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with more chemotherapy?
For instance, the very well-publicized
Canadian HD6 trial randomized earlystage Hodgkin lymphoma patients to
radiotherapy alone, ABVD alone, or
ABVD followed by extended field radiation therapy.1 This form of radical radiation
therapy is now obsolete and was stopped in
the 1980s; at that time, radiation was given
through the whole body, from the ears to
the pelvis and in full doses to every patient,
even for very small and localized tumors.
In HD6, patients received four cycles
of ABVD, with restaging of the disease
through CT scanning after two and four
cycles of therapy. If a patient’s CT scan
showed response after two cycles, they
received only two additional cycles of
ABVD (four total); if the CT scan did not
show response after two cycles, patients
received the full six cycles of ABVD.
The combined modality (two cycles of
ABVD followed by radiation therapy)
demonstrated significantly better disease
control than the ABVD-alone group –
who received double and, often, triple the
amount of chemotherapy.
Additionally, we have to weigh the risks
of the potential long-term toxicity of radiation therapy against the 10 to 15 percent risk
of treatment failure without radiation – and
the subsequent need for salvage therapy
with high-dose chemotherapy, radiation,
and stem cell transplantation. Salvage is a
very traumatic event for patients – in terms
of future health risks and the impact on
quality of life. When a patient with relapsed
disease has to drop out of college and think
about freezing her eggs because of salvage
therapy’s effects on fertility, I know this
could have been avoided.
Dr. Connors: As I mentioned, a very helpful
method of deciding who might benefit
from radiation therapy is with the use of
functional imaging with fluorodeoxyglucose
(FDG)-PET. Patients with advanced-stage
disease and a residual mass after six cycles
of ABVD but a negative PET scan have a
complete response and require no radiation.
Those with a positive PET scan may benefit
from IFRT, and it should definitely be provided if the field of treatment could be kept
small enough to minimize toxicity. About
one-quarter of patients with a residual mass
after ABVD will have a positive PET scan
and require such radiation.
For limited-stage disease, PET performed after two cycles of ABVD (PET2)
is powerfully prognostic. The approximately 80 percent of patients with a
negative PET2 have a 5 to 7 percent risk
of eventually relapsing if treatment is
completed with two more cycles of ABVD.
Choosing radiation instead of chemotherapy does reduce the risk of relapse,
but only cuts it in half, to approximately
3 percent. That means that more than
30 patients need to receive radiation to
benefit just one patient. That “benefit” is
just avoidance of relapse – a questionable
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ASH Clinical News
benefit when you consider that relapse can
usually be cured. Thus, for the 30 patients
not given radiation, we may risk two
instead of just one patient relapsing — but
29 patients will have avoided radiation.
In advanced-stage Hodgkin lymphoma,
PET performed after six cycles of ABVD
(PET6) is very useful in identifying patients with residual mass who do not need
radiation. We already know that patients
reaching a complete response assessed with
CT scanning after six cycles of ABVD gain
nothing from radiation. With strategic use
of PET, we can identify the three-quarters
of patients who have a residual mass seen
on CT but whose PET6 scan is negative
and will not require radiation.
“Treatment decisions should
be based on
evience that is
gathered carefully, described
precisely, and
interpreted
cautiously.”
—JOSEPH M. CONNORS, MD
Dr. Yahalom: I understand that chemotherapy-only advocates may want to use
the PET scan as a tool to tell if the patient
can spare the radiation, but that tool is not
working that well. Of course, PET scanning does give you more confidence when
selecting patients for additional ABVD.
As we have seen in the European H10
study, though, disease control is inferior
when radiation is removed – not to a great
degree, but still inferior.2
The H10 study randomized PET-negative patients after two cycles of ABVD to
an additional cycle of ABVD followed by
radiation therapy (the standard treatment)
or to two additional cycles of ABVD
(experimental treatment). After enrolling
1,137 patients, the investigators decided to
terminate the no-radiation therapy arms
due to an excessive number of failures in
that arm. Researchers concluded that they
would never be able to prove non-inferiority. When a patient is PET-negative and
does not receive radiation therapy, their
disease control will be inferior.2
The UK RAPID trial also used PET
scans to rule out radiation, using a very
simple design: Patients with early-stage
Hodgkin lymphoma received three
cycles of ABVD, and, if the PET scan
was negative, they were randomized to
receive either 30 Gy of IFRT or no further
treatment.3 This is the only study I know
of where the patients who are not receiving radiation are not being compensated
with more chemotherapy. However, my
concern is that investigators need a larger
number of patients – and a larger number
of events – to come to any definitive
conclusions, and the information so far
is premature and their statistics can be
interpreted in different ways.
Dr. Connors: I believe integrating a strategy using PET2 for limited-stage and PET6
for advanced-stage Hodgkin lymphoma
into standard practice maintains very
high cure rates while markedly reducing
use of radiation therapy. The main reason
the chemotherapy-alone approach has
become strongly favored is simply that it
avoids unnecessary treatment. No matter
how much safer one makes radiation by
decreasing dose and/or field size, it cannot
be made perfectly safe. With careful use
of PET scanning, we are able confine