Survival in adult stage I follicular lymphoma treated with and without radiotherapy – a population-based study

To the Editor,

Follicular lymphoma (FL) is the most common low grade lymphoma. Stage I FL is uncommon [1]. Current treatment options for stage I FL include observation, radiotherapy (RT) and combined modality therapy (CMT) with chemotherapy plus RT [1]. The treatment recommendations are not based on any randomized clinical trials. Previous studies have shown 40–50% 10-year disease-free survival with RT [2,3]. A retrospective study by Adwani et al. showed that survival rates of patients with early stage FL with deferred therapy were comparable to patients who received immediate treatment [4]. In this study, more than half of the patients did not require treatment at a median of six years or more. Seymour et al. published a prospective study evaluating CMT in the treatment of stage I–II indolent lymphoma. In this study, 102 patients with stage I and II indolent non-Hodgkin lymphoma were evaluated [5]. The majority of the patients (85) had FL. The rates of disease control with CMT were higher compared to previously reported rates with involved field RT. Interestingly, patients with bulky disease (≥ 5 cm) had borderline superior survival. National Comprehensive Cancer Network lists RT as a preferred treatment option for patients with localized FL [6].

We analyzed survival rates of stage I FL patients from Surveillance, Epidemiology and End Results (SEER) database treated with or without RT.

We selected patients with stage I FL diagnosed during 1992–2006 from SEER 18 database. The SEER 18 database (Nov 2012 submission) is a population-based cancer database sponsored by the National Cancer Institute. The SEER 18 database include following registries: San Francisco-Oakland SMSA, Connecticut, Detroit (Metropolitan), Hawaii, Iowa, New Mexico, Seattle (Puget Sound), Utah, Atlanta (Metropolitan), San Jose-Monterey, Los Angeles, Alaska Natives, Rural Georgia, Greater California, Kentucky, Louisiana, New Jersey and Greater Georgia.

We included patients with stage I FL as the first primary malignancy. We excluded the cases that were diagnosed at autopsy, from death certificate only, or were alive without survival data. We categorized patients into several cohorts based on race (white, black or others), gender (male or female), age groups (≤ 60 or > 60).

We analyzed one- and five-year relative survival (RS) rates using SEER*stat program. We used Z test to compare RS rates of patients treated with or without RT by age (18–60 years and > 60 years) and sex.

There were 28 196 pathologically confirmed FL patients in SEER 18 database during 1992–2006. Of 8240 patients with stage I disease, 6675 met entry criteria (Figure 1).

Figure 1. Consort diagram.

The median age of study patients was 64 years (range 18–98 years). A total of 49% of patients were men. Majority of the patients were white (90.6%). Majority of the patients (62.80%) did not receive RT. The one- and five-year RS rates of the patients were 97.5 ± 0.3% and 91.5 ± 0.6%, respectively.

The one- and five-year RS in patients were significantly higher for patients who received RT compared to those who did not receive RT – 99.9 ± 0.3% versus 96 ± 0.4% (p-value < 0.001) at one year and 97.3 ± 0.8% versus 88.1 ± 0.8% (p-value < 0.001) at five years. The survival rates were significantly higher in the RT group compared to no RT group for younger patients (one year: 99.5 ± 0.3% vs. 98.6 ± 0.3%; p-value = 0.03 and five years: 96.9 ± 0.8% vs. 92.6 ± 0.8%; p-value < 0.001) and older patients (one year: 100% vs. 94.3 ± 0.6%; p-value < 0.001 and five years: 97.5 ± 1.4% vs. 84.8 ± 1.2%; p-value < 0.001).

On subgroup analysis, one- and five-year RS rates were significantly higher in the RT group compared to no RT group for all cohorts (Table I).

Table I. Relative survival rates in follicular lymphoma.

			None			Beam radiation
Cohort	Age (years)	Survival time (months)	N	Relative Survival %	SE	N	Relative Survival %	SE	Z-value/p-value
Male and female	> 18	12	4192	96.00%	0.40%	2483	99.90%	0.30%	7.670/< 0.001
		60		88.10%	0.80%		97.30%	0.80%	8.354/< 0.001
	18–60	12	1652	98.60%	0.30%	1240	99.50%	0.30%	2.154/0.03
		60		92.60%	0.80%		96.90%	0.70%	4.257/< 0.001
	> 61	12	2540	94.30%	0.60%	1243	100.00%	0.00%	6.993/< 0.001
		60		84.80%	1.20%		97.50%	1.40%	7.091/< 0.001
Male	> 18	12	2016	95.60%	0.60%	1273	100.00%	0.00%	6.564/< 0.001
		60		86.50%	1.10%		98.50%	1.00%	7.325/< 0.001
Female	> 18	12	2176	96.40%	0.50%	1210	99.50%	0.40%	3.785/< 0.001
		60		89.50%	1.00%		95.90%	1.10%	3.923/< 0.001

N, number of patients; SE, standard error.

Patients with stage I FL have excellent prognosis. Our study indicates that less than half of the patients diagnosed with stage I FL receive radiation therapy. We also showed that patients treated with RT did have significantly superior survival rates compared to those who did not receive RT. The SEER programs maintain high quality data with case ascertainment of 98% [7]. SEER 18 database covers 27.8% of the US population [8], and is large enough to evaluate treatments. The results from SEER database are generalizable because they represent data from real-world clinical practice [9]. Some patients may not require treatment for long periods of time, based on the findings of the study by Adwani et al [4]. Unfortunately, we do not have reliable biomarkers to identify which patients might benefit from immediate treatment. More research is needed to answer this.

Similar to our findings, a low rate of RT utilization was observed in the National Lymphocare study [10]. The National Lymphocare study analyzed 471 patients with stage I FL. Among them, only 27% of the patients received RT. These findings suggest that utilization of RT for treatment of stage I FL is not widespread. This is despite the fact that current National Comprehensive Cancer Network guidelines list RT as the preferred treatment option for patients with localized FL [6]. Several factors including patient preference and physician bias may be responsible for this.

Strengths of our study include the large number of patients from a large geographic area, and long-term follow-up. There were several limitations. It is an observational study. SEER database does not have information on the chemotherapy used, co-morbid conditions, social habits, prognostic information (lactate dehydrogenase level, bulk of the tumor, blood counts).

In conclusion, this study showed that RS rates of stage I FL patients receiving RT were significantly better compared to those who did not receive RT.

Acknowledgments

The authors thank Dr. Katrina Rolen for critical review/editing of this manuscript.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.