ORIGINAL ARTICLE 
Annals of Nuclear Medicine Vol, 12, No. 6, 355-362, 1998 
201Tl SPECT as an indicator for early prediction of therapeutic effects in patients with non-small cell lung cancer 
Kazuyoshi SUGA, Norihiko KUME, Kazuya NISHIGAUCHI, Nobuhiko OGASAWARA, Akiko HARA, Gouji MIURA, Tsuneo MATSUMOTO and Naofumi MATSUNAGA 
Department of Radiology, Yamaguchi University School of Medicine 
This study retrospectively investigated the good parameters on thallium-201 chloride (201Tl) SPECT for early assessment of the therapeutic effects in patients with non-small cell lung cancer. 
Based on tumor response as determined by chest CT scan about 9 weeks after the end of irradiation with adjuvant chemotherapy, the subjects were divided to the responder group (tumor regression > 50%, n = 13) and non-responder group (tumor regression < 50%, n = 13). 201Tl SPECT was performed before and at the halfway through the course of therapy (average tumor dose, 27.4 Gy +-4.5) in all the patients. SPECT was conducted twice 15 min (early scan) and 120 min (delayed scan) after intravenous injection of 148 MBq (4 mCi) of 201Tl. Tumor-to-contralateral normal lung tissue count ratios on both scans were calculated as early and delayed uptake ratios (EUR and DUR), and a retention index (RI) was also derived from these ratios. 
In the responder group, a significant decrease in DUR and RI halfway through the therapy was observed compared to pretreatment (2.6+-0.6 vs. 3.5+-1.0 ; p < 0.01, and -2.3%+-25.5 vs. 37.4%+-17.8 ; p < 0.001, respectively), even though EUR did not change significantly (N.S.). By contrast, in the non-responder group, there were no significant changes in any of these parameters (N.S.). When comparing DUR and RI for the two groups halfway through the therapy, DUR and RI were significantly lower in the responder group (both; p < 0.01), but no significant difference was noted in EUR (N.S.), and the percent reduction in tumor size did not correlate with the percent decrease in DUR or RI (N.S.). 
These results indicate that the extent of decrease in DUR and RI after therapy can be a useful parameter for early assessment of the therapeutic effects in patients with non-small cell lung cancer. 
Key words: thallium-201 chloride, single photon emission computed tomography (SPECT), lung cancer, radiation therapy 
INTRODUCTION 
COMPUTED TOMOGRAPHY (CT) has been a standard method of measuring tumor size and assessing tumor response to radiation and/or chemotherapy. Nevertheless, this method is insufficient for assessing the therapeutic effects soon after starting therapy, since treated tumors may show signs of slow regression even in successful therapy.1-7 

Received August 3, 1998, revision accepted October 2, 1998. 
For reprint contact: Kazuyoshi Suga, M.D., Department of Radiology, Yamaguchi University School of Medicine, 1144 Kogushi, Ube, Yamaguchi 755-8505, JAPAN. 

Thallium-201-chloride (201Tl) has recently been proven useful for assessing the therapeutic response of a variety of malignant tumors,7-15 and our previous animal study using VX-2 tumors indicated that tumor 201Tl uptake was altered soon after irradiation.16 If we could assess tumor response soon after starting therapy, it would be beneficial when considering additional therapeutic regimens in some patients, and ultimately the patient's prognosis would improve. In this study, the authors retrospectively survey the parameters measured by 201Tl SPECT available for the early evaluation of therapeutic effects in treated patients with non-small cell lung cancer. 
MATERIALS AND METHODS 
Between September 1993 and April 1998 a total of 32 patients with non-small cell lung cancer (adenocarcinoma, 16; squamous cell carcinoma, 14; large cell carcinoma, 2) underwent 201Tl SPECT and CT scans before and approximately halfway through radiationtherapy (accumulated tumor dose: 27.4+-4.5 Gy) with or without adjuvant chemotherapy (cisplatin mainly; 1 course = 70-120 mg). The adjuvant chemotherapy was concomitantly performed during radiationtherapy. Local tumor response to therapy was assessed by follow-up CT scan about 9 weeks (average; 9.2+-1.3 weeks) after the therapy. The assessments of mediastinal and hilar lymph nodes were omitted because of the lack of histologic confirmation before the treatments. Of the 32 patients, a total of 26 (22 males and 4 females, average age, 65.3 yrs) were retrospectively analyzed in this study (Table 1). The remaining 6 patients were excluded because of difficulty in accurately defining the tumor borders due to secondary changes such as atelectasis or obstructive pneumonia or marked radiation pneumonitis. The 26 patients consisted of 13 patients in the responder group who had more than 50% tumor regression compared to pretreatment (12 males and 1 female; squamous cell carcinoma 7, adenocarcinoma 4 and large cell carcinoma 2), and 13 patients in the non-responder group who had less than 50% tumor regression (10 males and 3 females; adenocarcinoma 11, squamous cell carcinoma 2). Between these two groups there were no significant differences in tumor size before treatment (1948+-1475 mm2 vs. 2091+-1571 mm2; N.S.), in the radiation doses halfway through the course of treatment (26.9+-4.3 Gy vs. 28.0+-4.7 Gy; N.S.) or the doses added until the end of therapy (23.2+-4.2 Gy vs. 27.0+-5.3 Gy; N.S.), in the doses of cisplatin halfway through the course of treatment (114+-29 mg vs. 107+-10 mg; N.S.) or the total doses of cisplatin until the end of therapy (231+-18 mg vs. 241+-21 mg; N.S.). The standard classifications of tumor response are: complete response (CR; complete disappearance of the tumor), partial response (PR; more than 50% tumor regression), no change (NC; less than 50% tumor regression), and progressive disease (PD; tumor enlargement). The responder group included 2 patients with CR and 11 with PR, whereas the non-responder group included 8 patients with NC and 5 with PD. Separate informed consent was obtained prior to each SPECT study from all the patients. 
201Tl SPECT was conducted 15 min (early scan) and 120 min (delayed scan) after intravenous injection of approximately 148 MBq (4 mCi) of 201Tl chloride, using a three-detector gamma camera (Toshiba 9300A/HG, Tokyo, Japan) equipped with a low-energy collimator in a 64 x 64 matrix, and with 20%-windows centered over an 80 keV energy peak. A 360deg., SPECT of the chest was performed with an acquisition time of 20 sec/view for 64 steps. Contiguous transaxial images were reconstructed at 6.4 mm-thickness. No attenuation or scatter correction was performed. 
Chest CT scan was performed 2 or 3 days after 201Tl SPECT, with a Toshiba-900-S scanner at 5-mm slice sections and intervals. Tumor sizes were measured by the maximal tumor areas on sequential CT scans, and the product of width x length was designated as the tumor size. Geographic localization of 201Tl uptake by the tumor was determined by visual estimation, taking into account the location and intensity of abnormal tumor activity in comparison with the background of normal lung with reference to findings on CT scan. Quantitative analysis of tumor 201Tl uptake was determined by the regions of interest (ROIs) drawn manually inside the outer border of the tumors with positive accumulation of this agent.12 An identical ROI was drawn over the contralateral lung field, which was presumed to be normal on CT scan. The mean pixel counts for ROIs were measured, and the ratios of the lesion to contralateral lung tissue on both early and delayed scans were obtained, yielding early and delayed 201Tl uptake ratios (EUR and DUR) in the tumor.12,13 The 201Tl retention index (RI) was also calculated in order to evaluate the degree of 201Tl retention in the tumors, according to the following formula: RI = (delayed uptake ratio - early uptake ratio)/early uptake ratio x 100%.12 These measurements were performed without prior knowledge of treatment. To assess the correlation between tumor response and the parameters measured on 201Tl SPECT, group comparisons were performed by means of Student's t-test. Differences were considered significant when the p-value was less than 0.05. Linear regression analysis was performed with commercially available software (StatView 4.02 SE + Graphics; Abacus Concepts, Berkeley, Calf to assess the linear dependency between tumor reduction after therapy and the changes in the parameters measured by 201Tl SPECT. 
RESULTS 
The changes in EUR, DUR and RI halfway through the therapy are summarized in Table 1. Before treatment all of the tumors showed positive 201Tl uptake, and there were no significant differences in these parameters for the responder and non-responder groups (N.S.). All the tumors also remained positive for 201Tl uptake halfway through the therapy. In the responder group, EUR tended to decrease compared to pretreatment, but without significance difference (N.S.), whereas DUR and RI significantly decreased (both; p < 0.01) (Table 1, Figures 1, 3). When normalizing DUR and RI compared to the pretreatment values (100%), these parameters decreased to 68.4+-17.9% and -16.9+-17.8%, respectively. By contrast, in the non-responder group, none of these parameters was significantly changed compared pretreatment (N.S.) (Table 1, Figures 2, 3). When comparing DUR and RI halfway through the therapy for the two groups, these parameters were significantly lower in the responder group (both; p < 0.01), but no significant difference was noted in EUR (N.S.) (Table 1). A linear regression analysis showed that the percent reduction in tumor size halfway through the therapy was not correlated with the percent decrease in DUR or RI (N.S.) (Figure 4). 
DISCUSSION 
This retrospective study indicates that the delayed uptake ratio (DUR) and retention index (RI) can be changed rather soon after starting therapy in patients with non-small cell lung cancer, and that the extent of decrease in these two parameters can be predictive indicators for tumor response to therapy. Although several investigators have previously shown that DUR and RI were significantly decreased after completion of therapy in lung cancer patients with a good response to therapy,3,6-8 our results indicate that the reduction can occur soon after therapy. Furthermore, our results showed that DUR and RI changed independently of tumor volume after therapy, as indicated by no correlations with the reduction in tumor size. This indicates the superiority of 201Tl SPECT to morphologic CT scan in assessing therapeutic effects. The non-invasiveness and high sensitivity of this method in visualizing relatively small tumors also seems beneficial for early evaluation of therapeutic effects.13 
Since 201Tl retention in tumors on delayed SPECT scan may depend on the clearance of 201Tl from tumor tissues, the reduction in DUR and RI in our responder group indicates that 201Tl may result in a faster washout when the tumors respond well to therapy. If therapy is assumed to reduce tumor cell viability and the grade of malignancy, reduction of these parameters is consistent with a previously reported finding that 201Tl washed out more rapidly from benign tumors than from malignant tumors.13,14 There is also considerable evidence that these parameters are associated with malignant potential or tumor proliferative activity in lung cancer. Takekawa et al.15,16 demonstrated the association of tumor 201Tl uptake and intensity of Na-K ATPase staining in lung adenocarcinomas, and slower washout or increased retention of 201Tl in these neoplasms with high metastatic potential or poor differentiation. These investigators also showed that DUR was a reliable prognostic factor for survival in patients with various types of lung cancer.17 Yamaji et al.8 reported a significantly lower RI in patients with early recurrent lung cancer than in patients without recurrence after completion of therapy. Tonami et al.14 showed that this index was highest for small-cell lung carcinoma with early lymph node metastasis. In various malignant tumors other than lung cancer, the degree of 201Tl retention in tumors was also reported to be associated with the malignant potential or tumor proliferative activity.18-21 
Although a significant reduction in EUR compared to pretreatment was not observed in our patients in the responder group, this parameter might also have decreased significantly if the responder group had included a greater number of patients with complete response (CR). Although after accomplishment of radiationtherapy, Shimizu et al.6 demonstrated that EUR significantly decreased in the patients with lung cancer in the CR group compared to that in patients in the partial response (PR) + no change (NC) group. Their study included a greater number of patients in CR than in our study. Our previous animal study,11 although with a planar scintigram, revealed a dose-dependent reduction in EUR in VX-2 tumors soon (7 days) after irradiation with a concomitant reduction in Bromodeoxyuridine (BrdU) uptake (proliferative activity indicator) in tumor tissues. Other animal and clinical studies demonstrated that hardly any 201Tl was taken up by nonviable or necrotic tissues in treated tumors.5,22-26 Although a transient increase in EUR soon after radiationtherapy despite subsequent tumor regression has been reported in a limited number of patients with intracranial tumor,10 this phenomenon was not observed in any of our patients with CR response, as shown in Figure 1. Intracranial tumors may have different 201Tl kinetics after therapy because of the presence of the blood-brain barrier. 
In some patients with lung cancer, early evaluation of tumor response during therapy may be beneficial when devising an efficient approach to treatment or adjuvant therapeutic regimens such as bronchial arterial infusion therapy. The importance of early evaluation of tumor response will increase in the strategies of recently developing stereotactic radiationtherapy and radiosurgery. A limitation of our study is the lack of histologic proof of tumor response to treatment. Pathological assessment by biopsy during the course of treatment is the only definitive examination to confirm tumor response to treatment. Obtaining sequential biopsies is usually difficult and even dangerous in patients with lung cancer. As demonstrated in this preliminary study, 201Tl SPECT with measurements of EUR and RI at accumulated radiation doses of approximately 27 Gy can be a non-invasive procedure for assessing therapeutic effects, but concerning the best timing for 201Tl SPECT during treatment, further study is needed. A further long-term follow-up study or a prospective study is also needed to validate our interpretation of 201Tl SPECT. 
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