Cancer Res Treat. 2021;53(2):471-479.

Targeting Hypoxia Using Evofosfamide and Companion Hypoxia Imaging of FMISO-PET in Advanced Biliary Tract Cancer.

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제1저자 윤지선 · 교신저자 오도연

PMID 33091966 PMC8053876 DOI 10.4143/crt.2020.577 IF 4.2 혈액종양내과

소속 (3)

Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Department of Nuclear Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Abstract

PURPOSE Hypoxia is widely known as one of the mechanisms of chemoresistance and as an environmental condition which triggers invasion and metastasis of cancer. Evofosfamide is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard conjugated with 2-nitroimidazole. Biliary tract cancer (BTC) is known to contain large hypoxic area. This study evaluated the efficacy and safety of evofosfamide as a second-line treatment of advanced BTC.

MATERIALS AND METHODS Patients received evofosfamide at a dose of 340 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Primary end-point was progression-free survival (PFS) rate at 4-months (4m-PFSR). Secondary end-points included overall survival (OS), PFS, disease control rate (DCR), metabolic response by 18F-fluorodeoxyglucose positron emission tomography (PET), hypoxic parameters evaluated by 18F-fluoromisonidazole (FMISO) PET and toxicity.

RESULTS Twenty patients were treated with evofosfamide, with 16 response-evaluable patients. There was no objective response; stable disease was observed in nine patients, with a DCR of 56.25%. 4m-PFSR was 40.6%. Median PFS was 3.60 months (95% confidence interval [CI], 1.68 to 5.52). Median OS was 6.37 months (95% CI, 3.94 to 8.79). Reduction of tumor metabolic activity was observed in eight of 15 patients (53.3%). High baseline hypoxic parameters were associated with poor PFS. Change of hypoxic parameters between pretreatment and post-treatment reflected hypoxic-activated drug response. There was no treatment-related death.

CONCLUSION Evofosfamide as second-line treatment of advanced BTC showed acceptable safety and comparable efficacy to other agents. Changes in volumetric parameters measured with FMISO PET, showing the degree of tumor hypoxia, reflected the response to evofosfamide based on the mode of action.

Keywords

Biliary tract neoplasmsChemotherapyEvofosfamideHypoxiaPhase IITH302

Figures

**Fig. 1** The association between tumor hypoxia and prognosis. The cutoff value of hypoxic parameters measured by ¹⁸F-fluoromisonidazole positron emission tomography (FMISO PET) was obtained using maximally selected rank statistics. Progression-free survival (PFS) was statistically significantly longer in patients with low hypoxic parameters as measured by FMISO PET before evofosfamide treatment. (A) Patients with high maximum standardized uptake value (mSUV) measured using FMISO PET before treatment showed a shorter PFS than those with low mSUV values (2.07 months vs. 3.80 months, p=0.328). This was not statistically significant. (B) Patients with high hypoxic volume (HV) measured by FMISO PET before treatment showed a statistically significantly shorter PFS than those with low HV (1.97 months vs. 7.23 months, p=0.001). (C) Hypoxic lesion uptake referred to the value of HV multiplied by the average SUV value, and PFS was statistically significantly shorter than that of the HV group (2.07 months vs. 7.23 months, p=0.008).

**Fig. 2** The association between changes in tumor hypoxia and tumor response. (A) Parameters indicating the degree of hypoxia on ¹⁸F-fluoromisonidazole positron emission tomography showed a tendency to increase in patients with progressive disease (PD) after evofosfamide treatment. Statistical significance using Wilcoxon signed rank test was shown only in some parameters: hypoxic volume, hypoxic lesion uptake. (B) There was no significant change in the hypoxemia parameter in the stable disease (SD) group. HLU, hypoxic lesion uptake; HV, hypoxic volume; mSUV, maximum standardized uptake value; T/B, tumor to background ratio.

**Fig. 3** The association between changes in tumor hypoxia and progression-free survival. (A) Patients who showed increased maximum standardized uptake value measured by ¹⁸F-fluoromisonidazole positron emission tomography (FMISO PET) after treatment showed shorter progression-free survival than patients who did not. This was not statistically significant (1.80 months vs. 2.30 months, p=0.281). (B) Progression-free survival was shorter as the difference of hypoxic volume (HV) values measured by FMISO PET before and after treatment increased (1.97 months vs. 6.63 months, p=0.063). (C) Similar trend as HV was observed in the result of the comparison of hypoxic lesion uptake (2.07 months vs. 6.27 months, p=0.166).

**Fig. 4** Comparison of values evaluated using ¹⁸F-fluoromisonidazole positron emission tomography (FMISO PET) and ¹⁸F-fludeoxyglucose (FDG) PET before treatment. Spearman’s rank correlation coefficient was conducted to compare values of functional imaging tools. Values were considered significant for p < 0.05. White and black circles indicate patients with stable disease (n=8) and with progressive disease (n=7), respectively. (A, B) Hypoxic volume (HV) in FMISO PET was significantly associated with metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in FDG PET. (C, D) Hypoxic lesion uptake (HLU) in FMISO PET was significantly associated with MTV and TLG.

그림 출처: PubMed Central 공개 논문 (PMC8053876)

Conflict of interest statement

Conflicts of Interest. Author DYO: Research grant from AstraZeneca, Novartis, Array, Eli Lilly, Green Cross. Consultant/Advisory board for AstraZeneca, Novartis, Genentech/Roche, Merck Serano, Bayer, Taiho, ASLAN. Author JSY, SYK, KHL and GJC declare that they do not have any conflicts of interest.

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