Assessment of Toxic Effects Associated With Dose-Fractionated Radiotherapy Among Patients With Cancer and Comorbid Collagen Vascular Disease | Oncology | JAMA Network Open | JAMA Network
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Figure 1.  Toxic Effects by Dose-Fractionated Radiotherapy Regimen and CVD Diagnosis
Toxic Effects by Dose-Fractionated Radiotherapy Regimen and CVD Diagnosis

A, Unadjusted incidence of nonsevere and severe acute toxic effects. Nonsevere toxic effects were those lower than grade 3, and severe toxic effects were those at grade 3 or higher. B, Relative incidence of severe toxic effects among patients who developed an acute adverse reaction. C, Unadjusted incidence of severe late toxic effects. D, Relative incidence of severe late toxic effects. CF indicates conventional fractionation; CVD, collagen vascular disease; MH, moderate hypofractionation; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; and UH, ultrahypofractionation.

Figure 2.  Cumulative Incidence of CVD Symptom Flare by Dose-Fractionated Radiotherapy Regimen
Cumulative Incidence of CVD Symptom Flare by Dose-Fractionated Radiotherapy Regimen

Death was used as the competing event. CVD indicates collagen vascular disease.

Table 1.  Baseline Patient Characteristics by Dose-Fractionated Radiotherapy Regimen
Baseline Patient Characteristics by Dose-Fractionated Radiotherapy Regimen
Table 2.  Unadjusted Incidence of Acute and Late Toxic Effects by Grade Over 12 Years, Stratified by Dose-Fractionated Radiotherapy Regimen
Unadjusted Incidence of Acute and Late Toxic Effects by Grade Over 12 Years, Stratified by Dose-Fractionated Radiotherapy Regimen
Table 3.  Multivariable Analysis of Factors Associated With Acute and Late Toxic Effects
Multivariable Analysis of Factors Associated With Acute and Late Toxic Effects
1.
Davidson  A, Diamond  B.  Autoimmune diseases.   N Engl J Med. 2001;345(5):340-350. doi:10.1056/NEJM200108023450506 PubMedGoogle ScholarCrossref
2.
Pons-Estel  GJ, Alarcon  GS, Scofield  L, Reinlib  L, Cooper  GS.  Understanding the epidemiology and progression of systemic lupus erythematosus.   Semin Arthritis Rheum. 2010;39(4):257-268. doi:10.1016/j.semarthrit.2008.10.007 PubMedGoogle ScholarCrossref
3.
Kennedy  N, Walker  J, Hakendorf  P, Roberts-Thomson  P.  Improving life expectancy of patients with scleroderma: results from the South Australian Scleroderma Register.   Intern Med J. 2018;48(8):951-956. doi:10.1111/imj.13799 PubMedGoogle ScholarCrossref
4.
Samotij  D, Reich  A.  Biologics in the treatment of lupus erythematosus: a critical literature review.   Biomed Res Int. 2019;2019:8142368. doi:10.1155/2019/8142368 PubMedGoogle Scholar
5.
Safiri  S, Kolahi  AA, Hoy  D,  et al.  Global, regional and national burden of rheumatoid arthritis 1990-2017: a systematic analysis of the Global Burden of Disease study 2017.   Ann Rheum Dis. 2019;78(11):1463-1471. doi:10.1136/annrheumdis-2019-215920 PubMedGoogle ScholarCrossref
6.
Franks  AL, Slansky  JE.  Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer.   Anticancer Res. 2012;32(4):1119-1136.PubMedGoogle Scholar
7.
Partouche  L, Goulabchand  R, Maria  ATJ,  et al.  Biphasic temporal relationship between cancers and systemic sclerosis: a clinical series from Montpellier University Hospital and review of the literature.   J Clin Med. 2020;9(3):853. doi:10.3390/jcm9030853 PubMedGoogle ScholarCrossref
8.
Yu  K-H, Kuo  C-F, Huang  LH, Huang  W-K, See  L-C.  Cancer risk in patients with inflammatory systemic autoimmune rheumatic diseases: a nationwide population-based dynamic cohort study in Taiwan.   Medicine (Baltimore). 2016;95(18):e3540. doi:10.1097/MD.0000000000003540 PubMedGoogle Scholar
9.
Miller  KD, Nogueira  L, Mariotto  AB,  et al.  Cancer treatment and survivorship statistics, 2019.   CA Cancer J Clin. 2019;69(5):363-385. doi:10.3322/caac.21565 PubMedGoogle ScholarCrossref
10.
Delaney  G, Jacob  S, Featherstone  C, Barton  M.  The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines.   Cancer. 2005;104(6):1129-1137. doi:10.1002/cncr.21324 PubMedGoogle ScholarCrossref
11.
Urtasun  RC.  A complication of the use of radiation for malignant neoplasia in chronic discoid lupus erythematosus.   J Can Assoc Radiol. 1971;22(2):168-169.PubMedGoogle Scholar
12.
Ransom  DT, Cameron  FG.  Scleroderma—a possible contra-indication to lumpectomy and radiotherapy in breast carcinoma.   Australas Radiol. 1987;31(3):317-318. doi:10.1111/j.1440-1673.1987.tb01840.x PubMedGoogle ScholarCrossref
13.
Fleck  R, McNeese  MD, Ellerbroek  NA, Hunter  TA, Holmes  FA.  Consequences of breast irradiation in patients with pre-existing collagen vascular diseases.   Int J Radiat Oncol Biol Phys. 1989;17(4):829-833. doi:10.1016/0360-3016(89)90074-6 PubMedGoogle ScholarCrossref
14.
Teo  P, Tai  TH, Choy  D.  Nasopharyngeal carcinoma with dermatomyositis.   Int J Radiat Oncol Biol Phys. 1989;16(2):471-474. doi:10.1016/0360-3016(89)90344-1 PubMedGoogle ScholarCrossref
15.
Varga  J, Haustein  UF, Creech  RH, Dwyer  JP, Jimenez  SA.  Exaggerated radiation-induced fibrosis in patients with systemic sclerosis.   JAMA. 1991;265(24):3292-3295. doi:10.1001/jama.1991.03460240088033 PubMedGoogle ScholarCrossref
16.
Morris  MM, Powell  SN.  Irradiation in the setting of collagen vascular disease: acute and late complications.   J Clin Oncol. 1997;15(7):2728-2735. doi:10.1200/JCO.1997.15.7.2728 PubMedGoogle ScholarCrossref
17.
Rakfal  SM, Deutsch  M.  Radiotherapy for malignancies associated with lupus: case reports of acute and late reactions.   Am J Clin Oncol. 1998;21(1):54-57. doi:10.1097/00000421-199802000-00012 PubMedGoogle ScholarCrossref
18.
Ross  JG, Hussey  DH, Mayr  NA, Davis  CS.  Acute and late reactions to radiation therapy in patients with collagen vascular diseases.   Cancer. 1993;71(11):3744-3752. doi:10.1002/1097-0142(19930601)71:11<3744::AID-CNCR2820711144>3.0.CO;2-C PubMedGoogle ScholarCrossref
19.
Gold  DG, Miller  RC, Petersen  IA, Osborn  TG.  Radiotherapy for malignancy in patients with scleroderma: the Mayo Clinic experience.   Int J Radiat Oncol Biol Phys. 2007;67(2):559-567. doi:10.1016/j.ijrobp.2006.09.003 PubMedGoogle ScholarCrossref
20.
Dong  Y, Li  T, Churilla  TM,  et al.  Impact of rheumatoid arthritis on radiation-related toxicity and cosmesis in breast cancer patients: a contemporary matched-pair analysis.   Breast Cancer Res Treat. 2017;166(3):787-791. doi:10.1007/s10549-017-4438-7 PubMedGoogle ScholarCrossref
21.
Lin  D, Lehrer  EJ, Rosenberg  J, Trifiletti  DM, Zaorsky  NG.  Toxicity After Radiotherapy in Patients With Historically Accepted Contraindications to Treatment (CONTRAD): an international systematic review and meta-analysis.   Radiother Oncol. 2019;135:147-152. doi:10.1016/j.radonc.2019.03.006 PubMedGoogle ScholarCrossref
22.
Phan  C, Mindrum  M, Silverman  C, Paris  K, Spanos  W.  Matched-control retrospective study of the acute and late complications in patients with collagen vascular diseases treated with radiation therapy.   Cancer J. 2003;9(6):461-466. doi:10.1097/00130404-200311000-00005 PubMedGoogle ScholarCrossref
23.
Purswani  J, Oh  C, Sandigursky  S, Xiao  J, Gerber  NK.  No increase in acute or late toxicity in women with autoimmune diseases treated with hypofractionated breast radiation.   Int J Radiat Oncol Biol Phys. 2020;108(3)(suppl):e14. doi:10.1016/j.ijrobp.2020.07.1020 Google Scholar
24.
Hall  EJ, Giaccia  AJ. Radiobiology for the Radiologist. 8th ed. Wolters Kluwer; 2019.
25.
Lester-Coll  NH, Sher  DJ.  Cost-effectiveness of stereotactic radiosurgery and stereotactic body radiation therapy: a critical review.   Curr Oncol Rep. 2017;19(6):41. doi:10.1007/s11912-017-0599-0 PubMedGoogle ScholarCrossref
26.
National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0. US Dept of Health and Human Services; 2017. Accessed December 5, 2019. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf
27.
R: A Language and Environment for Statistical Computing. Version 3.6.0. R Foundation for Statistical Computing; 2019. Accessed August 2020. http://www.R-project.org/
28.
Package cmprsk: Subdistribution Analysis of Competing Risks. Version 2.2-10. CRAN; 2020. Accessed August 2020. https://cran.r-project.org/web/packages/cmprsk/index.html
29.
Lowell  D, Tatter  SB, Bourland  JD,  et al.  Toxicity of gamma knife radiosurgery in the treatment of intracranial tumors in patients with collagen vascular diseases or multiple sclerosis.   Int J Radiat Oncol Biol Phys. 2011;81(4):e519-e524. doi:10.1016/j.ijrobp.2011.02.056PubMedGoogle ScholarCrossref
30.
Dragun  AE, Harper  JL, Olyejar  SE, Zunzunegui  RG, Wazer  DE.  The use of adjuvant high-dose–rate breast brachytherapy in patients with collagen vascular disease: a collaborative experience.   Brachytherapy. 2011;10(2):121-127. doi:10.1016/j.brachy.2010.05.001 PubMedGoogle ScholarCrossref
31.
Robertson  JM, Clarke  DH, Pevzner  MM, Matter  RC.  Breast conservation therapy. severe breast fibrosis after radiation therapy in patients with collagen vascular disease.   Cancer. 1991;68(3):502-508. doi:10.1002/1097-0142(19910801)68:3<502::AID-CNCR2820680310>3.0.CO;2-V PubMedGoogle ScholarCrossref
32.
Flores  LT, Bennett  AV, Law  EB, Hajj  C, Griffith  MP, Goodman  KA.  Patient-reported outcomes vs clinician symptom reporting during chemoradiation for rectal cancer.   Gastrointest Cancer Res. 2012;5(4):119-124.PubMedGoogle Scholar
33.
Di Maio  M, Gallo  C, Leighl  NB,  et al.  Symptomatic toxicities experienced during anticancer treatment: agreement between patient and physician reporting in three randomized trials.   J Clin Oncol. 2015;33(8):910-915. doi:10.1200/JCO.2014.57.9334 PubMedGoogle ScholarCrossref
34.
Condit  PT, Ridings  GR, Coin  JW, Williams  GR, Mitchell  D  Jr, Boles  GW.  Methotrexate and radiation in the treatment of patients with cancer.   Cancer Res. 1964;24(9):1524-1533.PubMedGoogle Scholar
35.
Jung  M, Dimtchev  A, Velena  A, Dritschilo  A.  Combining radiation therapy with interstitial radiation-inducible TNF-α expression for locoregional cancer treatment.   Cancer Gene Ther. 2011;18(3):189-195. doi:10.1038/cgt.2010.69 PubMedGoogle ScholarCrossref
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    Original Investigation
    Oncology
    February 18, 2021

    Assessment of Toxic Effects Associated With Dose-Fractionated Radiotherapy Among Patients With Cancer and Comorbid Collagen Vascular Disease

    Author Affiliations
    • 1Department of Radiation Oncology, University of California, Los Angeles, Los Angeles
    • 2Department of Radiation Oncology, MD Anderson Cancer Center, University of Texas, Houston
    JAMA Netw Open. 2021;4(2):e2034074. doi:10.1001/jamanetworkopen.2020.34074
    Key Points

    Question  Is dose-fractionation associated with the incidence of toxic effects among patients with cancer and comorbid collagen vascular disease?

    Findings  In this cohort study of 197 adults with cancer and comorbid collagen vascular disease, the incidence of severe toxic effects was similar across multiple dose-fractionated radiotherapy regimens, including conventionally fractionated, moderately hypofractionated, and ultrahypofractionated radiotherapy; the unadjusted incidence of severe acute toxic effects was 5%, 7%, and 2%, respectively, while the unadjusted incidence of severe late toxic effects was 8%, 0%, and 2%, respectively. The receipt of hypofractionated radiotherapy was associated with a lower likelihood of developing late toxic effects in the multivariable analysis.

    Meaning  This study found that the incidence of severe toxic effects among patients with cancer and comorbid collagen vascular disease was similar across several dose-fractionated radiotherapy regimens.

    Abstract

    Importance  The adoption of alternative fractionated radiotherapy regimens for the treatment of patients with cancer and comorbid collagen vascular disease (CVD) is controversial among oncologists because of concerns about potentially severe toxic effects; however, the association between fractionated radiotherapy and toxic effects in the modern era has not been well studied.

    Objective  To compare acute and late toxic effects among patients with cancer and comorbid CVD who received dose-fractionated radiotherapy.

    Design, Setting, and Participants  This retrospective cohort study examined 197 adult patients with cancer and CVD who received radiotherapy at a single-institution tertiary academic center over a 12-year period (February 1, 2007, to April 30, 2019), with a median follow-up of 23 months (range, 0-108 months). Data were analyzed from February 1 to August 31, 2020.

    Exposures  Three dose-fractionated radiotherapy regimens: conventional fractionation (CF; ≤2 Gy per fraction), moderate hypofractionation (MH; >2 Gy to <5 Gy per fraction), and ultrahypofractionation (UH; ≥5 Gy per fraction).

    Main Outcomes and Measures  The main outcomes were the incidence and severity of acute and late radiotherapy-associated toxic effects, which were assessed separately by dose-fractionation regimen. Toxic effects occurring within 90 days after radiotherapy completion were considered acute, and toxic effects occurring after that 90-day period were considered late. Secondary goals were to identify covariates associated with toxic effects and to characterize the incidence of CVD symptom flares (defined as worsening clinical symptoms and/or worsening results [transient or permanent] on associated blood tests compared with baseline, as documented by managing physicians) after radiotherapy.

    Results  Of 197 patients with cancer and comorbid CVD (mean [SD] age, 69 [12] years; 134 women [68.0%]; and 149 White participants [75.6%]), 80 patients (40.6%) received CF radiotherapy, 55 patients (27.9%) received MH radiotherapy, and 62 patients (31.5%) received UH radiotherapy. The most common CVD diagnoses were rheumatoid arthritis (74 patients [37.6%]), psoriasis (54 patients [27.4%]), systemic lupus erythematosus (34 patients [17.3%]), and scleroderma (8 patients [4.1%]). The most common radiotherapy sites were the breast (48 patients [24.4%]), thorax (25 patients [12.7%]), central nervous system (24 patients [12.2%]), and prostate (23 patients [11.7%]). Data on acute toxic effects were available for 188 patients (95.4%) and missing for 9 patients (4.6%). Data on late toxic effects were available for 142 patients (72.1%) and missing for 55 patients (27.9%). Over 12 years, the unadjusted incidences of severe acute toxic effects associated with CF, MH, and UH radiotherapy were 5.4% (95% CI, 0.3%-10.5%), 7.4% (95% CI, 0.4%-14.4%), and 1.7% (95% CI, 0%-5.0%), respectively. The incidences of severe late toxic effects associated with CF, MH, and UH radiotherapy were 8.3% (95% CI, 1.3%-15.3%), 0%, and 2.2% (95% CI, 0%-6.4%), respectively. No significant associations were found between severe acute or late toxic effects by dose fractionation regimen. In the multivariable analysis, MH radiotherapy was associated with a lower likelihood of developing late toxic effects (odds ratio [OR], 0.21; 95% CI, 0.05-0.83; P = .03) compared with CF radiotherapy. Those who received UH radiotherapy had a lower likelihood of experiencing late toxic effects (OR, 0.22; 95% CI, 0.04-1.21; P = .08). A total of 19 of 80 patients (23.8%), 15 of 55 patients (27.3%), and 10 of 62 patients (16.1%) experienced CVD symptom flares after receiving CF, MH, and UH radiotherapy, respectively (P = .33).

    Conclusions and Relevance  In this study, the incidences of unadjusted severe toxic effects over 12 years were less than 10% and were not significantly associated with dose fractionation. When clinically indicated, patients with cancer and comorbid CVD may not require immediate exclusion from the receipt of currently used hypofractionated radiotherapy regimens.

    Introduction

    Collagen vascular disease (CVD) is a heterogeneous group of disorders characterized by the presence of autoantibodies and a dysregulated immune system. Patients with CVD have genetic polymorphisms that, together with environmental triggers, produce widespread inflammation that is associated with injury to connective tissues.1 Many patients with CVD have a higher baseline risk of developing site-specific cancers; thus, an increasing proportion of patients is expected to develop cancer as life expectancies increase with the use of new therapies.2-8 At least 50% of all patients with cancer require radiotherapy as part of their care; however, some oncologists have considered a diagnosis of CVD to be a relative contraindication to radiotherapy because of concerns about severe treatment-associated toxic effects.9,10

    Case studies have historically described disproportionately high incidences of severe toxic effects among patients with CVD who received radiotherapy.11-16 However, studies using more modern radiotherapy techniques have suggested otherwise.17-22 The recent CONTRAD (Toxicity After Radiotherapy in Patients With Historically Accepted Contraindications to Treatment) meta-analysis21 evaluated 621 patients with cancer, comorbid CVD, and inflammatory bowel disease who received radiotherapy from 1970 to 2018, reporting a 10% to 15% risk of experiencing any grade 3 or higher toxic effects, with a less than 5% risk of experiencing grade 4 toxic effects. The authors concluded that CVD and inflammatory bowel disease were not unconditional contraindications to radiotherapy.

    Contemporary radiotherapy clinics are increasingly adopting alternative dose-fractionated radiotherapy into clinical practice for the treatment of many cancers; however, there is controversy about adopting such approaches for patients with cancer and comorbid CVD based on concerns about compounding the risk of toxic effects.23 Available studies have reported toxic effects that are primarily associated with conventionally fractionated radiotherapy, and there is minimal data on the association between alternative dose-fractionated regimens and toxic effects in the modern era. Conventional fractionation delivers 1.8 Gy to 2.0 Gy per fraction to the targeted site, which minimizes long-term injury to surrounding healthy tissues while delivering a tumoricidal dose to the target. Hypofractionation is an alternative fractionation regimen that delivers larger (>2 Gy) doses per fraction over fewer treatments. Stereotactic radiosurgery and stereotactic body radiotherapy are highly precise forms of hypofractionation, in which fraction sizes of 5 Gy or higher are delivered conformally to a target site. The advantages of hypofractionation vs conventional fractionation include limiting tumor repopulation, escalating doses for durable local tumor control, requiring a shorter treatment course, and providing cost-effectiveness.24,25 However, radiobiological principles state that delivering a larger dose per fraction increases the risk of late toxic effects.24

    The association between dose fractionation and radiotherapy-associated toxic effects among patients with cancer and comorbid CVD warrants further research. The primary goal of this study was to assess the incidence of acute and late toxic effects separately by dose-fractionated regimen. The secondary goals were to identify covariates associated with toxic effects and to characterize the incidence of CVD symptom flares associated with radiotherapy by dose-fractionated regimen.

    Methods
    Study Population and Design

    The electronic database of the University of California, Los Angeles, Department of Radiation Oncology was searched to identify all patients with cancer and concurrent CVD diagnoses using the following keywords: collagen vascular disease, connective tissue disorder, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, discoid lupus, polymyositis, dermatomyositis, scleroderma, psoriasis, psoriatic arthritis, ankylosing spondylitis, and mixed connective tissue disorders. Patients were included in the cohort if they initiated radiotherapy in the department. Patients were excluded if they did not receive radiotherapy because this treatment was not clinically indicated, if they were lost to follow-up after consultation, if they chose to receive radiotherapy elsewhere, or if they chose to receive alternative therapies. Radiotherapy treatments were received at a single-institution tertiary academic center from February 1, 2007, to April 30, 2019. The study was approved by the institutional review board of the University of California, Los Angeles. A waiver of informed consent was granted owing to the retrospective nature of the study and the determination that the research involved minimal risk to participants, would not have adverse consequences for the rights and welfare of participants, and could not be practicably conducted without the waiver. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines for observational cohort studies.

    Data Collection and Review

    In the current investigation, data were manually abstracted from electronic medical records by a single radiation oncologist (S.M.Y.) using a uniform data abstraction form to review formatted and narrative data fields. Data were reviewed independently by 3 other radiation oncologists (A.R., P.L., and M.L.S.). Records on age, sex, ethnicity, CVD features, cancer diagnosis, and radiotherapy treatment were obtained. The CVD features included primary diagnosis, activity and symptom flares (defined as worsening clinical symptoms and/or worsening results [transient or permanent] on associated blood tests compared with baseline, as documented by managing physicians) before radiotherapy treatment, and the receipt of steroidal medications or disease-modifying antirheumatic drugs. Data on cancer diagnosis included histologic characteristics, cancer stage, year of diagnosis, and disease status (primary or recurrent). Radiotherapy treatment details included technique, receipt of previous treatments, dose-fractionated regimen, treatment dates, planning target volume, concurrent use of systemic therapies, date of last follow-up, and survival status. The biological effective dose was calculated to compare the total dose delivered across different fractionation approaches with a common numeric score (eMethods in the Supplement).

    Dose-fractionated radiotherapy regimens were defined as conventional fractionation (CF; ≤2 Gy per fraction), moderate hypofractionation (MH; >2 to <5 Gy per fraction), and ultrahypofractionation (UH; ≥5 Gy per fraction). Toxic effects occurring within 90 days after treatment completion were considered acute, and any toxic effects occurring after that 90-day period were considered late. Radiotherapy-associated toxic effects were graded using the Common Terminology Criteria for Adverse Events, version 526 (grade range, 1-5, with 1 indicating a mild or asymptomatic event and 5 indicating death). Toxic effects with grades of 3 or higher were considered severe.

    Statistical Analysis

    Descriptive statistics were reported for demographic characteristics, clinical features, and toxic effects incidence by dose fractionation group. We obtained 95% CIs for proportion for the primary end point via a simple asymptotic formula based on normal approximation. To assess the association between dose fractionation groups and categorical covariates, χ2 or Fisher exact tests were used, as appropriate. To assess the association between dose fractionation groups and continuous covariates, 1-way analysis of variance was used. Kruskal-Wallis test was used to assess the difference in median of continuous variable among groups.

    Univariate logistic regression analysis was performed to evaluate the association between acute and late toxic effects and the dose-fractionated regimen. Multivariable logistic regression analysis was conducted to assess this association, adjusting for other covariates including age, race, primary CVD diagnosis, CVD activity, cancer diagnosis, radiotherapy treatment site, use of concurrent systemic therapies, history of radiotherapy, planning target volume, and year of radiotherapy treatment. The overall significance of a categorical variable in the multivariable logistic regression model was assessed through the likelihood ratio test.

    The cumulative incidence of CVD symptom flares by dose fractionation group was estimated, with death as the competing event. The association between CVD symptom flares and dose fractionation group was assessed using Fine-Gray competing risk regression models, with and without adjusting for potential confounding variables, CVD activity, and medication receipt. The significance threshold was set at P = .05, and all tests were 2-sided. All analyses were conducted using R software, version 3.6.0 (R Foundation for Statistical Computing), with the cmprsk package.27,28 Data were analyzed from February 1 to August 31, 2020.

    Results
    Patient Characteristics

    The initial departmental database query identified 474 patients with cancer and a CVD diagnosis. A total of 197 patients (mean [SD] age, 69 [12] years; 134 women [68.0%]; and 149 White participants [75.6%]) were included in the study cohort, representing 247 radiotherapy treatment courses; 277 patients were excluded from the cohort because radiotherapy was not clinically indicated (170 patients [61.4%]), radiotherapy was received at a location other than our facility (11 patients [4.0%]), an alternative cancer treatment was chosen (1 patient [0.4%]), or loss to follow-up occurred after consultation (89 patients [32.1%]). Only 6 excluded patients (2.2%) received a recommendation against receiving radiotherapy because of CVD activity.

    Among 197 patients, the most common CVDs were rheumatoid arthritis (74 patients [37.6%]), psoriasis (54 patients [27.4%]), and systemic lupus erythematosus (34 patients [17.3%]). Eight patients (4.1%) had scleroderma. Eighty patients (40.6%) received CF radiotherapy, 55 patients (27.9%) received MH radiotherapy, and 62 patients (31.5%) received UH radiotherapy. The most common radiotherapy sites were the breast (48 patients [24.4%]), thorax (25 patients [12.7%]), central nervous system (24 patients [12.2%]), and prostate (23 patients [11.7%]). Characteristics of patients by dose fractionation group are summarized in Table 1. Differences in age were found among dose fractionation groups (mean [SD] age, 67 [12] years in the CF group vs 67 [14] years in the MH group vs 72 [10] years in the UH group). While most of the patients in all groups were White and female, the UH group included a numerically lower proportion of female participants (32 women [51.6%] vs 56 women [70.0%] in the CF group and 46 women [83.6%] in the MH group). Although no significant differences were observed in CVD subtypes or activity between dose fractionation groups, a lower proportion of participants in the UH group (29 patients [46.8%]) were receiving any CVD medications compared with those in the CF group (56 patients [70.0%]) and the MH group (36 patients [65.5%]).

    Substantial differences in cancer diagnoses, radiotherapy sites, and treatment techniques were observed among the 3 groups. Participants with breast cancer received CF radiotherapy (22 patients [27.5%]) or MH radiotherapy (29 patients [52.7%]) compared with UH radiotherapy (4 patients [6.5%]), while more patients with lung and genitourinary cancers (specifically prostate cancer) received UH radiotherapy (14 patients [22.6%] and 21 patients [33.9%], respectively) compared with CF radiotherapy (4 patients [5.0%] and 4 patients [5.0%], respectively) and MH radiotherapy (3 patients [5.5%] and 1 patient [1.8%], respectively), likely reflecting extant departmental practice patterns. Three-dimensional conformal radiotherapy and intensity-modulated radiotherapy treatment techniques were primarily used for CF radiotherapy (27 patients [33.8%] and 47 patients [58.8%], respectively) and MH radiotherapy (32 patients [58.2%] and 12 patients [21.8%], respectively), while brachytherapy (14 patients [22.6%]) and stereotactic body radiotherapy (48 patients [77.4%]) were used for UH radiotherapy. The mean planning target volume was smaller among both of the hypofractionation groups (mean [SD], 668 [1665] mL for the MH group and 156 [492] mL for the UH group) compared with the CF group (mean [SD], 3648 [17 190] mL) but was not significantly different (P = .18) among the 3 groups. The biological effective dose was significantly different among dose fractionation groups (mean [SD], 64.2 [16.7] Gy for the CF group; 54.6 [15.5] Gy for the MH group; and 84.8 [11.2] for the UH group; P = .03).

    Outcomes

    The median time from the start of radiotherapy to the date of the last follow-up was 23 months (range, 0-108 months). The median follow-up times after receipt of CF, MH, and UH radiotherapies were 24, 24, and 16 months, respectively (P = .20). Of 197 patients, 1 patient (0.5%) did not complete treatment, and 4 patients (2.0%) had incomplete records from which treatment completion could not be determined. Data on acute toxic effects were available for 188 patients (95.4%) and missing for 9 patients (4.6%); data on late toxic effects were available for 142 patients (72.1%) and missing for 55 patients (27.9%). Table 2 details the unadjusted incidence of acute and late toxic effects by dose fractionation group. Among participants with available data on acute toxic effects, 9 patients (4.8%) experienced severe toxic effects. The unadjusted incidences of severe acute toxic effects associated with CF, MH, and UH radiotherapies were 5.4% (95% CI, 0.3%-10.5%), 7.4% (95% CI, 0.4%-14.4%), and 1.7% (95% CI, 0%-5.0%), respectively. Severe acute toxic effects were not significantly associated with dose fractionation regimen or treatment technique. The incidences of unadjusted and relative severe acute toxic effects by dose fractionation group across CVD diagnoses are shown in Figure 1A, Figure 1B, and Figure 1C. Of 397 identified acute toxic effects, the most common were dermatitis (81 patients [20.4%]), pain (56 patients [14.1%]), and fatigue (52 patients [13.1%]).

    The unadjusted incidences of severe late toxic effects associated with CF, MH, or UH radiotherapies were 8.3% (95% CI, 1.3%-15.3%), 0%, and 2.2% (95% CI, 0%-6.4%), respectively. Severe late toxic effects were not significantly associated with dose fractionation or treatment technique. One of 8 patients (12.5%) with psoriasis and late toxic effects developed severe toxic effects after receiving UH radiotherapy, while no patients developed severe toxic effects after receiving CF or MH radiotherapy (Figure 1D). No patients with rheumatoid arthritis, systemic lupus erythematosus, or scleroderma developed severe toxic effects after receiving MH or UH radiotherapy. Three of 17 patients (17.6%) with rheumatoid arthritis developed severe toxic effects after receiving CF radiotherapy. Of 176 identified late toxic effects, the most common were pain (18 patients [10.2%]), skin hyperpigmentation (11 patients [6.3%]), and superficial soft tissue fibrosis (8 patients [4.6%]).

    Nineteen of 80 patients (23.8%; 95% CI, 14.5%-33.1%) receiving CF radiotherapy, 15 of 55 patients (27.3%; 95% CI, 15.5%-39.1%) receiving MH radiotherapy, and 10 of 62 patients (16.1%; 95% CI, 7.0%-25.2%) receiving UH radiotherapy experienced a CVD symptom flare. Dose fractionation regimen and treatment technique were not significantly associated with CVD symptom flares. The cumulative incidences of CVD symptom flare by dose fractionation group are shown in Figure 2. Overall, 22 of 197 patients (11.2%) died without experiencing a CVD symptom flare. No significant association was found between CVD symptom flare and dose fractionation regimen in both the unadjusted and adjusted Fine-Gray models. In the adjusted model, CVD activity was associated with a greater risk of experiencing a CVD symptom flare, with a subdistribution hazard ratio of 2.10 (95% CI, 1.11-3.99; P = .02). Of 44 participants who experienced a CVD symptom flare, 23 patients (52.3%) adjusted or changed their CVD medications (either disease-modifying antirheumatic drugs or steroidal medications). Five of 44 patients (11.4%) were diagnosed with CVD after completing radiotherapy.

    Logistic Analyses

    In the univariate analysis, UH radiotherapy was significantly associated with a lower likelihood of acute toxic effects (odds ratio [OR], 0.14; 95% CI, 0.05-0.35; P < .001) compared with CF radiotherapy. Both MH and UH regimens were associated with a lower likelihood of late toxic effects compared with CF radiotherapy (for MH radiotherapy, OR, 0.34 [95% CI, 0.14-0.83]; P = .02; for UH radiotherapy, OR, 0.28 [95% CI, 0.12-0.64]; P = .003).

    In the multivariable analysis, dose fractionation was associated with late toxic effects by the likelihood ratio test. The OR was 0.21 (95% CI, 0.05-0.83; P = .03) for MH radiotherapy and 0.22 (95% CI, 0.04-1.21; P = .08) for UH radiotherapy compared with CF radiotherapy. The treatment site was also associated with late toxic effects by the likelihood ratio test (P = .006). Radiotherapy that targeted musculoskeletal sites (of which 16 of 22 treatments were directed toward nonspinal bone) had an OR of 0.02 (95% CI, 0-0.36; P = .008) compared with radiotherapy that targeted the breast. Patients receiving multiple courses of radiotherapy had an OR of 8.58 (95% CI, 1.33-55.52; P = .02) for late toxic effects (Table 3).

    Discussion

    In this cohort study of 197 patients with cancer and comorbid CVD, the unadjusted incidence of severe acute toxic effects was less than 10% across all dose fractionation groups. The incidences of severe late toxic effects were also low and were not substantially different among patients who received conventionally fractionated vs hypofractionated radiotherapy. To our knowledge, before the present analysis, few studies have characterized the association of dose fractionation with radiotherapy-associated toxic effects in patients with CVD. Morris and Powell16 reported no substantial consequences associated with dose per fraction in univariate analysis among a cohort of 209 patients with CVD who primarily received CF or MH radiotherapy regimens. A retrospective study by Lowell et al29 comprising 14 patients with CVD (8 patients with rheumatoid arthritis, 5 patients with systemic lupus erythematosus, and 1 patient with scleroderma) observed no grade 3, grade 4, or rare toxic effects associated with gamma knife radiosurgery for intracranial tumors after a median of 16 months of follow-up. The median size of treated tumors was 5.0 cm3 (range, 0.14-7.8 cm3), and the dose to 50% isodose threshold ranged from 12 Gy to 25 Gy in a single treatment fraction.

    Dragun et al30 reported similar toxic effects and cosmetic profiles associated with adjuvant high-dose brachytherapy compared with other accelerated partial breast radiotherapy series among 9 women with early-stage breast cancer and CVD. All women were treated with multicatheter or balloon brachytherapy to 34 Gy in 10 fractions, for a median treatment volume of 45.5 cm3. Five of 9 women experienced grade 1 acute skin erythema, and 1 woman experienced wound dehiscence. Five women exhibited late skin induration, and 2 women experienced pain and telangiectasias. The CONTRAD meta-analysis21 included a modern series of contemporary radiotherapy techniques using both conventional and hypofractionated regimens. Although this meta-analysis did not specifically associate toxic effects with dose fractionation, it reported grade 3 or higher acute and late toxic effect rates of 11.7% (95% CI, 5.4%-19.6%) and 6.1% (95% CI, 1.4%-12.6%), respectively. Although no firm conclusions can be drawn from these studies, available data have thus far indicated low severe toxic effect rates across various dose fractionation regimens and are consistent with the findings from our study.

    Despite the radiobiological principle that delivering a higher radiotherapy dose per fraction will increase the risk of damage to late-responding tissues, the incidences of severe toxic effects were low among patients receiving hypofractionated and conventionally fractionated regimens in our study. In the multivariable analysis, the receipt of MH radiotherapy was significantly associated with a lower likelihood of developing any late toxic effects, and the receipt of UH radiotherapy also indicated a lower likelihood. Technological advances in image guidance and target localization have enabled radiation oncologists to deliver hypofractionated regimens safely and with smaller margins, and the smaller treatment volumes could mitigate the potential risks of developing severe toxic effects. Despite the higher total biological effective dose delivered to the targeted site with hypofractionation, the better preservation of healthy tissues may mitigate the development of severe toxic effects; thus, no differences in severe acute or late toxic effects were observed in this study.

    Broader use of hypofractionated regimens became possible after recent advancements in treatment techniques and image guidance. Therefore, time-dependent patterns of radiotherapy techniques and relatively shorter follow-up times with hypofractionation vs conventional fractionation could be confounding factors. In our study, patients receiving UH radiotherapy had a numerically (although not substantially) shorter follow-up time (16 months) compared with patients in the CF and MH groups (24 months). Treatment techniques were also not significantly associated with toxic effects or CVD symptom flares among patients in this study.

    Efforts to characterize the toxic effects associated with radiotherapy by CVD subtype have been inconsistent in previous studies because of the heterogeneity and relative paucity of patients with cancer and comorbid CVD. Morris et al16 reported a greater risk of late toxic effects over a 5-year period among patients with CVD who did not have rheumatoid arthritis (91%) compared with those who had rheumatoid arthritis (56%; P = .002). In contrast, a matched-control study reported that no differences in acute or late toxic effects were observed between patients with and without CVD, although an increase in late toxic effects among patients with rheumatoid arthritis was noted.18 Patients with systemic lupus erythematosus experienced a lower incidence of late toxic effects but a greater number of acute toxic effects than those in the matched-control group.

    Another matched-control study of 38 patients with CVD who did not have rheumatoid arthritis observed no difference in the incidence of acute or late toxic effects compared with patients in the control group without CVD; however, the researchers noted that patients with scleroderma had a greater incidence of grade 3 late toxic effects.22 Our study found that the incidence of severe acute toxic effects was similar across dose fractionation groups and CVD subtypes. Patients with psoriasis were observed to have an increased incidence of severe late toxic effects after receiving UH radiotherapy, while patients with rheumatoid arthritis experienced increases in severe late toxic effects after receiving CF radiotherapy.

    Patients and physicians alike have raised concerns regarding radiotherapy exposure and exacerbation of CVD symptoms, yet few case studies were available to elucidate this issue. Localized radiotherapy is hypothesized to increase the expression and circulation of self-antigens via basement membrane damage, cellular apoptotic debris, or necrosis and is thought to exacerbate CVD symptoms overall. One case report by Robertson et al31 described 2 patients with rheumatoid arthritis and scleroderma who experienced progression of underlying CVD symptoms while also developing worse cosmetic outcomes after receiving breast radiotherapy. The patient with rheumatoid arthritis had a rheumatoid factor titer of 1:320 but negative antinuclear antibodies before radiotherapy. Her CVD symptoms worsened while developing radiotherapy-associated breast fibrosis, which required additional nonsteroidal anti-inflammatory medications. Before receiving radiotherapy, the patient with scleroderma experienced arthritis and skin thickening in her upper and lower extremities. After 27 months since the completion of radiotherapy, her scleroderma progressed to her esophagus.

    In our study of 197 patients, CVD symptom flares occurred in approximately one-quarter of patients in each dose fractionation group, of which 52.3% adjusted their CVD medications to manage their symptoms. The proportion of CVD symptom flares in this cohort may be associated with CVD activity that occurred before the initiation of radiotherapy, as symptom flares were controlled or low among most patients in each fractionation group. In addition, these findings may be confounded by the progression of the CVD itself, independent of any cancer treatment.

    Limitations

    This study has several limitations. The relative scarcity of patients with cancer and comorbid CVD limits the study of radiotherapy-associated toxic effects to an examination of retrospective reviews, which are dependent on the accuracy of physician reports. These assessments may be heterogeneous and biased. Recent studies have indicated that physicians often underestimate the adverse effects experienced by patients; therefore, the true incidence of toxic effects or CVD symptom flares could be higher across some or all dose fractionation groups.32,33 The comparison of toxic effects by dose fractionation group was not performed against a matched control group of patients without CVD. Although patients with cancer and CVD may potentially have a higher risk of experiencing late toxic effects compared with those without CVD, the unadjusted incidences of both acute and late adverse toxic effects across all dose fractionation groups in this study were similar to those found in previous matched-control studies and the general population.18,22 Moreover, the decision to prescribe a particular dose regimen is based on clinical indication and various patient and disease-specific factors.

    This analysis included a heterogeneous number of CVD diagnoses, primary cancers, and treatment target sites. Each CVD diagnosis has a distinct natural history, relative radiosensitivity, and an extent and duration over which radiotherapy-associated toxic effects may develop and persist. Disease-modifying antirheumatic drugs are also variably used depending on CVD symptoms, with some drugs having relatively more radiosensitizing consequences than others.34,35 Hypofractionated radiotherapy is increasingly used for the treatment of certain cancers, such as prostate cancer, early-stage lung cancer, and select oligometastatic conditions, more than others. However, we were unable to evaluate the toxic effect incidence for every CVD diagnosis, primary cancer diagnosis, and treatment site because of the small subgroup samples and the likely difficulty in finding toxic effect differences with meaningful statistical power. Therefore, an evaluation of the safety of alternative dose fractionation regimens that includes these factors is still needed.

    Toxic effect outcomes from this study are reflective of current radiotherapy regimens that are the standard of care for patients with specific cancer diagnoses and disease sites. Ongoing efforts to evaluate the safety of hypofractionation for nonstandard indications are presently being conducted for use in the general population and will need to continue to be used with caution, especially among patients with comorbid CVD. Overall, the use of alternative fractionation regimens requires individualization to each patient’s clinical situation.

    Conclusions

    To our knowledge, this study is the first to examine the toxic effects associated with various dose-fractionated radiotherapy regimens for the treatment of patients with cancer and comorbid CVD in the context of modern technologies. The overall incidence of severe acute and late toxic effects across all dose fractionation groups was less than 10%. With recent technological advances enabling the delivery of high doses of radiation precisely and conformally, patients with CVD may not require immediate exclusion from the receipt of radiotherapy regimens as part of their cancer treatment when clinically indicated.

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    Article Information

    Accepted for Publication: November 24, 2020.

    Published: February 18, 2021. doi:10.1001/jamanetworkopen.2020.34074

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Yoon SM et al. JAMA Network Open.

    Corresponding Author: Percy Lee, MD, Department of Radiation Oncology, MD Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Unit 1422, Houston, TX 77030 (percylee@mdanderson.org).

    Author Contributions: Dr Yoon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Yoon, Steinberg, Raldow, Lee.

    Acquisition, analysis, or interpretation of data: Yoon, Chu, Ruan, Lee.

    Drafting of the manuscript: Yoon, Ruan, Raldow.

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

    Statistical analysis: Yoon, Chu, Ruan.

    Administrative, technical, or material support: Ruan, Steinberg, Lee.

    Supervision: Steinberg, Raldow, Lee.

    Conflict of Interest Disclosures: Dr Lee reported receiving grants from AstraZeneca and travel support from Varian and ViewRay outside the submitted work. No other disclosures were reported.

    References
    1.
    Davidson  A, Diamond  B.  Autoimmune diseases.   N Engl J Med. 2001;345(5):340-350. doi:10.1056/NEJM200108023450506 PubMedGoogle ScholarCrossref
    2.
    Pons-Estel  GJ, Alarcon  GS, Scofield  L, Reinlib  L, Cooper  GS.  Understanding the epidemiology and progression of systemic lupus erythematosus.   Semin Arthritis Rheum. 2010;39(4):257-268. doi:10.1016/j.semarthrit.2008.10.007 PubMedGoogle ScholarCrossref
    3.
    Kennedy  N, Walker  J, Hakendorf  P, Roberts-Thomson  P.  Improving life expectancy of patients with scleroderma: results from the South Australian Scleroderma Register.   Intern Med J. 2018;48(8):951-956. doi:10.1111/imj.13799 PubMedGoogle ScholarCrossref
    4.
    Samotij  D, Reich  A.  Biologics in the treatment of lupus erythematosus: a critical literature review.   Biomed Res Int. 2019;2019:8142368. doi:10.1155/2019/8142368 PubMedGoogle Scholar
    5.
    Safiri  S, Kolahi  AA, Hoy  D,  et al.  Global, regional and national burden of rheumatoid arthritis 1990-2017: a systematic analysis of the Global Burden of Disease study 2017.   Ann Rheum Dis. 2019;78(11):1463-1471. doi:10.1136/annrheumdis-2019-215920 PubMedGoogle ScholarCrossref
    6.
    Franks  AL, Slansky  JE.  Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer.   Anticancer Res. 2012;32(4):1119-1136.PubMedGoogle Scholar
    7.
    Partouche  L, Goulabchand  R, Maria  ATJ,  et al.  Biphasic temporal relationship between cancers and systemic sclerosis: a clinical series from Montpellier University Hospital and review of the literature.   J Clin Med. 2020;9(3):853. doi:10.3390/jcm9030853 PubMedGoogle ScholarCrossref
    8.
    Yu  K-H, Kuo  C-F, Huang  LH, Huang  W-K, See  L-C.  Cancer risk in patients with inflammatory systemic autoimmune rheumatic diseases: a nationwide population-based dynamic cohort study in Taiwan.   Medicine (Baltimore). 2016;95(18):e3540. doi:10.1097/MD.0000000000003540 PubMedGoogle Scholar
    9.
    Miller  KD, Nogueira  L, Mariotto  AB,  et al.  Cancer treatment and survivorship statistics, 2019.   CA Cancer J Clin. 2019;69(5):363-385. doi:10.3322/caac.21565 PubMedGoogle ScholarCrossref
    10.
    Delaney  G, Jacob  S, Featherstone  C, Barton  M.  The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines.   Cancer. 2005;104(6):1129-1137. doi:10.1002/cncr.21324 PubMedGoogle ScholarCrossref
    11.
    Urtasun  RC.  A complication of the use of radiation for malignant neoplasia in chronic discoid lupus erythematosus.   J Can Assoc Radiol. 1971;22(2):168-169.PubMedGoogle Scholar
    12.
    Ransom  DT, Cameron  FG.  Scleroderma—a possible contra-indication to lumpectomy and radiotherapy in breast carcinoma.   Australas Radiol. 1987;31(3):317-318. doi:10.1111/j.1440-1673.1987.tb01840.x PubMedGoogle ScholarCrossref
    13.
    Fleck  R, McNeese  MD, Ellerbroek  NA, Hunter  TA, Holmes  FA.  Consequences of breast irradiation in patients with pre-existing collagen vascular diseases.   Int J Radiat Oncol Biol Phys. 1989;17(4):829-833. doi:10.1016/0360-3016(89)90074-6 PubMedGoogle ScholarCrossref
    14.
    Teo  P, Tai  TH, Choy  D.  Nasopharyngeal carcinoma with dermatomyositis.   Int J Radiat Oncol Biol Phys. 1989;16(2):471-474. doi:10.1016/0360-3016(89)90344-1 PubMedGoogle ScholarCrossref
    15.
    Varga  J, Haustein  UF, Creech  RH, Dwyer  JP, Jimenez  SA.  Exaggerated radiation-induced fibrosis in patients with systemic sclerosis.   JAMA. 1991;265(24):3292-3295. doi:10.1001/jama.1991.03460240088033 PubMedGoogle ScholarCrossref
    16.
    Morris  MM, Powell  SN.  Irradiation in the setting of collagen vascular disease: acute and late complications.   J Clin Oncol. 1997;15(7):2728-2735. doi:10.1200/JCO.1997.15.7.2728 PubMedGoogle ScholarCrossref
    17.
    Rakfal  SM, Deutsch  M.  Radiotherapy for malignancies associated with lupus: case reports of acute and late reactions.   Am J Clin Oncol. 1998;21(1):54-57. doi:10.1097/00000421-199802000-00012 PubMedGoogle ScholarCrossref
    18.
    Ross  JG, Hussey  DH, Mayr  NA, Davis  CS.  Acute and late reactions to radiation therapy in patients with collagen vascular diseases.   Cancer. 1993;71(11):3744-3752. doi:10.1002/1097-0142(19930601)71:11<3744::AID-CNCR2820711144>3.0.CO;2-C PubMedGoogle ScholarCrossref
    19.
    Gold  DG, Miller  RC, Petersen  IA, Osborn  TG.  Radiotherapy for malignancy in patients with scleroderma: the Mayo Clinic experience.   Int J Radiat Oncol Biol Phys. 2007;67(2):559-567. doi:10.1016/j.ijrobp.2006.09.003 PubMedGoogle ScholarCrossref
    20.
    Dong  Y, Li  T, Churilla  TM,  et al.  Impact of rheumatoid arthritis on radiation-related toxicity and cosmesis in breast cancer patients: a contemporary matched-pair analysis.   Breast Cancer Res Treat. 2017;166(3):787-791. doi:10.1007/s10549-017-4438-7 PubMedGoogle ScholarCrossref
    21.
    Lin  D, Lehrer  EJ, Rosenberg  J, Trifiletti  DM, Zaorsky  NG.  Toxicity After Radiotherapy in Patients With Historically Accepted Contraindications to Treatment (CONTRAD): an international systematic review and meta-analysis.   Radiother Oncol. 2019;135:147-152. doi:10.1016/j.radonc.2019.03.006 PubMedGoogle ScholarCrossref
    22.
    Phan  C, Mindrum  M, Silverman  C, Paris  K, Spanos  W.  Matched-control retrospective study of the acute and late complications in patients with collagen vascular diseases treated with radiation therapy.   Cancer J. 2003;9(6):461-466. doi:10.1097/00130404-200311000-00005 PubMedGoogle ScholarCrossref
    23.
    Purswani  J, Oh  C, Sandigursky  S, Xiao  J, Gerber  NK.  No increase in acute or late toxicity in women with autoimmune diseases treated with hypofractionated breast radiation.   Int J Radiat Oncol Biol Phys. 2020;108(3)(suppl):e14. doi:10.1016/j.ijrobp.2020.07.1020 Google Scholar
    24.
    Hall  EJ, Giaccia  AJ. Radiobiology for the Radiologist. 8th ed. Wolters Kluwer; 2019.
    25.
    Lester-Coll  NH, Sher  DJ.  Cost-effectiveness of stereotactic radiosurgery and stereotactic body radiation therapy: a critical review.   Curr Oncol Rep. 2017;19(6):41. doi:10.1007/s11912-017-0599-0 PubMedGoogle ScholarCrossref
    26.
    National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0. US Dept of Health and Human Services; 2017. Accessed December 5, 2019. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf
    27.
    R: A Language and Environment for Statistical Computing. Version 3.6.0. R Foundation for Statistical Computing; 2019. Accessed August 2020. http://www.R-project.org/
    28.
    Package cmprsk: Subdistribution Analysis of Competing Risks. Version 2.2-10. CRAN; 2020. Accessed August 2020. https://cran.r-project.org/web/packages/cmprsk/index.html
    29.
    Lowell  D, Tatter  SB, Bourland  JD,  et al.  Toxicity of gamma knife radiosurgery in the treatment of intracranial tumors in patients with collagen vascular diseases or multiple sclerosis.   Int J Radiat Oncol Biol Phys. 2011;81(4):e519-e524. doi:10.1016/j.ijrobp.2011.02.056PubMedGoogle ScholarCrossref
    30.
    Dragun  AE, Harper  JL, Olyejar  SE, Zunzunegui  RG, Wazer  DE.  The use of adjuvant high-dose–rate breast brachytherapy in patients with collagen vascular disease: a collaborative experience.   Brachytherapy. 2011;10(2):121-127. doi:10.1016/j.brachy.2010.05.001 PubMedGoogle ScholarCrossref
    31.
    Robertson  JM, Clarke  DH, Pevzner  MM, Matter  RC.  Breast conservation therapy. severe breast fibrosis after radiation therapy in patients with collagen vascular disease.   Cancer. 1991;68(3):502-508. doi:10.1002/1097-0142(19910801)68:3<502::AID-CNCR2820680310>3.0.CO;2-V PubMedGoogle ScholarCrossref
    32.
    Flores  LT, Bennett  AV, Law  EB, Hajj  C, Griffith  MP, Goodman  KA.  Patient-reported outcomes vs clinician symptom reporting during chemoradiation for rectal cancer.   Gastrointest Cancer Res. 2012;5(4):119-124.PubMedGoogle Scholar
    33.
    Di Maio  M, Gallo  C, Leighl  NB,  et al.  Symptomatic toxicities experienced during anticancer treatment: agreement between patient and physician reporting in three randomized trials.   J Clin Oncol. 2015;33(8):910-915. doi:10.1200/JCO.2014.57.9334 PubMedGoogle ScholarCrossref
    34.
    Condit  PT, Ridings  GR, Coin  JW, Williams  GR, Mitchell  D  Jr, Boles  GW.  Methotrexate and radiation in the treatment of patients with cancer.   Cancer Res. 1964;24(9):1524-1533.PubMedGoogle Scholar
    35.
    Jung  M, Dimtchev  A, Velena  A, Dritschilo  A.  Combining radiation therapy with interstitial radiation-inducible TNF-α expression for locoregional cancer treatment.   Cancer Gene Ther. 2011;18(3):189-195. doi:10.1038/cgt.2010.69 PubMedGoogle ScholarCrossref
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