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1612 Part XI: Malignant Lymphoid Diseases Chapter 97: Hodgkin Lymphoma 1613

TABLE 97–4. Prognostic Factors for Hodgkin Lymphoma FDG-PET/CT imaging in early stage cHL remains controversial. Never-
theless, the National Comprehensive Cancer Network has incorporated
Limited Stage Advanced Stage interim PET-imaging into their guidelines, suggesting that early stage
EORTC GHSG International Collaborative Study cHL patients who are PET-negative after two cycles of ABVD may be
treated with chemotherapy alone, without radiotherapy. 158
Adverse Prognostic Factors Adverse Prognostic Factors
MMR ≥0.35 MMR ≥0.35 Age ≥45 years UNFAVORABLE LIMITED-STAGE HODGKIN
ESR >30 if ESR >30 if Stage IV LYMPHOMA
symptomatic symptomatic
ESR >50 if ESR >50 if Male sex Patients with “unfavorable” prognostic factors (large tumor bulk
asymptom- asymptomatic defined as a mass 10 cm or larger in diameter or more than one-third
atic of the transthoracic diameter, an ESR of 50 or greater, three or more
sites of tumor involvement, the presence of B symptoms, or the presence
>3 Ann >2 Ann Arbor White blood count ≥15 × 10 /L of extranodal sites [see Table 97–4]) require more intensive treatment
9
Arbor sites sites
than do patients not exhibiting any of these features. The EORTC and
158
Age ≥50 Extranodal Lymphocyte count <0.6 × 10 /L the Groupe d’Etude des Lymphomes de l’Adulte (GELA) reported results
9
disease or <8% from a randomized study (H9U) in which such “unfavorable” early stage
Massive Albumin <4 g/dL patients were randomized to treatment with either four or six cycles of
splenic ABVD or six cycles of BEACOPP, each followed by 30-Gy involved-
disease field radiotherapy. No significant differences were observed among
156
Presence of any factor is Hemoglobin <10.5 g/dL these three treatment arms, establishing four cycles of ABVD and 30
considered unfavorable Gy of involved field radiotherapy as a standard of care for these patients.
The GHSG subsequently randomized 1395 patients with unfavor-
Two-thirds of limited stage Factors summed to yield the inter-
patients have one or more national prognostic score 75% of able early stage Hodgkin lymphoma to four cycles of either ABVD or
adverse factors patients have a score of 1–3 BEACOPP baseline followed by either 20 Gy or 30 Gy of involved field radio-
therapy. In this study, four cycles of ABVD followed by 30 Gy of radio-
EORTC, European Organization for the Research and Treatment of therapy was the best approach, affording an 85 percent rate of “freedom
Cancer; ESR, erythrocyte sedimentation rate; GHSG, German Hodgkin from treatment failure” and an OS rate of approximately 95 percent after
Study Group; MMR, mediastinal mass ratio, which is the ratio of the 5 years, while maintaining a favorable toxicity profile. The adminis-
159
maximal width of a mediastinal mass relative to the maximal width of tration of only 20 Gy of radiotherapy following ABVD was found to be
the mediastinum, as measured by computed tomographic imaging.
clearly inferior to the other three treatment arms which all administered
30 Gy to this unfavorable group of patients. The subsequent GHSG
HD14 study reported an advantage in progression-free survival for
arm who had FDG-avid foci of disease after two cycles of ABVD were two cycles of escalated BEACOPP and two cycles of ABVD plus radi-
switched to the BEACOPP-escalated regimen for 2 cycles followed by ation therapy compared to four cycles of ABVD–radiation therapy, in
involved nodal radiotherapy. An independent data monitoring commit- a specified interim analysis, though no OS benefit was seen. After 3
160
tee stopped the study after a median followup of 1.1 years because of years, 90 percent of ABVD–radiation therapy patients were disease-free
inferior results in the experimental group, with a 1-year progression- compared to 96 percent treated with the BEACOPP–ABVD–radiation
free survival of only 94 percent compared to 100 percent in patients therapy regimen. The EORTC//LySA/FIL H10 trial randomized both
treated on the standard arm (p = 0.017). The independent data monitor- favorable and unfavorable early stage patients to either standard therapy
ing committee mandated that all patients on the experimental arm be or experimental, PET-response adapted therapy. Of the 519 “unfa-
101
crossed over to receive involved nodal radiotherapy. Interestingly, the vorable” patients evaluated in the interim analysis, 251 were random-
101
opposite conclusion was reached by investigators in England conduct- ized to standard ABVD for four cycles followed by 30 Gy of involved
ing a similarly designed trial, dubbed the “RAPID” trial. In this study, nodal radiotherapy, and 268 were randomized to PET-response adapted
102
patients with early stage cHL were given three cycles of ABVD followed therapy. Patients on the experimental arm received six cycles of ABVD
by a PET scan. Patients who were PET-negative after three cycles of without any radiotherapy if the PET scan was negative after the second
ABVD were randomized to either receive 30 Gy of involved field radio- cycle of ABVD, whereas PET-positive patients were switched to BEA-
therapy or no further treatment. Patients who were PET-positive after COPP for 2 cycles followed by radiotherapy. An independent data
escalated
three cycles received a fourth cycle of ABVD followed by involved field safety monitoring board stopped this trial after a median followup of
radiotherapy. An intent-to-treat analysis of the randomized PET-nega- only 1.1 years because of worse outcomes on the experimental, PET-re-
tive population revealed a 3-year progression-free survival of 94.5 per- sponse adapted arm, with 16 relapses in 268 cases compared to only
cent in the combined modality group compared to 90.8 percent in those nine relapses of 251 cases on the standard arm (hazard ratio of 2.4; 95
receiving only three cycles of ABVD (p = 0.23). An analysis of the data percent confidence intervals 1.4 to 4.4). 101
according to the treatment actually received revealed a 3-year progres-
sion-free survival of 97 percent in the combined modality group com-
pared to 90.7 percent in the ABVD-alone group (p = 0.03). There were ADVANCED DISEASE
no statistically significant differences in OS between the groups (97.1 vs. ABVD became the standard therapy for advanced Hodgkin lymphoma
99.5 percent, respectively; p = 0.07). The investigators conducting this by proving to be superior to the MOPP chemotherapy and equal to, but
trial concluded that the inferior progression-free survival in the group less toxic than, hybrid or alternating combinations with MOPP. 141,142,161–164
receiving ABVD alone was acceptable in order to avoid late complica- Specifically, the incidence of secondary myelodysplasia, leukemia, and
tions associated with radiotherapy. In view of the conflicting conclu- sterility was less with ABVD. The GHSG developed the BEACOPP regi-
sions derived from these two large phase III trials, the role of interim men (see Table 97–3) based upon mathematical modeling that indicated

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