Long-term outcomes for patients with limited stage follicular lymphoma

Involved regional radiotherapy versus involved node radiotherapy

Authors

Errata

This article is corrected by:

  1. Errata: Erratum: Long-term outcomes for patients with limited stage follicular lymphoma Volume 117, Issue 5, 1105, Article first published online: 19 October 2010

  • Presented in part at the Joint 15th Congress of the European Cancer Organization and 34th Congress of the European Society for Medical Oncology, Berlin, Germany, September 20-24, 2009.

Abstract

BACKGROUND:

Given the indolent behavior of follicular lymphoma (FL), it is controversial whether limited stage FL can be cured using radiotherapy (RT). Furthermore, the optimal RT field size is unclear. The authors of this report investigated the long-term outcomes of patients with limited stage FL who received RT alone and studied the impact of reducing the RT field size from involved regional RT (IRRT) to involved node RT with margins up to 5 cm (INRT≤5 cm).

METHODS:

Eligible patients had limited stage, grade 1 through 3A FL diagnosed between 1986 and 2006 and treated were with curative-intent RT alone. IRRT encompassed the involved lymph node group plus ≥1 adjacent, uninvolved lymph node group(s). INRT≤5 cm covered the involved lymph node(s) with margins ≤5 cm.

RESULTS:

In total, 237 patients were identified (median follow-up, 7.3 years) and included 48% men, 54% aged >60 years, stage IA disease in 76% of patients, elevated lactate dehydrogenase (LDH) in 7% of patients, grade 3A tumors in 12% of patients, and lymph node size ≥5 cm in 19% of patients. The 2 RT groups were IRRT (142 patients; 60%) and INRT≤5 cm (95 patients; 40%). At 10 years, the progression-free survival (PFS) rate was 49%, and the overall survival (OS) rate was 66%. Only 2 patients developed recurrent disease beyond 10 years. The most common pattern of first failure was a distant recurrence only, which developed in 38% of patients who received IRRT and in 32% of patients who received INRT≤5 cm. After INRT≤5 cm, 1% of patients had a regional-only recurrence. Significant risk factors for PFS were lymph nodes ≥5 cm (P = .008) and male gender (P = .042). Risk factors for OS were age >60 years (P < .001), elevated LDH (P = .007), lymph nodes ≥5 cm (P = .016), and grade 3A tumors (P = .036). RT field size did not have an impact on PFS or OS.

CONCLUSIONS:

Disease recurrence after 10 years was uncommon in patients who had limited stage FL, suggesting that a cure is possible. Reducing RT fields to INRT≤5 cm did not compromise long-term outcomes. Cancer 2010. © 2010 American Cancer Society.

Follicular lymphoma (FL) long has been recognized as having an indolent natural history with good long-term survival rates despite a high risk of recurrence. Approximately 25% of patients present with stage I or II disease, and their 10-year overall survival (OS) rate ranges from 52% to 79%.1-8 Retrospective series support the use of primary radiotherapy (RT) for patients who have limited stage FL and have demonstrated that approximately 41% to 53% of patients are free from recurrent disease at 10 years.1-4 However, there is limited information regarding the recurrence rate beyond 10 years and whether a clear plateau is achieved.4, 5, 8 Thus, whether limited stage FL can be truly “cured” remains the subject of controversy.

From the available published data, guidelines from the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) recommend primary RT for limited stage FL with curative intent.9-11 However, despite the evidence and these international guidelines, RT remains worrisomely under used in the treatment of limited stage FL.12

There is no universal consensus for a “standard” RT field size in the treatment of limited stage FL. In current clinical practice, involved field RT and involved regional RT (IRRT) fields are more commonly used.13 Yet to be defined is the ideal RT field size that is sufficient to optimize disease control while minimizing toxicity. The objectives of the current study were 1) to evaluate the long-term outcome of a population-based cohort of patients with FL who received RT alone with curative intent at the British Columbia Cancer Agency (BCCA) and 2) to evaluate whether a reduction in RT field size, from IRRT to involved lymph node RT (INRT), had an impact on the patterns of recurrence in this population.

MATERIALS AND METHODS

Patient Identification

The BCCA Lymphoid Cancer Database was used to identify all patients who were diagnosed with limited stage FL between January 1, 1986 and December 31, 2006. Limited stage was defined as Ann Arbor stage IA or IIA, nonbulky (<10 cm) disease with or without limited local extranodal extension. Eligible patients had received first-line RT alone that encompassed all known sites of disease with curative intent. Patients were excluded if their disease extended to >3 contiguous lymph node groups: These patients were typically managed with combined chemotherapy and RT if they were symptomatic, or with observation if they were asymptomatic. All tumors were biopsy-proven and were reviewed by a BCCA hematopathologist. Diagnoses were based on the standard, era-specific lymphoma classification systems and were restricted to those subgroups now categorized as FL according to World Health Organization (WHO) criteria. Patients with grade 3B FL were excluded from this study. All patients were staged with history, physical examination, chest radiograph, abdominal and pelvic computed tomography scans, bone marrow biopsy, and selected additional imaging as indicated for the assessment of localized symptoms. Fluorine-18 2-deoxy-D-glucose-positron emission tomography was not used for staging or RT planning. Serum lactate dehydrogenase (LDH) and complete blood counts also were measured at diagnosis. The medical records were reviewed for details on RT planning and sites of recurrence. Approval was obtained from the University of British Columbia–BCCA Research Ethics Board.

Radiotherapy for Limited Stage Follicular Lymphoma

At the BCCA, the Lymphoma Tumor Group is a multidisciplinary team, and management policies are driven by protocol. At the time of diagnosis, patients with grade 1 to 3A, limited stage FL are treated with RT alone according to prospectively defined guidelines. At a minimum, the RT field encompasses all sites of FL. From January 1986 to February 1998, the treatment policy was IRRT, which was defined as RT fields to encompass the involved lymph node group(s) plus prophylactic RT to at least 1 adjacent, uninvolved lymph node group. In March 1998, the RT policy was changed to include the involved lymph nodes only. The gross target volume (GTV) encompassed the sites of known disease. To account for physiologic movement and interfraction setup variation, margins up to 5 cm were added to form the planning target volume (PTV). Therefore, the total margin from GTV to PTV varied, depending on the anatomic site of the involved lymph nodes. We call this volume “involved lymph node RT with margins up to 5 cm” (INRT≤5 cm) to distinguish it from other published definitions of INRT.

All patients underwent treatment simulation in the treatment position. Because of the early treatment era, computed tomography simulation and 3-dimensional conformal RT were not mandatory requirements for this study. Radiotherapy was fractionated into 5 fractions per week, and patients received a minimum dose of 20 Gray (Gy). Multiple RT beams were used, and all beams were delivered daily. Portal imaging was performed for quality assurance.

Definitions of Treatment Failure

Treatment failure was defined as any recurrence of non-Hodgkin lymphoma. The first sites of recurrence were recorded as either infield, regional. or distant from the RT field. Infield failure was defined as a recurrence within the RT portal. Distant failure was defined as all other sites of recurrence outside the RT field. Regional failure was considered a subtype of distant failure and was applicable only to the INRT≤5 cm group. Regional failure was defined as a recurrence outside of the INRT≤5 cm field but within the involved region that would otherwise have been treated if IRRT had been used.

Statistical Analysis

All patients who commenced RT were included in the analyses with the intention to treat. Patients were followed to the closeout date of March 10, 2009. Progression-free survival (PFS) was determined from the date of diagnosis to the date of treatment failure; patients who died in sustained remission were censored at the date of death. Disease-specific survival (DSS) was measured from the date of diagnosis to the date of death from lymphoma; patients were censored at the date of either last follow-up or death from other causes or from treatment toxicity. OS was measured from the date of diagnosis to the date of death from any cause. The Kaplan-Meier method14, 15 was used for survival estimates, and comparisons were made using the log-rank test. Univariate analyses were performed to evaluate the impact of prognostic factors on survival. The Pearson chi-square test was used to compare the characteristics of patients in the IRRT and INRT≤5 cm groups, and the distribution of age was compared across these groups using the Mann-Whitney U test.

The prognostic factors that were chosen prospectively for the current analyses were age, sex, performance status, WHO grade, Ann Arbor stage, lymph node size, extranodal disease, serum LDH, and type of RT field. Multivariate analyses were performed using a Cox proportional-hazards regression analysis and the stepwise backward procedure to identify independent prognostic factors. The removal and entry levels of significance were P = .05 and P = .10, respectively. Patients who had unknown values for any prognostic factor were excluded from the multivariate analysis.

The multivariate analyses were repeated to assess the significance of RT field size while adjusting for other prognostic factors; this was performed again using a Cox proportional-hazards regression model. The initial model included all terms, and the covariates with the highest P values were eliminated progressively until all P values were <.1 except for the type of RT field, which was retained in the analysis at all steps to assess its significance. Thus, this analysis differs from the aforementioned multivariate analysis in that it guarantees that the RT field term will be retained in the final model.

RESULTS

Patient Characteristics

In the BCCA Lymphoid Cancer Database, 282 consecutive patients were identified who had a diagnosis of limited stage FL. Reasons for exclusion were a combination of chemotherapy and RT as part of the initial treatment in 31 patients, observation alone as the initial management strategy in 2 patients, palliative-intent RT in 8 patients, synchronous diffuse large B-cell lymphoma in 1 patient, synchronous Hodgkin lymphoma in 1 patient, and synchronous nonsmall cell lung cancer in 1 patient. No patients were treated with chemotherapy alone.

From this group, 237 eligible patients were identified who had limited stage FL and who received RT alone with curative intent. The median age was 61 years (range, 29-89 years), 48% of patients were men, and 75% of patients had a performance status of 0. Most patients had stage IA disease (76%), and 23% had extranodal involvement. According to the WHO classification, 54% of patients had grade 1 FL, 34% had grade 2 FL, and 12% had grade 3A FL. Thus, the distribution of patients according to the 2 RT groups was 142 patients in the IRRT group (60%) and 95 patients in the INRT≤5 cm group (40%) (Table 1).

Table 1. Patient Characteristics at Diagnosis
CharacteristicNo. of Patients (%) 
Total, n=237IRRT, n=142INRT≤5 cm, n=95P
  • IRRT indicates involved regional radiotherapy; INRT≤5 cm, involved node radiotherapy with margins up to 5 cm; LDH, lactate dehydrogenase; Gy, grays.

  • a

    P value indicates a statistically significant difference.

Median age, y615964.021a
Age >60 y128 (54)70 (49)58 (61).075
Sex, men113 (48)68 (48)45 (47).938
Performance state, ECOG   .700
 0179 (75)106 (75)73 (77) 
 1-260 (25)36 (25)22 (23) 
Grade   .948
 1129 (54)78 (55)51 (54) 
 280 (34)48 (34)32 (34) 
 3A28 (12)16 (11)12 (13) 
Stage   .004a
 IA179 (76)98 (69)81 (85) 
 IIA58 (24)44 (31)14 (15) 
Nodal size   .001a
 Completely excised18 (8)18 (13)0 (0) 
 <5 cm173 (73)98 (69)75 (79) 
 ≥5 cm46 (19)26 (18)20 (21) 
Extranodal disease55 (23)16 (11)39 (41)<.001a
Serum LDH level   .130
 Elevated16 (7)7 (5)9 (10) 
 ≤Normal210 (89)132 (95)78 (90) 
 Unknown11 (5)38 
Radiotherapy dose   <.001a
 30 Gy in 10 fractions78 (33)49 (35)29 (31) 
 35 Gy in 20 fractions79 (33)59 (42)20 (21) 
 Other80 (34)34 (24)46 (48) 

Comparing the 2 RT groups, extranodal involvement (P < .001) and lymph node size ≥5 cm (P = .001) were more frequent in the INRT≤5 cm group. However, stage II disease was more common in the IRRT group (P = .004) (Table 1).

The median follow-up for the patients who remained alive was 88 months (range, 22-262 months). Nine patients were lost to follow-up after 30 to 111 months. One patient failed to complete the planned treatment because of patient refusal and received only 9.75 Gy in 3 fractions of INRT≤5 cm.

Radiotherapy Dose

Radiotherapy was prescribed to total doses of 20 to 40 Gy. Larger RT fields were treated with 1.5 to 2 Gy per fraction. At the discretion of the treating physician, smaller RT fields were treated with 3 to 5 Gy per fraction. The most common fractionation schedules used were 35 Gy in 20 fractions (79 patients; 33%) and 30 Gy in 10 fractions (78 patients; 33%) (Table 1).

Overall Survival, Disease-Specific Survival, and Progression-Free Survival

The median PFS was 51 months, and the median OS was 80 months (Fig. 1a). The median DSS has not yet been reached. The OS rate was 85% at 5 years, 66% at 10 years, and 46% at 15 years. The DSS rate was 92% at 5 years, 82% at 10 years, 68% at 15 years, and 62% at 20 years. The PFS rate was 66% at 5 years, 49% at 10 years, 43% at 15 years.

Figure 1.

These Kaplan-Meier curves illustrate (a) overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS); (b) OS according to radiotherapy field size on univariate analysis for involved regional radiotherapy (IRRT) and involved lymph node radiotherapy (INRT); (c) DSS according to radiotherapy field size on univariate analysis; and (d) PFS according to radiotherapy field size on univariate analysis.

Patterns of Failure

The median time to recurrence was 34 months (range, 5-175 months). In total, 98 patients developed recurrent FL or transformed lymphoma, constituting an overall recurrence rate of 41%. Infield-only recurrences were infrequent and developed in 1% of all patients. The most common pattern of failure was distant recurrence without infield recurrence, which developed in 35% of all patients (Table 2). By definition, regional lymph nodes were not included in the INRT≤5 cm field, and regional-only recurrences were infrequent (1%). Compared with the IRRT group, the smaller RT fields in the INRT≤5 cm group did not result in an increased risk of distant failure without infield or regional recurrence (38% vs 32%, respectively).

Table 2. Patterns of Failure
 No. of Patients (%)
Total, n=237IRRT, n=142INRT≤5 cm, n=95
  1. IRRT indicates involved regional radiotherapy; INRT≤5 cm, involved node radiotherapy with margins up to 5 cm.

Total no. of recurrences98 (41)65 (45)32 (35)
Infield relapse only3 (1)2 (1)1 (1)
Distant relapse without infield relapse84 (35)54 (38)30 (32)
 Distant only825426
 Regional only11
 Regional and distant11
Distant and infield recurrence11 (5)9 (6)2 (2)

Radiotherapy Field Size and Risk Factors for Survival

The univariate analyses are presented in Table 3. Comparing the 2 RT groups in univariate analysis, OS was inferior in the INRT≤5 cm group (71% vs 59% at 10 years; P = .013) (Fig. 1b). However, there was no statistically significant difference in DSS (P = .142) or in PFS (P = .498) for patients who received IRRT (Fig. 1c) compared with patients who received INRT≤5 cm (Fig. 1d)

Table 3. Univariate Analyses of Progression-Free Survival, Disease-Specific Survival, and Overall Survival
VariableTotal No. (%), n=23710-Year PFS10-Year DSS10-Year OS
%P%P%P
  • PFS indicates progression-free survival; DSS, disease-specific survival; OS, overall survival; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; IRRT, involved regional radiotherapy; INRT≤5 cm, involved node radiotherapy with margins up to 5 cm.

  • a

    P value indicates a statistically significant difference.

  • b

    This variable was excluded from the univariate analysis.

Age, y  .203 .010a <.001a
 ≤60109 (46)49 89 87 
 >60128 (54)49 76 50 
Sex  .034a .073 .789
 Women124 (52)58 88 68 
 Men113 (48)41 75 65 
Performance state, ECOG  .460 .217 .042a
 0179 (76)46 83 70 
 1-258 (24)57 80 56 
Grade  .310 .035a .057
 1-2209 (88)50 84 68 
 3A28 (12)39 74 44 
Stage  .248 .991 .055
 IA179 (76)49 80 61 
 IIA58 (24)45 88 80 
Nodal size  .006a .205 .274
 Completely excised18 (8)77 94 76 
 <5 cm173 (73)50 79 62 
 ≥5 cm46 (19)28 87 78 
Extranodal disease  .095 .666 .105
 Absent182 (77)45 81 71 
 Present55 (23)63 85 52 
Serum LDH level  .076 .022a .026a
 Elevated16 (7)52 83 69 
 ≤Normal210 (89)31 67 44 
 Unknownb11 (5)      
Radiotherapy field size  .498 .142 .013a
 IRRT142 (60)48 85 71 
 INRT≤5 cm95 (40)50 78 59 

The final models in the multivariate analyses are presented in Table 4. Independent prognostic factors for inferior PFS were lymph node size ≥5 cm (P = .008) and male gender (P = .042), and there was a trend toward significance for age >60 years (P = .059). Prognostic factors for inferior DSS were age >60 years (P = .002), elevated LDH (P = .005), and male gender (P = .045). For OS, age >60 years (P < .001), elevated LDH (P = .007), lymph node size ≥5 cm (P = .016), and grade 3A tumors (P = .036) were poor prognostic factors. It is noteworthy that RT field size was not retained in the final models for any of the survival endpoints (Table 4), and adjustment for the other prognostic factors eliminated any prognostic influence of RT field size (Table 5).

Table 4. Final Models for the Multivariate Analyses of Progression-Free Survival, Disease-Specific Survival, and Overall Survival
VariablePFSDSSOS
PHR (95% CI)PHR (95% CI)PHR (95% CI)
  • PFS indicates progression-free survival; DSS, disease-specific survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; IRRT, involved regional radiotherapy; INRT≤5 cm, involved node radiotherapy with margins up to 5 cm.

  • a

    Baseline.

  • b

    This variable was excluded from the multivariate analysis.

Age.0591.490 (0.598-2.254).0023.112 (1.500-6.455)<.0015.380 (2.865-10.103)
 ≤60 ya
 >60 y
Sex.0421.530 (1.015-2.307).0452.014 (1.016-3.993)  
 Womena
 Men
ECOG performance status    .0881.584 (0.934-2.688)
 0a
 1-2
Tumor grade  .0732.357 (0.924-6.012).0362.196 (1.052-4.584)
 1-2a
 3A
Disease stage0.0991.466 (0.930-2.311)    
 IAa
 IIA
Lymph node size completely exciseda.008 .074 .016 
 <5 cm.0472.560 (1.011-6.481).0305.084 (1.168-22.133).0083.060 (1.340-6.988)
 ≥5 cm.0044.254 (1.584-11.404).1513.343 (0.644-17.370).2781.754 (0.635-4.845)
Extranodal disease.0810.610 (0.350-1.063)    
 Absenta
 Present
Serum LDH level.0911.791 (0.912-3.517).0053.659 (1.479-9.052).0072.775 (1.315-5.854)
 ≤Normal,a
 Elevated
 Unknownb
Radiotherapy field size      
 IRRTa
 INRT≤5 cm
Table 5. Final Models for the Multivariate Analyses Testing Radiotherapy Field Size and Adjusting for Other Prognostic Factors for Progression-Free Survival, Disease-Specific Survival, and Overall Survival
VariablePFSDSSOS
PHR (95% CI)PHR (95% CI)PHR (95% CI)
  • PFS indicates progression-free survival; DSS, disease-specific survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; IRRT, involved regional radiotherapy; INRT≤5 cm, involved node radiotherapy with margins up to 5 cm.

  • a

    Baseline.

  • b

    This variable was excluded from the multivariate analysis.

Age, y.0241.603 (1.064-2.414).0102.558 (1.248-5.243)<.0015.159 (2.738-9.718)
 ≤60a
 >60
Sex.0211.604 (1.074-2.395).0282.121 (1.085-4.147)  
 Womena
 Men
Performance state, ECOG    .0601.674 (0.978-2.865)
 0a
 1-2
Grade    .0412.155 (1.032-4.503)
 1-2a
 3A
Stage      
 IAa
 IIA
Nodal size Completely exciseda.002   .047 
 <5 cm.0222.987 (1.170-7.631)  .0282.639 (1.113-6.253)
 ≥5 cm.0015.344 (1.967-14.519)  .4091.550 (0.548-4.381)
Extranodal disease      
 Absenta
 Present
Serum LDH level  .0452.517 (1.020-6.209).0242.438 (1.127-5.276)
 ≤Normala
 Elevated
 Unknownb
Radiotherapy field size.0880.686 (0.444-1.058).2031.577 (0.782-3.178).2141.411 (0.820-2.428)
 IRRTa
 INRT≤5 cm

DISCUSSION

Radiotherapy alone is considered the current standard of care for the small proportion of patients presenting with stage I or II FL.13, 16 The NCCN and the ESMO have published guidelines recommending the use of RT with curative intent for limited stage FL.9-11 However, contrary to the published medical evidence and clinical practice guidelines, primary RT is markedly under used in limited stage FL. The National LymphoCare Study, a longitudinal study of 2738 patients with FL who were recruited over 3 years from 265 centers, reported that only 23.4% of patients with stage I FL received primary RT.12 Furthermore, 43% of patients with stage I FL received rituximab-containing regimens (either alone or in combination with chemotherapy) despite the lack of published evidence to support this as a curative approach.12 The authors of that report did not speculate on the underlying reason for this treatment pattern; however, the results strongly suggest that physician bias overrides the evidence-based guidelines.

At the BCCA, RT alone remains the recommended treatment for this patient population. Consistent with the published evidence, our results confirm the efficacy of RT alone for the treatment of limited stage FL. In our study, the 10-year PFS and OS rates were 49% and 66%, respectively, consistent with previously reported series. Late recurrences were rare, and only 2 recurrences occurred after 10 years, comparable to results from an earlier study in which the estimated risk beyond 15 years was 2%.8 These results suggest that a cure is possible with RT alone.

The Follicular Lymphoma International Prognostic Index (FLIPI) is a prognostic tool that is used currently to characterize risk groups, predict prognosis, and guide the management of patients with FL.17 Five independent prognostic parameters for OS are used in the FLIPI for determining the risk group: age, stage, hemoglobin level, LDH level, and the number of involved lymph node sites. Consistent with the FLIPI, our results indicate that age (P < .001) and LDH (P = .007) are highly significant prognostic factors for OS. However, the FLIPI has limitations and has been criticized for excluding some important clinical prognostic factors.18 Notably, lymph node size and WHO grade were not considered in the development of the FLIPI17; however, in our study both of those variables emerged as independent prognostic factors for OS. Previously published series also demonstrated that tumor bulk is associated with an inferior OS,3 PFS,5 and freedom from treatment failure7 in limited stage FL. These earlier results are consistent with our finding that lymph node size is a significant prognostic factor for PFS and OS (P = .008 and P = .016, respectively). In the published literature, grade is more controversial as a prognostic factor for FL, which may reflect the difficulties of reproducing the counts of centroblasts.19 Grade 3 is heterogeneous and is subdivided into grade 3A and 3B based on morphology; furthermore, differences in chromosomal alterations and clinical behavior also have been reported.16 On the basis of these features, it is believed that grade 3B is related more closely to diffuse large B cell lymphoma and that grade 3A is on a spectrum with grade 1 and 2 FL; therefore, most clinical trials of limited stage FL include patients with grade 1, 2, and 3A alike. However, in our series, grade 3A FL was associated with significantly inferior OS (P = .036) and a trend toward inferior DSS (P = .073) compared with grade 1 and 2 FL. This warrants further investigation.

The optimal management of grade 3A FL remains controversial, and this is highlighted by the differing recommendations in published treatment guidelines. According to the ESMO clinical recommendations, grade 3A FL should be managed akin to grade 1 and 2 FL.9 However, the NCCN Clinical Practice Guidelines in Oncology recommend treating both grade 3A and grade 3B FL according to diffuse large B-cell lymphoma protocols because, to date, a clinically significant difference has not been demonstrated between grade 3A FL and grade 3B FL.20 The optimal management of grade 3A FL is beyond the scope of our study; however, it is interesting to note that the 28 patients (12%) with grade 3A FL in our study had a significantly inferior OS. It is unclear whether these patients may have benefited from a more intensive treatment regimen.

The primary objective of reducing the RT field size is to lower the rates of radiation-induced morbidity without compromising disease control. The issue of RT field size has been investigated in a limited number of studies of FL. Pendlebury et al reported a small retrospective series of 58 patients and demonstrated that involved-field RT (IFRT) and extended-field RT (EFRT) resulted in similar survival outcomes.6 In another retrospective series of 80 patients, Wilder et al observed no significant difference in cause-specific survival or OS between EFRT, IRRT, and IFRT.5 Unfortunately, patterns of failure were not compared in those studies; therefore, it is unclear whether the larger EFRT field size reduced the incidence of distant recurrence. MacManus and Hoppe reported a lower rate of recurrence in patients who received large RT fields to cover lymph node groups on both sides of the diaphragm compared with patients who received RT to only 1 side of the diaphragm.4 However, those large fields are associated with increased risks of radiation-induced toxicities, and, to our knowledge, there is no clear evidence of improved OS to justify the increased morbidity.

Involved lymph node RT was proposed first by Girinsky et al for the treatment of limited stage Hodgkin lymphoma with combined chemotherapy and RT.21 The theoretical benefit of this smaller RT field size is to reduce the risks of radiation-induced toxicity and radiation-induced second malignancy in long-term survivors. Our group previously demonstrated that INRT≤5 cm is safe for patients who have favorable risk, limited stage Hodgkin lymphoma treated with combined chemotherapy and RT, with no detriment in PFS or OS observed after INRT≤5 cm compared with larger IFRT or EFRT fields.22 However, to our knowledge, the concept of INRT has not been previously applied to limited stage FL. Although it is a different disease entity, the theoretical benefit of reduced radiation-induced morbidity is a consistently valid objective. To our knowledge, this is the first study to compare the patterns of failure and survival after INRT≤5 cm and IRRT in patients with limited stage FL.

It is reassuring that infield recurrence alone was uncommon (1%) in this study, confirming RT as a highly effective local modality for FL. Distant-only recurrence was the most common pattern of failure in both RT groups. In the INRT≤5 cm group, only 1% of patients developed regional-only recurrences. Furthermore, RT field size was not a significant prognostic factor in multivariate analyses. Thus, reducing the RT field size from IRRT to INRT≤5 cm appears to be safe and effective in the treatment of limited stage FL.

One notable limitation of this study is that radiation-induced morbidity could not be assessed because of the retrospective study design. However, it is reasonable to extrapolate that smaller RT fields will translate to lower rates of radiation-induced toxicity and radiation-induced second malignancy in long-term survivors. Other limitations include the imbalance of prognostic factors between the 2 RT groups, the different treatment eras, and the relatively small number of patients. A large, randomized, prospective study will be required to investigate the rates of radiation-induced morbidity and to prove the equivalence of INRT≤5 cm and IRRT for survival endpoints. However, in view of the indolent nature of FL and the infrequency of limited stage disease, it is unlikely that such a study will be successfully completed in the future.

In conclusion, our results indicate that primary RT alone is a highly effective treatment for limited stage FL. At 10 years, the PFS rate was 49%, and recurrences beyond 10 years were rare, suggesting that RT alone is potentially curative. INRT≤5 cm appears to be a safe alternative to IRRT and is associated with a very low rate of regional-only recurrence. INRT≤5 cm is incorporated easily into current clinical practice; however, we caution that planning for INRT≤5 cm should be undertaken carefully, allowing adequate RT margins to the account for interfraction and intrafraction physiologic movement and setup variation during the course of RT.

CONFLICT OF INTEREST DISCLOSURES

Supported in part by the Turner Family Lymphoma Outcome Unit Fund, the Mary Toye Memorial Fund, and Terry Fox Foundation Program Project grant 019001.

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