Response Evaluation Criteria for Peripheral Nodal Lymphoma in Dogs (v1.0) - A Veterinary Co-operative Oncology Group (VCOG) Consensus Document: J Veterinary & Comparative Oncology, 2010; 8(4).

FREQUENTLY ASKED QUESTIONS (FAQs)

For individuals or organizations having FAQs that are not addressed by the FAQ answers and examples listed below, please submit them to the VCOG committee for evaluation and response, care of Dr. David Vail at vaild@svm.vetmed.wisc.edu. Every attempt will be made to answer queries within a 1-month time frame after the committee has reached consensus.

Q1. Are the published VCOG response evaluation criteria for peripheral nodal lymphoma in dogs meant to serve as a standard for practice in veterinary oncology?

A1. As stated in the guideline, the intent is to provide minimum guidelines for the description and comparison of treatment outcomes that are simple, repeatable and consistently applicable under the limitations that currently exist in veterinary oncology. It is intended that those conducting prospective studies will have the ability to adhere most carefully to this guideline. For retrospective studies, it is intended that authors strive to collect and report data consistent with the guideline to the extent that the data allow. This guideline is not meant to serve as a standard of practice in veterinary oncology

Q2. For multiple lymph nodes that are confluent at baseline, how should they be measured using callipers?

A2. Measure and record the longest diameter of the confluent mass and add into the sum of the longest diameters (if a target lesion).

Q3. What should be done if several unique lymph nodes at baseline become confluent at a follow-up evaluation?

A3. As in answer #1 above, measure the longest diameter of the confluent mass and record to add into the sum of the longest diameters (if a target lesion).

Q4. How should one lymph node be measured if on subsequent exams it is split into two?

A4. Measure the longest diameter of each lesion and add this into the sum (if a target lesion).

Q5. What should we record when target lesions become so small they are below the 10 mm ‘measurable’ size?

A5. Target lesion measurability is defined at baseline. Thereafter, actual measurements, even if <10 mm, should be recorded. If a lesion(s) becomes very small, such that the clinician considers it ‘too small to measure’, this guideline advises a default measurement of 5 mm should be applied whether or not the lesion remains palpable.

Q6. If a patient has several target lesions which have decreased in size to meet PR criteria and one has actually disappeared, does that patient have PD if the ‘disappeared’ target lesion reappears?

A6. Unless the sum of the longest diameters meets the PD criteria, the reappearance of a target lesion in the setting of PR (or SD) is not PD. The LD of the target lesion should simply be added into the sum. However, if the LD of the reappearing target lesion is ≥ 15 mm then this is PD, regardless of the sum LD as discussed further in question 8 below.

Q7. When measuring the longest diameter of target lesions in response to treatment, is the same axis that was used initially used subsequently, even if there is a shape change to the lesion that may have produced a new longest diameter?

A7. The longest diameter of the node should always be measured even if the actual axis is different from the one used to measure the node initially (or at different time point

during follow-up).

Q8. How large does a new peripheral lymph node have to be to count as progression? Does any small subcentimetre lesion qualify, or should the lesion be at least measurable?

A8. A ‘new’ lymph node is one that was not previously a target or non-target lesion. A new lesion that is a peripheral lymph node must be >15 mm in its LD to be considered a new lesion. If a new lesion identified by clinical examination is equivocal, (i.e. less than 15 mm) and could represent a previously overlooked lesion, continued therapy and/or follow-up evaluation will clarify if the new lesion truly represents progressive disease. If repeat examination at the next scheduled evaluation period confirms progression of the new lesion, the date of progressive disease will be defined as the date of initial new lesion suspicion; however, if the new lesion has not progressed (i.e., still < 15 mm and equivocal) at the next evaluation period then the date of progressive disease is deferred until unequivocal PD is documented.

Q9. Does the definition of progression depend on the status of all target lesions or only one?

A9. As per the VCOG 1.0 guideline, progression requires a 20 % increase in the mean sum of the longest diameters (Mean Sum LD) of all target lesions AND a minimum absolute increase of 5 mm in at least one of these target lesions. However, for target lesions <10 mm at nadir, an increase in LD of any single previously identified target lesion to ≥15 mm is also defined as PD.

Q10. The first response evaluation should not occur until day 42 following initiation of therapy. Since VCOG 1.0 guidelines recommend monthly follow-ups for the first 1.5 years, when should the next evaluation occur?

A10. The second evaluation should occur at approximately 2 months following initiation of treatment and then at least monthly after that point. It is realized that these are approximate dates and that recheck intervals may vary to some extent; however, this initial sequence will fit most current veterinary treatment protocol intervals without significantly compromising standardization of recheck frequency.

Q11. What should be done, regarding progression-free survival (PFS) measures if a monthly recheck is missed?

A11. In the absence of PD in a dog that has not received treatment between the last and the current evaluation visit, the PFS is deemed to be ongoing. However, in cases where the data are incomplete with respect to PFS, if at the current recheck visit the dog meets criteria for PD, the data should be censored at the last date at which progression status was adequately assessed or the first date of unscheduled new anti-lymphoma therapy whichever occurs earlier.

Q12. Abdominal radiographs were not obtained prior to initiation of treatment and, based on physical examination, the dog was not considered to have hepatic/splenic involvement. Following initiation of treatment the dog was considered to have a complete response. However, in the face of an otherwise complete response, an abdominal radiograph was obtained for an unrelated reason and the liver is clearly enlarged (hepatomegaly is not apparent on physical examination). According to the VCOG guideline, does this dog have progressive disease due to the finding of hepatomegaly on radiographs?

A12. The VCOG guideline suggests evaluation of the liver should be based on the same diagnostic modality used at baseline. However, the guideline also states that "A lesion identified on a follow-up study in an anatomical location that was not imaged at baseline is considered a new lesion and will indicate disease progression." In this case, it is suggested that additional diagnostics (e.g., needle aspirate cytology or biopsy) be used to document that the new non-target lesion indeed represents lymphoma. If the aspirate/biopsy is positive, by definition this dog is experiencing progressive disease. If the aspirate/biopsy is negative for lymphoma, then the radiographic evidence of hepatomegaly is not sufficient to meet criteria for PD.

EXAMPLES FOR CONSIDERATION:

EXAMPLE 1: A dog with generalized peripheral lymphadenopathy presents with mean baseline caliper measurements listed in the table below as longest diameter (LD) in millimeters. NOTE: As per the VCOG guidelines, these measurements represent the mean of values measured by two different trained individuals.

Days after treatment initiated

Peripheral node location

Right

mandibular

Left mandibular

Right

prescapular

Left

prescapular

Right

popliteal

Left Popliteal

Removed for diagnosis

Acceptable target-lesions: All but the right mandibular (below the 20 mm baseline minimum) and the removed popliteal lymph node are eligible as target-lesions.

Baseline Mean Sum LD of target-lesions: 32 + 38 + 41 + 37 = 148 mm.

Subsequent follow-up reveals the following:

Days after treatment initiated	Peripheral node location*
Days after treatment initiated	Right mandibular	Left mandibular	Right prescapular	Left prescapular	Right popliteal	Left Popliteal
0	18	32	38	41	Removed for diagnosis	37
21	NA	NA	NA	NA	-	NA
42	8	26	18	19	-	21
63	6	7	7	9	-	9
91	7	11	10	11	-	13
118	6	7	6	7	-	19

*Numbers in bold represent designated target lesions.

Day 21 Mean Sum LD of target lesions: measurements not performed per VCOG guideline.

Day 42 Mean Sum LD of target lesions: 26 + 18 + 19 + 21 = 84 mm.

Assessment of target lesion response recorded at day 42: Partial response. This represents a 43% decrease in the Mean Sum LD compared to baseline using the equation:

Percent difference for PR: Current Mean Sum LD – Baseline Mean Sum LD _{X 100}

Baseline Mean Sum LD

Day 63 Mean Sum LD of target lesions: 7 + 7 + 9 + 9 = 32 mm.

Assessment of target lesion response recorded at day 63: Complete response. All target lesions are palpably normal.

Day 91 Mean Sum LD of target lesions: 11 + 10 + 11 + 13 = 45 mm.

Assessment of target lesion response recorded at day 91: Still in remission. While the lymph node sum LD has increased more than 20% above nadir (day 63), which meets one of the criteria for PD, the LD of at least one of the target lesions must demonstrate an absolute increase of at least 5 mm compared to its nadir for PD to be defined and this has yet to occur in this scenario.

Day 118 sum LD of target lesions: 7 + 6 + 7 + 19 = 39 mm.

Assessment of target lesion response recorded at day 118: Progressive disease. While the lymph node Mean Sum LD has not increased more than 20% above nadir (day 63), the fact that one target lesions that was < 10 mm at nadir increased in LD to ≥ 15 mm meets the criteria of PD (see table 1 of VCOG 1.0).

Calculated progression-free survival (PFS) for this case: PFS = 118 days.

Learning Points Example 1:

· Nadir is at day 63 in this scenario (point of Smallest Mean Sum LD)

· Response assessments should be avoided prior to day 42. Therefore, no measurements recorded at the day 21 reevaluation. Note: if, in the clinician’s opinion, it is obvious that progression has occurred at the day 21 recheck which would necessitate alterations in therapy beyond the scheduled treatment, then measured assessments could have been performed.

· Note that after the first day 42 assessment, re-evaluations are approximates of monthly rechecks. Some variability will ultimately occur in real-world clinical cases.

· This example considered assessment of target lesions and did not cite status of non-target lesions or assessment for new lesions; for the purpose of simplicity only, it was assumed that there were no new lesions and the response of non-target lesions paralleled that of the target lesions.

· Percent changes in Mean Sum LD are not absolute with respect to response evaluation.

o In this example at day 91, while the increase in Mean Sum LD met one criteria for PD, because the other criteria (at least one target lesion must increase by a minimum of 5 mm) was not met, the remission was still in effect.

o Conversely, at day 118, while the Mean Sum LD increase did not meet criteria for PD, this was superseded by one target lesion: this single target lesion was 9 mm at nadir and increased to 19 mm at day 118. This met the criteria of an increase to ≥ 15 mm of a target lesion that was < 10 mm at its nadir. Therefore, the response was assessed as PD.

EXAMPLE 2: A dog with generalized peripheral lymphoma presents with mean baseline and post-therapy caliper measurements listed in the table below.

Days post-treatment	Peripheral node location*
Days post-treatment	Right Mandibular	Left Mandibular	Right prescapular	Left Prescapular	Right popliteal	Left popliteal
0	24	26	20	22	28	30
21	NA	NA	NA	NA	NA	NA
42	12	12	8	6	5	5
63	17	13	9	7	7	7

*Numbers in bold represent designated target lesions.

Acceptable target-lesions: All of the listed lymph nodes meet criteria for target lesions. However, the guideline sets a maximum of 5, therefore the right prescapular node was dropped as a target lesion as it was the smallest in size.

Baseline Mean Sum LD of target-lesions: 24 + 26 + 22 + 28 + 30 = 130 mm.

Day 42 Mean Sum LD of target lesions: 12 + 12 + 6 + 5 + 5 = 40 mm.

Assessment of response recorded at day 42: Partial response. This represents a 69% decrease in the Mean Sum LD compared to baseline using the equation:

Percent difference for PR: Current Mean Sum LD – Baseline Mean Sum LD _{X 100}

Baseline Mean Sum LD

Day 63 Mean Sum LD of target lesions: 17 + 13 + 7 + 7 + 7 = 51 mm.

Assessment of response recorded at day 63: Progressive disease. This represents a 27.5% increase in the Mean Sum LD compared to nadir (day 42) using the equation:

Percent difference for PD: Current Mean Sum LD – Smallest Mean Sum LD _{X 100}

Smallest Mean Sum LD

In addition, the second required criteria that at least one target lesion has increased by at least 5 mm in Mean Sum LD has been met.

Calculated progression-free survival (PFS) for this case: PFS = 63 days.

Learning Points Example 2:

· Nadir is at day 42 in this scenario (point of Smallest Mean Sum LD)

· Percent changes in Mean Sum LD are not absolute with respect to response evaluation.

o At day 63, both required criteria for progressive disease involving target lesions were met; an increase in Mean Sum LD of >20% AND an increase of 5 mm in Mean Sum LD of at least one target lesion.