ORIGINAL ARTICLE 

Annals of Nuclear Medicine Vol. 14, No. 6, 415-420, 2000 

Technetium-99m MIBI single photon emission computed tomography 
as an indicator of prognosis for patients with lung cancer 
-Preliminaly report-

Tsuyoshi KOMORI, Isamu NARABAYASHI, Ritsuo MATSUI, Kozo SUEYOSHI, Taizo ARATANI and Keita UTSUNOMIYA 

Department of Radiology, Osaka Medical College 

Purpose: We performed technetium-99m hexakis-2-methoxyisobutylisonitrile (Tc-99m MIBI) single photon emission computed tomography (SPECT) in 23 patients with primary lung cancer between July 1993 and March 1996. We evaluated the relationships among the uptake ratio, retention index and the prognosis after radiation therapy and/or chemotherapy. Materials and Methods: Tc-99m MIBI SPECT was performed at 30 minutes and at 3 hours after intravenous injection of 600 MBq of Tc-99m MIBI with three gamma camera detectors (GCA-9300A/HG) on transverse SPECT images. Regions of interest were set in the area of abnormal uptake of Tc-99m MIBI and in the contralateral normal lung. The ratio of uptake in the lesion to that in the contralateral normal lung was obtained on early images (early ratio; ER) as well as delayed images (dclayed ratio: DR). The retention index (RI) was calculated as follows: RI=(DR-ER)/ERx100. The ratio was compared with survival time and prognostic factors. Results: There was no correlation between ER and DR. The patients with high RI survived longer than those with low RI (median survival, 19.4 months vs. 9.4 months; p=0.0104 by the Mantel-Cox test). Conclusion: These results suggest that RI is the most useful among Tc-99m MIBI indices of primary lung cancer in predicting prognosis. 

Key words: technetium-99m-MIBI, lung cancer, prognosis, single photon emission computed tomography 


INTRODUCTION 

Technetium-99m hexakis-2-methoxyisobutylisonitrile (Tc-99m MIBI) is an approved myocardial perfusion imaging agent.1,2 It is an isonitrile with myocardial distribution proportional to regional blood flow. Intracellularly, it is sequestered largely within the mitochondria.3-5 Although many reports6-12 have described the accumulation of Tc-99m MIBI in various kinds of malignant tumors, there have been few clinical evaluations that included the uptake ratio of Tc-99m MIBI and prognosis. Some have reported that the washout of Tc-99m MIBI reflects the P-glycoprotein (Pgp),13-17 whereas one report 

 Received April 10, 2000, revision accepted September 11, 2000. 
 For reprint contact: Tsuyoshi Komori, M.D., Ph.D., Department of Radiology, Osaka Medical College, 2-7, Daigakumachi, Takatsuki, Osaka 569-8686. JAPAN. 

states that the uptake of Tc-99m MIBI correlates with the sensitivity of radiation therapy.18 The aim of this study was to evaluate the relationship between the prognosis and uptake ratio or washout rate of Tc-99m MIBI in patients with lung cancer. 


MATERIALS AND METHODS 

Case selection 
A total of 38 patients with primary lung cancer underwent Tc-99m MIBI single photon emission computed tomography (SPECT) at our institution between July 1993 and March 1996. We observed survival time from July 1993. Of those patients, 15 had undergone surgery. Therefore, we evaluated 23 patients (Table 1) - 20 men and 3 women (age range, 42-82 yr; mean age, 62.1+-10.4 yr). The performance status of all patients was grade 0. No patient had received treatment before the Tc-99m MIBI SPECT, but subsequently these patients received chemotherapy (Cisplatin, 80 mg/m2; Vindesine, 3 mg/m2) intravenously or through a bronchial artery, and 20-60 Gy radiation therapy. 
 Four patients at stage M2 died of lung cancer. 
 Informed consent was obtained from each patient. The histological diagnosis was obtained by biopsy or at surgery in all patients. The TNM classification for lung cancer was determined according to the guidelines of the American Joint Committee on Cancer.19 

Imaging 
Pulmonary SPECT was performed with a triple-head rotating gamma camera (GCA-9300A/HG, Toshiba) 30 minutes and 3 hours after intravenous injection of 600 MBq of Tc-99m MIBI. Ninety projections at 30 sec/view through a 360deg. rotation were obtained in 128x128 matrices with a slice thickness of 3.2 mm. Transverse, coronal and sagittal images were reconstructed. 
 No scatter or attenuation correction not done. The semi-quantitative methods were as follows: When the Tc-99m MIBI tomogram showed an abnormal uptake in a pulmonary lesion in early images, we added those slices and set irregular regions of interest (ROI) automatically at a maximum of 80% of the lesion. The normal ROI was set on the contralateral normal lung with transverse sections of early scans. With the delayed images, the ROI of the early images was copied. The background ROI, which was square, was set out of the body. The size was 20x40 pixels. The uptake ratios of tumor-to-normal tissues in the early image (early ratio; ER) and delayed image (delayed ratio; DR) were calculated as follows: 
   Uptake ratio=(T-B)/(N-B). 
Where T=a count of 80% of the tumor lesion; B=background count; N=normal lung count. 
 When the uptake of delayed images was washed out, we referred to the early images and set the ROI to the same region. The retention index (RI) was calculated as follows: 
   RI= (DR-ER)/ERx100. 

Statistical analysis 
We evaluated the relationships among the uptake ratio, retention index and the prognosis after radiation therapy and/or chemotherapy. We calculated the accumulated survival rate by the Kaplan-Meier method. To test for differences among the disease groups for the mean survival of ER, DR, and RI, the Mantel-Cox test was used. We considered results significant when the p value was less than 0.05. 


RESULTS 

The median follow-up time for the whole series was 13 months (range, 1-50 months). Table 1 shows the characteristics of the 23 patients. The Tc-99m MIBI uptake ratio was classified into 2 groups according to the mean value (ER, mean+-standard deviation [SD] of 2.1+-0.7; DR, 2.0+-0.7). The retention index was classified into 2 groups according to the mean value (mean+-SD of -6.5+-24.0). Tumors with a Tc-99m MIBI retention index (RI) of <= -6.5 were grouped as low Tc-99m MIBI RI, and those with a Tc-99m MIBI RI of > -6.5 were grouped as high Tc-99m MIBI RI. The high Tc-99m MIBI RI group survived longer than the low RI group (median survival, 19.4 months vs. 9.4 months, respectively) (Fig. 1). The overall difference was significant (p=0.0104). There was no significant difference between the high ER and low ER groups or between the high DR and low DR groups (Table 2). There was no significant difference between the high RI and low RI groups in the distribution of histological types (x2-test). 
 Figures 2 and 3 show representative cases in low and high RI groups, respectively. Patient 15 in Figure 2 and Patient 23 in Figure 3 were alive for 12 and 25 months, respectively. 


DISCUSSION 

Tc-99m MIBI, a relatively new imaging agent developed for the study of blood flow in cardiac muscles, is known to accumulate in various malignant tumors.6-12 Its advantages are a low exposure dose, high image quality and clear SPECT images. Tc-99m MIBI, a member of the isonitrile class of coordination compounds, is a lipophilic cation. The tumor uptake mechanism of Tc-99m MIBI is not well understood. It has been suggested that it binds to cytosol in tumor cells, as in the myocardium.1,2 The cationic charge and plasma membrane potentials of the tumor cell and the cellular mitochondrial content can play an important role in a tumor uptake of this agent,3 or the uptake may be caused by indirect phenomena, such as increased tumor blood now and capillary permeability. It has recently been reported that Tc-99m MIBI could be a substrate for PgP and thus extruded like chemotherapy drugs from cells.20-23 The retention of Tc-99m MIBI in cells depends on the activity of 170 kDa PgP coded on the mdr gene, which functions as an ATP-dependent efflux pump for many cytotoxic substances, mostly lipophilic cations. Tc-99m MIBI has been reported to be a ligand for this mdr-PgP,24 since cell accumulation of the complex has been reported to be inversely related to the level of PgP. Other studies have shown that verapamil and cyclosporin A, multi-drug resistant reversal agents, greatly enhanced accumulation of Tc-99m MIBI. Piwnica-Worms et al.25 showed a relationship between Tc-99m MIBI tumor uptake and mdr-PgP, implying the potential of Tc-99m MIBI scintigraphy as a noninvasive imaging test for mdr-PgP assessment. Tc-99m MIBI is reported to be a substrate of MDR-associated protein (MRP),26 MRP is related to the tolerance of CDDP thought the glutathione S transferase pi (GSTpi).27 Therefore, the accumulation of Tc-99m MIBI is related to the tolerance of CDDP indirectly. On the other hand, multifactorial drug tolerance has been reported in lung cancers.28,29 The cancer accumulation of Tc-99m MIBI and radiosensitivity has also been reported.30 Patients who have low Pgp indicate high RI and have high chemosensitivity, and in addition, patients with high RI also have many mitochondria rich cells that are aerobic, so it speculated that they also have high radiosensitivity. 
 The main option for treating advanced non-small cell lung carcinoma is chemotherapy and/or radiotherapy. It is difficult to predict the prognosis of non-small cell lung carcinoma by means of morphologic imaging techniques such as CT and magnetic resonance imaging (MRI). Clinically, Tc-99m MIBI images are useful in predicting the efficacy of chemotherapy in small cell lung cancer, malignant lymphoma and breast cancer.31-33 These reports show that chemotherapy is effective when Tc-99m MIBI accumulates in the tumor. We therefore evaluated the correlation between the uptake ratio, the retention index of Tc-99m MIBI SPECT and the prognosis. Our results showed that patients with a high RI had a good prognosis. This suggests that a high RI tumor has no tolerance for chemotherapy and contains tumor cells rich in mitochondrial components. There are some reports that indicate a correlation between Tc-99m MIBI uptake and the PgP level in other carcinomas.13-17 On the other hand, there have also been some studies on predicting the prognosis of lung cancer patients with Tl-201 , F-18 FDG and Methionine.34,35 These patients had long term survival when the uptake ratio was over 2.5 of Tl-201. W-J Shih found a significant linear correlation between survival and the inverse of the [11C]methionine uptake ratio in patients that died, with a correlation coefficient of 0.831 (p<0.001). These reports indicate a correlation between the uptake by the tumor and the prognosis. In this study, there was no significant correlation between ER and DR, but the high RI group had a better prognosis than the low RI group. Kao et al.36 reported that Tc-99m MIBI chest images have the potential to show a mdr-PgP expression in small cell lung carcinomas (n=15), and to predict patient prognosis and chemotherapy response. Our treatment method included radiotherapy, and we studied small and non-small cell lung carcinomas. No significant difference in prognosis was observed either between high ER and low ER groups or between the high DR and low DR groups. 
 Nevertheless, the high RI group showed a tendency to a good prognosis when combined with primary lung cancer therapy. It may also be necessary to select a more aggressive treatment protocol for low RI patients. Since this preliminary report includes only a few cases, further examinations with a larger number of cases and various histological types are necessary. 


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