Eiichi Ishikawa, Yoshihiro Muragaki, Tetsuya Yamamoto, Takashi Maruyama, Koji Tsuboi, Soko Ikuta, Koichi Hashimoto, Youji Uemae, Takeshi Ishihara, Masahide Matsuda, Masao Matsutani, Katsuyuki Karasawa, Yoichi Nakazato, Tatsuya Abe, Tadao Ohno and Akira Matsumura
Temozolomide (TMZ) may enhance antitumor immunity in patients with glioblastoma multiforme (GBM). In this paper the authors report on a prospective Phase I/IIa clinical trial of fractionated radiotherapy (FRT) concomitant with TMZ therapy, followed by treatment with autologous formalin-fixed tumor vaccine (AFTV) and TMZ maintenance in patients with newly diagnosed GBM.
Twenty-four patients (age 16–75 years, Karnofsky Performance Scale score ≥ 60% before initiation of FRT) with newly diagnosed GBM received a total dose of 60 Gy of FRT with daily concurrent TMZ. After a 4-week interval, the patients received 3 AFTV injections and the first course of TMZ maintenance chemotherapy for 5 days, followed by multiple courses of TMZ for 5 days in each 28-day cycle.
This treatment regimen was well tolerated by all patients. The percentage of patients with progression-free survival (PFS) ≥ 24 months was 33%. The median PFS, median overall survival (OS), and the actuarial 2- and 3-year survival rates of the 24 patients were 8.2 months, 22.2 months, 47%, and 38%, respectively. The median PFS in patients with a delayed-type hypersensitivity (DTH) response after the third AFTV injection (DTH-2) of 10 mm or larger surpassed the median length of follow-up for progression-free patients (29.5 months), which was significantly greater than the median PFS in patients with a smaller DTH-2 response.
The treatment regimen was well tolerated and resulted in favorable PFS and OS for newly diagnosed GBM patients. Clinical trial registration no.: UMIN000001426 (UMIN clinical trials registry, Japan).
Yoshihiro Muragaki, Takashi Maruyama, Hiroshi Iseki, Masahiko Tanaka, Chie Shinohara, Kintomo Takakura, Koji Tsuboi, Tetsuya Yamamoto, Akira Matsumura, Masao Matsutani, Katsuyuki Karasawa, Katsunori Shimada, Naohito Yamaguchi, Yoichi Nakazato, Keiki Sato, Youji Uemae, Tadao Ohno, Yoshikazu Okada and Tomokatsu Hori
The objective of the present study was analysis of results of the prospective clinical trial directed toward the evaluation of therapeutic efficacy of the administration of autologous formalin-fixed tumor vaccine (AFTV) concomitant with fractionated radiotherapy in cases of newly diagnosed glioblastoma multiforme.
Twenty-four patients were enrolled into the clinical trial, while 2 cases were excluded from the final analysis of results. The treatment protocol included aggressive tumor resection, fractionated radiotherapy up to a total dose of 60 Gy, and 3 concomitant courses of AFTV administered with an interval of one week at the late stage of irradiation. Two delayed-type hypersensitivity (DTH) tests were done—one 48 hours before the initial course of vaccination (DTH-1) and one 2 weeks after the third (DTH-2). All but one of the patients received salvage therapy at the time of tumor progression. The defined primary end point was overall survival; secondary end points were progression-free survival and safety of concomitant treatment.
The median duration of overall survival was 19.8 months (95% CI 13.8–31.3 months). The actuarial 2-year survival rate was 40%. The median duration of progression-free survival was 7.6 months (95% CI 4.3–13.6 months). Overall survival showed a statistically significant association with recursive partitioning analysis class (p < 0.05); progression-free survival showed a statistically significant association with p53 staining index (p < 0.05) and size of DTH-2 response (p < 0.001). AFTV injection concomitant with fractionated radiotherapy was well tolerated by all patients and in no case did treatment-related adverse effects exceed Grade 1 toxicity; adverse effects were limited to local erythema, induration, and swelling at the site of injection.
The results of this study demonstrate that AFTV treatment concomitant with fractionated radiotherapy may be effective in patients with newly diagnosed glioblastoma. Further clinical testing is warranted.