2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 2. Selected Risk-Adapted Treatment Approaches for Intermediate-Risk Pediatric Hodgkin Lymphoma
Chemotherapy (Number of Cycles) Radiation (Gy) Stage No. Patients Event-Free Survival (years) Survival (years)
COPP/ABV (6) 11 21, IF CS I/II*, CS IIB, CS III 394 84 (3) 100 (3)
OEPA/OPPA (2) � COPP (2) 8 20–35, IF II EA, IIB, IIIA 212 92 (5) N/A
OEPA/OPPA (2) � COPDAC (2) 15 20–35, IF II EB, III EA/B, IIIB, IVA/B 139 88.3 (5) 98.5 (5)
ABVE-PC (3–5) 18 21, IF IB, IIA, IIIA 53 84 (5) 95 (5)
Abbreviations: COPP, cyclophosphamide, vincristine, procarbazine, prednisone; ABV, doxorubicin, bleomycin, vinblastine; OEPA, vincristine etoposide, prednisone,
doxorubicin; OPPA, vincristine, procarbazine, prednisone, doxorubicin; COPDAC, cyclophosphamide, vincristine, prednisone, dacarbazine; ABVE-PC, doxorubicin,
bleomycin, vincristine, etoposide-prednisone, cyclophosphamide; E, extralymphatic; IF, involved-field radiation therapy.
* With adverse disease features defined as one or more of the following: hilar adenopathy, involvement of more than four nodal regions; mediastinal tumor with
diameter greater than or equal to one-third of the chest diameter, and node or nodal aggregate with a diameter greater than 10 cm.
studies is that because of effective retrieval therapy among
relapsed patients, overall survival did not differ among the
irradiated and nonirradiated groups.
Radiation Therapy for Intermediate/High-Risk HL
Concerns regarding long-term chemotherapy and RTrelated
toxicities have led to the development of divergent
therapeutic approaches for children and adolescents compared
with that of adults. In contrast to adult trials, clinical
trials for intermediate/high-risk pediatric HL typically use
RT as an adjunct to multiagent chemotherapy, with the goal
of reducing risk of relapse and preventing toxicity associated
with retrieval therapy. Combination chemotherapy including
vinca alkaloids, alkylating agents, anthracyclines, and
often etoposide provides the cornerstone of therapy (Tables 2
and 3). Gender-based regimens consider that male patients
are more vulnerable to gonadal toxicity from alkylating
agent chemotherapy and that female patients have a substantial
risk of breast cancer after chest RT. In this regard,
German Multi-Center investigators have undertaken a series
of gender-based risk-adapted trials aiming to reduce
gonadal toxicity in male patients while maintaining the
excellent disease-free survival accomplished with the OPPA/
COPP regimen. The DAL-HD-90 study established that
substitution of etoposide for procarbazine in the OPPA
combination (OEPA) in boys produces comparable EFS to
that of girls treated with OPPA and is associated with
hormonal parameters suggesting a lower risk of gonadal
toxicity. 13,14 In the GPOH-HD 2002 trial, substitution of
dacarbazine for procarbazine (OEPA-COPDAC) in boys produced
comparable results to standard OPPA-COPP in girls
when used in combination with IFRT. 15 Long-term follow-up
is needed to determine if restriction of alkylating agent
cumulative dose translates into improved rates of fertility
preservation.
Risk-adapted multiagent chemotherapy for intermediate/
high-risk HL is typically followed by consolidative RT to
involved sites of disease. Effective systemic therapy coupled
with advancements in diagnostic imaging has led to increasingly
restricted treatment fields that generally encompass
lymph node regions initially involved at the time of diagnosis;
field refinement is then routinely made to account for
tumor regression with chemotherapy. 16 IFRT is the most
common approach used in pediatric HL trials, although
some groups are now evaluating involved-nodal and limited
volume conformal (tailored field), intensity modulated, and
proton RT as approaches that further reduce potential
injury to normal tissues.
In the past decade, several trials have investigated the
benefit that adjuvant RT contributes to survival outcomes
among intermediate/high-risk children with HL who achieve
a complete response to multiagent chemotherapy. In the
CCG’s randomized controlled trial using COPP/ABV hybrid
chemotherapy, the projected 3-year EFS among patients
who achieved a complete response to initial therapy, was
92% (SE � 1.9%) for those randomized to receive low-dose
IFRT and 87% (SE � 2.2%) for those randomized to receive
no further therapy. 11 The difference in 3-year EFS was most
marked for stage IV patients randomized to receive
combined-modality therapy with IFRT (90%, SE � 5.5%)
compared with those randomized to receive chemotherapy
alone (81%, SE � 6.9%). Likewise, omission of RT for
patients completely responding to risk- and gender-based
OEPA/COPP or OPPA/COPP chemotherapy resulted in significantly
lower EFS in intermediate/high-risk patients compared
with irradiated patients (79% vs. 91%, p � 0.0008). 8
Notably, this study also demonstrated a survival benefit of
providing a 5–10 Gy RT boost to lymph node regions with
an “insufficient remission” following chemotherapy, thereby
overcoming the adverse prognostic implications of bulky
mediastinal lymphadenopathy. 17 For both studies, estimates
for overall survival did not differ between the irradiated
and nonirradiated groups because of successful salvage
therapy after relapse. 8,11
Contemporary trials have investigated if chemotherapy
and RT can be limited in patients who achieve a rapid early
Table 3. Selected Risk-Adapted Treatment Approaches for High-Risk Pediatric Hodgkin Lymphoma
HUDSON AND CONSTINE
Chemotherapy (Number of Cycles) Radiation (Gy) Stage No. Patients Event-Free Survival (years) Survival (years)
OEPA/OPPA (2) � COPP (4) 8 20–35, IF II EB, III EA/B, IIIB, IVA/B 265 91 (5) N/A
OEPA/OPPA (2) � COPDAC (4) 15 20–35, IF II EB, III EA/B, IIIB, IVA/B 239 86.9 (5) 94.9 (5)
ABVE-PC (3–5) 18 21, IF IB, IIA, IIIA 163 85 (5) 95 (5)
BEACOPP (4); COPP/ABV (4) (RER; girls) 19 None IIB, IIIB, IV 38 94 (5) 97 (5)
BEACOPP (4); ABVD (2) (RER; boys) 19 21, IF IIB, IIIB, IV 34
BEACOPP (8) (SER) 19 21, IF IIB, IIIB, IV 25
Abbreviations: OEPA, vincristine etoposide, prednisone, doxorubicin; OPPA, vincristine, procarbazine, prednisone, doxorubicin; COPP, cyclophosphamide,
vincristine, procarbazine, prednisone; COPDAC, cyclophosphamide, vincristine, prednisone, dacarbazine; ABVE-PC, doxorubicin, bleomycin, vincristine, etoposideprednisone,
cyclophosphamide; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; ABV, doxorubicin, bleomycin,
vinblastine; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; E, extralymphatic; IF, involved-field radiation therapy; RER, rapid early response; SER, slow early
response.
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