This document discusses primary central nervous system lymphoma (PCNSL). Some key points:
- PCNSL is a rare type of non-Hodgkin lymphoma confined to the brain, eyes, or spinal cord. It most commonly presents with neurocognitive symptoms in immunocompetent patients in their 50s-60s.
- Diagnosis involves brain imaging, biopsy, and ruling out systemic involvement. The standard treatment was whole brain radiation but this resulted in poor survival and neurotoxicity.
- Newer regimens combining high-dose methotrexate with other chemotherapy agents and reduced whole brain radiation have improved outcomes with median survival around 3 years and less neurotoxicity. Ongo
Brain metastasis is an advance diseases with poor overall prognosis management of which is full of controversies. This slide aims to make metastasis simplified.
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Dr Vandana, cranio spinal irradiation, radiotherapy, medulloblastoma, cancer, radiation, treatment, diagnosis, management, natural history of medulloblastoma, signs & symptoms of medulloblastoma,
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Primary brain tumours are a diverse group of neoplasm arising from different cells of the central nervous system.
It accounts for about 2% of all cancers with an overall annual incidence of 22 per 1,00,000 population.
Most common brain tumour in adults is Brain Metastasis.
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Management of acute lymphoblatic leukemia with light on etiology, clinical features, diagnosis and different aspects of management including chemotherapy and radiation therapy
Primary and secondary lymphoma of brain differences as regard location, imaging ,presentation and treatment. Different lines to treat pri.ary CNS lymphoma
This presentation is a short brief regarding the Brain tumor and the leading molecules used in the treatment of Brain tumor as BBB is a major limiting factor for the substances used in the treatment of brain cancer.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
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India is among the nations with the highest burden of bacterial infections.
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NDM‑1 ( New Delhi Metallo Beta lactamase 1, an enzyme which inactivates majority of Beta lactam antibiotics including carbapenems) was reported in 2008
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
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Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
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This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
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Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
2. • Primary central nervous system lymphoma (PCNSL) is an
extranodal non-Hodgkin lymphoma (NHL) confined to the
brain, leptomeninges, eyes, or spinal cord
10%
15%
<1%
3. Epidemiology
• PCNSL in immunocompetent patients is rare
• 4% of all intracranial neoplasms and 4% to 6% of all
extranodal lymphomas
• Incidence rate - 0.5 per 100,000 per year.
• Men > Women
• Median age of presentation with: • HIV:-31yrs
• Immunocompetent:-55-65 yrs
• Risk factors – immunosuppression—HIV,iatrogenic-organ
transplant,congenital – Ataxia telangiectasia,Wiskott Aldrich.
4. Pathogenesis
PCNSL is secondary to antigen-dependent activation of circulating B
cells, which subsequently localize to the CNS by expression of various
adhesion and extracellular matrix–related genes.
5.
6. • All PCNSL cells demonstrate IgHV genes that have high levels
of somatic mutations and show intraclonal heterogeneity
pointing towards their derivation from mutated germinal center
B cells.
• However, immunohistochemical evaluation suggests that
PCNSL are derived from postgerminal center B cells
• The majority of PCNSLs are of an activated B cell
immunophenotype.
• The proliferation index is usually high.
• A mutation activating MYD88 has been demonstrated in 40-94%
of all cases .
7. Clinical Presentation
Neurocognitive symptoms are the most common presenting
clinical features of PCNSL
• focal neurologic deficits (56% to 70%),
• mental status and behavioral changes (32% to 43%)
• symptoms of increased intracranial pressure (headaches,
nausea, vomiting, papilledema, 32% to 33%)
• seizures (11% to 14%)
depending on the site of CNS involvement.
8. • Secondary CSF and ocular involvement occurs in approximately 15% to
20% and 5% to 20% of PCNSL patients, respectively.
• Presenting symptoms of ocular involvement include eye pain, blurred
vision, and floaters.
• B symptoms such as weight loss, fevers, and night sweats are infrequent in
PCNSL
Physical examination should consist of
a lymph node examination, a testicular
examination in men, and a
comprehensive neurologic
examination.
9. Diagnosis
Imaging:
Gadolinium-enhanced brain magnetic resonance imaging
(MRI) scan is the most sensitive radiographic study for the
detection of PCNSL
• Imaging usually reveals a homogenously enhancing mass
lesion most often a single brain lesion (66%).
• supratentorial location (87%)
• Fronto- parietal lobes (39%)
• eyes (15% to 25%),
• CSF (7% to 42%)
• Spinal -rare
10. • D/D : multiple sclerosis, sarcoidosis, and occasional gliomas, that
have a similar appearance and transient response to corticosteroids.
Hypointense -- noncontrasted T1 scans
Isointense - T2-weighted images homogeneous contrast enhancement - T1 contrast
Reduced average diffusion coefficient
11. Histopathology:
• Diagnosis of PCNSL is typically made by stereotactic brain
biopsy, cerebrospinal fluid (CSF) analysis, or by analysis of
vitreous aspirate in patients with ocular involvement.
• Tissue diagnosis is essential despite classical MRI appearance
and response to steroids
Systemic Imaging :
To exclude extraneural disease
CT or CT/positron- emission tomography (PET) scans of the
chest, abdomen, and pelvis,
a bone marrow biopsy and aspirate
12. CSF analysis :
• A lumbar puncture should be performed .
• Total protein has been identified as an important prognostic factor
and should be analyzed in all patients
• CSF should be assessed by flow cytometry, cytology, and
immunoglobulin heavy-chain gene rearrangement.
• CSF should be sampled before or 1 week after surgical biopsy to
avoid false- positive results; a minimum of 3 mL and ideally 10 mL
should be sent for cytologic evaluation.
Eye Examination :
Slit-lamp examination -- to see the involvement of the optic nerve,
retina, or vitreous humor
14. Primary CNS DLBCL is composed of centroblasts or immunoblasts
clustered in the perivascular space, with reactive lymphocytes,
macrophages, and activated microglial cells intermixed with the
tumor cells.
15. • Most tumors express pan–B-cell markers, including CD19,
CD20, CD22, and CD79a.
• PCNSL harbors chromosomal translocations of the BCL6
gene, deletions in 6q, and aberrant somatic hypermutation in
proto-oncogenes including MYC and PAX5 and Inactivation
of CDKN2A.
• Gene Expression Profiling :
Type 3 large B-cell lymphoma
Germinal center B cell
Activated B-cell lymphoma
18. STAGING
• Proper Disease Evaluation.
• There is no staging system that correlates with prognosis or
response to treatment in PCNSL.
Ann Arbor
Staging
22. • PCNSL is highly sensitive to radiation and chemotherapy
Evolution Of Therapy :
23. Role Of Surgery :
• It is generally restricted to stereotactic biopsy due to
widespread and diffusely infiltrative tumor growth.
• A surgical resection increases the risk of permanent neurologic
deficits in a disease that often involves deep structures .
No survival benefit from subtotal or
gross total resection.
24. Corticosteroids
• Initial response rate upto 70%
• Corticosteroids should be avoided prior to a biopsy, as it
disrupts the cellular morphology, resulting in a nondiagnostic
pathologic specimen.
• Corticosteroids decrease tumor-associated edema and may
result in partial radiographic regression of the tumor.
• An initial response to corticosteroids is associated with a
favorable outcome in PCNSL
• Dexamethasone -4mg QID and taper dose accordingly
25. WBRT Alone
• Doses range from 36 to 45 Gy
• Therapy demonstrated response rates in excess of 75%, but
median overall survival of only 12-18 months and rapid
relapse
26. • There are lack of durable responses to radiation and associated
high risk of neurotoxicity.
• WBRT alone is no longer a recommended treatment for most
patients with PCNSL.
• As PCNSL is an infiltrative, multifocal disease, focal radiation
or radiosurgery is not recommended
27. WBRT + Chemotherapy
• HD-MTX was effective in patients with CNS metastases from
lymphoma or lymphoid leukemias, and when added to WBRT, it
enhanced response and prolonged survival in PCNSL.
• Intravenous, high-dose methotrexate (HD-MTX) at variable doses (1
to 8 g/m2), is utilized in combination with other chemotherapeutic
agents and/or WBRT .
• With the introduction of HD-MTX in combination with WBRT, ORR
remained high (71% to 94%) but outcomes improved, with a median
OS of 30 to 60 months and 5-year survival rates of 30% to 50%
28. Neurotoxicity
Clinical Features :
• Imaging changes evident after 6 months of RT
• Clinical changes >1 month
• Most commonly affected domains are attention , memory ,
executive function ,psychomotor speed.
• Neurotoxicity occurred in 100% of patients (>60yr) treated with
WBRT regimens
• In patients <60yrs—63%
Risk Factors :
• Age > 60yrs
• WBRT or WBRT + chemotherapy
29. • Imaging -- diffuse white matter disease and cortical-subcortical
atrophy.
• Autopsy -- white matter damage with gliosis, thickening of small
vessels, and demyelination.
• These changes are mainly attributed to the synergistic toxicity of
HD-MTX and WBRT, particularly at WBRT doses > 42 Gy.
IPCG Review :
• Most patients treated with WBRT containing regimens experienced
cognitive decline over time
• Most patients treated with chemotherapy alone regimens
experienced stabilization or improvement of cognitive functions
over time,even in the setting of white matter changes by MRI
30. CHOP in PCNSL
• Associated with transient response to brain lesions
• Frequent recurrences
No Role Of CHOP in
Primary CNS Lymphoma
31. Chemotherapy Principles
1) Drugs exhibiting moderate capability to cross the BBB that
can be safely administered at high doses to obtain therapeutic
concentrations in the CNS (methotrexate-MTX and
cytarabine-AraC).
1) Drugs able to cross the BBB and to reach therapeutic
concentrations in the CNS even when administered at
conventional doses (i.e. steroids and some alkylating agents
like thiotepa, ifosfamide, and temozolomide).
32. *High Dose Methotrexate*
• Its role was first recognized when it was discovered that patients who
had systemic NHL that relapsed in the CNS responded to high dose
MTX.
• Ability to penetrate BBB makes it an attractive agent
• Rapid infusion of high dose MTX over 3 hours greatly raises the drug
level in the CSF (Maximum therapeutic concentration in 4-6 hours
after the start of an infusion), and remains above the minimum
therapeutic concentration in the CSF up to 24 hrs
• MTX based regimens are the only regimens with a significant
advantage over RT alone .
• MTX doses 1 g/m2 result in tumoricidal levels in the brain
parenchyma and doses 3 g/m2 yield tumoricidal levels in the
cerebrospinal fluid
34. • Phase II trial
• 79 PCNSL patients
• Randomized to recieve either HD-MTX (3.5 g/m2, day 1 or
HD-MTX (3.5 g/m2, day 1) + cytarabine (2 g/m2 twice per
day, days 2 to 3).
• Each chemotherapy cycle was 21 days.
• All patients underwent consolidative WBRT after induction
chemotherapy.
• The HD-MTX + cytarabine arm had a higher proportion of
complete radiographic responses and a superior 3-year OS .
Methotrexate monotherapy Vs polychemotherapy
Ferreri et al
35. The addition of cytarabine to HD-MTX
and WBRT
• improved ORR from 40% to 69%
• Prolonged progression-free survival
(PFS) from 3 to 18 months
polychemotherapy is more
effective than single agent HD-MTX.
median progression-free survival
(PFS) with
HD-MTX as monotherapy is modest, at
only 12 to13 months
36.
37. Methotrexate Based Induction
Regimens
• Methotrexate plus Temozolomide (+/- Rituximab)
• MTX plus procarbazine and vincristine (MPV) (+/-
Rituximab)
• MTX plus cytarabine(+/- Rituximab)
• MTX, cytarabine, and thiotepa plus rituximab
(MATRix)
• Methotrexate Monotherapy
38.
39. Rituximab
• Rituximab - a chimeric monoclonal antibody targeting the
CD20 antigen on B lymphocytes
• When rituximab is administered intravenously at doses of 375
to 800 mg/m2, CSF levels from 0.1% to 4.4% of serum levels
are achieved.
• Despite limited CSF penetration, radiographic responses have
been observed in relapsed PCNSL patients treated with
rituximab monotherapy, and this antibody has been
incorporated into contemporary regimens for PCNSL.
40. 2-year progression-free survival
Group A : 36% (95% CI 31–41)
Group B : 46% (40–52)
Group C : 61% (55–67).
2-year overall survival
Group A : 42% (95% CI 36–48)
Group B : 56% (50–62)
Group C : 69% (64–74)
41. A typical schedule of rituximab when given with
MTX-based chemotherapy is to treat with :
weekly doses of rituximab (375 mg/m2) for the first
six weeks of induction therapy,
(or)
Rituximab on days 1 and 15 of every 28-day cycle
for up to eight doses
42. Endpoints Of Induction Therapy
Goal of induction therapy is to achieve a complete radiographic response
43. Consolidation
• Though high-dose MTX-based induction chemotherapy prolongs
survival over WBRT therapy alone, at least half of patients with
PCNSL who achieve a CR will relapse within five years.
• This may be due to residual systemic malignant cells that are
below the limits of detection using flow cytometry of peripheral
blood and PET CT imaging.
• Consolidation treatment should be considered for all patients in
CR or PR after induction.
• Patients with either stabilised or progressive disease should
receive a second line therapy.
45. 1.De Angelis (R-MPV)
• Procarbazine -- it has activity against NHL and can penetrate the blood-brain barrier
as a result of its lipophilic structure.
• Vincristine does not permeate the intact blood-brain barrier but may reach areas of
bulky disease where the integrity of the barrier is disrupted by tumor.
• It is a highly active agent against NHL and has a different toxicity profile from the
other drugs, making it attractive in a combination regimen.
2002
46.
47.
48. • 2002
• 102 newly diagnosed, immunocompetent patients with PCNSL
• Median PFS - 24.0 months and overall survival was 36.9
months.
• Age was an important prognostic factor
Median survival
• Patients < 60yrs – 50.4 months
• Patients > 60yrs -- 21.8 months(P < .001).
• Fifty-three percent of patients had grade 3 or 4 toxicity during
induction chemotherapy, half of which was hematologic
49. • Severe neurotoxicity is an unacceptable consequence of this
treatment
• Therefore, more effective and safer regimens must be
developed for patients with this disease, particularly for older
patients who are at greatest risk for the late consequences of
treatment.
• Toxicity is likely attributable to the potent combination of high
doses of intravenous methotrexate, a known neurotoxin,
intrathecal methotrexate, and cranial irradiation, a combination
known to produce leukoencephalopathy and cerebral toxicity
51. Results:
• 52 patients enrolled (Median Age 60 yrs)
• Median KPS 70
• 31 patients (60%) achieved CR and received rdWBRT
• 2 yr PFS 77%, Median PFS 7.7 yrs
• 3yr OS was 87%.
• Median OS was not reached.
• Cognitive function showed improvement in executive function
and verbal memory
Conclusion : R-MPV combined with rdWBRT and Cytarabine
with high response rates , Long term disease control and minimal
Neurotoxicity.
52.
53. 2.MTX plus cytarabine
• International phase II trial
• 79 patients age 18 to 75 years with PCNSL
• Four cycles of either
Arm A : MTX (3.5 g/m2 day 1)
Arm B : MTX (3.5 g/m2 day 1) plus cytarabine (2 g/m2 twice a
day on days 2 to 3) .
• Cycles of chemotherapy were administered every three weeks
and were followed by whole brain irradiation.
54. When compared with those assigned to MTX alone, patients
assigned the combination of MTX plus cytarabine had the
following significant outcomes:
• Higher rates of complete (46 versus 18 percent) and overall
response (69 versus 40 percent).
• Higher rates of severe (grade 3/4) hematologic toxicity (92
versus 15 percent). Granulocyte colony-stimulating factor
support and antimicrobial prophylaxis were strongly
recommended for patients receiving combination therapy.
• There were three toxic deaths among the patients receiving
combination therapy arm and one among the patients receiving
MTX alone.
56. MATRix Efficacy
0 12 24 36 48 60
Months
0,0
0,2
0,4
0,6
0,8
1,0
Probability,
PFS
Arm A
Arm B
Arm C
A
A vs. B= 0·06, HR= 0·68, 95%CI=0·45 - 1·02
A vs. C= 0·0001, HR= 0·66, 95%CI=0·53 - 0·81
B vs. C= 0·049, HR= 0·63, 95%CI=0·40 - 0·99
0 12 24 36 48 60
Months
0,0
0,2
0,4
0,6
0,8
1,0
Probability,
OS
Arm A
Arm B
Arm C
B
A vs. B= 0·14, HR= 0·73, 95%CI=0·48 - 1·11
A vs. C= 0·0004, HR= 0·65, 95%CI=0·52 - 0·83
B vs. C= 0·02, HR= 0·57, 95%CI=0·35 - 0·93
58. Outcomes after
2nd randomization
40 month follow up
2-year PFS
• WBRT-- 80% (95% CI 70–90)
• ASCT -- 69% (59–79)
(hazard ratio [HR] 1·50, 95% CI 0·83–
2·71; p=0·17).
2-year OS
• WBRT - 85% (95% CI 75–95)
• ASCT - 71% (60–82)
(HR 1·67, 95% CI 0·86–3·23; p=0·12
59. • An analysis limited to patients treated with the MATRix
regimen and consolidated by WBRT (n=23) or ASCT (n=24)
showed a 4-year overall survival of 85% (95% CI 71–99)
versus 83% (69–97; p=0·39)
• WBRT and ASCT are both feasible and effective as
consolidation therapies after high-dose methotrexate- based
chemoimmunotherapy in patients aged 70 years or younger
with primary CNS lymphoma.
• Neurocognitive evaluation: Worsening in some domains with
WBRT (attention and executive function) and improvements
with transplant.
• The risks and implications of cognitive impairment after
WBRT should be considered at the time of therapeutic
decision
61. Precis trial
• Oct 2008 and Feb 2014, 140 patients
• After two cycles of R-MBVP, overall response rates were
82% (CR + uCR = 24 %) and 77 % (CR + uCR = 23 %) in
arm A and arm B respectively.
• At the end of the induction chemotherapy, ORR was 74 %
(CR+ uCR = 44 %) and 67 % (CR+ uCR = 42 %) in arm A
and B respectively.
62. Arm B: ASCT
Arm A: WBRT
Progression-free survival
2-y PFS = 86.8% [76.6 – 98.3]
2-y PFS =63.2% [49.5 – 80.5]
Arm A Arm B
Median FU 33.2 mois (24.3 - 89.7) 33.8 mois (23.7 - 64.5)
65. • 46 patients in 12 centres
At a median follow-up of 4.9 years, the following outcomes were
noted:
• OS-2 + 72%
• 1 treatment related death(sepsis)
• No episodes of severe acute neurotoxicity were reported.
• The rate of CR to MT-R was 66%.
• The overall 2-year PFS was 0.57.
• The 2-year time to progression was 0.59, and for patients who
completed consolidation, it was 0.77.
• Patients age >60 years did as well as younger patients, and
the most significant clinical prognostic variable was treatment
delay.
• High BCL6 expression correlated with shorter survival.
66. Consolidation – 1.WBRT
• Whole brain should be irradiated 20 to 30 days after
chemotherapy as the disease is diffusely infiltrative
• No specified optimal dose
• Most protocols use a total dose of 40-45 Gy without a boost.
• Radiotherapy at standard dose (40-50 Gy WBRT) is associated
with considerable late chronic neurotoxicity, particularly in
elderly patients (usually defined as age >60).
• This complication consists of progressive leukoencephalopathy
with cognitive deterioration, associated with a significant
decrease in quality of life.
67. • Because of increased neurotoxicity, RT consolidation is not
recommended in patients over 60 in CR.
Strategies to minimize neurotoxicity :
1.To avoid WBRT in patients who are in CR after primary
chemotherapy.
• Two randomised phase III trials have shown that, consolidation
WBRT in MTX-based chemotherapy resulted in prolonged PFS
(eighteen months for the WBRT group compared to twelve months
in patients who did not receive WBRT) but without a difference in
OS (32 and 37 months, respectively).
68. 2. Reduction of the RT dose :
• In a multicentric phase II study, patients already in CR after
chemotherapy were treated with low dose WBRT (23.4 Gy).
• Compared to the use of higher doses (historical data), the
outcome was similar, but apparently there was better
neurotolerability.
• Median OS was not reached (median follow-up for survivors:
5.9 years) and 3-year OS was 87%.
• But owing to the lack of a control group in this trial, the benefit
of the consolidation treatment with low dose radiotherapy could
not be determined.
69.
70. 2. High dose chemotherapy and autologous
stem cell transplantation (HDC/ASCT)
• This was first investigated in relapsed or refractory PCNSL which
showed promising responses and survival rates.
• Conditioning with a thiotepa-based combination should be
preferred.
• A BCNU-thiotepa regimen seems to be the best compromise
between safety and effectiveness.
• However, no randomised trials demonstrating a benefit of this
concept over conventional combination chemotherapy have been
published and the impact on neurocognitive functions remains
obscure.
71. The NCCN guidelines refer to
HDC/ASCT as an alternative to
WBRT in patients who achieve CR
after an HD-MTX-containing
induction.
72. 3.Non Myeloablative chemotherapy
• Induction with polychemotherapy (MTX, temozolomide and
rituximab) followed by consolidation with etoposide and HD-
AraC in patients with stabilised or improved disease after
induction has been assessed.
• The association was evaluated in a highly selected population
in a multicentre phase II study. Results were encouraging.
Median OS had not yet been reached after a median follow-up
of 4.9 years.
• The results indicate that polychemotherapy alone can result in
excellent long-term survival.
73. • However, the potential benefit of prolonged polychemotherapy
compared to standard treatment involving WBRT or ASCT
needs to be confirmed in randomised trials (such as the
ongoing IESLG43 trial NCT02531841 comparing
BCNU/thiotepa ASCT to conventional ifosfamide-based
chemotherapy).
• The American Alliance/CALGB Inter- group is conducting a
randomised phase II trial that compares BCNU/thiotepa ASCT
to a non-myeloablative combination of etoposide and HD-
AraC in patients <70 years (NCT01511562).
76. • Elderly patients account for more than half of all the subjects
diagnosed with PCNSL.
• The risk of neurotoxicity is highest in this population
• Chemotherapy alone is the preferred option for this subgroup.
• The majority of PCNSL patients >60 years of age develop
clinical neurotoxicity after treatment with a WBRT-containing
regimen, and some of these patients die of treatment-related
complications, rather than recurrent disease.
• HD-MTX at doses of 3.5 to 8 g/m2 is well tolerated in elderly
patients with manageable grade 3 or 4 renal and hematologic
toxicity.
77. • In a multicenter, randomized, phase II trial of chemotherapy alone
in elderly patients with PCNSL.
• 98 patients were randomized to receive three cycles .
• Although trends favored the MPV-A regimen over the simpler,
less toxic MT regimen with respect to complete response rate,
PFS, and OS, none of these differences reached statistical
difference.
• Subsequent studies suggest that the addition of rituximab to both
MPV and MT could increase the radiographic response rate.
• Both of these chemotherapy regimens are options in elderly
PCNSL patients.
MPV-A MT
• Methotrexate 3.5 g/m2, days 1,D15
• Procarbazine 100 mg/m2, days 1-7
• Vincristine 1.4 mg/m2, days 1 and 15
one additional cycle of cytarabine (3 g/m2
per day for 2 consecutive days)
• Methotrexate 3.5 g/m2, days 1 and 15;
• Temozolomide 100 to 150 mg/m2, days 1
through 5 and 15 through 19
78. Intraocular Lymphoma
• The eye is another reservoir for PCNSL tumor cells.
• Chemotherapy efficacy depends on intraocular
pharmacokinetics.
• Systemic administration of MTX and ara-C can yield therapeutic
drug levels in the intraocular fluids and clinical responses have
been documented; however, drug concentrations in vitreous
humor are unpredictable and intraocular relapse is common.
• Thus patients with PCNSL and intraocular disease are treated
with HD-MTX–based chemotherapy followed by WBRT and
ocular irradiation, which results in better disease control.
80. Ocular radiation –
• Radiation dose of 35 to 40 Gy fractionated over five weeks.
• Patients require treatment of both eyes and will have an improvement
in their vision with vitreal clearing, but it is frequently followed by
xerophthalmia and chemosis.
Intravitreal MTX is highly active (remission in 100% of treated eyes)
but does not affect OS and is associated with important side effects in
73% of eyes and significant deterioration of visual acuity in 27% of
patients.
Intravitreal rituximab –intravitreal rituximab is safe and has activity
against primary intraocular lymphoma when administered alone or in
combination with MTX
81. Patients treated with intraocular therapy in
addition to systemic therapy appear to have a
longer median PFS, but similar overall survival
rates when compared with those who do not
receive dedicated ocular therapy.
82. Leptomeningeal Disease
• It may be given intrathecally, either by Ommaya reservoir or
lumbar puncture (12.5 mg/dose twice per week), until malignant
cells are no longer detected in the CSF.
• Thereafter, at least two more doses are given.
• Alternatively, high doses of MTX (8 g/m2) may be given by the
intravenous route. The latter routinely provides CSF levels
between 10-5 and 10-6 molar for 36 hours.
• Patients with leptomeningeal lymphoma
are also primarily treated with MTX.
83. • Alternative therapies include intrathecal slow-release
cytarabine (DepoCyt), 4-hydroxyperoxycyclophosphamide, or
systemic chemotherapy (carmustine, vincristine, high-dose
MTX, etoposide, and methylprednisolone)
• Radiotherapy is usually deferred in order to salvage relapsed
disease or to treat focal areas of symptomatic tumor.
• Intrathecal rituximab is currently under investigation for
leptomeningeal dissemination in patients with B cell
lymphomas.
84. Follow Up- Surveillance
• The majority of relapses occur during the first five years after
completion of treatment.
• The majority of patients with PCNSL who experience a relapse
will have a local recurrence within the brain or throughout the
neuraxis.
• The subarachnoid space is a site for relapse with subsequent
development of leptomeningeal disease. The eye is also a
potential site of relapse, while very few spinal cord relapses
occur.
• Systemic dissemination occurs in 7 to 10 percent of patients with
advanced PCNSL and tends to involve extranodal organs, such as
kidneys, skin, testicles, and uterus.
85. • Patients with PCNSL should be monitored closely for evidence
of worsening neurologic status, development of new deficits,
or recurrence of previously resolved symptoms signaling
disease progression, recurrence, or dissemination.
• Patients should be reassessed, after completion of therapy,
every three months for two years, then every six months for
three years, and later annually for at least five years
• At these visits perform a history and physical examination,
including a Mini-Mental State Examination, and a gadolinium-
enhanced MRI of the brain.
• Evaluation of the eyes and CSF is performed based upon
symptoms.
86. Relapse/Refractory PCNSL
• Prognosis of progressive or relapsed PCNSL is poor, with a
limited number of prospective, phase II studies for guidance on
management.
• They have a median survival of 2 months without additional
treatment .
• Patients should be reevaluated with an MRI of the brain, lumbar
puncture, and slit lamp examination of both eyes.
• Since systemic disease occurs in 7 to 10 percent of patients with
PCNSL, chest and abdominopelvic computed tomography (CT)
scans or PET-CT should be considered
87.
88.
89. • Whole brain radiation therapy (WBRT) in previously
nonirradiated patients. Stereotactic radiotherapy may be an
option for patients who have received WBRT . WBRT was
associated with an ORR of 74% to 79% and median OS of 10
to 16 months.
• High-dose cytarabine — High-dose cytarabine, either alone or
in combination with other cytostatic drugs, has been associated
with CR rates of 40 to 70 percent in small studies of patients
with relapsed or refractory PCNSL
• High-dose cytarabine plus etoposide was associated with a 47
percent response rate .The median overall survival was 18.3
months.
90. • Temozolomide plus rituximab —
Rituximab (750 mg/m2 on days 1, 8, 15, and 22)
temozolomide (100 to 200 mg/m2 on days 1 to 7 and 15 to 21)
The objective response rate - 53 percent
Median OS - 14 months and a median PFS- 7.7 months. Side
effects included myelosuppression with severe thrombocytopenia,
anemia, and leukopenia.
• Pemetrexed –
The use of pemetrexed in PCNSL is considered experimental.
Pemetrexed 900 mg/m2 was administered every three weeks
along with low-dose dexamethasone, folate, and B12
supplementation. The median progression-free and overall
survivals were 5.7 and 10.1 months, respectively.
91. Lenalidomide + Rituximab
MAINTENANCE
12 cycles (D1 = D28)
Lenalidomide (D1 to D21), 10 mg
Off trial
Prospective, Multicenter open-label Phase II Study
INDUCTION
8 cycles (D1=D28)
Rituximab (375 mg/m2 D1) + Lenalidomide (D1 to D21, 20-25 mg)
CR + Cru + PR SD + PD
Mandatory
anti-thrombotic
prophylaxis
ORR- 67%
Median PFS – 9.8months
Median OS- 15.4 months
92. Targeted Therapy
• Ibrutinib – BTK inhibitor, 560mg/day
The objective response rate was 77 percent (five complete and
five partial responses), including two patients with ongoing CRs
at 12 and 14 months. Median progression-free and overall
survival was 4.6 and 15 months, respectively.
• Weekly temsirolimus was associated with a complete or partial
response in 54 percent of 37 patients with heavily pretreated
disease, but most responses were not durable (median PFS 2.1
months),
94. Conclusion
• PCNSL is an uncommon subtype of NHL
• WBRT alone is palliative and is associated with neurotoxicity
• Methotrexate based polychemotherapy is standard therapy
• Optimal consolidation therapy after CR is not defined (High
dose therapy/ASCT,WBRT,chemotherapy)
• High dose therapy + ASCT is the promising therapy