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Treatments
> Factors that
Influence Treatment Decisions and Timing
Last update:
08/27/2010 |
TOPICS
Factors | When? |
Which? | Goal of Treatment?
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Would a clinical trial be appropriate for me?
Questions for your doctor
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TOPIC
SEARCH: PubMed |
Medscape
There
are many factors that influence treatments
decisions, particularly for patients with indolent lymphomas. It's an
ongoing and complex process, which involves understanding the risks
of the disease, as well as assessing the potential risks and benefits of
numerous treatment options. ...
(discussion continued below)
Summary of
factors that
can influence
the
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.
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Disease Characteristics |
Basis of Treatment
Decisions |
Patient Characteristics |
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Type of lymphoma
(cell type)
and it's expected natural history |
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Grade: indolent, intermediate, aggressive |
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Stage: localized or
widespread? |
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High or low-risk
clinical behavior?
Growth rate?
Discordant - growing faster in one location than another?
Emerging in new locations?
Sensitivity to initial therapies?
Causing symptoms?
serious or mild?
predictive of need to treat?
Suggests high-risk disease?
See FLIPI for a system of
estimating risk in follicular lymphoma
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Previously treated or
untreated?
Types and toxicities of prior
treatments |
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Response of lymphoma to
treatments and treatment types?
Sensitivity to initial therapy
Complete Response?
Partial Response?
Stable
Progressing during treatment?
Response to subsequent therapies |
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Location of tumors
Near vital organs?
Bone marrow involvement?
Affecting appearance or social confidence? |
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Bone marrow function
(blood counts) |
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Monitoring schedule for
accurate assessment of disease status? |
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Goal of treatment:
a) Durable remission (potential to cure?)
versus
b) Management - treat minimally as needed
IMPORTANT: the most appropriate goal of therapy can be based on both Disease and Patient
Characteristics, and not necessarily on patient preferences alone.
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Strength of evidence
for available therapies?
Best Practice (standard of care)?
Large controlled randomized trials?
Long follow up?
Findings reproduced by different groups?
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Balancing potential benefits versus risks (short and long term)
Proven to improve survival?
Can burn treatment bridges?
Fast acting? |
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How
different physicians may interpret the same data
Physician biases when
Best Practice is not established |
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Treating
physician is a lymphoma specialist or general oncologist? |
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Treating
physician is aware of clinical trials and willing to consider
referral to clinical trials? |
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Treating
physician can administer the full range of therapies?
RIT?, Stem Cell Transplant?
Clinical Trials? |
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Large cancer center, versus community center |
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Patient-physician communications |
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Availability of tissue to determine eligibility for targeted
therapy? |
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Age (chronological and physiological) |
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Performance |
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Blood counts |
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Comorbidities
(secondary conditions)?
Kidney (renal) and Liver (hepatic) function?
Diabetes?
Heart condition?
HIV/AIDS, Hepatitis, Autoimmune? |
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Preferences/temperament
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Tolerance for risk?
Note: Even inaction has risk; and depending on the
circumstances, under-treating or delaying treatment can be higher risk than
administering aggressive or immediate treatment. |
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Prefers treatment that
are easy to administer and least disruptive to
normal life? |
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Prefers treatment with
curative potential? |
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Will report symptoms
honestly and on a timely basis? |
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Our biases,
beliefs, and fears. |
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Quality of life
considerations:
significance of loss of hair,
fatigue, anxiety ... |
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Life Circumstances
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Informed about disease,
therapies and risks? |
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Financial
limitations? |
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Insurance
Limited/ none?
co-payment issues? |
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Supportive care at
home? |
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Ability to travel? |
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Responsibilities and
duties to others:
Employment Family, children
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GOAL OF TREATMENT
Job one: What is the most appropriate goal of treatment.
Durable remission with potential to cure?
versus Management - treat minimally as needed
Often the
treatment goal is based on:
-
risk of the disease - based on pathology results and clinical
behavior FLIPI
(rate of growth, sensitivity to treatments used so far)
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age - being young sometimes
favoring, or allowing for, more aggressive approaches to therapy
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strength of the
data* that
supports the goal of the treatment for your clinical setting:
a) the type of lymphoma
(MALT, Follicular, MCL...)
b) grade - indolent (slow
growing/stable), or aggressive
c) stage - areas of involvement and
tumor burden
(nodal,
localized, extranodal, degree of bone marrow involvement),
d) treatment history and
sensitivity to prior treatment types and duration of response to prior
therapy (Complete
response? PR (partial response?), Progression during treatment?)
*
Note: Response to a biologic, such as Rituxan, may not predict response to
chemotherapy, and vice versa.
e) your performance and
immune status, comorbidities (secondary conditions)
* Strength of Data: Is best
practice established?
Proven superior in comparative studies? ... Large controlled randomized trials?
Long follow up?
Reproduced by different groups?
Virtually every treatment approach has
potential tradeoffs:
An aggressive therapy might give a better chance for a complete
and more durable remission (or cure), but can have greater toxicities
in the short or long term.
However, if you take smaller risks with each treatment (less aggressive
therapy), you may need to treat more often (depending on the clinical
behavior of the lymphoma) and therefore the cumulative risk could be the same or greater with what seems to be the safer protocol.
... And even avoiding or delaying therapy has potential risks.
So
there's no avoiding risks, we just exchange one kind for another.
This is not to suggest that any choice is as good as another in all clinical
circumstances, only that in some instances a definitive best
choice will not exist. And we will need the help of our doctors to
sort this out.
The
Challenge of indolent disease:
There is no standard approach. No best
practice. Each case is unique. It can remain dormant for many
years, or progress and behave aggressively. Typically, indolent
lymphomas are sensitive to initial therapies.
It takes time to get reliable answers from clinical trials, because survival is long
for indolent lymphomas, and the
clinical course of individual patients is variable.
"Ultimately, it may well be that the optimal treatment will be determined
by patient clinical and biological characteristics." ~ Dr. Bruce
Cheson. Advances in the Treatment of Non-Hodgkin's Lymphoma - Dr.
Cheson Medscape
Can
indolent lymphomas be cured?
Only a minority of patients with advanced stage indolent lymphomas may be
cured, but emerging data suggests that the proportion could be
increasing.
See Can
we Cure Indolent Lymphomas?
WHEN TO TREAT?
Watch & wait (observation until symptomatic) became the standard approach for indolent lymphomas
because studies (circa 1979) indicated that early interventions with combination
therapies did not provide a survival advantage.
"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 histologic
types." Watchful waiting is still common practice today.
Click here
for more detail on Watchful Waiting and Monitoring Lymphomas
Q: How long
before I need treatment for indolent lymphoma?
The Time to initial
treatment can vary significantly. For follicular lymphoma "a
substantial proportion of patients may never require treatment." Source: Follicular lymphoma: a historical overview, Koen Van
Besien & Harry Schouten. Feb 2007
In one study "the median
(middle) time before requiring treatment was 31 months, and there have
been 19 patients who have not yet required therapy for periods of 3 to
104 months.
...
The median actuarial survival for all 44
patients was 121 months (~10 years). Source:
No initial therapy for stage III and IV non-Hodgkin's lymphomas of favorable histologic
types, Source: PMID:
369420 Also see related related
PubMed articles PubMed
Q: What are the signs and symptoms
that may indicated when to treat indolent lymphomas?
See also: GELF
criteria for need to treat.
Q: Is
indolent lymphoma ever treated early?
Yes. Stage I and II (localized) indolent lymphoma
are typically treated at diagnosis with curative intent with localized radiotherapy. The cure rate is about
50% according to some reports.
See for many published studies on this question: www.lymphomation.org
NOTE: You may want to ask your oncologist about use of PET and a bone marrow biopsy to confirm that the lymphoma is truly
localized. "PET may be useful in confirming limited disease in the few patients with early stage I disease, because these patients may be treated with local radiation."
Source
jnm.snmjournals.org
Q: What about managing lymphoma with herbs and
alternative therapies?
It's easy to be seduced by testimonials
made by individuals and groups claiming that natural life style changes
can change the course of the disease, but, unfortunately, there is no
clinical evidence to support these claims.
See for details: When
lay persons give medical
advice & The Problem with Testimonials
SELECTION OF TREATMENT?
The good first step is to
decide on the most appropriate goal of treatment ...
Is it to manage the disease by
treating minimally as needed?
or to achieve a durable remission
with combination therapy?
Note: Selecting the goal of
treatment and the protocol should be done in consultation with your
oncologist, because he or she is a medical professional and has
first-hand clinical information about your diagnosis, health status,
treatment history, and the clinical behavior of the lymphoma.
Getting a second opinion from a
*lymphoma specialist* is strongly
recommended.
General community oncologists may not be up-to-date on the latest
approaches to treating the many subtypes of lymphomas. Lymphoma
specialists will also be aware of investigational approaches that have
promise, such as new doses or combinations of proven therapies.
Most general oncologists will encourage you to seek a second opinion
about treatment and adopt the advise given by the specialist.
Overview of
Common Treatment Options for indolent lymphomas
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Watchful
Waiting (W&W)
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Judge
clinical behavior and avoid treatment before it's needed.
Some
patients with indolent lymphomas (a minority) never need treatment. |
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Intent to
manage (first line)
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Rituxan
x 4, or Rituxan x 8 (extended
dosing study) |
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Single
agent alkylators (Chlorambucil or Cyclophosphamide) or
steroids |
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Intent to
manage (second line and subsequent therapy)
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Rituxan
x 4, or Rituxan x 8 (extended dosing) |
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Single
agent alkylators (Chlorambucil or Cyclophosphamide) |
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Oral
low dose combination chemotherapy, such as PEP-C |
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Intent to
induce durable remission (first line for localized disease)
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localized
radiotherapy (stage I or stage II) |
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Intent to
induce durable remission (first or second line)
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Rituxan-based
Chemo (R = Rituxan) CHOP-R,
CVP-R, F-R, , FND-R |
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Rituxan-based
chemo, followed by extended dosing (maintenance) Rituxan |
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Radioimmunotherapy
(RIT) as single agent (study) |
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RIT
following combination chemotherapy (study) |
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Intent to
induce durable remission (second line and subsequent therapy)
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Autologous
stem cell rescue |
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Allogeneic
stem cell transplant |
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Radioimmunotherapy |
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Main source: NCCN Clinical Practice Guidelines in Oncology™
Non-Hodgkin's Lymphoma, 2008 http://www.nccn.org/professionals/physician_gls/PDF/nhl.
pdf (requires free registration)
Factors that my influence selection
of treatment
Factors that influence treatment timing
and type - when the goal is management:
Factors that influence treatment
selection - when the goal is a durable remission :
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The
disease - and treatment-specific data
from well-designed studies
that support the use of a treatment for your setting; |
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The treatment-related risks
compared to other treatments appropriate to this goal;
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Your age, general health, and
tolerance for risk; |
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Tumor burden and disease location; |
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You have a family member who is a
good match and is willing to donate stem cells; |
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Other
factors that
determine your eligibility for treatments |
Other factors that influence treatment
timing and type:
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The
disease - and treatment-specific data
from well-designed studies that support the use of a treatment for your setting; |
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Your physician's areas of expertise
and possible biases; |
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If your physician works with investigational
therapies; |
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What your insurance carrier will pay for; |
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The questions you ask, how well you
communicate your treatment goals and symptoms, and how informed you are about the disease
and the available treatments. |
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Other factors that
may determine your eligibility for treatments:
We recommend that you take an inventory
of these items (that describe your treatment setting) to help the
doctors you consult to more easily identify appropriate treatment
protocols.
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Diagnosis - lymphoma subtype (including phenotype
markers, such as CD20, CD19, etc.) |
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Treatment history - specific prior therapies or
treatment types - may be required, or may exclude you |
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Bone marrow involvement with lymphoma (greater
than 25% bilaterally for Bexxar/Zevalin) |
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Bone marrow (Hematopoietic) function - measured
by Hemoglobin, Lymphocytes, Platelets, Neutrophils |
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Co-morbidities - other conditions, such as heart
(cardiovascular) disease, HIV, Hepatitis B/C, and other infections |
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Kidney (Renal) function - measured by Creatinine |
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Liver (Hepatic) function - measured by
Bilirubin, AST and ALT |
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Lungs (Pulmonary) function - measured by a
variety of tests or observation |
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Neurological - such as history of seizures, CNS
involvement |
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Patient characteristics - age, gender, life
expectancy, pregnancy, etc. |
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Performance status - as measured by
performance
standards |
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Resources
-
The role of anthracyclines in combination chemotherapy for the
treatment of follicular lymphoma: retrospective study of the Intergruppo Italiano Linfomi on
761 cases. Leuk Lymphoma. 2003 Nov; 44(11): 1911-7. PMID: 14738142
| Related
articles
-
Grade 3 and anthracycline-containing [such as CHOP] treatments
Commentary from Experts PAL
Meet the Professors - a
provocative discussion among experts regarding first
treatment options for
advanced follicular lymphoma meettheprofessors.com
| PDF
-
Controversies in Follicular Lymphoma: "Who,
What, When, Where, and Why?"
Myron S. Czuczman
Hematology 2006:303-310. Abstract
| Full
Text | PDF
-
-
Follicular lymphoma:
chemotherapy and/or antibodies?
Michele Ghielmini Oncolog Institute of Southern
Switzerland www.bloodjournal.org
-
Rituximab as first-line and maintenance therapy for patients
with indolent non-hodgkin's lymphoma.
J Clin Oncol. 2002 Oct 15;20(20):4261-7. PMID:
12377971 | Related
articles
-
Leonard, John, MD * (Highly recommended)
Making Decisions about Treatment for NHL
LLS
PDF (8/9/05)
-
Approaches to treating non-Hodgkin's Lymphoma:
Dr Leonard nhlupdate
| Dr Coleman nhlupdate
| Dr Zelenetz nhlupdate
Dr. Cheson nhlupdate
| Dr Czuczman nhlupdate.com
| Dr Armitage nhlupdate.com
Audio files for patients: John Leonard, Mitchell Smith, Brad Kahl nhlupdate.com
-
High-Dose Therapy for Follicular Lymphoma Revisited: Not If, but
When? - Journal of Clinical Oncology, Vol 21, Issue 21 (November),
2003: 3894-3896 www.jco.org
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Background Information on Non-Hodgkin's Lymphoma, FDA PDF
| PDF-Help
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Cancer Treatment:
Determining the Best Long-Term Plan for You PDF
file - Maloney, Cha | PDF Help
-
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Current Therapies in the Treatment of Non-Hodgkin's
Lymphoma: Chemotherapy
Richard I. Fisher, MD - Medscape
(free login req.) - ** Comprehensive **
-
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Treatments of NHL (flowcharts) - MDACC PDF
| PDF-Help
-
-
Indolent, Stage I and Contiguous Stage II
Adult Non-Hodgkin’s Lymphoma ~ Best Practice Cancer.gov
Indolent, Recurrent
Adult Non-Hodgkin’s Lymphoma ~ Best Practice Cancer.gov
Indolent,
Noncontiguous Stage II/III/IV Adult Non-Hodgkin’s Lymphoma ~
Best Practice Cancer.gov
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Dr. John G. Gribben Institute of
Cancer, Barts and The London, Queen Mary School of Medicine, London,
United Kingdom
Indolent, Recurrent
Adult Non-Hodgkin’s Lymphoma ~ Best Practice Cancer.gov
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Dan L. Longo, MD, Scientific Director
National Institute on Aging Baltimore, Maryland
-
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R-CHOP
versus R-CVP in the treatment of follicular lymphoma: a
meta-analysis and critical appraisal of current literature pubmedcentral.nih.gov
*
Considerations for the younger patient with indolent lymphoma:
The goal of aggressive therapy is to get a durable response, and a possible cure.
It may be that the aggressive approach is more reasonable for the young
patient, especially if it's determined that you have high-risk
disease.
First, initial treatment provides the
best opportunity to succeed - there is less tumor burden, and your
health and the disease have not been affected adversely by prior
treatments. For example, cancer cells can adapt from multiple exposures
to single agent treatments, which can lead to more resistant disease
later on.
Second, younger persons can often rebound
better from the toxicities of strong treatment - and therefore may not be harmed as much
long term, even if the treatment fails to meet the goal. And if you
fail to realize a durable remission, you will have learned early that
you have high risk disease and can adapt the clinical plan accordingly.
Finally, if the treatment succeeds, you
may improve survival significantly - which is especially important to young patients who will reach survival expectations when still young. (Current
estimates for survival ranging from 7 to 18 years for follicular
lymphoma, depending in part on the age of the population.)
*
Considerations for the elderly or Infirm patient with indolent lymphoma:
Rituxan, and single agent chemotherapy
for management.
Radioimmunotherapy may be considered
instead of combination chemotherapy.
In conclusion, when first diagnosed with indolent
lymphoma ...
... we
suggest the
following:
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Try to objectively identify the risks of
the disease by tests and close observation
(How fast the lymphoma progresses or how well it responds to
initial management treatments).
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Become informed
about the disease and its treatments.
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Consult respected experts to discuss the risks and benefits of
all standard treatments,
and promising investigational options.
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Communicate your priorities and fears to your doctors.
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Honestly report
symptoms to your doctor.
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Consult with a specialist to determine the most appropriate goal of treatment - and the approach and timing that best
fit the
goal.
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Also ask about
the impact of the protocol under consideration on future treatment
options.
Conflict of Interest in Medical Decision-making?
Sometimes. But rarely is it unethical. See for
details: PAL
Why
should patients consult outside experts and become informed?
Even trained oncologists can have conflicts of interest, biases, or
gaps in knowledge - especially if he or she does not specialize in
lymphomas.
Investigators may have an intellectual bias about an investigational
therapy they are testing. A community doctor might have a bias
in favor of what is easiest to administer.
An HMO physician may prescribe what is least expensive. Another doctor
might be influenced, unconsciously or not, by sales promotions from
the drug industry.
Patients expressing their desire to continue working without
interruption may influence a busy physician to prescribe what meets
the immediate needs, without fully discussing possible negative
long-term implications of that treatment decision ...
Still another reason to seek a second opinion is that it sets up a
kind of peer review, which is likely to be an incentive for your local
community doctor to be more focused on your care and the decision
process. The good community doctor will encourage a second opinion by
experts, and will be willing to carry out the recommendations, when
possible ... or send you elsewhere when not.
We suggest
that
you avoid the following:
-
Start a treatment without
first consulting at least one lymphoma expert - unless symptoms or clear
dangers indicate a strong need to treat, and you are comfortable with
the rationale.
-
Base your
treatment decision on the outcomes
of other patients. Keep in mind that each lymphoma and patient can
be unique.
-
Believe conspiracy theories used to
promote unorthodox therapies. Consider that these theories require the
complicity of multiple scientists, doctors, and regulators - who also get cancer
and whose loved ones, spouses, parents, grandparents and children also
get cancer.
Strive to be objective: see Evaluating
Medical Claims and Data.
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Rank
Your Treatment Priorities
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Rank Your
Treatment Priorities
Using the items on the right,
create a list of your treatment priorities, most important first.
(The current order is random.)
When it's time to treat, this ranking list may
help you decide on the treatment that's best for you.
These priorities are primarily for indolent
(slow growing) lymphoma.
Return to top |
The treatment:
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is most likely to improve symptoms and get a
response
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offers a chance for a cure
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has the least risk of death
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has the least long term after effects -
secondary cancers,
arthritis, fatigue, mental confusion, immune suppression
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does not preclude the use of other promising
treatments in the future
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has the least short-term toxicity
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is easy to administer and is least disruptive to
normal life. |
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Big
Picture Questions
... when it's time to make a treatment decision
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Big
Picture Questions
Good questions to ask your doctor
when reviewing treatments
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When it comes time to make a
treatment decision, Dr. Maloney at the October 2002 Education Forum sponsored by LRF offered
the following rational guidelines.
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What is the goal of the treatment?
The goal of treatment could be the following: chance for a cure or long term disease-free
response, management with low toxicity, need to shrink a tumor that is causing problems
etc. (See Rank Your Priorities,
above.))
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What are the outcome data for the treatment?
Complete Response (CR) rate, Partial Response (PR) rate, duration of
Response, etc.
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What toxicity and/or risks are associated with the treatment?
(Long-term and short-term toxicity, mortality rate, etc.)
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How does the toxicity compare with other treatment options, that
may also be appropriate to the goal of treatment? |
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Can I still use standard treatments if this treatment doesn't
work?
Using specific chemotherapy agents might make it
difficult or impossible to harvest stem cells for a transplant, for
example.
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Does this treatment preclude the use of promising
investigational treatments in the future?
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First treatment as Assessment - A Boxing
Analogy
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Boxing,
watchful waiting, and first treatment - a lay perspective:
One way to look at watchful waiting is as an
assessment period. Like what prize fighters do in the early rounds as they
circle one another. That is, it's a time to size up the opponent to
determine how to proceed. Is my opponent fast or slow? Do I need to take a
chance early, or is he so docile that I need not take any risks at all?
Similarly, the response to first treatment, like a probing jab, is also
part of the assessment. It provides clues about how to proceed. Is my
opponent strong or weak, susceptible to damage, or is he hard as
nails?
(But be aware that lack of sensitivity to Rituxan does not predict
sensitivity to chemotherapy, and probably vice versa, because they these
agents have completely different mechanisms of action. So a single agent
chemotherapy might be tried after a round of Rituxan, for example, as part
of assessment and hopefully it will be a successful action as well.)
If both types of probing treatments fail to provide a significant benefit,
it may be time to plan for tougher later rounds, such as by harvesting
stem cells when the circumstance allows. It may also be to time to
consider taking risks in order to try to eliminate, instead of manage,
your opponent.
As always, timing's important - that is, when to expend your limited
resources. You may want to wait for signs that your opponent is weak, or
induce weakness by sequencing your offensive efforts with different
combinations.
But you also need to rest and recover in order to prepare for later
rounds. So watchful waiting can be a time to take proactive action to build
and improve your general health and performance.
Finally, when you are young and in good health it might be reasonable to
start aggressively because being young and fit you may be better able
to recover for the later rounds if needed. In general starting
aggressively, early, can be the best opportunity to win the fight
outright, or improve your chances in the later rounds if you achieve
a durable remission. But this does not mean that you execute the plan
before the opponent makes the first move ... is clearly on the offensive.
~ KarlS |
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