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RT in Aggressive NHL

Yong Chan Ahn, MD, PhD Department of Radiation Oncology

Samsung Medical Center

Sungkyunkwan University School of Medicine

Early stage DLBCL: Pre-Retuximab Era

• 4 randomized controlled trials:

SWOG 8736

ECOG 1484

GELA LNH 93-1

GELA LNH 93-4

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)

• 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)

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)

• 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)

Response Rate • Divergences in response assessments:

• Neither overall RR (N=1,198) nor CR (N=1,483) were different between groups

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%

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

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.

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.

Advanced stage DLBCL: Pre-Retuximab Era

• Aviles (Mexico), RCT, 1994

• Ferreri (Italy), Retrospective, 2000

• Schlembach (MDACC), Retrospective, 2000

• Aviles (Mexico), RCT, 2004

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

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

Post-Retuximab Era

• Retrospective experiences: MDACC; Duke

• RICOVER-60 vs RICOVER-NoRTh

• UNFOLDER trial – interim analysis

469 DLBCL Pts treated at MDACC (Jan 2001~Dec 2007)

Pts with CR RT (30-39.6 Gy) Pts with PR salvage CTx

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

• 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

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.

• 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.

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.

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?!

• 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)

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

Optimal RT Volume & Dose?

• SMC Data, 2010

• BCCA Data, 2012

• 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

IJROBP 2010

• Pts with stage I/II H&N DLBCL did not need whole-neck

irradiation.

• ILRT might reduce RT toxicity with favorable outcomes.

• 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

Cancer 2012

Cancer 2012

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)

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)