Radiation Oncology/NHL/Randomized

Non-Hodgkin's Lymphoma

Diffuse Large B-Cell

• 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 assesable 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

Mantle Cell

• GLSG (Germany) -- CHOP +/- Rituxan
  • Randomized. 122 untreated patients, advanced-stage MCL. Treated with Arm 1) CHOP vs. Arm 2) R-CHOP. Patients <=65 with CR/PR second randomization to ASCT vs. IFN-alpha. Patients >65 received IFN-alpha maintenance
  • 2005 PMID 15668467 -- "Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG)." (Lenz G, J Clin Oncol. 2005 Mar 20;23(9):1984-92.)
    • Outcome: R-CHOP better for CR (34% vs. 7%, SS), and TTF (21 months vs. 14 months, SS), but no difference in PFS or OS
    • Conclusion: Better response rate, but no diffference in PFS or OS

Other

• Mexico (1981-91) — 1996 - Treatment of non-Hodgkin's lymphoma of Waldeyer's ring: radiotherapy versus chemotherapy versus combined therapy. (Aviles A, Eur J Cancer B Oral Oncol. 1996 Jan;32B(1):19-23.)
  • 316 pts. Phase III. Stage I NHL of Waldeyer's ring. Randomized to extended-field RT alone, chemotherapy alone (CHOP or CHOP-like), or combined therapy with chemo + RT.
  • Median f/u 6.8 yrs. CR in 93%, 87%, 97%. 5-yr FFS 48%, 45%, 83% (SS); OS 56%, 58%, 90% (SS).
  • Conclusion: improved results with combined chemo+RT.