Impact of age on long-term mortality and net survival benefit of radiotherapy for early-stage follicular lymphoma from the SEER database (2000-2015)

doi:10.21203/rs.3.rs-1818923/v1

Background: The effect of age on long-term mortality and net survival benefit of radiotherapy (RT) for early-stage follicular lymphoma (FL) was not evaluated.

Methods: 8,803 patients with early-stage FL in the Surveillance, Epidemiology, and End Results (SEER) database (2000-2015) were identified for this study. Primary therapy included RT (27.0%), chemotherapy (CT, 29.3%), observation (24.1%), and other/unknown treatments (19.6%). Inverse probability of treatment weighting (IPTW) was conducted to balance the treatment arms. Relative survival (RS), the standardized mortality ratio (SMR), and transformed Cox regression were used to compare survival differences between treatments.

Results: The risk of dying from FL and other causes varied over time, dependent of patient age. RT had significantly higher 10-year OS (77.2%) and RS (96.1%), but lower SMR (1.77), compared with CT (65.2%; 82.6%; 2.92; P<0.001), observation (65.5%; 90.1%; 2.18; P<0.001), and other/unknown treatments (66.5%, P<0.001; 89.9%, P=0.136; 2.05, P<0.001). RT was an independent predictor of better OS and RS in multivariate analyses (P<0.001). No significant interaction between age and RT was identified for RS (P_interaction=0.305) or OS (P_interaction= 0.272), indicating similar survival benefits across all-ages patients.

Conclusions: RT was associated with long-term OS and net survival benefits in early-stage FL.

Follicular lymphoma

Radiotherapy

Relative survival

Age

The pattern and rate of mortality varied by age-group as old patients often die of other diseases other than FL beyond 5 years.
Radiotherapy was associated with higher long-term OS/RS and better SMR compared with other approaches, regardless of age.

Follicular lymphoma (FL) is the most common indolent lymphomas worldwide.^{1, 2} It is frequently seen in old patients (median age, 60 ~ 65 years).^{3, 4} 20–35% of patients present with early-stage disease. Given favorable outcomes,^5–15 radiotherapy (RT) has been recommended as the standard of care for early-stage FL.^{16, 17} However, less than 40% of early-stage patients received RT, instead of some form of systemic therapy or observation.^{3, 16–18} The lower use of RT may be due to doubts about its net survival benefit and concerns about treatment-related toxicity. Recently, diverse treatment strategies have resulted in similar overall survival (OS), thereby challenging RT as the standard of care.^18–22

Given the indolent clinical course of FL and an older age, early-stage patients have a long life expectancy, but are at a high risk of non-lymphoma-related death (non-LRD).^{8–10, 18} Interpretation of the results of FL studies examining the association between treatment strategies and outcomes is challenging. Some studies evaluating efficacy of RT versus chemotherapy (CT), observation, or immunotherapy, are compromised by their small sizes or the small number of events over short follow-up periods.^{18–21, 23} Moreover, background mortality rates vary with increasing age and follow-up time, as old patients often die of diseases other than FL. Hence, it is important to determine how age affects long-term mortality and RT efficacy in early-stage FL. Studies assessing OS − including background mortality − may underestimate the long-term benefit of RT, whereas studies assessing disease-specific survival (DSS) − excluding treatment-related death − might overestimate the benefit.^{10, 11, 24} Compared with observed survival, relative survival (RS) − excluding other causes of death but including disease- and treatment-related deaths − provides an objective way to account for mortality caused by competing risks or natural causes in the general population. There is an ongoing debate about whether early-stage FL patients treated with RT have excess mortality than equivalent groups from the general population.

Acknowledging discrepancies in treatment strategies, we conducted a large-scale study using the Surveillance, Epidemiology, and End Results (SEER) database to determine the impact of age on long-term mortality and net survival benefit of RT for early-stage FL.

Data collection and eligibility criteria

The SEER database (SEER 18 Regs November 2018 data submission 1975–2016) was queried for patients with newly-diagnosed FL between 2000 and 2015. The eligibility criteria were: (1) grade I or II; (2) stage I or II diseases; (3) age > 20 years-old; and (4) availability of follow-up information. The exclusion criteria were: (1) stage III-IV or unknown stage disease; (2) unknown cause of death; or (3) unknown radiotherapeutic method. Of 9,052 early-stage patients, 8,803 patients met the eligibility criteria and formed the study population (Supplemental Fig. 1A). Our institutional ethics review board approved this study.

Definitions and treatment

Variables were defined by the ICD code provided by the SEER database.^{25, 26} The primary site was classified as the supradiaphragmatic (ICD-O-3 770, 771, 773) or subdiaphragmatic lymph nodes (ICD-O-3 772, 774, 775), stomach (ICD-O-3 161–169), skin (ICD-O-3 440–449), and other sites. Year of diagnosis was classified as 2000–2004, 2005–2010, and 2011–2015. Patient age was analyzed as a continuous variable and a categorical variable, which was categorized into four groups: ≤40, 41−60, 61−80, and > 80 years.

Primary treatment was defined as RT (with or without CT; n = 2,377, 27.0%), CT (without RT; n = 2,581, 29.3%), observation (n = 2,118, 24.1%), and other/unknown treatments (n = 1,727, 19.6%).

Endpoints and statistical analysis

Primary endpoints were RS and standardized mortality ratio (SMR). Given median survival time of ~ 10 years, 10-year RS is considered the primary benchmark to assess the increased risk of mortality.

Survival data were analyzed using the Kaplan-Meier method and compared using the log-rank test. Differences among categorical variables and continuous variables were tested using the Chi-square test and the Kruskal-Wallis test. The propensity score-based inverse probability of treatment weighting (IPTW) approach was used to balance the treatment arms.²⁷ The standardized mean difference was used to evaluate covariate balance, with a value < 0.1 indicating acceptable balance.

RS was calculated using the Ederer II method, with the observed survival in the study cohort corrected for the expected survival in the age-, sex-, race-, and calendar year–matched general population.^28–30 The SMR was the ratio of observed mortality in the study cohort to the expected mortality in the matched general population. The life table and death rates in the general population were acquired from the SEER database. A SMR > 1.0 indicates worse than expected survival. Likelihood ratio tests of Poisson regression models were fitted to test the heterogeneity of the SMRs between subgroups. A transformed Cox proportional hazards model was fitted to compare the hazard ratio (HR) for RS among treatment groups.³¹ This model transformed each person’s time to the expected death rate at that time. A lower observed death rate at every expected death rate means a lower HR for RS. Splines were fitted to evaluate the proportion, the SMR, and the HR for RS by treatment, using age as a continuous variable; knots of splines were optimized based on the C-index and the Akaike information criterion. Multivariate normal distributions were used to simulate and plot the interaction between age and survival benefit. Statistical analyses were performed using the packages compareGroups, survival, relsurv, popEPi, MatchIt, survminer, simPH, smoothHR, and maxastat in R, version 3.6.1.

Baseline characteristics and treatment trends

The clinical characteristics are presented in Table 1. Median age was 63 years old; 55.7% of the patients were > 60 years old. The male-to-female ratio was 1:1.04. 63.5% of patients had stage I disease.

Table 1

Baseline clinical characteristics of early-stage follicular lymphoma patients stratified by primary treatment (2000–2015)
		Treatments
	All patients	RT	CT	Observation	Other/unknown
Characteristic	No. (%)	No. (%)	No. (%)	No. (%)	No. (%)	P^*
Total	8803	2377	2581	2118	1727
Age, median (IQR), years	63 (53.0, 73.0)	61 (51.0, 70.0)	62 (52.0, 72.0)	65 (55.0, 76.0)	64.0 (54.0, 75.0)	< 0.001
Gender						0.001
Male	4318 (49.1)	1243 (52.3)	1263 (48.9)	1008 (47.6)	804 (46.6)
Female	4485 (50.9)	1134 (47.7)	1318 (51.1)	1110 (52.4)	923 (53.4)
Race						< 0.001
White	7861 (89.3)	2112 (88.9)	2338 (90.6)	1865 (88.1)	1546 (89.5)
Black	375 (4.3)	76 (3.2)	100 (3.9)	109 (5.1)	90 (5.2)
Other	457 (5.2)	166 (7.0)	120 (4.6)	100 (4.7)	71 (4.1)
Unrecorded	110 (1.2)	23 (1.0)	23 (0.9)	44 (2.1)	20 (1.2)
Year of diagnosis						< 0.001
2000–2005	2060 (23.4)	641 (27.0)	644 (25.0)	284 (13.4)	491 (28.4)
2005–2010	2240 (25.4)	588 (24.7)	791 (30.6)	390 (18.4)	471 (27.3)
2010–2015	4503 (51.2)	1148 (48.3)	1146 (44.4)	1444 (68.2)	765 (44.3)
Primary site^#						< 0.001
Supradiaphragmatic lymph nodes	2145 (24.4)	705 (29.7)	432 (16.7)	445 (21.0)	563 (32.6)
Subdiaphragmatic lymph nodes	2769 (31.5)	642 (27.0)	929 (36.0)	743 (35.1)	455 (26.3)
Extranodal	2252 (25.6)	779 (32.8)	506 (19.6)	469 (22.1)	498 (28.8)
Other/unknown	1637 (18.6)	251 (10.6)	714 (27.7)	461 (21.8)	211 (12.2)
Ann Arbor stage						< 0.001
I	5589 (63.5)	1874 (78.8)	1138 (44.1)	1325 (62.6)	1252 (72.5)
II	3214 (36.5)	503 (21.2)	1443 (55.9)	793 (37.4)	475 (27.5)
Grade						< 0.001
I	2468 (28.0)	592 (24.9)	675 (26.2)	613 (28.9)	588 (34.0)
II	2858 (32.5)	803 (33.8)	803 (31.1)	650 (30.7)	602 (34.9)
Unknown	3477 (39.5)	982 (41.3)	1103 (42.7)	855 (40.4)	537 (31.1)
B symptoms						< 0.001
Present	767 (8.7)	153 (6.4)	375 (14.5)	154 (7.3)	85 (4.9)
Absent	5018 (57.0)	1523 (64.1)	1289 (49.9)	1266 (59.8)	940 (54.4)
Unrecorded	3018 (34.3)	701 (29.5)	917 (35.6)	698 (33.0)	702 (40.6)
Marital status						< 0.001
Married	5442 (61.8)	1566 (65.9)	1609 (62.3)	1252 (59.1)	1015 (58.8)
Divorced/separated/widowed	1779 (20.2)	439 (18.5)	529 (20.5)	437 (20.6)	374 (21.7)
Single/unmarried/domestic partner	1029 (11.7)	258 (10.9)	319 (12.4)	245 (11.6)	207 (12.0)
Unrecorded	553 (6.3)	114 (4.8)	124 (4.8)	184 (8.7)	131 (7.6)
Insurance status						< 0.001
Insured or any medicaid	5481 (62.3)	1430 (60.2)	1530 (59.3)	1564 (73.8)	957 (55.4)
Uninsured	134 (1.5)	31 (1.3)	51 (2.0)	32 (1.5)	20 (1.2)
Unrecorded	3188 (36.2)	916 (38.5)	1000 (38.7)	522 (24.6)	750 (43.4)
End point status						< 0.001
Alive	6718 (76.3)	1947 (81.9)	1847 (71.6)	1651 (78.0)	1273 (73.7)
Lymphoma-related death	931 (10.6)	156 (6.6)	395 (15.3)	209 (9.9)	171 (9.9)
Other death	1154 (13.1)	274 (11.5)	339 (13.1)	258 (12.2)	283 (16.4)
Abbreviations: IQR, interquartile range; RT, radiotherapy; CT, chemotherapy.
^*P value of independent Kruskal-Wallis test and chi-square test; ^#Unrecorded cases were excluded before the chi-square test of primary sites.

Treatment trends by study periods and age are summarized (Supplemental Fig. 2). The proportion of patients receiving RT decreased from 38.9% in 2000 to 23.6% in 2005, and remained constant (23.7%−27.7%) between 2006 and 2015. The utilization of RT decreased with increasing age up to 80 years (66.7%−15.4%). The decreased use of RT with increasing age (34.5%−19.3%) was accompanied by the increased use of observation (18.5%−33.1%; Supplemental Table 1).

Age-dependent effect on causes of death

931 (10.6%) patients died of FL, while 1,154 (13.1%) patients died of other causes. With median follow-up of 62 months, 10-year OS and RS were 68.9% and 89.3%, respectively. Patients were at higher risk of dying of FL than other causes within 5 years, and had a higher risk of dying from other causes than FL thereafter (Fig. 1A). 10-year cumulative incidence of LRD versus non-LRD were 13.4% and 17.7%, respectively; non-LRD included deaths due to cardiovascular diseases (5.5%), other cancers (1.7%), and other causes (10.5%).

There was an age-dependent effect on the causes of death and cumulative incidence of mortality. Patients were at a continuously increasing risk of mortality as their age increased (Fig. 1B-1F). In IPTW and multivariable analyses, older age was an independent adverse risk factor for OS (HR = 5.22, 95%CI, 4.61−5.91; P < 0.001; Fig. 1B), without an apparent cutoff point. Younger patients had a lower risk of LRD and non-LRD than older patients had, but they had a higher risk of LRD than non-LRD over time (Fig. 1C/1D). Older patients had a higher risk of dying of FL than other causes within 5 years, but had a higher risk of dying from other causes than FL thereafter (Fig. 1E/1F). The 10-year cumulative incidences of LRD and non-LRD in the age-groups of ≤ 40, 41−60, 61−80, and > 80 years were 4.5% and 2.8%, 7.0% and 5.5%, 15.3% and 21.5%, and 32.7% and 53.0% (Fig. 1C-1F), respectively.

Absolute OS benefit with RT

The OS rates between RT and other treatments continuously separated over time (Fig. 2). The unadjusted 5-year and 10-year OS were, respectively, 88.9% and 77.2% for RT, versus 77.8% and 65.2% for CT (HR 1.74, 95%CI, 1.55−1.96; P < 0.001), 80.3% and 65.5% for observation (HR 1.72, 95%CI, 1.51−1.96; P < 0.001), and 82.5% and 66.5% for other/unknown treatments (HR 1.53, 95%CI, 1.34−1.74; P < 0.001; Fig. 2A). Patients receiving RT tended to have stage I disease and extranodal involvement (Table 1). After IPTW adjustment, prognostic factors were balanced between the treatment arms (Supplemental Fig. 1B). The adjusted 5-year and 10-year OS were 86.0% and 72.8% for RT, respectively, versus 78.6% and 65.1% for CT (HR 1.42, 95%CI, 1.24–1.62; P < 0.001), 81.8% and 68.5% for observation (HR 0.26, 95%CI, 1.09–1.46; P = 0.002), and 83.5% and 69.1% for other/unknown treatments (HR 1.15, 95%CI, 0.99–1.33; P = 0.070, Fig. 2B). In the multivariable analysis, RT remained an independent predictor for better OS (0.78, 95%CI, 0.70–0.87; P < 0.001; Fig. 2C).

RT with CT (combined modality therapy [CMT]) or without CT (RT alone) showed similar OS. The unadjusted and IPTW-adjusted 10-year OS were 76.2% and 76.2% for CMT, versus 73.3% (HR 0.99, 95%CI, 0.78–1.25; P = 0.927) and 75.2% (HR 1.03, 95%CI, 0.78–1.35; P = 0.846) for RT alone.

Net survival benefit of RT

To correct a background mortality effect on OS, we evaluated the net survival benefit of RT relative to the general population. The lowest SMR and the highest RS rate were observed in patients receiving RT. The SMR was 1.77 (95%CI, 1.61−1.94) for RT, which was significantly lower than 2.92 (95%CI, 2.71−3.13; P < 0.001) for CT, 2.18 (95%CI, 1.98−2.38; P < 0.001) for observation, and 2.05 (95%CI, 1.86−2.24; P < 0.001) for other/unknown treatments.

The RS rate remained constant (as high as ~ 95%) for RT over 10 years, but the RS rate progressively decreased for other treatments (Fig. 3). The 5-year and 10-year RS were 98.5% and 96.1% for RT, versus 86.8% and 82.6% for CT (HR 0.71, 95% CI, 0.62−0.82; P < 0.001), 92.1% and 90.1% for observation (0.80, 95% CI, 0.69−0.92; P = 0.002), and 95.0% and 89.9% for other/unknown treatments (HR 0.90, 95% CI, 0.78−1.03; P = 0.136; Fig. 3A). After balancing the treatment arms by IPTW and controlling for covariates by multivariable analysis, RT was associated with a better RS (HR 0.78, 95%CI, 0.70−0.88; P < 0.001; Fig. 3B). Consistently, the observed death rate with RT was closer to the diagonal line, indicating a better RS for RT than for CT, observation, or other/unknown treatments. There was no significant difference in 10-year RS between RT alone and CMT (94.4% vs. 93.7%; HR 1.02, 95%CI, 0.78–1.33; P = 0.891).

Influence of age on the survival benefit of RT

Influence of age as a continuous variable on RS and SMR was examined. RT versus non-RT was associated with better RS (HR 0.78, 95%CI, 0.70−0.88; P < 0.001; Fig. 4A) and OS (HR 0.60, 95%CI, 0.54−0.67; P < 0.001). No significant interaction between age and RT versus non-RT was found for RS (P_interaction=0.305) and OS (P_interaction=0.272), indicating similar survival benefits for RT across all-ages patients. In natural spline analysis, the SMR for RT was lower (approaching 1) than that for CT or observation at all-ages up to 90 years, and that for other/unknown treatments after 50 years old (Fig. 4B).

Time-dependent effect on survival benefits of RT

The survival benefits of RT vs. non-RT changed rapidly within 10 years, but became relatively stable thereafter (Fig. 5). In this longitudinal assessment, HRs for OS and RS increased from 0.589 and 0.600 at 1 year to 0.755 and 0.741 at 10 years, and maintained thereafter. The finding indicated the necessity of 10-year follow-up to identify the survival benefit.

Sensitivity analyses

Sensitivity analyses showed that the OS and RS benefits of RT versus non-RT were robust, regardless of sex, race, stage, grade, primary site, B symptoms, or time periods (Supplemental Fig. 3), and were not affected by medical insurance status or additional CT (Supplemental Fig. 4).

This is the first study to quantitatively evaluate the influence of age on long-term mortality and net survival benefit of RT for early-stage FL. Although the cumulative incidence and pattern of LRD and non-LRD varied in an age-dependent manner, RT was associated with increased benefits of OS and RS over time. The 10-year OS and RS rates of 77.2% and 96.1% and SMR of 1.77 for RT were significantly better than CT, observation, or other/unknown treatments. RT versus non-RT was associated with better RS and SMR, regardless of age. The findings highlight the important role of RT in early-stage FL patients.

We found a linear pattern of increased mortality risk without an apparent age cutoff demarcating an OS difference in early-stage patients. The patterns and incidences of LRD and background mortality were not the same in all age-groups; patients over 60 years were at a higher risk of dying of other diseases than FL beyond 5 years of diagnosis. RT was associated with significantly better long-term OS and RS than CT, observation, or other/unknown treatments did, with an absolute gain of ~ 10% in 10-year OS and RS rates. In previous studies, the reported OS rates with RT were favorable at 5 years (85–97%), but decreased to 60–80% at 10 years.^5–15 As expected, we observed a persistent decrease in OS rates over time regardless of treatment. The most interesting and somewhat unexpected result of our analysis is that the RS rate of patients with RT remained constant (as high as ~ 95%) over 10 years, whereas patients with CT, observation, or other/unknown treatments had initially lower, continuously decreased RS rates. Given the 10-year RS rate of 96.1% and SMR of 1.77, the life expectancy of early-stage patients receiving RT was favorable. The constantly high RS rates over 10 years support the idea that most patients can be cured with RT and they dispel the notion that early-stage FL is incurable.

We confirmed, for the first time, that patients’ age, as a continuous variable, was an independent prognostic factor, but this might not be a contraindication for RT. RT versus non-RT was associated with better OS/RS and lower SMR in all age groups, after balancing treatment selection bias and adjusting for covariates. The beneficial effect of RT among patients of almost all ages indicates there is no apparent cutoff age to guide RT. As low RT dose of 24 Gy is well tolerated,^32–34 with only a 0.7% incidence of acute grade 3 to 4 toxicities at week 12,³⁴ the choice of curative RT for older patients still depends on individual comorbid risk factors, without considering older age as a risk factor. The evidence of long-term RS benefit of RT vs. non-RT approaches across the age spectrum should be communicated to the patient at each individual treatment decision.

Multiple studies with large sample sizes (n > 100) have demonstrated that RT provides excellent locoregional control (~ 95%) and long-term OS in early-stage FL.^5–12 Earlier comparative studies from the SEER (1973–2004) and National Cancer Data Base (1998–2012) have confirmed superior 10-year OS or DSS for RT than for CT or observation.^{34, 35} Despite this observation, only 27.0% of patients in the present study received initial RT. The decreased use of RT was simultaneously accompanied by the increased use of observation after the publication of the National LymphoCare Study (NLCS) in 2009 and 2012.^{3, 18} In addition, other studies reported satisfactory outcomes with CT, observation, immunotherapy, and immunochemotherapy. However, these studies were limited by their small sample size (n < 100),^{18–22, 36} short follow-up time (< 5 years),^{18, 21, 36} or lack of a comparative arm.²² Given the median survival time of ~ 10 years and high risk of non-LRD beyond 5 years in elderly patients, studies need to have a large sample size with an adequate number of patients at risk at 10 years (e.g., n > 200 in each treatment in this study), and long follow-ups to be able to show statistically significant survival differences between treatments. Previous studies with a small number of patients and few events have not been able to effectively analyze the value of non-RT approaches.^{18–22, 36} Moreover, we found the OS rates in early-stage patients decreased over time regardless of treatment, however, the OS differences persistently widened between RT and non-RT approaches over 10 years. Interestingly, RS rates remained as high as ~ 95% for RT over 10 years, but RS rates for other treatments continuously decreased. This time-dependent effect on OS and RS benefits of RT vs non-RT indicates the need for long follow-ups to define the greater survival difference between treatments. The 5-year survival as the primary benchmark of treatment success does not adequately reflect the continuously increasing risk of mortality experienced throughout the lifespan in indolent FL; and thereby any treatment strategies resulted in a similarly favorable 5-year OS.^18–22

This study has strengths. The large number of patients allowed us to effectively compare the long-term survival difference between treatments and evaluate RT benefit in early-stage FL. The RS and SMR benefits of RT represent valid endpoints for evaluating how an indolent FL affects life expectancy, and it is in some ways better than OS and DSS endpoints for quantitative evaluation of RT curability, particularly for older patients at higher competing risk of other deaths. Moreover, the finding of a time-dependent survival benefit of RT, regardless of age, is unique in early-stage FL.

This study also has several limitations. First, information on immunotherapy was not available. A randomized trial reported a significantly improved progression-free survival (PFS) but not OS, for a combination of CT or immunochemotherapy with standard RT.²³ Adding immunotherapy to RT may provide a unique combination for first-line therapy in early-stage FL.^{23, 37, 38} Another phase 3 trial comparing RT and RT with concurrent and maintenance rituximab is ongoing, with an appropriate primary endpoint of 10-year PFS (ClinicalTrials.gov Identifier: NCT01473628). Second, as FL staging varied during study periods, the treatment efficacy and prognosis might change accordingly. Because of improved selection and more accurate RT planning,^{12, 18, 39} incorporation of positron emission tomography (PET) staging into RT might have improved long-term outcomes.¹² Third, other unknown confounders, such as performance status and comorbidities, that might affect treatment bias and outcomes in comparisons between treatments were not collected, and hence, not accounted for in the analysis. We believe that further prospective study is needed to validate the findings of this SEER data analysis and explore the incorporation of RT with effective systemic therapy.

In summary, clinicians should be aware of the role of RT in maintaining higher long-term OS and RS and lower SMR regardless of age. We still consider RT to be a standard of care for early-stage FL in the modern era.

SEER, U.S., ICD, CT, RT, IPTW, RS, SMR, HR, RD

SUPPORT

This work was supported by grants from the “National Key Research and Development of China (2020AAA0109504)”. The funding sources had no influence on the design, conduct, or reporting of the study.

AUTHOR CONTRIBUTIONS

Z.Q.Z. and L.Y.X. conceived and designed the study. L.Y. and W.Y. collected and analyzed the data. L.Y., Z.Q.Z., and L.Y.X. wrote the manuscript with contributions from all the authors, who also interpreted the data, and read, commented on, and approved the final version of the manuscript.

All the authors are accountable for all aspects of the work.

Declaration of Competing Interest

The authors declare that they have no competing interests.

Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA: a cancer journal for clinicians 2016 Nov 12; 66(6): 443–459.
Sun J, Yang Q, Lu Z, He M, Gao L, Zhu M, et al. Distribution of lymphoid neoplasms in China: analysis of 4,638 cases according to the World Health Organization classification. American journal of clinical pathology 2012 Sep; 138(3): 429–434.
Friedberg JW, Taylor MD, Cerhan JR, Flowers CR, Dillon H, Farber CM, et al. Follicular lymphoma in the United States: first report of the national LymphoCare study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2009 Mar 10; 27(8): 1202–1208.
Dinnessen MAW, van der Poel MWM, Tonino SH, Visser O, Blijlevens NMA, de Jong D, et al. Stage-specific trends in primary therapy and survival in follicular lymphoma: a nationwide population-based analysis in the Netherlands, 1989–2016. Leukemia 2021 Jun; 35(6): 1683–1695.
Gospodarowicz MK, Bush RS, Brown TC, Chua T. Prognostic factors in nodular lymphomas: a multivariate analysis based on the Princess Margaret Hospital experience. International journal of radiation oncology, biology, physics 1984 Apr; 10(4): 489–497.
Denham JW, Denham E, Dear KB, Hudson GV. The follicular non-Hodgkin's lymphomas–I. The possibility of cure. European journal of cancer (Oxford, England: 1990) 1996 Mar; 32a(3): 470–479.
Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 1996 Apr; 14(4): 1282–1290.
Seymour JF, Pro B, Fuller LM, Manning JT, Hagemeister FB, Romaguera J, et al. Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2003 Jun 1; 21(11): 2115–2122.
Guadagnolo BA, Li S, Neuberg D, Ng A, Hua L, Silver B, et al. Long-term outcome and mortality trends in early-stage, Grade 1–2 follicular lymphoma treated with radiation therapy. International journal of radiation oncology, biology, physics 2006 Mar 1; 64(3): 928–934.
Campbell BA, Voss N, Woods R, Gascoyne RD, Morris J, Pickles T, et al. Long-term outcomes for patients with limited stage follicular lymphoma: involved regional radiotherapy versus involved node radiotherapy. Cancer 2010 Aug 15; 116(16): 3797–3806.
Lo AC, Campbell BA, Pickles T, Aquino-Parsons C, Sehn LH, Connors JM, et al. Long-term outcomes for patients with limited-stage follicular lymphoma: update of a population-based study. Blood 2020 Aug 20; 136(8): 1006–1010.
Brady JL, Binkley MS, Hajj C, Chelius M, Chau K, Balogh A, et al. Definitive radiotherapy for localized follicular lymphoma staged by (18)F-FDG PET-CT: a collaborative study by ILROG. Blood 2019 Jan 17; 133(3): 237–245.
Pendlebury S, el Awadi M, Ashley S, Brada M, Horwich A. Radiotherapy results in early stage low grade nodal non-Hodgkin's lymphoma. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology 1995 Sep; 36(3): 167–171.
Wilder RB, Jones D, Tucker SL, Fuller LM, Ha CS, McLaughlin P, et al. Long-term results with radiotherapy for Stage I-II follicular lymphomas. International journal of radiation oncology, biology, physics 2001 Dec 1; 51(5): 1219–1227.
Ng SP, Khor R, Bressel M, MacManus M, Seymour JF, Hicks RJ, et al. Outcome of patients with early-stage follicular lymphoma staged with (18)F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) and treated with radiotherapy alone. European journal of nuclear medicine and molecular imaging 2019 Jan; 46(1): 80–86.
NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas V4.2021. https://wwwnccnorg/professionals/physician_gls/pdf/b-cellpdf.
Dreyling M, Ghielmini M, Rule S, Salles G, Ladetto M, Tonino SH, et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology: official journal of the European Society for Medical Oncology 2021 Mar; 32(3): 298–308.
Friedberg JW, Byrtek M, Link BK, Flowers C, Taylor M, Hainsworth J, et al. Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2012 Sep 20; 30(27): 3368–3375.
Barzenje DA, Cvancarova Småstuen M, Liestøl K, Fosså A, Delabie J, Kolstad A, et al. Radiotherapy Compared to Other Strategies in the Treatment of Stage I/II Follicular Lymphoma: A Study of 404 Patients with a Median Follow-Up of 15 Years. PloS one 2015; 10(7): e0131158.
Sancho JM, García O, Mercadal S, Pomares H, Fernández-Alvarez R, González-Barca E, et al. The long term follow-up of early stage follicular lymphoma treated with radiotherapy, chemotherapy or combined modality treatment. Leukemia research 2015 Aug; 39(8): 853–858.
Tobin JWD, Rule G, Colvin K, Calvente L, Hodgson D, Bell S, et al. Outcomes of stage I/II follicular lymphoma in the PET era: an international study from the Australian Lymphoma Alliance. Blood advances 2019 Oct 8; 3(19): 2804–2811.
Advani R, Rosenberg SA, Horning SJ. Stage I and II follicular non-Hodgkin's lymphoma: long-term follow-up of no initial therapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2004 Apr 15; 22(8): 1454–1459.
MacManus M, Fisher R, Roos D, O'Brien P, Macann A, Davis S, et al. Randomized Trial of Systemic Therapy After Involved-Field Radiotherapy in Patients With Early-Stage Follicular Lymphoma: TROG 99.03. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2018 Oct 10; 36(29): 2918–2925.
Pugh TJ, Ballonoff A, Newman F, Rabinovitch R. Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a Surveillance, Epidemiology, and End Results database analysis. Cancer 2010 Aug 15; 116(16): 3843–3851.
SEER Registries: About SEER. https://seer.cancer.gov/about/.
Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 18 Regs Custom Data (with additional treatment fields), Nov 2018 Sub (1975–2016 varying) - Linked To County Attributes - Total U.S., 1969–2017 Counties, National Cancer Institute, DCCPS, Surveillance.
McCaffrey DF, Griffin BA, Almirall D, Slaughter ME, Ramchand R, Burgette LF. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Statistics in medicine 2013 Aug 30; 32(19): 3388–3414.
Ederer F, Axtell LM, Cutler SJ. The relative survival rate: a statistical methodology. National Cancer Institute monograph 1961 Sep; 6: 101–121.
Perme MP, Stare J, Estève J. On estimation in relative survival. Biometrics 2012 Mar; 68(1): 113–120.
Pohar M, Stare J. Making relative survival analysis relatively easy. Computers in biology and medicine 2007 Dec; 37(12): 1741–1749.
Stare J, Henderson R, Pohar M. An individual measure of relative survival. 2005; 54(1): 115–126.
Lowry L, Smith P, Qian W, Falk S, Benstead K, Illidge T, et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology 2011 Jul; 100(1): 86–92.
Hoskin PJ, Kirkwood AA, Popova B, Smith P, Robinson M, Gallop-Evans E, et al. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. The Lancet Oncology 2014 Apr; 15(4): 457–463.
Hoskin P, Popova B, Schofield O, Brammer C, Robinson M, Brunt AM, et al. 4 Gy versus 24 Gy radiotherapy for follicular and marginal zone lymphoma (FoRT): long-term follow-up of a multicentre, randomised, phase 3, non-inferiority trial. The Lancet Oncology 2021 Mar; 22(3): 332–340.
Vargo JA, Gill BS, Balasubramani GK, Beriwal S. What is the optimal management of early-stage low-grade follicular lymphoma in the modern era? Cancer 2015 Sep 15; 121(18): 3325–3334.
Shah BK, Ghimire KB. Survival in adult stage I follicular lymphoma treated with and without radiotherapy - a population-based study. Acta oncologica (Stockholm, Sweden) 2015 Jun; 54(6): 951–953.
Ruella M, Filippi AR, Bruna R, Di Russo A, Magni M, Caracciolo D, et al. Addition of Rituximab to Involved-Field Radiation Therapy Prolongs Progression-free Survival in Stage I-II Follicular Lymphoma: Results of a Multicenter Study. International journal of radiation oncology, biology, physics 2016 Mar 15; 94(4): 783–791.
Herfarth K, Borchmann P, Schnaidt S, Hohloch K, Budach V, Engelhard M, et al. Rituximab With Involved Field Irradiation for Early-stage Nodal Follicular Lymphoma: Results of the MIR Study. HemaSphere 2018 Dec; 2(6): e160.
Wirth A, Foo M, Seymour JF, Macmanus MP, Hicks RJ. Impact of [18f] fluorodeoxyglucose positron emission tomography on staging and management of early-stage follicular non-hodgkin lymphoma. International journal of radiation oncology, biology, physics 2008 May 1; 71(1): 213–219.

There is NO conflict of interest to disclose.

Impact of age on long-term mortality and net survival benefit of radiotherapy for early-stage follicular lymphoma from the SEER database (2000-2015)

Status:

Version 1

Abstract

Figures

Highlights

Introduction

Methods

Data collection and eligibility criteria

Definitions and treatment

Endpoints and statistical analysis

Results

Baseline characteristics and treatment trends

Age-dependent effect on causes of death

Absolute OS benefit with RT

Net survival benefit of RT

Influence of age on the survival benefit of RT

Time-dependent effect on survival benefits of RT

Sensitivity analyses

Discussion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1