ORIGINAL ARTICLE 
Annals of Nuclear Medicine Vol.9, No.2, 65-74, 1995 

Evaluation of Tl-201 SPECT for monitoring the treatment of pulmonary and mediastinal tumors 

Ryuichiro NAMBA, Isamu NARABAYASHI, Ritsuo MATSUI, Kozo SUEYOSHI, Yasunobu NAKATA, 
Kojiro TABUCHI and Tsuyoshi KOMORI 
Department of Radiology, Osaha Medical College 

Tl-201 single photon emission computed tomography (SPECT) was performed in 88 patients with pulmonary or mediastinal tumors in order to evaluate its usefulness for the detection of disease and for the assessment of the effect of treatment. We also examined mediastinal and hilar lymph node metastasis from lung cancer. Tl-201 SPECT showed abnormal accumulation on delayed images in all lung cancer patients with tumor diameters more than 12 mm. In the 14 operated lung cancer patients, mediastinal and hilar lymph node metastases with diameters of more than 15 mm were imaged, but one with a diameter of 9 mm was missed. The retention index (RI) was 27.52 +- 31.58 in malignant tumors and -13.67 +- 8.15 in benign tumors (p < 0.05). The RI was significantly lower after treatment than before treatment. The interval until tumor recurrence or reactivation tended to be longer in patients who showed a significant decrease in the RI after therapy. These findings suggest the usefulness of the RI as an index of therapeutic efficacy. 

Key words: Tl-201 SPECT, pulmonary and mediastinal tumors, therapeutic efficacy 

INTRODUCTION 

GALLIUM-67 CITRATE (Ga-67) and thallium-201 chloride (Tl-201) are widely used for tumor imaging. Tl-201 is primarily used for myocardial scintigraphy, but it was also reported to accumulate in tumors,1 and its clinical usefulness for tumor scintigraphy has been demonstrated.2-4 Tl-201 is particularly useful with regard to distinguishing between benign and malignant tumors, and the determination of tumor location is enhanced by its combination with SPECT.5.6 Moreover, because of its usefulness in qualitative diagnosis, which is difficult by morphological imaging techniques such as CT and MRI, it is possibly also applicable to the evaluation of therapeutic efficacy. In this study, Tl-201 SPECT was performed in patients with pulmonary and mediastinal tumors, and its usefulness for tumor detection and for assessment of the response to treatment was evaluated. 

MATERIALS AND METHODS 

A total of 88 patients (58 men and 30 women, aged from range 37 to 85 years; mean age: 65.3 years) with lung cancer or mediastinal tumors confirmed by surgical and/ or pathological examination were studied. They included 71 patients with primary lung cancer (42 untreated, 26 post-radiotherapy and/or chemotherapy and 3 in a post operative disease-free state), 10 with metastatic lung cancer (8 untreated, and two post- radiotherapy and/or chemotherapy), 6 with mediastinal tumors (one with malignant lymphoma, one with thymic cancer, two with thymoma, one with paraganglioma, and one with lymphadenopathy), and one with pulmonary hemangioma. A dose of 222 MBq of Tl-201 was injected intravenously and SPECT images were obtained at 1 5 min (early image) and 3 hr (delayed image) after injection by using a 3-headed gamma camera (GCA-9300A) equipped with low energy, general purpose parallel hole collimators. Data were acquired in 90 views over 360 degrees at 30 sec/ view. Images were obtained with a 128 x 128 matrix and a slice thickness of 3.2 mm. In addition, transverse, coronal, and sagittal images were reconstructed without attenuation correction. When Tl-201 uptake in the target area was defined as positive, we set regions of interest (ROIs) in the area with abnormal radioactivity, in the Early (Delayed) ratio =(count l/pixel - count 3/pixel)/ (count 2/pixel - count 3/pixel )

contralateral normal lung, and in the background (out of the lung field) on the early and delayed transaxial images (Fig. 1). Those transaxial planes which demonstrated the lesion clearly were selected and merged. We then calculated the uptake ratios on both early images (early ratio) and delayed images (delayed ratio), as well as the RI as follows: 

RI =Delayed Ratio Early Ratio / Early Ratio x 100 

 These parameters were compared with the histological diagnosis, the tumor diameter and the response to treatment as the tumor reduction after treatment. The tumor reduction and the RI reduction were calculated as follows: 

Tumor reduction =MAb X MIb - MAa x MIa / MAb X MIb X 100 
RI reduction = RIb - RIa/RIb X 100 
MAb: major axis of the tumor before treatment 
MAa: minor axis of the tumor after treatment 
RIb: RI before treatment 
RIa: RI after treatment 

Moreover, the RI after treatment was analyzed in relation to the length of time from treatment to tumor recurrence or recrudescence. Mediastinal and hilar lymph node metastases from lung cancer were examined in 14 operated lung cancer patients. 

RESULTS 

1) Evaluation of Tl-201 SPECT images 
Tl-201 SPECT was positive in all lung cancer patients with tumor diameters of 12 mm minimum in this study. It was negative in patients with smaller lung cancers and with benign tumor. In the patients with malignant mediastinal tumors, Tl-201 SPECT detected thymic cancer and malignant lymphoma. Among the benign mediastinal tumors, two thymomas showed abnormal Tl-201 accumulation on both early and delayed images. Contrast benign paraganglioma and lymphadenopathy did not show any abnormal accumulation on the delayed images. In the operated lung cancer patients, mediastinal and hilar lymph node metastases with diameters more than 15 mm were detected, but one with a diameter of 9 mm was not imaged (Case a, Table a). 

2) Evaluation of ER, DR, and RI 
Figure 2 presents the retention index (RI) values in comparison with the pathological types of lung cancer, and for malignant or benign lesions. The ER was 1.904 +- 0.572 in all malignant tumors and 2.115 +- 0.572 in benign lesions. The DR was 2.399 +- 1.017 in all malignant tumors and 1.775 +- 0.460 in benign lesions. There were no significant differences between malignant and benign tumors with respect to the ER and DR. In contrast the RI was 27.52 +- 31.58 in malignant tumors and -13.67 +- 8.15 in benign tumors, with a significant difference between malignant and benign lesions (p < 0.05). However, there were no significant differences among the three histological types of lung cancer.

3) Relationship between RI and tumor size 
Figure 3 presents the relationship between RI and tumor size. There was a tendency for the RI to increase as the tumor diameter became larger. The ER and DR also showed a similar trend to the RI. 

4) ER, DR, and RI in the treated and untreated groups of lung cancer 
Figure 4 compares the ER, DR, and RI values for the treated and untreated groups. The ER and DR showed no significant difference between the two groups. On the other hand, the RI differed significantly (p < 0.01) between the untreated group (27.52 +- 31.58) and the treated group (8.12 +- 20.98). 

5) Changes in the ER, DR, and RI aftertreatment 
Table 2 shows the 15 patients with lung cancer who underwent TI-201 SPECT both before and after treatment. As seen in Figure 5, the DR and RI decreased significantly after treatment (p < 0.01), while some patients showed an increase in the ER. 

6) Relationship between tumor response and RI 
As shown in Figure 6, the extent of tumor reduction after treatment was not correlated with the decrease in RI. The reduction in RI was slightly greater in patients with squamous cell carcinoma than those with adenocarcinoma. 

7) Relationship between the retention index aftertreatment and the length of time from treatment to tumor recurrence or recrudescence 
Table 3 shows the summary of 24 patients with lung cancer who were followed up after treatment. As shown in Figure 7, the retention index was significantly lower for patients who had developed recurrence or recrudescence within 6 months after treatment than for patients without recurrence or recrudescence. 

REPRESENTATIVE CASES 

Case l. 
A 56-year-old man was admitted to our hospital to evaluate an abnormal chest radiograph taken at a routine medical examination (Fig. 8a). A coin lesion approximately 15 mm in diameter was noted in the right upper lung (Fig. 8b). Tl-201 SPECT demonstrated an abnormal accumulation corresponding to the pulmonary lesion in both early and delayed images (Fig. 8c). No abnormal accumulation was noted in the mediastinum. The ER, DR, and RI values were 1.68, 1.74, and 3.6, respectively. At operation, a 15 x 10 x 15 mm well differentiated adenocarcinoma was found in S1 of the right lung and the pathological stage was I (TNM classification: T1N0M0)' 

Case 2. 
The patient was a 67-year-old woman with primary lung cancer (T4N2M1 small cell carcinoma). She underwent chest radiography because of a persistent dry cough. A lesion was noted at the right hilum along with atelectasis. Chest CT scans revealed enlargement of No. 5 lymph node (Fig. 9a). After two courses of systemic chemotherapy, CT scanning showed a small tumor remnant (Fig. 9b). The delayed SPECT images obtained after one course of chemotherapy showed Tl-201 accumulation in the residual tumor (Fig. 9c). After two courses of 
chemotherapy, the tumor was still observed on CT scans but there was no Tl-201 accumulation in SPECT images (Fig. 9d). The RI decreased from 11.1 to -15.9. No recurrence of this tumor was observed over the subsequent 9 months.

Case 3. 
The patient was a 74-year-old man with primary lung cancer (T2N2M1 small cell carcinoma). He developed a cough, bloody sputum, and fever in June 1993 and visited a local hospital. Plain X-ray and CT scanning of the chest showed a tumor measuring 3.5 x 3.5 cm in the right lower lung field (Fig. 10a, b). After two courses of systemic chemotherapy and radiotherapy (60 Gy), the tumor decreased to 1.5 x 1.0 cm in CT scans (Fig. 10c). Tl-201 SPECT before treatment showed abnormal accumulation at the tumor site in both early and delayed images (Fig. 10d). The ER, DR, and RI values were 1.66, 2.11, and 27.1, respectively. After treatments SPECT showed a decrease in the extent of Tl-201 accumulation but residual intense accumulation (Fig. 10e). The ER, DR, and RI values were 1.41, 1.79, and 27.0, respectively, with the RI showing little change. Chest CT scanning after 4 months revealed an increase in the tumor size. 

Case 4. 
A 58-year-old woman was admitted to our hospital for evaluation of an abnormal chest radiograph which was found during routine medical examination. A lesion measuring 10 x 10 mm was noted in the right middle lung field (Fig. 11a). Chest CT scanning demonstrated a 10 x 10 mm diameter coin lesion in the right S6 (Fig. 11b). Tl-201 SPECT showed marked abnormal accumulation at the tumor site in the early images, but no accumulation in the delayed images (Fig. 11c). The ER, DR, and RI values were 2.42, 11.57, and -35.l, respectively. The tumor was resected and was histologically proven to be a pulmonary sclerosing hemangioma. 

Case 5. 
A 57-year-old woman was admitted to our hospital to evaluate an abnormal chest radiograph obtained at routine medical examination. A mass was noted in the mediastinum (Fig. 12a). Chest CT showed a 3 x 4 cm mass in the middle mediastinum (Fig. 12b). Tl-201 SPECT demonstrated abnormal accumulation corresponding to a mediastinal lesion on early images, with washout on delayed images (Fig. 12c). The ER, DR, and RI values were 2.35, 2.10, and -10.6, respectively. Operative findings proved the existence of a 4 x 3 x 3 cm benign paraganglioma of the middle mediastinum. 

DISCUSSION 

At present, Tl-201 and Ga-67 are extensively used clinically as tumor-seeking radionuclides. Many recent reports have demonstrated that Tl-201 is more useful than Ga-67 in distinguishing benign tumors of the lungs from malignant ones, and in evaluating tumor metastasis to the pulmonary hilum and mediastinal lymph nodes.(~9 We assessed the clinical utility of Tl-201 SPECT in patients with pulmonary and mediastinal lesions. We noted marked Tl-20 1 accumulation by malignant pulmonary and mediastinal tumors larger than I .2 cm in diameter. In patients with benign tumors of the lung and mediastinum, Tl-20 1 accumulation was sometimes negative in the early images. Even when the early images were positive, Tl-201 accumulation decreased in the delayed images in most cases. 

Regarding the distinction between malignant and benign thyroid tumors, Ochi et al. reported that Tl-201 accumulation in malignant tumors tended to be persistent, whereas accumulation in benign tumors tended to decrease more rapidly.lo Tonami et al. reported that the RI was useful in distinguishing benign tumors from malignant ones.5.6 These previous findings were supported by the results of the present study. Our results indicate that Tl-201-negative tumors larger than 1.2 cm in diameter are likely to be benign, and that the RI provides a useful means of distinguishing benign TI-201-positive tumors from malignant ones. Several studies have examined differences in TI-201 accumulation among the various histological types of lung cancer. Tonami et al. found that the DR and RI varied significantly among the different histological types .8 Togawa et al . also reported that planar images obtained 30 min after intravenous injection of Tl201 showed more marked accumulation in adenocarcinoma than in squamous cell carcinoma or small cell carcinoma.11 In the present study, the RI was slightly higher for adenocarcinoma than for squamous cell carcinoma and small cell carcinoma. However there was no difference in the ER and DR between any two histological types of lung cancer. Some investigators have reported that tumor size is correlated with the Tl-201 positivity rate, similarly to the relationship between tumor size and Ga-67 positivity.9 In the present study, however, the ER, DR, and RI were not correlated with tumor size. 
We also investigated the utility of Tl-201 SPECT in assessing the efficacy of radiation therapy and chemotherapy on malignant pulmonary and mediastinal tumors. Some investigators have reported that Ga-67 uptake by lung cancer is related to the prognosis and survival time,11  and others reported the utility of Tl-201 scintigraphy in assessing the therapeutic effect on rabbit VX-2 tumors,12 but the present study is the first to use SPECT to examine the relationship between Tl-201 uptake by malignant mediastinal tumors and therapeutic efficacy. No significant difference was observed between the treated group (n = 25), which received radiation therapy and/or chemotherapy, and the untreated group (n = 45) in the ER and DR values, but the RI was significantly lower in the treated group. This indicates that the treatment affected the intratumor accumulation of Tl-201: it not only reduced the initial accumulation, but also increased the speed of efflux. If the therapy is assumed to reduce tumor cell viability and the grade of malignancy, this reduction in RI is consistent with the fact that Tl-201 is washed out more rapidly from benign tumors than malignant tumors. In fact, the RI was significantly lower after treatment than before treatment when Tl-201 SPECT was repeated in the same patients. This suggests the usefulness of the RI as an index of therapeutic efficacy. On the other hand, there was no relationship between the change in tumor size and the change in RI after treatment. This also indicates that the RI reflects a qualitative change in Tl-201 uptake rather than an alteration in tumor volume. As shown in Table 3 and Figure 7, the time to recurrence or recrudescence of the tumor tended to be longer in patients who showed a significant decrease in the RI after treatment than in those who showed only slight decrease. The RI appears therefore to decrease more markedly when the therapeutic effect is greater. In this respect, however, the relationship between RI and tumor recurrence or recrudescence must be studied further by following up more patients over a longer period. Evaluation of tumor response is important for determining the correct approach to treatment. Estimation of the time until tumor recurrence or recrudescence when using Tl-201 SPECT may allow more efficient follow-up of patients and indicate those who would benefit from additional treatment. 

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