Part of coming to terms with the diagnosis of a
lymphoma (or any cancer) is the challenge of understanding the
language of our doctors as it relates to our medical choices and even
what is covered by insurance and why.
A treatment protocol refers to an medical
intervention: the use of of one or more drugs or medical procedures,
such as combination chemotherapy, with anti-nausea
medications. A treatment protocol describes also the
schedule of therapies and doses, along with contingency plans - such
as actions to take if unusual side effects occur, such the use of
growth factors to address excessive neutropenia (low levels of
infection fighting cells).
A standard protocol is
that which has been clinically tested (in human subjects) and found
to provide clinical benefit as a treatment for a medical
condition. For some indications there are competing standards
of care - uncertainty about which is superior; for others there is a
clear gold standard of care, and use of another protocols
would be controversial, or perhaps unethical, outside of a clinical
BEST PRACTICE (Standard of Care): NCCN.org
PDF (login req.) | NCI Cancer.gov
Clinical benefit has a special meaning: it is what is proven to improve survival or quality of life, relative to the disease untreated or treated differently.
Note: Other measures of effectiveness used in trials (such as
Progression Free Survival) are surrogates that may predict clinical benefit, or may
not - depending on the magnitude of that measure (years
versus months) and if long-lasting side effects might offset that
short-term improvement latter on. For this reason, overall
survival is the most reliable measure of clinical benefit,
even if it can be challenging to measure for medical conditions
that have a very long clinical course - and numerous opportunities
to use other therapies.
On-label protocols: The drug
product label is a legal document that specifies the indications
and uses for which an agent or protocol has been approved by FDA for
marketing availability. However, once approved for one
medical indication, doctors may expand its use for related
conditions if it's scientifically plausible and/or validated by
smaller non-definitive published clinical studies.
Examples of full prescribing
information (the label): Rituxan
Off-label use of a
drug refers to use of an approved drug for which insufficient
testing has been done in a different disease or disease setting,
which can range from reasonable to reckless. For example,
prescribing Cytoxan for a headache would be reckless off-label use,
but maybe not reckless for an autoimmune condition. (based on
scientific plausibility but also smaller non-definitive published
Example: Maintenance Rituxan
after first line Rituxan-based chemotherapy would be off-label us
for follicular lymphoma, because clinical benefit has not been
established for that use of Rituxan.
Note: An important distinction
between off-label use of a drug and use of herbs or even
investigational agents is that the former has been tested in human
subjects and approved for a related condition, and therefore its
risks and the active dose has been well-characterized. However,
when off-label use becomes common, we should require the sponsor
to conduct clinical trials for the new indication, because
off-label use does not help us to understand risks and benefits
specific to the new indication - because the effects and outcomes
are not adequately captured in normal clinical practice.
are similar to off-label use of a drug. It allows doctors to
mix and match agents, or dosing, or scheduling in order to meet the unique
needs of the patient, such as any secondary conditions, and prior
treatments. Such protocols may latter become standard
protocols if studied in a controlled way and proven to provide
Off-Protocol Therapies (OPT) are protocols that the physician selects or modifies based on "conditions on the ground". It could be a mix and match of agents (standard, off-label, and sometimes investigational) , chosen to meet the unique clinical circumstances of the patient and treatment history.
are interventions that are being tested in human subjects for
numerous purposes, such as
(1) to identify the dose at which a new agent is
active and safe to administer.
(2) to test off-protocol therapies against the
standard of care in order to make progress - identify better or
safer protocols that provide clinical benefit.
(3) to expand the label so that an approved drug
or protocol can be used for a new or related indication, such as
radioimmunotherapy as pretreatment, prior to a stem cell
transplant, or use of regularly scheduled Rituxan after standard
Rituxan-based chemotherapy in first-treated follicular
Regarding study phases:
Phase 1: dose finding study - identify the
therapeutic window and maximum tolerated dose.
Phase II: refine the dose and capture signals of
toxicity and safety
Phase III: test the protocol against the standard
of care, or in a patient population refractory to the standard of
care, which can be an accelerated path to approval.
Expanded access to
A physician might file for permission of the drug
sponsor to provide access to an investigational agent when the
patient is ineligible for a clinical trial. See Expanded
Access for details.
are interventions administered for a fee based on theory without
having been tested or sufficiently tested. Such practices are
unethical and lack scientific integrity unless conducted in a
clinical trial ... which would change the classification to Investigational
(see above). See also CAM for more
therapy - use of multiple
agents with different mechanisms of action
Example: CVP-R (Cytoxan, Vincristine, Prednisone, and Rituxan)
therapy (sequential therapy) - a second treatment of a different
type, following induction therapy
Example: CVP chemotherapy, followed by a short rests,
followed by Radioimmunotherapy
therapy - giving additional therapy of the same type.
Example: Rituxan x 4 (standard protocols) followed by
Rituxan x 4 (extended therapy)
therapy - treatment that is given first to reduce tumor
burden, prior to maintenance, or consolidation
Example: CHOP-R (induction therapy), followed by maintenance
Rituxan or consolidation with radioimmunotherapy or
stem cell transplantation.
therapy - regularly scheduled therapy of lower toxic
agents given with intent to maintain a response to induction
Example: Rituxan x 4 every six months following CVP-R induction
therapy (low dose chemo) - lower doses of treatment
agents given on a continuous or daily basis.
Example: PEP-C protocol
- oral agents administered in combination on a
daily basis may theoretically maintain continuous serum drug levels sufficient to override
at least one mechanism of drug resistance.
- use of a single agent as treatment.
Example: Rituxan x 4 is single agent rituxan given four times.
therapy is given to prevent a complication of treatment
that is common for a given circumstance.
Example: Antibiotic therapy to prevent infection. Or,
Intrathecal therapy - the administered of treatment agents into
fluid bathing the spinal
cord and brain.
to prevent lymphoma from advancing into the central nervous
- to monitor the patient while in remission without treating it.
Example: In a patients who has received treatment for
lymphoma and achieved a remission, regularly scheduled monitoring
for relapse is often recommended instead of maintenance or consolidation
- treat as needed with lower-toxic protocols
to Cure (combination or sequential therapy, given
to achieve a durable remission.
- treatment with intent to relieve symptoms.
Example: Steroid therapy to reduce pain and inflammation, and
regress lymph nodes.
and wait (expectant management) - to monitor
the patient with indolent lymphoma, instead of treating.
Example: In a patient diagnosed with indolent lymphoma with
no symptoms, regularly scheduled monitoring of the condition is
often recommended instead of treatment.