Low-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.

Treatment Options for Recurrent Primary CNS Lymphoma.

Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m2) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.

Efficacy and toxicity with radiation field designs and concurrent temozolomide for CNS lymphoma.

There is no consensus on the treatment of central nervous system (CNS) lymphoma refractory to first-line methotrexate-based chemotherapy. Whole brain radiotherapy (WBRT) is sometimes used but may result in unacceptable neurocognitive dysfunction. We examined the efficacy and toxicities of WBRT with or without concurrent temozolomide in CNS lymphoma treatment. This single-institution IRB-approved retrospective study included adults with CNS lymphoma who received WBRT, either consolidative low-dose WBRT alone or low-dose WBRT with a focal boost to residual disease and were previously treated with high-dose methotrexate. The relationships between the WBRT regimen, concurrent temozolomide, and clinical outcomes and toxicities were assessed using proportional hazards and logistic regression models. A total of 45 patients with a median age of 64 years (range 24-74) treated from 2004 to 2019 were included. In total, 20 patients received concurrent temozolomide. In the WBRT + Boost cohort (n = 32), concurrent temozolomide resulted in better 2-year overall survival (OS) and progression free survival (PFS) (73% OS and 66% PFS) compared to patients treated without concurrent temozolomide (44% OS and 24% PFS). On multivariate analysis, concurrent temozolomide was associated with significantly better PFS (HR 0.28, P = .02). There were no significant differences between the two radiation groups or between those treated with or without concurrent temozolomide, with respect to significant acute hematologic, non-hematologic, and long-term neurocognitive toxicities (P > .05). In this study, concurrent temozolomide with radiotherapy in CNS lymphoma was associated with better PFS and was well tolerated. Low-dose WBRT with a boost is a safe and reasonable treatment approach for focal refractory disease. Prospective research that includes rigorous neurocognitive assessments is now warranted.

Tolerability of radiation with concurrent temozolomide and effect on survival in chemo-refractory CNS lymphoma.

e14554 Background: There is no consensus for the treatment of central nervous system lymphoma (CNSL) refractory to first line high dose methotrexate-based chemotherapy. Whole brain radiation (WBRT) has often been used but may lead to unacceptable neurocognitive dysfunction. We examined our institutional experience with treating CNSL with radiotherapy (RT) and concurrent temozolomide (TMZ) including the resultant acute and long term toxicities. Methods: This single institution IRB approved retrospective study examined treatment, toxicity, and outcome variables in adults with primary or secondary CNS lymphoma. Inclusion criteria were brain-directed RT and development of the treatment plan at our institution. Three main RT field designs were used, including low and high dose WBRT and low dose WBRT with a focal boost to residual disease (WBRT+boost). We assessed relationships between treatment approach (RT field design and concurrent TMZ use) and clinical outcomes and toxicities using multivariable logistic regression models and Kaplan-Meier methods. Toxicity was recorded using the Common Terminology Criteria for Adverse Events version 5. Results: A total of 93 patients with median age of 57 years (range 24 – 86) treated from 2004 – 2019 were included, and 26 patients received concurrent TMZ. The RT field design of low dose WBRT (median dose: 23.4Gy) plus focal boost (median dose: 21.6Gy) was associated with favorable overall survival (OS) and progression free survival (PFS) without any significant difference in Grade 3+ toxicity compared to low dose WBRT (p = 0.20) or WBRT without boost (p = 0.80). Concurrent TMZ with RT was associated with significantly improved OS (HR 0.46, p = 0.025) and CNS PFS (HR 0.49, p = 0.019). Four of nine (44%) Grade 3+ non-hematologic toxicities occurred in patients receiving concurrent TMZ (p = 0.40). The most common non-hematologic toxicities included fatigue and nausea. Long term neurocognitive dysfunction was similar whether or not patients received concurrent TMZ (21% in TMZ group vs 23% in non-TMZ group; OR 0.87, 95% CI 0.25 – 2.68, p = 0.82) and irrespective of RT field design (WBRT+boost vs low dose WBRT p = 0.25, WBRT+boost vs WBRT without boost p = 0.19). Conclusions: Our findings suggest that concurrent TMZ use with brain RT for chemo-refractory CNSL is a promising strategy, with improved survival and no major additional toxicity. Further research that includes rigorous neurocognitive assessments is needed in prospective clinical trials to guide treatment approaches using concurrent TMZ with brain RT in CNSL patients.

Randomized phase II study of rituximab, methotrexate (MTX), procarbazine, vincristine, and cytarabine (R-MPV-A) with and without low-dose whole-brain radiotherapy (LD-WBRT) for newly diagnosed primary CNS lymphoma (PCNSL).

2501 Background: MTX-based chemoradiotherapy is effective in PCNSL, but carries a risk of severe neurotoxicity (NT), especially in the elderly. In a phase II single arm study, R-MPV-A chemotherapy was combined with substantially reduced doses of radiotherapy (23.4 Gy), achieving prolonged progression free survival (PFS) and overall survival (OS) with acceptable NT. Because R-MPV-A had never been tested without radiotherapy, we conducted a randomized study to determine if the low doses of radiation played a role in the observed disease control, and to characterize NT as compared to chemotherapy alone. Methods: Patients were stratified by MSK RPA class and randomized to receive R-MPV-A with LD-WBRT (chemoRT arm) versus R-MPV-A alone (chemo arm). MTX dose was 3.5g/m2 infused over 2 hours. Filgrastim and pegfilgrastim support was given to all patients. LD-WBRT dose was 23.4 Gy (1.8 Gy X 13). The primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63, with one-sided alpha level of 0.15. Results: A total of 91 patients were randomized, of whom 4 were ineligible. Among eligible patients, 43 were enrolled in the chemoRT arm and 44 in the chemo arm. Median age was 66 (chemoRT) and 59 (chemo). Median KPS was 80 for both arms. Response rates following R-MPV were 81% (chemoRT) and 83% (chemo). In the chemoRT arm, 37 patients (86%) received LD-WBRT. After median follow-up of 55 months (m), the median ITT PFS was 25 m in the chemo arm and not reached in the chemoRT arm (HR 0.51; 95% CI [0.27, 0.95]; p = 0.015). The 2-year PFS was 54% (chemo) and 78% (chemoRT). Salvage radiotherapy has been given to 11 patients in the chemo arm. Median OS was not reached in either arm, with data still maturing. In both arms, most common grades 3 or 4 toxicities were anemia (27%), lymphopenia (41%), neutropenia (35%), thrombocytopenia (26%), ALT (23%) and AST (13%). One patient died from sepsis (chemo arm). As per investigators’ assessment, the rate of clinically defined moderate to severe NT was 11.4% (chemo) and 14% (chemoRT), p = 0.75. Conclusions: The study met the primary endpoint, demonstrating the addition of LD-WBRT to R-MPV-A improves PFS in newly diagnosed PCNSL. As per investigator’s assessment, NT rates were not statistically significantly increased, but further neuropsychological testing and neuroimaging analyses are ongoing to characterize cognitive decline and how it compares to other consolidation treatments. Clinical trial information: NCT01399372 .

RTHP-34. IMPROVED SURVIVAL IN CNS LYMPHOMA WITH SALVAGE LOW-DOSE WHOLE-BRAIN RADIOTHERAPY WITH FOCAL BOOST AND CONCURRENT TEMOZOLOMIDE

Abstract OBJECTIVE There is no standard salvage radiotherapy (RT) regimen, nor a consensus on the concurrent chemotherapy use in CNS lymphoma. We assessed the efficacy of low-dose whole-brain radiotherapy (WBRT) with focal-boost to the area of disease and concurrent temozolomide for the salvage treatment of CNS lymphoma. METHODS A single center retrospective study of CNS lymphoma patients seen between 01/2004 and 02/2019. The inclusion criteria were: diagnosis of CNS lymphoma, age > 18 years at diagnosis, radiation treatment to the brain, and formulation of plan at University of Michigan with at least one follow-up. Overall survival (OS) was determined by Kaplan Meier method. RESULTS Out of 93 patients (median age 58, 45% female), 73% were diagnosed with primary CNS lymphoma (n=68), and the remainder with secondary CNS lymphoma. Radiation modalities were WBRT alone (n=52), low-dose WBRT + focal boost (n=33) and focal RT alone (n=8). Twenty-six patients (28%) received concurrent temozolomide with radiation. Those who received WBRT+boost achieved complete response at a significantly higher rate than those who received WBRT alone (36% vs 17% respectively, p=0.047). The median OS among all groups was 45 months. There was a significant improvement in OS in patients receiving low-dose WBRT+boost compared to WBRT alone (median 65 vs 14 months respectively, p=0.016). OS was significantly longer in patients who received concurrent temozolomide than in those who did not (median 86 vs 23 months respectively, p=0.0287). CONCLUSIONS In CNS lymphoma salvage RT, a longer survival was observed with low-dose WBRT with focal-boost compared to WBRT alone, as well as with concurrent temozolomide. This result is limited by the selection bias to each of the treatment groups; however, the low-dose WBRT with focal-boost and concurrent temozolomide is a useful salvage alternative to standard WBRT as it may reduce long-term neurocognitive toxicity.

NCOG-05. IMPACT OF ADDITIONAL RITUXIMAB TO STANDARD THERAPY ON COGNITIVE PERFORMANCES IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA PATIENTS

Abstract BACKGROUND The goal of treatment of primary central nervous system lymphoma patients is to improve survival, without compromising neurocognitive functioning. The aim of this study was to analyze the effect of Rituximab and low-dose whole brain radiotherapy (WBRT) on cognition. METHODS 199 patients from a phase III trial (HOVON 105/ ALLG NHL 24), randomized to standard chemotherapy (and 30Gy WBRT for patients < 61 years-old only) with or without Rituximab, were asked to participate in a short neuropsychological evaluation (NPE) before and during treatment, and up to 2 years of follow-up or until progression. A difference in z-score, corrected for sex, age and education, of ≥ 1 point was considered as clinically relevant. The primary outcome was a difference over time between the arms in multiple cognitive domains, assessed by linear mixed models (LMM). Changes in cognitive performances between baseline and 24 months after treatment were assessed for both arms in cross-sectional analyses. Effect of WBRT was analyzed in irradiated patients only. RESULTS 105/199 patients completed at least one NPE; baseline characteristics were similar to the total trial population. Compliance was >60% at all evaluation points. No clinically relevant differences over time between the arms were seen in all domains in LMM analysis. Comparing changes from baseline to 24 months of follow-up, mean cognitive scores remained stable in both arms for attention, executive functioning (TMT B), and information processing speed. A clinically relevant improvement was seen in both arms for executive functioning (TMT A), memory and motor speed. In the irradiated patients (n=33) all scores remained stable after WBRT, up to 24 months of follow-up in all domains. CONCLUSION Cognitive performance remained stable or improved after treatment. Addition of Rituximab to standard treatment did not impact cognitive performance over time. After low-dose WBRT, cognition remained stable up to 2 years.

Balancing relapses versus cognitive impairment in primary central nervous system lymphoma: a single-center experience

ABSTRACTObjectives: The outcomes of primary central nervous system lymphoma (PCNSL) are much improved with multi-modality regimens. Unfortunately, in limited-resource countries, chemo-radiotherapy is the only option of curative-intent treatment. This study aimed to evaluate the effects of low-dose whole brain radiotherapy (WBRT) as a consolidation on disease control and long-term neurocognitive functions.Methods: We conducted a retrospective single-center study enrolling PCNSL patients from 2011 to May 2016 to evaluate the real-life treatment outcome and neurotoxicity from treatment especially radiotherapy.Results: Thirty-seven newly diagnosed immunocompetent PCNSL patients were treated with a high-dose methotrexate-based regimen with or without WBRT. The median age was 56 (range 16–78) years old. After chemotherapy, the overall response and complete response (CR) rates were 59.5% and 43.2%, respectively. All 6 partial response (PR) patients and 6 of 16 CR patients underwent radiotherapy. In 22 patients who achieved CR, the progression-free survival (PFS) of patients without WBRT was significantly inferior to the WBRT group with the hazard ratio of 4.7 (95% confidence interval 1.14–19.82, p = 0.03). The 3-year PFS were 35% and 78.75%, respectively, but there was no difference in overall survival. The serial Montreal Cognitive Assessment evaluations (20–72 months post chemotherapy) of 10 long-term CR patients revealed one dementia among three patients without WBRT and five mild cognitive impairments in seven patients with WBRT. Except for the dementia case, all the other patients can perform daily activities without assistance.Conclusion: The low-dose WBRT consolidation is associated with lower PCNSL relapses with only mild neurocognitive toxicity.

The French LOC Network for Primary CNS Lymphoma (PCNSL) Patients: What Can We Learn from a Large National Database?

BackgroundThe shared knowledge regarding management and outcome of PCNSL patients are usually based on results of clinical phase II studies that include limited series of selected patients, which imperfectly reflect the medical care in "real life".MethodsThe LOC network, certified by the national cancer institute (INCa), is a national network of expert centres for PCNSL. Since 2011, we are prospectively recording in the LOC database all newly diagnosed PCNSL patients from the 22 regional expert centres for PCNSL that cover the whole country. Data from PCNSL patients registered in the LOC database from January 2011 to March 18, 2016 were analyzed.ResultsData from 971 patients were available in the LOC database at the time of analysis: sex ratio: 1.05, median age: 67 (18-92), median Karnofsky Performance Status: 60 (20-100), diffuse large B cell lymphoma: 97%, ocular involvement: 20%, cerebrospinal (CSF) involvement: 18%. Diagnosis procedure was biopsy (80%), tumor resection (9%), vitrectomy (8%), CSF cytology (3%). Treatment was initiated either by a neuro-oncology or a haematology team in 38% and 62%, respectively. Median delay between first symptoms and onset of treatment was 62 days. First line treatment was high-dose (HD) methotrexate (MTX) based chemotherapy (CT) (90%), other chemotherapy regimen (6%), or palliative care (4%). The use of Rituximab has gradually increased from 50 % of patients between 2011 and 2013, up to 87 % of patients in 2016. 16 % of patients were included in prospective trials. After first-line induction chemotherapy, responder patients < 60 years received a consolidation treatment in 75 % of cases consisting of either whole brain radiotherapy (WBRT) (49 %) or HD CT with autologous stem cell transplantation (HD CT-ASCT) (26 %). Low dose WBRT (23,4) is being used in younger CR patients since 2014. In responder patients > 60 years, WBRT was seldom given (9%) according to national guideline, and HD CT-ASCT was offered to 1% of patients. Response rates to first-line treatment among evaluable patients (n = 655) were: complete response: 59%; partial response: 10%; stable disease: 3%; progressive disease: 28%. Relapse occurred in 42 % patients < 60 y and in 62 % in older patients. At relapse, second line chemotherapy, HD CT-ASCT, WBRT and palliative care were offered in 50%, 18%, 12%, 20% of patients respectively. With a median follow-up of 20.4 months, median progression free survival (PFS) was 9.9 months for the whole population (< 60 years: 34.6 months; > 60 years: 7.9 months). Median overall survival (OS) and 5-year OS were 30 months and 41% respectively (< 60 years: not reached, 68%; > 60 years: 15 months, 30%).ConclusionThe therapeutic practices in France reflect the current knowledge and controversies in PCNSL. Long-term survival has become frequent, especially among youngest patients who usually receive a consolidation treatment and to whom HD CT-ASCT can be offered at relapse. Relapse rate remains frequent and especially in elderly patients in whom consolidation treatment is omitted. Such an overview points out a couple of issues. Despite homogeneous treatments following national guidelines in accordance with the state of the art of medical care, standards of care are to be challenged, both for increasing the CR and decrease the relapse rates. The development of target and innovative therapies in PCNSL alone or in combinatorial regimen is needed.PFS and OS of patients according to age [Display omitted] [Display omitted] DisclosuresSoussain:Roche: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding. Ghesquieres:Mundipharma: Consultancy; Roche France: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Choquet:Janssen: Consultancy; Celgene: Consultancy. Morschhauser:Servier: Consultancy, Honoraria; Janssen: Honoraria; Gilead Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria.

Low-dose whole brain radiotherapy with tumor bed boost after methotrexate-based chemotherapy for primary central nervous system lymphoma.

PurposeThe purpose of this study is to evaluate the outcome of low-dose whole brain radiotherapy (WBRT) with tumor bed boost after methotrexate-based chemotherapy in the management of primary central nervous system lymphoma (PCNSL).Materials and MethodsWe retrospectively analyzed 64 patients with pathologically proven PCNSL between 2000 and 2011. Methotrexate-based chemotherapy with a median of five cycles was followed by radiotherapy to the whole brain and to the initial tumor bed. The median dose to the whole brain and to the tumor bed was 27 Gy (range, 18 to 36 Gy) and 50.4 Gy (range, 45 to 54 Gy), respectively.ResultsWith a median follow-up period of 27 months, 55 patients (85.9%) achieved complete response (CR). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 52.6% and 39.3%, respectively. In univariate analysis, factors associated with OS were age, performance status, involvement of deep structure, and CR to sequential chemoradiotherapy (CRT). These variables remained as significant factors for OS in multivariate analysis. CR to sequential CRT was the only positive factor associated with PFS (p=0.009). Neurologic toxicity was more common in elderly patients older than 60 years (p=0.025).ConclusionLow-dose WBRT with tumor bed boost after methotrexate-based chemotherapy might be an effective method for management of PCNSL.

Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) comprises approximately 5 % of all primary brain tumors. During the past two decades the incidence of PCNSL has increased, and as a result clinical research to determine the optimal treatment for PCNSL patients also has increased. Diagnosis is based on histopathologic findings traditionally established by biopsy only. More recent data raise controversy and challenges this biopsy-only paradigm, showing a potential advantage for surgical resection with progression-free survival (PFS) and overall survival (OS). Using high-dose intravenous (IV) methotrexate-based chemotherapy alone or as part of a regimen can lead to disease cure. The role of whole brain radiotherapy (WBRT) remains controversial and more frequently is omitted to avoid potential delayed neurocognitive effects, especially in patients older than age 60 years. Newer data from Memorial Sloan Kettering Cancer Center (MSKCC) using five cycles of Rituximab, Methotrexate, Vincristine, and Procarbazine (R-MVP) followed by low-dose WBRT (2,340 cgy), and then two cycles of Ara-C had excellent disease control with low neuro-toxicity and is now the basis of an ongoing RTOG (Radiation Treatment Oncology Group) trial comparing early versus delayed WBRT. Other chemotherapeutics and novel treatments, such as autologous stem cell transplantation, are being studied for potential use in PCNSL. Unlike many other primary brain tumors seen in adults, PCNSL is potentially curable; therefore, balancing treatment decisions with long-term neurocognitive effects and toxicities is crucial.

Neuropsychological effects of cranial radiation: current knowledge and future directions

Radiation is an invaluable therapeutic tool in the treatment of cancer, with well-established palliative and curative efficacy. As patient survival has improved, attention has focused on long-range treatment side effects. One such adverse effect, neuropsychological impairment, is incompletely understood. Much of the extant research has been directed at childhood leukemia survivors treated with low-dose whole-brain radiation. Less is known about the effects of high-dose focal or whole-brain radiation used in the treatment of brain lesions. This article reviews the scientific literature in this area, with greatest emphasis on methodologically rigorous studies. Research design considerations are discussed. Review findings suggest that low-dose whole-brain radiation (18 to 24 Gy) in children is associated with mild delayed IQ decline, with more substantial deficits occurring in children treated at a young age. A high incidence of learning disabilities and academic failure is observed in this population and may be caused by poor attention and memory rather than low intellectual level. Children who receive higher dose radiation for treatment of brain tumors experience more pronounced cognitive decline. At higher doses, whole-brain radiation, in particular, is linked to deleterious cognitive outcomes. Remarkably little is known about cognitive outcomes in irradiated adults. Preliminary findings indicate that certain cognitive functions, including memory, may be more vulnerable to decline than others. Suggestions for future research are proposed.