Primary central nervous system lymphoma is a clinically rare extranodal non-Hodgkin’s lymphoma (non-Hodgkinlymphoma, NHL) that mainly invades the brain parenchyma, with rare involvement of the cerebrospinal membrane, spinal cord and eyes, accounting for 1% to 2% of non-Hodgkin’s lymphomas [1] and 3.10% of primary brain tumors [2]. We already know that.
(1) immunodeficiency is a definite risk factor for primary CNS lymphoma, and its incidence is thousands of times higher in the acquired immunodeficiency syndrome (AIDS) population than in the general population [3], and is also high in patients with other types of immunodeficiency and in patients on long-term immunosuppressive drugs [4].
(2) Patients with immunocompetent primary CNS lymphoma tend to present with a single intracranial lesion, whereas AIDS patients almost exclusively present with multiple lesions.
(3) In immunocompetent patients with primary CNS lymphoma, the diffuse large B-cell phenotype accounts for 90% of all histologic types, with the rest being other B- or T-cell phenotypes.
(4) The overall prognosis of primary CNS lymphoma is worse than that of systemic lymphoma when the histology is the same; and some of the major chemotherapeutic agents used for systemic lymphoma, such as adriamycin and cyclophosphamide, are ineffective for primary CNS lymphoma. As a highly malignant tumor of the central nervous system, primary CNS lymphoma, neurosurgery is often only a diagnostic step, and its treatment is mainly a combination of cytotoxic drugs, radiation therapy and immunotherapy.
At present, the diagnosis and treatment model of primary CNS lymphoma in China is a comprehensive treatment with neurosurgery as the lead and multidisciplinary participation. Thus, neurosurgeons’ understanding of disease pathogenesis, diagnosis, treatment and regression will undoubtedly have a direct impact on the level of diagnosis and treatment of primary CNS lymphoma. Although primary CNS lymphoma is well documented in the professional literature, clinicians may still be confused about the following aspects.
(1) How does primary CNS lymphoma differ from systemic lymphoma? Where does it occur and how does it enter the central nervous system?
(2) Is a biopsy necessary to confirm the diagnosis of primary CNS lymphoma? Are there any specific biomarkers?
(3) How does functional MRI help in differential diagnosis and determination of outcome?
(4) What is the selection and combination of radiotherapy, chemotherapy and their new therapies? How to remedy refractory and recurrent primary CNS lymphoma? This article will attempt to review the above questions, citing the latest basic and clinical research advances.
I. Differences between primary CNS lymphoma and systemic lymphoma at the cellular and molecular levels
Although primary CNS lymphoma has some characteristics of extracranial lymphoma, it has its own unique gene and protein expression patterns.
1. CNSlargeB-celllymphoma (CNSLBCL) and systemiclargeB-celllymphoma (SLBCL) have some common immunomolecular phenotypic markers, but their biological characteristics are different. There are two subtypes of systemic large B-cell malignant lymphoma: the germinal center-derived B-cell type and the activated peripheral B-cell type [5]. Germinal center-derived B-cell lymphomas express the immunomarker molecule BCL-6 (B-celllymphoma6protein) and have a significantly better clinical prognosis than activated peripheral B-cell lymphomas. CNSLBCL also has a tendency to express BCL-6, but the clinical prognosis is much worse than that of germinal center-derived B-cell lymphoma. DNA sequencing studies revealed the presence of a common mutated form of somatic cells in the immunoglobulin variable region of CNSLBCL cells, suggesting that although tumor cells express BCL-6, a molecule specific to germinal center-derived B-cell lymphoma, they express BCL-6. marker BCL-6, they are derived from mature B cells that have undergone T-cell-dependent affinity maturation in the microenvironment of the germinal center [6].CNSLBCL also frequently express the immunomolecular phenotype marker MUM-1 (Mutatedmelanoma-associatedantigen1) of activated peripheral B-cell type lymphoma, whereas MUM-1 is never expressed in B-cell type lymphomas of germinal center origin [7].
2, CNS large B-cell lymphomas have different gene expression patterns than systemic large B-cell lymphomas.
Microarray studies found that at least 100 genes were upregulated in CNS B-cell lymphomas compared to systemic large B-cell lymphomas, including MYC and PIM1, as well as some proto-oncogenes that were mutated in primary CNS lymphomas [8]. STAT6 expression is also increased in primary CNS lymphoma cells and vascular endothelial cells, and STAT6 is a downstream mediator of IL-4 signaling. In patients with primary CNS lymphoma treated with high doses of methotrexate (MTX), STAT6 expression predicts early tumor progression and shortened patient survival. Some gene products differentially expressed in primary CNS and systemic lymphomas are components of the extracellular matrix in brain tissue and are not required for the lymph node microenvironment, such as osteopontin, chitinase-3-like1, collagen,typeVI,alpha1 , alpha1), and laminin alpha4 (laminin,alpha4). RGS13, which is differentially upregulated in primary CNS lymphomas, is also noteworthy because this protein plays a regulatory role in the response to chemotactic factors. There are also some specific genetic alterations in primary CNS lymphomas. For example, 40% of primary CNS lymphoma lesions have deletion of the CDKN2A gene, which encodes the oncoprotein p14ARF14 [9]. p14ARF14 acts to promote TP53 gene stabilization and inactivates certain cycle-dependent kinases to inhibit the cell cycle cycle. In 20% to 40% of patients with primary CNS lymphoma, TP53 gene inactivation occurs, whereas TP53 gene mutations are rare. This indicates the importance of p14ARF14 in the pathogenesis of primary CNS lymphoma [10]. Alterations in chromosome 12q were also observed in patients with primary CNS lymphoma, and cell cycle genes such as murinedoubleminute2 (MDM2) with cyclin-dependent kinase4 (CDK4) and oncogene GLI1 are localized here [11]. 66 The presence of chromosome 6q deletion in 66% of primary CNS lymphoma lesions is associated with reduced expression of proteintyrosinephosphatase,receptortype,K (PTPRK), a candidate oncogenic protein. Heterozygous deletion analysis, 6q deletion predicts shorter survival in patients with primary CNS lymphoma [12].
3, Malignant lymphocytes and B lymphocytes have CNS tropism.
Primary and secondary CNS lymphomas differ in their occurrence. It is more reasonable to speculate that systemic lymphomas form secondary lesions in the CNS as a result of malignant cells homing in and invading the CNS, whereas in primary CNS lymphomas, B lymphocytes that enter the CNS are transformed by proliferative stimuli and cause monoclonal lymphomas due to the lack of T-cell suppression in the CNS.
The role of Bcell-attractingchemokine-1 (BCA-1) (encoded by the CXCL13 gene) is to promote the homing of B lymphocytes to secondary lymphoid organs, including the brain and spinal cord. The chemokine BCA-1 has recently been shown to be widely expressed in primary CNS lymphomas [13], and the receptor gene CXCR5 for BCA-1 has also been found to be co-expressed in tumor cells, suggesting that CNS lymphoma cells are responsive to BCA-1 signaling [14]. In addition, CNS lymphomas also express another chemokine, stromalcell-derivedfactor-1 (SDF-1) (encoded by the CXCL12 gene) and its receptor at high levels [10]. In addition to chemokines, systemic B cells presumably may also express specific adhesion molecules that promote homing into the CNS, but to date no specific adhesion molecules have been identified in primary CNS lymphomas. The close association between the development of primary CNS lymphoma and EBV is mainly seen in patients with AIDS and those on long-term immunosuppression [15]. In AIDS, B cells infected with EBV develop uncontrolled proliferation and undergo malignant transformation due to loss of suppression by normal T cells. Not only does EBV have a role in CNS tropism in primary CNS lymphomas in the AIDS condition, but patients with systemic NHL who test positive for EBV and also have AIDS are also more likely to have CNS involvement compared to those who are EBV negative. In immunocompetent patients, primary CNS lymphoma is not associated with EBV infection.
II. Key procedures in the diagnosis of CNS malignant lymphoma
CNS malignant lymphoma lacks characteristic clinical manifestations, and imaging is often required for differential diagnosis. Tools for definitive diagnosis include high-resolution cranial imaging and additional imaging aimed at excluding systemic lymphoma, pathologic analysis of tumor samples obtained by stereotactic brain tissue biopsy, and cerebrospinal fluid flow cytology or cytologic analysis. Vitreous biopsy helps to confirm the diagnosis of intraocular lymphoma.
1. Imaging diagnosis of primary central nervous system lymphoma
The imaging presentation of primary CNS lymphoma has its pathological basis. Primary CNS lymphoma has rich distribution of reticular fibers, and the tumor body is rich in cellular components, with large nucleus and chromatin, little cytoplasm and lack of organelles, and abundant ribosomes, so the cellular water content is low; although the tumor cells in primary CNS lymphoma infiltrate around blood vessels in a cuff-like manner, the number of new blood vessels in the tumor body is low, and it is a lack of vascular tumor, and the cuff-like tumor cells infiltrate around blood vessels. The infiltration of cuff-like tumor cells around blood vessels leads to endothelial damage and blood-brain barrier destruction.
(1) Conventional magnetic resonance imaging (MRI): primary lymphoma in the brain typically shows equal or slightly low signal in T1WI and slightly low, equal or high signal in T2WI, and the FLAIR sequence is slightly high or high signal, and the signal is higher than the corresponding T2WI. Contrast-enhanced examinations often show significant homogeneous contrast enhancement, which is the result of contrast penetration into the extracellular space due to blood-brain barrier disruption. It is worth noting that brain lymphoma is an infiltrative tumor, and the enhancement of the lesion is only in the part of the tumor with blood-brain barrier disruption, while the part of the tumor that has been infiltrated by tumor cells without blood-brain barrier disruption does not show enhancement, and even the T1WI and T2WI signals are not abnormal. T2WI and FLAIR sequences can demonstrate non-enhancing tumor areas and cerebral edema of vascular origin.
(2) Functional imaging: Functional imaging has been playing an increasingly important role in the differential diagnosis, efficacy observation and prognosis determination of intracranial tumors, and is gradually gaining clinical recognition.
On DWI, the signal can be slightly high or high, or equal signal, but the former is more common; on ADC, the signal is equal or low. The DWI and ADC patterns are related to the abundance of reticular fibers in primary CNS lymphoma, the large nucleoplasmic ratio, and the restricted diffusion movement of water molecules due to the dense tumor cells and small extracellular space. Because malignant lymphoma cells are tightly arranged and lesions untreated with steroid hormones rarely undergo cystic degeneration and necrosis, their ADC values are generally lower than those of high-grade neuroepithelial tumors, and although there is still no accepted ADC threshold to distinguish between the two, lesions with lower ADC values tend to be diagnosed as brain malignant lymphomas. In a mouse model of non-Hodgkin’s lymphoma, ADC values are associated with tumor cell proliferation and also with changes in tumor cell density induced during treatment and treatment response [16]. low ADC values indicate high tumor cell density and short survival in primary CNS lymphoma [17]; ADC values can also be used to predict the effect of chemotherapy in patients with primary CNS lymphoma.
②Perfusion imaging: both CT perfusion and magnetic resonance perfusion imaging (perfusion-weighted MRI, PWI) can reflect the hemodynamic changes caused by tumors, and commonly used indicators include cerebralbloodvolume (CBV) and permeabilitysurface (PS). The quantitative accuracy of CT perfusion is higher than that of PWI, but the use of PWI is more widespread because of the preoperative MRI examination of brain tumors. Histologically, primary CNS lymphoma shows a kind of vascular central tumor cell infiltration, and the tumor not only lacks blood vessels but also often combines with occlusion of small blood vessels, endothelial cell damage and disruption of the blood-brain barrier, which can precisely reflect this unique growth pattern on PWI. This can be distinguished from high-grade neuroepithelial tumors.
(iii) Magnetic resonance spectroscopy: Primary CNS lymphomas show decreased N-acetylaspartate (NAA) and increased lipid, lactate and choline peaks on magneticresonancespectroscopy (MRS), but they are not specific, so it is difficult to distinguish them from other malignant tumors by MRS alone. other malignancies. Considering the hypermetabolic background of the brain, PET has limited diagnostic utility in primary CNS lymphoma. MRS and PET can be used as a complement to anatomic imaging in case of residual tumor or regression of disease.
With treatment of primary CNS lymphoma, DWI elevation due to diffusion limitation of water molecules may resolve within a few days, and the intensity and extent of MRI contrast enhancement decreases and then disappears or small fragments remain, while FLAIR imaging, although reduced in extent, continues to show evidence of disease on FLAIR imaging even years after tumor cure. Therefore, the presence of residual small pieces of enhancement and FLAIR imaging makes it difficult to conclude that there is a “complete response” to treatment.
2. Tissue biopsy and cytological diagnosis
Tissue biopsy is a necessary tool for the diagnosis of primary CNS lymphoma. However, there is a 4% risk of intracranial hemorrhage with stereotactic brain biopsy [18], and there are still 8% to 9% of patients with intracerebral lesions whose biopsies fail to confirm the diagnosis [19]. In addition, because corticosteroid therapy causes a transient and effective response in primary CNS lymphomas and reduces the diagnostic ability of stereotactic brain tissue biopsy, it is avoided before biopsy or postponed until 2 weeks after discontinuation of the drug [20]. In some special cases, the diagnosis can also be made by relying on imaging and CSF examination without the necessity of tissue biopsy. Primary CNS lymphoma that has a tendency to occur into the ventricles and adjacent meninges suggests that the tumor is prone to disseminate through the cerebrospinal fluid; meningeal lymphoma occurs in approximately 10% to 20% of patients with primary CNS lymphoma. Therefore, lumbar puncture must be performed in all patients, except for those with increased intracranial pressure contraindication. Repeated CSF cytology is also beneficial in the diagnosis of primary CNS lymphoma, but only 15% to 31% of patients are definitively diagnosed by this method [21].
Cerebrospinal fluid proteomics studies have identified approximately 80 proteins quantitatively elevated in the cerebrospinal fluid of patients with primary CNS lymphoma, of which antithrombin III expression levels are associated with reduced overall survival in patients with reexacerbation, a potential biomarker protein for primary CNS lymphoma, which can be used as an indicator for non-invasive diagnosis [22]. The development of primary CNS lymphoma in AIDS patients is closely related to EBV infection, and PCR detection of EBV has a high positive predictive value for primary CNS lymphoma [23]. If a patient with AIDS has a positive PCR test for EBV, and the results of PET or SPECT are consistent with those of a patient with primary CNS lymphoma, and an infection such as Toxoplasma gondii can be excluded, the diagnosis of primary CNS lymphoma can be confirmed directly without a tissue biopsy [24].
3. Exclusion diagnosis of systemic lymphoma
Ninety percent of patients with CNS lymphoma do not have concurrent systemic lymphoma, but a systemic evaluation is still essential because the presence or absence of systemic lymphoma is critical to diagnosis and treatment selection. Patients with primary CNS lymphoma should be diagnosed with stage IV NHL with CNS involvement if they are found to have evidence of concurrent systemic malignant lymphoma. the NCCN recommends CT scans of the chest, abdomen, and pelvis and considers PET imaging if necessary. Examination for systemic lymphoma also includes bone marrow biopsy, and recent evidence suggests that clonal rearrangements of the immunoglobulin heavy chain (IgH) gene suggest subclinical bone marrow involvement [25]. Testicular ultrasonography suggests that approximately 30% of testicular lymphomas metastasize to the brain. Routine blood and liver function tests should also be performed. Because primary CNS lymphoma is associated with HIV, screening for HIV is also important and provides a clue to the treatment of patients with co-morbid primary CNS lymphoma and HIV. Elevated serum lactatedehydrogenase (LDH) levels are indicative of poor prognosis [26]. The main influencing factors were
III. Principles of treatment for CNS lymphoma
CNS lymphoma has a short course, rapid progression, poor prognosis, and high lethality. Patients with newly diagnosed primary CNS lymphoma have a median survival of only 3 months without treatment. The disease is diffusely infiltrative in nature and surgery alone is not effective, with recurrence and progression soon after surgery. However, it has been established that some therapeutic interventions are effective in primary CNS lymphoma, such as steroid corticosteroid therapy, external irradiation, chemotherapy, and immunotherapy. As a result of the implementation of new combination therapies, the 5-year survival rate of patients with primary CNS lymphoma has been reported to increase to 30-40% [27]. However, in general, there is no optimal protocol for the treatment of primary CNS lymphoma.
1. Medical management of stable clinical status of occupying tumors of the brain and spinal cord can cause clinical crisis with catastrophic consequences. Therefore, depending on the severity of the clinical condition, patients with primary CNS lymphoma may require timely life-saving pharmacologic intervention or surgical decompression to gain time for further diagnosis and management. Primary CNS lymphoma lesions are sensitive to corticosteroids, which can not only kill tumor cells but also reduce tumor-induced edema with a response rate of up to 70% [20]. However, tumors can only maintain a temporary response to steroids, and steroids also reduce the diagnostic efficacy of surgical biopsy due to the disintegration of tumor cells, which may instead delay the time to confirm the diagnosis and take definitive treatment. Therefore, for patients with proposed malignant lymphoma, steroids should be given after the biopsy is completed if the condition permits. Surgical biopsy can only address the diagnosis, but direct surgical intervention is also possible when the primary CNS lymphoma has prominent occupying effects that result in increased intracranial pressure, acute brain herniation, or other neurosurgical crisis. It must be clear, however, that surgery, whether total or partial resection, does not result in an overall survival benefit for the patient. The median survival of surgical treatment alone is similar to that of untreated patients [28].
2. First-line treatment measures
(1) Radiation therapy: Total external brain irradiation alone used to be the basic treatment for primary central nervous system lymphoma. The results of a retrospective study showed that the overall response rate of radiation therapy was 90%, with a complete response rate of 60%. The median survival of patients with primary CNS lymphoma who received whole brain external irradiation alone was 12 to 18 months [29]. Because of the infiltrative and multifocal nature of primary CNS lymphoma lesions, wholebrainradiationtherapy (WBRT) is the preferred radiotherapy measure. Irradiation of the spinal cord where no lesions are found has no evidence to support an overall therapeutic benefit; most lesions recur in irradiated areas, suggesting that treatment failure is due to limitations of the radiation therapy itself rather than inadequate fields [30]. Lower doses of whole-brain irradiation treatment also reduce antitumor efficacy, with a decrease in both progression-free survival and overall survival when the dose is reduced from 45 to 30.6 Gy. A common side effect of whole brain irradiation is neurocognitive dysfunction. Approximately 2/3 of patients who have received whole brain irradiation develop delayed neurotoxicity leading to brain dysfunction, progressive dementia and urinary incontinence.
(2) Combination of radiation therapy and chemotherapy: The combination of whole brain irradiation and systemic chemotherapy improves the response rate to treatment and patient survival in primary CNS lymphoma, but the incidence of treatment-related neurotoxicity is also high. A combination regimen in non-AIDS patients with primary CNS lymphoma, in which MTX was administered systemically and intrathecally followed by two courses of systemic chemotherapy with cytarabine after whole-brain irradiation, showed a median overall survival of 42.5 months, much longer than in patients treated with radiation alone [27]. Neurotoxicity occurred in 24% of patients at follow-up and increased over the years. A European clinical report of combined methotrexate and whole brain irradiation showed that 63% of patients developed cognitive impairment despite a complete response to treatment [31]. In a study of combined radiotherapy for primary CNS lymphoma conducted by the RadiationTherapyOncologyGroup (RTOG), patients were given five courses of pharmacotherapy with high-dose methotrexate + vincristine + procarbazine systemically and methotrexate intrathecally before a total dose of 45 Gy of whole brain irradiation. and intrathecal administration of methotrexate [32]. The results showed that patients had a complete response rate of 36% to chemotherapy and 94% to the whole combination regimen, a median survival of 24 months, and an overall survival of 36.9 months, with a more significant improvement in overall survival in patients under 60 years of age (median survival of 50.4 months). The incidence of delayed neurotoxicity in this group was 15% and was often the cause of death [32]. Another subsequent study conducted by this organization aimed to reduce the dose of whole-brain irradiation by induction chemotherapy to reduce toxicity and prolong patient survival. Enrollees first received five to seven courses of rituximab + methotrexate + procarbazine + vincristine (R-MPV) combination chemotherapy; the subsequent dose of whole-brain irradiation was reduced to 23.4 Gy in patients who responded completely to chemotherapy, while the whole-brain irradiation remained at the standard dose of 45 Gy in other patients; after radiotherapy, patients received two additional courses of high-dose cytarabine chemotherapy. Patients had an overall response rate of 93% to this combination chemotherapy regimen and a complete response rate of 78% to chemotherapy. The 2-year survival rates for patients with complete and incomplete responses to induction chemotherapy prior to radiotherapy were 67% and 57%, respectively [33]. Other pre-radiotherapy chemotherapy induction regimens were teniposide + carmustine + methylprednisolone + cytarabine systemic chemotherapy and methotrexate intrathecal injection followed by 45 Gy whole brain irradiation. Patients had an overall response rate of 81% to this regimen, with a median overall survival of 46 months, but a high treatment-related lethality rate of 10% [34].
In a combined radiotherapy and chemotherapy regimen, should radiotherapy or chemotherapy be administered first? Chemotherapy administered before radiotherapy is the preferred regimen for the following reasons: chemotherapy-first combination regimens are less neurotoxic than radiotherapy-first combination regimens; disruption of the blood-brain barrier in primary CNS lymphoma facilitates drug distribution, whereas tumor shrinkage and blood-brain barrier closure due to radiotherapy-first reduces drug distribution in the brain; chemotherapy-first facilitates determination of the effectiveness of chemotherapy in the absence of coexisting radiotherapy variables (3) Chemotherapy alone: Although chemotherapy alone is not a treatment for tumor shrinkage and blood-brain barrier closure, it is not a treatment for the brain.
(3) Chemotherapy alone: Although primary CNS lymphomas have many of the pathological features of systemic lymphomas, the responsiveness of primary CNS lymphomas to known chemotherapeutic agents is significantly different from that of systemic lymphomas. For example, systemic combination chemotherapy with cyclophosphamide, adriamycin, vincristine, and corticosteroids is highly effective for systemic large B-cell lymphoma but not for primary CNS lymphoma, and even when combined with whole brain irradiation it does not increase the survival benefit for patients with primary CNS lymphoma [35]. Although studies suggest significant molecular differences between primary CNS lymphoma and systemic lymphoma, the difference in treatment response between the two is mainly attributed to the low permeability of chemotherapeutic agents to the blood-brain barrier. Drug distribution and pharmacokinetics are critical to the efficacy of primary CNS lymphoma. In patients with meningeal leukemia or meningeal carcinoma, methotrexate levels in the CNS are only 1/30th of systemic levels. methods to overcome the blood-brain barrier barrier barrier to drug entry into the CNS include intrathecal methotrexate injections, high doses of methotrexate administered systemically, and osmolytic drugs to open the blood-brain barrier. Clinical and pharmacokinetic data suggest that high-dose systemic administration of methotrexate is better for maintaining cytotoxic drug concentrations in the cerebrospinal fluid [36]. Retrospective studies also found no additional survival benefit from intrathecal administration of methotrexate in patients with primary CNS lymphoma who were already receiving systemic high-dose methotrexate therapy. Evaluations of methotrexate-based chemotherapy-only regimens concluded that chemotherapy-only regimens were also highly effective and could reduce the adverse effects of combination therapy with whole-brain irradiation. In a study at Sloan-Kettering Memorial Cancer Center in New York, of 13 elderly patients (median age 74 years) who received methotrexate-based chemotherapy regimens, 12 responded to treatment and 11 showed improved status; of the 9 patients who had cognitive impairment prior to treatment, 8 showed improvement in cognitive function and only 1 developed new cognitive in a progressive disease condition impairment that may have occurred with methotrexate-induced white matter encephalopathy [37]. In 1999, Massachusetts General Hospital evaluated the efficacy, toxicity and post-treatment quality of patients with primary CNS lymphoma treated with high-dose methotrexate monotherapy [38]. 31 immunocompetent patients with primary CNS lymphoma received high-dose methotrexate monotherapy at 8 gMm2 every 2 weeks; the dose was reduced in patients with poor renal function. The results showed that all patients responded to treatment, with 65% of patients having a complete response; patients’ behavioral status improved significantly, with a median Carlsbad score increasing from 40 to 90; median overall survival was >30 months; and 90% of patients with a complete response to treatment were alive at 2 years of treatment. Drug toxicity included leukopenia, non-oliguric acute renal failure, and mucositis, but was uncommon. A 2-year observation of the quality of survival and cognitive performance of a group of 11 patients with a complete response showed preserved cognitive and memory function in all patients. Since high-dose methotrexate-based chemotherapy regimens are less toxic than radiotherapy and radiotherapy-chemotherapy combinations, combinations of high-dose methotrexate and other agents have been proposed, such as high-dose methotrexate, temozolomide, rituximab (MTR) combination chemotherapy followed by continued combination chemotherapy with cytarabine and etoposide; other regimens include high-dose systemic methotrexate and intrathecal Other regimens include high-dose systemic methotrexate and intrathecal methotrexate, isocyclophosphamide, cyclophosphamide, cytarabine, prednisone, and vincristine.
3. Treatment of intraocular lymphoma The treatment regimen applicable to intraocular lymphoma is essentially similar to that for intracranial primary CNS lymphoma. 24-hour continuous intravenous high-dose methotrexate can bring the drug to cytotoxic levels in the anterior chamber of the eye within 7 hours. Both methotrexate and cytarabine are effective in intraocular lymphoma [39]. A clinical study of systemic application of methotrexate for the treatment of intraocular lymphoma showed that seven of nine patients had objective responsiveness, and four maintained drug responsiveness over 8 to 36 months of follow-up. Ocular radiation therapy is equally effective [40], but as with radiation therapy for intracranial primary CNS lymphoma, disabling reactions from radiation therapy, such as cataracts, retinal damage, and vision loss, are common. Clinical data using multiple intravitreal injections of methotrexate showed that almost all of the 36 patients with ocular lymphoma achieved clinical remission, and none of them had recurrence. Intravitreal rituximab was used to treat ocular lymphoma, and the drug concentration was maintained at >10 ngMml over 72 days. rituximab was also shown to be objectively effective in two patients with ocular lymphoma who could not tolerate intravitreal methotrexate injections [41].
4. Remedial treatment For patients with refractory or recurrent lesions, remedial measures can be taken, including retreatment with high-dose methotrexate, temozolomide therapy or combined chemotherapy regimens; remedial treatment with whole brain irradiation; immunotherapy; and intensive remedial chemotherapy + autologous stem cell transplantation. When such patients were retreated with high-dose methotrexate at Massachusetts General Hospital, they all achieved high treatment responsiveness, sustained remission, and tolerated drug toxicity [42]. 22 patients (median age 58 years) were treated with high-dose methotrexate after the first relapse of the lesion, 20 of whom achieved complete remission, with a median overall survival of 61.90 months. In one study, a combination chemotherapy regimen including procarbazine + lomustine + vincristine was given to 7 relapsed patients with an overall response rate of 86%, and 4 remained in progression-free survival 1 year after relapse. Results of a clinical trial looking at the effects of temozolomide remedial chemotherapy showed an overall response rate of 31% and a one-year survival rate of 31% in 36 patients [43]. Remedial treatment with 36 Gy of whole brain irradiation in patients who failed high-dose methotrexate induction therapy resulted in an overall response rate of 74% and a median overall survival of 10.90 months. Of the nine patients who received remedial therapy with stereotactic radiosurgery, five had recurrent lesions at irradiated distant sites and four survived one year [44]. Immunotherapy is a promising treatment for refractory and recurrent primary CNS lymphomas. Rituximab is a monoclonal antibody against CD2O, a cell surface protein expressed only in mature B cells and not in neurons or glial cells. Clinical trials have fully demonstrated the effectiveness of rituximab in the treatment of systemic B-cell lymphoma, and a combination regimen with rituximab has become the standard of care. The main problem with the use of rituximab for the treatment of primary CNS lymphoma is its low bioavailability in the central CNS, with drug concentrations in the cerebrospinal fluid being only 0.1% of serum concentrations [45], but rituximab has been found to maintain high drug concentrations in the cerebrospinal fluid of patients with meningeal lymphoma. A phase I clinical trial of intrathecal rituximab in nine patients with recurrent primary CNS lymphoma showed that four cases achieved a complete response and two cases showed a partial response; among them, two cases treated with 50 mg of rituximab triggered a dose-limiting toxic reaction and developed grade III hypertension [46]. However, the combination of intrathecal rituximab and liposome-mediated cytarabine was administered to 14 patients with lymphomatous meningitis, and no additional toxicity was found with moderate efficacy with this combination. The combination of rituximab and temozolomide is also one of the remedial therapeutic measures. Autologous stem cell transplantation is a new treatment modality that has been clinically recognized for the treatment of patients with relapsed and high-risk systemic lymphoma and has been applied in the treatment of primary central nervous system lymphoma. It is particularly effective in young relapsed patients, but treatment of older patients can trigger a higher treatment-related mortality. In a clinical study designed to observe the efficacy of enhanced remedial chemotherapy followed by autologous stem cell transplantation in patients with refractory and progressive primary CNS lymphoma, two courses of high-dose etoposide + cytarabine were administered, followed by pretreatment with leucovorin + cetapide + cyclophosphamide in chemotherapy-sensitive patients, and finally autologous stem cell transplantation. 27 of the 43 included patients received pretreatment and autologous stem cell transplantation, and 26 had complete remission; median overall survival was 18.30 months for all patients, compared with 58.60 months for those who received augmentation chemotherapy and stem cell rescue; three of them died from treatment-related toxic reactions after remedial therapy, two from sepsis, one from neurotoxic reactions, and one from brain biopsy after remedial therapy caused by hemorrhage. The results of this trial suggest that such remedial therapy should not be used in patients >60 years of age. An earlier study showed that of 7 elderly patients who received this treatment, 5 died from treatment-related causes. In another study, 28 patients with primary CNS lymphoma were treated with two days of induction chemotherapy with methotrexate (3.5 gMm2) and cytarabine (3 gMm2), followed by pretreatment with carmustine + etoposide + cytarabine + melphalan, and finally rescued with autologous stem cell transplantation. The objective response rate was 57% and the median progression-free survival was only 9.30 months, with one treatment-related death [47]. Stem cell transplantation. Three of the 23 patients died during treatment, all due to delayed neurotoxicity after whole brain irradiation. The overall two-year survival rate was 48%, compared with 61% for those who received autologous stem cell transplantation [48].
The cytotoxic drugs and radiation therapy currently used to treat primary CNS lymphoma are neurotoxic, especially whole brain irradiation, so it is important to investigate new therapies and treatment strategies that are more effective and less toxic. Options being evaluated include the application of pemetrexed chelator (a newly approved folic acid antagonist), the combination of methotrexate, procarbazine, and vincristine before the application of rituximab, and the evaluation of opening the blood-brain barrier.