Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Radiation Oncology
Published in: Radiation Oncology 1/2017

Open Access 01-12-2017 | Research

Carbon ion radiotherapy: impact of tumor differentiation on local control in experimental prostate carcinomas

Authors: Christin Glowa, Peter Peschke, Stephan Brons, Oliver C. Neels, Klaus Kopka, Jürgen Debus, Christian P. Karger

Published in: Radiation Oncology | Issue 1/2017

Login to get access

Abstract

Background

To summarize the research activities of the “clinical research group heavy ion therapy”, funded by the German Research Foundation (DFG, KFO 214), on the impact of intrinsic tumor characteristics (grading, hypoxia) on local tumor control after carbon (12C-) ion- and photon irradiations.

Methods

Three sublines of syngeneic rat prostate tumors (R3327) with various differentiation levels (highly (-H), moderately (-HI) or anaplastic (-AT1), (diameter 10 mm) were irradiated with 1, 2 and 6 fractions of either 12C-ions or 6 MV photons using increasing dose levels. Primary endpoint was local tumor control at 300 days. The relative biological effectiveness (RBE) of 12C-ions was calculated from TCD50-values (dose at 50% tumor control probability) of photons and 12C-ions and correlated with intrinsic tumor parameters. For the HI-subline, larger tumors (diameter 18 mm) were irradiated with either carbon ions, oxygen ions or photons under ambient as well as hypoxic conditions to determine the variability of the RBE under different oxygenation levels. In addition, imaging, histology and molecular analyses were performed to decipher the underlying mechanisms.

Results

Experimental results revealed (i) a smaller variation of the TCD50-values between the three tumor sublines for 12C-ions (23.6 - 32.9 Gy) than for photons (38.2 - 75.7 Gy), (ii) steeper dose-response curves for 12C-ions, and (iii) an RBE that increased with tumor grading (1.62 ± 0.11 (H) vs 2.08 ± 0.13 (HI) vs 2.30 ± 0.08 (AT1)). Large HI-tumors resulted in a marked increase of TCD50, which was increased further by 15% under hypoxic relative to oxic conditions. Noninvasive imaging, histology and molecular analyses identified hypoxia as an important radioresistance factor in photon therapy.

Conclusions

The dose-response studies revealed a higher efficacy of 12C-ions relative to photon therapy in the investigated syngeneic tumor model. Hypoxia turned out to be at least one important radioresistance factor, which can be partly overridden by high-LET ion beams. This might be used to increase treatment effectiveness also in patients. The results of this project served as a starting point for several ongoing research projects.
Literature
1.
Weyrather WK, Ritter S, Scholz M, Kraft G. RBE for carbon track-segment irradiation in cell lines of differing repair capacity. Int J Radiat Biol. 1999;75:1357–64.CrossRefPubMed
2.
Suzuki M, Kase Y, Yamaguchi H, Kanai T, Ando K. Relative biological effectiveness for cell-killing effect on various human cell lines irradiated with heavy-ion medical accelerator in Chiba (HIMAC) carbon-ion beams. Int J Radiat Oncol Biol Phys. 2000;48:241–50.CrossRefPubMed
3.
Furusawa Y, Fukutsu K, Aoki M, Itsukaichi H, Eguchi-Kasai K, Ohara H, Yatagai F, Kanai T, Ando K. Inactivation of aerobic and hypoxic cells from three different cell lines by accelerated (3)He-, (12)C- and (20)Ne-ion beams. Radiat Res. 2000;154:485–96.CrossRefPubMed
4.
Karger CP, Peschke P, Sanchez-Brandelik R, Scholz M, Debus J. Radiation tolerance of the rat spinal cord after 6 and 18 fractions of photons and carbon ions: experimental results and clinical implications. Int J Radiat Oncol Biol Phys. 2006;66:1488–97.CrossRefPubMed
5.
Saager M, Glowa C, Peschke P, Brons S, Grun R, Scholz M, Huber PE, Debus J, Karger CP. Split dose carbon ion irradiation of the rat spinal cord: dependence of the relative biological effectiveness on dose and linear energy transfer. Radiother Oncol. 2015;117:358–63.CrossRefPubMed
6.
Glowa C, Karger CP, Brons S, Zhao D, Mason RP, Huber PE, Debus J, Peschke P. Carbon ion radiotherapy decreases the impact of tumor heterogeneity on radiation response in experimental prostate tumors. Cancer Lett. 2016;378:97–103.CrossRefPubMed
7.
Koike S, Ando K, Oohira C, Fukawa T, Lee R, Takai N, Monobe M, Furusawa Y, Aoki M, Yamada S, Shimizu W, Nojima K, Majima H. Relative biological effectiveness of 290 MeV/u carbon ions for the growth delay of a radioresistant murine fibrosarcoma. J Radiat Res. 2002;43:247–55.CrossRefPubMed
8.
Tenforde TS, Tenforde SD, Crabtree KE, Parks DL, Schilling WA, Parr SS, Flynn MJ, Howard J, Lyman JT, Curtis SB. RBE values for radiation-induced growth delay in rat rhabdomyosarcoma tumors exposed to plateau and peak carbon, neon and argon ions. Int J Radiat Oncol Biol Phys. 1981;7:217–22.CrossRefPubMed
9.
Sorensen BS, Horsman MR, Alsner J, Overgaard J, Durante M, Scholz M, Friedrich T, Bassler N. Relative biological effectiveness of carbon ions for tumor control, acute skin damage and late radiation-induced fibrosis in a mouse model. Acta Oncol. 2015;54:1623–30.CrossRefPubMed
10.
Scholz M, Kellerer AM, Kraft-Weyrather W, Kraft G. Computation of cell survival in heavy ion beams for therapy. The model and its approximation. Radiat Environ Biophys. 1997;36:59–66.CrossRefPubMed
11.
Kanai T, Furusawa Y, Fukutsu K, Itsukaichi H, Eguchi-Kasai K, Ohara H. Irradiation of mixed beam and design of spread-out Bragg peak for heavy-ion radiotherapy. Radiat Res. 1997;147:78–85.CrossRefPubMed
12.
Inaniwa T, Kanematsu N. A trichrome beam model for biological dose calculation in scanned carbon-ion radiotherapy treatment planning. Phys Med Biol. 2015;60:437–51.CrossRefPubMed
13.
Peschke P, Karger CP, Scholz M, Debus J, Huber PE. Relative biological effectiveness of carbon ions for local tumor control of a radioresistant prostate carcinoma in the rat. Int J Radiat Oncol Biol Phys. 2011;79:239–46.CrossRefPubMed
14.
Karger CP, Peschke P, Scholz M, Huber PE, Debus J. Relative biological effectiveness of carbon ions in a rat prostate carcinoma in vivo: comparison of 1, 2, and 6 fractions. Int J Radiat Oncol Biol Phys. 2013;86:450–5.CrossRefPubMed
15.
Glowa C, Peschke P, Karger CP, Hahn EW, Huber PE, Debus J, Ehemann V. Flow cytometric characterization of tumor subpopulations in three sublines of the dunning R3327 rat prostate tumor model. Prostate. 2013;73:1710–20.PubMed
16.
Mena-Romano P, Cheng C, Glowa C, Peschke P, Pan L, Haberkorn U, Dimitrakopoulou-Strauss A, Karger CP. Measurement of hypoxia-related parameters in three sublines of a rat prostate carcinoma using dynamic (18)F-FMISO-PET-CT and quantitative histology. Am J Nucl Med Mol Imaging. 2015;5:348–62.PubMedPubMedCentral
17.
Isaacs JT, Heston WD, Weissman RM, Coffey DS. Animal models of the hormone-sensitive and -insensitive prostatic adenocarcinomas, dunning R-3327-H, R-3327-HI, and R-3327-AT. Cancer Res. 1978;38:4353–9.PubMed
18.
Nolden M, Zelzer S, Seitel A, Wald D, Muller M, Franz AM, Maleike D, Fangerau M, Baumhauer M, Maier-Hein L, Maier-Hein KH, Meinzer HP, Wolf I. The medical imaging interaction toolkit: challenges and advances : 10 years of open-source development. Int J Comput Assist Radiol Surg. 2013;8:607–20.CrossRefPubMed
19.
Debus C, Floca R, Norenberg D, Abdollahi A, Ingrisch M. Impact of fitting algorithms on errors of parameter estimates in dynamic contrast enhanced MRI. Phys Med Biol. 2017; doi: 10.​1088/​1361-6560/​aa8989.
20.
Nomiya T, Tsuji H, Kawamura H, Ohno T, Toyama S, Shioyama Y, Nakayama Y, Nemoto K, Tsujii H, Kamada T. A multi-institutional analysis of prospective studies of carbon ion radiotherapy for prostate cancer: a report from the Japan Carbon ion Radiation Oncology Study Group (J-CROS). Radiother Oncol. 2016;121:288–93.CrossRefPubMed
21.
Karger CP, Scholz M, Huber PE, Debus J, Peschke P. Photon and carbon ion irradiation of a rat prostate carcinoma: does a higher fraction number increase the metastatic rate? Radiat Res. 2014;181:623–8.CrossRefPubMed
22.
Tatum JL, Kelloff GJ, Gillies RJ, Arbeit JM, Brown JM, Chao KS, et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol. 2006;82:699–757.CrossRefPubMed
23.
Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501:346–54.CrossRefPubMed
24.
Good JS, Harrington KJ. The hallmarks of cancer and the radiation oncologist: updating the 5Rs of radiobiology. Clin Oncol. 2013;25:569–77.CrossRef
25.
Nomiya T, Nemoto K, Miyachi H, Fujimoto K, Takeda K, Ogawa Y, Takai Y, Yamada S. Relationships between radiosensitivity and microvascular density in esophageal carcinoma: significance of hypoxic fraction. Int J Radiat Oncol Biol Phys. 2004;58:589–96.CrossRefPubMed
26.
Yaromina A, Thames H, Zhou X, Hering S, Eicheler W, Dorfler A, Leichtner T, Zips D, Baumann M. Radiobiological hypoxia, histological parameters of tumour microenvironment and local tumour control after fractionated irradiation. Radiother Oncol. 2010;96:116–22.CrossRefPubMed
27.
Hirayama R, Uzawa A, Takase N, Matsumoto Y, Noguchi M, Koda K, Ozaki M, Yamashita K, Li H, Kase Y, Matsufuji N, Koike S, Masunaga S, Ando K, Okayasu R, Furusawa Y. Evaluation of SCCVII tumor cell survival in clamped and non-clamped solid tumors exposed to carbon-ion beams in comparison to X-rays. Mutat Res. 2013;756:146–51.CrossRefPubMed
28.
Wenzl T, Wilkens JJ. Theoretical analysis of the dose dependence of the oxygen enhancement ratio and its relevance for clinical applications. Radiat Oncol. 2011;6:171.CrossRefPubMedPubMedCentral
29.
Nakano T, Suzuki Y, Ohno T, Kato S, Suzuki M, Morita S, Sato S, Oka K, Tsujii H. Carbon beam therapy overcomes the radiation resistance of uterine cervical cancer originating from hypoxia. Clin Cancer Res. 2006;12:2185–90.CrossRefPubMed
30.
Mortensen LS, Johansen J, Kallehauge J, Primdahl H, Busk M, Lassen P, et al. FAZA PET/CT hypoxia imaging in patients with squamous cell carcinoma of the head and neck treated with radiotherapy: results from the DAHANCA 24 trial. Radiother Oncol. 2012;105:14–20.CrossRefPubMed
31.
Antonovic L, Brahme A, Furusawa Y, Toma-Dasu I. Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions. J Radiat Res. 2013;54:18–26.CrossRefPubMed
32.
Busk M, Mortensen LS, Nordsmark M, Overgaard J, Jakobsen S, Hansen KV, Theil J, Kallehauge JF, D'Andrea FP, Steiniche T, Horsman MR. PET hypoxia imaging with FAZA: reproducibility at baseline and during fractionated radiotherapy in tumour-bearing mice. Eur J Nucl Med Mol Imaging. 2013;40:186–97.CrossRefPubMed
33.
Zips D, Zophel K, Abolmaali N, Perrin R, Abramyuk A, Haase R, et al. Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer. Radiother Oncol. 2012;105:21–8.CrossRefPubMed
34.
Needles A, Heinmiller A, Sun J, Theodoropoulos C, Bates D, Hirson D, Yin M, Foster FS. Development and initial application of a fully integrated photoacoustic micro-ultrasound system. IEEE Trans Ultrason Ferroelectr Freq Control. 2013;60:888–97.CrossRefPubMed
Metadata
Title
Carbon ion radiotherapy: impact of tumor differentiation on local control in experimental prostate carcinomas
Authors
Christin Glowa
Peter Peschke
Stephan Brons
Oliver C. Neels
Klaus Kopka
Jürgen Debus
Christian P. Karger
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2017
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/s13014-017-0914-9

Other articles of this Issue 1/2017

Radiation Oncology 1/2017 Go to the issue

Research

Radiotherapy plus temozolomide in elderly patients with glioblastoma: a “real-life” report

Research

Radiotoxicity in robotic radiosurgery: proposing a new quality index for optimizing the treatment planning of brain metastases

Research

Intermediate-term outcome after PSMA-PET guided high-dose radiotherapy of recurrent high-risk prostate cancer patients

Research

An appraisal of analytical tools used in predicting clinical outcomes following radiation therapy treatment of men with prostate cancer: a systematic review

Research

Comparison of photon volumetric modulated arc therapy, intensity-modulated proton therapy, and intensity-modulated carbon ion therapy for delivery of hypo-fractionated thoracic radiotherapy

Research

Long-term prognostic significance of rising PSA levels following radiotherapy for localized prostate cancer – focus on overall survival