Leukemia & Lymphoma, 2014; Early Online: 1–8 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.961014
REVIEW
The role of radiation therapy in the management of primary central nervous system lymphoma Sarah A. Milgrom & Joachim Yahalom
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Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
with increasing frequency in immunocompetent patients, particularly in the elderly [4]. Patients typically present with focal neurological deficits and/or neurocognitive dysfunction. Signs and symptoms of increased intracranial pressure are possible but less common. Ocular involvement may result in visual disturbances. B symptoms are rare [6]. Magnetic resonance imaging (MRI) of the brain typically reveals one or multiple homogeneously contrast-enhancing lesions, often in the periventricular space [1]. A biopsy is indicated to confirm the diagnosis; however, a biopsy of the brain may be avoided if the cerebrospinal fluid (CSF) or vitreous fluid contains lymphoma cells. The histology is diffuse large B-cell lymphomas (DLBCL) in approximately 95% of cases of PCNSL. Epstein–Barr virus (EBV) has been implicated in PCNSL of immunocompromised patients. EBV is detected less commonly in PCNSL of immunocompetent patients, suggesting that the pathogenesis may differ based on immune status [7]. PCNSL has an aggressive course. The median survival of untreated patients is approximately 3 months [8]. Whole brain radiation therapy (WBRT) was the first effective treatment for PCNSL. Used alone, it induces rapid but transitory remissions, improving the median survival to 12–18 months [9]. Subsequently, chemotherapeutic agents have been combined with WBRT, resulting in improved long-term outcomes. Modern first-line therapy, consisting of high-dose methotrexate (HDMTX)-based chemotherapy in combination with WBRT, results in median survival rates of 36–60 months [10,11]. Poor performance status and advanced age are associated with unfavorable outcomes [11–14]. Owing to the uncommonness of PCNSL, knowledge regarding its optimal management is derived mainly from retrospective and small prospective phase II studies. Only one phase III trial is available, which is compromised by several flaws, as described below. Current potential indications for WBRT in PCNSL include: (1) consolidation in patients who have achieved a complete response (CR) to chemotherapy; (2) definitive therapy in patients who cannot receive chemotherapy; (3) salvage treatment in patients with refractory
Abstract Primary central nervous system lymphoma (PCNSL) is an aggressive neoplasm with a poor prognosis. Early studies of whole brain radiation therapy (WBRT) alone revealed a robust initial response but high rates of local recurrence with long-term follow-up. The addition of high-dose methotrexate (HDMTX)based chemotherapy improved the durability of disease control. However, delayed neurotoxicity emerged as an important complication, mainly in elderly patients. Therefore, researchers have investigated eliminating WBRT or reducing its dose. Multiple studies of chemotherapy alone have demonstrated inferior disease control. On the other hand, a phase III trial reported that WBRT may be deferred until relapse without compromising survival; however, this trial is fraught with flaws. A recent study of immunochemotherapy and dose-reduced WBRT demonstrated excellent outcomes. Currently, this regimen is being studied in a multi-institutional trial by the Radiation Therapy Oncology Group. WBRT maintains an important position in the armamentarium against PCNSL. This article aims to describe its evolving role. Keywords: Primary CNS lymphoma, PCNSL, radiation therapy, RT, whole brain radiation therapy, WBRT
Introduction Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma (NHL) that arises within the brain parenchyma or, less commonly, the leptomeninges, spinal cord or eye [1]. It represents 4% of primary intracranial neoplasms and 1–2% of all cases of NHL [2,3]. Its incidence in the United States is 0.47 cases per 100 000 person-years [4]. A major risk factor for PCNSL is long-term immunosuppression. Therefore, its prevalence in patients with solid organ transplant is 1–5% [5]. The risk of PCNSL was reported to be 2–6% in patients with acquired immune deficiency syndrome (AIDS) [5]; however, the incidence has been decreasing since the implementation of highly active anti-retroviral therapy [4]. On the other hand, PCNSL is being diagnosed
Correspondence: Joachim Yahalom, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. E-mail: [email protected] Received 8 June 2014; revised 17 August 2014; accepted 29 August 2014
1
BVAM, carmustine, vincristine, methotrexate, cytarabine; CHOD, cyclophosphamide, doxorubicin, vincristine, dexamethasone; CR, complete response; Cyt, cytarabine; HDMTX, high dose methotrexate; Ifos, ifosfamide; IT, intrathecal; IV, intravenous; MTX, methotrexate; NS, not stated; OS, overall survival; PCNSL, primary central nervous system lymphoma; PFS, progression-free survival; Pro, procarbazine; RT, radiation therapy; RTX, rituximab; TMZ, temozolomide; Vin, vincristine; WBRT, whole brain radiation therapy. *Initially all patients received WBRT to 45 Gy, then the trial was amended to reduce the dose to 36 Gy for patients who responded completely to induction chemotherapy. †Patients who responded completely to chemotherapy were treated with 45 Gy (1990–1995) or 30.6 Gy (1996–1999). ‡23.4 Gy for patients who responded completely to induction chemotherapy, 45 Gy for all others. §Initially all patients received HDMTX alone, then the trial was amended and all patients received HDMTX ⫹ ifosfamide. ¶Patients with a complete response to chemotherapy were randomized to 45 Gy WBRT vs. none. Patients with persistent or relapsed disease received 45 Gy WBRT.
57.5 63 53 551 (318 per protocol) RTOG 02-27 [47] G-PCNSL-SG-1 [24]
Morris et al. [31]
52
60
RTX, HDMTX, Pro, Vin, Cyt HDMTX, TMZ, RTX HDMTX ⫾ Ifos§
36 45 vs. none¶
Median 3.3 years (7.7 years for CR/23.4 Gy) 63.6% 2 years Median 18.3 months (RT arm) vs. 11.9 months (no RT arm) 23.4 vs. 45‡
Median 6.6 years (not reached for CR/23.4 Gy) 80.8% 2 years Median 32.4 months (RT arm) vs. 37.1 months (no RT arm)
NS 45 vs. 30.6† 59 57 (36 CR to chemotherapy)
102 RTOG 93-10 [11]
Bessell et al. [29]
41 54 52
56.5
Neurotoxicity
12 “severe delayed neurotoxicity,” 8 deaths In 1-year survivors: 0/13 (30.6 Gy); 1/12 (45 Gy and ⬍ 60 years old); 6/10 (45 Gy and ⱖ 60 years old) None, except decreased motor speed (CR/23.4 Gy) NS Sustained CR: 22/45 in RT arm (49%) vs. 9/34 (26%) in no RT arm 64% 2 years, 52% 3 years, 32% 5 years 36% 5 years Median 2 years 45 vs. 36*
48% 1 year, 28% 2 years 42% 2 years Median 60 months
OS PFS
NS Median 9.2 months NS
WBRT/boost dose (Gy) Chemotherapy Median age (years)
RTOG 83-15 [12] RTOG 88-06 [14] Abrey et al. [10]
In an attempt to improve the durability of the disease response, chemotherapy was added to WBRT. In RTOG
n
Combination chemotherapy and WBRT
Study
In extranodal lymphomas outside of the central nervous sytem (CNS), involved field RT alone is successful in the treatment of low volume, early stage disease. Extrapolating from this experience, RT was the first therapy used for PCNSL. PCNSL is often multifocal and diffusely infiltrative, so WBRT, rather than focal RT, was used to ensure that all disease was encompassed within the treatment volume. An early study of PCNSL was Radiation Therapy Oncology Group (RTOG) 83-15, a prospective phase II trial in which 41 patients were treated with WBRT to 40 Gy, followed by a 20 Gy boost to the tumor (Table I). Twenty-six patients had post-treatment computed tomography (CT) scans performed 4 months after the start of WBRT. Of these, 16 patients (62%) had a complete radiographic response and an additional five patients (19%) had an “almost complete response” [12]. These high rates of regression were consistent with the experience in treating NHL outside of the CNS, which had demonstrated the exquisite radiosensitivity of the disease. However, unlike in other lymphomas, the radiation response of PCNSL was not sustained in the majority of patients. Analysis of this study 3.3 years after its completion revealed that 27 of 41 patients (66%) had died of PCNSL. Although most patients ultimately recurred, it must be noted that some patients did achieve a durable response: six patients (15%) survived without evidence of disease at their last follow-up visit, with a median survival of 53.9 months from the start of WBRT and 54.5 months from diagnosis. The remaining eight patients (20%) died, without evidence of lymphoma, from intercurrent disease. For the total cohort, the median overall survival was 11.6 months from the start of WBRT and 12.2 months from diagnosis, with 48% surviving 1 year and 28% surviving 2 years. Patients with a Karnofsky Performance Status (KPS) of ⬍ 70% or age ⱖ 60 years experienced significantly worse survival (p ⱕ 0.004). Young, fit patients had substantially better outcomes: the 2-year survival was 46% for patients with a KPS ⱖ 70% and was 47% for patients ⬍ 60 years of age [12]. In RTOG 83-15, the majority of relapses occurred within the irradiated area. Disease recurred in the brain in 25 patients (61%). Of these recurrences, 21 (84%) involved the brain only and four (16%) involved the brain and other distant sites. Only three patients (7%) failed with distant metastases alone. The majority of recurrences in the brain were within the boost field (n ⫽ 22; 88%) [12]. Thus, long-term local control remained a challenge, despite the dramatic initial response to WBRT.
Table I. Representative summary of trials assessing WBRT in the upfront management of immunocompetent patients with PCNSL.
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WBRT alone as upfront therapy
40/20 41.4/18 45
The role of radiation therapy in treatment of primary central nervous system lymphoma
None CHOD MTX (IV and IT), Vin, Pro, Cyt MTX (IV and IT), Vin, Pro, Cyt CHOD ⫻ 1, BVAM ⫻ 2
or relapsed disease; (4) curative treatment in patients with rare histologies; and (5) palliative therapy in patients with symptomatic disease. This article aims to describe the evolving role of radiation therapy (RT) in the management of PCNSL.
NS 1 grade 5 encephalomalacia 13
S. A. Milgrom & J. Yahalom
66 NS (⬎ 60) 65
2
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The role of RT in PCNSL 88-06, 54 human immunodeficiency virus (HIV)-negative patients with PCNSL were treated with two cycles of cyclophosphamide, doxorubicin, vincristine and dexamethasone (CHOD), followed by WBRT to 41.4 Gy and a boost to the tumor for a total dose of 59.4 Gy. The median survival for the cohort was 16.1 months, with a 2-year overall survival rate of 42%. These outcomes were not significantly different from those seen in RTOG 83-15, suggesting that CHOD did not improve survival over WBRT alone [14]. This lack of effect likely resulted from poor penetration of CHOD across the blood–brain barrier. A significant improvement in outcomes was achieved with the addition of HDMTX-based chemotherapy to WBRT. At Memorial Sloan Kettering Cancer Center (MSKCC), 52 immunocompetent patients with PCNSL were treated with HDMTX, intrathecal methotrexate (ITMTX), vincristine and procarbazine. This regimen was followed by WBRT to 45 Gy, and then high-dose cytarabine. In this cohort, 18 patients (35%) relapsed at 3–35 months after diagnosis. The median survival was 60 months, significantly longer than had been observed previously. Young patients experienced particularly favorable outcomes. At the time of publication, patients ⬍ 60 years of age had been followed for a median of 50 months and had not yet reached their median overall or disease-free survival [10]. Given these impressive outcomes, this treatment regimen was assessed further in RTOG 93-10. In this phase II trial, 102 immunocompetent patients with PCNSL were treated with HDMTX, ITMTX, vincristine and procarbazine, followed by WBRT, and then high-dose cytarabine. Initially the WBRT dose was 45 Gy in 25 fractions; however, the study was amended to reduce this dose to 36 Gy in 30 twice-daily fractions for patients who responded completely to induction chemotherapy. In RTOG 93-10, the median overall survival was 36.9 months and median progression-free survival was 24 months [11]. Thus, this cooperative group study confirmed the marked survival benefit provided by the combination of HDMTX-based chemotherapy and WBRT, compared to PCNSL outcomes reported previously. However, while this regimen resulted in favorable oncologic outcomes, delayed neurotoxicity emerged as an important complication, particularly in patients over 60 years old. Late neurotoxicity was observed in 13 (25%) of the patients treated at MSKCC and in 12 (15%) of the patients treated on RTOG 93-10 [10,11]. The clinical presentation consisted of memory deterioration and personality change, sometimes followed by gait disturbance and urinary incontinence. Individuals over 60 years of age were particularly vulnerable to delayed neurocognitive effects. In fact, in the study from MSKCC, all patients who developed neurotoxicity, except for one, were ⬎ 60 years old [10]. A secondary analysis of RTOG 93-10 assessed the cognitive function of the patients who achieved a CR to induction chemotherapy and then received conventionally fractionated (45 Gy in 25 fractions) versus hyperfractionated (36 Gy in 30 fractions over 3 weeks) WBRT. At 8 months after treatment, mini-mental status examination (MMSE) scores improved in all patients, with no statistical difference according to WBRT fractionation schedule. At 2 years, the decline in MMSE
3
scores was less in patients who had received hyperfractionated versus conventionally fractionated WBRT; however, the rates were equivalent at 4 years [15]. These findings suggested that hyperfractionation delayed, but did not eliminate, the neurocognitive effects of chemoradiation therapy. Concerns regarding neurotoxicity, particularly in the elderly, have caused researchers to investigate eliminating WBRT from the primary treatment of PCNSL. Multiple retrospective and prospective phase II studies have demonstrated less effective disease control with the use of chemotherapy alone, when compared to the combination of MTX-based chemotherapy and WBRT. In one trial of single-agent HDMTX, without WBRT, the median progression-free survival was 12.8 months [16]. Another study of chemotherapy alone used HDMTX in combination with cytarabine, dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide, as well as ITMTX, prednisolone and cytarabine. In this trial, the median time to recurrence was 21 months [17]. However, when the same regimen was given without the IT chemotherapy, the median time to relapse was 8 months [18]. While IT chemotherapy likely improves disease control, it is unlikely to account for such a significant difference in outcomes. Therefore, the results of the earlier study are drawn into question and must be reproduced. Other groups have studied the use of high-dose chemotherapy (HDCT) with autologous stem-cell transplant (ASCT) [19–22]. Disease control has been suboptimal. For example, in one multicenter phase II study, 28 patients received induction HDMTX and cytarabine. Of these, 14 patients responded completely or partially and went on to receive high-dose carmustine, etoposide, cytarabine and melphalan (BEAM) with ASCT. At a median follow-up of 28 months, the median event-free survival time was only 5.6 months for the entire cohort and 9.3 months for the 14 patients who underwent ASCT [22]. Another study assessed the outcomes of 64 young (age ⬍ 60 years) patients with PCNSL for whom WBRT was omitted in favor of additional chemotherapy if a CR to HDMTX-based multi-agent chemotherapy was achieved. Patients with less than a CR were treated on an individual basis, typically with WBRT or HDCT/ASCT. The median progression-free survival was 12 months, significantly less than expected for this favorable cohort [23]. Taken together, these studies have shown inferior oncologic outcomes when WBRT was excluded from the upfront management of PCNSL. The German PCNSL Study Group (G-PCNSL-SG) reported the only prospective phase III study, which aimed to determine whether WBRT may be avoided in the primary setting without a detrimental effect on survival. The G-PCNSL-SG-1 trial randomized patients who achieved a CR to HDMTXbased chemotherapy to immediate consolidative WBRT (45 Gy) versus deferred WBRT at the time of relapse. Patients without a CR received high-dose cytarabine or WBRT. The trial was designed to show that omission of WBRT from firstline treatment does not compromise overall survival, using a non-inferiority margin of 0.9. In total, 551 patients entered the study, but only 411 were eligible for inclusion in the intent-to-treat population, and, after 93 serious protocol violations, only 318 were treated according to protocol. In this group of 318 patients, those who received WBRT experienced
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improved progression-free survival of 18.3 vs. 11.9 months; however, this difference did not meet statistical significance (p ⫽ 0.14). The median overall survival was not significantly different for the two groups (32.4 months in WBRT arm vs. 37.1 months in chemotherapy alone arm, hazard ratio [HR] 1.06, 95% confidence interval [CI] 0.80–1.40, p ⫽ 0.71) [24]. Because the 95% CI included 0.9, the authors did not meet their primary non-inferiority endpoint, despite the large number of patients enrolled. Although the authors did not meet their non-inferiority endpoint, some clinicians have proposed eliminating WBRT from upfront management, because there was no difference in overall survival between the two arms. Recent commentaries have argued why this conclusion should not be drawn [8,25,26]. First, poor protocol adherence complicates comparisons of the two arms. Strikingly, ∼40% of patients were excluded from the primary analysis, introducing significant bias. Additionally, the trial was compromised by multiple other flaws in design and execution, including low statistical power (60%), long accrual period, inclusion of small centers with little PCNSL experience, suboptimal chemotherapy use, lack of quality assurance and insufficient neurotoxicity evaluation. Furthermore, patients treated with chemotherapy alone were more likely to relapse and require salvage therapy, as demonstrated by the difference in progressionfree survival between the two arms. Both disease relapse and salvage therapy are themselves associated with neurologic and other morbidity that has not been studied adequately. In a recent position paper, Dr. Lisa DeAngelis, who pioneered and extensively studied modern PCNSL treatment, pointed out that a competing risks analysis, adjusting for the effect of relapse, demonstrates that approximately 24% of patients develop neurotoxicity at 5 years after WBRT, while the risk of PCNSL recurrence is twice the risk of neurotoxicity [25]. “Thus, uncontrolled PCNSL is the primary hurdle to both survival and good quality of life in most PCNSL patients. Prevention of relapse should be the primary research focus” [25]. Therefore, while the G-PCNSL-SG-1 findings are intriguing, the study does not definitively demonstrate that WBRT may be safely excluded from upfront management. An alternative strategy to excluding WBRT altogether is reducing the radiation field size or dose in appropriately selected patients, with the aim of maintaining good disease control while decreasing toxicity. Researchers from Japan addressed the question: can patients with PCNSL, particularly those with unifocal disease and those receiving combined modality therapy, be treated with focal RT rather than WBRT? The authors reviewed the outcomes of 43 patients with PCNSL who were treated with partial brain RT. All patients were treated with curative intent. The majority of patients had unifocal disease (74%) and received systemic chemotherapy (60%). The median partial brain RT dose was 50 Gy and median margin size was 4 cm from the tumor to field edge. The median survival of this cohort was 16 months. At 5 years, the rate of in-field recurrence was 57% and out-of-field, in-brain recurrence was 49%. Twelve of the 14 out-of-field recurrences were distant from the irradiated area and, thus, would not have been included in a more generous partial brain RT field
[27]. These findings demonstrate that focal RT results in high rates of relapse within the brain, outside of the irradiated area, suggesting that the whole brain must be treated when RT is used in PCNSL. Other researchers have investigated decreasing the RT dose, rather than field size, in appropriately selected patients with PCNSL. Recent studies have demonstrated a role for dose reduction in patients who achieve a CR to chemotherapy. Ferreri et al. published a retrospective, single-institution series of 33 immunocompetent patients with PCNSL who achieved a CR to HDMTX-based chemotherapy and then received consolidation WBRT. The authors found no significant difference in the relapse rates of patients treated with 30–36 Gy vs. ⱖ 40 Gy (30% vs. 46%, p ⫽ 0.24). On the other hand, they did observe significantly less neurologic impairment, as measured by MMSE, in patients treated with 30–36 Gy vs. ⱖ 40 Gy (p ⫽ 0.05) [28]. Taken together, these findings suggest that in patients with a CR to chemotherapy, escalating the WBRT dose above 36 Gy does not improve oncologic outcomes but does increase neurotoxicity. Based upon such findings, researchers have assessed outcomes after selectively dose-reducing WBRT in patients with PCNSL who achieve a CR to induction chemotherapy. First, a group from Spain and the United Kingdom reported outcomes of patients treated with one cycle of CHOD and two cycles of carmustine, vincristine, cytarabine and methotrexate (BVAM), followed by WBRT. In this series, 36 patients achieved a CR to chemotherapy and were treated with WBRT to 40 Gy (n ⫽ 20) or 30.6 Gy (n ⫽ 16). The 3-year risk of relapse was 30% for patients treated to 45 Gy vs. 65% for patients treated to 30.6 Gy (p ⫽ 0.08). In patients younger than 60 years of age, these rates were 25% vs. 79%, respectively (p ⫽ 0.06). An analysis of patients who achieved a CR to all treatment (chemotherapy and WBRT) revealed 3-year overall survival rates of 92% in patients receiving 45 Gy vs. 60% in those receiving 30.6 Gy (p ⫽ 0.04) [29]. Thus, reducing the WBRT dose in patients with a CR to this chemotherapy regimen resulted in an increased risk of relapse and mortality. On the other hand, a prospective study of dose-reduced WBRT and (possibly more effective) immunochemotherapy yielded excellent outcomes. The authors reported on 52 immunocompetent patients with PCNSL who received induction rituximab, HDMTX, procarbazine and vincristine (R-MPV). Patients were evaluated by MRI after five cycles. Those with a CR were treated with dose-reduced WBRT to 23.4 Gy. All others received two additional cycles of R-MPV and were re-assessed. Patients with a CR after seven cycles received dose-reduced WBRT (23.4 Gy); all others received standard WBRT to 45 Gy. After WBRT, all patients were treated with high-dose cytarabine. Two-thirds of the cohort were eligible for dose-reduced WBRT [30,31]. Patients were followed for a median of 5.9 years. In individuals who received reduced dose WBRT, the median PFS was 7.7 years (not reached in patients ⱕ 60 years old; 4.4 years in patients ⱖ 60 years old). The median OS was not reached. The 5-year OS was 80% (95% CI 66–94%) [31]. Patients in this trial underwent detailed neurocognitive testing designed to detect even subtle changes. Among 31 patients who received reduced dose WBRT, 12 were progres-
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The role of RT in PCNSL sion-free and completed neuropsychological evaluations for up to 48 months. Before treatment, cognitive impairment was present in several domains. After induction chemotherapy, there was a significant improvement in executive function (p ⬍ 0.01) and verbal memory (p ⬍ 0.05). There was no evidence of significant cognitive decline during the remainder of the follow-up period, with the exception of motor speed (p ⬍ 0.05). Minor fluctuations were detected in memory performance over time. There was no evidence of depressed mood, and self-reported quality of life remained stable throughout the follow-up period [31,32]. Thus, this treatment regimen provided excellent progression-free and overall survival, without late neurocognitive morbidity. These results suggest that selectively dose-reduced WBRT, in combination with R-MPV and cytarabine, achieves oncologic outcomes that are comparable to full-dose WBRT and better than chemotherapy alone. However, the drug regimen used in this trial has never been tested without WBRT. Therefore, it is possible that this combination of chemotherapeutic agents alone is sufficient to achieve these favorable outcomes. To answer this question, the RTOG is conducting a randomized phase II study. In RTOG 11–14, newly diagnosed patients with PCNSL are randomized to receive: (1) R-MPV, then WBRT to 23.4 Gy, then cytarabine vs. (2) R-MPV, then cytarabine, without WBRT. The primary outcome is progression-free survival. Additionally, all patients will undergo neuropsychological evaluation for 5 years. This trial will answer multiple important questions. We hypothesize that patients in the low-dose WBRT arm will experience improved progression-free survival, compared to those in the chemotherapy-alone arm. Additionally, we predict that the use of dose-reduced WBRT will result in improved neurocognitive outcomes, when compared to the full-dose WBRT used historically. Other ongoing trials are also addressing the impact of consolidative WBRT in PCNSL. HOVON (Hemato-Oncologie voor Volwassenen Nederland) 105 is a randomized phase III study in which newly diagnosed patients with PCNSL are randomized to receive HDMTX-based chemotherapy ⫾ rituximab. Then, patients with a complete or partial response receive cytarabine ⫾ WBRT [33]. Both RTOG 11-14 and HOVON 105 will provide a direct comparison of outcomes for patients who respond to chemotherapy and receive either consolidative WBRT or no additional therapy. The results are eagerly anticipated. Other trials are comparing the effect of two consolidative strategies: WBRT versus HDCT with ASCT. Multiple groups have reported their experiences treating PCNSL with consolidative HDCT and ASCT. Some of these trials maintained WBRT at low doses [34], while others omitted it entirely [19–22]. Most of these reports included small numbers of patients and some demonstrated suboptimal disease control. Furthermore, there has been no direct comparison of the outcomes associated with consolidative WBRT versus HDCT/ASCT. Ongoing studies are addressing this question. First, International Extranodal Lymphoma Study Group (IELSG) trial 32 is a randomized phase II study comparing different induction chemotherapy regimens (HDMTX ⫹ high-dose cytarabine ⫾ rituximab ⫾ thiotepa) and
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conventional WBRT vs. HDCT/ASCT (ClinicalTrials.gov identifier NCT01011920) [35]. Similarly, ANOCEF/GOELAMS (Association des Neuro-Oncologues d’Expression Française/Groupe Ouest Est d’étude des Leucémies Aiguës et autres Maladies du Sang) PRECIS is a phase II trial that randomizes patients to receive consolidative WBRT versus HDCT/ASCT after chemotherapy (ClinicalTrials.gov identifier NCT00863460) [36]. These studies will provide important data regarding the toxicity and outcomes associated with these two consolidative strategies.
Salvage therapy WBRT is an effective salvage therapy for refractory or recurrent PCNSL. A group from MSKCC reported retrospectively on 48 patients who received salvage WBRT for PCNSL that was refractory to (n ⫽ 24) or recurred after (n ⫽ 24) HDMTXbased chemotherapy. The median WBRT dose was 40 Gy (range 21.6–50.4 Gy). After salvage WBRT, 28 patients (58%) achieved a complete radiographic response and 10 (21%) a partial response. There was no difference in response rates between patients with refractory vs. recurrent disease or between patients who were ⬍ 60 vs. ⬎ 60 years old. The median survival from initiation of WBRT was 16 months, and the median time to PCNSL progression was 10 months. Fifteen patients (31%) had no subsequent disease recurrence after WBRT [37]. Another group reported retrospectively on 27 patients who failed initial HDMTX and then received salvage WBRT. The median WBRT dose was 36 Gy (range 19.6–40 Gy). Ten patients (37%) achieved a complete radiographic response and 10 (37%) a partial response to WBRT. At the time of maximal response, KPS improved in 12 patients (44%) and stabilized in six (22%). The median survival from initiation of WBRT was 10.9 months, and the median progression-free survival was 9.7 months [38]. In these institutional reports of salvage WBRT, late neurotoxicity was observed in 15–22% of patients. It was associated with patient age ⬎ 60 years, delivery of WBRT within 6 months of MTX and total WBRT doses ⬎ 36 Gy [37,38]. To date, no chemotherapy regimen has yielded better results than salvage WBRT [8]. The role of re-induction chemotherapy prior to salvage WBRT is unclear. Salvage chemotherapy, in combination with WBRT, may improve efficacy and reduce neurotoxicity by allowing lower WBRT doses. This question warrants study.
WBRT to treat rare PCNSL histologies DLBCL is the most common type of PCNSL and must be managed aggressively, as described above; however, some rare histologies may be treated effectively with RT only. For example, patients with primary dural or brain parenchymal marginal zone lymphoma (MZL) achieve excellent, durable local control with WBRT alone, or even with more limited involved field RT [39,40]. Rarely, Hodgkin lymphoma involves the CNS. Focal RT or WBRT, with or without chemotherapy, may provide durable disease control [41]. Additionally, patients with intracranial plasmacytoma may experience long-term disease-free survival following surgical resection and adjuvant RT [42].
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Radiation technique Due to the multifocal, infiltrative nature of PCNSL, a wholebrain field is used to encompass all disease. Left and right opposed lateral fields are weighted equally, and 6–10 MV photons are used most commonly. The fields are shaped with custom blocks or multi-leaf collimators. When designing blocks, special care must be taken not to exclude the anterior temporal lobes and cribriform plate from the field inadvertently. The posterior aspect of the eyes must be included within the field to ensure coverage of the optic nerve and retina, which are part of the CNS. Dose to the lenses from beam divergence is minimized if the anterior field edges are made coplanar by rotating the gantry or by placing the isocenter anteriorly between the lateral canthi. Furthermore, these maneuvers allow for a potential future isocentric match if the eyes, a common site of relapse, require irradiation at a later time. The inferior field edge is typically placed at the C2–C3 vertebral interspace (Figure 1). In the case of ocular involvement at the time of diagnosis, both globes are included for a portion of the treatment to receive a dose of 30–36 Gy. Some authors have advocated the use of craniospinal irradiation (CSI) because of the high incidence of leptomeningeal involvement by PCNSL. However, CSI has not been shown to improve survival, and it may cause significant toxicity [8,43]. Therefore, we do not recommend the use of CSI in the majority of cases. Instead, spinal RT should be used only in select cases, for example, to provide palliation of symptoms attributed to spinal lesions. Additionally, some authors have proposed using hippocampal- or scalp-sparing WBRT, in an attempt to minimize the side effects of treatment. Both techniques are technically feasible [44,45]. An important concern, however, is that these techniques may result in inadequate treatment of areas involved by PCNSL and thus may compromise disease control. It must be demonstrated that progression-free
survival of patients treated with these modified techniques is non-inferior to that of patients treated with standard WBRT, before they are used routinely.
Radiation dose In the upfront management of PCNSL, we recommend using the regimen published by Shah et al., according to which patients receive 23.4 Gy after a CR to R-MPV and prior to receiving cytarabine [30]. This reduced dose WBRT may be used only after a CR to chemotherapy and when further chemotherapy is given after WBRT. The physician must exercise clinical judgment in defining a CR. A small residual abnormality may persist on MRI that does not represent active disease. Such findings did not preclude patients from receiving lowdose WBRT in the MSKCC study. For patients with residual or recurrent disease after receiving chemotherapy, a salvage dose of 36–45 Gy should be used. In patients who are not candidates for chemotherapy and who will receive WBRT alone as definitive treatment, a dose of 40–50 Gy should be used. For palliation, a dose of 30–36 Gy is appropriate. In all cases, we recommend using conventional fractionation, with 1.8–2 Gy per fraction. Some researchers have proposed using hyperfractionation to improve the therapeutic ratio. Studies suggest that hyperfractionation may delay, but does not eliminate, neurotoxicity [15,19]. At this time, insufficient data exist regarding outcomes following hyperfractionated WBRT for it to be used in routine practice. However, studies of hyperfractionated WBRT are ongoing. For example, patients receiving WBRT on HOVON 105 will be treated to a total dose of 30 Gy at 1.5 Gy per fraction [33]. If hyperfractionated WBRT is associated with oncologic outcomes and toxicity rates that compare favorably with conventionally fractionated WBRT, it may become the standard regimen. We advise treating the whole brain to a single dose, without using a boost. We base this recommendation on the high risk of relapse within the brain at sites distant from lesions that were radiographically evident at diagnosis [27]. The role of a boost in patients with a partial response to chemotherapy is being investigated. In HOVON 105, patients with a partial response to chemotherapy will receive WBRT (20 fractions ⫻ 1.5 Gy), with a simultaneous boost to residual disease (20 fractions ⫻ 0.5 Gy ⫹ 1.5 Gy ⫽ 2 Gy). We eagerly anticipate the results of this trial.
Radiation toxicity Acute adverse events Temporary treatment-related effects may include alopecia, erythema and dry desquamation of the scalp. Some patients may experience fatigue, headache or inflammation of the external auditory canal or middle ear. Patients requiring treatment of the eye are likely to experience conjunctival irritation and dry eye. These acute effects typically resolve within 6–8 weeks of completion of WBRT.
Late adverse events Figure 1. Example of WBRT field used to treat a patient with PCNSL. The globes of the eyes are outlined.
All patients, particularly those requiring treatment of the eye, are at a high risk of cataracts. Patients requiring treatment
The role of RT in PCNSL of the eye may experience chronic dry eye. Those treated with WBRT doses ⬎ 35–40 Gy with conventional fractionation may experience some degree of permanent alopecia. Sensory neural hearing loss may occur when the middle ear receives doses ⬎ 45–50 Gy. As described above, neurocognitive decline may occur in some patients. The risk of neurocognitive dysfunction increases with age, total RT dose and co-administration of chemotherapy. Neurocognitive effects may be accompanied by urinary incontinence and gait disturbance, similar to the symptoms observed in normal pressure hydrocephalus.
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Conclusions and future directions The prognosis of PCNSL has improved significantly over the past decades, particularly for young patients. As survival improves, reducing late treatment-related morbidity is increasingly vital. Recent studies of immunochemotherapy combined with low-dose WBRT yielded excellent disease response rates and no late neurocognitive sequelae [30]. This regimen uses a response-adapted approach. Patients’ disease response is assessed during therapy and influences the next step in management, allowing for individualization of treatment: those patients with resistant disease receive intensification of treatment, while those with responsive disease receive less aggressive therapy. This approach allows the clinician to maximize disease control and minimize morbidity. Future studies of PCNSL should aim to continue to improve oncologic outcomes, while reducing the toxicity incurred by survivors. The paucity of PCNSL cases limits researchers’ ability to perform large, randomized studies. International cooperative trials will be necessary to define the optimal management approach. Additional research strategies that may complement prospective randomized trials have been suggested. These include the creation of a shared historical database with information from multiple studies. This database could provide outcome information to be compared with the results of future single arm studies with the same patient entry criteria. Additionally, randomized phase II trials may be an alternative method to compare therapeutic strategies [46]. Using these approaches, researchers will continue to make progress against PCNSL. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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of different fields and doses in patients in complete remission after upfront chemotherapy. Int J Radiat Oncol Biol Phys 2011;80: 169–175. [29] Bessell EM, Lopez-Guillermo A , Villa S, et al. Importance of radiotherapy in the outcome of patients with primary CNS lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy treatments. J Clin Oncol 2002;20:231–236. [30] Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 2007;25: 4730–4735. [31] Morris PG, Correa DD, Yahalom J, et al. Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol 2013;31:3971–3979. [32] Correa DD, Rocco-Donovan M, DeAngelis LM, et al. Prospective cognitive follow-up in primary CNS lymphoma patients treated with chemotherapy and reduced-dose radiotherapy. J Neurooncol 2009;91:315–321. [33] HOVON. Clinical picture: NHL (non Hodgkin lymphoma). HOVON 105 PCNSL/ALLG NHL24. Available from: www.hovon. nl/trials/trials-by-type/nhl.html?action ⫽ showstudie & studie_ id ⫽ 79&categorie_id ⫽ 1. [34] Colombat P, Lemevel A , Bertrand P, et al. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant 2006;38:417–420. [35] ClinicalTrials.gov. Trial for patients with newly diagnosed primary central nervous system (CNS) lymphoma. Available from: http://clinicaltrials.gov/ct2/show/NCT01011920?term ⫽ NCT0101192 0&rank ⫽ 1. [36] ClinicalTrials.gov. Cranial radiotherapy or intensive chemotherapy with hematopoietic stem cell rescue for primary central nervous system lymphoma in young patients (PRECIS). Available from: http:// clinicaltrials.gov/ct2/show/study/NCT00863460?term ⫽ NCT0086346 0&rank ⫽ 1.
[37] Hottinger AF, DeAngelis LM, Yahalom J, et al. Salvage whole brain radiotherapy for recurrent or refractory primary CNS lymphoma. Neurology 2007;69:1178–1182. [38] Nguyen PL, Chakravarti A , Finkelstein DM, et al. Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma. J Clin Oncol 2005;23:1507–1513. [39] Puri DR, Tereffe W, Yahalom J. Low-dose and limited-volume radiotherapy alone for primary dural marginal zone lymphoma: treatment approach and review of published data. Int J Radiat Oncol Biol Phys 2008;71:1425–1435. [40] Park I, Huh J, Kim JH, et al. Primary central nervous system marginal zone B-cell lymphoma of the basal ganglia mimicking lowgrade glioma: a case report and review of the literature. Clin Lymphoma Myeloma 2008;8:305–308. [41] Gerstner ER, Abrey LE, Schiff D, et al. CNS Hodgkin lymphoma. Blood 2008;112:1658–1661. [42] Bindal AK, Bindal RK , van Loveren H, et al. Management of intracranial plasmacytoma. J Neurosurg 1995;83:218–221. [43] Cruz-Sanchez FF, Artigas J, Cervos-Navarro J, et al. Brain lesions following combined treatment with methotrexate and craniospinal irradiation. J Neurooncol 1991;10:165–171. [44] Gondi V, Tolakanahalli R, Mehta MP, et al. Hippocampalsparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2010;78:1244–1252. [45] Roberge D, Parker W, Niazi TM, et al. Treating the contents and not the container: dosimetric study of hair-sparing whole brain intensity modulated radiation therapy. Technol Cancer Res Treat 2005;4:567–570. [46] Ferreri AJ, Abrey LE, Blay JY, et al. Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002. J Clin Oncol 2003;21:2407–2414. [47] Glass J, Won M, Schultz CJ, et al. Preirradiation chemotherapy with methotrexate, rituximab, and temozolomide and post-irradiation temozolomide for primary central nervous system lymphoma: RTOG 0227 phase II study results. J Clin Oncol 2013;31(15 Suppl.): Abstract 2033.
REVIEW
The role of radiation therapy in the management of primary central nervous system lymphoma Sarah A. Milgrom & Joachim Yahalom
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Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
with increasing frequency in immunocompetent patients, particularly in the elderly [4]. Patients typically present with focal neurological deficits and/or neurocognitive dysfunction. Signs and symptoms of increased intracranial pressure are possible but less common. Ocular involvement may result in visual disturbances. B symptoms are rare [6]. Magnetic resonance imaging (MRI) of the brain typically reveals one or multiple homogeneously contrast-enhancing lesions, often in the periventricular space [1]. A biopsy is indicated to confirm the diagnosis; however, a biopsy of the brain may be avoided if the cerebrospinal fluid (CSF) or vitreous fluid contains lymphoma cells. The histology is diffuse large B-cell lymphomas (DLBCL) in approximately 95% of cases of PCNSL. Epstein–Barr virus (EBV) has been implicated in PCNSL of immunocompromised patients. EBV is detected less commonly in PCNSL of immunocompetent patients, suggesting that the pathogenesis may differ based on immune status [7]. PCNSL has an aggressive course. The median survival of untreated patients is approximately 3 months [8]. Whole brain radiation therapy (WBRT) was the first effective treatment for PCNSL. Used alone, it induces rapid but transitory remissions, improving the median survival to 12–18 months [9]. Subsequently, chemotherapeutic agents have been combined with WBRT, resulting in improved long-term outcomes. Modern first-line therapy, consisting of high-dose methotrexate (HDMTX)-based chemotherapy in combination with WBRT, results in median survival rates of 36–60 months [10,11]. Poor performance status and advanced age are associated with unfavorable outcomes [11–14]. Owing to the uncommonness of PCNSL, knowledge regarding its optimal management is derived mainly from retrospective and small prospective phase II studies. Only one phase III trial is available, which is compromised by several flaws, as described below. Current potential indications for WBRT in PCNSL include: (1) consolidation in patients who have achieved a complete response (CR) to chemotherapy; (2) definitive therapy in patients who cannot receive chemotherapy; (3) salvage treatment in patients with refractory
Abstract Primary central nervous system lymphoma (PCNSL) is an aggressive neoplasm with a poor prognosis. Early studies of whole brain radiation therapy (WBRT) alone revealed a robust initial response but high rates of local recurrence with long-term follow-up. The addition of high-dose methotrexate (HDMTX)based chemotherapy improved the durability of disease control. However, delayed neurotoxicity emerged as an important complication, mainly in elderly patients. Therefore, researchers have investigated eliminating WBRT or reducing its dose. Multiple studies of chemotherapy alone have demonstrated inferior disease control. On the other hand, a phase III trial reported that WBRT may be deferred until relapse without compromising survival; however, this trial is fraught with flaws. A recent study of immunochemotherapy and dose-reduced WBRT demonstrated excellent outcomes. Currently, this regimen is being studied in a multi-institutional trial by the Radiation Therapy Oncology Group. WBRT maintains an important position in the armamentarium against PCNSL. This article aims to describe its evolving role. Keywords: Primary CNS lymphoma, PCNSL, radiation therapy, RT, whole brain radiation therapy, WBRT
Introduction Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma (NHL) that arises within the brain parenchyma or, less commonly, the leptomeninges, spinal cord or eye [1]. It represents 4% of primary intracranial neoplasms and 1–2% of all cases of NHL [2,3]. Its incidence in the United States is 0.47 cases per 100 000 person-years [4]. A major risk factor for PCNSL is long-term immunosuppression. Therefore, its prevalence in patients with solid organ transplant is 1–5% [5]. The risk of PCNSL was reported to be 2–6% in patients with acquired immune deficiency syndrome (AIDS) [5]; however, the incidence has been decreasing since the implementation of highly active anti-retroviral therapy [4]. On the other hand, PCNSL is being diagnosed
Correspondence: Joachim Yahalom, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. E-mail: [email protected] Received 8 June 2014; revised 17 August 2014; accepted 29 August 2014
1
BVAM, carmustine, vincristine, methotrexate, cytarabine; CHOD, cyclophosphamide, doxorubicin, vincristine, dexamethasone; CR, complete response; Cyt, cytarabine; HDMTX, high dose methotrexate; Ifos, ifosfamide; IT, intrathecal; IV, intravenous; MTX, methotrexate; NS, not stated; OS, overall survival; PCNSL, primary central nervous system lymphoma; PFS, progression-free survival; Pro, procarbazine; RT, radiation therapy; RTX, rituximab; TMZ, temozolomide; Vin, vincristine; WBRT, whole brain radiation therapy. *Initially all patients received WBRT to 45 Gy, then the trial was amended to reduce the dose to 36 Gy for patients who responded completely to induction chemotherapy. †Patients who responded completely to chemotherapy were treated with 45 Gy (1990–1995) or 30.6 Gy (1996–1999). ‡23.4 Gy for patients who responded completely to induction chemotherapy, 45 Gy for all others. §Initially all patients received HDMTX alone, then the trial was amended and all patients received HDMTX ⫹ ifosfamide. ¶Patients with a complete response to chemotherapy were randomized to 45 Gy WBRT vs. none. Patients with persistent or relapsed disease received 45 Gy WBRT.
57.5 63 53 551 (318 per protocol) RTOG 02-27 [47] G-PCNSL-SG-1 [24]
Morris et al. [31]
52
60
RTX, HDMTX, Pro, Vin, Cyt HDMTX, TMZ, RTX HDMTX ⫾ Ifos§
36 45 vs. none¶
Median 3.3 years (7.7 years for CR/23.4 Gy) 63.6% 2 years Median 18.3 months (RT arm) vs. 11.9 months (no RT arm) 23.4 vs. 45‡
Median 6.6 years (not reached for CR/23.4 Gy) 80.8% 2 years Median 32.4 months (RT arm) vs. 37.1 months (no RT arm)
NS 45 vs. 30.6† 59 57 (36 CR to chemotherapy)
102 RTOG 93-10 [11]
Bessell et al. [29]
41 54 52
56.5
Neurotoxicity
12 “severe delayed neurotoxicity,” 8 deaths In 1-year survivors: 0/13 (30.6 Gy); 1/12 (45 Gy and ⬍ 60 years old); 6/10 (45 Gy and ⱖ 60 years old) None, except decreased motor speed (CR/23.4 Gy) NS Sustained CR: 22/45 in RT arm (49%) vs. 9/34 (26%) in no RT arm 64% 2 years, 52% 3 years, 32% 5 years 36% 5 years Median 2 years 45 vs. 36*
48% 1 year, 28% 2 years 42% 2 years Median 60 months
OS PFS
NS Median 9.2 months NS
WBRT/boost dose (Gy) Chemotherapy Median age (years)
RTOG 83-15 [12] RTOG 88-06 [14] Abrey et al. [10]
In an attempt to improve the durability of the disease response, chemotherapy was added to WBRT. In RTOG
n
Combination chemotherapy and WBRT
Study
In extranodal lymphomas outside of the central nervous sytem (CNS), involved field RT alone is successful in the treatment of low volume, early stage disease. Extrapolating from this experience, RT was the first therapy used for PCNSL. PCNSL is often multifocal and diffusely infiltrative, so WBRT, rather than focal RT, was used to ensure that all disease was encompassed within the treatment volume. An early study of PCNSL was Radiation Therapy Oncology Group (RTOG) 83-15, a prospective phase II trial in which 41 patients were treated with WBRT to 40 Gy, followed by a 20 Gy boost to the tumor (Table I). Twenty-six patients had post-treatment computed tomography (CT) scans performed 4 months after the start of WBRT. Of these, 16 patients (62%) had a complete radiographic response and an additional five patients (19%) had an “almost complete response” [12]. These high rates of regression were consistent with the experience in treating NHL outside of the CNS, which had demonstrated the exquisite radiosensitivity of the disease. However, unlike in other lymphomas, the radiation response of PCNSL was not sustained in the majority of patients. Analysis of this study 3.3 years after its completion revealed that 27 of 41 patients (66%) had died of PCNSL. Although most patients ultimately recurred, it must be noted that some patients did achieve a durable response: six patients (15%) survived without evidence of disease at their last follow-up visit, with a median survival of 53.9 months from the start of WBRT and 54.5 months from diagnosis. The remaining eight patients (20%) died, without evidence of lymphoma, from intercurrent disease. For the total cohort, the median overall survival was 11.6 months from the start of WBRT and 12.2 months from diagnosis, with 48% surviving 1 year and 28% surviving 2 years. Patients with a Karnofsky Performance Status (KPS) of ⬍ 70% or age ⱖ 60 years experienced significantly worse survival (p ⱕ 0.004). Young, fit patients had substantially better outcomes: the 2-year survival was 46% for patients with a KPS ⱖ 70% and was 47% for patients ⬍ 60 years of age [12]. In RTOG 83-15, the majority of relapses occurred within the irradiated area. Disease recurred in the brain in 25 patients (61%). Of these recurrences, 21 (84%) involved the brain only and four (16%) involved the brain and other distant sites. Only three patients (7%) failed with distant metastases alone. The majority of recurrences in the brain were within the boost field (n ⫽ 22; 88%) [12]. Thus, long-term local control remained a challenge, despite the dramatic initial response to WBRT.
Table I. Representative summary of trials assessing WBRT in the upfront management of immunocompetent patients with PCNSL.
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WBRT alone as upfront therapy
40/20 41.4/18 45
The role of radiation therapy in treatment of primary central nervous system lymphoma
None CHOD MTX (IV and IT), Vin, Pro, Cyt MTX (IV and IT), Vin, Pro, Cyt CHOD ⫻ 1, BVAM ⫻ 2
or relapsed disease; (4) curative treatment in patients with rare histologies; and (5) palliative therapy in patients with symptomatic disease. This article aims to describe the evolving role of radiation therapy (RT) in the management of PCNSL.
NS 1 grade 5 encephalomalacia 13
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66 NS (⬎ 60) 65
2
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The role of RT in PCNSL 88-06, 54 human immunodeficiency virus (HIV)-negative patients with PCNSL were treated with two cycles of cyclophosphamide, doxorubicin, vincristine and dexamethasone (CHOD), followed by WBRT to 41.4 Gy and a boost to the tumor for a total dose of 59.4 Gy. The median survival for the cohort was 16.1 months, with a 2-year overall survival rate of 42%. These outcomes were not significantly different from those seen in RTOG 83-15, suggesting that CHOD did not improve survival over WBRT alone [14]. This lack of effect likely resulted from poor penetration of CHOD across the blood–brain barrier. A significant improvement in outcomes was achieved with the addition of HDMTX-based chemotherapy to WBRT. At Memorial Sloan Kettering Cancer Center (MSKCC), 52 immunocompetent patients with PCNSL were treated with HDMTX, intrathecal methotrexate (ITMTX), vincristine and procarbazine. This regimen was followed by WBRT to 45 Gy, and then high-dose cytarabine. In this cohort, 18 patients (35%) relapsed at 3–35 months after diagnosis. The median survival was 60 months, significantly longer than had been observed previously. Young patients experienced particularly favorable outcomes. At the time of publication, patients ⬍ 60 years of age had been followed for a median of 50 months and had not yet reached their median overall or disease-free survival [10]. Given these impressive outcomes, this treatment regimen was assessed further in RTOG 93-10. In this phase II trial, 102 immunocompetent patients with PCNSL were treated with HDMTX, ITMTX, vincristine and procarbazine, followed by WBRT, and then high-dose cytarabine. Initially the WBRT dose was 45 Gy in 25 fractions; however, the study was amended to reduce this dose to 36 Gy in 30 twice-daily fractions for patients who responded completely to induction chemotherapy. In RTOG 93-10, the median overall survival was 36.9 months and median progression-free survival was 24 months [11]. Thus, this cooperative group study confirmed the marked survival benefit provided by the combination of HDMTX-based chemotherapy and WBRT, compared to PCNSL outcomes reported previously. However, while this regimen resulted in favorable oncologic outcomes, delayed neurotoxicity emerged as an important complication, particularly in patients over 60 years old. Late neurotoxicity was observed in 13 (25%) of the patients treated at MSKCC and in 12 (15%) of the patients treated on RTOG 93-10 [10,11]. The clinical presentation consisted of memory deterioration and personality change, sometimes followed by gait disturbance and urinary incontinence. Individuals over 60 years of age were particularly vulnerable to delayed neurocognitive effects. In fact, in the study from MSKCC, all patients who developed neurotoxicity, except for one, were ⬎ 60 years old [10]. A secondary analysis of RTOG 93-10 assessed the cognitive function of the patients who achieved a CR to induction chemotherapy and then received conventionally fractionated (45 Gy in 25 fractions) versus hyperfractionated (36 Gy in 30 fractions over 3 weeks) WBRT. At 8 months after treatment, mini-mental status examination (MMSE) scores improved in all patients, with no statistical difference according to WBRT fractionation schedule. At 2 years, the decline in MMSE
3
scores was less in patients who had received hyperfractionated versus conventionally fractionated WBRT; however, the rates were equivalent at 4 years [15]. These findings suggested that hyperfractionation delayed, but did not eliminate, the neurocognitive effects of chemoradiation therapy. Concerns regarding neurotoxicity, particularly in the elderly, have caused researchers to investigate eliminating WBRT from the primary treatment of PCNSL. Multiple retrospective and prospective phase II studies have demonstrated less effective disease control with the use of chemotherapy alone, when compared to the combination of MTX-based chemotherapy and WBRT. In one trial of single-agent HDMTX, without WBRT, the median progression-free survival was 12.8 months [16]. Another study of chemotherapy alone used HDMTX in combination with cytarabine, dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide, as well as ITMTX, prednisolone and cytarabine. In this trial, the median time to recurrence was 21 months [17]. However, when the same regimen was given without the IT chemotherapy, the median time to relapse was 8 months [18]. While IT chemotherapy likely improves disease control, it is unlikely to account for such a significant difference in outcomes. Therefore, the results of the earlier study are drawn into question and must be reproduced. Other groups have studied the use of high-dose chemotherapy (HDCT) with autologous stem-cell transplant (ASCT) [19–22]. Disease control has been suboptimal. For example, in one multicenter phase II study, 28 patients received induction HDMTX and cytarabine. Of these, 14 patients responded completely or partially and went on to receive high-dose carmustine, etoposide, cytarabine and melphalan (BEAM) with ASCT. At a median follow-up of 28 months, the median event-free survival time was only 5.6 months for the entire cohort and 9.3 months for the 14 patients who underwent ASCT [22]. Another study assessed the outcomes of 64 young (age ⬍ 60 years) patients with PCNSL for whom WBRT was omitted in favor of additional chemotherapy if a CR to HDMTX-based multi-agent chemotherapy was achieved. Patients with less than a CR were treated on an individual basis, typically with WBRT or HDCT/ASCT. The median progression-free survival was 12 months, significantly less than expected for this favorable cohort [23]. Taken together, these studies have shown inferior oncologic outcomes when WBRT was excluded from the upfront management of PCNSL. The German PCNSL Study Group (G-PCNSL-SG) reported the only prospective phase III study, which aimed to determine whether WBRT may be avoided in the primary setting without a detrimental effect on survival. The G-PCNSL-SG-1 trial randomized patients who achieved a CR to HDMTXbased chemotherapy to immediate consolidative WBRT (45 Gy) versus deferred WBRT at the time of relapse. Patients without a CR received high-dose cytarabine or WBRT. The trial was designed to show that omission of WBRT from firstline treatment does not compromise overall survival, using a non-inferiority margin of 0.9. In total, 551 patients entered the study, but only 411 were eligible for inclusion in the intent-to-treat population, and, after 93 serious protocol violations, only 318 were treated according to protocol. In this group of 318 patients, those who received WBRT experienced
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improved progression-free survival of 18.3 vs. 11.9 months; however, this difference did not meet statistical significance (p ⫽ 0.14). The median overall survival was not significantly different for the two groups (32.4 months in WBRT arm vs. 37.1 months in chemotherapy alone arm, hazard ratio [HR] 1.06, 95% confidence interval [CI] 0.80–1.40, p ⫽ 0.71) [24]. Because the 95% CI included 0.9, the authors did not meet their primary non-inferiority endpoint, despite the large number of patients enrolled. Although the authors did not meet their non-inferiority endpoint, some clinicians have proposed eliminating WBRT from upfront management, because there was no difference in overall survival between the two arms. Recent commentaries have argued why this conclusion should not be drawn [8,25,26]. First, poor protocol adherence complicates comparisons of the two arms. Strikingly, ∼40% of patients were excluded from the primary analysis, introducing significant bias. Additionally, the trial was compromised by multiple other flaws in design and execution, including low statistical power (60%), long accrual period, inclusion of small centers with little PCNSL experience, suboptimal chemotherapy use, lack of quality assurance and insufficient neurotoxicity evaluation. Furthermore, patients treated with chemotherapy alone were more likely to relapse and require salvage therapy, as demonstrated by the difference in progressionfree survival between the two arms. Both disease relapse and salvage therapy are themselves associated with neurologic and other morbidity that has not been studied adequately. In a recent position paper, Dr. Lisa DeAngelis, who pioneered and extensively studied modern PCNSL treatment, pointed out that a competing risks analysis, adjusting for the effect of relapse, demonstrates that approximately 24% of patients develop neurotoxicity at 5 years after WBRT, while the risk of PCNSL recurrence is twice the risk of neurotoxicity [25]. “Thus, uncontrolled PCNSL is the primary hurdle to both survival and good quality of life in most PCNSL patients. Prevention of relapse should be the primary research focus” [25]. Therefore, while the G-PCNSL-SG-1 findings are intriguing, the study does not definitively demonstrate that WBRT may be safely excluded from upfront management. An alternative strategy to excluding WBRT altogether is reducing the radiation field size or dose in appropriately selected patients, with the aim of maintaining good disease control while decreasing toxicity. Researchers from Japan addressed the question: can patients with PCNSL, particularly those with unifocal disease and those receiving combined modality therapy, be treated with focal RT rather than WBRT? The authors reviewed the outcomes of 43 patients with PCNSL who were treated with partial brain RT. All patients were treated with curative intent. The majority of patients had unifocal disease (74%) and received systemic chemotherapy (60%). The median partial brain RT dose was 50 Gy and median margin size was 4 cm from the tumor to field edge. The median survival of this cohort was 16 months. At 5 years, the rate of in-field recurrence was 57% and out-of-field, in-brain recurrence was 49%. Twelve of the 14 out-of-field recurrences were distant from the irradiated area and, thus, would not have been included in a more generous partial brain RT field
[27]. These findings demonstrate that focal RT results in high rates of relapse within the brain, outside of the irradiated area, suggesting that the whole brain must be treated when RT is used in PCNSL. Other researchers have investigated decreasing the RT dose, rather than field size, in appropriately selected patients with PCNSL. Recent studies have demonstrated a role for dose reduction in patients who achieve a CR to chemotherapy. Ferreri et al. published a retrospective, single-institution series of 33 immunocompetent patients with PCNSL who achieved a CR to HDMTX-based chemotherapy and then received consolidation WBRT. The authors found no significant difference in the relapse rates of patients treated with 30–36 Gy vs. ⱖ 40 Gy (30% vs. 46%, p ⫽ 0.24). On the other hand, they did observe significantly less neurologic impairment, as measured by MMSE, in patients treated with 30–36 Gy vs. ⱖ 40 Gy (p ⫽ 0.05) [28]. Taken together, these findings suggest that in patients with a CR to chemotherapy, escalating the WBRT dose above 36 Gy does not improve oncologic outcomes but does increase neurotoxicity. Based upon such findings, researchers have assessed outcomes after selectively dose-reducing WBRT in patients with PCNSL who achieve a CR to induction chemotherapy. First, a group from Spain and the United Kingdom reported outcomes of patients treated with one cycle of CHOD and two cycles of carmustine, vincristine, cytarabine and methotrexate (BVAM), followed by WBRT. In this series, 36 patients achieved a CR to chemotherapy and were treated with WBRT to 40 Gy (n ⫽ 20) or 30.6 Gy (n ⫽ 16). The 3-year risk of relapse was 30% for patients treated to 45 Gy vs. 65% for patients treated to 30.6 Gy (p ⫽ 0.08). In patients younger than 60 years of age, these rates were 25% vs. 79%, respectively (p ⫽ 0.06). An analysis of patients who achieved a CR to all treatment (chemotherapy and WBRT) revealed 3-year overall survival rates of 92% in patients receiving 45 Gy vs. 60% in those receiving 30.6 Gy (p ⫽ 0.04) [29]. Thus, reducing the WBRT dose in patients with a CR to this chemotherapy regimen resulted in an increased risk of relapse and mortality. On the other hand, a prospective study of dose-reduced WBRT and (possibly more effective) immunochemotherapy yielded excellent outcomes. The authors reported on 52 immunocompetent patients with PCNSL who received induction rituximab, HDMTX, procarbazine and vincristine (R-MPV). Patients were evaluated by MRI after five cycles. Those with a CR were treated with dose-reduced WBRT to 23.4 Gy. All others received two additional cycles of R-MPV and were re-assessed. Patients with a CR after seven cycles received dose-reduced WBRT (23.4 Gy); all others received standard WBRT to 45 Gy. After WBRT, all patients were treated with high-dose cytarabine. Two-thirds of the cohort were eligible for dose-reduced WBRT [30,31]. Patients were followed for a median of 5.9 years. In individuals who received reduced dose WBRT, the median PFS was 7.7 years (not reached in patients ⱕ 60 years old; 4.4 years in patients ⱖ 60 years old). The median OS was not reached. The 5-year OS was 80% (95% CI 66–94%) [31]. Patients in this trial underwent detailed neurocognitive testing designed to detect even subtle changes. Among 31 patients who received reduced dose WBRT, 12 were progres-
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The role of RT in PCNSL sion-free and completed neuropsychological evaluations for up to 48 months. Before treatment, cognitive impairment was present in several domains. After induction chemotherapy, there was a significant improvement in executive function (p ⬍ 0.01) and verbal memory (p ⬍ 0.05). There was no evidence of significant cognitive decline during the remainder of the follow-up period, with the exception of motor speed (p ⬍ 0.05). Minor fluctuations were detected in memory performance over time. There was no evidence of depressed mood, and self-reported quality of life remained stable throughout the follow-up period [31,32]. Thus, this treatment regimen provided excellent progression-free and overall survival, without late neurocognitive morbidity. These results suggest that selectively dose-reduced WBRT, in combination with R-MPV and cytarabine, achieves oncologic outcomes that are comparable to full-dose WBRT and better than chemotherapy alone. However, the drug regimen used in this trial has never been tested without WBRT. Therefore, it is possible that this combination of chemotherapeutic agents alone is sufficient to achieve these favorable outcomes. To answer this question, the RTOG is conducting a randomized phase II study. In RTOG 11–14, newly diagnosed patients with PCNSL are randomized to receive: (1) R-MPV, then WBRT to 23.4 Gy, then cytarabine vs. (2) R-MPV, then cytarabine, without WBRT. The primary outcome is progression-free survival. Additionally, all patients will undergo neuropsychological evaluation for 5 years. This trial will answer multiple important questions. We hypothesize that patients in the low-dose WBRT arm will experience improved progression-free survival, compared to those in the chemotherapy-alone arm. Additionally, we predict that the use of dose-reduced WBRT will result in improved neurocognitive outcomes, when compared to the full-dose WBRT used historically. Other ongoing trials are also addressing the impact of consolidative WBRT in PCNSL. HOVON (Hemato-Oncologie voor Volwassenen Nederland) 105 is a randomized phase III study in which newly diagnosed patients with PCNSL are randomized to receive HDMTX-based chemotherapy ⫾ rituximab. Then, patients with a complete or partial response receive cytarabine ⫾ WBRT [33]. Both RTOG 11-14 and HOVON 105 will provide a direct comparison of outcomes for patients who respond to chemotherapy and receive either consolidative WBRT or no additional therapy. The results are eagerly anticipated. Other trials are comparing the effect of two consolidative strategies: WBRT versus HDCT with ASCT. Multiple groups have reported their experiences treating PCNSL with consolidative HDCT and ASCT. Some of these trials maintained WBRT at low doses [34], while others omitted it entirely [19–22]. Most of these reports included small numbers of patients and some demonstrated suboptimal disease control. Furthermore, there has been no direct comparison of the outcomes associated with consolidative WBRT versus HDCT/ASCT. Ongoing studies are addressing this question. First, International Extranodal Lymphoma Study Group (IELSG) trial 32 is a randomized phase II study comparing different induction chemotherapy regimens (HDMTX ⫹ high-dose cytarabine ⫾ rituximab ⫾ thiotepa) and
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conventional WBRT vs. HDCT/ASCT (ClinicalTrials.gov identifier NCT01011920) [35]. Similarly, ANOCEF/GOELAMS (Association des Neuro-Oncologues d’Expression Française/Groupe Ouest Est d’étude des Leucémies Aiguës et autres Maladies du Sang) PRECIS is a phase II trial that randomizes patients to receive consolidative WBRT versus HDCT/ASCT after chemotherapy (ClinicalTrials.gov identifier NCT00863460) [36]. These studies will provide important data regarding the toxicity and outcomes associated with these two consolidative strategies.
Salvage therapy WBRT is an effective salvage therapy for refractory or recurrent PCNSL. A group from MSKCC reported retrospectively on 48 patients who received salvage WBRT for PCNSL that was refractory to (n ⫽ 24) or recurred after (n ⫽ 24) HDMTXbased chemotherapy. The median WBRT dose was 40 Gy (range 21.6–50.4 Gy). After salvage WBRT, 28 patients (58%) achieved a complete radiographic response and 10 (21%) a partial response. There was no difference in response rates between patients with refractory vs. recurrent disease or between patients who were ⬍ 60 vs. ⬎ 60 years old. The median survival from initiation of WBRT was 16 months, and the median time to PCNSL progression was 10 months. Fifteen patients (31%) had no subsequent disease recurrence after WBRT [37]. Another group reported retrospectively on 27 patients who failed initial HDMTX and then received salvage WBRT. The median WBRT dose was 36 Gy (range 19.6–40 Gy). Ten patients (37%) achieved a complete radiographic response and 10 (37%) a partial response to WBRT. At the time of maximal response, KPS improved in 12 patients (44%) and stabilized in six (22%). The median survival from initiation of WBRT was 10.9 months, and the median progression-free survival was 9.7 months [38]. In these institutional reports of salvage WBRT, late neurotoxicity was observed in 15–22% of patients. It was associated with patient age ⬎ 60 years, delivery of WBRT within 6 months of MTX and total WBRT doses ⬎ 36 Gy [37,38]. To date, no chemotherapy regimen has yielded better results than salvage WBRT [8]. The role of re-induction chemotherapy prior to salvage WBRT is unclear. Salvage chemotherapy, in combination with WBRT, may improve efficacy and reduce neurotoxicity by allowing lower WBRT doses. This question warrants study.
WBRT to treat rare PCNSL histologies DLBCL is the most common type of PCNSL and must be managed aggressively, as described above; however, some rare histologies may be treated effectively with RT only. For example, patients with primary dural or brain parenchymal marginal zone lymphoma (MZL) achieve excellent, durable local control with WBRT alone, or even with more limited involved field RT [39,40]. Rarely, Hodgkin lymphoma involves the CNS. Focal RT or WBRT, with or without chemotherapy, may provide durable disease control [41]. Additionally, patients with intracranial plasmacytoma may experience long-term disease-free survival following surgical resection and adjuvant RT [42].
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Radiation technique Due to the multifocal, infiltrative nature of PCNSL, a wholebrain field is used to encompass all disease. Left and right opposed lateral fields are weighted equally, and 6–10 MV photons are used most commonly. The fields are shaped with custom blocks or multi-leaf collimators. When designing blocks, special care must be taken not to exclude the anterior temporal lobes and cribriform plate from the field inadvertently. The posterior aspect of the eyes must be included within the field to ensure coverage of the optic nerve and retina, which are part of the CNS. Dose to the lenses from beam divergence is minimized if the anterior field edges are made coplanar by rotating the gantry or by placing the isocenter anteriorly between the lateral canthi. Furthermore, these maneuvers allow for a potential future isocentric match if the eyes, a common site of relapse, require irradiation at a later time. The inferior field edge is typically placed at the C2–C3 vertebral interspace (Figure 1). In the case of ocular involvement at the time of diagnosis, both globes are included for a portion of the treatment to receive a dose of 30–36 Gy. Some authors have advocated the use of craniospinal irradiation (CSI) because of the high incidence of leptomeningeal involvement by PCNSL. However, CSI has not been shown to improve survival, and it may cause significant toxicity [8,43]. Therefore, we do not recommend the use of CSI in the majority of cases. Instead, spinal RT should be used only in select cases, for example, to provide palliation of symptoms attributed to spinal lesions. Additionally, some authors have proposed using hippocampal- or scalp-sparing WBRT, in an attempt to minimize the side effects of treatment. Both techniques are technically feasible [44,45]. An important concern, however, is that these techniques may result in inadequate treatment of areas involved by PCNSL and thus may compromise disease control. It must be demonstrated that progression-free
survival of patients treated with these modified techniques is non-inferior to that of patients treated with standard WBRT, before they are used routinely.
Radiation dose In the upfront management of PCNSL, we recommend using the regimen published by Shah et al., according to which patients receive 23.4 Gy after a CR to R-MPV and prior to receiving cytarabine [30]. This reduced dose WBRT may be used only after a CR to chemotherapy and when further chemotherapy is given after WBRT. The physician must exercise clinical judgment in defining a CR. A small residual abnormality may persist on MRI that does not represent active disease. Such findings did not preclude patients from receiving lowdose WBRT in the MSKCC study. For patients with residual or recurrent disease after receiving chemotherapy, a salvage dose of 36–45 Gy should be used. In patients who are not candidates for chemotherapy and who will receive WBRT alone as definitive treatment, a dose of 40–50 Gy should be used. For palliation, a dose of 30–36 Gy is appropriate. In all cases, we recommend using conventional fractionation, with 1.8–2 Gy per fraction. Some researchers have proposed using hyperfractionation to improve the therapeutic ratio. Studies suggest that hyperfractionation may delay, but does not eliminate, neurotoxicity [15,19]. At this time, insufficient data exist regarding outcomes following hyperfractionated WBRT for it to be used in routine practice. However, studies of hyperfractionated WBRT are ongoing. For example, patients receiving WBRT on HOVON 105 will be treated to a total dose of 30 Gy at 1.5 Gy per fraction [33]. If hyperfractionated WBRT is associated with oncologic outcomes and toxicity rates that compare favorably with conventionally fractionated WBRT, it may become the standard regimen. We advise treating the whole brain to a single dose, without using a boost. We base this recommendation on the high risk of relapse within the brain at sites distant from lesions that were radiographically evident at diagnosis [27]. The role of a boost in patients with a partial response to chemotherapy is being investigated. In HOVON 105, patients with a partial response to chemotherapy will receive WBRT (20 fractions ⫻ 1.5 Gy), with a simultaneous boost to residual disease (20 fractions ⫻ 0.5 Gy ⫹ 1.5 Gy ⫽ 2 Gy). We eagerly anticipate the results of this trial.
Radiation toxicity Acute adverse events Temporary treatment-related effects may include alopecia, erythema and dry desquamation of the scalp. Some patients may experience fatigue, headache or inflammation of the external auditory canal or middle ear. Patients requiring treatment of the eye are likely to experience conjunctival irritation and dry eye. These acute effects typically resolve within 6–8 weeks of completion of WBRT.
Late adverse events Figure 1. Example of WBRT field used to treat a patient with PCNSL. The globes of the eyes are outlined.
All patients, particularly those requiring treatment of the eye, are at a high risk of cataracts. Patients requiring treatment
The role of RT in PCNSL of the eye may experience chronic dry eye. Those treated with WBRT doses ⬎ 35–40 Gy with conventional fractionation may experience some degree of permanent alopecia. Sensory neural hearing loss may occur when the middle ear receives doses ⬎ 45–50 Gy. As described above, neurocognitive decline may occur in some patients. The risk of neurocognitive dysfunction increases with age, total RT dose and co-administration of chemotherapy. Neurocognitive effects may be accompanied by urinary incontinence and gait disturbance, similar to the symptoms observed in normal pressure hydrocephalus.
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Conclusions and future directions The prognosis of PCNSL has improved significantly over the past decades, particularly for young patients. As survival improves, reducing late treatment-related morbidity is increasingly vital. Recent studies of immunochemotherapy combined with low-dose WBRT yielded excellent disease response rates and no late neurocognitive sequelae [30]. This regimen uses a response-adapted approach. Patients’ disease response is assessed during therapy and influences the next step in management, allowing for individualization of treatment: those patients with resistant disease receive intensification of treatment, while those with responsive disease receive less aggressive therapy. This approach allows the clinician to maximize disease control and minimize morbidity. Future studies of PCNSL should aim to continue to improve oncologic outcomes, while reducing the toxicity incurred by survivors. The paucity of PCNSL cases limits researchers’ ability to perform large, randomized studies. International cooperative trials will be necessary to define the optimal management approach. Additional research strategies that may complement prospective randomized trials have been suggested. These include the creation of a shared historical database with information from multiple studies. This database could provide outcome information to be compared with the results of future single arm studies with the same patient entry criteria. Additionally, randomized phase II trials may be an alternative method to compare therapeutic strategies [46]. Using these approaches, researchers will continue to make progress against PCNSL. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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[37] Hottinger AF, DeAngelis LM, Yahalom J, et al. Salvage whole brain radiotherapy for recurrent or refractory primary CNS lymphoma. Neurology 2007;69:1178–1182. [38] Nguyen PL, Chakravarti A , Finkelstein DM, et al. Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma. J Clin Oncol 2005;23:1507–1513. [39] Puri DR, Tereffe W, Yahalom J. Low-dose and limited-volume radiotherapy alone for primary dural marginal zone lymphoma: treatment approach and review of published data. Int J Radiat Oncol Biol Phys 2008;71:1425–1435. [40] Park I, Huh J, Kim JH, et al. Primary central nervous system marginal zone B-cell lymphoma of the basal ganglia mimicking lowgrade glioma: a case report and review of the literature. Clin Lymphoma Myeloma 2008;8:305–308. [41] Gerstner ER, Abrey LE, Schiff D, et al. CNS Hodgkin lymphoma. Blood 2008;112:1658–1661. [42] Bindal AK, Bindal RK , van Loveren H, et al. Management of intracranial plasmacytoma. J Neurosurg 1995;83:218–221. [43] Cruz-Sanchez FF, Artigas J, Cervos-Navarro J, et al. Brain lesions following combined treatment with methotrexate and craniospinal irradiation. J Neurooncol 1991;10:165–171. [44] Gondi V, Tolakanahalli R, Mehta MP, et al. Hippocampalsparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2010;78:1244–1252. [45] Roberge D, Parker W, Niazi TM, et al. Treating the contents and not the container: dosimetric study of hair-sparing whole brain intensity modulated radiation therapy. Technol Cancer Res Treat 2005;4:567–570. [46] Ferreri AJ, Abrey LE, Blay JY, et al. Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002. J Clin Oncol 2003;21:2407–2414. [47] Glass J, Won M, Schultz CJ, et al. Preirradiation chemotherapy with methotrexate, rituximab, and temozolomide and post-irradiation temozolomide for primary central nervous system lymphoma: RTOG 0227 phase II study results. J Clin Oncol 2013;31(15 Suppl.): Abstract 2033.
