The change in ATP content within tumors has been used to predict response rates. Ohtsubo described a linear relationship between decreases in tumor cell ATP content and decreases in cell survival when cells were heated in vitro using a range of temperatures (21
). This provides a rationale for considering change in tumor ATP content as a surrogate for cell viability. Glickson (13
) and Vaupel (22
) used 31-P MRS to measure changes in 31-P metabolites in response to hyperthermia. Vaupel used graded thermal doses by changing the time of heating at 43.5C and found that inorganic phosphate (Pi) increased with heating time, whereas all ATP peaks declined (22
Sijens et al., found that the ATP/Pi ratio in a murine mammary carcinoma increased slightly 18hr following 42C heating for 15 min (23
). For higher temperatures, however, there was a temperature-dependent decline in the ATP/Pi ratio. At 45C the ratio decreased by more than a factor of 10 (). In a thermoradiotherapy trial in sponteneous canine soft tissue sarcomas, 31-P MRS was performed prior to and 24h after the first hyperthermia treatment (24
). When ATP/Pi was plotted as a function of the median temperature achieved during hyperthermia, the temperature dependence of the ATP/Pi ratio was strikingly similar to that found in the murine mammary adenocarcinoma (). In a parallel trial in human soft tissue sarcomas in which thermoradiotherapy was administered prior to surgical resection, a decrease in adenosine triphosphate/phosphomonoester (ATP/PME) after the first hyperthermia treatment was associated with more necrosis in resected tumors (24
) (). Thus, in all of these models, the decrease in ATP observed at higher temperatures was consistent with increased thermal cytotoxicity and this quantification of ATP using MRS may have value as a measure of thermal treatment efficacy.
Figure 1 Changes in ATP/Pi, as measured from 31-P MRS, are temperature dependent. (A) Data from mouse mammary carcinoma grown in the flank measured 18 h after local heating for 15 min at the designated temperature. Figure reproduced with permission from the author (more ...)
DCE-MRI has been used to both predict and assess effects of thermal therapy on tumor response. In human soft tissue sarcomas treated neoadjuvantly with thermochemotherapy, there was an association between loss of contrast medium uptake and extent of necrosis (25
). Craciunescu et al., developed a semi-quantitative scoring scheme to describe the pattern and kinetics of contrast enhancement prior to the onset of treatment in 20 patients with locally advanced breast cancer (26
). The scoring system has three components: the first is related to morphology and comes from whether the shape of the enhancement pattern as described by the MR parametric maps is centrifugal or centripetal. The second and third components are physiologic, one related to tumor vascularity/permeability and the other to tumor extracellular extravascular space, as defined by the washin and washout parameters (). Tumors with a higher score were more likely to respond clinically compared to tumors with a lower score. Low scores were in tumors that likely had relatively poor perfusion. Although based on a very low number of patients, the specificity and sensitivity were 78 and 91%, respectively (p=0.002).
Figure 2 DCE-MRI perfusion patterns in locally advanced breast cancer (26). Left panel shows a cetrifugal pattern, with central contrast medium filling seen in the washin and washout parameters (top vs. bottom). Right panel is a tumor exhibiting a centripetal (more ...)
Assessing the effect of hyperthermia on tumor metabolism through PET imaging of glucose analogues is a powerful way to evaluate efficacy. Progressive loss of uptake of fluoro-deoxyglucose (FDG) as assessed with PET imaging has been found to be related to the amount of necrosis found in excised high grade soft tissue sarcomas that had been treated preoperatively with thermoradiotherapy (27
). Westerterp et al., performed serial FDG PET studies in 17 patients with esophageal cancer who were treated preoperatively with paclitaxel, cisplatin, radiotherapy and hyperthermia (29
). Patients with greater decreases in FDG uptake after two weeks of treatment had more necrosis in the resected tumor specimen. The positive and negative predictive values were both 75% in this limited series (). In an additional report, reduction in FDG PET uptake was a good indicator of pathologic response in 20 rectal cancer patients treated with radiotherapy, 5FU and hyperthermia (30
). In this study, the second PET imaging study was done after therapy was completed, so it was not tested as a predictor of response.
Figure 3 Receiver Operating Curve for prediction of pathologic CR rate following thermochemoradiotherapy, using change in FDG PET uptake after two weeks of treatment (29). The receiver operating curve assesses the true positive rate (Y axis) as a function of the (more ...)
In summary, there are several methods that appear to reflect the degree of direct cytotoxicity elicited from thermotherapy trials that integrate radiation and/or chemotherapy. Early changes in these parameters may allow accurate prediction of the response at the end of therapy, or at the time of surgical resection. In one study, a single measurement of pretreatment tumor perfusion characteristics was predictive of response (26
). In most other studies, a pretreatment determination was compared to a second observation at some point early in the treatment course. Though multiple imaging sessions is a strength of noninvasive tumor imaging, the need for two measurements can occasionally be problematic, as discussed later.