About Lymphoma > Remissions, Responses, and Survival Terms

Last update: 09/05/2016
 

Disease state:
Remission | Systemic Disease | Tumor Burden | Stable Disease | Progressing Disease | Tumor Burden
  
Treatment Outcomes and Response: 
Partial Response | Complete Response | Molecular Response | Survival endpoints

Clinical
Remission

  Return to top

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.  A remission can be complete or partial as described below.  

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

Cure is the eradication of all the bad cells.   There is no test at this time (2014) that can prove that cure was achieved with therapy - that the remission will endure and the lymphoma will never return.   The feasibility of curing lymphoma depends on the type of lymphoma and sometimes the stage.  Hodgkins lymphoma, for example, has a high cure rate (about 80 to 90%) with standard therapy.  Indolent lymphomas may be cured when caught early (localized stage) but cure is uncommon when diagnosed at an advanced stage - perhaps only 10 to 20% by some estimates as of this writing.

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

The detectable amount of disease might be described as:
    

	no evidence of disease (NED)
	residual, minimal
	measurable
	localized
	low tumor burden
	high tumor burden
	widespread (stage IV)
	bulky ....

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. 

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 cells.   

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. 

Cure is the usual goal of therapy for aggressive lymphoma.  That cure is possible for indolent follicular NHL is suggested by the increasing number of patients with no detectable disease 4 to 12 years after treatment - attributed to Rituxan-based chemo protocols and Radioimmunotherapy. However, it's important to note that it's common for indolent lymphoma to recur after treatment - sometimes many years later.

Stable Disease
(remission)

Return to top

Sometimes lymphomas can regress spontaneously without treatment, and is described as a spontaneous remission. 
 

Also see: Spontaneous Regression  Lymphomation.org

Progressing or 
Active Disease

Return to top

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.
 

Also see: Symptoms  Lymphomation.org

Tumor burden

Return to top

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.
	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.
	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.

Partial Response (PR)

to treatment

Return to top

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 resolve later.

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:

Cheson criteria:

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 SPD.
	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
(CR)

Return to top

Cheson criteria: 

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

1. 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).

2. 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.

3. 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 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).

Residual lymphoid masses after treatment?  See below

 

Molecular
Remission
(MR)

or

Minimal Residual Disease Negative

Return to top

TOPIC SEARCH: PubMed

A molecular remission is when there is no evidence of disease found with very sensitive tests called PCR  

See Minimal Residual Disease (MRD) for details about this test.

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.   

Cheson Criteria
(used in clinical trials)

Return to top

Complete response

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 atypia).

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 design

Return to top

"Not everything that counts can be counted;
not everything that can be counted, 
counts." ~ A. Einstein

Residual lymphoid masses after treatment? 

Following treatment "a 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: 12644887   

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” cells.

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 is done.

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* 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):.

New: "Indeterminate Response" (IR) describes status of disease until confirmed as flare/pseudo-progression or true PD by either biopsy or subsequent imaging.

"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.
	Progression free survival (PFS) - measures time to progression, relapse, and to death from any cause.

Survival and Evaluation of Response 

Some commonly used abbreviations

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. 

Related Articles and Resources

Return to top