… 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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