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Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Chemotherapy in newly diagnosed primary (2010) 2(4) 273292 DOI: 10.1177/ central nervous system lymphoma ! The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/ Nooshin Hashemi-Sadraei and David M. Peereboom journalsPermissions.nav Abstract: Primary central nervous system lymphoma (PCNSL) accounts for only 3% of brain tumors. It can involve the brain parenchyma, leptomeninges, eyes and the spinal cord. Unlike systemic lymphoma, durable remissions remain uncommon. Although phase III trials in this rare disease are difficult to perform, many phase II trials have attempted to define standards of care. Treatment modalities for patients with newly diagnosed PCNSL include radiation and/or chemotherapy. While the role of radiation therapy for initial management of PCNSL is controversial, clinical trials will attempt to improve the therapeutic index of this modality. Routes of chemotherapy administration include intravenous, intraocular, intraventricular or intra-arterial. Multiple trials have outlined different methotrexate-based chemotherapy regimens and have used local techniques to improve drug delivery. A major challenge in the management of patients with PCNSL remains the delivery of aggressive treatment with preservation of neurocognitive function. Because PCNSL is rare, it is important to perform multicenter clinical trials and to incorporate detailed measurements of long-term toxicities. In this review we focus on different chemotherapeutic approaches for immunocompetent patients with newly diagnosed PCNSL and discuss the role of local drug delivery in addition to systemic therapy. We also address the neurocognitive toxicity of treatment. Keywords: bloodbrain barrier disruption, chemotherapy, high-dose chemotherapy, intra-arterial chemotherapy, intraocular chemotherapy, intrathecal chemotherapy, methotrex- ate, neurocognitive toxicity, primary central nervous system lymphoma Correspondence to: Introduction low incidence of these tumors making adequately David M. Peereboom Primary central nervous system lymphoma powered phase III trials difficult to conduct Brain Tumor and Neuro-Oncology Center/ (PCNSL) is a rare cancer accounting for less [Muldoon et al. 2007]. This paper reviews the Taussig Cancer Center, than 3% of brain tumors [CBTRUS, 2009]. role of various routes of chemotherapy delivery 9500 Euclid Avenue R35, Cleveland, OH 44195, USA The vast majority of PCNSLs are diffuse large for the treatment of immunocompetent patients peerebd@ccf.org B-cell lymphomas, and unlike systemic diffuse with newly diagnosed PCNSL. Nooshin Hashemi-Sadraei large B-cell non-Hodgkin lymphoma (NHL), Hematology and Medical Oncology/Taussig Cancer PCNSL remains confined to the CNS (brain par- Although combined chemotherapy and radiation Center, Cleveland, enchyma, leptomeninges, eyes and the spinal therapy has produced response rates of up to OH, USA cord) in most patients. In addition, unlike sys- 8090% and median overall survival (OS) close temic lymphoma, durable remissions remain to 5 years in PCNSL [Shah et al. 2007; uncommon. The mean age of patients is approx- Gavrilovic et al. 2006; Omuro et al. 2005b; imately 60 years [Abrey et al. 2006; Ferreri et al. DeAngelis et al. 2002; Abrey et al. 2000], neuro- 2003]. Several treatment modalities have been cognitive toxicity has been a major limitation of employed for these patients: combined modality this paradigm [Abrey et al. 1998, 2000]. Delayed therapy with whole brain radiation therapy neurotoxicity presents with memory deteriora- (WBRT); systemic chemotherapy alone; tion and personality changes early in the course, intrathecal (IT) chemotherapy; and intraocular followed by gait disturbance and urinary inconti- chemotherapy. A major difficulty in defining the nence; these complications are generally perma- optimal therapy for patients with PCNSL is the nent [Abrey et al. 1998, 2000]. Risk factors for http://tam.sagepub.com 273 Therapeutic Advances in Medical Oncology 2 (4) neurotoxicity include radiotherapy, older age the regimens differ significantly making general- (particularly over 60 years), IT chemotherapy izations difficult to assert. and chemotherapy after WBRT [Illerhaus et al. 2009; Omuro et al. 2005a; Correa et al. 2004; The prognosis and outcome of treatment appears Abrey et al. 1998; Blay et al. 1998] although to differ between younger and older patients. some studies do not agree entirely with the Among studies that included mostly younger above correlations. For example Blay and collea- patients, one of the best response rates achieved gues reported no association between age or IT was reported in a small number of patients by chemotherapy and late neurotoxicity [Blay et al. Sandor and colleagues, in which all 14 patients 1998] and Illerhaus and colleagues reported no achieved a complete or partial response [Sandor clinical signs of severe neurotoxicity in elderly et al. 1998]. The patients were relatively younger patients provided they were treated without (median age 57) compared with other studies WBRT [Illerhaus et al. 2009]. Up to 83% of where WBRT was excluded from the treatment. patients older than 60 years of age who receive The dose of MTX in this study was higher than WBRT for the treatment of PCNSL develop all other combination chemotherapy regimens neurotoxicity [Abrey et al. 2000]. As a result, (8.4 g/m over 24 h). Although the regimen con- older patients who survive may have a poor qual- sisted of thiotepa, vincristine and high-dose ity of life. In addition, this study failed to dem- MTX, it also included IT MTX and cytarabine. onstrate a survival advantage to the use of WBRT High-grade toxicities included severe leukoence- as part of a combined treatment regimen in this phalopathy, grade 34 neutropenia in 50% of population of patients (32 versus 33 months for cycles, ileus and seizures. The three patients patients who received WBRT versus deferred with leukoencephalopathy were 66, 67 and 69 WBRT, respectively) [Abrey et al. 2000]. These years old, confirming the adverse effect of age findings raise the question as to whether patients on the toxicities of high-dose MTX or other with PCNSL should receive WBRT at diagnosis drugs used in this regimen [Sandor et al. 1998]. and if it could be avoided without compromising Some more recent studies with different regimens response rate or survival. have replicated good responses or survival out- comes with different regimens. A recent study Systemic delivery of chemotherapy of combination chemotherapy in a relatively small number of young patients (median age 53 Combination chemotherapy years) showed a response rate of 77% but high Different combinations of chemotherapy have relapse rates with the omission of IT therapy been used in the treatment of PCNSL (Table 1). [Pels et al. 2009]. An older study from the same Because systemic NHL is treated with com- group, where IT chemotherapy was part of the bination chemotherapy rather than monother- protocol, however, demonstrated a much lower apy, one could argue that optimal management relapse rate in the younger patient population requires this approach in treatment of PCNSL [Pels et al. 2003]. Median time to treatment as well. failure and OS were not reached after median follow up of 32 months in the patient group Most methotrexate (MTX)-based combination younger than 60 years, which was more consis- regimens use significantly lower doses than are tent with some other studies dedicated to youn- used in monotherapy (MTX dose 15 g/m ger patients. versus 8 g/m in monotherapy) [Illerhaus et al. 2009; Pels et al. 2009; Omuro et al. 2007; Other recent studies on younger patients, have Hoang-Xuan et al. 2003]. The response rates reported outcome with different regimens and and median survival range between 48% and modalities of therapy, including single-agent 100% and 15 and 50 months, respectively MTX [Yang et al. 2009], intra-arterial (IA) [Illerhaus et al. 2009; Pels et al. 2003, 2009; chemotherapy [Angelov et al. 2009], high-dose Omuro et al. 2007; Hoang-Xuan et al. 2003; chemotherapy followed by stem-cell rescue Sandor et al. 1998]. Although the data suggest [Illerhaus et al. 2008; Montemuro et al. 2007], that younger patients [Angelov et al. 2009; Pels and regimens which include WBRT as part of et al. 2009; Sandor et al. 1998] may have protocol [Shah et al. 2007; Omuro et al. 2005b; improved response rates with combination che- DeAngelis et al. 2002]. The median age in all of motherapy compared with older patients these reports is in the fifties and with few excep- [Illerhaus et al. 2009; Hoang-Xuan et al. 2003], tions [Yang et al. 2009; Illerhaus et al. 2008] 274 http://tam.sagepub.com N Hashemi-Sadraei and DM Peereboom http://tam.sagepub.com 275 Table 1. Chemotherapy-only regimens for initial therapy of primary central nervous system lymphoma. Chemotherapy regimen N Median Median MTX Response Median Median Comment Reference age KPS dose rate % OS PFS (g/m ) (CRþ PR) (months) (months) MTX alone MTX 31 63 40 8 100 30 16.6 Followed by Guha-Thakurta et al. maintenance [1999] MTX 37 60 70 8 35 25 10 Herrlinger et al. [2005] MTX 25 60 80 8 74 55 12.8 Batchelor et al. [2003] MTX 16 52 90 8 57 50 NR Yang et al. [2009] MTX 31 74 70 3.58 97 37 7.1 30 patients started Zhu et al. [2009] with 8 g/m Combination MTX, TMZ 23 68 60 3 55 35 8 Omuro et al. [2007] MTX, thiotepa, VCR, dexametha- 14 57 NR 8.4 100 NR 16.5 MTX 1.5 g/m over Sandor et al. [1998] sone and IT CXT 1 h, then 300 mg/m / h 24 h MTX, CCNU, PCB, methylpredni- 50 72 50 1 48 14 6.8 Hoang-Xuan et al. [2003] solone and IT CXT MTX, VCR, ifosfamide, cytarabine, 65 62 70 5 71 50 21* MTX 0.5 g/ Pels et al. [2003] cyclophosphamide, dexametha- m 30 min, then sone and IT CXT 4.5 g/m 23.5 h MTX, PCB, VCR, IT CXT and 57 65 70 3.5 90 29# 7# 26 were treated with Gavrilovic et al. [2006] post-radiation cytarabine CXT alone (update from Abrey et al. [2000]) MTX, VCR, ifosfamide, cytarabine, 18 53 80 5 77 NR 8* MTX 0.5 g/ Pels et al. [2009] cyclophosphamide, m 30 min, then dexamethasone 4.5 g/m 23.5 h MTX, PCB, CCNU 30 70 60 3 71 15 5.9 Illerhaus et al. [2009] IA MTX with BBBD and combina- 149 54 70 2.5 82 37 21.6 Retrospective study; Angelov et al. [2009] tions with etoposide, cyclopho- various CXT sphamide, PCB combinations HDC/ASCT MTX, cytarabine, BEAM 28 53 70 3.5 57 NR 5.6** Abrey et al. [2003] MTX, busulfan, thiotepa 23 55 70 8 83 20 17** Response-adapted Montemurro et al. [2007] WBRT MTX, cytarabine, thiotepa, 13 54 90 8 62 25 25T Response-adapted Illerhaus et al. [2008] carmustine WBRT *Time to treatment failure. **Event-free survival. 2.5 g days 1 and 2 (5 g/cycle). Data for the 26 patients treated with CXT alone. Not mentioned directly in paper: data extrapolated from KaplanMeier plot. ORR post-induction CXT. T ¸ Update per Gerstner et al. [2008]. BEAM, carmustine/etoposide/cytarabine/melphalan; CCNU, lomustine; CR, complete response rate; CXT, chemotherapy; HDC/ASCT, high-dose chemotherapy followed by autologous stem-cell transplant; IT, intrathecal; KPS, Karnofsky performance score; MTX, methotrexate; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response rate; TMZ, temozolomide; PCB, procarbazine; VCR, vincristine; WBRT, whole brain radiation therapy. Therapeutic Advances in Medical Oncology 2 (4) where response rate has been in the range of with comorbidities, although this regimen had 5060%, response rates to chemotherapy in this significant toxicities. The addition of procarba- young population has ranged between 80% and zine and CCNU to MTX appeared to improve 90% [Angelov et al. 2009; Montemuro et al. survival but at the expense of added hematologi- 2007; Shah et al. 2007; Omuro et al. 2005b; cal toxicities and poor tolerance in this vulnerable DeAngelis et al. 2002]. Comparison of survival population [Illerhaus et al. 2009]. Thoughtful outcomes between these studies is more difficult patient selection is critical to minimize toxicity because of the different modalities and inclusion for this subgroup of patients. of WBRT in some of the protocols. Other studies of combination chemotherapy Studies in older patients have attempted to without WBRT achieved response and survival develop regimens that are more appropriate for rates closer to that achieved by regimens that patients unable to undergo radiation therapy. include WBRT (see Table 1 for details on Hoang-Xuan and colleagues reported results of response rates and survival). Abrey and collea- a MTX (1 g/m )-based combination chemother- gues reported excellent response rates and OS apy in patients with median age 72 years and data on a group of patients who received combi- median Karnofsky performance score (KPS) of nation chemotherapy including IT chemotherapy 50%. Response rates were 48% and OS was followed by WBRTand postradiation chemother- only 14 months, which is only slightly better apy [Abrey et al. 2000]. High-dose MTX, IT than historical survival rates with WBRT alone MTX, procarbazine and vincristine were [Hoang-Xuan et al. 2003; Nelson et al. 1992]. included in the preradiation induction regimen. The high-grade toxicities were mainly hemato- Of the 52 patients enrolled, 30 patients received logical, hepatic and renal and resulted in dose radiation and the other 22 patients did not reductions in 26% of the patients and disconti- receive radiation, mainly due to their age. Upon nuation of treatment in 8% of patients. While completion of induction chemotherapy, objective most of the patients preserved their cognitive response rate (ORR) was 90%. The ORR at com- function and their performance status or pletion of all treatment was 94% and the median showed some improvement until disease pro- OS for the 52 patients was 60 months. This study gression, 8% of patients manifested neurologic showed older age and worse performance status decline based on the mini-mental state examina- predicted poor outcomes regardless of the treat- tion (MMSE) test, and 12% developed worsen- ment modality. Interestingly, the addition of radi- ing performance status. The results of this study ation to the treatment regimen of elderly patients were still encouraging because it offered a treat- did not improve outcome when compared those ment option for vulnerable patients with a lower who did not receive radiation. The cause of death rate of long-term side effects compared with between the two groups were, however, very dif- standard radiation treatment while preserving a ferent; the group which deferred radiation mostly similar or slightly better outcome [Hoang-Xuan died of progressive disease but the group who et al. 2003]. received radiation died of complications of treat- ment [Abrey et al. 2000]. A recent European study reported on patients over 65 years of age or patients with comorbid- More recently, Gavrilovic and colleagues updated ities, who were felt not to be eligible for a con- the study by Abrey et al. [2000]. This report pub- current trial of high-dose chemotherapy with lished a 10-year follow up and confirmed the pre- autologous stem-cell rescue [Illerhaus et al. vious findings of worse survival in older patients, 2009]. Thirty patients with a median age of 70 regardless of the use of WBRT. The median OS, years received 3 cycles of MTX (3 g/m ), procar- however, decreased from 60 months to 51 bazine and lomustine (CCNU). WBRT was months in all patients but was not reached in reserved for patients who did not respond to che- younger patients (age <60 years). By contrast, motherapy. Two patients received WBRT after the median survival in the older patients was 29 relapse. Only 9 of 30 patients were able to com- months, similar to the subgroup which received plete all three cycles of therapy. Ten patients only chemotherapy (this group also consisted of stopped therapy due to toxicities and two had mainly older patients) [Gavrilovic et al. 2006]. fatal toxicities. The median OS was 15 months, Interestingly, the median progression-free sur- and the 5-year OS estimate was 33%. This result vival (PFS) was very long (129 months), and was encouraging for older patients and patients the authors concluded that the combined 276 http://tam.sagepub.com N Hashemi-Sadraei and DM Peereboom modality regimen was likely responsible for the of 100% (65% complete responses [CR], 35% prolonged survival unlike some other studies partial responses [PR]). Median PFS was 17 where salvage chemotherapy may play a major months, and the median OS was 30 months. role in survival [Gavrilovic et al. 2006]. A multi- Most importantly, the regimen was well tolerated with an acceptable rate of myelosuppression center study with regimen similar to that used in and reversible renal insufficiency. This study the Abrey et al. study also produced a very high also documented preservation of cognitive and ORR (94% response rate to pre-irradiation memory skills in addition to an overall improve- chemotherapy). This study again showed the ment in the KPS (median 90 versus 40 at impact of age on outcome. The median OS was diagnosis). 50 months for younger patients (age <60 years) compared with 22 months in older patients Two subsequent multicenter studies repeated [DeAngelis et al. 2002]. similar MTX regimens using 8 g/m but failed Owing to concerns about treatment-related to reproduce these favorable results; both studies toxicities in the older patients, single-agent reported minimal side effects but the response chemotherapy has also been evaluated, and the rates were lower (CR 65% in the Guha-Thakurta results appear promising. As discussed in more et al. study versus 30% in the Herrlinger et al. study detail in the following section, a study of 31 and 52% in the Batchelor et al. report) [Batchelor patients with median age of 74 reported an excel- et al. 2003a; Herrlinger et al. 2002]. lent ORR (97%) and median survival of 37 months. The regimen was generally well tolerated One multicenter trial closed with only 37 of 105 with less than 10% grade 3 or 4 toxicities patients enrolled after an interim analysis demon- [Zhu et al. 2009]. strated a low CR rate of 30% [Herrlinger et al. 2002]. The other study delivered MTX in induc- There is no consensus on the optimal combination tion, maintenance and consolidation phases over regimen or dose of MTX. There remains active the course of 12 months. Of 23 evaluable patients 52% achieved CR [Batchelor et al. 2003a] debate regarding the best route of drug delivery (Table 1). and about the role of intraventricular or IA che- motherapy [Angelov et al. 2009; Pels et al. 2003, These results appear to be superior to historical 2009; Omuro et al. 2007.]. The most significant series treated with WBRT alone [Nelson et al. acute toxicities of combined chemotherapeutic 1992] but appear to be inferior to some studies regimens include myelosuppression, hepatitis, of combination chemotherapy or chemotherapy renal dysfunction, venous thrombosis, vincristine- combined with WBRT [Pels et al. 2003; Abrey induced neuropathy, mucositis, sepsis, Ommaya et al. 2000; Sandor et al. 1998; DeAngelis et al. reservoir infection, allergic reaction to procarba- 1992]. Despite a better a side-effect profile (see zine and ileus [Illerhaus et al. 2009; Pels et al. 2003, below) it may be necessary to add additional 2009; Omuro et al. 2007; Hoang-Xuan et al. 2003; agents to high-dose MTX in order to improve Abrey et al. 2000]. These side effects must be response and survival rates [Batchelor et al. weighed against the potential benefits with 2003a]. consideration of the population being treated. MTX alone Several differences between these three trials In an attempt to minimize acute and late toxici- highlight questions related to the use of chemo- ties in management of PCNSL, many studies therapy for patients with PCNSL. Despite a have investigated the role of single-agent chemo- strikingly low baseline KPS (median 40) in the therapy (MTX unless patient has renal insuffi- Guha-Thakurta et al. study, outcomes compared ciency) and deferred WBRT (see Table 1). favorably to the trials of Herrlinger et al. and Batchelor et al. demonstrating a significant ben- Guha-Thakurta and colleagues reported the efit of single-agent MTX for severely ill patients. results of induction MTX (8 g/m ) followed by A difference between the studies is the duration indefinite maintenance therapy at 3.5 g/m at of treatment. In the Guha-Thakurta et al. and 3-month intervals [Guha-Thakurta et al. 1999]. Batchelor et al. studies patients received MTX This study reported response rates and median until CR or no further improvement was demon- survival comparable to prior radiation therapy strated while those in the Herrlinger et al. trial based studies. This protocol achieved an ORR who did not achieve a CR had MTX stopped http://tam.sagepub.com 277 Therapeutic Advances in Medical Oncology 2 (4) after six cycles. This difference appears to be This single-institution report describes 16 important, since patients in the Guha-Thakurta patients in a younger cohort (median age 52) et al. trial required a median of six cycles to with performance scores (median KPS 90) achieve a CR. Consistent with this observation, higher than those in prior studies (see Table 1). Herrlinger et al. reported that relapses occurred Patients received MTX 8 g/m for three cycles as only in patients whose treatment was stopped induction followed by maintenance at a dose of prematurely, suggesting that maintenance ther- 3.5 g/m . Despite the relatively favorable patient apy may have an important role [Batchelor selection, the response rates were not superior to et al. 2003a; Herrlinger et al. 2002; Guha- prior studies with eight CRs (50%) and one PR Thakurta et al. 1999]. (7%) (ORR 56%). In contrast, the response durations were long and the survival rates high. Among these studies, Batchelor et al. reported The median OS of all patients was 50 months, details on acute and long-term toxicities of the but the median survival of the patients with CR treatment; which were described as modest in had not been reached at the time of publication this report [Batchelor et al. 2003b]. Almost half [Yang et al. 2009]. Another recent retrospective of the patients had no grade 3 or 4 toxicity. study of elderly (median age 74 years) used MTX MMSE testing was performed but not all patients monotherapy. Despite the need for dose reduc- returned for their follow-up testing. Of the 19 tion in many patients (71% of the population), patients that had at least one follow-up MMSE the response rate was very high; ORR was 97% score, only one declined from baseline (from 29 (60% CR and 37% PR) with CRs achieved after to 27). The cognitive evaluation in this study was a median of only four cycles. Most of the toxici- very basic (MMSE) and was likely biased against ties were reversible and overall, it was felt that patients with worse neurocognitive function, as high-dose MTX was tolerated well in this those patients may not have been able to com- population and associated with good outcome plete the follow-up evaluations. However, when [Zhu et al. 2009]. compared to results from prior reports, which included radiation therapy, these findings were Although many studies have tested either encouraging. single agents or combination chemotherapeutic regimens, few studies directly compared MTX- Neurotoxicity was more common and severe in only regimens with MTX-based combinations. the report by Herrlinger and colleagues, although A recent randomized multicenter phase II trial evaluated in a different way [Herrlinger et al. suggested benefit, including higher response 2005]. Of the 27 patients who survived at least rates, event free and OS with the addition of 12 months, 20 were evaluated by magnetic reso- high-dose cytarabine to MTX. Chemotherapy nance imaging (MRI) for evidence of neurotoxi- in this study was followed by WBRT. The com- city. Therapy was associated with significant bination therapy included MTX 3.5 g/m on day increase in leukoencephalopathy load in seven 1 followed by cytarabine 2 g/m twice daily on of those patients, two of which had received che- days 2 and 3. The ORRs were 69% and 40% motherapy alone without salvage WBRT. This with the cytarabine combination and MTX study estimated 34% of patients will develop sig- alone, respectively. The 3-year failure-free sur- nificant leukoencephalopathy 4 years after ther- vival was 38% and 21% in the combination and apy. Although the rate of chemotherapy alone single-agent groups, respectively. In addition, the associated leukoencephalopathy was estimated respective OS rates were 46% and 32% [Ferreri as high as 10%, it still compared favorably to et al. 2009]. As expected, this study reported the 58% in the group that received WBRT more hematologic and infective toxicities in the [Herrlinger et al. 2005]. MMSE scores increased combination chemotherapy group and MTX in all patients, however, neuropsychologic test dose reduction occurred more often in the batteries revealed some cognitive impairment, group receiving combined chemotherapy than pointing out to the insensitivity of MMSE to in the MTX alone group [Ferreri et al. 2009]. assess cognitive aspects thoroughly [Herrlinger et al. 2005]. Another question in the treatment of PCNSL is the role for consolidation therapy after CR has A recent study from South Korea readdressed been achieved. A retrospective study of 122 the issue of high-dose MTX monotherapy patients who were in CR after initial MTX- and deferred WBRT [Yang et al. 2009]. based chemotherapy failed to demonstrate a 278 http://tam.sagepub.com N Hashemi-Sadraei and DM Peereboom survival benefit in patients who received consoli- In order to limit neurotoxicity, more recent stu- dation therapy with high-dose cytarabine, WBRT dies have investigated ASCT without radiation or both [Ekenel et al. 2008]. Thus, many ques- therapy. Montemurro and colleagues performed tions in the use of single agents and combinations a study with tandem transplants using MTX and ASCR and allowed patients with no response to remain open to investigation. the conditioning regimen or less than a complete High-dose chemotherapy followed by remission after the transplants to receive WBRT. autologous stem-cell rescue The response rate was 83% but the median OS of High-dose chemotherapy followed by autologous 20 months was inferior to that of similar studies. stem-cell rescue (HDC/ASCR) has been an This study also reported disappointingly high accepted treatment modality for aggressive sys- rates of severe neurotoxicity (3 of 9 patients temic lymphoma, used mostly at the time of who received WBRT) and was therefore closed relapse or refractory disease [Wrench and prematurely [Montemurro et al. 2007]. Gribben, 2008; Smith et al. 2002a]. This approach has been used as a second-line treat- Illerhaus and colleagues conducted a pilot study ment for PCNSL, and several studies have inves- similar to their phase II report in 2006, where tigated the role of this treatment modality to they dose-intensified chemotherapy (increased consolidate remission after induction therapy. the number of chemotherapy cycles and the thio- When used as first-line therapy for newly diag- tepa dose within the conditioning regimen) and nosed patients with primary CNS lymphoma, also restricted WBRT to patients who did not results have been variable [Ferreri et al. 2008]. respond completely to chemotherapy [Illerhaus et al. 2008]. Thirteen patients enrolled in this Abrey and colleagues reported outcomes of HDC/ study with a response rate of 62% to chemother- ASCR in patients with newly diagnosed PCNSL apy. Except for two patients with symptomatic who had responded to induction chemotherapy disease progression after chemotherapy, all 11 [Abrey et al. 2003]. The induction therapy in other patients underwent HDC/ASCT, which this study was systemic MTX 3.5 g/m and cytar- resulted in seven CRs and four PRs. Overall, 5 abine and the regimen used prior to infusion of of 13 patients received WBRT at some point stem cells was BEAM (BCNU, etoposide, cytar- through treatment due to disease progression or abine and melphalan). Only 14 of the 28 patients PR post-transplant [Illerhaus et al. 2008]. When in the study underwent autologous stem-cell compared with the data by Montemurro et al., transplantation (ASCT), 13 of whom relapsed this study had better results and when compared within 7 months of transplant. Eight of these with the prior study by Illerhaus et al., which patients relapsed at a median of 2.3 months after included WBRT in the protocol, the 3-year OS transplant [Abrey et al. 2003]. Thus, the response was 77% in the study with deferred WBRT rate to induction chemotherapy was poor (ORR versus 5-year OS of 69% in ASCT followed by 57%), and among those who underwent trans- WBRT. It is important to note that the setting of plant, the rate of early relapse was very high. the studies were different; the former study was a phase II multicenter study with 30 patients In contrast to the Abrey et al. study, subsequent [Illerhaus et al. 2006] whereas the latter was a trials intensified their induction chemotherapy by single-center pilot study with results reported adding other agents and/or increasing the dose of based on 13 patients [Illerhaus et al. 2008]. MTX up to 8 g/m . In addition, the pretransplant This pilot study, however, did not report any conditioning regimen was changed to a thiotepa- neurotoxicity and the authors concluded that based chemotherapy in one study and post- reserving WBRT as salvage therapy for non- transplant radiation therapy was added in all responders or partial responders would improve studies [Colombat et al. 2006; Illerhaus et al. toxicity profile and not compromise survival 2006; Brevet et al. 2005]. Response rate in these outcome [Illerhaus et al. 2006, 2008]. studies improved to the range of 70100%, but because these studies also added WBRT, compar- Although some of these results sound encoura- ison of other outcomes with chemotherapy-only ging, it is important to remember most of the studies is difficult. These studies concluded that patients entered in trials of ASCT were younger HDC ASCT was feasible in younger patients and had better performance status than many with newly diagnosed PCNSL and carries an other studies with chemotherapy-alone regimens, acceptable toxicity profile. which makes interpretation of results and http://tam.sagepub.com 279 Therapeutic Advances in Medical Oncology 2 (4) comparison between trials more difficult. The drug delivery by methods such as altered admin- best induction chemotherapy and preparative istration schedules (IV bolus versus IV infusion), conditioning regimen has yet to be defined. It is intra-arterial (IA), and IA after osmotic BBB dis- also important to consider transplant-related ruption (BBBD). In a rat glioma model, MTX morbidity (and mortality) when considering reached a fivefold higher area under curve (AUC) HDC/ASCT as a treatment choice. Among when administered by bolus compared with reports of HDC/ASCT, it appears that limiting 4-hour infusion [Dukic et al. 2000]. radiation therapy to those who experience pro- gressive disease has been associated with Reversible osmotic BBBD followed by IA chemo- promising outcome in some studies and should therapy (IA/BBBD) delivers substantially higher be investigated further. concentrations to the CNS when compared with IV administration. BBBD enhances the CNS Challenge of the bloodbrain barrier penetration of systemically administered MTX Like other brain tumors, one of the major chal- by 50100-fold in animal models [Neuwelt lenges in treatment with chemotherapeutic et al. 1980]. In human studies using contrast- agents remains the delivery of therapeutic con- enhanced neuroimaging, MTX delivery to the centrations of drugs to the CNS. A study of tumor and immediate surrounding brain bloodbrain barrier (BBB) permeability in a rat increased after BBBD compared with IA delivery brain tumor model demonstrated a large hetero- without BBBD. MTX persisted longer within geneity of microvascular leakage; the vasculature brain tissue after BBBD [Neuwelt et al. 1981]. within and around the brain tumors has a wide This delivery technique has been used across range of permeabilities, from normal capillaries centers in the United States, Canada and Israel with no (BBB) leakage to a tumor vasculature with acceptable morbidity and mortality that allows free entry of large molecules [Ewing [Angelov et al. 2009; McAllister et al. 2000; et al. 2006]. Dahlborg et al. 1996; Neuwelt et al. 1991]. A comprehensive review of IA/BBBD for Binding of the chemotherapy agent to plasma PCNSL is beyond the scope of this manuscript, protein (e.g. chlorambucil, etoposide, melphalan, but this method of chemotherapy delivery has vincristine and paclitaxel), high molecular weight been reviewed elsewhere [Angelov et al. 2009; drugs (e.g. vincristine, vinblastine, paclitaxel and Jahnke et al. 2006a; Doolittle et al. 2000; etoposide) and drugs subjected to active efflux McAllister et al. 2000]. transport (e.g. paclitaxel, vincristine, vinblastine, doxorubicin and etoposide) are among the major A recent report summarized the multi- factors that contribute to poor chemotherapeutic institutional experience of 149 newly diagnosed uptake across the BBB [Muldoon et al. 2007]. (with no prior WBRT) patients with PCNSL treated with IA/BBBD MTX from 1982 to Although MTX crosses the BBB, far less is mea- 2005 [Angelov et al. 2009]. These patients surable in the brain tissue than in the serum. received a median of 16 IA/BBBD treatments in High-dose MTX (>1 g/m ) has been shown to 8-monthly courses. CRs occurred in 57% of be an independent factor correlating with sur- patients with a 5-year PFS of 31%. The median vival [Blay et al. 1998]. Thus, MTX is adminis- OS was 3.1 years but 25% of patients lived at tered in high doses, up to 8 g/m , in order to least 8 years. Low-risk patients (age <60 and achieve therapeutic drug concentrations in the KPS 70) had a median OS of approximately tumor and surrounding brain. Intravenous (IV) 14 years with a plateau after 8 years suggesting doses less than 1 g/m , similar to what has been that some patients may have achieved cure. The used in the treatment of other malignancies out- most frequent complication was periprocedural side the brain, reach CNS concentrations gener- focal seizures, not resulting in permanent neuro- ally felt not to be cytotoxic [Morris and Abrey, logical dysfunction or uncontrolled seizures. 2009; Muldoon et al. 2007]. Thus, doses greater Strokes, however, occurred in 11 (7.4%) than 1 g/m are considered necessary for ade- patients, 4 (2.7%) of whom were left with per- quate delivery to the CNS [Blay et al. 1998]. manent neurologic deficits. The most important drawback of IA/BBBD has been the need for gen- To overcome the obstacle of the BBB and to eral anesthesia and the potential for neurovascu- improve drug delivery into brain tumor tissue, lar complications of the procedure. On the other multiple studies have attempted to enhance hand, with the caveats of a retrospective analysis, 280 http://tam.sagepub.com N Hashemi-Sadraei and DM Peereboom outcomes with IA/BBBD appear to be similar or were multicenter trials. With these caveats, it better than those accomplished with combination appears that lower dose IV MTX with IT MTX chemotherapy and/or brain irradiation, but with- in the DeAngelis et al. trial produced pre- out the neurocognitive sequelae associated with irradiation response rates (64%) roughly in the brain irradiation. range of those accomplished in the more recent trials of high-dose MTX alone (35% and 74% in Intrathecal drug delivery Herrlinger et al. and Batchelor et al., respec- Leptomeningeal involvement in PCNSL occurs tively). When compared with the study by in 37% of patients [DeAngelis et al. 1992], Batchelor et al., the addition of IT chemotherapy but pathological involvement in autopsies is does not seem to have added to response rates seen in 100% of patients, probably due to the (64% after IV and IT MTX versus 74% after periventricular location of most PCNSL lesions IV MTX alone) [Batchelor et al. 2003b]. These [Schaumburg et al. 1972]. IT chemotherapy data suggest that as long as high-dose IV MTX is attempts to improve cerebrospinal fluid (CSF) used, IT chemotherapy can be omitted, but if drug delivery; thus, many studies of PCNSL high levels cannot be administered due to included IT chemotherapy. This strategy allows patients’ comorbidities, etc., IT chemotherapy for high drug concentration in the meninges and may need to be included in the regimen. CSF with low total dose and minimal systemic side effects [DeAngelis et al. 1992; Balis and Although no prospective studies have compared Poplack, 1989]. regimens with and without IT therapy, a rela- tively large retrospective multicenter study of When given intravenously, the MTX concentra- 378 patients reported no additional survival ben- tion ratio between plasma and CSF is approxi- efit from IT chemotherapy in patients who have mately 100:1 [Ettinger et al. 1982]. Although received high-dose MTX-based regimen [Ferreri higher IV doses of MTX increase CSF concen- et al. 2002b]. Two-year OS was 51% for the trations, an increase in IV dose from 3.0 to group of patients who received IT chemotherapy 8.0 mg/m yields only a modest increase in CSF (n¼ 81) and 50% for the group which did not concentration that is not statistically different receive IT chemotherapy (n¼ 79, p¼ 0.4). [Borsi and Moe, 1987; Ettinger et al. 1982]. Interestingly, further analysis of results did not The serum half-life of MTX after a 24-hour show any correlation between dose of IV MTX 2 2 infusion is 2.24.6 hours depending on the sys- (12.9 g/m /course versus 3 g/m /course) or temic dose [Borsi and Moe, 1987], while intra- positive CSF cytology and benefit from IT Ommaya administration produces a CSF half-life chemotherapy [Ferreri et al. 2002b]. of up to 48 hours [Shapiro et al. 1975]. Another retrospective study that attempted to One of the early studies that included IT chemo- answer this question was a single-institution therapy evaluated 46 patients for evidence of lep- case-controlled study comparing these two tomeningeal lymphoma, 17 (37%) of whom had groups of patients both of whom had received either meningeal infiltration on biopsy or positive high-dose MTX (3.5 g/m or higher) [Khan CSF cytology [DeAngelis et al. 1992]. In the 31 et al. 2002]. IT MTX did not improve disease patients who received preradiation chemother- control or survival and the CSF relapse rate was apy, a relatively low dose of IV MTX (1 g/m ) similar in the two groups. In the group with no IT was used but all patients received six doses of therapy, patients with leptomeningeal tumor at intra-Ommaya MTX regardless of positive diagnosis had no leptomeningeal relapse, demon- biopsy or cytology. Patients in this subgroup, strating effective treatment with systemic chemo- when compared post hoc with those who received therapy alone. All patients received a relatively radiation therapy alone, had improved PFS and high dose of MTX over short period of time (at OS with fewer brain and meningeal relapses with least 3.5 g/m delivered over 2 hours) [Khan et al. no spinal cord relapses [DeAngelis et al. 1992]. 2002]. CSF penetration of MTX is affected by the It is difficult to conclude the role of IT chemo- rate of drug delivery and slower infusions of MTX therapy from this trial. Two more recent trials, (e.g. 8 g/m over 24 hours) may not achieve however, add some context to these earlier data cytotoxic CSF levels [Morris and Abrey, 2009; [Batchelor et al. 2003b; Herrlinger et al. 2002]. Khan et al. 2002; Vassal et al. 1990]. Rapid infu- Of note, the DeAngelis et al. trial was a sion of MTX significantly increased concentra- single-center study while the two latter studies tions of MTX in the CSF in a study comparing http://tam.sagepub.com 281 Therapeutic Advances in Medical Oncology 2 (4) 3-hour infusion versus 6-hour infusion schedules the patient population in the 2003 study by Pels ( p< 0.001) and resulted in significant parenchy- et al. (MTX 5 g/m and median age 53 years), mal tumor volume reduction [Hiraga et al. 1999]. which could have adversely affected the out- These results suggest that the rapid infusion comes in these studies [Illerhaus et al. 2009; of systemic MTX used in the Khan et al. study Omuro et al. 2007]. It is also important to achieved cytotoxic CSF concentrations thus recall that the study by Omuro et al. was observa- explaining the lack of additional benefit from tional in contrast to the others which were pro- IT chemotherapy. Thus, treatment of CSF com- spective. The NABTT 96-07 study used a higher partment may be achieved with HD-MTX dose of MTX alone (8 g/m ) and achieved an alone provided it is given over a short infusion ORR similar to the study by Pels (74% without (e.g. 24 hours). IT compared with ORR 71% with IT therapy) but PFS was inferior when IT therapy was omit- Further support for this hypothesis came from a ted (PFS 13 versus 21 months). The median OS, study of combined systemic and intraventricular however, was comparable in the two studies (OS chemotherapy which attempted to reproduce 50 versus 55 months) [Gerstner et al. 2008; Pels results from a prior study [Pels et al. 2003, et al. 2003]. 2009]. The more recent study omitted intraven- tricular therapy because 19% of the patients in Overall, it is reasonable to consider IT MTX for the earlier trial had suffered from Ommaya res- those patients with a positive CSF cytology, or in ervoir infections [Pels et al. 2003]. MTX was regimens where lower doses of MTX are deliv- delivered at 5 g/m over 24 hours in both trials. ered over longer periods of time. It is probably The results of the newer study without intraven- reasonable to withhold IT chemotherapy in those tricular therapy were clearly inferior to those of patients who have no detectable subarachnoid the study with intraventricular treatment. In fact, disease and who can receive higher dose of the study closed prematurely after an interim MTX over shorter infusion periods. analysis revealed an unacceptably high number of relapses in both the brain and the leptome- Chemotherapy and the blood ocular barrier ninges. Although ORRs were comparable Intraocular lymphoma (IOL) is a very rare dis- (interim analysis 76% without intraventricular ease and refers to infiltration of the vitreous therapy and 86% with intraventricular therapy humor, retina and optic nerve by malignant lym- in the age-matched group), the time to treatment phocytes. It can be seen independently or in asso- failure (TTF) and the response duration ciation with PCNSL (known as primary IOL appeared to be inferior in the study without intra- [PIOL]) or in the setting of systemic lymphoma. ventricular therapy (median TTF and maximum PIOL can occur as the presenting picture in CNS response duration [MRD] 8 and 10 months, lymphoma or as a site of relapse. This disease respectively, compared with TTF and MRD not should be distinguished from orbital involvement reached after median follow up of 26 months, in the context of systemic lymphoma, which p< 0.01) [Pels et al. 2009]. mostly involves the choroid [Whitcup et al. 1993]. The diagnosis of IOL can be very difficult The results of this study favor IT/intraventricular and is usually made by vitrectomy/choroidal/ therapy as part of the therapeutic regimen. retinal biopsy or clinical ophthalmic examination Although more patients in later trial (without [Grimm et al. 2007; Batchelor et al. 2003b]. intraventricular therapy) appeared to have radio- graphic evidence of leptomeningeal involvement Patients with PIOL often develop CNS involve- at relapse, this finding was not confirmed by CSF ment during course of their disease. The exact analysis [Pels et al. 2009]. When comparing the rate of CNS involvement and overlap between results of the 2003 study by Pels et al. with some the two sites of disease is unknown. In up to studies using chemotherapy regimens without IT half of the cases of ocular lymphoma, the eyes therapy, the results appear to be better in the were the initial site of disease, and as many as study by Pels et al. [Illerhaus et al. 2009; Yang 80% of patients will eventually develop brain dis- et al. 2009; Omuro et al. 2007; Batchelor et al. ease [Grimm et al. 2007; Peterson et al. 1993; 2003a; Herrlinger et al. 2002]. However, some of Char et al. 1988]. It appears that the natural those studies used a lower dose of MTX (3.0 g/ history of patients with PCNSL with ocular dis- m ) and were designed for an older population semination is similar to that in patients with iso- with median age 68 and 70 years compared with lated parenchymal brain lymphoma, and survival 282 http://tam.sagepub.com N Hashemi-Sadraei and DM Peereboom rates are not worse when there is ocular involve- including thiotepa, vincristine, cyclophospha- ment at diagnosis [Grimm et al. 2007; Abrey et al. mide and rituximab [Hormigo et al. 2004; 2006; Ferreri et al. 2003]. Ferreri et al. 2002a; Sandor et al. 1998]. Like the BBB, the bloodretinal barrier and the Sustained cytotoxic concentrations of MTX and bloodaqueous barrier hinder diffusion of drugs of cytarabine in the ocular compartment are from the blood into ocular tissues [Jahnke et al. achievable after IV administration of the drug 2007]. The retinal vessels and the retinal pigment [Batchelor et al. 2003b; de Smet et al. 1996; epithelium appear to limit drug delivery into the Baumann et al. 1986]. High-dose IV MTX intraocular space. Like PCNSL, it is believed that (8 g/m ) has been studied in patients with the bloodretinal barrier may limit the effect of ocular lymphoma. In one study, 7 of 7 patients chemotherapeutic agents at concentrations non- with concurrent PCNSL and IOL had CRs of toxic to other organs. This has led to a number of their brain disease but 3 of 7 relapsed in the studies investigating different treatment modal- eyes requiring orbital radiation, to which they ities including focal therapy. responded. The ocular response was sustained in four of seven patients [Batchelor et al. 2003b]. Because the eye can serve as a reservoir of untreated disease that increases the risk of recurrence, the Cytarabine has produced mixed results. High- eradication of ocular lymphoma is critical in treat- dose IV cytarabine alone produced one CR in ment this disease whether or not it presents in con- six patients but good ORRs (5/6) [Strauchen junction with parenchymal brain lymphoma. et al. 1989] leading to additional trials of combi- Treatment options for ocular lymphoma include nation regimens. Combination IT cytarabine/ high-dose systemic chemotherapy, IT chemother- MTX-based regimens yielded response rates as apy, myeloablative chemotherapy with ASCT, high as 100% with no ocular relapses [Mason intravitreous chemotherapy and radiation therapy and Fischer, 2003; Sandor et al. 1998]. IV [Itty et al. 2009; Soussain and Hoang-Xuan, or IT cytarabine in combination with IV 2009; Frenkel et al. 2008; Grimm et al. 2007; MTX and/or radiation produced varied response Gunduz et al. 2006; Isobe et al. 2006; Hormigo rates (68100%) and relapse rates (060%) et al. 2004; Abrey et al. 2003; Batchelor et al. [Hormigo et al. 2004; Ferreri et al. 2002a; 2003b; Ferreri et al. 2002a; Valluri et al. 1995]. Valluri et al. 1995]. Focal radiotherapy is commonly used but is Systemic chemotherapy alone or in combination associated with high cerebral relapse rates and with ocular þ/ WBRT has also been studied radiation-related side effects including optic neu- with response rates as high as 100% in mixed ropathy, retinopathy, glaucoma, dry eye syn- populations of PCNSL and ocular lymphoma. drome, corneal defects and cataracts leading to Some studies have shown better survival and visual loss in long-term survivors [Jahnke et al. lower ocular failure rates in patients treated 2007; Ferreri et al. 2002a; Buggage et al. 2001; with chemotherapy plus ocular irradiation when Char et al. 1988]. In addition, for patients who compared with chemotherapy alone [Ferreri et al. later need whole brain radiation, the juxtaposi- 2002a], but ocular radiation can lead to serious tion of the whole brain field with the previously side effects such as dry eye syndrome, cataracts, irradiated ocular field can result in local overdos- glaucoma, optic neuropathy and retinopathy, ing if the fields overlap or underdosing if a gap leading in some cases to permanent visual loss exists between the fields. [Jahnke et al. 2007]. Unfortunately, most of the data on treatment of ocular lymphoma comes Most of the reports on treatment of IOL with from patients treated on larger PCNSL trials systemic chemotherapy have included parenchy- rather than on studies specifically for patients mal disease as well as IOL in their patient popu- with ocular lymphoma. Therefore, interpretation lation. Although most of the regimens are and application of results to this subpopulation MTX-based, others have included agents is difficult. known to cross the bloodocular barrier such as cytarabine, ifosfamide or trofosfamide [Jahnke HDC/ASCR has been studied in few trials which et al. 2005a, 2005b, 2007; Strauchen et al. have included small numbers of patients with 1989; Baumann et al. 1986] or agents established ocular disease. These studies have addressed in the treatment of systemic lymphoma, newly diagnosed patients [Abrey et al. 2003] http://tam.sagepub.com 283 Therapeutic Advances in Medical Oncology 2 (4) and patients with refractory or recurrent disease median of 17 months from the time of their [Soussain et al. 2001, 2008]. Ocular response ocular diagnosis. Twelve patients (46%) survived rates are generally good, but relapse rates includ- for median of 2 years from the time of ocular ing ocular relapses remain high. This approach diagnosis. Eight patients (30%) have survived has had some promising results but because of for over 3 years after the last injection with a comorbidities and other risks associated with median of 63 months. No patients had an HDC/ASCT, stem-cell transplant remains ocular recurrence. Interestingly, 24 of 26 patients experimental. were clear of ocular lymphoma at the end of the second month of the treatment. The procedure Owing to the toxicities of radiation and systemic can be considered feasible; 17 (39%) patients’ chemotherapy, and questions regarding thera- eyes completed the treatment protocol, which peutic concentrations of certain systemic che- consisted of total of 25 injections, and 23 motherapeutic agents in the eye, some studies patients’ eyes (52%) did not complete the entire have addressed the benefit of intraocular therapy treatment protocol but all were cleared clinically for the treatment of ocular lymphoma. de Smet of malignant cells. et al. reported cytological clearance of the tumor achieved by intravitreal injections of MTX and Complications from intraocular chemotherapy thiotepa in addition to systemic and IT chemo- with MTX appear to be mostly transient, and therapy a patient who had recurrent intraocular unlike focal radiation therapy to eye, less likely lymphoma after radiotherapy and IT chemother- lead to permanent visual loss. Complications apy [de Smet et al. 1999]. Intravitreal MTX include keratopathy, maculopathy, cataract levels were measured and tumoricidal concentra- (acceleration of existing cataract), neovascular tions were documented 5 days after injection, glaucoma, vitreous hemorrhage, optic atrophy which is longer than that achieved following and sterile endophthalmitis [Frenkel et al. 2008; systemic drug delivery [de Smet et al. 1999]. Smith et al. 2002b]. Intraocular rituximab has also recently been tried successfully without There is no consensus on best intraocular regi- significant short-term toxicity and multiple injec- men and duration of treatment. Two recent stu- tions appear to be well tolerated [Itty et al. 2009; dies have used intravitreal injections of MTX in Kitzmann et al. 2007]. However, further studies induction, consolidation and maintenance phases using combination chemotherapy agents such (biweekly injections followed by weekly followed as MTX and rituximab are needed. by monthly injections over a year) [Frenkel et al. 2008; Smith et al. 2002b]. The relative impact of different treatment modalities on outcome of patients with PCNSL In a small study of four patients with ocular and ocular disease has not been studied exten- lymphoma, intraocular MTX in addition to sys- sively. One retrospective multicenter study of temic therapy with IA chemotherapy and BBBD 22 patients reported improvements in PFS resulted in complete remission of all patients with (12 versus 5.5 months) and cerebral relapse no relapse during the follow-up period (up to 19 rates following systemic chemotherapy compared months) [Fishburne et al. 1997]. Another study with focal therapy. Most of the patients who of intraocular MTX with systemic and IA che- received focal therapy in this study received radi- motherapy reported complete remission in all ation therapy, and only three patients had 16 patients. Three patients experienced ocular received intraocular chemotherapy [Jahnke et al. relapse but achieved second remissions with 2006b]. More recently, a large retrospective further intraocular MTX [Smith et al. 2002b]. study in seven countries reported on two groups of patients: those with brain lymphoma and Frankel et al. published a 10-year experience of ocular dissemination [Grimm et al. 2008], and 26 ocular lymphoma patients treated with intra- those with isolated ocular lymphoma (PIOL) vitreal MTX [Frenkel et al. 2008]. They reported [Grimm et al. 2007]. no intraocular recurrences and no serious adverse effects. The population in this study also In the later report by Grimm et al., some of the included patients with a history of parenchymal patients with lymphoma involving the eyes and PCNSL and patients in remission from prior sys- brain parenchyma at diagnosis had received temic lymphoma. Fourteen patients (53%) died dedicated ocular therapy in addition to systemic of their CNS or systemic lymphoma within a therapy for their brain disease. The dedicated 284 http://tam.sagepub.com N Hashemi-Sadraei and DM Peereboom ocular therapy included ocular radiotherapy, MMSE has a low sensitivity for detecting cogni- intraocular MTX or both. Although the PFS tive impairment in brain tumor patients, and it is appeared slightly better with the addition of very important that comprehensive neurocogni- dedicated ocular therapy it did not impact OS. tive evaluations are incorporated into outcome Risk of progression and pattern of failure was not studies of CNS lymphoma patients. affected by the initial therapeutic approach sug- Cognitive outcome: chemotherapy with WBRT gesting that the addition of dedicated ocular One of the early studies on late-onset treatment- therapy did not add to the efficacy of systemic related neurotoxicity reported that approximately therapy alone [Grimm et al. 2008]. one-third of patients treated with combined modality therapy developed neurotoxicity In the report by Grimm et al. on patients with [Abrey et al. 1998]. The main symptoms were PIOL, some patients received focal therapy dementia, gait imbalance, urinary incontinence alone (intraocular MTX, ocular radiotherapy) and worsening performance status, which devel- and some received extensive therapy (systemic oped after a median time of 13 months from chemotherapy, WBRT). Of those patients who diagnosis. Importantly, there was a significant relapsed, 47% relapsed in brain but focal therapy association between older age group patients alone did not increase risk of brain relapse. (age >60 years) and development of these side Treatment did not affect PFS or OS either, sug- effects [Abrey et al. 1998]. gesting that focal therapy alone did not compro- mise outcomes in PIOL [Grimm et al. 2007]. Correa evaluated PCNSL survivors and com- pared results between patients who had received Although large studies dedicated to PIOL are WBRT þ/ chemotherapy with patients who lacking, review of the literature suggests that the received chemotherapy alone [Correa et al. best initial therapy in patients with PIOL is focal 2004]. The group that had received WBRT was intraocular chemotherapy. Intraocular chemo- younger than the chemotherapy-alone group and therapy appears to be feasible, safe, with few long-term side effects, and offers survival rates had longer follow up. All patients in the and relapse patterns similar to that of more chemotherapy-alone group were 60 years of age extensive therapy [Grimm et al. 2007]. Among or older. Unfortunately, the details of their ther- patients with concomitant parenchymal brain apy were not outlined in the report. The baseline and ocular involvement, the addition of intraocu- cognitive assessment was performed post- lar chemotherapy to systemic therapy can treatment and a subgroup of these patients was improve PFS without significant additional side followed again after 8 months. Patients who effects, but the addition of this therapy will not received chemotherapy alone had significantly improve survival rates or impact local relapse. better scores in some cognitive domains than did patients treated with WBRT þ/ chemother- Neurocognitive toxicity of therapy apy. Older patients who received chemotherapy Current treatment for PCNSL often involves alone were cognitively significantly less impaired than older patients who received WBRT as part high-dose MTX-based chemotherapy with or of their treatment. Interestingly, patients treated without WBRT. Although this treatment pro- with chemotherapy only (all 60 years and older) longs survival, neurotoxicity, especially in the were also significantly less impaired in memory delayed form, poses a substantial and feared than patients younger than 60 years of age who complication [Correa et al. 2004, 2009; Harder received WBRT. In patients treated with WBRT et al. 2004; DeAngelis et al. 1992]. MTX and þ/ chemotherapy, there were no significant dif- WBRT each may cause CNS damage, but there ferences in memory performance between youn- appears to be synergistic toxicity when these two ger patients and older patients [Correa et al. modalities are combined [Correa et al. 2004; 2004]. This study documented the occurrence Crossen et al. 1994]. Cognitive disturbances are critically important when choosing a treatment of WBRT-related neurotoxicity regardless of age. modality for more vulnerable subgroups of patients. Some older studies have used MMSE A multicenter European study evaluated patients to evaluate for cognitive disturbances but this who received MBVP chemotherapy (methylpred- test was not developed for brain tumor patients nisolone, MTX, teniposide, BCNU) in addition or for assessment of treatment-related morbidity to IT MTX, IT cytarabine and hydrocortisone [Correa et al. 2004; Weitzner and Meyers, 1997]. followed by WBRT [Harder et al. 2004]. http://tam.sagepub.com 285 Therapeutic Advances in Medical Oncology 2 (4) Extensive neuropsychological and quality-of-life cognitive function (memory and executive assessments were performed. This study had a function) in patients with more severe white young group of patients (median age 44 years). matter changes (Fazekas grade 23 white All had a complete tumor response without evi- matter changes) [Correa et al. 2009; Fazekas dence of tumor activity and were at least 6 et al. 1987]. There was also a mild increase in months post-treatment. The results were com- treatment-related white-matter disease following pared with matched control subjects with sys- treatment, seen mainly in older patients (age >60 temic hematological malignancies treated with years).These findings are consistent with prior systemic chemotherapy or non-CNS radiother- evidence of delayed treatment-related neurotoxi- apy. Cognitive impairment was significantly city in older patients [Correa et al. 2004; Harder higher in the PCNSL group despite a complete et al. 2004]. tumor response, suggesting that cognitive distur- Cognitive outcome: chemotherapy bances resulted from treatment rather than without WBRT tumor. The authors argued that combined mod- One of the early reports on cognitive outcome of ality treatment for PCNSL is associated with cog- chemotherapy for PCNSL evaluated patients nitive impairment even in patients younger than who received MTX-based chemotherapy. Seven 60 years of age [Harder et al. 2004]. of the 14 patients had formal neurocognitive assessments, two of whom, the oldest in the A large study of combined modality therapy fol- group, experienced severe neurologic deteriora- lowed by WBRT in elderly patients demonstrated tion. One of these patients had had a stroke no acute high-dose MTX-related neurotoxicity and had white-matter changes consistent with was observed. Nineteen percent of patients had multiple infarcts prior to therapy. Similar to MRI evidence of leukoencephalopathy, and 7% studies of radiation-induced neurotoxicity, age demonstrated clinical evidence of late neurotoxi- appeared to be the most significant predictor of city. The results, however, were not segregated neurocognitive outcome in this report [Sandor according to whether the patients received WBRT or not [Jahnke et al, 2005a]. et al. 1998]. A recently study reported prospective neuropsy- Later, a group in Germany reported stable cog- chologic evaluation in patients with PCNSL who nitive function in their patients and have not received induction chemotherapy followed by identified particular worsening in cognitive per- reduced dose WBRT and consolidation chemo- formance among elderly patients [Fliessbach therapy [Correa et al. 2009]. These patients et al. 2003; Pels et al. 2003]. Pels and colleagues received rituximab, MTX, procarbazine and reported serious neurocognitive decline only in vincristine (R-MPV) as induction therapy. All two patients, one that was attributed to tumor patients had a CR after R-MPV and received relapse and the second to residual tumor. However, they performed detailed neuropsycho- 23.4 Gy of WBRT. After completion of WBRT, all but one patient received two cycles of logical evaluation in 22 of 65 patients in a trial of systemic and intraventricular chemotherapy and high-dose cytarabine (ARA-C) consolidation reported no cognitive decline in these patients. chemotherapy. After induction therapy scores Some patients developed therapy induced improved and during the follow-up period, cog- white-matter changes on MRI, but these did nitive performance and self-reported quality of not correlate with their neuropsychological life remained relatively stable suggesting that scores. Interestingly, patients older than 60 treatment with R-MVP and reduced-dose years had lower scores at diagnosis, but their cog- WBRT was not associated with significant cogni- nitive performance did not decline more than tive decline, at least within the follow-up period their younger counterparts [Pels et al. 2003]. of 2 years. However, there was a trend towards decline in verbal memory during the first year of follow up. This decline did not continue through Some authors argue that because cognitive dis- the second year. Overall, there was no significant turbances are one of the known symptoms of cognitive decline up to 24 months postche- PCNSL, post-treatment scores in patients in motherapy. Although there were no significant remission, rather than pretreatment measures correlations between treatment related white should serve as baseline. In order to evaluate matter changes and cognitive test performance, for long-term post-treatment side effects, there was a mild decline in some aspects of follow-up evaluations should be compared with 286 http://tam.sagepub.com N Hashemi-Sadraei and DM Peereboom the post-treatment baseline scores [Fliessbach by assessment of cognitive abilities in patients et al. 2005]. An update of the German study with relapsed or progressive disease one could described 23 patients who were in complete not distinguish treatment related from disease- remission for at least 12 months. Ninety five per- related cognitive toxicity, and thus limited their report to patients who achieved long-term CR. cent of patients showed improved or stable cog- Results were reported in separate reports and nitive function suggesting that combination overall, most of these patients, and notably chemotherapy with high-dose MTX does not older population (age over 60), appeared to negatively impact cognitive function long term have cognitive improvement or preservation of and in fact may improve performance in many their cognitive function relative to pretreatment patients [Fliessbach et al. 2005]. For a sizeable fraction of patients, however, cognitive deficits status at follow up between 1 to 7 years after noted at baseline persisted [Fliessbach et al. achieving CR [McAllister et al. 2000; Dahlborg 2005]. et al. 1996]. Another study that confirms prior findings is an These studies, with recognition of their pitfalls, update of the report by Herrlinger and collea- suggest there is delayed neurotoxicity associated gues, which describes long-term outcome of with WBRT, which impacts not only older treatment with regard to neurotoxicity and qual- patients (age above 60 years), but also signifi- ity of life [Herrlinger et al. 2005]. Patients in this cantly impairs outcomes in younger patients study received high-dose MTX initially, and at [Harder et al. 2004]. Lowering the dose of the time of relapse received either WBRT or WBRT may cause less long-term neurocognitive other salvage chemotherapy. Like the prior toxicity [Correa et al. 2009], but this remains to study by Pels and colleagues, although 10% of be proven in older patients and for longer patients who received chemotherapy alone follow-up periods. Interestingly, one of the few (without salvage radiation) developed severe modalities to show preserved and improved cog- leukoencephalopathy, there was no meaningful nitive function in older population (age over 60) was IA chemotherapy with BBBD [Angelov et al. correlation between white-matter changes and 2009; Neuwelt et al. 2005; McAllister et al. 2000; cognitive deficits. Six of 10 long-term survivors Dahlborg et al. 1996; Crossen et al. 1992]. who had remained tumor free for at least 48 months were evaluated with a battery of neurop- Conclusion sychological tests; 5 of these patients had received Although chemotherapy as a single modality has chemotherapy alone and 1 had received WBRTat an established role in the management of newly the time of relapse. All patients showed mild- diagnosed PCNSL, much room for improvement to-moderate cognitive disturbance, which sug- exists. Clinical judgment will need to augment gests late neurotoxicity should be considered as the data from relatively small clinical trials as a possible side effect of chemotherapy-alone the low incidence of this disease precludes ade- regimens. The authors concluded that polyche- quately powered randomized trials. It appears motherapy regimens cause less-severe neurotoxi- that single-agent high-dose MTX can work well city than traditional WBRT. Interestingly, for provided that it is given over a short infusion. reasons not completely clear, this study also While combination chemotherapy has good reports higher acute toxicities and worse response oncologic rationale and has proven effective, rates when compared with similar studies, which careful patient selection is required for its safe at the time resulted in early closure of the study use. Radiation therapy has been avoided in [Batchelor et al. 2003b; Herrlinger et al. 2002, most patients given the neurocognitive toxicity 2005; Guha-Thakurta et al. 1999]. associated with traditional fraction sizes and IA/BBBD total doses. Lower doses and twice-daily dosing Long-term cognitive outcomes were reported designed to minimize toxicity, however, are cur- separately in a subset of patients treated with IA rently in clinical trials and deserve consideration. chemotherapy-based BBBD [Angelov et al. More intensive approaches using HDC/ASCR or 2009]. Neuropsychologic assessments included IA/BBBD need further study although involve a comprehensive battery of tests to evaluate dif- considerable invasiveness. The role of focal ther- ferent cognitive domains [Neuwelt et al. 2005; apy to address ocular and CSF involvement con- McAllister et al. 2000; Dahlborg et al. 1996; tinues to evolve. Small series of intravitreal and Crossen et al. 1992]. The authors argued that IT regimens using rituximab have been reported http://tam.sagepub.com 287 Therapeutic Advances in Medical Oncology 2 (4) Borsi, J.D. and Moe, P.J. (1987) A comparative study but need formal testing in clinical trials. As ther- on the pharmacokinetics of methotrexate in a dose apeutic regimens are refined the quality of life range of 0.5 g to 33.6 g/m 2 in children with acute and neurocognitive function of patients with lymphoblastic leukemia. Cancer 60: 513. PCNSL will hopefully improve. Brevet, M., Garidi, R., Gruson, B., Royer, B., Vaida, I. and Damaj, G. (2005) First-line autologous stem cell transplantation in primary CNS lymphoma. Eur J Conflict of interest statement Haematol 75: 288292. The authors declare they have no conflicts of interest. Buggage, R.R., Chan, C.C. and Nussenblatt, R.B. (2001) Ocular manifestations of central nervous system lymphoma. Curr Opin Oncol 13: 137142. 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Therapeutic Advances in Medical Oncology – SAGE
Published: Mar 17, 2010
Keywords: blood-brain barrier disruption; chemotherapy; high-dose chemotherapy; intra-arterial chemotherapy; intraocular chemotherapy; intrathecal chemotherapy; methotrexate; neurocognitive toxicity; primary central nervous system lymphoma
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