Treatment/Prognosis

Question 1

What is the management paradigm for an immunocompetent pt with PCNSL and KPS ≥40?

Answer 1

PCNSL management paradigm: high-dose Mtx (good CNS penetration) based regimen. If CR: consider: high-dose chemo with stem cell rescue, high-dose cytarabine +/– etoposide, or low-dose WRT.

If no CR: WBRT, or consider high-dose cytarabine +/– etoposide, or best supportive care.

Question 2

What is the management paradigm for a KPS <40?

Answer 2

Give steroids. If KPS improves, chemo, otherwise WBRT (24–36 Gy WBRT then boost to 45 Gy). (NCCN 2018)

Question 3

What is the 1st intervention in a symptomatic pt after Bx?

Answer 3

The use of high-dose steroids is the 1st intervention in a symptomatic pt after Bx.

Question 4

If a pt is suspected of harboring PCNSL, why should steroids not be started right away before obtaining a Bx?

Answer 4

Tumor regression (in 90%) with subsequent Bx yielding nondiagnostic results; Bx 1st → start of steroids (upfront steroids only for unstable pts)

Question 5

How does the RT response differ b/t PCNSL and other types of extranodal NHL?

Answer 5

PCNSL is very radioresistant (5-yr OS is 4%). Extranodal NHL response is 90%.

Question 6

How did the IELSG determine the prognostic groups that may predict for better survival?

Answer 6

Fererri AJ et al.: 378 pts from 1980–1999, HIV– with CNS lymphoma. All were treated with various regimens (+/– chemo, +/– RT). (JCO 2003)

Question 7

How do survival outcomes differ b/t CRT and RT alone?

Answer 7

MS is ∼44 mos (CRT) vs. ∼10–18 mos (RT alone). 5-yr OS is 30% (CRT) vs. 5% (RT alone).

Question 8

What % of pts are long-term survivors?

Answer 8

∼15%–20% long-term survival in contemporary clinical trials of Mtx-based chemo (+/– RT).

Question 9

What is the outcome of pts with ocular lymphoma?

Answer 9

The outcome of pts with ocular lymphoma is uniformly fatal. MS is only 6–18 mos.

Question 10

Is cyclophosphamide HCl/doxorubicin/Oncovin/prednisone (CHOP) effective against PCNSL? Is cyclophosphamide HCl/doxorubicin/Oncovin/dexamethasone (CHOD) effective?

Answer 10

No. There is ineffective blood–brain barrier penetration. 3 RCTs, including RTOG 8806 (Schultz C et al., JCO 1996), demonstrated no benefit of CHOP or CHOD.

Question 11

What pts should be considered for WBRT after chemo and to what dose?

Answer 11

This should be decided based on the response to chemo. In general should be given to younger pts, as WBRT may increase neurotoxicity especially in pts >60 yrs. The dose depends on the response. For CR after chemo, give WBRT 23.4 Gy in 1.8 Gy fx. If

Question 12

What were the results of the phase II trial on R-MPV f/b reduced-dose consolidative WBRT and cytarabine (Morris PG et al., JCO 2013)?

Answer 12

This was a multicenter phase II study of 52 pts receiving induction rituximab (Rituxan), Mtx, procarbazine, and vincristine (R-MPV) for 5–7 cycles, f/b reduced dose WBRT (23.4 Gy) for a CR or standrad WBRT (45 Gy) for nonCR. 60% had CR and rcvd reduced dose WBRT, with 3-year OS of 87% and 2-yr PFS of 77%. There was min neurotoxicity.

Question 13

Which study demonstrated that an RT boost is not beneficial for PCNSL?

Answer 13

RTOG 8315 (phase II): WBRT 40 Gy → CD to 60 Gy. MS was 11.5 mos. 80% failed in the boost field.

Question 14

What does the Memorial MSKCC data demonstrate on the use of high-dose Mtx + WBRT and the relation of age to developing neurotoxicity?

Answer 14

MSKCC data: phase II, 52 pts. MS was 60 mos. High-dose Mtx × 5 cycles (3.5 g/m2) was Alt intrathecal Mtx (12 mg) → procarbazine/vincristine + WBRT 45 Gy → high-dose cytosine arabinoside (Ara-C) (intravenous 3 mg × 2). Of those aged >60 yrs, some did not rcv RT. Survival was the same b/t no RT vs. RT, but DFS was worse if there was no RT. Those >60 yrs who rcvd RT had ↑ risk of neurotoxicity (83%) vs. age <60 yrs (6%). With chemo alone, only 1 pt developed neurotoxicity. (Abrey LE et al., JCO 2000)

Question 15

In the Abrey study, what was the response rate to pre-RT chemo?

Answer 15

CR 56% and PR 33% (ORR 89%). (Abrey LE et al., JCO 2000)

Question 16

In RTOG 9310, did 36 Gy (1.2 Gy bid) benefit PCNSL pts when compared to 45 Gy (conventional qd) WBRT?

Answer 16

RTOG 9310 (Fisher B et al., J Neurooncol 2005): no difference in control and survival, but worse neurotoxicity (23% vs. 4%); prospective study of Abrey chemo regimen → 45 Gy vs. 36 Gy bid (if CR to chemo) (63 pts rcvd 45 Gy, and 16 pts rcvd 36 Gy. MS was 37 mos).

Question 17

What were the results of RTOG 0227?

Answer 17

RTOG 0227 (Glass J et al., JCO 2016) was a phase I/II study of induction chemo with Mtx, rituximab, and TMZ, f/b hyperfractionated WBRT (hWBRT; 36 Gy in 1.2 Gy bid) and subsequent TMZ. In phase I, 13 pts rcvd increasing doses of TMZ, and in phase II, 53 pts were treated. 2-yr OS and PFS of 81% and 64%, respectively, were significantly improved compared to historical controls from RTOG 9310 (see above). 66% had G3/4 toxicity before hWBRT, and 45% had G3/4 toxicity attributed to hWBRT. Cognitive function and QOL improved/stabilized after hWBRT.

Question 18

What did the RCT of +/- consolidative WBRT by Thiel et al. show (JCO 2010)?

Answer 18

This was a multicenter, randomized phase III, noninferiority trial of 318 pts treated with high-dose Mtx + ifosfamide +/– WBRT. There was no OS difference (32.4 mos WBRT vs. 37.1 mos no WBRT). There was improved PFS in the WBRT arm but neurotoxicity was more common in the WBRT arm (49% vs. 26%).

Question 19

What are the CR rates with chemo and deferred RT after chemo?

Answer 19

Several phase II trials have tested this approach of chemo with deferred RT, with CR rates ranging from 42% to 61%, and OS from 14 to 55 mos. However some pts did not achieve CR and need WBRT, and even among those with CR, ∼half relapse.

Question 20

In pts with failure after high-dose Mtx without prior RT, what are the Tx options?

Answer 20

If the response duration >12 mos, options include: re-treating with high-dose Mtx, other systemic therapy, high-dose therapy with stem cell rescue. If the response duration <12 mos, WBRT or involved field RT with/without chemo, or consider high-dose therapy with stem cell rescue.

Question 21

What is the typical response rate to salvage WBRT for pts failing initial chemo?

Answer 21

CR 37%–58% and PR 21%–37% (Nguyen PL et al., JCO 2005; Hottinger AF et al., Neurology 2007)

Question 22

What critical volumes need to be covered with WBRT?

Answer 22

The post retina and CNS down to C2 need to be covered.

Question 23

What volumes are treated with RT if the pt presents with an ocular primary?

Answer 23

WBRT to C2, + bilat orbits with opposed lats to 36 Gy → CD to WBRT + post retina to 45 Gy

Question 24

How should AIDS+ PCNSL be treated?

Answer 24

The optimal therapy has not been well defined. High-dose Mtx therapy with steroids and antiretroviral therapy has been shown to offer palliation for up to 12–18 mos. In very select pts, can consider rituximab plus high-dose Mtx. WBRT has historically been the standard Tx, which leads to CR rates of 20%–50%, but survival is still very poor, ∼3.5 mos.

Question 25

What was the Tx regimen in RTOG 93–10? What was the MS?

Answer 25

Intravenous/intrathecal Mtx/vincristine/procarbazine → WBRT to 45 Gy → intravenous cytarabine. MS was 3 yrs. (DeAngelis LM et al., JCO 2002)

Question 26

What options are there for leptomeningeal PCNSL?

Answer 26

Intrathecal Mtx or high-dose Mtx. Alternative therapies include slow release cytarabine, systemic chemo, or CSI to 36 Gy with a boost to 45–50 Gy.

Question 27

What is the Tx paradigm for ocular lymphoma?

Answer 27

Ocular lymphoma Tx paradigm: RT to 36 Gy or intraocular chemo

Question 28

What is the rationale for omitting WBRT in the elderly with PCNSL?

Answer 28

Neurotoxicity in older pts (Abrey LE et al., JCO 2000): 80% of pts >60 yo had neurocognitive defects after 45 Gy; 6% if <60 yo. Some pts >60 yo did not get WBRT and had similar OS (worse DFS with no WBRT, however).

Question 29

What is the WBRT dose for PCNSL after CR to chemo?

Answer 29

24–36 Gy. Consider omitting RT altogether if the pt is >60 yo.

Question 30

What is the WBRT dose for PCNSL after PR to chemo?

Answer 30

36–45 Gy WBRT; focal CD to gross Dz to 45 Gy

Question 31

What is 1 additional systemic option after RT, especially after PR to initial chemo?

Answer 31

Consolidation high-dose cytarabine +/- etoposide is an additional option after RT.

Question 32

What is the role of rituximab in PCNSL? How can it be incorporated, and what studies support its use?

Answer 32

Can be used with Mtx/procarbazine/vincristine) as induction regimen → dose-reduced WBRT to 23.4 Gy if CR (45 Gy if PR) → Ara-C consolidation.

MSKCC data (Shah GD et al., JCO 2007): 2-yr OS, 67%, 2/3 pts had CR

Morris PG et al., JCO 2013: 3-yr OS 87%, 60% had CR

Question 33

What is another consolidative option in pts with a CR to chemo?

Answer 33

High-dose chemo with stem cell rescue, based on several single-arm phase II studies. 1 multicenter phase II study (Illerhause G et al., Blood 2012) of 79 pts (<65 yrs) rcvd induction chemo with Mtx, cytarabine, thiotepa and rituximab → high-dose carmustine/thiotepa + auto HCT (only those without CR after HCT, n = 10, had WBRT). The CR was 27% after induction chemo and 77% after HCT. The 2-year OS was 87%.

Question 34

What did RTOG 8315 investigate? What did it show?

Answer 34

RTOG 8315: RT alone/dose escalation (40 Gy + 20 Gy boost). There was high LR in the brain at 61% and significant neurotoxicity with higher doses. (Nelson DF et al., IJROBP 1992)

Question 35

Which recent randomized international phase II study investigated the use of induction cytarabine for PCNSL? What did it find?

Answer 35

IELSG (Ferreri AJ et al., Lancet 2009): randomized to 4 cycles of Mtx vs. Mtx/cytarabine → WBRT. CR rates were 18% vs. 46% and ORR 40% and 69%, respectively.

Question 36

What regimen was used in CALGB 50202 and what were the results?

Answer 36

Mtx, TMZ, and rituximab (MT-R) f/b etoposide/cytarabine consolidation (EA), with no WBRT. CR is 66% with 2-yr PFS of 57%—comparable to previous regimens with WBRT. (Rubenstein JL et al., JCO 2013)