Relapsing Hodgkins Disease in Childhood Pushing The Paradigm to New Heights

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Relapsing Hodgkins Disease in ChildhoodPushing
The Paradigm to New Heights
Sherif Abouelnaga M.D. Professor Pediatric
Hematology Oncology National Cancer
Institute Cairo University

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What we Need To Learn

• Interactivity
• Self learning
• Team working
• Critical thinking
• Patient focused

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Evidence Based Practice
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What is evidence based practice?

• Evidence based practice (EBP) is the thorough,
  concise, and sensible use of the current best
  evidence in making decisions about the care of
  individual patients.
• Evidence base practice considers
• the benefits and risk of other patient management
  strategies,
• and the role of patients values and preferences
  in trading off those benefits and risks.

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What does evidence based medicine do?

• Evidence-based medicine puts less emphasis on
• intuition,
• unsystematic clinical experience,
• and pathophysiologic rationale as
  sufficient grounds for clinical decision-making,
• However,it
• stresses the examination of evidence from
  clinical research.

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Did you know that

• Annually
• 20,000 journals
• 17,000 new books
• MEDLINE
• 4,000 journals
• 6 Million references
• 400,000 new entries yearly

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Change your view

• From How do I keep up with new developments in
  medicine?
• To What developments in medicine do I need to
  keep up with?

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The 4 steps to Evidence Based Practice are

• What is the question?
• How do I find the evidence?
• Are the methods valid?
• What are the results?

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WHEN TO SEARCH FOR EVIDENCE

• When a patient problem is concerning you
• or
• when a patient presents with a common problem you
  encounter often

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What is Meta-Analysis?
- Meta-analysis is a statistical technique for
combining the findings from independent
studies. - Meta-analysis is most often used to
assess the clinical effectiveness of healthcare
interventions. - It does this by combining data
from two or more randomized control trials. -
Meta-analysis of trials provides a precise
estimate of treatment effect, giving due weight
to the size of the different studies included.
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What we Need To Learn

• - Interactivity
• - Self learning
• -Team working
• - Critical thinking

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Introduction

• Considering that curative therapy has been
  available for Hodgkins disease for more than 30
  years, oncologists treating children and
  adolescents with the disease have an expectation
  of long term survival for these patients.

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• -Inspection of the HD mortality curve gives
  cause for satisfaction with the progress of the
  last 30 years.
• -The most recent 5 -year disease free survival is
  81.

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Treatment Results of Pediatric Chemotherapy Alone
Trials
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TREATMENT RESULTS OF NORTH AMERICAN PEDIATRIC
COMBINED MODALITY TRIALS


Outcome/yrChemotherapy
Radiation Rx Stage
patients EFS DFS RFS
SurvivalStanford 3 MOPP/3ABVD
15-25 Gy,IF CS/PS l-lV
57 96 /6.7 - -
93/6.7 6 MOPP
15-25 Gy,IF PS l-lV
55 - -
90/15 89St. Jude 4-5 COPP/3-4 ABVD
20 Gy, IF CS ll-lV
85 - 93/5
- 93Pediatric Onc Gp 4
MOPP/4 ABVD -
CS/PS llB,lllA,lllB-lV 80
80/5 - - 87 4
MOPP/4 ABVD 21 Gy, total
CS/PS llB,lllA,lllB-Vl 62 77/3
- - 91
lymphoid
irrad. Toronto 6 MOPP
20-30 Gy, EF CS l-lllA
57 - -
80/10 85
25-30 Gy, EF CS lllB-
lVCCG 6 ABVD
21Gy, EF PS lll-lV
54 87/4 -
- 90 12 ABVD
21Gy, regional PS lll-lV
64 87/3 -
- 89Intergroup Hodgkins 6 MOPP
35Gy, IF
PS l-ll 97
- - 95/5 90
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Treatment Results of European and South American
Pediatric Combined Modality
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Hodgkins Disease viewed as better cancer to treat

• For many physicians, patients with HD have been
  the bright spot in their practice because they
  are a group who uniformly respond well to therapy
  and overcome their disease.

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Long term side effects the price of cure

• Unfortunately, long after their exit from
  pediatric practices, the true cost of curative
  therapy becomes readily apparent as aging
  survivors develop a variety of medical
  complications unquestionably predisposed by their
  antineoplastic therapy.

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Goal to minimize side effects

• The desire to prevent or reduce treatment
  sequelae, especially second malignancies and
  cardiopulmonary dysfunction, has continued to
  motivate therapeutic modifications over the last
  several decades.

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Hodgkins Disease remains the leading cause of
death.

• While these complications adversely affect
  quality of life and increase the risk of early
  mortality, HD remains the leading cause of death
  observed in several cohort studies of long-term
  pediatric survivors, understanding the need to
  proceed cautiously with therapy refinement that
  does not compromise disease control.

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• The value of experience is not in seeing much,
  but in seeing wisely.
• Sir William Osler, physician 1849-1919

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Refractory/Relapse Patterns

• Progression on therapy
• Primary refractory
• Early relapse(lt 12 months)
• Late relapse (gt12 months)

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Relapsed/Refractory Disease

• lt10with primary refractory disease
• Most relapses occur with first 3 years
• Late relapses ( up to 10 years) may occur
• Lymphocyte predominant disease
• After stem cell transplantation
• Spectrum of relapse after contemporary
  risk-adapted therapy has not been established

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Outcome After Relapse

• Sites of disease
• Localized
• Advanced
• Previous treatment
• Modality RT or CTX or CMT
• Intensity high or low
• Response to therapy
• Responsive
• Refractory
• Timing of relapse
• Early (lt12 mos)
• Late(gt12 mos)
• Very late (gt5 years)

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Long-term Implications of Relapse

• Increased risk of treatment complications
• Alkylators gonadal dysfunctional, sec. AML
• Anthracyclines cardiovascular dysfunction
• Radiation, thyroid, cardiovascular, pulmonary,
  and gonadal dysfunction and second cancers
• Increased risk of early mortality

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Treatment Options After Relapse

• Chemotherapy
• Radiation therapy
• High dose chemotherapy followed by hematopoietic
  stem cell transplant
• Autologous stem cells
• Allogeneic stem cells
• Experimental therapy
• Palliative therapy

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Choosing Salvage Therapy

• Did patient ever achieve CR?
• Was CR durable (lt1 year)?
• Is the relapse nodal or extra nodal?
• Is the stage at relapse early or advanced?
• Was primary therapy low or standard-intensity?

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Relapse after Radiation Alone

• Chemotherapy salvage effective in
• 55-80
• Addition of involved-field radiation (if
  possible) improves outcome.
• Factors predicting favorable outcome
• Site (nodal vs. extra nodal)
• Stage (early vs. advanced)
• Histology ( LP and NS vs. MC)

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Relapse After Low-Intensity Therapy

• Definition of low-intensity therapy
• lt 4 cycles of non-cross resistant chemotherapy
  radiation
• 6 cycles of non-cross resistant chemotherapy not
  including
• Alkylating agents
• Radiation therapy

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Relapse After Low-Intensity Therapy Treatment
Options

• Localized or late
• -Conventional therapy with intensification of
• Alkylating agents
• Anthracyclines
• Radiation
• -Dose-intensive compacted regimen

• Widespread or early
• Intensive cyto-reduction followed by
• Autologous stem cell transplant
• Involved-0field radiation

Long term outcomes in patients who relapse after
low-intensity therapy have not been established
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Relapse After Standard Intensity Therapy

• Definition of standard-intensity therapy
• 6 cycles of non cross-resistant chemotherapy
  low-dose, involved-field radiation
• gt8 cycles of non cross-resistant chemotherapy
  alone

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Relapse after Standard Intensity Therapy Options

• -Standard intensity non cross-resistant
  chemotherapy.
• Intensification of alkylating agent therapy
• Addition of etoposide
• -Involved-field radiation (if possible).
• -High dose cyto-reduction chemotherapy followed
  by stem cell transplant.

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Cytoreduction Regimens

• -ICE Ifosfamide, Carboplatin, Etoposide
• -MIEDHD MTX, Ifosfamide, Etoposide,
  Dexamethasone
• -MIME Methylguazone,Ifosfamide, Methotrexate,
  Etoposide
• -ESHAP/ASHAP Etoposide, Adriamycin, Solumedrol,
  HD AraC, Cisplatin
• -IV Ifosfamide, vinorelbine

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Outcome Following Relapse After Standard
Intensity Therapy

• -Limited success with standard intensity
  chemotherapy regimens for unfavorable relapse
  features
• 10-50 disease-free and overall survival
• -Better outcomes with high dose chemotherapy and
  stem cell transplant
• 25-80 disease-free and overall survival

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Hematopoietic Stem Cell Transplant

• -HSCT involved-field radiation
• Autologous
• Allogeneic
• a. Myeloablative
• b. Non-myeloblative

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• A fish In the tank
• A true Japanese story

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• To study the phenomena of disease without books
  is to sail an uncharted sea, while to study books
  without patients is not to go to sea at all.
• Sir William Osler

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Hodgkins Disease-Results of ASCTInduction
Failure

• Author, Year N PFS OS Early F/U
• NRM
• Chopra, 1993 46 33 -- -- 5 yrs.
• Prince, 1996 30 34 51 10 3 yrs.
• Reece, 1995 30 38 -- 17 8 yrs.
• Lazarus, 1999 122 38 50 12 3 yrs.
• Andre, 1999 86 25 35 8 5 yrs.
• Sweetenham, 1999 175 32 36 14 5 yrs.
• Jostings, 2000 70 31 43 9 4 yrs.
• Ferme, 2002 157 38 50 12 4 yrs.
• Moskowitz, 2004 75 45 48 9 10 yrs.

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Hodgkins DiseaseFirst Relapse after Chemotherapy

• -Some patients cured with radiotherapy or
  chemotherapy alone
• -Adverse prognostic factors
• Initial CR durationlt 1 year
• B symptoms
• Extra nodal disease
• Older age
• Stage III/IV at diagnosis

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Result of ACSTRelapse after CR lt 1 year
?
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Results of ACSTFirst Relapse after gt1 yr CR
?Author, Year N PFS OS Early NRM F/U
Chopra, 1993 16 57 -- -- 5 yrs.
Nademanee, 1995 37 63 -- -- 2 yrs.
Bierman, 1993 43 47 -- -- 5 yrs. Wheeler,
1997 32 48 -- -- 3 yrs. Brice, 1997 146
-- 73 -- 4 yrs. Yuen, 1997 22 52 55
-- 4 yrs. Reece, 1998 22 77 80 0 8
yrs. Sureda, 2001 167 52 -- -- 5 yrs.
Schmitz, 2002 29 75 -- -- 3yrs. ??
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Allogeneic HSCT

• Disadvantages
• Strict patient selection
• Insufficient donors
• Immunosuppression requirement
• Increase NRM
• Second cancers

• Advantages
• Normalcy of HSC
• Prompt engraftment
• Reduction of secondary
• Cancers
• No tumor cell contamination
• GVD effect

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Results of Allo- HCSTHLA Identical Sibling
Donors

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Hodgkin LymphomaAllo versus Auto HSCT

• IBMTR data 1986-1992 showed no advantage to
  allogeneic HSCT, but only 50 had KPSgt 90 and
  only 20 were in remission
• Akpek (2001) showed lower relapse rates after
  allo HSCT than autografting. No second cancers in
  allografted pt. but persistent risk for
  autografted patients.

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Reduced Intensity Conditioning

• Relies on immunoablative regimen rather than
  myeloablation.
• Reduced NRM rates in heavily pre- treated and
  older patients( 8-12)
• Reduces pulmonary toxicity (3.8)
• GVHD and relapse remain problematic
• Delayed time to disease response

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A Business Rule of the Thumb

• You can not manage what you can not measure

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Rationale for Role of Radiation

• High dose chemotherapy still fails to cure a
  significant number of patients.
• Many patient with refractory recurrent disease
  following chemotherapy do not exhibit cross
  resistance to radiation.
• Most patients relapse in previously involved
  nodal sites.

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Cytoreductive/ConsolidativeXRT in Transplant

• Goals
• Cytoreduction/ consolidation (treatment of bulk)
• Immunosuppression (often combined with TBI)
• Questions
• What is the efficacy?
• Appropriate timing-pre- vs.. post-transplant

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Outcome after Relapse

• -Any recurrence with limited prior therapy,
  usually good outcome
• Radiation alone
• Low- intensity therapy
• Primary refractory or early relapse with advanced
  stage uniformly poor outcome
• Late relapse after standard intensive therapy
  intermediate outcome
• Very late relapse, usually good outcome
• Lymphocyte predominant disease

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Summary of Recommendations
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Summary of Recommendations
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Summary of Recommendations
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• To raise new questions, new possibilities, to
  regard old problems from a new angle, requires
  creative imagination and marks real advance in
  science.
• Albert Einstein, Nobel Prize for Physics

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The Road Ahead Caring and Courage