Targeted therapies might require SGR calculations to evaluate the full spectrum of tumor response

Figures 6, 7 display tumor responses evaluable in the clinic. RESIST 1.1 criteria follow for comparison.

1. Disease stabilization (complete inhibition of pre-therapy SGR)

The marker or tumor's inherent growth rate is inhibited causing it or its surrogate marker value to remain unchanged during therapy.

2. Uninterrupted growth

The tumor or marker continues its calculated pre-therapy growth rate without change during therapy. The growth noted in the surrogate marker or tumor after therapy is predictable and equal to the projected tumor growth based on the calculated SGR before the start of therapy.

3. Tumor "response" of varied degree (note: at the time of response evaluation the tumor may be larger than the pre-therapy value)

Tumor or marker growth is inhibited and at post-therapy response evaluation the tumor or its surrogate marker is less than the projected value. This response may be difficult to identify since the tumor or its marker may have reached a size greater than before the start of therapy however, tumor or marker post therapy is not as large as projected based on the pre-therapy SGR Figure 7. A computer calculation comparing pre- and post-therapy SGR is required to accurately quantify this response category. TR (treatment response) is easily calculable and offers an objective and continuous value for the degree of response. TR is used as either a "tumor response" or "tumor marker response", to quantitate the effect of thera py. This continuous variable is useful to directly compare treatment efficacy between differing therapies.

Mehrara [71] defined some limitations for the current use of treatment response including: 1) PR and CR as defined in RECIST and other methods are no longer of value for quantifying responses to cytostatic/cytolentic drugs. Combinations of cytolytic and cytostatic/cyto-lentic therapies add further difficulty to response interpretation. A further problem arises when drugs are used at the extremes of dosing where tumor-killing activity may change from cytostatic/cytolentic to cytolytic and vise versa. 2) Classically, no consideration is given to the persistence of tumor SGR and or its inhibition during the course of therapy. Clinically, this is a trap for the oncologist if response is based solely in terms of whether the tumor marker or size is decreased at the end of therapy 3) The advantage of TR as a continuous variable (as opposed to a discrete variable used to compartmentalize responses such as CR, PR, SD) is that TR is a measurement of inhibitory (+TR) as well as accelerating (-TR) drug effects and is directly comparable between therapies and independent of mechanism of drug action.

A simple statement that the marker or tumor is larger post therapy is no longer adequate to evaluate tumor responses.

4. The size of the tumor or its surrogate marker decreases after therapy.

This may be a partial or complete return to normal, manifest by partial or complete disappearance of tumor/marker abnormality.

5. Tumor acceleration and deceleration

Tumor acceleration occurs when the tumor or marker growth rate (SGR) after therapy is greater than the pre-therapy or baseline SGR and SGR = (SGR after Rx - SGR before Rx) / (t2-t1) is a negative value. Tumor growth rate acceleration is positive and may indicate the presence of a tumor-accelerating mutation or an unexpected untoward drug effect.

Tumor deceleration occurs when SGR before therapy is greater than SGR after therapy and is expressed as: SGR deceleration = (SGR after Rx - SGR before Rx) / (t2 -11) this is a negative value.

The rate of change calculations are based on the pre-therapy calculated SGR and its rate of change is calculated at the end of therapy and is expressed as: Acceleration or deceleration of the SGR: ASGR / At. Or EDITOR use (SGR2-SGR1)/(T2-T1).

Note: In the presence of multiple tumor targets the sum of tumor diameters or volumes is used as an approximation. Clonal heterogeneity (a mosaic of tumors growing at different growth rates and or demonstrating a mixed response) may make some tumors inadequate for analysis.

In 1999 an attempt to write a specific dogma evaluating tumor response resulted in the RECIST 1.0 criteria, later updated 2009 as RECIST 1.1 [73]. Note the absence of drug-response based on the concept of projected tumor growth.

RECIST 1.1 criteria

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

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__be considered stable disease however one lumor's growth was delayed!

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Tumor specilic growth rales

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Hypothetical growth curves of 3 tumors with tumor specilic growth rates ranging Irom 0.231 %/d to 0.77%/d, In only one tumor does treatment delay growth. However, all tumors would be considered stable disease according to current response criteria, which define stable disease as increase in tumor size ot less than 20%.

Figure 8. Weber [74] reveals the difficulty of classifying real growth inhibition within the RECIST1.1 criteria of stable disease. Real or suppressed tumor growth is illustrated by the pink growth curve only.

Figure 8. Weber [74] reveals the difficulty of classifying real growth inhibition within the RECIST1.1 criteria of stable disease. Real or suppressed tumor growth is illustrated by the pink growth curve only.

Weber noted that the RECIST 1.1 disease stabilization category does not differentiate between a drug that slows tumor growth and the complete lack of drug effect Figure 8. The RECIST 1.1 definition for disease progression is >5 mm absolute increase in size in addition to >20% increase compared with the nadir. In this figure, though all three tumors do not meet the progressive disease criteria and thus would be termed stable, the growth of the third was slowed by therapy. Though all three are termed stable, note the subtle difference between the two tumors showing a continued and uninterrupted pre-therapy growth rate (SGR), compared to the slowed growth rate of the tumor depicted by the red line. Surely there is a drug effect vs. the red tumor. This active drug could be overlooked in spite of its potential to increase survival if maintained for a sufficient period of time.

In a review of a group of patients treated with targeted therapies, Tourneau [75] revealed clinical evidence where investigators overlooked subtle cytostatic/cytolentic (slowing of SGR) drug activity Figure 6, 8. The group analyzed 50 patient participants in 18 targeted therapy drug trials. Among the 44 patients who withdrew from study because of disease progression according to the investigators' assessment, 18 patients (41%) demonstrated a favorable slowing trend in tumor specific growth rate. Among the 18, 5 had disease progression according to RECIST 1.1 according to retrospective reassessment of on-study imaging and occurrence of no new lesion during study treatment. Their preliminary evaluation concluded that a substantial proportion of patients treated with targeted agents were removed from protocol in spite of possibly benefitting from therapy.

Ferte et al. [76] studied metastatic renal cell carcinoma patients treated with sorafenib (Nexa-var) and everolimus (Afinitor). Analysis of tumor SGR clearly revealed drug effects that would have been missed had RECIST response criteria been applied. Tumor response was assessed before, during, at the time of tumor progression and after drug discontinuation. Tumor growth rate was computed by dividing tumor shrinkage by the time between two related evaluations (% RECIST x 100 /day).

In two different patient populations (IGR and TARGET) tumor growth rate significantly decreased following sorafenib (-23.6 vs. 20 (IGR) and -19 vs. 22 (TARGET)) and everolimus (-5.2 vs. 30 (IGR)). The great majority of patients (IGR) had a decrease in the tumor growth rate during vs. before therapy, regardless of the RECIST evaluation, both with sorafenib (28/29) or everolimus (36/37). Growth rate after sorafenib or everolimus interruption was significantly higher than at the time of progression in both settings (IGR) (14.6 vs. 31 and 17.9 vs. 32.1 respectively). No significant difference was observed between growth rate before or after therapy for either sorafenib or everolimus (IGR). They concluded that SGR evaluation revealed: 1) better evaluation of tumor response, regardless of RECIST criteria, 2) had independent prognostic value, 3) the possibility that continuation of sorafenib or everolimus after disease progression might be beneficial to patients by sustaining a continued suppression of tumor growth.

The following section presents a model of tumor growth rate expressed as an executable algorithm in the form of an Apple App that quantitates subtle changes of tumor specific growth rate (SGR).

Sum of target lesions over time in the five patients with a change in growth rate who were taken off study because of progressive disease according to RECIST 1,1 and who had no new lesion during treatment. These patients could have benefitted from therapy. Among the 44 patients who withdrew from the study because of disease progression according to the investigators' assessment, 18 patients (41%) had a decrease in tumor Specific growth rate Among these 1B patients, the 5 patients illustrated above had disease progression according to RECIST 11 Modified From C Le Tourneau etal. British Journal of Cancer (2012) 106(5), 854 - 857,

Sum of target lesions over time in the five patients with a change in growth rate who were taken off study because of progressive disease according to RECIST 1,1 and who had no new lesion during treatment. These patients could have benefitted from therapy. Among the 44 patients who withdrew from the study because of disease progression according to the investigators' assessment, 18 patients (41%) had a decrease in tumor Specific growth rate Among these 1B patients, the 5 patients illustrated above had disease progression according to RECIST 11 Modified From C Le Tourneau etal. British Journal of Cancer (2012) 106(5), 854 - 857,

Figure 9. Following a patient's tumor size often reveals subtle changes in the slope of the tumor measurement or marker growth curve as revealed above. These subtle changes in growth rate are not associated with a significant decrease of tumor size or marker value. As Le Tourneau et al. and Ferte et al. demonstrate, subtle changes in tumor growth rate are not evaluated as a response when applying RECIST 1.1 criteria nevertheless, they do represent a true cytostatic effect of targeted therapies that may translate into a meaningful prolonged survival.

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