Radiotherapy in DLCL is often worthwhile. Dr. Joachim Yahalom Memorial Sloan-Kettering, New York

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1 Radiotherapy in DLCL is often worthwhile Dr. Joachim Yahalom Memorial Sloan-Kettering, New York

2 The case for radiotherapy Past: Pre-Rituximab randomized trials Present: R-CHOP as backbone, retrospective data Upcoming data: Finally, a randomized trial with RT question (UNFOLDER) Data on value of RT to bulky sites PET as treatment- or RT dose- modifier Shrinking the involved RT field (involved-node or involved site)- New ILROG Guidelines Adaptive RT dose

3 Chemo alone vs. CMT pre-rituximab trials Trial Pt. Characteristics No. Treatment Arms Results p-value SWOG, 1998 Median age: 59 Normal LDH: 80% PS 0-1: 97% % stage II: 33% Excl. bulky stage II 401 CHOPx3+RT CHOPx8 5-yr PFS: 77% 5-yr OS: 92% 5-yr PFS: 64% 5-yr OS: 72% p=0.03 p=0.02 ECOG, 2004 Median age: 59 PS 0-1: 92% % stage II: 68% % bulky: 31% 399 CHOPx8: RT If CR (n=215) no RT If PR (n=71) RT 6-yr FFS: 70% 6-yr OS: 79% 6-yr FFS: 53% 6-yr OS: 67% 6-yr FFS: 63% 6yr OS: 69% p=0.05 p=0.23 LNH Median age: 47 Normal LDH, PS 0-1 % stage II: 32% % bulky: 11% 647 CHOPx3+RT ACVBP 5-yr EFS: 74% 5-yr OS: 81% 5-yr EFS: 82% 5-yr OS: 90% p<0.001 p=0.001 LNH Median Age: 68 Normal LDH, PS 0-1 % stage II: 32% % bulky: 9% 574 CHOPx4+RT CHOPx4 5 yr EFS: 64% 5-yr OS: 68% 5-yr EFS: 61% 5-yr OS: 72% p=0.56 p=0.54

4 SWOG 8736 randomized trial Stage II 32% Bulky 3%

5 SWOG 8736 trial Chemotherapy alone compared with chemotherapy plus RT for localised intermediate and high grade lymphoma Miller et al 1998 NEJM 339 (1) PFS and OS curves of began to overlap at 7 years and at 9 years after treatment, respectively

6 Miller TP, et al., ASH, STILL UNPUBLISHED

7 Pt. Characteristics No. Treatment Arms Results p-value Median age: 59 Normal LDH: 80% PS 0-1: 97% % stage II: 33% Excl. bulky stage II 401 CHOPx3+RT CHOPx8 5-yr PFS: 77% 5-yr OS: 92% 5-yr PFS: 64% 5-yr OS: 72% p=0.03 p= RT can substitute for 5 cycles of CHOP and provide significantly better outcome - Increased cardiac toxicity with prolonged chemo - Excellent outcome in pts with SA IPI of 0 treated with CHOPx3 +RT - Updated data at median f/u of 8.2 yrs: FFS and OS curves overlapped - Is CHOPX3 adequate for all? Miller. NEJM, 1998 Miller. ASH, 2001

8 ECOG 1484 randomized trial Stage II- 68% Bulky- 31% Ex nodal- 47%

9 ECOG 1484 Pt. Characteristics No. Treatment Arms Results p-value Median age: 59 % stage II: 68% % bulky: 31% 399 CHOPx8: If CR (n=215) RT no RT 6-yr FFS: 70% 6-yr OS: 79% 6-yr FFS: 53% 6-yr OS: 67% p=0.05 p=0.23 If PR (n=71) RT 6-yr FFS: 63% 6yr OS: 69% 50% of registered were not randomized - Not powered to detect < 20% increase in OS with RT - 20% of CR pts did not receive assigned treatment - More bulky pts in RT arm vs observation arm: 26% vs 17% - No information on type of mortality events when median age of survivors is over 70. Horning. JCO, 2004

10 % Time to Progression in CR Patients According to Consolidation % TTP Yr RT Obs p = 0.06 RT (79) Obs (93) Years

11 CHOP +/- RT for Limited Stage Aggressive NHL % OS in CR Patients Yr RT Obs p = 0.24 Update of ECOG Trial 1484 OS CR 30 Gy CR Obs PR 40 Gy Years

12 GELA LNH 93-1 randomized trial Stage II-32% Bulky-11%

13 GELA LHN 93-1 (age<60) Pt. Characteristics No. Treatment Arms Results p-value Median age: 47 Normal LDH, PS 0-1 % stage II: 32% % bulky: 11% 647 CHOPx3+RT ACVBP 5-yr EFS: 74% 5-yr OS: 81% 5-yr EFS: 82% 5-yr OS: 90% p<0.001 p= No difference in non-bulky (<10 cm) pts. - ACVBP: established survival advantage over 8 cycles of CHOP in advanced-stage pts - High rate of short and long-term toxicity of ACVBP - Difficult to justify ACVBP in low-risk pts Reyes. NEJM, 2005

14 GELA NHL 93-4 randomized trial Stage II- 32% Bulky - 8%

15 GELA LNH 93-4 (age>60) Pt. Characteristics No. Treatment Arms Results p-value Median Age: 68 Normal LDH, PS 0-1 % stage II: 32% % bulky: 8% 574 CHOPx4+RT CHOPx4 5 yr EFS: 64% 5-yr OS: 68% 5-yr EFS: 61% 5-yr OS: 72% p=0.56 p= Long delay between chemo to RT (median 7 weeks) - 12% pts did not receive RT as assigned, 23% underdosed. No quality assurance reported. - 23% failure in RT field (34% with local component) - More deaths from lymphoma progression in the RT arm (70 vs 65) difficult to explain - More deaths from SM in the RT arm (20 vs 9), though only 3 of 20 SM were in-field Bonnet. JCO, 2007

16 Large cohort studies failing to show increased SM risk with addition of RT: BNLI: Retrospective cohort study of 2,456 NHL pts SIR of solid cancer in no-rt cohort: 1.0 (95% CI, ) SIR of solid cancer in RT cohort: 1.2 (95% CI, ) SEER: Retrospective cohort study of 77,823 NHL pts : SIR of SM in no-rt cohort: 1.13 (95% CI, ) SIR of SM in RT cohort: 1.18 (95% CI, ) GISL: Retrospective cohort study of 1,280 DLBCL pts: SIR of SM in no-rt cohort: 1.16 (95% CI, ) SIR of SM in RT cohort: 0.92 (95% CI, ) Mudie et al. JCO 24:1568, 2006; Tward et al. Cancer 107:108, 2006; Sacchi et al. Haematologica 93: 298, 2008

17 Significant Dose-Related Cardiac Toxicity of Doxorubicin-Based Chemo: HR: 1.29, p< SEER-Medicare: - 9,438 patients age>65 with DLBCL (42% received doxo-based chemo) - Cox model after adjustment for age, gender, race, comorbidity, cardiac risk factors: HR for CHF no doxo chemo ref 1-3 cycles: cycles: 1.24 > 6 cycles: 1.47 Hershman. JCO 2008

18 Significantly Reduced Cardiac Mortality in Pts Treated with RT- May be Due to Use of Less Chemo: SEER Study: - 15,454 pts with stage I-II DLBCL diagnosed between from SEER database (39% received RT) - Significantly reduced risk of cardiac mortality with RT use (RR 0.74, 95% CI ) - MVA showed persistent protective effect of RT after controlling for age, gender, race stage, and extranodal disease Pugh. IJROBP 2010

19 Limited Disease ~ Aggressive Histology (SWOG 0014) Treatment Plan WEEKS R CHOP + R CHOP + R CHOP + R Involved-Field Radiotherapy (IFRT) R = Rituximab CHOP = cyclophosphamide, 750mg/m 2 doxorubicin, 50mg/m 2 vincristine, 2.0mg prednisone, 100mg x 5days IFRT = GY

20 SWOG Limited Stage 4xR + 3x CHOP + IFRT (40-46 Gy) Persky et al., J Clin Oncol 2008

21 Benefit of consolidative Radiation Therapy in Patients with DLBC treated with R-CHOP achieving CR (291 pts) Phan et al JCO 28 (27) % 73% 19 % 14 % Overall Survival Progression Free Survival 5 yr OS and PFS for stage I and II disease - R-CHOP + RT 92% and 82%, respectively; no RT, OS and PFS were 73% (P =.0007) and 68% (P =.0003), Improvements in PFS and OS also seen for minority with stage III and IV disease receiving RT. None of the patients experienced treatment failure in the RT field.

22 MD Anderson Experience 469 pts with DLBCL (30% received consolidative RT) Among 291 pts treated with R-CHOP and achieved CR, RT associated with significantly higher 5y OS and PFS MVA: RT associated with significantly improved PFS (HR, 0.19) and OS (HR, 0.32) Phan. JCO, 2010

23 Randomize patients in CR

24 Second Interim analysis by DSMC pts. July 2012 UNFOLDER Study (Germany) Age <60 aaipi=1 or aaipi=0 with bulky disease >7.5cm Randomize patients in CR

25 Reducing RT field in limited stage DLBCL Reducing the field from involved or regional field to involved site field was effective and safe. Pre-chemotherapy involved nodes No increase in in-field or marginal failures. Campbell B et al from Vancouver- Cancer 2012 INRT IFRT

26 IFRT Pre-chemotherapy involved nodes INRT 5cm

27 Patterns of failure Total (n = 288) IFRT (n = 138) INRT 5cm (n = 150) Total relapses 22% 23% 21% Infield relapse only 2% 2% 1% Distant relapse without infield relapse Distant only Marginal only Marginal + distant 17% 17% 17% % 13% 2% 2% Distant + infield relapse 3% 4% 3%

28 BNLI STUDY DESIGN PATIENT ELIGIBLE LOW GRADE LYMPHOMA INTERMEDIATE OR HIGH GRADE LYMPHOMA RANDOMISE RANDOMISE 24Gy 12 fractions 40-45Gy 45Gy fractions 30Gy 15 fractions 40-45Gy 45Gy fractions

29 30 Gy vs Gy Median f/u 5.6 yrs: 30 Gy Gy p-value (n=319) (n=321) CR 82% 83% - 5y FFLP 82% 84% y OS 64% 68% 0.29 Caveats: Included pts treated with RT alone or receiving salvage/palliative RT No chemo data, mostly without rituximab Lack of functional imaging to determine response to chemo Lowry et al Radiother Oncol 2011

30 When will RT exert the most benefit? Distribution of disease is restricted to site(s) that can be encompassed in a contiguous limited RT field RT can reduce the need for long intensive and more toxic chemotherapy Elderly patients (poor tolerance, limited salvage options) Bulky disease or extranodal disease Sub-optimal response to chemotherapy (PET positive or?) Special sanctuary sites (testis, CNS)

31

32 PET-Based Treatment Algorithm for Consolidative Radiation Therapy PET Neg Observe R-CHOP x 6-8 Residual 2cm PET Pos XRT If feasible Sehn et al., ASH 2010, Abstract # 854

33 Overall Survival According to PET Status and XRT (n=187) Percent Survival Pos PET-No XRT Pos PET-XRT Neg PET Time (years) Sehn et al., ASH 2010, Abstract #

34 SWOG Approach for Limited Stage 4xR + 3x CHOP + IFRT (40-46 Gy Persky et al., J Clin Oncol 2008