膠質母細胞瘤之個人化治療: 以影像生物標記預測腫瘤進展模式與發展對應之腫瘤內藥物傳輸系統

Abstract

膠質母細胞瘤為成人最常見原發型腦瘤。同步放化療後最常見的進展型態為局部或照野內復發，約佔72%–96.8%，而遠端轉移或照野外復發約佔2%–28%。病人開刀前若有腫瘤周邊水腫大範圍延伸以及腫瘤位於腦室和胼胝體交界處，存活較差並有多樣化進展型態。 我們以影像生物標記，分類膠質母細胞瘤病人的腫瘤進展型態，包括侷限型、中間型和擴散型，與相對應不同的存活狀況。再根據不同分類，提出相對應的膠質母細胞瘤放射治療目標劃定與劑量給予，決定個人化的治療策略。侷限型膠質母細胞瘤僅有小於10%的人腫瘤會延伸大於原腫瘤界線兩公分，然而擴散型病人，超過70%會有腫瘤移動超過原腫瘤界線兩公分的情況。和侷限型的病人相比，擴散型的病人存活狀況較差。我們的臨床研究顯示需要根據膠質母細胞瘤影像生物標記制定個人化的治療策略。 無論侷限型或擴散型，原腫瘤處是膠質母細胞瘤復發最常見的位置。提高腫瘤局部控制的最好策略之一，就是腫瘤內藥物注射再加上局部放射治療。我們比較各種腫瘤內藥物傳輸方式，包括藥片、熱塑型水膠和對流加壓注射，比較藥物釋放安全性與輻射增強效果，設計一個基礎研究探討腫瘤內藥物傳輸方式，以便臨床應用。 為達到未解決的臨床需求，我們合成一個新的藥物結合水狀凝膠與卡鉑進行腫瘤內藥物注射。經過全面性的生物材料、細胞與動物實驗，我們成功證實水狀凝膠與卡鉑是一個安全、有效、方便的藥物組合。腫瘤內卡鉑凝膠注射保有放射化學治療的協同效果，而且沒有嚴重的治療副作用。單次腫瘤內水狀凝膠與卡鉑注射的藥物持續釋放，簡化給藥過程與接續的放射治療，有助應用在臨床腦瘤治療。

Glioblastoma is the most prevalent primary brain tumor of adults. The most common progression patterns after concurrent chemoradiotherapy are local and in-field (72%–96.8%), and the rates of distant and out-field recurrence range from 2% to 28%. The extensive preoperative edema (EPE) (edema extent ≥ 2 cm from the tumor edge) and tumor located at synchronous subventricular zone and corpus callosum (sSVZCC) are associated with poor survival and diverse progression patterns of glioblastoma. We combined the imaging biomarkers, EPE and sSVZCC invasion, to classify glioblastomas progression patterns, including confined, intermediate, and extensive types, with different survivals. According to the classification, we proposed the corresponding RT target volume delineations and dose prescriptions to personalize treatment strategies for glioblastomas. Less than 10% of patients with EPE- (confined type) have tumor progression extending beyond the 2-cm margin from the preoperative tumor edge, while more than 70% glioblastomas with EPE+/SVZCC+ (extensive type) have tumor migration beyond the 2-cm margin from the preoperative tumor edge along the preoperative edema areas. Compared with patients with confines type glioblastoma, those with extensive type have poorer survival. Our clinical study demonstrated the need for developing individualized irradiation strategies for glioblastomas according to the imaging biomarkers of EPE and sSVZCC invasion. The tumor bed is the most common recurrence area of glioblastomas either confined or extensive types. One of the strategies to increase the local tumor control is intratumoral drug delivery combining with local radiotherapy (RT). We compared the drug release and safety features of intratumoral delivery modalities (wafer, thermogelling hydrogel, and convection-enhanced delivery) and the radiosensitizing effects among anti-cancer drugs (carmustine, carboplatin, and cisplatin) to propose a basic investigation on the intratumoral drug delivery for further clinical application. To satisfy the unmet clinical need for glioma treatment, we compounded a novel drug combination of oxidated hyaluronic acid/adipic acid dihydrazide hydrogel and carboplatin for intratumoral injection. Through the comprehensive biomaterial, cell, and animal experiment design, we significantly demonstrated that hydrogel carboplatin is a safe, effective, and convenient drug combination. Intratumoral hydrogel carboplatin injection simplified the method and frequency of intratumoral hydrogel carboplatin delivery and remained the RT synergistic effect without causing severe toxicity, which makes intraoperative single drug injection with subsequent RT a feasible and potential clinical treatment for glioblastomas.