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Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma
Radiotherapy and Oncology xxx (2015) xxx–xxx
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Original article
Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma Rahul R. Parikh a,⇑, Michael L. Grossbard b, Louis B. Harrison c, Joachim Yahalom d a Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick; b Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, Division of Hematology-Oncology; c Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa; and d Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, New York, United States
a r t i c l e
i n f o
Article history: Received 3 June 2015 Received in revised form 20 October 2015 Accepted 21 October 2015 Available online xxxx Keywords: IMRT Hodgkin lymphoma Survival NCDB
a b s t r a c t Purpose: The purpose of this study was to compare outcomes with Hodgkin lymphoma (HL) patients receiving IMRT (intensity-modulated radiation therapy), versus those receiving 2D/3D-CRT (3-dimensional conformal RT) in a large observational cohort. Patients and methods: We evaluated patients diagnosed with stage I–IV HL from 1998 to 2011 from the National Cancer Database (NCDB). The association between IMRT use vs. 2D/3D-CRT, co-variables, and outcome was assessed in a Cox proportional hazards model. Propensity score (PS) matching was performed to balance known confounding factors. Survival was estimated using the Kaplan–Meier method. Results: Of the 76,672 patients with HL within the NCDB, 12,393 patients with stage I-IV HL received RT (median dose = 30.6 Gy) and were eligible for this study, and 6013 patients analyzed for overall survival. The cohort had a median follow-up of 6.2 years and median age of 37 years (range: 18–90). The RT modalities used were: 2D/3D-CRT (n = 11,491, 92.7%) or IMRT (n = 902, 7.3%). Patients were more likely to receive IMRT if they were of male gender, early stage, no ‘‘B” symptoms, and treated at comprehensive cancer programs (all p < 0.05). During this time period, there was a significant decrease in use of 2D/3D-CRT from 100% to 81.5%, with a subsequent increase in IMRT utilization from 0% to 18.5%. Five-year overall survival for patients receiving 2D/3D-CRT (n = 5844) was 89.9% versus 95.2% for those receiving IMRT (n = 169; HR = 0.45; 95% CI, 0.23–0.91, p = 0.02). After PS-matching based on clinicopathologic characteristics, IMRT use remained associated with improved overall survival (HR = 0.40; 95% CI, 0.16–0.97, p = 0.04). Conclusions: Our study reveals that HL patients receiving modern RT techniques were associated with an improvement in overall survival. This may have been related to patient selection, access to improved staging and management, or improvements in treatment technology. This represents the only study examining survival outcomes of advanced RT modalities, which may be considered on a case-by-case basis for highly selected patients with HL. Ó 2015 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2015) xxx–xxx
There will be an estimated 9050 new cases of Hodgkin lymphoma (HL) in the U.S. in 2015, with an estimated 1150 new deaths in 2015 [1]. Historically, excellent survival rates for HL were attributed to the efficacy of definitive extended-field RT (EFRT) [2,3], but with concerning treatment-related morbidity. In fact, Kaplan et al. found dramatic improvements in overall survival (OS) in patients with HL with the advent of megavoltage linear accelerator and advances in treatment planning capabilities [4]. Combining safer chemotherapy with reduced field and dose, modern conformal RT led to further improvements in disease control [5,6].
⇑ Corresponding author at: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08903, United States. E-mail addresses: [email protected], [email protected] (R.R. Parikh).
There are few disease sites in which advanced radiotherapy modalities, such as IMRT (intensity-modulated RT), have been associated with improvements in outcome when compared to historical techniques such as 2D or 3D-CRT (conformal radiation therapy). For example, IMRT has also demonstrated improvements in disease control and quality of life in head and neck cancer and prostate cancer patients [7]. Cancer patients that require escalation of RT dose may require IMRT to prevent high doses of irradiated volume to nearby organs at risk and provide maximal cure rates [8–11]. For HL patients treated in the era of in the era of dose de-intensification, early dosimetric studies have demonstrated improved sparing of vital structures with IMRT, when compared to optimized 3D-CRT plans [12]. Paradoxically, despite the need for dose de-escalation, these advanced RT modalities may be helpful to decrease death from late-term morbidity.
http://dx.doi.org/10.1016/j.radonc.2015.10.022 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
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Survival benefit of IMRT for Hodgkin lymphoma
Despite evidence of improved event-free survival with the addition of consolidation RT [6], many centers continue to omit RT in the treatment of lymphoma because of concern for late radiation side effects and effectiveness of salvage therapy. To minimize late-term toxicity while maintaining high cure rates, radiation oncologists have found ways to deliver RT by effectively reducing the radiation dose needed to control lymphoma to 20–30 Gy [13]; by further reducing the treatment field from EFRT to IFRT to involved-site RT (ISRT) techniques as delineated by the ILROG Guidelines for HL [14]; and by delivering more conformal RT through modalities such as IMRT [15]. We used the National Cancer Database (NCDB) on stage I–IV HL patients to answer the primary endpoint of whether IMRT (compared to 2D/3D-CRT) impacted upon overall survival. As secondary endpoints, we examined the relationship between clinical and sociodemographic parameters, with use of advanced RT modality, and overall survival. We also examined the trends of IMRT utilization from 1998 to 2011. Our hypothesis was that the increased use of IMRT improves outcomes over historical methods. Patients and methods Data source The National Cancer Database (NCDB), a national hospital-based oncology database, was used to conduct a retrospective, cohort study of HL patients diagnosed from 1998 through 2011. As a joint project of the American College of Surgeons’ Commission on Cancer and the American Cancer Society, it is a prospectively collected registry from 1500 hospitals representing 75% of all cancers diagnosed in the U.S. with accumulated data on approximately 29-million cancer cases. Variables captured include basic demographics, socioeconomic characteristics, cancer staging, treatment course, and vital status. This study period reflected a time during which inclusion of RT was accepted standard treatment for HL. At the time of analysis, 2011 data were the most recent data available. Study patients The flow CONSORT diagram in Fig. 1 shows the study exclusion criteria used to define the cohort. All patients (n = 76,672) diagnosed with classical HL from 1998 to 2011 were initially included. Only patients within the age range of 18–90 with Stage I–IV HL were included. Patients were excluded if they did not receive 2D/3D-CRT or IMRT or without a coded utilization of RT. For purposes of minimizing confounding effects from all known covariates, we also excluded patients with any missing data points in all clinicopathologic parameters of interest. As displayed in the flow CONSORT diagram (Fig. 1), with the above inclusion criteria, the study analysis was limited to 12,393 patients. Study variables Our variable of main interest was modality of radiation therapy (RT) utilized. This parameter was grouped into 2D and 3D-CRT versus IMRT. Demographic and clinical data included gender, race/ ethnicity (white, black, or other), age (640 vs. >40), indicators of income and education based on area of residence derived from Census data(the proportion of adults without a high school diploma according to patients’ zip code of residence was categorized as <14%, 14–19.9%, 20–28.9%, and P29%, based on national quartiles and used as proxies for patient socioeconomic status), median household income, insurance status (categorized as private, Medicare, Medicaid, or uninsured), treatment facility type (categorized as Community Cancer Program, Comprehensive
Community Cancer Program, and Academic/Research Program [including NCI-designated Comprehensive Cancer Centers]), geographic region (categorized into 9 predefined regions), Charlson–Deyo co-morbidity Score (CDCS) (categorized 0, 1, and 2+), clinical stage, involved site (categorized as head & neck, mediastinum/chest, or not otherwise specified [NOS]/other), presence of ‘‘B” symptoms, distance from facility (classified as <12.5 miles, 12.5–50 miles, P50 miles), and vital status. The outcome variable-overall survival (OS) was calculated from the date of diagnosis to December 31, 2011, the date of death, or the date of last contact, whichever occurred first. Statistical analysis Categorical and continuous variable distributions were assessed by using standard descriptive statistics. Using chi-square tests, we assessed the association of RT modality with age, gender, race, socioeconomic status (education level, household income), insurance status, facility type, stage, involved site of disease, distance from facility, presence of B-symptoms, and CDCS. Overall survival after planned intervention was the primary outcome. Kaplan– Meier survival curves were stratified by RT modality, and logrank tests were performed. Propensity score analysis As an observational cohort, use of particular RT modality was likely not random, and may be influenced by patient and disease-related characteristics, potentially leading to biased survival estimates due to confounding. Thus, rather than traditional covariate adjustment via multivariate hazards modeling, propensity score (PS) adjustments to our Cox model may have significant advantages when analyzing large observational cohorts like SEER or NCDB [16]. We calculated PS using multivariate logistic regression with the exposure variable (IMRT vs. 2D/3D-CRT) as the intervention of interest, and then subsequently compared the match samples with overall survival as the outcome of interest. The estimated PS was the used to match patients with similar propensity to receive the specific RT modality based on nearest neighbor matching without replacement using calipers of width equal 0.2 SD of the logit of the propensity score. The success in achieving covariate balance was evaluated using standardized differences of means <0.1 (<10% difference between the arms) indicative of acceptable balance. As two important prognostic factors, the Charlson–Deyo co-morbidity score (CDCS) and the presence of ‘‘B” symptoms, were coded only from 2004 onward, our propensity score analysis was restricted to patients diagnosed in 2004–2006, with available survival data (n = 3436). Cox proportional hazards model Unadjusted associations of individual covariates with survival were described using univariate Cox proportional hazards model. A multivariate Cox proportional hazards model was then fitted to estimate the hazard ratios associated with RT-use and other covariates with respect to OS and their 95% confidence intervals (CI’s), after adjustment for the propensity score. The criterion p < 0.05 was used for retaining interactions in the model. In accordance with NCDB participant user file data-use agreements, survival analysis excluded patients (n = 6380) diagnosed from 2007 to 2011, to allow for at least 5 years of follow-up for all patients. Thus, the survival analysis cohort was a total of 6013 patients. Survival was calculated in months from date of diagnosis to date of last contact or confirmed death. All statistical analyses were performed using statistical software STATA version 12.1. For all statistical testing, we used a
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
R.R. Parikh et al. / Radiotherapy and Oncology xxx (2015) xxx–xxx
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Fig. 1. CONSORT diagram. The primary analysis includes 12,393 patients with Stage I–IV HL, all of whom received RT within their treatment program.
two-sided significance level of p = 0.05. Institutional review board exemption was obtained from the Mount Sinai Beth Israel Cancer Center Institutional Review Board. Results Descriptive statistics The primary analysis examines 12,393 patients with stage I–IV HL who met inclusion criteria. Median age was 37 years (range: 18–90); 52% were male and 48% were female. Table 1 summarizes patient clinicopathologic characteristics by RT modality. The RT modalities used were: 2D/3D-CRT (n = 11,491, 92.7%) or IMRT (n = 902, 7.3%). All patients received RT to a median dose of 30.6 Gy (similar for both 2D/3D-CRT and IMRT group). The mean RT dose for the IMRT group was approximately 46.0 Gy, while the mean RT dose for the 2D/3D-CRT group was 39.0 Gy. Multiagent chemotherapy was given to 98.2% of the patients. Majorities of patients were white (86%), young age (58%), earlystage (86%), no ‘‘B” symptoms (70%), low CDCS (91%), and favorable insurance status (94%). Fifty-seven percent of patients were treated
at comprehensive community cancer programs and 30% were treated at academic/research program facilities (10% at community cancer programs). The involved sites treated with RT included head and neck (2164; 19.6%), mediastinum/chest (3185; 28.9%), and NOS/other (5672; 51.5%). Patients were more likely to receive IMRT if they were of male gender, early-stage, head and neck site involved, no ‘‘B” symptoms, and treated at comprehensive cancer programs (all p < 0.01; Table 1). There was no difference in use of 2D/3D-CRT versus IMRT based on insurance status, socioeconomic status, or distance from treatment facility (all p P 0.05).
Survival analysis The median follow-up for the entire cohort was 6.2 years. As seen in the unadjusted univariate analysis, the use of IMRT was associated with an improvement in OS (HR = 0.45; 95% CI, 0.23– 0.91, p = 0.02; Table 2). The use of chemotherapy was associated with an improvement in OS (p < 0.01, Table 2). Also, younger age, female gender, white race, higher education level, household
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
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Survival benefit of IMRT for Hodgkin lymphoma
Table 1 Patient characteristics according to RT Modality. Parameter
Patients RT modality (n) 2D/3DIMRT CRT (%) (%)
p-value
Overall
12,393
n/a
902 (7.3)
6523 5870
52.2 47.8
58.7 41.3
Race White Black Other
10,675 1162 556
86.2 9.4 4.4
85.4 9.4 5.2
Age (years) 640 >40
5173 7220
41.5 58.5
44.7 55.3
Clinical stage I II III IV
2933 7173 1027 636
24.6 60.8 8.9 5.7
29.1 62.4 6.2 2.3
0.37
0.06
<0.0001*
<0.0001*
Involved site (treated with RT) Head & neck Mediastinum/chest NOS/other
2164 3185 5672
18.3 30.1 51.6
36.8 13.0 50.2
Presence of ‘‘B” symptoms No Yes
6805 2907
69.7 30.3
73.8 26.2
Charlson/Deyo co-morbidity score 0 1 2
11.245 868 186
91.4 7.1 1.5
91.9 6.7 1.4
2258 9872
18.5 81.5
19.8 80.2
Education (% not HS graduate in pt’s zip code) P 29% 20–28.9% 14–19.9% <14% Median household income (pt’s zip code) <$30,000 $30,000–34,999 $35,000–45,999 P$46,000
The propensity score adequately balanced known variables affecting treatment selection or OS. After the adjustment, the risk of death remained lower in patients receiving IMRT when compared to 2D/3D-CRT (HR = 0.40; 95% CI, 0.16–0.97, p = 0.04; Table 2). Also, chemotherapy use, younger age, facility type, lower clinical stage, mediastinum/chest site, absence of ‘‘B” symptoms, lower CDCS, and favorable insurance status remained significant predictors of decreased risk of death (all p < 0.01; Table 2). OS was not significantly different amongst additional parameters such as race, education, income, or distance from treating facility (all p P 0.05). Utilization of advanced RT modalities During this study time period from 1998 to 2011, there was a significant decrease in use of 2D/3D-CRT from 100% to 81.5%, with a subsequent increase in IMRT utilization from 0% to 18.5% (Fig. 3).
0.01*
Discussion 0.84
0.33
0.97 1587 2542 2988 4592
13.6 21.7 25.6 39.1
13.5 21.8 24.9 39.8 0.87
1280 1914 3408 5108
10.9 16.3 29.1 43.7
11.5 16.7 29.3 42.5
1342 7126
11.1 57.4
7.2 59.1
3758 167
30.1 1.4
33.5 0.2
Chemotherapy No Yes
195 10,979
1.7 98.3
1.9 98.1
Distance from treating RT facility <12.5 miles 12.5–50 miles P50 miles
7452 3647 1289
60.1 29.5 10.4
61.1 28.1 10.8
Facility type Community Cancer Program Comprehensive Community Cancer Program Academic/Research Program Other
Propensity score analysis <0.0001*
Gender Male Female
Insurance status Not insured/medicaid Insured (medicare/private insurance/managed care)
*
11,491 (92.7)
The 5-year unadjusted OS was 89.9% for patients who received 2D/3D-CRT vs. 95.2% for those who received IMRT (p = 0.02, logrank test; Fig. 2). For the PS-adjusted cohort, 5-year OS was 90.1% for patients who received 2D/3D-CRT vs. 96.2% for those who received IMRT (p = 0.03, logrank test; not shown).
<0.0001*
0.77
0.83
Statistically significant.
income, favorable insurance status, presence of ‘‘B” symptoms, mediastinum/chest site, and higher CDCS were associated with an increase in OS (all p < 0.01). Within the univariate model, patients treated at comprehensive cancer centers or academic/ research programs were found to have a superior overall survival (HR = 0.87; 95% CI, 0.81–0.92, p < 0.01).
In the current study, we found that patients with stage I–IV HL receiving IMRT experienced a superior OS than those patients receiving 2D/3D-CRT. After adjusting for known confounding variables in the propensity score analysis, the OS benefit of advanced RT modalities, such as IMRT, remained statistically significant (HR = 0.40). Importantly, the selection by radiation oncologists to utilize IMRT (over 2D/3D-CRT) may be one of the reasons for the superior outcome as smaller disease volumes may have been easier to plan with IMRT. In addition, we suspect that patient access to extensive staging and imaging workup may have been superior in the IMRT cohort and perhaps leading to reduced cardiac toxicity. As salvage therapy for relapses is quite successful in clinical practice, the survival benefit is unlikely to be related to better disease control. The associated survival benefit of IMRT was also independent from distance to facility, or socioeconomic factors such as income level, education, or insurance status. As a contemporary cohort in the literature, representing >75% of nationwide diagnoses of HL, advanced RT modalities were significantly underutilized at community cancer programs. As comprehensive and academic/research cancer centers may have greater access to employ IMRT techniques, this capability appears to be associated with prolonged survival for patients with HL. Additionally, patients at comprehensive or academic institutions may receive more aggressive chemotherapy regimens [with associated morbidities] and perhaps RT-specific techniques were required to minimize further damage to nearby organs at risk in these ‘‘pretreated” patients. Interestingly, there was a consistent increase in the use of IMRT for patients with HL from 1998 to 2011, with more than a 6-fold difference in modern years. In 2003, approximately one-third of radiation oncologists in the U.S. used IMRT, particularly for head and neck malignancies and genitourinary tumors, with the primary goals to escalate conventional doses [17]. However, lack of necessary equipment may be a barrier to early adoption of IMRT, but with the paradoxical aims of dose de-escalation for HL patients, practitioners may look to IMRT to aid in decreasing dose to nearby organs at risk (OAR) in efforts to limit late-term toxicity. Because the increasing costs of IMRT delivery may not be sustained by
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
5
R.R. Parikh et al. / Radiotherapy and Oncology xxx (2015) xxx–xxx Table 2 Unadjusted and PS-adjusted analysis for overall survival (OS). Prognostic factor
Unadjusted univariate analysis (OS)
Propensity score adjusted, analysis (OS)
HR (95% CI)
HR (95% CI)
p-value 0.02*
p-value 0.04*
RT modality 2D/3D-CRT IMRT
1.00 (Ref.) 0.45 (0.23–0.91)
Chemotherapy No Yes
1.00 (Ref.) 0.33 (0.31–0.36)
Age (years) at diagnosis 640 >40
0.20 (0.19–0.21) 1.00 (Ref.)
Gender Male Female
1.00 (Ref.) 0.81 (0.77–0.84)
Race White Black Other
1.00 (Ref.) 1.10 (1.04–1.17) 0.83 (0.75–0.93)
0.001 0.001
1.00 (Ref.) 1.06 (0.73–1.52) 0.52 (0.27–1.00)
0.77 0.05
Education P29% 20–28.9% 14–19.9% <14%
1.00 0.84 0.78 0.62
(Ref.) (0.79–0.89) (0.73–0.83) (0.59–0.66)
<0.0001* <0.0001* <0.0001*
1.00 0.99 1.01 0.75
(Ref.) (0.71–1.40) (0.72–1.40) (0.54–1.03)
0.97 0.97 0.08
Median household income <$30,000 $30,000–34,999 $35,000–45,999 P$46,000
1.00 0.90 0.77 0.62
(Ref.) (0.84–0.96) (0.73–0.82) (0.58–0.66)
0.001* <0.0001* <0.0001*
1.00 0.81 0.80 0.65
(Ref.) (0.56–1.18) (0.57–1.12) (0.47–0.90)
0.28 0.19 0.01*
Insured status Insured (medicare/private ins/managed care) Not insured/medicaid
1.00 (Ref.) 4.57 (4.39–4.75)
Facility type Community Cancer Program Comprehensive Community Cancer Program Academic/Research Program Other
1.00 0.87 0.74 1.10
(Ref.) (0.81–0.92) (0.70–0.79) (0.96–1.26)
<0.0001* <0.0001* 0.18
1.00 0.73 0.60 0.35
Distance from treating RT facility <12.5 miles 12.5–50 miles P50 miles
1.00 (Ref.) 0.88 (0.84–0.92) 1.00 (0.95–1.07)
<0.0001* 0.82
1.00 (Ref.) 0.83 (0.66–1.04) 0.94 (0.59–1.47)
0.11 0.78
Clinical stage I II III IV
1.00 0.70 1.68 2.50
<0.0001* <0.0001* <0.0001*
1.00 0.61 1.59 2.23
<0.0001* 0.004* <0.0001*
Presence of ‘‘B” symptoms No Yes
1.00 (Ref.) 1.84 (1.71–1.99)
Charlson/Deyo co-morbidity score 0 1 2
1.00 (Ref.) 2.89 (2.67–3.13) 4.32 (3.86–4.82)
1.00 (Ref.) 0.40 (0.16–0.97) <0.0001*
<0.0001* 1.00 (Ref.) 0.08 (0.05–0.11)
<0.0001*
<0.0001* 0.18 (0.14–0.23) 1.00 (Ref.)
<0.0001*
0.03* 1.00 (Ref.) 0.80 (0.65–0.98)
<0.0001*
(Ref.) (0.66–0.75) (1.58–1.78) (2.36–2.65)
<0.0001* 1.00 (Ref.) 6.44 (5.26–7.87) (Ref.) (0.55–0.98) (0.43–0.84) (0.05–2.55)
(Ref.) (0.48–0.78) (1.16–2.18) (1.58–3.14)
<0.0001*
0.04* 0.003* 0.30
<0.0001* 1.00 (Ref.) 1.44 (1.17–1.77)
<0.0001* <0.0001*
1.00 (Ref.) 4.23 (3.25–5.50) 6.43 (4.24–9.75)
<0.0001* <0.0001*
HR = Hazard ratio; CI = confidence intervals; Ref. = reference group; * Statistically significant.
the current unfavorable reimbursement model for community practitioners [18,19], in the future, we may see a redistribution of advanced RT modalities to academic/research centers. In the current healthcare environment, practitioners may be forced to weigh the long-term benefits of disease control and favorable toxicity profile(s) against the financial costs and uncertainties of advanced modalities such as IMRT. Future studies should utilize a decision-analytic model to compare the quality-adjusted life expectancy of HL patients managed with or without advanced RT techniques, similar to those performed previously [20].
Interestingly, within the NCDB data through 2011, we discovered that <1% of all HL patients were treated with proton beam therapy (PBT) (n = 40; data not shown). With highly conformal IMRT available at most centers, the use of PBT remains controversial but has been adopted by the most current NCCN guidelines [21]. Following the early trends of IMRT adoption, the lack of available equipment, practitioners’ expertise, and comfort level of managing beam uncertainties may explain the underutilization of PBT. However, with >30 PBT centers in several stages of development nationwide, and its potential role in clinical trials for HL
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
6
Survival benefit of IMRT for Hodgkin lymphoma
Fig. 2. Unadjusted Overall Survival (OS) by RT Modality. The 5-year unadjusted OS was 89.9% for patients who received 2D/3D-CRT vs. 95.2% for those who received IMRT (p = 0.02, logrank test).
Fig. 3. Percentage of HL patients undergoing 2D/3D-CRT and IMRT, between 1998 and 2011, by year of diagnosis.
patients [22], we expect the experience with this modality to increase significantly. Nonetheless, modern technologies such as deep-inspiration breath hold (DIBH), IMRT, volumetric modulated arc therapy (VMAT), and intensity-modulated proton therapy (IMPT), coupled with modern field designs, such as ISRT, appear promising in the treatment of HL. For example, multiple studies have displayed the dosimetric benefit of IMRT over 2D/3D-CRT for patients with HL. Typically, 3D-CRT plans employ AP/PA plans and have found the mean lung dose can be significantly reduced by approximately 12–14% with IMRT when compared to 3D-CRT [23]. Additional structures such as the heart, coronary arteries, esophagus, and spinal cord appear to be spared to a greater extent with IMRT treatment plans when compared to optimized 3D-CRT plans [12]. The time of the above publications appear to coincide with the significant nationwide decrease in the use of 3D-CRT in the current study to <90% of all HL patients after 2008.
Conversely, in female patients, the extent of lung and normal breast volume exposed to lower doses of radiation appear to be greater with IMRT versus 3D-CRT [12]. Similarly, concerns of utilizing IMRT in younger patients may be the integral dose-greater volume of normal tissue receiving low doses of radiation, while attempting to spare the nearby critical organs. Using a non-linear dose-risk model, a comparative dosimetric study found that IMRT or VMAT might theoretically increase the risk of cancer induction in breasts, lungs, and thyroid, when compared to 3D-CRT, due to the integral dose of concern [24]. Yet, no study is available at this point to prove or disprove this concern. The current study reflects the practitioners’ gender-specific fears as male patients in the NCDB were more likely to receive IMRT than their matched female counterparts. As approximately 30% of the studied patients were treated to the mediastinum/chest, a potential clinical explanation of improved OS with the inclusion of IMRT techniques may be
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
R.R. Parikh et al. / Radiotherapy and Oncology xxx (2015) xxx–xxx
explained by the reduction of irradiated cardiac tissue. Studies have found the relative risk of death from cardiovascular disease persists >20 years after treatment and is related to exposure to anthracycline/alklyating agents, RT doses >30 Gy, and use of supra-diaphragmatic fields [5]. Also, field reduction to the ‘‘involved-node” has been estimated to reduce 25-year absolute excess risk of cardi-ac events by 5.1% when compared to traditional mantle fields [5]. Aleman et al. found that the main cause of death among HL survivors 20 years after treatment was related to cardiovascular disease (relative risk = 6.3) rather than lymphoma [25]. Recent population-based study of major coronary events in patients who underwent RT for breast cancer found major coronary events increased linearly with the mean dose to the heart by 7.4%/Gy, with no threshold dose, with coronary events starting within the first 5 years after RT and continuing for 30 years later [26]. Thus, the potential for cumulative cardiotoxicity in patients pre-treated with anthracycline-based chemotherapy is high and advanced RT modalities such as IMRT may offer significant risk reduction during consolidation RT. As opposed to extracted billing claims utilized in various SEER studies [27,28] to demonstrate reimbursement policy’s influence on the adoption of a specific modality, our study uses validated data coded from individual institutions submitted to the NCDB, thus removing inherent assumptions of treatment delivery. Nevertheless, there are several limitations to this study. First, the current study assumes that consolidation RT is prescribed in all patients with HL. From previous analysis of this database, it is likely that up to 50% of patients from the entire database were not prescribed RT [29]. It may be those selected to receive RT (all cases in current study) had a pre-treatment likelihood (based on unknown parameters) of worsening cardiac disease much lower than those left untreated. Second, although the multivariate analysis adjusts for measured, known covariates, we were unable to control for unknown confounders due to limitations of parameters coded within the NCDB. Thus, the superior survival of the relatively small IMRT cohort may be due to patient selection, such as extent of disease volume requiring treatment. We also cannot estimate cause-specific survival or incidence of secondary malignancy because cause of death was not coded within this database. Third, this study has limited follow-up to detect late-term RT-induced morbidity and mortality. Therefore, we may only generate hypotheses of potential benefits advanced RT modalities provide, without a casual relationship of the improved outcomes with IMRT. Nonetheless, the survival benefit associated with IMRT observed in the current study may be due to unknown factors associated with this RT modality, rather than IMRT itself. It may be that patients receiving this advanced radiotherapeutic technique are exposed to a higher level of care (i.e. PET staging, bone marrow biopsy, extensive pathology review, quality of RT field/volume verifications, and supportive therapy) when compared to patients receiving non-IMRT treatment. Although advanced RT modalities may avoid potential cardiac morbidity, it is unlikely that this study has sufficient follow-up to detect treatment-related cardiac morality. Therefore, we would suggest that the use of IMRT may serve as a reasonable surrogate marker for oncologic care associated with (rather than a causative intervention) superior overall survival. In summary, this study demonstrates a striking nationwide adoption of IMRT for the treatment of stage I–IV HL in light of previously published dosimetric evidence-linking these utilization trends with overall survival. Indeed, current radiation techniques may minimize long-term effects of radiotherapy, but the question remains unanswered whether all patients will benefit from IMRT over traditional techniques. It may be that a subset of risk-stratified patients (e.g. bulky mediastinal disease with incomplete response after chemotherapy) can be identified who may be the most appropriate candidate for IMRT. We recommend
7
a multidisciplinary approach when choosing wisely the most appropriate RT modality for the individual patient. Conflicts of interest statement All authors state that there are no known conflicts of interested associated with this work and there has been no financial support for this work. Acknowledgments The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator. The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5–29. [2] Kaplan HS. The radical radiotherapy of regionally localized Hodgkin’s disease. Radiology 1962;78:553–61. [3] Peters MV, Middlemiss KC. A study of Hodgkin’s disease treated by irradiation. Am J Roentgenol Radium Ther Nucl Med 1958;79:114–21. [4] Kaplan HS. Long-term results of palliative and radical radiotherapy of Hodgkin’s disease. Cancer Res 1966;26:1250–3. [5] Maraldo MV, Brodin NP, Aznar MC, Vogelius IR, Munck AF, Rosenschold P, Petersen PM. Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma. Ann Oncol 2013;24:2113–8. [6] Raemaekers JM, Andre MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, et al. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 2014;32:1188–94. [7] Tribius S, Bergelt C. Intensity-modulated radiotherapy versus conventional and 3D conformal radiotherapy in patients with head and neck cancer: is there a worthwhile quality of life gain? Cancer Treat Rev 2011;37:511–9. [8] Co J, Mejia MB, Dizon JM. The evidence of effectiveness of intensity modulated radiotherapy versus two dimensional radiotherapy in the treatment of nasopharyngeal carcinoma: meta analysis and a systematic review of the literature. Head Neck 2014. [9] DeLaney TF, Liebsch NJ, Pedlow FX, Adams J, Weyman EA, Yeap BY, et al. Longterm results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. J Surg Oncol 2014;110:115–22. [10] Dolezel M, Odrazka K, Zouhar M, Vaculikova M, Sefrova J, Jansa J. Comparing morbidity and cancer control after 3D-conformal (70/74 Gy) and intensity modulated radiotherapy (78/82 Gy) for prostate cancer. Strahlenther Onkol 2015. [11] Sahgal A, Chan MW, Atenafu EG, Masson-Cote L, Bahl G, Yu E. Image-guided intensity modulated radiation therapy (IG-IMRT) for skull base chordoma and chondrosarcoma: preliminary outcomes. Neuro-oncology 2014. [12] Girinsky T, Pichenot C, Beaudre A, Ghalibafian M, Lefkopoulos D. Is intensitymodulated radiotherapy better than conventional radiation treatment and three-dimensional conformal radiotherapy for mediastinal masses in patients with Hodgkin’s disease, and is there a role for beam orientation optimization and dose constraints assigned to virtual volumes? Int J Radiat Oncol Biol Phys 2006;64:218–26. [13] Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A, et al. Reducedintensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 2012;379:1791–9. [14] Specht L, Yahalom J, Illidge T, Berthelsen AK, Constine LS, Eich HT, et al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG). Int J Radiat Oncol Biol Phys 2014;89:854–62. [15] Weber DC, Peguret N, Dipasquale G, Cozzi L. Involved-node and involved-field volumetric modulated arc vs. fixed beam intensity-modulated radiotherapy for female patients with early-stage supra-diaphragmatic Hodgkin lymphoma: a comparative planning study. Int J Radiat Oncol Biol Phys 2009;75:1578–86. [16] Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127:757–63. [17] Mell LK, Roeske JC, Mundt AJ. A survey of intensity-modulated radiation therapy use in the United States. Cancer 2003;98:204–11.
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Survival benefit of IMRT for Hodgkin lymphoma
[18] Cox JV, Ward JC, Hornberger JC, Temel JS, McAneny BL. Community oncology in an era of payment reform. American Society of Clinical Oncology educational book/ASCO American Society of Clinical Oncology Meeting. 2014: e447–52. [19] American Society of Clinical Oncology. Potential approaches to sustainable, long-lasting payment reform in oncology. J Oncol Practice 2014;10:254–8. [20] Ng AK, Weeks JC, Mauch PM, Kuntz KM. Decision analysis on alternative treatment strategies for favorable-prognosis, early-stage Hodgkin’s disease. J Clin Oncol 1999;17:3577–85. [21] Hoppe RT, Advani RH, Ai WZ, Ambinde RF, Aoun P, Bello CM. Hodgkin lymphoma, version 2.2012 featured updates to the NCCN guidelines. J Natl Compr Canc Netw 2012;10:589–97. [22] Hoppe BS, Flampouri S, Zaiden R, Slayton W, Sandler E, Ozdemir S. Involvednode proton therapy in combined-modality therapy for hodgkin lymphoma: results of a phase II study. Int J Radiat Oncol Biol Phys 2014 [in press]. [23] Goodman KA, Toner S, Hunt M, Wu EJ, Yahalom J. Intensity-modulated radiotherapy for lymphoma involving the mediastinum. Int J Radiat Oncol Biol Phys 2005;62:198–206. [24] Weber DC, Johanson S, Peguret N, Cozzi L, Olsen DR. Predicted risk of radiationinduced cancers after involved field and involved node radiotherapy with or
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Original article
Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma Rahul R. Parikh a,⇑, Michael L. Grossbard b, Louis B. Harrison c, Joachim Yahalom d a Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick; b Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, Division of Hematology-Oncology; c Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa; and d Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, New York, United States
a r t i c l e
i n f o
Article history: Received 3 June 2015 Received in revised form 20 October 2015 Accepted 21 October 2015 Available online xxxx Keywords: IMRT Hodgkin lymphoma Survival NCDB
a b s t r a c t Purpose: The purpose of this study was to compare outcomes with Hodgkin lymphoma (HL) patients receiving IMRT (intensity-modulated radiation therapy), versus those receiving 2D/3D-CRT (3-dimensional conformal RT) in a large observational cohort. Patients and methods: We evaluated patients diagnosed with stage I–IV HL from 1998 to 2011 from the National Cancer Database (NCDB). The association between IMRT use vs. 2D/3D-CRT, co-variables, and outcome was assessed in a Cox proportional hazards model. Propensity score (PS) matching was performed to balance known confounding factors. Survival was estimated using the Kaplan–Meier method. Results: Of the 76,672 patients with HL within the NCDB, 12,393 patients with stage I-IV HL received RT (median dose = 30.6 Gy) and were eligible for this study, and 6013 patients analyzed for overall survival. The cohort had a median follow-up of 6.2 years and median age of 37 years (range: 18–90). The RT modalities used were: 2D/3D-CRT (n = 11,491, 92.7%) or IMRT (n = 902, 7.3%). Patients were more likely to receive IMRT if they were of male gender, early stage, no ‘‘B” symptoms, and treated at comprehensive cancer programs (all p < 0.05). During this time period, there was a significant decrease in use of 2D/3D-CRT from 100% to 81.5%, with a subsequent increase in IMRT utilization from 0% to 18.5%. Five-year overall survival for patients receiving 2D/3D-CRT (n = 5844) was 89.9% versus 95.2% for those receiving IMRT (n = 169; HR = 0.45; 95% CI, 0.23–0.91, p = 0.02). After PS-matching based on clinicopathologic characteristics, IMRT use remained associated with improved overall survival (HR = 0.40; 95% CI, 0.16–0.97, p = 0.04). Conclusions: Our study reveals that HL patients receiving modern RT techniques were associated with an improvement in overall survival. This may have been related to patient selection, access to improved staging and management, or improvements in treatment technology. This represents the only study examining survival outcomes of advanced RT modalities, which may be considered on a case-by-case basis for highly selected patients with HL. Ó 2015 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2015) xxx–xxx
There will be an estimated 9050 new cases of Hodgkin lymphoma (HL) in the U.S. in 2015, with an estimated 1150 new deaths in 2015 [1]. Historically, excellent survival rates for HL were attributed to the efficacy of definitive extended-field RT (EFRT) [2,3], but with concerning treatment-related morbidity. In fact, Kaplan et al. found dramatic improvements in overall survival (OS) in patients with HL with the advent of megavoltage linear accelerator and advances in treatment planning capabilities [4]. Combining safer chemotherapy with reduced field and dose, modern conformal RT led to further improvements in disease control [5,6].
⇑ Corresponding author at: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08903, United States. E-mail addresses: [email protected], [email protected] (R.R. Parikh).
There are few disease sites in which advanced radiotherapy modalities, such as IMRT (intensity-modulated RT), have been associated with improvements in outcome when compared to historical techniques such as 2D or 3D-CRT (conformal radiation therapy). For example, IMRT has also demonstrated improvements in disease control and quality of life in head and neck cancer and prostate cancer patients [7]. Cancer patients that require escalation of RT dose may require IMRT to prevent high doses of irradiated volume to nearby organs at risk and provide maximal cure rates [8–11]. For HL patients treated in the era of in the era of dose de-intensification, early dosimetric studies have demonstrated improved sparing of vital structures with IMRT, when compared to optimized 3D-CRT plans [12]. Paradoxically, despite the need for dose de-escalation, these advanced RT modalities may be helpful to decrease death from late-term morbidity.
http://dx.doi.org/10.1016/j.radonc.2015.10.022 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
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Survival benefit of IMRT for Hodgkin lymphoma
Despite evidence of improved event-free survival with the addition of consolidation RT [6], many centers continue to omit RT in the treatment of lymphoma because of concern for late radiation side effects and effectiveness of salvage therapy. To minimize late-term toxicity while maintaining high cure rates, radiation oncologists have found ways to deliver RT by effectively reducing the radiation dose needed to control lymphoma to 20–30 Gy [13]; by further reducing the treatment field from EFRT to IFRT to involved-site RT (ISRT) techniques as delineated by the ILROG Guidelines for HL [14]; and by delivering more conformal RT through modalities such as IMRT [15]. We used the National Cancer Database (NCDB) on stage I–IV HL patients to answer the primary endpoint of whether IMRT (compared to 2D/3D-CRT) impacted upon overall survival. As secondary endpoints, we examined the relationship between clinical and sociodemographic parameters, with use of advanced RT modality, and overall survival. We also examined the trends of IMRT utilization from 1998 to 2011. Our hypothesis was that the increased use of IMRT improves outcomes over historical methods. Patients and methods Data source The National Cancer Database (NCDB), a national hospital-based oncology database, was used to conduct a retrospective, cohort study of HL patients diagnosed from 1998 through 2011. As a joint project of the American College of Surgeons’ Commission on Cancer and the American Cancer Society, it is a prospectively collected registry from 1500 hospitals representing 75% of all cancers diagnosed in the U.S. with accumulated data on approximately 29-million cancer cases. Variables captured include basic demographics, socioeconomic characteristics, cancer staging, treatment course, and vital status. This study period reflected a time during which inclusion of RT was accepted standard treatment for HL. At the time of analysis, 2011 data were the most recent data available. Study patients The flow CONSORT diagram in Fig. 1 shows the study exclusion criteria used to define the cohort. All patients (n = 76,672) diagnosed with classical HL from 1998 to 2011 were initially included. Only patients within the age range of 18–90 with Stage I–IV HL were included. Patients were excluded if they did not receive 2D/3D-CRT or IMRT or without a coded utilization of RT. For purposes of minimizing confounding effects from all known covariates, we also excluded patients with any missing data points in all clinicopathologic parameters of interest. As displayed in the flow CONSORT diagram (Fig. 1), with the above inclusion criteria, the study analysis was limited to 12,393 patients. Study variables Our variable of main interest was modality of radiation therapy (RT) utilized. This parameter was grouped into 2D and 3D-CRT versus IMRT. Demographic and clinical data included gender, race/ ethnicity (white, black, or other), age (640 vs. >40), indicators of income and education based on area of residence derived from Census data(the proportion of adults without a high school diploma according to patients’ zip code of residence was categorized as <14%, 14–19.9%, 20–28.9%, and P29%, based on national quartiles and used as proxies for patient socioeconomic status), median household income, insurance status (categorized as private, Medicare, Medicaid, or uninsured), treatment facility type (categorized as Community Cancer Program, Comprehensive
Community Cancer Program, and Academic/Research Program [including NCI-designated Comprehensive Cancer Centers]), geographic region (categorized into 9 predefined regions), Charlson–Deyo co-morbidity Score (CDCS) (categorized 0, 1, and 2+), clinical stage, involved site (categorized as head & neck, mediastinum/chest, or not otherwise specified [NOS]/other), presence of ‘‘B” symptoms, distance from facility (classified as <12.5 miles, 12.5–50 miles, P50 miles), and vital status. The outcome variable-overall survival (OS) was calculated from the date of diagnosis to December 31, 2011, the date of death, or the date of last contact, whichever occurred first. Statistical analysis Categorical and continuous variable distributions were assessed by using standard descriptive statistics. Using chi-square tests, we assessed the association of RT modality with age, gender, race, socioeconomic status (education level, household income), insurance status, facility type, stage, involved site of disease, distance from facility, presence of B-symptoms, and CDCS. Overall survival after planned intervention was the primary outcome. Kaplan– Meier survival curves were stratified by RT modality, and logrank tests were performed. Propensity score analysis As an observational cohort, use of particular RT modality was likely not random, and may be influenced by patient and disease-related characteristics, potentially leading to biased survival estimates due to confounding. Thus, rather than traditional covariate adjustment via multivariate hazards modeling, propensity score (PS) adjustments to our Cox model may have significant advantages when analyzing large observational cohorts like SEER or NCDB [16]. We calculated PS using multivariate logistic regression with the exposure variable (IMRT vs. 2D/3D-CRT) as the intervention of interest, and then subsequently compared the match samples with overall survival as the outcome of interest. The estimated PS was the used to match patients with similar propensity to receive the specific RT modality based on nearest neighbor matching without replacement using calipers of width equal 0.2 SD of the logit of the propensity score. The success in achieving covariate balance was evaluated using standardized differences of means <0.1 (<10% difference between the arms) indicative of acceptable balance. As two important prognostic factors, the Charlson–Deyo co-morbidity score (CDCS) and the presence of ‘‘B” symptoms, were coded only from 2004 onward, our propensity score analysis was restricted to patients diagnosed in 2004–2006, with available survival data (n = 3436). Cox proportional hazards model Unadjusted associations of individual covariates with survival were described using univariate Cox proportional hazards model. A multivariate Cox proportional hazards model was then fitted to estimate the hazard ratios associated with RT-use and other covariates with respect to OS and their 95% confidence intervals (CI’s), after adjustment for the propensity score. The criterion p < 0.05 was used for retaining interactions in the model. In accordance with NCDB participant user file data-use agreements, survival analysis excluded patients (n = 6380) diagnosed from 2007 to 2011, to allow for at least 5 years of follow-up for all patients. Thus, the survival analysis cohort was a total of 6013 patients. Survival was calculated in months from date of diagnosis to date of last contact or confirmed death. All statistical analyses were performed using statistical software STATA version 12.1. For all statistical testing, we used a
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
R.R. Parikh et al. / Radiotherapy and Oncology xxx (2015) xxx–xxx
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Fig. 1. CONSORT diagram. The primary analysis includes 12,393 patients with Stage I–IV HL, all of whom received RT within their treatment program.
two-sided significance level of p = 0.05. Institutional review board exemption was obtained from the Mount Sinai Beth Israel Cancer Center Institutional Review Board. Results Descriptive statistics The primary analysis examines 12,393 patients with stage I–IV HL who met inclusion criteria. Median age was 37 years (range: 18–90); 52% were male and 48% were female. Table 1 summarizes patient clinicopathologic characteristics by RT modality. The RT modalities used were: 2D/3D-CRT (n = 11,491, 92.7%) or IMRT (n = 902, 7.3%). All patients received RT to a median dose of 30.6 Gy (similar for both 2D/3D-CRT and IMRT group). The mean RT dose for the IMRT group was approximately 46.0 Gy, while the mean RT dose for the 2D/3D-CRT group was 39.0 Gy. Multiagent chemotherapy was given to 98.2% of the patients. Majorities of patients were white (86%), young age (58%), earlystage (86%), no ‘‘B” symptoms (70%), low CDCS (91%), and favorable insurance status (94%). Fifty-seven percent of patients were treated
at comprehensive community cancer programs and 30% were treated at academic/research program facilities (10% at community cancer programs). The involved sites treated with RT included head and neck (2164; 19.6%), mediastinum/chest (3185; 28.9%), and NOS/other (5672; 51.5%). Patients were more likely to receive IMRT if they were of male gender, early-stage, head and neck site involved, no ‘‘B” symptoms, and treated at comprehensive cancer programs (all p < 0.01; Table 1). There was no difference in use of 2D/3D-CRT versus IMRT based on insurance status, socioeconomic status, or distance from treatment facility (all p P 0.05).
Survival analysis The median follow-up for the entire cohort was 6.2 years. As seen in the unadjusted univariate analysis, the use of IMRT was associated with an improvement in OS (HR = 0.45; 95% CI, 0.23– 0.91, p = 0.02; Table 2). The use of chemotherapy was associated with an improvement in OS (p < 0.01, Table 2). Also, younger age, female gender, white race, higher education level, household
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
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Survival benefit of IMRT for Hodgkin lymphoma
Table 1 Patient characteristics according to RT Modality. Parameter
Patients RT modality (n) 2D/3DIMRT CRT (%) (%)
p-value
Overall
12,393
n/a
902 (7.3)
6523 5870
52.2 47.8
58.7 41.3
Race White Black Other
10,675 1162 556
86.2 9.4 4.4
85.4 9.4 5.2
Age (years) 640 >40
5173 7220
41.5 58.5
44.7 55.3
Clinical stage I II III IV
2933 7173 1027 636
24.6 60.8 8.9 5.7
29.1 62.4 6.2 2.3
0.37
0.06
<0.0001*
<0.0001*
Involved site (treated with RT) Head & neck Mediastinum/chest NOS/other
2164 3185 5672
18.3 30.1 51.6
36.8 13.0 50.2
Presence of ‘‘B” symptoms No Yes
6805 2907
69.7 30.3
73.8 26.2
Charlson/Deyo co-morbidity score 0 1 2
11.245 868 186
91.4 7.1 1.5
91.9 6.7 1.4
2258 9872
18.5 81.5
19.8 80.2
Education (% not HS graduate in pt’s zip code) P 29% 20–28.9% 14–19.9% <14% Median household income (pt’s zip code) <$30,000 $30,000–34,999 $35,000–45,999 P$46,000
The propensity score adequately balanced known variables affecting treatment selection or OS. After the adjustment, the risk of death remained lower in patients receiving IMRT when compared to 2D/3D-CRT (HR = 0.40; 95% CI, 0.16–0.97, p = 0.04; Table 2). Also, chemotherapy use, younger age, facility type, lower clinical stage, mediastinum/chest site, absence of ‘‘B” symptoms, lower CDCS, and favorable insurance status remained significant predictors of decreased risk of death (all p < 0.01; Table 2). OS was not significantly different amongst additional parameters such as race, education, income, or distance from treating facility (all p P 0.05). Utilization of advanced RT modalities During this study time period from 1998 to 2011, there was a significant decrease in use of 2D/3D-CRT from 100% to 81.5%, with a subsequent increase in IMRT utilization from 0% to 18.5% (Fig. 3).
0.01*
Discussion 0.84
0.33
0.97 1587 2542 2988 4592
13.6 21.7 25.6 39.1
13.5 21.8 24.9 39.8 0.87
1280 1914 3408 5108
10.9 16.3 29.1 43.7
11.5 16.7 29.3 42.5
1342 7126
11.1 57.4
7.2 59.1
3758 167
30.1 1.4
33.5 0.2
Chemotherapy No Yes
195 10,979
1.7 98.3
1.9 98.1
Distance from treating RT facility <12.5 miles 12.5–50 miles P50 miles
7452 3647 1289
60.1 29.5 10.4
61.1 28.1 10.8
Facility type Community Cancer Program Comprehensive Community Cancer Program Academic/Research Program Other
Propensity score analysis <0.0001*
Gender Male Female
Insurance status Not insured/medicaid Insured (medicare/private insurance/managed care)
*
11,491 (92.7)
The 5-year unadjusted OS was 89.9% for patients who received 2D/3D-CRT vs. 95.2% for those who received IMRT (p = 0.02, logrank test; Fig. 2). For the PS-adjusted cohort, 5-year OS was 90.1% for patients who received 2D/3D-CRT vs. 96.2% for those who received IMRT (p = 0.03, logrank test; not shown).
<0.0001*
0.77
0.83
Statistically significant.
income, favorable insurance status, presence of ‘‘B” symptoms, mediastinum/chest site, and higher CDCS were associated with an increase in OS (all p < 0.01). Within the univariate model, patients treated at comprehensive cancer centers or academic/ research programs were found to have a superior overall survival (HR = 0.87; 95% CI, 0.81–0.92, p < 0.01).
In the current study, we found that patients with stage I–IV HL receiving IMRT experienced a superior OS than those patients receiving 2D/3D-CRT. After adjusting for known confounding variables in the propensity score analysis, the OS benefit of advanced RT modalities, such as IMRT, remained statistically significant (HR = 0.40). Importantly, the selection by radiation oncologists to utilize IMRT (over 2D/3D-CRT) may be one of the reasons for the superior outcome as smaller disease volumes may have been easier to plan with IMRT. In addition, we suspect that patient access to extensive staging and imaging workup may have been superior in the IMRT cohort and perhaps leading to reduced cardiac toxicity. As salvage therapy for relapses is quite successful in clinical practice, the survival benefit is unlikely to be related to better disease control. The associated survival benefit of IMRT was also independent from distance to facility, or socioeconomic factors such as income level, education, or insurance status. As a contemporary cohort in the literature, representing >75% of nationwide diagnoses of HL, advanced RT modalities were significantly underutilized at community cancer programs. As comprehensive and academic/research cancer centers may have greater access to employ IMRT techniques, this capability appears to be associated with prolonged survival for patients with HL. Additionally, patients at comprehensive or academic institutions may receive more aggressive chemotherapy regimens [with associated morbidities] and perhaps RT-specific techniques were required to minimize further damage to nearby organs at risk in these ‘‘pretreated” patients. Interestingly, there was a consistent increase in the use of IMRT for patients with HL from 1998 to 2011, with more than a 6-fold difference in modern years. In 2003, approximately one-third of radiation oncologists in the U.S. used IMRT, particularly for head and neck malignancies and genitourinary tumors, with the primary goals to escalate conventional doses [17]. However, lack of necessary equipment may be a barrier to early adoption of IMRT, but with the paradoxical aims of dose de-escalation for HL patients, practitioners may look to IMRT to aid in decreasing dose to nearby organs at risk (OAR) in efforts to limit late-term toxicity. Because the increasing costs of IMRT delivery may not be sustained by
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
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R.R. Parikh et al. / Radiotherapy and Oncology xxx (2015) xxx–xxx Table 2 Unadjusted and PS-adjusted analysis for overall survival (OS). Prognostic factor
Unadjusted univariate analysis (OS)
Propensity score adjusted, analysis (OS)
HR (95% CI)
HR (95% CI)
p-value 0.02*
p-value 0.04*
RT modality 2D/3D-CRT IMRT
1.00 (Ref.) 0.45 (0.23–0.91)
Chemotherapy No Yes
1.00 (Ref.) 0.33 (0.31–0.36)
Age (years) at diagnosis 640 >40
0.20 (0.19–0.21) 1.00 (Ref.)
Gender Male Female
1.00 (Ref.) 0.81 (0.77–0.84)
Race White Black Other
1.00 (Ref.) 1.10 (1.04–1.17) 0.83 (0.75–0.93)
0.001 0.001
1.00 (Ref.) 1.06 (0.73–1.52) 0.52 (0.27–1.00)
0.77 0.05
Education P29% 20–28.9% 14–19.9% <14%
1.00 0.84 0.78 0.62
(Ref.) (0.79–0.89) (0.73–0.83) (0.59–0.66)
<0.0001* <0.0001* <0.0001*
1.00 0.99 1.01 0.75
(Ref.) (0.71–1.40) (0.72–1.40) (0.54–1.03)
0.97 0.97 0.08
Median household income <$30,000 $30,000–34,999 $35,000–45,999 P$46,000
1.00 0.90 0.77 0.62
(Ref.) (0.84–0.96) (0.73–0.82) (0.58–0.66)
0.001* <0.0001* <0.0001*
1.00 0.81 0.80 0.65
(Ref.) (0.56–1.18) (0.57–1.12) (0.47–0.90)
0.28 0.19 0.01*
Insured status Insured (medicare/private ins/managed care) Not insured/medicaid
1.00 (Ref.) 4.57 (4.39–4.75)
Facility type Community Cancer Program Comprehensive Community Cancer Program Academic/Research Program Other
1.00 0.87 0.74 1.10
(Ref.) (0.81–0.92) (0.70–0.79) (0.96–1.26)
<0.0001* <0.0001* 0.18
1.00 0.73 0.60 0.35
Distance from treating RT facility <12.5 miles 12.5–50 miles P50 miles
1.00 (Ref.) 0.88 (0.84–0.92) 1.00 (0.95–1.07)
<0.0001* 0.82
1.00 (Ref.) 0.83 (0.66–1.04) 0.94 (0.59–1.47)
0.11 0.78
Clinical stage I II III IV
1.00 0.70 1.68 2.50
<0.0001* <0.0001* <0.0001*
1.00 0.61 1.59 2.23
<0.0001* 0.004* <0.0001*
Presence of ‘‘B” symptoms No Yes
1.00 (Ref.) 1.84 (1.71–1.99)
Charlson/Deyo co-morbidity score 0 1 2
1.00 (Ref.) 2.89 (2.67–3.13) 4.32 (3.86–4.82)
1.00 (Ref.) 0.40 (0.16–0.97) <0.0001*
<0.0001* 1.00 (Ref.) 0.08 (0.05–0.11)
<0.0001*
<0.0001* 0.18 (0.14–0.23) 1.00 (Ref.)
<0.0001*
0.03* 1.00 (Ref.) 0.80 (0.65–0.98)
<0.0001*
(Ref.) (0.66–0.75) (1.58–1.78) (2.36–2.65)
<0.0001* 1.00 (Ref.) 6.44 (5.26–7.87) (Ref.) (0.55–0.98) (0.43–0.84) (0.05–2.55)
(Ref.) (0.48–0.78) (1.16–2.18) (1.58–3.14)
<0.0001*
0.04* 0.003* 0.30
<0.0001* 1.00 (Ref.) 1.44 (1.17–1.77)
<0.0001* <0.0001*
1.00 (Ref.) 4.23 (3.25–5.50) 6.43 (4.24–9.75)
<0.0001* <0.0001*
HR = Hazard ratio; CI = confidence intervals; Ref. = reference group; * Statistically significant.
the current unfavorable reimbursement model for community practitioners [18,19], in the future, we may see a redistribution of advanced RT modalities to academic/research centers. In the current healthcare environment, practitioners may be forced to weigh the long-term benefits of disease control and favorable toxicity profile(s) against the financial costs and uncertainties of advanced modalities such as IMRT. Future studies should utilize a decision-analytic model to compare the quality-adjusted life expectancy of HL patients managed with or without advanced RT techniques, similar to those performed previously [20].
Interestingly, within the NCDB data through 2011, we discovered that <1% of all HL patients were treated with proton beam therapy (PBT) (n = 40; data not shown). With highly conformal IMRT available at most centers, the use of PBT remains controversial but has been adopted by the most current NCCN guidelines [21]. Following the early trends of IMRT adoption, the lack of available equipment, practitioners’ expertise, and comfort level of managing beam uncertainties may explain the underutilization of PBT. However, with >30 PBT centers in several stages of development nationwide, and its potential role in clinical trials for HL
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
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Survival benefit of IMRT for Hodgkin lymphoma
Fig. 2. Unadjusted Overall Survival (OS) by RT Modality. The 5-year unadjusted OS was 89.9% for patients who received 2D/3D-CRT vs. 95.2% for those who received IMRT (p = 0.02, logrank test).
Fig. 3. Percentage of HL patients undergoing 2D/3D-CRT and IMRT, between 1998 and 2011, by year of diagnosis.
patients [22], we expect the experience with this modality to increase significantly. Nonetheless, modern technologies such as deep-inspiration breath hold (DIBH), IMRT, volumetric modulated arc therapy (VMAT), and intensity-modulated proton therapy (IMPT), coupled with modern field designs, such as ISRT, appear promising in the treatment of HL. For example, multiple studies have displayed the dosimetric benefit of IMRT over 2D/3D-CRT for patients with HL. Typically, 3D-CRT plans employ AP/PA plans and have found the mean lung dose can be significantly reduced by approximately 12–14% with IMRT when compared to 3D-CRT [23]. Additional structures such as the heart, coronary arteries, esophagus, and spinal cord appear to be spared to a greater extent with IMRT treatment plans when compared to optimized 3D-CRT plans [12]. The time of the above publications appear to coincide with the significant nationwide decrease in the use of 3D-CRT in the current study to <90% of all HL patients after 2008.
Conversely, in female patients, the extent of lung and normal breast volume exposed to lower doses of radiation appear to be greater with IMRT versus 3D-CRT [12]. Similarly, concerns of utilizing IMRT in younger patients may be the integral dose-greater volume of normal tissue receiving low doses of radiation, while attempting to spare the nearby critical organs. Using a non-linear dose-risk model, a comparative dosimetric study found that IMRT or VMAT might theoretically increase the risk of cancer induction in breasts, lungs, and thyroid, when compared to 3D-CRT, due to the integral dose of concern [24]. Yet, no study is available at this point to prove or disprove this concern. The current study reflects the practitioners’ gender-specific fears as male patients in the NCDB were more likely to receive IMRT than their matched female counterparts. As approximately 30% of the studied patients were treated to the mediastinum/chest, a potential clinical explanation of improved OS with the inclusion of IMRT techniques may be
Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022
R.R. Parikh et al. / Radiotherapy and Oncology xxx (2015) xxx–xxx
explained by the reduction of irradiated cardiac tissue. Studies have found the relative risk of death from cardiovascular disease persists >20 years after treatment and is related to exposure to anthracycline/alklyating agents, RT doses >30 Gy, and use of supra-diaphragmatic fields [5]. Also, field reduction to the ‘‘involved-node” has been estimated to reduce 25-year absolute excess risk of cardi-ac events by 5.1% when compared to traditional mantle fields [5]. Aleman et al. found that the main cause of death among HL survivors 20 years after treatment was related to cardiovascular disease (relative risk = 6.3) rather than lymphoma [25]. Recent population-based study of major coronary events in patients who underwent RT for breast cancer found major coronary events increased linearly with the mean dose to the heart by 7.4%/Gy, with no threshold dose, with coronary events starting within the first 5 years after RT and continuing for 30 years later [26]. Thus, the potential for cumulative cardiotoxicity in patients pre-treated with anthracycline-based chemotherapy is high and advanced RT modalities such as IMRT may offer significant risk reduction during consolidation RT. As opposed to extracted billing claims utilized in various SEER studies [27,28] to demonstrate reimbursement policy’s influence on the adoption of a specific modality, our study uses validated data coded from individual institutions submitted to the NCDB, thus removing inherent assumptions of treatment delivery. Nevertheless, there are several limitations to this study. First, the current study assumes that consolidation RT is prescribed in all patients with HL. From previous analysis of this database, it is likely that up to 50% of patients from the entire database were not prescribed RT [29]. It may be those selected to receive RT (all cases in current study) had a pre-treatment likelihood (based on unknown parameters) of worsening cardiac disease much lower than those left untreated. Second, although the multivariate analysis adjusts for measured, known covariates, we were unable to control for unknown confounders due to limitations of parameters coded within the NCDB. Thus, the superior survival of the relatively small IMRT cohort may be due to patient selection, such as extent of disease volume requiring treatment. We also cannot estimate cause-specific survival or incidence of secondary malignancy because cause of death was not coded within this database. Third, this study has limited follow-up to detect late-term RT-induced morbidity and mortality. Therefore, we may only generate hypotheses of potential benefits advanced RT modalities provide, without a casual relationship of the improved outcomes with IMRT. Nonetheless, the survival benefit associated with IMRT observed in the current study may be due to unknown factors associated with this RT modality, rather than IMRT itself. It may be that patients receiving this advanced radiotherapeutic technique are exposed to a higher level of care (i.e. PET staging, bone marrow biopsy, extensive pathology review, quality of RT field/volume verifications, and supportive therapy) when compared to patients receiving non-IMRT treatment. Although advanced RT modalities may avoid potential cardiac morbidity, it is unlikely that this study has sufficient follow-up to detect treatment-related cardiac morality. Therefore, we would suggest that the use of IMRT may serve as a reasonable surrogate marker for oncologic care associated with (rather than a causative intervention) superior overall survival. In summary, this study demonstrates a striking nationwide adoption of IMRT for the treatment of stage I–IV HL in light of previously published dosimetric evidence-linking these utilization trends with overall survival. Indeed, current radiation techniques may minimize long-term effects of radiotherapy, but the question remains unanswered whether all patients will benefit from IMRT over traditional techniques. It may be that a subset of risk-stratified patients (e.g. bulky mediastinal disease with incomplete response after chemotherapy) can be identified who may be the most appropriate candidate for IMRT. We recommend
7
a multidisciplinary approach when choosing wisely the most appropriate RT modality for the individual patient. Conflicts of interest statement All authors state that there are no known conflicts of interested associated with this work and there has been no financial support for this work. Acknowledgments The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator. The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5–29. [2] Kaplan HS. The radical radiotherapy of regionally localized Hodgkin’s disease. Radiology 1962;78:553–61. [3] Peters MV, Middlemiss KC. A study of Hodgkin’s disease treated by irradiation. Am J Roentgenol Radium Ther Nucl Med 1958;79:114–21. [4] Kaplan HS. Long-term results of palliative and radical radiotherapy of Hodgkin’s disease. Cancer Res 1966;26:1250–3. [5] Maraldo MV, Brodin NP, Aznar MC, Vogelius IR, Munck AF, Rosenschold P, Petersen PM. Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma. Ann Oncol 2013;24:2113–8. [6] Raemaekers JM, Andre MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, et al. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 2014;32:1188–94. [7] Tribius S, Bergelt C. Intensity-modulated radiotherapy versus conventional and 3D conformal radiotherapy in patients with head and neck cancer: is there a worthwhile quality of life gain? Cancer Treat Rev 2011;37:511–9. [8] Co J, Mejia MB, Dizon JM. The evidence of effectiveness of intensity modulated radiotherapy versus two dimensional radiotherapy in the treatment of nasopharyngeal carcinoma: meta analysis and a systematic review of the literature. Head Neck 2014. [9] DeLaney TF, Liebsch NJ, Pedlow FX, Adams J, Weyman EA, Yeap BY, et al. Longterm results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. J Surg Oncol 2014;110:115–22. [10] Dolezel M, Odrazka K, Zouhar M, Vaculikova M, Sefrova J, Jansa J. Comparing morbidity and cancer control after 3D-conformal (70/74 Gy) and intensity modulated radiotherapy (78/82 Gy) for prostate cancer. Strahlenther Onkol 2015. [11] Sahgal A, Chan MW, Atenafu EG, Masson-Cote L, Bahl G, Yu E. Image-guided intensity modulated radiation therapy (IG-IMRT) for skull base chordoma and chondrosarcoma: preliminary outcomes. Neuro-oncology 2014. [12] Girinsky T, Pichenot C, Beaudre A, Ghalibafian M, Lefkopoulos D. Is intensitymodulated radiotherapy better than conventional radiation treatment and three-dimensional conformal radiotherapy for mediastinal masses in patients with Hodgkin’s disease, and is there a role for beam orientation optimization and dose constraints assigned to virtual volumes? Int J Radiat Oncol Biol Phys 2006;64:218–26. [13] Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A, et al. Reducedintensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 2012;379:1791–9. [14] Specht L, Yahalom J, Illidge T, Berthelsen AK, Constine LS, Eich HT, et al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG). Int J Radiat Oncol Biol Phys 2014;89:854–62. [15] Weber DC, Peguret N, Dipasquale G, Cozzi L. Involved-node and involved-field volumetric modulated arc vs. fixed beam intensity-modulated radiotherapy for female patients with early-stage supra-diaphragmatic Hodgkin lymphoma: a comparative planning study. Int J Radiat Oncol Biol Phys 2009;75:1578–86. [16] Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127:757–63. [17] Mell LK, Roeske JC, Mundt AJ. A survey of intensity-modulated radiation therapy use in the United States. Cancer 2003;98:204–11.
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Please cite this article in press as: Parikh RR et al. Association of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.10.022