RECIST 1.1

Response Evaluation Criteria In Solid Tumors

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RECIST is a standard way to measure the response of a tumor to treatment.  
It provides objective criteria to determine whether a tumor disappears, shrinks, stays the same or gets bigger. 
This is called complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD).

In this article we describe the five easy steps to follow when you want to use RECIST 1.1.

in addition a brief overview is given of variations of RECIST and some other response systems.

Baseline Study - five easy steps

1. Is the study eligible for RECIST?

Radiographic studies that may be used:

  • CT is the preferred imaging modality. See table for specific issues.
  • MRI may be used in some instances. Use the same criteria as for CT.
    MR acquisition parameters should be specified and optimised.
    The parameters should be consistent during the trial.
  • Chest X-ray is used if lesions are clearly defined and surrounded by aerated lung.
    The minimal size of target lesions must be ≥ 20mm.

Ultrasound is not used for RECIST due to operator dependency.

2. Choose “target lesions”

Choose preferrably large well-described lesions to measure with a maximum of two per organ and a maximum of five for the whole study.

Lymph nodes can be used as target lesions provided that the maximum short axis diameter exceeds 15 mm.
Nodes <10 mm are regarded as normal, while nodes 10-15mm are regarded as pathologic but not suited for target lesions.
They can be used as non-target lesions.

Measurement includes hypervascular rim

When a lesion has a hypervascular rim, this is included in measuring the longest diameter. 

The CT images in the arterial and portovenous phase of a 71-year-old male show liver metastases of a neuro-endocrine tumour of the esophagus.
The large hypervascular rim is included in the measurement of the largest diameter.


An exception to measuring the longest diameter is in patients with malignant pleural mesothelioma.
The non-spherical growth pattern in this disease makes reproducible long axis measurements difficult.
Therefore not the longest diameter, but the tumour thickness perpendicular to the chest wall is used.
This measurement has a good correlation with outcome.

Hier nog afbeelding van mesothelioom met meting...

Lesions that are not suitable for target lesions are listed in the table.

Truely unmeasurable lesions like leptomeningeal disease, ascites, effusions, inflammatory breast disease, and lymphangitic involvement of skin or lung are not qualified for target lesions.

Bone lesions with identifiable soft tissue component: only the soft tissue component may serve as target lesion (only if ≥ 10mm).

Lesions located in an area, that has been subjected to loco-regional therapy, are considered non-measurable.

Suspected cystic metastases may apply, however if concomitant solid metastases are present rather use those.

Some tumors have other criteria for follow up like lymphoma or GIST tumors.

Non-measurable lesions

Example of non-measurable lesions in a patient with lymphangitis carcinomatosa and another patient with ascites.

These findings are used as non-target lesions and in the follow up it is determined whether there is complete disappearance, partial disappearance or progression.
No exact measurements are made.

Osteblastic metastases
Osteblastic bone metastases are non-measurable lesions.

The left CT image is of a 80-year-old male with osteoblastic bone metastases of a non-small-cell lung carcinoma.

Hier nog uitleg waarom het niet meetbaar is...


Osteolytic metastases
Lytic or mixed lytic-blastic bone metastases with identifiable soft tissue component can be considered as measurable lesions if they meet the measurability criteria. 

The CT image on the right is of a 69-year-old female with osteolytic bone metastases of a solitary fibrous tumour of the left shoulder.  
This metastasis is suitable for measurement and can be used as target lesion.

Sometimes the largest lesion is not the most suitable for reproducible repeated measurements.
This CT image is of a 61-year-old male with gastric cancer and lymph node metastases.
There is a large lobulated mobile gastric tumor.
We can assume, that on a follow up examination it can not be reproduced in the same way.
Therefore this mobile tumor is not suitable as target lesion, but can be used as non-target lesion.

Continue with next image...

At a lower level there is an enlarged lymph node which is more suitable to be used a target lesion (arrow).

3. Calculate Sum of Length Diameters

Hier een voorbeeld van patient waarbij five targets gemeten worden...

Non-target lesions: miliary lung metastases of ovarian cancer.

4. Identify non-target lesions

What are “non-target” Lesions”?
Non-target lesions are all other disease related lesions that do not meet the criteria for a target lesion like pleural fluid, ascites and miliairy lung metastases, or those lesions that are supernumerary because the maximum number of 5 target lesions had been reached.
You do not measure these lesions.
Just mention them in the report and in the follow up look for disappearance, partial response or progression.

The CT image with maximum intensity projection of a 34-year-old female with miliary lung metastases of ovarian cancer.
The metastases cannot be used as target lesions because they are too small.
They can be used as non-target lesions and can be mentioned as a single item in the radiology report.

5. Report

The baseline radiology report should contain the following elements:

  1. Modality and parameters.
  2. Description of the target lesions. Each with localization, table position and size.
  3. Description of non-target lesions.
  4. Other incidental relevant  findings. 
  5. Conclusion with number of target lesions and their localization and clinically important incidental findings.


Follow up study

Is the study technically comparable to previous?

For follow-up studies, the same imaging modality should be used as for the baseline study and identical imaging parameters should be used, like slice-thickness, contrast protocol etc.

Identify same target lesions

Orientation
If the orientation of longest diameter varies during follow-up, measure the longest diameter (fig).

Dos and dont's

  • Do consider “new” lesions in an area of the body that was not imaged during baseline (for example brain metastases) as  truly “new”, thereby forcing overall response to progressive disease. 
  • Do measure the short axis of mesothelioma.
  • Don't change target lesions during follow-up studies: “once a target lesion, always a target lesion”
  • Don’t change measurements on previous studies
  • Don't measure lesions after treatment by RF ablation or cryoablation, because the ablated area is often larger than the original tumor.
  • Don't regard “new” sclerotic bone lesions as progressive disease as they may represent filling-in of previously lytic lesions that were not detected at baseline. 

Fragmentation
If the lesion breaks into separate fragments between baseline and follow-up, the sum of longest diameters (SLD) of the fragments should be calculated.
Vice versa if lesions coalesce, then measure the longest diameter of the merged lesion only.

Too small to measure
If a target lesion becomes “too small to measure” during follow-up (i.e. < 10mm), then a default measurement value of 5mm is assigned to prevent potential false classification of complete response.

The images are of a patient with a primary lung tumour.
At baseline, the longest diameter is well above 10 mm, therefore this was assigned as a target lesion.
During follow-up the long-axis diameter dropped below 10 mm, which is the lower limit for considering a lesion as target lesion.
However, since this is a follow-up measurement, the target lesion still counts up to the sum of the diameters (SLD) and a default value of 5mm was assigned. 

Cavitating lesions
Cavitation can occur during treatment.
Cavitating lesions should be continuously measured in their longest diameter.
A different assessment can be provided if the sum of diameters does not adequately correspond to the patients response assessment.

Theses CT images are of a 32-year-old male with a pulmonary metastasis of a malignant peripheral nerve sheath tumour. Cavitation occured after treatment with pazopanib, but the size remained the same. 

Betekent dit dat de meting ongewijzigd blijft??

Lymph node target lesion 18mm at baseline (left). At follow up only 4mm.

Calculate SLD

If during follow-up the short-axis diameter of a lymph node drops below 15 mm, the measurements are continued and still count for calculation of the SLD.

In this case the baseline short axis diameter is 18mm.
This was a target lesion.
At follow-up, the short-axis diameter dropped below 15mm. However the measurements are continued and the 4mm diameter counts up for the SLD. 

Wat betekent dit precies. Is er nu sprake van CR of PR en waarom. Klieren zie je vaak niet helemaal verdwijnen alleen kleiner worden...

Behaviour of non-target lesions

CT images in a 73-year-old male with progressive liver metastases of colorectal carcinoma.
This is an example of unequivocal progression of non-target lesions in the liver.

Even if there is partial response of other lesions or even disappearance, this is still progressive disease.

The sclerotic bone lesions in b and d are not new metastases but an osteoblastic reaction.

New lesions

Hier nog een voorbeeld van een nieuwe lesie, waardoor PD....

Any new lesion means progressive disease, but not every newly detected lesion is always a true new lesion.

In osteolytic bone metastases it can be difficult to determine if a sclerotic lesion that is detecting during follow up is truely a new lesion.

The CT images are of a 50-year-old female with bone metastases of a breast carcinoma.
At baseline (a), there is an osteolytic lesion in a thoracic vertebral body (arrow).
After chemotherapy, the thoracic osseous lesion has not changed in size, but has become completely osteoblastic (arrow in b), representing a good response. 

In the lumbar vertebra no visible metastases were seen in the baseline scan (c).
The ‘new’ sclerotic lesions in the lumbar vertebra (arrowheads in d), are considered to be small osteolytic metastases that the baseline CT failed to identify. 
They became visible due to the osteoblastic reaction.

PET

FDG-PET can be complementary to diagnostic CT imaging in assessment of disease progression, especially in case of a possible new lesion.
A positive FDG-PET at follow-up, with a negative FDG-PET at baseline, is a sign of progressive disease based on the new lesion.
Without an FDG-PET examination at baseline, findings are dependent on current and previous CT findings.

Reappearance of lesions

Disappearance and subsequent reappearance of a lesion in follow-up examinations should continue to be measured.
Depending on the disease status, a reappearing lesion can be considered either progressive disease, when the previous examination showed complete response or otherwise the maximal diameter should be added to the SLD for a calculated response.

The rationale is that most lesions do not disappear but are under the detection level of the employed imaging modality.

Wat is de tekst bij de plaatjes??

Response

To determine the response of a tumor in the follow up, we have to look at the target- and non-target lesions and look for any new lesions.

Progressive Disease (PD)

  • ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study. This is called the Nadir. This includes the baseline sum if that is the smallest on the study.
  • In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
  • The appearance of one or more new lesions is always considered progression.
  • Unequivocal progression of non-target lesions is also considered progression

Stable Disease (SD)

  • Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of length diameters (SLD) while on the study.

Partial Response (PR)

  • At least a 30% decrease in the sum of length diameters (SLD) of target lesions, as compared to baseline sum diameters.

Complete Response (CR)

  • Disappearance of all target and non-target lesions.
  • Any pathological lymph nodes must have reduction in short axis to <10 mm.

Overall response

The overall response is based on the response of all tumor related findings (table).

For instance any progression ( >20% increase) of target or non-target lesions or any new lesion means progressive disease no matter how the other lesions reacted.

Response in only non-target lesions

In some patients there are no suitable target lesions that can be measured and there are only non-target lesions.
In these cases you have to make an estimation of the response (table).

Radiology report

The radiology report of each follow-up study should contain the following elements:

Report
Modality and parameters
Description of target lesions with localization, table position and    size
Description of non-target lesions and comparison: unchanged, decreased or increased in size.
New lesions?
Incidental relevant findings 

Conclusion
Number of target lesions and their localization, overall impression of non-target lesions, clinically important incidental findings.

The table shows an example of a follow up report.

Dit misschien als voorbeeld van hoe het niet moet en vervolgens een report van hoe het wel moet...

Other Response systems

Choi criteria for GIST

The Choi criteria are based on RECIST and developed for assessing treatment response in patients with GIST (gastrointestinal stromal tumours) treated with imatinib (3).
Usually decrease in tumour size occurs in the course of treatment, however this doesn’t necessarily reflect tumour response.
Sometimes tumour size can increase due to internal haemorrhage, necrosis or myxoid degeneration. 

Major difference Choi response criteria in comparison to RECIST 1.1.is the introduction of tumour attenuation as an additional response parameter

Reduction in tumour size is usually minimal in the early posttreatment response assessment, while significant changes in internal characteristics like tumour attenuation, nodularity, and number of vessels will occur.

The CT images of a 82-year-old male show liver metastases of a GIST at baseline (arrowheads).
All metastases decrease somewhat in size after treatment with imatinib, but the most remarkable difference is a decrease in density.
This is considered to be a good response according to the Choi criteria.

Before the introduction of the Choi response criteria, recurrent or progressive disease used to be determined by an increase in tumour size and/or identification of new locations of disease.
Although increase in tumour size remains an important parameter for evaluating disease response, recurrent disease can occur within the treated tumor without increasing tumor size. 

The CT images in a 66-year-old male show liver metastases of a GIST at diagnosis (a).
At 3 months after treatment with imatinib there is a good response (b).
At a follow up scan at 1 year there is a  recurrence (arrow in c).
At a  follow-up after 2nd line treatment with sunitinib there is still tumor progression (d).


mRECIST for Hepatocellular carcinomas

Tumour response assessment based on changes in size alone can be deceptive when applied to hepatocellular carcinoma (HCC) treated with targeted or interventional therapies.
In 2000, the European Association for the Study of the liver (EASL) assembled an expert panel on HCC which suggested that the optimal method for treatment response assessment in HCC should be the estimation of viable tumour with contrast enhanced imaging.
These new criteria were based on RECIST 1.1 and referred to as modified RECIST (mRECIST) with the most important feature of defining viable tumour as uptake of contrast agent during arterial phase dynamic imaging (CT or MRI).

Ther table shows extra recommendations for the assessment of tumor response in non-target lesions in patients with HCC and cirrhosis.

Measurement rules in assessing response:

  • Measurement of viable tumor on CT or MRI in the arterial phase.
  • The same plane should be used to measure the longest diameter, but not necessarily the same level or measurement direction.
  • Measurement should avoid any major intervening areas of necrosis.

Rules of progression:

  • A newly detected liver nodule will be categorized as HCC (PD) when size >1 cm and typical enhancing pattern (hypervascularization in arterial phase with washout in portovenous or late phase).
  • New liver nodules >1 cm with atypical enhancement patters can be diagnosed as HCC (PD) when >/= 1 cm interval growth in subsequent CT or MRI.
  • Progressive disease will be determined in retrospect at the time it was first detected by imaging.

The CT images of a 86-year-old male with hepatocellular carcinoma.The CT image of the liver of a 96-year-old male with HCC in the late arterial phase shows a hypervascular tumour in the right liver lobe (arrowheads).
The tumor is well delineated from the surrounding parenchyma.
In the portal-venous phase the HCC is hardly distinguishable from the liver parenchyma due to early washout of contrast.

iRECIST for immune therapy

iRECIST represents a modified RECIST 1.1 for immune-based therapeutics.
The immunotherapeutic agents induce a different tumour response in comparison to standard chemotherapeutic agents. 


The new mechanism of actions of these drugs, with immune and T-cell activation, can cause uncommon patterns of tumour response that look like tumour flare, termed pseudoprogression (4).
These patients meet the criteria for disease progression according to traditional response criteria like RECIST, but demonstrate late and durable responses. 

The main criteria to objectively evaluate tumour response are mostly unaltered from RECIST 1.1, but the major modification in iRECIST consists of the idea of resetting the bar if RECIST 1.1 progression is followed by reduction of tumour load at the next assessment. 

iRECIST is not a treatment decision guideline, but rather provides a consistent framework for data management in clinical trials of immune-based therapies.


New lesions:

  • Assessed per RECIST 1.1
  • Not included in the sum of the diameters (SoD) for target lesions identified at baseline
  • Recorded separately on radiologic report (iSoD)

RECIL for lymphoma

Wordt RECIL ook nog behandeld met evt verschillen met Lugano?
Wat wordt in de dagelijkse praktijk gebruikt?

Lugano Classification

The Lugano Classification was the result of  the 12th International Conference on Malignant Lymphoma in Lugano, Switzerland.
This new classification represents revised recommendations regarding the use of the Cheson and Deauville criteria.
It incorporates FDG-PET into standard staging and response evaluation of FDG-avid nodal lymphomas.
Essentially all histologies are included except chronic lymphocytic leukemia (small lymphocytic lymphoma), lymphoplasmacytic lymphoma (Waldenstrom’s macroglobulinemia), mycosis fungoides, and marginal zone NHLs, unless there is a suspicion of aggressive transformation.

Example bi-dimensional measurement with perpendicular diameters for calculating the sum of the product of perpendicular diameters for multiple lesions.

CT images in a 56-year-old male with diffuse large B-cell lymphoma (DLBCL) before (a) and after (b) treatment with R-CHOP chemotherapy.

Coronal reconstructed CT images in the same patient show hepatosplenomegaly before (a) and normalization of hepatic and splenic size after (b) treatment with R-CHOP chemotherapy. Splenomegaly is defined as a vertical length >13 cm.
Hepatic size is not a reliable measure of hepatic involvement by lymphoma.

Begeleidende tekst...