Original Article

Long-Term Outcomes for Patients With

Limited Stage Follicular Lymphoma
Involved Regional Radiotherapy Versus Involved Node Radiotherapy

Belinda A. Campbell, MBBS, FRANZCR1; Nick Voss, FRCPC, FRCR1; Ryan Woods, MSc2;
Randy D. Gascoyne, MD, FRCPC3; James Morris, MD, FRCPC1; Tom Pickles, MD, FRCPC, FRCR1;
Joseph M. Connors, MD, FRCPC4; and Kerry J. Savage, MD, FRCPC4

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, unin-
volved 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 dis-
ease 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 ¼ .008) and male gender (P ¼ .042). Risk factors for OS were age >60 years (P < .001), ele-
vated LDH (P ¼ .007), lymph nodes 5 cm (P ¼ .016), and grade 3A tumors (P ¼ .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 out-
comes. Cancer 2010;116:3797–806. V C 2010 American Cancer Society.

KEYWORDS: involved node radiotherapy, follicular lymphoma, patterns of failure, long-term survival.

Follicular lymphoma (FL) long has been recognized as having an indolent natural history with good long-term sur-
vival 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 Eu-
ropean Society for Medical Oncology (ESMO) recommend primary RT for limited stage FL with curative intent.9-11

Corresponding author: Belinda A. Campbell, MBBS, FRANZCR, Peter MacCallum Cancer Centre, 7 St. Andrews Place, East Melbourne, Victoria 3002, Australia; Fax:
(011) 61-3-9656-1424; belinda.campbell@petermac.org
1
Department of Radiation Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; 2Department of Surveillance and Outcomes Unit, Brit-
ish Columbia Cancer Agency, Vancouver, British Columbia, Canada; 3Department of Pathology, British Columbia Cancer Agency, Vancouver, British Columbia, Can-
ada; 4Department of Medical Oncology, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada
Presented in part at the Joint 15th Congress of the European Cancer Organization and 34th Congress of the European Society for Medical Oncology, Berlin, Ger-
many, September 20-24, 2009.
DOI: 10.1002/cncr.25117, Received: August 17, 2009; Revised: October 13, 2009; Accepted: October 21, 2009, Published online May 24, 2010 in Wiley Inter-
Science (www.interscience.wiley.com)

Cancer August 15, 2010 3797

Original Article
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 opti-
mize 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 iden-
tify all patients who were diagnosed with limited stage FL
between January 1, 1986 and December 31, 2006. Lim-
ited stage was defined as Ann Arbor stage IA or IIA, non-
bulky (<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 chemo-
therapy and RT if they were symptomatic, or with obser-
vation if they were asymptomatic. All tumors were
biopsy-proven and were reviewed by a BCCA hematopa-
thologist. Diagnoses were based on the standard, era-spe-
cific 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 tomog-
raphy scans, bone marrow biopsy, and selected additional
imaging as indicated for the assessment of localized symp-
toms. Fluorine-18 2-deoxy-D-glucose-positron emission
tomography was not used for staging or RT planning. Se-
rum 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.
3798
Radiotherapy for Limited Stage
Follicular Lymphoma
At the BCCA, the Lymphoma Tumor Group is a multi-
disciplinary 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 move-
ment 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 distin-
guish 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 con-
sidered 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
Cancer August 15, 2010

survival (PFS) was determined from the date of diagno-
sis 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 toxic-
ity. 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 com-
parisons were made using the log-rank test. Univariate
analyses were performed to evaluate the impact of prog-
nostic 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 distribu-
tion of age was compared across these groups using the
Mann-Whitney U test.
The prognostic factors that were chosen prospec-
tively 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 propor-
tional-hazards regression analysis and the stepwise back-
ward procedure to identify independent prognostic
factors. The removal and entry levels of significance were
P ¼ .05 and P ¼ .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 consecu-
tive patients were identified who had a diagnosis of lim-
ited 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,
Cancer August 15, 2010
INRT for Limited Stage FL/Campbell et al
synchronous diffuse large B-cell lymphoma in 1 patient,
synchronous Hodgkin lymphoma in 1 patient, and syn-
chronous nonsmall cell lung cancer in 1 patient. No
patients were treated with chemotherapy alone.
From this group, 237 eligible patients were identi-
fied 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 involve-
ment. 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).
Comparing the 2 RT groups, extranodal involve-
ment (P < .001) and lymph node size 5 cm (P ¼ .001)
were more frequent in the INRT
5 cm group. However,
stage II disease was more common in the IRRT group (P
¼ .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 treat-
ment 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.
3799
Original Article

Table 1. Patient Characteristics at Diagnosis

No. of Patients (%)

Characteristic Total, IRRT, INRT£5 cm, P
n5237 n5142 n595
Median age, y 61 59 64 .021a
Age >60 y 128 (54) 70 (49) 58 (61) .075
Sex, men 113 (48) 68 (48) 45 (47) .938

Performance state, ECOG .700

0 179 (75) 106 (75) 73 (77)
1-2 60 (25) 36 (25) 22 (23)

Grade .948
1 129 (54) 78 (55) 51 (54)
2 80 (34) 48 (34) 32 (34)
3A 28 (12) 16 (11) 12 (13)

Stage .004a
IA 179 (76) 98 (69) 81 (85)
IIA 58 (24) 44 (31) 14 (15)

Nodal size .001a

Completely excised 18 (8) 18 (13) 0 (0)
<5 cm 173 (73) 98 (69) 75 (79)
‡5 cm 46 (19) 26 (18) 20 (21)
Extranodal disease 55 (23) 16 (11) 39 (41) <.001a

Serum LDH level .130

Elevated 16 (7) 7 (5) 9 (10)
£Normal 210 (89) 132 (95) 78 (90)
Unknown 11 (5) 3 8

Radiotherapy dose <.001a

30 Gy in 10 fractions 78 (33) 49 (35) 29 (31)
35 Gy in 20 fractions 79 (33) 59 (42) 20 (21)
Other 80 (34) 34 (24) 46 (48)

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.

Patterns of Failure in the INRT
5 cm group (71% vs 59% at 10 years; P ¼

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 recur-
rence rate of 41%. Infield-only recurrences were infrequent
and developed in 1% of all patients. The most common pat-
tern of failure was distant recurrence without infield recur-
rence, 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 re-
gional recurrence (38% vs 32%, respectively).
Radiotherapy Field Size and Risk
Factors for Survival
The univariate analyses are presented in Table 3. Compar-
ing the 2 RT groups in univariate analysis, OS was inferior
.013) (Fig. 1b). However, there was no statistically signifi-
cant difference in DSS (P ¼ .142) or in PFS (P ¼ .498)
for patients who received IRRT (Fig. 1c) compared with
patients who received INRT
5 cm (Fig. 1d)
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 ¼
.008) and male gender (P ¼ .042), and there was a
trend toward significance for age >60 years (P ¼ .059).
Prognostic factors for inferior DSS were age >60 years
(P ¼ .002), elevated LDH (P ¼ .005), and male gender
(P ¼ .045). For OS, age >60 years (P < .001), elevated
LDH (P ¼ .007), lymph node size 5 cm (P ¼ .016),
and grade 3A tumors (P ¼ .036) were poor prognostic
factors. It is noteworthy that RT field size was not
retained in the final models for any of the survival end-
points (Table 4), and adjustment for the other

3800 Cancer August 15, 2010

 INRT for Limited Stage FL/Campbell et al

Figure 1. These Kaplan-Meier curves illustrate (a) overall survival (OS), disease-specific survival (DSS), and progression-free sur-
vival (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.

Table 2. Patterns of Failure

No. of Patients (%)

Total, IRRT, INRT£5 cm,
n5237 n5142 n595
Total no. of recurrences 98 (41) 65 (45) 32 (35)
Infield relapse only 3 (1) 2 (1) 1 (1)

Distant relapse without infield relapse 84 (35) 54 (38) 30 (32)

Distant only 82 54 26
Regional only 1 — 1
Regional and distant 1 — 1
Distant and infield recurrence 11 (5) 9 (6) 2 (2)

IRRT indicates involved regional radiotherapy; INRT
5 cm, involved node radiotherapy with margins up to 5 cm.

prognostic factors eliminated any prognostic influence
of RT field size (Table 5).
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 longitudi-
nal study of 2738 patients with FL who were recruited

Cancer August 15, 2010 3801

Original Article

Table 3. Univariate Analyses of Progression-Free Survival, Disease-Specific Survival, and Overall

Survival

10-Year 10-Year 10-Year OS

PFS DSS
Variable Total No. % P % P % P
(%), n5237

Age, y .203 .010a <.001a

£60 109 (46) 49 89 87
>60 128 (54) 49 76 50

Sex .034a .073 .789

Women 124 (52) 58 88 68
Men 113 (48) 41 75 65

Performance state, ECOG .460 .217 .042a

0 179 (76) 46 83 70
1-2 58 (24) 57 80 56

Grade .310 .035a .057

1-2 209 (88) 50 84 68
3A 28 (12) 39 74 44

Stage .248 .991 .055

IA 179 (76) 49 80 61
IIA 58 (24) 45 88 80

Nodal size .006a .205 .274

Completely excised 18 (8) 77 94 76
<5 cm 173 (73) 50 79 62
‡5 cm 46 (19) 28 87 78

Extranodal disease .095 .666 .105

Absent 182 (77) 45 81 71
Present 55 (23) 63 85 52

Serum LDH level .076 .022a .026a

Elevated 16 (7) 52 83 69
£Normal 210 (89) 31 67 44
Unknownb 11 (5)

Radiotherapy field size .498 .142 .013a

IRRT 142 (60) 48 85 71
INRT£5 cm 95 (40) 50 78 59

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 radio-
therapy with margins up to 5 cm.
a
P value indicates a statistically significant difference.
b
This variable was excluded from the univariate analysis.

over 3 years from 265 centers, reported that only 23.4%
of patients with stage I FL received primary RT.12 Fur-
thermore, 43% of patients with stage I FL received rituxi-
mab-containing regimens (either alone or in combination
with chemotherapy) despite the lack of published evi-
dence 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 evi-
dence-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%, respec-
tively, consistent with previously reported series. Late
recurrences were rare, and only 2 recurrences occurred af-
ter 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

3802 Cancer August 15, 2010

 INRT for Limited Stage FL/Campbell et al

Table 4. Final Models for the Multivariate Analyses of Progression-Free Survival, Disease-Specific
Survival, and Overall Survival

PFS DSS OS
Variable P HR (95% CI) P HR (95% CI) P HR (95% CI)

Age .059 1.490 (0.598-2.254) .002 3.112 (1.500-6.455) <.001 5.380 (2.865-10.103)
£60 ya
>60 y

Sex .042 1.530 (1.015-2.307) .045 2.014 (1.016-3.993)

Womena
Men

ECOG performance status .088 1.584 (0.934-2.688)

0a
1-2

Tumor grade .073 2.357 (0.924-6.012) .036 2.196 (1.052-4.584)

1-2a
3A

Disease stage 0.099 1.466 (0.930-2.311)

IAa
IIA

Lymph node size .008 .074 .016

completely exciseda
<5 cm .047 2.560 (1.011-6.481) .030 5.084 (1.168-22.133) .008 3.060 (1.340-6.988)
‡5 cm .004 4.254 (1.584-11.404) .151 3.343 (0.644-17.370) .278 1.754 (0.635-4.845)

Extranodal disease .081 0.610 (0.350-1.063)

Absenta
Present

Serum LDH level .091 1.791 (0.912-3.517) .005 3.659 (1.479-9.052) .007 2.775 (1.315-5.854)
£Normal,a
Elevated
Unknownb

Radiotherapy field size

IRRTa
INRT£5 cm

PFS indicates progression-free survival; DSS, disease-specific survival; OS, overall survival; HR, hazard ratio; CI, confi-
dence interval; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; IRRT, involved regional radio-
therapy; INRT
5 cm, involved node radiotherapy with margins up to 5 cm.
a
Baseline.
b
This variable was excluded from the multivariate analysis.

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 ¼ .007) are highly significant
prognostic factors for OS. However, the FLIPI has limita-
tions and has been criticized for excluding some impor-
tant clinical prognostic factors.18 Notably, lymph node
size and WHO grade were not considered in the develop-
ment of the FLIPI17; however, in our study both of those
variables emerged as independent prognostic factors for
OS. Previously published series also demonstrated that tu-
mor 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 ¼ .008 and P ¼ .016, respectively). In the pub-
lished literature, grade is more controversial as a prognos-
tic factor for FL, which may reflect the difficulties of
reproducing the counts of centroblasts.19 Grade 3 is heter-
ogeneous 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

Cancer August 15, 2010 3803

Original Article

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

PFS DSS OS
Variable P HR (95% CI) P HR (95% CI) P HR (95% CI)
Age, y .024 1.603 (1.064-2.414) .010 2.558 (1.248-5.243) <.001 5.159 (2.738-9.718)
£60a
>60

Sex .021 1.604 (1.074-2.395) .028 2.121 (1.085-4.147)

Womena
Men

Performance state, ECOG .060 1.674 (0.978-2.865)

0a
1-2

Grade .041 2.155 (1.032-4.503)

1-2a
3A

Stage
IAa
IIA

Nodal size .002 .047

Completely exciseda
<5 cm .022 2.987 (1.170-7.631) .028 2.639 (1.113-6.253)
‡5 cm .001 5.344 (1.967-14.519) .409 1.550 (0.548-4.381)

Extranodal disease
Absenta
Present

Serum LDH level .045 2.517 (1.020-6.209) .024 2.438 (1.127-5.276)

£Normala
Elevated
Unknownb

Radiotherapy field size .088 0.686 (0.444-1.058) .203 1.577 (0.782-3.178) .214 1.411 (0.820-2.428)
IRRTa
INRT£5 cm

PFS indicates progression-free survival; DSS, disease-specific survival; OS, overall survival; HR, hazard ratio; CI, confi-
dence interval; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; IRRT, involved regional radio-
therapy; INRT
5 cm, involved node radiotherapy with margins up to 5 cm.
a
Baseline.
b
This variable was excluded from the multivariate analysis.

series, grade 3A FL was associated with significantly infe-
rior OS (P ¼ .036) and a trend toward inferior DSS (P ¼
.073) compared with grade 1 and 2 FL. This warrants fur-
ther investigation.
The optimal management of grade 3A FL remains
controversial, and this is highlighted by the differing rec-
ommendations 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 On-
cology 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 treat-
ment regimen.
The primary objective of reducing the RT field size
is to lower the rates of radiation-induced morbidity with-
out 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 se-
ries of 58 patients and demonstrated that involved-field

3804 Cancer August 15, 2010


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 differ-
ence 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 dia-
phragm 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 toxic-
ities, 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 Gir-
insky et al for the treatment of limited stage Hodgkin lym-
phoma 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 Hodg-
kin 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 con-
sistently 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 multi-
variate 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 radia-
tion-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 limita-
Cancer August 15, 2010
INRT for Limited Stage FL/Campbell et al
tions include the imbalance of prognostic factors between
the 2 RT groups, the different treatment eras, and the rela-
tively small number of patients. A large, randomized, pro-
spective 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. How-
ever, in view of the indolent nature of FL and the infre-
quency 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 al-
ternative 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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