General guidelines for
Hodgkin’s Lymphoma treatment
The current standard is the result of careful clinical
trials that demonstrated three principles:
i) ABVD is the preferred chemotherapy based on both
efficacy and safety,
ii) combined-modality therapy (chemotherapy + radiation
therapy) is superior to wide-field radiation therapy alone
iii) there is no advantage of wide-field radiation therapy
over involved-field radiation therapy when given in
combination with chemotherapy.
goal to review this topic and provide context
to assist practitioners and patients in their
At the beginning of the 20th Century, it was one of the
first cancers to demonstrate impressive responses to the
Rene Gilbert,Vera Peters and Henry Kaplan-Hodgkin
disease was curable with radiation especially limited
development of nitrogen mustard in the 1940s-
Advanced Hodgkin disease is curable
-combination chemotherapy (MOPP, ABVD)
potential late complications--secondary leukemia and solid
tumors, infertility, cardiovascular and pulmonary disease,
but also hypothyroidism, soft tissue effects, and
First reported - early 1970s with MOPP alone-results
A Cochrane analysis of clinical trials comparing
predominantly alkylator-based chemotherapy alone with
CMT, in which the RT component was generally involvedfield treatment, showed superior tumor control and
overall survival (OS) in patients treated with CMT.
However, most of the aforementioned trials, including
the majority that contributed to the meta-analysis,
incorporated chemotherapy regimens now known to be
inferior to ABVD and thus do not properly inform current
Six trials inform decisions to use
chemotherapy plus IFRT
EORTC H8 Trial
age, sex, stage, mediastinal disease, B-symptoms, erythrocyte
sedimentation rate [ESR], and histologic subtype).
STNI VS MOPP-ABV X 3cycles + IFRT
-5-year event-free survival (EFS; 74% vs 98%)
- 10-year OS (92% vs 97%)
- superior in the CMT arm.
Ferme C, Eghbali H et al. Chemotherapy plus involved-field radiation in early-stage
Hodgkin’s disease. N Engl J Med. 2007;357(19):1916-1927
MOPP-ABV x 6 cycles + IFRT
MOPP-ABV x4 cycles+ IFRT
MOPP-ABV x 4 cycles +STNI.
RESULTS- No significant differences among the treatment
arms were detected for either EFS or OS
STNI alone could no longer be recommended in stage I or II
disease and that a reduced volume of radiation fields, from
STNI to IFRT, did not compromise outcome.
remaining 4 trials incorporated CMT in all
treatment arms and tested radiation field size
and/or dose, and types and duration of
ABVDX 4 cycles +STNI
ABVDX 4 cycles + IFRT
29% of patients had unfavorable characteristics (bulky disease,
pulmonary hilar disease, E-lesions, or B-symptoms).
RESULT:median follow-up -116 months
Conclusion:no differences were detected in 12-year freedom from
progression (93% vs 94%) EFS (87% vs 91%) and OS (96% vs 94%)
between the STNI and IFRT arms
Bonadonna G, Bonfante V, Viviani S, Di Russo A, Villani F, Valagussa P. ABVD plus subtotal nodal versus involvedfield radiotherapy in early-stage Hodgkin’s disease: long-term results. J Clin Oncol. 2004;22(14):2835-2841.
Death-6 deaths/136 patients in this trial
3 from Hodgkin lymphoma
1 cardiovascular event (during ABVD treatment),
1 hepatitis, and 1 acute leukemia.
secondary cancers in the STNI arm-3 , IFRT arm-none
ABVD followed by IFRT could be considered an effective
and safe modality in early Hodgkin disease with either
favorable or unfavorable presentation.
HD10 trial design
CS IA, IB, IIA, IIB without RF, N=1190
4 x ABVD
4 x ABVD
2 x ABVD
2 x ABVD
Design- non inferiority Trial
primary endpoint -freedom from treatment failure (FFTF)
median follow-up of 79 months
Engert et al. ASH 2009; Abstract 716
Arm D-The 8-year FFTF on this arm(D) of the trial was 86%
-8-year survival was 95%.
10 deaths resulting from Hodgkin lymphoma, 12 from toxicity of
treatment, 11 from secondary cancer, and 9 from cardiovascular
CONCLUSION- the arm that included 2 cycles of ABVD and 20 Gy
IFRT was considered to be noninferior with respect to FFTF and was
associated with less severe toxicity and was thus concluded by the
authors to be optimum therapy.
HD11 trial design
CS I, IIA with risk factors a-d,
CS IIB with risk factors c, d
(a: large mediastinal mass, b: extranodal involvement, c: elevated ESR, d: ≥3
Borchmann et al. ASH 2009; Abstract 717
GHSG 2009 – HD11
primary endpoint – FFTF
median follow-up of 82 months
5-year FFTF was inferior in the 4 ABVD 20 Gy arm (81%
vs 85%-87%), although no difference in 5-year
survival (94%-95%) was observed
4 ABVD+30 Gy arm was concluded to be noninferior to
the BEACOPP regimens and was recommended as the
treatment of choice because of the greater toxicity of
among these 356 patients, the 5-year FFTF was 85%
and survival was 94%
7 deaths from Hodgkin lymphoma, 5 from treatment
toxicity, 3 from secondary cancers, and 5 from
Stanford G4 study.
single arm trial of Stanford V chemotherapy plus 30 Gy IFRT.
Stanford and the Northern California Kaiser Hospitals.
stage I or II disease
Exclusion-B-symptoms or large mediastinal adenopathy
Stanford V chemotherapy x8weeks +30 Gy “modified” IFRT
N= 87 ,median follow up was 10.6 years.
The 10-year freedom from disease progression and OS are both
There were 4 deaths: 2 from transplantationrelated complications, one from metastatic
colon cancer, and one from swine flu.
The authors concluded that this regimen was
safe and highly effective.
National Cancer Institute of
Canada (NCIC) Clinical Trials Group (NCIC CTG) Eastern Cooperative
Oncology Group (ECOG) HD.6 trial
patients with nonbulky stage I or IIA disease were randomized
to receive ABVD alone or radiation-based treatment.
unfavorable cohorts: those with any one of age 40 years, ESR
50, mixed cellularity or lymphocyte depleted histology, and/or 3
or more disease sites
control arm, those in the favorable-risk cohort received STNI
alone, unfavorable risk cohort patients received 2 cycles of
ABVD followed by STNI.
Experimental arm: therapy was the same for both risk groups:
4-6 cycles of ABVD, with the number of cycles dependent on
rapidity of response documented by computed tomographic
N=405 patients, eligible- 399
primary outcome was 12-year survival
median follow up of 11.3 years
12-year survival was superior in patients randomized to receive
chemotherapy alone (94% vs 87%; hazard ratio [HR] 0.05; P .04)
12-year freedom from progressive disease (FFPD) was inferior
(87% vs 92%; HR 1.91; P .05)
The difference in OS was attributed to fewer deaths from
causes other than progressive Hodgkin lymphoma in
those allocated to ABVD alone (6 vs 20)
deaths from progressive Hodgkin lymphoma were
similar (6 vs 4).
There were 10 deaths from second cancers among those
assigned to radiation and 4 in those randomized to ABVD
In subset analyses
no differences in either 12-year FFPD (89% vs 87%; HR
0.88; P .82) or 12-year survival (98% vs 98%; HR 1.09; P
.95) were detected between the ABVD alone and
radiation therapy groups among the favorable cohorts.
In the unfavorable cohorts, 12-year FFPD was inferior in
those allocated to ABVD (86% vs 94%; HR 3.23; P .006),
whereas 12-year survival was superior (92% vs 81%; HR
0.47; P .04).
Treatment with ABVD alone is associated with superior
long-term OS because it is associated with fewer deaths
from other causes
THE TREATMENT OF LIMITED-STAGE
HODGKIN LYMPHOMA: A
Is radiation therapy alone ever an option for
the treatment of early-stage Hodgkin
The use of radiation therapy alone for the treatment of
classic Hodgkin lymphoma was abandoned more than a
Clinical trials comparing STNI and CMT demonstrated an
improved EFS,low toxicity for CMT
Hence in classical Hodgkin lymphoma CMT is the
Nodular lymphocyte predominant
The GHSG evaluated retrospectively patients treated on
their sequential trials with extended-field RT (EFRT),
CMT, or IFRT and found no differences in outcome
related to the intensity of therapy.
ESMO&NCCN guidelines recommend
IFRT alone -stage I disease
stage II disease-OPTION
What extent of irradiation is indicated
in the setting of combined modality
IFRT is accepted as the standard in combined
modality therapy programs for stage 1A,IIA
What about chemotherapy alone for
nonbulky stage I or II Hodgkin lymphoma?
NCIC CTG HD6
favorable cohort--no significant difference in outcome
between treatment with ABVD or STNI
unfavorable cohort--12-year OS after ABVD treatment
was 92% and the freedom from disease progression was
86%. The OS in the radiation-containing regimen
(ABVDx2 plus STNI) was only 81%, despite the superior
freedom from disease progression (94%).
extent of radiation used was outdated and that this was
likely to have contributed to the excess deaths
NCIC CTG trial used RT that violates current standards
with respect to both volume and dose of irradiation in
the CMT setting.
What criticisms or concerns does the NCIC
CTG trial raise for radiation oncologists?
current standard for radiation volume in combined modality
therapy programs is IFRT. STNI exceeds the volume of IFRT by 3to 5-fold
IFRT -lower doses to the breasts, lungs, and heart in nearly all
All irradiated patients treated to their clinically uninvolved
spleens and para-aortic nodes, exposing them to risks of
infection, cardiac disease, and secondary malignancy.
Involved field irradiation for these patients would never have
included those volumes
All women ,who were irradiated received irradiation to
bilateral axillary nodes, exposing them to a risk of breast
cancer, although it is probable that no more than 25% of
women would have had either axilla irradiated with IFRT
and the reduction in mean breast tissue dose would be
All irradiated patients in this trial had treatment to the
entire mediastinum, exposing them to cardiac risks,
whereas this would not have been the case for patients
treated with IFRT who had an uninvolved mediastinum
The risk for radiation-related cancer is proportional to the
irradiation of smaller volumes is associated with a lower risk for
breast cancer in women and so patients irradiated in this trial
were at greater risk for radiation-related complications than if
they had been treated with IFRT.
risk for cardiac complications increases as the volume of heart
23 deaths among the 139 patients in the ABVD plus STNI
group. This included 9 deaths from secondary cancer.
There were 2 deaths from cardiac events (identical to the
ABVD arm), 3 from infection, and one each from
Alzheimer disease, drowning, suicide, respiratory failure,
The impact of these deaths resulted in a 12-year OS for ABVD
plus STNI of only 81%.
The number of patients who developed any second cancer was
23 in the radiation therapy groups and 10 in the ABVD group.
Among the 23 cancers in the radiation therapy group, location
relative to the radiation fields is not noted; however, 6 were in
the pelvis and unlikely to have been irradiated
The risk that radiation oncologists perceive is that these
results will be interpreted incorrectly to imply a negative
impact for radiation Therapy
Many of the risks associated with radiation therapy in
this trial would not be risks with
contemporary radiation therapy
Another risk that radiation oncologists perceive is that
these results will be translated into clinical practice for
patients with bulky stage Ior II Hodgkin lymphoma.
This trial only addressed patients with nonbulky disease.
Patients with bulky disease are at greater risk for relapse,
and clinical trials of the EORTC and GHSG, which
incorporate radiation therapy, should be used to inform
treatment practice for these patients
What is the current standard for radiation
therapy in combined modality therapy?
Standard-IFRT--treatment to the entirety of a lymphoid region
involved node radiotherapy (INRT)
-Developed by EORTC/GELA
- irradiated volume is less and a smaller volume of radiation
treatment must be associated with less risk for late effects
What does the future hold for the management
of patients with early-stage Hodgkin lymphoma?
We need Adaptive treatment.
NCCN already recommends chemotherapy alone or
combined modality therapy.
The NCIC CTG trial incorporated adaptive therapy in
defining the number of cycles of chemotherapy to be
used (4-6) based on the rapidity of a complete response.
However, more than 60% of patients were treated with 6
cycles of ABVD according to this trial design.
Ideally, if IFRT can be effective in preventing relapse, it
could be refined even further (eg, INRT)
reducing the number of cycles of chemotherapy from 4-6 to
as few as 2, and thereby reducing the potential late risks of
Identification of those patients most likely to benefit from the
addition of radiation therapy remains a challenge.
A promising technique is interim positron emission tomography
(PET) imaging, following 2 or 3 cycles of chemotherapy, to
identify patients with a slow or inadequate response to
Currently, clinical trials in the GHSG (HD16), EORTC-GELA (H10),
and in the United Kingdom (RAPID Trial) are testing this concept
THE TREATMENT OF LIMITEDSTAGE HODGKIN LYMPHOMA: A
Treatment options -nonbulky stage I or IIA
1.CMT 2-4 cycles of ABVD + IFRT (GHSG HD10, HD11 trials)
2.chemotherapy alone with ABVD(NCIC CTG/ECOG HD6 trial)
There is no RCT comparing these 2 options
In this section, a synthesis will be provided to argue that
treatment with ABVD alone is reasonable, appropriate and,
for many patients, may be preferred.
This information will be presented in 4 tiers:
1.reports of primary results
2. interpretation of other trial-specific conclusions
3. integration of hypothesis-generating data
4.additional context and supposition.
objective -compare the 12-year survivals of patients with
nonbulky stage I or IIA Hodgkin lymphoma treated with
ABVD alone with patients given treatment that included
At 12 years, OS
94% -assigned to ABVD alone ,87% -STNI
with differences because of more deaths in the STNI arm
from causes other than progressive Hodgkin lymphoma or
early treatment complication (20 vs 6)
HD.6 trial illustrates the dilemma of evaluating long-
term OS as the primary endpoint in a limited-stage
Hodgkin lymphoma trial
therapeutic advances will undoubtedly occur in the
In this case, advances include recognition that STNI is
excessive, outdated, and probably contributed to the
results and conclusions.
3 results from HD.6 and associated conclusions form a
second tier of evidence and best inform today’s decisionmaking.
These findings relate to disease control and survival
outcomes of patients assigned to ABVD alone and to the
topic of surrogate outcomes.
The observed 12-year FFPD associated with ABVD was
87%. These results were inferior to those observed in the
HD.6 control arm (92%) and might be assumed to be inferior
to those associated with modern CMT.
Logical extensions might then suggest that treatment
that includes IFRT will have fewer late effects than
observed with HD.6 control arm therapy, meaning that
modern CMT may be associated with superior disease
control, a reduced need for subsequent therapy, fewer
late effects, and OS that is as good or better than
observed with ABVD alone. However, important existing
data do not support these assumptions
we have witnessed in our lifetimes dramatic improvements in the
treatment of Hodgkin lymphoma, a disease that previously had been
considered to be fatal.
This progress has been the result of detailed clinical observations,
carefully conducted clinical trials, the refinement of existing treatments,
the development of novel therapies, and the collaboration of specialists
across the breadth of medicine.
Functional assays, genetic profiling, and the introduction of biologic
therapies all hold promise for the future and may enable us to be more
selective in defining treatment for individual patients.
The existing debate will become moot when these advances are realized.
Adverse Prognostic Factors
The International Prognostic Score (IPS) is based on seven factors:
three clinical and four laboratory values .
Patients are given a score of from 0 to 7, and disease can
be categorized as low (0–1), intermediate (2–3), or high (4–7) risk.