LymphomaLymphomaLymphoma Lymphoma Current Current

ApproachApproach

Bouthaina Dabaja M DBouthaina Dabaja M DBouthaina Dabaja,M.DBouthaina Dabaja,M.DUT MD Anderson UT MD Anderson

C C tC C tCancer CenterCancer Center

No disclosuresNo disclosuresNo disclosuresNo disclosures

OverviewOverview

HodgkinHodgkin’’s Lymphoma (standard treatment):s Lymphoma (standard treatment):

OverviewOverview

gg y p ( )y p ( )–– Early diseaseEarly disease–– Early UnfavorableEarly Unfavorable–– AdvancedAdvanced

Aggressive Lymphoma:Aggressive Lymphoma:–– DLBCL (early stage I and II): DLBCL (early stage I and II):

–– standard chemotherapy and role of radiationstandard chemotherapy and role of radiation–– Other aggressive types: PCNSL,NK cell, PML, TesticularOther aggressive types: PCNSL,NK cell, PML, Testicular

Low grade lymphoma:Low grade lymphoma:Follicular lymphomaFollicular lymphoma–– Follicular lymphomaFollicular lymphoma

–– MALT LymphomaMALT Lymphoma

HodgkinHodgkin’’s Lymphomas Lymphoma

Unique history:Unique history:

HodgkinHodgkin s Lymphomas Lymphoma

Unique history:Unique history:

Discovered 1832Discovered 1832Radiation used in 1930 Radiation used in 1930 Wide field 1950 (Kaplan, Peters)Wide field 1950 (Kaplan, Peters)MOPP 60MOPP 60’’ssABVD 70ABVD 70’’s s Hi h t hi dHi h t hi dHigh cure rate achieved High cure rate achieved Live long to see what we have doneLive long to see what we have done

HodgkinHodgkin’’s Lymphoma we s Lymphoma we gg yychanged the survival changed the survival

Hodgkin's Lymphoma by Era

n = 21671 0

Hodgkin's Lymphoma by Era

n = 21671 0

rviv

al

1.0

.9

.8

.7

.6 rviv

al

1.0

.8

.6

19701980

1990 1990

1980

Cum

Sur

.5

.4

.3

.2

1Cum

Sur

.4

.2

1960 1970

1960

Disease Specific Survival (y)

403020100

.1

0.0

Overall Survival (y)

4030201000.0

British Columbia

HL DiagnosisHL DiagnosisHL DiagnosisHL Diagnosis

Most common is Nodular sclerosis, Most common is Nodular sclerosis, unimodalunimodal with with younger age, Mixed cellularity older ageyounger age, Mixed cellularity older age

Viral association:Viral association:EBV (40%),EBV (40%),HIV (less common), HIV (less common), ( ),( ),Autoimmune disease (MTX)Autoimmune disease (MTX)

Family history, increased in first degree relativesFamily history, increased in first degree relatives

Presentation identifying risk group Presentation identifying risk group

SStage according to Ann Arbortage according to Ann ArborSites location and numberSites location and numberSites location and numberSites location and numberPresence of B symptoms Presence of B symptoms (>38 C), > 10% body weight loss, (>38 C), > 10% body weight loss,

drenching night sweatsdrenching night sweats

Presence of Bulk:Presence of Bulk:Presence of Bulk:Presence of Bulk:–– MediastinalMediastinal: 10 cm or >1/3 of mediastinum at T5: 10 cm or >1/3 of mediastinum at T5--6 on UR 6 on UR

CXRCXR–– > 5cm any mass else where> 5cm any mass else where

Age > 45Age > 45Male genderMale genderLaboratory:Laboratory:Laboratory: Laboratory:

Sedimentation rateSedimentation rateHemoglobin < 10g/dlHemoglobin < 10g/dlHigh LDH, High b2 High LDH, High b2 microglobulinmicroglobulin (advanced stage)(advanced stage)High WBC count > 15000 < 8% lymphocytes ( advanced stage)High WBC count > 15000 < 8% lymphocytes ( advanced stage)High WBC count > 15000, < 8% lymphocytes ( advanced stage)High WBC count > 15000, < 8% lymphocytes ( advanced stage)Albumin< 4 (advanced stage)Albumin< 4 (advanced stage)

HL DiagnosisHL DiagnosisHL DiagnosisHL Diagnosis

B cell in originB cell in originReedReed-- Sternberg cells (multinucleate)+mononuclear Sternberg cells (multinucleate)+mononuclear HHodgkin cellsodgkin cellsggCD30 positiveCD30 positiveCoCo--Express CD 15Express CD 15

PAX 5: identity keeper of B lymphocytes, used PAX 5: identity keeper of B lymphocytes, used when CD20 or CD79 are not detected.when CD20 or CD79 are not detected.

Normal KaryotypeNormal Karyotype

HL DiagnosisHL DiagnosisHL DiagnosisHL Diagnosis

Classical Hodgkin:Classical Hodgkin:Nodular Sclerosis (RS +fibrosis+inflammatory cells Nodular Sclerosis (RS +fibrosis+inflammatory cells

eosinophiles and plasma cells)eosinophiles and plasma cells)Mixed Cellularity (RS, inflammatory cells)Mixed Cellularity (RS, inflammatory cells)Lymphocyte rich (RS + lymphocytes no eos. or neut.)Lymphocyte rich (RS + lymphocytes no eos. or neut.)Lymphocyte depleted (rarely mentioned)Lymphocyte depleted (rarely mentioned)

Lymphocyte predominance (germinal B cell) with aLymphocyte predominance (germinal B cell) with aLymphocyte predominance (germinal B cell) with a Lymphocyte predominance (germinal B cell) with a nodular growth pattern.nodular growth pattern.

Diffuse pattern might not exist: may be T cell rich Large cell Diffuse pattern might not exist: may be T cell rich Large cell or lymphocyte rich classical HL or lymphocyte rich classical HL y p yy p y

HL PresentationHL PresentationHL PresentationHL Presentation

Asymptomatic supraAsymptomatic supra--diaphragmaticdiaphragmaticWaxing and waning (inflammatory background)Waxing and waning (inflammatory background)Mixed cellularity: abdominal,Mixed cellularity: abdominal, older age, male, advanced older age, male, advanced stage, b symptoms, rare stage, b symptoms, rare mediastinalmediastinal site, developing site, developing countries, countries,

Contiguous involvementContiguous involvementContiguous involvementContiguous involvementNeck and inguinal nodes without Neck and inguinal nodes without mediatinummediatinum is rareis rare

Liver and marrow rarely involvedLiver and marrow rarely involvedLiver and marrow rarely involvedLiver and marrow rarely involved

Bone marrow involvement/ the need for BM biopsy:Bone marrow involvement/ the need for BM biopsy:P i i i l i h b lk/b /P i i i l i h b lk/b /Positivity correlate with bulk/b symptoms/stagePositivity correlate with bulk/b symptoms/stageBaseline is always helpfulBaseline is always helpful

HL DiagnosisHL DiagnosisHL DiagnosisHL Diagnosis

Staging work up: Staging work up: Core biopsy Not a FNACore biopsy Not a FNA

Laboratory work CBC, diff, plats, ESR, LDH, liver function, Laboratory work CBC, diff, plats, ESR, LDH, liver function, albumin, albumin, creatcreat. BUN, pregnancy test, HIV. BUN, pregnancy test, HIV

PET CT with contrastPET CT with contrastPET CT with contrastPET CT with contrast

Bone marrow biopsy Bone marrow biopsy Comorbid conditions:Comorbid conditions:Comorbid conditions:Comorbid conditions:

autoimmune diseaseautoimmune diseaseHeart diseaseHeart diseaseFamily history of cancerFamily history of cancerHepatitisHepatitisViral infectionsViral infections

Identify the risksIdentify the risksIdentify the risksIdentify the risks

GHSG EORTC StanfordRisk Factors a- Bulky

mediastinuma-Bulkymediastinum

a-Bulky mediastinum

b-Extranodal b- Age >=50 b-Age>=40b Extranodal disease

b Age 50ESR>=50 with no

b Age 40

c-ESR>=50 with no 3-B symptomsOr > 30 with B

c-B symptomsOr >=30 with B symptoms

c- ESR >=50

Or >=30 with B symptoms

symptoms

d->=3 nodal sites d- >=4 nodal sites d->=3 nodal sites

Sites of DiseaseSites of Disease

1 2

34

Unfavorable (GHSG)

Identify the risksIdentify the risksGHSG EORTC Stanford

Risk Factors a- Bulky mediastinum a-Bulky mediastinum a-Bulky mediastinum

b E t d l di b A 50 b A 40b-Extranodal disease b- Age >=50ESR>=50 with no

b-Age>=40

c-ESR>=50 with no 3-B symptomsOr >=30 with B symptoms

c-B symptomsOr >=30 with B symptoms

c- ESR >=50

d->=3 nodal sites d->=4 nodal sites D->=3 nodal sites

GHSG EORTC StanfordF bl CS I II CS I II CS I IIFavorable CS I-II

No risk factorsCS I-IINo risk factors

CS I-IINo risk factors

Unfavorable CS I IIA with >=1 CS I IIA with >=1 CS I IIA with >=1Unfavorable CS I- IIA with >=1 risk factor CS IIB with c or d not a+b (otherwise

CS I- IIA with >=1 risk factor

CS I- IIA with >=1 risk factor

advanced)

Why are we here todayWhy are we here todayWhy are we here todayWhy are we here today

GHSG EORTC StanfordGHSG EORTC Stanford

Favorable:2ABVD+20 Gy

CS I-IINo risk factors

CS I-IINo risk factors

CS I-IINo risk factorsy

IFRT

GHSG 10

Unfavorable

1-4 ABVD2-

CS I- IIA with >=1 risk factor CS IIB with c or d not a+b for HD 11

CS I- IIA with >=1 risk factor

CS I- IIA with >=1 risk factor

2-2BEACOPPes.+2ABVD

not a+b for HD 11

+ 30 Gy IFRTGHSG 11,14

Shifting from Extensive Radiation to combined Shifting from Extensive Radiation to combined d litd lit

Radiation alone and lack of Imaging Radiation alone and lack of Imaging

modalitymodality

ad at o a o e a d ac o ag gad at o a o e a d ac o ag gStaging LaparotomyStaging Laparotomy

EORTC 6: clinical stage is sufficient for:EORTC 6: clinical stage is sufficient for:EORTC 6: clinical stage is sufficient for:EORTC 6: clinical stage is sufficient for:stage Istage I--II, No B, No bulky, ESR<30II, No B, No bulky, ESR<30

Combined chemoCombined chemo--radiation started with MOPPradiation started with MOPPCombined chemoCombined chemo radiation started with MOPPradiation started with MOPP

Trials with MOPP are not relevant to todayTrials with MOPP are not relevant to today’’s practice s practice

Introduction of ABVDIntroduction of ABVDstep 1step 1step 1step 1

ABVD Introduced in 1975:ABVD Introduced in 1975:Milan Randomized trial Milan Randomized trial

–– advanced stage advanced stage –– ABVD was found superiorABVD was found superior

6 cycles of ABVD 6 cycles of ABVD 300mg/m2 Adriamycin 300mg/m2 Adriamycin

–– Tolerance is 450Tolerance is 450--500 mg/m2 IVP 500 mg/m2 IVP

ABVD establishedABVD established

CALGB in US compared ABVD to MOPP toCALGB in US compared ABVD to MOPP to

ABVD establishedABVD established

CALGB in US compared ABVD to MOPP to CALGB in US compared ABVD to MOPP to MOPP ABVD in advanced stage no MOPP ABVD in advanced stage no radiationradiationradiation radiation

Canellos 2002 NEJMCanellos 2002 NEJM

Type of chemotherapyType of chemotherapy

Stanford V introduced 1995Stanford V introduced 1995Stanford V introduced 1995Stanford V introduced 1995reported on for both early and advanced stage reported on for both early and advanced stage 8 or12 weeks of chemotherapy8 or12 weeks of chemotherapy8 or12 weeks of chemotherapy 8 or12 weeks of chemotherapy RRadiation from 20 to 36 adiation from 20 to 36 GyGy

EExcellent outcomexcellent outcomeEExcellent outcome xcellent outcome LLow toxicityow toxicity

Step 2: delete extensive radiation as sole Step 2: delete extensive radiation as sole modalitymodality

GHSG HD7 GHSG HD7 addition of 2 ABVD to EFRTaddition of 2 ABVD to EFRTdramatically improved the FFF from 75% to 91% at 5 yearsdramatically improved the FFF from 75% to 91% at 5 yearsdramatically improved the FFF from 75% to 91% at 5 years dramatically improved the FFF from 75% to 91% at 5 years

(Engert 2007)(Engert 2007)

Fred Hutchinson 348 CS I II A no Bulky or B symptoms Fred Hutchinson 348 CS I II A no Bulky or B symptoms randomized to STLI or CMT 3 DV and STLI randomized to STLI or CMT 3 DV and STLI closed early for the marked superiority of chemotherapyclosed early for the marked superiority of chemotherapy

(Press 2001 )(Press 2001 )

Comparing extensive to IF +chemotherapyComparing extensive to IF +chemotherapy

Trials comparing extended field to IF+ chemotherapyTrials comparing extended field to IF+ chemotherapyBonnadonna et alBonnadonna et al

showing no OS or FFP in early favorableshowing no OS or FFP in early favorableshowing no OS or FFP in early favorableshowing no OS or FFP in early favorable

EORTC/GELA H8FEORTC/GELA H8F3 MOPP/ABVD +IFRT vs STLNI 3 MOPP/ABVD +IFRT vs STLNI superiority was shown but neither are accepted now superiority was shown but neither are accepted now

(Ferme 2007 )(Ferme 2007 )

H8UH8UH8U H8U 2 of the three arms compared 4 MOPP/ABV2 of the three arms compared 4 MOPP/ABVfollowed by EFRT or IFRT followed by EFRT or IFRT 7 y EFS 86% and 84%7 y EFS 86% and 84%

HD 8 GHSG 1204 with CS I II HL HD 8 GHSG 1204 with CS I II HL randomized to COPP + ABVD randomized to COPP + ABVD followed by extended RT or IFRTfollowed by extended RT or IFRTMEDIAN FU 54 M 5Y FFF 86% VS 84% (O.56) OS 91 AND 92%MEDIAN FU 54 M 5Y FFF 86% VS 84% (O.56) OS 91 AND 92%

IFRT meaning in these trials was unclearIFRT meaning in these trials was unclear

(Engert 2003)

At the door of what we do todayAt the door of what we do todayNo use for extended fieldNo use for extended field

At the door of what we do todayAt the door of what we do today

No use for MOPPNo use for MOPPNow we need to tailor combined modality based on risk Now we need to tailor combined modality based on risk factorsfactorsShould avoid falling into the trap of the side effects thatShould avoid falling into the trap of the side effects thatShould avoid falling into the trap of the side effects that Should avoid falling into the trap of the side effects that results for the early approachesresults for the early approaches

Second malignanciesSecond malignancies

What are the side effectsWhat are the side effectsSecond malignanciesSecond malignancies

Solid tumors Continuous with time, no plateau, associated with :Solid tumors Continuous with time, no plateau, associated with :EF radiationEF radiationHi h dHi h dHigh dosesHigh dosesMantle fieldMantle fieldYounger ageYounger age25 years of follow up the risk 28% 25 years of follow up the risk 28% 34% < 20 of age developed breast cancer, 22% age 2034% < 20 of age developed breast cancer, 22% age 20--29, 18 fold the risk 29, 18 fold the risk g p , gg p , g ,,of general population for all cancers, 8 Fold breast, 38 thyroid, 11 cervix, of general population for all cancers, 8 Fold breast, 38 thyroid, 11 cervix, 11 for GI11 for GI

Hematological malignancy: is highest at 5Hematological malignancy: is highest at 5--10 years 10 years Over 1000 patients treated with ABVD in contrast to MOPP noOver 1000 patients treated with ABVD in contrast to MOPP noOver 1000 patients treated with ABVD in contrast to MOPP no Over 1000 patients treated with ABVD in contrast to MOPP no increased incidence of SM (increased incidence of SM (valagussavalagussa 1982, 488)1982, 488)Travis 2003 breast cancer is dependent on dose 42 Travis 2003 breast cancer is dependent on dose 42 GyGy to as low as 4 to as low as 4 GyGy, confirmed by Van , confirmed by Van LeeuwenLeeuwen,,pediatrics: (pediatrics: (InskipInskip 2009) a linear radiation dose response was 2009) a linear radiation dose response was b d ith ti t RR f 6 4 t 20b d ith ti t RR f 6 4 t 20 GG d 11 8 t 40d 11 8 t 40 GGobserved with estimate RR of 6.4 at 20 observed with estimate RR of 6.4 at 20 GyGy and 11.8 at 40 and 11.8 at 40 GyGy..

Heart diseaseHeart disease55--7% risk at 10years7% risk at 10years1010--20% at 1020% at 10--20 years20 years8 fold increase in 8 fold increase in valvularvalvular diseasediseaseAll associated with radiationAll associated with radiation

What are the side effects?What are the side effects?Heart disease and breast cancerHeart disease and breast cancer

Involved Involved field Not Extendedfield Not Extended/ / MantleMantleMantleMantle--Lower dose Lower dose 2020--30 30 GyGy Not 45Not 45--50G50G50Gy50Gy--1.8 Gy1.8 Gy--2gy/day and NOT 3 2gy/day and NOT 3 GyGy/port/portNo CobaltNo Cobalt

Current studies on the riskCurrent studies on the risk

Hodgson et al validated radiobiological model Hodgson et al validated radiobiological model taking into consideration cell initiation, inactivation and taking into consideration cell initiation, inactivation and proliferation after varying doses of radiation therapy proliferation after varying doses of radiation therapy p y g pyp y g pyto quantify the excess riskto quantify the excess risk

compared mantle 35 Gy given historically to IFRT 20 Gycompared mantle 35 Gy given historically to IFRT 20 Gythe estimated relative risk was in agreement with the literaturethe estimated relative risk was in agreement with the literaturethe estimated relative risk was in agreement with the literature the estimated relative risk was in agreement with the literature

with the modern treatment using IFRT to 35 Gywith the modern treatment using IFRT to 35 Gythere was an estimated reduction by 63% and 21% for there was an estimated reduction by 63% and 21% for breast and lung cancer, breast and lung cancer, potential reductions of 77% and 57% for IFRT at 20 Gy potential reductions of 77% and 57% for IFRT at 20 Gy

Hancock et al showed:Hancock et al showed:a dose above 30 Gy is significantly associated with cardiac riska dose above 30 Gy is significantly associated with cardiac riska dose above 30 Gy is significantly associated with cardiac risk a dose above 30 Gy is significantly associated with cardiac risk diseasedisease

De bruin showed lower risk of breast cancer with smaller De bruin showed lower risk of breast cancer with smaller fi ld f di tifi ld f di tifield of radiationfield of radiation

Here is what we achievedHere is what we achievedRadiation alone Radiation alone –– EORTC,GHSG HD7 showed CTRT EORTC,GHSG HD7 showed CTRT

is equivalent to EF RTis equivalent to EF RTis equivalent to EF RTis equivalent to EF RT

MOPP or MOPP/ABVMOPP or MOPP/ABVMOPP or MOPP/ABVMOPP or MOPP/ABV–– trial Established ABVD (equivalent OS)trial Established ABVD (equivalent OS)

Extended Field with CT (HD8)Extended Field with CT (HD8)–– ABVD +EF vs. ABVD +IF ABVD +EF vs. ABVD +IF

Drop the dose of RTDrop the dose of RT–– Loeffler compared 40 vs. 30 GyLoeffler compared 40 vs. 30 Gy

Drop staging laparotomyDrop staging laparotomy

GHSG 10 early favorable HLGHSG 10 early favorable HLEarly favorable: low risk stage Early favorable: low risk stage

GHSG 10 early favorable HLGHSG 10 early favorable HLy gy g2x2 randnomisation2x2 randnomisationMedian FU of 5 years Median FU of 5 years FFF 93 % 30GY vs 92% 20GyFFF 93 % 30GY vs 92% 20Gy

GHSG 10 early favorable HLGHSG 10 early favorable HL

Early Unfavorable GHSG 11Early Unfavorable GHSG 11Early Unfavorable GHSG 11Early Unfavorable GHSG 11

GHSG 11 early unfavorable HLGHSG 11 early unfavorable HL

All arms were equivalent, only ABVD +20 Gy was inferior

GHSG 14 early unfavorable HLGHSG 14 early unfavorable HL

1528 patients assigned to :4 ABVD +30Gy RTOr 2 BEACOPPes+2 ABVD+30 Gy RTOr 2 BEACOPPes 2 ABVD 30 Gy RT

5% gain in FFT and 6.2% gain in PFS

Combination of ChemotherapyCombination of ChemotherapypypyFuture GHSG 13Future GHSG 13

Stages I, II without RF (HD13)Stages I, II without RF (HD13)

AVDAVD

AVAV

ABVABV

ABVD ABVD

A B C D

AVD

30 Gy IF- RT

AVABVABVD

30 Gy IF- RT30 Gy IF- RT 30 Gy IF- RT30 Gy IF- RT 30 Gy IF- RT30 Gy IF- RT 30 Gy IF- RT

Treatment ofTreatment ofTreatment of Advanced HodgkinTreatment of Advanced Hodgkin’’ssTreatment of Treatment of Treatment of Advanced HodgkinTreatment of Advanced Hodgkin ss

Longo et al in 80Longo et al in 80’’ssLongo et al in 80Longo et al in 80 s s MOPP can give a DFS of 66% at 10 yearsMOPP can give a DFS of 66% at 10 years

Santoro et al.:Santoro et al.:superioritysuperiorityp yp yof ABVD+RT (fig)of ABVD+RT (fig)

2 US trials tested 2 US trials tested ABVD vs. MOPP alt. ABVD vs. MOPP/ABV ABVD vs. MOPP alt. ABVD vs. MOPP/ABV

equally effectiveequally effective

Stanford V in advanced stageStanford V in advanced stage

MSKCC experience Stanford experienceMSKCC experience Stanford experienceMSKCC experience Stanford experienceMSKCC experience Stanford experience

Italian study challenging Stanford V in favor of ABVD Italian study challenging Stanford V in favor of ABVD O CO Ccompared to MOPPEBVCADcompared to MOPPEBVCAD

BEACOPPBEACOPP

GHSG HD 9 comparedGHSG HD 9 compared

BEACOPPBEACOPP

GHSG HD 9 compared GHSG HD 9 compared BEACOP BEACOP escalated.escalated. Vs BEACOPPVs BEACOPPbaselinebaseline

Vs. COPP/ABVD Vs. COPP/ABVD

HD 12 HD 12 BEACOPPBEACOPP

Treatment ofTreatment ofFinal Analysis of HD 12Final Analysis of HD 12Treatment of Treatment of Final Analysis of HD 12Final Analysis of HD 12

MetaMeta--analysis on the role of radiation in advanced HLanalysis on the role of radiation in advanced HLMetaMeta analysis on the role of radiation in advanced HLanalysis on the role of radiation in advanced HL

Since the meta analysis Role of Since the meta analysis Role of radiation in advancedradiation in advanced

GELA H89 GELA H89

radiation in advancedradiation in advanced

EORTC showed no benefitEORTC showed no benefit

HD 12 showed a benefit if residual HD 12 showed a benefit if residual on CT (10% in observation arm got RTon CT (10% in observation arm got RT

Use of RT in advancedUse of RT in advancedUse of RT in advancedUse of RT in advancedIndian ExperienceIndian Experience

No consensus yet for advanced stage

Laskar JCO 2003

Use of RT in advanced Pediatric data Use of RT in advanced Pediatric data (Nachman)(Nachman)(Nachman)(Nachman)

All t i l d d-All stages included -COPP/ABV

Group 1= early no RFGroup 1= early no RFGroup 2= early +AFGroup 3= stage IV

Nachman 2002 JCO

Standard of CareStandard of CareStandard of Care Standard of Care

Stage I,IIA No risk factorsStage I,IIA No risk factors

ABVD 2 cycles +IFRT/ INRT 20 GyABVD 2 cycles +IFRT/ INRT 20 GyABVD 2 cycles IFRT/ INRT 20 GyABVD 2 cycles IFRT/ INRT 20 GyStage I,IIA + risk factorsStage I,IIA + risk factors

ABVD 4 cycles + IFRT/ INRT 30 GyABVD 4 cycles + IFRT/ INRT 30 GyABVD 4 cycles + IFRT/ INRT 30 GyABVD 4 cycles + IFRT/ INRT 30 Gy2 BEACOPPes.+2 ABVD +IFRT 30 Gy2 BEACOPPes.+2 ABVD +IFRT 30 Gy

Advanced stageAdvanced stageAdvanced stageAdvanced stage6ABVD or BEACOPP ? IFRT for bulky sites/ 6ABVD or BEACOPP ? IFRT for bulky sites/ residual mass on CTresidual mass on CTresidual mass on CTresidual mass on CT

Hot topicsHot topicsHot topicsHot topics

Chemotherapy alone/ using PET to stratifyChemotherapy alone/ using PET to stratify

Use Use of RT in advanced stageof RT in advanced stage

Use Use of RT in relapsed /of RT in relapsed /BMTBMT

Use of technology to decrease side effectsUse of technology to decrease side effects

Canadian Trial: Chemotherapy aloneCanadian Trial: Chemotherapy alone405 t t I405 t t I IIA b lkIIA b lk405 pts stage I405 pts stage I--IIA non bulkyIIA non bulky

Canadian Trial: Chemotherapy Canadian Trial: Chemotherapy llalonealone

OS

-14 additional second cancers were reported, 10 in radiation arm-Use of extended field is not justified

Canadian Trial: Chemotherapy aloneCanadian Trial: Chemotherapy aloneCanadian Trial: Chemotherapy aloneCanadian Trial: Chemotherapy alone

Problems:Problems:Problems:Problems:–– Use of Extended Field Use of Extended Field

Chemotherapy to EF+ChemotherapyChemotherapy to EF+ChemotherapyChemotherapy to EF+ChemotherapyChemotherapy to EF+Chemotherapy–– Use of more chemotherapyUse of more chemotherapy

6 cycles of chemotherapy6 cycles of chemotherapy6 cycles of chemotherapy6 cycles of chemotherapy

HD6/NCIC 2012 treatment

Stanford: Stanford: LongLong--term followterm follow--up is available from up is available from retrospective data onretrospective data on chemo+modernchemo+modern XRTXRTretrospective data on retrospective data on chemo+modernchemo+modern XRTXRT

Advani et al., IJROBP 2011

H10 EORTC /GELA ROLE OF PET IN H10 EORTC /GELA ROLE OF PET IN EARLY FAVORABLEEARLY FAVORABLEEARLY FAVORABLEEARLY FAVORABLE

H10 EORTC /GELA ROLE OF PET IN H10 EORTC /GELA ROLE OF PET IN EARLY FAVORABLEEARLY FAVORABLEEARLY FAVORABLEEARLY FAVORABLE

PET in HD 15PET in HD 15Role of PET /HD 15Role of PET /HD 15PET in HD 15PET in HD 15Role of PET /HD 15Role of PET /HD 15

Use of PETUse of PETUse of PETUse of PET

HDHD--16: Early stages:16: Early stages: 2 ABVD2 ABVD PET: neg: 1 ABVD NO RTPET: neg: 1 ABVD NO RTPET pos: 2 BEA escPET pos: 2 BEA esc PET+:RTPET+:RT

HDHD--17: Intermed.stages:17: Intermed.stages: 2BEA esc PET neg: 2 ABVD no RT2BEA esc PET neg: 2 ABVD no RTPET pos: 2 BEA esc +/PET pos: 2 BEA esc +/-- RTRT

HDHD--18: Adv. Stages: 18: Adv. Stages: neg neg 44--6 ABVD6 ABVD PET negPET neg nilnil

2 BEA2 BEA PETPET2 BEA esc2 BEA esc PETPETpospos 22--4 BEA esc PET4 BEA esc PET neg: nilneg: nil

PETPET pos: RTpos: RT

Use of RT Use of RT Progression, relapse, BMTProgression, relapse, BMT

1-Radiation has to be usedin any radiotherapy naïve patients

IFRT Can not be the sole modalityIFRT Can not be the sole modality

2-For primary progressive transplant has T b th t tTo be the next step

Radiation can be considered before salvage chemo or transplant

3-In the setting of transplant radiation3 In the setting of transplant radiation has to be given either before or after

What is Involved field?What is Involved field?It is the involved fieldIt is the involved field

Yahalom & Mauch, 2002

That is what it meansThat is what it meansThat is what it meansThat is what it means

What is Involved field?What is Involved field?I i h i l d fi ldI i h i l d fi ldIt is the involved fieldIt is the involved field

What is Involved What is Involved nodal?nodal?

It is the involved It is the involved site?site?

• PET CT can• PET CT can change the contouring ( 36% )

• yet no evidence on outcomeoutcome

• To be on the safe side we h ldshould use

both

CT postive PET CT postive PET negative wait negative wait

for chemofor chemo

Steps to Steps to INRTINRTINRTINRT

LiverSpleen

HeartKidney Heart

Word of caution?Word of caution?Word of caution?Word of caution?

1-PET negative CT positive if regressafter chemo should be includedafter chemo should be included 2-CT can not be reliable with no contrast 3-PET positive should be included3-PET positive should be included

If prechemo imaging is missing we resortIf prechemo imaging is missing we resort To involved site.

You have to see to treatYou have to see to treat

INRT radiation:INRT radiation:

You have to see to treatYou have to see to treat

INRT radiation:INRT radiation:–– Do you know the location of disease, do you Do you know the location of disease, do you

have all prechemo imaginghave all prechemo imaginghave all prechemo imaging have all prechemo imaging Did you scan patient in treatment positionDid you scan patient in treatment position

–– Do you know the internal motionDo you know the internal motion–– Do you know lymphoma CTVDo you know lymphoma CTVDo you know lymphoma CTVDo you know lymphoma CTV–– Use breath hold, IMRT, Proton, CT on rail.Use breath hold, IMRT, Proton, CT on rail.

Breath hold / CT on Breath hold / CT on rail for mediastinalrail for mediastinalrail for mediastinal rail for mediastinal

casescases

Breath hold /CT on railfor abdominal lymphomalymphoma

Lymphocyte predominantLymphocyte predominantPathology:

Negative CD 15,30gCD 20 + ,CD 45+,L&H cells, EMA-

Early stage common 80%

Neck presentation

R t d l t tiRare extranodal presentation

European Task Force LymphomaEuropean Task Force Lymphoma

Diehl JCO1999

European Task Force LymphomaEuropean Task Force Lymphomap y pp y p

European Task Force LymphomaEuropean Task Force Lymphoma

European Task Force LymphomaEuropean Task Force Lymphomap y pp y p

LymphocyteLymphocyte--Predominant Hodgkin LymphomaPredominant Hodgkin LymphomaA Retrospective Multicenter Study of the Australasian A Retrospective Multicenter Study of the Australasian

Radiation Oncology Lymphoma GroupRadiation Oncology Lymphoma Group

Long-Term Outcome after Radiotherapy Alone for

Cancer 2005

Lymphocyte predominantLymphocyte predominantDose 30 Gy is sufficient

6 Gy boost can be added for bulky disease

Involved field

Long follow d dneeded

Aggressive LymphomaAggressive Lymphoma

Aggressive LymphomaAggressive Lymphomai WHOi WHOwe are using WHOwe are using WHO

Working formulation:Working formulation:–– LowLow--intermediateintermediate--high high

Based on morphologyBased on morphologyBased on morphologyBased on morphology–– Ignored Ignored immunophenotypingimmunophenotyping–– MissingMissing: Mantle: Mantle, MALT, , MALT,

Anaplastic, viral, TAnaplastic, viral, T--subtypessubtypes

WHO based on:WHO based on:WHO based on:WHO based on:–– Clinical,Clinical,–– ImmunophenotypingImmunophenotypingy gy g–– CytogeneticsCytogenetics

Working formulationWorking formulationWorking formulationWorking formulation

Working formulationWorking formulationWorking formulationWorking formulation

Mantle cell Chronic lymphocytic leukemiaCD 10-, CD 5- CD23 –T 11, 14Aggressive behavior

Chronic lymphocytic leukemiaCD5+ CD10-CD23+Trisomy 3

dAggressive behaviorGI involvement

Low grade

Large B cell LymphomaLarge B cell LymphomaSubtypes, it is not one entity!Subtypes, it is not one entity!

Proposed revision of the WHO 2008Proposed revision of the WHO 2008Proposed revision of the WHO 2008Proposed revision of the WHO 2008

EtiologyEtiologygygystill unknown for moststill unknown for most

HIV ith l CD4 tHIV ith l CD4 tHIV with low CD4 count HIV with low CD4 count HyperHyper--endemic malaria and childhood EBV = endemic malaria and childhood EBV = BurkittBurkittEBV infection=EBV infection=EBV infection=EBV infection=Angioimmnoblastic,T/NK cell, lymphomatous hyperplasia Angioimmnoblastic,T/NK cell, lymphomatous hyperplasia

Gluten enteropathy =Gluten enteropathy =Gluten enteropathy Gluten enteropathy enteropathic associated T cell lymphomaenteropathic associated T cell lymphoma

Immunosuppression: primary or secondaryImmunosuppression: primary or secondaryChronChron’’s, use of methotrexate, use of interferon, kidney transplants, use of methotrexate, use of interferon, kidney transplant

Chronic inflammation Chronic inflammation (accumulation of abnormal growth promoting cytokines cells IL6(accumulation of abnormal growth promoting cytokines cells IL6(accumulation of abnormal growth promoting cytokines cells IL6(accumulation of abnormal growth promoting cytokines cells IL6

Genes signature: Genes signature: ggActivated BActivated B--cell vs. Germinal center B cell likecell vs. Germinal center B cell like

Upfront risk stratificationUpfront risk stratification

Diagnosis/Pathology: Core biopsyDiagnosis/Pathology: Core biopsyImmunohistochemistry (Hans algorithm)Immunohistochemistry (Hans algorithm)Immunohistochemistry (Hans algorithm) Immunohistochemistry (Hans algorithm)

BCL6, CD10, MUM1/IRF4 BCL6, CD10, MUM1/IRF4

Gene expression profileGene expression profileGC B cellGC B cellABCABCPMLPML

Morphologic Morphologic ImmunoblasticImmunoblasticC t bl tiC t bl tiCentroblasticCentroblastic

Typical panel: Typical panel: CD20+, CD45+, CD3CD20+, CD45+, CD3--, CD138, CD138--, BCL2, , BCL2, BCL6 CBCL6 C mycmycBCL6, CBCL6, C--mycmyc

Identify the double hit Identify the double hit

Upfront risk stratificationUpfront risk stratificationPresentation: 6Presentation: 6thth decade, 1/3 bulky disease, 40 % decade, 1/3 bulky disease, 40 % extranodalextranodal, 20% marrow , 20% marrow involvementinvolvementStaging work up: blood work, b2 Staging work up: blood work, b2 microglobulinmicroglobulin, liver kidney function, PET , liver kidney function, PET g g p ,g g p , gg , y ,, y ,CT/diagnostic CT with contrastCT/diagnostic CT with contrastDetermine special locations: Determine special locations: paranasalparanasal sinus, sinus, testicular_____braintesticular_____brain invasion invasion

LP is neededLP is needed

Adverse factor

Risk group Number of factors

5 year DFS(%)

5 year OS (%)

Age > 60 Low 0-1 70 73PS ≥ 2 Low/Intermedi

ate2 50 51

LDH > normal High/Intermediate

3 49 43

Extranodal 4-5 40 26sites ≥ 2 Stage III-IV

Prognostic factors modelPrognostic factors modelAPLESAPLESAPLESAPLES

The International Non Hodgkin'sThe International Non-Hodgkin's Lymphoma Prognostic Factors ProjectNEJM, 1993

For practical PurposesFor practical Purposesb f d idi thb f d idi thbefore deciding on therapybefore deciding on therapy

Limited :Limited :Limited : Limited : Stage I and IIStage I and IINo B symptomsNo B symptomsNo B symptomsNo B symptoms< 10 cm mass< 10 cm mass

Advanced:Advanced:Advanced:Advanced:Stage III and IVStage III and IVB symptomsB symptomsy py p> 10 cm> 10 cm

IPI score, gene signature, Ki 67%, IPI score, gene signature, Ki 67%, , g g , ,, g g , ,double hit. double hit.

Limited stage DLBCLLimited stage DLBCLgg

Reason for using CHOPReason for using CHOPReason for using CHOPReason for using CHOP

Limited stage DLBCLLimited stage DLBCLLimited stage DLBCLLimited stage DLBCL

Cyclophosphamide 750mg/m2

Doxorubicine 50 mg/m2

Vincristine 1.4 mg/m2 not exceeding 2mg

Prednisone 40 mg/m2Prednisone 40 mg/m2

CHOP vs. RCHOPCHOP vs. RCHOPCHOP vs. RCHOP CHOP vs. RCHOP

ACVBP ACVBP

Adriamycin 75mg/m2y g

Cyclophosphamide 1200/m2

Vindesine 2m/m2Vindesine 2m/m2

Bleomycine 10mg day 1,5

Prednisone 60mg/m2 d1-5

Methotrexate 3g/m2 + LeucovorinEtoposide 300mg/m2Ifosphamide 1500/m2Cytarabine 100mg/m2

GELA

DADA--EPOCHEPOCH--RR

Wilson NCI

Treatment DLBCLTreatment DLBCLTreatment DLBCLTreatment DLBCL

Limited stage:Limited stage:Limited stage: Limited stage: –– Chemotherapy +RadiationChemotherapy +Radiation

Role of Radiation in early stageRole of Radiation in early stage–– The benefit is still challenged The benefit is still challenged gg

Role of RadiotherapyRole of RadiotherapyRole of RadiotherapyRole of Radiotherapy

4 trials determine the standard:4 trials determine the standard:4 trials determine the standard:4 trials determine the standard:–– ECOG, SWOG, 2 GELAECOG, SWOG, 2 GELA

2 diff t t k h b t2 diff t t k h b t–– 2 different take home message between 2 different take home message between medical oncologist and the radiation medical oncologist and the radiation oncologistoncologistoncologistoncologist

ECOG 1484ECOG 1484Despite more bulky disease in RT arm-PR had excellent DFS 63% at 6y-6% gain in OS not statistically significant6% gain in OS not statistically significant-5,10,15 estimates: RT group 82%, 78%,78%

No RT group 71, 67%,64%

73%3%

56%

75%56%

Horning JCO 2004

SWOG 8736 SWOG 8736 8 CHOP vs 3 CHOP+RT8 CHOP vs 3 CHOP+RT8 CHOP vs. 3 CHOP+RT8 CHOP vs. 3 CHOP+RT

77% 82%

64%72%

Stage I bulky, stage II, 1 Stage I bulky, stage II, 1 extranodalextranodalDose 40Dose 40--55Gy55GyMore cardiac death in 8 CHOPMore cardiac death in 8 CHOP

Miller 1998

SWOG 8736 SWOG 8736 8 CHOP vs 3 CHOP+RT8 CHOP vs 3 CHOP+RT8 CHOP vs. 3 CHOP+RT8 CHOP vs. 3 CHOP+RT

Updated results: Updated results: OS curves cross at 9 years OS curves cross at 9 years DFS cross at 7 yearsDFS cross at 7 years

15 Late relapses (515 Late relapses (5--10) in abbreviated chemo arm10) in abbreviated chemo arm15 Late relapses (515 Late relapses (5 10) in abbreviated chemo arm10) in abbreviated chemo arm8 in the chemotherapy arm8 in the chemotherapy arm

OS IPI score 0 =94%OS IPI score 0 =94%

OS IPI =1 =71%OS IPI =1 =71%

More chemotherapy is needed for higher risk patientsMore chemotherapy is needed for higher risk patients

Miller 1998

GELA 89GELA 89--01: < 60 years01: < 60 yearsACVBP vs 3CHOP/ RTACVBP vs 3CHOP/ RTACVBP vs. 3CHOP/ RTACVBP vs. 3CHOP/ RT

90%

81%90%

81%

••Median time to relapse was 21 m vs. 15 mMedian time to relapse was 21 m vs. 15 mBut the Relapse at initial site:But the Relapse at initial site:pp41 % (ACVBP) vs. 23% (CHOP+RT)!!41 % (ACVBP) vs. 23% (CHOP+RT)!!Out of field 38%(ACVBP) vs. 72% Out of field 38%(ACVBP) vs. 72% (CHOP+RT)(CHOP+RT)

••16 second malignancies16 second malignancies(7 ACVBP, 9 CHOP+RT ((7 ACVBP, 9 CHOP+RT (3/9 in field3/9 in field))

GELA > 60GELA > 604CHOP vs. 4 CHOP+RT4CHOP vs. 4 CHOP+RT

Relapse:chemo 47 % initial site

61%

64%

chemo 47 % initial sitechemo RT 21% initial site

Inferior outcome for both armsInspite of the low risk group

72%

68%

Conclusions from the 4 trialsConclusions from the 4 trials

Alth h SWOG d GELA 93Alth h SWOG d GELA 93 11Although SWOG and GELA 93Although SWOG and GELA 93--1 are 1 are used to refute the role of radiationused to refute the role of radiation–– The real message is radiation can not The real message is radiation can not

replace inadequate replace inadequate chemotherapychemotherapyI hI h Ri i bRi i bIn the preIn the pre--Rituximab eraRituximab eraHigher dose, large field of radiationHigher dose, large field of radiationNon consistency in patients Non consistency in patients characteristics or outcomecharacteristics or outcome

Bullky is a continuousVariable, > 10 cm suggested

Pfreundschuh 2008

Phan 2010

Phan 2010

Radiation in advanced DLBCLRadiation in advanced DLBCLRadiation in advanced DLBCLRadiation in advanced DLBCL

Conclusion for limited stage DLBCLConclusion for limited stage DLBCL

Consolidation radiation should be recommended Consolidation radiation should be recommended for limited stage,for limited stage,Abbreviated chemo should be cautiously given to:Abbreviated chemo should be cautiously given to:

Worrisome featuresWorrisome featuresHead neck sitesHead neck sitesN t t CNSN t t CNSNext to CNSNext to CNSBulky sitesBulky sitesHigh Ki67%High Ki67%High Ki67%High Ki67%

IFRT/INRTIFRT/INRTIFRT/INRTIFRT/INRT30 Gy30 Gy-- 6 Gy boost (for residual mass on CT)6 Gy boost (for residual mass on CT)

PET negative CT residual massPET negative CT residual massMDACCMDACCMDACCMDACC

Role of PET scanRole of PET scan

There was a complete agreement on the interim PET reading in 68-71% 3 nuclear medicine physician blinded to the actual results

Trials as of now are conflicting for the benefit (GELA vs. Italian)As of now it should not be used to determine the length of therapyAs of now it should not be used to determine the length of therapyOr the need for RT

Interim PET can not be fully trustedInterim PET can not be fully trusted

MDACC data role of midterm PETMDACC data role of midterm PET

51.

00

51.

00

Positive Midterm PET is predictive DFS,OS for al 296 0.

250.

500.

75O

vera

ll su

rviv

al

0.25

0.50

0.75

Ove

rall

surv

ival

0.00

0 2 4 6 8 10Interval FU Years

Mid cycle PT = Negative Mid cycle PT = Positive

0.00

0

0 2 4 6 8 10Interval FU Years

Mid cycle PT = Negative Mid cycle PT = Positive

Positive Midterm PET is no predictive DFS,OS all patients receiving consolidation RT

751.

00

751.

00al

0.25

0.50

0.7

Ove

rall

surv

ival

0.25

0.50

0.7

Pro

gres

sion

free

sur

viva

0.00

0 2 4 6 8 10Interval FU Years

Mid cycle PT = Negative Mid cycle PT = Positive

0.00

0 2 4 6 8 10Interval FU Yearsanalysis time

Mid cycle PT = Negative Mid cycle PT = Positive

Intensive chemotherapyIntensive chemotherapypypy

RCHOP 14RCHOP 14ACVBPACVBPDADA--EPOCH REPOCH RHigh dose therapy/Transplant No evidenceHigh dose therapy/Transplant No evidenceHigh dose therapy/Transplant, No evidenceHigh dose therapy/Transplant, No evidence

How to manage stage II DLBCLHow to manage stage II DLBCLPETPET-- large infiltrative mass in the gastrohepatic ligament infiltrating the large infiltrative mass in the gastrohepatic ligament infiltrating the

How to manage stage II DLBCLHow to manage stage II DLBCLg g p g gg g p g g

adjacent lesser curvature of the stomach. Discrete adenopathy is identified adjacent lesser curvature of the stomach. Discrete adenopathy is identified along the common hepatic artery and portocaval nodesalong the common hepatic artery and portocaval nodes

St IIE

R CHOP

Stage IIE

R-CHOPX cycles?XRT

TreatmentTreatmentTreatmentTreatmentPre-Chemo

Primary mediastinal lymhomaPrimary mediastinal lymhomaPrimary mediastinal lymhomaPrimary mediastinal lymhoma

Young femalesYoung femalesggStage I and IIStage I and IIPrognosis is controversialPrognosis is controversialRadiation is standard in most centersRadiation is standard in most centers–– 39.6 Gy to initial involved sites39.6 Gy to initial involved sites

Chemotherapy:RCHOP or RMACOB Chemotherapy:RCHOP or RMACOB –– Reported 3 years DFS 70Reported 3 years DFS 70--80%80%

Duplicating the outcome and feasibility of administering the regimen Duplicating the outcome and feasibility of administering the regimen

Chemotherapy toxicity was not mentioned (4% death from previous publication)Chemotherapy toxicity was not mentioned (4% death from previous publication)–– Who survived therapy?Who survived therapy?

S d li i hS d li i h idid i h f ll ii h f ll iSecond malignancy with Second malignancy with EtoposideEtoposide is worth followingis worth following

Dose paintingDose paintingDose paintingDose painting

Dose 30Dose 30 39 639 6 GyGyDose 30Dose 30--39.6 39.6 GyGy

Primary mediastinalPrimary mediastinalPrimary mediastinalPrimary mediastinal

I I do not want to give RT to every bodydo not want to give RT to every bodylth h i h d i flth h i h d i f

I am suggesting to use radiation in casesI am suggesting to use radiation in cases

although in my hand is very safealthough in my hand is very safe

I am suggesting to use radiation in cases I am suggesting to use radiation in cases that is neededthat is needed

Do not give more chemotherapy to avoidDo not give more chemotherapy to avoid–– Do not give more chemotherapy to avoid Do not give more chemotherapy to avoid radiationradiation

–– Causing risk of deathCausing risk of deathgg

–– Depletion of marrowDepletion of marrow

–– Risk of second leukemia from Risk of second leukemia from EtoposideEtoposide containingcontaining

–– CHF formCHF form AnthracyclineAnthracycline containing regimenscontaining regimens–– CHF form CHF form AnthracyclineAnthracycline containing regimenscontaining regimens

–– Bulk Bulk of disease has to be taking into of disease has to be taking into considerationconsiderationconsiderationconsideration

Any doxorubicin use associated with 29 %Any doxorubicin use associated with 29 %Any doxorubicin use associated with 29 % Any doxorubicin use associated with 29 % CHFCHF

B t ti t ld l > 65B t ti t ld l > 65–– But patients were elderly > 65 But patients were elderly > 65

–– And another SEER dataAnd another SEER data

Diffuse Large B cell LymphomaDiffuse Large B cell LymphomaDiffuse Large B cell LymphomaDiffuse Large B cell Lymphoma

Paranasal sinus

PCNSLPML PBL

DLBCL: TesticleDLBCL: Testicle

Staging: LP is neededStaging: LP is neededStaging: LP is neededStaging: LP is neededStage I but give 6 RCHOP no exceptionStage I but give 6 RCHOP no exceptionRadiation to the testis 30 GyRadiation to the testis 30 GyCNS prophylaxis IT MTX or HD MTXCNS prophylaxis IT MTX or HD MTXp p yp p y

NK cell nasal lymphomaNK cell nasal lymphomaNK cell nasal lymphomaNK cell nasal lymphoma

Rare but aggressiveRare but aggressiveCD 56 +CD 56 +Early stageEarly stageEarly stageEarly stageRadiosensitive: Dose response 50.4 GyRadiosensitive: Dose response 50.4 Gy--54 54 GyGyyyRadiation outcome: Best local control 40Radiation outcome: Best local control 40--67%67%Ch th h d t lCh th h d t lChemotherapy has a modest roleChemotherapy has a modest role

Primary CNS LymphomaPrimary CNS Lymphoma

Treatment: HD MTX basedTreatment: HD MTX basedWhole brain radiation + eyes up to anterior chamberWhole brain radiation + eyes up to anterior chamberWhole brain radiation + eyes up to anterior chamberWhole brain radiation + eyes up to anterior chamber–– Age 60 is cutoff for neurotoxicityAge 60 is cutoff for neurotoxicity–– Dose used to be 45 Gy?Dose used to be 45 Gy?

St l ith t i it t d t 30 % ithSt l ith t i it t d t 30 % ith–– Struggle with neurotoxicity reported up to 30 % with Struggle with neurotoxicity reported up to 30 % with WBRT (>60 years of age)WBRT (>60 years of age)

30 patients treated with MTX based +R followed by WBRT 23.4 if CR2 year PFS 57% OS 67%2 year PFS 57%, OS 67%Reduced dose of RT was not associated with neurocognitive declineExcellent disease control

ConclusionsConclusions

11 Radiation improve DFS inRadiation improve DFS in11--Radiation improve DFS in Radiation improve DFS in early stage especially in bulky early stage especially in bulky disease (ECOG SWOG)disease (ECOG SWOG)disease (ECOG,SWOG)disease (ECOG,SWOG)22--Abreviated chemotherapy Abreviated chemotherapy should be used with caution should be used with caution s ou d be used t caut os ou d be used t caut oRadiation is indicated in sites:Radiation is indicated in sites:–– Testis 30 Gy, paranasal Testis 30 Gy, paranasal y, py, p

sinuses 40Gy, PCNSL 23.4 sinuses 40Gy, PCNSL 23.4 Gy,PML 30Gy,PML 30-- 39.6 Gy (bulky 39.6 Gy (bulky disease)disease)disease)disease)

Low grade LymphomasLow grade Lymphomasg y pg y p

Low grade LymphomasLow grade LymphomasLow grade LymphomasLow grade Lymphomas

Follicular LymphomaFollicular Lymphoma

B cell in origin in > 90%B cell in origin in > 90%2020 30% at least will transform30% at least will transform2020--30% at least will transform 30% at least will transform The majority will present with advanced The majority will present with advanced stagestagestagestage–– Median survival 6Median survival 6--10 years10 years–– 50% BM involvement at presentation50% BM involvement at presentation50% BM involvement at presentation50% BM involvement at presentation

Only 20% are localized (curablity?)Only 20% are localized (curablity?)T(14;18) is pathognomonicT(14;18) is pathognomonicT(14;18) is pathognomonicT(14;18) is pathognomonicNodal and extranodal presentationNodal and extranodal presentation

FLIPI scoreFLIPI scoreFLIPI score FLIPI score

Follicular LymphomaFollicular LymphomaFollicular LymphomaFollicular Lymphoma

Stage I II vs IIIStage I II vs III IVIVStage I,II vs. III, Stage I,II vs. III, IVIV

Grade 1,2 vs. 3a,Grade 1,2 vs. 3a,3b3b–– Presence of Large cellsPresence of Large cells

Standard of care we do not have oneStandard of care we do not have one

No standard of careNo standard of careSingle agent chemotherapySingle agent chemotherapyAlkylating agentsAlkylating agentsRituximabRituximab

With chemo, maintenance, with With chemo, maintenance, with bendamustinebendamustine

InterferonInterferonValcadeValcade ((proteosomeproteosome inhibitor)inhibitor)ValcadeValcade ((proteosomeproteosome inhibitor)inhibitor)FludarabineFludarabineCyclophosphamideCyclophosphamideCyc op osp a deCyc op osp a deAggressive chemotherapyAggressive chemotherapyTransplantTransplantObservationObservation

Involved field radiation for stage IInvolved field radiation for stage I--II G 1II G 1--22

ObservationObservationStanford approachStanford approachStanford approachStanford approach

43 patients stage I,II grade 1,243 patients stage I,II grade 1,2

MDACC/combined modalityMDACC/combined modalityMDACC/combined modalityMDACC/combined modality

10 year OS 80%

What is the standard of careWhat is the standard of carestage I,II grade 1,2stage I,II grade 1,2

Varies among physiciansVaries among physiciansIF radiation is given:IF radiation is given:IF radiation is given:IF radiation is given:–– Definitive: organ +draining lymphaticsDefinitive: organ +draining lymphatics

Dose 30Dose 30--36 Gy36 Gyyy–– Adjuvant: involved field Adjuvant: involved field

Dose 30 GyDose 30 Gy–– 24 Gy can be used24 Gy can be used

Grade 3 a,b: managed like aggressive Grade 3 a,b: managed like aggressive lymphoma :lymphoma :back to same argumentback to same argumentlymphoma :lymphoma :back to same argumentback to same argument

Stage III IVStage III IVStage III,IVStage III,IV

No role for radiationNo role for radiationNo role for radiationNo role for radiation2x 2 Gy can be suggested in some 2x 2 Gy can be suggested in some h t f d i thih t f d i thishort of doing nothingshort of doing nothing

MALT LymphomaMALT Lymphoma

MALT LymphomaMALT LymphomaMALT LymphomaMALT Lymphoma

Prognostic Factors Prognostic Factors ggMALT LymphomaMALT Lymphoma

Poor prognostic factors:Poor prognostic factors:T (11;14)T (11;14)T (11;14)T (11;14)Bulky diseaseBulky diseaseAge > 60Age > 60Age > 60Age > 60Large cell componentLarge cell componentHi h LDH b2Hi h LDH b2 i l b lii l b liHigh LDH,b2 High LDH,b2 microglubulinmicroglubulinPoor KPSPoor KPS

Gastric MALTGastric MALTGastric MALTGastric MALT

Gastric is the most commonGastric is the most commonGastric is the most common.Gastric is the most common.If Associate with H pylori, treatment If Associate with H pylori, treatment

ith ATB ill hi CR i 2/3ith ATB ill hi CR i 2/3with ATB will achieve CR in 2/3 caseswith ATB will achieve CR in 2/3 cases

Sites of InvolvementSites of InvolvementSites of InvolvementSites of Involvement

Be aware of skin malt

Set UpSet Up

Disposition:Disposition:Disposition:Disposition:

30 Gy in 20 Fractions of 1 5 Gy each30 Gy in 20 Fractions of 1 5 Gy each30 Gy in 20 Fractions of 1.5 Gy each30 Gy in 20 Fractions of 1.5 Gy each

TreatmentTreatmentTreatmentTreatmentRadiation 30 Gy/20 FxRadiation 30 Gy/20 Fx

Stomach

ConclusionsConclusionsConclusionsConclusions

Follicular Lymphoma:Follicular Lymphoma:Follicular Lymphoma:Follicular Lymphoma:–– Radiotherapy alone 30 Gy (boost 36yGy)Radiotherapy alone 30 Gy (boost 36yGy)

Ch th + di ti (30 G )Ch th + di ti (30 G )–– Chemotherapy+ radiation (30 Gy)Chemotherapy+ radiation (30 Gy)–– Protocol: RadioimmunotherapyProtocol: Radioimmunotherapy

MALT: Stomach +perigastric areaMALT: Stomach +perigastric area30 Gy/20 Fx30 Gy/20 Fx

PlasmacytomaPlasmacytomayy

History History and physicaland physicalCBC, differential and plateletsCBC, differential and plateletsBUN, BUN, creatininecreatinine, electrolytes, albumin, LDH, calcium, electrolytes, albumin, LDH, calciumBetaBeta--22--microglobulinmicroglobulinQuantitative Quantitative immunoglobulinsimmunoglobulinsSerum protein electrophoresis (SPEP), serum Serum protein electrophoresis (SPEP), serum immunofixationimmunofixation electrophoresis electrophoresis (SIFE)(SIFE)24 hour urine protein electrophoresis (UPEP), free light chains (FLC)24 hour urine protein electrophoresis (UPEP), free light chains (FLC)Skeletal surveySkeletal surveyMRI T, L S spineMRI T, L S spineUnilateral bone marrow aspirate and biopsy and flow Unilateral bone marrow aspirate and biopsy and flow cytometrycytometryConsider PET scanConsider PET scanFor For extramedullaryextramedullary plasmacytomaplasmacytoma: CT and MRI of affected area: CT and MRI of affected area

PlasmacytomaPlasmacytomayy

If anemia, hypercalcemia, renal failure due to multiple myeloma If anemia, hypercalcemia, renal failure due to multiple myeloma and/orand/or

If bone survey with greater than 1 bone lesion, If bone survey with greater than 1 bone lesion, and/orand/or

If bone marrow with clonal plasma cells If bone marrow with clonal plasma cells and/orand/or

MM--protein greater than 2 grams/dL protein greater than 2 grams/dL and/orand/or

24 hour urine protein greater than or equal to 500 mg/day 24 hour urine protein greater than or equal to 500 mg/day and/orand/or

MRI spine with additional lesions MRI spine with additional lesions and/or and/or Decreased uninvolved Decreased uninvolved immunoglobulinsimmunoglobulins

PlasmacytomaPlasmacytomaPlasmacytomaPlasmacytoma

PlasmacytomaPlasmacytomaPlasmacytomaPlasmacytoma

Value of Protein for outcomeValue of Protein for outcome

Reed 2011, Wild C 2002Wilder Cancer 2002

Factors predictive:Factors predictive:Factors predictive: Factors predictive: –– Tumors > 5 cm more failureTumors > 5 cm more failure

P lP l ii–– ParanasalParanasal sinusessinuses–– Lower RT dose < 35 was not associated with Lower RT dose < 35 was not associated with

higher local failurehigher local failurehigher local failurehigher local failure

Th d t 45Th d t 45 GG–– The dose to use 45 The dose to use 45 GyGyCan be lower to areas at marginsCan be lower to areas at margins

Radiation FieldRadiation Field

MRI+ PET +CTMRI+ PET +CTMRI+ PET +CTMRI+ PET +CT–– MRI pick the marrow signalMRI pick the marrow signal

CT lytic lesionCT lytic lesion–– CT lytic lesionCT lytic lesion–– PET actual activityPET actual activity

11 2 i2 i11-- 2 cm margin2 cm marginDose 35Dose 35--45 Gy according to size and critical 45 Gy according to size and critical organsorgansorgansorgans

Vertebral body: No one up one downVertebral body: No one up one downLong bone: Do not treat the whole boneLong bone: Do not treat the whole boneLong bone: Do not treat the whole boneLong bone: Do not treat the whole bone

Multiple MyelomaMultiple Myeloma

Palliative rolePalliative rolePain controlPain controlPrevent fracturePrevent fractureRelieve nerve pressureRelieve nerve pressure

Field: very small (Field: very small (No above and belowNo above and below))Save the marrowSave the marrowBe able to retreatBe able to retreat

Very sensitiveVery sensitiveDose 20Dose 20--24 24 GyGyEven 15 Even 15 GyGy can do itcan do it

Systemic therapy to be considered;Systemic therapy to be considered;Immunotherapy and steroidsImmunotherapy and steroids

Leukemia: Craniospinal/WBRT/TBILeukemia: Craniospinal/WBRT/TBI

Case 1Case 1 # 733129# 733129Mycosis FungoidesMycosis Fungoides

Path: Mycosis FungoidesPath: Mycosis FungoidesProminent epidermotropismPautrier microabscessPautrier microabscessCD 25+ CD3+, CD4+T cell receptor rearrangmentT cell receptor rearrangmentNumerous CD30+ large cells

ibl l ll t f tipossible large cell transformation

Stanford Dual Beam TechniqueStanford Dual Beam Technique

Long SSD with scatter/degrader, dual fields, 6 treatment positions

MDACC TSEI TechniqueMDACC TSEI Technique

60o

PEV

TSEI Treatment PositionTSEI Treatment Position(AP/PA)(AP/PA)(AP/PA)(AP/PA)

Fingers and thumb Fingers and thumb t th & t d dt th & t d dFingers and thumb Fingers and thumb t th & t d dt th & t d dtogether & extendedtogether & extendedPalms of the hands Palms of the hands facing directly towards orfacing directly towards or

together & extendedtogether & extendedPalms of the hands Palms of the hands facing directly towards orfacing directly towards orfacing directly towards or facing directly towards or directly away from the directly away from the beambeam

facing directly towards or facing directly towards or directly away from the directly away from the beambeambeambeamFeet shoulder width apartFeet shoulder width apartPatientPatient’’s chin raised tos chin raised to

beambeamFeet shoulder width apartFeet shoulder width apartPatientPatient’’s chin raised tos chin raised toPatientPatient s chin raised to s chin raised to expose the skin under expose the skin under the chin and the neckthe chin and the neck

PatientPatient s chin raised to s chin raised to expose the skin under expose the skin under the chin and the neckthe chin and the neckArms parallel to plateArms parallel to plateArms parallel to plateArms parallel to plate

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Ann Oncol 2005

Modern TreatmentModern TreatmentComparing Chemo/IFRT vs. RTComparing Chemo/IFRT vs. RT

-No second malignancies at 11.6 years of Follow up

Koontz JCO 2006

Cumulative incidence of CVD 12% at 5 yCumulative incidence of CVD 12% at 5 yCumulative incidence of CVD 12% at 5 y, Cumulative incidence of CVD 12% at 5 y, 22% at 10y.22% at 10y.

40% h d RT k d 30% RT40% h d RT k d 30% RT40% had RT to neck and 30% RT to 40% had RT to neck and 30% RT to mediastinummediastinum

LymphocyteLymphocyte--Predominant Hodgkin LymphomaPredominant Hodgkin LymphomaA Retrospective Multicenter Study of the AustralasianA Retrospective Multicenter Study of the AustralasianA Retrospective Multicenter Study of the Australasian A Retrospective Multicenter Study of the Australasian

Radiation Oncology Lymphoma GroupRadiation Oncology Lymphoma Group

LymphocyteLymphocyte--Predominant Hodgkin Predominant Hodgkin LymphomaLymphomaLymphomaLymphoma

A Retrospective Multicenter Study of A Retrospective Multicenter Study of the Australasian Radiation Oncology the Australasian Radiation Oncology

Lymphoma GroupLymphoma Group

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Ann Oncol 2005