Reduced-dose Whole-brain Radiotherapy Research Articles

Is reduced-dose whole-brain radiotherapy also feasible in primary CNS lymphoma for curative or salvage purpose?

Recently, reduced-dose whole-brain radiotherapy (WBRT) has been used to treat primary central nervous system lymphoma (PCNSL). However, whether reduced-dose WBRT is also an acceptable option for curative or salvage purposes has not yet been reported. We analyzed the clinical outcomes of patients with PCNSL who received radiotherapy for curative or salvage purposes and compared the clinical outcomes according to the WBRT dose. A total of 66 patients were divided into two groups: those treated with 30Gy (2Gy per fraction) or less WBRT (low-dose WBRT, n = 34) and those treated with more than 30Gy WBRT (high-dose WBRT, n = 32). The median WBRT dose was 25.2 and 49.6Gy in low-dose and high-dose WBRT groups, respectively. The median total radiotherapy dose, including the boost dose, was 50Gy (range, 36.0-55.8Gy). The 3-year overall survival and progression-free survival were 77.8% and 29.8%, respectively. Intracranial relapse occurred in 31 patients (47.0%) at a median of 27 months after RT. Overall survival and progression-free survival did not differ between the two groups. The 3-year intracranial disease control rate did not differ between the two groups (35.2% vs. 41.6%, p = 0.300). Grade 3 or higher neurological toxicities were observed in six patients, of whom five were in the high-dose WBRT group. Reduced-dose WBRT in curative and salvage treatments for PCNSL had no significant negative effect on the intracranial disease control rate or survival. Therefore, without impaired efficacy, use of reduced-dose WBRT appears promising for reduction of neurotoxicity.

Long-term outcomes with reduced-dose whole-brain radiotherapy and a stereotactic radiosurgery boost for primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is an aggressive diffuse large B-cell lymphoma. Treatment approaches are historically associated with neurotoxicity, particularly with high-dose whole-brain radiotherapy (WBRT). We hypothesized that reduced dose-WBRT (rd-WBRT) followed by a stereotactic radiosurgery (SRS) boost could provide durable disease control without significant adverse effects. We retrospectively reviewed PCNSL patients treated with rd-WBRT plus an SRS boost at Duke University between 2008 and 2021. Progression-free survival and overall survival (OS) were estimated using competing risk and Kaplan-Meier methods. We identified 23 patients with pathologically confirmed PCNSL. Median age at diagnosis was 69 years (Q1Q3: 52-74) and median Karnofsky Performance Scale (KPS) was 80 (Q1Q3: 70-80). Median follow-up was 21 months. Median doses for rd-WBRT and SRS were 23.4 Gy (Q1Q3: 23.4-23.4) and 12 Gy (Q1Q3: 12-12.5), respectively. The cumulative incidence of intracranial progression at 2 years was 23% (95% CI: 8-42). Six patients (26%) developed distant radiographic progression while 2 patients (9%) developed both distant and local progression. Ten patients (44%) were alive without progression at last follow-up. By Kaplan-Meier estimate, the 2-year OS was 69% (95% CI: 46-84). There were no reported grade 3 + radiation-induced toxicities. The combination of rd-WBRT with an SRS boost appears well-tolerated with durable intracranial control. This approach may represent a treatment option for select patients, such as those with progressive or refractory disease. Further prospective studies are needed to validate these findings and determine whether this approach could be incorporated into consolidation strategies.

Reduced-dose WBRT combined with SRS for 1–4 brain metastases aiming at minimizing neurocognitive function deterioration without compromising brain tumor control

Background and purposeTo minimize cognitive decline without increasing brain tumor recurrence (BTR) by reduced-dose whole-brain radiotherapy (RD-WBRT) (25 Gy, 10 fractions) + stereotactic radiosurgery (SRS) in patients with ≤ 4 brain metastases. Materials and methodsEligible patients with ≤ 4 brain metastases on contrast-enhanced MRI and Karnofsky Performance Status ≥ 70. The primary endpoint was the non-inferiority of BTR at distant sites in the brain (BTR-distant)-free survival at 6 months compared to that of the standard dose (SD)-WBRT (30 Gy, 10 fractions) + SRS arm in a randomized clinical trial (JROSG99-1) of SRS with/without SD-WBRT. Secondary endpoints included BTR at any brain sites (BTR-all) and neurocognitive function assessed by a six-test standardized battery. ResultsForty patients from seven institutions were enrolled (median age 69 years). The primary tumor site was a lung in 28 patients; 20 patients had a solitary brain metastasis. The median survival time was 19.0 months (95 %CI: 13.8 %–27.5 %). The BTR-distant-free survival at 6 months was 76.9 % (59.5 %–87.7 %), which is comparable to that of historical control although predetermined non-inferiority (>71 %) could not be confirmed (p = 0.16). The cumulative incidence of BTR-all at 6 months accounting for the competing risk of death was 23.0 % (11.4–37.1), which was not worse than that of historical control (p = 0.774). The frequency of the cumulative incidence of persistent cognitive decline at 6 months was 48.6 % under the [>2.0 SD in ≥ 1 test] definition. ConclusionsRD-WBRT may yield comparable intracranial tumor control when combined with SRS, and may reduce the risk of neurocognitive decline compared to that after SD-WBRT.

Reduced-dose WBRT as consolidation treatment for patients with primary CNS lymphoma: an LOC network study

AbstractThe optimal consolidation strategy for primary central nervous system lymphoma (PCNSL) remains controversial. Preventing radio-induced neurotoxicity of consolidation treatment through reduced-dose whole-brain radiotherapy (rdWBRT) at a dose of 23.4 Gy is an interesting alternative to conventional WBRT in patients aged <60 years. From the LOC Network (Network for Oculo-cerebral Lymphomas) database, we retrospectively selected patients with PCNSL aged <60 years who showed complete (CR) or unconfirmed CR after high-dose methotrexate–based chemotherapy and had received consolidation rdWBRT as the first-line treatment. If available, prospective neuropsychological follow-ups were reported. Twenty-nine patients diagnosed between 2013 and 2018 met the study selection criteria. Nine (31%) patients experienced relapse during the follow-up, with a median time from radiotherapy to recurrence of 8.7 months (interquartile range, 4-11.5). Five of those patients received salvage treatment and consolidation with intensive chemotherapy and autologous stem cell transplantation. Progression-free survival rates were 89% (95% confidence interval [CI] 79%-100%), 72% (95% CI, 56%-88%), and 69% (95% CI, 52%-85%) at 1, 2, and 5 years, respectively. Overall survival rates were 100%, 89% (95% CI, 79%-100%), and 86% (95% CI, 74%-99%) at 1, 2, and 5 years, respectively, and were consistent with those observed for standard-dose WBRT (sdWBRT). No prognostic factor was identified. The results of the 36-month neuropsychological follow-up for a subset of patients appeared reassuring, with most patients exhibiting maintenance of or improvements in their baseline conditions. Our results, combined with phase 2 study results, support the use of rdWBRT instead of sdWBRT as a consolidation treatment in <60-year-old patients showing CR after induction treatment.

A narrative review of consolidation strategies for young and fit patients with newly-diagnosed primary central nervous system lymphoma

Introduction The modern treatment of patients with primary central nervous system lymphoma (PCNSL) consists of two phases: induction, currently represented by a high-dose-methotrexate-based polychemotherapy, and consolidation. The optimal consolidation therapy has not been defined yet, but several strategies, such as whole-brain radiotherapy (WBRT), high-dose chemotherapy supported by autologous stem cell transplantation (HDC/ASCT) or non-myeloablative chemotherapy, have been addressed in important randomized trials. Areas covered This review provides an overview of the current role of consolidation strategies in young and fit patients with newly-diagnosed PCNSL. Publications in English language, peer-reviewed, from high-quality international journals, edited from 2003 to 2021 were identified on PubMed. Expert opinion Consolidation treatment significantly improved outcomes of PCNSL. Radiotherapy had represented for years the only choice in the consolidation therapy, but large randomized trials have demonstrated that HDC/ASCT is equally effective and associated with lower neurotoxicity risk in patients younger than 65-70 years. Encouraging results have been obtained using reduced-dose WBRT, while a recent randomized trial failed to demonstrate that consolidation with non-myeloablative chemotherapy is more effective than HDC/ASCT in PCNSL patients. A personalized consolidation treatment, driven also by a response prediction model based on radiological and molecular details, may improve the management of PCNSL patients.

A Retrospective Analysis of R-MPV Plus Response-adapted Whole-brain Radiotherapy for Elderly Patients with Primary Central Nervous System Lymphoma.

Objective Few reports have described the real-world outcomes of rituximab, methotrexate (MTX), procarbazine, and vincristine (R-MPV) plus response-adapted whole-brain radiotherapy (WBRT) for elderly patients with primary central nervous system lymphoma (PCNSL). We evaluated the outcome of this regimen. Methods We evaluated >60-year-old patients with newly diagnosed PCNSL who received R-MPV plus WBRT from January 2010 to December 2019 at Toyohashi Municipal Hospital. The patients' characteristics, regimen enforcement, response rate, survival, and toxicity were analyzed. Patients Ten patients were consecutively enrolled. Their median age was 69 years old, and 60% had a performance status of 3 or 4 before induction therapy. Results Seven patients achieved a complete response after induction, and all 10 patients achieved a complete response after consolidation. Seven received reduced-dose WBRT at 23.4 Gy, and 2 received WBRT at 45 Gy. The median follow-up was 44.4 months; the 3-year progression-free survival and overall survival rates were 60% and 80%, respectively; and the cumulative incidence of relapse was 40%. The incidence of symptomatic delayed neurotoxicity was 70%. Of the 7 patients who received reduced-dose WBRT, 4 (57%) developed delayed neurotoxicity, including 1 severely affected patient. Only one patient survived without relapse and delayed neurotoxicity. The ratio of patients who developed relapse or delayed neurotoxicity that impaired daily life was 33% and 100% in the MTX high- and low-intensity groups, respectively. Conclusion This regimen in elderly patients is unsatisfactory because of delayed neurotoxicity. We should consider maintaining an adequate MTX intensity, postponing or minimizing WBRT, and choosing high-dose consolidation therapy for select patients.

Narrative review of primary central nervous system lymphoma: treatment-related neurotoxicity

: Delayed treatment-related neurotoxicity is a frequent complication among long-term survivors of primary central nervous system lymphoma (PCNSL), and many patients experience cognitive difficulties that interfere with their ability to function at pre-diagnosis levels. This article provides a comprehensive review of cognitive functioning in adult patients with PCNSL according to treatment modality, and it includes articles reporting the results of standardized cognitive assessments. The literature review indicated that cognitive functions were assessed with standardized neuropsychological tests in a relatively limited number of studies. Most studies reported diffuse cognitive impairment at baseline and prior to treatment, likely related to the disease, and improvement following induction high-dose methotrexate (HD-MTX)-based chemotherapy. Studies that assessed cognitive functions systematically months to years after HD-MTX-based chemotherapy and consolidation whole-brain radiotherapy (WBRT) reported cognitive impairment and white matter abnormalities in most patients. The cognitive domains often disrupted by treatment adverse effects include attention, executive functions, graphomotor speed, and memory. Among patients treated with HD-MTX-based chemotherapy or blood brain barrier disruption (BBBD) chemotherapy alone, there was evidence of stable or improved cognitive performance and quality of life (QoL) over time, with subsets of patients showing cognitive decline. Recent prospective randomized longitudinal studies comparing treatment modalities have reported stable or improved cognitive functions over time among most patients treated with HD-MTX-based chemotherapy alone or followed by consolidation with high-dose chemotherapy and autologous stem cell transplantation (ASCT), and cognitive decline in patients treated with consolidation WBRT; although reduced-dose WBRT was associated with less pronounced neurotoxicity. Additional collaborative, randomized, prospective longitudinal studies including standardized assessments of cognitive functions are needed to improve our knowledge and understanding of treatment-related neurotoxicity in this population.

Reduced-dose whole-brain radiotherapy with tumor bed boost after upfront high-dose methotrexate for primary central nervous system lymphoma.

PurposeThis retrospective study compares higher-dose whole-brain radiotherapy (hdWBRT) with reduced-dose WBRT (rdWBRT) in terms of clinical efficacy and toxicity profile in patients treated for primary central nervous system lymphoma (PCNSL).Materials and MethodsRadiotherapy followed by high-dose methotrexate (HD-MTX)-based chemotherapy was administered to immunocompetent patients with histologically confirmed PCNSL between 2000 and 2016. Response to chemotherapy was taken into account when prescribing the radiation dose to the whole brain and primary tumor bed. The whole brain dose was ≤23.4 Gy for rdWBRT (n = 20) and >23.4 Gy for hdWBRT (n = 68). Patients manifesting cognitive disturbance, memory impairment and dysarthria were considered to have neurotoxicity. A median follow-up was 3.62 years.ResultsThe 3-year overall survival (OS) and progression-free survival (PFS) were 70.0% and 48.9% with rdWBRT, and 63.2% and 43.2% with hdWBRT. The 3-year OS and PFS among patients with partial response (n = 45) after chemotherapy were 77.8% and 53.3% with rdWBRT, and 58.3% and 45.8% with hdWBRT (p > 0.05). Among patients with complete response achieved during follow-up, the 3-year freedom from neurotoxicity (FFNT) rate was 94.1% with rdWBRT and 62.4% with hdWBRT. Among patients aged ≥60 years, the 3-year FFNT rate was 87.5% with rdWBRT and 39.1% with hdWBRT (p = 0.49). Neurotoxicity was not observed after rdWBRT in patients aged below 60 years.ConclusionrdWBRT with tumor bed boost combined with upfront HD-MTX is less neurotoxic and results in effective survival as higher-dose radiotherapy even in partial response after chemotherapy.

Longitudinal cognitive assessment in patients with primary CNS lymphoma treated with induction chemotherapy followed by reduced-dose whole-brain radiotherapy or autologous stem cell transplantation.

The standard treatment for primary central nervous system lymphoma (PCNSL) involves induction methotrexate-based chemotherapy with or without consolidation whole brain radiotherapy (WBRT). As WBRT carries a substantial risk for cognitive impairment, alternative consolidation treatments have been used to reduce neurotoxicity, including reduced-dose WBRT (rdWBRT) or high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT). In this study, we characterized cognitive functions in PCNSL patients achieving long-term remission following rdWBRT or HDC-ASCT. PCNSL patients completed cognitive evaluations at diagnosis, post-induction chemotherapy, and yearly up to 5years following rdWBRT or HDC-ASCT. Quality of life (QoL), white matter (WM) disease, and cortical atrophy (CA) on MRI were assessed at similar intervals. Performance was impaired on most cognitive tests at diagnosis. Linear mixed model analyses in each group showed statistically significant improvement from baseline up to year 3 in attention/executive functions, graphomotor speed, and memory; however, there was a decline in attention/executive functions and memory after year 3 in both groups. WM abnormalities increased over time in both groups, but more patients treated with rdWBRT developed CA and WM changes. There were no significant longitudinal group differences in cognitive performance or QoL. Results indicated improvement in cognitive function up to 3years post-treatment, but a decline at later time points and an increase in brain structure abnormalities in both groups. The findings suggest that rdWBRT and HDC-ASCT may be associated with delayed neurotoxicity in progression-free patients and underscore the need for long-term follow-up to characterize cognitive dysfunction in PCNSL patients.

Primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL), confined to the brain, eyes, spinal cord or leptomeninges without systemic involvement. Overall prognosis, diagnosis and management of PCNSL differ from other types of NHL. Prompt diagnosis and initiation of treatment are vital to improving clinical outcomes. PCNSL is responsive to radiation therapy, however whole-brain radiotherapy (WBRT) inadequately controls the disease when used alone and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined, however HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials address the role of rituximab, and of consolidative treatment using ASCT or reduced-dose WBRT. Despite high tumor response rates to initial treatment, many patients have relapsing disease with very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on age, previous treatment and response, performance status and comorbidities at the time of relapse. Novel therapeutics targeting underlying tumor biology include small molecule inhibitors of B-cell receptor, cereblon, and mammalian target of rapamycin signaling, and immunotherapy programmed cell death 1 receptor inhibitors and chimeric antigen receptor T cells.

Diagnosis and management of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole-brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced-dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017;123:4314-24. © 2017 American Cancer Society.

Whole brain radiation dose reduction for primary central nervous system lymphoma patients who achieved partial response after high-dose methotrexate based chemotherapy.

The whole brain radiotherapy (WBRT) dose for primary central nervous system lymphoma (PCNSL) patients who achieved complete response after induction chemotherapy was recently reduced to 23.4 Gy, but the optimal radiation dose for patients who achieved partial response (PR) is controversial. The aim of this study was to investigate the feasibility of reduced-dose WBRT for patients who achieved PR. We retrospectively reviewed the medical records of PCNSL patients who were treated with high-dose methotrexate based chemotherapy. We compared treatment outcomes between the patients who received WBRT at either 36 Gy or 45 Gy. The overall survival (OS) and intracranial progression-free survival (IC-PFS) was 66.3% and 42.6% at 5 years, respectively. There was no significant difference in treatment outcomes between the patients who received 36 Gy and 45 Gy, especially among patients who achieved PR. Three-year OS was 100% and 83.3% for 36 Gy and 45 Gy group, respectively (P = 0.313). Three-year IC-PFS was 60.0% and 66.7% for 36 Gy and 45 Gy group, respectively (P = 0.916). Findings of our study might provide a possibility for dose-reduction in patients achieving PR to induction chemotherapy, which may in turn reduce delayed neurologic sequelae. However, the number of patients included in this study was too small to lead to a concrete conclusion, thus further study is needed.

Central Nervous System Relapse in Patients with Diffuse Large B-Cell Lymphoma: Analysis of Incidence and Prognostic Factors

The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone) has significantly improved the outcome of diffuse large B-cell lymphoma (DLBCL). However, its secondary involvement in the central nervous system (CNS) is still a fatal event, and optimal therapeutic strategies have remained to be established. Combined immunochemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy and high-dose cytarabine is currently in use for patients with CNS relapse, though treatment outcome has not been evaluated enough. In the present study, we aimed to analyze the incidence and prognosis of CNS relapse of aggressive B-cell lymphoma in comparison with those of systemic relapse in the era of rituximab-containing regimens. We also estimated the risk factors and prognostic factors for CNS relapse.We retrospectively analyzed 278 consecutive adult patients (≥16 years old) who were diagnosed as DLBCL or primary mediastinal large B-cell lymphoma (PMLBL) at The University of Tokyo Hospital, Tokyo, Japan, from August 2003 through August 2013. We excluded patients who had CNS or intraocular involvement at diagnosis since those patients had received high-dose methotrexate-based therapy instead of R-CHOP. Four to six courses of intrathecal administration of methotrexate were performed in patients with adrenal gland, testis or breast involvement as prophylaxis for CNS relapse.The median follow-up period was 42 months, and the median age was 66 years (range, 23-91). Overall, 67 patients (24.1%) had relapse at any site, of which 24 patients (35.8%) had CNS involvement. The median interval between initial diagnosis and the occurrence of secondary CNS involvement was 212 days, and 15 of the 24 patients (62.5%) had CNS relapse within 1 year from the initial diagnosis. Multivariate analysis revealed that multiple or diffuse extranodal involvement at initial diagnosis (hazard ratio [HR] 3.74, 95% confidence interval [CI] 1.28-10.91; P<0.01) was associated with the development of CNS relapse against non-CNS relapse. Chromosomal abnormality was investigated in 112 patients, of which 38 had abnormal karyotypes as identified by G-banding analysis for lymph nodes. Patients with CNS relapse more frequently harbored chromosomal abnormalities compared with those without relapse in univariate analysis (P=0.01).We also analyzed the survival of patients with primary CNS lymphoma (PCNSL) as a control. Only two (7%) of 27 patients with PCNSL died during the follow-up period. Five-year OS from initial diagnosis was 92.3% (95% CI: 82.5-100.0%), and was significantly better than that for patients with CNS relapse (33.9%, 95% CI: 17.3-66.3%, P<0.01).Among 24 patients with CNS relapse, eight (33%) had systemic lesions other than CNS when diagnosed as CNS relapse, and four (17%) patients newly developed systemic lesions while treated for CNS relapse. Patients without concurrent systemic lesions attained a rather good prognosis by chemo-radiotherapy, while those harboring concurrent systemic lesions had dismal outcome (one-year OS after the diagnosis of relapse: 74.0% versus 12.4%, P<0.01, Figure 1, systemic relapse was treated as a time-dependent covariate).These results indicate that controlling systemic lesions as well as CNS ones is essential for treating patients with secondary CNS involvement of DLBCL. CNS lesions would be well controlled with R-MPV implementation as salvage therapy, nevertheless we should be careful for concurrent systemic lesions which might require different therapeutic strategies. [Display omitted] DisclosuresNannya:Chugai Pharmaceutical CO., LTD: Speakers Bureau; Pfizer: Research Funding. Kurokawa:Chugai Pharmaceutical CO., LTD: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding.

Reply to M.C. Chamberlain

Cancer and Leukemia Group B (CALGB) 50202 was the first clinical trial to demonstrate the feasibility of dose-intensive consolidative chemotherapy in the multicenter setting for newly diagnosed patients with primary CNS lymphoma (PCNSL). The CALGB 50202 regimen consists of a novel induction regimen, consisting of twice-weekly high-dose methotrexate1,2 in combination with weekly rituximab,3–6 plus monthly temozolomide (MT-R).7–9 Rituximab is administered for six doses, during the first 6 weeks of induction, an interval during which the blood-brain barrier may be most significantly disrupted by angiotropic lymphoma.10,11 Patients who achieved a complete response to MT-R received high-dose, infusional etoposide in combination with twice-daily, high-dose cytarabine, over 4 days12–16 (Table 1). Two thirds of the patients achieved a complete response with MT-R induction, the median progression-free survival (PFS) at 2 years was 59%, the median PFS was 4 years and the 4-year overall survival probability was 65%. As noted in the editorial17 that accompanies the article, the results of 50202 are comparable or superior to results obtained in other prospective multicenter trials that included whole-brain radiotherapy. Notably, the striking PFS of those who completed consolidation dose-intensive chemotherapy replicates the institutional experience with this regimen in PCNSL, dating to 2001.13 Moreover, for the first time in a clinical trial in PCNSL, patients age 60 years or older had outcomes similar to younger patients, highlighting another significant advantage of the dose-intensive consolidation approach used in 50202 compared with consolidative whole-brain radiotherapy. The recent finding that patients with PCNSL age 60 years or older have inferior outcomes with even reduced-dose whole-brain radiotherapy would seem to further underscore the advantage of dose-intensive chemotherapeutic consolidation.18 Regarding the question of whether CALGB 50202 is practice-changing, considering the outcomes obtained with the 50202 regimen in the multicenter setting, and the preponderance of evidence that brain radiotherapy, even at reduced doses, is neurotoxic19–21 and associated with a long-term increased risk of de novo secondary brain neoplasms,22,23 we ask the question, what hematologist/oncologist, neurologist, or patient with PCNSL would recommend or prefer to receive whole-brain radiotherapy, at any dose, as consolidation in first remission, if dose-intensive chemotherapeutic consolidation is available as an option? Table 1. CALGB (Alliance) 50202 Regimen To address the comments of Chamberlain24 regarding the rationale for the number of cycles of methotrexate used, and the role of rituximab, temozolomide and etoposide, we suggest a review of the explanations and references provided in the text of the manuscript and in Table 1 of this letter, as well as an assessment of the outcomes of patients treated in CALGB 50202 (Fig 2 of the publication), with a 2-year PFS that is without precedent in a multicenter study involving chemotherapy without brain radiotherapy in PCNSL.25,26 In regards to the number of doses of cytarabine at consolidation, Chamberlain should note that similar schedules of high-dose cytarabine actually are in fact used to treat other hematologic malignancies that are associated with poor prognosis, such as mantle-cell lymphoma and acute myelogenous leukemia.27–31 We certainly agree with Chamberlain, however, that there is a significant need to improve the 50202 regimen and advocate that the best means to contribute to this effort and to enhance outcomes for PCNSL patients is via active participation in prospective clinical trials such as CALGB 51101, the successor and an intergroup study and first randomized trial for PCNSL that does not involve brain radiotherapy. Notably, given the correlative end points embedded within the trial, participation in this important study by the hematology/oncology and neuro-oncology community will also significantly enhance our understanding of the patient with PCNSL's quality of life and disease biology, creating a foundation for trials that address molecular targets and prognostic risk groups and lead to further improvements in outcomes in this previously highly refractory form of non-Hodgkin lymphoma.32

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

A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine in primary CNS lymphoma. Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor. Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50 to 100). Thirty-one patients (60%) achieved a CR after R-MPV and received rdWBRT. The 2-year PFS for this group was 77%; median PFS was 7.7 years. Median overall survival (OS) was not reached (median follow-up for survivors, 5.9 years); 3-year OS was 87%. The overall (N = 52) median PFS was 3.3 years, and median OS was 6.6 years. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and follow-up scores remained relatively stable across the various domains (n = 12). All examined MRIs (n = 28) displayed a Fazekas score of ≤ 3, and no patient developed scores of 4 to 5; differences in ADC values did not predict response (P = .15), PFS (P = .27), or OS (P = .33). R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.

Prospective cognitive follow-up in primary CNS lymphoma patients treated with chemotherapy and reduced-dose radiotherapy.

High-dose chemotherapy and whole brain radiotherapy (WBRT) can prolong survival in primary CNS lymphoma (PCNSL) patients, but is often associated with clinically significant cognitive decline. In this study we assessed neuropsychological functioning prospectively in newly diagnosed PCNSL patients treated with induction chemotherapy followed by reduced-dose WBRT. Twelve patients underwent neuropsychological evaluations at diagnosis, after induction chemotherapy, and 6 and 12 months after WBRT. Nine patients completed additional cognitive evaluations 18 and 24 months post-treatment. At diagnosis, patients had impairments in Executive Functions, Verbal Memory, and Motor Speed. There was a significant improvement in Executive Functions (P < 0.01) and Verbal Memory (P < 0.05) following induction chemotherapy, and scores remained relatively stable up to 12 months post-treatment. Among the nine patients who completed a 2-year follow-up, there was a significant improvement in the Executive domain (P < 0.05) and a trend toward a decline in the Verbal Memory domain. Executive and Verbal Memory functions improved following induction chemotherapy, likely due to decreased tumor burden and discontinuation of corticosteroid and anticonvulsant medications. There was no significant cognitive decline up to 24 months post-chemotherapy and reduced-dose WBRT in this group of PCNSL patients, however, difficulties in Verbal Memory and Motor speed persisted over the follow-up period.

Combined Immunochemotherapy With Reduced Whole-Brain Radiotherapy for Newly Diagnosed Primary CNS Lymphoma

Our goals were to evaluate the safety of adding rituximab to methotrexate (MTX)-based chemotherapy for primary CNS lymphoma, determine whether additional cycles of induction chemotherapy improve the complete response (CR) rate, and examine effectiveness and toxicity of reduced-dose whole-brain radiotherapy (WBRT) after CR. Thirty patients (17 women; median age, 57 years; median Karnofsky performance score, 70) were treated with five to seven cycles of induction chemotherapy (rituximab, MTX, procarbazine, and vincristine [R-MPV]) as follows: day 1, rituximab 500 mg/m2; day 2, MTX 3.5 gm/m2 and vincristine 1.4 mg/m2. Procarbazine 100 mg/m2/d was administered for 7 days with odd-numbered cycles. Patients achieving CR received dose-reduced WBRT (23.4 Gy), and all others received standard WBRT (45 Gy). Two cycles of high-dose cytarabine were administered after WBRT. CSF levels of rituximab were assessed in selected patients, and prospective neurocognitive evaluations were performed. With a median follow-up of 37 months, 2-year overall and progression-free survival was 67% and 57%, respectively. Forty-four percent of patients achieved a CR after five or fewer cycles, and 78% after seven cycles. The overall response rate was 93%. Nineteen of 21 CR patients received the planned 23.4 Gy WBRT. The most commonly observed grade 3 to 4 toxicities included neutropenia (43%), thrombocytopenia (36%), and leukopenia (23%). No treatment-related neurotoxicity has been observed. The addition of rituximab to MPV increased the risk of significant neutropenia requiring routine growth factor support. Additional cycles of R-MPV nearly doubled the CR rate. Reduced-dose WBRT was not associated with neurocognitive decline, and disease control to date is excellent.

Combined immunochemotherapy with reduced dose whole brain radiotherapy (WBRT) for newly diagnosed patients with primary CNS lymphoma (PCNSL)

1518 Background: High-dose methotrexate based chemotherapy combined with WBRT for patients (pts) with newly diagnosed PCNSL has been shown to improve disease control and overall survival. However, disease recurrence is common and treatment-related neurotoxicity is an increasingly recognized complication. We hypothesized that the addition of Rituximab to Methotrexate, Procarbazine and Vincristine (MPV) might improve overall survival and disease control, similar to that seen with R-CHOP. Also decreasing the dose of WBRT in patients who achieve an initial CR may diminish the risk of treatment related neurotoxicity. This study was designed to determine the safety and efficacy of combined immunochemotherapy followed by reduced dose WBRT. Methods: Seventeen pts (7 men; median KPS 80%) of a planned 30 pts have been enrolled from August 2002 to September 2003. 14 (7M) were treated, 3 were not eligible. Each pt received 500 mg/m2 of rituximab on day 1, MTX 3.5 gm/m2 with VCR 1.4 mg/m2 on day 2. Procarbazine 100 mg...