Treatment-induced lesions in newly diagnosed glioblastoma patients undergoing chemoradiotherapy and heat-shock protein vaccine therapy

Abstract

Objectives: Treatment-induced lesions represent a great challenge in neuro-oncology. The aims of this study were (i) to characterize treatment induced lesions in glioblastoma patients treated with chemoradiotherapy and heat-shock protein (HSP) vaccine and (ii) to evaluate the diagnostic accuracy of diffusion weighted imaging for differentiation between treatment-induced lesions and tumor progression.

Methods: Twenty-seven patients with newly diagnosed glioblastoma treated with HSP vaccine and chemoradiotherapy were included. Serial magnetic resonance imaging evaluation was performed to detect treatment-induced lesions and assess their growth. Quantitative analysis of the apparent diffusion coefficient (ADC) was performed to discriminate treatment-induced lesions from tumor progression. Mann-Whitney U-test and receiver operating characteristic (ROC) curves were used for analysis.

Results: Thirty-three percent of patients developed treatment-induced lesions. Five treatment-related lesions appeared between end of radiotherapy and the first vaccine administration; 4 lesions within the first 4 months from vaccine initiation and 1 at 3.5 years. Three patients with pathology proven treatment-induced lesions showed a biphasic growth pattern progressed shortly after. ADC ratio between the peripheral enhancing rim and central necrosis showed an accuracy of 0.84 (95% CI 0.63-1) for differentiation between progression and treatment-induced lesions.

Conclusion: Our findings do not support the iRANO recommendation of a 6-month time window in which progressive disease should not be declared after immunotherapy initiation. A biphasic growth pattern of pathologically proven treatment-induced lesions was associated with a dismal prognosis. The presence of lower ADC values in the central necrotic portion of the lesions compared to the enhancing rim shows high specificity for detection of treatment-induced lesions.

Keywords: Chemoradiotherapy; Glioblastoma; Heat-shock proteins; Immunotherapy; Magnetic resonance imaging.

FIG 1.

Evolution of the contrast enhancing lesion volume over time in cases of early treatment-induced lesions and retrospective application of iRANO criteria. All cases of early treatment-induced lesions start before 4 months post vaccine initiation. In 3 cases of treatment-induced lesions, a biphasic pattern is observed with a second period of worsening after stabilization or improvement (dashed lines). This biphasic patter was associated to bad prognosis despite histopathological diagnosis of treatment-induced lesions.

FIG 2.

Inclusion and exclusion flow chart for quantitative ADC assessment.

FIG 3.

(A) Box and whiskers plot depicting the distributions of the peripheral/central ADC ratio in the tumor progression and treatment-induced lesions groups (p=0.023). (B) Receiver operating characteristic curve for the detection of treatment-induced lesions by using the peripheral/central ADC ratio (positive state corresponds to treatment-induced lesion).

FIG 4.

Examples depicting the inverted ADC pattern in treatment-induced lesions compared to progressive tumor. Lower ADC values are centrally located in the treatment-induced lesion depicted in the upper row versus peripherally in the case of tumor progression in the lower row. Histopathological evaluation in the case featured in the upper row showed necrotic tissue without recurrent neoplasm. The patient was alive 3 years after this scan. In the case featured in the lower row, histopathological evaluation showed mostly viable tumor and the patient died 1 year after this scan.