoring known cancers

– Data on 41,145 scans (2006) and 70,358 scans (2009)

– “Results strongly suggest it is unlikely that new useful information will be obtained by extending the coverage of certain cancer types and indications only under CED.”

2013 National Coverage Determination (NCD)– Further expands coverage for subsequent treatment

strategy (3-scan limit) and ends FDG-PET data collection

Medicare CED and Oncologic PET

2010 NCD for NaF-PET; CED required

2011 NOPR opens NaF-PET registry

2014 NOPR submits request for coverage of NaF-PET (5/15/2014)

Oncologic FDG-PET: Final Decision Summary

• Three-scan limit clearly motivated by CMS concern that PET is widely used for surveillance, which is non-covered

• Virtually no evidence that using PET (or other advanced imaging) for surveillance improves patient outcomes

• Surveillance has substantial costs ($$, radiation exposure, downstream testing, patient anxiety)

• We need to either get the evidence or change referring physician behavior and patient expectations

NOPR (NaF-PET): Results• Prostate cancer (Hillner et al., J Nucl Med 2014;55:574)

‒ 68% of all patients

‒ 1,024 Initial staging

‒ 1,997 Suspected first osseous metastasis

‒ 510 Suspected progression of osseous metastases

‒ Treat vs. non-treat change in intended management in 44% to 52% (imaging-adjusted 12% to 16%)

• Other cancers (Hillner et al., J Nucl Med 2014; 55:1054)

‒ Similar results (lower impact with suspected first osseous metastasis than for prostate cancer)

Strengths of the NOPR Data• “Real world” data• Timely data• Very large patient cohorts• Current technology (≥ 85% PET/CT)• Good observational studies usually match controlled

studies in magnitude and direction of effect (Concato NEJM 2000; Benson NEJM 2000; Ionnanidis JAMA 2001)

• Results similar to more tightly managed single-institution studies (e.g., Hillner 2004) and to Australian studies with outcome validation

NOPR Limitations

• Data “quality”• Potential that physicians may have been influenced by

the knowledge that future Medicare reimbursement might be influenced by their responses

• No control group– A fundamental problem with observational studies– Neither historical nor contemporaneous controls adequate

• Collected change in “intended” management, not actual management– Partially addressed by linking NOPR plans to claims data

NOPR: Intended vs. Claims-inferred Management

• NOPR data (2006-2008) linked to Medicare claims• For restaging/suspected recurrence of 6 most prevalent

cancers, 30-day agreement of post-PET plan and claims-inferred action (PPV) ranged from 27.3% (prostate, surgery only) to 80.9% (kidney, watching)

• For initial staging of 5 most prevalent cancers, 60-day agreement of post-PET therapy plan and claims-inferred action (PPV) ranged from 30.4% (ovary, RT) to 89.5% (SCLC, systemic therapy)

• Agreement similar to that in Australian studies

Hillner et al., Med Care 2013; 51:361, Hillner et al., J Nucl Med 2013;54:2024

Australian Prospective Studies of Impact of PET

Agreement in Post-PET Plan and Actual Care (2003-2006)

Cancer Pts Centers Indication Change in Plan

F/U (mo.)

Agree-ment

Ovarian 90 3 SR 58.9 6 67.8 Esophagus 129 5 IS 38.0 12 53.2 Lymphoma 74 6 IS 34.0 6 74.3 Colorectal 93 4 SR 65.6 6 62.0 Colorectal 98 4 Resect

Hepatic 49.0

6

70.1

Head/Neck 71 3 IS 33.8 3 74.7

SR: Suspected Recurrence. IS: Initial Staging

NOPR Limitations• Unknown if management changes were in the correct

direction or improve long-term outcomes– Using management change as surrogate requires prior data

on test accuracy and value of therapies• Defining the relevant long-term outcomes for a diagnostic

(instead of therapeutic) procedure is controversial• NOPR does not address:

– Whether PET should be used in lieu of or as a complement to other imaging techniques

– The optimal sequencing of CT, MRI and PET.– How much ‘better’ PET is than next best method

Major Problem with the NOPR Paradigm

• Tradeoff between data quantity/quality and access• Consequence of the self-funded model with non-

engaged participants (You get what you pay for!)• Possible solutions

– Funding of participating sites/referring MDs• More detailed clinical data • Information about actual management/outcomes

– Better data quality will require engaged/educated participants

Medicare Coverage of New Oncologic PET Radiopharmaceuticals

• As of 3/7/13, national non-coverage removed for new FDA-approved oncologic PET radiopharmaceuticals

• Coverage at local Medicare Administrative Contractor (MAC) discretion

• C-11 choline is first example

• Remains to be seen if this is really a better approach than National Coverage Analysis

CMS PET RegistriesWhat’s Next?

A National Study to Evaluate the Clinical Utility of Amyloid PET

Study Chair: Gil D. Rabinovici

Co-chairs: Maria C. Carrillo, Constantine A. Gatsonis, Bruce E. Hillner, Barry A. Siegel, Rachel A. Whitmer

PET Amyloid Imaging• FDA approved as imaging biomarkers of amyloid deposits

• 4/2012 18F-florbetapir

• 10/2013 18F-flutemetamol

• 3/2014 18F-florbetaben

• 9/2013 CMS NCD for amyloid PET: will cover only under CED one

study per patient with intent to :

‒ Develop better treatments or prevention strategies for AD, or, as

a strategy to identify subpopulations at risk for developing AD

‒ Resolve clinically difficult differential diagnoses (e.g., FTD vs.

AD) with goal of improving health outcomes

IDEAS-Study.org

After a Two-Year Gestation: IDEAS

• An open-label, longitudinal cohort study to assess the impact of amyloid PET on patient-oriented outcomes in individuals meeting Appropriate Use Criteria for amyloid PET

• Primary hypothesis: In diagnostically uncertain cases, knowledge of amyloid PET status will lead to significant changes in patient management, and this will translate into improved medical outcomes

IDEAS-Study.org

Specific Aims

Aim 1: To assess the impact of amyloid PET on patient management at 90 days

‒ Management plans recorded via pre- and post-PET case report forms completed by dementia expert

Aim 2: To assess the impact of amyloid PET on hospital admissions and emergency room visits at 12 months

‒ Medicare claims of study participants compared to those of concurrent propensity-matched controls who have not had amyloid PET

IDEAS-Study.org

IDEAS Study• Much more complicated study than NOPR

‒ Will collect more detailed information from referring MDs, as well as images (for future analysis)

‒ Patient-centered outcomes (Aim 2) most important to CMS

• Estimated sample size‒ Aim 1: 11,050 subjects for 30% change in management

composite endpoint

‒ Aim 2: 18,448 subjects for 10% relative reduction in hospitalization, ER visits

• Expected study cost $20M (excluding cost of scans)

• Timeline to coverage: at least 5 years

IDEAS-Study.org

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Conclusions

• NOPR has successfully used one pathway to help achieve coverage for PET in cancer

• But pathway quite slow and burdensome• Clinical trials of new molecular imaging

tracers and methods must focus, from the outset, on obtaining evidence of improved patient outcomes

• Coverage with evidence development should become a standard approach for evaluating new tracers