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1614 Part XI: Malignant Lymphoid Diseases Chapter 97: Hodgkin Lymphoma 1615

a moderate increase in chemotherapy dose intensity would result in a for 8 cycles of BEACOPP escalated (91.9 percent vs. 95.3 percent) as a result
significant increase in the cure rate. In the original HD9 study, BEA- of higher treatment-related mortality and secondary malignancies with
COPP was given in “standard” and “escalated” versions, the latter facil- the latter regimen. 173
itated by granulocyte colony-stimulating factor use, and was compared Numerous investigations are underway to determine if interim
with the cyclophosphamide, vincristine (Oncovin), procarbazine, pred- PET scans can direct more-intensive treatment with escalated BEA-
nisone (COPP)–ABVD regimen. Patients with initial tumors equal COPP to the subgroup that benefits. 95,97,100,174,175 Likewise, interim and
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to or greater than 5 cm or residual radiographic disease received 36-Gy end-of-treatment PET scans are being used to direct the use of consol-
radiotherapy after chemotherapy. The 5- and 10-year results demon- idative radiotherapy. 95,174–177 Although there is great enthusiasm regard-
strated a significant progression-free and OS advantage for escalated ing this approach to direct subsequent treatment, it is notable that the
BEACOPP compared to COPP–ABVD. 143,144 The cure rates in excess majority of patients remaining PET-positive after four cycles of esca-
of 80 percent for escalated BEACOPP are the best ever recorded for a lated BEACOPP appear to be cured by the planned therapy, in contrast
large phase III trial in advanced Hodgkin lymphoma. The superiority to findings with ABVD. 177
of escalated BEACOPP was observed regardless of the clinical interna- The Stanford group took an alternate approach to advanced
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tional prognostic score. Despite these outcomes, BEACOPP has not Hodgkin lymphoma by abbreviating the duration of therapy and reduc-
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been universally accepted as the new standard in advanced Hodgkin ing cumulative drug doses in the Stanford V regimen. This approach
lymphoma because of concerns about the acute toxicity, which includes appeared highly successful in institutional and phase II cooperative
greater need for hospitalization and transfusion, and late toxicity, which group trials; however, three randomized controlled trials have failed to
includes male and female sterility and an increased risk of second- show improved progression-free survival compared to standard ABVD
ary leukemia. 165–168 In addition, approximately two-thirds of patients chemotherapy. 179–181 The impressive efficacy of brentuximab vedotin
received radiotherapy in the HD9 study. Two randomized clinical trials in relapsed and refractory cHL 182,183 has also led to investigations into
from Italy subsequently confirmed the superiority of BEACOPP over its incorporation into front-line regimens. This drug consists of an
ABVD for the end point of progression-free survival. 169,170 In the first anti-CD30 monoclonal antibody conjugated to a highly potent antitu-
trial, BEACOPP (four escalated dose cycles plus two standard cycles) bulin cytotoxic drug, monomethyl auristatin E. Phase I studies revealed
was compared to ABVD; all patients were to receive consolidation unacceptable pulmonary toxicity when brentuximab vedotin was
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radiotherapy for bulky or residual disease. BEACOPP yielded signifi- incorporated into the full ABVD regimen, presumably as a result of
cantly superior progression-free survival compared to ABVD although augmenting the pulmonary toxicity of bleomycin. Omission of bleomy-
no difference in OS was observed. In the second study, patients were cin, however, allows safe and effective combination therapy with bren-
169
randomized to ABVD versus four cycles of standard and four cycles tuximab vedotin concurrently with AVD, with 96 percent of patients
of escalated BEACOPP with preplanned retreatment and high-dose achieving complete remission. An international phase III randomized
184
170
therapy and autologous transplantation for treatment failures. This comparison of standard ABVD versus brentuximab vedotin + AVD is
study also showed a significantly higher progression-free survival for underway for patients with advanced cHL.
the BEACOPP arm but no difference in OS (Table 97–5). The EORTC The use of radiotherapy as a consolidation to combination chemo-
20012 Trial randomized patients with “high-risk” advanced stage Hodg- therapy in advanced cHL is controversial. Encouraging data from single
kin lymphoma with an international prognostic scale score of 3 to 7 institutions in adults and children were not borne out in randomized
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to treatment with either BEACOPP (four escalated cycles + four stan- trials, some of which were criticized as underpowered. Furthermore,
171
dard cycles) or ABVD. Progression-free survival was improved in the chemotherapy regimens have evolved over the time span of these stud-
BEACOPP arm but there was no statistically significant improvement ies. The application of 30 Gy involved-field radiotherapy to patients
in event-free or OS compared to ABVD. In each of the four cited in complete remission after MOPP–ABV was studied in an adequately
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trials, the hazard ratio for relapse with BEACOPP was approximately powered phase III trial. No significant difference in failure-free
185
0.5. Standards of care in advanced Hodgkin lymphoma continue to be survival was observed. Of note, all patients in partial remission received
debated in view of the lack of a survival benefit with the BEACOPP pro- 40 Gy on this study and their outcome was not different from complete
gram, which benefits approximately 15 percent of patients while expos- remission patients. The GHSG HD12 study randomized patients to
ing 100 percent of patients to more toxicity. observation or consolidation radiotherapy, with the incorporation of
Efforts to reduce the risk of treatment-related morbidity of esca- a central review panel, following BEACOPP. The final analysis of this
lated BEACOPP have included studying the combination of four cycles study reported a slight decrease in the freedom from treatment fail-
of escalated and four cycles of standard BEACOPP and eliminating ure if radiotherapy was omitted in patients who had persistent radio-
radiation therapy. In the GHSG HD12 trial, four standard cycles of graphic abnormalities on CT imaging after chemotherapy (90.4 percent
BEACOPP plus four escalated cycles performed similarly to eight cycles vs. 87 percent after 5 years), but no difference was seen in patients with
of escalated BEACOPP, with freedom from treatment failure rates of bulk disease in complete response after chemotherapy. Unfortunately,
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85 percent and 86 percent, respectively, 5 years after treatment. In this FDG-PET imaging was not routinely used in this trial. The two Ital-
study, there was a slight trend for worse failure-free survival in patients ian studies comparing ABVD with BEACOPP mentioned above rou-
with residual radiographic masses on end-of-treatment CT imaging tinely incorporated consolidation radiation therapy for residual or
who did not received consolidative radiotherapy (90 percent after bulky disease. 169,186 The HD15 study limited the use of radiotherapy to
5 years with radiotherapy and 87 percent without it, p = 0.08). The patients with positive PET scans after four cycles of chemotherapy. With
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subsequent HD15 trial randomized 2182 patients with newly diagnosed this approach, only 12 percent of patients received radiotherapy and the
advanced stage cHL to receive either eight cycles of BEACOPP escalated , six progression-free survival rate among PET-negative patients, who did
173
cycles of BEACOPP escalated , or eight cycles of the BEACOPP-14 regimen. not receive radiotherapy, was 96 percent after 1 year. In sum, the
Patients with a persistent mass after chemotherapy measuring 2.5 cm or data do not support the routine use of radiotherapy following a full
larger that was FDG-avid on an end-of-treatment FDG-PET imaging course of chemotherapy in advanced Hodgkin lymphoma. However,
received consolidative radiotherapy (30 Gy). Freedom from treatment the role of this potent treatment in patients with an early incomplete
failure was similar for all three treatment arms but 5-year OS was sig- response or following a brief course of chemotherapy is likely to be
nificantly better for patients receiving six cycles of BEACOPP escalated than more significant. 177,178

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