# Radiation Oncology/NHL/Treatment high grade

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
* Non-Hodgkin lymphoma: Main Page | Randomized
* Overview: Overview |
* Follicular |
* Diffuse large B-cell |
* MALT |
* Nodal marginal zone |
* Mantle cell |
* CLL/SLL |
* Lymphoblastic |
* Burkitt |
* NK/T cell |
* Anaplastic large cell |
* Primary CNS Lymphoma
* Treatment:
* Aggressive |
* Specific sites |
* Radioimmunotherapy

## Aggressive Lymphomas

* Diffuse large B-cell lymphoma
* NK/T-cell lymphoma
* Anaplastic large cell lymphoma

## Limited-stage aggressive histology

Three subgroups of patients with different outcomes and recommended treatment: Based on Stage-modified International Prognostic Index Proposed classification:
    From PMID 15210737 (No abstract), Miller TP. "The limits of limited stage lymphoma." J Clin Oncol. 2004 Aug 1;22(15):2982-4.
* "Very Limited" - Stage I or IE with 0 stage-modified risk factors.
    90% 5-yr survival. Treat with CHOP(3) + RT.
* "Limited" - Stage I, IE, II, IIE (no bulky II) with 1 or more risk factors
    70% 5-yr survival. Treat with CHOP(3) + RT.
* "Advanced" - Bulky II or bulky IIE.
    50% 5-yr survival. Treat with CHOP(8).

## Historical Overview

* RT alone standard of care until 1980. For laparotomy-verified Stage I, results very excellent. For non-verified Stage I, and particularly Stage II, results were poor
** Stage I: all comers 5-year OS ~50%; laparotomy-staged 5-year OS >90%
** Stage II: all comers 5-year OS ~20%; laparotomy-staged 35-55%
* University of Chicago experience suggested that recurrences were not prevented by extended fields, and that Stage II patients should be treated with chemotherapy
* Around 1980, several small trials demonstrated that adding chemotherapy after RT improved survival. The intent was to control microscopic systemic disease and reduce the size of the radiation fields.
** Stage I: 5-year RFS 94-100%
** Stage II: 5-year RFS 72-78%
* Based on experience in advanced disease, observational studies around the same time suggested that chemotherapy alone was sufficient. CHOP became established as the standard therapy in Stage III/IV disease, and began to be used for Stage I/II trials as well
* This resulted in SWOG-8736 Phase III trial, which compared CHOP x8 cycles alone to CHOP x3 cycles with involved field RT, in low risk patients (Stage I and non-bulky Stage II). Early results showed a survival benefit for the combined arm, and established it as the standard of care
* Unfortunately, long-term update (abstract only) showed an excess distant failure rate in the combined modality arm after 5 years, suggesting that CHOP x3 is not sufficient to control the systemic disease in these patients
* ECOG-1484 Phase III trial randomized higher risk patients (Stage I bulky/extranodal and Stage II) to CHOP x8 cycles alone versus CHOP x8 cycles + involved field RT. There was a disease-free survival benefit, but no overall survival benefit
* GELA 93-1 Phase III trial evaluated CHOP x4 + involved field RT with dose-intense ACVBP in IPI=0 patients <60 years old. There was a clear survival benefit to ACVBP. This strategy however did not gain wide acceptance in the USA due to its toxicity
* Finally, GELA 93-4 Phase III trial compared CHOP x4 alone versus CHOP x4 + involved field RT in IPI=0 patients >60 years old. There was no difference in EFS or OS. However, follow-up is still short, and there is a concern about more long-term failures as in SWOG-8736
* The already complicated situation became even more complicated with the introduction of Rituxan. Several trials established CHOP-R as superior to CHOP
* The exact role of RT and CHOP-R in the treatment of Stage I/II aggressive lymphomas needs to be clarified

## Primary RT

* British National Lymphoma Investigation, 2004 (1974-1997) PMID 15026794 -- "Long-term follow-up of patients treated with radiotherapy alone for early-stage histologically aggressive non-Hodgkin's lymphoma." (Spicer J, Br J Cancer. 2004 Mar 22;90(6):1151-5.)
** Retrospective. 377 patients treated with RT alone for early-stage diffuse large-cell lymphoma
** 10-year cause-specific survival: <60 years 75% vs. >60 years 47% (SS)
** Conclusion: RT alone not sufficient, even in elderly
* 1986 PMID 3518561 — "Factors predicting survival in adults with stage I and II large-cell lymphoma treated with primary radiation therapy." (Kaminski et al, Ann Intern Med 1986)
** 148 pts. Stage I-II large cell lymphoma, treated with RT with or without adjuvant chemo.
** 5-yr freedom-from-relapse was 25% and OS 35% for those with RT on one side of diaphragm; for those with transdiaghragmatic RT or RT + chemo, FFR and OS both 67%.

## Chemo-RT
### RT +/- Chemotherapy

* PMID 6406037, 1983 (1974-78) — "A randomized study of radiotherapy versus radiotherapy plus chemotherapy in stage I-II non-Hodgkin's lymphomas." Nissen NI et al. Cancer. 1983 Jul 1;52(1):1-7.
** Randomized. 73 pts. Stage I-II. Extended field RT +/- vincristine, streptonigrin, cyclophosphamide and prednisone. Fewer relapses in combined modality group but overall survival similar.

### Rituximab-Chemotherapy +/- RT

Ongoing
* DSHNHL-2004-3
-- "Phase III Randomized Study of Immunochemotherapy Comprising Rituximab, Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine, and Prednisone (R-CHOP) With Versus Without Radiotherapy in Patients With Previously Untreated, Low-Risk, Aggressive, B-Cell Non-Hodgkin's Lymphoma". Also known as UNFOLDER 21/14 study.
** Arm 1: R-CHOP-21 x6 alone
** Arm 2: R-CHOP-21 x6 + IFRT
** Arm 3: R-CHOP-14 x6 alone
** Arm 4: R-CHOP-14 x6 + RT
* MD Anderson; 2010 (2001-2007) PMID 20713859 -- "Benefit of Consolidative Radiation Therapy in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP Chemotherapy." (Phan J, J Clin Oncol. 2010 Aug 16. [Epub ahead of print])
** Retrospective. 469 patients, DLBCL. Stage I-II 40%, Stage III-IV 60%. Chemo 6+ cycles R-CHOP in 70%, RT given IFRT 30-39.6 Gy in 30% after chemo CR. Median F/U 3 years
** Outcome: On MVA, RT influenced OS and PFS. In matched-pair analysis (Stage I 44 pairs, all stages 74 pairs), RT improved OS (HR 0.5 and 0.3)
** Conclusion: Significant improvement in OS and PFS in patients who received consolidative RT after R-CHOP
* SWOG 0014 (2000-2002) PMID 18413640 -- "Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014." (Persky DO, J Clin Oncol. 2008 May 10;26(14):2258-63. Epub 2008 Apr 14.)
** Phase II. 60 patients, aggressive NHL, limited-stage disease and at least one adverse prognostic factor (nonbulky Stage II, age >60, WHO PS2, elevated LDH). R-CHOP x3 followed by IFRT 40-46 Gy. Median F/U 5.3 years
** Outcome: 2-year PFS 93%, 4-year PFS 88%. 2-year OS 95%, 4-year OS 92%. Compares favorably with historical SWOG 8736 4-year PFS 78% and OS 88%
** Conclusion: Addition of R to CHOP + IFRT met prespecified criteria of efficacy; but continued relapse

### Pre-Rituximab Chemotherapy +/- RT

* GELA LNH93-4 (France) (1993-2002) -- CHOP x4 vs. CHOP x4 + RT
** Randomized. Stopped early after no difference on interim analysis and new evidence showing Rituximab benefit. 576 patients. Age >60, localized Stage I-II aggressive lymphoma, IPI 0. Arm 1) CHOP x4 alone vs. Arm 2) IF-RT 40 Gy (involved nodes/extranodal + adjuacent uninvolved nodes)
** 7-year update, 2007 PMID 17228021 -- "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." (Bonnet C, J Clin Oncol. 2007 Mar 1;25(7):787-92.)
*** 5-year EFS: CHOP 61% vs. CHOP/RT 64% (NS). Survival affected by Stage II and male sex
*** Relapses: CHOP local 47%, distal 37%, both 16%; CHOP-RT in-field 21%, out-of-field 66%, both 13%
*** Second cancers: 29 (14%); 9 in CHOP alone vs. 20 in CHOP-RT
*** Subset analysis (49 patients) showed no benefit to RT in bulky disease either (small #)
*** Conclusion: No advantage to adding RT
** Comment: As a result of this study and GELA93-1, GELA abandoned RT in first line treatment of localized aggressive lymphoma. CHOP-R is used instead
** Editorial PMID 17228015 -- "Role of radiation therapy in localized aggressive lymphoma." (Ng AK, J Clin Oncol. 2007 Mar 1;25(7):757-9.)
* GELA LNH93-1 (France)(1993-2000) -- ACVBP vs. CHOP x3 + RT
** Randomized. 647 patientss, <61 years, localized Stage I or II aggressive lymphoma (Working Formulation: diffuse mixed, diffuse large (80%), or immunoblastic; or anaplastic according to Kiel), no age-adjusted IPI adverse features. Stage I 67%, extranodal involvement 49%, bulky disease 73%. Arm 1) CHOP x 3 + involved-field RT vs Arm 2) ACVBP plus sequential chemo consolidation (MTX, leucovorin, etoposide, ifosfamide, Ara-C). RT one month after last cycle of CHOP, 39.6 Gy. Involved field was involved nodal group and adjacent uninvolved nodes.
** 5-years; 2005 PMID 15788496 - "ACVBP versus CHOP plus Radiotherapy for Localized Aggressive Lymphoma." (Reyes F, N Engl J Med. 2005 Mar 24;352(12):1197-205.) Median F/U 7.7 years
*** Outcome: 5-year EFS ACVBP 82% vs CHOP-RT 74% (SS), true for both bulky and non-bulky subsets; OS 90% vs 81% (SS)
*** Conclusion: In younger patients, ACVBP + consolidation is better than CHOP x3 + RT
** Comment: ACVBP arm used higher doses of doxorubicin and cytoxan with higher dose intensity than CHOP and used a consolidation phase with different drugs not used during induction.
* National Medical Center, Mexico (1989-97) -- Residual disease: RT vs. Observation
** Randomized. 166 patients, DLBCL, high-intermediate/high clinical risk, with residual disease (<5 cm mass) after chemotherapy. Arm 1) RT 30/20 vs Arm 2) observation.
** 2005 PMID 16260856 — "Residual disease after chemotherapy in aggressive malignant lymphoma: the role of radiotherapy." (Aviles A, Med Oncol. 2005;22(4):383-7.) Median F/U 13.5 years
*** Outcome: 10-yr PFS RT 86% vs observation 32% (SS). Of 57 relapses in the observation arm, 31 were in the site of initial residual disease, 23 disseminated. 10-year OS 89% vs 58% (SS).
*** Conclusion: Salvage RT improves outcome in patients with residual disease after chemotherapy
* SWOG 8736 (1988-1995) -- CHOP x8 vs CHOP x3 + RT
** Randomized. 401 patients, intermediate/high grade (Working Formulation), Stage I-IE, or non-bulky (<=10 cm) II/II-E. 67% Stage I, 73% IPI 0-1. Arm 1) CHOP x 8 vs Arm 2) CHOP x 3 + involved field RT. RT dose was 40 Gy, with a boost to 50 Gy for residual disease (majority received 45-50 Gy)
** 5-years; 1998 PMID 9647875 — "Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma." (Miller TP, N Engl J Med. 1998 Jul 2;339(1):21-6.)
*** Outcome: 5-yr PFS CHOP-RT 77% vs CHOP 64% (SS), OS 82% vs 72% (SS). PFS by IPI: 0-1 77%, 2 60%, 3 34%
*** Toxicity: 2 deaths (CHOP arm neutropenia, RT arm RILD), Grade 4 CHOP 40% vs. RT 30% (p=0.06)
*** Conclusion: CHOP x3 + RT superior to CHOP x8
** 8-years; 2001 Abstract "CHOP Alone Compared to CHOP Plus Radiotherapy for Early Stage Aggressive Non-Hodgkin's Lymphomas: Updated of the SWOG Randomized Trial." (Miller TP, Blood 98: 724A, 2001, abstr 3024.) Median F/U 8.2 years
*** Outcome: 7-year FFS curves overlap (NS), 9-year OS curves overlap (NS). Continuous decline, with no plateau
*** By risk factors (age >60, elevated LDH, PS >1, Stage II): 5-year OS no RFs 94%, 1 RF 71%, 3 RFs 50%
*** Conclusion: Excess late (>5 years) relapses and deaths in CHOPx3-RT arm negate initial benefit. CHOPx3 + RT remains best standard treatment for Stage I and non-bulky Stage II, but optimal treatment may include more/different systemic chemo
** Histology; 2004 ASH Abstract -- "Histologic Subtypes Do Not Confer Unique Outcomes in Early-Stage Lymphoma: Long-Term Follow-Up of SWOG 8736." (Spier CM, Blood (ASH Annual Meeting Abstracts) 2004 104: Abstract 3263)
*** Outcome: 10-year OS and FFS no difference, no survival plateau. No difference by histology. Only 1 CNS failure (in a patient with testis involvement; none in Burkitt's Lymphoma)
*** Conclusion: Histology should not be used to exclude early stage intermediate/high grade patients
** Comment: Trial was trying to address if addition of RT can reduce amount of chemo required. Results from the abstract update suggest that 3 cycles of CHOP are insufficient, even in this reasonably low risk population, due to higher rate of late (>5 years) failures
* ECOG 1484 (1984-1992) - CHOP x 8 + RT vs CHOP x8
** Randomized. 352 patients, 172 assessable for +/- RT. Diffuse aggressive lymphoma (Working Formulation: diffuse large cell (80%), diffuse mixed large cell and small cell, and diffuse small cleaved cell). Stage I with risk factors (mediastinal or retroperitoneal involvement; or bulky disease > 10 cm), Stage IE, Stage II-IIE (68%). Patients in CR after 8 cycles of CHOP were randomized to Arm 1) 30 Gy involved-field RT vs Arm 2) observation. If PR, 40 Gy.
** 6-years; 2004 PMID 15210738 — "Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group study 1484." (Horning SJ, J Clin Oncol. 2004 Aug 1;22(15):3032-8. Epub 2004 Jun 21.) Median F/U for CR patients 12 years
*** CHOP x8 outcome: 69% assessable. CR 71% (n=172 assessable for +/- RT), PR 29% (treated with RT). Most patients with Stage II bulky disease had PR
*** RT randomization outcome (n=172): 6-year DFS RT 73% vs. control 56% (SS, p=0.05). 10-year OS 68% vs. 65% (NS)
*** RT boost outcome (n=71): 31% CR rate, median OS 9.9 years. Overall, 10-year DFS 78% for all patients treated with chemo + RT
*** Conclusion: After CHOP x8, low-dose RT provided better local control and DFS, with no impact on OS

### Historical Series

* British Columbia (1980-98)
** 308 pts. Chemo x 3 followed by involved-field RT.
** 2002 PMID 11773170 — "Brief chemotherapy and involved-region irradiation for limited-stage diffuse large-cell lymphoma: an 18-year experience from the British Columbia Cancer Agency." Shenkier TN et al. J Clin Oncol. 2002 Jan 1;20(1):197-204.
*** Median f/u 86 mo. OS and PFS 80% and 81% at 5 years and 63% and 74% at 10 years. Subgroups with high risk disease based on IPI had worse outcomes and need more aggressive treatment.
** 1987 PMID 3296898, 1987 — "Brief chemotherapy and involved field radiation therapy for limited-stage, histologically aggressive lymphoma." Connors JM et al. Ann Intern Med. 1987 Jul;107(1):25-30.
*** Original report
* Milan, 1993 (1985-90) - PMID 8478665 — "Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I or II histologically aggressive non-Hodgkin's lymphomas." Tondini C et al. J Clin Oncol 1993 Apr;11(4):720-5.
** Non-randomized. 183 pts. CHOP x 4 (or x6 if only PR). RT to 40 Gy to involved sites and 36 Gy to adjacent uninvolved regions.
** CR 98% after chemo/RT. 5-year RFS and OS 83%.
* Tucson/British Columbia, 1989 - PMID 2671279 — "Long-term follow-up and analysis for prognostic factors for patients with limited-stage diffuse large-cell lymphoma treated with initial chemotherapy with or without adjuvant radiotherapy." Jones SE et al. J Clin Oncol. 1989 Sep;7(9):1186-91.
** 142 pts. Two prospective trials, treated with CHOP with or without RT.
** RFS 82% at 5 yrs. No difference between groups.
* NCI, 1989 PMID 2788716 -- "Treatment of localized aggressive lymphomas with combination chemotherapy followed by involved-field radiation therapy." (Longo DL, J Clin Oncol. 1989 Sep;7(9):1295-302.)
** Prospective. 47 patients, Stage I/IE with aggresive lymphoma. Treated with Pro-MACE-MOPP x4 cycles followed by 40 Gy IFRT. Median F/U 3.5 years
** Outcome: 96% CR; toxicity 5% hospital admissions
** Conclusion: Safe and effective

## Primary Chemotherapy
### CHOP +/- Rituxan

* DSHNHL RICOVER-60 (2000-2005) -- CHOP-14 vs. CHOP-21, R-CHOP vs. CHOP
** Randomized, 4 arms. 1222 patients, DLBCL, age >60. Stage I-II 50%, Stage III-IV 50%. 2x2 design, CHOP-14 6 cycles vs. 8 cycles; and Rituximab vs. placebo. Arm 1) CHOP-14 x6 vs. Arm 2) CHOP-14 x8 vs. Arm 3) R-CHOP-14 x6 vs. Arm 4) R-CHOP-14 x8. RT 36 Gy given if initial bulky disease or extranodal disease (34%). Primary end point EFS.
** 3-years; 2008 PMID 18226581 -- "Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60)." (Pfreundschuh M, Lancet Oncol. 2008 Feb;9(2):105-16. Epub 2008 Jan 15.)
*** Outcome: 3-year EFS CHOP-14 x6 47% vs. CHOP-14 x8 53% vs. R-CHOP-14 x6 66% vs. R-CHOP-14 x8 63%; OS 68% vs. 66% vs. 78% vs. 72%. Using CHOP-14 x6 cycles as baseline, all intensified regimens SS improved EFS; OS only for R-CHOP-14 x6 cycles
*** Conclusion: Six cycles of R-CHOP-14 should be preferred treatment in elderly, no benefit for more cycles of chemo
* GELA 98-5 (1998-2000) -- CHOP vs. R-CHOP
** Randomized. 399 pts. 60-80 years old, Stage II-IV. Randomized to CHOP x8 vs R-CHOP x8 (both arms CHOP-21)
** 5-years, 2005 PMID 15867204 -- "Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte." (Feugier P, J Clin Oncol. 2005 Jun 20;23(18):4117-26.). Median F/U 5-years. Median follow-up 5 yrs.
*** 5-year EFS: CHOP 29% vs. R-CHOP 47% (SS). Median EFS CHOP 1.1 years vs. R-CHOP 3.8 years (SS)
*** 5-year outcomes: PFS 30% vs. 54% (SS); DFS 45% vs. 66% (SS); OS 45% vs. 58% (SS)
** 2002: PMID 11807147 — "CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma." Coiffier B et al. N Engl J Med. 2002 Jan 24;346(4):235-42.
** Conclusion: Addition of Rituxan leads to significant improvement for elderly patients; benefit in both low- and high-risk groups by IPI
* ECOG 4494 / CALGB / SWOG Intergroup -- CHOP vs. R-CHOP
** Abstract, 45th annual ASH meeting (Dec 2003) — "Rituximab-CHOP versus CHOP with or without maintenance rituximab in patients 60 years of age or older with diffuse large B-cell lymphoma (DLBCL): an update." Habermann TM et al. Blood 2004; 104:40a (abstract 127).
* MabThera trial -- CHOP vs. R-CHOP
** Randomized. 18 countries. 824 patients, <60 with DLBCL, Stage II-IV, IPI 0-1, or bulky Stage I. Treated with CHOP x6 vs. CHOP-R x6. RT given for bulky and extranodal disease
** 3 years, 2006 PMID 16648042 -- "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." (Pfreundschuh M, Lancet Oncol. 2006 May;7(5):379-91.). Median F/U 2.8 years
*** 3-year outcomes: OS CHOP-R 93% vs. CHOP 84% (SS), EFS 79% vs. 59% (SS)
*** Prognostic groups: favorable (IPI=0, no bulk) and unfavorable (IPI=1, bulk, or both)
*** Conclusion: CHOP-R is effective

### ACVBP vs. CHOP

* GELA, 2003 - PMID 12920037 - "Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma." Tilly H et al. Blood. 2003 Dec 15;102(13):4284-9.
** Randomized. Poor-risk aggressive NHL, elderly pts (ages 61-69), at least one aggressive factor on age-adjusted IPI. Randomized to ACVBP vs CHOPx8. No XRT. ACVBP consisted of induction phase and CNS prophylaxis followed by sequential consolidation. 635 pts.
** No diff in CR. 5-year event free survival 39% (ACVBP) vs 29%, and overall survival 46% vs 38%. More CNS relapses in CHOP group.
** Conclusion: Despite higher toxicity, ACVBP results in better EFS and OS

### Historical Series

* 1980 PMID 7002279, 1980 — "Management with chemotherapy only of stage I and II malignant lymphoma of aggressive histologic types." Cabanillas F et al. Cancer. 1980 Dec 1;46(11):2356-9.
** 30 pts. CR in 88%. 85% freedom-from-relapse.
* 1979 PMID 85006, 1979 — "Chemotherapy of localised histiocytic lymphoma." Miller TP. Lancet. 1979 Feb 17;1(8112):358-60.
** Original CHOP paper by Miller and Jones?

### Chemotherapy regimens

* CHOP - cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone
** H is for hydroxydaunomycin (doxorubicin). O is for Oncovin (vincristine).
* ACVBP doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone.
** Often used with a consolidation chemotherapy regimen using different drugs.
* Hyper-CVAD - cytoxan, vincristine, Adriamycin, decadron
* RICE - Rituxan, Ifosfamide, Carboplatin, Etoposide
* ESHAP - Etoposide, Methylprednisolone (Solu-medrol), High-dose Ara-C, and Cisplatinum
For CSF prophylaxis:
* IV and intrathecal methotrexate and ara-C

### Chemotherapy technique

* USA Survey, 2004 PMID 15381684 -- "Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin's lymphoma: a nationwide study." (Lyman GH, J Clin Oncol. 2004 Nov 1;22(21):4302-11.)
** Survey. 567 oncology practices, 4522 patients treated with CHOP, CHOP-R, CNOP.
** Relative dose-intensity (RDI): 53% patients received RDI less than 85% of minimum 6-cycles; Elderly: 60% patients received <85% of minimum RDI
** Predictors: age >60, advanced disease, poor PS, no prophylactic colony-stimulating factor use
** Conclusion: Patients frequently receive reduced dose in potentially curable NHL; better support recommended

## RT technique

Dose-Response
* British National Lymphoma Investigation; 2011 (1997-2005) PMID 21664710 -- "Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial." (Lowry L, Radiother Oncol. 2011 Jul;100(1):86-92.)
** Randomized, 640 pts w/ stage I-IV, aggressive non-Hodgkin's lymphomas, mostly DLBCL. Most treated as part of first-line therapy; 79% received prior chemotherapy. Control arm: 40-45 Gy in 2 Gy fractions. Experimental arm: 30 Gy in 15 fractions.
** No difference in complete response rate, freedom from local progression, overall survival between dose levels. 5-year freedom from local progression 83.5% high dose vs. 82.2% low dose.
** Separate group of indolent NHL randomized to 40-45 Gy vs 24 Gy also showed no difference in outcomes.
* Review: PMID 12633576, 2003 — "Influence of differing radiotherapy strategies on treatment results in diffuse large-cell lymphoma: a review." Nieder C et al. Cancer Treat Rev. 2003 Feb;29(1):11-9.
** For pts achieving CR, 30 - 30.6 Gy for <6 cm tumor, 40 Gy for 7-10 cm, 45 Gy for larger. For less than CR, insufficient data.
* MDACC; 2001 (1988-96) PMID 11163493 -- "Dose-response analysis for radiotherapy delivered to patients with intermediate-grade and large-cell immunoblastic lymphomas that have completely responded to CHOP-based induction chemotherapy." (Wilder RB, Int J Radiat Oncol Biol Phys. 2001 Jan 1;49(1):17-22.)
** 294 pts w/ Stage I-IV, intermediate-grade or large-cell immunoblastic lymphomas. Treated on 2 prospective trials.
** Recommend dose of 30 Gy - 30.6 Gy for tumors < 3.5 cm with CR after 3 cycles of chemotherapy. Recommend 39.6 Gy for tumors 3.5-10 cm with CR. Recommend 45 Gy for tumors > 10 cm with CR.
* U. Florida; 1999 PMID 10348285 -- "The impact of radiotherapy dose and other treatment-related and clinical factors on in-field control in stage I and II non-Hodgkin's lymphoma." (Kamath SS, Int J Radiat Oncol Biol Phys. 1999 Jun 1;44(3):563-8.)
** 285 pts w/ Stage I-II NHL (72 low grade, 92 intermediate to high grade, 21 unclassified). 159 treated w/ RT alone, 126 combined modality.
** 95 treatment failures with 12 in-field failures. Most failures occurred in contiguous non-irradiated areas.
Whole-abdomen irradiation
* Washington University; 1994 (1978-1990) PMID 8029434 -- "Non-Hodgkin lymphoma: whole-abdomen irradiation as an adjuvant to chemotherapy." (Valicenti RK, Radiology. 1994 Aug;192(2):571-6.)
** Retrospective. 39 patients with abdominal NHL, modified three-way abdomen irradiation
** Toxicity: decreased blood counts, enteritis
** Conclusion: Safe adjunct to chemo