Using FDG-PET to Measure Early Treatment Response in Head and Neck Squamous Cell Carcinoma: Quantifying Intrinsic Variability in Order to Understand Treatment-Induced Change

BACKGROUND AND PURPOSE:Quantification of both baseline variability and intratreatment change is necessary to optimally incorporate functional imaging into adaptive therapy strategies for HNSCC. Our aim was to define the baseline variability of SUV on FDG-PET scans in patients with head and neck squamous cell carcinoma and to compare it with early treatment-induced SUV change.MATERIALS AND METHODS:Patients with American Joint Committee on Cancer stages III-IV HNSCC were imaged with 2 baseline PET/CT scans and a third scan after 1–2 weeks of curative-intent chemoradiation. SUV_max and SUV_mean were measured in the primary tumor and most metabolically active nodal metastasis. Repeatability was assessed with Bland-Altman plots. Mean percentage differences (%ΔSUV) in baseline SUVs were compared with intratreatment %ΔSUV. The repeatability coefficient for baseline %ΔSUV was compared with intratreatment %ΔSUV.RESULTS:Seventeen patients had double-baseline imaging, and 15 of these patients also had intratreatment scans. Bland-Altman plots showed excellent baseline agreement for nodal metastases SUV_max and SUV_mean, but not primary tumor SUVs. The mean baseline %ΔSUV was lowest for SUV_max in nodes (7.6% ± 5.2%) and highest for SUV_max in primary tumor (12.6% ± 9.2%). Corresponding mean intratreatment %ΔSUV_max was 14.5% ± 21.6% for nodes and 15.2% ± 22.4% for primary tumor. The calculated RC for baseline nodal SUV_max and SUV_mean were 10% and 16%, respectively. The only patient with intratreatment %ΔSUV above these RCs was 1 of 2 patients with residual disease after CRT.CONCLUSIONS:Baseline SUV variability for HNSCC is less than intratreatment change for SUV in nodal disease. Evaluation of early treatment response should be measured quantitatively in nodal disease rather than the primary tumor, and assessment of response should consider intrinsic baseline variability.

FDG-PET is the most widely used functional imaging technique in head and neck squamous cell carcinoma. Pretreatment imaging has a significant role in initial staging, prognosis assessment, and target delineation.¹ Posttreatment FDG-PET has become an important tool for the assessment of residual disease in cervical lymph nodes.^2,3 Another area of active investigation is the use of PET to monitor therapy response during treatment. PET performed early in treatment (intratreatment PET) could detect favorable or unfavorable metabolic changes before anatomic changes are evident and could help determine whether a particular therapeutic strategy should be maintained or changed. This approach could enhance the choice of initial treatment and facilitate the use of adaptive radiation therapy strategies, including dose escalation, selection of nonresponding patients for new molecularly targeted therapies, or discontinuation in favor of primary surgery, among other options.⁴Early response assessment with FDG-PET has been evaluated in lymphoma, soft-tissue sarcoma, and esophageal and lung cancers.^5–8 Findings that early treatment changes in glucose metabolism can predict histopathologic response or survival have led to proposals of using standardized uptake value cutoff values to stratify patients by outcome.^5–7 One of the largest studies of neoadjuvant chemotherapy for esophageal cancer identified responders with high sensitivity by using 0% SUV decrease as a cutoff (ie, any decrease in SUV),⁵ and the authors concluded that a decrease in SUV of any magnitude would indicate an early treatment response. In practice, using such small changes to signify treatment response should be viewed with caution, for it is known that PET scans repeated days or even hours apart without intervening treatment can vary considerably in terms of SUV.^9–13The significance of this phenomenon is that change observed during the course of treatment must be greater than inherent baseline variability to correctly attribute the observed change to the treatment itself. Intrinsic variability of SUV in the absence of treatment reflects biologic, technical, and observer variation. This fluctuation was observed recently in HNSCC in a study that evaluated change in SUV_max on pretreatment PET/CT scans that were performed on different scanners.¹³ The authors warned about the need to account for variability in PET biomarkers in clinical protocols. Wahl et al,¹⁴ who proposed criteria for the Positron Emission Response Criteria in Solid Tumor (PERCIST) trial, also stated that more studies were needed to address questions concerning the reproducibility of baseline quantitative readings and PET response during the initial phases of treatment. Data are sparse, but baseline tumor PET metabolic activity for tumors outside the head and neck can vary by 10%–16% in single-center studies^9–12 and up to 39% in multicenter studies.¹¹Quantification of both baseline variability and intratreatment change is necessary to optimally incorporate functional imaging into adaptive therapy strategies for HNSCC. The aim of this prospective study was to define the intrinsic (pretreatment) variability of tumor SUV and compare it with early treatment-induced (intratreatment) change in patients with HNSCC. We hypothesized that intratreatment changes in HNSCC would be larger than the intrinsic variability in metabolic activity in patients responding favorably to treatment. A secondary aim was to determine whether the magnitude of intrinsic variability differed between primary tumor and nodal metastases or according to the parameter used to describe SUV, namely SUV maximum (SUV_max) or SUV_mean.     

Tissue gradients of energy metabolites mirror oxygen tension gradients in a rat mammary carcinoma model.

PURPOSE: It has been shown that oxygen gradients exist in R3230AC tumors grown in window chambers. The fascial surface is better oxygenated than the tumor surface. The purpose of the present study was to determine whether gradients exist for energy metabolites and other end points related to oxygen transport. METHODS AND MATERIALS: Imaging bioluminescence was used to measure ATP, glucose, and lactate in cryosections of R3230AC tumors. Mean vessel density and hypoxic tissue fraction were assessed using immunohistochemistry. Tumor redox ratio was assessed by redox ratio scanning. RESULTS: Lactate content and hypoxic fraction increased, whereas ATP, glucose, redox ratio, and vessel density decreased from the fascial to the tumor surface. CONCLUSIONS: The data support a switch from aerobic to anaerobic metabolism concomitant with the PO2 gradient. The vascular hypoxia that exists in perfused vessels at the tumor surface leads to macroscopic tissue regions with restricted oxygen availability and altered metabolic status. Methods to reduce tumor hypoxia may have to take this into account if such gradients exist in human tumors. The results also have implications for hypoxia imaging, because macroscopic changes in PO2 (or related parameters) will be easier to see than PO2 gradients limited to the diffusion distance of oxygen.     

Improved survival in advanced Hodgkin's disease with the use of combined modality therapy

To compare the effectiveness of combined modality therapy and chemotherapy alone for the treatment of advanced Hodgkin's disease (Stages IIB-IV), records of 154 patients who achieved a complete or partial response to induction combination chemotherapy were analyzed. Sixty-seven patients received consolidation radiotherapy and 87 patients received no further treatment. Thirty of 154 patients participated in a prospective randomized trial of the Southeastern Cancer Study Group (SEG). Ten-year actuarial survival (Hodgkin's disease deaths only) was 93% for the combined modality therapy patients compared with 59% for the chemotherapy alone patients (p less than 0.0005). Combined modality therapy patients had an 87% 10-year actuarial freedom from relapse as opposed to 56% for the chemotherapy alone patients (p less than 0.0005). Relapse occurred in 33 of the chemotherapy alone patients, 28 (85%) being in sites involved at initial diagnosis. Seven combined modality therapy patients recurred with only two true in-field failures. Multi-variate analysis demonstrated treatment (combined modality) as the only variable affecting outcome. Patients prospectively treated with combined modality therapy in the Southeastern Cancer Study Group trial also showed a statistically significant improvement in both survival and freedom from relapse compared with patients receiving chemotherapy only. There was no apparent increase in toxicity from using combined modality therapy compared with chemotherapy. Three chemotherapy patients and one combined modality therapy patients developed acute leukemia.     

Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment

PURPOSE: The objectives of this study were to evaluate effects of hyperthermia on tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with spontaneous soft tissue sarcomas prior to and after local hyperthermia. METHODS AND MATERIALS: Tumor pO2 was measured using an Eppendorf polarographic device, pHe using interstitial electrodes, and blood flow using contrast-enhanced magnetic resonance imaging (MRI). RESULTS: There was an overall improvement in tumor oxygenation observed as an increase in median pO2 and decrease in hypoxic fraction (% of pO2 measurements <5 mm Hg) at 24-h post hyperthermia. These changes were most pronounced when the median temperature (T50) during hyperthermia treatment was less than 44 degrees C. Tumors with T50 > 44 degrees C were characterized by a decrease in median PO2 and an increase in hypoxic fraction. Similar thermal dose-related changes were observed in tumor perfusion. Perfusion was significantly higher after hyperthermia. Increases in perfusion were most evident in tumors with T50 < 44 degrees C. With T50 > 44 degrees C, there was no change in perfusion after hyperthermia. On average, pHe values declined in all animals after hyperthermia, with the greatest reduction seen for larger T50 values. CONCLUSION: This study suggests that hyperthermia has biphasic effects on tumor physiologic parameters. Lower temperatures tend to favor improved perfusion and oxygenation, whereas higher temperatures are more likely to cause vascular damage, thus leading to greater hypoxia. While it has long been recognized that such effects occur in rodent tumors, this is the first report to tie such changes to temperatures achieved during hyperthermia in the clinical setting. Furthermore, it suggests that the thermal threshold for vascular damage is higher in spontaneous tumors than in more rapidly growing rodent tumors.