Role of RT in aggressive non-Hodgkin's lymphoma -- presented at Koean Cancer Association in June 2014.

1. 1
RT in Aggressive NHL
Yong Chan Ahn, MD, PhD
Department of Radiation Oncology
Samsung Medical Center
Sungkyunkwan University School of Medicine

2. Early stage DLBCL:
Pre-Retuximab Era
• 4 randomized controlled trials:
SWOG 8736
ECOG 1484
GELA LNH 93-1
GELA LNH 93-4

5. SWOG 8736:
CHOP #8 vs. CHOP #3 + RT (40-55 Gy)
• CHOP #8: more cardio- and myelotoxicity
• CHOP #3 + RT: may be inadequate in some subgroup
• Overlap of FFS and OS between groups on update with
8.2 yrs’ F/U (Miller. ASH 2001)

6. • Underpowered study: 172 Pts; 50% of registered Pts
were not randomized; 20% of CR Pts did not receive
assigned Tx
• No causes of death provided; CHOP #8 is quite toxic.
ECOG 1484:
CHOP #8 ± RT (30-40 Gy)

7. GELA LNH 93-1 (<60 years):
ACBVP #3 vs. CHOP #3 + IFRT (40 Gy)
• CHOP + IFRT: 23 % of recurrences within RT field only;
significantly worse than SWOG CHOP + IFRT
• ACVBP: 41% of recurrences at initial site only;
significantly toxic & not justified (20% hospitalization)

8. • Poor compliance in RT delivery: median 5 wks’ delay of RT;
12% no RT as assigned; 23% under-dosed RT
• CMT: 21% of recurrences in RT field only; 66% outside only
• CTx alone: 47% of recurrences at initial site only; 37% at
distant site only
GELA LNH 93-4 (>60 years):
CHOP #4 ± IFRT (40 Gy)

9. Response Rate
• Divergences in response assessments:
• Neither overall RR (N=1,198) nor CR
(N=1,483) were different between groups

10. Patterns of Failure
Trials # Relapses
# Isolated relapses
at initial sites
Crude isolated
relapse rate
ECOG
CHOP #8 (N=93) 31 15 (48%) 16.1%
CHOP #8 + RT (N=79) 17 3 (17%) 3.8%
GELA 93-1
ACVBP (N=318) 42 17 (41%) 5.3%
CHOP #3 + RT (N=329) 78 18 (23%) 5.5%
GELA 93-4
CHOP #4 (N=277) 79 37 (47%) 13.4%
CHOP #4 + RT (N=299) 66 14 (21%) 4.7%

11. Progression-free Survival
• Heterogeneity in groups:
– ECOG 1484: insufficient data for ITT analysis
– GELA LNH 93-1: considerable differences in
intensity and duration of CTx in both arms
• PFS was longer for CMT

12. Overall Survival
• Results could not be pooled d/t
heterogeneity.
• No clear evidence on OS improvement by
adding RT.
Toxicity
• Results could not be pooled d/t differences
in reporting.
• RT appeared to be well tolerated.

13. Summary
• RT prolongs PFS, with no impact on OS.
• RT must be considered an option for
patients who cannot tolerate high dose or
prolonged schedule of CTx.

14. Advanced stage DLBCL:
Pre-Retuximab Era
• Aviles (Mexico), RCT, 1994
• Ferreri (Italy), Retrospective, 2000
• Schlembach (MDACC), Retrospective, 2000
• Aviles (Mexico), RCT, 2004

15. Ferreri et al. (Retrospective, 2000)
94 patients Tx arms Results p
Median 58 yrs
Stage III/IV (31%/69%)
•Bulky (≥10cm): 40%
•Semibulky (6-9cm): 60%
CR after CHOP-like
CTx  RT or no RT
<RT dose>
- EF: med 38 Gy
- IF: med 40 Gy
<Bulky>
Med TTR: 41+ vs 18 m
5-yr OS: 73% vs 57%
<Semi-bulky>
Med TTR: 26+ vs 20 m
5-yr OS: 59% vs 41%
0.05
0.05
0.01
0.09
• Prolonged TTR and improved 5-yr OS by RT:
• Dose ≥36 Gy was related to longer OS.
• IFRT and EFRT were similar.
• No Tx-related death.
• No RT-related 2nd malignancy.
Oncology 2000;58:219–226

16. Aviles et al. (RCT, 2004)
341 patients Tx arms Results p
Median 53-57 yrs
Stage IV
Bulky Dz: ≥ 10 cm
Clinical risk: high,
high intermediate
CTx  CR:
Randomized:
RT (40 Gy) (N=168)
Obs (N=173)
5-yr EFS:
82% vs. 55%
5-yr OS:
87% vs. 66%
0.01
0.01
• More frequent relapse at initial site in Obs arm
(63%) than in RT arm (7%).
• RT was well-tolerated with acceptable toxicity.
• RT improved EFS and OS in Pts with worse prognostic
factors.  RT should be part of initial Tx in this setting.
Leuk Lymphoma 2004;45:1385-1389

17. Post-Retuximab Era
• Retrospective experiences: MDACC; Duke
• RICOVER-60 vs RICOVER-NoRTh
• UNFOLDER trial – interim analysis

18. 469 DLBCL Pts treated at MDACC
(Jan 2001~Dec 2007)
Pts with CR  RT (30-39.6 Gy)
Pts with PR  salvage CTx

19. Longer OS/PFS by matched-pair analyses:
• Pt who received 6-8 cycles of R-CHOP ± RT
• 3 factors: bulky status, response, IPI score
• 44 pairs in stage I/II, 74 pairs in stage I~IV

20. • No in-field failure in Pts receiving RT!
Stage + RT - RT p
5-Y OS
I/II 92% 73% 0.0007
III/IV 89% 66% 0.008
5-Y PFS
I/II 82% 68% 0.003
III/IV 76% 55% 0.003

21. Summary of MDACC Data
• Lessons from 4 randomized trials:
– RT achieved LC at original disease site when
used with Abb-CTx.
– Abb-CTx failed to control disease at distant
sites and was responsible for inferior outcome.
• Bulky disease did not affect outcome in
relation to RT:
– All Pts (± bulky Dz) benefited from RT.
– This signifies importance of RT as
complementary to CTx.

22. • 79 stage III-IV DLBCL (1991 to 2009)
• CR following med #6 CTx: R-CHOP (65%);
CHOP (22%); other (13%)
• Consol ISRT (med 25 Gy) in 38 (48%) Pts.

23. Summary of Duke Data
• Improved in-field control (92% vs. 69%,
p=0.028) and EFS (85% vs. 65%, p=0.014)
• No OS difference (85% vs. 78%, p=0.15)
• Pts with stage III-IV DLBCL who achieve CR
on post-CTx imaging have improved in-
field control and EFS with low-dose
consolidation RT.

25. Between January 2001 and June 2004
124 CR Pts after R-CHOP14  IFRT (30 Gy) vs. Obs
“Closed prematurely”
Acute toxicity was mild and well tolerated.
IFRT in mediastinal B-cell lymphoma who achieved CR
remain as the best.
10-year PFS 10-year OS
IFRT (N=63) 72% 72%
Obs (N=61) 20% 31%
p <0.001 <0.001
Incredible?!

26. • Best arm of RICOVER-60 trial (N=117) vs
RICOVER-noRTh (N=47) in Pts with bulky Dz:
#6 R-CHOP-14+2R ± IFRT (36 Gy)

27. Additive RT to bulky
sites abrogates
bulky disease as a
risk factor and
improves outcome
of elderly patients
with aggressive B-
cell lymphoma.
ITT Per protocol

29. Optimal RT Volume & Dose?
• SMC Data, 2010
• BCCA Data, 2012

30. • 86 Pts with stage I/II H&N DLBCL
– CHOP-based CTx + ILRT
• 38-54 Gy (median 41.4 Gy) in 1.8 or 2.0 Gy/ fx (daily)
– Mostly 40-45 Gy (for 94.2%)
• ILRT = similar to INRT in Hodgkin lymphoma
 CTV: Pre-CTx gross tumor with 1 cm margin
– Restricted by post-CTx anatomic limits
– Total margin from CTV to field edge was 1~2 cm
IJROBP 2010

31. IJROBP 2010
• Pts with stage I/II H&N DLBCL did not need whole-neck
irradiation.
• ILRT might reduce RT toxicity with favorable outcomes.

32. • Limited stage DLBCL (Stage IA/IIA, non-bulky Dz)
• #3 CHOP or CHOP-like CTx and RT
• 1981~1996: IFRT (N=138)
• 1996~2007: INRT ≤ 5cm (Pre-CTx volume + ≤5 cm)
(N=150)
Optimal RT field
Cancer 2012

33. Cancer 2012

34. Cancer 2012

37. Toxicity Issue
• Significant dose-related cardiac toxicity by
Doxorubicin-based CTx.
(Hershman et al, JCO 2008)
• Reduced cardiac toxicity by less CTx in
CMT.
(Pugh et al, IJROBP 2010)
• No increased 2nd cancer risk by additional
RT in large cohort studies.
(Mudie et al, JCO 2006, Tward et al, Cancer 2006, Sacchi et al Haematologica
2008)

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