Primary central nervous system (CNS) lymphoma, a rare CNS neoplasm associated with high mortality, is responsive to therapeutic interventions. In Part 1 of our two-part coverage of this entity, we provided an overview of the epidemiology of primary CNS lymphoma, followed by a discussion of the diagnostic and staging evaluation, and a review of current prognostication systems. In Part 2, we discuss the management of primary CNS lymphoma, focusing in particular on systemic therapies and radiation. With respect to systemic therapies, we provide details of a variety of regimens built around a backbone of high-dose methotrexate. Future directions for the treatment of primary CNS lymphoma are reviewed as well. These include optimization of consolidation regimens and the pursuit of novel agents.
Primary central nervous system (CNS) lymphoma is a rare and aggressive CNS neoplasm with a high morbidity and often fatal outcomes. However, a subset of patients may be cured. Along with timely and accurate diagnosis, optimal management is key to maximizing a patient’s chances of a good outcome. Once initiated, therapeutic management most often centers on systemically delivered chemotherapy. Systemic therapies have been evaluated alone or in conjunction with intrathecally administered agents, as well as in combination with radiation therapy (RT). Most studies have been retrospective series and uncontrolled trials. The paucity of randomized trials has made the therapeutic landscape and recommendations complicated and occasionally contradictory. Treatment decisions need to be guided by clear therapeutic objectives and goals (eg, symptom control, delay of progression, or cure), taking into account the patient’s general condition. Even in patients without evidence of disease after treatment, there is the potential for disease recurrence; thus, long-term (5 years or more) imaging follow-up is recommended.
Improved understanding of this disease will facilitate optimization of its management both now and in the future. Our goal in this review is to provide clinicians with a comprehensive overview by covering the key investigations that have brought us to our current state of knowledge, as well as studies that may guide future interventions.
Although no single regimen has been established as the standard of care for newly diagnosed or recurrent primary CNS lymphoma, some central principles are generally agreed upon—which we will elucidate. We will also provide interpretations of the results of the single phase III trial and the numerous phase II trials that help inform clinical care—which currently varies considerably at the regional, institutional, and individual physician levels. We have structured our discussion by treatment modality—ie, surgical interventions, RT, systemic therapies, and intrathecal therapies (Table 1).
Primary CNS lymphoma is a disseminated CNS disease with the potential to recur outside of the boundaries of focal therapies such as surgery and focal RT. It is also very responsive to both systemic therapies and RT. Consequently, surgical interventions other than diagnostic tissue biopsy have no established role at this time in the management of most patients with primary CNS lymphoma. Historical data have shown an inferior overall survival (OS) in patients who underwent tumor resection as opposed to biopsy only, further supporting this recommendation. Nevertheless, given improved imaging and surgical techniques, some investigators have recently been reconsidering the role of surgical resection.[2-4] An unplanned post-hoc analysis of the German Primary CNS Lymphoma Study Group 1 trial, a phase III study of 526 patients that investigated the role of RT, found a significant improvement in OS (hazard ratio [HR], 1.33; P = .024) and progression-free survival (PFS; HR, 1.39; P = .005) in the patients who underwent craniotomy with some tumor resection (n = 137) compared with those who had biopsy alone (n = 379). Interestingly, no difference in OS or PFS was noted between patients who underwent gross total resection and those who underwent subtotal resection. At most academic centers, however, biopsy alone in suspected primary CNS lymphoma is still the most frequently employed approach and is recommended by the majority of thought leaders in the field, although data on national and international trends are lacking.
After a diagnosis of primary CNS lymphoma is established, patients move forward with treatment that may incorporate RT, systemic therapy, intrathecal therapy, or a combination of these. RT, while rarely used nowadays as a single treatment modality for newly diagnosed primary CNS lymphoma, had early on demonstrated a clear therapeutic benefit. RT covering both the whole brain and posterior orbits, termed whole-brain radiotherapy (WBRT), is the most frequently utilized approach because of the potential for out-of-field failures. Focal RT is not routinely recommended due to the diffuse nature of the disease. Although rates of response to radiation monotherapy are high, responses are usually short-lived and patients tend to have disease recurrence within a few months. In a series of 132 patients treated with radiation monotherapy in Japan in the 1990s, the median OS was 18 months and the 5-year OS was poor as well, with survival rates below 20%. The required radiation dose threshold is higher in primary CNS lymphoma than in the visceral manifestation of lymphoma: doses between 30 and 50 Gy are required. Among patients who had a complete response (CR) to chemotherapy, higher relapse and reduced survival rates were observed in patients who received WBRT at a dose of 30.6 Gy, compared with patients who received 45 Gy. In the phase II Radiation Therapy Oncology Group (RTOG) 8315 trial, 41 patients with primary CNS lymphoma were treated with RT only; patients received 40 Gy of WBRT followed by a 20-Gy boost to the tumor plus a 2-cm margin. Median OS was 12 months, and recurrence in the brain occurred in 61% of patients, with more relapses in the 60-Gy region, suggesting that there is no clear dose-response relationship for doses greater than 40 Gy. Currently, radiation monotherapy is considered in patients with poor performance status or medical comorbidities (eg, renal failure, pleural effusion, ascites) that preclude the effective use of systemic therapies. In this setting, RT alone can palliate symptoms, induce radiographic regression of tumor, and prolong survival.
RT is also utilized as consolidation therapy after induction with systemic therapy in patients younger than 60 years. In patients who received initial high-dose methotrexate (HD-MTX) regimens (detailed further on), WBRT was employed as a component of the consolidation regimen. While HD-MTX regimens followed by WBRT lead to high response rates and sustained responses in many patients, a subset of patients can develop serious neurotoxicity about 7 months after treatment; this is typically characterized by dementia, ataxia, and urinary incontinence (a clinical picture suggestive of normal-pressure hydrocephalus). In one phase II trial, patients ≥ 60 years old who had received both HD-MTX and WBRT had a 100% incidence of neurotoxicity at 24 months, while those < 60 years old had a 30% incidence at 96 months. This syndrome of neurotoxicity can be caused by both MTX and RT, but the combination is synergistic and more toxic if RT precedes the MTX.
Concerns of synergistic neurotoxicity have led to consideration of avoiding WBRT consolidation following chemotherapy in patients with primary CNS lymphoma, especially if they are older than 60 years. Studies have demonstrated that eliminating WBRT from treatment regimens results in a higher likelihood of recurrence, but this difference does not appear to translate into an OS decrement. The German Primary CNS Lymphoma Study Group phase III trial randomized 524 patients to HD-MTX–based chemotherapy with or without WBRT to 45 Gy in 1.5-Gy fractions. The addition of upfront WBRT significantly prolonged PFS, most prominently in patients who did not achieve a CR following chemotherapy, but this benefit did not translate into an OS difference. In patients with disease less sensitive or insensitive to HD-MTX, WBRT was observed to be more effective than high-dose cytarabine. The addition of upfront WBRT led to greater decreases in patient-reported cognitive functioning and global health status, as well as lower values on the Mini–Mental State Examination.
Current research is focusing on reducing the risk of neurotoxicity from RT without compromising long-term disease control. A phase II study evaluated the effectiveness and toxicity of reduced-dose WBRT (23.4 Gy) in patients who achieved a CR following MTX-based chemotherapy. The estimated 2-year OS and PFS rates in these 19 patients were 89% and 79%, respectively. At a follow-up of 12 months, none of the patients treated with reduced-dose RT had developed treatment-related dementia on neurocognitive studies. This approach was further evaluated in a multicenter phase II study of rituximab, MTX, procarbazine, and vincristine (R-MPV) followed by consolidative WBRT to 23.4 Gy in patients who achieved a post-chemotherapy CR. Consolidative cytarabine was given after RT. Of the 52 patients enrolled, 60% achieved a CR after R-MPV, with a 2-year PFS rate of 77% and a 3-year OS rate of 87%. Cognitive assessments demonstrated improvement in executive function and verbal memory after R-MPV, with stability of follow-up scores.
As with other CNS malignancies, the ability to reach therapeutic concentrations of efficacious agents has been a central concern in the utilization of systemic therapies in the treatment of primary CNS lymphoma. The blood-brain barrier (BBB) limits the ability of many substances to reach the CNS. However, this barrier is abnormal in the setting of contrast-enhancing disease, and is anatomically variable as well as temporally dynamic with respect to its robustness.
A number of methods have been used in attempts to overcome the limitations on treatment efficacy associated with the BBB. The first clearly successful effort in primary CNS lymphoma involved the use of HD-MTX (> 2 g/m2; Table 2). While lower doses of MTX are unable to penetrate into the CNS in effective concentrations, higher doses are able to do so. The serum area under the curve of MTX, and thus the CNS concentrations associated with it, correlates with survival outcomes in patients with primary CNS lymphoma. Because MTX is renally cleared, baseline and close ongoing monitoring of renal function is essential. In addition, MTX can crystalize in the renal tubules, further impairing renal function. Thus, aggressive pre- and posttreatment hydration and urine alkalinization are necessary. Dose reduction is necessary in some patients because of impaired renal clearance. In some patients with very poor renal function, HD-MTX is not a therapeutic option. Additionally, because MTX accumulates in third-space fluids, such as pleural effusions or ascites, its use is typically avoided in patients in whom these entities are found. Finally, HD-MTX regimens are highly immunosuppressive. This can be further exacerbated by concomitant steroid treatment. Immunosuppression leads to a risk of infection, including Pneumocystis carinii pneumonia (PCP). Therefore, patients undergoing chemotherapy for primary CNS lymphoma will often require growth factor support and prophylaxis against PCP, most often with trimethoprim/sulfamethoxazole (3 times a week) or pentamidine inhalation (monthly).
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