management of early stage hodgkin's disease.

1. MANAGEMENT OF HODGKIN’S DISEASE
EARLY STAGE
DR. DHARMENDRA SINGH
MD PGT
DEPT. OF RADIOTHERAPY
I.P.G.M.E.& R. KOLKATA

2. On the basis of histology and pattern of growth
A heterogeneous group of lymphoid neoplasm
that originate from lymphoid organs .
LYMPHOMA
Pre germinal,
Germinal
centre
of lymph node
LYMPHOMA
HODGKIN’S
LYMPHOMA
NON HODGKIN’S
LYMPHOMA

3. 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 cells
Or
Mononuclear RS cells
Reed Sternberg(RS)
cells

4. 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.

5. 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

6. 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%

7. CLASSICALHL
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

8. Clinical Features
Pattern of lymph node involvement is CONTIGUOUS

9. 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.

10. 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 .

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

12. WORKUP
History & physical examination
CBC, ESR
LFT, 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)

13. 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.

14. Nuclear medicine
The 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.

15. 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.

16. Stage IV
Stage I Stage II Stage III

17. 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

18. 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 X
I. Mediastinal adenopathy include mass > 10 cm
II. Ratio of max. width of mediastinal mass to max.
intrathoracic diameter is > 1 : 3
III.Ratio of mediastinal mass to chest diameter at the T5-6 > .35

19. 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

20. Risk factors & treatment groups
On the basis of different trials early stage Hodgkin’s lymphoma have
Prognostic factors
Bulky disease
Extra nodal
involvement
Elevated ESR
≥ 3 LN areas

21. Rx methods including
Weekly small doses for
Several weeks.
Massive single dose to
Involved site.
1902 by
Pusey
using X
ray
Radiation alone
Evolution of Radiation alone
Another tree of
Chemotherapy is in
Evolution during
same time

22. Total nodal
radiotherapy
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

23. Bilateral cervical ,
supraclavicular,
infraclavicular,
axillar , hilar,
mediastinal.
Mantle field
Mantle field without
mediastinal & hilar
LNs.
Mini Mantle
Mantle field without
axillary LNs.
Modified Mantle

24. 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

25. 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

26. Chin mastoid process tip line.
Lower border T10/11
Junction
of lateral
margin
of
pectorali
s with
deltoid
muscle,
inferiorly
– inferior
border of
scapula
/T7

27.  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

28. 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)

29.  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

30. 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

31. Doses
involved nodes 36 to 40Gy
uninvolved 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.

32.  Fatigue ,nausea,vomiting,dry cough
 Occipital hair loss
 Sore throat
 Skin reactions
 Dysphagia
 Myelosupression
Acute effects of RT

33. 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

34. Late side effects of RT
Subclinical 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.

35. 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

36. Agent Dose Limiting Toxicity
Nitrogen Mustard BMT, N&V, Leukemogenic
Vincristine Neurotoxicity, constipation & ANS disturbance
Procarbazine BMT, N&V, Leukemogenic, Infertility, Psychotic
reactions, hypertensive crisis with MAO inhibitor
Cyclophosphamide BMT (Thrombocytopenia), SIADH, N&V, Bladder
toxicity
Chlorambucil BMT (Neutropenia, Anemia), N&V, Leukemia
Vinblastine BMT (Neutropenia), Mucositis, Hypertension
Doxorubicin BMT, Alopecia, N&V, Diarrhea, Cardiac, RT recall
Bleomycin Fever, Skin toxicity, Pulmonary toxicity
DTIC BMT, Flu like syndrome , Hepatic vein thrombosis
Etoposide BMT (leucopenia & neutropenia), Leukemia
Cisplatin Neurotoxicity, Ototoxicity, Nephrotoxicity

37. 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

38. MOPP
Nitrogen Mustard 6 mg/m2 I/V D1 and D8
Vincristine (Oncovine) 1.4 mg/m2 IV D1and D8
Procarbazine 100 mg/m2 D1 to D14
Prednisone 40 mg/m2 D1 to D 14
28 day cycle.
A highly toxic regimen
Special 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 : Hematological
Infertility and premature menopause
Neurotoxicity : Due to vincristine
Toxicity
Result
CR of 81% documented
Long term disease free
survival rates (10 yrs)
in the range of 56%

39. COPP
Cyclophosphamide 650 mg/m2 D1 and D8
Vincristine 1.5mg/m2 D1 and D8
Procarbazine 100 mg/m2 D1 to D 14
Prednisone 40 mg/m2 D1 to D 14
28 day cycle.
MOPP variants
Nitrogen Mustard 6mg/m2 IV D1 and D8
Vinblastine 6 mg/m2 IV D1 and D8
Procarbazine 100 mg/m2 PO D1 to D14
Prednisone 40 mg PO D1 to D14
MVPP
BCVPP BCNU 100mg/m2 IV D1
Cyclophosphamide 600 mg/m2 IV D1
Vinblastine 5 mg/m2 PO D1
Procarbazine 50 mg/m2 PO D1 and 100 mg/m2 D2 to D20
Prednisone 40mg PO D1 to D20

40. ABVD
Inj. Adriamycin 25 mg/m2 IV D1 and D15
Inj. Bleomycin 10 U/m2 IV D1 and D15
Inj. Vinblastine 6 mg/m2 IV D1 and D15
Inj. Dacarbazine 375 mg/m2 D1 and D15
28 day cycle.
Toxicity MOPP ABVD
Leucopenia 56% 45%
Thrombocytopenia 16% 15%
Paraesthesias 72% 5%
Loss of Hair 48% 75%
Skin Changes - 40%
Stage set for
evaluation of
ABVD.

41. 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

42. Bulky disease
Extra nodal sites
≥ 3 nodal sites
ESR >50 in absence of B symptoms
ESR >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.

43. Stage I/II favourable Stage I/II unfavourable
ABVD 2-4 cycles
IFRT
Follow up
ABVD 4-6 cycles
IFRT
Follow up

44. Treatment of
Stage I/II
(favourable)
ABVD 2-4
Restage
with
PET CT
Deauville
1-3
Deauville
5b
Deauville
5a
Deauville
4
IFRT
Biopsy
Restage
Deauville
1-3
Deauville
4-5
N
P
IFRT
Biopsy
Biopsy
Biopsy
P
N
N
P
NP
IFRT
Refr
acto
ry
Ref
Follow
up
IFRT
Follow
up

45. Treatment of
Stage I/II
(unfavourable)
Bulky
ABVD 4
Restage
with
PET CT
Deauville
1-3
Deauville
5b
Deauville
5a
Deauville
4
ABVD 2 IFRT
Follow
up
IFRT
ABVD 2 Restage
Deauville 1-3
Deauville 4-5a
Deauville 5b
Biopsy
Biopsy
N
P
P
N
IFRT to
bulky site
Refract
ory

46. 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

47. Treatment of
Stage I/II
(unfavourable)
Nonbulky
ABVD 2
Restage
with
PET CT
Deauville
1-2
Deauville
5b
Deauville
5a
Deauville
3-4
ABVD 2-4
IFRT
ABVD 4
Follow
up
ABVD 4
IFRT
Close
Follow
up
Biopsy
Biopsy
N
P
P
N
Refra
ctory
ABVD 4

48. Dose of radiation in CMT Non bulky stage I/II 20-30 Gy
Non bulky stage IB/IIB 30 Gy
Bulky 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 2
IFRT 30 Gy
For stage I with risk factors or
stage II.
ABCD 6
For stage III/IV

49. Stanford V regimen 8 weeks or 2 cycles
Inj. Mechlorethamine 6mg/m2 iv D1
Inj. Doxorubicin 25mg/m2 ivD1 ,D15
Inj. Vinblastine 6mg/m2 iv D1, D15
Inj. Bleomycin 5U/m2 iv D8, D22
Inj. Vincristine 1.4 mg/m2 iv D8,D22
Inj. Etoposide 60mg/m2 iv D15, D16
Tab. Prednisone 40mg/m2 PO alternate day
for 6 weeks.
Escalated BEACOPP 21 day cycle
Tab. Cyclophosphamide 1200mg/m2 PO D1
Inj.Doxorubicin 35mg/m2 iv D1
Inj. Etoposide 200mg/m2 ivD1-3
Tab. Procarbazine 100mg/m2 PO D1-7
Tab. Prednisone 40mg/m2 PO D1-14
Inj. Vincristine 1.4mg/m2 in D8
Inj. Bleomycin 10U/m2 iv D8

50. Borders of involved field
1-2 cm above the tip of
mastoid & mid point
through the chin
2 cm below the clavicle
If SCV
uninvolved
, I/L
transverse
process.
If SCV
involved
,C/L
transverse
process.
Including
medial 2/3
rd of
clavicle
Cervical /SCV
unilateral
Block
Laryngeal
Post.
Cervical
cord
Lung .

51. Mediastinum/hilum
C5-C6 interspace –
top of larynx if
SCV involved,
bottom of larynx if
SCV not involved
5 cm below the
carina,
or 2 cm below
prechemotherapy
GTV
Postchemoth
erapy
GTV + 1.5 cm
margin

52. Axillary field
C5-C6 interface
Lower tip of the
scapula, or 2 cm
below lowest
axillary node
Flash
axilla
Ipsilateral
transverse
process.
Include
vertebral
bodies if SCV
involved

53. Thank you