1. HODGKIN LYMPHOMA IN CHILDREN
Dr.M.Shamvil Ashraf
Children Cancer Hospital,
Karachi.

2. Hodgkin Lymphoma One of the most curable cancer in children
There are different effective treatment approaches
Can be cured with limited resources

3. Epidemiology Developed Countries Karachi Data
5 - 6% of childhood cancers
Male:Female 3-4:1 in <10y
Male:Female 1.3:1 in >10y
Bimodal age peak- adolescent/young adult, 50yo
Uncommon in <10 yrs
Karachi Data
10% of childhood cancers
Male:Female 4.7:1 in <10y
Male:Female 1.7:1 in >10y
> 5 years 24%
>10years 62%

4. Biology
Inflammatory milieu with rare multinucleated giant cells (Reed-Sternberg cells) or large mononuclear cell variants (Hodgkin’s or lacunar cells)
R-S cell appears to arise from preapoptotic germinal center B cells (no Ig production), although rarely may arise from T cells

5. RS cells

6. Lacunar Cells

7. Cellular Classification
Classical HL (CD15, CD30 +, B cell markers )
nodular sclerosis (50-60%)
mixed-cellularity (20-30%)
lymphocyte rich (<5%)
lymphocyte depleted (5-15%)
Nodular Lymphocyte Predominant HL (5%) (CD15 -, CD30 +/-, B cell markers +)

8. Pathological Subtypes; Karachi Data
13 (16.2%)
2 (2.5%)
21 (26%)
44 (55%)

9. Clinical Presentation
Painless adenopathy (80%)
B symptoms (25-30%)
fever >380C x 3 days
wt loss >10% of body wt. over 6 mo
drenching night sweats
Bulky disease (20%)
med mass >1/3 of internal thoracic diameter
node/nodal aggregate >6 cm

10. Clinical Presentation
15% to 20% of patients will have noncontiguous extranodal involvement
The most common sites of extranodal involvement are the lung, liver, bones, and bone marrow

11. Hodgkin vs TB
Most common differential especially if limited to cervical
Often put on ATT without definitive diagnosis
Biopsy is essential

12. Diagnosis Excision Biopsy of Node
Needle Biopsy of mass if excision not possible
FNAC is not recommended in children

13. Staging Ann Arbor staging system I-IV “A” vs “B”
“E”- extralymphatic disease resulting from direct extension of involved LN region
“S”- splenic disease
ideally want pathologic confirmation of noncontiguous extralymphatic involvement (Stage IV disease)

14. Ann Arbor Staging
Stage I: Involvement of single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)
Stage II: Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single extralymphatic organ or site and its regional lymph node(s) with involvement of one or more lymph regions on the same side of the diaphragm (IIE)
Stage III: Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), by involvement of the spleen (IIS), or both (III E+S)
Stage IV: Disseminated (multifocal) involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (non-regional) nodal involvement.

16. Staging Workup Imaging CXR U/Sound
CT scan of neck, chest, abdomen and pelvis
Gallium
PET Scan
Other Tests
Bone marrow aspirate and trephine only in
Patients with stage II B or more
Bone scan only in stage III or more
Blood tests
CBC
LDH
Urea, Cr, electrolytes, Ca, Mg, LFTs
Hepatitis screening

17. Therapy: History XRT alone cured early stage disease 1960s- MOPP
1970s- ABVD
Combined modality therapy (CMT)‏ Chemotherapy and radiation 17 17

18. Therapy History
Good results were obtained but at the cost of severe late toxicities
XRT ; profound musculoskeletal growth retardation and increase the risk for cardiovascular disease and secondary solid malignancies in children
Chemotherapy induced gonadal injury,cardiovascular disease and SMN

19. Combination Chemotherapy Regimens Commonly Used for Children and Young Adults with Hodgkin Lymphoma
ABVD
doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine
ABVE
doxorubicin (Adriamycin), bleomycin, vincristine, etoposide
VAMP
vincristine, doxorubicin (Adriamycin), methotrexate, prednisone
OPPA +/- COPP
vincristine, prednisone, procarbazine, doxorubicin, cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine
COPP/ABV
cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine, doxorubicin (Adriamycin), bleomycin, vinblastine
BEACOPP
bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine

20. Hodgkins Therapy in 90`s
Prognostic factors and risk grouping concept introduced
Radiation dose and field were reduced
Involved Field Radiotherapy introduced
Chemotherapy regimen were manipulated
to reduce cumulative dose and avoid long term toxicities

21. Determining Risk Assignment21

22. Chemotherapy Options 22

23. Current Approaches
Current approaches use chemotherapy with or without LD-IFRT
An exception to this general approach is selected patients with stage I, completely resected, nodular lymphocyte-predominant Hodgkin lymphoma, whose initial treatment may be surgery alone.
The number of cycles and intensity of chemotherapy may be determined by the rapidity and degree of response, as is the radiation dose and volume.

24. Approach for Developing Countries
Chemotherapy Alone
If radiotherapy is not available
Pediatric radiotherapy service is not developed
Good result (up to 80% survival) can be obtained as shown by Indian Experience
(Arya et al)

25. Approach for Developing Countries
Chemotherapy with Radiotherapy only for bulky residual disease
Excellent result can be achieved with this approach as shown by our experience at Children Cancer Hospital

26. CCH Data Retrospective study
From Aug All the patients with histopathological diagnosis of Hodgkin Lymphoma, up to 20 years of age were included
Mean age: 9.9 yrs
Pts. included in the study – 80

27. Treatment Strategy At CCH
Chemotherapy used was alternating courses of
ABVD (adriamycin, bleomycin, vincristine and dacarbazine)
COPDAC (cyclophophamide, vincristine, prednisolone and dacarbazine)
Radiotherapy was reserved only for the pts. with significant residual disease at the end of chemotherapy

28. Response Assessment
CT scan of all the sites positive on pre treatment scan was repeated after 2 cycles
Bone marrow or bone scan was repeated only if it was positive initially
For good responder CT was repeated after 6 cycles
PET scan could not be performed because of non-availability

29. Response Assessment Criteria
CR was taken as complete resolution of all measurable disease, clinically and radiologically
>80% response was taken as good response
60 to 80% was taken as partial response
<60% was taken as poor response or stable disease
Any increase in the size of an existing lesion or appearance of any new lesion during treatment was taken as progressive disease

30. Response Adapted Therapy
Low risk patients with CR after 2 courses received 4 courses
All other pts were given 6 – 8 courses depending upon the response (CR + 2 courses)
11(13.7%) pts received 4 courses
Majority of pts 56 (70%) received 6 courses

31. Radiation Therapy
Radiation therapy was reserved only for the pts with residual disease at the end of chemo
only 8 (10%) needed radiation
Stage II A – 1 pt
Stage II B – 1 pt
Stage III B – 3 pts
Stage III BS – 1 pt
Stage IV – 2 pts

32. Results
74 (92%) pts achieved first remission (CR) after 2 courses of chemotherapy
Only one pt. died during chemotherapy due to meningitis
One pt. relapsed on treatment and was switched to second line treatment
4 (5%) pts relapsed 2 – 12 months after completion of chemotherapy
3 yrs OS 98% and EFS 92%

34. Progressive/Relapsed Ds
Prognostic factors:
progressive ds or relapse at <1y from end of treatment
B symptoms
extranodal ds
response to salvage therapy 34 34

35. Chemotherapy Options Salvage therapies (with harvest)‏
ICE, EPIC,mini-BEAM, DHAP, ASHAP, bortezomib/ifos/vinorelbine (AHOD 0521)‏, GDP (PMH)
Autologous transplant
conditioning: CBV, BEAM, VP16/melphalan
BEAM plus immunomodulation (AHOD 0121)‏- closed 35

36. Refractory Disease Gemcitabine/Vinorelbine AHOD 0321- closed
eligibility: >/= 2 prior regimens
beware non-cardiogenic pulmonary edema
may require 4-6 cycles to see response
Vinblastine, lomustine, VP16
New agents/targeted therapies 36 36

37. Late Effects Cardiotoxicity and Musculoskeletal problems are now rare
Endocrine
Thyroid ; Hypothyroidism
Fertility;
Increased risk of ovarian failure in women
Oligospermia and sterility in men
Second Malignant Neoplasm

38. Conclusion
Chemotherapy alone in majority of patients with Hodgkin Lymphoma can yield excellent outcome
Most of Hodgkin Disease pts can be managed without the use of radiotherapy, thereby minimizing the adversity associated with radiation, specially in young children
Hodgkin Lymphoma can be cured within limited resources
Monitoring for late effects is important