Radiotherapy in leukemias

1. RADIOTHERAPY IN LEUKEMIAS
DR KIRAN

2. Leukemia are the Group of malignant disorders
of the hematopoietic tissues characteristically
associated with increased numbers of white
cells in the bone marrow and / or peripheral
blood.
Virchow (1845) first coined the term
LEUKEMIA.

4. Acute Lymphoblastic Leukemia(ALL)
• Neoplastic disease which results from a mutation in a
single lymphoid progenitor cell at one of several discrete
stages of development
• B Cell or T Cell
• Most common childhood tumor acute leukemia, ~80%
• Incidence in adults ~20%
• Bimodal distribution of occurrence:
– Peak at age 2-5
– Second increased incidence after age 50

5. Classification of ALL
French American British Classification:
• L1: small uniform blasts (pediatric ALL)
• L2: larger, more variable sized blasts (adult ALL)
• L3: uniform cells with basophilic and sometimes
vacuolated cytoplasm (mature B cell ALL)

6. Treatment of ALL:
-Induction of remission
- Intensification and/or Consolidation
-Maintenance therapy
-CNS prophylaxis.
• Induction: Glucocorticoid, Vincristine, L-Asparginase.
High risk patients – Additional Anthracyclins (Adult ALL).
Following induction and achieving CR: Intensification with
Antimetabolites like Ara-C, Methotrexate, L-Asparginase

7. • Maintenance treatment: 2-3 yrs with weekly low dose
Methotrexate and Mercaptopurine.
• Adult ALL with L3 subtype: High dose Methotrexate,
Cyclophosphamide, Ara-C in combination with Vincristine,
Steroids, L-Asparginase, Doxorubicin had improved remission
rates.
• Relapsed ALL: Second induction with Vincristine, Prednisolone,
L-Asparginase, Anthracyclin with or without Methotrexate,Ara-
C.
• 2nd remission: 70 – 90%.-Treatment: Allogenic Transplantation /
Consolidative Chemo.

8. • Presence of CNS involvement: IT + RT.
• Testicular relapse: Bilateral testicular irradiation.
• 2nd remission: 70 – 90%.
• Treatment: Allogenic Transplantation / Consolidative Chemo.

9. DEFINITION OF RISK GROUPS
ALL BFM 95
STANDARD RISK (6 CRITERIA)
-Prednisone good response(blasts <1000 /microlit of
peripheral blood on day 8) after a 7 day prednisone
prephase(pred-gr)
- Wbc <20,ooo/micro lit and age >1-<6 years
-A complete remission on day 33 (m1-marrow)
-No translocation t(9:22) or bcr/abl recombination
-No translocation t(4:11) or mll /af 4 recombination
-No T – immunology

10. MEDIUM RISK GROUP
(4+1 or more)
-Leukemic cells <1000/microlit in the peripheral blood
on day 8(prednisone–gr)
-Complete remission on day 33(m1-marrow)
- No translocation t (9:22) or bcl/abl recombination
- No translocation t(4:11) or mll/af 4 recombination
-Leukocytes more than 20,000 /microlit,age less than
one year or more than 6 years

11. HIGH RISK GROUP(EVERY CRITERION)
• More than 1000/ microlit leukemic cells in
peripheral blood on day 8 (pred=pr)
• No complete remission on day 33
• Translocation t(9:22) or bcr/abl recombination
• Translocation t(4:11) or mll/af4 recombination

12. DEFINITION OF CNS STATUS
CNS STATUS 1(NEGATIVE):
• no clinical evidence of a cns disease
• no imaging-ct/mri -evidence of cns lesion
• normal fundoscopic finding
• blast free csf

13. CNS STAUS 2 (NEGATIVE):
• Blasts unambiguously identified, rbc:wbc <100:1 on cytopsin
preparation of csf with a cell count of <5/microlit- non
traumatic un contaminated csf
• Blasts identified, rbc:wbc >100:1 on cytopsin
• Preparation of csf- traumatic blood contaminated csf
• Traumatic lp (blood contaminated csf)

14. CNS STATUS 3(POSITIVE)
• A mass lesion in the brain and or meninges on ct/mri
• cranial nerve palsy unrelated to other origin even if the csf is
blast free or no circumscribed space occupying lesion on
mri/ctscan
• pure retinal involvement with blast free csf and no mass on
ct/mri
• non traumatic lp with a csf cell count of >5/microlit

16. RADIATION THERAPY IN ALL
• PROPHYLACTIC CRANIAL IRRADIATION
• THERAPEUTIC CRANIAL IRRADIATION
• THERAPEUTIC CRANIAL AND NEURAXIS
RADIATION
• TESTICULAR IRRADIATION
• MEDIASTINAL IRRADIATION
• TOTAL BODY IRRADIATION – BMT CONDITIONING
COMBINED MODALITY WHY ?
IT therapy therotically undertreates the ventricular spaces and
cerebral and cerebellar sulci and gross disease extending to
brain substance .Cranial RT with it, Later cover the spinal
subarachnoid space

17. COMBINED MODALITY WHY ?
CSF formation in brain ventricles by choroid
plexus-ivf- cerebral aqueduct to 4th ventricle
communicates with sub arachnoid space-csf
resobption by arachnoid villi in the dural sinuses.
IT therapy therotically undertreates the ventricular
spaces and cerebral and cerebellar sulci and gross
disease extending to brain substance
Cranial RT with it, Later cover the spinal
subarachnoid space
Reduction of the spine dose than brain during csi for
meningeal leukemia.

18. CRANIAL PROPHYLAXIS
CHILDREN AND ADOLESCENTS<18YRS) WITH
MEDIUM RISK GROUP WITH T-ALLAND ALL
HIGH RISK GROUP PATIENTS
NO RT FOR STANDARD RISK AND MEDIUM RISK
PATIENTS (EXCEPT T -ALL)

19. CNS PROPHYLAXIS:
• 1st CNS prophylaxis addressed in 1960s.
• Simulation: Supine position with Thermoplastic head cast.
• Volumes:
Prophylactic CNS therapy- entire intracranial subarachnoid
space .
Key Margins at skull base:
Cribriform plate- (lowest point of anterior cranial fossa-in
midline at level typically below orbital roof)
-Lower limit of temporal fossa.

20. • Lower border at Inferior margin of 2nd cervical vertebra
• Incl. of post. retina & orbital apex, subtending extension of
subarach. space around optic nerves- stand.
• Include post.orbit and globe – spare ant.globe and lens .
• Accept dose appr. 20% to lens to cover cribriform plate.
• Custom block improve T/t compared to MLC.

21. 2D Planning:

23. • To avoid diverging beam edges going into opposite eye, one of
the following techniques can be used:
1. Beams can be angled posteriorly by 2 to 3 degree ( using right
and left anterior obliques).
2. Half beam block- central axis of the beam placed behind the eye
lens

24. CRANIAL IRRADIATION
DOSAGE
• CHILDREN LESS THAN ONE YEAR- NO
IRRADIATION
• ONE TO TWO YEARS -12 GY
• MORE THAN 2 YEARS-18 GY
• ADULTS 24-30Gy

25. • Energy: >6Mv not to be used.
• Standard RT Dose: Pediatric ALL – 18Gy in 10 fractions.
• BFM type ALL – 12Gy in 8 fractions.
SJCRH- V & VI: (1962 – 1967)
• CSI to 24Gy in 15-16 fractions decreased isolated CNS relapse
from 67% – 4%.
• Full spinal RT was associated with Acute myelosuppression &
Late musculoskeletal hypoplasia.

27. Study – vii:
• CSI + IT MTX – had roughly 8% CNS relapse.
• SJCRH – VIII: (1972 – 1975)
• All patients were given 24Gy Cranial RT + IT MTX and
randomized to one of the 4 maintenance regimens.
• 1. Weekly IV MTX with Cranial RT.
• 2. Oral MTX + 6-Mercaptopurine.
• 3. Oral MTX + Mercaptopurine + Cyclophosphamide.
• 4. Same 3 drugs + Ara-C.
Incidence of CNS relapse : 5.0%, 1.5%, 20%, 11.4%.

28. Children’s Cancer Study Group (CCSG):
Trial #101:
1. 24Gy CSI + Extended field RT encompassing liver, spleen, Gonads.
2. 24Gy CSI alone.
3. 24Gy Cranial RT + IT MTX.
4. IT MTX alone.
One interesting sub analysis of a systematic review of Cranial RT for
ALL looked 809 patients across 7 trials comparing different doses of
radiation.
18Gy to 21Gy Vs 24Gy.
• No difference in CNS / Non CNS relapse rates.

29. St. Jude Total XV Trial:
• 498 patients were treated without cranial RT
• 5yr event free survival – 86.6%.
• Currently, Children’s Oncology Group: Reduced Cranial Doses
in current ALL trials.
• 3yr CNS relapse rate is 18% who did not receive cranial RT
compared to 7% who did in cases of T-Cell ALL.

30. AIEOP – 91:
• Omits Cranial RT with more IT chemo.
• Had higher significant CNS relapse.
• 3yr event free survival – 62%.
• Compared to 88% for BFM-90 patients who received Cranial
RT.
• Reduction in RT dose to 18Gy in 10 fractions with IT MTX
yielded comparable disease control rates as 24Gy.
Dana Farber Cancer Institute ALL Consortium:
• Role of Hyperfractionated RT 0.9Gy twice daily compared to
standard fractionation 1.8Gy daily to 18Gy.
• Excellent control rates were observed with both the regimens.

31. MENINGEAL LEUKEMIAAT DIAGNOSIS:
• 3-5% patients will have clinically detectable CNS involvement at
time of Diagnosis.
• Considered as High risk leukemia with cranial RT.
• Cranial RT doses may vary from 18-25Gy.
• 5yr DFS rates are around 70% at present.
• Delay in RT upto 12 months was found to be safe as long as
intensive CT is being given first.
• This avoids marrow compromise.

32. • CNS relapse rates are <10% with modern CT.
• Recent trials using intensive CT + RT had 5yr OS of 50-70%.
• Doses: 24Gy to brain, 10 – 15 Gy to Spine.
• Superior outcomes were achieved with CSI.
• Selected high risk cases with CNS relapse – Allogenic
transplants.
• Preperative regimen: TBI.

33. Summary of Cranial RT for Initial ALL Management
In summary, cranial RT may be used to prevent CNS relapse of
leukemia.
From a historical perspective that considered the brain as a
sanctuary site, cranial RT has been well documented to
improve outcomes for selected patients with pediatric ALL.
With concerns about late sequela and improvements in
systemic therapy including agents that can better penetrate
the blood–brain barrier, cranial RT is used much less
frequently in the upfront management of ALL.
Overall, only 15% to 20% of pediatric ALL patients who have
high-risk features require cranial RT currently.
In current practice, cranial radiation is employed selectively in
high-risk ALL patients.

34. TESTICULAR IRRADIATION:
• Testicular involvement in Leukemia at Diagnosis is approx. 2%.
and it is a Poor prognostic situation.
• Gonads & Scrotum can be irradiated with photons / electrons.
• Patient in ” Frog Leg Position” , penile shaft taped onto
abdomen.
• One retrospective series from the Memorial Sloan-Kettering
Cancer Center suggests that for TBI/ cyclophosphamide
preparative regimens, the risk of testicular relapse is
significantly reduced with a local boost to the scrotum of 4 Gy
to bring the total testicular dose to 16 to 20 Gy.

35. e
• If Mv beams are used then Bolus to be used to avoid superficial
over-dosing.
• Young Boys – if scrotum / testes thickness is <2cms then 250Kv
orthovoltage x-rays to be used.
• Doses: 24Gy in 1.5 to 2.0Gy per fraction.
• If testicular Boost is given with TBI for Hematopoietic stem cell
transplant,
• Dose: 4Gy in 1 fraction or 2Gy in 2 fractions.

36. TESTICULAR RELAPSE
• testicular relapse-unilateral or bilateral
painless but hard swelling of the testis (volume
>2) and a biopsy should be done.
• common with t cell all usually follows
systemic and cns relapse poor prognostic
factor.
• 1970-5%-15% with high dose mtx-<2%
management:both intensive systemic therapy
and local radiotherapy(18gy in 9#)

37. TESTICULAR IRRADIATION:
• Testicular irradiation is administered via a
single anterior portal with the use of electron
beam of appropriate energy or low enrgy
photons.
• Patient in a supine position and the penile
shaft tapped up and over the symphysis pubis
rectangular field with minimum of 5 mm
margin to the scrotum (includes both testis and
epididymis)

38. TESTICULAR IRRADIATION
• 10X10 CMS CONE PROVIDES ADEQUATE COVERAGE
• MOST APPROPRIATE ELECTRON ENERGY -9 TO 12 MEV
• A POLYSTERENE /LEAD BLOCK IS USED TO SUPPORT TESTIS
AND SHIELD THE PERINEUM
• SKIN APPOSITION OF THE BEAM CAN BE ACHIEVED BY
ANGLING THE GANTRY

39. TESTICULAR IRRADIATION
• IN THE ABSENCE OF ELECTRON BEAMS LOW ENERGY
PHOTONS CAN BE USED(4 TO 6 MV).
• TO ACHIEVE DOSE HOMOGENICITY 0.5 TO 1 CMS OF BOLUS
OVER THE ENTIRE SCROTAL AREA MAY BE NECESSARY.
• SHIELDING OF THE UNDER LYING PERINEAL TISSUE IS
PROBLAMATIC THE EXIT DOSE WILL BE HIGH.

40. MEDIASTINAL IRRADIATION:
• IF A MEDIASTINAL TUMOR RECEDES <30% OF ITS
ORIGINAL SIZE BY DAY 33(MEASUREMENT CRITERIA
–MAXIMAL DIAMETER TAKEN AT D5), THEN PHASE II
OF THE SAME PROTOCOL IS TO BE CONTINUED.
• IF THE MEDIASTINAL TUMOR HAS NOT
COMPLETELY RECEEDED BY DAY 33 (REMAINING
TUMOR >30% OF ORIGINAL SIZE), THEN THE PATIENT
IS PLACED IN THE HIGH RISK GROUP.
• IF ANY RESIDUAL TUMOR REMAINS IN THE CT /MRI
AFTER A WEEK OF PROTOCOL THAT CAN BE
RESECTED FOR HPE AND MOLECULAR GENETICS

41. MEDIASTINAL IRRADIATION
• IF INFILTRATES ARE FOUND CONSIDER
MEDIASTINAL IRRADIATION.
• DOSE-30-40 GY
• ALL T CELL PHENOTYPE WILL RECEIVE
CONSOLIDATION RT.

42. TOTAL BODY IRRADIATION- BMT CONDITIONING
• TBI-cytotoxic and immunosuppresive agent.
• eliminate residual leukemia and equally effective in
medullary and extramedullary region.
• it permits engraftment of donor immune and
haematopoietic cells.
• the donor immune cells generate the graft versus
leukemia effect, an important component in the
eradication of host leukemia.

43. TOTAL BODY IRRADIATION
• allogenic transplant-all in second remission after
an early relapse,high risk ALL after first
remission.
• dose-200 cgy given in bid with 6 hour inter
fraction intervel 3 days to the total dose of 12 gy .
• dose rate average 8 to 10cgy per
minute(maximum up to 15 cgy).
• in high risk patients CNS positive disease cranial
boost- 12gy,testicular boost in case of
involvement 18gy a week
• preceding the tbi-all bfm 2002

44. AML

46. Treatment of AML:
• Classic induction therapy with Anthracyclins (D1 –D3) and
Cytarabine (7 Days).
• Most common used: Daunorubicin & Idarubicin.
• Some induction regimens have also added Etoposide.
• Patients with <60yrs – CR of 70-80%.
Older patients – CR of 50-60%.
Patients with Secondary AML following chemo for other cancers –
CR of 40-60%.

47. • >60yrs patients with AML, intermediate / unfavourable
cytogenetics are considered for Low intensity Palliative
treatment.
• Low dose agents: Azacitidine, Cytarabine, Decitabine.
• AML patients who remain in remission for 3yrs have high
chances of being cured.
• Consolidative treatment: 2nd line Induction therapy: Etoposide,
6-Mercaptopurine, Amasacrine, 5-Azacytidine, Methotrexate.

48. • Role of CNS prophylaxis for AML – not well defined because CNS
relapse rates are infrequent (5-10%).
• CHLOROMA:
• Other names: Myeloid Sarcoma.
Granulocytic Sarcoma.
• Associated with AML and Myeloproliferative disorders.
• Solid masses of Leukemic infiltrates.
• Derives from myeloid cells which contain myeloperoxidase, has
greenish colour on gross inspection.

49. • Sites: Periosteum, Skin, Soft tissues, GIT, Spine, Epidural
spaces, Meninges.
• OS better than AML.
• Long term disease control – Same systemic therapy used for
AML.
• AML sensitive to RT- symptomatic and measureable response
apparent after 12-15 Gy
• Consolidative therapy effective at 18 Gy
• Lesions with incomplete response to CT- 21-27Gy

50. CML: WHO classification of chronic
myeloproliferative diseases
• Chronic myelogenous leukemia [Ph chromosome,
t(9;22)(q34;q11),BCR/ABL-positive]
• Chronic neutrophilic leukemia
• Chronic eosinophilic leukemia (and the hypereosinophilic
syndrome)
• Polycythemia vera
• Chronic idiopathic myelofibrosis (with extramedullary
hematopoiesis)
• Essential thrombocythemia
• Chronic myeloproliferative disease, unclassifiable

52. TREATMENT OF CML:
• 1st effective therapy for chronic Leukemias was RT to spleen &
Liver in 1902.
• Present: RT is given only in palliative seeting to relieve painful
splenomegaly.
• Imatinib: Relatively non toxic oral medication effective in CML
in both chronic and accelerated phases.
• Used as upfront therapy for CML along with recent drugs like
Dasatinib & Nilotinib.

53. SPLENIC IRRADIATION:
Massive splenomegaly cases:
• 1. CML
• 2. CLL
• 3. Hairy cell Leukemia.
• 4. Marginal zone Lymphomas.
• Leukemic infiltration of spleen will respond well to low doses of
RT.
• Elderly patients with co-morbidities: Palliative Splenic RT will
have less risk than Splenectomy.

54. • Anterior and Posterior opposed portals are used.
• Leukemic infiltration: 0.25 – 1.0Gy fractions to whole Spleen 2-
3 times a week with doses titrated to response and hematologic
tolerance.
• Total dose: 4 – 10Gy.
• Not more than 20Gy is required.
• Fibrotic, large spleen will not respond to RT.

55. CLL

58. TREATMENT OF CLL:
• Standard treatment of CLL is Single agent Chlorambucil with or
without Prednisolone.
• A purine analog – Fludarabine had high response rate.
• Overall response rates with Chlorambucil – 37% and
Fludarabine – 63%.
• Median survival of 56 months Vs 66 months.
• Recently combination of Fludarabine, Cyclophosphamide,
Rituximab had high complete remission rate of around 70%
with median time to progression of 80 months.

59. Allogenic transplantation had been increased in past decade.
• Patients with 17p Chromosome deletion respond well to
Allografting.
• Indications for Allografting:
• By European Group For Blood & Marrow Transplantation.
• 1. Early relapse following chemo.
• 2. Resistance to Fludarabine.
• 3. Chromosome 17p Deletion.
• 4. Richeter’s Transformation.

60. RADIOTHERAPEUTIC EMERGENCIES:
• Mediastinal adenopathy leading to air way or spinal cord
compression from epidural disease – 1.5 – 2Gy for 1-3 #.
• Cranial nerve palsies – 10 – 15Gy to Base of Skull to try and
reverse neurologic deficits.
• Extreme Leukocytosis with Blast counts of >75,000 to 1,00,000 /
microlitre as blast cells are adhesive to vessel wall leading to
Leukostasis.
• 6 – 10Gy to be given.

61. SEQUELAE OF RADIOTHERAPY:
• Somnolence Syndrome:
• Approximately 1 month following cranial radiation, up to 40%
to 50% of patients may develop lethargy, irritability, anorexia,
and even fevers.
• Associated with electroencephalographic abnormalities and CSF
pleocytosis.
• Self-limited and reverses within 1 to 3 weeks.
• Glucocorticoids may be helpful (acute).
• Two reports suggest that incidence of this syndrome is
reduced if patients receive steroids during cranial RT.

62. Pituitary Dysfunction:
• Endocrine function affected- dose and age dependant
manner.
• Growth hormone (GH) deficiency most common
abnormality.
• Age <5 years at the time of RT
• Higher RT doses & young age- increased incidence GH
def.
• More common after 24 Gy than 18 Gy.
• Precocious puberty- dose to hypothalamic-pituitary
region-18 Gy

63. Cognitive Dysfunction:
• Intellectual and psychological impairments
• RT to blame- studies for lowering dose or eliminating it
• CT may also be causing similar effect.
• Result of white matter injury- deficits in speed of
information processing.
• In children <5 years - most pronounced in those <3
years

64. • Reduction in radiation dose from 24 Gy to 18 Gy has not
consistently reported to result in a lower cognitive difficulties.
• SJCRH group has reported that up to 22% to 30% of children
have such deficits after 18 Gy, 24 Gy, or no cranial RT.
• No obvious differences between standard or hyperfractionated
RT in terms of late neurotoxicity reported.

65. Leukoencephalopathy:
• Early PCI studies-significant incidence months after RT
• Highest with cranial RT as low as 24 Gy + IV MTX.
• Demyelinating condition initiated by endothelial damage &
subsequent cytokine cascade with ischemic microinfarct
• Rare after doses of <20 Gy.

66. Secondary Malignancies:
• SJCRH-1962 and 1998-cumulative incidence - 4.2% and 10.9%
at 15 and 30 years, respectively.
• Those after 20 yrs-lower-gr. malig. - meningiomas & BCC
• Other secondary cancers - gliomas, parotid gland tumors,
thyroid cancers, and sarcomas (bone and soft tissue).
• Secondary brain tumours - evenly split between
meningiomas and high-grade gliomas.

67. Testicular Effects from RT:
• Gonadal dysfunction is quite rare.
• Direct effects from testicular irradiation - very common.
• Doses as low as 1 Gy, even from scattered dose from adjacent
external-beam fields, will cause transient oligospermia or
azoospermia.
• Higher doses, those used in TBI or therapeutic testicular radiation,
would be expected to cause permanent infertility.
• Low serum testosterone levels or delayed puberty are unusual with
doses <29 Gy to testes.
• Incidence of Leydig cell dysfunction - very low.

68. Thank you.