2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

RADIOTHERAPY FOR PEDIATRIC HODGKIN LYMPHOMA
response to dose-intensive chemotherapy regimens. These
studies have been facilitated by assessment of interim or end
of chemotherapy response based on anatomic or functional
changes on computed tomography or functional imaging like
positron emission tomography. The Pediatric Oncology
Group utilized a response-based therapy utilizing dosedense
ABVE-PC (doxorubicin, bleomycin, vincristine,
etoposide-prednisone, cyclophosphamide) for patients with
unfavorable advanced-stage disease in combination with 21
Gy IFRT. 18 The dose-dense approach permitted reduction in
chemotherapy exposure in 63% of patients who achieved a
rapid early response to three ABVE-PC cycles. Five-year
EFS was comparable for rapid early responders (86%) and
slow early responders (83%) treated with three and five
cycles of ABVE-PC, respectively, followed by 21 Gy IFRT.
The CCG (CCG-59704) evaluated response-adapted therapy
featuring four cycles of the dose-intensive BEACOPP
(bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine,
procarbazine, prednisone) regimen followed by a
gender-tailored consolidation for pediatric patients with
stage IIB, IIIB with bulk disease, and IV HL. 19 For rapid
early responding girls, an additional four courses of COPP/
ABV (without IFRT) were given in an effort to reduce breast
cancer risk. Rapid early responding boys received two cycles
of ABVD followed by IFRT. Slow early responders received
four additional courses of BEACOPP and IFRT. Rapid early
response (defined by resolution of B symptoms and greater
than 70% reduction in tumor volume) was achieved by 74%
of patients after four BEACOPP cycles and 5-year EFS
among the cohort is 94% (median follow-up 6.3 years). 19
Results from this study support that early intensification
followed by less intense response-based therapy results in
high EFS. However, the potential for late treatment effects
on cardiopulmonary and gonadal function have not been
evaluated.
Radiation Therapy in Refractory/Relapsed HL
The generally excellent outcome of children and adolescents
with HL limits opportunities to evaluate retrieval
therapy. This is particularly true in regard to the benefits of
using RT in the setting of refractory/relapsed disease. Uniformly,
chemotherapy is the recommended retrieval therapy,
with the choice of specific agents, dose-intensity, and
number of cycles determined by the initial therapy, disease
characteristics at progression/relapse, and response to retrieval
therapy. In children with localized favorable (relapse
after 12 months after completing therapy) disease recurrences
whose original therapy involved reduced cycles of
risk-adapted therapy, IRFT consolidation may be offered
following treatment with more intensive conventional chemotherapy.
Autologous hematopoietic cell transplantation
(autoHCT) is the recommended approach for patients who
develop refractory/relapsed disease during or within 1 year
after completing therapy. 20 Results of investigations
(largely comprised of adult patients) evaluating the use of
IFRT immediately before or after transplant have been
conflicting in their support of a potential benefit conferred by
RT. 21-23 However, most studies are limited by their retrospective
nature, nonrandom treatment assignments, and
small patient numbers. Nevertheless, IFRT is often used to
consolidate local control in individuals with refractory/recurrent
disease, especially in those who have limited or bulky
sites of disease recurrence or persistent disease that does
not completely respond to salvage chemotherapy. In the
latter, local radiotherapy can be considered to promote local
disease resolution before autoHCT rather than as consolidation
following autoHCT. However, concerns regarding toxicity
have prevented the use of IFRT as a standard adjuvant to
high-dose chemotherapy and autoHCT in HL. Prospective
trials are needed to definitely establish the long-term risks
and survival benefits provided by inclusion of RT in salvage
therapy approaches.
Advances in the Delivery of Radiation
As previously stated, contemporary protocols are testing
field reductions from involved lymph node regions to involved
nodal sites. In addition, the standard technique for
radiation delivery in pediatric HL is a two-dimensional
CT-based approach. However, three-dimensional conformal
radiation therapy (3DCRT), intensity-modulated RT
(IMRT), or proton therapy may be offer the ability to reduce
exposure to critical normal tissues such as heart, lungs, and
developing breast tissue. Uncertainty exists about the potential
for increased late effects from IMRT, particularly
secondary malignancy, bacause IMRT results in a lower
dose to a larger volume compared with conventional techniques.
Unfortunately, any benefits of lower doses to critical
organs, or changes (either an increase or decrease) in the
potential for a subsequent malignancy, will not be testable
for many years.
Conclusion
The role of RT in the treatment of pediatric HL has
evolved considerably over the last 50 years, primarily motivated
by the desire to avoid its adverse long-term effects.
Although elimination of RT has been a key focus of contemporary
trials, this modality continues to play an important
role in optimizing survival outcomes for many children and
adolescents with the disease. For those with low-risk HL,
the addition of low-dose IFRT permits reduction in chemotherapy
duration or intensity and thus the potential doserelated
toxicity of anthracyclines, alkylating agents, and
bleomycin that may preserve cardiopulmonary and gonadal
function. For those with intermediate/high-risk HL, the
superior disease-free survival demonstrated by some trials
may ultimately translate into a survival benefit by avoiding
the need for more toxic salvage therapy. In the setting of
disease with suboptimal chemotherapy response, RT consolidation
provides an effective alternative modality to enhance
tumor control. Until the availability of validated biologically
based prognostic factors, the inclusion of RT consolidation in
pediatric HL treatment regimens will continued to be guided
by prognostic factors at diagnosis correlated with disease
burden and chemotherapy responsiveness as assessed by
functional imaging. For patients who require RT to optimize
disease control, advances in radiation technology and reduced
volume radiation strategies are anticipated to greatly
reduce exposure to normal tissues and the subsequent risk
of late RT-associated toxicity. 24
Acknowledgements
Research grant support: Dr. Hudson is supported in part by
the Cancer Center Support (CORE) grant CA 21765 from the
National Cancer Institute and by the American Lebanese Syrian
Associated Charities (ALSAC).
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