Abstract
Primary CNS lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma with the worst outcomes amongst all extranodal lymphomas. There is a scarcity of data on real-world outcomes of primary CNS lymphoma (PCNSL) owing to the rarity of the disease. This study analyzed the demographic patterns, risk stratification, treatment regimens used, & outcomes of patients treated at Tata Memorial Center Mumbai, India. This is a retrospective analysis of newly diagnosed primary CNS lymphoma patients treated at our centre over seven years from January 2013 to December 2019. A total of 142 patients with PCNSL were diagnosed during this period. Thirty (21.1%) patients were deemed ineligible for any systemic or local therapies,ten patients were referred to other hospitals, two patients had relapsed disease, and one was excluded because age less than 18 years. Finally 99 patients were included in the final analysis. Among these 99 patients,72 patients (72.7%) were < 60 years,70 (70.7%) patients had Eastern cooperative oncology group (ECOG) performance status (PS) less than equal to 2. DLBCL was the most common histology (86.4%) while rests were high grade B cell NHL NOS (11.4%),Burkitt’s Lymphoma(1%),Peripheral T-cell Lymphoma NOS (1.2%). Only one of 99 patients was positive for HIV serology. Multiple intracranial lesions were found in 59.5%. Surgical resection was performed in 28.4% of patients. Out of 63 patients in whom the International extranodal lymphoma study group (IELSG) score is available, 34(54%) were IELSG high-risk groups. As per Memorial Sloan Kettering Cancer Center (MSKCC) risk grouping, patients were almost equally distributed in all the risk groups, with 32(32.3%) patients in risk group 1 (age < 50 years), 36(36.4%) patients in risk group 2 (age > 50 years, KPS > = 70), and 31(31.3%) patients in risk group 3 age > 50 years, KPS < 70). First-line treatment with high dose methotrexate (HD-MTX) based regimens was administered to 92 (92.9%) patients, and 72.8% of these patients received rituximab. Of these 92 patients, 59 (64.1%) patients could complete induction, and 52 patients received consolidation. Thirty-one patients received high dose cytarabine based chemo consolidation, one patient underwent high dose chemotherapy followed by autologous stem cell transplantation (ACST), and 19 patients received whole-brain radiotherapy (WBRT) and 1 patient received temozolomide as consolidation regimen. Thus only 52 patients completed the entire course of induction with consolidation therapy. The response to treatment was assessed using International PCNSL Collaborative Group Criteria. Post completion of consolidation, 49(94.2%) patients had a complete response. With a median follow-up duration of 39.2 months, the median progression-free survival (PFS) and the median overall survival (OS) of the patients taken into the analysis (N = 99) were 21 and 37 months respectively. On multivariate analysis, age < 60 yrs, > = 5 HD-MTX cycles received & the use of rituximab predicted better OS.Outcomes of patients with PCNSL treated with HD-MTX based therapy are comparable to reported literature however a large proportion of patients do not undergo required treatment despite the curable nature of disease.
Supplementary Information
The online version supplementary material available at 10.1007/s12288-022-01557-7.
Keywords: Primary CNS Lymphoma, Clinical features, Treatment, Real world data, Outcomes
Introduction
Primary CNS lymphoma is a high-grade extranodal non-Hodgkin’s lymphoma that is confined to the brain, spinal cord, leptomeninges, and/or eye [1]. It is a rare malignancy accounting for 2–6% of all primary brain tumors & approximately 1–2% of all non-Hodgkin’s lymphoma [2]. It predominantly occurs in persons of 60 to 70 years age and more than 90% are diffuse large B-cell lymphoma(DLBCL) histologically.
PCNSL has an aggressive clinical course and poorer outcomes compared to other systemic lymphomas of similar histological types. In the last 3 decades, the treatment of PCNSL has greatly shifted from WBRT as the sole form of treatment to high dose methotrexate-based (HD-MTX) chemotherapy regimens. It has resulted in a significant improvement in median overall survival (OS) from 10–15 months with WBRT alone to over 32 to 37 months with high-dose methotrexate (HDMTX)–based chemotherapy [3]. There were several studies addressing the optimal consolidation strategy to reinforce the post-induction response and increase survival. While high dose cytarabine/etoposide based consolidation regimens are popular and effective, [4] high dose chemotherapy with autologous stem cell transplantation has shown promising results in single-arm studies,[5–7] and recently from phase 2 studies [8, 9]. WBRT as a consolidation regimen is only used in patients deemed unfit for intensive chemotherapy [9].
Despite these improvements, failure to induction chemotherapy is a major problem with nearly one third of patients failing to achieve complete remission and significant proportion of patients still relapse after completion of consolidation therapy [10]. These improvements in survival have not been reflected in patients treated outside the context of a clinical trial or in population-based cohorts studies [11–13]. Apart from these, the delivery of high dose methotrexate, monitoring and management of its associated toxicities is not possible in resource-constrained settings [14].
Management of PCNSL is difficult in resource-limited settings in countries like India. Firstly, being a rare tumor, the timely diagnosis of the disease is often missed due to limited availability of expertise and difficulty in doing biopsy of the lesion [15]. Second, the resemblance of the PCNSL lesion with other brain tumors & benign pathologies may lead to inadvertent use of steroids further delaying the diagnosis [16].
Our study aimed to understand the clinical profile, current treatment practices, toxicities, outcomes, and the various challenges in the management of our patients treated at a single institution with uniform treatment protocols and resources.
Material & Methods
In this study, we examined the electronic medical records of all newly diagnosed patients of primary CNS lymphoma at our center from January 2013 to December 2019. Data collected includes demographic information, data on comorbidities, clinical characteristics, and radiologic presentation, diagnostic workup, treatment, response to treatment, side effects, and relapse. The response to treatment was assessed using the International PCNSL Collaborative Group criteria (IPCG) (supplementary appnedix Table 1) [17].
PFS is defined as the period from the date of diagnosis to the date of progression, relapse or death. OS is defined as the time period from the date of diagnosis to the date of death due to any cause. Probability estimates for PFS & OS were calculated using the Kaplan–Meier method. Log-rank test was used to measure the effect of various variables on the PFS & OS and multivariate analysis was performed with the multivariate Cox proportional hazards regression model. A p-value less than 0.05 was considered significant. Analyses were performed using SPSS 23.0 software (SPSS Inc., Chicago, IL). The study was approved by the institutional ethics committee (Approval no – 900,782).
Treatment Details
All patients prior to start of therapy were evaluated for the diagnosis & risk stratification of the PCNSL which includes Magnetic resonance imaging (MRI) brain, whole-body positron emission tomography (PET-CT), bone marrow studies, CSF examination, serum lactate dehydrogenase (LDH). All patients were assessed for fitness of HD-MTX based therapy which includes DTPA GFR, ECG & 2D Echo. Patients were risk stratified as per the IELSG [18] and/or MSKCC risk classification ( Supplementary appendix Table 2 [19].
HD-MTX based induction was administered as per either the DeAngelis [20] or CALGB-MTR [21] protocol. HD-MTX was administered at a dose of 3.5 to 8 gm/m2 every 2 weekly for a total of 5–8 doses as per standard dosing guidelines and with leucovorin rescue. Response assessment MRI Brain was done post 4 cycles of HD-MTX regimen & post 8 cycles of HD-MTX. Patients underwent response assessment with MRI brain post induction and consolidation. Most of the patients who achieved complete response after induction chemotherapy were treated with chemotherapy-based consolidation except those treated as per DeAngelis protocol went on to receive WBRT as consolidation therapy till 2015. Patients who failed to achieve complete response after induction chemotherapy were treated with WBRT consolidation. For consolidation, patients receiving treatment as per DeAngelis protocol received WBRT followed by two cycles of high dose cytarabine as described by DeAngelis et al. However, patients receiving CALGB-MTR protocol, received reduced dose EA consolidation due to toxicity (prolonged myelosuppression and fungal pneumonia) in the first patient. Doses used were etoposide 100 mg/m2 day 1–3 and cytarabine 2 gm/m2 twice daily on day 1–3. Most of the patients who registered between 2013 and 2015 received the DeAngelis protocol and in the later part most patients received CALGB-MTR.
Results
A total of 142 patients were diagnosed with PCNSL at our center during the study period. Amongst these, 2 patients had relapsed disease after receiving treatment elsewhere, one was diagnosed at age less than 18 years, 30 were unfit for systemic treatment and while 10 patients took treatment at another center after diagnosis and were excluded from the analysis (Fig. 1). Total of 99 patients were included in the final analysis and their baseline characteristics have been summarized in Table 1. The median age of the study population was 56 years (range 30- 84 years), and the majority were males (59.6%). The performance status at the time of presentation was ECOG 2 or less 70 (70.7%) patients. The main presenting symptoms were cognitive impairment in 49 (49.4%), focal neuro deficits in 64 (64.6%), features of raised intracranial pressure (ICP) (headache/vomiting) in 55 (55.5%), seizures in 23(23.2%) patients. Ocular involvement was documented by ophthalmological evaluation in 9(9.09%) patients of which 3 patients had vitreous biopsy results and the rest of the 6 patients had vitreous deposits confirmed by the ophthalmologist. On the baseline MRI brain,40(40.4%) patients had a single lesion, and the location in most of the patients (71.7%) was deep (periventricular regions, basal ganglia, brainstem, and/or cerebellum). CSF analysis was available in 75 patients. CSF was involved by lymphoma cells in 10 patients (10.38%) of which 7 patients had both CSF flow cytometry & cytology positive & 3 patients had only CSF flow cytometry positive. CSF protein was elevated in 42 patients. The diagnosis was made by histopathological examination in 95 patients and 4 patients by MRI brain(in these 4 patients histological diagnosis cannot be done due to inaccessible location of the tumor). DLBCL was the most common histological subtype (83), while 10 patients had high-grade B-cell NHL NOS, 1 had Burkitt’s Lymphoma and 1 had PTCL NOS. IELSG scores were available for 63 patients and only 5 patients (8%) were in the low-risk group (IELSG intermediate risk-24 (38%) and high risk-34 (54%). As per Memorial Sloan Kettering Cancer Center (MSKCC) risk grouping, patients were almost equally distributed in all the risk groups, with 32(32.3%) patients in risk group 1 (age < 50 years), 36(36.3%) patients in risk group 2 (age > 50 years, KPS > = 70), and 31(31.4%) patients in risk group 3 (age > 50 years, KPS < 70).
Fig. 1.
Flowchart for the study
Table 1.
Demographic characteristics of patients at diagnosis
| Demographic characteristics (N = 99) | Median (range) or Absolute number |
Percentages |
|---|---|---|
| Median Age, years | 56 (30–84) | |
| Age distributions | ||
| 18–59 | 72 | 71.28% |
| 61–69 | 18 | 17.82% |
| 70–79 | 7 | 6.93% |
| 80–89 | 2 | 1.98% |
| Sex ratio Male: Female | 1.5:1 | |
| Median KPS | 70 (30–90) | |
| ECOG | ||
| < 2 | 70 | 69.3% |
| >=3 | 29 | 28.71% |
| Symptoms at diagnosis | ||
| Cognitive impairment | 49 | 48.51% |
| Focal neuro deficits | 64 | 63.36% |
| Features of raised ICP (Headache/Vomiting) | 55 | 54.45% |
| Seizures | 23 | 22.77% |
| Ocular involvement documented by an ophthalmologist | 9 | 8.91% |
| MRI | ||
| Single vs multiple lesion | 40 vs 59 | |
| Deep lesion (Periventricular region, brain stem, basal ganglia, cerebellum) | 71 | 71.7% |
| Infratentorial lesion(n = 99) | 39 | 39.4% |
| CSF workup (n = 75) | ||
| Elevated CSF protein | 42 | 56% |
| CSF involvement by lymphoma | 10 | 13.3% |
| Elevated serum LDH(n = 86) | 59 (191 to 641) | 68.6% |
| Positive HIV serology | 1 | |
| IELSG score (n = 63) | ||
| Low risk | 5 | 8% |
| Intermediate risk | 24 | 38% |
| High risk | 34 | 54% |
| MSKCC class(n = 99) | ||
| Group 1 (Age < 50 years) | 32 | 32.3% |
| Group 2 (Age > 50 years, KPS > = 70) | 36 | 36.4% |
| Group 3 (Age > 50 years, KPS < 70) | 31 | 31.3% |
| Time points | ||
| Time from registration to diagnosis | 8 days (0–148 days) | |
| Time from symptoms onset to diagnosis | 2 months (1–26 months) | |
| Time from diagnosis to treatment | 8 days (0–154 days) | |
| Diagnostic methods | ||
| Histology based | 95 | |
| Imaging-based diagnosis | 4 | |
| Histology(n = 94) | ||
| DLBCL | 83 | 86.4% |
| Burkitt’s lymphoma | 1 | 1.04% |
| High grade B-cell NHL NOS | 10 | 11.4% |
| PTCL-NOS | 1 | 1.2% |
| Details of surgical procedure(n = 95) | ||
| Debulking | 27 | 28.4% |
| Biopsy only | 68 | 71.6% |
Treatment Characteristics
The treatment characteristics of the first-line treatment are tabulated in Table 2. Ninety-two out of 99 patients received HD-MTX-based treatment regimens. Five patients were unfit for HDMTX based therapy and so received upfront palliative whole-brain radiotherapy & temozolomide. One patient received palliative chemotherapy with Rituximab and Temozolomide. One patient had undergone surgical excision of the solitary lesion and presented to us after 12 months. His disease was confirmed to be DLBCL, and repeat imaging did not show any evidence of residual or recurrent lesion. He did not receive any form of systemic chemotherapy and is in remission at the last follow at 3.5 years from surgical excision. The median time from the onset of symptoms to the initiation of treatment was 2 months (range 1 to 26 months) while it was 8 days from the date of diagnosis to the initiation of treatment (range, 0 to 154 days).
Table 2.
Treatment characteristics
| Main characteristics of Ist line treatment | ||
|---|---|---|
| HD-MTX-based chemotherapy | 92 | 92.9% |
| Upfront WBRT and Temozolomide | 5 | 5.05% |
| Rituximab-Temozolomide | 1 | 1.01% |
| Only surgical excision | 1 | 1.01% |
| Characteristics of HD-MTX based therapy N = 92 | ||
| Median number of cycles | 5 (range 1–9) | |
| Chemotherapy protocols N = 92 | ||
| CALGB with Rituximab | 45 | 48.91% |
| CALGB without Rituximab | 2 | 2.17% |
| DeAngelis with Rituximab | 20 | 21.7% |
| DeAngelis without Rituximab | 21 | 22.82% |
| Single agent MTX | 3 | 3.26% |
| HD-MTX-Ara-C -Rituximab | 1 | 1.08% |
| Non HD-MTX based regimen (Temozolomide + Rituximab) | 1 | 1.08% |
| Use of Rituximab N = 92 | 67 | 72.8% |
| Consolidation characteristics N = 52 | ||
| Consolidation after induction | 52 | |
| Etoposide + cytarabine consolidation | 15 | 28.8% |
| Single agent cytarabine consolidation | 16 | 30.76% |
| HDCT-ASCT | 1 | 1.92% |
| Only temozolomide | 1 | 1.92% |
| WBRT | 19 | 36.5% |
| Cytarabine consolidation after WBRT | 12/19 | |
Induction therapy
The median number of HD-MTX cycles received was 5 (range, 1 to 9 cycles). The majority of patients received HD-MTX at a dose ranging from 3 to 8 gm/m [2] dose with 83.6% patients receiving methotrexate doses of more than 5 gm/m2. Eleven patients had delayed clearance of methotrexate requiring treatment modification. Six patients developed renal dysfunction after HD-MTX therapy, out of which 2 had delayed clearance of methotrexate. Among the 6 patients with renal dysfunction, the regimen was changed to high dose cytarabine chemotherapy in 2, methotrexate dose reduction was done in 2 and further induction chemotherapy was stopped in 2. Additionally, 2 patients required methotrexate dose reduction due to transaminitis. Rituximab was used in 67(72.8%) patients at a dose of 375 mg/m2 weekly for a total of 6 weeks during the induction.
Out of 92 patients who were started on induction therapy, 59 (64%) could complete the entire course of induction chemotherapy. Among the 33 patients who could not complete the induction, 9 patients had progression of the disease, 6 patients died during induction,4 patients defaulted between induction, 5 patients had worsening of performance status and were planned for best supportive care, 5 patients had received induction regimen outside TMH with no details available and 4 patients had HD-MTX induced toxicities which have been mentioned below.
Consolidation Therapy
Among the patients who completed the induction therapy (n = 59), 52 received consolidation after the induction therapy. Two patients progressed before receiving consolidation while 7 patients were lost to follow up. Consolidation therapy was chemotherapy based in 31 patients and whole-brain RT (WBRT) in 19 patients. Of the 19 patients who received WBRT, 12 of them also received 2 cycles of cytarabine after radiation as per DeAngelis protocol. Only 1 patient underwent ASCT as consolidation therapy while another patient received only temozolomide as a consolidation regimen.
Toxicity & Mortality During Induction and Consolidation
Toxicity details during induction & consolidation are tabulated in Table 3. Grade 3 or 4 hematologic toxicities during induction were febrile neutropenia in 4 patients while anemia & thrombocytopenia were found in 7 & 5 patients respectively. In grade 3 or 4 non hematologic toxicities, the most common toxicities were methotrexate-induced acute kidney injury which occurred in 6 patients (in 2 patients HD-MTX therapy was stopped & in the rest 4 patients methotrexate dose was modified), and pneumonia which occurred in 3 patients. Apart from that leukoencephalopathy, methotrexate-induced hepatotoxicity & pulmonary toxicity happened in 1 patient each. One patient had acute coronary syndrome during HD-MTX infusion.
Table 3.
Toxicities
| In Induction (N = 92) | In Consolidation (N = 52) | ||||||
|---|---|---|---|---|---|---|---|
| Hematological (Grade 3 or 4) | Non-hematological (Grade 3 or 4) |
Hematological | Non-hematological | ||||
| Anemia (n = 7) | 7.6% | Pneumonia (n = 3) | 3.2% | Anemia (n = 16) | 17.3% | Diarrhoea(n = 1) | 1.08% |
| Febrile neutropenia (n = 4) | 4.3% | Acute kidney injury (n = 6) | 6.5% | Febrile neutropenia (n = 11) | 11.95% | Pneumonia (n = 1) | 1.08% |
| Thrombocytopenia (n = 5) | 5.4% | Leukoencephalopathy (n = 1) | 1.08% | Thrombocytopenia(n = 12) | 13.04% | Soft tissue infection (n = 1) | 1.08% |
| Pulmonary toxicity (n = 1) | 1.08% | Mucositis (n = 1) | 1.08% | ||||
| Hepatic toxicity (n = 1) | 1.08% | Cerebellar toxicities (n = 1) | 1.08% | ||||
Grade 3 or 4 hematologic toxicities during consolidation were febrile neutropenia in 11 patients while anemia and thrombocytopenia in 16 and 12 patients respectively. Among grade 3 or 4 non-hematologic toxicities pneumonia, diarrhea, soft tissue infection, mucositis, and cerebellar toxicity occurred in 1 patient each.
There were 41 deaths recorded during the study period. Twenty-seven patients died due to progression of disease while on treatment and 6 died due to progression or relapse after completion of treatment. Four patients died during induction (3 due to septic shock & 1 due to cardiac arrest due to unknown cause), 1 patient died during consolidation due to myocardial infarction 3 patients died in remission due to unrelated causes who were under observation after completion of their treatment.
Response to Treatment
Of the 92 patients who have received induction chemotherapy with HD-MTX based regimens, 68 patients had a response assessment scan available. Post Induction the overall response rate (ORR)(n = 68) was 83.8% (Complete response [CR]: 61.8%, partial response [PR]:22%), progressive disease (PD)(n = 68) was seen in 16.2% of patients. For the patients who received consolidation treatment the final overall response rate (ORR)(n = 52) was 96.1% (CR 94.2%, PR 1.9%) & progressive disease(n = 52) in 3.9% patients Table 4.
Table 4.
Response
| Response | Post induction (N = 68) | Post consolidation response (N = 52) |
|---|---|---|
| ORR n = 68 | ||
| CR | 42 (61.8%) | 49 (94.2%) |
| PR | 15 (22%) | 1 (1.9%) |
| Progressive disease | 11 (16.2%) | 2 (3.9%) |
The median follow-up was 39.2 months (range 0.49 to 77 months). The median PFS of the whole study population(n = 99) was 21 months (95% confidence interval [CI] 12.8—29.1) (Fig. 2). The corresponding 2- and 5-year PFS rate was 43% (95% CI 37.5% to 48.5%) and 31.3% (95% CI 24.8% to 37.8%). The median PFS of the entire cohort(n = 142) was 13 months (Fig. 3). The median OS of the whole study population (n = 99) was 37 months (95% confidence interval [CI] 7.2–66). The corresponding 2- and 5-year survival rate was 52% (95% CI % 46.2% to 57.8%) and 43.4% (95% CI 36.4% to 50.4%) (Fig. 2). The median OS of the entire cohort(n = 142) was 23 months (Fig. 3).
Fig. 2.
Progression free survival and Overall survival of the study populations (N = 99)
Fig. 3.
Progression free survival & Overall survival of the entire cohort (N = 142)
Prognostic Factors
The factors significantly affecting the PFS (Tabulated in Table 5) (Fig. 4) and OS (Tabulated in Table 6) (Fig. 5)by univariate analysis include age, ECOG PS, the total number of HD-MTX cycles administered, the use of rituximab in induction therapy, and MSKCC risk grouping. Out of these, none of the factors were, statistically significant in multivariate analysis of PFS.
Table 5.
Prognostic factors for PFS
| Prognostic factors for PFS (N = 99) | |||||
|---|---|---|---|---|---|
| Factors | Univariate analysis | Multivariate analysis | |||
| No of patients | Median PFS (95% CI) | p-value | HR (95% CI) | p-value | |
| Age | |||||
| Age < 60 | 71 | 26.8 months ( 7.1 – 46.5) | 0.02 | 1.47 (0.74 – 2.9) | 0.26 |
| Age > 60 | 28 | 9.39 months ( 6.05 – 12.7) | |||
| ECOG | |||||
| ECOG < = 2 | 70 | 25 months(12.1 –37.8) | 0.005 | 1.52 (0.73 – 3.1) | 0.25 |
| ECOG > = 3 | 29 | 7 months (1.9 –12) | |||
| Induction protocol | |||||
| CALGB-MTR | 48 | 26 (9.3–42.6) | 0.08 | ||
| DeAngelis | 41 | 13 (8.2 – 17.7) | |||
| Number of HD-MTX cycles received | |||||
| < 5 | 44 | 9 months (0.1 -18) | 0.005 | 0.58 (0.31 – 1.07) | 0.08 |
| > = 5 | 55 | 44.4 months (16.1–71) | |||
| Rituximab | |||||
| Rituximab used | 68 | 26 months(4.9 – 47) | 0.005 | 1.6 (0.87 – 2.5) | 0.12 |
| Rituximab not used | 31 | 8 months(4 – 11.9) | |||
| Consolidation used | |||||
| Chemotherapy consolidation | 33 | 44.7 months | 0.204 | ||
| WBRT consolidation | 19 | 60.5 months | |||
| MSKCC group | |||||
| Group 1 (Age < 50 years) | 32 | 34 months (8.8–59.1) | 0.03 | 1.14(0.73–1.7) | 0.55 |
| Group 2 (Age > 50,KPS > = 70) | 36 | 21 months (3.9 -38) | |||
| Group 3 (Age > 50,KPS < 70) | 31 | 9 months (5.2 – 12.7) | |||
Fig. 4.
Factors predicting progression free survival on univariate analysis
Table 6.
Prognostic factor for OS
| Prognostic factors for OS(N = 99) | |||||
|---|---|---|---|---|---|
| Factors | Univariate analysis | Multivariate analysis | |||
| No of patients | Median OS(95%CI) | p-value | HR (95% CI) | p-value | |
| Age | |||||
| Age < 60 | 71 | Not reached | < 0.0001 | 2.5 (1 -5.8) | 0.03 |
| Age > 60 | 28 | 9 months(4.2 -13.7) | |||
| ECOG | |||||
| ECOG < = 2 | 70 | Not reached | < 0.0001 | 1.4 (0.62 -3.5) | 0.37 |
| ECOG > = 3 | 29 | 11 months (4.7 -17.2) | |||
| Induction protocol | |||||
| CALGB-MTR | 48 | Not reached | 0.008 | 0.59 (0.23 -1.5) | 0.28 |
| DeAngelis | 41 | 15 months (8 -21.9) | |||
| Number of HD-MTX cycles received | |||||
| < 5 | 44 | 15 months(1.2 – 28.7) | 0.001 | 0.4 (0.18 -0.88) | 0.02 |
| > = 5 | 55 | Not reached | |||
| Rituximab used or not | |||||
| Rituximab used | 68 | Not reached | < 0.0001 | 3.7 (1.5 -8.7) | 0.003 |
| Rituximab not used | 31 | 8 months(1.4- 14.5) | |||
| Consolidation used | |||||
| Chemotherapy consolidation | 33 | Not reached | 0.46 | ||
| WBRT consolidation | 19 | Not reached | |||
| MSKCC Group | |||||
| Group 1 (Age < 50 years) | 31 | Not reached | 0.01 | 1.4 (0.82 – 2.3) | 0.2 |
| Group 2 (Age > 50,KPS > = 70) | 38 | 60 months (0 -127) | |||
| Group 3(Age > 50,KPS = 70) | 31 | 11 months (6.9 -15) | |||
| Delay in symptoms to treatment | |||||
| < 2 months | 52 | 60.5 months (9.5 -111) | 0.75 | ||
| > 2 months | 47 | 25.1 months(1.29 – 48.9) | |||
Fig. 5.
Factors predicting overall survival in univariate analysis
For OS, in univariate analysis, in addition to all the above-mentioned factors, the induction chemotherapy regimen also had a significant prognostic impact. Though not statistically significant, there was a difference in overall survival on the basis of delay in starting of treatment. In multivariate analysis for OS, the number of age of the patients, number of HD-MTX cycles received & the use of rituximab retained significant prognostic value (Fig. 6).
Fig. 6.
Factors predicting overall survival in Multivariate analysis
Discussion
This is a single institutional analysis of patients with primary CNS lymphoma diagnosed & treated during a period of 7 years (January 2013 to December 2019). This large series highlights the presentation characteristics, treatment pattern, outcomes and challenges in the management of primary CNS lymphoma.
In our study out of 142 patients diagnosed with PCNSL, 30 (20.9%) did not receive any treatment because of the poor general condition at presentation. This is possibly due to delayed diagnosis and rapid deterioration that is typical of PCNSL. Besides lack of awareness about this rare diagnosis amongst the primary care physicians, availability of diagnostic tests especially the access to stereotactic biopsy is likely to be the reason for the same. The proportion of patients not receiving treatment is unfortunately large in our series but it’s similar to reports from other study in India.22
The median age of patients in our study is 56 years and patients in the age group above 60 years comprised 27% of the study population. Other studies from India reported a similar young age, [22–27] though the data from the western countries shows the median age of at least one decade higher than that of the Indian population [28, 29]. Advanced age is not only a strong independent prognostic factor but also a key risk factor for the higher incidence of treatment-related toxicity. The median OS in patients aged more than 60 years was merely 9 months whereas it was not reached in patients < 60 years (p = 0.0001) which suggests the poor prognosis in this group of patients despite likelihood of selection bias.
In our study, the median time from onset of symptoms to the diagnosis was 2 months. Patients who have received treatment early (i.e., in less than 2 months from diagnosis) have fared better in terms of OS compared to those who received late treatment (60.5 months vs 25.1 months). This observation underlines the importance of prompt diagnosis and treatment.
When compared to the west, our cohort had a higher number of patients with multiple lesions (60%) & with clinical features of raised intracranial tension (55/100 patients). These could have contributed to the much higher number of our patients with a poorer performance status (ECOG 3 or more 29%) [30, 31]. Retrospective data across the country also shows a similar incidence of multiple intracranial lesions (60–75%) [23–25, 32] which usually is lower (34%) in western studies [30, 31].
In our study, only 1 case was HIV -associated PCNSL and it is similar to the rates published in other studies across India which is much less as compared to existing literature from other centers across the world [22, 25, 32, 33]. This is consistent with decline in incidence of PCNSL in HIV positive patients with universal access to highly active antiretroviral treatment [26, 34].
Surgical debulking was done in 28% of patients which is lower than other studies in India, in which it ranged around 45–57% [22, 32]. Debulking, though shown to be associated with better outcome, is usually not recommended as it can be associated with procedure related morbidity and a less invasive and safer procedure like stereotactic biopsy is advised for diagnosis. This could be further facilitated by better radiological characterization of the lesions and highlights the need for studies looking at novel biomarkers for diagnosis like cytokines and liquid biopsy in CSF and or blood. In this study, the most common histology was DLBCL (87%) which is very much similar to data from other centers in India [22–27, 32, 34].
HD-MTX based induction was well tolerated in our study patients. Grade 3 or more hematological toxicities are low and are comparable to the western studies [20, 21]. With monitoring of methotrexate levels, leucovorin rescue and adequate hydration the toxicity is low and manageable in the vast majority of patients. The consolidation regimen of high dose etoposide and cytarabine as described in the CALGB study could not be used due to poor tolerance. The modified EA consolidation was a necessary modification, and it was well tolerated.
Overall response rate to the induction regimen was 83.8% (CR: 61.8%, PR: 22%) and progressive disease was seen in 16.2% of patients [35, 36]. This is comparable to that reported in western literature. Addition of rituximab to the induction regimen has led to an improvement in survival outcomes. The median OS with and without rituximab usage during induction was not reached and 8.7 months respectively, (p = 0.0001). The improvement is similar to that reported in other Indian & western literature, [22, 32, 37] though the phase 3 HOVON 105/ALLG 24 intergroup trial has failed to show any EFS benefit with the addition of rituximab [38]. In our study the number of HD-MTX cycles received had a significant impact on both the progression-free survival & overall survival, reinforcing the fact that adherence to the treatment protocol and completion of all HD-MTX cycles is a key factor determining the outcome.
Consolidation WBRT was given in 33.3% of patients, chemotherapy-based consolidation in 57.1%, ASCT in 1.7%, and 8.7% of patients did not receive any consolidation therapy. In the majority of the patients who received WBRT, it was given as part of the DeAngelis protocol in the early study period before 2016 use declined later. This is in line with the trend of decline in use of WBRT for consolidation due to concern regarding neurotoxicity. In our study, we have used reduced dose consolidation regimens than done with CALGB MTR regimen & only 1 patient has undergone an autologous transplant, but the outcome post consolidation was comparable to the western and Indian literature.
Besides retrospective in nature, limited follow-up duration and highly selected study population are important limitations of our study. Despite this, we demonstrate the feasibility of often complex HD-MTX based therapy and outcome comparable to that reported in literature. Besides the issue of early treatment failures, our study emphasizes the need of awareness amongst the primary care physicians, prompt diagnosis and timely start of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.
Declarations
Conflict of interest
We have no conflict of interest to declare.
Ethical Approval
The study was approved by the institutional ethics committee (Approval no – 900,782).
Footnotes
Publisher's Note
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