Primary Central Nervous System Lymphoma
BACKGROUND
What are the incidence and median age at Dx of primary central nervous system lymphoma (PCNSL)?
1,000 cases/yr of PCNSL; median age 55 yrs (immunocompetent) vs. 35 yrs (immunocompromised)
What % of primary brain tumors are PCNSL?
∼4%
What is the sex predilection, and how does it relate to immunocompetency?
Immunocompetent pts: males > females (2:1)
AIDS pts: 95% males
What risk factors are often associated with CNS lymphoma?
Immunodeficiency (congenital or acquired) and EBV infection
What type of non-Hodgkin lymphoma (NHL) is most often associated with PCNSL?
Diffuse large B-cell lymphoma is most often associated with PCNSL.
What % of PCNSL has ocular involvement?
15% of PCNSL has ocular involvement (vitreous, retina, choroid > optic nerve) that is typically bilat.
What is the most common genetic alteration seen in PCNSL?
The most common genetic alteration in PCNSL is the gain of chromosome 12 (12p12–14), which corresponds to the amplification of MDM2 to enhance p53 suppression
If the pt presents with ocular lymphoma, what % later develop CNS involvement?
75% of pts who present with ocular lymphoma develop CNS involvement.
With what is orbital lymphoma often associated?
Systemic NHL is often associated with orbital lymphoma.
What % of pts present with isolated spinal cord/meningeal involvement?
<5% of pts present with isolated spinal cord/meningeal involvement.
What proportion of pts present with CSF involvement?
One-third of pts present with CSF involvement.
What % of pts present with PCNSL but have a negative systemic lymphoma workup?
Nearly all pts (>95%) who present with PCNSL have a negative lymphoma workup, so if lymphoma is found outside the CNS, it is NHL with involvement of the CNS.
What are the high-risk features of systemic NHL that increase the risk of CNS mets?
Burkitt, lymphoblastic lymphoma, immunocompromised pt, BM+, parameningeal presentation (nasopharynx, paranasal sinuses), and testicular relapse
What % of pts present with multifocal Dz?
Immunocompetent pts: 50%
AIDS pts: 100%
What % of pts with grossly unifocal Dz are actually microscopically multifocal?
>90% of pts with grossly unifocal Dz are microscopically multifocal.
What % of AIDS pts develop CNS lymphoma?
2%–13% of AIDS pts develop CNS lymphoma. Invariably all are EBV+.
What has happened to the incidence of PCNSL over the past 30 yrs?
There has been a dramatic increase (3-fold) in immunocompetent and immunocompromised PCNSL pts.
In what regions of the CNS does PCNSL arise?
Brain, spinal cord, leptomeninges, and globe (retina, vitreous)
What virus has been associated with PCNSL?
EBV has been associated with PCNSL (60% of immunocompromised cases).
Are B cells normally found in the CNS?
No. They develop as part of the pathologic process.
What is the more radioresistant NHL: intracranial or extracranial?
Intracranial. Per RTOG 8315, pts received 40 Gy WBRT + 20 Gy boost and 25 of 41 pts (61%) failed in the brain.
What % of PCNSLs are supratentorial?
The majority of PCNSLs (75%) are supratentorial.
WORKUP/STAGING
With which CNS symptoms do patients present?
Focal neurologic deficits (70%), neuropsychiatric/personality change (frontal lobe involvement [43%]), ↑ ICP ([33%] HA, n/v, CN VI deficit, blurred vision), seizures, leg weakness, urinary incontinence/retention, and ocular Sx (blurry vision)
With which systemic symptoms do patients present?
Fever, night sweats, and weight loss (80%)
All PCNSLs are what stage? What type of NHL?
All PCNSLs are stage IE. PCNSL is considered an extranodal NHL.
What brain location and specific structures are commonly involved?
The #1 location is the frontal lobe, often the deep white matter and frequently periventricular (↑CSF spread).
What are considered deep structures of the brain according to the International Extranodal Lymphoma Study Group (IELSG)?
Corpus callosum, basal ganglia, brainstem, and cerebellum
How is the Dx of ocular lymphoma made?
The Dx of ocular lymphoma is made by vitrectomy.
What infectious etiology is often confused with CNS lymphoma?
Toxoplasmosis is the infectious etiology often confused with CNS lymphoma.
What is the DDx?
Secondary metastatic lymphoma, other primary brain tumors, metastasis, abscess, hemorrhage, multiple sclerosis, sarcoidosis, and toxoplasmosis in AIDS
What is the workup of a pt suspected of having CNS lymphoma (per NCCN)?
Suspected CNS lymphoma workup: H&P (ophthalmic slit lamp exam to r/o ocular involvement), CBC, CMP, LDH, EBV titer, HIV status, CSF cytology (if safe), MRI, and tissue Bx, consider BM Bx, testicular US (men >60 yo)
What imaging studies should be performed?
MRI brain (MRI spine if Sx or CSF+), CT C/A/P, and SPECT (if immunocompromised)
What clinical scenario and testing results obviate the need for Bx for a definitive Dx?
In an AIDS pt, +EBV and +SPECT lead to a sensitivity/specificity of 90%–100%. If both are negative, treat empirically for toxoplasmosis. If only 1 is positive, perform a tissue Bx.
How does CNS lymphoma appear on MRI?
Indistinct fluffy borders, periventricular location common, T1 enhancement with gadolinium, and ring enhancement (due to central necrosis, often seen in AIDS)
When is PCNSL more likely to be multifocal?
PCNSL is more likely to be multifocal when the pt is immunocompromised (50%–80% of such pts).
What chemical abnormalities are seen in the CSF of pts with CNS lymphoma?
↑ Protein (85%), ↓ glucose (33%), ↑ LDH, ↑ β2-microglobulin
What additional tests are necessary for AIDS pts with a possible Dx of CNS lymphoma?
Toxoplasmosis titer (r/o this and other opportunistic infections) and BM Bx
How can the Dx of PCNSL be most definitively established?
Bx brain/globe or CSF sampling
What additional workup is done for pts with suspected PCNSL?
Additional PCNSL workup: H&P with neurology emphasis (include visual/spinal Sx), MRI brain +/– spine, and ocular slit lamp exam. Consider PET/CT and/or testicular US for elderly men (per NCCN), labs (basic, LDH, HIV, toxoplasmosis, +/– BM Bx), and LP with cytology if such testing would be safe.
What are the 5 poor prognostic factors for PCNSL according to the IELSG?
Poor prognostic factors for PCNSL:
1. Age >60 yrs
2. ECOG performance status >1
3. Elevated LDH
4. Elevated CSF protein
5. Deep brain involvement
(Fererri AJ et al., JCO 2003)
What is the 2-yr OS for pts with 0–1, 2–3, and 4–5 factors?
2-yr OS for these pts is 80%, 50%, and 15%, respectively. (Fererri AJ et al., JCO 2003)
What are other prognostic factors for PCNSL?
Poor response to chemo, AIDS, and multifocality
Who are considered “good-risk” immunocompromised pts with PCNSL?
Non-HIV immunosuppression and HIV+ with CD4 >200
TREATMENT/PROGNOSIS
What is the management paradigm for a immunocompetent pt with PCNSL and KPS ≥40?
PCNSL management paradigm: high-dose methotrexate (Mtx) (good CNS penetration) or multiagent chemo. If there is a CR, observe (particularly >60 yrs). Use RT for recurrence.
What is the management paradigm for a KPS <40?
Give steroids. If KPS improves, chemo, otherwise WBRT (per NCCN).
What is the 1st intervention in a symptomatic pt after Bx?
The use of high-dose steroids is the 1st intervention in a symptomatic pt after Bx.
If a pt is suspected of harboring PCNSL, why should steroids not be started right away before obtaining a Bx?
Tumor regression (in 90%) with subsequent Bx yielding nondiagnostic results; Bx 1st → start of steroids (upfront steroids only for unstable pts)
How does the RT response differ between PCNSL and other types of extranodal NHL?
PCNSL is very radioresistant (5-yr OS is 4%). Extranodal NHL response is 90%.
How did the IELSG determine the prognostic groups that may predict for better survival?
Fererri AJ et al.: 378 pts from 1980–1999, HIV– with CNS lymphoma. All were treated with various regimens (+/– chemo, +/– RT). (JCO 2003)
How do survival outcomes differ between CRT and RT alone?
MS is 40 mos (CRT) vs. 12 mos (RT alone). 5-yr OS is 30% (CRT) vs. 5% (RT alone).
What is the outcome of pts with ocular lymphoma?
The outcome of pts with ocular lymphoma is uniformly fatal. MS is only 6–18 mos.
Is cyclophosphamide HCl/doxorubicin/Oncovin/prednisone (CHOP) effective against PCNSL? Is cyclophosphamide HCl/doxorubicin/Oncovin/dexamethasone (CHOD) effective?
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.
Which study demonstrated that an RT boost is not beneficial for PCNSL?
RTOG 8315 (phase II): WBRT 40 Gy → CD to 60 Gy. MS was 11.5 mos. 80% failed in the boost field.
What does the Memorial Sloan Kettering Cancer Center (MSKCC) data demonstrate on the use of high-dose Mtx + WBRT and the relation of age to developing neurotoxicity?
MSKCC data: phase II, 52 pts. MS was 60 mos. High-dose Mtx × 5 cycles (3.5 g/m2) was alternated with 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 between 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)
In the Abrey study, what was the response rate to pre-RT chemo?
CR 56% and PR 33% (ORR 89%). (Abrey LE et al., JCO 2000)
In RTOG 9310, did 36 Gy (1.2 Gy bid) benefit PCNSL pts when compared to 45 Gy (conventional qd) WBRT?
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).
What study examined the feasibility of observation after CR to high-dose Mtx?
NABTT 96–07, phase II study (Batchlor T et al., JCO 2003): intravenous high-dose Mtx (8 g/m2) was given every 2 wks until CR or until 8 cycles. Once there was a CR, the pt rcvd 2 → high-dose Mtx q2wks and 11 cycles of high-dose Mtx q28d. MS was not reached at 22.8 mos. There was no neurotoxicity. CR was 52%, and PR was 22%.
In pts with failure after high-dose Mtx, what salvage RT regimens/doses are used?
45 Gy. Recent Massachusetts General Hospital data suggests 36 Gy WBRT (Nguyen PL et al., JCO 2005). MS s/p RT was 10.9 mos, and overall MS was 30 mos. There was neurotoxicity in 3 pts >60 yrs and in those who rcvd >36 Gy (31% vs. 0%).
What is the typical response rate to salvage WBRT for pts failing initial chemo?
CR 37% and PR 37% (Nguyen PL et al., JCO 2005)
What critical volumes need to be covered with WBRT?
The post retina and CNS down to C2 need to be covered.
What volumes are treated with RT if the pt presents with an ocular primary?
WBRT to C2, + bilat orbits with opposed lats to 36 Gy → CD to WBRT + post retina to 45 Gy
How should AIDS+ PCNSL be treated?
Trial of toxoplasmosis antibiotics. If there is no response, consider Bx. Chemo is not well tolerated. Consider intrathecal Mtx. Consider palliative WBRT alone (30–45 Gy). If the pt is severely immunocompromised, consider HAART 1st.
Why is chemo not preferred in AIDS-related PCNSL?
Chemo is not preferred in AIDS-related PCNSL b/c CD4 counts are already low (usually <50).
What is the Tx paradigm in such severely immunocompromised HIV pts?
Immunocompromised HIV pt Tx paradigm: WBRT to 36–45 Gy with concurrent HAART
What was the Tx regimen in RTOG 93–10? What was the MS?
Intravenous/intrathecal Mtx/vincristine/procarbazine → WBRT to 45 Gy → intravenous cytarabine. MS was 3 yrs. (DeAngelis LM et al., JCO 2002)
What options are there for leptomeningeal PCNSL?
Intrathecal Mtx or CSI to 36 Gy with a boost to 45–50 Gy
What is the Tx paradigm for ocular lymphoma?
Ocular lymphoma Tx paradigm: RT to 36 Gy or intraocular chemo
What is the rationale for omitting WBRT in the elderly with PCNSL?
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).
What is the WBRT dose for PCNSL after CR to chemo?
24–36 Gy. Consider omitting RT altogether if the pt is >60 yo.
What is the WBRT dose for PCNSL after PR to chemo?
36–45 Gy WBRT; focal CD to gross Dz to 45 Gy
What prospective data support RT omission/deferral after high-dose chemo (Mtx/Ara-C)?
German data support RT omission/deferral following high-dose chemo. (Pels H et al., JCO 2003, Jahnke K et al., Ann Oncol 2005)
What is 1 additional option after RT, especially after PR to initial chemo?
Consolidation Ara-C is an additional option after RT.
What is the role of rituximab (Rituxan) in PCNSL? How can it be incorporated, and what studies support its use?
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 was 67% and two-thirds of pts had a CR (these pts were able to rcv reduced-dose RT).
What did RTOG 8315 investigate? What did it show?
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)
Which recent randomized international phase II study investigated the use of induction cytarabine for PCNSL? What did it find?
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.
What regimen was used in CALGB 50202 and what were the results?
Mtx, temozolomide, and rituximab (MT-R) followed by 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)
TOXICITY
What is the dose tolerance of the lacrimal gland?
The dose tolerance of the lacrimal gland is 36 Gy.
What was the toxicity rate in the RTOG 93–10 study?
RTOG 93–10: 15% had severe delayed neurotoxicity (especially if >60 yo). (DeAngelis LM et al., JCO 2002)
What was the Tx-related mortality for pts treated with chemo alone in the German trials?
In German trials, Tx-related mortality with chemo alone was 9%.
Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. (Pels H et al., JCO 2003)
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