Hodgkin's lymphoma early stage management

MANAGEMENT OF HODGKIN’S DISEASEEARLY STAGE

DR. DHARMENDRA SINGHMD PGT DEPT. OF RADIOTHERAPYI.P.G.M.E.& R.KOLKATA

On the basis of histology and pattern of growth

A heterogeneous group of lymphoid neoplasm that originate from lymphoid organs .

LYMPHOMA

Pre germinal,Germinal

centreof lymph

node

LYMPHOMA

HODGKIN’S LYMPHOMA

NON HODGKIN’S LYMPHOMA


B-lymphoid malignancy characterized by the presence of large ATYPICAL cells.

Basically of 2 types &

present in background of inflammatory

cells

Mono nucleated

Multinucleated

Hodgkin’s cellsOr

Mononuclear RS cells

Reed Sternberg(RS) cells

Reed Sternberg cells

Hodgkin’s cells

Large cells 15-45 µm.More than one nuclei.Each nuclei having identical nucleolus.Abundant of cytoplasm.

Similar to RS cells , except in containing single nucleus.Commonly seen in lymphocyte predominant subtype.

VARIANTS OF RS CELLS

Lacunar RS cells .Multilobulated nucleus with large hollow space in cytoplasm

Lymphohistocytic(Lymphocyte predominant) RS cells. Polypoid nucleus like pop corn kernels with moderately abundant cytoplasm

Pleomoprphic RS cells.Nucleus having multiple irregular nucleolus

Mummy RS cellls/Crippled cells.Compact nucleus , no nucleolus and basophilic cytoplasm

Variants of RS cells is the basis of classification of Hodgkin’s lymphoma.

IMPORTANCE OF VARIANTS OF RS CELLS


CLASSICAL HL NODULAR LYMPHOCYTE PREDOMINANT HL

95% 5%

CLA

SSIC

AL

HL

NODULAR SCLEROSIS ( 60-80%)

MIXED CELLULARITY( 15-30%)

LYMPHOCYTE RICH( 5%)

LYMPHOCYTE DEPLETED

< 1%

m/c Mediastinal HL

m/c in India

Best prognosis

Worst prognosis

Clinical Features

Pattern of lymph node involvement is CONTIGUOUS

Clinical Features

Painless swelling of one or more lymph nodes, without a recent infection.

Symptoms stemming from pressure of swollen lymph nodes on nearby organs or structures. They may include a, cough shortness of breath, abdominal pain or swelling, a Horner's syndrome (a neurological problem affecting the face and , eyes due to damage to nerves in the neck), nerve pain and leg swelling.

Fever, either persistent or alternating with periods of normal temperatures, for 14 consecutive days or longer. These fevers usually occur twice daily, usually in the late afternoon and early evening, and rarely are greater than 102° F

Drenching night sweats and/or chills lasting for 14 consecutive days or longer.

Unintentional weight loss (more than 10% over six months).

Total body itching.


NON HODGKIN’S LYMPHOMA

Age Young adults More common in 40-70 yrs

B Symptoms

40% 20%

Spread Contiguous Multiple remote nodal groups involved

Stage at presentation

>80% early stage I and II

>80% late stage III and IV

Nodal groups

Cervical ,thoracic, para-aortic

Mesenteric , para-aortic , thoracic , cervical .

Lymph node regions adopted for staging purpose at Rye symposium on Hodgkin’s disease in 1965.

WORKUP

History & physical examinationCBC, ESRLFT, LDH, Albumin, Urea, Creatinine.Pregnancy test for women of child bearing age.Chest X-ray.CT contrast enhanced.PET scan.Bone marrow biopsy.Echocardiography.For Selected cases:Pulmonary function test(escalated BEACOPP to be used)Pneumococcal vaccination(splenic RT is planned)HIV testing(older patients with advanced stage)

NODAL DISEASE & IMAGING TECHNIQUE

Cross sectional imaging

The introduction of CT scan had major impact on the way lymphoma was staged.

The ability of the CT Scan to demonstrate enlarged LN throughout the body, and associated abnormality in soft tissue structure.

CT Scan become the modality of choice for staging following biopsy .

There is no special advantage of MRI over CT Scan in detection of LNs except for some special cases. As detection of LNs depends on the size criteria.??? LN enlargement is due to lymphoma or inflammation

Is there any lymphoma in normal sized LN as per CT Scan.

Nuclear medicineThe distinction is possible with use of Radio-isotopic studies

FDG PET Scan

Gallium 67 Scan

Less sensitive for LN < 2 cm

& below diaphragm LN

due to low resolution of γ

camera.

Disadvantages of Ga 67 scan

is not seen with FDG PET

scan , thus PET scan is preferred.

Role of PET /CT scan

This imaging technique, when used carefully in conjunction with standard testing, increases the sensitivity of lesion detection, provides an opportunity to monitor the quality of response during treatment, permits separation of fibronecrotic scar tissue from viable tumor, and adds prognostic information.

(A) Shows a coronal section of a patient with involvement of several lymph node regions and the spleen(B) shows a sagittal section of a patient with abdominal lymph node and bone marrow involvement.

Stage IV

Stage I Stage II Stage III

The Ann Arbor staging classification , developed in 1971, is a four-stage system formulated to provide prognostic information and to guide therapeutic decisions.

Staging

Stage I Involvement of single lymph node region (I) or of single extralymphatic organ or site (IE)

Stage II Involvement of two or more lymph node regions on the same side of the diaphragm alone (II) or with involvement of limited, contiguous extralymphatic organ or tissue (IIE)

Stage III Involvement of lymph node regions on both sides of the diaphragm (III), which may include the spleen (IIIS) or limited, contiguous extralymphatic organ or site (IIIE), or both (IIISE)

Stage IV Diffuse or disseminated foci of involvement of one or more extralymphatic organs or tissues, with or without associated lymphatic involvement

In 1988, a meeting was held in the Cotswolds, England, where revisions to the Ann Arbor staging system were made.

The following main changes were made: (1) The use of computed tomography (CT) scanning is allowed to assess disease involvement below the diaphragm.

(2) For stage II disease, the number of anatomic nodal sites is indicated by a subscript (e.g., stage II3).

(3) For stage III disease, upper and lower abdominal involvement was subdivided as III1 and III2,respectively.

(4) Bulky disease is denoted by XI. Mediastinal adenopathy include mass > 10 cmII. Ratio of max. width of mediastinal mass to max.

intrathoracic diameter is > 1 : 3III.Ratio of mediastinal mass to chest diameter at

the T5-6 > .35

Management of early stage Hodgkin’s lymphoma

Early Stage : Lymphoma confined to only one side of diaphragm.

Stage IA/B &

II A/B

Radiotherapy alone

Chemotherapy alone

Combined modality

Risk factors & treatment groups

On the basis of different trials early stage Hodgkin’s lymphoma have Prognostic factors

Bulky disease

Extra nodal involvemen

t

Elevated ESR

≥ 3 LN areas

Rx methods including Weekly small doses for Several weeks.Massive single dose toInvolved site.

1902 by Pusey

using X ray

Untill 1920

Rx were

associated

with darastic

complication

1925, Gilbert used concept of irradiation of adjacent site

1950-1966, Vera

Peters studied

patterns of

spread &

confirmed

Gilbert’s

concept.

In 1973, Kaplan made the point that localized Hodgkin's disease could by cured by radiotherapy

1953, Co

replaced X-

ray units &

higher

doses

allowed.

1966, Lukes laid

out the principles

of staging

necessary for an

approach to

treatment.

Radiation alone

Evolution of Radiation alone

Another tree of Chemotherapy is

in Evolution during same time

Total nodal radiotherap

y

Extended field

radiotherapy

Involved field

radiotherapy

Involved site

radiotherapy

All LN of both sides of

diaphragm

Multiple involved &

uninvolved LN groups of one

side of diaphragm

Field is limited to site of clinically

involved LN groups

Most limited radiation field , includes only involved LN.

30-45 Gy

20-30 Gy

Bilateral cervical , supraclavicular, infraclavicular, axillar , hilar, mediastinal.

Mantle field

Mantle field without mediastinal & hilar LNs.

Mini Mantle

Mantle field without axillary LNs.

Modified Mantle

Inverted “Y “field

Para aortic ,bilateral pelvic,B/L inguinal-femoral lymphatics are involved.Splenic lymphatics are also included in case of its involvement.

Total nodal irradiation

Mantle + Inverted Y + Spleen

Simulation with

Arms - up (to pull axillary LN from chest to

allow for more lung blocking)

or Arms akimbo

(to shield humeral heads and minimize tissue in SCV folds) Head extended This ensures the exclusion of the oral cavity and teeth from the RT fields, and decreases the dose to the mandible

Mantle field

Chin mastoid process tip line.

Lower border T10/11

Junction of

lateral margin

of pectoralis with deltoid muscle, inferior

ly – inferior border

of scapula

/T7

Superiorly - 1.5 to 2cm below the clavicle in order to treat the infraclavicular nodes

Laterally - blocks shield lung & atleast 1cm lung included in lower axilla & 2-4cm of lung in upper axilla in order to treat the axillary lymph nodes

Medially – 1.5-2cm margin around lateral border of tumor

Blocks:Larynx on AP field Humeral heads on AP and PA fields PA cord block (if dose >40 Gy) Lung block Laryngeal block – 2cm wide block from thyroid notch to cricoid.

Posterior spinal cord block – 1.5 cm block from top of field to Bottom of c7 vertebral body in posterior mantle field.

**If pericardial or mediastinal extension, include entire heart to 15 Gy, then block apex of heart. After 30 Gy, block heart beyond 5 cm inferior to carina (unless residual disease).

Lung block

Para aortic field

Paraaortic field covers the paraaortic, celiac, splenic, & hepatic portal lymph nodes as well as splenic pedicle or spleen

Upper border – matched with mantle

Inferior border - at the L4-L5 interspace

Lateral border – edges of transverse processes or about 1.5-2cm lat to border of vertebral bodies (width of 8-10cm)

Superior border – matched with paraaortic field (upper border of L5)

Inferior border – lower border of ischial tuberosity

Laterally - field shaped with blocks to spare iliac wing bone marrow without compromising coverage of iliac lymph nodal chain

Central block - 4 cm block extending from the inferior edge of field & superiorly to sacroiliac joint to protect bladder and rectum.

Pelvic field

Extended mantle field

To avoid need of matching mantle and paraaortic fields

Includes mantle & paraaortic in a single port

T/t delivered in approximately one half the time required for separate fields

↑ed probability of bone marrow suppression & acute morbidities with larger volume treatment

Doses involved nodes 36 to 40Gyuninvolved nodes 30Gy

Side effects of RT

Side effects of RT depend on the irradiated volume, the dose administered, and the technique employed.

They are also influenced by the extent and type of prior chemotherapy, if any, and by the patient's age.

Fatigue ,nausea,vomiting,dry cough

Occipital hair loss

Sore throat

Skin reactions

Dysphagia

Myelosupression

Acute effects of RT

Lhermitte's sign: <5% of patients may feel an electric shock sensation radiating down the backs of both legs when the head is flexed

Seen within 6 weeks to 3 months after mantle-field RT.

Pneumonitis and pericarditis: occur in <5% of patients who have extensive mediastinal disease.

Subacute side effects of RT

Late side effects of RTSubclinical Hypothyroidism in 50% patients who receive >30Gy to neck region

Herpes zooster in first few years in 10-15% patients

Streptococcus pneumoniae and H influenzae infection following splenic radiation.

Infertility: Irradiation to pelvic field effects fertility. It can be prevented by gonadal shielding & oophropexy

Secondary Malignancies: (1-3%)Increased risk of secondary solid tumors (most commonly, lung, breast, and stomach cancers, as well as melanoma) 10 or more years after treatment.

Effects on Bone and Muscle Growth: In children, high-dose irradiation affects bone and muscle growth and may result in deformities

Coronary Artery Disease: Increased risk of coronary artery disease with mediastinal irradiation.

World war

II ,use of

nitrogen

mustard

showed

myelosupressiv

e effect of

nitrogen

mustard.

1946 use of nitrogen mustard in HL found to be effective.

1947

Peterson

published

his report

of N2

mustard on

HL

1970 MOPP regimen described by Devita Jr.

1974- 1982 ,at Milan cancer

Inst. Compared ABVD vs MOPP.

Long term toxicity of RT leads many

investigators to search for CT only approach

for HL.CT may be

single agent or combined.

Evolution of Chemotherapy alone

Agent Dose Limiting Toxicity

Nitrogen Mustard BMT, N&V, LeukemogenicVincristine Neurotoxicity, constipation & ANS disturbanceProcarbazine BMT, N&V, Leukemogenic, Infertility, Psychotic

reactions, hypertensive crisis with MAO inhibitorCyclophosphamide BMT (Thrombocytopenia), SIADH, N&V, Bladder

toxicityChlorambucil BMT (Neutropenia, Anemia), N&V, LeukemiaVinblastine BMT (Neutropenia), Mucositis, HypertensionDoxorubicin BMT, Alopecia, N&V, Diarrhea, Cardiac, RT recall Bleomycin Fever, Skin toxicity, Pulmonary toxicityDTIC BMT, Flu like syndrome , Hepatic vein thrombosisEtoposide BMT (leucopenia & neutropenia), LeukemiaCisplatin Neurotoxicity, Ototoxicity, Nephrotoxicity

Response rates were in the order of 50-60%

CR were much lower in the tune of 10-30%

Responses were not durable with unmaintained remissions lasting ~ 3 months.

Patients on maintenance chemotherapy had remissions lasting for ~ 8 months.

Therefore multi agent CCT began to be developed

Problem with Single agent

MOPPNitrogen Mustard 6 mg/m2 I/V D1 and D8Vincristine (Oncovine) 1.4 mg/m2 IV D1and D8Procarbazine 100 mg/m2 D1 to D14Prednisone 40 mg/m2 D1 to D 1428 day cycle.

A highly toxic regimenSpecial precautions indicated while handling nitrogen mustard – can cause vesication on contact with skin or mucosa.Main dose limiting toxicity is myelopsuppresssion and it may appear as early as 24 hrs after drug administration.Prior to availability of effective anti emetic agents nausea and vomiting were severe enough to merit indoor admission in all patients prior to chemotherapy.Additional late toxicity also substantial:

2nd malignancies : HematologicalInfertility and premature menopauseNeurotoxicity : Due to vincristine

Toxicity

Result

CR of 81% documentedLong term disease free survival rates (10 yrs) in the range of 56%

COPPCyclophosphamide 650 mg/m2 D1 and D8Vincristine 1.5mg/m2 D1 and D8Procarbazine 100 mg/m2 D1 to D 14Prednisone 40 mg/m2 D1 to D 1428 day cycle.

MOPP variants

Nitrogen Mustard 6mg/m2 IV D1 and D8Vinblastine 6 mg/m2 IV D1 and D8Procarbazine 100 mg/m2 PO D1 to D14Prednisone 40 mg PO D1 to D14

MVPP

BCVPP BCNU 100mg/m2 IV D1Cyclophosphamide 600 mg/m2 IV D1Vinblastine 5 mg/m2 PO D1Procarbazine 50 mg/m2 PO D1 and 100 mg/m2 D2 to D20Prednisone 40mg PO D1 to D20

ABVDInj. Adriamycin 25 mg/m2 IV D1 and D15Inj. Bleomycin 10 U/m2 IV D1 and D15Inj. Vinblastine 6 mg/m2 IV D1 and D15Inj. Dacarbazine 375 mg/m2 D1 and D1528 day cycle.

Toxicity MOPP ABVDLeucopenia 56% 45%Thrombocytopenia 16% 15%Paraesthesias 72% 5%Loss of Hair 48% 75%Skin Changes - 40%

Stage set for

evaluation of ABVD.

Combined modality

HL is highly chemosensitive .With the help of chemotherapy ,it is possible to reduce both dose and extent of irradiation ,while still maintaining high cure rates.

Trials NCI-C , India (TATA

MEMORIAL), H9F,CCG have shown that

addition of RT after CR of CT improves EFS and

some trials OS

ABVD RT

STANFORD V

BEACOPP escalated

RT

RT

Bulky diseaseExtra nodal sites≥ 3 nodal sitesESR >50 in absence of B symptomsESR >30 in presence of B symptoms.

Risk factors

Presence of these risk factors leads to stage unfavourable.

Absence of these factors leads to stage favourable.

Stage I/II favourable Stage I/II unfavourable

ABVD 2-4 cyclesIFRT

Follow up

ABVD 4-6 cyclesIFRT

Follow up

Treatment of Stage I/II

(favourable)

ABVD 2-4

Restage

with PET CT

Deauville1-3

Deauville5b

Deauville5a

Deauville4

IFRT

Biopsy

Restage

Deauville

1-3Deauvill

e4-5

N

P

IFRTBiops

y

Biopsy

Biopsy

P

N

N

P

NP

IFRT

Refractory

Ref

Followup

IFRT

Followup


(unfavourable)

Bulky

ABVD 4

Restage

with PET CT

Deauville1-3

Deauville5b

Deauville5a

Deauville4

ABVD 2 IFRT

Follow up

IFRT

ABVD 2

Restage

Deauville 1-3

Deauville 4-5a

Deauville 5b

Biopsy

Biopsy

N

P

P

NIFRT to bulky site

Refractory

ABVD 4

Restaging

Deauville 4

ABVD 2

Restaging

Deauville 1-3

Deauville 5b

Deauville 4-5a

IFRT

Biopsy Biopsy

N P P N

IFRT or Refractory

IFRT

Follow up

Follow up

Follow up with close interval


(unfavourable)

Bulky


(unfavourable)

Nonbulky

ABVD 2

Restage

with PET CT

Deauville1-2

Deauville5b

Deauville5a

Deauville3-4

ABVD 2-4IFRT

ABVD 4

Followup

ABVD 4IFRT

CloseFollowup

Biopsy

Biopsy

N

P

P

N

Refractory

ABVD 4

Dose of radiation in CMT

Non bulky stage I/II 20-30 GyNon bulky stage IB/IIB 30 GyBulky disease all stage 30-36 Gy

Treatment options for NLPHL

IFRT 30 Gy

For satge IA, withoutriskfactors

If gross ds. is completely excised

30 Gy is sufficient.

ABCD 2IFRT 30 Gy

For stage I with risk factors or stage II.

ABCD 6 For stage III/IV

Stanford V regimen 8 weeks or 2 cycles

Inj. Mechlorethamine 6mg/m2 iv D1Inj. Doxorubicin 25mg/m2 ivD1 ,D15Inj. Vinblastine 6mg/m2 iv D1, D15Inj. Bleomycin 5U/m2 iv D8, D22Inj. Vincristine 1.4 mg/m2 iv D8,D22Inj. Etoposide 60mg/m2 iv D15, D16Tab. Prednisone 40mg/m2 PO alternate day for 6 weeks.

Escalated BEACOPP 21 day cycleTab. Cyclophosphamide 1200mg/m2 PO D1Inj.Doxorubicin 35mg/m2 iv D1Inj. Etoposide 200mg/m2 ivD1-3Tab. Procarbazine 100mg/m2 PO D1-7Tab. Prednisone 40mg/m2 PO D1-14Inj. Vincristine 1.4mg/m2 in D8Inj. Bleomycin 10U/m2 iv D8

Borders of involved field

1-2 cm above the tip of mastoid &

mid point through the chin

2 cm below the clavicle

If SCV uninvolve

d , I/L transvers

e process.If SCV

involved ,C/L

transverse

process.

Including medial 2/3 rd of clavicle

Cervical /SCV

unilateral

BlockLaryngea

l Post.

Cervical cord

Lung .

Mediastinum/hilumC5-C6 interspace –

top of larynx ifSCV involved,

bottom of larynx ifSCV not involved

5 cm below thecarina,

or 2 cm belowprechemotherapy

GTV

PostchemotherapyGTV + 1.5 cmmargin

Axillary field

C5-C6 interface

Lower tip of thescapula, or 2 cm

below lowestaxillary node

Flash axilla

Ipsilateral transverseprocess.Include

vertebralbodies if

SCVinvolved

Thank you

Health & Medicine

Hodgkin's lymphoma early stage management