lymphoma and leukemia of the nervous system || chemotherapy for primary central nervous system...

Chapter 8Chemotherapy for Primary Central NervousSystem Lymphoma

Tracy Batchelor, Andrew Grigg, and Eckhard Thiel

Introduction

Chemotherapy alone is considered the standard of care for patients with newly diag-nosed, systemic diffuse large B-cell lymphoma. Historically, whole brain radiationtherapy (WBRT) or WBRT in combination with chemotherapy have been the mostcommonly accepted therapeutic regimens for PCNSL. However, the high incidenceof neurotoxicity in patients >60 years of age who receive WBRT as a compo-nent of their therapeutic regimen has led to interest in the use of chemotherapyalone and deferral of WBRT in PCNSL patients. Initial efforts with chemother-apy were disappointing as the limited blood-brain barrier (BBB) penetration ofthe drugs in the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine,prednisone) regimen resulted in poor outcomes in PCNSL patients treated with thisstandard NHL combination [1, 2]. However, a number of chemotherapy regimenshave been developed for the PCNSL population, utilizing drugs with acceptableBBB penetration and demonstrated anti-lymphoma activity. Historically, the lack ofprospective, randomized controlled trials has slowed advances in chemotherapy forPCNSL. However, this situation is rapidly changing with a recent focus on the devel-opment of multicenter, randomized trials for the PCNSL patient population. Thischapter will focus on chemotherapeutic approaches to PCNSL, including treatmentof newly diagnosed PCNSL, elderly patients with PCNSL, relapsed or refractoryPCNSL, and the role of intrathecal chemotherapy. The evolution from chemother-apy to high-dose chemotherapy and autologous stem cell transplantation is reviewedin Chapter 9.

The International PCNSL Collaborative Group (IPCG) has published consensusguidelines for the assessment of response in PCNSL patients treated on thera-peutic clinical trials (Table 8.1) [3]. These guidelines are being incorporated into

T. Batchelor (B)Stephen E. and Catherine Pappas Center for Neuro-Oncology, Departments of Neurology andRadiation Oncology, Division of Hematology and Oncology, Massachusetts General Hospital,Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USAe-mail: [email protected]

141T. Batchelor, L.M. DeAngelis (eds.), Lymphoma and Leukemiaof the Nervous System, DOI 10.1007/978-1-4419-7668-0_8,C© Springer Science+Business Media, LLC 2012

142 T. Batchelor et al.

Table 8.1 International primary CNS lymphoma collaborative group (IPCG) guidelines forresponse assessment in clinical trials

Response Brain imagingCorticosteroiddose Eye exam CSF cytology

CR No enhancingdisease

None Normal Negative

uCR No enhancingdisease

Any Normal Negative

Minimal enhancingdisease

Any Minor RPEabnormality

Negative

PR 50% decrease inenhancement

N/A Minor RPEabnormality ornormal

Negative

No enhancingdisease

N/A Decrease in vitreouscells or retinalinfiltrate

Persistent orsuspicious

PD 25% increase inenhancement

N/A Recurrent or newdisease

Recurrent orpositive

Any new site ofdisease

SD All scenarios not covered by responses above

Adapted from Abrey et al. [3].Abbreviation: CR, complete response; uCR, unconfirmed complete response; N/A, not applicable;PR, partial response; PD, progressive disease; RPE, retinal pigment epithelium.

prospective clinical trials of chemotherapy, which will allow some comparisonacross studies. The IPCG has also recommended a cognitive assessment instrumentfor serial use in patients treated on clinical trials as neurocognitive outcome is acritical endpoint that should be assessed in this population [4].

Corticosteroids

Although corticosteroids may rapidly reduce tumor size and decrease tumor-associated edema in PCNSL patients, these medications should be withheld priorto diagnostic biopsy in clinically stable patients who are suspected of havingPCNSL based on imaging studies. Corticosteroids have a direct lymphocytolyticeffect that may disrupt cellular morphology and lead to diagnostic inaccuracy atthe time of microscopic analysis in patients undergoing biopsy. Despite an ini-tial response to corticosteroids, most PCNSL patients quickly relapse and requirealternate treatment strategies. Nevertheless, initial radiographic response to corti-costeroids in newly diagnosed PCNSL patients is a favorable prognostic markerwith an overall survival (OS) of 117 months in responders versus 5.5 months innon-responders [5].

8 Chemotherapy for Primary Central Nervous System Lymphoma 143

Chemotherapy for Newly Diagnosed PCNSL

A number of cytotoxic agents have been studied in the PCNSL populationeither alone or in combination, and the key drugs are summarized in Table 8.2.Methotrexate, a folate antagonist that interrupts DNA biosynthesis, is the most effec-tive and widely used drug for PCNSL. However, due to its high degree of ionizationat physiologic pH methotrexate is associated with poor penetration of the BBB.Using microdialysis catheters, investigators measured the penetration of methotrex-ate (administered at a dose of 12 g/m2) into high-grade brain tumor tissue [6]. Theratio of the area under the methotrexate concentration-time curve in brain extracellu-lar fluid to plasma ranged from 0.28–0.31 in the region of contrast-enhancing tumor.Thus, high-dose systemic methotrexate is necessary for adequate CNS penetrationwith doses of 2–8 g/m2 commonly administered in the PCNSL population. At thesesystemic doses, cytotoxic levels of methotrexate are also achieved in the CSF, andthe need to use intrathecal chemotherapy to treat microscopic or macroscopic tumorin the leptomeninges can probably be avoided in most PCNSL patients [7]. In aretrospective review of 45 patients with PCNSL treated with methotrexate-basedregimens, slow creatinine clearance (< 85 ml/min) and a high area-under-the-curve(AUC) for methotrexate (AUC > 1,100 μmol·h·l–1) were two factors associated withsignificant improvement in survival [8]. However, slow creatinine clearance was alsoassociated with severe toxicity. Based on these observations, it was recommendedthat studies of methotrexate-based chemotherapy in PCNSL patients include amethotrexate dose ≥ 3 g/m2 as a 4–6 h infusion given every 3–4 weeks. However,many investigators continue to recommend administration of methotrexate over3–4 h every 10–14 days.

In a phase II, multicenter study of methotrexate monotherapy the drug wasadministered at a dose of 8 g/m2 to 25 PCNSL patients as a 4-h infusion every14 days, as induction therapy followed by 12 maintenance cycles every 28 days atthe same dose [9, 10]. The proportion of patients who achieved a complete response(CR) was 52% (13/25) and the median number of cycles and time to CR was 6and 12 weeks, respectively. The median PFS was 12.8 months, the median OS was55.4 months, and the median disease-specific survival had not been reached at 72.3months. In this study, 5 of the 25 patients treated with methotrexate alone achieved aCR and had not relapsed after a median follow-up of 6.8 years. Toxicity was modestwith 13/25 patients experiencing no dose-limiting adverse effects. In another studyof 75 patients with PCNSL using the same dose and schedule, the CR proportionwas only 29.7% with a median PFS of 10 months and median OS of 25 months [11].However, the maximum number of induction cycles of methotrexate was capped at6 in this study. As noted previously, 6 cycles was the median number of doses toreach CR in the previously cited methotrexate monotherapy study, and more induc-tion cycles may have resulted in a higher proportion of patients who achieved aradiographic CR.

While methotrexate monotherapy may be effective for a subset of patients, theresponse proportion appears to be higher and the durability of response appears tobe longer in patients who receive polychemotherapy. There have been a number


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of phase II trials conducted using methotrexate-based, multi-agent chemotherapyregimens without WBRT as noted in Table 8.3.

In one of the first, multicenter, randomized trials reported in the PCNSLpatient population 79 subjects aged 18–75 years were randomized to receive eithermethotrexate alone (3.5 g/m2) every 3 weeks versus methotrexate (3.5 g/m2 onday 1) plus cytarabine (2 g/m2 BID on days 2 and 3) every 3 weeks [13]. Althoughpatients in each arm subsequently received WBRT, the radiographic response tochemotherapy was determined prior to radiation. Complete/partial radiographicresponses were achieved in 18%/22% of methotrexate patients and 46%/23% ofmethotrexate + cytarabine patients, respectively. Grade 3–4 hematological toxi-city was more common in the methotrexate + cytarabine arm (92%) versus themethotrexate arm (15%). This study confirmed observations from non-randomizedtrials that methotrexate-containing combination regimens achieve higher radio-graphic response rates compared to methotrexate monotherapy.

A multi-agent regimen consisting of methotrexate, cytarabine, vincristine, ifos-famide, cyclophosphamide, and i.t. methotrexate/cytarabine/prednisolone was stud-ied in a phase II trial of 65 patients and was associated with a 71% overall responserate (ORR) and a median OS of 50 months [14]. Despite these promising results,6 patients died from treatment-related complications and 12 patients experiencedOmmaya reservoir infections.

In some combination regimens, rituximab, a humanized monoclonal antibodyagainst the CD20 antigen on B-lymphoma cells, has been incorporated, althoughit is not yet known whether this agent will improve outcomes in PCNSL patientsto the extent that it has for patients with systemic B-cell lymphomas. Rituximabconcentrations in CSF are 0.1% of plasma levels when it is administered at a stan-dard dose of 375 mg/m2 intravenously, indicating poor BBB penetration [15]. In areport of 4 PCNSL patients administered I123–labeled rituximab, there was weaktumor uptake in only 1 out of 4 patients [16]. However, in another study of the90Y-labeled anti-CD20 antibody ibritumomab tiuxetan target accumulation of theantibody was observed in 4 out of 6 PCNSL patients assessed by SPECT imag-ing with 111In-labeled ibritumomab tiuxetan [17]. Moreover, radiographic responseswere reported to rituximab alone in 5/12 patients with refractory or relapsed PCNSLin a pilot study [18]. Despite these limited data, rituximab is being incorporatedinto chemotherapy regimens for patients with both newly diagnosed and relapsedPCNSL under the assumption that rituximab penetration into contrast-enhancingtumor may be higher in the context of a disrupted blood brain barrier. In a singleinstitution study, rituximab was added to a commonly used chemotherapy regimenfor patients with newly diagnosed PCNSL, methotrexate, procarbazine, vincristine(MPV), and 78% of patients achieved a CR after 6 cycles [19]. While this CRproportion is higher than that historically observed for MPV, further studies arenecessary to validate this result and to define the ultimate role of i.v. rituximab inthe treatment of PCNSL.

Blood brain barrier disruption (BBBD) is a strategy aimed at circumventingthe BBB in order to deliver higher concentrations of chemotherapeutics to theCNS (Fig. 8.1). In one report, this method was associated with complete radio-graphic responses in 40/53 patients with PCNSL treated with intra-arterial (i.a.)


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Fig. 8.1 Blood brain barrier disruption. Contrast-enhanced CT scans of the basal ganglia ofa 61 year-old woman with a primary CNS lymphoma, indicating that the permeability of theblood-tumor barrier is inconsistent for a given patient or even a given tumor nodule. a CT scandemonstrating a bright, uniformly enhancing lesion in the right basal ganglia. The hypodense sig-nal in the brain tissue around the tumor (arrowheads) should be noted. b CT scan obtained afterosmotic BBBD. CT scans were obtained 30 min after the first BBBD treatment, to confirm andassess the grade of BBBD. The patient underwent right internal carotid artery disruption in theanterior and middle cerebral artery distributions (arrows). Opening of the BBB around the tumorin the area of the peritumoral hypodense signal evident in the CT scan in (a) should be noted(courtesy of Edward Neuwelt [42] – with permission)

methotrexate (5 g), intravenous cyclophosphamide, and etoposide following BBBDwith i.a. mannitol [20]. Long-term follow-up of the subjects who achieved CR in thisstudy demonstrated maintenance of cognitive function in this population of patientstreated without WBRT. In a pooled analysis of 149 patients treated with i.a. MTXfollowing osmotic BBBD, the CR proportion was 57.8% with a median OS of 3.1years [21]. Unique toxicities of BBBD include seizures, stroke, and venous throm-boembolism. BBBD is technically complex and should only be performed in centerswith expertise and experience in the technique.

Predictors of Chemotherapy Response

Since PCNSL is a densely cellular tumor, there may be restricted or low diffusionof brain water molecules within the tumor on diffusion-weighted MRI, and appar-ent diffusion coefficient (ADC) imaging may be useful as a biomarker of responseto methotrexate. In one report of 18 immunocompetent PCNSL patients treateduniformly with methotrexate-based chemotherapy low, pre-therapeutic ADC val-ues (increased tumor cell density) correlated with shorter progression-free survivaland reduced overall survival [22]. Conversely, reduction of ADC values after start ofmethotrexate-based chemotherapy was associated with improved outcomes. Given


that ADC maps are part of a standard MRI acquisition sequence, this observationcan be readily explored in future prospective trials of chemotherapy in the PCNSLpatient population.

Chemotherapy in Elderly PCNSL Patients

Chemotherapy alone is an attractive option in elderly patients with PCNSL asthis group is at highest risk of neurotoxicity with regimens that contain WBRT.However, the ability of elderly patients to tolerate high doses of methotrexate orpolychemotherapy regimens remains a concern. Several prospective studies havebeen conducted to address this issue.

In a multicenter analysis of 154 patients, 89 > 60 years and 21 > 70 years,methotrexate 4 g/m2 administered as a 4-h intravenous infusion biweekly wassafe regardless of age when the dose was adapted to the glomerular filtration rate,calculated prior to each methotrexate infusion [23].

In a single-institution study of methotrexate administered at doses of 3.5–8 g/m2

every 2 weeks to 31 newly diagnosed PCNSL patients over the age of 70, the reg-imen was well-tolerated with 0, 3.2, 6.5% of patients experiencing grade III orIV renal, gastrointestinal or hematological toxicities, respectively [24]. However,87.9% of methotrexate cycles required dose reduction due to impaired creatinineclearance. Sixty percent of patients achieved a CR and 36.7% achieved a PR. Themedian PFS and OS were 7.1 and 30 months, respectively.

In a phase II study, methotrexate (3 g/m2 on days 1, 10, 20) and temozolomide(100 mg/m2 on days 1–5) were administered to 23 patients with newly diagnosedPCNSL over the age of 60 [25]. In patients who achieved a PR or CR, 5 monthlycycles of methotrexate and temozolomide were subsequently administered. GradeIII or IV nephrotoxicity and hematotoxicity were observed in 3 patients and 5patients, respectively. However, no neurotoxicty was observed in these patients. Thecomplete radiographic response proportion was 55%; the event-free survival was 8months and the OS was 35 months.

A more intensive polychemotherapy regimen was studied in a phase II studyof 30 elderly, newly diagnosed PCNSL patients with a median age of 70. Inthis study, methotrexate, procarbazine, and CCNU were administered as three45-day cycles [26]. Twelve out of 27 patients (44%) achieved a CR and 8/27(29.6%) achieved a PR. There were 2 treatment-related deaths. The 5-year OS was33%, while 6 out of 8 long-term survivors had no evidence of treatment-relatedneurotoxicity.

A phase II trial examining methotrexate (3.5 g/m2), vincristine, and procarbazinefor newly diagnosed PCNSL patients was initially designed to administer WBRT inthe post-chemotherapy setting [27]. However, for patients older than 60 years ofage, the WBRT was eliminated at the mid-point of the study. At the terminationof the trial, older patients treated with the chemotherapy alone had an identicalmedian OS of 29 months to those who received both chemotherapy and WBRT.Although survival was the same, those patients who received chemotherapy alone


had a higher incidence of tumor progression and they died of tumor, whereas thosewho received WBRT had a lower risk of tumor progression, but tended to die ofneurotoxicity.

These studies in elderly PCNSL patients indicate that chemotherapy approachesare feasible, relatively non-toxic, and are associated with promising radiographicresponse proportions, survival, and low rates of neurotoxicity. However, subjectswho meet study eligibility criteria and are enrolled into clinical trials represent aselected patient population and these results may not be generalizable to all elderlyPCNSL patients.

Intrathecal Chemotherapy

A controversial issue in the management of PCNSL has been the role of intrathecalchemotherapy. Historical comparisons have determined that there appears to be noimprovement in OS when intrathecal methotrexate is added to regimens that alreadyinclude high doses of i.v. methotrexate [28]. By administering methotrexate system-ically, the risk of Ommaya reservoir placement, extra-CSF drug delivery, chemicalmeningitis, and infection can be avoided. As mentioned above, the i.v. dose must besufficiently high and administered over a rapid enough time interval for methotrex-ate to penetrate into the CSF and tumor. In one prospective study of 18 patients,a polychemotherapy regimen was administered without intrathecal chemotherapy[29]. Although the radiographic CR proportion was 53%, the median time to pro-gression for responders was only 10 months, shorter than that previously reportedfor this same regimen when intrathecal chemotherapy was included. Although theauthors contend that this early relapse was possibly due to the omission of intrathe-cal chemotherapy, this conclusion is speculative and should be confirmed in a larger,randomized trial. For patients with concurrent brain and leptomeningeal lymphoma,intrathecal chemotherapy may be recommended. Ommaya reservoir placement isthe most efficient and safest way to deliver intrathecal chemotherapy. Repeated lum-bar punctures are uncomfortable for patients and may result in inconsistent deliveryof chemotherapy into the subarachnoid space. If a patient requires a ventricular-peritoneal shunt (VPS) and intrathecal chemotherapy, a VPS with an “on-off” valveis an option. Although not systematically studied, these shunts theoretically allowthe treating physician to temporarily halt CSF drainage into the peritoneum afterinstillation of chemotherapy.

Salvage Chemotherapy

Despite aggressive treatment, most patients with PCNSL will progress or relapseand will become potential candidates for salvage therapy [30]. Optimal managementof relapsed or refractory PCNSL has yet to be determined and has only been studiedin small clinical trials or case series using heterogeneous therapies (Table 8.4). In


Table 8.4 Selected salvage chemotherapy regimens for relapsed or refractory PCNSL

Reference Treatment N Pts with PR/CR OS (months)

[31] MTX 22 20 61.9[40] HDT/ASCT 27 26 58.6[39] PCV 7 6 >16[32] TMZ 23 6 3.5[33] TMZ + rituximab 15 8 14[34] TMZ + rituximab 7 7 8[36] Topotecan 27 9 8.4[37] Topotecan 15 6 35[38] VIA 16 6 41% at 12 months

Abbreviations: Pts, patients; HDT, high dose chemotherapy; ASCT, autologous stemcell transplantation; PCV, procarbazine, lomustine, vincristine; TMZ, temozolomide;VIA, etoposide, ifosfamide, cytarabine; OS, overall survival

general, prognosis for patients with relapsed or refractory PCNSL is poor with amedian survival of approximately 4.5 months.

For patients who initially experienced a CR to a chemotherapy regimen thatincluded methotrexate, re-treatment with methotrexate alone at the time of relapsemay be effective [31]. Twenty-two patients who previously achieved a CR tomethotrexate were treated again at relapse with methotrexate (8 g/m2) and the ORRwas 91% and the median OS was 61.9 months. While this represents a highlyselected, treatment-sensitive population, this approach represents one option for thisgroup of PCNSL patients.

Temozolomide, an alkylating agent with good CSF penetration, was associatedwith a 26% radiographic response proportion in 23 patients previously treated withmethotrexate-containing chemotherapy with or without WBRT [32]. Rituximab wasadded to temozolomide in 2 studies of relapsed or progressive PCNSL, yieldingmedian survival times of 8 and 14 months [33, 34].

Intraventricular rituximab (10–25 mg) was feasible in a Phase I study of patientswith relapsed or refractory lymphomatous meningitis [35]. Toxicity was limited.Unexpected observations from this study were a radiographic response of brainparenchymal lymphoma in 1 case and 2 patients with intraocular lymphoma whoexperienced disease resolution or clinical improvement in vision.

Topotecan, a topoisomerase I inhibitor with good CSF penetration, was admin-istered to 27 patients with relapsed or refractory PCNSL. The ORR was 33% with9 patients achieving a complete or partial response, and the overall survival was 8.4months [36]. However, 8 of 12 patients still alive at 6 months exhibited symptomsof neurotoxicity. In another study of 15 patients with relapsed or refractory PCNSL,3/15 (20%) patients achieved a CR, 3/15 (20%) patients achieved a PR, median PFSwas 2 months, and median OS was 35 months [37]. Toxicity was mainly hemato-logical in both of these studies. Combination studies of topotecan with other agentshave not been conducted in the PCNSL patient population.


Other chemotherapy salvage regimens studied include etoposide, ifosfamide,and cytarabine (VIA) and procarbazine, lomustine, and vincristine (PCV) [38, 39].Using VIA, the 12-month OS was 41% and with PCV, it was 57%.

In a study of refractory or relapsed PCNSL or ocular lymphoma, 43 patientswere treated with cytarabine and etoposide, with a subset of these patients offeredsubsequent high-dose chemotherapy with thiotepa, busulfan, and cyclophosphamidefollowed by autologous stem cell transplantation (HDT/ASCT) [40]. Twenty-sevenpatients received HDT/ASCT and 26/27 of these patients entered CR and achievedmedian PFS and OS durations of 41.1 and 58.6 months, respectively. Althoughthis study included a highly selected salvage patient population, these results areencouraging and should be confirmed in other studies of this approach in relapsedor refractory PCNSL patients.

Future Directions

Chemotherapy alone for newly diagnosed PCNSL patients is an increasinglyaccepted therapeutic strategy and may reduce the incidence of neurotoxicity com-pared to regimens that include WBRT, especially among elderly patients. Intrathecalchemotherapy may not be necessary in PCNSL patients treated with high dosesof intravenous methotrexate, although this has not been definitively established.Based on encouraging results obtained with high-dose chemotherapy followed byautologous stem cell transplantation in the relapsed and refractory PCNSL patientpopulation, this approach is now being investigated in the newly diagnosed PCNSLpopulation and will be reviewed in Chapter 9. However, the optimal therapeuticstrategy for patients with newly diagnosed and relapsed or refractory PCNSL hasyet to be defined. An increasing number of multicenter, randomized trials are beingconducted in this patient population using standardized entry criteria and outcomeassessment, and these investigations hold much promise in defining standards ofcare for PCNSL.

References

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