EARLY, INTERMEDIATE EARLY, INTERMEDIATE AND ADVANCED AND ADVANCED

HODGKIN’S LYMPHOMA: HODGKIN’S LYMPHOMA: MODERN TREATMENT MODERN TREATMENT

STRATEGIES STRATEGIES

INTRODUCTIONINTRODUCTION Hodgkin’s disease (HD) is potentially curable malignant Hodgkin’s disease (HD) is potentially curable malignant

lymphoma lymphoma Thomas Hodgkin 1852 described it Thomas Hodgkin 1852 described it It is defined in terms of –microscopic appearance & expression It is defined in terms of –microscopic appearance & expression

of cell surface markersof cell surface markers WHO classified HD into five types- nodular sclerosis, mixed WHO classified HD into five types- nodular sclerosis, mixed

cellularity, lymphocyte depleted, lymphocyte rich HD cellularity, lymphocyte depleted, lymphocyte rich HD {collectively called classic HD} & non lymphocyte predominant {collectively called classic HD} & non lymphocyte predominant HD (NLPHD)HD (NLPHD)

Neoplastic cell in HD is Reed-Sternberg (RS) cell: it comprises Neoplastic cell in HD is Reed-Sternberg (RS) cell: it comprises 1-2% of total tumor mass remainder are variety of mixed 1-2% of total tumor mass remainder are variety of mixed inflammatory cellsinflammatory cells

Most RS cells are of B-cell origin derived from lymph node Most RS cells are of B-cell origin derived from lymph node germinal centre but no longer able to express antibodies, T-cell germinal centre but no longer able to express antibodies, T-cell origin in 1-2% cases onlyorigin in 1-2% cases only

RS cell consistently express CD 30 (Ki-1) & CD 15 (Leu M1) RS cell consistently express CD 30 (Ki-1) & CD 15 (Leu M1) antigens. CD 30 is a marker of lymphocyte activation, CD15 is a antigens. CD 30 is a marker of lymphocyte activation, CD15 is a marker of late granulocyte, monocyte & activated T cell not marker of late granulocyte, monocyte & activated T cell not normally expressed on B cell lineagenormally expressed on B cell lineage

INTRODUCTIONINTRODUCTION Nodular sclerosis HD: 60-80% of all cases, affects mainly Nodular sclerosis HD: 60-80% of all cases, affects mainly

adolescents & young adults, involves mediastinum and other adolescents & young adults, involves mediastinum and other supra diaphragmatic sitessupra diaphragmatic sites

MC HD: 15-30% of all cases, commonly affects abdominal lymph MC HD: 15-30% of all cases, commonly affects abdominal lymph nodes and spleen, pt. usually presents in advanced stage, nodes and spleen, pt. usually presents in advanced stage, common in HIV pt.common in HIV pt.

LD HD: <1% of cases, affects mainly old age and HIV +VE pt., LD HD: <1% of cases, affects mainly old age and HIV +VE pt., usually present with advanced stage, cells shows expression of usually present with advanced stage, cells shows expression of EB virus proteinEB virus protein

LR HD: 5% of cases, requires immunohistochemical diagnosis, LR HD: 5% of cases, requires immunohistochemical diagnosis, clinically similar to MC HDclinically similar to MC HD

NLPHD: 5% of cases, RS cells are infrequent or absent, pop corn NLPHD: 5% of cases, RS cells are infrequent or absent, pop corn cells (nuclei like exposed kernel of corn) are seen, CD 19 & CD 20 cells (nuclei like exposed kernel of corn) are seen, CD 19 & CD 20 +VE (B cell antigens), -ve for CD 15 & CD 30, diagnosis is +VE (B cell antigens), -ve for CD 15 & CD 30, diagnosis is immunohistochemical- express J chain and display CD 45 & ema immunohistochemical- express J chain and display CD 45 & ema (epithelial membrane antigen)(epithelial membrane antigen)

Frequency of HD: US-2.7 cases/100,000, internationally-rare in Frequency of HD: US-2.7 cases/100,000, internationally-rare in Japan and china. In developing countries incidence of MC HD & Japan and china. In developing countries incidence of MC HD & LD HD is higher in contrast NS HD in developed cpuntries.LD HD is higher in contrast NS HD in developed cpuntries.

STAGINGSTAGING Ann Arbor (1971) staging is used- it is a clinical staging and assessed by Ann Arbor (1971) staging is used- it is a clinical staging and assessed by

clinical examination, history and imaging, when staging laparotomies are clinical examination, history and imaging, when staging laparotomies are used as part of staging disease extent is designated as pathologic staging- used as part of staging disease extent is designated as pathologic staging-

Stage1: denotes a single lymph node area or single extra nodal site Stage1: denotes a single lymph node area or single extra nodal site Stage2: denotes two or more lymph nodes area on same side of diaphragm Stage2: denotes two or more lymph nodes area on same side of diaphragm Stage3: lymph node areas on both sides of diaphragmStage3: lymph node areas on both sides of diaphragmStage4: denotes disseminated or multiple involvement of extra nodal organs. Involvement Stage4: denotes disseminated or multiple involvement of extra nodal organs. Involvement

of liver or bone marrow is stage4of liver or bone marrow is stage4 For staging classification spleen is considered to be a lymph node area and For staging classification spleen is considered to be a lymph node area and

involvement of spleen is denoted with suffix Sinvolvement of spleen is denoted with suffix S A or B designations denotes presence or absence of B symptomsA or B designations denotes presence or absence of B symptoms B designation includes presence of one or more of : fever (>38°C), drenching B designation includes presence of one or more of : fever (>38°C), drenching

night sweats & unexplained loss of >10% of body weight within preceding 6 night sweats & unexplained loss of >10% of body weight within preceding 6 mths. A designation is absence of these. An X designation indicates bulky mths. A designation is absence of these. An X designation indicates bulky diseasedisease

Splenic involvement: 1/3 of all pts, 2/3 of MC HD pts, 1/3 of LD HD & NS HD Splenic involvement: 1/3 of all pts, 2/3 of MC HD pts, 1/3 of LD HD & NS HD ptspts

When liver or bone marrow involvement is present spleen is likely to be When liver or bone marrow involvement is present spleen is likely to be involved.involved.

Spread of HD takes place via: lymphatic, hematogenous & direct extensionSpread of HD takes place via: lymphatic, hematogenous & direct extension

INTRODUCTIONINTRODUCTION

Morbidity & Mortality: 5 yrs disease Morbidity & Mortality: 5 yrs disease specific survival rate- stage1 & 2 specific survival rate- stage1 & 2 (90%), stage 3 (84%), stage 4 (65%).(90%), stage 3 (84%), stage 4 (65%).

HD more common in males than HD more common in males than females & in males particularly in females & in males particularly in childrenchildren

Age incidence is bimodal peaking in Age incidence is bimodal peaking in 15-34 yrs & >55 yrs. NS HD in 15-15-34 yrs & >55 yrs. NS HD in 15-34 yrs & MC HD in old & children34 yrs & MC HD in old & children

CLINICAL DIFFERENCES CLINICAL DIFFERENCES B/W HD & NHLB/W HD & NHL

HDHD NHLNHL

1.Cellular derivation unresolved1.Cellular derivation unresolved 90% B – cell, 10% T- cell, rarely 90% B – cell, 10% T- cell, rarely monocyticmonocytic

2.Localised to a single group of LN 2.Localised to a single group of LN Involvement of multiple peripheral LNInvolvement of multiple peripheral LN

3.Spreads by contiguity3.Spreads by contiguity Non contiguous spreadNon contiguous spread

4.Mesnteric LN & Waldeyer's ring 4.Mesnteric LN & Waldeyer's ring rarely involvedrarely involved

Commonly involvedCommonly involved

5.Exta nodal involvement uncommon5.Exta nodal involvement uncommon CommonCommon

6.BM involvement uncommon6.BM involvement uncommon CommonCommon

7.Chromosomal translocation yet to be 7.Chromosomal translocation yet to be describeddescribed

CommonCommon

8. Curability >75%8. Curability >75% <30-40%<30-40%

CLINICAL CLINICAL PRESENTATIONPRESENTATION

Most common is asymptomatic LAP (80% cases), above diaphragm, Most common is asymptomatic LAP (80% cases), above diaphragm, non tender. >1/2 have mediastinal LAP at diagnosis & this is non tender. >1/2 have mediastinal LAP at diagnosis & this is sometimes the initial manifestation. Sub diaphragmatic presentation sometimes the initial manifestation. Sub diaphragmatic presentation of HD is unusual & more common in older malesof HD is unusual & more common in older males

Constitutional symptoms: fever, unexplained wt loss, night sweats- Constitutional symptoms: fever, unexplained wt loss, night sweats- 40% cases. PUO seen occasionally in MC HD older pt with abdominal 40% cases. PUO seen occasionally in MC HD older pt with abdominal site of disease. Intermittent fever in 35% cases, infrequently Pel – site of disease. Intermittent fever in 35% cases, infrequently Pel – Ebstein fever is seen (1-2 weeks of high fever f/b afebrile period of 1-Ebstein fever is seen (1-2 weeks of high fever f/b afebrile period of 1-2 weeks)2 weeks)

Unusual presentations: unexplained itching, cutaneous disorders Unusual presentations: unexplained itching, cutaneous disorders such as erythema nodosum & itchthyosiform atrophy, paraneoplastic such as erythema nodosum & itchthyosiform atrophy, paraneoplastic cerebellar degeneration , nephrotic syndrome, immune hemolytic cerebellar degeneration , nephrotic syndrome, immune hemolytic anemia & thrombocytopenia, hypercalcemia & pain in lymph node anemia & thrombocytopenia, hypercalcemia & pain in lymph node region on alcohol ingestion (is specific for HD but is seen in <10% of region on alcohol ingestion (is specific for HD but is seen in <10% of pts)pts)

Back/bone pain is rare.Back/bone pain is rare. Physical examination: palpable painless LAP, rubbery consistency- Physical examination: palpable painless LAP, rubbery consistency-

cervical (60-80%),axillae (6-20%), inguinal (6-20%). Waldeyer’s ring cervical (60-80%),axillae (6-20%), inguinal (6-20%). Waldeyer’s ring or occipital/ epitrochlear LAP rare. Splenomegaly, hepatomegaly, or occipital/ epitrochlear LAP rare. Splenomegaly, hepatomegaly, SVC syndrome due to mediastinal LAP, CNS symptoms ( multi focal SVC syndrome due to mediastinal LAP, CNS symptoms ( multi focal leukoencephalopathy)leukoencephalopathy)

ETIOLOGYETIOLOGY

Epstein- Barr virus in 50% cases- Epstein- Barr virus in 50% cases- more in MC HD (60-70%) than NS HD more in MC HD (60-70%) than NS HD (15-30%)(15-30%)

100% of HIV associated HD are EBV 100% of HIV associated HD are EBV +ve+ve

HIV infection is associated with HIV infection is associated with higher incidence of HD, but HD is not higher incidence of HD, but HD is not a AIDS defining neoplasma AIDS defining neoplasm

HLA-DP allele more common in HDHLA-DP allele more common in HD

INVESTIGATIONSINVESTIGATIONS BIOCHEMICAL: ESR- elevated level poor BIOCHEMICAL: ESR- elevated level poor

prognosis, LDH- correlate with bulk of prognosis, LDH- correlate with bulk of disease, CBC- anemia of chronic disease, disease, CBC- anemia of chronic disease, lymphopenia, neutrophilia, eosinophilia. lymphopenia, neutrophilia, eosinophilia. Serum creatinine – for nephrotic syndrome, Serum creatinine – for nephrotic syndrome, ALP- liver/bone marrow involvement, elevated ALP- liver/bone marrow involvement, elevated serum calcium and sodium, hypoglycemia serum calcium and sodium, hypoglycemia (due to presence of insulin auto antibodies)(due to presence of insulin auto antibodies)

HIV test : as anti retroviral therapy can HIV test : as anti retroviral therapy can improve outcome in +ve ptsimprove outcome in +ve pts

Serum cytokines: IL 6, IL 10 & soluble CD 25 Serum cytokines: IL 6, IL 10 & soluble CD 25 (IL 2 receptor)(IL 2 receptor)

INVESTIGATIONSINVESTIGATIONS CECT- chest, abdomen & pelvis to look for LAP, splenomegaly with or CECT- chest, abdomen & pelvis to look for LAP, splenomegaly with or

without focal parenchymal abnormality, lung nodules or parenchymal without focal parenchymal abnormality, lung nodules or parenchymal infiltrates, mediastinal mass (LAP)infiltrates, mediastinal mass (LAP)

Mediastinal LAP is a very common finding in classic HD but Mediastinal LAP is a very common finding in classic HD but uncommon in NLPHDuncommon in NLPHD

Gallium 67 scan/PET scan. PET scan is more sensitive than Ga 67 Gallium 67 scan/PET scan. PET scan is more sensitive than Ga 67 scanscan

A pretreatment scan is valuable as a baseline comparison for PET A pretreatment scan is valuable as a baseline comparison for PET scan obtained to assess response to therapyscan obtained to assess response to therapy

Staging laparotomies (biopsy of liver, splenectomy & biopsy from Staging laparotomies (biopsy of liver, splenectomy & biopsy from multiple lymph nodes i.e. para aortic, mesenteric, portal & splenic multiple lymph nodes i.e. para aortic, mesenteric, portal & splenic hilar region if enlarged) were once popular for most patients with HD hilar region if enlarged) were once popular for most patients with HD but are now done rarely because of an increased reliance on systemic but are now done rarely because of an increased reliance on systemic rather than local therapy. The procedure can be helpful in rare cases rather than local therapy. The procedure can be helpful in rare cases where radio therapy is considered as sole t/t of early stage HDwhere radio therapy is considered as sole t/t of early stage HD

Other tests: pleural tap, lumbar puncture where indicatedOther tests: pleural tap, lumbar puncture where indicated A histological diagnosis is always required: excision LN Bx is required A histological diagnosis is always required: excision LN Bx is required

as LN architecture is important for histological classification as LN architecture is important for histological classification In neck LAP due to H&N cancer FNA is advised as initial diagnostic In neck LAP due to H&N cancer FNA is advised as initial diagnostic

step f/b excisional biopsy if squamous cell histology is excludedstep f/b excisional biopsy if squamous cell histology is excluded

UNFAVORABLE FACTORS UNFAVORABLE FACTORS IN EARLY STAGE HDIN EARLY STAGE HD

These helps in whether a pt has high or lo These helps in whether a pt has high or lo risk of proving resistant to therapy. following risk of proving resistant to therapy. following factors are considered unfavorable for pt factors are considered unfavorable for pt with stage 1 or 2 disease & if present will with stage 1 or 2 disease & if present will increase the intensity of recommended initial increase the intensity of recommended initial therapy:therapy:

1.1. Bulky disease: defined as mediastinal mass >1/3 of intra Bulky disease: defined as mediastinal mass >1/3 of intra thoracic diameter on CXRAY or >35% of thoracic thoracic diameter on CXRAY or >35% of thoracic diameter at vertebral level T5-6 or >10 cm in diameter diameter at vertebral level T5-6 or >10 cm in diameter on ct scanon ct scan

2.2. ESR ≥ 50 if pt is otherwise asymptomaticESR ≥ 50 if pt is otherwise asymptomatic

3.3. > 3 sites of HD involvement> 3 sites of HD involvement

4.4. The presence b symptoms The presence b symptoms

5.5. The presence of extra nodal diseaseThe presence of extra nodal disease

INTERNATIONAL INTERNATIONAL PROGNOSTIC SCORE FOR PROGNOSTIC SCORE FOR

ADVANCED HDADVANCED HD It is a survey of characteristics at diagnosis & It is a survey of characteristics at diagnosis &

outcome of 5,141 HD pts with either advanced outcome of 5,141 HD pts with either advanced stage disease (stage 3 or 4) or earlier stage stage disease (stage 3 or 4) or earlier stage with systemic features or bulky disease. Of the with systemic features or bulky disease. Of the following characteristics each contribute following characteristics each contribute independently to an increased risk for HD independently to an increased risk for HD progression despite therapy:progression despite therapy:

1.1. S. albumin <4g/dlS. albumin <4g/dl2.2. Hb <10.5g/dlHb <10.5g/dl3.3. Male sexMale sex4.4. Stage 4 disease Stage 4 disease 5.5. Age ≥ 45 yrsAge ≥ 45 yrs6.6. WBC count ≥ 15,000WBC count ≥ 15,0007.7. Lymphocytes count < 600/mm³ or < 8% of total countLymphocytes count < 600/mm³ or < 8% of total count

IPS 0-1: 90% overall survival rates, ≥ 4 only IPS 0-1: 90% overall survival rates, ≥ 4 only 59%59%

PRINCIPAL OF THERAPYPRINCIPAL OF THERAPY Advances in t/t have sought: minimize t/t given to pts with Advances in t/t have sought: minimize t/t given to pts with

early stage low risk disease & safely maximize t/t for pts early stage low risk disease & safely maximize t/t for pts with disease refractory to standard therapieswith disease refractory to standard therapies

Combined modality therapy (CMT): radio therapy (XRT) & Combined modality therapy (CMT): radio therapy (XRT) & chemotherapy is preferred approach in most pts chemotherapy is preferred approach in most pts

Early stage: CMT has synergistic effect limits total Early stage: CMT has synergistic effect limits total exposure to any on agentexposure to any on agent

Advanced stage: involved field XRT used for sites of Advanced stage: involved field XRT used for sites of persistent disease following chemotherapy. XRT to sites of persistent disease following chemotherapy. XRT to sites of disease that were bulky at diagnosis is a standard feature disease that were bulky at diagnosis is a standard feature of Stanford V regimen of Stanford V regimen

A +ve PET scan following therapy correlates strongly with A +ve PET scan following therapy correlates strongly with high risk of relapse , an early attainment of -ve PET scan in high risk of relapse , an early attainment of -ve PET scan in ABVD therapy is a +ve prognostic indicatorABVD therapy is a +ve prognostic indicator

PET/CT scans should be obtained at least 3 weeks & PET/CT scans should be obtained at least 3 weeks & preferably 6-8 weeks following last therapy preferably 6-8 weeks following last therapy

GOAL OF THERAPYGOAL OF THERAPY To induce a complete remission (CR) which is To induce a complete remission (CR) which is

“disappearance of all evidence of disease” evaluated “disappearance of all evidence of disease” evaluated by PET/CT, physical examination & BM examination (if by PET/CT, physical examination & BM examination (if appropriate)appropriate)

A partial response (PR) IS “regression of measurable A partial response (PR) IS “regression of measurable disease & no new site of disease”disease & no new site of disease”

Despite high rate of cure many HD pts relapse: in Despite high rate of cure many HD pts relapse: in these salvage chemotherapy f/b high dose these salvage chemotherapy f/b high dose chemotherapy with autologous stem cell support is chemotherapy with autologous stem cell support is indicatedindicated

NLPHD is clinically distinct from classic HD , presents NLPHD is clinically distinct from classic HD , presents at early stage which can be treated with local at early stage which can be treated with local measures (surgery / radiation) or followed expectantly, measures (surgery / radiation) or followed expectantly, some cases can transform into aggressive NHL some cases can transform into aggressive NHL

RADIATION THERAPYRADIATION THERAPY Classic HD: in combination with chemotherapy Classic HD: in combination with chemotherapy

involved field RT (encompasses only areas of involved field RT (encompasses only areas of observed disease) is used, in regional field therapy observed disease) is used, in regional field therapy adjacent lymph regions are also involvedadjacent lymph regions are also involved

Other fields of historical interests are: Mantle field – Other fields of historical interests are: Mantle field – covering mediastinal cervical & axillary nodes. covering mediastinal cervical & axillary nodes. Inverted Y field – covering para aortic, pelvic & Inverted Y field – covering para aortic, pelvic & inguinal nodes. Sub-total nodal irradiation – mantle inguinal nodes. Sub-total nodal irradiation – mantle field + para aortic nodesfield + para aortic nodes

Doses in CMT are: 30-36 Gy for bulky disease 20-30 Doses in CMT are: 30-36 Gy for bulky disease 20-30 Gy for non bulky disease, when used alone doses are Gy for non bulky disease, when used alone doses are – 30-40 Gy– 30-40 Gy

NLPHD: involved field radiotherapy is recommended NLPHD: involved field radiotherapy is recommended for stage 1A & 2A for stage 1A & 2A

CHEMOTHERAPYCHEMOTHERAPY Induction regimens are those which are given as initial HD Induction regimens are those which are given as initial HD

t/t:t/t:1.1. MOPP: (mechlorethamine, vincristine, procarbazine, prednisone) MOPP: (mechlorethamine, vincristine, procarbazine, prednisone)

was first effective therapy developed by Vincent Devita at national was first effective therapy developed by Vincent Devita at national cancer institute in mid 1960s & is primarily of historical cancer institute in mid 1960s & is primarily of historical importanceimportance

2.2. ABVD (adriamycin, bleomycin, vincristine, dacarbazine): designed ABVD (adriamycin, bleomycin, vincristine, dacarbazine): designed in Italy by Gianni Bonadonna in early 1970s, now standard in Italy by Gianni Bonadonna in early 1970s, now standard regimen for HD, superior to MOPP in terms of disease free survival regimen for HD, superior to MOPP in terms of disease free survival & has lower incidence of sterility & secondary leukemia & has lower incidence of sterility & secondary leukemia

3.3. Stanford V: created at Stanford university by Sandra Honning, Stanford V: created at Stanford university by Sandra Honning, comprises: doxorubicin, vinblastine, mustard, bleomycin, comprises: doxorubicin, vinblastine, mustard, bleomycin, vincristine, etoposide & prednisone. Administered weekly vincristine, etoposide & prednisone. Administered weekly alternating myelosuppressive & non myelosuppressive agents for alternating myelosuppressive & non myelosuppressive agents for two weeks. Involved field RT at the conclusion of 12 weeks two weeks. Involved field RT at the conclusion of 12 weeks regimen is an important part of this regimen. Advantages – broad regimen is an important part of this regimen. Advantages – broad spectrum of drugs, limits exposure & potential side effects of any spectrum of drugs, limits exposure & potential side effects of any single drugsingle drug

4.4. BEACOPP ( bleomycin, etoposide, doxorubicin, cyclophosphamide, BEACOPP ( bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone): developed in Germany by vincristine, procarbazine, prednisone): developed in Germany by Valker Diehl. Dose intensified version of BEACOPP with higher Valker Diehl. Dose intensified version of BEACOPP with higher doses of etoposide, adriamycin, and cyclophosphamide & addition doses of etoposide, adriamycin, and cyclophosphamide & addition of G-CSF for neutrophil support (called ESCALATED BEACOPP) is of G-CSF for neutrophil support (called ESCALATED BEACOPP) is useful in unfavorable advanced HD but it is associated with greater useful in unfavorable advanced HD but it is associated with greater hematologic toxicity & higher incidence of secondary malignancies hematologic toxicity & higher incidence of secondary malignancies including AMLincluding AML

SALVAGE SALVAGE CHEMOTHERAPYCHEMOTHERAPY

Pts who failed induction are candidate for thisPts who failed induction are candidate for this Includes drugs complementary to those failed during Includes drugs complementary to those failed during

induction induction Commonly used regimens are: ICE (ifosfamide, Commonly used regimens are: ICE (ifosfamide,

carboplatin, etoposide) & ESHAP (etoposide, carboplatin, etoposide) & ESHAP (etoposide, methylprednisolone, cytaarabine, cisplatin)methylprednisolone, cytaarabine, cisplatin)

High dose chemotherapy with BM transplantation: High dose chemotherapy with BM transplantation: HDC ablates BM then reinfusion of pts own HDC ablates BM then reinfusion of pts own hematopoietic stem cells (HSC) or donor’s stem cells hematopoietic stem cells (HSC) or donor’s stem cells is done, HSC are obtained by pheresis of peripheral is done, HSC are obtained by pheresis of peripheral blood lymphocytes blood lymphocytes

Conditioning regimen used is BEAM (BCNU, Conditioning regimen used is BEAM (BCNU, etoposide, cytaarabine, melphalan). HSC are etoposide, cytaarabine, melphalan). HSC are administered on day 0 following BEAM.administered on day 0 following BEAM.

STAGE WISE STAGE WISE MANAGEMENTMANAGEMENT

EARLY STAGE LOW RISK DISEASE: EARLY STAGE LOW RISK DISEASE: includes stage 1A or 2A classic HD includes stage 1A or 2A classic HD without unfavorable factors – without unfavorable factors – generally receives 4 cycles of ABVD generally receives 4 cycles of ABVD or 8 cycles of Stanford V f/b involved or 8 cycles of Stanford V f/b involved field radiotherapy. If RT field radiotherapy. If RT contraindicated or not possible then 2 contraindicated or not possible then 2 additional cycles of chemotherapy to additional cycles of chemotherapy to be given following attainment of CRbe given following attainment of CR

INTERMEDIATE STAGEINTERMEDIATE STAGE

EARLY STAGE WITH EARLY STAGE WITH UNFAVOURABLE FACTORS: UNFAVOURABLE FACTORS: includes stage 1 or 2 with bulky includes stage 1 or 2 with bulky disease with or without unfavorable disease with or without unfavorable factors – 4-6 cycles of ABVD or 12 factors – 4-6 cycles of ABVD or 12 weeks Stanford V f/b involved field weeks Stanford V f/b involved field RT RT

ADVANCED OR HIGH RISK ADVANCED OR HIGH RISK DISEASEDISEASE

Include stage 1 or 2 with B symptoms or stage 3 or Include stage 1 or 2 with B symptoms or stage 3 or 4 4

NCCN (national comprehensive cancer network) NCCN (national comprehensive cancer network) guidelines – either 4 cycles of ABVD or 12 weeks guidelines – either 4 cycles of ABVD or 12 weeks of Stanford V f/b restaging with PET/CT scan, if pt of Stanford V f/b restaging with PET/CT scan, if pt has +ve results following ABVD additional 2 cycles has +ve results following ABVD additional 2 cycles are given once CR achieved involved field RT is are given once CR achieved involved field RT is given. If after 12 weeks of Stanford V pt is in CR given. If after 12 weeks of Stanford V pt is in CR or PR then involved field RT is givenor PR then involved field RT is given

EMSO (European society for molecular oncology) EMSO (European society for molecular oncology) recommends – 8 cycles of ABVD or standard dose recommends – 8 cycles of ABVD or standard dose BEACOPP with involved RT applied only to tumors BEACOPP with involved RT applied only to tumors initially >7.5 cm or to sites of residual disease initially >7.5 cm or to sites of residual disease following chemotherapy following chemotherapy

NLPHDNLPHD

Early stage: local excision or Early stage: local excision or involved field RT or expectant involved field RT or expectant management. Advanced stage management. Advanced stage treated as NHL with regimen R-treated as NHL with regimen R-CHOP (cyclophosphamide, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, doxorubicin, vincristine, prednisone, rituximab)rituximab)

HD WITH HIVHD WITH HIV

Treated simultaneously with HAART Treated simultaneously with HAART (2 NRTI+1PI+1NNRTI)(2 NRTI+1PI+1NNRTI)

RELAPSED OR PRIMARY RELAPSED OR PRIMARY REFRACTORY DISEASEREFRACTORY DISEASE

HD which has never entered CR or HD which has never entered CR or relapsed after CR – HDC with HSC relapsed after CR – HDC with HSC transplantation is donetransplantation is done

Steps: salvage chemotherapy → CR Steps: salvage chemotherapy → CR (IF POSSIBIE) → collect HSC from (IF POSSIBIE) → collect HSC from pts blood freeze them → give pts blood freeze them → give myeloablative chemotherapy BEAM myeloablative chemotherapy BEAM → transfuse pt’s HSC into blood → if → transfuse pt’s HSC into blood → if HDC fails → allogenic HSC HDC fails → allogenic HSC tranplantationtranplantation

FOLLOW UP OF FOLLOW UP OF PATIENTSPATIENTS

Most relapse in first 3 yrs after therapyMost relapse in first 3 yrs after therapy Follow every 2-4 mths for first 1-2 years Follow every 2-4 mths for first 1-2 years

& every 3-6 mths for next 3-5 yrs& every 3-6 mths for next 3-5 yrs FU examinations: FU examinations:

1.1. History & physical examinationHistory & physical examination2.2. CBC, LDH, ESR, glucose, lipidsCBC, LDH, ESR, glucose, lipids3.3. TSH: annually in pts of H&N RTTSH: annually in pts of H&N RT4.4. CXRay & CT scan of chest every 3-6 mths for first CXRay & CT scan of chest every 3-6 mths for first

2-3 yrs then at least annually up to 5 yrs2-3 yrs then at least annually up to 5 yrs5.5. Abdomen & pelvis CT every 3-12 mths (if Abdomen & pelvis CT every 3-12 mths (if

indicated)indicated)6.6. PET scan not specifically recommendedPET scan not specifically recommended7.7. Spiral CT chest 5 yrs after for lung cancerSpiral CT chest 5 yrs after for lung cancer8.8. Mammography in female pts annually from 40 yrs Mammography in female pts annually from 40 yrs

or 5-8 yrs after RTor 5-8 yrs after RT

LATE COMPLICATIONS OF LATE COMPLICATIONS OF THERAPYTHERAPY

Treatment related causes exceeds HD as Treatment related causes exceeds HD as predominant causes of death at 15 yrs, predominant causes of death at 15 yrs, these include: these include:

1.1. Cardiac diseasesCardiac diseases2.2. Pulmonary fibrosisPulmonary fibrosis3.3. Secondary cancer / leukemia: low risk with current Secondary cancer / leukemia: low risk with current

regimen . MDS / acute leukemia seen in first 3-8 yrs regimen . MDS / acute leukemia seen in first 3-8 yrs following t/tfollowing t/t

4.4. Breast cancer: mantle radiation, MOPPBreast cancer: mantle radiation, MOPP5.5. Solid tumors: most common secondary malignancy Solid tumors: most common secondary malignancy

following HD is lung cancerfollowing HD is lung cancer6.6. Infertility: MOPP – permanent, not permanent with Infertility: MOPP – permanent, not permanent with

ABVD & Stanford VABVD & Stanford V7.7. INFECTIONSINFECTIONS8.8. HypothyroidismHypothyroidism9.9. Lhermite syndromeLhermite syndrome

CURRENT CLINICAL CURRENT CLINICAL RESEARCHRESEARCH

Three current trials analyze combined Three current trials analyze combined modality protocols comparing ABVD modality protocols comparing ABVD with more intense regimens : EORTC, with more intense regimens : EORTC, H9V & GHSD HD11. studies are H9V & GHSD HD11. studies are comparing 4 cycles of ABVD with 4 comparing 4 cycles of ABVD with 4 cycles of BEACOPP & RT is limited to cycles of BEACOPP & RT is limited to involved field at dose of 20-30 Gyinvolved field at dose of 20-30 Gy

Milan trial sufficiently answered that Milan trial sufficiently answered that radiation fields can be reduced to the radiation fields can be reduced to the involved sites after adequate involved sites after adequate chemotherapy chemotherapy

FUTURE STRATEGIES FOR FUTURE STRATEGIES FOR ADVANCED STAGE HDADVANCED STAGE HD

The aim of any modern t/t in such The aim of any modern t/t in such cases is to: maintain good results cases is to: maintain good results with current therapies, reaching with current therapies, reaching cure rates of >85% but reduce the cure rates of >85% but reduce the still too high acute and lng term still too high acute and lng term toxicitytoxicity

DO WE NEED DO WE NEED CONSOLIDATED CONSOLIDATED

RADIATION?RADIATION? EORTC trial demonstrated that after reaching a CR after 8 EORTC trial demonstrated that after reaching a CR after 8

cycles of effective chemotherapy do not benefits from cycles of effective chemotherapy do not benefits from additive RTadditive RT

80% of secondary AML/MDS in this study were seen in RT 80% of secondary AML/MDS in this study were seen in RT arm, PR pts however showed benefit from complimentary arm, PR pts however showed benefit from complimentary radiation & fared as good as primary CR ptsradiation & fared as good as primary CR pts

GHSG HD12 study demonstrated that after 8 cycles of GHSG HD12 study demonstrated that after 8 cycles of chemotherapy there was no difference b/w RT or non RT chemotherapy there was no difference b/w RT or non RT armsarms

HD 15 trial of GHSG that only pts with PET +ve residual HD 15 trial of GHSG that only pts with PET +ve residual disease are treated with 30 Gy radiationdisease are treated with 30 Gy radiation

Therefore consolidated RT should only be given to HD pts Therefore consolidated RT should only be given to HD pts that only reached a PR after 6-8 course of ABVD or have a that only reached a PR after 6-8 course of ABVD or have a minor response (<70%) with residual nodal lesionminor response (<70%) with residual nodal lesion

Using an escalated BEACOPP for advanced HD only a Using an escalated BEACOPP for advanced HD only a minority (<20%) pts need RT to residual lesions <2.5 cm, minority (<20%) pts need RT to residual lesions <2.5 cm, PET imaging might help to distinguish b/w scar and vital PET imaging might help to distinguish b/w scar and vital tumor tissue in residual lesiontumor tissue in residual lesion

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