Primary central nervous system lymphoma (PCNSL) is a rare but aggressive malignancy that accounts for approximately 3% of all primary CNS cancer. New studies have changed the landscape of PCNSL treatment paradigms and expectations for outcome.
Figure. Brain images show the resolution of contrast enhancing tumor over the course of treatment, with residual areas of encephalomalacia in bilateral medial frontal lobes
Primary central nervous system lymphoma (PCNSL) is a rare but aggressive malignancy that accounts for approximately 3% of all primary CNS cancers, although if secondary CNS involvement by systemic lymphoma is included, the proportion of all CNS malignancies is approximately 6%.1 It is more common in older individuals, with a median age at diagnosis of 65 years. Treatment strategies for PCNSL have evolved over the past 15 years. Whereas whole brain radiation therapy was historically considered the standard of care for PCNSL, treatments with high dose methotrexate, CNS penetrating chemotherapy, and autologous stem cell transplantation have led to improved survival rates of up to 82% at 2 years, 77% at 5 years, and 35% at 10 years.2,3 The progress in treatment of PCNSL has been accompanied by careful attention to the quality of life for survivors, an important element of which is neurocognitive function.
Neurocognitive deficits can occur in PCNSL as a direct effect of the CNS disease. Tumor infiltration may occur as a focal contrast enhancing lesion on MRI or can involve widespread bilateral cortical and subcortical regions. The lesion and surrounding edema cause neurologic symptoms, including cognitive and behavioral changes in approximately 50% of patients.4
PCNSL is treated in an induction phase followed by a consolidation phase. The goal of induction treatment is to achieve complete remission (CR), usually defined as a complete regression of contrast enhancing tumor on MRI, which leads to improvement in the acute neurocognitive symptoms. In patients who achieve complete remission, neurocognitive changes can persist as symptoms of neurological damage done by the initial disease, although many patients report only minimal changes from their personal baseline. After obtaining complete remission, the goal of consolidative therapy is to balance the efficacy of the treatment against the risk of inducing progressive neurocognitive decline.
In a landmark review of the PCNSL treatment literature, Correa and colleagues5 reported that the use of whole brain radiation therapy in combination with chemotherapy was more frequently associated with adverse neurocognitive outcomes than was the use of chemotherapy alone. However, the literature was limited at that time because inconsistent and unreliable methods were used in the measurement of cognitive function.
The International PCNSL Collaborative Group (IPCG) proposed guidelines for the study of outcomes in lymphoma, including appropriate assessment of neurocognitive function.6 These guidelines stipulate that cognition should be serially measured with standardized, reliable tests that are sensitive to tumor and treatment effects. The neurocognitive domains that have been demonstrated to be most vulnerable include attention, executive function, memory, and fine motor dexterity. A formal assessment of quality of life is also recommended.
Using these methods, a prospective study of PCNSL patients who had achieved complete remission confirmed that those treated with high-dose methotrexate and whole brain radiation therapy were more likely than those treated with high-dose methotrexate alone to have deficits on tests of attention and memory at a median of 16 months after treatment.7 The relevance of the neuropsychological test findings was demonstrated by the fact that patients treated with high-dose methotrexate were more likely to remain employed than patients who also received whole brain radiation therapy. The neurotoxic effects of combined therapy have further been shown to correlate with widespread T2 abnormalities on MRI, which are twice as extensive in patients receiving whole brain radiation therapy as part of their treatment than in patients who do not receive radiation.8,9
Although the deleterious effects of standard dose whole-brain radiation therapy on neurocognitive function are well known, recent studies have suggested that a reduced dose regimen may be associated with less neurotoxicity.10,11 A prospective study examined treatment efficacy and cognitive outcome of combination therapy, which included induction chemotherapy (5-7 cycles of rituximab, methotrexate, procarbazine and vincristine) followed by consolidative whole brain radiation therapy at a reduced dose (23.4 Gy over 13 fractions). Although cognitive impairment was common at the time of diagnosis, neurocognitive symptoms improved after induction chemotherapy, and there was no evidence of cognitive decline in the patients who were progression free at 4-years posttreatment. However, these data require confirmation in multicenter, prospective studies with long-term, serial assessment of neurocognitive function.
More recently, treatment strategies have been developed that combine the efficacy of high-dose methotrexate with subsequent myeloablative therapy using a combination regimen of high-dose chemotherapy agents followed by autologous stem cell transplantation. In a study by Omuro and colleagues12 induction chemotherapy with rituximab, methotrexate, procarbazine, and vincristine was followed by the collection of peripheral blood stem cells. The patients who had complete remission in response to induction and successful stem-cell collection underwent myeloablative therapy with thiotepa and cyclophosphamide followed by stem-cell reinfusion and supportive therapy. Neurocognitive outcome was assessed with prospective and repeated neuropsychological evaluation following IPCG guidelines. Overall and progression-free survival were near 80% at 5 years. At a median follow up of 24 months, there was a clear pattern of improvement on tests of memory and attention, and a corresponding increase in self-reported quality of life for these patients.
These studies have changed the landscape of PCNSL treatment paradigms and expectations for outcome. Patients and families can hope for long-term survival, without as much concern for progressive neurocognitive decline and dementia. However, a substantial proportion of patients acquire deficits at the time of presentation, which may persist and impact quality of life chronically, as the following case illustrates.
Mr A began to develop personality change, characterized by reduced communication, flat affect, and lack of emotional responsiveness. He became impulsive, spending excessively and gambling. These concerns led to brain imaging, which revealed multifocal enhancing lesions, including extensive bifrontal involvement. Biopsy showed diffuse large B cell lymphoma. There was no lymphoma identified elsewhere in his body. He was treated with rituximab, methotrexate, procarbazine, vincristine, and cytarabine for 6 months. Brain imaging studies since that time have shown stable appearance of bifrontal ex-vacuo lesions in the medial prefrontal white matter, with no evidence of recurrence (Figure).
Neuropsychological evaluation was initially conducted during induction treatment, about 3 months after initial presentation, at which time Mr. A showed marked personality change and executive dysfunction. Over the ensuing 6 months, his cognitive function improved, but there was a persistent organic mood and personality change. Follow up evaluations at 12 months and 18 months after diagnosis have shown stable mild executive dysfunction and persistent organic affective disorder. The neuropsychology team assisted the patient and family with education, therapy to address behavioral issues, and supported a gradual return to supervised part-time vocational activity. He remained disabled however, and his personality and relationships are permanently changed compared with baseline.
To manage ongoing neurocognitive issues, the IPCG recommends integration of neuropsychology in the care of PCNSL as early as possible. Our current program design includes a brief neuropsychological evaluation at the time of induction therapy, with follow-up neuropsychology assessment at 3 to 6 month intervals during the first year of treatment, and more sparsely thereafter. The goal of neuropsychological care is to identify cognitive and behavioral needs, facilitate care for those issues, and enhance quality of life for patients and their family.
Dr Parsons is Neuropsychology Section Head and a staff member, Cleveland Clinic Center for Behavioral Health and Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland, OH; Dr Batchelor is Professor of Neurology, Harvard Medical School, Stephen E. and Catherine Pappas Center for Neuro-Oncology, and Director, Division of Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Boston, MA.
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