hematologic malignancies · 2020-04-08 · advanced stage dlbcl: bulk and skeletal 49 yo m with...
TRANSCRIPT
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… A Guide to the ILROG Guidelines
Hematologic Malignancies:
February 27, 2020
John P. Plastaras, MD, PhD
Associate Professor
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Disclosures
Steering Committee of ILROG, and chair the Education
Committee
Co-chair of the Lymphoma Committee for the American Board
of Radiology
ASTRO Scientific Committee (Heme, Vice-Chair)
My wife is on ASTRO Board of Directors, ACGME, RRC
I am receiving support from Merck (free drug) for a clinical trial
we are doing at Penn
Unfortunately, no financial disclosures
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Outline
What ILROG guidelines are out there?
Solitary Plasmacytoma and Multiple Myeloma
Low-Grade Lymphomas
Hodgkin Lymphoma
Insights into “Involved Site” Radiotherapy (ISRT)
Treating the Mediastinum
DLBCL
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Who is making guidelines currently?
National Comprehensive Cancer Network (NCCN)
European Society for Medical Oncology (ESMO)
Children’s Oncology Group (COG)
American Radium Society (ARS) adopted the Appropriateness
Criteria program from the American College of Radiology
(ACR)
International Lymphoma Radiation Oncology Group (ILROG)
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ESMO Guidelines: Medical Oncology
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ESMO Guidelines: Hematologic Diseases Waldenstrom's macroglobulinaemia
Chronic myeloid leukaemia
Newly diagnosed and relapsed mantle cell lymphoma
Multiple myeloma
Newly diagnosed and relapsed follicular lymphoma
Extranodal diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma
Acute lymphoblastic leukaemia
Peripheral T-cell lymphomas
Diffuse large B cell lymphoma
Chronic lymphocytic leukaemia
Hairy cell leukaemia
Philadelphia chromosome-negative chronic myeloproliferative neoplasms
Myelodysplastic syndromes
Hodgkin lymphoma
Primary cutaneous lymphoma
Acute myeloblastic leukaemia in adult patients
Gastric marginal zone lymphoma of MALT type
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NCCN Guidelines for Hematologic Diseases
Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Chronic Myeloid Leukemia
Hairy Cell Leukemia
Hodgkin lymphoma
Multiple Myeloma
Waldenström's Macroglobulinemia / Lymphoplasmacytic
Lymphoma
Myelodysplastic Syndromes
Myeloproliferative Neoplasms
B-cell Lymphomas
Primary Cutaneous Lymphomas
T-Cell Lymphomas
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Guidelines for Supportive Care
ESMO:
• Chemotherapy and radiotherapy-induced nausea and vomiting
• Oral and gastrointestinal mucosal injury
• Management of refractory symptoms at the end of life and the use of
palliative sedation
• Advanced care planning in palliative care
• Bone health in cancer patients
• Cancer, fertility and pregnancy
• Cardiovascular toxicity induced by chemotherapy, targeted agents and
radiotherapy
NCCN:
• Survivorship
• Palliative Care
• others
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Current ILROG Guidelines 2014:
• Nodal non-Hodgkin lymphoma
• Hodgkin lymphoma
2015:
• Primary cutaneous lymphomas
• Extranodal lymphomas
• Pediatric Hodgkin lymphoma
2018:
• Lymphoblastic Lymphoma
• Central Nervous System Leukemia
• Extramedullary Leukemia/Chloroma
• Total Body Irradiation
• Solitary Plasmacytoma and Multiple Myeloma
• Relapsed/Refractory Hodgkin Lymphoma
• Relapsed/Refractory Diffuse Large B-Cell Lymphoma
• Proton therapy for adults with mediastinal lymphomas
2019:
• Optimal use of imaging
2020:
• ISRT Mini-Atlas
• “Making Every Single
Gray Count: Involved
Site Radiation
Therapy Delineation
Guidelines for
Hematological
Malignancies”
• Not exactly a
guideline, but a
supplementary
resource
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ILROG.org Easy Links to All the Guidelines
Major Limitation of
ILROG Guidelines:
No current mechanism
to maintain
“evergreen” status, so
they are aging quickly.
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Plasma Cell Diseases: Picking Dose
61 M with newly diagnosed multiple
myeloma with a path comp fx at T11.
T9 infiltrated as well. Back pain.
62 M with solitary plasmacytoma of the
nasopharyngeal wall, < 1 cm, resected
2.5 Gy x 8 = 20 Gy 1.8 Gy x 22 = 39.6 Gy
Treatment Approach?
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Plasma Cell Disease Guidelines
Solitary BONY plasmacytomas:
• SBPs <5 cm: total dose 35 to 40 Gy
– for small SBPs it is acceptable to prescribe 35 Gy, which has differed
from NCCN
• SBPs >/= 5 cm: total dose 40 to 50 Gy
Solitary EXTRAMEDULLARY plasmacytomas
• SEPs: total dose 40 to 50 Gy (if small, well-defined, or post-excision with
positive margins, 40 Gy is acceptable.)
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Myeloma Palliation Doses:
For bony sites, where the goal is limited to symptom relief: 8-30 Gy
(8 Gy x 1, 20 Gy in 5, 30 Gy in 10).
• 8 Gy x1 preferred for bone disease with poor predicted survival
• 20 to 30 Gy in 10 to 15 preferred RT volumes are large or retreatment
For epidural disease with spinal cord compression, or bulky mass,
when durable local control is desired: 30 Gy in 10 to 15
• consider glucocorticoids to prevent pain flare
Trend: lowered doses overall to mitigate marrow toxicity
• Active trial (Leslie Ballas is PI) for 2 Gy x 2.
• 2.5 x 10 for cord compression?
• 2.5 Gy x 8, 4 Gy x 5, 8 Gy x 1.
• “New Paradigm for Radiation in Multiple Myeloma: lower yet effective
dose to avoid radiation toxicity.” Elhammali A, et al. Haematologica.
2020 Jan 9.
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Limited Stage Low Grade Lymphomas
31 M with left submandibular gland mass, FNA showed “may be
compatible with a CD5+ mature B Cell neoplasm”
Underwent TORS excision, piecemeal resection (3 chunks). Left him with
speech defect, tongue and facial numbness, but a diagnosis of marginal
zone lymphoma. Margins? Treatment Approach?
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ISRT Volumes Without Chemo?
“…in clinical situations that require RT as the primary modality…the
CTV should be more generous in this clinical situation and also
encompass lymph nodes in the vicinity that, although of normal size,
might contain microscopic disease that will not be treated when no
chemotherapy is given.”
RT Alone is used with CURATIVE intent in:
• Stage I/II follicular lymphoma
• Stage IE marginal zone lymphoma
• Stage I/II Nodular Lymphocyte Predominant Hodgkin
Lymphoma
• Relapsed/refractory HL or NHL
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ISRT with RT Alone: How Much Margin?
British Columbia retrospective of limited
stage follicular lymphoma defined
“Involved Site” RT as 5 cm margin or less
• Adjust according to what toxicities worry you
• I will add 2-5 cm of nodal volume depending on
what is adjacent (e.g. parotid)
Bonus planning tip:
• Bone marrow is the most important OAR given
future systemic therapies once these patients
relapse and need treatment
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Non-Nodal NHL: Extranodal and Skin
pCNS, Orbital, Head & Neck (incl thyroid), NK/T-cell, Breast,
Lung, Testicular, bone, abdomen/Pelvis, bowel
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Dose Considerations for Indolent NHL
Indolent nodal lymphomas, stage I/II with curative intent:
• 24-30 Gy in 12-15 fx
Marginal zone lymphomas with curative intent:
• Salivary: 24 Gy
• Gastric: 30 Gy (but maybe 24 Gy?)
• Orbit: 24 Gy (but maybe 4 Gy?)
• Other sites (thyroid, cutaneous, pulmonary): 24-30 Gy
Advanced stage or palliative intent indolent B-cell NHL:
• 2 Gy x 2, but realize that local control may not be as durable
Palliation of cutaneous T-cell lymphoma:
• 4 Gy x 2 or 8 Gy x 1 for localized CTCL/MF
• 12 Gy for total skin electron treatment
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Basics of Hodgkin Lymphoma Treatment
Early stage, favorable: • ABVD x 2 + 20 Gy IFRT (HD10)
Early stage, unfavorable: • ABVD x 4 + 30 Gy IFRT (HD11)
Advanced stage (IIB bulky, III/IV):• ABVD x 6 (or BEACOPP in Europe)
• RT for partial response, bulky disease
Relapsed/refractory: • 2nd line chemo +/- RT +/- transplant
• Brentuximab (CD30 ADC) and PD1 inhibitors
Palliation
EORTC H10 Style:
- 2 vs. 3 sites of
disease can be F
- ABVD x 3 for F
- 30 Gy regardless U/F
- BEACOPP
escalation for DS3-4
after PET2
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Relevant Guidelines: Hodgkin Lymphoma
2019
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Early Stage Mediastinal Hodgkin
25-year old woman received ABVD x 4 for an unfavorable risk,
Stage IIA classic Hodgkin lymphoma of the mediastinum.
Pre-chemotherapy PET/CT (fused to planning CT), in DIBH
What ISRT Volume would you use?
Post
Chemo
Mass
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A B
C D
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ISRT with Combined Modality Treatment
Contour the post-chemotherapy tissue volume, which contained the
initially involved lymphoma tissue, taking into account tumor
shrinkage, respecting normal structures that were never involved by
lymphoma (lungs, chest wall, muscles, esophagus)
Be a bit more generous when in doubt
Connect CTV’s when nodal volumes are less than 5 cm apart
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Minimizing Dose to OARs: Mediastinum
21 F with unfavorable risk classic Hodgkin lymphoma (per
GHSG criteria – 3 sites of disease, non-bulky, ESR <50, no
extranodal sites). Upper mediastinum and bilateral SCV.
• ABVD x 2 → Deauville (5PS) 2. AVD x 2 more (4 cycles total)
Treatment Approach?
Decreases dose to lungs and heart
Requires confirmatory method to ensure breath hold
position is reproducible
Free Breathing Deep Inspiratory Breath Hold
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DIBH and Protons: Which has more value?
Rechner LA et al. Radiother Oncol. 2017 Oct;125(1):41-47. Life years lost attributable to late effects after radiotherapy for
early stage Hodgkin lymphoma: The impact of proton therapy and/or deep inspiration breath hold.
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Minimizing Dose to OARs: Mediastinum
21 F with unfavorable risk classic Hodgkin lymphoma (per
GHSG criteria – 3 sites of disease, non-bulky, ESR <50, no
extranodal sites)
• ABVD x 2 → Deauville (5PS) 2. AVD x 2 more (4 cycles total)
Deep breath hold?
3D? IMRT? Proton?
Dose constraints for
substructures?
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New Era: Stricter Dose Requirements
Continued controversial role of RT in combination with
chemo, so pressure is on to make RT safe
Era of ISRT has allowed very conformal techniques to
prioritize certain OAR’s over others
Many new technological options to achieve lower dose
constraints
• 3D, IMRT (fixed/VMAT), protons
• Positioning: special angle board, DIBH
Selective use of combined modality vs. chemo only when
options exists and RT plan looks like it will be ugly
• Cardiophrenic disease (breath hold may make it worse)
• Use the aortic valve/LAD take off as a discussion point with med oncs
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Case: Advanced Stage DLBCL
49 yo M with Stage IVB DLBCL s/p R-CHOP x 6 with complete
metabolic response. Both skeletal involvement (T5) and bulky
retroperitoneal/mesenteric adenopathy (mesentery, paracaval,
interaortocaval, para-aortic regions, total diameter 9.4 x 4.1)
Treatment Approach?
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Relevant Guidelines: Aggressive NHL
2019
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Basics of Aggressive NHL (DLBCL)
Limited Stage (I/II)
• R-CHOP x 6, radiate partial response, bulk (>7.5 cm), or
skeletal dz
• or R-CHOP x 3-4 + consolidative radiation (30-40 Gy)
Advanced Stage (III/IV)
• Indications for RT after R-CHOP x 6
– radiate partial response
– bulk (>7.5 cm)
– skeletal dz (30-36 Gy)
Relapsed/Refractory
• 2nd line chemo +/- RT +/- transplant
Palliation
• RT for symptom control, local control, oligoprogression, bridge
to next systemic therapy
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Aggressive NHL Dose Considerations
Upfront DLBCL after chemo: 30-40 Gy
• 30 Gy if DS 1-3
• Boost to higher doses for DS4
Upfront Double Hit DLBCL (myc/bcl2 or bcl6)
• Correct dose is unknown, but I tend to lean toward higher end of dose
spectrum when consolidating
Upfront Primary Mediastinal Large B-cell lymphoma (PMBCL)
• Avoid radiation if given DA-R-EPOCH if possible
• After R-CHOP x 6: 30-40 Gy depending on PET response
Relapsed/Refractory DLBCL
• DS1-3 with salvage chemo and ASCT: 30-36 Gy
• Transplant ineligible, curative intent: 45-55 Gy
• Palliative intent with limited life expectancy: hypofractionated schedule
of 8-30 Gy
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Advanced Stage DLBCL: Bulk and Skeletal
49 yo M with Stage IVB DLBCL s/p R-CHOP x 6 with complete
metabolic response. He is eferred for consideration of consolidative
RT to sites of skeletal involvement (T5).
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Relapsed/Refractory DLBCL
57F p/w B symptoms and CD10+ B-cell lymphoma in
December, Stage IVB at dx
• R-EPOCH x6c completed
• 1 month later, progressed in PA nodes
• 1 cycle R-DHAP with stable to progressive disease
• Recommended for CAR T-cell therapy (Kymriah) and started systemic
bridging venetoclax
Referred for “bridging” radiation therapy to painful,
“chemorefractory” mesenteric nodal conglomerate, measuring
6.2 x 5.8 cm
Pre-bridging-RT PET/CT
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Combining with Biologics: Guidelines?
4DCT sim fused to PET-CT scan
PTV = GTV + 7mm
20 fraction SIB volumetric arc plan
• 220cGy / fx to GTV (4400 cGy)
• 180 cGy / fx to PTV (3600 cGy)
Acute toxicity: G1 nausea
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Biologic Explosion in Lymphomas
Hodgkin Lymphoma:
• Brentuximab-vedotin
– Anti-CD30 antibody with microtubule disrupting agent
• PD1 Blockade
• CART therapies?
Non-Hodgkin Lymphoma:
• CD20 agents (rituximab, ofatumumab, obinutuzumab, etc.)
• PI3K/MTOR
• Proteasome inhibitors
• BTK inhibitors (ibrutinib)
• BITEs (bispecific T-cell engager antibody, CD19/CD3) (blinatumomab)
• Immunomodulators: Revlimid, PD1 Blockade, CART 19
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Future of ILROG Guidelines
Mechanism to update aging guidelines
Make them easier to reference at point of care
Potential unmet needs:
• Palliation?
• Indolent Lymphomas?
• Extranodal expansion?
• Combination with biologic agents?
Stay tuned for more help with contouring
• ILROG Education Committee: Terezakis, Hoppe, Gunther
– eContour and EduCase collaborations
Learning heme radiation 1 tweet at a time:
• @ILROGTeam
ILROG Sponsored ACGME Resident Away Rotation
• AROPC, application on ILROG.org
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Conclusions
ILROG Guidelines should help us move RT for
hematologic malignancies into modern era, using
contour-based planning
Trends in heme radiation community move fast, so
guidelines are aging
Please join ILROG, use the website which is new
and improved!
Good luck on the SA-CME
Now for more contouring…
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