A 10-year experience with treatment of high and standard risk Hodgkin
disease: Six cycles of tailored BEACOPP, with interim scintigraphy, are
effective and female fertility is preserved
Eldad J. Dann,1,6* Zeev Blumenfeld,2,6Rachel Bar-Shalom,5,6Irit Avivi,1,6
Menachem Ben-Shachar,3Odelia Goor,7Diana Libster,8Diana Gaitini,4,6Jacob M. Rowe,1,6
and Ron Epelbaum3,6
Therapy of Hodgkin lymphoma (HL) is designed to prolong survival and minimize toxicity. A total of 124
patients with newly diagnosed HL and adverse prognostic factors were prospectively studied between July,
1999 and August, 2005. Patients with early unfavorable and advanced disease were eligible for the study.
Patients were assigned to therapy based on international prognostic score (IPS). Those with IPS ? 3
received three cycles of escalated BEACOPP (EB). All others received two cycles of standard BEACOPP
(SB). Subsequent therapy was prospectively assigned according to early interim GA67or positron emission
tomography (PET)/computerized tomography (CT). Four cycles of EB or SB were administered following a
positive or negative scan, respectively. Complete remission rate, 10-year progression free (PFS), and overall
survival (OS) were 97, 87, and 88%, respectively, at a median follow-up of 89 months (5–144). PFS and OS
were similar in both groups. Fertility status was assessed in 38 females aged <40 years; 94% of females
younger than 40 years preserved their cyclic ovarian function. Nineteen conceived during follow-up for 30
pregnancies, delivering 24 babies. Deliveries were reported up to 7 years from diagnosis. Predictive value
of negative interim Ga67or PET/CT was 87 and 93%, respectively. Six cycles of tailored BEACOPP, for
patients with adverse prognostic factors, provide encouraging long-term PFS and OS, and fertility is pre-
served in most females. Am. J. Hematol. 87:32–36, 2012.
C 2011 Wiley Periodicals, Inc.
The use of more intensive regimens, such as escalated BEA-
COPP (EB), including bleomycin, vincristine, procarbazine,
prednisone and increased doses of etoposide, doxorubicin, and
cyclophosphamide, administered as initial therapy for Hodgkin
lymphoma (HL), has provided improved rates of 5- and 10-year
progression free survival (PFS; 87 and 82%, respectively) com-
pared with standard regimens (69 and 64%, respectively) as
reported in two randomized trials [1,2]. However, EB is associ-
ated with a 3% risk of secondary leukemia , significantly
reduced ovarian reserve in all treated women, reflected by a
low anti-Mullerian hormone level  and permanent amenor-
rhea, reported in 51% of patients at a 3.2-year follow-up .
The PFS superiority was not translated into a statistically signifi-
cant survival benefit in the trial of the Gruppo Italiano per lo Stu-
dio dei Linfomi (92% vs. 84%) . However, a survival benefit
of 86% versus 75% was found in the trial by the German Hodg-
kin Study Group . These data suggest that the risk-benefit ra-
tio for intensifying therapy is not advantageous for all patients.
Therefore, individual adjustment of dose intensity according to
predefined risks and early response assessment, based on in-
terim scintigraphy results, may become one of the pivotal tools
to address the crucial issue of early and late treatment toxicities
in patients with HL, with a particular impact on the preservation
of fertility in women.
In the current trial, patients were assigned to initial treat-
ment according to their risk categories (Fig. 1A), and ther-
apy was prospectively adjusted based on the response
evaluated by scintigraphy at the end of two cycles of treat-
ment (Fig. 1B). Gallium Ga67–SPECT, used until the year
2001, was further substituted with FDG-PET/computerized
tomography (CT) scanning, which has become standard
The aim of the study was to assess PFS, overall survival
(OS), and post-therapy fertility status in patients with HL
treated with risk adapted tailored BEACOPP regimen for
six cycles only.
Between July, 1999 and August, 2005, a prospective multicenter
study for patients with classical HL, aged 18–65 years, was conducted.
One hundred and eight patients who had at least a 12-month follow-up
were previously reported at a median follow-up of 47 months .
Hereby, a longer median follow-up (89 months) and a long-term fertility
outcome are described in the cohort of 124 patients, comprising 16
additional individuals who were treated before August, 2005, but were
not included in the previous analysis due to their short follow-up at the
time of evaluation. Characteristics of the patients are presented in
Table I. Individuals at an early disease stage with favorable prognostic
features were excluded from the trial. Patients were enrolled in the
study if they met the criteria presented in Fig. 1a. Patients with HL
stages I and II and with B symptoms or a bulky mediastinal mass or
stages III and IV were defined according to the international prognostic
score (IPS)  and were further subdivided into two groups using the
risk stratification strategy, as previously reported . Subjects with an
early unfavorable disease and those with an IPS ? 2 (standard risk
patients) received two cycles of standard BEACOPP (SB). High-risk
patients, with IPS ? 3, were treated with two cycles of EB. A subse-
quent therapeutic regimen was established based on the results of
Conflict of interest: Nothing to report
*Correspondence to: Eldad J. Dann, MD, Department of Hematology and
Bone Marrow Transplantation, Rambam Health Care Campus, P.O. Box
9602, Haifa 31096, Israel. E-mail: firstname.lastname@example.org
1Department of Hematology and Bone Marrow Transplantation, Rambam
Health Care Campus, Haifa, Israel;
Health Care Campus, Haifa, Israel;3Department of Oncology, Rambam Health
Care Campus, Haifa, Israel;4Department of Radiology, Rambam Health Care
Campus, Haifa, Israel;
Care Campus, Haifa, Israel;6Bruce Rappaport Faculty of Medicine, Techn-
ion, Israel Institute of Technology, Haifa, Israel;7Department of Hematology,
Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;
Hadassah Mount Scopus Hospital, Jerusalem, Israel
2Department of Gynecology, Rambam
5Department of Nuclear Medicine, Rambam Health
Received for publication 27 July 2011; Revised 31 August 2011; Accepted 6
Am. J. Hematol. 87:32–36, 2012.
Published online 12 September 2011 in Wiley Online Library (wileyonlinelibrary.com).
C 2011 Wiley Periodicals, Inc.
American Journal of Hematology
scintigraphy (Ga67scan or F18FDG-PET/CT) performed after two
cycles of chemotherapy. Patients with negative interim study were
treated with additional four cycles of SB, whereas those with positive
interim scanning had four additional cycles of EB (Fig. 1b). Scintigraphy
was performed to all patients at diagnosis and early during treatment,
that is, GA67scan—after the first or second cycle—or hybrid FDG-
PET/CT after the second cycle. Functional imaging results were ana-
lyzed in conjunction with all other relevant patient data.
Interim scan was defined as positive for lymphoma in the presence
of any focus of increased uptake that could not be related to physio-
logic biodistribution of the tracer or to a known benign process. A nega-
tive study showed no foci of increased uptake unrelated to physiologic
or benign tracer uptake. Patients had scans following completion
of chemotherapy and then every 6 months for the first 2 years of
follow-up and once during the third year. Involved-field radiation therapy
at the end of chemotherapy was planned for patients with a bulky
mediastinal mass of ?10 centimeters on CT and for those with residual
scintigraphic uptake of a single lesion following six cycles of chemo-
therapy. This study was performed in accordance with Helsinki Guide-
lines, was registered on the NCT website (registration # 00305149),
and all patients signed informed consent.
Chemotherapy was given as previously reported . Cycles were
repeated every 21 days. When compared with SB, EB included
increased doses of cyclophosphamide, doxorubicin, and etoposide .
G-CSF (filgrastim) was given to the patients treated with EB or to any
other patient with febrile neutropenia or with a treatment delay associ-
ated with incomplete neutrophil recovery. Dose reduction due to EB-
related toxicity wasgraded from
was decreased accordingly if a preceding cycle was accompanied with
febrile neutropenia for ?5 days . Since 2002, prednisone dosage
has been reduced from 14 days to 1 week only.
levelsI toIV,and therapy
defined as the time from study entry until lymphoma progression or
death, as a result of any cause. The secondary endpoint was OS. All
patients were included in the intention-to-treat analysis. Complete
remission (CR), primary resistant disease (PRD), and relapse were
defined according to revised response criteria .
PFS and OS were described using the Kaplan–Meier curve  and
log-rank test. The v2test was used to compare proportions between differ-
ent groups. Analysis was performed using SPSS 15 (SPSS, Chicago, IL).
One hundred and twenty-four patients were enrolled at four
hospitals; patient demographics are shown in Table I. One
hundred and nineteen patients achieved CR (96%). Five
patients had a primary resistant disease (4%) presented as
progression on therapy or within 3 months from the end of
therapy. Seven patients (6%) experienced disease relapse
4–42 months after the end of therapy. Among 12 patients
with treatment failure, seven had an IPS ? 2 and five had an
IPS ?3. With a median follow-up of 89 months (5–144), the
10-year PFS for all patients was 87% (95% CI 5 81–93) and
OS was 88% (95% CI 5 82–94; Fig. 2a,b).
Six patients had protocol violations, that is, three had
therapy started with SB instead of EB and three received
the first cycle of EB instead of SB. Three patients (two
from the standard risk and one from the high risk groups)
did not undergo an interim scintigraphy and received SB
following the second cycle of therapy. All of them are
included in the intention-to-treat analysis.
Radiation therapy was administered to 47 patients (38%),
including 29 with a bulky mediastinal mass, six with a resid-
ual uptake on the scan at the end of therapy and 12 for
other reasons. Twenty-six patients (47%) in the standard
risk group received involved-field radiation therapy after
chemotherapy, opposite to only 12 patients in the high risk
group (26%; P < 0.02).
Seventy-seven patients were defined as having a standard
risk disease and therapy was started with two cycles of SB.
Ga67or positron emission tomography (PET) F18DG became
negative in 28 of 34 (82%) and 35 of 41 (85%) patients, respec-
tively. Patients with a negative scintigraphy received six cycles
of SB. In 12 patients, a residual pathologic uptake was revealed
and their chemotherapy was changed to EB; however, disease
progressed in two of them. In this cohort of 77 patients, three
had PRD (4%) and four (5%) subsequently relapsed. The 10-
year PFS and OS for this group were 87% (95% CI 5 79–95)
and 88.3% (95% CI 5 81–95), respectively (Fig. 2c,d).
The primary endpoint of the study was PFS
patients (IPS ? 3) were started with EB (numbers are marked in black). Patients with early unfavorable and those with IPS ? 2 had two cycles of SB (numbers are
marked in grey). Following two cycles of chemotherapy, additional therapy was determined according to the results of the interim scintigraphy.
(a) Initial treatment based on pretherapy risk stratification and (b) treatment schema. Initial two cycles were based on pretreatment evaluation. Only high-risk
TABLE I. Patient Demographics
Parametern 5 124
Age–median (range) years
B symptoms Yes/No
(Stage I/II, no bulk, no B symptoms)
Age > 50
ESR > 50
ISP 0-2/ISP 3-7
American Journal of Hematology 33
Among 47 high-risk patients (IPS ? 3), early Ga67or PET
F18DG scan became negative in 13 of 18 (72%) and 22 of 28
(78%) studies, respectively. Therapy was subsequently
reduced to SB in 34 patients (79%). Seven patients received
six cycles of EB. Two patients had PRD and four relapsed.
The 10-year PFS and OS for this group were 87% (95% CI
5 77–97) and 87.7% (95% CI 5 78–97), respectively (Fig.
Fifty-one interim Ga67scans and 69 PET/CT scans were
performed. Following interim positive Ga67or PET/CT, dis-
ease progression was found in 1 of 11 and 2 of 12 patients,
respectively. The calculated positive predictive value (PPV)
was 9% for the Ga67test and 17% for PET/CT; however,
as therapy was escalated based on a positive imaging
result, a true PPV cannot be calculated with this study
design. The negative predictive value (NPV) for long-term
freedom from progression of Ga67scans and PET/CT was
36 of 41 (88%) and 53 of 57 (93%), respectively (P 5 NS).
Progression was revealed in three of 23 patients with
interim positive scintigraphy, two of these individuals had
PRD with multiple new sites of uptake and one had a late
relapse. The 10-year PFS in patients with negative interim
scintigraphy was 87% compared with 83% in individuals
with a positive interim study, P 5 0.5 (NS). These findings
show that a similar long-term outcome can be obtained in
different risk groups with therapy tailoring.
Thirty-eight women aged < 40 years (18–37, median 27)
were treated in this cohort. Two had PRD and were not
evaluated for fertility, because further therapy was given to
them. Fertility status was evaluated in 36 women. Data
regarding the number of pregnancies, cyclic ovarian func-
tion (COF), premature ovarian failure (POF), GNRH agonist
(triptorelin) administration, and number of born babies are
shown in Table II. COF was resumed in 34 of 36 (94%).
Ten women were older than 30 years at diagnosis, two of
them (aged 35 and 37 years) developed POF. Thirty preg-
nancies were reported in 19 patients, aged 19–31 (median
25) years at diagnosis. Eleven women conceived once, six
conceived twice, one thrice, and one five times. Four
women elected to terminate pregnancy, one of them due to
fetus deformity. Two women miscarried and one is now
pregnant. Twenty three healthy babies were born, and one
baby had coarctation of aorta that was operated on (Table
II). Twenty-six of the 38 females were cotreated with six
cycles of GnRH agonist triptorelin (Decapeptyl 3.75 mg) for
6 months. No differences in COF were demonstrated
between the patients treated with the GnRH agonist and
those who did not receive this therapy, which may be attrib-
uted to the low rate of ovarian failure (6%) in these patients.
EB was associated with a significantly higher toxicity com-
pared with SB, which led to a 40% hospitalization rate per
cycle versus 8 and 39% grades III and IV neutropenia ver-
sus 10%, respectively (P < 0.001). Dose reduction was
reported in 23 of 151 cycles of EB (15%) and 23 of
573 cycles of SB (4%). Sixty of 124 patients were hospital-
ized during the treatment period (48%); 31 patients—once;
18—twice; four—thrice, and seven—four times. Hepatic tox-
icity grades III and IV occurred in three patients following
EB. Therapy was reduced to SB in two of them after the first
cycle, and it was completely discontinued in the third patient.
Grade III cardiac toxicity was diagnosed in three patients fol-
lowing EB, resulting in therapy reduction to SB. An additional
patient developed pericarditis after the second cycle of SB.
All these individuals recovered from their toxicity before the
next cycle of chemotherapy. One patient had small bowel
10-year overall survival for all patients, (c) 10-year progression-free survival for patients with standard risk and high risk disease, and (d) 10-year overall survival for
patients with standard risk and high risk disease.
Progression-free survival and overall survival for all patients and according to patient risk groups. (a) 10-year progression-free survival for all patients, (b)
34 American Journal of Hematology
obstruction following the first cycle of SB and refused further
chemotherapy. In three patients, aseptic necrosis of the fe-
mur head evolved after treatment: in two patients, following
14 days and in one patient following 7 days of steroid ther-
apy taken with each cycle of chemotherapy. Since 2002, du-
ration of prednisone therapy has been reduced to 1 week
only. One patient suddenly died at home after four cycles of
SB, presumably from a cardiac event. In four patients, a sec-
ond malignancy was revealed during the follow-up: one
breast carcinoma, two non-Hodgkin lymphoma; the fourth
patient with primary resistant disease, who underwent high-
dose chemotherapy together with stem cells rescue, devel-
oped a secondary myelodysplastic syndrome that could be
related either to primary or salvage therapy.
HL treatment has remarkably developed over the past
two decades. Standard therapeutic regimens provide a
5-year event free survival (EFS) of 72–81% for patients
with a low IPS (?2) and of 64–69% for individuals with a
higher IPS . Diehl et al.  reported that intensive ther-
apy, such as eight cycles of EB, is more effective in terms
of freedom from treatment failure; however, this was
achieved at the cost of multiple episodes of febrile neutro-
penia, increased risk for secondary leukemia and early
menopause for women in their fertility age [3,5,8]. Such tox-
icity served as rationale for further studies investigating
indications for dose reduction. Similar outcomes were dem-
onstrated in patients receiving eight cycles of EB and four
cycles of EB 1 four cycles of SB [2,12]. These results sug-
gest that only a small subpopulation of patients require a
full EB course. Many individuals receiving eight cycles of
EB may have achieved a similar PFS with combinations of
SB or doxorubicin, bleomycin, vinblastine, dacarbazine
(ABVD) and thus, significant toxicity could have been
avoided. In this study, cumulative chemotherapy given for
six cycles was reduced compared to eight cycles adminis-
tered in the study performed by the German Hodgkin Study
Group  and only seven patients (6%) received six cycles
of EB in our trial (Fig. 1b). The Italian Lymphoma Study
Group reported results of a three-arm randomized trial for
patients with advanced HL . Three hundred and six
patients were randomized and treated with either six cycles
of ABVD, four cycles of EB 1 two cycles of SB or the car-
boplatin, etoposide, cyclophosphamide (CEC) protocol .
Five-year PFS for 100 patients in the BEACOPP arm was
81% with OS of 92%, demonstrating that six cycles may be
beneficial to the majority of patients.
Viviani et al.  recently assessed the need for aggressive
upfront therapy in a randomized study. The 7-year PFS in the
group of patients treated with 4EB14SB was 85%, which is
very similar to the results of the current study, where only six
cycles of tailored BEACOPP were given. The PFS in the
ABVD cohort was significantly inferior (73%); however, 15 of
45 patients in this arm were in continuous remission after sal-
vage chemotherapy followed by an autologous transplant, op-
posite to three of 20 subjects in the BEACOPP arm. In both
groups, the incidence of MDS/secondary leukemia was 1%. It
has been clearly shown that six to eight cycles of ABVD were
insufficient for 27% of patients and a third of those patients
could be salvaged with high-dose chemotherapy and stem
cells rescue. It has also been demonstrated that disease
progression following the BEACOPP regimen is a grave prog-
Current ongoing studies are aimed at tailoring therapy
based on interim PET/CT [14–16] and identifying the
subgroup of patients requiring intensified therapy (EB or
BEACOPP-14) versus those who could do well with stand-
In this study, an individual risk-adapted approach was
applied for therapy consideration (Fig. 1b). Ten-year PFS
was 83% in patients with positive interim PET/CT com-
pared with 93% for those with a negative interim study
(NS), and thus, the former patients could have therapy
de-escalation from EB to SB in case of high-risk HL or
could be given six cycles of SB in case of standard risk
HL (n 5 105). Only 15% of high risk patients needed six
cycles of EB and 15% of standard risk patients had their
therapy escalated. This study suggests that 85% of
patients can do as well with reduction of their therapy and
thus could be spared the toxicity of eight or four cycles of
This decision making is supported by studies demon-
strating that a negative interim Ga67SPECT or PET corre-
lated with high PFS rates [17–19]. Recently, the superiority
of F18DG-PET over Ga67in terms of specificity, sensitivity,
and accuracy was confirmed . Both the Italian and
Danish Study Groups reported a 94–97% EFS for patients
with negative interim PET. Therapy was not modified
according to PET results in all these patients, treated
mostly with the ABVD protocol [20,21]. PPV observed in
the present trial is substantially lower (?17%) than previ-
ously reported (38–90%) [18,19,21–23]. This is consistent
with findings of the two trials demonstrating inferior PPV of
interim PET/CT (30%) following the EB regimen [24,25].
There are several explanations to this difference. In this
study, results of interim scintigraphy served as the corner-
stone for therapy escalation and in all likelihood, the
successful intervention decreased the predicted disease
progression rate. A similar effect was demonstrated by
Gallamini et al. in a retrospective study reporting that
patients with positive interim PET following two cycles of
ABVD could be salvaged by four cycles of EB 1 four
cycles of SB with a failure free survival of 62% .
Another explanation of the lower PPV observed in our study
may be related to the fact that findings of patients with a
minimal residual uptake, considered positive in the current
trial, would have been regarded negative in other studies.
In trials conducted by Hutching et al.  and Gallamini
et al. , the uptake above that of the mediastinal blood
TABLE II. Ovarian Function and Fecundity in Female Patients with HL Younger Than 40 Years of Age, Presented According to Chemotherapy and GNRH
Agonist (triptorelin) Administration
Preserved cyclic ovarian functionPPDPremature ovarian failure PregnanciesPregnant women Newborns
All patients (n 5 38)
With triptorelin (n 5 26)
sBEACOPP 3 6 (n 5 17)
sBP 3 2 1 escBP 3 4 (n 5 2)
escBP 3 2 1 sBP 3 4 (n 5 6)
esc BEACOPP 3 6 (n 5 1)
No triporelin (n 5 12)
sBEACOPP 3 6 (n 5 7)
sBP 3 2 1 escBP 3 4 (n 5 3)
escBP 3 2 1 sBP 3 4 (n 5 2)
American Journal of Hematology35
pool was used as a cutoff between negative and positive Download full-text
results. A further shift of denominator to the uptake above that
of the liver blood pool was used in the retrospective study by
Gruppo Italiano Terapie Innovative nei Linfomi (GITIL) .
The same criteria are currently used by Barrington et al. in the
ongoing RATHL study, where positive PET/CT following two
cycles of ABVD leads to therapy escalation .
Similar to previous trials [18,19,22], our data provide
evidence that the predictive value of negative PET is supe-
rior to PPV. The 10-year follow-up of the present study
provides data demonstrating a major benefit of this thera-
peutic approach for young women in terms of fertility pres-
Behringer et al.  observed permanent amenorrhea in
32 and 66.7% of patients following eight cycles of SB or
EB, respectively, whereas in our study, 94% of women
reported preservation of their COF after six cycles of
tailored BEACOPP. Nineteen women spontaneously con-
ceived during the follow-up. One third of female patients in
this cohort received chemotherapy that included several
cycles of EB, seven of them became pregnant and others
had their COF preserved. The fecundity data obtained in
the current study substantially differ from those reported
following eight cycles of EB . None of the 19 patients
randomized in the latter study to receive GNRH agonist
versus oral contraceptive prior to chemotherapy had a nor-
mal level of anti-Mullerian hormone after therapy and their
ovarian follicle preservation rate was zero. These findings
concur with the concept of our study suggesting that treat-
ment should be personalized and reduction of chemother-
apy dose with or without concomitant use of GNRH agonist
promotes fertility preservation in most women. Recently,
Behringer et al. evaluated fecundity following two cycles of
EB plus two cycles of ABVD. Motherhood rate and COF in
this cohort were found to be similar to those of patients
given four cycles of ABVD, while a higher rate of mother-
hood was reported in women coadministered with a GNRH
agonist . The current study, albeit not randomized, has
demonstrated that a negative interim PET/CT result is reas-
suring and may suggest that dose reduction is safe.
In conclusion, for patients with adverse prognostic fac-
tors, six cycles of tailored BEACOPP have proved to be
beneficial, with 10-year PFS and OS of 87 and 88%,
respectively; incidence of secondary leukemia of 1% and
preserved fertility in most females.
ongoing, which could elucidate the optimal schedule for
chemotherapy adjustment in patients with HL .
EJD was the principal investigator, wrote the article, and
takes primary responsibility for the article. ZB recruited the
patients and was responsible for fertility preservation con-
sultation. RBS interpreted the data. IA recruited the
patients. MBS recruited the patients. OG recruited the
patients. DL recruited the patients. DG interpreted the data.
JMR wrote the article. RE recruited the patients.
The authors thank Sonia Kamenetsky for her devoted sec-
retarial support. They also thank Dorit Dottan for thoughtful
data management and Nili Stein for statistical analysis.
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