Is There an Indication for First Line Radiotherapy in Primary CNS Lymphoma?
Abstract
:Simple Summary
Abstract
1. Introduction
2. Methods
3. Results of Clinical Trials
3.1. Radiation as Monotherapy in First Line Setting—Lessons from the Past
3.2. MTX Based Chemotherapy Can Confer Long Term Survival—Is Standard Dose Consolidating WBRT Beneficial?
3.3. Consolidating WBRT vs. ASCT
3.4. Combination of High-Dose Chemotherapy and Consolidating Reduced Dose Cranial Irradiation—Merging the Best of Two Worlds?
3.5. Neurotoxicity after Radiotherapy for CNS-Lymphoma—“The Brain Is an Unforgiving Organ” [20]
3.6. Local Radiotherapy of Residual Disease after Chemotherapy—A New Option?
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Author (Year) | Trial | Patient Number | Inclusion Criteria (Age/KPS) | Chemotherapy | Radiotherapy | Endpoint (PFS/OS) | Remarks/Neurotoxicity |
---|---|---|---|---|---|---|---|
Nelson et al. (1992) RTOG 8315 [9] | Phase II Single-arm | N = 41 | ≥18 y, no HIV, no systemic lymphoma, KPS: ≥40 | - | WBRT: SD: 1.8 Gy, ED: 40 Gy + boost tumor: 20 Gy | Median OS: 11.6 m 88% failure in 60 Gy region | Prognostic factors: KPS (p = 0.002) sex (p = 0.032) |
DeAngelis et al. (1992) [11] | Phase II Single arm, Group R: late patients | N = 47 A) N = 31 R) N = 16 | no HIV | Group A: 1 × MTX 1 g/m2 + 6 × 12 mg MTX i.th., Consolidation after RT: 2 × AraC 3 g/m2, Group R: RT alone | Group A and R: WBRT: SD: 2 Gy, ED: 40 Gy + boost: SD: 1.8 Gy, ED: 14.4 Gy | PFS: A: 41 m, R: 10 m OS: A: 42.5 m, R: 21.7 m | In pts with multiple lesions: no boost but WBRT: ED: 50 Gy; dementia in 3/31 patients |
O’Brien et al. (2000) [12] | Phase II Single arm | N = 46 | newly diagnosed PCNSL, only brain—no systemic lymphoma, no HIV, ECOG: 0–3 | 1 × MTX 1 g/m2—if CSF positive: intrathecal AraC as long as CSF positive, and 3 times more | WBRT: SD: 1.8 Gy, ED: 45 Gy + boost to tumor bed: SD: 1.8 Gy, ED: 5.4 Gy | median OS: 33 m 2 y-OS: 62% 2 y-PFS: 65% | >3 lesions: no boost, but ED: 50.4 Gy; if CSF positive: CSI: SD: 1.5 Gy, ED: 35 Gy; severe neurotox in 6 pts. |
Bessell et al. (2002) [13] | Phase II, multicenter | N = 57 SD) N = 31 LD) N = 26 | no HIV, 70 y ≥ age, only brain—no systemic lymphoma | 1 cycle CHOD + 2 cycles BVAM | sd-WBRT: SD: 1.8 Gy, ED: 45 Gy + boost: SD: 2 Gy, ED: 10 Gy; rd-WBRT after CR: SD: 1.8 Gy, ED: 30.6 Gy | 3y-risk of relapse: sd-WBRT: 29%; rd-WBRT: 70% 3y-OS: 55% 3y-OS after CR: no significant difference between SD and LD | CR: sd-WBRT: 68% rd-WBRT: 77%; cogn. decline in CR 1 y after rd-WBRT: 0/13; after sd-WBRT: 6/10 ≥ 60 y |
Bessell et al. (2001) [25] | Phase II Single arm | N = 31 | no HIV, only brain—no systemic lymphoma | 1 cycle CHOD + 2 cycles BVAM | WBRT: SD: 1.8 Gy, ED: 45 Gy + boost SD: 2 Gy, ED: 10 Gy; if CSF positive: + CSI: SD: 1.4 Gy, ED: 35 Gy | median OS: 38 m 5 y-OS: 31% | age +/− 60 y major predictor; dementia occurred in 5/8 (62%) ≥ 60 |
DeAngelis et al. (2002) RTOG 9310 [14] | Phase II, multicenter | N = 102 N (RT) = 82 | newly diagnosed PCNSL, only brain—no systemic lymphoma, no HIV KPS: ≥50 | 5 cycles (MTX 2.5 mg/m2, vincristine, procarbazine) + 5 × 12 mg MTX i.th.—consolidation after RT: 2 × HD-AraC 3 g/m2 | RT-Group: SD: 1.8 Gy, ED: 45 Gy, amendments: if CR, SD: 1.2 Gy 2× daily, ED: 36 Gy, if PR: SD: 1.8 Gy, ED: 45 Gy | median OS: 36.9 m <60: 50.4 m >60: 21.8 m 2 y-OS: 64% median PFS: 24 m <60: 38.8 m >60: 11.1 2 y-PFS: 50% | 15% severe neurologic toxicities, chemo: 53% Grade 3–4 toxicity |
Thiel et al. (2012) [3] | Phase III, randomized | N = 551 | newly diagnosed PCNSL, ≥18 y, no systemic lymphoma, life expectancy ≥2 m, no immunosuppression (Incl. HIV), KPS: ≥30 | (S): 05/2000–08/2006: HD-MTX (4 g/m2), 6 × 14-days-cycles 09/2006-05/2009: HD-MTX (same) + Ifo (1.5 g/m2), d: 3–5, 6 cycles (E): no CR: HD-AraC, 4× | Standard (S): SD: 1.8 Gy, ED: 45 Gy WBRT Experimental (E): only chemo | median OS: S: 32.4 m, E: 37.1 m median PFS: S: 18.3 m, E: 11.9 m Initial CR 47% arm before WBRT: 36% arm without WBRT: 58% | Primary endpoint OS (non-inferiority-margin 0.9) was not met, 318 patients treated per protocol; neurotoxicity more common after WBRT 49% vs. 26%; |
Morris et al. (2013) [5] | Phase II, single-arm | N = 52 | newly diagnosed PCNSL, ≥18 y, no HIV, no systemic lymphoma KPS: all | R-MPV: 5–7 cycles Consolidation: AraC after RT | CR: rd-WBRT SD: 1.8 Gy, ED: 23.4 Gy, no boost No CR: sd-WBRT: 1.8 Gy, ED: 45 Gy, no boost | median PFS: rd: 7.7 y vs. all: 3.3 y; 2 y-PFS rd: 77%; median OS: rd: 3 y-OS: 87%, median OS not reached vs. all median OS: 6.6 y | 60% achieved initial CR and later rdWBRT; no significant cognitive decline during the follow-up period, except for motor speed (p < 0.05). |
Glass et al. (2016) RTOG 0227 [15] | Phase (I+) II (Phase I TMZ) | (Ph.I: N = 13) Ph. II: N = 53 | newly diagnosed PCNSL, ≥18 y, only brain—no systemic lymphoma, no HIV | 5 cycles (rituximab + MTX (3.5 g/m2)) + 2 cycles TMZ, for 5 days (100–200 mg/m2) Consolidation: 10 cycles TMZ 200 mg/m2, for 5days | hyperfractionated WBRT: SD: 1.2 Gy twice-daily, ED: 36 Gy | 2 y-OS: 80.8% 2 y-PFS: 63.6% median OS: 7.5 y median PFS: 5.4 y | Mean improvement in MMSE: 2.1Decline: 3% |
Ferreri et al. (2017) IELSG32 [16] | international randomized Phase II | N = 219 N = 118 (2nd random.: 59:59) | newly diagnosed PCNSL, only brain—no systemic lymphoma, no HIV, 18–70 y, ECOG 0–3 | 1st random: 4 cycles of: A) MTX 3.5 mg/m2 + Ara B) MTX 3.5 mg/m2 + AraC + rituximab C) MTX 3.5 mg/m2 + AraC + rituximab + thiotepa 2nd random.: (D or E) E) carmustine-thiohepa conditioned ASCT | D) WBRT: SD: 1.8 Gy, ED: 36 Gy PR: + boost: SD: 1.8 Gy, ED: 9 Gy | 2 y-PFS: (p = 0.17) D): 80%, E): 69% 2 y-OS: (p = 0.12) D) 85%, E) 71% 4 y-OS: (p = 0.39) MATRix +D) or E): D) 85%, E) 83% CR before D: 54%, total CR after D: 95% CR before E: 53%, total CR after E: 93% | Chemo: MATRix (Group C) “best”: 4 y OS: 80%, 2nd randomization not designed to prove superiority of either arm, 2 deaths after ASCT (infections); mild cognitive decline after WBRT |
Houillier et al. (2019) Precis [17] | Phase II, randomized, 2-arm-study | N = 140 analysed: N = 38 in each arm | newly diagnosed PCNSL, 18–60 y | 2 cylces R-MBVP (rituximab, MTX, VP16, BCNU) + 2 cylces R-AraC (+2× intrathecal AraC if CSF pos.)ArmB: thiotepa, busulfan, CPM with ASCT | Arm A: WBRT: SD: 2 Gy, ED: 40 Gy | 2 y-PFS: A: 63%, B: 87% 2 y-OS: A: 75%, B: 66% 4 y-OS: A: 64%, B: 66% Initial CR rate: 46% | Treatment related deaths ASCT: 5 pts = 11% of per protocol population, WBRT: 1 pt; more neurotoxicity after WBRT |
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Seidel, C.; Viehweger, C.; Kortmann, R.-D. Is There an Indication for First Line Radiotherapy in Primary CNS Lymphoma? Cancers 2021, 13, 2580. https://doi.org/10.3390/cancers13112580
Seidel C, Viehweger C, Kortmann R-D. Is There an Indication for First Line Radiotherapy in Primary CNS Lymphoma? Cancers. 2021; 13(11):2580. https://doi.org/10.3390/cancers13112580
Chicago/Turabian StyleSeidel, Clemens, Christine Viehweger, and Rolf-Dieter Kortmann. 2021. "Is There an Indication for First Line Radiotherapy in Primary CNS Lymphoma?" Cancers 13, no. 11: 2580. https://doi.org/10.3390/cancers13112580