Imaging the tumour microenvironment in rectal cancer: Decline in tumour blood flow during radiotherapy predicts good outcome

Kine Mari Bakke; Sebastian Meltzer; Endre Grøvik; Anne Negård; Stein Harald Holmedal; Lars Tore Gyland Mikalsen; Arne Engebret Færden; Lars Gustav Lyckander; Frida Marie Ihle Julbø; Atle Bjørnerud; Kjell-Inge Gjesdal; Anne Hansen Ree; Kathrine Røe Redalen

doi:10.1016/j.phro.2023.100417

Imaging the tumour microenvironment in rectal cancer: Decline in tumour blood flow during radiotherapy predicts good outcome

Phys Imaging Radiat Oncol. 2023 Jan 23:25:100417. doi: 10.1016/j.phro.2023.100417. eCollection 2023 Jan.

Authors

Kine Mari Bakke¹, Sebastian Meltzer¹, Endre Grøvik^{2

3}, Anne Negård^{4

5}, Stein Harald Holmedal⁴, Lars Tore Gyland Mikalsen^{6

7}, Arne Engebret Færden⁸, Lars Gustav Lyckander⁹, Frida Marie Ihle Julbø^{1

10}, Atle Bjørnerud^{6

11}, Kjell-Inge Gjesdal^{4

12}, Anne Hansen Ree^{1

5}, Kathrine Røe Redalen³

Affiliations

¹ Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
² Møre and Romsdal Hospital Trust, Ålesund.
³ Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
⁴ Department of Radiology, Akershus University Hospital, Lørenskog, Norway.
⁵ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁶ Department of Diagnostic Physics, Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
⁷ Department of Life Sciences and Health, Oslo Metropolitan University, Oslo, Norway.
⁸ Department of Digestive Surgery, Akershus University Hospital, Lørenskog, Norway.
⁹ Department of Pathology, Akershus University Hospital, Lørenskog, Norway.
¹⁰ Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norway.
¹¹ Department of Physics, University of Oslo, Oslo, Norway.
¹² Sunnmøre MR-klinikk, Ålesund, Norway.

Abstract

Background and purpose: Measuring rectal tumour response to radiation is pivotal to restaging patients and for possibly stratification to a watch-and-wait strategy. Recognizing the importance of the tumour microenvironment, we investigated a less explored quantitative imaging marker assessing tumour blood flow (BF) for its potential to predict overall survival (OS).

Materials and methods: 24 rectal cancer patients given curative-intent neoadjuvant radiotherapy underwent a multi-echo dynamic magnetic resonance imaging (MRI) sequence with gadolinium contrast for quantification of tumour BF before either 25x2 Gy (n = 18) with concomitant chemotherapy or 5x5 Gy (n = 6). CD34 staining of excised tumour tissue was performed and baseline blood samples were analysed for lactate dehydrogenase (LDH) and angiopoietin-2 (ANGPT-2). Tumour volumes were measured before and after treatment. After subsequent surgery, ypTN scoring assessed tumour response. Cox regression for 5-year OS analysis and t-test for group comparisons were performed.

Results: The change in tumour BF (ΔBF) during neoadjuvant radiotherapy was a significant marker of OS, whereas tumour stage and volume were not related to OS. All patients with >20 % decline in BF were long-term survivors. Separating cases in two groups based on ΔBF revealed that patients with increase or a low decrease had higher baseline LDH (p = 0.032) and ANGPT-2 (p = 0.028) levels.

Conclusion: MRI-assessed tumour ΔBF during neoadjuvant treatment is a significant predictor of OS in rectal cancer patients, making ΔBF a potential quantitative imaging biomarker for treatment stratification. Blood LDH and ANGPT-2 indicate that non-responding tumours may have a hypoxic microenvironment resistant to radiotherapy.

Keywords: Blood flow; MRI; Perfusion; Rectal cancer; Response assessment.