Initial Treatment of Advanced (Stage III-IV) Classic Hodgkin Lymphoma

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Initial treatment of advanced (stage III-IV) classic

Hodgkin lymphoma
Authors: Joachim Yahalom, MD, Ann S LaCasce, MD
Section Editor: Arnold S Freedman, MD
Deputy Editor: Alan G Rosmarin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2022. | This topic last updated: Apr 16, 2021.
INTRODUCTION
Classic Hodgkin lymphoma (cHL) refers to lymphomas that are characterized by malignant
Reed-Sternberg cells in a reactive cellular background, which generally arises within a lymph
node area and spreads in an orderly fashion to contiguous areas of lymph nodes [1]. Once the
diagnosis of cHL has been established, subsequent therapy is based upon the stage of the
disease, as currently defined by the Cotswolds classification ( table 1). (See "Pretreatment
evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)
In this discussion, advanced stage cHL refers to clinical stage (CS) III and IV disease. CS III
describes involvement of lymph nodes or lymphoid structures on both sides of the diaphragm.
CS IV refers to diffuse or disseminated involvement of one or more extranodal organs or
tissues, with or without lymph node disease. (See "Pretreatment evaluation, staging, and
treatment stratification of classic Hodgkin lymphoma".)
The initial treatment of advanced stage cHL will be reviewed here. The following are discussed
separately:
● The evaluation of the patient before, during, and after therapy. (See "Monitoring of the
patient with classic Hodgkin lymphoma during and after treatment".)
● The treatment of favorable early stage cHL. (See "Treatment of favorable prognosis early
(stage I-II) classic Hodgkin lymphoma".)
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● The treatment of unfavorable early stage cHL. (See "Treatment of unfavorable prognosis
early (stage I-II) classic Hodgkin lymphoma in adults".)
● The treatment of relapsed or refractory cHL. (See "Treatment of relapsed or refractory

classic Hodgkin lymphoma".)
● The treatment of nodular lymphocyte predominant Hodgkin lymphoma. (See "Treatment

of nodular lymphocyte-predominant Hodgkin lymphoma".)
● Management of the adult survivor of cHL. (See "Approach to the adult survivor of classic
Hodgkin lymphoma".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC
The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer
care. Important issues include balancing the risk from treatment delay versus harm from
COVID-19, ways to minimize negative impacts of social distancing during care delivery, and
appropriately and fairly allocating limited health care resources. These issues and
recommendations for cancer care during the COVID-19 pandemic are discussed separately.
● (See "COVID-19: Considerations in patients with cancer".)
PRETREATMENT EVALUATION
Studies — The initial evaluation of a patient with cHL must establish the precise histologic
subtype, the extent and sites of disease, and the performance status of the patient. This
evaluation is described in detail separately. (See "Clinical presentation and diagnosis of classic
Hodgkin lymphoma in adults".)
International prognostic score — Patients with advanced stage cHL can be further divided
into prognostic groups using the international prognostic score (IPS), which incorporates seven
factors (ie, serum albumin, hemoglobin, gender, age, stage, white blood cell count, and
absolute lymphocyte count) to delineate six prognostic groups with very different rates of
freedom from progression at five years, demonstrating that even among those with advanced
stage disease the prognosis is quite variable ( table 2) (calculator 1). (See "Pretreatment
evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on
'International Prognostic Score (IPS)'.)
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INITIAL TREATMENT
General approach
Choice of initial therapy — Combination chemotherapy with ABVD (doxorubicin, bleomycin,

vinblastine, and dacarbazine) ( table 3) is the preferred therapy for most patients with
advanced cHL [2-5].
For select patients, acceptable alternative regimens include BV+AVD (brentuximab vedotin,
doxorubicin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin,
cyclophosphamide, vincristine, procarbazine, and prednisone) ( table 4):
● ABVD is administered every 14 days, and two treatments are considered one 28-day cycle.
Response to therapy is assessed by positron emission tomography (PET) after two cycles
of chemotherapy (PET2). A full course of ABVD treatment is six cycles and, as such, the
total duration of chemotherapy is 24 weeks. Adverse events include cytopenias,
nausea/vomiting, neuropathy, bleomycin-associated pulmonary toxicity, and long-term
cardiopulmonary complications. (See 'ABVD chemotherapy' below and 'Response adapted
therapy' below.)
● BV+AVD adds brentuximab vedotin, but eliminates bleomycin from the ABVD backbone.
BV+AVD is repeated every 14 days in 28-day cycles, two treatments are considered one
cycle, and six cycles of chemotherapy require 24 weeks. Cytokine support is needed to
lessen infectious complications. Acute adverse events include cytopenias, and peripheral
neuropathy; long-term toxicities are less well defined. (See 'BV+AVD' below.)
● BEACOPP may have particular utility in younger patients with a high-risk disease (eg,
international prognostic score [IPS] ≥4). BEACOPP is administered with growth factor
support on days 1 and 8 of a 21-day cycle for four to eight treatment cycles (a total 12 to
24 weeks of chemotherapy). Four or six cycles of escalated BEACOPP (eBEACOPP) is at
least as effective and less toxic than eight cycles of eBEACOPP, which was shown to be
superior to standard (baseline) BEACOPP or COPP/ABVD. When compared with ABVD,
eBEACOPP has more toxicity, including bone marrow suppression, secondary
malignancies, and sterility. Escalated BEACOPP should only be used for younger patients
(<60 years), because toxicities are particularly severe in older patients. It is unknown how
eBEACOPP affects the ability to provide effective salvage therapy (eg, autologous
hematopoietic cell transplantation) to patients who relapse. (See 'BEACOPP chemotherapy'
below and 'Response adapted therapy' below.)
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For most patients with advanced stage cHL, we suggest treatment with ABVD, although
eBEACOPP is a reasonable alternative, as discussed below. Compared with ABVD, eBEACOPP
achieves superior progression-survival (PFS) at five years and may result in superior overall
survival (OS), but this advantage may be lost over time due to second malignancies and cardiac
toxicity, which account for the majority of late deaths [6]. The greatest potential benefit of
eBEACOPP is seen with IPS ≥4. Details on the efficacy and toxicities associated with these
regimens are presented in detail in the sections that follow.
The antibody-drug conjugate brentuximab vedotin (BV; anti-CD30 antibody complexed with
monomethyl auristatin E) was effective and well-tolerated when combined with AVD
(doxorubicin, vinblastine, and dacarbazine) in a phase 1 study of initial treatment of advanced
stage cHL [7]. After more than five years of follow-up, treatment of 26 patients with BV+AVD
achieved 92 percent failure-free survival and 100 percent overall survival [8]. No unexpected
toxicities were detected and the two patients who relapsed achieved a second remission.
Importantly, addition of BV to ABVD caused excessive pulmonary toxicity that was not seen
when BV was combined with AVD (ie, no bleomycin). A phase III study is underway to test BV
plus AVD versus ABVD. Additional details regarding BV are presented separately. (See
"Treatment of relapsed or refractory classic Hodgkin lymphoma".)
Despite guidelines for the treatment of cHL, there must remain room for individualization of
care to accommodate concerns about the risks of relapse versus toxicity. As an example,
availability of effective salvage therapy for relapsed disease (eg, immunotherapy) may influence
concerns regarding treatments associated with a higher risk of recurrence but less toxicity.
Response adapted therapy — Mid-treatment positron emission tomography (PET) has

prognostic value. Although modification of therapy based on PET after two cycles of
chemotherapy (PET2) is often done in clinical practice, its use remains controversial. Initial
studies suggest that treatment de-escalation may be safe in PET2 early responders; data
regarding treatment escalation in patients without an early response are currently inconclusive.
PET-response adapted therapy will be discussed here. The prognostic value of mid-treatment
PET is presented separately. (See "Monitoring of the patient with classic Hodgkin lymphoma
during and after treatment", section on 'Radiologic studies'.)
Use of mid-treatment PET-response adapted therapy must closely follow the methods used in
trials that demonstrated its efficacy. It should take into account the method for PET
interpretation, pre-treatment PET/computed tomography (CT) results, initial therapy, timing of
the scan, and cutoff values. It is also important to consider the individual patient’s preferences,
values, and risk factors. As an example, a decision to de-escalate ABVD to AVD (ie, bleomycin
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withdrawal) based on a negative PET2 scan may be especially attractive to a patient with
additional risk factors for bleomycin toxicity (eg, older age, underlying pulmonary disease,
active smokers), but less important for others.
There is a paucity of data regarding the preferred approach for patients with a positive PET2
scan (ie, Deauville score of 4 or 5). Outside of a clinical trial, many clinicians will continue ABVD
therapy for a PET2 negative scan (ie, Deauville 1-3) or switch to eBEACOPP for patients with a
positive PET2 scan.
Randomized studies that support treatment de-escalation based on PET2 early response
include:
● A multicenter trial reported equivalent outcomes in 935 patients who were randomly
assigned to de-escalation with four additional cycles of AVD versus four additional cycles
of ABVD after achieving a negative PET2 scan following two cycles of ABVD for advanced
stage cHL [9]. This study, RATHL (Response-Adapted Therapy in Advanced Hodgkin
Lymphoma), included patients with stages IIB to IV disease or stage IIA with adverse
features (ie, bulky disease or at least three involved sites, who constituted 42 percent of
participants). AVD and ABVD achieved equivalent three-year progression-free survival (PFS;
84 versus 86 percent, respectively) and overall survival (OS; 98 versus 97 percent).
Omission of bleomycin lowered the incidence of fatigue and respiratory events and led to
better preservation of pulmonary function.
● German Hodgkin Study Group HD18 reported equivalent five-year PFS with four cycles of
escalated BEACOPP (eBEACOPP) versus either six or eight cycles of eBEACOPP in >1000
patients with advanced stage cHL who achieved PET2 negativity after two cycles of
eBEACOPP [10]. Four cycles of eBEACOPP was associated with fewer severe infections, less
organ toxicity, and no deaths (versus six deaths in patients treated with six or eight cycles).
● AHL2011 randomly assigned 823 patients with advanced stage cHL to standard care using
eBEACOPP versus de-escalation to ABVD for a negative PET2 scan following two cycles of
eBEACOPP [11]. In the PET-driven arm, treatment de-escalation to ABVD was achieved for
84 percent of patients, while 12 percent continued to receive eBEACOPP because of a
positive PET2 scan. Compared with the standard eBEACOPP arm, patients on the PET-
driven arm achieved equivalent five-year PFS (86 percent) with less toxicity.
Treatment escalation for positive PET scan can achieve results that are superior to
historical controls treated with six to eight cycles of ABVD, but randomized trials are
necessary to confirm a benefit to escalation of therapy. The following studies are
informative:
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● In HD18, addition of rituximab (R) to eBEACOPP did not improve outcomes in patients
whose PET scan was positive after two cycles of eBEACOPP [10]. Five-year PFS was 90
versus 88 percent in the 434 PET-2 positive patients who were randomly assigned to six
additional cycles of eBEACOPP versus six additional cycles of R-eBEACOPP.
● In the RATHL study (above), the 172 patients with a PET score of 4 or 5 after two cycles of
ABVD were nonrandomly assigned to BEACOPP with estimated three-year PFS and OS
rates of 68 and 88 percent, respectively [9].
● In GITIL/FIL HD 0607, 150 patients with positive PET scan after two cycles of ABVD were
randomly assigned to four cycles of eBEACOPP followed by standard BEACOPP with or
without rituximab; three-year PFS was 63 versus 57 percent, respectively [12].
● SWOG S0816 reported two year PFS of 64 percent among 64 patients who received
escalated BEACOPP after PET-2 positive scan [13].
ABVD chemotherapy — ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) is the

standard initial chemotherapy for patients with cHL ( table 4) [14]. ABVD is administered every
14 days in 28-day cycles ( table 3). Patients are monitored with imaging studies for response
during treatment and receive two cycles of chemotherapy beyond best response, up to six
cycles (24 weeks). (See "Monitoring of the patient with classic Hodgkin lymphoma during and
after treatment".)
ABVD efficacy — Approximately 80 percent of patients with advanced stage cHL will attain a
complete response after treatment with ABVD [14-21]. Up to one-quarter of patients will have
disease progression requiring further therapy; half of those will have long-term survival with
autologous hematopoietic cell transplantation. OS rates at 4, 7, and 10 years are approximately
90, 75, and 55 percent, respectively.
The efficacy of ABVD has been demonstrated in many prospective trials. These trials have
shown ABVD to be superior to MOPP and to have equal efficacy and less toxicity than
alternating MOPP-ABVD and MOPP/ABV hybrids [2,15]. Initial studies comparing ABVD with
BEACOPP demonstrated similar OS rates. Trials comparing ABVD with BEACOPP are presented
below. (See 'BEACOPP efficacy' below.)
ABVD toxicity — ABVD is associated with both acute and long-term toxicity.
Acute — The most common severe (grade 3/4) acute toxicities seen with ABVD include
neutropenia (34 percent), nausea/vomiting (13 percent), and alopecia (31 percent) [21]. Severe
myelosuppression is rare when ABVD is administered alone [17], and treatment should not be
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held for neutropenia. Because of the modest incidence of neutropenia, prophylactic treatment
with granulocyte colony-stimulating factor (G-CSF) is not required [22,23]. Severe infections,
anemia, and thrombocytopenia are not common, occurring in 2, 5, and 3 percent of patients,
respectively [21]. The rate of anticipatory nausea and vomiting has decreased substantially with
the development and routine use of potent antiemetic agents. (See "Prevention and treatment
of chemotherapy-induced nausea and vomiting in adults".)
Bleomycin-induced pulmonary toxicity may occur quite often (approximately 20 to 30 percent of

patients) and usually develops subacutely while on therapy or up to six months after treatment.
Bleomycin-induced pulmonary toxicity adversely affects survival in patients who are treated for
cHL. In one study, it was associated with a mortality rate of 4.2 percent and with a significantly
decreased five-year OS (63 percent in patients who developed bleomycin-induced pulmonary
toxicity as compared with 90 percent in those who are unaffected) [24]. The omission of
bleomycin in patients who developed bleomycin-induced pulmonary toxicity (either
symptomatic or asymptomatic) had no impact on response rates or survival. (See "Bleomycin-
induced lung injury".)
Acute reactions to bleomycin, including fever, the hyperpyrexia syndrome, and anaphylactoid
reactions have also been described. (See "Infusion reactions to systemic chemotherapy",
section on 'Bleomycin'.)
Long term — Long-term complications of ABVD include bleomycin-related pulmonary

toxicity and doxorubicin-associated cardiotoxicity. There does not appear to be an increased
rate of myelodysplasia or secondary leukemia, and fertility is preserved in the majority of
patients.
ABVD may result in late bleomycin-related pulmonary toxicity, particularly when used in
combination with mediastinal irradiation. Fatal pulmonary complications have occurred
[15,24,25]. Following ABVD, there may be a significant decline in median forced vital capacity
and diffusing capacity (DLCO) [25-27]. The diagnosis and management of bleomycin-induced
lung injury is presented separately. (See "Bleomycin-induced lung injury".)
● In one study of 60 early-stage patients with cHL receiving ABVD with or without
mediastinal irradiation, 53 percent reported dyspnea on exertion or cough during ABVD,
37 percent had a significant decline in pulmonary function, and 23 percent required
discontinuation of bleomycin [27]. At longer follow-up, only one patient reported
persistent dyspnea with minimal exertion.
● In another study of 141 patients treated with bleomycin-containing chemotherapy for

newly diagnosed cHL, pulmonary toxicity was diagnosed in 25, with a subsequent
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mortality of 24 percent, all in patients >40 years of age [24]. Other reported risk factors for
the development of this complication include mediastinal irradiation, treatment with G-
CSF, and use in children [24,26,28-30].
Cardiomyopathy is a recognized complication of doxorubicin therapy but is not commonly seen

in patients receiving ABVD. Patients who are treated with six cycles of ABVD receive a total
doxorubicin dose of 300 mg/m2; cardiomyopathy is rarely seen in patients who receive a total
dose less than 400 mg/m2. However, ABVD may be associated with a risk of long-term cardiac
toxicity. A large British study documented that the risk for myocardial infarction after treatment
with ABVD alone (without radiotherapy) was 7.8 times higher than that the age-adjusted normal
population [31]. Children appear to be more susceptible to doxorubicin cardiotoxicity [28,29].
(See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity"
and "Prevention and management of anthracycline cardiotoxicity".)
ABVD does not result in a high incidence of permanent azoospermia or amenorrhea [17,32,33].
In one study, for example, azoospermia and oligospermia after ABVD occurred in 36 and 20
percent of patients, respectively, with recovery to normal values in all cases [32,33].
The 15-year cumulative risk of acute myeloid leukemia after ABVD has been estimated to be
less than 1 percent. (See "Second malignancies after treatment of classic Hodgkin lymphoma",
section on 'Acute leukemia'.)
BV+AVD — BV+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) is built on

the backbone of ABVD but adds brentuximab vedotin (an anti-CD30 antibody complexed with
monomethyl auristatin) and eliminates bleomycin. BV+AVD is an acceptable alternative to ABVD
and may be preferable for patients at higher risk for pulmonary toxicity (eg, older age,
underlying pulmonary disease, active smokers). Advanced stage cHL is treated with six cycles of
BV+AVD.
Short-term outcomes with BV+AVD are at least as favorable as ABVD [7,8]. BV+AVD causes less
pulmonary toxicity and more peripheral neuropathy and neutropenia. In one study, patients
who were treated with BV+AVD had 100 percent five-year survival and only 2 of 26 patients
relapsed [7].
ECHELON-1 is a phase III trial that randomly assigned >1300 patients with stage III or IV cHL to
BV+AVD versus ABVD [8]. The study reported that BV+AVD achieved marginally superior results
at two years for the primary outcome, modified progression-free survival (mPFS; 82 versus 77
percent, respectively; HR 0.72, 95% CI 0.60 to 0.98); mPFS is a composite measure that included
time to progression, death, and non-complete response with use of subsequent anticancer
therapy. OS did not differ significantly between the trial arms. While a statistically significant
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benefit for the primary outcome was seen, some experts challenge the clinical relevance of an
improvement in mPFS.
Some toxicities were higher with BV+AVD, and growth factor support is needed with this
treatment. Neutropenia was more common with BV+AVD than ABVD (58 versus 45 percent,
respectively), but G-CSF reduced the frequency of febrile neutropenia to 11 percent of patients
treated with BV+AVD [8]. Peripheral neuropathy occurred in 67 percent of patients on BV+AVD
and 43 percent of patients on ABVD, but most neuropathy was temporary or at least partially
reversible. Pulmonary toxicity (grade 3/4) was greater with ABVD (3 versus 1 percent,
respectively). Cost may also influence selection of this treatment because BV+AVD, especially
considering the need for G-CSF, is considerably more expensive than ABVD.
Brentuximab vedotin is approved by the US Food and Drug Administration for previously
untreated advanced stage cHL [34].
BEACOPP chemotherapy — The German Hodgkin's Lymphoma Study Group (GHSG) developed

the BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine,
and prednisone) regimen ( table 4) that can be given in standard or escalated doses [35-37].
When compared with standard ABVD, escalated BEACOPP produces superior progression-free
survival (PFS) rates, but has increased toxicity (ie, neutropenia and infections) and no clear
advantage in overall survival (OS) [21,38]. While indirect comparisons suggest that escalated
BEACOPP may result in superior five-year survival, longer follow-up is needed to see whether
this translates into superior long-term survival [6]. Complete response rates with BEACOPP are
approximately 80 to 95 percent with five-year PFS and OS rates of 81 and 92 percent,
respectively.
Regimens — Multiple versions of BEACOPP have been developed. Eight cycles of escalated

BEACOPP was initially shown to be superior to standard (baseline) BEACOPP or COPP/ABVD [39].
In a subsequent randomized trial, compared with eight cycles, six cycles of escalated BEACOPP
resulted in superior freedom from treatment failure and OS [40]. In other studies, four cycles of
escalated BEACOPP were administered followed by four cycles of either escalated or standard-
dose BEACOPP, depending upon the response to the first four cycles.
● Standard-dose BEACOPP (also known as baseline BEACOPP) – When compared with ABVD
and MOPP, dose intensity was increased in the BEACOPP regimen by adding etoposide and
increasing the frequency of treatment cycles (from every 28 days to every 21 days),
thereby providing more chemotherapy in a shorter time period [41].
● Escalated BEACOPP – Further dose intensification was accomplished with the escalated
BEACOPP regimen, which is also repeated at 21-day intervals. This regimen has increased
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doses of doxorubicin (from 25 to 35 mg/m2), cyclophosphamide (from 650 to 1250

mg/m2), and etoposide (from 100 to 200 mg/m2) [39]. Hematologic growth factor support
was added on day 8. [42]
BEACOPP efficacy — Eighty to 95 percent of patients with advanced cHL will attain a complete
response with BEACOPP. Up to 20 percent (higher rates with baseline BEACOPP than escalated
BEACOPP) will have disease progression by five-years and will require further therapy. The OS
rate at five years is approximately 92 percent. When compared with ABVD, BEACOPP provides
better initial tumor control, but no difference in event-free survival or OS when relapsed or
refractory disease is managed with high dose chemotherapy followed by autologous stem cell
support.
Several randomized trials have compared BEACOPP with ABVD-based therapy [21,38,39,41-47].
Taken together, these studies demonstrate that BEACOPP is associated with higher response
rates and better rates of PFS than those seen with ABVD, but no improvement in OS. This was
best illustrated in a 2011 meta-analysis that included data from four randomized trials with a
total of 2868 adult patients with newly diagnosed advanced stage or unfavorable early stage
cHL [48]. BEACOPP resulted in significantly longer PFS (hazard ratio 0.53; 95% CI 0.44-0.64), but
no different in OS (hazard ratio 0.80; 95% CI 0.59-1.09). BEACOPP was associated with
significantly more severe hematologic toxicity, infections, and occurrence of myelodysplastic
syndrome and acute myeloid leukemia.
It appears that the degree of the PFS benefit may be greatest among the highest risk patients.
However, this comes at the cost of increased toxicity with no clear improvement in OS when
compared with ABVD alone. Initial treatment with BEACOPP exposes approximately 73 percent
of patients with advanced stage cHL (those cured by ABVD) to excess toxicity that may include
such effects as sterility and secondary malignancies. In comparison, initial treatment with ABVD
avoids these toxicities in the majority of patients, but requires that approximately one in eight
patients proceed to high dose chemotherapy and autologous stem cell rescue at progression, a
treatment with potential complications of acute toxic effects, sterility, and secondary
malignancies. (See 'BEACOPP toxicities' below.)
Reducing the number of escalated BEACOPP treatment cycles from eight to six results in
superior efficacy and less toxicity [40]. In another study, outcomes were equivalent, but toxicity
was less, for patients who were randomly assigned to a total of four cycles versus six or eight
cycles of escalated BEACOPP after they achieved a negative PET scan following two cycles of
escalated BEACOPP, as described above [10]. (See 'Response adapted therapy' above.)
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There have been no direct comparisons of four or six cycles of escalated BEACOPP versus ABVD.
A network meta-analysis of 14 trials with a total of 9993 patients with advanced stage cHL
followed for a median of 5.9 years suggested that, when compared with ABVD, six cycles of
escalated BEACOPP resulted in superior OS at five years (95 versus 88 percent; hazard ratio
0.38, 95% CI 0.20-0.75) [6]. There were no direct comparisons between these two treatment
options, and 711 and 1670 patients had received six cycles of escalated BEACOPP and ABVD,
respectively. There were limited data regarding toxicity, and follow-up is too short to determine
how an expected increase in long-term toxicity following BEACOPP may impact long-term
survival.
BEACOPP toxicities — Common complications of BEACOPP therapy include bone marrow

suppression, infection, nausea, hair loss, second malignancies, and sterility. The treatment-
related mortality (TRM) rate among patients enrolled on clinical trials of BEACOPP is
approximately 2 percent [49]. Higher TRM is seen in older patients (≥40 to 50 years) and those
with a poor performance status (ECOG PS ≥2).
Short term — BEACOPP, especially increased dose BEACOPP, is associated with more

acute toxicities than ABVD [39,50]. Patients who received increased dose BEACOPP in clinical
trials had a higher incidence of grade 3/4 hematologic toxicities, including leukopenia (98
versus 22 percent with ABVD), thrombocytopenia (70 versus 3 percent), and anemia (66 versus 5
percent). Other acute grade 3/4 toxicities that occurred in more than 10 percent of patients
included infection (22 versus 2 percent with ABVD), nausea (20 versus 13 percent), and hair loss
(79 versus 31 percent). The administration of erythropoietin in conjunction with BEACOPP
decreases the number of red cell transfusions required during therapy, but has no impact on
treatment associated fatigue [51].
We suggest not treating patients ≥60 years old with BEACOPP, because of its toxicity in older
patients. Of 42 patients age 66 to 75 who received standard dose BEACOPP, 21 percent died of
acute toxicity [52].
Acceptable rates of TRM can be achieved with escalated BEACOPP when given by experienced
centers to young patients with a good performance status. Retrospective analysis of 3402
patients enrolled on prospective trials of escalated BEACOPP (HD9, HD12, HD15) reported a
TRM rate of 1.9 percent [49]. Neutropenic infections accounted for the majority of deaths (56 of
64; 88 percent). TRM was highest among older patients and those with a poor performance
status. Age and performance status (PS) could be used to divide patients into risk groups with
different TRM rates:
● Age <40 years with ECOG PS <2 (2164 patients) – TRM 0.7 percent
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● Age <40 years with ECOG PS ≥2 (108 patients) – TRM 0.9 percent
● Age 40 to 49 years with ECOG PS <2 (592 patients) – TRM 1.7 percent
● Age 40 to 49 years with ECOG PS ≥2 (40 patients) – TRM 15 percent
● Age ≥50 years with ECOG PS <2 (453 patients) – TRM 5.7 percent
● Age ≥50 years with ECOG PS ≥2 (45 patients) – TRM 13.3 percent
Another analysis examined the impact of bleomycin and vincristine dose reductions in 3309
patients with cHL enrolled on prospective trials of escalated BEACOPP (HD12, HD15) [53]. A
minority of patients received fewer than five cycles of bleomycin (4.7 percent) or fewer than
four cycles of vincristine (6.6 percent). When compared with those who received more cycles of
these agents, these patients had similar rates of PFS or OS at five years. These results suggest
that discontinuation of bleomycin or vincristine due to drug toxicity does not impact the efficacy
of BEACOPP in this population.
Long term — The main long-term complications of BEACOPP are second malignancies

and sterility [54]. The following findings have been noted in prospective trials:
● At five years, the rate of secondary acute leukemia was significantly higher with escalated
BEACOPP compared with BEACOPP or COPP/ABVD (2.5 versus 0.6 and 0.4 percent,
respectively) [39]. The rate at 10 years was higher than that at five years only with
BEACOPP (1.5 versus 0.6 percent) [44].
● At five years, non-Hodgkin lymphoma developed in 1.0, 0.9, and 2.7 percent of patients
receiving escalated BEACOPP, standard BEACOPP, or COPP/ABVD, respectively [39]. The
frequency of non-Hodgkin lymphoma was similar at 10 years [44].
● At 10 years, the overall rates of secondary malignancy were 6.8, 8.9, and 6.7 percent of
patients treated with escalated BEACOPP, baseline BEACOPP, and COPP-ABVD, respectively
[44].
The overall issue of secondary malignancies following the treatment of cHL is discussed in detail
separately. (See "Second malignancies after treatment of classic Hodgkin lymphoma".)
Gonadal toxicity also appears to be a significant risk with BEACOPP regimens. Women have
high rates of amenorrhea and infertility, while men commonly develop azoospermia [55,56].
Neither oral contraceptives not GnRH-analogues have been effective in preserving fertility in
this population [57].
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Data on gonadal toxicity were reported for 417 male and 232 female survivors of advanced
stage cHL treated with BEACOPP on the German HD15 trial and followed for a median of four
years [58]. Women tested for anti-müllerian hormone, a marker of ovarian reserve, consistently
demonstrated depletion of the ovarian follicle pool suggesting that they would have a poor
response to in vitro fertilization. When compared with older women, a higher percentage of
women <30 years were able to recover menstrual activity (82 versus 45 percent). While
approximately half of female survivors expressed a desire to have children, only 15 percent
reported successful pregnancies. The majority (89 percent) of men had evidence of
oligospermia, and approximately 20 percent had low testosterone levels (<2.8 ng/L). Twelve
men were able to successfully father children, 2 after natural fertilization and 10 after assisted
reproduction.
IS THERE A ROLE FOR RADIATION?
Overview — The role of consolidation radiotherapy (RT) after chemotherapy induction for

advanced stage cHL is controversial. The addition of RT to initial chemotherapy appears to
improve freedom from progression, but not survival [59,60]. Proponents advocate its use
because the majority of relapses following systemic chemotherapy for cHL are in previously
involved or unirradiated sites [61,62]. Opponents of its use question its necessity and raise
concerns about the long-term side effects. (See 'Radiation toxicity' below.)
Most clinicians agree that RT is probably not beneficial and potentially detrimental in patients
without initially bulky disease who achieve a complete remission (CR) with ABVD and will receive
an additional two cycles of ABVD.
Whether or not consolidative RT should be administered to patients with initial bulky

mediastinal disease (>10 cm or >1/3 the chest diameter) remains an unresolved issue. Factors
to be taken into account when making this decision include the patient's age, sex, history of
prior radiation, and the size and location of the proposed radiation field. We suggest the use of
consolidation RT after ABVD for most patients with initial bulky mediastinal disease.
Field and dose — The International Lymphoma Radiation Oncology Group (ILROG) of experts
has published field and dose guidelines for modern RT in cHL [63]. Involved site radiation
therapy (ISRT) is preferred over larger radiation fields. ISRT is based on the initial involved
volume in the treated site and reduced in consideration of the node regression after
chemotherapy such that most uninvolved normal organs are spared of radiation. For most
cases, ISRT results in significantly smaller radiation fields than the involved field radiation used
previously. These guidelines detail the design and technique considerations [63]. For patients
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who achieve a CR with chemotherapy, the recommended radiation dose for consolidation ISRT
is 30 Gy. For those with residual abnormalities of borderline significance on PET, the dose to the
residual abnormal site can be increased to 36 Gy. Further details regarding ISRT are presented
separately. (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma",
section on 'Radiation field size'.)
Radiation efficacy
General — Numerous prospective and retrospective studies have evaluated the use of

consolidation RT in patients with advanced stage cHL with mixed results [2,61,62,64-72]. The
interpretation of these studies has been controversial. Many randomized trials did not contain
adequate numbers of patients to detect a survival benefit [59]. Thus, they suffer from possible
false-negative outcomes (type 2 error) due to insufficient power. This problem is magnified in
some studies by the attrition of patients who fail to achieve CR, or who refuse randomization
following chemotherapy.
After ABVD — Indications for RT after ABVD include initial bulky mediastinal disease (>10 cm
or >1/3 the chest diameter) and/or the presence of residual abnormalities on imaging studies
after completion of chemotherapy (ie, partial response [PR]). RT is probably not beneficial in
patients without initially bulky disease who achieve a CR with ABVD and will receive an
additional two cycles of ABVD. A possible exception to this is in patients with nodular sclerosis
cHL who may have improved tumor control with RT [60]. (See 'General' above.)
While the optimal use of adjuvant radiation remains ill-defined as part of initial therapy in
patients with advanced stage cHL, its use is further discussed below. The decision to
incorporate adjuvant radiation into the treatment plan after ABVD must be individualized.
Factors to be taken into account when making this decision include the patient's age, sex,
history of prior radiation, and the size and location of the proposed radiation field. Given this
information, we use the following approach to determining whether a patient should receive
consolidation RT:
● For patients with advanced stage cHL and initial bulky mediastinal disease (>10 cm or >1/3
the chest diameter), we suggest the use of consolidation RT after ABVD rather than
observation. The radiation dose is usually 30 to 36 Gy, and depends upon field size, initial
disease volume, and response to chemotherapy. Observation may be appropriate for
select patients, such as young women in whom substantial breast tissue would be
included in the radiation fields.
● For patients with nonbulky advanced stage cHL who achieve a CR with ABVD, we suggest
observation rather than the use of consolidation RT.
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● Patients treated with ABVD who achieve a PR, with residual PET abnormalities, should
undergo biopsy of the suspected residual disease. If the biopsy demonstrates residual
disease, additional therapy is administered as appropriate for relapsed/refractory disease.
Alternatively, consolidation with RT or close observation with short interval follow-up may
be chosen in select circumstances in which a biopsy may prove difficult or dangerous, or
when PET residual abnormality is of borderline significance.
Complete remission — The omission of RT for patients who achieve a CR with ABVD is

supported by a phase III European Organisation for Research and Treatment of Cancer (EORTC)
trial that randomly assigned 333 patients to consolidation RT or observation after the
achievement of a CR with a MOPP/ABV hybrid regimen [73]. When compared with patients who
received RT, patients who did not receive RT had similar rates of event-free survival (77 versus
73 percent) and overall survival (85 versus 78 percent) at eight years. Patients who received RT
had a nonsignificant trend towards a higher rate of secondary cancer at eight years (13 versus 6
percent). However, there are several limitations to this trial: the chemotherapy regimen
(MOPP/ABV hybrid) is no longer in use due to its excessive toxicity; most patients received eight
cycles of chemotherapy and still the fraction of patients randomized in CR was only 65 percent,
and, most patients with bulky disease were not randomized. It is also unexplained why the
excess in leukemia cases that was reported only in CR patients who received low-dose radiation
consolidation has not been observed in the larger group of partial responders who have all
received radiation as well.
Partial response — The use of RT in patients with a PR after ABVD is supported by the

EORTC trial described above. In this same trial, 247 patients achieved a PR after MOPP/ABV, 227
of whom were given consolidation RT [73]. When compared with those who had achieved a CR
after MOPP/ABV, those patients who received RT after achieving a PR had similar rates of event-
free survival (76 percent) and overall survival (84 percent) at eight years. In this trial, response
was determined using computed tomography (CT) criteria. It is likely that a percentage of
patients who achieve a PR by CT criteria had fibrosis rather than residual cHL suggesting that
some of these patients were potentially overtreated. Response criteria now incorporate findings
from PET scans. (See "Monitoring of the patient with classic Hodgkin lymphoma during and
after treatment", section on 'Response categories'.)
Bulky disease — Bulky mediastinal disease (>10 cm or >1/3 the chest diameter) is an

adverse prognostic marker in patients with advanced stage cHL [74]. The use of consolidation
RT in this group of patients is largely based upon retrospective analyses.
● A nonrandomized study of RT embedded within a randomized trial of chemotherapy

(ABVD versus two other multidrug regimens) in newly diagnosed advanced stage cHL
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included 222 patients who received RT mostly due to bulky disease or incomplete
response [72]. Although the radiation group included mostly patients with these
unfavorable features, the addition of consolidation RT resulted in superior progression-
free survival (hazard ratio [HR] 0.40, 95% CI 0.23-0.69). Overall survival was also
significantly better for those who received RT (HR, 0.47; 95% CI 0.29-0.77). Median follow-
up was seven years.
● A single-center retrospective analysis of 104 patients with stage III cHL who achieved a CR
after ABVD and followed for a median of 5.8 years compared outcomes between the 40
patients who received consolidative RT and those who did not [75]. Patients who did not
receive RT had inferior rates of disease-free survival at five (78 versus 94 percent) and 10
(45 versus 81 percent) years, and lower rates of overall survival at five (91 versus 98
percent) and 10 (72 versus 80 percent) years post-treatment. The potential benefit from RT
appeared to be greatest for patients with initial disease above the diaphragm.
Although not definitive, these observations provide support for combined modality treatment
in patients with initially bulky disease even if a CR has been documented by PET/CT scan,
especially if initial PET response remains above Deauville level 2 (ie, uptake greater than
mediastinum) [76]. Additional support for this approach comes from the extrapolation of data
from patients with early stage disease with bulky mediastinal disease, which suggests that the
addition of RT to chemotherapy results in significantly higher disease-free survival rates and a
trend towards improved overall survival. (See "Treatment of unfavorable prognosis early (stage
I-II) classic Hodgkin lymphoma in adults", section on 'Combined modality therapy (CMT)'.)
After BEACOPP — The addition of RT improves freedom from treatment failure rates in

patients with advanced stage cHL who have residual disease after the completion of BEACOPP
[77]. However, patients with advanced stage cHL who still have residual disease on CT scan after
escalated BEACOPP but are PET-negative maintain a progression-free survival rate of 94 to 96
percent without receiving additional RT [40,78].
Therefore, our current approach to the use of consolidation therapy for patients treated with
BEACOPP is dependent on their response to the initial chemotherapy:
● For patients who achieve a CR after BEACOPP, we suggest observation rather than RT.
● For patients who have residual disease on PET scan after BEACOPP, we suggest the use of
consolidation RT rather than observation.
Radiation toxicity — The side effects of RT depend largely on the area irradiated, the dose of
radiation, and the technique employed. RT techniques have changed dramatically over the past
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few decades resulting in uncertainty regarding the long-term side effects of RT.
In addition, there may be differences in both short-term and long-term toxicities when different
combination chemotherapeutic regimens are combined with RT. Although many of the short-
term toxicities can be avoided by administering sequential rather than concurrent
chemotherapy and radiation, combinations of both treatments have the potential to increase
late complications, most notably, secondary malignancies and cardiopulmonary toxicity.
Approximately half of patients who received upper mediastinal or neck irradiation will develop
hypothyroidism. (See "Approach to the adult survivor of classic Hodgkin lymphoma", section on
'Late complications'.)
Acute side effects — Acute side effects of RT include fatigue and a mild sun-exposure-like
dermatitis in the involved field ( table 5). Irradiation of the head and neck can result in dry
mouth, change in taste, and pharyngitis. Subdiaphragmatic irradiation is associated with a loss
of appetite, nausea, and increased bowel movements. Myelosuppression can occur if more than
one field is irradiated. (See "Overview of gastrointestinal toxicity of radiation therapy".)
Complications occurring in fewer than 5 percent of patients include:
● Mediastinal irradiation can be associated with radiation pneumonitis and/or acute

pericarditis. (See "Radiation-induced lung injury".)
● Radiation of the cervical and/or thoracic spinal cord can be associated with Lhermitte sign
(electric shock-like sensation down the backs of the legs with neck flexion), that typically
presents within six weeks to three months of treatment, and generally resolves
spontaneously.
Cardiac and pulmonary toxicity — Mediastinal RT for cHL may be a cause of late cardiac
disease including constrictive or effusive pericarditis, conduction abnormalities, valvular
defects, accelerated coronary artery atherosclerosis, or direct myocardial injury. (See
"Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)
The dose of RT and field size are important risk factors for cardiac morbidity. Current practice,
which restricts the dose to the whole heart, blocks the subcarinal region part way into
treatment, limits concurrent exposure to cardiac toxins such as anthracyclines, and permits
lower radiation dose and volume by the use of pre-irradiation chemotherapy, may be associated
with a lower risk of cardiac toxicity.
Pulmonary fibrosis can develop as a result of RT or chemotherapy for advanced cHL. Decreased
diffusing capacity (DLCO) and restrictive changes may be detected by pulmonary function
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testing prior to the onset of symptoms. Children may be more likely to show enhanced toxicity
after combined modality treatment because of the increased sensitivity of the lung to damage
from bleomycin [79]. (See "Bleomycin-induced lung injury" and "Radiation-induced lung injury".)
Adding gemcitabine or thoracic irradiation increases the risk of bleomycin lung toxicity,
whether it is administered prior to or simultaneously with bleomycin. However, the rates of
symptomatic pulmonary complications in patients treated with ABVD and radiation do not seem
to be greater than after radiation alone [17,27]. In one study of 60 patients with early stage cHL
receiving ABVD with or without mediastinal irradiation, 53 percent reported dyspnea on
exertion or cough during ABVD and 37 percent had a significant decline in forced vital capacity
(FVC) and DLCO [27]. Following RT, there was a further decrease in FVC, but functional status
was not significantly altered.
Other chemotherapy regimens have also been associated with increased RT-associated
pulmonary toxicity. In two studies in advanced stage cHL that used gemcitabine together with
other agents, including bleomycin, severe pulmonary toxicity, including treatment-related
fatalities, were recorded, leading to the termination of these treatment programs [80,81].
Unacceptable rates of pulmonary toxicity have been observed in two of three studies of
patients with early stage cHL treated with vinblastine, bleomycin, and methotrexate plus
radiation [82-84].
Second malignancy — RT for cHL has been associated with an increased risk of developing
second malignancies. It is difficult to quantify the magnitude of this risk with modern RT
because of the long latency for solid tumors, the potential contribution of chemotherapy, and
the major recent changes in RT technique. The use of lower doses of RT and limited field size
may reduce the risk of second cancers [85,86]. This is discussed in more detail separately. (See
"Second malignancies after treatment of classic Hodgkin lymphoma".)
IS THERE A ROLE FOR TRANSPLANT?
Hematopoietic cell transplantation (HCT) is not recommended for patients with cHL in first
remission. Instead, HCT is reserved for the treatment of relapsed disease. (See "Treatment of
relapsed or refractory classic Hodgkin lymphoma", section on 'Hematopoietic cell
transplantation (HCT)'.)
Attempts to identify a high-risk population that might benefit from early HCT have been
unsuccessful. Such a strategy would require the ability to clearly identify poor-risk patients
because of the 5 to 10 percent early mortality and the appreciable risk of late myelodysplastic
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syndrome or acute myeloid leukemia associated with HCT. Although a variety of prognostic
factors can help to risk stratify patients with cHL, it has proven difficult to identify a group of
patients at very high risk for recurrence.
An international trial randomly assigned 163 patients with poor-risk disease who achieved CR or
PR with four initial cycles of an ABVD-containing regimen to high dose chemotherapy plus
autologous HCT versus an additional four cycles of conventional chemotherapy [87]. Poor-risk
disease was defined as the presence of at least two of the following features: high lactate
dehydrogenase level, large mediastinal mass, involvement of more than one extranodal site,
anemia, and inguinal involvement. After a median of 48 months, the five-year failure-free
survival rate was 75 percent in the high dose arm and 82 percent in the conventional arm, and
the five-year overall survival rate was 88 percent for both arms.
MODIFICATION FOR SPECIAL POPULATIONS
Pregnancy — Approximately 3 percent of patients will be pregnant at the time cHL is

diagnosed. The management of such patients must take into account the effect of treatment on
the fetus and the mother. This is discussed in more detail separately. (See "Management of
classic Hodgkin lymphoma during pregnancy".)
Older adults — There is a bimodal age distribution curve for cHL. The pattern of age-specific
incidence differs by geographic location and appears to parallel the level of industrial
development. In the United States and other economically advantaged countries, there is one
peak in young adults (approximately age 20 years) and one in older age (approximately age 65
years). (See "Hodgkin lymphoma: Epidemiology and risk factors", section on 'Age and race'.)
The assessment of an older adult with cHL includes those studies used for the pretreatment
evaluation of younger adults with cHL in addition to more specific investigations of physical
functioning, nutrition, and comorbid conditions. Comprehensive geriatric assessment of cancer
patients is presented separately. (See "Comprehensive geriatric assessment for patients with
cancer".)
Treatment of older adults (ie, ≥60 years old) with cHL has not been well studied, and older
adults should be encouraged to participate in clinical trials. Older adults have accounted for a
minority of patients included in randomized trials and they are more likely to have
comorbidities that can limit treatment options and increase the risk of toxicity [88-92]. However,
older adults should be offered curative therapy such as that used for younger adults whenever
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possible. The amount of chemotherapy administered in the initial treatment of cHL affects
overall survival.
For most older adults with cHL treated outside of a clinical trial, we suggest treatment with
ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). This is primarily based on the
larger general experience with ABVD across all populations and increased toxicity with more
intensive therapy. BEACOPP should not be used in patients ≥60 years old. (See 'Choice of initial
therapy' above.)
We believe that bleomycin should not be routinely omitted or dose-reduced, except as

described below. We perform pulmonary function tests after two treatment cycles and omit
bleomycin from subsequent cycles in patients who develop symptomatic or asymptomatic
bleomycin-induced pulmonary toxicity during treatment. In addition, we often omit bleomycin
from subsequent cycles in those attaining a PET score of 1, 2, or 3 after two cycles of ABVD as
described above. (See 'Response adapted therapy' above.)
Examples of patients for whom bleomycin may reasonably be omitted include:
● Age >80 years, very frail, or unlikely to be cured

● Creatinine clearance ≤5 mL/minute
● Active smokers and/or significant underlying pulmonary disease
Because older patients are vulnerable to potentially severe bleomycin toxicity, some experts
have advocated omitting bleomycin in older patients to minimize pulmonary toxicity [92].
However, studies in early stage disease reported higher rates of treatment failure when
bleomycin is omitted from ABVD, and it is unknown whether the routine omission of bleomycin
in ABVD compromises cure rates [93]. Randomized trials have also shown that the omission of
bleomycin reduces the rate of pulmonary toxicity among older adults receiving four cycles of
chemotherapy, but not among those receiving two cycles [94]. Prospective studies are
evaluating novel approaches that omit bleomycin (eg, substituting brentuximab vedotin for
bleomycin [95]). Use of such regimens should be restricted to the clinical trial setting.
Importantly, adding brentuximab vedotin without omitting bleomycin results in unacceptably
high rates of potentially fatal pulmonary toxicity [96].
In a retrospective analysis of 147 older adults (≥60 years) treated with ABVD for newly
diagnosed cHL of all stages, 117 (80 percent) achieved a complete remission and the estimated
overall survival rate at five years was 67 percent [92]. Toxicity necessitated changes to the
treatment schedule/dose in 48 patients. Severe (grade 3/4) toxicity occurred in 63 patients (43
percent) and included pulmonary toxicity (26 percent), hematologic toxicity (10 percent), and
infection (3 percent). There were 15 treatment-related deaths, including seven deaths due to
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pulmonary toxicity. Pulmonary toxicity developed at a median of five months from the first cycle
and was not clearly predicted by clinical features (eg, underlying lung disease, tobacco history,
age, radiotherapy, or G-CSF use). This study emphasizes the potential curability of cHL in older
adults and the need for close monitoring during therapy.
In contrast, BEACOPP has been associated with unacceptable toxicities in patients over the age
of 60. In one study, of 42 patients age 66 to 75 who received standard dose BEACOPP, 21
percent died of acute toxicity [52].
The relatively poor results for elderly patients are accompanied by difficulties in maintaining
dose intensity with standard cHL regimens. In an attempt to improve outcomes, prospective
trials have evaluated the use of other regimens in this population. However, none of these has
demonstrated superior outcomes in a randomized trial. As examples:
● In one small study employing CHOP (cyclophosphamide, doxorubicin, vincristine,

prednisone) for elderly cHL patients, dose intensity was maintained with this every three
week regimen and good results were achieved [97].
● In another study of 59 older adults treated with the novel combination of prednisone,
vinblastine, doxorubicin, gemcitabine (PVAG), toxicity was acceptable and rates of
complete response, progression-free survival at three years, and overall survival at three
years were 78, 66, and 58 percent, respectively [98].
● One trial evaluated single agent brentuximab vedotin in 27 frail older adults (median age
78 years) with previously untreated cHL (63 percent advanced stage) [99]. The overall
response rate was 92 percent (73 percent complete). After a median follow-up of 17
months, the median progression-free survival was 10.5 months. Median overall survival
had not been reached, and survival times ranged from 5 to 25 months. Peripheral
neuropathy was seen in the majority of patients (78 percent) and reports of severe
neuropathy occurred in the presence of coexisting diabetes mellitus and hypothyroidism.
Good response rates were also reported in an abstract presentation of a phase 2
multicenter study that evaluated sequential brentuximab vedotin plus AVD (doxorubicin,
vinblastine, and dacarbazine) as first-line treatment in elderly patients with cHL [100].
Evaluation in larger populations is needed. However, these and similar studies suggest a
future role for brentuximab vedotin in patients otherwise too frail to tolerate standard
curative regimens.
Adolescents — It appears that adult treatment protocols may be safe and provide comparable
efficacy to pediatric protocols in the treatment of adolescents with cHL [101]. (See "Overview of
Hodgkin lymphoma in children and adolescents".)
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HIV-infected patients — Treatment of patients with HIV who develop cHL is complicated by

their immunocompromised state and also requires specific treatment for their HIV. As such,
treatment of these patients is discussed in more detail separately. (See "HIV-related
lymphomas: Treatment of systemic lymphoma" and "HIV infection and malignancy:
Management considerations", section on 'Hodgkin lymphoma'.)
MONITORING DURING THERAPY
Patients with cHL are re-evaluated at regular intervals during treatment to assess the response.
(See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment".)
FOLLOW-UP
After the completion of therapy, patients are assessed for disease response using the
International Working Group response criteria that incorporates findings on computed
tomography (CT) and positron emission tomography (PET) scans. (See "Monitoring of the
patient with classic Hodgkin lymphoma during and after treatment", section on 'Response
categories'.)
Patients treated for cHL must also be followed at regular intervals to assess for recurrent
disease and long-term complications of therapy. (See "Approach to the adult survivor of classic
Hodgkin lymphoma", section on 'Post-treatment management' and "Approach to the adult
survivor of classic Hodgkin lymphoma", section on 'Late complications'.)
CLINICAL TRIALS
Often there is no better therapy to offer a patient than enrollment onto a well-designed,
scientifically valid, peer-reviewed clinical trial. Additional information and instructions for
referring a patient to an appropriate research center can be obtained from the United States
National Institutes of Health (www.clinicaltrials.gov).
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Management of
Hodgkin lymphoma".)
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INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient education" and the keyword(s) of interest.)
● Beyond the Basics topics (see "Patient education: Hodgkin lymphoma in adults (Beyond
the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow
transplantation) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Once the diagnosis of classic Hodgkin lymphoma (cHL) has been established, subsequent
therapy is based upon the stage of the disease, as currently defined by the Cotswolds
classification ( table 1). In this discussion, advanced stage cHL refers to clinical stage (CS) III
and IV disease. CS III describes involvement of lymph nodes or lymphoid structures on both
sides of the diaphragm. CS IV refers to diffuse or disseminated involvement of one or more
extranodal organs or tissues, with or without lymph node disease. (See "Pretreatment
evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)
● For most patients with advanced stage cHL, we suggest response adapted ABVD
(doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy ( table 3) rather
than alternative chemotherapy regimens ( table 4) (Grade 2B). The preference for ABVD
in this setting is informed by the favorable balance of outcomes versus toxicity, and long
experience with this regimen. (See 'General approach' above.)
Other acceptable regimens for advanced stage cHL include:
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• BV+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) (see

'BV+AVD' above)
• BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine,

procarbazine, and prednisone) (see 'BEACOPP chemotherapy' above)
Selection of an alternative to ABVD is informed by comorbid medical conditions,

physician/institutional experience, and patient preference. Such considerations must
weigh short- and long-term outcomes and toxicities. (See 'General approach' above.)
● The number of cycles of ABVD chemotherapy is informed by the response on positron

emission tomography (PET) scan after two treatment cycles (PET2; ie, response adapted
therapy). Patients who attain a PET2 score of 1, 2, or 3 ("PET2-negative") may reasonably
complete therapy with four additional cycles of AVD (without bleomycin). The decision for
an individual patient must take into account the risk of pulmonary toxicity with further
bleomycin versus the potentially small increase in relapse with bleomycin omission. This
approach is most attractive for those at high risk for bleomycin toxicity (eg, older age,
underlying pulmonary disease, active smokers). Younger patients who wish to minimize
their chance of relapse may choose to complete therapy with four more cycles of ABVD.
(See 'Response adapted therapy' above.)
● The role of consolidation radiotherapy (RT) after chemotherapy induction for advanced
stage cHL is controversial. RT appears to improve freedom from progression but not
overall survival. Its use depends primarily upon the initial chemotherapy administered and
the patient's response to that chemotherapy. (See 'General' above.)
● The decision to proceed with adjuvant radiation after ABVD must be individualized. Factors
to be taken into account when making this decision include the patient's age, sex, history
of prior radiation, and the size and location of the proposed radiation field. In general, we
use the following approach:
• For patients with advanced stage cHL and initial bulky mediastinal disease (>10 cm or
>1/3 the chest diameter), we suggest the use of consolidation involved site RT after
ABVD rather than observation (Grade 2C). The radiation dose is usually 30 to 36 Gy,
and depends upon field size, initial disease volume, and response to chemotherapy.
(See 'After ABVD' above.)
• For patients with nonbulky advanced stage cHL who achieve a complete remission with
ABVD, we suggest observation rather than the use of consolidation RT (Grade 2B).
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• Patients treated with ABVD who achieve a partial response, with residual PET
abnormalities, should undergo biopsy of the suspected residual disease. If the biopsy
demonstrates residual disease, additional therapy is administered as appropriate for
relapsed/refractory disease. Alternatively, consolidation with RT or close observation
with short interval follow-up may be chosen in select circumstances in which a biopsy
may prove difficult or dangerous or when PET residual abnormality is of borderline
significance.
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge Steven Horwitz, MD, who contributed
to earlier versions of this topic review.
Use of UpToDate is subject to the Terms of Use.
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cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine (BEACOPP)
regimen is probably related to the combination of gemcitabine and bleomycin: a report of
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Topic 4689 Version 56.0
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GRAPHICS
Lugano classification for staging of lymphomas (derived from Ann Arbor

staging with Cotswolds modifications)
Stage I — Involvement of a single lymph node region (eg, cervical, axillary, inguinal, mediastinal) or
lymphoid structure such as the spleen, thymus, or Waldeyer's ring.
Stage II — Involvement of 2 or more lymph node regions or lymph node structures on the same side
of the diaphragm. Hilar nodes should be considered to be "lateralized" and when involved on both
sides, constitute stage II disease. For the purpose of defining the number of anatomic regions, all
nodal disease within the mediastinum is considered to be a single lymph node region, and hilar
involvement constitutes an additional site of involvement. The number of anatomic regions should be
indicated by a subscript (eg, II-3).
Stage III — Involvement of lymph node regions or lymphoid structures on both sides of the
diaphragm. This may be subdivided stage III-1 or III-2: stage III-1 is used for patients with
involvement of the spleen or splenic hilar, celiac, or portal nodes; and stage III-2 is used for patients
with involvement of the paraaortic, iliac, inguinal, or mesenteric nodes.
Stage IV — Diffuse or disseminated involvement of 1 or more extranodal organs or tissue beyond
that designated "E," with or without associated lymph node involvement.
All cases are subclassified to indicate the absence (A) or presence (B) of the systemic symptoms of
significant unexplained fever, night sweats, or unexplained weight loss exceeding 10% of body weight
during the 6 months prior to diagnosis.
The designation "E" refers to extranodal contiguous extension (ie, proximal or contiguous extranodal
disease) that can be encompassed within an irradiation field appropriate for nodal disease of the
same anatomic extent. More extensive extranodal disease is designated stage IV.
Bulky disease: A single nodal mass, in contrast to multiple smaller nodes, of 10 cm or ≥⅓ of the
transthoracic diameter at any level of thoracic vertebrae as determined by CT; record the longest
measurement by CT scan. The term "X" (used in the Ann Arbor staging system) is no longer necessary.
The subscript "RS" is used to designate the stage at the time of relapse.
CT: computed tomography.
Adapted from:
1. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of
patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989; 7:1630.
2. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment
of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014; 32:3059.
Graphic 66651 Version 9.0
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The International Prognostic Score for Hodgkin lymphoma
One point is given for each of the characteristics below present in the patient, for a total score
ranging from zero to seven
Serum albumin <4 g/dL
Hemoglobin <10.5 g/dL
Male gender
Age >45 years
Stage IV disease
White blood cell count ≥15,000/microL
Absolute lymphocyte count <600/microL and/or <8 percent of the total white blood cell count
When applied to an initial group of 5141 patients with advanced Hodgkin lymphoma treated prior to
1992 with combination chemotherapy with or without radiation therapy, five-year overall survival (OS)
and freedom from progression (FFP) rates according to score were as follows[1] :
Score Five-year FFP, percent Five-year OS, percent
0 84 89
1 77 90
2 67 81
3 60 78
4 51 61
5 or more 42 56
When applied to 740 patients with advanced Hodgkin lymphoma treated with curative intent with
doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) from 1980 to 2010, five-year OS and FFP
rates according to score were as follows[2] :
Score Five-year FFP, percent Five-year OS, percent
0 88 98
1 84 97
2 80 91
3 74 88
4 67 85
5 or more 62 67
References:
1. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project
on Advanced Hodgkin's Disease. N Engl J Med 1998; 339:1506.
6/19/22, 4:27 PM 4689
2. Moccia AA, Donaldson J, Chhanabhai M, et al. International Prognostic Score in Advanced-Stage Hodgkin's
Lymphoma: Altered Utility in the Modern Era. J Clin Oncol 2012; 30:3383.
6/19/22, 4:27 PM 4689
ABVD chemotherapy for Hodgkin lymphoma[1]
Cycle length: 28 days.
Dose and
Drug Administration Given on days
route
Doxorubicin 25 mg/m2 IV Dilute in 50 mL normal saline (NS) Days 1 and 15

and administer over three to five
minutes through a central line or IV
push through a peripheral line.
Bleomycin* 10 units/m2 IV Dilute in 50 mL NS and administer Days 1 and 15

over 10 minutes or IV push through a
peripheral line.
Test dose of 2 units given one hour

before full dose can be considered for
the first cycle.¶
Vinblastine 6 mg/m2 IV Administer over one minute. Days 1 and 15
Dacarbazine 375 mg/m2 IV Central line: Dilute in 250 mL of 5% Days 1 and 15

dextrose (D5W) and administer over
30 minutes.
Peripheral line: Dilute in 500 mL of

D5W and administer over 60 minutes.
Dacarbazine should be protected

from light.
Pretreatment considerations:
Emesis risk HIGH (>90% frequency of emesis).

Refer to UpToDate topic on "Prevention and treatment of chemotherapy-
induced nausea and vomiting in adults".
Prophylaxis for Premedicate with acetaminophen prior to administration of the full

infusion bleomycin dose. Some clinicians administer a bleomycin test dose before
reactions the first cycle.
Refer to UpToDate topic on "Infusion reactions to systemic chemotherapy".
Vesicant/irritant Doxorubicin and vinblastine are vesicants.

properties Refer to UpToDate topic on "Extravasation injury from chemotherapy and
other non-antineoplastic vesicants".
Infection Primary prophylaxis with G-CSF is generally not indicated, and G-CSF is
prophylaxis avoided in some centers because of concerns that concurrent use may
increase bleomycin lung toxicity.
Refer to UpToDate topic on "Bleomycin-induced lung injury".
6/19/22, 4:27 PM 4689
Dose A dose reduction in bleomycin of at least 25% is recommended for patients

adjustment for with creatinine clearance 10 to 50 mL/min, and at least 50% reduction for
baseline liver or clearance <10 mL/min. Chemotherapy dose adjustments for doxorubicin
renal and vinblastine are needed in patients with cholestasis.
dysfunction Refer to UpToDate topics on "Chemotherapy hepatotoxicity and dose
modification in patients with liver disease: Conventional cytotoxic agents"
and "Chemotherapy hepatotoxicity and dose modification in patients with
liver disease: Molecularly targeted agents" and "Chemotherapy
nephrotoxicity and dose modification in patients with renal insufficiency:
Conventional cytotoxic agents".
Monitoring parameters:
Assess CBC with differential, electrolytes, renal function, and liver function prior to each
treatment cycle.
Cumulative doxorubicin dose should be monitored. Measure left ventricular ejection fraction
prior to first cycle, then as clinically indicated.
Monitor for respiratory complaints or unexplained findings on lung exam (eg, rales). Maximum
bleomycin lifetime dose not to exceed 400 mg. Measure pulmonary diffusion capacity before
first cycle and then per institutional policy.
Suggested dose modifications for toxicity:
Myelotoxicity No routine dose modifications; G-CSF is not routinely administered unless

previous cycles were complicated by infection or fever in setting of
neutropenia.
Refer to the UpToDate topic on "Use of granulocyte colony stimulating
factors in adult patients with chemotherapy-induced neutropenia and
conditions other than acute leukemia, myelodysplastic syndrome, and
hematopoietic cell transplantation".
Pulmonary Bleomycin should be discontinued in patients with documented or strongly

toxicity suspected bleomycin-induced lung injury.
Neuropathy For severe paresthesias and/or constipation, the dose of vinblastine may
be reduced by 50%; vinblastine should be discontinued permanently if an
adynamic ileus occurs.
If there is a change in body weight of at least 10%, doses should be recalculated.
This table is provided as an example of how to administer this regimen; there may be other
acceptable methods. This regimen must be administered by a clinician trained in the use of
chemotherapy, who should use independent medical judgment in the context of individual
circumstances to make adjustments, as necessary.
6/19/22, 4:27 PM 4689
IV: intravenous; G-CSF: granulocyte colony stimulating factors; AST: aspartate aminotransferase;
ALT: alanine aminotransferase; CBC: complete blood count; WBC: white blood cell.
* 1 mg bleomycin = 1 unit bleomycin.
¶ A test dose of bleomycin before the first dose is recommended by the manufacturer;[2] however,
many institutions no longer perform this test dose. Refer to UpToDate topic on infusion reactions to
systemic chemotherapy.
References:
1. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP
alternating with ABVD. N Engl J Med 1992; 327:1478.
2. Bleomycin sulfate injection. United States Prescribing Information. US National Library of Medicine.
dailymed.nlm.nih.gov (Accessed on January 3, 2012).
6/19/22, 4:27 PM 4689
Chemotherapeutic regimens used for the treatment of Hodgkin lymphoma
Regimen Dosage and schedule Frequency
ABVD[1]
Doxorubicin 25 mg/m2 IV on days 1 and 15 Repeat cycle every 28 days
Bleomycin 10 units*/m2 IV on days 1 and

15
Vinblastine 6 mg/m2 IV on days 1 and 15
Dacarbazine 375 mg/m2 IV on days 1 and 15
BV+AVD[2]
Brentuximab vedotin 1.2 mg/kg IV on days 1 and 15 Repeat cycle every 28 days
Doxorubicin 25 mg/m2 IV on days 1 and 15
Vinblastine 6 mg/m2 IV on days 1 and 15
Dacarbazine 375 mg/m2 IV on days 1 and 15
Escalated BEACOPP[3,4]
Bleomycin 10 units*/m2 IV on day 8 Repeat cycle every 21 days
Etoposide 200 mg/m2 IV on days 1

through 3¶
Doxorubicin 35 mg/m2 IV on day 1¶
CyclophosphamideΔ 1250 mg/m2 IV on day 1¶
Vincristine 1.4 mg/m2 (maximum 2 mg) IV

on day 8
Procarbazine 100 mg/m2 oral on days 1

through 7
Prednisone 40 mg/m2 oral on days 1

through 14
G-CSF SQ starting on day 8
IV: intravenous; SQ: subcutaneous; G-CSF: granulocyte colony-stimulating factor.
* 1 unit = 1 mg bleomycin.
¶ Note that these doses are for the Escalated BEACOPP regimen. The Baseline BEACOPP regimen
differs from Escalated BEACOPP because the doses of three of the drugs are reduced:
Etoposide 100 mg/m2 (instead of 200 mg/m2 )
Doxorubicin 25 mg/m2 (instead of 35 mg/m2 )
Cyclophosphamide 650 mg/m2 (instead of 1250 mg/m2 )
6/19/22, 4:27 PM 4689

Δ Mesna, total dose is the same as that of cyclophosphamide, administered: 20 percent IV at hour 0;
40 percent orally at hour 2; 40 percent orally at hour 5.
◊ Vinblastine dose reduced to 4 mg/m2 and vincristine dose to 1 mg/m2 (maximum 2 mg) during
cycle 3 for patients 50 years of age or older.
References:
1. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP
alternating with ABVD. N Engl J Med 1992; 327:1478.
2. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's
lymphoma. N Engl J Med 2018; 378:331.
3. Dann EJ, Bar-Shalom R, Tamir A, et al. Risk-adapted BEACOPP regimen can reduce the cumulative dose of
chemotherapy for standard and high-risk Hodgkin lymphoma with no impairment of outcome. Blood 2007; 109:905.
4. Eich HT, Diehl V, Görgen H, et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients
with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin
Oncol 2010; 28:4199.
6/19/22, 4:27 PM 4689
Toxicities associated with combination chemotherapy and radiation therapy

for Hodgkin lymphoma
Acute toxicities
Alopecia
Nausea and vomiting
Diarrhea
Mucositis
Paresthesias and neuropathy
CNS confusion
Anemia, leukopenia, and thrombocytopenia
Disulfiram-like reaction following alcohol while taking procarbazine
Delayed toxicities
Secondary malignancies
Acute myelogenous leukemia
Acute lymphoblastic leukemia
Non-Hodgkin lymphoma
Melanoma
Sarcoma
Breast, gastric, lung, and thyroid cancers
Pulmonary complications
Bleomycin lung toxicity
Pulmonary fibrosis
Cardiac complications
Cardiomyopathy
Accelerated atherosclerotic heart disease
Pericardial fibrosis
Endocrine complications
Infertility
Hypothyroidism
6/19/22, 4:27 PM 4689
Contributor Disclosures
Joachim Yahalom, MD No relevant financial relationship(s) with ineligible companies to disclose. Ann S
LaCasce, MD Grant/Research/Clinical Trial Support: Forty Seven [Lymphoma].
Consultant/Advisory Boards:
Bristol-Myers Squibb [Hodgkin lymphoma DSMB].
Speaker's Bureau: Research To Practice [Lymphoma].
All
of the relevant financial relationships listed have been mitigated. Arnold S Freedman, MD Other Financial
Interest: Bayer [Lymphoma DSMB].
All of the relevant financial relationships listed have been
mitigated. Alan G Rosmarin, MD No relevant financial relationship(s) with ineligible companies to
disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

Initial Treatment of Advanced (Stage III-IV) Classic Hodgkin Lymphoma

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Initial Treatment of Advanced (Stage III-IV) Classic Hodgkin Lymphoma

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Initial treatment of advanced (stage III-IV) classic

● The treatment of relapsed or refractory cHL. (See "Treatment of relapsed or refractory

● The treatment of nodular lymphocyte predominant Hodgkin lymphoma. (See "Treatment

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC

● (See "COVID-19: Considerations in patients with cancer".)

Choice of initial therapy — Combination chemotherapy with ABVD (doxorubicin, bleomycin,

Response adapted therapy — Mid-treatment positron emission tomography (PET) has

ABVD chemotherapy — ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) is the

ABVD toxicity — ABVD is associated with both acute and long-term toxicity.

Bleomycin-induced pulmonary toxicity may occur quite often (approximately 20 to 30 percent of

Long term — Long-term complications of ABVD include bleomycin-related pulmonary

● In another study of 141 patients treated with bleomycin-containing chemotherapy for

Cardiomyopathy is a recognized complication of doxorubicin therapy but is not commonly seen

BV+AVD — BV+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) is built on

BEACOPP chemotherapy — The German Hodgkin's Lymphoma Study Group (GHSG) developed

Regimens — Multiple versions of BEACOPP have been developed. Eight cycles of escalated

doses of doxorubicin (from 25 to 35 mg/m2), cyclophosphamide (from 650 to 1250

BEACOPP toxicities — Common complications of BEACOPP therapy include bone marrow

Short term — BEACOPP, especially increased dose BEACOPP, is associated with more

● Age 40 to 49 years with ECOG PS ≥2 (40 patients) – TRM 15 percent

Long term — The main long-term complications of BEACOPP are second malignancies

IS THERE A ROLE FOR RADIATION?

Overview — The role of consolidation radiotherapy (RT) after chemotherapy induction for

Whether or not consolidative RT should be administered to patients with initial bulky

General — Numerous prospective and retrospective studies have evaluated the use of

Complete remission — The omission of RT for patients who achieve a CR with ABVD is

Partial response — The use of RT in patients with a PR after ABVD is supported by the

Bulky disease — Bulky mediastinal disease (>10 cm or >1/3 the chest diameter) is an

● A nonrandomized study of RT embedded within a randomized trial of chemotherapy

After BEACOPP — The addition of RT improves freedom from treatment failure rates in

Complications occurring in fewer than 5 percent of patients include:

● Mediastinal irradiation can be associated with radiation pneumonitis and/or acute

IS THERE A ROLE FOR TRANSPLANT?

MODIFICATION FOR SPECIAL POPULATIONS

Pregnancy — Approximately 3 percent of patients will be pregnant at the time cHL is

We believe that bleomycin should not be routinely omitted or dose-reduced, except as

Examples of patients for whom bleomycin may reasonably be omitted include:

● Age >80 years, very frail, or unlikely to be cured

● In one small study employing CHOP (cyclophosphamide, doxorubicin, vincristine,

HIV-infected patients — Treatment of patients with HIV who develop cHL is complicated by

MONITORING DURING THERAPY

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

Other acceptable regimens for advanced stage cHL include:

• BV+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) (see

• BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine,

Selection of an alternative to ABVD is informed by comorbid medical conditions,

● The number of cycles of ABVD chemotherapy is informed by the response on positron

Use of UpToDate is subject to the Terms of Use.

9. Johnson P, Federico M, Kirkwood A, et al. Adapted Treatment Guided by Interim PET-CT

49. Wongso D, Fuchs M, Plütschow A, et al. Treatment-related mortality in patients with

escalation study. Lancet Oncol 2013; 14:1348.

Lugano classification for staging of lymphomas (derived from Ann Arbor

CT: computed tomography.

Graphic 66651 Version 9.0

The International Prognostic Score for Hodgkin lymphoma

Serum albumin <4 g/dL

Hemoglobin <10.5 g/dL

Age >45 years

White blood cell count ≥15,000/microL