Current Therapies in the Treatment of Non-Hodgkin's Lymphoma:
Richard I. Fisher, MD - Medscape
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We believe that shared decision
making is important,
especially when there is no standard of care and the type of lymphoma
you have has an indolent (slow progressing) course.
treatment following diagnosis: ...
44 non-protocol patients, followed
since 1963, in whom initial treatment was withheld until required to
evaluate the pace of disease and the necessity of treatment;
112 previously untreated patients who
have participated in prospectively randomized clinical trials since
For all 44 "deferred" patients,
the median time before requiring treatment was 31 months, and there have
been 19 patients who have not yet required therapy for periods of 3 to
The median actuarial survival for all 44
patients was 121 months (~10 years).
At 4 years, the actuarial survival of the
44 patients with deferred treatment is 77.3%, compared with 83.2% for
the 112 protocol patients (P = 0.60).
(0.60 is not statistically significant)
Careful observation without initiation of
therapy is an appropriate option in the management of patients with
relatively asymptomatic advanced non-Hodgkin's lymphomas of favorable
Also see related PubMed articles on deferring
treatment - PubMed
Uncharted approach to managing indolent NHL:
Can treating early with combinations of biologics and immune-based therapies
improve both survival and quality of life?
Can this approach delay the need for cytotoxic therapies significantly, or perhaps indefinitely, for a
significant number of patients?
Unfortunately, we're not likely to find the answer to these questions -- mainly because of how our drug evaluation system works and the
nature of indolent NHL.
It's a catch 22: Using biologics and immune-based therapies prior to
chemotherapy is plausible, and preliminary data with the
frontline use of Rituxan shows it has potential, however, it's more
difficult to prove clinical benefit in this setting, mainly because the
clinical course of untreated indolent NHL is so variable.
Because of this, drug sponsors don't often test new drugs in this setting,
especially therapies that will have modest effects as single agents, and
despite the reasonable expectation that this approach will have more potential in chemo-naive
pts. -- and there is less expected risk to patients.
Instead, almost all new treatments for indolent NHL are evaluated in previously treated
Because drug sponsors know that these patients have
a more predictable time to progression, presumably because the disease has
come to a point that it once needed to be treated, and probably because of
the side effects of cytotoxic therapies received -- suppression and damage
to immunity, additional DNA hits to surviving malignant cells ...
We need to ask the NCI, investigators, and
to be brave and design studies of this type. It may well be what's
needed to make significant progress against both indolent and aggressive
Factors that may determine
treatment timing and approach:
When the goal of treatment is cure, treatments are
- all aggressive NHL at any stage (combination
- some indolent localized, stage I/ II, lymphomas
NOTE: There is some evidence that some individuals
with stage III/IV indolent lymphomas may have improved survival and
possible cures with experimental
combination therapies, but most data shows no benefit to early initiation
of treatment in this setting.
that help to determine when to start treatment are the characteristics of the lymphoma at
diagnosis as determined by the pathology report, it's actual
clinical behavior, and other factors. Here's
type and pattern and how this might predict the
expected clinical course and response to treatment:
- if the cell type or pattern
predicts the NHL will typically grow rapidly and will be
resistant to standard therapies, you might consider more
aggressive approaches or investigational therapies.
- how fast or slow the NHL is likely to progress:
- Aggressive NHL is treated early and
aggressively; the goal is cure.
- Slow growing indolent NHL has no standard
approach as described below.
- how widespread the lymphoma. See more below.
Timing factors specific to indolent (slow growing) NHL:
-- how widespread the lymphoma is:
- Clinical behavior as determined by
observation, imaging and other tests.
- Pathology reports can only estimate your clinical course.
- Indolent NHL can have long periods of
stability and sometimes spontaneous
- Some lymphomas diagnosed as indolent are
- Overall tumor burden and/or areas of bulky
- It might be important to treat before a
tumor becomes "bulky" (a lymph nodes
greater than 10 cm.) in order to optimize treatment
- Areas of
- The location of the tumors can often
determine when treatment is needed, not just the tumor
burden -- such as evidence of real or threatened organ
and how it affects your quality of life.
- Your age and treatment
Factors that influence treatment selection for NHL:
There is no apparent standard treatment
for indolent follicular lymphomas.
timing and choice of therapy
Illustrates the complexity of treatment decisions - and how they can interact;
and how each case and lymphoma can be unique, thus treatments may need
to be tailored accordingly.
Management approaches (treat minimally, only as needed):
relatively low-toxic therapies to control or regress disease on an
as-need basis. Choose
therapies that are least likely to compromise effectiveness of
subsequent treatments. So far, this approach is at least as good as
aggressive frontline approaches for indolent NHL, and perhaps better. 
Reserve aggressive combination therapies (CHOP) for a time when
transformation occurs. (About 25% to 35% of patients exhibit
transformation by 10 years. 
Possible caveats: Over time the disease is likely to become more wide spread,
more heterogeneous (variable), and could
develop mutations that make it more aggressive and/or resistant to
- Watchful waiting until symptoms, marked
progression, or when approaching bulky disease.
- Manage with mild single-agent treatments first,
such as Chlorambucil, applied only when needed.
- Initial frontline use of Rituxan (experimental)
- Re-treatment with single-agent or combination
therapies, or Rituxan as needed.
- Treat refractory disease with Zevalin, and in the near future, Bexxar.
- Vaccines have been tried experimentally.
- Many additional options are available in clinical
Also see Uncharted Approaches, in the
NOTE: When the NHL does not respond to initial
treatments (it usually does), strong aggressive therapies
may be more appropriate, and the goal of treatment might switch
to cure, or obtaining a durable complete response.
Essential for individuals with aggressive or transformed disease.
Combine and/or sequence effective therapies in established or new ways
-- or with new agents -- in order to maximize response and
effectiveness. Your best chance for a cure is to
treat early while the malignant clones are more homogeneous, less wide spread, and of fewer number.
This approach might be more appropriate experimentally for individuals
with indolent NHL who are young have a higher tolerance for risk; and for
individuals with clinically aggressive indolent NHL that's refractory
to initial mild treatments.
Possible caveats: Increased toxicities. May increase risks of
secondary cancers, although this risk is often low. Increased chance of treatment-related mortality for
some approaches. For
indolent NHL, there is no definitive proof that aggressive treatments can improve
overall survival. But always, you must weigh the
treatment-associated risks against the risks of particular type of
lymphoma that your are dealing with.
Some Common Approaches:
- Combination chemotherapy with Rituxan for CD20
- Radiotherapy, which may cure if treated when in
stage I or II.
Consolidation with chemotherapy and/or Rituxan might be considered.
- Combination chemotherapy, sequenced with vaccines
- Combination chemotherapy, sequenced with
- Aggressive combination chemotherapy, followed by
a stem cell transplant. (Experimental
for indolent NHL.)
- Milder combination chemotherapy, followed by a mini
 - Horning S, Rosenberg S: The
natural history of initially untreated low-grade non-Hodgkins
lymphomas. N Engl J Med 311:1471-1475, 1984.)