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1610 Part XI: Malignant Lymphoid Diseases Chapter 97: Hodgkin Lymphoma 1611

areas of known or bulky disease and doses have been lowered, coinci- randomizing patients between four cycles of ABVD, AV, ABV, or AVD
dent with addition of systemic chemotherapy. Furthermore, initial dis- plus 30 Gy involved-field radiotherapy. The AV and ABV arms were
ease reduction with chemotherapy results in less radiation exposure to closed early because of clearly inferior outcomes, and subsequent anal-
the neck, female breast, heart, and lungs, all of which are anticipated to ysis suggests that the AVD arm is also worse than the full four-drug
result in fewer late complications. Advances in radiotherapy techniques combination. 151
deliver more precise dose distributions, sparing normal tissues. The first The high cure rate with current limited chemotherapy and low-
modern combination chemotherapy program was the MOPP regimen dose radiotherapy creates a high standard for comparison with alter-
devised by Devita and colleagues. The national mortality figures for native treatment approaches. Nevertheless, considerable interest exists
22
cHL decreased by more than 60 percent in the decade that followed in devising management strategies omitting radiotherapy altogether,
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the introduction of MOPP. Bonadonna and colleagues developed an largely motivated by desires to avoid secondary malignancies and late
145
important alternative regimen for the treatment of cHL. ABVD, which cardiopulmonary complications. This approach is particularly favored
was effective in the treatment of patients who had failed MOPP 139,140 for women younger than age 30 years, who have a very high risk of
and offered a more favorable toxicity profile. ABVD subsequently developing breast cancer if treated with mediastinal radiotherapy. 145,152
became the preferred primary chemotherapy regimen, alone or in Canellos and colleagues treated 71 patients with early stage, favorable
combination with radiotherapy. 141,142 Of the multiple alternative chemo- cHL with six cycles of ABVD without radiotherapy and achieved a
therapy regimens introduced for the treatment of advanced cHL, only 5-year failure-free survival of 92 percent. A single institution study
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the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, of ABVD versus ABVD plus radiotherapy demonstrated no significant
prednisone, procarbazine (BEACOPP) combination developed by Diehl progression-free survival difference between the treatment arms, but
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and colleagues has demonstrated superior cure rates in multiple phase this trial accrued relatively small numbers of patients. A phase III
III studies. 143,144 Table 97–3 describes the drugs, doses, and schedules of North American study assigned 405 patients with previously untreated
combination chemotherapy programs effective in the management of stage IA or IIA nonbulky Hodgkin lymphoma to treatment with ABVD
Hodgkin lymphoma. alone for four to six cycles or subtotal nodal radiation therapy, with or
without ABVD. Among those assigned to subtotal nodal radiation ther-
apy, patients who had a favorable risk profile received subtotal nodal
FAVORABLE, LIMITED-STAGE DISEASE radiation therapy alone and patients with an unfavorable risk profile
Favorable, limited-stage Hodgkin lymphoma is typically defined in received two cycles of ABVD plus subtotal nodal radiation therapy.
North America as asymptomatic stage I or II supradiaphragmatic dis- After a median followup of 11.3 years, the overall survival (OS) was
ease with no bulky sites. A more restrictive definition is used in Europe 94 percent among those receiving ABVD alone, compared to 87 percent
based on the number of Ann Arbor sites, ESR, age and extranodal sites, for those receiving subtotal nodal radiation therapy (p = 0.04). The rates
as well as bulky disease (Table 97–4). Approximately 35 percent of of freedom from disease progression were 87 percent and 92 percent
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stages I and II patients meet this more limited definition of favorable in the two groups, respectively (p = 0.05). The investigators concluded
disease. For many years, extended-field (subtotal lymphoid) radiother- that treatment with ABVD therapy alone was superior because of a
apy administered after staging laparotomy, was the treatment of choice lower rate of death from secondary malignancies and other causes,
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for early stage, favorable Hodgkin lymphoma. A change in that stan- although critics have emphasized that the large fields and high doses
dard was compelled by the observation that the overall mortality rate of radiotherapy used in this trial are obsolete and that modern radio-
from other causes, particularly second cancers, exceeded deaths result- therapy techniques would be anticipated to have much more favorable
ing from Hodgkin lymphoma at 15 to 20 years. Early studies from outcomes. In a European trial, the epirubicin, bleomycin, vinblastine,
145
Stanford University demonstrated that involved-field radiotherapy plus prednisone (EBVP) regimen was tested against the same chemotherapy
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chemotherapy produced results equivalent or superior to wide-field plus 20- or 30-Gy involved-field radiotherapy. Inferiority of the EBVP
radiotherapy. Subsequently, several randomized trials demonstrated combination without radiotherapy resulted in the trial’s early closure.
146
the superiority of involved-field radiotherapy plus anthracycline- A Cochrane meta-analysis of randomized controlled trials comparing
containing chemotherapy compared to extended-field radiotherapy in chemotherapy alone with combined modality therapy concluded that
early stage favorable Hodgkin lymphoma. 147,148 adding radiotherapy to chemotherapy improves tumor control and OS
The next series of clinical trials were designed to test the optimal in patients with early stage Hodgkin lymphoma. 157
number of cycles of chemotherapy and the volume and dose of radio- Current studies are focused on assessing the potential role
therapy when both modalities are used in limited Hodgkin lymphoma. of interim FDG-PET scanning as a means of identifying patients
The Milan Tumor Institute documented disease control in more than (PET-negative) for whom radiotherapy can be omitted. The Euro-
95 percent of early stage cHL patients treated with four cycles of ABVD pean Organization for Research and Treatment of Cancer (EORTC),
and radiotherapy, with no advantage seen for extended- field radiother- the Lymphoma Study Association (LySA), and Fondazione Italiana
apy compared to involved-field radiotherapy. Similarly, no advantage Linfomi (FIL) H10 trial randomized 1137 patients with untreated
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to more extensive radiation in combination with chemotherapy was supradiaphragmatic clinical stage I/II cHL to either standard therapy
observed in a German Hodgkin Study Group (GHSG) study. A com- or an experimental, PET-response-adapted approach. Patients on the
150
parison of two versus four cycles of ABVD chemotherapy paired with trial were stratified into favorable and unfavorable cohorts based on
20 Gy or 30 Gy radiotherapy was made in a four-arm trial conducted by the presence or absence of adverse risk factors (age ≥50 years, more
the GHSG, evaluating patients with “favorable” early stage cHL, defined than four involved nodal areas, presence of mediastinal bulk [medias-
as patients with two or fewer sites of disease, no masses larger than tinum-to-thorax ratio ≥0.35], or ESR ≥50 mm without B symptoms or
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10 cm, a normal ESR, and no extranodal sites of disease. This trial pro- ESR ≥30 mm with B symptoms). The favorable group was random-
duced equivalent outstanding outcomes for all four arms, with 91 to 93 ized to either standard therapy with three cycles of ABVD chemother-
percent freedom from treatment failure after 5 years, and established apy followed by involved nodal radiotherapy (30 Gy + 6 Gy boost), or
two cycles of ABVD followed by 20 Gy of involved field radiotherapy as “experimental therapy” in which patients whose interim PET scans after
a new standard of care for early stage, favorable cHL. In a subsequent two cycles of ABVD were negative received two more cycles of ABVD
study, the GHSG evaluated eliminating drugs from the ABVD regimen, (total of four cycles) but no radiotherapy. Patients in the experimental

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