Haematology Flashcards
What is Tumour Lysis syndrome?
Increase uric acid, calcium, K, PO4, serum Cr (more common with aggressive tumours)
eg, diffuse large B cell lymphoma [DLBCL],
Burkitt lymphoma,
high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 gene rearrangements
What is the Epidemiology and risk factors for Hodgkin’s Lymphoma?
Incidence (Australian statistics)
- 800 cases annually
- Represents 10% of all lymphomas
- Uncommon malignancy (0.5% of all cancers)
Gender distribution varies with subtype
Median age = 30 years, bimodal at 70
- Most common cancer adolescents/young adults (not young children)
- Good prognosis 98%
- Rarely familial/geographic clustering
6% of childhood cancers
M:F ratio 2.5:1 for children <5yr; 1:1 for children 15-19yr
EBV found in 60% of childhood cases
Aetiology
1) EBV-related a. Most relevant for mixed cellularity and lymphocyte-depleted subtypes 2) Smoking 3) Socioeconomic status a. High SE = nodular sclerosing b. Low SE = mixed cellularity 4) Immunosuppression a. Generally results in EBV-related 5) Familial a. Related to HLA variability (multi-gene) b. No single high-risk allele
What is the pathogenesis for Hodgkin’s Lymphoma?
EBV-mediated
Often EBV-mediated ○ Latent infection ○ Leads to expression of LMP1 protein § Assists in evasion of apoptosis § Activates NF-kB pathway § Upregulates PD-L1 expression (Contributes to evasion of T cell immunity) EBV infection alone is not sufficient for Hodgkin's Lymphoma ○ Very common infection, but malignancy is rare ○ Abnormal HLA variations likely increase susceptibility ○ Immunodeficiency eg HIV more EBV related lymphoma
Somatic Hypermutation
Clonal Immunoglobin heavy-chain (IgH) re-arrangements are characteristic in Reed-Sternberg cells ○ This leads to somatic hypermutation Activation of NK-kB transcription factor is a common event ○ Further mutational events are broad and poorly understood Leads to a cell with varied and broad mutational profiles
What are the subtypes of Hodgkin’s Lymphoma?
1) Classical Hodgkin’s
a. Nodular Sclerosing (70%)
b. Mixed Cellularity (20%)
c. Lymphocyte Rich (5%)
d. Lymphocyte Depleted (<1%)
2) Nodular Lymphocyte Predominant Hodgkin’s (5%)
Describe the pathology for classic Hodgkin’s Lymphoma
Macroscopic
○ Rubbery nodes with abnormal morphology
§ Effacement of the nodal architecture
§ Variable fibrosis (prominent in nodular sclerosing)
Microscopic ○ General § Effacement of normal nodal architecture § Infiltration with heterogenous lymphocytic infiltrate ○ Reed-Sternberg cells are diagnostic, with mixed inflammatory background § Large abnormal lymphocytes with multi-lobulated nuclei Prominent nucleolus and abundant cytoplasm Further aspects vary by subtype: NB all treated the same mmunohistochemistry ○ POS = CD15 & CD30 pos (RS cells) & PAX5 ○ NEG = CD19/20 (B-cell), CD3 (T-cell), CD45 (leukocyte common antigen) ○ EMA= epithelial membrane antigen No clonal cells on flow cytometry (RS cells too infrequent) PDL1 ○ overexpression of PD1 ligands including PD-L1 and PD-L2 common on RS cells ○ copy no. variation and genetic alterations at chromoseome 9p24.1 and increased JAK2 signalling account for majority of cases with overexpression of PDL1/2 ○ PDL1/2 alterations are a defining feature of HL and result in very high expression of PDL1/2 on the cell surface § protects from T cell mediated killing ○ PDL1 expression and MHC class II positivity on RS cells are predictors of favourable outcome after PD1 blockade
Describe the pathology for Nodular lymphocyte predominant Hodgkin’s Lymphoma
Similar behaviour to Follicular lymphoma
Macroscopic
○ Rubbery nodes with abnormal morphology
○ Effacement of the nodal architecture
Microscopic
○ RS cells are infrequently seen
○ Lymphocytic and histiocytic (L&H) cells are much more plentiful
§ Multilobed nuclei and thin nuclear membrane ("popcorn cells")
○ Heterogenous inflammatory infiltrate remains
Immunohistochemistry
○ POS = CD20 (B cell), CD45 (leucocyte common antigen), PAX5
○ NEG = CD15, CD30 (RS cells), CD3 (T cell marker)
What is the relationship between HIV and Hodgkin’s Lymphoma?
HL is a non AIDS defining cancer
Relationship between HIV and EBV
- Immunological factors:
· HIV+ pt are immunosuppressed with decrease CD4 T cells-> decreased cellular surveillance mechanism and increases risk of malignancies, including HL
· HIV infection leads to Chronic B cell activation and cytokine dysregulation which promote lymphoproliferative disorders
- Co-infection
· Coinfection of HIV and EBV lead to higher prevalence of EBV in the host (x8), due to impaired immune response -> result in EBV persistence and oncogenic process.
· HIV pt are also more susceptible to other oncogenic virus eg HHV-8
- Clinical feat of HL in HIV pts
· HL in HIV+ pt are more aggressive and more advanced at dx
· Higher incidence of atypical and extranodal presentation
· Subtype mixed cellularity and lymphocyte depleted are more common
- Impact on HIV progression and treatment
· Risk of HL increases with more advanced HIV disease, but HL can still occur in pts on preserved immune system while on ART
· HIV pt have lower tolerance to chemo regimen due to immunosuppression and potential organ compromise, increase risk of opportunistic infection and complications
· ART has changed the outcomes of HL in HIV+ pts
· ART has extended life expectancy in HIV+ pt hence more likely to develop cancer prognosis and outcome
- Prognosis and surveillance
· If HIV is well controlled, outcome and RR of HL is similar to normal population
· Longterm surveillance- continuous monitoring of both HIV related complication and secondary malignancies is crucial
What are the prognostic factors for Hodgkin’s Lymphoma?
Patient Factors
- Age
- Performance Status
- B-symptoms
Tumour Factors
- Lugano Stage
○ Including number of nodal sites
- Size/bulk of tumour
- Blood markers
○ ESR
○ Hb (<105)
○ WCC (>15)
○ Lymphopaenia (<0.6)
○ Albumin (<40)
- Presence of EBV
○ Inferior prognosis
- Extranodal disease
Treatment Factors
- Incorporation of radiotherapy into management
- High-volume treatment centre
Describe the presentation and history/ examination for Hodgkin’s Lymphoma
Presentation
- Usually presents with painless, superficial enlarged LN , often contiguous LN chains in a predictable manner
- Later in disease course»_space; haematogenous spread occurs with vascular invasion
- Majority supradiaphragmatic disease, isolated infra-diaphragmatic disease in 3-7%
- Approx 60-70% present with cervical and/or SCF LN
- 30% axillary
- Majority 50-60% mediastinal
- Involvement of abdominal organs uncommon
- Only 10-15% had extranodal disease
○ Bone, BM, lung, liver
○ CNS rare
- 25% have B symptoms (fevers, night sweats, weight loss >10%)before LN; carriers worse prognosis in both early and advanced disease
- Alcohol induced painful lymphadenopathy (Mechanism ?prostaglandins ?vasodilation) unclear prognostic significance
Consultation
- History ○ HPI § Palpable lymphadenopathy (non-tender) □ Duration and tempo of disease § Mediastinal mass □ Incidental on CXR □ Painful □ Superior vena cava syndrome § Constitutional symptoms 25% □ Fever □ Night sweats (drenching) □ Weight loss (10% within 6mo) § Cutaneous itch (pruritis) (not a B symptom) § Alcohol induced pain occurring minutes after intake and localising to regions of LN § May have multiple GP visits but delayed diagnosis ○ PMHx: § Previous radiotherapy or chemotherapy § Immunosuppression (including HIV) ○ Medications § Immunosuppression ○ Social: § Smoking ○ Family History § Lymphomas - Examination ○ General inspection ○ Lymphatic examination § Cervical § Axillary § Epitrochlear § Inguinal § Popliteal ○ Abdominal palpation § Hepatomegaly § Splenomegaly
What would be you’re workup for Hodgkin’s Lymphoma?
Work-Up
- Bloods ○ FBC + ESR (prognostic) ○ EUC, CMP and LFT ○ LDH ○ HepB/HepC/HIV serology (pre-chemotherapy) ○ Vitamin D (people with normal vitamin D do better) ○ pregnancy - Histopathology ○ Excisional biopsy preferred § Large amounts of tissue may be required to identify the scant RS cells ○ Core biopsy is a reasonable alternative § FNAB is insufficient - FDG-PET (staging) -uptake by all the reactive cells - Cardiac TTE ○ LVEF prior to anthracycline chemotherapy - Lung function tests ○ Prior to bleomycin ○ Prior to radiotherapy - Fertility management - Routine bone marrow biopsy is NOT routine anymore, PET is sufficient for assessment of bone involvement ○ FDG-PET has sufficient sensitivity ○ A study of 454 HL pt: Stage I/II disease on PET, none had a positive BMT
Describe the Cotsworld staging for Lymphoma.
Describe the Lugano Classification for Lymphoma. Also the factors impacting unfavourable Hodgkin’s Disease.
Suffixes
- A/B = presence or absence of constitutional symptoms
- E = involvement of extralymphatic organs (for stage I or II only)
- X = bulky disease (old system, not commonly used)
HD Favourable vs unfavourable:
3-BEE
3+ lymph nodes
Bulky mediastinum >1 third/10cm
ESR >50, or B symptoms ESR>30
Extranodal disease
Describe the unfavourable favourable risk grouping for Hodgkins lymphoma
Describe the Deauville scoring for Lymphoma.
PET-response to chemotherapy
Deauville X = new areas of uptake unlikely related to lymphoma
Describe the general approach to management of Lymphoma patients
Many patients are young, and so treatment should be considered in this context
Risk base response adapted treatment.
Survival excellent, aim to decrease long term morbidity.
Most cases are chemosensitive, and OS is 86%
1) Discussion and consideration of late toxicities 2) Fertility a. Referral/Consultation for fertility preservation b. bHCG for all female patients of appropriate age 3) Smoking cessation 4) Psychosocial input a. Preferably within the context of a AYA service
Long-term follow-up (late effects clinic) is required
- Primary cancer surveillance
- Secondary cancer surveillance
- Late effects surveillance
Describe the management of early stage (Stage I + II) Hodgkin’s Lymphoma.
ABVD = adriamycin (doxorubicin), bleomycin, Vinblastine, Dacarbazine. 1 cycle = 1 month, chemo given fortnightly (D1 and D15)
SE: Adriamycin cardiac (sharp increase risk doses >400 mg/m2), Bleomycin pulmonary/allergic reaction, Vinblastine haematologic, dacarbazine nausea and vomiting, alopecia
BEACOPP =bleomycin, etoposide, (A) doxorubicin, cyclophosphamide, (O) vincristine, procarbazine, prednisolone, 21 day cycle, chemo day 1, 8
(Not for >65yo -high mortality)
○ More etop and procarbazine which are carcinogenic
○ Less bleomycin and adriamycin then ABVD
Similar response rates with all chemo, however BEACOPP slightly better cure rates; at cost of significant toxicity including development of secondary acute myeloid leukemia/MDS and sterility
-A Deauville 5 score post initial chemo would warrant a biopsy to inform subsequent therapy. If a biopsy is not feasible, treatment should be escalated (NCCN).
NOTE:
- Chemotherapy alone protocols result in inferior PFS (H10-F and H10-U trials)
○ Radiotherapy should in general not be omitted
○ Exception is –> unfavourable risk disease, with 2x2 chemotherapy, with CMR on PET4 (HD17)
Describe the management of Advanced stage (Stage III + IV) Hodgkin’s Lymphoma.
Consider including stage IIX (bulky disease) in the advanced stage treatment protocols
- Excluded from many early-stage trials
Chemotherapy
- x2 ABVD -> restage with PET ○ If CMR -> x4 AVD (RATHL) ○ If D4+ -> x3 BEACOPPesc -> Restage with PET § CMR -> x1 BEACOPPesc +/- ISRT § D4+ -> biopsy -> treat as refractory if positive - x6 Bv-AVD (from ECHELON-1) -> restage with PET ○ D4+ -> biopsy -> treat as refractory if positive - esc-BEACOPP in patients <60, those with neuropathy. ○ 4 cycles then repeat PET - Brentuximab only on PBS for relapsed/refractory disease
Radiotherapy
GHD0607 and HD0801 showed no statistically significant benefit of RT for bulky disease ○ If PET2(-), PET6(-) - After completion of chemotherapy, perform a PET6 ○ If CMR, deliver 30Gy ISRT ○ If D4+, consider Bx § If positive additional therapy as per relapsed/refractory disease § Alternatively: deliver 36Gy ISRT
Describe the management of Nodular lymphocyte predominant Hodgkin’s lymphoma.
All treatment decisions need to be made in the context of natural history:
- Indolent progression
- Excellent prognosis (even with advanced disease)
- Typically asymptomatic at most stages
What would be your approach to managing relapse/ refractory Hodgkin’s Lymphoma?
- Goal is to achieve cure while limiting toxicity and complications from Tx.
- Generally salvage/targeted chemo - > PET-> If CR then ASCT if eligible.
○ Can use sequential chemo, RT for any PET positive site before ASCT, targeted chemo, or immuno to help achieve CR before ASCT
○ Cure 50% with ASCT
○ ASCT long term toxicity: AML, MDS, infertility
If ineligible for ASCT, then consider single agent/comb chemo, targeted chemo, immuno, and/or RT - Decision for RT must balance between LC vs longterm toxicity
○ Factors to consider:
§ RT for CR prior to HCT or consolidation in pts with CR who had bulky disease at relapse
□ Consolidation RT can be given prior to ASCT in p who had PR
□ Consolidation RT can be given after ASCT in pt who had bulky disease at relapse
○ Although no RCT data, several studies showed RT can control limited residual disease and contribute to improved prognosis
○ late first relapse- salvage chemo followed by RT without ASCT is an option for pt with late relapse ( several years)-> long term OS 50-80%.
○ Palliation RT with/without chemo for symptom relief - Chemo 6-8x then PET/CT
○ Localized area of metabolically active dx→ RT
○ Widespread metabolically active dx→ stem cell tx (if older + not suitable for tx- then give RT) - Prognosis depends on
○ Relapse free interval (most relapse will present within 2-3yrs)
○ Initial therapy (CT or not)
○ response to salvage chemo- If CR on PET-> 93% 2yrs PFS - Note:
○ For patients who relapse or become refractory, secondary therapies are often successful in providing another remission and may even cure the disease.
○ Multiple treatment options available but depend on several factors:
§ timing of the relapse (better if >12mo),
§ ECOG,
§ anaemia,
§ scope of disease,
§ suitability for further chemo/RT,
§ response to salvage chemo
○ Salvage RT dose up to 40Gy, yield higher RR and LC. Higher dose = more durable response if tolerated.
○ RT also play cytoreduction and consolidation in peritransplantation period in some programs to decrease rate of ASCT failures. 30-36Gy is recommended within 6 weeks post stem cell infusion.
- Generally salvage/targeted chemo - > PET-> If CR then ASCT if eligible.
Describe manage of Hodgkin’s Lymphoma in pregnancy
Management
- First trimester
○ Greatest fetal risk in this trimester due to implantation/embryogenesis and major manifestation of drug toxicity are spontaneous abortion or major morphological abnormalities.
○ Defer until second/third trimester if possible
§ Asymptomatic, non-bulky, sub-diaphragmatic
§ Need treatment if progressive disease/symptomatics/threatened well being (e.g. spinal cord compression, SVCO)
○ If need to treat:
§ ABVD*
§ Can give vinblastine alone then ABVD
- Second / third trimester
○ Defer to third trimester / post partum if possible- this allow adequate staging and selection of appropriate therapy
§ Don’t defer if: Bulky, stage III-IV, symptomatic
○ If treating:
§ ABVD
§ RT - only if must be given for local control of troubling symptoms above the diaphragm
□ Shield abdomen
□ Whole fetus dose <0.1Gy
- Post-partum
○ Treat as per normal
- Adverse fetal effects
○ Intrauterine growth restriction
○ Decreased IQ
○ Malformations
○ Low birth weight
○ Premature
○ Stillborn
○ Gonadal//ovarian damage
○ Carcinogenesis
- Indications for termination
○ Relapse -> needs autologous stem cell transplant
○ Prognosis - unable to care for baby
Need to discuss: Effects of treatment on future fertility
What is the evidence for non-risk adaptive management of favourable risk, early stage Hodgkin’s Lymphoma?
Note: Be aware “H” trials are for EORTC risk classifications, while “HD” trials are for GHSG risk classifications.
HD7 trial (Engert, 2007)
- 650 patients with favourable risk disease randomised to
○ 30Gy IFRT with 10Gy boost
○ 2x ABVD with same RT
- Outcomes
○ No difference in OS
○ RT alone resulted in inferior FFTF (67% vs 88%)
○ No difference in second malignancy risk
HD10 trial (Engert, 2010)
- Pre-PET era (1998-2003)
- 1370 patients with favourable risk disease randomised in 2x2 fashion to
○ 4 cycles vs 2 cycles of ABVD
○ 30Gy vs 20Gy IFRT
- Outcomes
○ No difference in OS or FFTF for any comparison
§ I.e. 4x ABVD + 30Gy was not superior to 2x ABVD + 20Gy
4x ABVD and 30Gy both independently increased toxicity
What is the evidence for management of unfavourable risk, early stage Hodgkin’s Lymphoma?
HD11 trial (Eich, 2010) = current standard of care
(4x ABVD+30Gy)
- 1570 patients with unfavourable risk disease randomised in 2x2 fashion to
○ 4 cycles BEACOPP vs 4 cycles of ABVD
○ 30Gy vs 20Gy IFRT
- Outcomes
○ The only inferior arm was 4x ABVD + 20Gy IFRT
§ Inferior to 4x ABVD + 30Gy
○ 20Gy is acceptable if combined with 4x BEACOPP
HD14 (von Tresckow, 2012)
- 1655 patients with unfavourable risk disease randomised to
○ 4x ABVD + 30Gy IFRT
○ 2x ABVD + 2x BEACOPP + 30Gy IFRT
- Outcomes
○ BEACOPP improves 5 year FFTF rates (87.7% vs 94.8%)
○ No difference in OS
○ Marked increase in G3+ toxicity with BEACOPP (87.1% vs 50.7%)
H10-U trial (Andre, 2017)
- 1137 patients with favourable risk disease received 2x ABVD and then a PET, before being randomised to
○ Non-adaptive (1x ABVD + 30Gy INRT)
○ Adaptive approach
§ If CMR (D1-2), then 2x ABVD
§ If PR, 2x BEACOPPesc + INRT
- Outcomes
○ Following negative PET2, omission of RT could not be deemed non-inferior (5 year PFS –> HR 1.45)
○ Following positive PET2, BEACOPPesc improved 5 year PFS compared with standard non-adaptive arm (HR 0.42)
○ 10year update (2024): PFS no stat difference (2-4%)
HD17 (Borchmann, 2021)
- 1100 patients with unfavourable risk disease were given 2x ABVD + 2x BEACOPP, before a repeat PET
○ Non-adaptive (30Gy IFRT)
○ Adaptive
§ If CMR (D1-2), nil firther
§ If PR, 30Gy IFRT
- Outcomes
○ Following negative PET4, omission of RT was deemed non-inferior (5 year PFS difference of 2.2%)
○ Non-inferiority was sustained in bulky disease subgroup
What is the evidence for PET risk adaptive management of favourable risk, early stage Hodgkin’s Lymphoma?
Randomised PET Directed Therapy Trials for Early Stage Favourable HL (UK rapid, H10, HD16)
-PET does not mean omission of RT (ISRT cannot be omitted from SOC if interim PET D 1-2) without change in PFS and OS, ommission of RT as part of shared care with patient factors
-Allows de-escalation of chemo or escalation of chemo
H10 trial (Andre, 2017)
- 1137 patients with favourable/ unfavourable risk disease received 2x ABVD and then a PET, before being randomised to
○ Non-adaptive (1x ABVD (x2 ABVD for unfav) + 30Gy INRT) = ABVDx3 + INRT 30Gy
○ Adaptive approach
§ If CMR (D1-2), then 2x ABVD (fav) or 4x ABVD (Unfav)
§ If PR, 2x BEACOPPesc + INRT
- Outcomes
○ Following negative PET2, omission of RT could not be deemed non-inferior (5 year PFS –> HR 15.8)
○ Update 10 year (2024) PFS difference:
§ ABVD + RT = 99%, ABVDx4 = 85% p0.001
§ Both arms 4% secondary malignancy
○ Following positive PET2, BEACOPPesc improved 5 year PFS compared with standard non-adaptive arm (HR 0.42)
HD16 trial (Fuchs, 2019)
- 1150 patients with favourable risk disease received 2x ABVD and then a PET, before being randomised to
○ Non-adaptive (20Gy IFRT)
○ Adaptive approach
§ If CMR (D1-2), nil further
§ If PR, proceed to INRT
- Outcomes
○ Following negative PET2, omission of RT could not be deemed non-inferior (5 year PFS –> HR 1.78)
○ 2024 update: Per protocol 5year PFS better with RT 93% vs 86% p 0.04 =7%
○ No detriment to survival
UK RAPID
- Looked to demonstrate non-inferiority of x3 cycles of ABVD and if PET negative observation
○ Was not able to show non-inferiority, but the prognosis of HL with or without RT is still very good *
- 602 pts RCT ABVDx3 and PET negative observation vs 30Gy IFRT
- RT gives 3-6% PFS advantage*
CALGB 50604 –not randomised. ABVDx2 PET neg ABVD x2 = ABVDx4. PFS = 91% = acceptable
Acceptable to quote in patients you wish to avoid RT in
Describe the evidence for management of advanced stage Hodgkin’s Lymphoma.
EORTC trial (Aleman, 2007)
- 739 patients with advanced disease were given 6x MOPP chemotherapy and stratified and randomised to
○ If CR, randomised to
§ Observation
§ IFRT
○ If PR, given 30Gy IFRT
- Outcomes
○ 8 year PFS and OS for PR patients was 76% and 84% respectively
§ Not significantly different to either CR arm
§ Suggestive of good benefit to RT for PR
○ No benefit to additional RT in the CR arm
○ Note that PR patients had bulky disease more often than CR disease
Retrospective review (Phan, 2011)
- 118 patients with stage III disease were reviewed
- Outcomes
○ Presence of bulky disease was associated with worse DFS
○ Mediastinal RT was associated with improved DFS and OS
- Extrapolate that RT for patients with bulky disease improves outcomes
RATHL trial
- IIA unfavourable or advanced disease (III, IV), Interim PET neg
- ABVD x2
○ If PET positive (centre choice)
§ Esc BEACOPP x3
§ BEACOPP-14 x4
○ If PET negative (randomised)
§ ABVD or AVD x4
- No difference if OS or PFS in PET negative group. 7 years PFS 80%
- No difference between esc-BEACOPP or BEACOPP in PET positive group
- ABVD x2 followed by 4 cyles AVD accepatble
GHSG Escalated BEACOPP for advanced stage
- Randomised baseline BEACOPP (bleomycin, etoposide, adriamycin, cylophosphamide, vincristine, procarbazine and prednisone) + escalated BEACOPP
- Improvement in FFTF and OS in esc BEACOPP
- There have been other RCT comparing escBEACOPP with ABVD, all have favoured escBEACOPP PFS
ECHELON 1- Brentuximab (Swap bleomycin for brentuximab) 2018
- Phase 3, Stage III-IV Hodgkin lymphoma
- Brentuximab vedotin, doxorubicin, vinblastin and dacarbazine (A+AVD) vs ABVD
- Radiation was allowed for PRs PET+ and >2.5cm
- 6yr OS 94% vs 89%
- Improved OS with A+AVD
Describe your Involved site radiotherapy technique for Hodgkin’s Lymphoma
Involved Site Radiotherapy
Patients
1) Favourable Risk - Stage I-II (20Gy)
2) Unfavourable Risk - Stage I-II (30Gy)
3) Advanced Disease with Initial Bulk (30Gy)
Pre-simulation
MDT discussion
Fertility consideration
- bHCG in all females
- Fertility preservation
Smoking cessation
Aim commencement 4-6 weeks post-chemo
Simulation
Supine with arms above head -decide if up or down or abducted
Bra off
Vacbag
DIBH if superior mediastinum Generous CT (2mm with contrast)
Fusion
Pre-chemotherapy PET
Dose prescription Favourable risk
- PET neg 20Gy/10F
Unfavourable risk
- 30Gy/15F -(don’t need any higher)
Advanced disease (with bulk)
- 30Gy/15F
- Boost to 36Gy/18F if residual disease
Children 19.8-25.5Gy see ILROG guideline
VMAT technique or butterfly IMRT (women)
10 days per fortnight
Volumes
GTV (residual)
- Residual disease on PET
CTV
- Use pre-chemo volume to establish superior/inferior margins (note PET free breathing)
○ Consider extra 1cm sup/inf if significant imaging uncertainty
- Use current CT to delineate radial margins (tumour shrinkage)
○ Infiltrated chest wall/muscle
CTVboost
- GTV + 1cm
ITV
- Consider if mediastinal disease
PTV
- CTV + 7mm
Target Verification
Daily CBCT
OARs
Bilateral lung
- V20 < 30%
- V5 < 50%
Heart
- Mean < 5Gy (critical 15Gy) (similar to 1 cycle ABVD)
Breast
- Mean < 4Gy (critical 15Gy)
Spinal Cord
- Dmax < prescribed dose
Thyroid V30<60%
Describe the difference between EFRT, IFRT, ISRT, INRT; in Lymphoma Treatment
- movement to decrease field of RT to ↓acute and long term tox, whilst maintaining survival rates
- EFRT: extended field, includes clinically involved and adjacent clinically uninvolved sites (eg. mantle, inverted Y)
- IFRT: limited to involved regions eg. mediastinal + low bilateral SCF (entire mediastinum)
- Large fields, now reserved for salavge patients of patients who fail chemotherapy and are not suitable for further lines of more intense chemo
- Defined as the anatomical boundaries of a whole lymphatic region
- ISRT: only pre- and post-chemo nodal volumes + limited margin of healthy tissue to accommodate uncertainties in determining pre-chemo tumour volume
○ originally involved SITE,
○ ISRT preferred by ILROG
○ volume accounts for tumour shrinkage,αnatomy changes post chemo, spares adjacent uninvolved organs - ‘Generous’ ISRT for early/indolent stage lymphomas as no chemo
- For extra-nodal disease: CTV generally consists of the entire organ (Stomach, thyroid). Partial organ ISRT is well defined CTV volume e.g. orbit, breast. Uninvolved LN not targeted○ consider an ITV
○ PTV expansion appropriate for site/immobilisation/image guidance - INRT: includes pre-and post chemo nodal volumes + ver limited margin of healthy tissue (5-10mm)
○ requires optimal pre-chemo PET/CT acquired with pt in treatment position, fused with post chemo imaging
considered form of ISRT with more strict requirements for pre chemo imaging
What is the prognosis of Hodgkin’s Lymphoma based on risk group/ stage?
How would you follow up a patient with Hodgkin’s Lymphoma?
Follow-Up
* Clinical review every three months for the first two years (shared care) ○ Clinical examination ○ FBC, ESR at each visit * Clinical review every six months for years 3-5 ○ Clinical examination ○ FBC, ESR at each visit * Annual surveillance thereafter for late effects ○ Long-term follow-up required especially for NLPHL * Single FDG-PET at 12 weeks post RT * Consider routine CT every 6-12 months for the first two years ○ Minimise, particularly in the young * Consider annual TFTs if neck irradiated ○ Up to 60% hypothyroid. 1/3000 risk of cancer * Consider TTE and carotid US ○ Stress echo at 10 years ○ Coronary artery exposure * Consider early breast screening ○ 10 years after RT ○ Age 40 years
Survivorship
cardiac, -IHD, heart failure, valve dysfunction
secondary cancer (9% @ 30 years)
Breast cancer -high dose 30Gy = 25% cancer
No risk if age >35
48.5% @ 40 years (20% general population
More chronic health conditions (40%)
Fatigue -exercise phyiologist
Discuss the expected toxicity after lymphoma treatment.
Toxicity
- In 1st 10yrs after treatment- most likely to die from HD; after that more likely to die from Rx related toxicity (in particular cancer + cardiac dx).
- Second malignancy
○ ~15% at 15yrs (higher than other cancer treated in young pts- ? genomic instability in pts with HD). Relative risk related to age at treatment. Survival after diagnosis of cancer is poor.
§ ALL. 3% risk at 15yrs. Most pts die within a year of diagnosis.
§ NHL. 1.5% risk at 15yrs (latency ~7yrs)
§ Solid tumours (75% of all 2nd malignancies), 12% risk at 15 yrs. Main solid tumours: lung, breast due to XRT. Other sites: thyroid, GI, bone + soft tissue, melanoma.
- Cardiac dx
○ IF MHD <4-4.5Gy, then risk is insignificant. However each increase in MHD >5Gy, yields the same excess risk of cardiac event as an increase in Anthracycline dose of 50mg/m2 (eg. 1x cycle of ABVD or CHOP)
Latent toxicities of Cardiac dx: arrhythmias, MI, pericarditis, myocarditis, pericardial effusion, pericardial fibrosis, cardiac death.
○ Stanford data (1998) 3.9% survivors died from cardiac dx at 10yrs. RR death 3.1, but only in pts getting > 30Gy to mediastinum.
○ Related to XRT field size, risk lingers even 30+ yrs after Rx.
- Thyroid failure
○ Due to XRT lower neck
○ ~50% pts
- Infertility
○ Esp. procarbazine, alkylating agents
What is the epidemiology and risk factors for DLBCL?
Incidence
- Around 2000 people diagnosed annually
- Most common form of non-Hodgkin lymphoma (30% of all lymphomas)
Median age is 60 years
Slight male predominance (1.5:1)
Clinically aggressive, rapid but curable
Often arises in LNs but can be present anywhere
70% of cases are nodal
30% are extranodal
- GIT most common extranodal
- Testes, eyes, Mediastinum, CNS
Aetiology
1) Previous low-grade lymphoma a. Transformation (e.g. follicular, CLL) 2) Immunosuppression a. Iatrogenic (organ transplant) b. HIV-associated 3) Environmental exposures a. Hair dyes b. Pesticides
Limited familial link
Describe the pathogenesis for DLBCL
Pathogenesis
* Cell of Origin 'GCB vs ABC' ○ DLBCL can arise from two B-cell ancestor cells § Germinal-centre type (CD10, BCL6) --> favourable § Activated B-cell type (MUM1) ~50% § "Type 3" * BCL-6 ○ One of the key mutations that occurs is the overexpression of BCL6 gene (near 100% of cases) § Usually functions as an anti-apoptotic gene § Over-expression leads to down-regulation of pro-apoptotic genes such as p53 ○ Multiple rearrangements exist to manifest this change § t(3:14) --> BCL6 and IGH is present in 30% * BCL2: ○ Inhibit apoptosis: primary function of the BCL2 gene is to inhibit apoptosis, the programmed cell death mechanism in cells. By doing so, it helps regulate cell survival and maintain a balance between cell death and cell growth. Cell Survival: Proteins encoded by the BCL2 gene are integral to the survival of cells, as they prevent the activation of caspases, which are enzymes that play a key role in initiating apoptosis. * TP53 ○ Separate to the BCL6-mediated down-regulation, p53 mutations are common in DLBCL § Loss of function mutations § Deletions ○ Again, this impairs apoptosis and cell-cycle arrest machinery
Double-hit and triple-hit
* MYC rearrangements occur in 10% of patients ○ Associated with a very poor prognosis ○ Rearrangements often involve the IGH (chomosome 14) or BCL6 (chromosome 3) genes * When combined with BCL2 or BCL6 rearrangements, prognosis is particularly poor * Terminology: ○ Double-expressor = based on IHC (protein over-expression) ○ Double-hit = based on ISH/genotyping (genetic rearrangement) * Both forms are associated with poor prognosis
Low grade lymphomas can develop into high grade through transformation
Triggered by accumulation of additional transforming mutations
Describe the pathology of primary B-Cell Mediastinal Lymphoma.
Aggressive rapidly progressive, anterior mediastinal mass causing obstruction.
Arises from thymic B cell mass in 20-40yo, female
Micro: mimics DLBCL or hodgekins –sheets of large lymphocytes, clear cytoplasm dense collagen deposition (compartmental fibrosis)
IHC
Pos: CD19 , 20, 79a, CD45, BCL6 (same as DLBCL)
CD30 (same as hodgekins)
Negative:
Immunoglobulin (DLBCL), CD15 (Hodgekins), CD 3,4,5,8, EBV
Describe the pathology of DLBCL
Macroscopic
- Large matted lymphadenopathy
- Effacement of normal nodal architecture
Microscopic
- Diffuse growth pattern with effacement of normal nodal architecture
- Sheets or large cells: transformed mature proliferating B cells
○ Nuclei enlarged 5x normal lymphocytes
○ Resemble centroblasts (pale abundant cytoplasm with non-cleaved nuclei)
○ Large, irregular and multi-lobulated nuclei
- Mod- High proliferation index (Ki67 often > 70%)
Immunohistochemistry
- POS = CD19, CD20, CD79a (indicating B cell lymphoma, Non hodgkin type), surface Ig (often IgM) (stain positive for B cell markerts), CD45
○ GCB-type = CD10 (=GCB type), BCL6
○ ABC-type = MUM1 (50%)
○ Poor prognostic = FISH-MYC, BCL2 t(14:18)
CD5
§ p53
- NEG = CD3, CK
Molecular
- 30% have t(3:14) –> BCL6 and IGH
- 30% have t(14:18) –> BCL2 and IGH (as in follicular lymphoma)
Describe the prognostic factors for DLBCL
Patient Factors
- Age
- Performance status
- Constitutional symptoms (B symptoms)
- Serum markers
○ LDH above ULN
Tumour Factors
- Histological grade (i.e. aggressive lymphoma)
- Lugano Stage
○ Number of nodal sites
○ Number of extranodal sites (>1)
- Histological subtype
○ GCB vs ABC (ABC worse)
- Gene expression
○ Double/triple hit
- p53
- “Bulk of disease” (usually defined as > 7-10cm)
Treatment Factors
- Response to first-line therapy (PET evaluation)
Describe the presentation and history/examination for a patient with DLBCL.
Presentation
Clinically aggressive
Often arises in LNs but can be present anywhere
70% of cases are nodal
30% are extranodal
- GIT most common extranodal
- Testes, eyes, Mediastinum, CNS, thyroid, bone, kidney, liver, breast and skin
20% stage I disease
40% disease limited to one side of diaphrgam (stage II)
20% above and below
40% widespread with extranodal (Lung, liver, kidney, BM; in contrast of PRIMARY extranodal)
30% of pt reprot B symptoms
Consultation
- History ○ HPI § Palpable lymphadenopathy (non-tender) □ Duration and tempo of disease (typically rapidly growing) § Emergency presentation is common □ SVCO □ Spinal Cord Compression □ Tumour lysis syndrome □ Airway obstruction □ Renal obstruction § Constitutional symptoms □ Fever □ Night sweats (drenching) □ Weight loss (10% within 6mo) § Cutaneous itch ○ PMHx: § Previous radiotherapy or chemotherapy § Previous low-grade lymphoma § Immunosuppression (including HIV) ○ Medications § Immunosuppression ○ Social: § Smoking ○ Family History § Lymphomas - Examination ○ General inspection ○ Lymphatic examination § Cervical § Axillary § Epitrochlear § Inguinal § Popliteal ○ Abdominal palpation § Hepatomegaly § Splenomegaly
Describe the investigations you would organise for a patient with DLBCL
Work-Up
- Bloods ○ FBC ○ EUC, CMP and LFT ○ LDH ○ HepB/HepC/HIV serology (pre-chemotherapy) - Histopathology ○ Excisional biopsy preferred § Large amounts of tissue may be required ○ Core biopsy is a reasonable alternative § FNAB is insufficient
Staging
- FDG-PET (staging) - Consider lumbar puncture if at high-risk of CNS involvement ○ Subtypes (double-hit DLBCL, Burkitt's, ATCL) ○ HIV-associated ○ Location (epidural/eye, bone marrow, kidney/adrenal, testicular, paranasal sinus) - Routine bone marrow biopsy is NOT required (only to confirm limited stage) ○ FDG-PET has sufficient sensitivity ○ Additionally, BM can be omitted for stage III DLBCL because does not change management - Lumbar puncture/MRI if high risk disease - Opthalmic assessment if CNS - Testicular Ex + US - GI endoscopy and biopsy if seen on PET
Pre-treatment
- Cardiac TTE ○ LVEF prior to anthracycline chemotherapy - Lung function tests ○ Prior to bleomycin ○ Prior to radiotherapy
What would be your considerations prior to treatment of a patient with DLBCL
General Approach
Most patients should be treated with curative intent
- Even stage IV disease is curable
Considerations prior to treatment
- Performance status and fitness
- Organ function
○ TTE (anthracyclines)
○ PFTs (RT +/- bleomycin)
- Risk of CSF involvement
○ May need LP
○ Consider CNS prophylaxis (HD-MTX or IT-MTX)
- Consider fertility
Describe the management of early stage, non-bulky, IPI low DLBCL
In general:
Favour chemotherapy alone if non-bulky
Describe the management of early stage, non-bulky, IPI high DLBCL
Describe the management of early stage, bulky DLBCL
Key Points
- If initially bulky disease ○ Should have combined modality therapy (RT improves OS and PFS) ○ Give 36Gy ISRT - Should perform a post-chemotherapy FDG-PET before proceeding - If FDG-avid residual disease after chemotherapy Give 40Gy ISRT
Describe the toxicity of CHOP chemotherapy in DLBCL
CHOP: cyclophosphamide, doxorubicin, vincristine, prednisolone, 6 doses every 21 days
Toxicity:
* Cyclophosphamide: alopecia, myelosuppression, N&V, infertility, 2nd leukaemia
* Doxorubicin: cardiac, lifetime dose, myelosupp, 2nd leuk
* Vincristine: PN, not much myelosupp
* Pred: high dose for 5 days, cytotoxic to WBC
Note: Pt who are exposed to HBV are at risk of reactivation during treatment with RCHOP-> NEED antiviral prophylaxis or periodic HBV DNA monitoring and antiviral treatment in the case of reactivation
Describe the management of Advanced stage DLBCL
- Induction chemotherapy with 6x R-CHOP
○ No rationale for maintenance rituximab- Use PETCT to assess response to chemo and guide need for RT
- Consideration should be given to consolidation radiotherapy -> to improve PFS, OS and LC benefit
○ Indications for consolidation RT
§ Initially bulky disease >7.5cm
§ Skeletal metastases
§ Extranodal sites of disease
§ Metabolic partial response
○ Technique
§ 36Gy ISRT if complete metabolic response
* consider dose reducing to 30Gy/15F if large volume with CMR
40Gy ISRT if residual avidity
Describe CNS Prophylaxis in management of NHL
- CNS relapse of NHL is usually fatal despite Tx.
- CNS IPI used by haematologist as score to stratify risk
Prophylaxis desirable in high risk cases for CNS relapse - Use in
○ CSF positive
○ Adrenal, renal and Testicular, (NB prophylactic treatment also of contralat testicle)
○ Paranasal sinus
○ BM involvement - Retro analysis:>1 extranodal site and ↑LDH independent predictors of CNS relapse.
Usually given as intrathecal methotrexate (+/- cytarabine) or IV high dose MTX.
- CNS IPI used by haematologist as score to stratify risk
Discuss management of Relapsed DLBCL
Relapse
* More than 30% of DLBCL relapse, 1/100000 annually
* Refractory/Relapse disease 3yr PFS 37% and 3yr OS 49%
* Important prognostic factors: initial prognostic factors, nature of previous treatment and time interval
* Dx- core biopsy should be repeated before proceeding with 2nd line therapy
* Re-staging
* Treatment:
○ IF good PS, salvage Rituximab and chemo followed by HDC and ASCT (only 50% of pts proceed to ASCT)
* R-DHAP, R-ICE, R-GDP (less toxic), BEAM
* R-GEMOX if cannot tolerated high dose therapy. Pixantrone is a new anthracycline with less cardiac toxicity
○ IFRT or iceberg RT may be used in limited stage disease
○ No role for maintenance rituximab
○ Allogeneic transplant (may be considered in pt with refractory disease, early relapse or relapse after ASCT)
* Site of further relapse after ASCT is usually the original site of relapse or refractory disease. PARMA trial-> consolidation RT can reduce this despite CR to salvage chemotherapy
* Indication for RT in relapse/refractory disease–> reduce LRR and improve RFS
○ Localised relapse/refractory disease that can be encompassed by RT with acceptable toxicity
○ IF disseminated disease, RT to selected area
* Locoregional site with Incomplete response to salvage chemo
* Dominant skeletal relapse
* Site where LC is critical eg. threatened spinal cord, nerve root compression, SVCO, aerodigestive or urological tract obstruction
* Peri-transplant RT for potential cytoreduction residual active disease
Describe the management of Testicular DLBCL and Primary mediastinal DLBCL
Testicular
- Orchidectomy
- 6x R-CHOP chemotherapy
- CNS prophylaxis (IT or HD-MTX)
- 30Gy/15F to contralateral testis
○ 15% risk of relapse
Primary Mediastinal DLBCL –generally bulky at dx
- Limited stage (encompassable with RT field)
○ 6x RCHOP + 36Gy ISRT (same as DLBCL)
* If giving R-CHOP need RT, if not need more aggressive chemo DA-REPOCH
○ 6-8x R-EPOCH alone (if PET complete response no RT)
§ If PET positive –biopsy –consider salvage
§ RT not effective if large residual
- Advanced stage (unencompassable)
○ 6-8x R-CHOP (+ 36Gy ISRT if disease limited to chest)
○ 6-8x R-EPOCH alone
Describe the evidence for management of Non-bulky DLBCL
Summary:
- RT is associated with improvement in OS when there is initial bulk
- This benefit is uncertain in non-bulky disease
○ Chemotherapy alone could be considered
SEER analysis (Ballonoff, 2008) ○ 13420 patients with early-stage DLBCL were analysed § 41% had received RT ○ Outcomes § Use of RT was associated with a significant CSS and OS benefit □ This persists to 15 years of follow-up □ This persists on multivariate analysis LYSA 02-03 randomised trial (Lamy, 2018) Radiation deescalation is ok for nonbulky ○ 334 patients with stage I-II DLBCL without bulk and IPI=0, completed R-CHOP-14 chemo and proceeded to PET § If CMR achieved, randomised to 40Gy RT consolidation vs observation ○ Outcomes § Addition of RT did not improve EFS or OS at 5 years ○ RICOVER-60 (Pfreundschuh, 2008) § 1222 elderly (>60yo) patients with DLBCL (any stage or IPI) were enrolled on RICOVER-60 and randomised to □ 6 vs 8 cycles of CHOP □ With or without 8x rituximab □ 36Gy ISRT allowed if bulky disease § Outcomes □ 8 cycles of chemotherapy was not superior to 6 cycles for OS or PFS □ Addition of rituximab to 6x CHOP improved OS (HR 0.63) and PFS (HR 0.50) □ No major differences between 6x R-CHOP vs 8x R-CHOP § Thus, 6x R-CHOP is the preferred approach
Choice of Chemotherapy
FLYER trial (Poeschel, 2019) ○ 592 patients with stage I-II non-bulky DLBCL (favourable IPI score) were randomised to § 4 vs 6 cycles of R-CHOP § Non-inferiority design ○ Outcomes § 4 cycles was non-inferior to 6 cycles □ 3 year PFS 96% (4x) vs 94% (6x) No difference in 3-year OS (99% vs 98%)
Describe the evidence for management of Bulky DLBCL
○ RICOVER-noRTh (Held, 2014) Radiation de-escalation is not ok for bulky
§ Patients on the preferred arm (6x R-CHOP with 36Gy RT for bulky disease) were compared with a prospective cohort where RT was not allowed
□ Neither arm had RT for nonbulky disease (RT only if bulky disease)
§ Outcomes
□ On multivariate analysis, RT for bulky disease was associated with improved 3yr PFS and OS
○ 3yr OS 65 -> 90% (HR 4.3; p=0.002)
○ 3yr PFS 62 -> 88% (HR 4.4; p=0.001)
□ RT abrogates the prognostic impact of disease bulk (should be standard of care)
UNFOLDER (Pfreundschuh, 2018) ○ Patients with stage I-II favourable IPI DLBCL were randomised to § 6x R-CHOP-14 vs 6x R-CHOP-21 § Consolidation RT for bulk vs observation ○ Trial closed early due to significant benefit in the RT arm ○ Outcomes § RT was associated with improved 3-year EFS (84% vs 68%) □ No difference in 3yr OS § No difference in chemotherapy arms (EFS, PFS, OS)
Describe the evidence for RT Dose in NHL
UK-based randomised phase III trial (Lowry, 2011)
○ RT dose recommended for indolent NHL is 24Gy and 30Gy in aggressive NHL.
○ 161 patients with indolent NHL and 640 patients with aggressive NHL
§ Indolent = 24Gy/12F vs 40-45Gy
§ Aggressive = 30Gy/15F vs 40-45Gy
○ Outcomes
§ No difference in ORR in either group
□ Indolent (93% vs 92%)
□ Aggressive (91% vs 91%)
§ No difference in in-field progression
□ Indolent (HR 1.09)
□ Aggressive (HR 0.98)
§ No difference in PFS or OS
Describe the evidence for management of advanced stage DLBCL
MDACC retrospective study (Phan, 2010)
- Of 279 patients with advanced stage DLBCL, 39 had bulky disease
○ 23 of these received RT
- Outcomes
○ RT was associated with improved OS and PFS
RICOVER-60 - any stage
§ Outcomes
□ 8 cycles of chemotherapy was not superior to 6 cycles for OS or PFS
□ Addition of rituximab to 6x CHOP improved OS (HR 0.63) and PFS (HR 0.50)
□ No major differences between 6x R-CHOP vs 8x R-CHOP
RICOVER-noRTh trials - any stage
□ On multivariate analysis, RT for bulky disease was associated with improved PFS and OS
□ RT abrogates the prognostic impact of disease bulk (should be standard of care)
Freeman 2021- Risk-adapted era supporting using PETCT to select people who need Consolidative RT
- 723 pt, Retrospective, PETCT guided approach. 6-8x RCHOP -> Omit RT if PETCT neg vs ISRT if PETCT pos.
- PETCT Neg => No RT 3yr TTP 83%, 3yr OS 87%
- PETCT Pos => RT 3yr TTP 76% 3yr OS 80%
○ Note: Even PETCT Neg Bulky >10cm had similar outcome to those without bulk suggesting that EOT PETCT can reliably guide selective administration of consolidative RT
Describe the evidence for management of relapsed DLBCL
CAR-T cells
ZUMA-1 trial phase II single arm multi centre trial
-Axi-cell autologus anti-CD19 CAR-T cell therapy
-Demonstrated durable response in patients with refraction DLBCL, 5 year follow up 30% of patients achieved durable response
- Polatuzumab vedotin (pola), an anti-CD79b antibody drug conjugate (ADC) linked with monomethyl auristatin E (MMAE), in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP), essentially replacing vincristine in the CHOP backbone - Pola-R-CHP superior to R-CHOP in adult patients with newly diagnosed DLBCL with IPI >2 (PFS) - Toxicity ad no OS benefit - ?Emerging new front-line management instead of R-CHOP for DLBCL, trials emerging
What are the indication for radiotherapy in DLBCL?
Indications for Radiotherapy
* first-line management:
○ chemo minimisation strategy in LS-DLBCL
§ consider R-CHOPx4c →ISRT (SWOG 8736)
§ of value to elderly pt, where longer courses of chemo associated with ↑ risk of myelosuppression, infections, treatment related mortality (& late effects less relevant)
○ consolidation therapy in sites with higher risk of local relapse
§ initial bula ≥ 7.5cm (RICOVER-60-no-RT)
§ non-bulky initial SUV ≥15 (5yr LRFS 100→69%)
§ residual mass. >2cm on CT despite PET EOT neg
§ no RCT data to quantify benefit of consolidation RT (and unlikely, as pt in non-RT arms of UNFOLDER closed early due to higher event rates in pt not assigned to RT
○ conversion of incomplete metabolic responses after initial immunochemotherapy to complete response
§ nuclear how to manage pt who are PET EOT negative
§ no prospective evidence to omit RT in pt with initial bulky and/or extra lymphatic disease
Aggressive NHL dose considerations
* Upfront DLBCL after chemo: 30-40 Gy. Give 30 Gy if DS 1-3. Boost to higher doses if DS4.
* Upfront double-hit DLBCL: Correct dose is unknown, but may lean toward the higher end of the dose spectrum when consolidating.
* Upfront PMBCL:
○ Avoid RT if given DA-R-EPOCH if possible.
○ After R-CHOP x6, given 30-40 Gy depending on PET response.
* Relapsed/refractory DLBCL:
○ Localized disease, Bulky > 5 cm [PARMA], incomplete response to salvage chemo or ASCT, skeletal involvement, critical sites where LC is important.
○ Cytoreduction prior to ASCT: 40-50 Gy or higher if refractory.
○ DS1-3 with salvage chemo and ASCT: 30-36 Gy. Residual avidity: 40-50 Gy.
○ Transplant ineligible, curative intent: 45-55 Gy.
○ Palliative intent with limited life expectancy: hypofractionated schedule of 8-30 Gy.
Discuss the management of breast lymphoma
- Epidemiology: Rare (1% of extranodal lymphomas), Assoc w Breast feeding and pregnancy
- Histology:
- 50% DLBCL
- Follicular lymphoma
- Marginal zone lymphoma
- Biologic behaviour: 10-30% of breast DLBCL have CNS involvement
- Treatment:
- Aggressive
w R-CHOPx6 + RT 30Gy/15#
w Consider CNS prophylaxis - Indolent
w IFRT 24Gy/12# - Mastectomy not recommended
- Aggressive
- RT technique
- CTV = whole breast (uninvolved LNs need not be included)
- Dose: 30Gy/15F
- Technique as per breast carcinoma
- Outcomes
- Good LC with RT
- 5yr OS 50%
- Histology:
Describe your radiotherapy technique for DLBCL
Involved Site Radiotherapy
Patients
1. Stage I-II disease (chemo-de-escalation)
2. Stage I-II disease (bulky)
3. Stage III-IV disease (bulky)
Pre-simulation
MDT discussion
Fertility consideration
- bHCG in all females
- Fertility preservation
Smoking cessation
Simulation
Supine with arms above head
Vacbag
DIBH if superior mediastinum
Generous CT (2mm with contrast)
Fusion
Pre-chemotherapy PET
Dose prescription
Single dose-level
- 30Gy/15F (if chemo de-escalation)
- 36Gy/18F (if bulky)
- 40Gy/20F (if FDG-avid residual disease)
VMAT technique
10 days per fortnight
Volumes
GTVpre
- Gross disease on pre-chemo CT and PET
GTVres
- Gross residual disease on post-chemo PET
CTV
- Use GTV volume to establish superior/inferior margins
○ Consider extra 1-2cm superior/inferior to account for imaging uncertainty
- Use current CT to delineate radial margins
ITV
- Consider if mediastinal disease
PTV
- CTV + 7mm
Target Verification
Daily CBCT
Discuss the work up and management of ocular lymphoma
- Assoc with poor prognosis
- 2 patterns of intra-ocular lymphoma
○ Commonly assoc with CNS involvement:
□ Optic n, retina, vitreous; usually high grade
□ 20% PCNSL have ocular involvement at diagnosis
□ 80% of ocular lymphomas will develop CNS lymphoma (latency ~1y)
□ Present with blurred vision or floaters (identified by slit-lamp examination)
□ Most pts eventually develop bilat dx
□ Dx: lymphoma cells in vitreous sample
○ Lymphoma of the uveal tract:
§ Commonly assoc with visceral involvement; choroids, ciliary body, iris
§ Bilat dx common, although Sx usually affect 1 eye more
§ Usually DLBCL
§ DDx: inflammatory syndrome: uveitis, conjunctivitis, glaucoma - Biologic behaviour
- Brain relapse was universal in older series, however recent data suggest many patients do not relapse in the brain after eye-directed therapy alone and if they do, salvage options remain effective
- Majority present with pathologic or clinical suspicion of bilateral ocular involvement
w Although most series have treated both eyes, if there is no suspicious of disease in the contralateral eye, it is reasonable to treat only the involved eye
- Workup:
- Full ophthalmologic review
- Brain/orbital MRI
- Ocular coherence tomography and US- to assess extent and nature of lesion
- Biopsy- vitrectomy bx or cytology/ flow cytometry of the vitrous fluid or tissue bx
- Lumbar puncture and CSF evaluation for cytology and raised prot levels.
- Optimal Rx approach not well-defined
- Management
- The globe is not well treated by systemic therapy
- Options include
w Definitive RT alone
w Intra-ocular methotrexate
w Rituximab- either sytemically or intravitreally injected
w Steroids to reduce inflammation and oedema
- RT technique
- CTV: Globe of the eye(s), optic nerve(s) to the level of the chiasm
- PTV: 5mm expansion
- Technique:
w If both eyes are involved (or there is suspicion of bilateral involvement) an opposed lateral beam arrangement should include both globes and the optic nerves to the chiasm. The isocentre should be set at the posterior border to reduce divergence in case of need for subsequent WBRT.
w If only one eye is involved, the field is limited to the involved eye using conformal RT or IMRT, or wedge pair - Dose: 36Gy/20F
- Outcome:
- Rx results poor: high local failure, RT provides temporary palliation, MS 6-18m
- For relapse: intra-vitreal MTX
- 2 patterns of intra-ocular lymphoma
Describe the epidemiology, biological behaviour and management of primary testicular lymphoma
- Special considerations: High risk CNS site
- General management: R-CHOP, IT MTX + RT to contralateral testes
- Epidemiology
- I:
w 1-7% of all testicular cancer
w Most common testicular tumour in >60 yo - A: Mostly elderly men >60 years
- S: Men
- I:
- Pathology
- 80-90% of all primary testicular lymphomas are DLBCL, the rest are either plasmacytic, Burkitt’s, mantle cell lymphoma, LG follicular lymphoma or T-cell lymphoma.
- Has altered surface adhesion molecules- hence the propensity to disseminate to extranodal sites
- Majority ABC pattern.
- Common mutation MYD88
- Biologic behaviour
- Majority present with st I/II disease, IPI 0-2, no B sx
- Tendency to disseminate to contralateral testis and CNS (meningeal or parenchymal) → 40-50%
- Poor prognosis (even if stage I) cf. DLBCL at other sites
- Usually unilateral, but 10% can have bilateral involvement
- Aggressive behaviours- spread to multiple extranodal sites: lung, pleura, skin, soft tissue and waldeyer’s ring
- Prognosis
- median PFS 4 years
- 5 yr OS ~50% (all stages)
- Median OS 5 years
- Failures usually within 1-3 years of initial Rx, survival after failure is short
- Extranodal recurrence in ~70% (+/- nodal disease)
- Most common sites of failure
w Contralateral testis (30%)
w CNS (30%)
w Other less common sites: bone, skin, BM, lung, soft tissue, adrenals, liver, GIT + spleen
- Refractory/Relapsed- no std therapy defined.-
> HDCT + ASCT. clinical trials - RT technique:
- Sim: be present during sim to confirm position and setup, Frog-leg, penis lifted and taped to abdominal wall, scrotum supported and immobilised with bolus under and around the scrotum
- Dose: 30Gy/15F
- Target volume
w Ipsilateral (if not removed by surgery) and contralateral testis
Technique: Anterior electron field with energy calculated according to thickness of scrotum/testis. Bolus may be required
Discuss the work up and management of Osteolymphoma
- Epidemiology: Rare; median age 60yrs
- Prognosis: 5y OS 50%, 80% LC.
- Histology: Majority DLBCL (90%)
- Location: Any bone, usually diaphysis (central portion), often multifocal dx.
- Investigations
- Bloods, bx, imaging incl MRI, PET, BMAT
- Large proportion pts have dx elsewhere, therefore Ix for other sites of involvement
- Natural History:
- Majority present with stage IE disease
- ~10% have polyostotic presentation (multiple bone)
w Most common bones involved: femurs, pelvic bones, tibia and fibula - Often recur at multiple sites, exclusively bone (i.e. different disease to systemic lymphoma)
- Good prognostic factors: age <60, Nodes, LDH, ECOG 0, mono-ostotic dx
- RT technique:
- Volume
w CTV: Prechemotherapy GTV (preferably on MRI) with margins to accommodate uncertainties in subclinical tumour extension and quality of imaging and fusion
w PTV = CTV + 0.5-1cm depending on site and immobilisation - Dose:
w After chemo, complete regression of PET activity may not be clear at time of RT
w 30-40Gy depending on certainty that a CR has been achieved with chemotherapy
- Volume
In general what is the management of extra-nodal DLBCL
30-40% of DLBCL present as extranodal DLBCL with no nodal involvement
[ILROG]
Volume:
* Whole organ/ Compartment irradiation is the most widely reported approach for many sites (eg, stomach, thyroid, breast) and is mandatory for sites in which disease is usually multifocal (eg, primary CNS lymphoma).
* Partial organ irradiation is appropriate for unifocal DLBCL involving long bones when disease extent is well defined on baseline PET and MRI
* For DLBCL of lung and skin, RT is confined to the tissue volume involved before systemic therapy.
Dose: 30-36Gy
What is the prognosis for DLBCL?
Components of IPI score
- Age > 60 years
- ECOG 2+
- Lugano Stage III - IV
- 2+ extranodal sites
- Elevated LDH
CNS Internal Prognostic Index
Describe the epidemiology for follicular lymphoma.
Incidence (Australian statistics)
- 1500 cases annually
- Second most common variant of non-Hodgkin Lymphoma (25%)
Slight female predominance (1:1.5)
Median age 60-65 years
Aetiology
No strong aetiological causes known
Family history
- First degree relatives
Describe your follow up for a patient with DLBCL.
Follow-Up
* Clinical review every three months for the first two years (shared care) ○ Clinical examination ○ FBC, LDH at each visit * Clinical review every six months for years 3-5 ○ Clinical examination ○ FBC, LDH at each visit * Annual surveillance thereafter for late effects * Single FDG-PET at 12 weeks post RT * Consider routine CT every 6-12 months for the first two years ○ Minimise, particularly in the young * Consider annual TFTs if neck irradiated * Consider TTE and carotid US * Consider early breast screening ○ 10 years after RT ○ Age 40 years
Describe the pathology for follicular lymphoma.
Macroscopic
- Variable degree of effacement of normal nodal structure
- Retention of follicular/nodular pattern with some disordering
○ Higher-grade disease may have a more diffuse pattern
Microscopic
- Follicular proliferation and expansion within the LN: uniformly appearing, numerous, closely packed follicles
- Two cell types are present = small and large cells proliferate
○ Centrocytes (small cells with scant cytoplasm and cleaved nuclear contours)
▪ (Most cells)
○ Centroblasts (larger cells with more cytoplasm and open nuclear chromatin)
○ Instead of combination of B cells (CD20+) and some T cells (CD3+), follicles are composed of mostly B cell positive for BCL-2
- Two types of pattern
○ Nodular (lower-grade)
Diffuse (higher-grade) –> loss of normal follicular dendritic cell meshwork
Immunohistochemistry
- POS = CD19/CD20/CD79a (B-cell markers), CD10/BCL6 (germinal centre), BCL2
- NEG = CD3/CD4/CD8 (T-cell markers)
Molecular
- t(14:18) –> IGH/BCL2 translocation
BCL6 rearrangement can be seen in grade 3a/3b disease
Describe the pathogenesis of follicular lymphoma
Originates from the follicular cells in the germinal centre of the LN
Varying proportions of centrocytes and centroblasts with at least partial follicular growth pattern.
Pathogenesis
Strongly associated with BCL2 translocations (BCL2 = anti-apoptotic protein)
Characteristic translocation is the t(14:18)
- IGH and BCL2
BCL2 is an anti-apoptotic gene –> upregulation
- Very few apoptotic bodies are seen
List the WHO 5th edition subtypes of follicular lymphoma
NEW WHO 5th edition 2023:
- Classic follicular lymphoma
○ Gr 1,2,3a –grading by counting centroblasts is unreliable and treated the same
- Follicular large B (was grade 3B) -treat like DLBCL
- Predominatnly diffuse FL
- FL with unusual cytological feature (large centrocytes, high KI67)
○ Subavriants; blastoid, large centrocyte
○ Favourable prognosis
○ Diffuse growth, CD23, 10 pos.
- Other
- In situ follicular B-cell neoplasm
Paediatric-type follicular lymphoma
Duodenal-type follicular lymphoma
Primary cutaneous follicle center lymphoma
Discuss the natural history of follicular lymphoma.
Early follicular lymphoma is incurable but has an indolent long waxing and waning natural history with good prognosis, 10Yr PFS 80-90%
In 10-20% of pt, it can spontanenously regress in some patient without needing treatment
- Upfront RT can improve PFS and OS compared to observation.
- It also decreases the risk of malignant transformation
Very radiosensitive and chemosensitive, after RT, LC >90% with <5% infield recurrence. Most of the recurrence are out of field (75%) and 25% are DM+.
In advanced stages, it natural disease is also variable with 50% have DM+ at dx. There is 2-5%/yr risk of transformation to DLBCL. 30% of pt transform into DLBCL. Transformed DLBCL from follicular lymphoma are more aggressive than primary DLBCL.
Upfront treatment is depending on the modified GELF criteria.
Richters transformation: usually DLBCL, but also Burkitt’s
Path feat: Loss of follicular architecture and accumulation of large tumour cells resembling aggressive NHL cells with increasing centroblast and high ki67
What are the prognostic factors for Follicular lymphoma?
Patient Factors
- Age (>60 years)
- Performance status
- Blood results
○ Hb level (<120g/L)
○ Serum LDH level (above ULN)
- Symptomatology
Tumour Factors
- Lugano staging
○ Bone marrow involvement
- Number of nodal regions involved (>4)
- Serum beta-2 microglobulin
- High Ki67
Treatment Factors
- Contraindications/ access to treatment
FLIPI was developed for overall survival and established in the pre-rituximab era. In contrast, FLIPI-2 was designed for progression-free survival, and, in its development cohort, more than one-half of patients had been treated with rituximab-containing regimens.
“BBASH 6”
B2 Microglobulin high
BM involved
Age >60
Size >6cm
Hb <120
Discuss the presentation and history for a patient with follicular lymphoma.
Presentation
- Subacute, or chronic asymptomatic peripheral lymphadenopathy
- Indolent: may persist, or wax and wane over years
- Abdominal, pelvic or retroperitoneal LN can be bulky without symptoms
- Nodal masses not locally invasive and destructive
- LN invovlement not in an orderly manner
- Early haematogenous dissemenation is common
- B symptoms in less than 20% (if present should consider transformation)
FL is mainly a nodal disease, but involvement of the spleen and bone marrow is frequently encountered.
Consultation
- History ○ HPI § Palpable lymphadenopathy (non-tender) □ Duration and tempo of disease □ Commonly waxes and wanes § Splenomegaly or hepatomegaly § Constitutional symptoms □ Fever □ Night sweats (drenching) □ Weight loss (10% within 6mo) ○ PMHx: § Previous radiotherapy or chemotherapy § Immunosuppression (including HIV) ○ Medications § Immunosuppression ○ Social: § Smoking ○ Family History § Lymphomas - Examination ○ General inspection ○ Lymphatic examination § Cervical § Axillary § Epitrochlear § Inguinal § Popliteal ○ Abdominal palpation § Hepatomegaly § Splenomegaly
How would you work up a patient with follicular lymphoma?
Work-Up
- Bloods ○ FBC + ESR (prognostic) ○ EUC, CMP and LFT ○ LDH ○ HepB/HepC/HIV serology (pre-chemotherapy) ○ B2 microglobulin - Histopathology ○ Excisional biopsy referred § Large amounts of tissue may be required ○ Core biopsy is a reasonable alternative § FNAB is insufficient - FDG-PET (staging) - Routine bone marrow biopsy IS required to confirm limited stage (if PET negative) ○ 85% have bone marrow involvement at diagnosis ○ FDG-PET alone has insufficient sensitivity - Only if considering chemotherapy: ○ Cardiac TTE § LVEF prior to anthracycline chemotherapy ○ Lung function tests § Prior to bleomycin § Prior to radiotherapy
Describe the management of Stage I and Stage II Follicular lymphoma.
Stage I
- Therapeutic options include: ○ Curative radiotherapy (Generous ISRT as no chemo planned) ○ Observation alone ▪ Watchful waiting for G1-2, stage I/II FL may be appropriate in some patients, as ~50% of patients will avoid treatment at 15y. However, the rate of transformation to DLBCL can be as much as 20% (decreased to < 5% with RT) * Guidelines do not recommend this approach - Low-dose radiotherapy is associated with high-rates of durable control ○ 24Gy/12F (or 30Gy/15F) § Modified ISRT (or IFRT) § Generous volumes to incorporate some surrounding lymphoid tissue (not getting chemo for microscopic disease) ○ 36Gy/20# for bulky sites >5cm ○ Outcomes § Local control 90%, but up to 40% relapse out of field, (25% in PET era) § 10 year relapse-free survival of 50% § Median OS >15 years
Stage II
- Therapeutic options can be as per Stage I or stages III-IV ○ Observation ○ Definitive Radiotherapy ○ Systemic therapy - Only consider RT if disease can be safely and easily encompassed by one radiotherapy field
In general what factors should be taken into account when managing follicular lymphoma?
Any treatment decisions should consider the overall context
- Age and performance status
- Current burden of disease
- Current symptomatology
- Kinetics of disease
True cure is rarely feasible (even in stage I disease)
- However, long-term durable control is often achieved
All grade 3b patients should be managed as per DLBCL (high-grade)
Discuss the management for Stage III/IV follicular lymphoma.
Stage III and IV
- Cure cannot be achieved, regardless of treatment approach - Upfront therapy does not result in: ○ Improved OS ○ Reduction in risk of transformation to high-grade disease ○ RCT indolent FL § local control 24Gy/12F =90-98% vs 4Gy/2F = 80-96% Also included marginal zone lymphoma 50-70% complete response ○ Therefore, there is no rationale for routine upfront therapy - Most patients should be observed in the first instance ○ 10-20% of cases have spontaneous regression - Indications for upfront chemotherapy(GELF criteria) § L337 BBEAMSS ○ LDH Elevated or beta-2-microglobulin ○ 3 areas >3cm (extensive nodal disease) ○ Bulky >7cm ○ ○ B symptoms ○ Elevated lymphocytes>5 ○ Asctes/effusion ○ Marrow failure or neut <1, platelets<100 ○ Symptoms -compression ○ Splenic symptoms - Active treatment options: ○ Chemotherapy - improve RR and PFS, but no OS benefit § Single agent Rituximab § Rituximab + bendamustine § R-CHOP (high-grade disease) ○ Chemotherapy + Rituximab - improve RR, PFS and OS cf chemo alone ○ Myeloablatic Tx and ASCT - prolong PFS after Chemo, but no OS benefit ○ Radioimmunotherapy (Zevalin Y-90 attached to CD20 antibody)- prolong PFS after chemo, no OS benefit - Rituximab maintenance every 2 months for 2 years is recommended after immunochemotherapy- improve mPFS 10 vs 4yr - Palliative RT: 70-90% (4-24gy) local control @ 5 years
Discuss the management of relapsed follicular lymphoma.
○ If relapse/ progression> strongly recommended to repeat bx to exclude transformation to an aggressive lymphoma (Richters transformation)
○
○ Adverse prognostic factors: B sx, bulky dx, >2 relapses, LDH >400, Hb <120
○ Median OS:
* 0 factor- >6yrs
* 1 factor- 2yrs
* 2+ factors- 8.5months
○ Treatment options
* No adverse factors: watch+ wait, CT, Rituximab
* 1+ factor depends on age
election of salvage treatment is dependent on previous efficacy and duration of response- prefer non cross-resistant regimen eg. Bendamustine after CHOP, or vice versa
* IF low disease burden-> rituximab alone can be considered
* IF short remission after Chemo-> then lenalidomide+ Rituximab
* Radioimmunotherapy could be considered in elderlies who are not fit for chemo
* consider HDCT + ASCT if early relapse; consider allo SCT if late relapse
* IF rituximab duration <6mo-> then give obinutuzumab-bendamustine
○ Proportion + duration of response ↓with each episode of treatment. ○ Radioimmunotherapy (Zevalin/Bexxar) recently showing promise. CR 60-80% in relapsed/refractory dx. ○ Palliative RT- for symptomatic sites * RR 80-90% with low dose 4Gy/2F. * Well tolerated, can give high dose XRT or subsequent CT if needed. * NB: RCT (MRC) shows inferior RR and LC with 4Gy than with 24Gy so if durable response required, give higher dose. ○ Maintenance can prolong PFS and OS in relapsed disease. Rituximab every 3 mo for 2 years.
Describe transformed follicular lymphoma and its management.
- Up to 70% transform to higher grade lymphoma during course of dx.
- Histological transformation of FL occurs approx. 1-2% per year, and is assoc w/ rapid progression of lymphadenopathy, infiltration of extranodal sites, development of systemic symptoms, elevated serum lactate dehydrogenase, hypercalcemia, and often a poor prognosis.
○ In most cases, the pathology is consistent with DLBCL. Less commonly, FL evolves into Burkitt lymphoma, high grade B cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements (“double-hit” lymphoma), or into precursor lymphoid neoplasms (blastic/blastoid transformation). HT includes FL that evolves to grade 3b FL- Clinical feat:
○ Rapid progression of lymphadenopathy
○ Invasion of new unusual extranodal site- esp. CNS, pleura, bone, liver mass.
○ B-Symptoms out of proportion to dx extent:
○ ↑ LDH (esp. sudden. marked), ↑ Ca. fever, night sweat, WT loss
○ Early treatment failure ( 2 years)
○ PET >SUV10
○ Advanced Stage - Path feat: Loss of follicular architecture and accumulation of large tumour cells resembling aggressive NHL cells with increasing centroblast and high ki67
- Poor prognosis post-transformation: mOS 1-2y
○ possibly improved in cohort of patients who had never been exposed to systemic therapy prior to transformation - Treatment: no data from randomised trials to support optimal treatment for these patients as they are often excluded from clinical trials
○ Consider Rituximab monotherapy or combination with antracycline-based chemo eg. R-CHOP
* Retrospective reviews show an improved OS with anthrax-based chemo + Rituximab
○ Little impact of anthracycline based CT; possible role of autologous SCT
○ High grade follicular lymphoma: (G3)
* Stage 1-2:
▪ Manage as per DLBCL
* 3-6x RCHOP + ISRT 30Gy/15# for CR
* Stage 3-4:
▪ Palliation
▪ RT: as per boom-boom 4Gy/2#
- Clinical feat:
- Histological transformation of FL occurs approx. 1-2% per year, and is assoc w/ rapid progression of lymphadenopathy, infiltration of extranodal sites, development of systemic symptoms, elevated serum lactate dehydrogenase, hypercalcemia, and often a poor prognosis.
Discuss paediatric follicular lymphoma and its management
- FL variant originally described in children, but rarely occurs in adults.
- Characterised by typically
○ localised disease
○ absence of BCL2 aberrations
○ lack of t(14;18)
○ grade III histolog, and
○ A high proliferation rate.
It shows a much more indolent disease course and can be managed with local therapy only, despite displaying histologically more aggressive features.
- Characterised by typically
What is the evidence for managing early stage follicular lymphoma.
Summary:
- Radiotherapy is associated with OS benefit in early-stage FL
Addition of chemotherapy does not improve OS in this group
There is a PFS advantage however
TROG 99.03 trial (MacManus, 2018)
○ 150 patients with stage I-II low-grade follicular lymphoma were randomised to
§ 30Gy IFRT alone
§ IFRT + 6x CVP chemotherapy (rituximab added during trial)
○ Outcomes
§ 10 year PFS was superior in the chemo arm (59% vs 41%)
§ No difference in 10 year OS (95% vs 87%; p=0.40)
§ Updated data presented in ESTRO 2023 (MFU 11.3yrs)- systemic therapy esp with Rituximab increased PFS and sig reduced risk of death/transformation to aggressive lymphoma (most benefit in PET staged pt). No OS benefit
NCDB analysis (Vargo, 2015) ○ Retrospective analysis of 35961 patients with stage I-II and grade 1-2 follicular lymphoma § 63% were stage I ○ Outcomes § RT use declined from 37% to 24% between 1999 and 2012 § RT was associated with improved OS (10 year OS 68% vs 54%) □ This association remained independently valid on multivariate analysis
How would your work up and stage a gastric MALT?
Evaluation
* Bloods- FBC, UECs, LDH, serum protein electrophoresis
* Exam:
w Look for other sites of MALT lymphoma ie eyes, ears, nose, throat, LN, spleen, skin
* H.pylori breath test
* CT CAP, Ba studies (gastric)
* Bone marrow bx (10% bm infiltration)
* Endoscopy and bx
w Important: multiple sites including duodenum to exclude other involved areas
* Tumour biopsy should be tested for H pylori
w FISH or PCR testing for t(11;18) to identify tumors unlikely to respond to H Pylori treatment
* Infectious agent presence e.g. H.pylori serology.
* Endoscopic USS stomach (look for depth invasion + LN presence).
Staging: (for gastric lymphoma)
* NOT as per Ann Arbor (does not incorporate depth of tumour invasion which is known to affect prognosis)
* Lack of no unifying staging system makes interpreting trials difficult
* Most widely accepted: Lugano staging system
Describe the management of H Pylori Positive Stage I-II gastric MALT.
Stage 1-2:
H Pylori positive:
* HP eradication therapy with triple tx (PPI + clarithromycin + amoxicillin or metronidazole for those allergic to penicillin)
w No randomized clinical trials comparing diff treatment options in this population
w Prospective single-arm studies and retrospective reviews look at H Pylori tx vs RT vs surgery - H pylori treatment is preferred treatment given low side effects and treatment efficacy (up-to-date) [ 50-80% CR, median time to clear 15mo, 7yr LF 22%]
* Needs 3 monthly endoscopy + biopsy post treatment to ensure disease response, recurrence or development of adenocarcinoma, then 6 monthly for two years, annual
w Treatment failures: localized RT with curative intent
w Resection: usually not indicated unless perforation, bleeding or obstruction
* RT indicated if:
w t(11;18)
w Penetration deeper than submucosa or LN+ (stage II)
w High-grade dx
w Progression/persistence despite H. pylori therapy
w H.pylori negative (can still trial triple therapy, but unlikely to respond)
* XRT- CR near 100%, high cure rate, low toxicity. Dose 24Gy/12F (Lowry study)
* CT is another option in abx resistant lymphoma - e.g. chlorambucil, Rituximab
* Surgery indicated if risk of perforation. If complete gastrectomy then RT not required, but RT should be given if partial gastrectomy.
* Salvage options after RT:
w CHOP CT- high RR but relapse common. Use if CI to XRT or advanced dx
w Rituximab
w Surgery - but morbidity
H Pylori negative:
* RT is indicated
* Ritux is an option for those where RT is contraindicated
* Endoscopy + biopsy after 3-6 months
Evidence:
* Several single arm, trials and large retrospective series look at H Pylori treatment as treatment for gastric MALT. Comparison is limited due to lack of consensus of response evaluation and definition of CR. Summary of trials:
w Almost all patients able to clear HP – 20% needed a second course of therapy
w Histologic CR in 50-80%
w Median time to clear was 15months
w Median FU 7 years, 16/74 relapsed (22%)
* Aviles (Med Oncol 2005): 241 pts, randomized trial, early stage low grade gastric MALT, randomized to surgery vs RT vs chemotherapy
w No diff in OS
w Mild acute and late toxicities
* Schmelz (J gastro 2019): prospective multicenter trial, 102 patis stage 1E or 21E, refractory or HP negative pts randomized to 25.2Gy vs 36Gy RT
w 76% showed a complete remission at 3 months.
w All pts achieved stable CR regardless of dose
w Presence of t(11;18) and monoclonality of tumour cells were predictors for persistent lymphoma post eradication therapy
w Overall: most HP+, low grade gastric MALT will respond to eradication therapy. In those who dose, dose reduced RT with 25Gy is reasonable
Describe the management of H Pylori negative Stage I-II gastric MALT.
H Pylori negative:
* RT is indicated
* Ritux is an option for those where RT is contraindicated
* Endoscopy + biopsy after 3-6 months
Evidence:
* Several single arm, trials and large retrospective series look at H Pylori treatment as treatment for gastric MALT. Comparison is limited due to lack of consensus of response evaluation and definition of CR. Summary of trials:
w Almost all patients able to clear HP – 20% needed a second course of therapy
w Histologic CR in 50-80%
w Median time to clear was 15months
w Median FU 7 years, 16/74 relapsed (22%)
* Aviles (Med Oncol 2005): 241 pts, randomized trial, early stage low grade gastric MALT, randomized to surgery vs RT vs chemotherapy
w No diff in OS
w Mild acute and late toxicities
* Schmelz (J gastro 2019): prospective multicenter trial, 102 patis stage 1E or 21E, refractory or HP negative pts randomized to 25.2Gy vs 36Gy RT
w 76% showed a complete remission at 3 months.
w All pts achieved stable CR regardless of dose
w Presence of t(11;18) and monoclonality of tumour cells were predictors for persistent lymphoma post eradication therapy
w Overall: most HP+, low grade gastric MALT will respond to eradication therapy. In those who dose, dose reduced RT with 25Gy is reasonable
Compare and contrast the types of orbital lymphoma
What is the treatment for Orbital MALT?
- Asymptomatic + Chlamydia positive:
w Consider treatment with abx i.e doxy
Radiotherapy:
* Dose:
w Stage 1: 24-30Gy
* Lowry paper: 24Gy/12#
w Disseminated: 4Gy/2# “boom boom”
w [ILROG guidelines] from 2020 suggest 4/2 [is acceptable] for orbital low grade lymphomas (e.g. MZL, MALT, etc).
* Boom boom typically has a CR of 50% and a 2y local failure of 25% for low-grade lymphoma
w Doses of >36Gy assoc with significant toxicity: ischemic retinopathy, corneal ulceration, optic atrophy, neovascular glaucoma, risk of vision loss
Ongoing small trial of 100 4Gy/2# = 90% complete response. If fail give remaining 20Gy
Describe the staging for mycosis fungoides/ sezary syndrome
Presentation: T2- 40%, T1-25%, T3-25%, T4-10%.
* ‘Premycotic’ phase
* Non-specific, slightly scaling skin lesions that wax and wane over a period of years
* May respond to topical corticosteroids
* Biopsies non-diagnostic
* ‘Patch’ phase (T1<10% body surface/T2>10% body surface)
* Histologic findings
* Epidermal lymphocytes with medium to large, extremely convoluted nuclei
* Haloed epidermal lymphocytes
* Pautrier’s microabscesses
Immunophenotype: CD2, 3, 4, 5 +ve, CD45RO+ve, CLA +ve; CD8-ve CD30-ve
* PCR for Tcell receptor rearrangement (ie clonal)
* ‘Plaque’ phase (T1/T2)
* Density of neoplastic cells within dermis increases
* Degree of epidermotropism more exaggerated
* ‘Tumour’ phase (T3)
* Ulcerating or fungating tumours
* Very dense dermal infiltrate involving full breadth of dermis, often extending into subcutaneous fat
* Infection of often cause of death
* Erythroderma (T4)
* Generalised erythroderma ie >80% body involved with patches and plaques, intense pruritus, hyperkeratosis of palms and soles
* Metastases to non-cutaneous sites
* Lymph nodes
* Lung
* Liver
What is the diagnostic criteria for mycosis fungoides?
Diagnostic Criteria- need 4pts to dx MF
* Diagnosis of MF can be made using the point-based algorithm by EORTC which is based on clinical, histopathologic, molecular, and immunopathologic criteria:
* Clinical criteria: persistent and/or progressive patches and plaques plus (two points given if two of the following are present, one point is given if one of the following is present): lesions in a non-sun-exposed location, size/shape variation of lesions, poikiloderma
* Histopathologic criteria: Superficial lymphoid infiltrate present plus (two points are given if both of the following are present, one point is given if only one of the following is present): epidermotropism (lymphocytes in epidermis) without spongiosis (epidermal oedema common in benign skin conditions), lymphoid atypia.
* Molecular biological criteria: If clonal TCR gene rearrangement is present, give one point.
* Immunopathologic criteria: Give one point if any of the following is present: <50% of the T cells express CD2, CD3, or CD5; <10% of the T cells express CD7; there is discordance of the epidermal and dermal cells with regard to expression of CD2, CD3, CD5, or CD7.
Describe the management for mycosis fungoides/ sezary syndrome
Topical Chemotherapy
Topical Nitrogen Mustard (mechlorethamine)
* Effectively for T1/T2 dx. All skin daily, then only on clinically affected areas→ maintenance tx for 2m. High relapse, but respond to further Rx.
Phototherapy
* UVB or PUVA (psoralen + UVA photoCT).
* Psoralen orally 2 hrs pre UVA; intercalates with DNA upon exposure to UVA.
* Given 3x/wk until CR, + maintenance up to 1 year.
Radiotherapy
* MF is exquisitely radiosensitive. E or KV RT
* Useful for individual plaques: dose 15Gy/5F, with high likelihood local control.
* TSE considered for thick plaque lesions or pts who failed topical CT or photoTx.
* CR 80% of T1/2. 50% relapse at 1yr, but durable response achieved with more TSE.
* TSE followed by topical nitrogen mustard.
* ↑ CR with TSE in T2 dx vs. topical nitrogen or PUVA. But no ↑ OS.
RT Technique (good coverage Gunderson)
i) Localised fields:
* Palliation of areas of bulky dx or symptomatic skin dx
* Target volume 4-5mm depth for patches/plaques, or to depth of tumours.
* Clinical mark-up. Add 2-3 cm laterally to encompass microscopic dx.
* Choose beam E for adequate dose at depth. KV <1.5cm; E >1.5cm.
* Control rate >95% with 30Gy.
* Dose:
* 15Gy/5F prescribed to 90% isodose with E;
* IF poor PS pts, single # 4 or 8Gy.
ii) TSE RT:
* Indications: thickened plaques, failed topical CT. Delivered with curative intent.
* Target volume = epidermis + dermis
* Dose: * 36Gy/18F to skin surface, 2Gy/F, 2 days per week. Hence, takes 9 weeks OR * 36G/18F to skin surface, 2Gy/F, 5d/wk with 2 wk break in middle. * ICRU 23 * 6MeV
Describe the technique and side effects of total skin electron bream treatment
- Technique:
Stanford technique:
* Pt undressed with light underwear stands on rotating table in a wooden frame at 3.5m from linac. Patient rotates through 6 positions involving 6 feet positions and twisting motions. (3 positions/fraction, 1 fraction over 2 days)
* Scattering filter (clear perspex) at 20cm from the patient for dose uniformity + minimise photon contamination (have guidelines for max photon dose)
* Position – alternate arms up/down + leg front/back; start at diff angle to gantry each day (smooth out dose distn)
§ Day 1: AP, RAO, LAO
§ Day 2: PA, RPO, LPO
* TLDs to check doses received, esp. sites where may get underdosing (skin flexures) + need boost (50 TLDs/day)
* 2 fields for treatment with beam angled down @ 72 and up @ 108 degrees (dep on height of pt)
§ Gap at centre calculated so get 90% dose in centre but no sig overlap
§ Beam divergence matched for sup/inf beams
* High dose rate used to reduce treatment time.
* Coverage to about 1cm (90% isodose)
* Dose uniformity +/- 10%.
* 6MeV used. (beam degraded to equivalent of 4.2Mev). 80% isodose > 4mm so epidermis + dermis in high dose region. 20% isodose line should be <20mm from skin to minimise dose to deeper structures.
* 80% isodose should receive minimum total dose 26Gy
* Electron boost to scalp, perineum, soles of feet, axillae, under breasts + to bulky tumours that are not receiving adequate dose at depth. Max 20Gy/5F.
* Shields:
§ eyes- external shields (can boost eyelids if required with internal lead shields after)- lead lined googles
§ nail beds (fingers + toes).- lead nail bed gloves
§ scrotum/penis - if concerned about fertility - lead line cricket box
SEs of TSE:
* Acute- erythema + dry desquamation 10Gy. Oedema + blistering 25Gy.
* Subacute- alopecia (at 25Gy), temporary loss of finger + toenails
* Late- chronically dry skin + inability to sweat properly for 6-12 months. Telangiectasia + uneven pigmentation. ↑ risk of cutaneous malignancy.
Describe burkitts lymphoma
- Doubling time 24hrs, highly aggressive, usu children or HIV+
- Characteristic translocation and deregulation of MYC gene on Chr 8
- Sporadic type present with abdo mass+ ascites
○ Patients with limited stage dx have excellent prognosis.
NO ROLE for RT, even in localised dx, limited stage disease.
○ Treat: Aggressive chemotherapy regimen
§ CODOX-M (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate) with
§ IVAC (ifosfamide, cytarabine, etoposide, and intrathecal methotrexate)
○ High rate of CNS relapse, hence requires CNS prophylaxis.
○ Disseminated disease, responsive to chemotherapy
BMT at 1st relapse.○ Survival decreases with age (SEER data)
§ 5yr OS
□ <19yo 85%
□ 20-39yo: 60%
□ 40-59yo: 50%
□ >60yo: 33%
Describe peripheral T-Cell lymphoma and its management.
- Lymphoma of mature (post-thymic) T-cells →express either CD4 or CD8.
- Treatment
w Trial
w Induction chemo: CHOP (>60) or CHOEP (+Etoposide) (<60), if <60yo x6-8
* Add brentuximab if CD30+
w Consolidation:
* ISRT for early disease/bulky, CR to chemo
* Autologous SCT in chemosensitive patients indicated if high risk features exist even at first CR
w HR features = high IPI score, anaplastic large cell and ALK negative
* ISRT + SCT localised but high IPI; localised with PR to chemo)
- Treatment
Describe Extranodal NK/T-cell lymphoma Nasal type and its management
- Localized, aggressive and destructive disease that rarely involves LN. Extensive necrosis and angioinvasion.
- Presentation:
w Mostly presents in nose and paranasal sinuses (other extranodal sites- palate, trachea, skin, GIT)
w Risk of CNS involvement (in advanced stage disease) and local recurrence
w Highly aggressive, poor response, short OS - Prognosis: Poor 5yr OS 40-60%
w High Px w/ localised dx
w Low Px w/ Extranasal sites - Treatment (no RCTs, retrospective and small prospective series only):
w SMILE (Dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide regime) preferred to CHOP-> RTx IFRT (50Gy/25Fr)-> Autologous SCT (if young) (SMILE now being used in upfront setting due to promising response to L-asparaginase)
w SCT : no consensus. consider if CR pts, young pts
w CNS prophylaxis if 3/4 of the NKPI (NK/T Cell lymphoma Prognostic index):- this determine 5yr OS and risk of CNS involvement without prophylaxis:
* Presence of B symptoms (fever/chills, drenching night sweats, weight loss)
* Stage III or IV disease
* Elevated LDH
* Regional lymph node involvement
- Presentation:
Compare MGUS and Smouldering Myeloma.
Compare Solitary plasmacytoma and multiple myeloma
What is the staging for multiple myeloma?
What is the expected prognosis and follow up for plasmacytoma and myeloma?
Complete remission of 40-60%
Follow-Up
- Clinical review every three months for the first two years ○ Clinical history and examination ○ FBC, EUC, CMP, LDH, serum FLC, EPG/iEPG - Clinical review every six months for the indefinite future ○ Clinical history and examination ○ FBC, EUC, CMP, serum FLC, EPG/iEPG - Consider urine Bence Jones as indicated - Imaging as indicated only Routine annual imaging for solitary plasmacytoma & smouldering myeloma
What is the risk stratification and staging for leukaemia?
High risk ALL:
* all adults
* Older children > 6-7yo
* T-cell phenotype
CNS2-3 disease
What is your radiotherapy technique for TBI?
Presim:
- Haem MDT discussion, Ensure complete remission with induction chemo
- Consent
- Baseline blood (daily blood test during TBI)
- Assess baseline renal, pulmonary and hepatic function—Acquire baseline function for each.
- Baseline ophthalmologic examination.
- Testicular examination +/- USS to rule out testicular involvement with leukaemia.
- Counsel on family planning and sperm banking if needed
- Counsel on sex abstinence or protected sex with contraception after RT
- ensure no previous RT delivered
- Smoking cessation
- Coordinate Start date of TBI with stem cell transplant, chemo dates, and Timing of admission
- Ensure no active infection
- Premed with ondansetron and Dex 4mg daily before each RT
SIM:
- Present during mock up sim to oversee and check set up with physicist and RT
- Set up: Arm on chest, supine with full body vacbag. knee and hip flexion and knee block blocks if height > 165cm
- Perspex blocks on either side of the head and rice bags for neck compensation
- Perspex shielding for spoiler at 15cm from the pt bed (in between the gantry and bed)
- Measurement taken for extended FSD (gantry at 90 degree with rotated collimator, 40x40cm, pt planned at extended FSD ~4m on either side of the room)
- Use light field to check pt is completely covered by the treatment beam
- CT sim whole body
Dose and technique
- Dose: 12Gy/6F BD , 2Gy/F, 6 hour apart, over 3 days until the day of stem cell transplant, Prescribed to MPD, isocentre 2cm from umbilicus
- Opposed lateral, 6MV photons, extended SSD 365cm
- turn pt at 180 degree (rather than gantry) for each field.
- Dose rate 5-7 cgy/min for ALARA and reduce need for shielding of lung, heart and kidneys
Volume:
- Whole body – based on measurement from FSD and divergence rather than CT-volume based
OAR:
- Lung mean dose < 10Gy
- Lens Dmax <8Gy
- Perspex block decrease dose to brain and head
Target verification:
- Ion chamber placed in between thighs for in vivo dosimetry
- multiple TLDs in the body- bilateral head, neck, chest , hip and groin
