Assessing Care Value for Older Patients Receiving Radiotherapy With or Without Cisplatin or Cetuximab for Locoregionally Advanced Head and Neck Cancer | Geriatrics | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Figure 1.  Propensity Score Distributions
Propensity Score Distributions

CRT indicates chemoradiotherapy; RT, radiotherapy.

Figure 2.  Total 3-Month Medicare Spending
Total 3-Month Medicare Spending

Three-month spending totals (inflation-adjusted to 2017 US dollars) for patients receiving radiotherapy (RT) only, RT with cisplatin, and RT with cetuximab are broken down by indication. Whiskers indicate 95% CIs. DME indicates durable medical equipment; HHA, home health aide.

Table 1.  Baseline Characteristics of Patients Undergoing Radiotherapy
Baseline Characteristics of Patients Undergoing Radiotherapy
Table 2.  Propensity Score–Matched Cox Proportional Hazards Model for Patients Receiving Radiotherapy Only, With Cisplatin, or With Cetuximab
Propensity Score–Matched Cox Proportional Hazards Model for Patients Receiving Radiotherapy Only, With Cisplatin, or With Cetuximab
Table 3.  Negative Binomial Regression Models of Rates of Emergency Department Visits and Inpatient Admissions for Patients Receiving Radiotherapy Only, With Cisplatin, or With Cetuximab
Negative Binomial Regression Models of Rates of Emergency Department Visits and Inpatient Admissions for Patients Receiving Radiotherapy Only, With Cisplatin, or With Cetuximab
1.
Young  RC.  Value-based cancer care.  N Engl J Med. 2015;373(27):2593-2595. doi:10.1056/NEJMp1508387PubMedGoogle ScholarCrossref
2.
Schnipper  LE, Davidson  NE, Wollins  DS,  et al; American Society of Clinical Oncology.  American Society of Clinical Oncology statement: a conceptual framework to assess the value of cancer treatment options.  J Clin Oncol. 2015;33(23):2563-2577. doi:10.1200/JCO.2015.61.6706PubMedGoogle ScholarCrossref
3.
Bonner  JA, Harari  PM, Giralt  J,  et al.  Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.  N Engl J Med. 2006;354(6):567-578. doi:10.1056/NEJMoa053422PubMedGoogle ScholarCrossref
4.
Bonner  JA, Harari  PM, Giralt  J,  et al.  Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.  Lancet Oncol. 2010;11(1):21-28. doi:10.1016/S1470-2045(09)70311-0PubMedGoogle ScholarCrossref
5.
Riaz  N, Sherman  E, Koutcher  L,  et al.  Concurrent chemoradiotherapy with cisplatin versus cetuximab for squamous cell carcinoma of the head and neck.  Am J Clin Oncol. 2016;39(1):27-31. doi:10.1097/COC.0000000000000006PubMedGoogle ScholarCrossref
6.
Xiang  M, Holsinger  FC, Colevas  AD, Chen  MM, Le  Q-T, Beadle  BM.  Survival of patients with head and neck cancer treated with definitive radiotherapy and concurrent cisplatin or concurrent cetuximab: a Surveillance, Epidemiology, and End Results-Medicare analysis.  Cancer. 2018;124(23):4486-4494. doi:10.1002/cncr.31708PubMedGoogle ScholarCrossref
7.
Gillison  ML, Trotti  AM, Harris  J,  et al.  Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial.  Lancet. 2019;393(10166):40-50. doi:10.1016/S0140-6736(18)32779-XPubMedGoogle ScholarCrossref
8.
Ward  MC, Reddy  CA, Adelstein  DJ, Koyfman  SA.  Use of systemic therapy with definitive radiotherapy for elderly patients with head and neck cancer: a National Cancer Data Base analysis.  Cancer. 2016;122(22):3472-3483. doi:10.1002/cncr.30214PubMedGoogle ScholarCrossref
9.
Baxi  SS, O’Neill  C, Sherman  EJ,  et al.  Trends in chemoradiation use in elderly patients with head and neck cancer: changing treatment patterns with cetuximab.  Head Neck. 2016;38(S1)(suppl 1):E165-E171. doi:10.1002/hed.23961PubMedGoogle ScholarCrossref
10.
Juarez  JE, Choi  J, John  MS, Abemayor  E, TenNapel  M, Chen  AM.  Patterns of care for elderly patients with locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys. 2017;98(4):767-774. doi:10.1016/j.ijrobp.2017.01.209
11.
ClinicalTrials.gov. Radiation therapy with durvalumab or cetuximab in treating patients with locoregionally advanced head and neck cancer who cannot take cisplatin. Bethesda, MD: National Library of Medicine; 2017. https://clinicaltrials.gov/ct2/show/NCT03258554. Accessed June 26, 2019.
12.
Caroline  B, Sundus  Y, Dawn  D, Carol  G, Susan  M.  Cost analysis of cetuximab (Erbitux) plus radiotherapy (ERT) versus concomitant cisplatin plus radiotherapy (CRT) within an NHS oncology unit (single institution): a pilot study.  Br J Radiol. 2016;89(1068):20160105. doi:10.1259/bjr.20160105PubMedGoogle Scholar
13.
National Cancer Institute, DCCPS, Surveillance Research Program. Surveillance, Epidemiology, and End Results (SEER) Program research data (1973-2015). http://www.seer.cancer.gov. Published November 2016. Accessed June 7, 2017.
14.
US Bureau of Economic Analysis. Personal consumption expenditures: services: health care (chain-type price index). Federal Reserve Bank of St. Louis. https://fred.stlouisfed.org/series/DHLCRG3Q086SBEA. Accessed August 12, 2018.
15.
Greene  FL, Page  DL, Fleming  ID,  et alAJCC Cancer Staging Manual. 6th ed. New York: Springer-Verlag.
16.
Healthcare Delivery Research Program. Comorbidity SAS macro. Bethesda, MD: Healthcare Delivery Research Program, National Cancer Institute; 2014. https://healthcaredelivery.cancer.gov/seermedicare/considerations/macro-2014.html. Accessed April 28, 2018.
17.
Austin  PC.  Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies.  Pharm Stat. 2011;10(2):150-161. doi:10.1002/pst.433PubMedGoogle ScholarCrossref
18.
Wickham  H.  Elegant Graphics for Data Analysis. New York: Springer-Verlag; 2009.
19.
Therneau  TM, Grambsch  PM.  Modeling Survival Data: Extending the Cox Model. New York: Springer; 2000. doi:10.1007/978-1-4757-3294-8
20.
Ho  DE, Imai  K, King  G, Stuart  EA.  MatchIt: nonparametric preprocessing for parametric causal inference.  J Stat Softw. 2011;42(8):1-28. doi:10.18637/jss.v042.i08Google ScholarCrossref
21.
Magrini  SM, Buglione  M, Corvò  R,  et al.  Cetuximab and radiotherapy versus cisplatin and radiotherapy for locally advanced head and neck cancer: a randomized phase II trial.  J Clin Oncol. 2016;34(5):427-435. doi:10.1200/JCO.2015.63.1671PubMedGoogle ScholarCrossref
22.
Fojo  T, Grady  C.  How much is life worth: cetuximab, non-small cell lung cancer, and the $440 billion question.  J Natl Cancer Inst. 2009;101(15):1044-1048. doi:10.1093/jnci/djp177PubMedGoogle ScholarCrossref
23.
Criss  SD, Mooradian  MJ, Sheehan  DF,  et al.  Cost-effectiveness and budgetary consequence analysis of durvalumab consolidation therapy vs no consolidation therapy after chemoradiotherapy in stage III non-small cell lung cancer in the context of the US health care system  [published online December 13, 2018].  JAMA Oncol. 2018. doi:10.1001/jamaoncol.2018.5449PubMedGoogle Scholar
24.
Goulart  B, Ramsey  S.  A trial-based assessment of the cost-utility of bevacizumab and chemotherapy versus chemotherapy alone for advanced non-small cell lung cancer.  Value Health. 2011;14(6):836-845. doi:10.1016/j.jval.2011.04.004PubMedGoogle ScholarCrossref
25.
Goldstein  DA, Chen  Q, Ayer  T,  et al.  First- and second-line bevacizumab in addition to chemotherapy for metastatic colorectal cancer: a United States-based cost-effectiveness analysis.  J Clin Oncol. 2015;33(10):1112-1118. doi:10.1200/JCO.2014.58.4904PubMedGoogle ScholarCrossref
26.
Chouaid  C, Atsou  K, Hejblum  G, Vergnenegre  A.  Economics of treatments for non-small cell lung cancer.  Pharmacoeconomics. 2009;27(2):113-125. doi:10.2165/00019053-200927020-00003PubMedGoogle ScholarCrossref
27.
de Souza  JA, Seiwert  TY. A value framework in head and neck cancer care. Presented at the: American Society of Clinical Oncology Annual Meeting; 2014; Chicago, Illinois. https://meetinglibrary.asco.org/record/91067/edbook#fulltext. Accessed February 10, 2019.
28.
Saltz  LB.  Perspectives on cost and value in cancer care.  JAMA Oncol. 2016;2(1):19-21. doi:10.1001/jamaoncol.2015.4191PubMedGoogle ScholarCrossref
29.
Ben-Aharon  O, Magnezi  R, Leshno  M, Goldstein  DA.  Association of immunotherapy with durable survival as defined by value frameworks for cancer care.  JAMA Oncol. 2018;4(3):326-332. doi:10.1001/jamaoncol.2017.4445PubMedGoogle ScholarCrossref
30.
Reeder-Hayes  KE, Meyer  AM, Hinton  SP, Meng  K, Carey  LA, Dusetzina  SB.  Comparative toxicity and effectiveness of trastuzumab-based chemotherapy regimens in older women with early-stage breast cancer.  J Clin Oncol. 2017;35(29):3298-3305. doi:10.1200/JCO.2016.71.4345PubMedGoogle ScholarCrossref
Original Investigation
October 17, 2019

Assessing Care Value for Older Patients Receiving Radiotherapy With or Without Cisplatin or Cetuximab for Locoregionally Advanced Head and Neck Cancer

Author Affiliations
  • 1Stanford University School of Medicine, Stanford, California
  • 2Department of Otolaryngology–Head and Neck Surgery, Stanford University School of Medicine, Stanford, California
  • 3Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California
JAMA Otolaryngol Head Neck Surg. 2019;145(12):1160-1167. doi:10.1001/jamaoto.2019.2381
Key Points

Question  What is the value of cetuximab chemoradiotherapy compared with radiotherapy alone for older patients with locoregionally advanced head and neck cancer?

Findings  In this cohort study of 1091 older patients with stages III to IVB head and neck cancer, radiotherapy with cetuximab treatment was not associated with improved survival compared with radiotherapy alone, but radiotherapy with cisplatin was associated with improved survival. Cetuximab use was associated with higher Medicare spending but not with higher rates of inpatient admission compared with radiotherapy alone, unlike radiotherapy with cisplatin.

Meaning  Despite performing better on some Medicare quality metrics, cetuximab appears to be of low value for older patients with advanced disease; composite metrics should be used in the future to assess care quality within the context of outcomes and treatment cost.

Abstract

Importance  Clinicians frequently use radiotherapy with cetuximab over radiotherapy only or radiotherapy with cisplatin because of a perceived survival and tolerability advantage, but scant data are available to support this perception.

Objective  To measure the 3 aspects of value (quality, outcomes, and cost) in older patients receiving radiotherapy only, radiotherapy with cisplatin, or radiotherapy with cetuximab for locoregionally advanced head and neck cancer.

Design, Setting, and Participants  For this cohort study, patient records were obtained from the Surveillance, Epidemiology, and End Results Program (SEER)–Medicare outcomes and claims database from January 1, 2004, to December 31, 2014. Participants were 65 years or older; received a diagnosis between 2006 and 2013 of stages III to IVB head and neck cancer; had only 1 cancer on record; and did not undergo surgical intervention. Data analysis was conducted from February 5, 2018, to March 27, 2019.

Exposures  Patients were divided into exposure arms on the basis of their first-line therapy or identified chemoradiotherapy and radiotherapy regimen.

Main Outcomes and Measures  Overall survival was analyzed by propensity score matching Cox proportional hazards regression models, quality by measuring 90-day emergency department (ED) visit and inpatient admission rates, and costs by assessing 90-day total Medicare spending.

Results  The overall cohort included 1091 patients, of whom 815 (74.7%) were male; the mean (SD) age was 73.9 (6.6) years. Patients receiving radiotherapy with cisplatin had higher overall survival compared with those receiving radiotherapy only (adjusted hazard ratio [HR], 0.64; 95% CI, 0.47-0.87). This finding was not seen in patients receiving radiotherapy with cetuximab (adjusted HR, 0.95; 95% CI, 0.75-1.20), compared with the radiotherapy only group, and it persisted after stratifying patients by age. The ED visit (adjusted incidence rate ratio [IRR], 1.72; 95% CI, 1.30-2.30) and inpatient admission (adjusted IRR, 1.48; 95% CI, 1.12-1.98) rates in the 90 days after treatment start were higher in patients receiving radiotherapy with cisplatin compared with those treated with radiotherapy only. Patients receiving radiotherapy with cetuximab had a higher rate of ED visits (adjusted IRR, 1.38; 95% CI, 1.05-1.82) compared with those in the radiotherapy only group. The 90-day after-treatment spending for patients receiving radiotherapy with cetuximab was $48 620 (95% CI, $46 466-$50 775) compared with $33 009 (95% CI, $31 499-$34 519) for radiotherapy with cisplatin and $27 622 (95% CI, $25 118-$30 126) for radiotherapy only.

Conclusions and Relevance  In this cohort study, no survival difference, a higher rate of ED visits but not of inpatient admissions, and higher spending were observed in patients receiving radiotherapy with cetuximab compared with patients receiving radiotherapy only. The findings suggest that radiotherapy alone should be maintained as a treatment arm in evaluation of novel therapeutics for locoregionally advanced head and neck cancer in older and sicker patients.

Introduction

The value of health care is often described as a function of quality, outcomes, and cost.1,2 In the realm of cancer care, value has been the subject of debate in recent years with the approval of several new expensive systemic therapeutic agents. In head and neck cancer in particular, this debate has centered on the use of cetuximab in combination with radiation therapy or other systemic therapies for curative intent.

In advanced-stage head and neck cancer, adding cetuximab to radiotherapy was shown to be associated with improved survival,3,4 and the treatment has since been used extensively in this patient population. More recent randomized clinical trial data have presented a complicated picture of the comparison between radiotherapy with cetuximab and more traditional platinum-based chemoradiotherapy (CRT).4,5 In addition, subgroup analysis and retrospective data have shown the survival advantage of cetuximab in older patients to be particularly unclear,4,6 and cetuximab was found to be inferior to cisplatin CRT for treatment of human papillomavirus–positive disease.7 Regardless, clinicians frequently treat older patients, especially those who are not able to tolerate cisplatin, with cetuximab systemic therapy8 in addition to radiotherapy, a trend continuing through at least 20169,10 with unclear advantages. These recent results and associated practice changes raise questions regarding cetuximab’s value, especially as we test it against more expensive immunotherapy options.11

Investigating cancer care value and quality, however, comes with its own challenges, especially in the retrospective setting. The Centers for Medicare & Medicaid Services (CMS) has regarded health care utilization rates measured by inpatient admissions and emergency department (ED) visits as markers of high-quality care. Both the CMS Innovation Center Oncology Care Model and the CMS OP-35 (outpatient quality measures) include these metrics and encourage clinicians to designs systems and processes to avoid unplanned hospital-based care. Data from the United Kingdom suggest that differences in resource use exist between patients treated with radiotherapy with cetuximab and patients treated with radiotherapy with cisplatin,12 but evidence of health care utilization of the various treatment pathways in head and neck cancer care is lacking in the United States. Thus, in the treatment of stages III to IVB head and neck cancer in patients 65 years or older, assessment of the value of cetuximab is complex.

In this study, we sought to better define the value of cetuximab by assessing the 3 aspects of value (quality, outcomes, and cost) among patients aged 65 and older receiving either radiotherapy only, radiotherapy with cisplatin, or radiotherapy with cetuximab for locoregionally advanced head and neck cancer. The lessons learned about cost and care quality from the cetuximab era may be crucial in the coming years.

Methods
Data Source

This retrospective cohort study used data from the Surveillance, Epidemiology, and End Results (SEER) Program–Medicare database from January 1, 2004, to December 31, 2014, which links cancer registry data from SEER13 with insurance claims from Medicare. The SEER Program collects incident cancer cases from population-based registries that draw from approximately 30% of the US population. This study received institutional review board exemption from the Stanford University School of Medicine because it uses deidentified data. Informed consent was not required for this reason.

Definitions

We selected patients with primary tumors of the oral cavity, oropharynx, hypopharynx, and larynx, according to International Classification of Diseases for Oncology site codes. Patients were included if they received a diagnosis between January 1, 2006, and December 31, 2013; were 65 years or older at diagnosis; had stages III to IVB disease; had only 1 cancer on record; and did not undergo surgical intervention (eFigure 1 in the Supplement). To adequately capture treatment and hospitalization claims, we selected patients who were enrolled in Medicare Part A and B without health maintenance organization co-coverage for 12 months before and 5 months after diagnosis.

We searched inpatient and outpatient Medicare claims for radiotherapy and chemotherapy treatment using Healthcare Common Procedure Coding System codes (eTable 1 in the Supplement). Data sources within the SEER-Medicare database are shown in eTable 2 in the Supplement. Patients were divided into exposure arms on the basis of their first-line therapy. Patients were categorized as receiving radiotherapy if they had a minimum of 30 radiotherapy claims within 3 months of diagnosis with no more than 14 days between continuous claims. Chemotherapy was limited to the use of cisplatin and cetuximab. Chemotherapy claims within 14 days of the radiotherapy start date were classified as concurrent, more than 90 days after the radiotherapy start date were classified as radiotherapy only, and more than 14 days before or during 14 to 90 days after the radiotherapy start date were excluded. Treatment groups included in the analysis were radiotherapy only, radiotherapy with cetuximab, and radiotherapy with cisplatin.

The main outcomes in this study were overall survival (OS), inpatient admissions, ED visits, and total health care spending in 3 months after treatment start. Overall survival data were abstracted from the Patient Entitlement and Diagnosis Summary File. Inpatient admissions were counted from the Medicare Provider Analysis and Review file, and ED visits were assessed using revenue center codes and CMS Place of Service codes in the physician and outpatient claims. Emergency department visits that resulted in an inpatient admission were excluded from analysis to prevent double counting. Spending was calculated from the Medicare perspective by totaling reimbursed line-item spending by Medicare for each patient in the 3 months after their first radiotherapy or chemotherapy claim. Spending was adjusted for inflation to 2017 US dollars using the Personal Consumption Expenditures health care service index.14

We used the Patient Entitlement and Diagnosis Summary File in the SEER-Medicare data to abstract covariates for these patients. The variables included age, sex, race/ethnicity, site, and TNM stage grouping (American Joint Commission on Cancer Cancer Staging Manual, 6th edition).15 Comorbidities, excluding cancer, were assessed using the composite Charlson Comorbidity Index, and claims were extracted using the SEER-Medicare SAS macro.16

Statistical Analysis

In our descriptive analyses, we used 95% CIs to compare across groups. For deidentification reasons, cell sizes with values less than 11 were collapsed for display. We used Kaplan-Meier methods and multivariable Cox proportional hazards regression models to evaluate OS. The multivariable Cox models were adjusted for age, sex, site, stage, and Charlson Index, and the CRT treatment groups were compared with radiotherapy only as a reference. We evaluated the proportional hazards assumption, and because it was not met for sex, stage, and site, the models were stratified on these variables owing to varying baseline hazards.

To account for indication bias in the treatment received, we conducted 2 subgroup propensity score–matched analyses to compare OS among patients receiving radiotherapy only compared with that among those receiving radiotherapy with cetuximab or radiotherapy with cisplatin. Propensity scores were calculated using age, sex, site, and Charlson Index. Nearest-neighbor matching was performed 1:1 without replacement, and caliper size was set to 0.15 of the SD of the logit of the propensity score.17 Covariate balance was assessed by evaluating absolute standardized differences or differences in proportion between groups, which were balanced across groups (absolute standardized difference <10%) except for age in the cetuximab group and Charlson Index in the cisplatin group. The Cox models were then stratified by matched pair, and CIs were calculated using robust SEs to account for correlated observations. The median observation time was 23 months, and the median time to censoring was 37 months across the entire cohort.

Inpatient admissions and ED visits were analyzed as count data. Because the data were overdispersed (μ<<σ2), negative binomial regression models were judged to be more appropriate than Poisson models. These models were adjusted for age, sex, site, stage, and Charlson Index. Missing data constituted 6.1% in 1 variable (Charlson Index); thus, we proceeded in all models with a complete-case analysis (eTable 3 in the Supplement). Because we were interested in the association between age and survival, models and analyses were stratified by age 65 to 74 years or by age 75 years or older.

We extracted and managed the data in SAS, version 9.4 using SAS Enterprise Guide, version 7.1 (SAS Institute Inc). Matching, statistical analysis, and data visualization was performed in R, version 4.3.1 (R Foundation for Statistical Computing), using, among others, the ggplot,18 survival,19 and MatchIt20 packages. Data analysis was conducted from February 5, 2018, to March 27, 2019.

Results
Baseline Characteristics

Between January 1, 2006, and December 31, 2013, 1091 patients met the study’s inclusion criteria (eFigure 1 in the Supplement) and were categorized as having received 1 of 3 regimens: radiotherapy only, radiotherapy with cisplatin, or radiotherapy with cetuximab (Table 1). This cohort consisted of 135 patients (12.4%) with oral cavity, 583 (53.4%) with oropharyngeal, and 373 (34.2%) with laryngeal or hypopharyngeal malignant neoplasms. The mean (SD) age in the overall cohort was 73.9 (6.6) years, with 815 male patients (74.7%). Across all treatment groups, 28.2% patients had a Charlson Index of 0 and 33.3% had an Index of 3 or higher.

Survival Outcomes

In unmatched, unadjusted survival analysis, the Kaplan-Meier method demonstrated statistically significant divergence of the OS curves among the 3 groups (eFigure 2 in the Supplement). When stratified by age, this observation persisted. Median survival was higher among patients receiving radiotherapy with cisplatin (57 months) compared with radiotherapy only (22 months) or radiotherapy with cetuximab (28 months). Cox models adjusted for age, sex, site, stage, and the Charlson Index demonstrated statistically significantly higher OS among patients receiving radiotherapy with cisplatin (adjusted hazard ratio [HR], 0.68; 95% CI, 0.54-0.87) compared with those receiving radiotherapy only (eTable 4 in the Supplement). Patients receiving radiotherapy with cetuximab did not have a statistically significantly different OS (adjusted HR, 0.96; 95% CI, 0.77-1.18).

To account for considerable indication bias in this analysis, we conducted 2 propensity score–matched analyses to make comparisons between radiotherapy only and the 2 CRT treatments. The shapes of propensity score distributions between the radiotherapy only and radiotherapy with cetuximab groups were found to be similar, unlike the shapes between the radiotherapy only and radiotherapy with cisplatin groups (Figure 1). The matched cohort comprised 215 patients in each group in the radiotherapy only or radiotherapy with cetuximab analysis and 170 patients in each radiotherapy only group or radiotherapy with cisplatin group analysis; after matching, groups were balanced for all covariates except for age in the cetuximab group and the Charlson Index in the cisplatin group (standardized mean difference, –17.3% vs –25.0%) (eTable 5 in the Supplement).

Cox models (Table 2) adjusted for age, sex, site, stage, and the Charlson Index demonstrated statistically significantly higher OS among patients of all ages receiving radiotherapy with cisplatin (adjusted HR, 0.64; 95% CI, 0.47-0.87) compared with those receiving radiotherapy only. This higher OS was not seen among those receiving radiotherapy with cetuximab (adjusted HR, 0.95; 95% CI, 0.75-1.20). When stratified by age, patients aged 65 to 74 years receiving radiotherapy with cisplatin had statistically significantly better survival (adjusted HR, 0.63; 95% CI, 0.42-0.93) compared with those receiving radiotherapy only, although this finding was not seen among patients receiving radiotherapy with cetuximab (adjusted HR, 0.80; 95% CI, 0.54-1.18). Among patients aged 75 years, those receiving radiotherapy with cisplatin (adjusted HR, 0.65; 95% CI, 0.39-1.06) and radiotherapy with cetuximab (adjusted HR, 1.14; 95% CI, 0.84-1.54) were not observed to have statistically significantly different survival from patients receiving radiotherapy only.

Quality

In an unmatched analysis, we further examined the rates of ED visits and inpatient admissions among patients receiving radiotherapy only, radiotherapy with cisplatin, or radiotherapy with cetuximab therapy. Individuals receiving radiotherapy with cisplatin had a 72% higher rate (adjusted incidence rate ratio [IRR], 1.72; 95% CI, 1.30-2.30) of ED visits and inpatient admissions (adjusted IRR, 1.48; 95% CI, 1.12-1.98) overall, compared with patients receiving radiotherapy only (Table 3), and patients receiving radiotherapy with cetuximab had a 38% higher rate (adjusted IRR, 1.38; 95% CI, 1.05-1.82). When stratified by age, patients receiving radiotherapy with cisplatin who were older than 75 years were found to have almost twice the rate of ED visits compared with patients receiving radiotherapy only (adjusted IRR, 1.99; 95% CI, 1.27-3.16). Patients receiving radiotherapy with cetuximab who were older than 75 years had 66% higher rate of ED visits (adjusted IRR, 1.13; 95% CI, 1.13-2.45). No statistically significant differences were found between treatment groups for inpatient admissions for patients aged 65 to 74 years, but patients older than 75 years who were receiving radiotherapy with cisplatin had more than twice the adjusted rate of admissions (adjusted IRR, 2.31; 95% CI, 1.48-3.64). This was not observed among patients aged 75 or older receiving radiotherapy with cetuximab (adjusted IRR, 1.23; 95% CI, 0.83-1.84).

Spending

Total Medicare spending for 90 days after treatment start was also analyzed among the 3 groups, adjusted for inflation to 2017 US dollars and separated by indication (Figure 2). These spending figures were also categorized by reason for line-item spending. In general, spending for patients receiving radiotherapy with cetuximab was $48 620 (95% CI, $46 466-$50 775) compared with $33 009 (95% CI, $31 499-$34 519) for radiotherapy with cisplatin and $27 622 (95% CI, $25 118-$30 126) for radiotherapy only. Outpatient infusion services and chemotherapy spending (which includes all medication-infusion spending) was $16 969 (95% CI, $16 366-$17 573) for radiotherapy with cetuximab compared with $1489 (95% CI, $1369-$1609) for radiotherapy with cisplatin and $103 (95% CI, $49-$156) for radiotherapy only.

Discussion

This study evaluated the treatment of older patients with locoregionally advanced (stage III to IVB) head and neck cancer from 3 perspectives of OS outcomes, ED visit and inpatient admission rates, and Medicare spending. In a propensity score–matched cohort, we found that OS was higher among patients 65 years or older who were receiving radiotherapy with cisplatin compared with those receiving radiotherapy only. This OS was not seen among patients receiving radiotherapy with cetuximab compared with those receiving radiotherapy only. Emergency department visit rates were considerably higher among those receiving radiotherapy with cisplatin and radiotherapy with cetuximab compared with those receiving radiotherapy only, and this association was increased in older patients. Inpatient admission rates were only higher among patients receiving radiotherapy with cisplatin. The mean total Medicare spending in the period of 3 months after the start of treatment was highest for patients receiving radiotherapy with cetuximab (more than 75% higher than for patients receiving radiotherapy only). A large portion of this difference consisted of higher chemotherapy spending.

A large number of randomized clinical trials evaluating cetuximab have been conducted in the past 10 years. In the 5-year subgroup analysis4 of the trial by Bonner et al3, although radiotherapy with cetuximab was associated with a significant improvement in survival compared with radiotherapy only, age younger than 65 years was associated with a potential increased advantage from cetuximab. Other studies, both randomized5,21 and retrospective,6 have also challenged the notion that cetuximab is a safer alternative to cisplatin that is also efficacious. The recent RTOG 1016 study7 showed that, in a randomized cohort of human papillomavirus–positive patients with T1-T2, N2a-N3, and M0 disease or T3-T4, N0-N3, and M0 disease (classified according to the American Joint Commission on Cancer Cancer Staging Manual, 7th edition), radiotherapy with cetuximab was inferior to radiotherapy with cisplatin with regard to OS. Baxi et al9 observed, using the SEER-Medicare database, that from 2001 to 2009, CRT (particularly cetuximab) increased and surgical interventions and radiotherapy only decreased in a population-based cohort of older patients with locoregionally advanced head and neck cancer. From then through 2016, rates of concurrent systemic therapy among older adults increased,8 with a considerable portion of these patients receiving cetuximab.10

In this study, we observed a similarity in propensity of treatment between the groups receiving radiotherapy only and radiotherapy with cetuximab but not between those receiving radiotherapy only and radiotherapy with cisplatin. This finding suggests that age and sickness are associated with the use of cetuximab for CRT in this older patient population. Although propensity score matching is limited in its ability to create comparable cohorts of patients, the measured baseline characteristics of the radiotherapy with cetuximab and radiotherapy-only groups were similar, suggesting that these patients likely had a more consistent patient profile.

Early trials3 demonstrated the efficacy of cetuximab, but its real-world value may be limited given that patients who are too old or too sick to receive cisplatin may not benefit from the addition of systemic therapy. The addition of systemic therapy in this patient population may be desirable for various clinical and psychosocial reasons, but this treatment pathway in a highly comorbid group of people may be associated with poor value (similar outcomes but inferior quality and higher costs). Furthermore, our results suggest that radiotherapy alone may still be appropriate in the treatment of locoregionally advanced head and neck cancer in patients who cannot tolerate cisplatin, which is important to consider in the design of clinical trials. The NRG HN 004 is a new trial11 comparing concurrent CRT with durvalumab (an anti-PD-L1 immune checkpoint inhibitor) and CRT with cetuximab in those who cannot take cisplatin owing to age, comorbidities, or hearing loss. The study design includes a 12-month tail of immunotherapy treatment, the cost of which is greater than $100 000. However, the ongoing study does not include a radiotherapy-only arm, a decision that from a value perspective, may impair the field’s future ability to ask whether a potentially higher-value treatment pathway exists for older adults and comorbid patients.

Nevertheless, if durvalumab shows a statistically significant survival advantage over cetuximab, the value of this advantage would need to be assessed because of the increased costs. We believe the data support that this discussion is nuanced, and considering a radiation-only arm may have been worthwhile. National cooperative trials between increasingly expensive chemotherapeutic agents may establish a relative superiority between those treatments but may provide little evidence on whether systemic therapy is necessary and valuable in the first place. If cetuximab and durvalumab have equivalent outcomes, the cost of head and neck cancer care may substantially increase without increasing value.

Health care utilization of drugs like cetuximab is critical to address as we balance questions of treatment effectiveness with the limited resources in modern US health care.22 US data on cetuximab’s costs in head and neck cancer are scant, but a British study into the costs of care reported that cetuximab remains the more expensive option compared with cisplatin, even after taking into account the differences in percutaneous gastrostomy tube use and cost of additional care and interventions.12 The present results showed that the 3-month Medicare spending on patients receiving radiotherapy with cetuximab was higher in general compared with those receiving radiotherapy only or radiotherapy with cisplatin, largely owing to infusion services and chemotherapy spending.

Findings across oncology regarding spending, cost-utility and cost-effectiveness, and value are mixed. In lung cancer, durvalumab consolidation therapy compared with no consolidation for stage III non–small cell lung cancer was found in a simulated model to be cost-effective at the $100 000 per quality-adjusted life year (QALY) threshold, with an incremental cost-effectiveness ratio of $67 421 per QALY.23 Bevacizumab with chemotherapy compared with chemotherapy alone was not cost-effective for both stage IIIB to IV non–small cell lung cancer24 (with an incremental cost-effectiveness ratio of $560 000 per QALY) and metastatic colorectal cancer25 (with an incremental cost-effectiveness ratio of $364 083 per QALY). Especially among older adults, however, trial evidence and cost-utility analyses are lacking, making the assessment of spending, cost-utility and cost-effectiveness, and value methodologically fraught.26

In 2015, the American Society of Clinical Oncology published a conceptual framework2 of net health benefit (NHB) to consider the question of outcomes more critically. This model weighs a treatment pathway’s benefits and adverse effects to specify and communicate its overall use. However, the relative importance of treatment complications should be balanced with cost and outcomes, and this point may be where the concept of net health benefit comes into play. Understanding the concerns and sometimes competing priorities of various stakeholders with regard to outcomes, such as survival, toxic effects, and revisits, will be critical for improving value in head and neck cancer care. The potential changes to payment models make it important to align incentive structures in reimbursement through the development of more effective composite quality metrics that do not reward clinicians for using less effective treatments that are less likely to trigger quality penalties. The value problem posed by the rising cost of systemic agents,27 particularly in the immuno-oncology space, is not unique to head and neck cancer.28 In the metastatic setting, with current pricing schemes, immuno-oncology agents have been found to not reach efficacy thresholds under modern health care value frameworks established by the American Society of Clinical Oncology.29 Given that these agents are increasingly added to the treatment regimens for locoregionally advanced disease, continuing to ensure that improvements in outcomes and care quality (both objective and patient reported) are commensurate with higher costs will be important.

Limitations

This study has a number of limitations. First, the requirement of uninterrupted entitlement coverage for these patients for a period of 18 months restricted the development of the cohort and may have introduced bias. However, providing uninterrupted coverage is standard practice in claims data analysis and is required to avoid misclassification bias. Second, we were unable to assess p16/human papillomavirus positivity or performance status for these patients because of the limitations in the SEER data. In addition, we could not take into consideration the details of radiotherapy or the dose of administered chemotherapy as previously described.6,30 Third, although we used propensity score matching to reduce indication bias, we were limited by the differences among treatment groups and potential unmeasured confounders.

Conclusions

In this study, older patients with locoregionally advanced head and neck cancer who were receiving radiotherapy with cetuximab did not have improved survival compared with those receiving radiotherapy only, but patients receiving radiotherapy with cisplatin had improved survival compared with their counterparts who were receiving radiotherapy only. Cetuximab CRT was associated with higher 3-month Medicare spending but not with a higher rate of inpatient admissions compared with radiotherapy only, unlike the radiotherapy with cisplatin treatment. Thus, cetuximab appears to be of low value for older patients with advanced-stage head and neck cancer. Balancing costs and outcomes in cancer treatment in a nuanced way may be necessary, taking into account the views of various stakeholder groups. These study results appear to have implications for the assessment of value for patients with head and neck cancer and suggest that composite metrics are needed that evaluate quality in the context of OS and treatment cost.

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Article Information

Accepted for Publication: July 2, 2019.

Corresponding Author: Vasu Divi, MD, Department of Otolaryngology–Head and Neck Surgery, Stanford University School of Medicine, 801 Welch Rd, Stanford, CA 94305 (vdivi@stanford.edu).

Published Online: October 17, 2019. doi:10.1001/jamaoto.2019.2381

Author Contributions: Mr Saraswathula and Dr Divi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Saraswathula, Chen, Divi.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Saraswathula, Chen, Divi.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Saraswathula.

Obtained funding: Divi.

Administrative, technical, or material support: Chen, Colevas, Divi.

Supervision: Chen, Divi.

Conflict of Interest Disclosures: Dr Colevas reported receiving personal fees from Cota Inc, KeyQuest Health, LOXO Oncology, Aduro Biotech, Pfizer, Cue Biopharma, and IQVIA RDS; receiving grants and personal fees from ATARA Biotherapeutics; and receiving grants from Threshhold Pharmaceuticals, AstraZeneca, Innate Pharma, Bristol Squibb Pharmaceuticals, CellSight Technologies Inc, Tessa Therapeutics, Exelixis, Cullinan, and Abbvie outside the submitted work. No other disclosures were reported.

Funding/Support: These data were accessed using the Stanford Center for Population Health Sciences Data Core, which was supported by Clinical and Translational Science Award UL1 TR001085 from the National Institutes of Health (NIH) and by internal Stanford funding. Collection of these data was supported by the California Department of Public Health (CDPH), mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s SEER Program under contract HHSN261201000140C (Cancer Prevention Institute of California), contract HHSN261201000035C (University of Southern California), and contract HHSN261201000034C (Public Health Institute); and the Centers for Disease Control and Prevention (CDC) National Program of Cancer Registries, under agreement #U58DP003862-01 (CDPH).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The interpretation and reporting of these data are the sole responsibility of the authors. The ideas and opinions expressed herein are those of the authors, and endorsement by the CDPH, the NIH, and the CDC or their contractors and subcontractors is not intended nor should be inferred.

Additional Contributions: We thank the Stanford Medical Scholars Program. We also acknowledge the efforts of the National Cancer Institute; the Office of Research, Development, and Information; the Centers for Medicare and Medicaid Services; Information Management Services; and the SEER tumor registries in creating this database.

References
1.
Young  RC.  Value-based cancer care.  N Engl J Med. 2015;373(27):2593-2595. doi:10.1056/NEJMp1508387PubMedGoogle ScholarCrossref
2.
Schnipper  LE, Davidson  NE, Wollins  DS,  et al; American Society of Clinical Oncology.  American Society of Clinical Oncology statement: a conceptual framework to assess the value of cancer treatment options.  J Clin Oncol. 2015;33(23):2563-2577. doi:10.1200/JCO.2015.61.6706PubMedGoogle ScholarCrossref
3.
Bonner  JA, Harari  PM, Giralt  J,  et al.  Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.  N Engl J Med. 2006;354(6):567-578. doi:10.1056/NEJMoa053422PubMedGoogle ScholarCrossref
4.
Bonner  JA, Harari  PM, Giralt  J,  et al.  Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.  Lancet Oncol. 2010;11(1):21-28. doi:10.1016/S1470-2045(09)70311-0PubMedGoogle ScholarCrossref
5.
Riaz  N, Sherman  E, Koutcher  L,  et al.  Concurrent chemoradiotherapy with cisplatin versus cetuximab for squamous cell carcinoma of the head and neck.  Am J Clin Oncol. 2016;39(1):27-31. doi:10.1097/COC.0000000000000006PubMedGoogle ScholarCrossref
6.
Xiang  M, Holsinger  FC, Colevas  AD, Chen  MM, Le  Q-T, Beadle  BM.  Survival of patients with head and neck cancer treated with definitive radiotherapy and concurrent cisplatin or concurrent cetuximab: a Surveillance, Epidemiology, and End Results-Medicare analysis.  Cancer. 2018;124(23):4486-4494. doi:10.1002/cncr.31708PubMedGoogle ScholarCrossref
7.
Gillison  ML, Trotti  AM, Harris  J,  et al.  Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial.  Lancet. 2019;393(10166):40-50. doi:10.1016/S0140-6736(18)32779-XPubMedGoogle ScholarCrossref
8.
Ward  MC, Reddy  CA, Adelstein  DJ, Koyfman  SA.  Use of systemic therapy with definitive radiotherapy for elderly patients with head and neck cancer: a National Cancer Data Base analysis.  Cancer. 2016;122(22):3472-3483. doi:10.1002/cncr.30214PubMedGoogle ScholarCrossref
9.
Baxi  SS, O’Neill  C, Sherman  EJ,  et al.  Trends in chemoradiation use in elderly patients with head and neck cancer: changing treatment patterns with cetuximab.  Head Neck. 2016;38(S1)(suppl 1):E165-E171. doi:10.1002/hed.23961PubMedGoogle ScholarCrossref
10.
Juarez  JE, Choi  J, John  MS, Abemayor  E, TenNapel  M, Chen  AM.  Patterns of care for elderly patients with locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys. 2017;98(4):767-774. doi:10.1016/j.ijrobp.2017.01.209
11.
ClinicalTrials.gov. Radiation therapy with durvalumab or cetuximab in treating patients with locoregionally advanced head and neck cancer who cannot take cisplatin. Bethesda, MD: National Library of Medicine; 2017. https://clinicaltrials.gov/ct2/show/NCT03258554. Accessed June 26, 2019.
12.
Caroline  B, Sundus  Y, Dawn  D, Carol  G, Susan  M.  Cost analysis of cetuximab (Erbitux) plus radiotherapy (ERT) versus concomitant cisplatin plus radiotherapy (CRT) within an NHS oncology unit (single institution): a pilot study.  Br J Radiol. 2016;89(1068):20160105. doi:10.1259/bjr.20160105PubMedGoogle Scholar
13.
National Cancer Institute, DCCPS, Surveillance Research Program. Surveillance, Epidemiology, and End Results (SEER) Program research data (1973-2015). http://www.seer.cancer.gov. Published November 2016. Accessed June 7, 2017.
14.
US Bureau of Economic Analysis. Personal consumption expenditures: services: health care (chain-type price index). Federal Reserve Bank of St. Louis. https://fred.stlouisfed.org/series/DHLCRG3Q086SBEA. Accessed August 12, 2018.
15.
Greene  FL, Page  DL, Fleming  ID,  et alAJCC Cancer Staging Manual. 6th ed. New York: Springer-Verlag.
16.
Healthcare Delivery Research Program. Comorbidity SAS macro. Bethesda, MD: Healthcare Delivery Research Program, National Cancer Institute; 2014. https://healthcaredelivery.cancer.gov/seermedicare/considerations/macro-2014.html. Accessed April 28, 2018.
17.
Austin  PC.  Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies.  Pharm Stat. 2011;10(2):150-161. doi:10.1002/pst.433PubMedGoogle ScholarCrossref
18.
Wickham  H.  Elegant Graphics for Data Analysis. New York: Springer-Verlag; 2009.
19.
Therneau  TM, Grambsch  PM.  Modeling Survival Data: Extending the Cox Model. New York: Springer; 2000. doi:10.1007/978-1-4757-3294-8
20.
Ho  DE, Imai  K, King  G, Stuart  EA.  MatchIt: nonparametric preprocessing for parametric causal inference.  J Stat Softw. 2011;42(8):1-28. doi:10.18637/jss.v042.i08Google ScholarCrossref
21.
Magrini  SM, Buglione  M, Corvò  R,  et al.  Cetuximab and radiotherapy versus cisplatin and radiotherapy for locally advanced head and neck cancer: a randomized phase II trial.  J Clin Oncol. 2016;34(5):427-435. doi:10.1200/JCO.2015.63.1671PubMedGoogle ScholarCrossref
22.
Fojo  T, Grady  C.  How much is life worth: cetuximab, non-small cell lung cancer, and the $440 billion question.  J Natl Cancer Inst. 2009;101(15):1044-1048. doi:10.1093/jnci/djp177PubMedGoogle ScholarCrossref
23.
Criss  SD, Mooradian  MJ, Sheehan  DF,  et al.  Cost-effectiveness and budgetary consequence analysis of durvalumab consolidation therapy vs no consolidation therapy after chemoradiotherapy in stage III non-small cell lung cancer in the context of the US health care system  [published online December 13, 2018].  JAMA Oncol. 2018. doi:10.1001/jamaoncol.2018.5449PubMedGoogle Scholar
24.
Goulart  B, Ramsey  S.  A trial-based assessment of the cost-utility of bevacizumab and chemotherapy versus chemotherapy alone for advanced non-small cell lung cancer.  Value Health. 2011;14(6):836-845. doi:10.1016/j.jval.2011.04.004PubMedGoogle ScholarCrossref
25.
Goldstein  DA, Chen  Q, Ayer  T,  et al.  First- and second-line bevacizumab in addition to chemotherapy for metastatic colorectal cancer: a United States-based cost-effectiveness analysis.  J Clin Oncol. 2015;33(10):1112-1118. doi:10.1200/JCO.2014.58.4904PubMedGoogle ScholarCrossref
26.
Chouaid  C, Atsou  K, Hejblum  G, Vergnenegre  A.  Economics of treatments for non-small cell lung cancer.  Pharmacoeconomics. 2009;27(2):113-125. doi:10.2165/00019053-200927020-00003PubMedGoogle ScholarCrossref
27.
de Souza  JA, Seiwert  TY. A value framework in head and neck cancer care. Presented at the: American Society of Clinical Oncology Annual Meeting; 2014; Chicago, Illinois. https://meetinglibrary.asco.org/record/91067/edbook#fulltext. Accessed February 10, 2019.
28.
Saltz  LB.  Perspectives on cost and value in cancer care.  JAMA Oncol. 2016;2(1):19-21. doi:10.1001/jamaoncol.2015.4191PubMedGoogle ScholarCrossref
29.
Ben-Aharon  O, Magnezi  R, Leshno  M, Goldstein  DA.  Association of immunotherapy with durable survival as defined by value frameworks for cancer care.  JAMA Oncol. 2018;4(3):326-332. doi:10.1001/jamaoncol.2017.4445PubMedGoogle ScholarCrossref
30.
Reeder-Hayes  KE, Meyer  AM, Hinton  SP, Meng  K, Carey  LA, Dusetzina  SB.  Comparative toxicity and effectiveness of trastuzumab-based chemotherapy regimens in older women with early-stage breast cancer.  J Clin Oncol. 2017;35(29):3298-3305. doi:10.1200/JCO.2016.71.4345PubMedGoogle ScholarCrossref
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