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Analysing Tumour Growth Delay Data from Animal Irradiation Experiments with Deviations from the Prescribed Dose.

ABSTRACT: The development of new radiotherapy technologies is a long-term process, which requires proof of the general concept. However, clinical requirements with respect to beam quality and controlled dose delivery may not yet be fulfilled. Exemplarily, the necessary radiobiological experiments with laser-accelerated electrons are challenged by fluctuating beam intensities. Based on tumour-growth data and dose values obtained in an in vivo trial comparing the biological efficacy of laser-driven and conventional clinical Linac electrons, different statistical approaches for analysis were compared. In addition to the classical averaging per dose point, which excludes animals with high dose deviations, multivariable linear regression, Cox regression and a Monte-Carlo-based approach were tested as alternatives that include all animals in statistical analysis. The four methods were compared based on experimental and simulated data. All applied statistical approaches revealed a comparable radiobiological efficacy of laser-driven and conventional Linac electrons, confirming the experimental conclusion. In the simulation study, significant differences in dose response were detected by all methods except for the conventional method, which showed the lowest power. Thereby, the alternative statistical approaches may allow for reducing the total number of required animals in future pre-clinical trials.

SUBMITTER: Karsch L

PROVIDER: S-EPMC6769440 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Analysing Tumour Growth Delay Data from Animal Irradiation Experiments with Deviations from the Prescribed Dose.

Karsch Leonhard L Beyreuther Elke E Eger Passos Doreen D Pawelke Jörg J Löck Steffen S

Cancers 20190831 9

The development of new radiotherapy technologies is a long-term process, which requires proof of the general concept. However, clinical requirements with respect to beam quality and controlled dose delivery may not yet be fulfilled. Exemplarily, the necessary radiobiological experiments with laser-accelerated electrons are challenged by fluctuating beam intensities. Based on tumour-growth data and dose values obtained in an in vivo trial comparing the biological efficacy of laser-driven and conv ...[more]

PMID: 31480456

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Project description:BACKGROUND: Although two-dimensional (2-D) monolayer cell cultures provide important information on basic tumor biology and radiobiology, they are not representative of the complexity of three-dimensional (3-D) solid tumors. In particular, new models reproducing clinical conditions as closely as possible are needed for radiobiological studies to provide information that can be translated from bench to bedside. METHODS: We developed a novel system for the irradiation, under sterile conditions, of 3-D tumor spheroids, the in vitro model considered as a bridge between the complex architectural organization of in vivo tumors and the very simple one of in vitro monolayer cell cultures. The system exploits the same equipment as that used for patient treatments, without the need for dedicated and highly expensive instruments. To mimic the passage of radiation beams through human tissues before they reach the target tumor mass, 96-multiwell plates containing the multicellular tumor spheroids (MCTS) are inserted into a custom-built phantom made of plexiglass, the material most similar to water, the main component of human tissue. RESULTS: The system was used to irradiate CAEP- and A549-derived MCTS, pre-treated or not with 20 ?M cisplatin, with a dose of 20 Gy delivered in one session. We also tested the same treatment schemes on monolayer CAEP and A549 cells. Our preliminary results indicated a significant increment in radiotoxicity 20 days after the end of irradiation in the CAEP spheroids pre-treated with cisplatin compared to those treated with cisplatin or irradiation alone. Conversely, the effect of the radio- chemotherapy combination in A549-derived MCTS was similar to that induced by cisplatin or irradiation alone. Finally, the 20 Gy dose did not affect cell survival in monolayer CAEP and A549 cells, whereas cisplatin or cisplatin plus radiation caused 100% cell death, regardless of the type of cell line used. CONCLUSIONS: We set up a system for the irradiation, under sterile conditions, of tumor cells grown in 3-D which allows for the use of the same dose intensities and schedules utilized in clinical practice. This irradiation system, coupled with 3-D cell cultures, has the potential to generate information that could be used to individually tailor radiotherapy.

Project description:BACKGROUND: Clinical and experimental studies have shown that laparoscopy preserves the immune response and can give better clinical results than laparotomy. However, the use of laparoscopy for the treatment of cancer patients is still controversial due to the risk of port-site and haematogenous metastases and increased tumour growth. The purpose of this experimental study was to assess tumour growth and the mechanism of differential tumour behaviour after laparoscopy and laparotomy. METHODS: Seventy-five young, male Wistar rats were randomly assigned to one of two experiments. Experiment 1: 45 animals were inoculated subcutaneously with Walker carcinosarcoma 256 cells and were subdivided into three groups of 15 rats. Control group la was submitted to anaesthesia only, group 1b received carbon dioxide (CO(2)) pneumoperitoneum,while group 1c received a laparotomy. Animals were sacrificed on postoperative day (POD) 7; tumours were excised and weighed to evaluate tumour growth. Nucleolar organiser regions identified by silver staining (AgNORs) were analysed to evaluate cell proliferation. Experiment 2: 30 rats were submitted to the same procedures as before, with ten animals in each group (2a, 2b, 2c), and a delayed-type hypersensitivity response (DTH) was used to evaluate the immune function. RESULTS: The average tumour mass was 1.76 g in group 1a, 2.81 g in group 1b and 4.21 g in group 1c (p < 0.05). The AgNOR expression results were similar in the three groups. The immune function was better preserved in the control group (2a: average inflammatory area on POD1 = 106 mm(2) and on POD2 = 128.18 mm(2)), than in the pneumoperitoneum group (2b: average inflammatory area on POD1 = 79.75 mm(2) and on POD2 = 126.93 mm(2)); the worst results were in the laparotomy group (2c: average inflammatory area on POD1 = 33.33 mm(2) and on POD2 = 61.32 mm(2)).There were significant differences between groups 2a and 2c and between 2b and 2c. CONCLUSION: Laparotomy stimulates a greater tumour growth than CO(2) pneumoperitoneum, but there is no difference in tumour cell proliferation. The cellular immune function is better preserved in animals submitted to CO pneumoperitoneum than in the laparotomized animals. These results suggest a relationship between a weaker immune response and a greater tumour growth.

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Analysing Tumour Growth Delay Data from Animal Irradiation Experiments with Deviations from the Prescribed Dose.

Publications

Analysing Tumour Growth Delay Data from Animal Irradiation Experiments with Deviations from the Prescribed Dose.

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