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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

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Hodgkin Lymphoma

Patients whose radiation therapy field essentially encompasses anterior mediastinum; namely, the majority of malignant lymphoma patients with mediastinal involvement.

As for consolidative RT used in patients with early-stage Hodgkin lymphoma, the RT field must essentially include the mediastinum.

Malignant anterior mediastinal tumors essentially include lymphomas and thymomas. The location of mediastinum is anatomically close to several critical organs such as heart, lung, and breasts, which might be affected meaningfully when the mediastinal region is irradiated. There have been quite a few studies investigating long-term toxicities concerning the above critical organs and risks of secondary malignancies related to treatment regimens combining chemotherapy and mediastinal radiotherapy. With the advancement of modern radiotherapy, highly conformal and intensity modulated radiotherapy have become a radiotherapeutic standard in recent years. However, most previous studies analyzed patients treated in the era of 2D techniques rather than conformal 3D plans. Almost inevitably, a large volume of the heart and lung was irradiated via the 2D technique with which substantial dose levels might be given to these organs unavoidably. Certainly long-term radiotherapy related toxicities are significantly associated with the dose and volume irradiating the normal organs at risk. Relying on the techniques of modern conformal radiotherapy and the contemporary strategy of multimodality therapy, the dose and volume irradiating the heart and lung were considerably reduced. Therefore, objective tools including heart echocardiography and lung function test will be utilized in this prospective study to evaluate and monitor mainly the patients diagnosed as malignant lymphoma who are recommended to receive mediastinal radiotherapy in the era of modern treatment strategy and techniques.

The participants potentially included in the current study are mainly lymphoma patients with mediastinal malignant lymphoma or patients whose radiation therapy field essentially encompasses anterior mediastinum. Patients are prospectively enrolled in this study after physicians' clinical judgement. After signing the consent form, the recruited patient will receive comprehensive pre-radiotherapy evaluations, including cardiac echocardiography, laboratory tests (BNP, and NT-pro BNP), and lung function tests. Participants who are particularly female patients under the age of 45 will receive pre-radiotherapy breast echocardiography. Radiotherapy treatment planning of both photon and proton respectively will be simulated on Eclipse® treatment planning system. Subsequently participants will receive mediastinal RT within one month after being enrolled in the study. Eligible patients should receive standard multidisciplinary treatment as the tumor board at our institute has suggested. Modern radiotherapy techniques comprise all available modalities in our hospital, including photon or proton beams, intensity-modulated radiotherapy, volumetric modulated arc therapy, image-guidance, and breathing control system. The prescription of treatment field designing and dose scheme will comply with our institutional protocols and updated cancer treatment guidelines. Participants will receive longitudinal follow-up examinations at 3, 6, 9, 12, 18, 24, 36 months after the start of RT course. Standardized examinations include the above mentioned cardiac echocardiography and relevant tests.

It is anticipated that long-term mediastinal RT-related late effects are prospectively and longitudinally surveyed through consistent heart examinations and lung function tests. Long-term effects are expected to be lower with using maturely and widely adopted modern RT techniques. Therapeutic and survival outcomes are expected to be satisfactory, achieving the international level in this prospective observational study focusing on mainly lymphoma patients with mediastinal involvement who are suggested and scheduled to receive mediastinal RT as part of the combined modality treatment.

This study aims to standardize the application of clinical examinations including cardiac echocardiography, lung function tests, and relevant laboratory tests as part of objective tools for monitoring patients' cardiac and pulmonary functions after receiving mediastinal RT. Therefore, it is expected that the risk factors of predisposing patients to develop cardiac toxicities after chemoradiation particularly including mediastinal RT will be explored and identified. In addition objectivity of BNP (or NT-pro BNP) will also be verified in combination with the objective measurement and findings obtained from cardiac echocardiography. It is anticipated that our study would be an important and leading one that integrates radiation oncology, hematology, cardiology, and pulmonology into prospective and longitudinal cardiopulmonary surveillance carried out for mainly malignant lymphoma patients undergoing mediastinal RT in this era of modern chemoradiation.

Lymphoma Patients Undergoing Mediastinal Radiotherapy in the Era of Modern Chemoradiation

A Prospective Observational Study With Longitudinal Cardiopulmonary Surveillance in Lymphoma Patients Undergoing Mediastinal Radiotherapy in the Era of Modern Chemoradiation

The outcome assessed by cardiac echocardiography. Our study use the standard imaging modality -cardiac echocardiography

The outcome assessed by plasma concentrations of BNP and NT-proBNP

The outcome assessed by lung function test. The lung function tests contain following four tests: "Determination of F. R. C" \& "Diffusion capacity rate" \& "Screening sporometry before \& after B. D." and "Simple bronchodilator test".

The outcomes assessed by echocardiography

Overall survival time, indicated by the time from the date of recruitment to the date of expiring

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
Lymphoma Patients Undergoing Mediastinal Radiotherapy in the Era of Modern Chemoradiation	NCT03969693	Mediastinal Lym... Hodgkin Lymphom... Non Hodgkin Lym...	Standard treatm...	15 Years - 80 Years	Chang Gung Memorial Hospital
Lymphoma Patients Undergoing Mediastinal Radiotherapy in the Era of Modern Chemoradiation	NCT03969693	Mediastinal Lym... Hodgkin Lymphom... Non Hodgkin Lym...	Standard treatm...	15 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

Spots Global Cancer Trial Database for standard treatment protocol with combined chemoradiation