MRI Perfusion Study in Head and Neck Cancers for Early Prediction of Response to Radiotherapy: A Preliminary Study

Transcription

1 MRI Perfusion Study in Head and Neck Cancers for Early Prediction of Response to Radiotherapy: A Preliminary Study 1 Takeo Takahashi, 1 Norinari Honda, 2 Makoto Hosono, 1 Shinya Oku, 1 Hisato Osada, 1 Atsushi Abe, 1 Wataru Watanabe, 1 Mikito Hondo, 1 Keiichiro Nishimura 1 Department of Radiology, Saitama Medical Center, Saitama Medical School, 1981 Kamodatsujido-cho, Kawagoe, Saitama , Japan. 2 Department of Radiology, Kinki University School of Medicine, 377-2, Ohnohigashi, Osakasayama, Osaka , Japan. SUMMARY Purpose: This study investigated sequential changes in tumor perfusion and assessed the clinical significance in the prediction of outcome of patients with head and neck cancers treated with radiotherapy. Methods: MR perfusion imaging was performed in 11 patients with head and neck cancers. Two sequential studies were obtained for each patient: immediately before radiotherapy and after a dose of 20 Gy (early during radiotherapy). Perfusion images of tumors were obtained using T1-weighted gradientecho (Fast SPGR) imaging. During bolus injection of Gd-DTPA, dynamic MRI images were recorded from the same slice. Tumor perfusion was evaluated from the time - signal intensity curve after Gd-DTPA injection, and the maximum signal intensity of Key words: MRI, tumor perfusion, head and neck cancer, radiotherapy, reoxygenation the tumor (SImax; maximum value of SI in tumor / SI of background). Results: There was significant difference in the peak signal intensity between the CR group and PR group at 20 Gy irradiation. The relative signal intensity at 20 Gy was significantly higher than that of pre-therapy in the CR group. The SImax ratio (SImax (20 Gy) / SImax (pretherapy)) was for the CR group and for the PR group. Conclusion: High tumor perfusion early during the course of therapy predicts a good response to radiation therapy in head and neck carcinoma. This phenomenon may be related to reoxygenation of the tumor early during radiotherapy. INTRODUCTION Radiotherapy plays a very important role in the management of patients with head and neck cancers, not only in early-stage lesions but also in advanced tumors. Assessment of response to radiotherapy is thus extremely important. It is necessary to identify high-risk patients who are likely to fail with radiotherapy as early as possible. Correspondence to Dr. Takeo Takahashi, Department of Radiology, Saitama Medical Center, Saitama Medical School, 1981, Kamodatsujido-cho, Kawagoe, Saitama , JAPAN Tel.: ; Fax: taketaka@saitama-med.ac.jp 219

2 Takeo Takahashi Conventionally, the response to radiotherapy is assessed by the response rate of the tumor. However, the response to radiotherapy is often clinically difficult to predict before or early during therapy when major therapeutic decisions about the treatment regimen are made. If poor tumor response could be predicted earlier, other and more effective treatment could be implemented. Tumor vascularity, oxygenation status and cell cycle have long been suggested as important factors influencing the response to radiation therapy. However, these factors are often difficult to evaluate with currently available methods. 1 We examined temporal change in the tumor perfusion pattern between before radiotherapy and early during radiotherapy. MR perfusion imaging has made it possible to study the tumor microvasculature more accurately, reliably, and noninvasively. 2, 3 There are few reports of the changes in tumor perfusion between before treatment and early during radiotherapy in head and neck cancers. We examined whether the changes in tumor perfusion early during radiotherapy would be useful for early prediction of the final response to radiotherapy. MATERIALS AND METHODS MRI perfusion studies were performed prospectively in 11 patients with squamous cell carcinoma and one adenoid cystic carcinoma of head and neck cancer. These patients (9 men and 2 women; aged 42-81) had 2 nasopharyngeal carcinomas, 4 oropharyngeal carcinomas, 1 hypopharyngeal carcinomas, 2 supraglottic carcinomas, 1 gingiva carcinoma, and 1 salivary gland carcinoma. According to the TNM classification of the 1997 UICC staging system, the patients in stages II, III and IV numbered 1, 4 and 6, respectively (Table 1). All patients were inoperable because of the advanced stage. Five of 11 patients were treated by radiation therapy combined with concomitant low-dose cisplatin (CDDP). A total dose of Gy (2 Gy, 5 times / week) was given by 4 MV X ray. Five mg/day of CDDP was administered intravenously within 1h after irradiation. The patients were treated using two lateral parallel opposing fields encompassing the primary tumor and cervical lymph nodes, and boosted for the primary lesion with a localized field after Gy. Exposure of the spinal cord was limited to 40 Gy. MRI protocol Two serial MRI studies were obtained prospectively in each patient; pre-radiotherapy (just before the initiation of radiotherapy) and early during radiotherapy (after a radiation dose of about 20 Gy in 2 weeks). Each MRI examination was performed on the same 1.5 T superconducting magnet scanner. After a bolus injection of Gd-DTPA (0.1 mmol / Kg), dynamic images (T1WI) were obtained every 20 s for 2 min from the start of the injection. The imaging parameters used were gradient echo sequence (Fast SPGR), TR 11 ms, TE 2.2 ms, section thickness of 6 mm, and acquisition matrix of 256 x 128. Dynamic images were obtained with a single section location corresponding to the level of the most appropriate abnormalities seen on unenhanced MR in patients with head and neck cancers. Signal intensity (SI) was measured in the region of interest (ROI) in tumors for each patient, and the relative signal intensity ratio (SI in tumor / SI of background) of the region where the tumor initially existed was measured. The ROI in each patient is the primary site of the tumor. Conventional enhanced T1WI were obtained immediately after the dynamic series was completed. Table 1. Patient characteristics pp 220

3 MRI perfusion study in head and neck cancers In the quantitative perfusion analysis of radiation effects in dynamic MRI, a time-relative signal intensity curve after an injection of Gd-DTPA in the ROI of each examination was plotted. Tumor perfusion was evaluated by a timerelative SI curve at pre-radiotherapy and at 20 Gy of radiotherapy (early during radiotherapy). We assessed the change of the time-si curve at 20 Gy of radiotherapy compared with that pre-radiotherapy. The maximum relative signal intensity (SImax), i.e., the signal intensity in the tumor / signal intensity of background was also measured. We assessed the change between SImax pretherapy and SImax at 20 Gy, and calculated the SImax ratio (SImax at 20 Gy / SImax pre-radiotherapy). The results of radiotherapy were clinically evaluated by radiologists and graded as complete remission (CR), partial remission (PR), > 50% reduction of the tumor, < 50% reduction of the tumor (NR), and progression of disease (PD) one month after radiotherapy. The tumor size on MRI images was measured in two dimensions. The correlation between tumor perfusion early during radiotherapy (20 Gy) and the response to radiotherapy was assessed. Statistical analysis was performed by the Mann-Whitney test. Figure 2. Perfusion analysis; Time-relative SI (relative signal intensity) curve of tumor for CR group after injection of Gd- DTPA. The curve shows intense enhancement pretherapy (o) and increased enhancement early during radiotherapy (20 Gy) ( ). The signal intensity of the tumor reached a peak at 60 to 80 s. The relative signal intensity at 20 Gy was significantly higher than that pretherapy at 40, 60, 80, and 100 s. Bars show +SE. RESULTS In the clinical examination, complete remission (CR) and partial remission (PR) were obtained in 7 and 4 cases, respectively (Table 1). Typical dynamic susceptibilitycontrast MR images of the head and neck cancer are shown in Fig. 1. Dynamic MRI showed early enhancement of the oropharyngeal tumor before radiation therapy (Fig. 1b). After 20 Gy of radiotherapy, the size of the tumor was almost the same, and early enhancement of the tumor was also Figure 3. Perfusion analysis: Time-relative SI (relative signal intensity) curve of tumor for PR group after injection of Gd- DTPA. There was no significant difference in time / signal intensity curve between pretherapy ( ) and 20 Gy ( ) in the PR group. Bars show +SE. Figure 1a Figure 1b Figure 1. Oropharyngeal carcinoma before radiotherapy. Oropharyngeal tumor is demonstrated on T1-weighted image just after Gd-DTPA injection (a), and dynamic image at 60 s after injection of Gd-DTPA (b). Early enhancement in the tumor is shown. visualized. The time-relative SI curves of tumors in both CR and PR groups after an injection of Gd-DTPA are shown in Fig. 2 and Fig. 3. The relative SI of the tumor reached a peak at s in the CR group, whereas it peaked later than 80 s in the PR group at 20 Gy irradiation. The slope of the time-signal intensity curve of the CR group was steeper than that of the PR group at 20 Gy irradiation. The signal intensity curve of the CR group was higher than that of the pp 221

4 Takeo Takahashi PR group. There was a difference in peak signal intensity after 40 s between the CR group and PR group at 20 Gy irradiation. In the CR group, the relative SI at 20 Gy was significantly higher than that pre-therapy at 40, 60, 80, and 100 s (p < 0.05) (Fig. 2). On the other hand, there was no significant difference in the time-si curves between preradiotherapy and 20 Gy in the PR group (Fig. 3). There was a relationship between the increase in tumor perfusion early during therapy (20 Gy / 2 week) and the response to radiotherapy. The mean values of the SImax ratio were for the CR group and for the PR group. DISCUSSION It is said that several biological factors play important roles in radiotherapy treatment. Recruitment, repopulation and reoxygenation in radiotherapy treatment are radiobiologically important for the response to radiotherapy. Nakano 4 reported a transient increase in the growth fraction at 9 Gy of radiotherapy for patients with cervical squamous cell carcinoma and proposed that this phenomenon was due to the recruitment of G 0 cells in the proliferating phase. Oka and Nakano reported that a high growth fraction at 9 Gy indicated a good prognosis for patients with cervical squamous cell carcinoma who underwent radiotherapy alone. 5 This result describing recruitment early during radiotherapy was related to the response to radiotherapy and patient outcome. As the cell cycle of neoplastic cells moved to radiosensitive distribution from the resting phase, it is thought that the radiation effect on the tumor increased. Another important factor in radiosensitivity is hypoxia. Hypoxic cells have been considered to be critical in determining the patient outcome of radiotherapy. Hypoxia usually decreases the radiosensitivity of tumors. Intratumoral hypoxia is associated with poor prognosis in cervical cancers, and head and neck cancers. 6,7 However, there are few reports about the course of oxygenation during radiation therapy. Reoxygenation is an important phenomenon during radiotherapy. It is considered that fractionated radiotherapy eliminates well-oxygenated tumor cells, and continuous movement of previously hypoxic cells into the compartment of well-oxygenated cells occurs. It is also thought that hypoxic tumor cells, following a dose of radiation, are reoxygenated as the tumor shrinks. Urano demonstrated that hypoxic tumor cells of fibrosarcoma FSa-II were reoxygenated and also repopulated during a treatment period between 10 and 20 fractions. 8 Dunst 9 showed a significant increase in po 2 after 2 weeks of radiotherapy in primary hypoxic tumors of cervical cancers. The patients with well-oxygenated pretreatment tumors and with an increase of po 2 at about 20 Gy achieved a good response to radiotherapy. 9 We considered that tumor perfusion at 20 Gy (10 fractions) of radiotherapy clinically reflected the recruitment and reoxygenation of tumor cells. In this study, we assessed tumor perfusion using MRI at 20 Gy of radiotherapy. Lyng 10 reported that there was a correlation between po 2 and perfusion, and the Gd-DTPAinduced signal enhancement in MR images of tumors was correlated with perfusion and cell density. Moreover, Fujii showed that the initial rise in signal intensity after contrast medium administration reflected the degree of tumor vascularity. 11 In our study, the slope of the time-si curve was steep, indicating high perfusion in the CR group. The perfusion analysis in our study supports the concept that tumor blood supply, tumor perfusion, and oxygenation play important roles in the prediction of response to radiation therapy. T1-weighted dynamic MR imaging has been used to evaluate vascularity in intracranial tumors. 12 To increase the tumor-to-normal adjacent tissue signal contrast, fatsuppressed contrast-enhanced T1-weighted images were useful for the detection of head and neck tumors. 13 Baba described that dynamic MRI was useful in the evaluation of radiation therapy in head and neck cancers. 14 In this study, elevated tumor perfusion at 20 Gy was revealed in CR patients. The mean values of the SImax ratio were for the CR group and for the PR group. It was considered that reoxygenation might occur at 20 Gy of radiotherapy. Mayr reported that high tumor perfusion before therapy and increasing or persistent high perfusion early during the course of therapy appeared to be favorable in uterine cervical cancers. 15 He further revealed that high tumor perfusion in early therapy (20-22Gy) showed a strong correlation with local control in cervical cancer. The improved blood and oxygen supply may result in the reoxygenation of previously hypoxic cells. In our preliminary study, we revealed that the increment of tumor perfusion early during radiotherapy was related to the response to radiotherapy. Increased tumor perfusion at 20 Gy was significantly recognized compared with pre-radiotherapy in the CR group. It was therefore considered to be a favorable prognostic factor for good response to radiotherapy. It was thought that tumor perfusion at 20 Gy will be useful for the prediction of irradiation effects. REFERENCES 1. Kallinowski F, Zander R, Hoeckel M, Vaupel P. Tumor tissue oxygenation as evaluated by computerized-po 2 -histography. Int J Radiat Oncol Biol Phys 1990; 19: Brix G, Rempp K, Gückel F, et al. Quantitative assessment of tissue microcirculation by dynamic contrast-enhanced MR imaging. Adv MRI Contrast 1994; 2: Maeda M, Itoh S, Kimura H, Iwasaki T, Hayashi N,Yamamoto K, Ishii Y, Kubota T. Vascularity of meningiomas and neuromas: 222

5 MRI perfusion study in head and neck cancers Assessment with dynamic susceptibility-contrast MR imaging. AJR 1994; 163: Nakano T, Oka K. Transient increase of growth fraction during fractionated radiation therapy for cervical carcinoma. Cancer 1993; 72: Oka K, Suzuki Y, Nakano T. High growth fraction at 9 Grays of radiotherapy is associated with a good prognosis for patients with cervical squamous cell carcinoma. Cancer 2000; 89: Höckel M, Knopp C, Schlenger K, Vorndran B, et al. Intratumoral po 2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 1993; 26: Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997; 38: Urano M, Nishimura Y, Yaes R. The relative significance of repopulation and hypoxic clonogens in the fractionated radiotherapy of a mouse tumor. Radiat Res 1995; 142: Dunst J, Hänsgen G, Lautenschläger C, et al. Oxygenation of cervical cancers during radiotherapy and radiotherapy + cisretinoic acid/interferon. Int J Radiat Oncol Biol Phys 1999; 43: Lyng H, Vorren AO, Sundfor K, Taksdal I, Lien HH, Kaalhus O, Rofstad EK. Assessment of tumor oxygenation in human cervical carcinoma by use of dynamic Gd-DTPA-enhanced MR imaging. J Magn Reson Imaging 2001; 14: Fujii K, Fujita N, Hirabuki N, Hashimoto T, Miura T, Kozuka T. Neuromas and meningiomas: Evaluation of early enhancement with dynamic MR imaging. Am J Neuroradiol 1992; 13: Nägele T, Petersen D, Klose U, et al. Dynamic contrast enhancement of intracranial tumors with snapshot-flash MR imaging. AJNR 1993; 14: Ross MR, Schomer DF, Chappell R, Enzmann DR. MR imaging of head and neck tumors: Comparison of T1-weighted contrastenhanced fat-suprressed images with conventional T2-weighted and fat spin-echo T2-weighted images.ajr 1994; 163: Baba Y, Furusawa M, Murakami R, Yokoyama T, Sakamoto Y, Nishimura R, Yamashita Y, Takahashi M, Ishikawa T. Role of dynamic MRI in the evaluation of head and neck cancers treated with radiation therapy. Int J Radiat Oncol Biol Phys 1997; 37: Mayr NA, Yuh WTC, Magnotta VA, Ehrhardt JC, Wheeler JA, et al. Tumor perfusion studies using fast magnetic resonance imaging tequnique in advanced cervical cancer: A new noninvasive predictive assay. Int J Radiat Oncol Biol Phys 1996; 36: