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Scott Ramsey and Veena Shankaran
J Natl Compr Canc Netw 2012;10:1037-1042
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Managing the Financial Impact of Cancer Treatment: The Role of
Clinical Practice Guidelines
1037
Journal of the National Comprehensive Cancer Network
The Last Word
Managing the Financial Impact of Cancer Treatment:
The Role of Clinical Practice Guidelines
The rising cost of cancer treatment in the United States poses a significant challenge
to health systems, government and private insurers, and individual patients. To some
degree, cancer treatment costs are rising due to inappropriate, non–evidence-based
use of expensive new technologies and drugs. However, adherence to evidence-based
clinical practice guidelines does not necessarily guarantee that cancer treatment will
be less costly or optimally cost-effective. Although clinical practice guidelines may
endorse many acceptable evidence-based treatment options, the financial implications
of different treatment decisions within these guidelines can vary significantly. In
the case of first-line treatment for metastatic colorectal cancer (CRC) and gastric
cancer, for example, the cost of 6 months’ treatment varies widely while the clinical
effectiveness of these regimens is comparable. Patients’ out-of-pocket payments
for various treatment regimens may also vary significantly. In the setting of rapidly
rising cancer treatment costs, it is essential that clinical practice guidelines begin to
incorporate economic information from the patient and health system perspectives to
minimize the financial impact of cancer care on patients and society.
The Influence of Clinical Practice Guidelines
Clinical practice guidelines play a vital role in providing oncologists and patients with
evidence-based cancer treatment algorithms. Clinical practice guidelines also broadly
influence what patients, health delivery systems, and health insurers pay for cancer
care. The economic impact of treatment decision-making on these stakeholders has
been of great interest recently.
Patients are increasingly faced with high copayments and other treatment-related
expenses, which may not only cause significant anxiety but also may limit their ability
to pay for basic necessities such as food and housing.1 In a recent population-based
survey of patients with CRC receiving adjuvant chemotherapy, 38% experienced
severe financial hardship (defined as accruing debt, borrowing money from friends or
family, selling/refinancing their primary home, or ≥ 20% decline in income).2 From
a societal standpoint, cancer treatment costs in the United States are projected to
increase by as much as 39% by 2020.3 Although efforts to discourage the use of non–
evidence-based procedures, tests, and treatments may help curb these rising costs to
some degree, the high variability in the costs of evidence-based treatments remains
an economic challenge for patients and other key stakeholders.4–6 Reducing the
financial burden of cancer treatment while maintaining high-quality care will require
a coordinated national strategy. In this commentary, we argue that oncology clinical
practice guidelines have a key role in this national effort.
Scott Ramsey, MD, PhD
Scott Ramsey, MD, PhD, is a full
member in the Cancer Prevention
Program at Fred Hutchinson
Cancer Research Center, where
he directs the Research and
Economic Assessment in Cancer
and Healthcare (REACH)
group, a multidisciplinary team
devoted to clinical and economic
evaluations of new and existing
cancer prevention, screening,
and treatment technologies.
He is also a Professor in the
School of Medicine, School of
Pharmacy, at the University of
Washington. Trained in medicine
and economics, his primary
research interest is in studying the
economic aspects of new medical
technologies. Dr. Ramsey is a
leader in the field of comparative
effectiveness research, past
President of the International
Society of Pharmacoeconomics
and Outcomes Research, and
has served on the Institute of
Medicine’s National Cancer Policy
Forum.
Current Role of Clinical Practice Guidelines
Clinical practice guidelines are intended primarily to summarize scientific evidence,
formulate best practice recommendations, and reduce variations in care. Practice
guidelines in oncology reflect the opinion of expert clinicians regarding single or
multiple evidence-based approaches to treating an individual with cancer. Selecting
among the range of acceptable treatment options depends on clinical assessment of
characteristics, such as performance status, medical comorbidity, and prior treatment.
The ideas and viewpoints
expressed in this editorial are
those of the author and do not
necessarily represent any policy,
position, or program of NCCN.
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Scott Ramsey, MD, PhD, and Veena Shankaran, MD
1038
The Last Word
Ramsey and Shankaran
Choosing Between Multiple Guideline-Supported
Treatment Options
Veena Shankaran, MD
Veena Shankaran, MD, is an
Assistant Professor of Medical
Oncology at The University of
Washington. Her clinical focus is
in gastrointestinal cancers. She
is also an Assistant Member in
the Clinical Research Division
at Fred Hutchinson Cancer
Research Center and recently
completed a Masters degree in
the Pharmaceutical Outcomes,
Research, and Policy Program
at the University of Washington
School of Pharmacy. Her research
focuses on the impact of cancer
treatment costs on individual
patients and decision-making
about high-cost oncology drugs in
advanced cancers.
In addition to clinical factors such as performance status and medical comorbidity,
other patient characteristics may influence selection of a particular treatment regimen
from a range of acceptable options. Characteristics such as distance to infusion center
and convenience (eg, pills vs. infusion) may also influence decisions. These factors are
not routinely addressed in clinical practice guidelines, but patients and physicians can
usually sort out how these issues might factor into the treatment plan.
However, the potential financial impact of treatment choices on patients, health
systems, and health insurers can be difficult to predict. Patients and physicians often
have very little advance knowledge about copayments for chemotherapeutics or
supportive medications. Further, many oncologists in the United States do not know
the differential total costs associated with one chemotherapy regimen versus another.8
Clinical guidelines list a number of “acceptable” treatment options, but rarely address
the financial variability of those options. Given the rising cost of cancer care, we
believe that physicians and patients need to understand the financial implications
of their treatment decisions. The next question, however, is whether guidelines
can—and should—report expected financial outcomes for regimens considered to be
therapeutically acceptable based on clinical evidence.
Examples: Variability in CRC and Gastric Cancer
Treatment Recommendations
Clinical practice guidelines that support several evidence-based treatment options
without reference to cost may result in very different financial outcomes for insurers,
health systems, and patients. We present 2 examples of the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines) for first-line therapy in metastatic
cancer to illustrate this issue.
Metastatic CRC
Several first-line treatment options exist for patients with good performance status who
can tolerate intensive therapy. Some of these options depend on KRAS mutational
status, which has been shown to predict responsiveness to the anti–epidermal growth
factor receptor (EGFR) antibodies cetuximab and panitumumab.9,10 Bevacizumab, a
monoclonal antibody against vascular endothelial growth factor (VEGF), has also
been shown to improve survival in the first-line treatment setting.11 Many of the
first-line CRC regimens endorsed in the NCCN Guidelines are outlined in Table 1.12
Although median survival is relatively comparable between regimens (range, 21.3–
28.0 months), Medicare reimbursement rates vary significantly from one regimen
to the next (range, $2200–$10,000 per treatment cycle). Patients with metastatic
CRC may receive multiple regimens over time (Table 1), potentially minimizing
cost savings seen with the first regimen; however, the treatment duration may also be
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Most oncology guidelines do not explicitly incorporate nonclinical factors, such as
treatment cost, expected patient out-of-pocket financial burden, or cost-effectiveness,
into the guideline development process.
Public and private health insurers commonly use guidelines and compendia to
support reimbursement decisions. The NCCN Drugs & Biologics Compendium, for
example, is recognized by the Centers for Medicare and Medicaid Services (CMS)
and UnitedHealthcare as a standard reference for oncology coverage policy.7
1039
The Last Word
Financial Impact of Clinical Practice Guidelines
Table 1 First-Line Combination Regimens in the NCCN Guidelines for Metastatic Colorectal Cancer
Medicare Reimbursement
Regimen and Dosing Schedule
Median OS
1 Cyclea
6 moa
mFOLFOX6 +
bevacizumab13,14
Every 14 days:
Oxaliplatin, 85 mg/m2 IV, day 1
Leucovorin, 400 mg/m2 IV, day 1
5-FU, 400 mg/m2 IV bolus, day 1
5-FU, 1200 mg/m2/day CIV, days 1 and 2
Bevacizumab, 5 mg/kg, day 1
21.3 mo
$5005.42
$60,065.04
CapeOx +
bevacizumab15–17
Every 21 days:
Oxaliplatin, 130 mg/m2 IV, day 1
Capecitabine, 850–1000 mg/m2 PO bid, days 1–14
Bevacizumab, 7.5 mg/kg, day 1
21.3 mo
$10,077.15
$80,617.16
FOLFIRI +
bevacizumab17,18
Every 14 days:
Irinotecan, 180 mg/m2 IV, day 1
Leucovorin, 400 mg/m2 IV, day 1
5-FU, 400 mg/m2 IV bolus, day 1
5-FU, 1200 mg/m2/day CIV, days 1 and 2
Bevacizumab, 5 mg/kg IV, day 1
28.0 mo
$2247.60
$26,971.08
mFOLFOX6 +
panitumumab10,b,c
Every 14 days:
Oxaliplatin, 85 mg/m2 IV, day 1
Leucovorin, 400 mg/m2 IV, day 1
5-FU, 400 mg/m2 IV bolus, day 1
5-FU, 1200 mg/m2/day CIV, days 1 and 2
Panitumumab, 6 mg/kg, day 1
23.9 mo
$6534.97
$78,419.6
FOLFIRI +
cetuximab9,19,b
Every 14 days (cetuximab either every 7 or 14
days):
Irinotecan, 180 mg/m2 IV, day 1
Leucovorin, 400 mg/m2 IV, day 1
5-FU, 400 mg/m2 IV bolus, day 1
5-FU, 1200 mg/m2/day CIV, days 1 and 2
Cetuximab, 400 mg/m2 IV first infusion, then 250
mg/m2 IV weekly
OR
Cetuximab 500 mg/m2 IV, day 1 every 2 weeks
23.5 mo
$4399.62
$52,795.44
FOLFIRI +
panitumumabb
Every 14 days:
Irinotecan, 180 mg/m2 IV, day 1
Leucovorin, 400 mg/m2 IV, day 1
5-FU, 400 mg/m2 IV bolus, day 1
5-FU, 1200 mg/m2/day CIV, days 1 and 2
Panitumumab, 6 mg/kg, day 1
NA
$3777.11
$45,325.37
FOLFOXIRI20
Every 14 days:
Irinotecan, 165 mg/m2 IV, day 1
Oxaliplatin, 85 mg/m2 IV, day 1
Leucovorin, 400 mg/m2 IV, day 1
5-FU, 1600 mg/m2/day CIV, days 1 and 2
22.6 mo
$2910.77
$34,929.20
Abbreviations: BSA, body surface area; CIV, continuous intravenous infusion; IV, intravenous; OS, overall survival; PO, orally.
a
Medicare reimbursement rate based on 2012 average sale price; dosing calculations based on weight 70 kg and BSA 1.7 m2
b
For patients with KRAS wild-type only.
c
In the cited clinical trials, panitumumab was combined with FOLFOX4; however, NCCN Guidelines list mFOLFOX6 +
panitumumab as a first-line treatment option.
longest with the first regimen. Thus, the financial impact
of this initial decision is significant.
Metastatic Gastric Cancer
For patients with metastatic gastric cancer, several firstline treatment options supported by the NCCN Guidelines
are available, ranging from single drugs to 3-drug
combinations. For patients with excellent performance
status, the NCCN Guidelines endorse multiple 3-drug
combinations. In a first-line gastric cancer clinical trial
that used a 2 x 2 factorial design to compare 4 different
triple-drug regimens, all regimens were associated with
comparable response and median survival rates, but
toxicity profiles varied. As in the previous example for
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Initial Regimen
and Study
1040
The Last Word
Ramsey and Shankaran
Table 2 Triple-Drug First-Line Systemic Chemotherapy Options for
Metastatic Gastric Cancer in the NCCN Guidelines
Regimen and
Dosing Schedulea
Median
OS, (m)
DCF21
Every 28 days:
Docetaxel, 75 mg/m2 IV, day 1
Cisplatin, 75 mg/m2 IV, day 1
5-FU, 1000 mg/m2/day CIV, days 1–5
ECF22
Medicare Reimbursement
1 Cycleb
6 mob
9.2
$1534.43
$9206.56
Every 21 days:
Epirubicin, 50 mg/m2 IV, day 1
Cisplatin, 60 mg/m2 IV, day 1
5-FU, 200 mg/m2/day CIV, days 1–21
9.9
$104.98
$839.84
ECX22
Every 21 days:
Epirubicin, 50 mg/m2 IV, day 1
Cisplatin, 60 mg/m2 IV, day 1
Capecitabine, 625 mg/m2 PO bid, days 1–21
9.9
$2269.06
$18,152.51
EOF22
Every 21 days:
Epirubicin, 50 mg/m2 IV, day 1
Oxaliplatin, 130 mg/m2 IV, day 1
5-FU, 200 mg/m2 CIV, days 1–21
9.3
$4420.67
$35,365.32
EOX22
Every 21 days:
Epirubicin, 50 mg/m2 IV, day 1
Oxaliplatin, 130 mg/m2 IV, day 1
Capecitabine, 625 mg/m2 PO bid, days 1–21
11.2
$7184.75
$57,478.03
Abbreviations: BSA, body surface area; CIV, continuous intravenous infusion; IV, intravenous; OS, overall survival; PO, orally.
Dosing calculations based on weight of 70 kg and BSA of 1.7 m2.
b
Medicare reimbursement rate based on 2012 average sale price; dosing calculations based on weight of 70 kg and BSA of 1.7m2.
a
metastatic CRC, the cost associated with one treatment
cycle varies widely among regimens (range $100–$7000;
Table 2). Because many patients with gastric cancer do
not reach second- or third-line therapy, choice of first-line
treatment can have a dramatic impact on overall costs
associated with treatment.
Out-of-Pocket Expenses
Importantly, the out-of-pocket expenses associated
with particular chemotherapy regimens can vary widely
depending on the patient’s insurance plan and state of
residence. A Medicare patient without a supplemental
insurance plan, for example, may be responsible for 20%
of the costs of all chemotherapeutics (infusional and
capecitabine), whereas a patient with a supplemental plan
may have complete coverage for these drugs. Although
capecitabine is covered under Medicare Part B, many
other oral chemotherapeutics used in other diseases (eg,
sunitinib and erlotinib) are covered under Medicare Part
D, which means that patients receiving these drugs often
reach the $4700 out-of-pocket “donut hole” in coverage
very early on in their treatment course.
Except in certain states that have legislation requiring
that oral chemotherapeutics be covered as a medical
benefit rather than an outpatient prescription, many
patients with commercial insurance might experience
very high copayments for oral chemotherapeutics,
including capecitabine. Under some insurance plans with
tiered formularies, these copayments may be as high as
50% of the total monthly cost for the drug. The variability
in patient prescription plans and drug coverage policies
for oral chemotherapeutics can profoundly impact a
patient’s treatment-related financial experience. Further,
the out-of-pocket expenses associated with a new regimen
are difficult to predict, making preemptive conversations
about anticipated costs difficult.
Ignoring Nonclinical Issues Reduces the
Potential Impact of Practice Guidelines
The costs of chemotherapy regimens commonly used in
metastatic CRC and gastric cancer vary greatly. Practice
guidelines that give equal weight to these regimens
create a situation in which accepted variations may
produce vastly different economic outcomes for patients
and society while producing potentially equivalent
clinical outcomes. In particular, high out-of-pocket
expenses associated with oral chemotherapeutics can
result in nonadherence and, in turn, poorer response
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Number 8 | August 2012
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Initial Regimen
and Study
The Last Word
1041
Financial Impact of Clinical Practice Guidelines
A Way Forward: Acknowledging Economic
Issues in Practice Guidelines
We believe it is crucial that the oncology community
take the lead in encouraging cost-effective prescribing
practices and developing supplementary information that
allows clinicians and patients to understand the personal
financial consequences of specific therapeutic options.
Below, we describe 4 items that could be incorporated into
clinical practice guidelines today to move toward this goal:
• Identify a minimal clinical difference among
therapeutic choices and group therapies that are
equivalent within that range.
• Identify the lowest cost option to patients within a
group of acceptable alternatives, based on minimal
clinical differences.
• Provide information to oncologists and patients on
the expected total costs and personal financial costs
of recommended regimens.
• Develop practice guidelines language that allows
health insurers to promote care that minimizes
financial burden to patients and health systems.
We acknowledge that these recommendations create
additional burdens for organizations that produce clinical
practice guidelines. Obtaining information on expected
patient out-of-pocket and total costs requires surveying
health insurers and tracking current drug prices. These tasks
are not impossible, however. With the possible exception of
drugs included in Part D, Medicare coverage policies are fairly
uniform nationally, making it a relatively straightforward
task to estimate patient copayments and deductibles for
common regimens. Medicare’s Web site also provides some
information to help patients understand their potential outof-pocket expenses (www.medicare.gov).
Coverage policies among commercial insurance plans
contain more variability, but regular surveys of the most
common oncology drug policies in the largest plans could
provide valuable data. In addition, many drug manufacturers
now produce budget impact analyses of their products
and share these with insurance plans that request them.
Guidelines groups could similarly request these analyses to
inform the guideline development process.
Conclusions
Any treatment decision in oncology, even those based
on strong clinical evidence, can have major financial
impacts on patients, insurers, and society. Particularly in
situations where many evidence-based treatment options
exist, clinicians have tremendous influence over the cost
of cancer treatment. Moving forward, incorporation of
cost information into guidelines development will help
increase awareness of the economic implications of
routine clinical decision-making and reduce the financial
burden of cancer treatment on patients and society.
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The Last Word
Ramsey and Shankaran
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Oncol 2008;26:2013–2019.
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