Download Document

Progress in the Treatment of Late
Effects
Daniel A. Mulrooney, MD, MS
Division of Cancer Survivorship
St. Jude Children’s Research Hospital
Cancer Survival, 0–14 Years of Age
SEER Program 1975-2005
100
Survivorship Statistics*
80
2000
1998
1994
Proportion Surviving
1990
1985-89
60
1980-84
1975-79
• In 2005, estimated 328,600
childhood cancer
survivors in the U.S.
• Estimated 366,000 by 2010
40
• 1 in 680 is a childhood
cancer survivor (ages 20
to 50 years)
20
0
0
5
10
15
20 Years from Diagnosis
* Source: NCI Office of Cancer Survivorship, Mariotto et al, CEBP, 2009
Late Mortality in 5+ Year Survivors
0.85
0.90
0.95
US Female
US Male
0.80
0.75
0.70
Survival function estimate
1.00
All Cause Mortality
SMN
Cardiac
Pulmonary
5
10
SMR
95% CI
15.2
7.0
8.8
13.9 – 16.6
5.9 – 8.2
6.8 – 11.2
15
20
Female
25
Years since diagnosis
Mertens, et al, JNCI 2008
Male
30
35
CCSS
CHILDHOOD CANCER SURVIVOR STUDY
Late Mortality in 5+ Year Survivors
Armstrong et al, JCO 2009
Improving Outcomes Through Late Effects
Research
CANCER SURVIVORS
Health-related
and QOL
Outcomes
Cancer
Diagnosis and
Treatment
“Secondary “
Prevention
Evidence-based
Clinical Care
Guidelines
“Primary”
Prevention
High-risk Groups
Development of
Intervention
Strategies
Implementation
Robison & Bhatia, Cancer Epi Bio Prev 2008
Clinical Trials of
Efficacy
Improving Outcomes Through Late
Effects Research
• Primary Prevention
– Before disease is
present
– Aims to prevent disease
from occurring
– Example: encouraging
patients to protect
themselves from
excessive sun exposure
to avoid skin cancer
• Secondary Prevention
– After disease has
occurred
– Before symptoms
develop
– Find and treat early
– Example: checking
suspicious skin growths
for possible cancer
• Tertiary Prevention
− treatment of disease after symptoms have developed
Objectives
• What has been learned from childhood cancer
survivors
• Historical trends in childhood cancer treatments
and changes made due to late-effects research
• Education and resources to facilitate risk-based
care
– Children’s Oncology Group Long-Term Follow-Up
Guidelines for Survivors of Childhood, Adolescent and
Young Adult Cancers
Acute Lymphoblastic Leukemia
Pui et al, NEJM 2006
Acute Lymphoblastic Leukemia
CNS Leukemia
• Prevention – 1◦ or 2◦
• Cranial/Spinal radiation
• Late Effects:
• Second cancer
• Brain tumors
• Stroke
• Endocrine dysfunction
• Growth
• Weight management
• Cognitive function
• School performance
• Intrathecal chemotherapy
Second Neoplasms (SN)
in Childhood Cancer Survivors
Cumulative incidence [%]
25
20
Any SN
15
NMSC
10
SMN
5
Meningioma
0
5.0
10.0
15.0
20.0
Years since diagnosis
25.0
30.0
Friedman, et al. JNCI 2010
Second Neoplasms (SN)
in Childhood Cancer Survivors
SN
Cumulative incidence [%]
25
NMSC
SMN
Meningioma
RT
20
15
No RT
10
RT
RT
No RT
No RT
5
RT
No RT
0
10
20
Friedman, 2010
30
10
20
30
10
20
Years since diagnosis
30
10
20
30
Acute Lymphoblastic Leukemia
CNS Leukemia
Pui et al, NEJM 2009
Hodgkin Lymphoma
Percent
All-Cause Mortality (Hodgkin Lymphoma)
in the Childhood Cancer Survivor Study (CCSS)
100
90
80
70
60
50
40
30
20
10
0
13%
39%
0
5
10
15
20
25
Years from Diagnosis
Armstrong et al., JCO, 2009
30
35
Cumulative Incidence of Chronic Health Conditions
Among 1876 Hodgkin Lymphoma Survivors
1
Any Chronic
Condition
0.9
Cumulative Incidence
0.8
0.7
Standardized Mortality Ratios
0.6
0.5
0.4
Second cancer
24.0
Cardiac
13.8
Severe,
disabling,
lifethreatening
condition
0.3
0.2
0.1
0
0
5
10
15
20
Years since diagnosis
Oeffinger et al., NEJM, 2006
25
30
Evolution of Role of Radiation
1960
More is better
Used enthusiastically
and extensively as
means to reduce or
avoid chemotherapy
related toxicity and
enhance or sustain
disease control
2012
Less is better
Used reluctantly
and sparingly as
means to enhance
and sustain
disease control
Similar trend in evolution of role of chemotherapy
Radiation Therapy – Hodgkin Lymphoma
Mantle
Upper abdomen
Mantle
Musculoskeletal Late Effects
Risk factors
• Younger age
(prepubertal)
• Higher total dose
(> 20 Gy)
• Higher fraction
dose ( 2 Gy)
• Larger treatment
field
• Epiphysis in
treatment field
Breast Cancer after Hodgkin lymphoma in
girls receiving radiation
Cumulative incidence
0.30
SIR=55
0.20
0.10
20%
0.0
15.0
JCO 2003; 21:4386-94
25.0
35.0
Age in years
45.0
Breast Cancer after Hodgkin lymphoma in
girls receiving radiation
- Reduction in
RT volume
decreased
risk of breast
cancer.
- 30-year CI of
breast cancer:
26% in women
treated before
age 21 years
DeBruin et al, JCO 2009
Radiation Therapy – Hodgkin Lymphoma
Involved Field RT
Involved Node RT
Progress in Survival of Pediatric Hodgkin
Lymphoma: 5-Year Survival Rates
100
90
80
Percent
70
60
50
40
30
20
10
0
1975-77
1978-80
1980-83
1984-86
1987-89
1990-92 1993-2003
35-44 Gy Extended-field RT
15-25.5 Gy Involved-field RT
Risk-adapted
Non-cross resistant
chemotherapy (MOPP)
Alternative chemotherapy
regimens (ABVD)
Response-based
Surgical staging
Clinical staging
Gender-directed
treatment approach
Ries, et al., SEER Cancer Statistics, 1975-2005
Finding the Balance: Therapy Options and
Toxicity for Pediatric Hodgkin Lymphoma
Combined Modality Therapy
Reduce toxic exposures
Enhance anti-tumor activity
May confer additive toxicities
Radiation Therapy
Chemotherapy
MOPP
ABVD
Etoposide
Growth defects
Second cancers
Thyroid dysfunction
Cardiac dysfunction • Infertility • Cardiomyopathy • Secondary
leukemia
Pulmonary fibrosis • Secondary • Pulmonary
leukemia
fibrosis
Risk for reported cardiac conditions by cardiac
radiation dose among 14, 358 survivors in the
CCSS*
MI
CHF
Valves
1.0
1.0
1.0
< 500 cGy
0.7 (0.4-1.4)
0.9 (0.6-1.4)
0.6 (0.4-1.0)
500-1499
0.6 (0.1-2.5)
1.3 (0.7-2.5)
1.4 (0.7-2.9)
1500-3499
2.4 (1.2-4.9)
2.2 (1.4-3.5)
3.3 (2.1-5.1)
> 3500
3.6 (1.9-6.9)
4.5 (2.8-7.2)
5.5 (3.5-8.6)
No RT
* Adjusted for sex, age at cancer diagnosis, treatment era,
anthracycline dose, and use of cisplatin, bleomycin,
cyclophosphamide and vincristine.
Mulrooney DA, et al. BMJ 2009
Anthracycline-Related CHF
Blanco JG, et al. J Clin Oncol. 2012
Consider Competing Risks
Anthracycline-Related Cardiomyopathy
Low risk features
• Anthracycline dose < 100 mg/m2
• Radiation impacting heart < 15 Gy
Low
Moderate
High
High risk features
•
•
•
•
•
Age < 5 years at treatment
Anthracycline dose > 250-300 mg/m2
Radiation impacting heart > 35 Gy
Combined modality therapy
Decline in function during therapy
Does Everybody Need the Same Intensive
Therapy?
Risk-adapted
• Disease stage
• Involved sites:
–
–
–
–
# nodal sites
Hilar nodes
Nodal v. extranodal
Extranodal extension
• B-symptoms
• Tumor bulk
• Tumor histology
– NLPHL v. classical
• Other lab parameters
Age/Gender-directed
• Young: cardiac,
musculoskeletal
• Boys: gonadal toxicity
• Girls: breast cancer
Response-based
• Using early response
assessed by anatomic
and functional imaging
to truncate or escalate
therapy
Risk Group Designations
Low: Localized/Favorable
• Stage IA/IIA
No tumor bulk
Mediastinal ratio < 33%
Lymph nodes < 4-6 cm
No extranodal extension
< 3-4 involved nodal regions
Intermediate
• Stage I/IIA or IIIA
Tumor bulk
Mediastinal ratio  33%
Lymph nodes  4-6 cm
Extranodal extension
 3-4 involved nodal regions
• Some stage IIB
High: Advanced/Unfavorable
• Some stage IIB, stage IIIB, stage IVA/B
Who can be cured without alkylators?
• Localized favorable:
– Excellent outcomes with 2-4 ABVD or derivative.
– Radiation may not be necessary in some
– Limited doses of etoposide associated with negligible
risk of secondary leukemia
• Localized unfavorable & advanced:
– Outcome may be compromised if alkylators omitted
– Need to consider risk for cardiotoxicity if
anthracycline regimen used to avoid alkylators,
especially if combined with thoracic radiation.
– Substitution of etoposide for alkylators offers potential
benefits of enhancement of anti-neoplastic activity
and protection of gonadal function.
Who can be cured without radiation?
• Many patients can be cured
with non-cross-resistant
chemotherapy alone.
• Most effective regimens use
greater number of cycles of
alkylator-based regimens.
• Radiation appears to improve
event-free survival in
advanced, symptomatic, bulky
disease. However, overtime
overall survival is lower.
Metzger et al, JAMA 2012
Salvage rate is higher in
patients who fail after
treatment with
chemotherapy alone.
Persistent Therapeutic Dilemmas
• How to define optimal therapy?
–
–
–
–
Who can be cured without alkylators?
Who can be cured without radiation?
Is there a safe dose of anthracycline?
Is there benefit from intensifying therapy?
• How to integrate new agents and noncytotoxic therapy?
Brain Tumors
Medulloblastoma
• Most common CNS malignancy in
childhood
• 20% of primary CNS tumors
• Mean age: 3-4years
• More common in males
• Presentation
– 72% are located in posterior fossa
– 12% are hemisphere
– 7% are pineal
• Very invasive
– CNS metastases in 11-43% at presentation
– Extraneural spread
Allen et al., J Neurosurg 1982;57:446.
Medulloblastoma - Therapy
RX
surgery RT
- 1930
1930-35
1932-47
1980
1991
1990
1990
1994
5yr EFS
Chemo
0%
local
0%
local+ CS
53%
CVp
64%
MOPP
68%
CCNU/Vcr
65%
CDDP/VP16
74%
CDDP/Vcr/CCNU 85%
Therapeutic Balance
Neurocognitive
Endocrinopathies
Radiation necrosis
Stroke
Hearing loss
Secondary tumors
Efficacy
Toxicity
Therapy
Medulloblastoma - Therapy
• Surgery
• Radiotherapy
– Local: 5400 – 5940 cGy
– Craniospinal
• High Risk: 3600 cGy
• Standard Risk: 2340 cGy
• Chemotherapy (active agents)
– Vincristine, lomustine, cisplatin, etoposide,
cyclophosphamide
Predicted Mean Change in IQ
Average Risk
(2340 cGy CSI)
High Risk
(3600 cGy CSI)
Age≥7
-0.42 points/yr
-1.56 points/yr
Age<7
-2.41 points/yr
-3.71 points/yr
St. Jude Medulloblastoma-96 Trial
Gajjar et. al., Lancet Oncology, 2006
SJMB96 – Reduction in chemotherapy
Vincristine
Cisplatin
Number of doses
8
Standard
SJMB96
7
6
5
4
3
2
1
Number of doses
35
30
25
20
15
10
5
0
Standard
SJMB96
Regimen
0
Standard
SJMB96
Regimen
SJMB 96 Vincristine 1.5 mg/m2
SJMB 03 Vincristine 1.0mg/m2
SJMB 96 – 5 yr risk event free survival
Gajjar et. al., Lancet Oncology, 2006
136 sections detailing exposurebased potential late effects and
screening recommendations
 Grading of evidence linking
exposure to potential late effect
 Second (adult) cancer screening
recommendations for standard
and high risk groups
 Health Links for patient education

www.survivorshipguidelines.org
Guideline Organization
Guideline Organization
Improving Outcomes Through Late Effects
Research
CANCER SURVIVORS
Health-related
and QOL
Outcomes
Cancer
Diagnosis and
Treatment
“Secondary “
Prevention
Evidence-based
Clinical Care
Guidelines
“Primary”
Prevention
High-risk Groups
Development of
Intervention
Strategies
Implementation
Robison & Bhatia, Cancer Epi Bio Prev 2008
Clinical Trials of
Efficacy
Conclusion
• Lessons learned from childhood cancer survivors is
impacting current cancer treatment and will
influence the care of future patients (primary
prevention).
• Survivorship research is also impacting the care of
current survivors (secondary prevention) who need
ongoing risk-based care
– Providers need to understand cancer-related health risks.
– Survivors and families need to understand cancer-related health
risks.
– Survivors, families and providers need to communicate.
Questions