In recent years, the incidence of primary central nervous system lymphoma (PCNSL) has been increasing with improved diagnostic techniques, increased incidence of AIDS, and increased use of organ transplants and immunosuppressive drugs, and its incidence is increasing at the highest rate among intracranial tumors. PCNSL is considered a potentially curable disease compared to non-Hodgkin’s lymphoma of extracranial origin, but the current status of treatment is not ideal due to the low incidence of this disease and the lack of effective consortia among research centers. In fact, for many years, the treatment of PCNSL seems to have reached a “bottleneck” stage: high-dose methotrexate is still the main therapeutic agent, but its side effects and application are cumbersome, and the efficacy of other drugs alone or in combination is still controversial. In recent years, many new drugs have made some progress in the first and second line treatment of PCNSL. This article will review the current status and prospects of PCNSL drug therapy in the context of recent literature reports and ongoing clinical trials.
1. Overview of PCNSL
PCNSL is an aggressive extranodal non-Hodgkin’s lymphoma (Non) confined to the brain, cerebrospinal membranes, spinal cord, and eyes, and is a rare invasive, multigenic malignancy [1]. PCNSL accounts for only 2% to 3% of NHL and 0.5% to 2% of primary intracranial tumors. It can occur at any age, with a peak incidence of 45-70 years. Recent literature has shown that the incidence of PCNSL in immunocompromised and immunocompetent patients has increased year by year over the past 20 years, and the incidence of PCNSL in the elderly in particular has increased more significantly. In addition, due to the HIV epidemic and the use of immunosuppressive drugs, PCNSL in immunocompromised populations has increased significantly, and the risk of PCNSL in HIV patients is 3600 times higher than in the general population. The survival rate of PCNSL patients is still very low according to the current level of treatment, and the factors that influence it are mainly HIV infection and advanced age.
Numerous clinical studies have shown no significant survival benefit with complete tumor resection or extensive subtotal resection versus stereotactic biopsy only. Therefore, PCNSL is operated only for the purpose of obtaining a definitive pathological diagnosis without conventional wide excision. PCNSL is extremely sensitive to chemotherapy and radiotherapy, similar to systemic non-Hodgkin’s lymphoma. However, its low control rate and high relapse rate result in a poor prognosis with a 5-year survival rate of only 25%. Whole brain radiotherapy (WBRT) is effective in improving survival compared to surgery alone or glucocorticoid therapy alone; however, radiotherapy-associated delayed neurotoxicity has become a serious complication of radiotherapy, especially in the elderly. Although chemotherapy has long been considered the primary treatment for systemic large B lymphocytes (DLBCL), several studies have shown that treatment regimens for DLBCL such as cyclophosphamide, hydroxyzolomycin (Adriamycin), vincristine, and prednisone/prednisone (CHOP) failed to show significant efficacy compared with radiotherapy alone, and therefore the ability of the drug to cross the blood-brain barrier is considered to be the basis for clinical efficacy [14,15 Therefore, the ability of the drugs to cross the blood-brain barrier is considered to be the basis for clinical efficacy [14,15].
2. First-line chemotherapy regimens
2.1 Methotrexate (MTX) single-agent regimen.
Methotrexate is the most effective and commonly used single agent for the treatment of PCNSL. methotrexate exhibits excellent reflectivity and control rates with few side effects at medium and high doses. methotrexate is a water-soluble chemotherapeutic agent that is effective in killing tumor cells at blood concentrations in both the brain parenchyma and cerebrospinal fluid when administered at doses greater than 1 g/m2. loeffler et al. were the first to observe that the application of Loeffler et al. were the first to observe that patients with NHL who applied MTX rarely had CNS tumor recurrence and metastasis, and reported that the median survival time of PCNSL patients treated with intravenous or intrathecal MTX followed by radiotherapy could reach 44 months [10].
2.2 Methotrexate-based multidrug combination chemotherapy regimens.
For example, MPV regimen (methotrexate, procarbazine, vincristine); MBVP regimen: [methotrexate, carmustine, teniposide, methylprednisolone]; BOMES regimen [carmustine, vincristine, etoposide, methotrexate, methylprednisolone]; BVAM regimen [methotrexate, carmustine, vincristine, cytarabine]; MTV regimen [methotrexate, cetepe Vincristine], etc. Trials in various clinical centers have shown that the multidrug combination regimen is superior to single-agent methotrexate, but the optimal combination chemotherapy regimen remains to be determined [11].
2.3 Chemotherapy combined with whole brain radiotherapy.
Several regimens have been used in combination with radiotherapy. A commonly used regimen is the combination of methotrexate 3.5 g/m2, methylbenzylhydrazine and vincristine, with or without intrathecal methotrexate 12 mg, followed by WBRT and consolidating cytarabine therapy [MPV-A]. This regimen was shown to have a low incidence of toxicity, including in the middle-aged and elderly. It can also be applied in patients with creatinine clearance below 40 ml/min who have already been treated. Very good survival outcomes have been obtained, but a high incidence of neurotoxicity remains, and in a recent phase II study, rituximab was added to the chemotherapy regimen (R-MPV) and the whole-brain radiotherapy dose was reduced to 23.4Gy achieving complete remission (CR) in patients; methotrexate doses ranging from 0.5 to were applied, and other agents have been added, including cytarabine, methylbenzhydryl vincristine, etoposide, (carazepam) carmustine, isocyclophosphamide, desoxorubicin, cetiprazole, and cyclophosphamide. Different trial conditions (single-center or multi-center), different follow-up durations, and different methods of neurotoxicity assessment make comparisons between studies more difficult.
3. Second-line chemotherapy regimens
3.1 High-dose methotrexate
3.2 Temozolomide
3.3 Pemetrexed
The application of pemetrexed for the treatment of recurrent PCNSL started in November 2005 (NCT00276783, NCT00424242, funded by the National Cancer Institute and Northwestern University. The basis is that pemetrexed is an antitumor drug that acts on multiple targets in folate metabolism, inhibiting the activity of thymidylate synthase, dihydrofolate reductase, and glycinamide nucleotide formyltransferase, thereby inhibiting nucleotide biosynthesis. It is the same as methotrexate as a folic acid antagonist, similar in structure, but with more targets and simpler application, without hydration, alkalization and detoxification. Raizer et al [10] also studied the level of pemetrexed in the cerebrospinal fluid and showed that the cerebrospinal fluid level was about 1% to 3% of the plasma level. The results of a clinical trial of pemetrexed for recurrent PCNSL were finally published in Cancer in 2012, which showed a progression-free survival of 45% disease at 6 months after 5 cycles of chemotherapy with pemetrexed 900 mg/m2, a treatment efficiency of 55%, and a disease control rate of 91%. And our findings are consistent with foreign reports and were also compared with temozolomide regimen in this study.
4. Treatment options for elderly patients
Methotrexate (MTX) monotherapy regimen: Methotrexate is the most effective and commonly used single agent for the treatment of PCNSL. methotrexate has shown excellent reflectivity and control rates with few side effects at medium and high doses. methotrexate is a water-soluble chemotherapeutic agent that is effective in killing tumor cells both in the brain parenchyma and in the cerebrospinal fluid when administered at doses greater than 1 g/m2. Loeffler et al. were the first to observe that NHL patients treated with MTX rarely had CNS tumor recurrence and metastases, and reported that PCNSL patients treated with intravenous or intrathecal MTX followed by radiotherapy had a median survival time of 44 months [26].
Methotrexate-based multidrug combination chemotherapy regimens: e.g., MPV regimen (methotrexate, procarbazine, vincristine); MBVP regimen: methotrexate, carmustine, teniposide, methylprednisolone; BOMES regimen: carmustine, vincristine, etoposide, methotrexate, methylprednisolone; BVAM regimen: methotrexate, carmustine, vincristine, cytarabine; MTV regimen: methotrexate, cetiapine, vincristine, etc. Trials in various clinical centers have shown that the multidrug combination regimen is superior to single-agent methotrexate, but the best combination chemotherapy regimen is yet to be determined [27]
5, chemotherapy combined with radiotherapy treatment
Chemotherapy combined with radiotherapy: several regimens have been used in combination with radiotherapy, a commonly used regimen is the combination of methotrexate 3.5 g/m2, methylbenzylhydrazine and vincristine, with or without intrathecal methotrexate 12 mg, followed by WBRT and consolidating cytarabine therapy (MPV C A regimen). This regimen was shown to have a low incidence of toxicity, including in the middle-aged and elderly. It can also be applied in patients with creatinine clearance below 40 ml/min who have already been treated. Although very good survival outcomes have been achieved, a high incidence of neurotoxicity remains. In a recent phase II study, rituximab was applied to a chemotherapy regimen (R – MPV) with a reduced dose of whole brain radiotherapy to 23.4 Gy and resulted in patients achieving complete remission (CR). Different trial conditions (single or multicenter), different follow-up durations, and different methods of neurotoxicity assessment make comparisons between studies difficult [28].
6, Elderly PCNSL patients treated with chemotherapy only
Older adults account for 55% of PCNSL patients and have higher delayed neurotoxicity and shorter PFS and OS, and chemotherapy-only therapy has been administered in this particular group of patients. Due to decreased creatinine clearance and nephrotoxicity in these patients, a lower dose of methotrexate is often required, which increases the need for other drugs to be combined with methotrexate. Prophylactic granulocyte colony-stimulating factor is increasingly used in clinical practice, thus facilitating the continued application of these high doses to avoid decreases in effective brain concentrations due to decreases in drug concentrations. In the second phase of the study, 50 patients aged >60 years were given relatively low doses of the drug.
60 years old were given relatively low doses of methotrexate (1 g/m2) with CCNU (lomustine), methylphenidate, methylprednisolone plus intrathecal methotrexate and cytarabine 40 mg, without combined radiotherapy [29]. This treatment regimen was well tolerated with a significant reduction in neurotoxicity with an ORR of 48%, median PFS of 10 months and median OS of 14 months, respectively.
7, Treatment of relapsed or refractory PCNSL
According to foreign literature, approximately 35% to 60% of patients relapse within 2 years of PCNSL diagnosis, and patients with relapse have a poor prognosis with a median survival of approximately 8 to 18 months, for which there is no standard treatment protocol [30,31]. In young patients who have not been irradiated, WBRT remains one of the most effective salvage treatments, although neurotoxicity may still occur [32]. Promising results have also been reported with salvage autologous stem cell transplantation therapy. However, it remains uncertain which chemotherapy is most appropriate for elderly patients who are not candidates for radiotherapy and autologous stem cell transplantation. In two retrospective studies, temozolomide was used to achieve a median OS of 8 to 14 months in an intensive regimen with melphalan in combination [33,34]. In another study, the effect of a single agent topotecan group (n = 27 cases) was analyzed, with an ORR of 33% and a median OS of 8.4 months. small studies also analyzed the combination of methylphenidate, and vincristine, as well as etoposide, isocyclophosphamide and cytarabine, finding very limited efficacy in both cases [35]. In conclusion, these studies suggest that the prognosis of patients with relapsed or refractory PCNSL without salvage WBRT or high-dose methotrexate in shock therapy and autologous stem cell transplantation is very limited.
8. High-dose chemotherapy and autologous stem cell transplantation
High-dose chemotherapy and autologous stem cell transplantation (HDC C ASCT) is an emerging alternative to PCNSL treatment and has been investigated in newly diagnosed disease.Soussain et al. reported a study of an induction chemotherapy salvage regimen using cytarabine and etoposide (CYVE) followed by (responder) HDC- ASCT with high-dose tiotipine, mariculan and cyclophosphamide [36 ]. This therapy achieved good results with a median PFS of 12 months and a median OS (N = 43) of 18 months in a prospective phase II clinical trial. In conclusion, the available study protocols, support the use of HDC – ASCT as salvage therapy for PCNSL because of its ability to increase BBB infiltration, but further studies are still needed as a means to replace WBRT in pre-preliminary trials.
9. Challenges faced
Early complications of whole brain radiotherapy in PCNSL patients include headache, nausea, fatigue, and skin damage. In the past, late complications such as cerebral leukomalacia and radionecrosis were uncommon due to the short prognosis of patients. However, as patient survival improved and the number of long-term surviving patients increased, radiotherapy-related cerebral leukomalacia ensued and became a serious complication of radiotherapy combined with high-dose methotrexate treatment, reaching nearly 25% of all patients and almost 100% incidence in the elderly [37], patients with this complication present with severe progressive dementia accompanied by significant memory loss, executive dysfunction, psychomotor retardation, gait ataxia and sphincter incontinence, culminating in death in many cases. The expectation of neurotoxicity and the distinction between neurotoxicity and cognitive impairment caused by the disease itself has become a challenge, as it requires rigorous neuropsychological and quality-of-life evaluations, as well as long-term follow-up and specialized statistical analysis methods.
In conclusion, PCNSL remains a challenge that requires additional exploration and large, prospective randomized controlled studies to determine the best treatment modality.