Phase 2 Study of Dose-Reduced Consolidation Radiation Therapy in Diffuse Large B-Cell Lymphoma

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Clinical Investigation

Phase 2 Study of Dose-Reduced Consolidation Radiation Therapy in Diffuse Large B-Cell Lymphoma Chris R. Kelsey, MD,* Gloria Broadwater, MS,y Olga James, MD,z Junzo Chino, MD,* Louis Diehl, MD,x Anne W. Beaven, MD,k Catherine Chang, MD,* Bridget F. Koontz, MD,* and Leonard R. Prosnitz, MD* *Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina; y Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina; zDepartment of Radiology, Division of Nuclear Medicine, Duke University Medical Center, Durham, North Carolina; xDepartment of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina; and kDepartment of Medicine, Division of Medical Oncology, University of North Carolina Medical Center, Chapel Hill, North Carolina Received Oct 19, 2018. Accepted for publication Feb 26, 2019.

Summary This phase 2 study tested the hypothesis that the dose of consolidation radiation therapy can be reduced from 30 Gy to 20 Gy in diffuse large B-cell lymphoma. All patients (n Z 62) achieved a complete metabolic response after chemo-immunotherapy according to positron emission tomography-computed tomography imaging. Bulky disease was present in 40%. Five-year local control using

Purpose: To evaluate the feasibility of reducing the dose of consolidation radiation therapy (RT) in diffuse large B-cell lymphoma. Methods and Materials: This phase 2 study enrolled patients with diffuse large B-cell lymphoma, not otherwise specified and primary mediastinal (thymic) large B-cell lymphoma in complete response on positron emission tomography-computed tomography imaging after 4 cycles of a rituximab/anthracycline-containing combination chemotherapy regimen. Consolidation RT used a dose of 19.5 to 20 Gy. The primary endpoint was 5-year freedom from local recurrence. Results: Sixty-two patients were enrolled between 2010 and 2016. Stage distribution was as follows: I to II (n Z 49, 79%) and III to IV (n Z 13, 21%). Bulky disease (defined as 7.5 cm or 10 cm) was present in 23 (40%) and 16 (28%) patients, respectively. Chemotherapy was R-CHOP (then list the drugs) in 58 (94%) and REPOCH (then list the drugs) in 4 (6%) with a median of 6 cycles. With a median follow-up of 51 months, 7 patients developed disease progression (6 outside the RT field, 1 within the RT field). Freedom from local recurrence at 5 years was 98%

Reprint requests to: Chris R. Kelsey, MD, Department of Radiation Oncology, DUMC 3085, Durham, NC 27710. Tel: (919) 6685214; E-mail: [email protected] This study was financially supported by the Department of Radiation Oncology at Duke University Medical Center. Int J Radiation Oncol Biol Phys, Vol. -, No. -, pp. 1e6, 2019 0360-3016/$ - see front matter Ó 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ijrobp.2019.02.055

This study was presented at the 2017 American Society of Therapeutic Radiation Oncology Annual Meeting. San Diego, CA; September 2427, 2017. Disclosures: none.

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20 Gy was 98%. Progression-free survival was 83%. A lower dose of radiation therapy is expected to decrease both acute and long-term side effects of therapy.

(90% lower confidence bound, 88%). Progression-free and overall survival at 5 years were 83% and 90%, respectively. Conclusions: With more effective systemic therapy (e.g., addition of rituximab) and more refined chemotherapy response assessment (e.g., positron emission tomography-computed tomography), the dose of RT in combined modality treatment programs may potentially be reduced to 20 Gy. This achieves excellent local control with the potential to decrease acute and long-term side effects. Ó 2019 Elsevier Inc. All rights reserved.

Introduction Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, comprises a heterogeneous group of neoplasms with multiple morphologic variants and subtypes described in the current World Health Organization classification.1 Combined-modality therapy, consisting of chemotherapy followed by consolidation radiation therapy (RT), is an established treatment paradigm. Multiple randomized studies, with different eligibility criteria and design, have been conducted to evaluate the role of RT in DLBCL. Although many have demonstrated a clinical benefit with RT, either by allowing administration of less chemotherapy2 or by decreasing the risk of relapse,3,4 other studies have not been confirmatory.5,6 Although the role of consolidation RT in DLBCL continues to be refined, recent data from prospective trials,7 large databases analyses,8-11 and single-institutional studies12 suggest that RT continues to play an important role. The acute side effects and, more importantly, longterm risks of RT are closely related to dose. The standard dose is 30 Gy, established in the pre-rituximab era when chemotherapy response was assessed with computed tomography (CT). This phase 2 study was developed to test our hypothesis that the dose of RT could be lowered without compromising local tumor control when a complete response was achieved with positron emission tomography (PET)-CT after optimal systemic therapy (e.g., addition of rituximab).13,14

Methods and Materials This institutional review boardeapproved prospective phase 2 study enrolled adult patients (18 years old) with histologically confirmed DLBCL, not otherwise specified (NOS) and primary mediastinal B-cell lymphoma (PMBCL) (ClinicalTrials.gov identifier NCT03681535). Eligibility criteria included receipt of at least 4 cycles of a rituximab/anthracycline-containing combination chemotherapy regimen and a negative postchemotherapy PET-CT by the International Harmonization Project criteria.15 The chemotherapy regimen administered was left to the discretion of the medical oncologist. The Deauville 5-point scale was adopted in 2013, with a negative scan defined as scores 1 through 3. PET-CT scans of patients enrolled

before this trial amendment were reviewed by a nuclear medicine physician and scored retrospectively using the 5point scale. Postchemotherapy laboratory requirements included an absolute neutrophil count 1500, platelet count 40,000, and negative pregnancy test in women of childbearing potential. Conditions for ineligibility included other DLBCL subtypes (e.g., primary central nervous system lymphoma) or any contraindication to irradiation. RT was required to begin within 12 weeks of the final cycle of chemotherapy. Both 3-dimensional conformal and intensity modulated RT techniques were allowed. For patients with stage I to II disease, all sites of original involvement were encompassed in the radiation fields. For patients with stage III to IV disease, treatment volumes were individualized based on the clinical presentation, but with the aim of including all sites of disease if feasible. The planned radiation dose was 19.5 to 20 Gy with daily fractions of 1.5 to 2 Gy. All patients, regardless of disease bulk, received this dose. RT field design was consistent with modern principles of involved-site RT.16,17 The clinical target volume included the original extent of disease, typically delineated by fusing the prechemotherapy PETCT with the planning CT scan, adjusted to account for changes in anatomy after lymphoma regression. A clinical target volume expansion, typically 1 to 2 cm, but no larger than 5 cm, was used to account for imaging and positioning uncertainties in treating a postchemotherapy target. A final planning target volume was designed to account for potential daily set-up error and/or target motion from respiration. Daily on-board imaging was recommended to minimize daily set-up error. Patients were seen in follow-up per institutional policy, typically every 3 months for the first 2 years, every 6 months until year 5, and annually thereafter. Acute side effects developing within 90 days of completing RT were scored using the Common Terminology Criteria for Adverse Events v4.0. Potential late effects from treatment were also recorded.

Statistics The primary endpoint was 5-year freedom from local recurrence (ie, local control) estimated using the KaplanMeier method. Freedom from local recurrence was defined as time from RT administration to local failure, with patients censored at the time of last follow-up or death.

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Patients progressing at distant sites were followed for evidence of subsequent local failure. In randomized trials evaluating consolidation RT in the pre-rituximab era, crude in-field failure rates after CHOP (cyclophosphamide, doxorubicin, vinctristine, and prednisone) and RT (30-40 Gy) ranged between 4% and 7%.3,6,18 This study was powered to evaluate whether actuarial local control at 5 years with a lower dose of RT (19.5-20 Gy) remained 90%. The lower 90% confidence bound of the 5-year local control rate was to be calculated; if 0.84, the study would be considered a success. Based on exponential survival, this decision rule is equivalent to testing the null hypothesis (H0: P  .84) versus the alternative (HA: P  .94). Two interim analyses based on the cumulative incidence of local control events (numbers of events/ person-years follow-up) were planned at approximately 3 and 6 years from study activation to monitor for an unacceptably high local failure rate. Secondary endpoints included progression-free survival and overall survival. Because of the small number of events observed, the beta product confidence procedure method for right censored data was used to estimate confidence intervals for survival endpoints.19 Statistical analyses were conducted using SAS v9.4 (SAS Institute, Inc., Cary, NC) and R version 3.5.0 (2018-04-23).20 Figures were generated using SPSS v25.0 (IBM, Armonk, NY).

Results Sixty-two patients were enrolled between 2010 and 2016 at 3 hospitals within the Duke University Health System. The majority of patients had DLBCL, NOS (81%) with stage I to II presentations (79%). Bulky disease (defined as 7.5 cm or 10 cm) was present in 23 (40%) and 16 (28%) patients, respectively. Skeletal involvement was present in 12 (19%). Additional patient characteristics are found in Table 1. Chemotherapy consisted of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in the majority of patients (n Z 58, 94%). R-EPOCH (rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin) was administered to 4 (6%), given in a dose-adjusted fashion in 2 (3%). Three patients with PMBCL and 1 patient with DLBCL, NOS received R-EPOCH. The number of chemotherapy cycles was 4 (n Z 21, 34%), 5 (n Z 2, 8%), or 6 (n Z 39, 63%). The median interval between the final cycle of chemotherapy and PET-CT imaging was 20 days. The PET-CT chemotherapy response assessment using the Deauville 5-point scale was 1 (23, 37%), 2 (23, 37%), or 3 (15, 24%). One patient with PMBCL treated in the preDeauville period was thought to have achieved a complete response with residual uptake consistent with thymic rebound, but was scored retrospectively as having a Deauville 4 response. The median interval between the

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Dose-reduced RT for DLBCL Table 1

Patient characteristics (n Z 62)

Characteristic Sex Male Female Age, y Histology DLBCL, NOS PMBCL Stage I II III IV IPI 0-1 2 3 4-5 Missing Extranodal disease Skeletal involvement Size of largest tumor Bulky disease 7.5 cm 10 cm Chemotherapy R-CHOP R-EPOCH* Cycles 4 5 6 Deauville score 1 2 3 4y

Median (range)

n (%) 28 (45) 34 (55)

58 (24-86) 50 (81) 12 (19) 24 25 4 9

(39) (40) (6) (15)

39 14 5 2 2 35 12

(63) (23) (8) (3) (3) (56) (19)

6 (1-20) 23 (40) 16 (28) 58 (94) 4 (6) 21 (34) 2 (3) 39 (63) 23 23 15 1

(37) (37) (24) (2)

Abbreviations: DLBCL, NOS Z diffuse large B-cell lymphoma, not otherwise specified; IPI Z International Prognostic Index; PMBCL Z primary mediastinal (thymic) B-cell lymphoma; RCHOP Z rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-EPOCH Z rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin. * Two patients received dose-adjusted R-EPOCH. y Initial interpretation was thymic rebound.

final cycle of chemotherapy and initiation of RT was 1.2 months.

Clinical outcomes Criteria for study continuation were met at 2 interim analysis time points with 85 and 185 person-years of follow-up, respectively. With a median follow-up for all patients of 51 months (range, 1-91; 271 person-years of follow-up), 7 patients developed disease progression (1 within the RT field, and 6 outside the RT field). The 1

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local recurrence developed in a 26-year-old female who presented with a 6-cm PMBCL and received 6 cycles of dose-adjusted R-EPOCH. Her postchemotherapy PET-CT was negative (Deauville 3), and she received 20 Gy of consolidation RT. One year later on surveillance imaging, she was found to have a hypermetabolic mass at the original site of disease. Excisional biopsy showed classical Hodgkin lymphoma, nodular sclerosis type (pathologic review confirmed it as a pathologic entity distinct from the original biopsy results) with all gross disease resected and negative postsurgical PET-CT findings. She did not receive any further therapy and is disease free 6 years later. This was scored as a local failure. Freedom from local failure was 98% at 5 years (95% confidence interval [CI], 83%-99%) with an observed lower 90% confidence interval bound of 88% (Fig. 1). Six patients relapsed outside the RT field during the follow-up period, 4 originally presenting with early-stage disease and 2 with advanced disease. All had DLBCL, NOS. Four patients were treated with salvage chemotherapy followed by autologous stem cell transplant and are currently in remission. One patient who was not a candidate for stem cell transplant received second line chemotherapy and at subsequent progression enrolled on hospice and has expired. The final patient had stage II DLBCL with testicular involvement and developed 3 enhancing intracranial masses 5 years later that were never biopsied. The patient’s condition rapidly declined, and the patient died. This was assumed to be central nervous system progression from lymphoma. Thus, 2 of the 7 relapsing patients died of their disease. Additionally, 1 patient with stage II DLBCL died at the age of 91 years of other causes while still in remission 4 years after completing therapy. Progression-

1.0

1.0 0.9 0.8 0.7 0.6 Proportion

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Overall Survival Progression-Free Survival

0.5 0.4 0.3 0.2

Number at Risk (Overall Survival) 62 58 35 Number at Risk (Progression-Free Survival) 62 53 32

0.1

14 13

0.0 0

1

2

3

4

5

6

7

Years

Fig. 2. Kaplan-Meier estimates of overall survival and progression-free survival in patients treated with dosereduced radiation therapy for diffuse large B-cell lymphoma. free and overall survival at 5 years were 83% (95% CI, 67%-93%) and 90% (95% CI, 73%-98%), respectively (Fig. 2).

Acute and late toxicity Grade 2 acute toxicity developed in 11 patients (18%), most commonly odynophagia (Table 2). Two patients (3%) developed grade 3 nonhematologic toxicity, consisting of oral mucositis requiring hospitalization and ear fullness requiring tympanostomy tube insertion. There were 3 cases

0.9

Table 2

0.8

Acute grade 2 toxicity

Freedom from Local Recurrence

Toxicity 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Number at Risk 62 57

0.0 0

1

2

34 3

4

13 5

6

7

Years

Fig. 1. Kaplan-Meier estimates of freedom from local recurrence in patients treated with dose-reduced radiation therapy for diffuse large B-cell lymphoma.

Nonhematologic toxicity Ear fullness Dental caries Dysphagia Odynophagia Dysgeusia Gastroesophageal reflux Oral mucositis Nausea/vomiting Non-cardiac chest pain Pneumonitis Post-nasal drip Hematologic toxicity Neutropenia Leukopenia Maximum overall AE

Grade 2

Grade 3

Grade 4

1 (2%) 1 2 7 1 1

(2%) (3%) (11%) (2%) (2%)

2 2 1 1

(3%) (3%) (2%) (2%)

1 (2%)

11 (18%)

1 (2%) 1 (2%) 4 (6%)

1 (2%) 1 (2%)

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of grade 3 to 4 hematologic toxicity. Four secondary cancers developed during the follow-up period. These included a papillary thyroid cancer, 2 squamous cell carcinomas of the skin, and a grade 1 papillary carcinoma of the kidney. None developed within the RT field. All were successfully treated surgically. Two patients developed cardiac complications. One patient was diagnosed with an idiopathic cardiomyopathy immediately after finishing chemotherapy, and another patient was found to have a depressed ejection fraction during routine follow-up. Neither patient received mediastinal RT. No other long-term complications related to RT were observed.

Discussion In this prospective phase 2 trial, reducing the dose of consolidation RT from 30 to 20 Gy in the setting of modern chemo-immunotherapy regimens and PET-CT response assessment did not compromise local tumor control. Only 1 local failure developed after a median follow-up of 51 months. This patient relapsed after receiving doseadjusted R-EPOCH and 20 Gy RT for PMBCL but was found to have nodular sclerosis Hodgkin lymphoma on excisional biopsy, raising the suspicion that the patient had a grey zone lymphoma at diagnosis (B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma). There were no other local failures, despite a high prevalence of clinical factors traditionally associated with local recurrence, including bulky disease and skeletal involvement (40% and 19% of patients, respectively). The advantage of consolidation RT in DLBCL was first established with the Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group randomized trials.3,21 In the ECOG trial, all patients received a full course of chemotherapy (8 cycles of CHOP) and were in a complete response by CT imaging. Consolidation RT (30 Gy) improved progression-free survival, the primary endpoint of the study. Of 79 patients who received RT, there were only 3 local failures (96% local control) compared with 15 local failures in 93 patients who were observed (84% local control). Our study was patterned after the ECOG trial with 3 notable differencesdall patients also received rituximab, were in complete response by PET-CT, and 20 Gy of RT was used for consolidation. A high rate of local control (98%) was maintained despite a lower dose of RT. Few studies have evaluated the optimal dose in combined-modality treatment programs for DLBCL. A British National Lymphoma Investigation randomized study showed no difference in freedom from local progression, progression-free survival, or overall survival between 30 Gy and 40 to 45 Gy.22 Five-year freedom from local progression was 84% with 40 to 45 Gy and 82% with 30 Gy. Most, but not all, patients in this study were

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irradiated after chemotherapy, but only w10% of patients received rituximab. PET-CT was not used. Several institutional studies have shown high (w95%100%) rates of local control when w30 to 36 Gy is given after a complete response by PET-CT to systemic therapy.12,23,24 Our study suggests even lower doses may be adequate, even in the presence of bulky disease or skeletal involvement, situations where higher doses (36-40 Gy) have historically been administered. The role of RT in DLBCL continues to evolve in the modern era as systemic therapy is optimized. In the RICOVER-60 trials, in a nonrandomized but prospective comparison, 6 cycles of R-CHOP-14 with 2 additional cycles of rituximab was compared with the same regimen with consolidation RT (36 Gy) for patients with bulky (7.5 cm) or extralymphatic involvement.7 Patients received RT in the setting of both complete and partial response. The addition of RT significantly improved both event-free and overall survival. Similarly, in the UNFOLDER trial, conducted by the German High Grade Non-Hodgkin Lymphoma Study Group, treatment arms without RT to bulky (defined as 7.5 cm) or extralymphatic disease were closed early because of inferior event-free survival on a planned interim analysis (data unpublished, presented at American Society of Hematology 2012). On the other hand, results from the The Lymphoma Study Association/The French Acute Leukaemia and Blood Diseases West-East Group 02-03 trial failed to show an improvement with consolidation RT in patients with nonbulky, early-stage DLBCL when a complete response had been achieved on PET-CT after 4 to 6 cycles of R-CHOP. Five-year event-free survival was 89% with R-CHOP and 92% with R-CHOP plus RT (P Z .18). Several nuances of the study required consideration when interpreting the results. The study population was favorable with bulky disease excluded and 94% of patients having a stage-modified International Prognostic Index of 0 to 1. A significant number of patients (19%) had all disease resected at the time of diagnosis, diluting the effect of further local consolidation therapy. Patients were randomized and analyzed regardless of the postchemotherapy PET-CT response. Finally, despite the noninferiority trial design, no per-protocol analysis was presented.

Conclusions With more effective systemic therapy (e.g., addition of rituximab) and more refined chemotherapy response assessment (e.g., PET-CT), the dose of RT in combinedmodality treatment programs may potentially be further reduced to 20 Gy. This is expected to decrease the severity of acute side effects, reduce the risk of long-term complications particularly in younger patients, and utilize less health care resources. A confirmatory study is being organized by the International Lymphoma Radiation Oncology Group.

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References 13. 1. Swerdlow SH, Campo E, Harris NL, et al. In: Bosman F, Jaffe E, Lakhani SR, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008. 2. Stephens DM, Li H, LeBlanc ML, et al. Continued risk of relapse independent of treatment modality in limited-stage diffuse large B-cell lymphoma: Final and long-term analysis of Southwest Oncology Group Study S8736. J Clin Oncol 2016;34:2997-3004. 3. Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 2004;22:3032-3038. 4. Martinelli G, Gigli F, Calabrese L, et al. Early stage gastric diffuse large B-cell lymphomas: Results of a randomized trial comparing chemotherapy alone versus chemotherapy þ involved field radiotherapy. (IELSG 4). [corrected]. Leuk Lymphoma 2009;50:925-931. 5. Lamy T, Damaj G, Soubeyran P, et al. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood 2018;131:174-181. 6. Bonnet C, Fillet G, Mounier N, et al. CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: A study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2007;25:787-792. 7. Held G, Murawski N, Ziepert M, et al. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol 2014;32:1112-1118. 8. Ballonoff A, Rusthoven KE, Schwer A, et al. Outcomes and effect of radiotherapy in patients with stage I or II diffuse large B-cell lymphoma: A surveillance, epidemiology, and end results analysis. Int J Radiat Oncol Biol Phys 2008;72:1465-1471. 9. Dabaja BS, Vanderplas AM, Crosby-Thompson AL, et al. Radiation for diffuse large B-cell lymphoma in the rituximab era: Analysis of the National Comprehensive Cancer Network lymphoma outcomes project. Cancer 2015;121:1032-1039. 10. Parikh RR, Yahalom J. Older patients with early-stage diffuse large Bcell lymphoma: The role of consolidation radiotherapy after chemoimmunotherapy. Leuk Lymphoma 2017;58:614-622. 11. Vargo JA, Gill BS, Balasubramani GK, et al. Treatment selection and survival outcomes in early-stage diffuse large B-cell lymphoma: Do we still need consolidative radiotherapy? J Clin Oncol 2015;33:3710-3717. 12. Phan J, Mazloom A, Jeffrey Medeiros LJ, et al. Benefit of consolidative radiation therapy in patients with diffuse large B-cell

14.

15. 16.

17.

18.

19.

20. 21.

22.

23.

24.

lymphoma treated with R-CHOP chemotherapy. J Clin Oncol 2010; 28:4170-4176. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the RCHOP study in the treatment of elderly patients with diffuse large Bcell lymphoma: A study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005;23:4117-4126. Pfreundschuh M, Tru¨mper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7:379-391. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-586. Yahalom J, Illidge T, Specht L, et al. Modern radiation therapy for extranodal lymphomas: Field and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 2015;92:11-31. Illidge T, Specht L, Yahalom J, et al. Modern radiation therapy for nodal non-Hodgkin lymphoma-target definition and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 2014;89:49-58. Reyes F, Lepage E, Ganem G, et al. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 2005; 352:1197-1205. Fay MP, Brittain EH, Proschan MA. Pointwise confidence intervals for a survival distribution with small samples or heavy censoring. Biostatistics 2013;14:723-736. Team RC. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2013. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med 1998;339:21-26. Lowry L, Smith P, Qian W, et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: A randomised phase III trial. Radiother Oncol 2011;100:86-92. Dorth JA, Chino JP, Prosnitz LR, et al. The impact of radiation therapy in patients with diffuse large B-cell lymphoma with positive postchemotherapy FDG-PET or gallium-67 scans. Ann Oncol 2011;22: 405-410. Halasz LM, Jacene HA, Catalano PJ, et al. Combined modality treatment for PET-positive non-Hodgkin lymphoma: Favorable outcomes of combined modality treatment for patients with non-Hodgkin lymphoma and positive interim or postchemotherapy FDG-PET. Int J Radiat Oncol Biol Phys 2012;83:e647-e654.