Responses, and Survival Terms
Disease | Tumor Burden | Stable
Disease | Progressing Disease |
Treatment Outcomes and Response:
Partial Response | Complete
Response | Molecular Response |
There can be more than one definition for each term - depending on
who you ask.
Remission is the absence of disease activity in patients with a chronic illness.
Complete remission is the
absence of active disease 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).
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.
detectable amount of disease might be described as:
Systemic (widespread) disease:
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
You might think of lymphocytes
(blood cells) as fish, able to swim freely throughout the body.
Other cancer types are more like trees, which belong to specific areas
(normally rooted in place), such as liver, or prostate
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.
residual disease is difficult to detect:
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
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
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)."
Why treatment is sometimes continued
when no disease is detected?
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
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
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.
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
Note: some immunotherapies may cause lymph nodes
to increase in size temporarily.
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
MR imaging of the body: generally the
neck, chest, abdomen, and pelvis - but CT and MRI cannot
distinguish between active and necrotic (dead) lesions.
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
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.
PCR: a sensitive test that
measures very small amounts of a translocation of a gene that is
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
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
response is when at least a 50% reduction in
measurable tumor burden is measured - compared to tumors measured by a
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.
The clinical value of a PR seems to depend on the
behavior of the lymphoma. If it is low-risk,
indolently-behaving, lymphoma a PR has more value than otherwise.
Also, when interpreting the scans it can be
important to know if it is CT or PET-based. The latter seems a
more reliable determinant of PR ... Sometimes residual lesions that
show up on CT are not metabolically viable (like scar tissue) and
The purpose of detailed criteria for PR, as defined
in the Cheson criteria, is to make it easier to compare results across
different clinical trials:
Partial Response (PR)
A partial response requires the following:
> 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.
No increase in the size of the other nodes, liver, or spleen
Splenic and hepatic nodules must regress by at least 50% in the
With the exception of splenic and hepatic nodules, involvement of other organs is considered assessable and not measurable disease.
No new sites of disease
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.
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 Deydrogenase (LDH)]
definitively assignable to NHL
All lymph nodes and nodal masses must have regressed to normal size.
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).
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.
Bone marrow, if positive at baseline, must be histologically negative for lymphoma.
Complete Response, unconfirmed (CRu)
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
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
Residual lymphoid masses after treatment?
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.
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
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
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.
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
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.
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.
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.
Therefore, we may soon be determining complete remission
molecularly in all patients with NHL."
Role of the molecular staging and response in the management
of follicular lymphoma patients. Leuk Lymphoma. 2006
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.
The significance of circulating cells carrying t(14;18) in
long remission from follicular lymphoma. J Clin Oncol. 1991
The clinical significance of molecular response in indolent
follicular lymphomas. Blood. 1998 Apr 15;91(8):2955-60. PMID:
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:
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:
(used in clinical trials)
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Criteria of Complete Response (CR)
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
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).
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.
Bone marrow, if positive at baseline, must be histologically negative for lymphoma.
Complete Response, unconfirmed (CRu)
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
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
Limitations of Imaging and other end points in study
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"Not everything that counts can be counted;
not everything that can be counted,
counts." ~ A. Einstein
Residual lymphoid masses after treatment?
residual mass persisting on CT after treatment poses a common clinical dilemma: it may indicate the presence of viable lymphoma, which requires further treatment, or it can be benign, consisting of only
fibrotic and necrotic tissues." PMID:
For this reason PET or Gallium scans may be used after treatment to help differentiate active disease from scar tissue.
NOTE: Lymphoid tumors are made up of the accumulated abnormal
lymphocytes but also supportive tissue of different cell types:
“epithelial cells and also there is supporting tissue, called connective
tissue which is there to support the epithelial cells”. These
cells are sometimes referred to in shorthand as tumor “stromal”
Our understanding is that the macrophages (immune cells) will eventually
"gobble up" this necrotic material after successful therapy, which
explains why the treated “tumor” continues to shrink well after therapy
NOTE: The delayed shrinking of lymphoid tumor can lead to
questionable conclusions of the causal effect of subsequent therapy
– standard, investigational, and alternative, because the tumor in
some cases would have resolved with more time.
PET scans are used to help distinguish between necrotic and viable tumor
following treatment, but this test is not perfect … can produce false
positives due to inflammation.
Biomarkers for response?
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 study is a type of study that says what it's trying to demonstrate as true in advance. Like calling your shot in
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
||Progression free survival (PFS) -
measures time to progression, relapse, and to death from any
and Evaluation of Response
Some commonly used abbreviations
Complete Response Unconfirmed
Disease Free Survival
Event Free Survival
No evidence of disease
Overall (Actuarial) Survival at a fixed time
Molecular (by PCR) remission
p-value (less than .05 is considered significant)
Progress free survival
Time to Progression
Confidence Interval provided as a % range
Watchful Waiting; observation; treat expectantly
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.
Survival or Overall Survival (OS): A measures of the
number of patient who are still alive following treatment in a fixed
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
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
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
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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