Additional Survival Benefit of Involved-Lesion Radiation Therapy After R-CHOP Chemotherapy in Limited Stage Diffuse Large B-Cell Lymphoma

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation

Additional Survival Benefit of Involved-Lesion Radiation Therapy After R-CHOP Chemotherapy in Limited Stage Diffuse Large B-Cell Lymphoma Jeanny Kwon, MD,* Il Han Kim, PhD,*,y,z Byoung Hyuck Kim, MD,* Tae Min Kim, PhD,x and Dae Seog Heo, PhDx *Department of Radiation Oncology and yCancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; zInstitute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea; and xDepartment of Internal Medicine, Seoul National University Hospital, Seoul, Korea Received Aug 14, 2014, and in revised form Dec 11, 2014. Accepted for publication Dec 23, 2014.

Summary This study showed that involved-lesion radiation therapy, which could reduce toxicity by using smaller RT fields than involved-field radiation therapy, even after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, may improve both progression-free survival and overall survival in patients with limited stage diffuse large B-cell lymphoma, especially in patients with bulky disease or elevated serum lactate dehydrogenase.

Purpose: The purpose of this study was to evaluate the role of involved-lesion radiation therapy (ILRT) after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in limited stage diffuse large B-cell lymphoma (DLBCL) by comparing outcomes of R-CHOP therapy alone with R-CHOP followed by ILRT. Methods and Materials: We identified 198 patients treated with R-CHOP (median, 6 cycles) for pathologically confirmed DLBCL of limited stage from July 2004 to December 2012. Clinical characteristics of these patients were 33% with stage I and 66.7% with stage II; 79.8% were in the low or low-intermediate risk group; 13.6% had B symptoms; 29.8% had bulky tumors (7 cm); and 75.3% underwent 6 cycles of R-CHOP therapy. RT was given to 43 patients (21.7%) using ILRT technique, which included the prechemotherapy tumor volume with a median margin of 2 cm (median RT dose: 36 Gy). Results: After a median follow-up of 40 months, 3-year progression-free survival (PFS) and overall survival (OS) were 85.8% and 88.9%, respectively. Multivariate analysis showed 6 cycles of R-CHOP (PFS, PZ.004; OS, PZ.004) and ILRT (PFS, PZ.021; OS, PZ.014) were favorable prognosticators of PFS and OS. A bulky tumor (PZ.027) and response to R-CHOP (PZ.012) were also found to be independent factors of OS. In subgroup analysis, the effect of ILRT was prominent in patients with a bulky tumor (PFS, PZ.014; OS, PZ.030) or an elevated level of serum lactate dehydrogenase (LDH; PFS, PZ.004; OS, PZ.012). Conclusions: Our results suggest that ILRT after R-CHOP therapy improves PFS and OS in patients with limited stage DLBCL, especially in those with bulky disease or an elevated serum LDH level. Ó 2015 Published by Elsevier Inc.

Reprint requests to: Il Han Kim, MD, PhD, Department of Radiation Oncology, Seoul National University College of Medicine, 101 Daehak-ro,

Int J Radiation Oncol Biol Phys, Vol. 92, No. 1, pp. 91e98, 2015 0360-3016/$ - see front matter Ó 2015 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ijrobp.2014.12.042

Jongno-gu, Seoul, 110-744, Republic of Korea. Tel: 82-2-20722528; E-mail: [email protected] Conflict of interest: none.

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Introduction Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma and the most common lymphoid neoplasm in adults (1). During recent decades, as chemotherapy has evolved, combination chemotherapy has become established as a standard treatment, but the role of radiation therapy (RT) remains controversial. The Eastern Cooperate Oncology Group (ECOG) 1484 trial showed enhanced local control and disease-free survival by adding RT to chemotherapy in cases of localized aggressive lymphoma (2). However, the Groupe d’Etude des Lymphomes de l’Adulte (GELA) Lymphome Non Hodgkinien (LNH) 93-1 study (3) demonstrated no advantage conferred by sequential RT. Southwest Oncology Group trial 8736 (4) suggested that 3 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy with RT provided survival improvement and reduced treatment-related toxicity compared with 8 cycles of CHOP therapy at initial publication, but their updated data, which have not been published, showed that the survival differences observed between the 2 arms disappeared after long-term follow-up (5). The addition of rituximab to CHOP (R-CHOP) chemotherapy significantly improved clinical outcomes in several randomized trials without RT. In particular, the MinT trial reported a 93% 3-year overall survival (OS) rate in stage IIIV patients (6, 7). In the R-CHOP era, these improvements raised the question whether RT after chemotherapy was still necessary. Unfortunately, the randomized study that could give us the answer has not yet been published. Phan et al (8) reported significant benefits in OS and progression-free survival (PFS) from consolidative RT after R-CHOP therapy across all stages, although that study was performed retrospectively. However, no adequate comparative data for R-CHOP versus R-CHOP followed by RT support the above result. Moreover, most published studies analyzed heterogeneous patient groups with stages I to IV (8, 9). On the other hand, remarkable advances have been made in RT techniques for DLBCL. Some recent studies have demonstrated that limited-field RT, not encompassing all clinically involved regions with or without contiguous nodal or extranodal sites but including originally involved sites with a suitable margin, showed promising results not inferior to those of involved-field radiation therapy (IFRT) (10, 11). Involved-lesion RT (ILRT), which is one of the limited field RTs close to the recent involved-site RT (ISRT) concept by National Comprehensive Cancer Network (NCCN) guideline, has also been used in the last decade in our institution. However, previous randomized studies that reported clinical benefits of added RT in DLBCL did not clearly define RT fields, and thus, it remains uncertain that a reduced field with ILRT could maintain such benefits without compromising efficacy. Thus, the purpose of this study was to identify the role of ILRT in the R-CHOP era. We limited patients to those with localized DLBCL in view of the heterogeneity of the

International Journal of Radiation Oncology  Biology  Physics

disease and compared the treatment outcomes of R-CHOP therapy alone with those of R-CHOP followed by ILRT.

Methods and Materials Patient identification We identified 213 consecutive patients treated for newly pathologically confirmed DLBCL of limited stage in Seoul National University Hospital from July 2004 to December 2012. Fifteen of the 213 patients who did not receive R-CHOP chemotherapy were excluded, and the remaining 198 patients who were treated with R-CHOP with or without ILRT and in whom treatment response was evaluated after chemotherapy were included. Primary central nervous system lymphoma was excluded. With the approval of our Institutional Review Board, we performed a retrospective chart review and collated patient demographics, treatment, and clinical outcomes. Patients underwent staging work-up as follows: medical history including B symptoms, physical examination, Eastern Cooperative Oncology Group (ECOG) performance status, complete blood count, serum lactate dehydrogenase (LDH) concentration, neck-chest-abdomen computed tomography (CT), positron-emission tomography/CT (PET/CT), and bone marrow biopsy. Pathologic review was performed in all patients, and Ki-67 (the proliferative index) was evaluated in 90.9% of subjects. Limited stage and bulky disease were defined as Ann Arbor stages I or II and any tumor mass measuring 7 cm regardless of site, respectively. Because various definitions of bulky disease have been previously used, we used 7 cm as the cutoff value according to physician’s preference. We also calculated International Prognostic Index (IPI) scores (12) for all patients.

Treatments All patients received R-CHOP chemotherapy, which was administered intravenously for 3 weeks. Most cases with initial bulky disease or failure to achieve complete response to R-CHOP were referred to a radiation oncologist after chemotherapy. Patients with poor tolerance to R-CHOP were also considered for RT after 3 or 4 cycles of R-CHOP. Consistently during the study period, RT was delivered to the initial tumor volume prior to chemotherapy for all lesions with a median 2 cm (range, 0.5-2 cm) clinical tumor volume margin with or without boost to residual lesion. Uninvolved adjacent nodal regions were not included in the clinical tumor volume. Adjacent uninvolved organs were avoided during contouring to prevent them from being exposed to unnecessary irradiation when initial tumor volume regressed after chemotherapy. Similar principles were also applied to extranodal disease. Only the initially involved parts of extranodal sites were treated. Additional

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PTV expansion of 0.3 to 0.5 cm was performed to account for setup variation. Median RT dose was 36 Gy (range, 2554 Gy) at 1.8 to 2 Gy per fraction. The 3-dimensional conformal RT technique was used in most patients (74.4%), whereas the conventional RT technique and intensity modulated RT were used in 13.9% and 2.3% of patients, respectively.

Response evaluation We assessed response to R-CHOP according to consensus guidelines issued by the imaging subcommittee of International Harmonization Project in Lymphoma (13). Briefly, complete response (CR) was defined as negative fluorodeoxyglucose (FDG) uptake in a PET-positive tumor prior to R-CHOP therapy regardless of size of residual lesion on CT or, in case of variable FDG-avid or FDGe avidity unknown tumors, disappearance of extranodal lesion or regression of nodal lesion to normal size on CT. To avoid ambiguous assessment, we classified other responses that did not meet the above definition of CR as non-CR.

Endpoints and statistical analysis PFS and OS were evaluated as clinical endpoints. PFS was defined as duration between the date of first R-CHOP administration and the date of progression, recurrence, death, or last available follow-up. OS was defined as time between the date of first R-CHOP administration to death or last available follow-up. Statistical analysis was performed using SPSS version 21.0 software (IBM Corp., Armonk, NY). Pearson c2 test was used to determine the significance of intergroup differences in discontinuous variables, and the independent t test was used for continuous variables. Survival probabilities were estimated using the Kaplan-Meier method, and comparisons of survival according to clinical parameters were performed using the log-rank test. Multivariate analysis was performed using Cox regression hazard analysis with the backward conditional selection method (variables with P values of >.10 were sequentially removed from the model at each step). P values of <.05 were considered statistically significant.

Results Patient characteristics and survival outcomes Patient characteristics are summarized in Table 1. Median patient age was 55 years (range, 17-92 years of age), and the male-to-female ratio was 1.13:1. Two-thirds of the 198 patients (66.7%) were at stage II, and 79.8% were in the low or low-intermediate IPI risk group. Most patients (66.2%) received 6 cycles of R-CHOP therapy. Forty-three patients (21.8%) received R-CHOP followed by ILRT. The

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CR rate after R-CHOP therapy was 84.8%, whereas the progression rate was 1% not withstanding R-CHOP. We compared the characteristics of patients treated with R-CHOP with those of R-CHOP followed by ILRT (Table 1), and no significant differences in age, sex, performance status, stage, IPI risk group, and response to R-CHOP therapy were found. However, a significantly higher proportion of patients receiving R-CHOP and ILRT had an elevated level of serum LDH and bulky tumor and received fewer than 6 cycles of R-CHOP therapy. The median follow-up duration was 40 months (range, 2-110 months) for all patients. Overall, 3-year PFS and OS were 85.8% and 88.9%, respectively. Median PFS and OS were not reached.

Survival analyses Univariate analysis showed that clinical characteristics, that is, age <60; ECOG status 0 or 1; absence of B symptoms; stage I; normal serum LDH levels; low or low-intermediate risk; nonbulky tumor; 6 to 8 cycles of R-CHOP; and CR to R-CHOP were significantly associated with improved PFS and OS (Table 2). A Ki-67 rate of <50% had a marginally significant effect on PFS (PZ.079) but not on OS (PZ.279). However, ILRT following R-CHOP therapy was not found to be a significant factor of PFS or OS (3-year PFS Z 92.7% vs 83.9%, respectively, PZ.130; 3-year OS Z 95.0% vs 87.1%, respectively, PZ.141). Multivariate analysis was performed to adjust for confounding factors. Factors significant by univariate analyses were included in the Cox proportional hazard model. Although univariate analysis revealed that ILRT did not significantly affect survival outcome, ILRT was included in the model because: (1) significant imbalances of baseline characteristics were observed between R-CHOP and R-CHOP with ILRT groups; and (2) survival curves showed a benefit for ILRT (Fig. 1). Table 3 shows results of multivariate analysis. PFS was significantly improved by 6 to 8 cycles of R-CHOP (PZ.004) and additional ILRT (PZ.021). Furthermore, bulky tumor (PZ.027), 6 to 8 cycles of R-CHOP (PZ.004), non-CR to R-CHOP therapy (PZ.012), and ILRT (PZ.014) showed significant effects on OS.

Impact of ILRT according to clinical parameters Exploratory subgroup analysis was performed to evaluate the potential effects of ILRT on PFS or OS with respect to risk factors. In 59 patients with a bulky tumor, 20 patients received ILRT, and their PFS and OS rates were significantly higher than those of patients who did not receive ILRT (PFS, PZ.014; OS, PZ.030) (Fig. 2). On the other hand, ILRT did not confer a survival benefit in patients with a nonbulky tumor (PFS, PZ.862; OS, PZ.652). Serum LDH was elevated in 81 patients, and the 24 patients who received ILRT had better PFS and OS rates than those who

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Table 1

Comparison of patient characteristics according to additional radiation therapy RT (), nZ155

Characteristic Age Median (y) Sex Male Female ECOG 0.1 2 B symptomz Absent Present Stage I II Extranodal disease Absent Present Serum LDHz 225 (IU/L) >225 (IU/L) IPI risk group Low to intermediate High intermediate to high Bulky tumor <7 cm 7 cm Ki-67z <50 50 Cycles of R-CHOP <6 cycles 6-8 cycles Response to R-CHOP CR Non-CR

%

RT (þ), nZ43

N

%

n

n

%

P

55

(range, 17-92)

55.6

105 93

53.0 47.0

82 73

52.9 47.1

23 20

53.5 46.5

.946y

183 15

92.4 7.6

142 13

91.6 8.4

41 7

95.3 16.3

.413y

170 27

85.9 13.6

136 18

87.7 11.6

34 9

79.1 20.9

.119y

66 132

33.3 66.7

48 107

31.0 69.0

18 25

41.9 58.1

.180y

73 125

36.9 63.1

56 99

36.1 63.9

17 26

39.5 60.5

.682y

116 81

58.6 40.9

97 57

62.6 36.8

19 24

44.2 55.8

.027y

158 40

79.8 20.2

122 33

78.7 21.3

36 7

83.7 16.3

.469y

139 59

70.2 29.8

116 39

74.8 25.2

23 20

53.5 46.5

.007y

46 134

25.6 74.4

38 105

24.5 67.7

8 29

18.6 67.4

.538y

49 149

24.7 75.3

31 124

20.0 80.0

18 25

41.9 58.1

.003y

168 30

84.8 15.2

134 21

86.5 13.5

34 9

79.1 20.9

.232y

.127*

51.51

Abbreviations: CR Z complete response; ECOG Z Eastern Cooperative Oncology Group; IPI Z International Prognostic Index; LDH Z lactate dehydrogenase; R-CHOP Z rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; RT Z radiation therapy. * Independent-sample t test. y Pearson c2 test. z Information for B symptom, serum LDH, and Ki-67 was unavailable for 1, 1, and 18 patients, respectively.

did not (PFS, PZ.004; OS, PZ.012) (Fig. 2). On the other hand, no differences in PFS or OS rates were observed between patients with a normal serum LDH according to ILRT (PFS, PZ.312; OS, PZ.523). Stage II patients also benefited more from ILRT than stage I patients. Of the 132 patients with stage II, 25 received ILRT. In these 25 patients, PFS was significantly prolonged (95.8% vs 78.1%, respectively, at 3 years, PZ.041), and OS also tended to increase (95.7% vs 82.8%, respectively, at 3 years, PZ.096). On the other hand, stage I patients achieved favorable outcomes regardless of ILRT (PFS of 97.8% vs 88.5%, respectively, at 3 years, PZ.137; OS of 97.8% vs 94.4%, respectively, at 3 years, PZ.477). Marginally significant prolongation of PFS and OS by

combining ILRT was also observed in cases with non-CR to R-CHOP (PFS of 87.5% vs 53.5%, respectively, at 3 years, PZ.054; OS of 85.7% vs 52.2%, respectively, at 3 years, PZ.064) and Ki-67 50 (PFS of 92.7% vs 79.3%, respectively, at 3 years, PZ.079; OS of 96.3% vs 84.1%, respectively, at 3 years, PZ.081).

Patterns of failure During follow-up, failure occurred in 18 patients. The dominant site of first failure was in the initial tumor bed (12 of 18 cases [66.7%]). Of these 12 cases, 5 (41.7%) were accompanied by simultaneous distant failure. Of the 18

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ILRT after R-CHOP in limited stage DLCBL

Table 2 Univariate analysis for progression-free survival and overall survival Characteristics Age <60 60 Sex Male Female ECOG 0.1 2 B symptoms Absent Present Stage I II Serum LDH 225 (IU/L) >225 (IU/L) IPI risk group Low to low intermediate High intermediate to high Bulky tumor <7 cm 7 cm Ki-67 <50 50 Cycles of R-CHOP <6 cycles 6-8 cycles Response to R-CHOP CR Non-CR Radiation therapy No Yes

3-year PFS (%) 94.1 74.2

P*

3-year OS (%)

P*

<.0001 95.0 <.0001 80.2

86.8 84.8

.911

90.5 87.2

.367

87.7 62.5

.002

91.2 61.9

.001

88.0 70.7

.027

91.7 69.8

.003

95.1 81.5

.012

96.9 85.3

.023

89.2 80.5

.019

91.9 84.2

.034

<.0001 91.6 77.5

.002

89.6 69.8

.006

93.7 77.5

.003

93.5 82.3

.079

93.5 86.8

.279

74.0 89.5

.004

76.0 92.9

.001

<.0001 93.2 <.0001 63.3

83.9 92.7

.130

87.1 95.0

patients (9.8%), and grade 4 anemia was not reported. Grade 1 to 2 peripheral neurotoxicity was observed in 65 of 170 patients (38.2%). Three patients died of infection (2 of pneumonia, 1 of liver abscess), occurrences that were superimposed on treatment-related neutropenic fever. In addition, 1 patient had chemotherapy-induced acute myeloid leukemia diagnosed, and another patient developed severe bone marrow suppression due to chemotherapy after treatment completion. RT-induced toxicity was mild in most cases. Of the 43 patients who underwent ILRT, grade I or II toxicity was observed in 6 (gastrointestinal in 4, dermatitis in 1, and xerostomia in 1) and in 4 (gastrointestinal in 3, mucositis in 1) patients, and all these symptoms were relieved by conservative management. No chronic toxicity grade 3 or secondary malignancy caused by RT was observed.

Discussion

90.5 74.8

89.5 64.3

95

.141

Abbreviations: CR Z complete response; ECOG Z Eastern Cooperative Oncology Group; IPI Z International Prognostic Index; OS Z overall survival; PFS Z progression-free survival; R-CHOP Z rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. * Log-rank test.

patients with failure, only 2 (11.1%) received ILRT; 1 experienced isolated distant failure and the other failure at both initial and distant sites. The crude local control rate of R-CHOP with ILRT was 97.7%.

Treatment-associated toxicities Toxicities were graded using Common Terminology Criteria for Adverse Events version 4.03. During chemotherapy, grade 3 to 4 neutropenia was observed in 95 of 196 patients (48.5%). Grade 3 to 4 neutropenic fever occurred in 60 of 196 patients (30.6%). Grade 3 anemia occurred in 19 of 194

In the current study, we evaluated patients with limited stage DLBCL treated with R-CHOP therapy or R-CHOP with ILRT. Multivariate analysis showed that ILRT following R-CHOP administration was a significant prognostic factor for improved PFS and OS. It was remarkable that the impact of ILRT was confirmed in stage I-II patients with relatively favorable features (30% had bulky disease and a CR rate of 85% after receiving R-CHOP). Furthermore, the influence of ILRT was more prominent in patients with initial bulky disease or an elevated concentration of serum LDH. No complete randomized controlled trial has been published to assess the role of RT in the setting of R-CHOP chemotherapy. Thus, NCCN guidelines recommend 6 cycles of R-CHOP “with or without RT” for stage I-II or 3 cycles of R-CHOP with RT for nonbulky (<10 cm) disease. However, Phan et al (8) concluded that 6 to 8 cycles of R-CHOP did not obviate the need for RT (OS hazard ratio [HR] was 0.52; PFS HR was 0.45). Similarly, most of our patients received 6 to 8 cycles of R-CHOP, and multivariate analysis showed that 6 to 8 cycles of R-CHOP and RT were independent prognostic factors of PFS and OS. According to our results regarding failure patterns, failures at initial sites accounted for more than half of all failures. This predominant failure at primary-involved sites may have been due to the relatively small proportion of patients treated with additional ILRT in the present study. The excellent crude local control rate achieved in the ILRT group (97.7%) concurs with historical results. Campbell et al (11) reported a distant component relapse rate of 20% but an infield relapse rate of only 5% in limited stage DLBCL after 3 cycles CHOP or CHOP-like chemotherapy plus IFRT or involved-node RT. Dorth et al (14) also showed that the failure rate at initially uninvolved sites (9.6%) was double that of involved sites (4.1%) after consolidative RT in stage I-II DLBCL. Even for patients with advanced stage, consolidative RT after CR was

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Kwon et al.

A Progression-free survival

1.0 0.8

RT (-) P=.130

0.6 0.4

B

RT (+)

1.0

RT (-)

0.8

P=.141 0.6 0.4 0.2

0.2 0.0

Fig. 1.

RT (+)

Overall survival

96

3-year PFS : RT (+), 92.7% (95% CI, 84.9-100.0%) RT (-), 83.9% (95% CI, 77.8-90.0%)

0 No. at risk RT (-) 149 RT (+)

42

12

3-year OS: RT (+), 95.0% (95% CI, 88.3-100.0%) 0.0 RT (-), 87.1% (95% CI, 81.4-92.8%)

48

60

121

24 36 Months 98 76

59

39

30

14

21

44

0 No. at risk RT (-) 149

8

RT (+)

43

12

48

60

123

24 36 Months 99 78

60

46

39

31

15

8

22

(a) Progression-free survival (PFS) and (b) overall survival (OS) according to the receipt of radiation therapy (RT). the outcomes of R-CHOP with IFRT reported by Phan et al (8), that is, 82% and 92%, respectively, for 5-year PFS and OS in stage I/II DLBCL. In addition, Yu et al (10) conducted a retrospective study of patients diagnosed with limited stage head and neck DLBCL and treated with RT, which was delivered to prechemotherapy tumor volumes with a 1-cm margin after chemotherapy (83.7% received CHOP, and 16.3% received R-CHOP therapy) and reported excellent outcomes (5-year OS and PFS rates were 89.2% and 88.9%, respectively). As mentioned above, this small ILRT field could provide outcomes comparable to previous largefield RT. As shown by the current study, ILRT achieved excellent local control without inducing severe toxicity.

associated with improved local control and PFS (15). It is not surprising that RT diminishes the local failure rate to approximately 5% by controlling local microscopic disease, and this could contribute to improve survival outcomes as it does in other malignancies. Recently, NCCN guidelines adapted ISRT technique. These guidelines specify a smaller field size for ISRT than that used conventionally for IFRT; that is, the guideline states RT should be delivered only to the initial involved volume with an appropriate margin. The concept of ILRT in the present study is similar to ISRT. In our group receiving R-CHOP with ILRT, estimated PFS and OS rates at 5 years were 92.7% and 95%, respectively, which is not inferior to

Table 3

Multivariate analysis for progression-free survival and overall survival PFS

Characteristics Stage I II IPI risk group Low to low intermediate High intermediate to high Bulky tumor <7 cm 7 cm Cycles of R-CHOP <6 cycles 6-8 cycles Response to R-CHOP CR Non-CR Radiation therapy No Yes

OS

P*

HR (95% CI)

P*

HR (95% CI)

.106

1 2.80 (0.81-9.73)

.126

1 3.22 (0.72-14.45)

.066

1 2.24 (0.95-5.31)

-

.069

1 2.15 (0.94-4.91)

.027

1 2.83 (1.12-7.11)

.004

1 0.31 (0.14-0.69)

.004

1 0.25 (0.10-0.63)

.068

1 2.35 (0.94-5.85)

.012

1 3.55 (1.32-9.56)

.021

1 0.23 (0.07-0.80)

.014

1 0.15 (0.03-0.68)

Abbreviations: CI Z confidence interval; CR Z complete response; HR Z hazard ratio; IPI Z International Prognostic Index; OS Z overall survival; PFS Z progression-free survival; R-CHOP Z rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. * Cox proportional hazard model with backward conditional selection.

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RT (+)

0.6

P=.014

No. at risk RT (-) 37

25

RT (+)

18

19

24 Months 21 15

0.4 0.2 0.0

3-year OS : RT (+), 94.4% (95% CI, 83.8-100.0%) RT (-), 68.5% (95% CI, 52.8-84.2%) 12

11

0 No. at risk RT (-) 37

8

RT (+)

19

36

48

15 11

D

1.0

P=.030

0.6

3-year PFS : RT (+), 94.4% (95% CI, 83.8-100.0%) RT (-), 64.3% (95% CI, 48.6-80.0%) 12

20

26

24 Months 21 15

36

48

15

11

11

9

1.0

RT (+)

0.8

RT (+)

0.8 RT (-)

0.6

P=.004

0.4 0.2 0.0

RT (+)

RT (-)

0.4 0.2

97

0.8 RT (-)

0

Progression-free survival

1.0

0.8

0.0

C

B

Overall survival

Progression-free survival

1.0

3-year PFS : RT (+), 100% RT (-), 72.0% (95% CI, 59.8-84.2%)

0 No. at risk RT (-) 55

12

RT (+)

22

23

40

24 Months 32 18

Overall survival

A

ILRT after R-CHOP in limited stage DLCBL

RT (-) 0.6

P=.012

0.4 0.2 0.0

3-year OS : RT (+), 100% RT (-), 77.2% (95% CI, 65.8-88.6%) 12

19

0 No. at risk RT (-) 54

9

RT (+)

36

48

26 12

24

36

48

40

24 Months 33

27

19

22

18

13

10

Fig. 2. Progression-free survival (PFS) and overall survival (OS) according to receipt of radiation therapy (RT) in patients with bulky disease (a and b) and in patients with elevated serum lactate dehydrogenase (c and d). The question of whether the effect of RT differs according to certain risk factors, especially bulky status, has not been completely resolved. Phan et al (8) demonstrated that all patients benefited from RT regardless of tumor bulk. This finding contradicts ours; however, the definitions of bulky tumor mass used in the 2 studies differ. Phan et al (8) defined a bulky tumor as having a mass of 5 cm, whereas we used a definition of 7 cm, and in the current study, a definite survival gain by ILRT was only apparent in patients with a tumor of 7 cm. Similarly, the effects of RT in bulky disease are supported by 2 recent prospective trials conducted by the Deutsche Studiengruppe fu¨r Hochmaligne Non-Hodgkin-Lymphome (DSHNHL). In the Rituximab With CHOP Over 60 Years (RICOVER-60) trial, which compared 6 cycles of R-CHOP biweekly followed by 2 additional cycles of R plus IFRT with the same chemotherapy without IFRT, RT was administered to sites of initial bulky disease (7.5 cm) and extralymphatic involvement. It was found that the lack of RT significantly compromised 3-year EFS and tended to be associated with inferior PFS and OS (16). Another ongoing trial, called UNFOLDER (where UNFOLDER is Rituximab and

Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With B-Cell Non-Hodgkin’s Lymphoma), is being conducted in young DLBCL patients with IPI 0-1 and bulky tumor (7.5 cm). Initially, patients were assigned to 1 of 4 arms as follows: those receiving 6 biweekly cycles of R-CHOP with or without RT or six 3weekly cycles of R-CHOP with or without RT. However, after interim analysis, the arms without RT were eliminated due to compromised OS and PFS. The above-mentioned studies suggest that the need for RT increases with tumor size. However, it remains to be determined by prospective trial whether RT could be omitted in nonbulky diseases. In our study, the other factor found to influence survival outcomes by multivariate analysis was response to RCHOP. Patients with non-CR to R-CHOP therapy had significantly compromised OS and tended to have inferior PFS. In our subgroup analysis of patients with non-CR, ILRT provided marginally significant improvements in PFS (PZ.054) and OS (PZ.064) despite an insufficient number of patients. Not surprisingly, previous studies have also indicated that non-CR after chemotherapy is an unfavorable factor. However, the role of RT in cases of non-CR after

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R-CHOP is still unclear. Halasz et al (17) showed that nonCR to R-CHOP therapy can be successfully complemented by IFRT in patients with a positive PET scan after chemotherapy. Dorth et al (18) also showed that persistent metabolically active lymphoma after R-CHOP or CHOP therapy can be effectively treated by consolidative RT. These findings suggest another role for RT as a complementary option after R-CHOP. However, further comparative prospective controlled studies are needed with other treatment options, such as high-dose chemotherapy with autologous stem cell rescue. Nevertheless, patients who cannot tolerate such intensive chemotherapy due to poor general medical condition should be considered for complementary RT in order to reduce treatment-related morbidities. To the best of our knowledge, this study is 1 of the first to evaluate the role of ILRT in the modern R-CHOP therapy era. All our patients received R-CHOP chemotherapy. However, there is still a paucity of data regarding ILRT with sufficient follow-up. Therefore, we believe that our results contribute meaningfully to the research. Furthermore, recently revised response criteria incorporating PET/ CT were included in the present study, whereas most previous studies used historical criteria proposed by Cheson at al (19) in 1999, which could not reflect metabolic response. In addition, we tried to include all consecutive patients and only applied primary CNS lymphoma as an exclusion criterion to minimize selection bias. Nonetheless, the study is inevitably limited by its retrospective nature. Furthermore, the follow-up duration was not long enough to detect delayed recurrence or death after 5 years, and the relatively small number of patients treated with ILRT may have limited our ability to draw definitive, statistically powered conclusions.

Conclusions In conclusion, our results suggest ILRT after R-CHOP therapy has an additive effect on PFS and OS in limited stage DLBCL, particularly in patients with bulky disease or an elevated concentration of serum LDH. In terms of RT techniques, ILRT is feasible and may improve local control and survival and decrease RT-related toxicities by reducing field size. Further well-designed prospective studies are required to confirm the role of modern RT technique after R-CHOP therapy.

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