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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
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
HODGKIN’S LYMPHOMA
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.
HODGKIN’S LYMPHOMA
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
Treatment of Stage I/II
(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
Treatment of Stage I/II
(unfavourable)
Bulky
Treatment of Stage I/II
(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