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Primary Central Nervous System Lymphoma

Standard treatment protocol with combined chemoradiation

Chi-Cheng Chuang, M.D.

Shinn-Yn Lin, M.D.

Background. Primary central nervous system lymphoma (PCNSL) is an uncommon disease. Conventional treatment has consisted of either whole brain radiotherapy (WBRT) or methotrexate (MTX)-based combined modality therapy combining chemotherapy and cranial irradiation. The treatment principles at our institute have been quite consistent in the past, sticking to the treatment protocol reported by Memorial Sloan-Kettering Cancer Center in 1990s. No matter what the dosage of MTX is, it is well-established that the addition of chemotherapy to cranial RT significantly improved survival outcomes. However, it was found that delayed treatment-related cognitive sequelae emerged as a significant debilitating complication of combined modality treatment in patients with PCNSL, especially when effective treatment can achieve disease control and better survival rates. Furthermore, the specific contribution of the disease per se and various treatment modalities to cognitive impairment remains to be clarified because the neurotoxic potential of combined modality treatments is difficult to differentiate when each can result in cognitive dysfunctions respectively.

Treatment-related neurotoxicity could be demonstrated by virtue of several meaningful indicators, including neurobehavioral assessments, neuroimaging outcomes, and even measures of quality-of-life (QoL).

Methods. Therefore, this one-year individual research will be a prospective observational cohort study with a longitudinal assessment of neurobehavioral functions, neuroimaging, and quality of life for newly-diagnosed patients with primary CNS lymphoma at our institute. According to our cancer center, it is estimated that there would be around 25 cases of newly-diagnosed primary CNS lymphoma at our institute every year. By virtue of multidisciplinary management and teamwork consisting of neurosurgery, hematology, radiation oncology, neuroimaging expertise, and surgical pathology, investigators will attempt to recruit all potentially eligible patients with newly-diagnosed primary CNS lymphoma. Most importantly, the neuropsychologists will participate in our research project, in an effort to integrate the neurobehavioral outcomes into this prospective study. Accordingly, a battery of neuropsychological measures is used to evaluate neurobehavioral functions for the studied patients. The battery is composed of ten standardized neuropsychological tests, covering four domains sensitive to disease and treatment effects (executive function, attention, verbal memory, psychomotor speed), and QoL questionnaires.

Expected results. This prospective cohort study aims to explore and evaluate patients with PCNSL who are newly-diagnosed by using a standard battery of neurobehavioral functions plus neuroimaging studies. It is anticipated investigators will investigate and correlate neurotoxicity indicators in newly-diagnosed patients with PCNSL who are treated with cranial radiotherapy combined with or without MTX-based chemotherapy according to the multidisciplinary treatment guidelines implemented at a single institute.

Prospective Neurobehavioral Outcomes Follow-up in Primary CNS Lymphoma Patients Treated With Cranial Radiotherapy Combined With or Without MTX-based Chemotherapy According to the Multidisciplinary Treatment Guidelines Implemented at a Single Institute

Neurocognitive assessment including :

Trail Making Test.

Neurocognitive assessment including :

Word Sequence Learning Test.

Neurocognitive assessment including :

Mini Mental Status Examination.

Neurocognitive assessment including :

Paced Auditory Serial Addition Test-Revised

Neurocognitive assessment including :

Modified Card Sorting Test.

Neurocognitive assessment including :

Semantic association of verbal fluency.

Neurocognitive assessment including :

Wechsler Adult Intelligence Scale (WAIS-III-R).

Questionnaires include:

Beck Depression Inventory.

Questionnaires include:

Beck Anxiety Inventory.

Questionnaires include:

National Taiwan University Irritability Scale Self- Evaluation (NTUIS-Self).

Questionnaires include:

National Taiwan University Irritability Scale-Family Evaluation (NTUIS-Family).

Chang Gung Memorial Hospital

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Cytarabine

Methotrexate

Each freshly-diagnosed patient with primary CNS lymphoma will be treated with combined chemoradiation in a sandwiched way, in which 2 cycles of induction chemotherapy with intravenous methotrexate (MTX in a conventional dose of 1g/m2) and intrathecal MTX are followed by a complete course of hyperfractionated WBRT and then high-dose cytarabine for 2 cycles.

A treatment protocol of combined chemoradiation delivered in the manner of hyperfractionated conformal whole-brain radiation therapy

Primary central nervous system lymphoma (PCNSL) is an uncommon disease. Conventional treatment has consisted of either whole-brain radiation therapy (WBRT) or methotrexate (MTX)-based combined modality therapy integrating chemotherapy with cranial irradiation in a sandwiched manner. No matter whether the dosage of MTX is high or conventional, combining chemotherapy with WBRT greatly improves intracranial tumor control and even survival outcomes. However, delayed treatment-related neurotoxicity and neurocognitive sequelae emerged as a significant debilitating complication in PCNSL patients, especially when effective combined chemoradiation can achieve disease control and long-term survival rates. Therefore, by delivering hyperfractionated conformal WBRT plus SIB, this prospective cohort study aims to accomplish both optimal intracranial control and minimal WBRT induced neurocognitive decline. Additionally, by administering objective multi-domain neurobehavioral/neurocognitive assessments, the change in neurocognitive functions (NCFs) before and after the course of hyperfractionated conformal WBRT will be investigated and analyzed.

According to the treatment guidelines for treating newly-diagnosed PCNSL patients, combined chemoradiation in which the WBRT course is sandwiched between initial courses of MTX and the later courses of chemotherapy with Ara-C is the treatment of mainstay at our institute. Employing the technique of a conformal CT treatment planning, the WBRT course is delivered in the manner of hyperfractionation with a reduced cumulative dose of 3600 cGy in 30 fractions during 3-4 weeks, administered twice daily in 1.2 Gy - fractions with at least 6 hours between fractions. By virtue of multidisciplinary management and teamwork including neurosurgery, hematology, radiation oncology, and neuroimaging expertise, it is attempted to recruit all potentially eligible patients with newly-diagnosed PCNSL. Most importantly, a professional neuropsychologist participates in this research project to integrate neurobehavioral outcomes into the prospective study. Accordingly, a battery of neuropsychological measures is used to evaluate predetermined NCFs for the studied patients. The test battery is composed of six standardized neuropsychological tests, covering four domains sensitive to disease and treatment effects (executive function, attention, verbal memory, information processing). The primary outcome measure is the change in patients' capability of information processing indicated by the Paced Auditory Serial Addition Test-Revised (PASAT-R), from the baseline before receiving the WBRT course to the follow-up after undergoing the entire courses of combined chemoradiation.

This prospective cohort study aims to thoroughly examine newly diagnosed PCNSL patients by using a standard battery of neurobehavioral/neurocognitive functions. Additionally, a better intracranial disease control is expected since the WBRT course relies on a highly conformal treatment planning integrated with the individualized arrangement of simultaneous integrated boost (SIB) to escalate the focal dose irradiating the originally involved site(s). Moreover, WBRT-related neurocognitive sequelae might be significantly less likely to occur because the WBRT course is delivered in the fashion of hyperfractionation, indicating a significantly lower dose per fraction and a reduced cumulative dose. Furthermore, it is anticipated the investigators will analyze which neurobehavioral domain would predict the treatment-related neurocognitive impacts to the largest extent in newly diagnosed PCNSL patients treated with cranial RT combined with or without MTX based chemotherapy according to the multidisciplinary treatment guidelines implemented at a single institute.

Prospective Neurobehavioral Functions in Newly-diagnosed Patients With Primary CNS Lymphoma Treated With Hyperfractionated Conformal Whole-brain Radiation Therapy Plus Simultaneous Integrated Boost

Prospective Neurobehavioral Evaluation in Newly-diagnosed Patients With Primary CNS Lymphoma Treated With Hyperfractionated Conformal Whole-brain Radiation Therapy Plus Simultaneous Integrated Boost

The Paced Auditory Serial Addition Test-Revised is an assessment of information processing, used to assess the capacity and speed of information processing, as well as sustained and divided attention.

The Word Sequence Learning Test is an assessment of verbal memory. To evaluate auditory memory of verbal information without context.

The Modified Card Sorting Test is an assessment of executive function, related to conceptual formation and mental shifting.

The Trail Making Test is an assessment of speed and flexibility, used to measure the ability of visual attention and task switching.

The Semantic Association of Verbal Fluency Test is an assessment of verbal fluency, related to frontal and temporal cortex.

A measure of the ability of phonemic and semantic variants.

Neurocognitive assessment including: Paced Auditory Serial Addition Test-Revised

Questionnaires include: Beck Depression Inventory (BDI). The Beck Depression Inventory is a 21-question multiple-choice self-report inventory, used psychometric tests for measuring the severity of depression.

The BDI contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs used differ from the original:

0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; 29-63: severe depression.

Questionnaires include: Beck Anxiety Inventory (BAI). The Beck Anxiety Inventory (BAI) is a 21-question multiple-choice self-report inventory that is used for measuring the severity of anxiety in children and adults.

The BAI contains 21 questions, each answer being scored on a scale value of 0 (not at all) to 3 (severely). Higher total scores indicate more severe anxiety symptoms. The standardized cutoffs are:

0-7: minimal anxiety; 8-15: mild anxiety; 16-25: moderate anxiety; 26-63: severe anxiety.

Questionnaires include: National Taiwan University Irritability Scale Self Evaluation(NTUIS-Self), National Taiwan University Irritability Scale-Family Evaluation (NTUIS-Family).

The National Taiwan University Irritability Scale (NTUIS) is a self-reported scale with validated and reliable psychometric properties, to specifically evaluate irritability.

The NTUIS required patients to examine their irritability before and after disease.

The NTUIS is a 6-point Likert scale with 18 items. Each item was rated 1 (totally non-matched to patient's conditions) to 6 (totally matched to patient's conditions) with descriptions anchoring each matching level. Since "excessive emotional (e.g. anger and annoyance) and behavioural (e.g. verbal aggression) responses to stimuli" were used as the operational definition of irritability, the items considering anger, verbal aggression and annoyance were selected.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Prospective Neurobehavioral Outcomes Follow-up in Primary CNS Lymphoma Patients Treated With Cranial Radiotherapy Combined With or Without MTX-based Chemotherapy According to the Multidisciplinary Treatment Guidelines Implemented at a Single Institute	NCT02655744	Primary Central...	Standard treatm...	18 Years - 84 Years	Chang Gung Memorial Hospital
Prospective Neurobehavioral Functions in Newly-diagnosed Patients With Primary CNS Lymphoma Treated With Hyperfractionated Conformal Whole-brain Radiation Therapy Plus Simultaneous Integrated Boost	NCT04006561	Primary CNS Lym... Brain Lymphoma	A treatment pro...	18 Years - 80 Years	Chang Gung Memorial Hospital
Prospective Neurobehavioral Outcomes Follow-up in Primary CNS Lymphoma Patients Treated With Cranial Radiotherapy Combined With or Without MTX-based Chemotherapy According to the Multidisciplinary Treatment Guidelines Implemented at a Single Institute	NCT02655744	Primary Central...	Standard treatm...	18 Years - 84 Years	Chang Gung Memorial Hospital

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