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Treatment >  Treatment Protocols by Type - and related terms

Last update: 03/30/2010

What's Clinical Benefit?
Types: StandardOn-Label | Off-label | Off-Protocol Therapy  | Investigational
Expanded Access
Alternative? | Treatment Terminology


See also Understanding Cancer Treatments

Overview and Basic Terms

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 trial.

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 | TreandaZevalin 

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 studies).   

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.

Off-protocol therapies 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 clinical benefit. 

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.

Investigational protocols 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 lymphoma. 

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 investigational drugs

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.

Alternative protocols 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 detail.

Treatment Terms


Combination therapy - use of multiple agents with different mechanisms of action 

Example: CVP-R (Cytoxan, Vincristine, Prednisone, and Rituxan)


Consolidation therapy (sequential therapy) - a second treatment of a different type, following induction therapy

Example:  CVP chemotherapy, followed by a short rests, followed by Radioimmunotherapy


Extended therapy - giving additional therapy of the same type.

Example:  Rituxan x 4 (standard protocols) followed by Rituxan x 4 (extended therapy)


Induction therapy - treatment that is given first to reduce tumor burden, prior to maintenance, or consolidation treatment.

Example: CHOP-R  (induction therapy), followed by maintenance Rituxan or consolidation with radioimmunotherapy or stem cell transplantation.


Maintenance therapy - regularly scheduled therapy of lower toxic agents given with intent to maintain a response to induction therapy. 

Example: Rituxan x 4 every six months following CVP-R induction therapy.


Metronomic 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. 


Monotherapy - use of a single agent as treatment.

Example: Rituxan x 4 is single agent rituxan given four times.


Prophylactic 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 the cerebrospinal fluid bathing the spinal cord and brain. to prevent lymphoma from advancing into the central nervous system.  


Surveillance - 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 treatment.


Treatment goals: 

Management - treat as needed with lower-toxic protocols


Intent to Cure (combination or sequential therapy, given to achieve a durable remission.


Palliative (supportive) care - treatment with intent to relieve symptoms.

Example: Steroid therapy to reduce pain and inflammation, and regress lymph nodes.


Watch 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.

Stem cell transplant treatment phases:

Induction phase - conventional doses of chemo are used to reduce tumor burden.


Mobilization/harvesting phase - use of growth factors or other treatments that leads to the proliferation and mobilization of stem cells from the bone marrow into the bloodstream. These cells are then harvested using a process called apheresis in order to replace the stem cells that will be ablated (killed) during the conditioning phase of treatment.  

What is apheresis? medlib.med.utah.edu
"The process of apheresis involves removal of whole blood from a patient or donor. Within an instrument that is essentially designed as a centrifuge, the components of whole blood are separated. One of the separated portions is then withdrawn and the remaining components are retransfused into the patient or donor."


Conditioning phase - high-dose therapy that wipes out or "conditions" the immune system and bone marrow in preparation for the stem cells harvested previously.  This phase might include Total Body Irradiation (TBI), and more recently, high dose bexxar - an investigational alternative to TBI.


Engraftment phase - the stem cells are given back to the patient to reconstitute the immune system. Sometimes purging techniques are used to clean the stem cells of residual tumor cells prior to engraftment, or shortly after.

See also Understanding Cancer Treatments



Disclaimer:  The information on Lymphomation.org is not intended to be a substitute for 
professional medical advice or to replace your relationship with a physician.
For all medical concerns,  you should always consult your doctor. 
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