Cost-Effectiveness Analysis of Intensity Modulated Radiation Therapy Versus 3-Dimensional Conformal Radiation Therapy for Anal Cancer

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation

Cost-Effectiveness Analysis of Intensity Modulated Radiation Therapy Versus 3-Dimensional Conformal Radiation Therapy for Anal Cancer Joseph C. Hodges, MD, MBA,* Muhammad S. Beg, MD,y Prajnan Das, MD, MS, MPH,z and Jeffrey Meyer, MD, MS* *Department of Radiation Oncology and yDivision of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; and zDepartment of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas Received Jun 19, 2013, and in revised form Jan 21, 2014. Accepted for publication Feb 6, 2014.

Summary Intensity modulated radiation therapy (IMRT) is costineffective as compared with 3-dimensional conformal radiation therapy (3DCRT) for the treatment of anal cancer. However, the results were highly sensitive to key treatment- and diseasespecific variables, implying that any modest improvements in local control or patient-reported utility due to an improved toxicity profile would lead to cost-effectiveness of IMRT over 3DCRT.

Purpose: To compare the cost-effectiveness of intensity modulated radiation therapy (IMRT) and 3-dimensional conformal radiation therapy (3D-CRT) for anal cancer and determine disease, patient, and treatment parameters that influence the result. Methods and Materials: A Markov decision model was designed with the various disease states for the base case of a 65-year-old patient with anal cancer treated with either IMRT or 3D-CRT and concurrent chemotherapy. Health states accounting for rates of local failure, colostomy failure, treatment breaks, patient prognosis, acute and late toxicities, and the utility of toxicities were informed by existing literature and analyzed with deterministic and probabilistic sensitivity analysis. Results: In the base case, mean costs and quality-adjusted life expectancy in years (QALY) for IMRT and 3D-CRT were $32,291 (4.81) and $28,444 (4.78), respectively, resulting in an incremental cost-effectiveness ratio of $128,233/QALY for IMRT compared with 3D-CRT. Probabilistic sensitivity analysis found that IMRT was cost-effective in 22%, 47%, and 65% of iterations at willingness-to-pay thresholds of $50,000, $100,000, and $150,000 per QALY, respectively. Conclusions: In our base model, IMRT was a cost-ineffective strategy despite the reduced acute treatment toxicities and their associated costs of management. The model outcome was sensitive to variations in local and colostomy failure rates, as well as patient-reported utilities relating to acute toxicities. Ó 2014 Elsevier Inc.

Reprint requests to: Joseph C. Hodges, MD, MBA, University of Texas Southwestern, Department of Radiation Oncology, 5801 Forest Park Rd,

Int J Radiation Oncol Biol Phys, Vol. -, No. -, pp. 1e11, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.02.012

Dallas, TX 75390. Tel: (214) 645-7668; E-mail: joseph.hodges@ utsouthwestern.edu Conflict of interest: none.

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Hodges et al.

Introduction

Methods and Materials

The definitive treatment of anal cancer with concurrent chemotherapy and radiation therapy has progressed technologically with the use of intensity modulated radiation therapy (IMRT). A recent phase 2 study utilizing concurrent IMRT and 5-fluorouracil (5FU) and mitomycin-C (MMC) showed statistically significant improvements in acute grade 3 (G3) gastrointestinal (GI), acute G3 dermatologic, acute grade 2 (G2) hematologic toxicity, and a shorter median treatment duration due to a decrease in treatment-related breaks as compared with the 5FU/ MMC arm of Radiation Therapy Oncology Group (RTOG) protocol 9811 (1, 2). Although the primary endpoint of reducing grade G2 GI and genitourinary (GU) toxicity was not met, the above-mentioned gains represent a marked improvement in the acute toxicity experienced by patients. The local control (LC), colostomy-free survival, colostomy failure (CF), and overall survival (OS) rates were similar when comparing IMRT and 3-dimensional conformal radiation therapy (3D-CRT) at 2 years (3). Given the increasing cost of healthcare delivery in the United States, which is in large part due to emerging technologies, novel treatment alternatives understandably face cost-effectiveness scrutiny (4). Although IMRT is more costly than 3D-CRT when comparing absolute reimbursement, improvements in toxicity profiles could justify this up-front difference in cost. Thus, we have performed a cost-effectiveness analysis of IMRT versus 3D-CRT, focusing on the key patient, disease, and treatment parameters that drive the cost-effectiveness of either strategy.

Decision model We designed a Markov model to simulate the clinical history of a 65-year-old patient with squamous cell cancer of the anus eligible for curative-intent treatment with concurrent chemotherapy and radiation (Fig. 1). Markov simulation allows hypothetical cohorts of patients to transition between different health states in fixed increments of time (5). In this model a patient received 3D-CRT or IMRT concurrently with chemotherapy. We assumed that acute toxicities involving dermatologic, GI, hematologic, sexual, and GU systems resolved after 3 months, consistent with the definition of acute toxicity used as the primary endpoint in RTOG 0529. Thus, patients were subjected to transient acute toxicities related to treatment when they were subjected to utility decrements and then transitioned to a state of no evidence of disease, in which utility was equipoise. Patients could then remain in a state of no evidence of disease or experience late toxicity, local or distant progression, salvage abdominoperineal resection (APR) and colostomy, salvage chemotherapy, or palliative care. Patients remained in these disease states, recovered, or died of disease or background age-adjusted mortality rates. Late toxicities, although experienced equally given existing data between treatments, were included to test their impact in the sensitivity analyses (SA) (6). Late toxicities were assumed to be chronic and included dermatologic, GI, GU, and sexual side effects.

IMRT

3D-CRT Acute >=G3 GU

Acute >=G3 Derm

Acute >=G2 Sexual

Acute >=G3 GI

Acute >=G2 Heme

Late GU

Late Derm

NED

Late GI

Late Sexual

ALL States

Distant Failure

Local Failure

Salvage/ Palliative Chemo

APR Palliative Care

Death from Disease

Death Other Causes

Fig. 1. Markov model. 3D-CRT Z 3-dimensional conformal radiation therapy; APR Z abdominoperitoneal resection; Derm Z dermatologic; GI Z gastrointestinal; GU Z genitourinary; Heme Z hematologic; IMRT Z intensity modulated radiation therapy; NED Z no evidence of disease.

Volume -  Number -  2014

This analysis was performed from the payer perspective, and a lifetime horizon was used. The model was created and analyzed by use of TreeAge Pro Healthcare 2012 (TreeAge Software, Williamstown, MA).

Cost-effectiveness: IMRT for anal cancer

3

included in the model. The utility of a colostomy, progression, palliative chemotherapy, distant progression, and palliative care was taken from surgical literature and a cost-effectiveness analysis evaluating palliative chemotherapy (15-17).

Assumptions and probabilities Costs The base case assumptions of the model and the probability distributions applied to the variables under probabilistic sensitivity analysis (PSA) are noted in Table 1. All probabilities, utilities, and costs were extracted from the published literature as well as institutional and local Medicare coverage cost data.

Efficacy On the basis of the 2-year local failure (LF) probabilities (23% and 20%) and CF probabilities (10% and 8%) for RTOG 9811 (5FU/MMC arm) and RTOG 0529, respectively, and lack of convincing data suggesting a difference in efficacy, we assumed equal efficacy endpoints for IMRT and non-IMRT treatments (3). The OS was also extrapolated from the prior RTOG 9811 experiences and was assumed to be 78% at 5 years (2). The acute toxicities that were statistically different between RTOG 9811 and RTOG 0529 were used in the base case, whereas the rest of the toxicities were assumed to be equivalent (7). Even though RTOG 9811 had longer treatment periods on average and higher rates of treatment breaks compared with RTOG 0529, we assumed no impact on LC with treatment breaks but did construct the model to evaluate this in SA because treatment-related breaks adversely impacting LC have been reported in 2 separate analyses of RTOG trials (8, 9). It was assumed grade 4 dermatologic and gastrointestinal toxicity led to significant and expected treatment-related breaks. Thus, the model assumed a significant and expected treatment-related break rate of up to 8% as reported from the initial publication of RTOG 9811. This was assumed in the base case for both IMRT and 3D-CRT and varied on sensitivity analysis (29).

Utility (quality of life) The utility values used in the model were extracted from several published sources, as noted in Table 1. We estimated some utilities indirectly based on European series, which followed quality of life with European Organization for Research and Treatment of Cancer forms that have been mapped to general heath state utility instruments (ie, EQ-5D) (10-14). The various G3 toxicities were assumed to have an impact on acute quality of life and as such a decline in utility (10). Given no clear impact of acute toxicity on long-term utility, we assumed no difference in long-term utility between treatments, although this was evaluated in SA (6). Grade 2 toxicity was assumed to have a utility similar to baseline and thus was not explicitly

Radiation-related costs were based on the final 2014 local Medicare payment schedules for free-standing facilitybased billing (Table 2). The costs of managing treatmentrelated toxicities, APR, and colostomy care were estimated on the basis of clinical care at our institutions, surgical literature, and through expert opinion (18, 19).

Sensitivity analysis First-order or deterministic 1- and 2-way SA were performed to investigate the impact on the model when adjusting the base case assumptions. When a strategy was both more effective and less costly, that strategy is described as dominating the alternative treatment. If a therapeutic approach was not only more effective but also more costly, the incremental cost-effectiveness ratio (ICER) was described. Only the key parameters on 1-way SA were compared in 2-way SA.

Probabilistic sensitivity analysis Probabilistic sensitivity analysis (PSA) was performed to address the uncertainties inherent in the model assumptions that were most likely to affect the cost-effectiveness according to the results of the deterministic 1 and 2-way SA. On the basis of the 1 and 2-way deterministic SA, we tested the following variables in the PSA: CF, G3 GI toxicity, acute treatment utility of G3 GI toxicity, treatmentrelated breaks, and LF after treatment-related breaks. Recognizing a paucity of prospective data comparing IMRT and 3D-CRT on which to base these distributions, the probability distributions for all these variables were triangular, as noted in Table 1. A total of 100,000 patients were used in the Monte Carlo simulation for PSA.

Results Model validity This model was extensively calibrated in accordance with health economic modeling good practices (20). The key parameters calibrated were CF, OS, and acute and late treatment-related toxicities. The model predicted a 5-year OS of 78% for both IMRT and 3D-CRT, which was consistent with the 78% 5-year OS from RTOG 9811 (2). The model predicted 2-year CF of 10%, consistent with RTOG 9811 and RTOG 0529 (3). The acute toxicities were calibrated to match those of the comparison between RTOG

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Hodges et al. Table 1

Probabilities, utility values, and costs used in the study Event

Probabilities Age Colostomy failure 3D-CRT IMRT Local failure 3D-CRT IMRT Treatment break (G4 Derm or GI toxicity) 3D-CRT IMRT Local failure with treatment break Death 3D-CRT IMRT Distant failure, 3D-CRT and IMRT Failure after salvage APR Death after LRF With salvage APR No salvage APR Death after chemo metastatic Early toxicity, 3 mo Acute toxicity duration Derm toxicity(G3)z 3D-CRT IMRT GI toxicity (G3)z 3D-CRT IMRT GU toxicity(G3) 3D-CRT IMRT Sexual dysfunction (G3) 3D-CRT IMRT Heme toxicity (G2) z 3D-CRT IMRT Heme toxicity (G 3) 3D-CRT IMRT Late toxicity Late toxicity duration Derm toxicity (G3), 3D-CRT and IMRT Derm toxicity (G4), 3D-CRT and IMRT GI toxicity (G3), 3D-CRT and IMRT GI toxicity (>G4), 3D-CRT and IMRT GU toxicity(G3), 3D-CRT and IMRT

Base case (time)

Calibrated model value

PSA distribution triangle (min/most/max)

10% (2 y)y

8%/10%/12%

Reference

65 y 10% (2 y)* 8% (2 y) 23% (2 y)* 20% (2 y)

8%* 1.9% 23% at (2 y) 22% (5-y OS 78%)* 91% (2-y OS) 88% (2-y OS) 13% (5 y)

(29) (3) (29) (3)

22% (5-y OS 78%)y

0%/1.9%/8% 23%/23%/30%

(29) (3) (29) (2) (2) (3) (2)

57% (5 y)

(26, 27)

55% (5 y) 72% (5 y) 67.8% (5 y)

(26, 27) (28)

3 mo

0 mo-6 mo

49%* 23%*

49%y 23%y

36%* 21%*

36%y 21%y

3.4% 1.9%*

1.9%y

(29) (7)

1.2% 3.8%*

3.8%y

(29) (7)

85%* 73%*

85%y 73%y

(29) (7)

(29) (7)

15%/21%/36%

61% 58% Lifetime 3.1%*

(29) (7) 3.1%y

1.5% 3.2%*

6 mo-lifetime (2, 24) (2, 24)

3.3%y

1.5% 0.6%*

(29) (7)

(2, 24) (2, 24)

0.65%y

(2, 24) (continued on next page)

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Cost-effectiveness: IMRT for anal cancer

Table 1 (continued ) Event Patient-reported sexual dysfunction, 3D-CRT and IMRT Utilities NED, 3D-CRT and IMRT base case Derm G3 GI G3 toxicity GU G3 toxicity Sexual G3 toxicity Heme G3 toxicity Colostomy Salvage chemotherapy Local progression Distant progression Palliative care Death Costs 3D-CRT IMRT Local recurrence workup CT CPT 74170 Proctoscopy CPT 45305 Consult CPT 99205 Pathology 88304 Total NED follow-up (NCCN) CT CPT 74170 annual Anoscopy q 3-6 mo Follow-up q 3-6 mo Total annual follow-up/ monthly Palliative care Palliative chemotherapy Cisplatin and 5FU G3 Derm toxicity Analgesics, topical arcotics Domeboro Hydrogel pads Vigilon Cool Magic G4 Derm toxicity Longer use of G3 management G3 GI toxicity (diarrhea) Hospital IVF DRG 641 CC G4 GI toxicity (diarrhea) Hospital IVF DRG 640 MCC G3 GU toxicity GU consult 99205 Cystoscopy CPT 52204 G2 sexual toxicity Dilator Estrogen gel Viagra/Cialis

Base case (time) 55%*

0.80 early (<6 mo) 0.80 late (>6 mo) 0.2 or 0.6 0.2 or 0.6 0.2 or 0.6 0.2 or 0.6 0.3 or 0.5 0.78 0.6 0.5 0.4 0.33 0 $11,835 $17,671 $325.06 $706.26 $173.50 $23.13* $1227.63/once $67/mo* $325.06 $48.00 $72.72 $805/$67 $2834/mo

Calibrated model value 54%

PSA distribution triangle (min/most/max)

y

Reference (24)

(10-14)

0.56/0.60/0.70

(10) (10) (10) (10) (30) (15,16) (17) (17) (30) (17)

LCD 2014 LCD 2014 (26)

(26)

(32) (17, 28)

$500/mo $50/mo $25/mo $100/mo $150/mo $200/mo G3 þ 50%

$3923

$6279 $2057/once* $173/once $1884/once $60/mo* $40 once $60/mo $60/mo

UTSW data Red Book

UTSW data UTSW data Red Book UTSW data UTSW data Red Book UTSW data UTSW data UTSW data UTSW data (31) UTSW data UTSW data Red Book (continued on next page)

5

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International Journal of Radiation Oncology  Biology  Physics

Hodges et al. Table 1 (continued ) Event

Base case (time)

G3 Sexual toxicity Ob-Gyn consult 99205 Dilator Estrogen gel Male libido medication G2 Heme toxicity CPT 85025 and 80047 Hgb <10-8 g/dL ANC <1500-1000/mm3 Platelets <75K-50K/mm3 G3 Heme toxicity Outpatient ransfusion PT 63430, 038x, 039x Hgb 8-6.5 g/dL ANC 1000-500 Platelets <50K-25K/mm3 G4 Heme toxicity Admission DRG 811 MCC Hgb <6.5 g/dL ANC <500 Platelets <25K/mm3 APR colostomy Colostomy care

$100/mo* $173 $40 once $60/mo $60/mo

Calibrated model value

PSA distribution triangle (min/most/max)

Reference (31) UTSW data UTSW data Red Book (32) UTSW data UTSW data Red Book

$30/mo*

(33) UTSW data UTSW data Red Book

$1325/once

$7118

(34, 35)

$33,383 $279/mo

(18) (19)

Abbreviations: 3D-CRT Z 3-dimensional conformal radiation therapy; APC Z ambulatory payment code; APR Z abdominoperitoneal resection; CPT Z Common Procedure Terminology; CT Z computed tomography; Derm Z dermatologic; G Z grade; GI Z gastrointestinal; GU Z genitourinary; Heme Z hematologic; IMRT Z intensity modulated radiation therapy; K Z thousand; LCD Z Local Coverage Determination for Medicare; LRF Z local regional failure; NCCN Z National Comprehensive Cancer Network; NED Z no evidence of disease; PSA Z probabilistic sensitivity analysis; Red Book Z Red Book Online. Thompson Reuters. * Used in model. y Calibration result. z Significantly different between Radiation Therapy Oncology Group protocols 9811 and 0529.

9811 and RTOG 0529 (7). Given a recent report showing very low rates of late toxicity for IMRT patients, the late complications were calibrated to be equivalent to those reported in RTOG 9811, as listed in Table 1 (6). In summary, the calibration strongly suggested our model emulated the actual disease process after IMRT or 3D-CRT treatment for anal cancer, with several parameters showing excellent calibration. In the base case, mean costs and quality-adjusted life expectancy in years (QALYs) for IMRT and 3D-CRT were $32,291 (4.81) and $28,444 (4.78), respectively, resulting in an ICER of $128,233/QALY for IMRT compared with 3D-CRT. In the base case, IMRT would be cost-ineffective given the accepted conservative willingness to pay (WTP) threshold of $50,000/QALY (21). However, with a more relaxed WTP of $100,000/QALY, which is often used for emerging technologies and therapies, IMRT approaches cost-effectiveness (22, 23).

One-way SA Given our near-equipose base case assumptions, IMRT was a cost-ineffective option. Table 3 highlights variables

that showed sensitivity in the model. The optimal strategy was dependent on several key parameters, including CF, LF, LF after treatment-related breaks, G3 acute GI toxicity, G4 acute GI toxicity, acute treatment toxicityerelated utility, up-front cost of treatment, cost of management of G3 acute GI toxicity, and aggressive inpatient management of >G2 hematologic toxicity. The 1-way SA revealed that the ICER was near $100,000/QALY, with improvements for IMRT in LC, CF, grade 3 GI, and hematologic toxicity.

Two-way SA Two-way SA were performed on the variables that were most influential in the 1-way analyses and are shown in Table 4, highlighting as expected that IMRT is dominated by 3D-CRT when associated with higher CF rates (ie, >10% CF at 2 years. ). However, even with equal CF assumed, the 2-way SA revealed that the model was highly sensitive to small relative improvements in the acute treatment toxicityerelated utility for IMRT. Although there are no data to suggest any differences in CF or LF between the modalities, which was the base case

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Cost-effectiveness: IMRT for anal cancer

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Costs associated with 3D-CRT and IMRT Description

CPT Code

3D-CRT

Global

IMRT

Global

Consult level 4 Simulation Complex simulation Simple simulation Complex treatment device Treatment planning Treatment planning, complex CT planning for treatment planning Special treatment procedure* Physics plan Basic dose calculation Radiation therapy dose plan IMRT MLC treatment device for IMRT Weekly physics 3D planning Isodose plan Treatment/management Treatment management, 5 treatments Treatment delivery 3D Treatment delivery IMRT Port films Total

99205

1

207.91

1

207.72

77290 77280 77334

1 2 1

513.30 549.58 152.00

1 2 1

513.30 549.58 152.00

77263 77014(TC) 77470

1 1 1

166.97 125.21 156.38

1 1 1

166.97 125.21 156.38

77300 77301 77338 77336 77295 77315

8 0 0 6 1 1

67.94 0 0 75.77 489.626 137.35

7 1 1 6 0 0

67.94 1981.12 506.60 75.77 0 0

77427 77414 77418 77417

6 28 0 4

186.86 255.76 0 14.08 $11,835

6 0 28 4

186.86 0 400.19 14.08 $17,671

Abbreviations as in Table 1. 2014 Local Coverage Determination Medicare-LCD. * CPT code 77470 only used when necessary per guidelines.

assumption, the model was built to study the impact of LF, CF, and any potential treatment break impact on failures. Thus, the SA showed that any improvement in CF at 2 years for IMRT leads to an ICER of <$50,000/QALY. Table 4 scrutinizes the potential impact of treatment breaks on LFs, showing that IMRT would clearly become even more cost-effective, with a modest relative decrease in LF due to fewer treatment breaks. Furthermore, Table 5 highlights the sensitivity of the model to acute treatment-related utility and rates of grade 3 GI toxicity. For instance, as the utility of the state of grade 3 GI toxicity worsens and as the rate of grade 3 GI toxicity decreases, then IMRT approaches costeffectiveness, with an ICER consistently below $100,000/ QALY. Likewise, as the probability of grade 3 GI toxicity decreases and as the cost to manage grade 3 GI toxicity increases above $5000, which is not uncommon for inpatient management of grade 3 GI toxicity, then IMRT quickly approaches an ICER of <$100,000/QALY.

Probabilistic sensitivity analysis The IMRT parameters varied within the PSA are shown in Table 1. We evaluated uncertainties in the model variables that showed sensitivity in the 1- and 2-way sensitivity analyses, including CF at 2 years, grade 3 GI toxicity rates, and utility associated with grade 3 GI toxicity, treatment breaks, and LF after treatment breaks. The probabilities that

IMRT would be cost-effective at societal WTP thresholds of $50,000, $100,000, and $150,000 per QALY were 22%, 47%, and 65%, respectively.

Discussion In this study we have shown that despite its more favorable acute toxicity profile, IMRT is a cost-ineffective treatment for patients with anal cancer, for a WTP threshold of $50,000/QALY. However, it is clear on SA that this result was highly sensitive to slight improvements in patientreported utility, LF, and CF. The model also showed sensitivity to scenarios in which decreased G3 GI costs and toxicity rates led to cost savings for the IMRT patient cohort. Moreover, the analysis highlighted the key parameters that determine the therapy with the highest value: the model was most sensitive to CF and LF at 2 years, overall acute treatment side effects and their associated utility and costs, and the potential impact of treatment breaks on LC. The main variables that drove the cost-effectiveness of IMRT were both LF and CF at 2 years. One would expect this finding given that higher rates of LF and CF expose patients to the morbidity, mortality, and costs of salvage APR and colostomy. Thus, given this intuitive sensitivity to LF and CF, we explored the factors that may increase the risk for LF or CF. The finding that any slight associated increase in LF after significant and expected

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Hodges et al. Table 3

One-way sensitivity analysis comparing the ICER of IMRT with 3D-CRT Preferred treatment (ICER) Parameter

Probabilities Colostomy failure (2 y) 3D-CRT IMRT Local failure (2 y) 3D-CRT IMRT Treatment break Treatment break 3D-CRT IMRT Death (5 year) 3D-CRT and IMRT Acute treatment toxicity duration Grade 4 acute Derm toxicity 3D-CRT IMRT Grade  3 Acute GI toxicityx 3D-CRT IMRT Grade 4 Acute GI toxicity 3D-CRT IMRT Utilities NED Base Case Early (<6 mo) Late (> 6 mo) Individual acute toxicities Derm G3 GI G3 toxicity GU G3 toxicity Sexual G3 toxicity Heme G3 toxicity Individual late toxicities Derm G3 GI G3 toxicity GU G3 toxicity Sexual G3 toxicity Costs 3D-CRT IMRT Grade 3 Derm toxicity Grade 3 GI toxicity Grade 4 GI toxicity Grade 3 Heme toxicity Grade 4 Heme toxicity

Range

Lower limit

Upper limit

5-15% 5-15%

3D-CRT* IMRTz ($31K/Q)

IMRTy ($67K/Q) 3D-CRT*

10-30% 10-30% 8-40%

3D-CRT* IMRTz ($26K/Q) IMRT ($129K/Q)

IMRTz ($36K/Q) 3D-CRT* IMRTz ($26K/Q)

0-10% 0-10%

IMRT ($129K/Q) IMRT ($129K/Q)

IMRT ($129K/Q) IMRT ($129K/Q)

0-50% 1 mo-3 mo

IMRT ($116K/Q) IMRT ($129K/Q)

IMRT ($132K/Q) IMRT ($116K/Q)

0%-10% 0%-5%

IMRT ($129K/Q) IMRT ($129K/Q)

IMRT ($129K/Q) IMRT ($129K/Q)

30%-60% 10%-40%

IMRT ($137K/Q) IMRT ($101K/Q)

IMRTy ($67K/Q) IMRT ($202K/Q)

0%-10% 0%-5%

IMRT ($136K/Q) IMRT ($129K/Q)

IMRT ($115K/Q) IMRT ($131K/Q)

0.7-0.90 0.7-0.90

IMRT ($242K/Q) IMRT ($129K/Q)

IMRT ($101K/Q) IMRT ($128K/Q)

0.5-0.8 0.5-0.8 0.5-0.8 0.5-0.8 0.4-0.8

IMRT IMRT IMRT IMRT IMRT

($127K/Q) ($101K/Q) ($128K/Q) ($110K/Q) ($105K/Q)

IMRT IMRT IMRT IMRT IMRT

($176K/Q) ($143K/Q) ($128K/Q) ($132K/Q) ($142K/Q)

0.5-0.8 0.5-0.8 0.5-0.8 0.5-0.8

IMRT IMRT IMRT IMRT

($125K/Q) ($103K/Q) ($113K/Q) ($112K/Q)

IMRT IMRT IMRT IMRT

($169K/Q) ($141K/Q) ($114K/Q) ($115K/Q)

$8000-18,000 $10,000-20,000 $25-200 $2000-15,000 $5000-30,000 $750-45,000 $2500-45,000

IMRT ($224K/Q) IMRT* IMRT ($129K/Q) IMRT ($143K/Q) IMRT ($117K/Q) IMRT ($126K/Q) IMRT ($112K/Q)

IMRT* IMRT ($223K/Q) IMRT ($125K/Q) IMRTy ($70K/Q) IMRTy ($91K/Q) IMRT* IMRT*

Abbreviations: ICER Z incremental cost-effectiveness ratio; Q Z quality-adjusted life-year. Other abbreviations as in Table 1. * Treatment dominates. y >$50-100K/Q (entries with no footnote symbols, >$100/Q). z <$50K/Q. x Significantly different between Radiation Therapy Oncology Group protocols 0529 and 9811.

treatment-related breaks leads to IMRT being cost-effective highlights the great value in further understanding the implication of this relationship, especially in light of RTOG 0529 showing a decrease in overall treatment duration with

IMRT compared with patients treated on the 5FU/MMC arm of RTOG 9811. Regarding the model’s lack of sensitivity to G3 hematologic toxicity, although RTOG 0529 showed a

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Table 4 Select 2-way sensitivity analyses: Cost-effectiveness (ICER) varying colostomy failure at 2 years for IMRT versus acute toxicity IMRT utility and local failure (LF) at 2 years after treatment break Colostomy failure at 2 y for IMRT Overall acute IMRT toxicity utility 0.58 0.6 0.62 0.64 0.66 0.68 0.70 LF at 2 y after significant and expected treatment-related breaks 23%, base case assumption 24% 25% 26% 28% 30%

5%

6%

8%

9%

IMRTz $32K/Q IMRTz $31K/Q IMRTz $30K/Q IMRTz $29K/Q IMRTz $28K/Q IMRTz $27K/Q IMRTz $26K/Q

IMRTz $34K/Q IMRTz $33K/Q IMRTz $32K/Q IMRTz $31K/Q IMRTz $29K/Q IMRTz $28K/Q IMRTz $27K/Q

IMRTz $45K/Q IMRTz $44K/Q IMRTz $43K/Q IMRTz $42K/Q IMRT $40K/Q IMRTz $39K/Q IMRTz $38K/Q

IMRTy $64K/Q IMRTy $61K/Q IMRTy $58K/Q IMRTy $56K/Q IMRTy $54K/Q IMRTy $51K/Q IMRTz $49K/Q

10%, same as 3D-CRT IMRT $133K/Q IMRT $128K/Q IMRT $127K/Q IMRTy $94K/Q IMRTy $88K/Q IMRTy $77K/Q IMRTy $70K/Q

12% 3D-CRT* 3D-CRT* 3D-CRT* 3D-CRT* 3D-CRT* 3D-CRT* 3D-CRT*

Significant and expected treatment-related breaks for IMRT 0

2%

4%

6%

IMRT $128K/Q IMRTy $81K/Q IMRTy $64K/Q IMRTy $52K/Q IMRTz $44K/Q IMRTz $41K/Q

IMRT $128K/Q IMRTy $89K/Q IMRTy $74K/Q IMRTy $59K/Q IMRTy $53K/Q IMRTz $49K/Q

IMRT $128K/Q IMRTy $92K/Q IMRTy $81K/Q IMRTy $73K/Q IMRTy $65K/Q IMRTy $60K/Q

IMRT $128K/Q IMRTy $102K/Q IMRTy $95K/Q IMRTy $89K/Q IMRTy $82K/Q IMRTy $60K/Q

8%, same as 3D-CRT IMRT $128K/Q IMRT $129K/Q IMRT $129K/Q IMRT $129K/Q IMRT $129K/Q IMRT $129K/Q

10% IMRT $128K/Q 3D-CRT* 3D-CRT* 3D-CRT* 3D-CRT* 3D-CRT*

Abbreviations as in Tables 1 and 3. * Treatment dominates. y >$50-100K/Q (entries with no footnote symbols, >$100/Q). z <$50K/Q.

difference in G2 but not G3 hematologic toxicity, it is not surprising that hematologic toxicity did not affect the model because only G3 hematologic management leads to significantly increased cost of management (eg, transfusion, inpatient admission for neutropenic fever). Grade 3 hematologic toxicity was very similar between RTOG 0529 and RTOG 9811 (7). Likewise, the lack of sensitivity to G3 dermatologic toxicity is likely due to the conservative assumptions of G3 dermatologic toxicityerelated utility decrement and relatively low cost of managing these side effects for the short term during which patients experience these transient toxicities. Finally, as noted in Table 4, the cost-effectiveness of the model is exquisitely sensitive to treatment utility. This is expected because utility assumptions affect all patients, whereas LF and treatment-related breaks impact only a small fraction of patients. The sensitivity of the model to utility assumptions also highlights the inherent value in

studying patient-reported outcomes and utility, especially for a technology that is more expensive while offering an improved toxicity profile. There are several potential limitations to our model. First, there are no phase 3 data comparing IMRT and 3DCRT. We rely on comparisons of IMRT against historically similar arms from RTOG trials. Data on efficacy and longterm toxicity from IMRT are still maturing, and although we widely varied these assumptions, this is not a substitute for robust prospectivedand preferably randomizedddata. Moreover, the CF rates and late complications of IMRT need to be closely followed because there are limited longterm data on outcomes for patients treated with IMRT. A recent large series of IMRT with long-term follow up showed reassuring and comparable long-term toxicity as compared with historical 3D-CRT late complications (6). Because we assumed equivalent long-term toxicity, our model essentially only accounted for short-term acute

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International Journal of Radiation Oncology  Biology  Physics

Hodges et al.

Table 5 Select 2-way sensitivity analyses: Cost effectiveness (ICER) varying probability of acute GI G3 toxicities, utility of GI G3, and cost of GI G3 toxicity Probability of acute GI G3 toxicities for IMRT Parameter Utility of GI G3 toxicity 0.56 0.58 0.60, base case assumption 0.62 0.64 Cost of GI G3 toxicity $2000 $3923, base case assumption $5000 $10,000 $15,000

10%

15%

20%

IMRTy $98K/Q IMRT $101K/Q IMRT $101K/Q IMRT $104K/Q IMRT $106K/Q

IMRT $109K/Q IMRT $111K/Q IMRT $112K/Q IMRT $115K/Q IMRT $117K/Q

IMRT $121K/Q IMRT $124K/Q IMRT $127K/Q IMRT $128K/Q IMRT $130K/Q

IMRT $107K/Q IMRTy $92K/Q IMRTy $84K/Q IMRTz $46K/Q IMRT*

IMRT $116K/Q IMRT $101K/Q IMRTy $94K/Q IMRTy $59K/Q IMRT*

IMRT $125K/Q IMRT $112K/Q IMRT $106K/Q IMRTy $74K/Q IMRTz $43K/Q

21% same as 3D-CRT

25%

36%

IMRT $124K/Q IMRT $127K/Q IMRT $128K/Q IMRT $131K/Q IMRT $132K/Q

IMRT $137K/Q IMRT $139K/Q IMRT $141K/Q IMRT $143K/Q IMRT $144K/Q

IMRT $189K/Q IMRT $189K/Q IMRT $189K/Q IMRT $189K/Q IMRT $189K/Q

IMRT $143K/Q IMRT $128K/Q IMRT $121K/Q IMRTy $97K/Q IMRTy $70K/Q

IMRT $149K/Q IMRT $140K/Q IMRT $135K/Q IMRT $131K/Q IMRTy $91K/Q

IMRT $192K/Q IMRT $189K/Q IMRT $188K/Q IMRT $182K/Q IMRT $176K/Q

Abbreviations as in Tables 1 and 3. * Treatment dominates. y >$50-100K/Q (entries with no footnote symbols, >$100/Q). z <$50K/Q.

toxicity, but the model was built to include long-term toxicity to test the sensitivity of long-term toxicity. There was no inherent sensitivity to long-term late toxicities in the model, as shown in Table 3. Additionally, there are few reported data on the health state utilities and patient-reported outcomes for anal cancer patients who have been treated with either 3D-CRT or IMRT (24). Therefore, it should be a priority to further study patient preferences, especially over the short term to which our model has shown greatest sensitivity. Short-term utilities are not always well captured by traditional measurements, and this study highlights the need for further investment in short-term patient-level preference willingness-to-pay utility algorithms in technology assessment trials within RTOG (25).

Conclusion Given currently available information, IMRT is a costineffective strategy for treating anal cancer, despite the reduced acute treatment-related toxicities and reduced costs associated with managing these toxicities. However, the results were highly sensitive to key treatment- and diseasespecific variables, implying that any modest improvements in LC or patient-reported utility due to an improved toxicity

profile would lead to cost-effectiveness of IMRT over 3D-CRT.

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