Treatments or About
Lymphoma > Remissions,
Responses, and Survival Terms
Last update: 04/25/2008
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Disease state:
Remission | Systemic
Disease | Tumor Burden | Stable
Disease | Progressing Disease | Tumor
Burden |
Treatment Outcomes and Response:
Partial Response | Complete
Response | Molecular Response | Survival
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Clinical Remission
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Remission is the state of
absence of disease activity in patients with a chronic illness.
Complete remission is the
absence of disease active with no evidence of disease as indicated by
imaging, such as CT and PET, and sometimes by bone marrow biopsy. Molecular remission is
a complete remission with no evidence of disease in the blood cells and/or bone marrow
using sensitive PCR tests (this test is most commonly used in clinical
trials). See details below
Terms that are commonly used to
describe the activity or state of the disease include:
stable, regressing, active,
progressing and remission (stable or regressing disease). Labs
and imaging tests are used
to estimate the disease state and activity, each test has
strengths and weaknesses. No test (except a biopsy) can be used
to definitively diagnose a lymphoma. For example, an
enlarged lymph node could be from benign causes (such as infection),
or as a result of accumulating lymphoma cells - or residual scar
tissue following treatment. The normal size of most lymph
nodes is about 1 cm. |
Systemic Disease
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The
detectable amount of disease might be described as:
Systemic (widespread) disease:
Lymphoma
cells (abnormal lymphocytes) can be found in
lymph nodes, lymph vessels, blood, spleen, bone marrow - virtually
anywhere a normal lymphocyte can go to fight infection. Thus,
lymphoma is considered a systemic disease even if found
predominately in lymph nodes. Lymphoma is sometimes found outside the
lymphatic system in skin, breast, liver and so on - so-called extranodal
disease.
Sometimes patients are diagnosed early with localized disease
in one or two sites (stage I or stage
II). Localized disease is often
treated with localized radiotherapy with
intent to cure. Minimal or
residual disease is difficult to detect: Lymphoma cells
are so small that imaging tests cannot detect minimal disease.
The most sensitive test for residual disease (lymphoma cells that may
have survived treatment is PCR (see below.), however, testing negative
for PCR in the blood or marrow does not mean residual disease does not
exist in lymph nodes or other areas.
Lymphoma cells are hard to
see: Lymphocytes are small cells, 7-9 µm
in diameter in blood smears, and are the second most common white
blood cell type, comprising about 30 % of the leukocyte population in
peripheral blood....
Lymphocytes travel in the blood, but they routinely leave capillaries
and wander through connective tissue. Therefore, lymphocytes may
be normally encountered at any time in any location. They even enter
epithelial tissue, crawling between the epithelial cells. They reenter
circulation via lymphatic system channels (hence their name)."
www.siumed.edu
Why treatment is sometimes continued
when no disease is detected? Ultimately,
the duration of the response to treatment is the best
measure of how successful treatment has been. Duration of
response is how long you have no clinical signs of
disease.
So the full course of treatment is many times given even after there's no sign of
disease with imaging with the goal of eliminating as many abnormal cells as possible (the assumed small amounts of
residual disease) so that the duration of the response will be as long as possible ... and (dare we say it) so you have a better potential to cure the disease,
which is the complete eradication of the disease. That cure is possible
even for indolent follicular NHL is suggested but not proven by the increasing number of patients with no detectable disease 4 to 12 years after treatment - thanks to Rituxan-based chemo protocols and
Radioimmunotherapy.
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Stable Disease
(remission)
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A
patient is considered to have stable or regressing disease when they
do not experience symptoms and when lymph nodes or other lesions not
growing or are regressing in size.
Sometimes clinically observed inactivity of the disease is
described as a remission.
Sometimes lymphomas can regress spontaneously
without treatment, and is described as a spontaneous remission.
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Progressing or
Active Disease
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A
patient is considered to have progressing disease when they
experience symptoms (fever, night sweats, etc.) and when lymph nodes
increase in size or new enlarged lymph nodes are observed.
Increases in lymph nodes can have other explanations, such as
inflammation resulting from infection.
Inflamed nodes are sometimes called reactive nodes or swollen
glands.
Note: some immunotherapies may cause lymph nodes
to increase in size temporarily.
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Tumor burden
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Tumor
burden as an estimate of the amount of disease that may exist in lymph nodes or in other areas. It's often described as
minimal, low, or high ... the term
is a kind of short-hand way for doctors to describe the clinical
status of the patient
Normal lymph nodes may be between 1 and 2 cm in size. In lymph nodes accumulating lymphoma cells
can increase the size of lymph nodes beyond normal size, but enlarged lymph nodes can also result from benign causes, such as infection.
Tumors (clusters of abnormal lymphocytes) can also exist in extranodal areas (skin, spleen, ...) and may be called
lesions.
 | CT and
MR imaging of the body: generally the
neck, chest, abdomen, and pelvis - but CT and MRI cannot
distinguish between active and necrotic (dead) lesions. PET
scans, can distinguish between active and necrotic lesions,
but it does not accurately describe the margins or size of the abnormally
sized lymph nodes or lesions (tumors that may exist in extranodal
sites).. |
| Bone marrow
biopsy: a sample of marrow extracted from the pelvis bone.
Note: Only a positive finding is conclusive, because a
relatively small small sample is taken from the marrow, which by
chance might not contain abnormal cells.
Bone marrow involvement
is common in lymphoma and can
be reversed by treatment.
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| PCR: a sensitive test that
measures very small amounts of a translocation of a gene that is
commonly expressed
by lymphoma cells.
BCL-2 is a protein that is produced as a result of a
translocation of a gene that is common in lymphomas. PCR
testing can be used to detect very small amounts of this protein
in the blood or bone marrow. When this test is is negative
(a good result), it means that there may be no abnormal cells in
the blood or marrow. This condition - BCL-2 negative - is
associated with longer duration of response to treatment in some
studies, and is sometimes called a molecular
remission. |
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Bulky disease is a condition in which the amount of
tumor burden is considered high and that it might influence the
ability to benefit optimally from treatment.
A node measuring 7 to 10 cm might be considered bulky,
but there's no absolute
measure of bulky disease, and patient with this description of
tumor burden can also respond very well to treatment. |
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Partial
Response (PR)
to Treatment
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Partial
response is when at least a 50% reduction in
measurable tumor burden is measured. As the name suggests, some
residual disease is observed in a partial response. You may be
considered in remission after a partial response if your
disease is not active at this point and symptoms disappear that
prompted the need for treatment -- that is you have stable disease.
Cheson criteria:
Partial Response (PR)
A partial response requires the following:
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> 50% decrease in SPD of the six largest dominant nodes or nodal masses. These nodes or masses should be selected according to the following features: (a) they should be clearly measurable in at least two perpendicular dimensions, (b) they should be from as disparate regions of the body as possible, and (c) they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved. |
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No increase in the size of the other nodes, liver, or spleen |
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Splenic and hepatic nodules must regress by at least 50% in the
SPD. |
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With the exception of splenic and hepatic nodules, involvement of other organs is considered assessable and not measurable disease. |
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No new sites of disease |
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Complete
Response
(CR) to Treatment
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A
Complete Response to
treatment is when lesions are not detected
by CT imaging and other tests. If CT imaging and a bone marrow test show no evidence
of disease, it is a more rigorously defined a complete response.
Sometimes in general practice (not in a clinical trial) a CR is
declared based on CT imaging results alone, even when no bone marrow
test is performed.
Cheson criteria:.
Complete Response (CR)
A complete response requires the following:
Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities [e.g., lactate dehydrogenase (LDH)]
definitively assignable to NHL
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All lymph nodes and nodal masses must have regressed to normal size (:51.5 cm in their greatest transverse diameter for nodes ;:::1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before treatment must have decreased to < 1 cm in their greatest transverse diameter after treatment, or by more than 75% in the
sum of the products of the greatest diameters (SPD).
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The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and must not be palpable on physical examination. Similarly, other organs considered to be enlarged before therapy due to involvement by lymphoma, such as liver and kidneys, must have decreased in size.
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Bone marrow, if positive at baseline, must be histologically negative for lymphoma.
Complete Response, unconfirmed (CRu)
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CRu includes those patients who fulfill criteria 1 and 3 above, but with one or more of the following features:
* A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by more than 75% in the SPD.
Individual nodes that were previously confluent must have regressed by more than 75% in their SPD compared with the size of the original mass.
* Indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural
atypical).
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Molecular
Remission
(MR)
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TOPIC SEARCH: PubMed
BCL-2 is a pro-survival protein that is produced as a result of a
translocation of a gene - (t(14:18) - that is common in b-cell lymphomas.
PCR testing
can be used to detect very small amounts of this gene in the blood
or bone marrow.
When the PCR test is negative (a good result),
it means that there may be no abnormal cells in
the blood or marrow, which might be described as a molecular remission
In summary, a molecular remission is when clearance of
t(14:18) - positive cells from blood and/or bone marrow is determined by
sensitive PCR tests.
The clinical significance of an molecular remission is still not clear, but achieving this kind or response has been associated
with longer duration of response among the participants in some
studies.
PCR tests are generally given after a complete
response to treatment has been determined using CT and bone marrow, mainly in clinical trials.
A limitation of the test is that
it can only show the status of the compartment tested: the blood or marrow.
A conversion to negative appears to be a good prognostic indicator, but not
definitively, because the test can't determine the t:14:18 status in nodal or
other areas.
When bcl-2 / t:14:18 shows positive in the blood after chemo and then converts to negative after vaccine suggests to me that the vaccine is active
... but not necessarily resulting in clinical benefit, because it's probably
easier for the immune system to "delete" tumors that are circulating in the
blood. But I think it reinforces the concept that using vaccine in patients
with minimal residual disease is a plausible idea.
| Minimal disease detection has been markedly
improved through the use of sensitive molecular techniques,
specifically PCR. This technique facilitates the detection of over
80% of B-cell NHL with t(14;18) and 40% of those with t(11;14) and
is capable of reproducibly detecting one tumor cell with a bcl-2
rearrangement in 106 normal cells.
166,
205,
249
Gribben and colleagues demonstrated that following treatment of
advanced stage bcl-2–positive NHL with combination chemotherapy,
approximately 50% of patients' bone marrows became histologically
normal.
166
However, all marrows remained positive for a bcl-2 rearrangement
as assessed by PCR demonstrating that a molecular complete
remission had not been achieved. Following aggressive therapy with
high-dose ablative therapy and autologous bone marrow
transplantation, those patients who consistently lack a bcl-2
translocation in the bone marrow and the peripheral blood, have a
highly significantly better disease-free survival than patients
with PCR-detectable disease.
207,
208
In contrast to these studies with high-dose ablative therapy, it
is controversial as to whether the presence of t(14;18)+
detectable cells in the peripheral blood and marrow of patients
with stage III/IV disease following conventional therapy
correlates with the outcome.
210,
250
This approach, until recently, would only apply to patients with
amplifiable break points. However, the generation primers specific
for the Ig heavy-chain gene DNA sequence of CDRIII regions through
the use of consensus VH and JH primers permits the detection of
lymphoma cells by PCR in about 70% of cases where a known
amplifiable translocation cannot be detected.
251
Therefore, we may soon be determining complete remission
molecularly in all patients with NHL."
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| Role of the molecular staging and response in the management
of follicular lymphoma patients. Leuk Lymphoma. 2006
Jun;47(6):1018-22. PMID:
16840191
This analysis shows that bcl-2 rearrangement in blood and bone
marrow is frequently detected at staging, even in stage I disease.
Absence of the bcl-2 rearrangement is related to a better EFS
[Event Free Survival] and the achievement of a molecular response
in peripheral blood after therapy is associated with a better EFS.
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The significance of circulating cells carrying t(14;18) in
long remission from follicular lymphoma. J Clin Oncol. 1991
Sep;9(9):1527-32. PMID:
1875216
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The clinical significance of molecular response in indolent
follicular lymphomas. Blood. 1998 Apr 15;91(8):2955-60. PMID:
9531606 PubMed
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Prolonged clinical and molecular remission in patients with
low-grade or follicular non-Hodgkin's lymphoma treated with
rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol.
2004 Dec 1;22(23):4711-6. Epub 2004 Oct 13. Erratum in: J Clin
Oncol. 2005 Jan 1;23(1):248. PMID:
15483015
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Rituximab as first-line monotherapy in low-grade follicular
lymphoma with a low tumor burden. Anticancer Drugs. 2001 Jun;12
Suppl 2:S11-4. Review. PMID:
11508931
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Cheson
Criteria
(used in clinical trials) |
Cheson
Criteria of Complete Response (CR)
A complete response requires the following:
Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities [e.g., lactate dehydrogenase (LDH)]
definitively assignable to NHL
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All lymph nodes and nodal masses must have regressed to normal size (:51.5 cm in their greatest transverse diameter for nodes ;:::1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before treatment must have decreased to < 1 cm in their greatest transverse diameter after treatment, or by more than 75% in the
sum of the products of the greatest diameters (SPD).
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The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and must not be palpable on physical examination. Similarly, other organs considered to be enlarged before therapy due to involvement by lymphoma, such as liver and kidneys, must have decreased in size.
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Bone marrow, if positive at baseline, must be histologically negative for lymphoma.
Complete Response, unconfirmed (CRu)
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CRu includes those patients who fulfill criteria 1 and 3 above, but with one or more of the following features:
• A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by more than 75% in the SPD. Individual nodes that were previously confluent must have regressed by more than 75% in their SPD compared with the size of the original mass.
• Indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural
atypia).
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Stable Disease (SD)
Stable disease is defined as disease that is measurable but not active
or progressing (less than a PR as described above) but not progressive disease (see below).
Progressive Disease (PD)
50% increase from nadir (lowest point) in the SPD of any previously identified abnormal node.
Appearance of any new lesion during or at the end of therapy
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher Rl, Connors JM, et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. J Clin Onco11999; 17:1244-53
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Limitations of Imaging and other end points in study
design
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"Not everything that counts can be counted; not everything that can be counted,
counts." ~ A. Einstein
It' widely accepted that what's needed is a reliable biomarker that unambiguously shows the status of the disease. It might be a composite biomarker, for example, such as multiple factors in the blood. The importance of reliable, objective, and measurable indications of outcomes (endpoints) is that it helps reduce study bias - methods in studies that lead to false conclusions. For a new biomarker to be used in this way it would have to be validated in
prospective* studies.
*Prospective study is a type of study that says what it's trying to demonstrate as true in advance. Like calling your shot in
billiards.
An improvement in Survival is considered the ultimate composite endpoint. It's an
unambiguous measure of clinical benefit. The problem is that it takes a great deal of time to prove a survival benefit* for indolent or chronic disease. So surrogate endpoints are needed that may *reasonably* predict that a therapy provides clinical benefit - a survival advantage, or improvement in symptoms that does not negatively impact on survival.
(* Regarding Survival benefit: Studies can only reliably compare outcomes for groups. For example: You
randomly assign people to different groups to avoid patient selection bias. You try to objectively measure outcomes. You compare the median (average) survival (or
a surrogate marker) of group A with group B to see which did better. . .... But no study can prove a
survival benefit in individual cases.)
Response, and response duration can mislead as endpoints for clinical benefit, because you also have to factor in the toxicities that were realized to achieve the response. How these exposures may limit future options,
for example ... So endpoints selected in many trials are considered surrogates that may suggest that an intervention provides clinical benefit, such as:
Reponse Rate (RR), Complete Response Rate (CRR), Time to Progress
(TTP), Time to Treatment Failure (TTF), Time to Next Treatment (TNT), Disease Free Survival
(DFS), and Freedom from Treatment Failure (FFTF):.
"Freedom from treatment failure (FFTF)
was defined as the time from random assignment to the occurrence of
one of the following events: death as a result of any cause,
progressive disease, no CR at the end of protocol treatment, relapse,
or nonstudy treatment. HL-specific FFTF was defined as the time from
random assignment to the occurrence of HL-specific events including
progressive disease, no CR after primary treatment, nonstudy
treatment, relapse, or death as a result of HL. Death caused by acute
toxicity was not calculated as an HL-specific event." www.jco.org/cgi/content/full/23/22/5052
Other outcome measures:
| Time to Next Treatment and Time to Next
Chemotherapy Treatment.
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| Progression free survival (PFS) -
measures time to progression, relapse, and to death from any
cause. |
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Survival
and Evaluation of Response
Some commonly used abbreviations
CR
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Complete Response
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CRu
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Complete Response Unconfirmed
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DFS
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Disease Free Survival
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EFS
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Event Free Survival
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NED
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No evidence of disease
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OS
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Overall (Actuarial) Survival at a fixed time
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MR
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Molecular (by PCR) remission
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p=
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p-value (less than .05 is considered significant)
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PFS
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Progress free survival
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PR
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Partial response
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TTP
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Time to Progression
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CI
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Confidence Interval provided as a % range
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w&w
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Watchful Waiting; observation; treat expectantly
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Endpoints,
such as Time to Progression and Overall Survival help to measure and
compare clinical outcomes for different treatments in clinical
trials. Here are some common endpoints that you may read about
when reviewing papers and abstracts on the results of clinical trials
for treatments of lymphoma.
Actuarial
Survival or Overall Survival (OS): A measures of the
number of patient who are still alive following treatment in a fixed
time interval.
Event free survival (EFS):
A measure of the number of patients who are still alive and have not
had a relapse (the event) following treatment in a fixed time
interval.
These terms are often used to evaluate and compare
responses to therapies (outcomes) in clinical studies. They do not
measure or predict individual outcomes, but are used to show how
effective the treatment was for a given group of patients in a
specific time interval.
For example: After 84 month the actuarial
survival rate was 93.1% and event-free survival rate was 87.3% for a
given therapy.
Time to Progression (TTP) is a measure used to estimate the response to
treatment, generally in a clinical trial setting. As such it is
often called an endpoint. It goes something like this:
You get a baseline scan, usually CT, before
treatment to measure tumor burden. A second CT after treatment measures the response, generally
as a % of decrease in tumor burden (50% or greater being a Partial Response, and a CR indicating a Complete Response.)
From that point the time interval between the response to treatment and the time the disease starts to show evidence of growing (or recurring if a CR), is Time To Progression. Of course how often CTs are taken can affect this measure greatly, so TTP can only be an
estimate.
Progression free survival (PFS) measures time to progression, relapse, and to death from any
cause. The rationale for including "death from any
cause" - even if not apparently related to the disease or
treatment - is that it's not always possible to know what's related;
and accidental or unrelated causes will balance out when comparing
groups treated with different protocols.
Disease Free Interval is similar to
Time To Progression, but it differs in that it only relates to complete responses (CRs), because
"free" indicates no disease measurable. So only a person who has had a CR can be among those measured for disease free
interval; for partial responders this term does not apply. |
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