Elsevier

Clinical Positron Imaging

Volume 2, Issue 3, May–June 1999, Pages 159-171
Clinical Positron Imaging

Tumor Treatment Response Based on Visual and Quantitative Changes in Global Tumor Glycolysis Using PET-FDG Imaging: The Visual Response Score and the Change in Total Lesion Glycolysis

https://doi.org/10.1016/S1095-0397(99)00016-3Get rights and content

Abstract

“Functional” tumor treatment response parameters have been developed to measure treatment induced biochemical changes in the entire tumor mass, using positron emission tomography (PET) and [F-18] fludeoxyglucose (FDG). These new parameters are intended to measure global changes in tumor glycolysis. The response parameters are determined by comparing the pre- and posttreatment PET-FDG images either visually from the change in image appearance in the region of the tumor, or quantitatively based on features of the calibrated digital PET image. The visually assessed parameters are expressed as a visual response score (VRS), or visual response index (VRI), as the estimated percent response of the tumor. Visual Response Score (VRS) is recorded on a 5 point response scale (0–4): 0: no response or progression; 1: 1–33%; 2: >33%–66%; 3: >66%–99%; and 4: >99%, estimated response, respectively. The quantitative changes are expressed as total lesion glycolysis TLG or as the change in TLG during treatment, also called δTLG or Larson-Ginsberg Index (LGI), expressed as percent response. The volume of the lesion is determined from the PET-FDG images by an adaptive thresholding technique. This response index is computed as, δTLG (LGI) = {[(SUVave)1 * (Vol)1 – (SUVave)2 * (Vol)2]/[(SUVave)1 * (Vol)1]} * 100. Where “1” and “2” denote the pre- and posttreatment PET-FDG, scans respectively. Pre- and posttreatment PET-FDG scans were performed on a group of 41 locally advanced lung (2), rectal (17), esophageal (16) and gastric (6) cancers. These patients were treated before surgery with neoadjuvant chemo-radiation. Four experienced PET readers determined individual VRS and VRI blinded to each other as well as to the clinical history. Consensus VRS was obtained based on a discussion. The interobserver variability captured by intraclass correlation coefficient was 89.7%. In addition, reader reliability was assessed for the categorized VRS using Kendall's coefficient of concordance for ordinal data and was found to be equal to 85% This provided assurance that these response parameters were highly reproducible. The correlation of δTLG with % change in SUVave and % change in SUVmax, as widely used parameters of response, were 0.73 and 0.78 (P < .0001) respectively. The corresponding correlation of VRI were 0.63 and 0.64 (P < .0001) respectively. Both δTLG and VRI showed greater mean changes than SUV maximum or average (59.7% and 76% vs. 46.9% and 46.8%). We conclude that VRS and δTLG are substantially correlated with other response parameters and are highly reproducible. As global measures of metabolic response, VRS, VRI and δTLG (LGI) should provide complementary information to more commonly used PET response parameters like the metabolic rate of FDG (MRFDG), or the standardized uptake value (SUV), that are calculated as normalized per gram of tumor. These findings set the stage for validation studies of the VRS and δTLG as objective measures of clinical treatment response, through comparison to the appropriate gold standards of posttreatment histopathology, recurrence free survival, and disease specific survival in well characterized populations of patients with locally advanced cancers.

Introduction

The use of PET-FDG in oncology, for staging and diagnosis of suspected tumor recurrence is now one of the most rapidly expanding areas in nuclear medicine and indeed all of diagnostic imaging. The application of PET-FDG to the differential diagnosis of the pulmonary nodule as well as the staging and detection of recurrence for lung and colorectal cancer are particularly important to clinical oncology.1 The value of the PET technique in detecting the presence of cancer in these situations is the result of the rapid improvements in sensitivity for detection of small volume tumor based on recent advances in PET imaging instrumentation.

Positron emission tomography (PET) may have a special potential for accurate and rapid monitoring of cancer treatment response, based on metabolic imaging of changes in tumor metabolism. Our objective in this paper, was to describe the conceptual development and performance characteristics of two tumor response parameters obtained with PET-FDG imaging, the visual response score (VRS) and change in total lesion glycolysis, (δTLG) also called the Larson-Ginsberg Index (LGI). Unlike commonly used parameters of response, such as the Standardized Uptake Value (SUV), or the local glucose metabolic rate (LGMR), that are normalized per unit mass, our new parameters are intended to evaluate the global metabolic response of the entire lesion to treatment.

Measuring the response of tumors to anticancer therapy is most commonly done using radiographic procedures that provide images of anatomic changes that occur during treatment. Chest x-ray, CT, MRI are modalities that are usually employed for response measurements. Typical response criteria include a complete response (CR), in which the tumor mass disappears: PR, in which there is a greater than 50% reduction in the product of the maximum two diameters measured perpendicular to one another in the tumor; minimal response, when the reduction in the product of two diameters is more than 75% but less than 50%; and stable disease, when the tumor reduction is 25% greater than baseline measurements.2

Despite the recognized limitations of sensitivity for measuring the lower limit of tumor response in the total tumor mass, radiographic responses have been found to be very useful clinically for defining prognosis of treated patients and for determining if a given treatment is effective. For example, in patients with non-small cell lung cancer (NSCLC), Gralla showed that patients with CT criteria for complete response had the longest survival; patients with partial response, intermediate survival; and patients with no response or progression, the shortest survival.3 It is perhaps surprising, given the sensitivity of radiographic methods, that there is such a good correlation between radiographic response and patient treatment outcome. It seems that radiographic methods accurately monitor a trend of response and this trend, either favorable or unfavorable, may accurately predict patient outcome in many clinical situations.

It is evident that the evaluation of tumor response by CT and other anatomic-based imaging methods can be confounded by numerous factors. These include the situation where a tumor mass does not change in size, despite death of tumor cells. In this case, fibrous tissue, edema of tissues as a direct treatment effect, may cause a persistent mass despite a histopathologic response. For these reasons, there are a number of situations in which radiographic response does not correlate well with treatment outcome. This is especially true in regard to the persistent mediastinal mass post-treatment with Hodgkin's disease; in the esophageal and gastric cancers, where masses may persist despite other evidence of response. Another difficult area is in bony involvement by tumor where non-specific bone changes on x-ray and bone scan can mask tumor response.

Differentiating edema and posttreatment scarring from tumor persistence or recurrence is a common problem in colorectal cancer, brain tumor and intra-thoracic tumors. An additional problem with anatomic measures is the time it takes for the mass to change size when responding or progressing. This time can be in the order of weeks to months. These relatively slow changes can make clinical care difficult, especially if an ineffective and toxic therapy is being employed.

The limitation of anatomic based imaging methods for monitoring treatment response is well known and has led to a search for alternatives. Advances in imaging methods that are capable of quantitative assessment of biochemical features of tumors may offer important clinical advantages. Examples of this type of functional imaging technology include magnetic resonance imaging (MRI) and spectroscopy (MRS); PET, single photon emission tomography (SPECT). There is a general view that these methodologies are at a point in their technical evolution as to be ripe for application to clinical trials in oncology. The National Cancer Institute has issued a recent request for proposals, RFA Ca 98-024 based on these ideas.

In this regard, PET-FDG imaging seems to be a promising functional modality for assessing tumor response. Modern PET instruments have limits of detection for human tumor in clinical imaging that approach 7–10 mm in diameter, or about 2.5 times the intrinsic PET detection resolution under optimal conditions of use. Thus, the detection limits are similar to spiral CT, although the regions of the body where PET imaging is optimal is different. In general PET is less sensitive to small volume disease in the lung because of motion degradation over the time required to capture the images. On the other hand, PET can detect small volume disease in lymph nodes, when spiral CT imaging is negative. But PET combines this resolution with the ability to assay biochemical properties of tumors. For example, although FDG imaging of the accelerated glycolysis of tumors is the most commonly applied clinically, positron emitting radiotracers that are applicable to assessing additional key metabolic processes of tumors have been recently developed. These include labeled amino acids and nucleosides and these will undoubtedly be applied more extensively for imaging important biochemical features of tumors in the near future. We can expect that detection limits will get ever smaller, as PET resolution improves below the current range of 3.5 mm for modern BGO based systems, down to 1–2 mm resolution that is possible with current experimental LSO systems.4

Thus, positron emission tomography (PET) seems to have special potential for providing a more accurate and rapid method for monitoring cancer treatment response in the clinical situations where changes in the anatomic features of the mass do not track with the response of the tumor cells within the mass. PET relies on the metabolism of viable cells within the tumor mass, to produce its images. In so far as the metabolic marker is tumor cell specific, the PET image will reflect the metabolic status of the treated tumor. Thus sequential tumor uptake of a metabolic tracer as measured by PET can in principle provide a quantitative response parameter that reflects a treatment induced biochemical change in the sensitive tumor. Because the response to treatment is a killing of cells, an ideal PET method would also accurately reflect the number of viable cells present in the tumor posttreatment over multiple decades of cell-kill.

Histopathologic assessment of tumor response remains an important standard against which diagnostic imaging methods must be compared. The advantage of histopathologic examination is resolution, so that in principle, even a few cells are detectable in the post-treatment specimen. Of course, sampling error of a mass may miss a few residual cells in a small volume biopsy post treatment. In some cases, the entire tumor is removed after treatment, and so a thorough evaluation of the tumor can be made to search for residual cancer cells. A complete tumor specimen is normally available after neoadjuvant treatment protocols are used. In patients with locally advanced cancers. these protocols are becoming very popular to reduce the size of the tumor mass and to downstage the tumor if possible, before surgery.5 The posttreatment specimen includes the entire tumor, and is removed at surgery.

A histopathologic scoring system has been developed that evaluates the degree of response of locally advanced tumor. This pathology score is based on the following principle. After treatment, the tumor responds by replacing dead tumor cells with fibrosis. The fraction of the total tumor that has been replaced with fibrous tissue is graded as the percentage response in the tumor.35

The ultimate correlation for any assessment of response, including this histopathologic scoring system, is the ability to predict progression free survival time and disease specific survival time. Obviously, the presence of residual tumor, means that response is incomplete. The pathologic scoring system is as follows: 0) no response or progression; 1) 1–33% response; 2) >33%–66% response; 3) >66%–99% response; and 4) >99% response, respectively. In lung cancer, where this histopathologic scoring system has been evaluated most thoroughly, this concept seems to hold up well, and the complete responders have a long recurrence-free survival. Also, a preliminary study in 80 patients undergoing a neoadjuvant protocol in locally advanced rectal cancers, showed a good correlation between disease-specific survival time and response score (D. Klimstra, personal communication).

Thus, histopathologic scoring will likely give us important response information in the setting of locally advanced cancers treated with a neoadjuvant presurgical protocol, but even pathology must be considered a somewhat imperfect gold standard. The best gold standard, is the outcome of the patient, including time to disease-specific survival time and progression free survival.

Based on these considerations, we have formulated a hypothesis, that global changes in tumor metabolism as measured by PET-FDG scanning will be the optimal method for evaluating tumor treatment response in the clinical setting because a metabolic change in the tumor is less likely to be confounded by extraneous factors that make treatment response problematic by anatomic based methods. The development of VRS and δTLG sets the stage for testing this hypothesis of clinical response in locally advanced cancers. PET-FDG VRS and δTLG should provide practical clinical parameters with pathologic assessment as well as the ultimate gold standards of recurrence free survival time and disease specific survival time. If successful, these global methods for metabolic changes in tumors during treatment could be applied to other metabolic PET tracers as well.

Section snippets

Patients

Patients with locally advanced aerodigestive tract tumors were studied with PET, before and after neo-adjuvant presurgical treatment. A total of 41 patients were studied, with locally advanced malignancies. The patients had in common that they were patients undergoing neoadjuvant treatment before definitive surgical resection. These patients were all patients who had undergone pre- and posttreatment PET scans for locally advanced solid tumors with esophageal cancer, rectal cancer, gastric

Response Parameters

The response parameters (R) of PET volume, SUVmaximum SUVaverage, total lesion glycolysis (TLG), were computed for all lesions pre and post therapy.

Results

The following parameters were computed for the primary tumor in the 41 patients studied, based on pre and post-therapy PET-FDG scans: VRS, VRI, PET Volume, δTLG (LGI), SUVmaximum, and SUVaverage. A summary of all the measurement parameters is shown in Table 1. A summary of the treatment response parameters organized by visual response score is shown in Table 2. The graphical distributions of the response parameters, pre- and posttreatment, are shown in Figure 2.

Table 2 is organized by consensus

Discussion

In this paper we present two new PET-FDG estimates of global glucose tumor response that are intended to provide complementary information in comparison to metabolic rate or standardized uptake values (SUV). The visual response is readily performed based on a simple comparison of the pre- and posttreatment image in the region of the tumor. The quantitative estimates of global tumor response, TLG (SUV-cc), δTLG or LGI (% response), are computed based on the pre and post treatment tumor volume

Summary

We studied 41 patients with locally advanced aerodigestive tract tumors using PET-FDG imaging, using attenuation corrected whole body images obtained before and after chemoradiation therapy. Currently used, mass specific measures of tumor metabolism such as SUV and metabolic rate estimates of uptake of FDG are useful parameters for predicting tumor biology. We have developed two new response parameters that may be more suited to measurement of tumor response, the VRS and the LGI. These

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