Effects of oxygen on intrinsic radiation sensitivity: A test of the relationship between aerobic and hypoxic linear-quadratic (LQ) model parametersa)

Carlson, David J.; Stewart, Robert D.; Semenenko, Vladimir A.

doi:10.1118/1.2229427

Cited by 126 publications

(145 citation statements)

References 92 publications

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“…In practice, hypofractionation of 3-5 times rather than single fractionation is often used expecting to increase reoxygenation for hypoxic cells. In actual situations, the value   for a tumor or a specific organ (or tissue) may vary depending on its volume due to the oxygen effect (20) and other factors such as the cell cycle.…”

Section: Resultsmentioning

confidence: 99%

A Mathematical Study to Select Fractionation Regimen Based on Physical Dose Distribution and the Linear–Quadratic Model

Mizuta

Sugiyama

Date

et al. 2012

International Journal of Radiation Oncology*Biology*Physics

107

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Mizuta 2 AbstractPurpose: Hypofractionated irradiation is often used in precise radiotherapy instead of conventional multi-fractionated irradiation. We propose a novel mathematical method for selecting a hypofractionated or multi-fractionated irradiation regime based on physical dose distribution adding to biological consideration.Methods and Materials: The linear quadratic (LQ) model was employed for the radiation effects on tumor and normal tissues, especially OARs. Based on the assumption that the OAR receives a fraction of the dose intended for the tumor, the minimization problem for the damage effect on the OAR was treated under the constraint that the radiation effect on the tumor is fixed.Results: For an N-time fractionated irradiation regime, the constraint of tumor lethality was described by an N-dimensional hypersphere. The total dose of the fractionated irradiations was considered for minimizing the damage effect on the OAR under the hypersphere condition. It was found that the advantage of hypofractionated or multi-fractionated irradiation therapies depends on the magnitude of the ratio of  parameters for the OAR and the tumor in the LQ model and the ratio of the dose for the OAR and the tumor.Conclusions: The present mathematical method shows that the multi-fractionated irradiation Mizuta 3 with a constant dose is better if the ratio of  for the OAR and the tumor is less than the ratio of the dose for the OAR and the tumor, while hypofractionated irradiation is better otherwise.

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Section: Resultsmentioning

confidence: 99%

A Mathematical Study to Select Fractionation Regimen Based on Physical Dose Distribution and the Linear–Quadratic Model

Mizuta

Sugiyama

Date

et al. 2012

International Journal of Radiation Oncology*Biology*Physics

107

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“…The higher (albeit low in absolute terms) recurrence rate seen in the ELIOT trial might therefore be because of the lower oxygen saturation of the tissues being irradiated as it is well known that tissue ischaemia reduces the effectiveness of radiation. [134][135][136][137][138][139][140][141] In addition, theoretically, some at-risk tissue such as the retracted skin and subcutaneous breast tissue and the prepectoral tissue behind the shield would not receive any radiation while exposing more raw surface to tumour seeding.…”

Section: Other Trialsmentioning

confidence: 99%

An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with early-stage breast cancer (the TARGIT-A trial)

Vaidya

Wenz

Bulsara

et al. 2016

Health Technol Assess

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BackgroundBased on our laboratory work and clinical trials we hypothesised that radiotherapy after lumpectomy for breast cancer could be restricted to the tumour bed. In collaboration with the industry we developed a new radiotherapy device and a new surgical operation for delivering single-dose radiation to the tumour bed – the tissues at highest risk of local recurrence. We named it TARGeted Intraoperative radioTherapy (TARGIT). From 1998 we confirmed its feasibility and safety in pilot studies.ObjectiveTo compare TARGIT within a risk-adapted approach with whole-breast external beam radiotherapy (EBRT) over several weeks.DesignThe TARGeted Intraoperative radioTherapy Alone (TARGIT-A) trial was a pragmatic, prospective, international, multicentre, non-inferiority, non-blinded, randomised (1 : 1 ratio) clinical trial. Originally, randomisation occurredbeforeinitial lumpectomy (prepathology) and, if allocated TARGIT, the patient received it during the lumpectomy. Subsequently, the postpathology stratum was added in which randomisation occurredafterinitial lumpectomy, allowing potentially easier logistics and a more stringent case selection, but which needed a reoperation to reopen the wound to give TARGIT as a delayed procedure. The risk-adapted approach meant that, in the experimental arm, if pre-specified unsuspected adverse factors were found postoperatively after receiving TARGIT, EBRT was recommended. Pragmatically, this reflected how TARGIT would be practised in the real world.SettingThirty-three centres in 11 countries.ParticipantsWomen who were aged ≥ 45 years with unifocal invasive ductal carcinoma preferably ≤ 3.5 cm in size.InterventionsTARGIT within a risk-adapted approach and whole-breast EBRT.Main outcome measuresThe primary outcome measure was absolute difference in local recurrence, with a non-inferiority margin of 2.5%. Secondary outcome measures included toxicity and breast cancer-specific and non-breast-cancer mortality.ResultsIn total, 3451 patients were recruited between March 2000 and June 2012. The following values are 5-year Kaplan–Meier rates for TARGIT compared with EBRT. There was no statistically significant difference in local recurrence between TARGIT and EBRT. TARGIT was non-inferior to EBRT overall [TARGIT 3.3%, 95% confidence interval (CI) 2.1% to 5.1% vs. EBRT 1.3%, 95% CI 0.7% to 2.5%;p = 0.04; Pnon-inferiority = 0.00000012] and in the prepathology stratum (n = 2298) when TARGIT was given concurrently with lumpectomy (TARGIT 2.1%, 95% CI 1.1% to 4.2% vs. EBRT 1.1%, 95% CI 0.5% to 2.5%;p = 0.31; Pnon-inferiority = 0.0000000013). With delayed TARGIT postpathology (n = 1153), the between-group difference was larger than 2.5% and non-inferiority was not established for this stratum (TARGIT 5.4%, 95% CI 3.0% to 9.7% vs. EBRT 1.7%, 95% CI 0.6% to 4.9%;p = 0.069; Pnon-inferiority = 0.06640]. The local recurrence-free survival was 93.9% (95% CI 90.9% to 95.9%) when TARGIT was given with lumpectomy compared with 92.5% (95% CI 89.7% to 94.6%) for EBRT (p = 0.35). In a planned subgroup analysis, progesterone receptor (PgR) status was found to be the only predictor of outcome: hormone-responsive patients (PgR positive) had similar 5-year local recurrence with TARGIT during lumpectomy (1.4%, 95% CI 0.5% to 3.9%) as with EBRT (1.2%, 95% CI 0.5% to 2.9%;p = 0.77). Grade 3 or 4 radiotherapy toxicity was significantly reduced with TARGIT. Overall, breast cancer mortality was much the same between groups (TARGIT 2.6%, 95% CI 1.5% to 4.3% vs. EBRT 1.9%, 95% CI 1.1% to 3.2%;p = 0.56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1.4%, 95% CI 0.8% to 2.5% vs. 3.5%, 95% CI 2.3% to 5.2%;p = 0.0086), attributable to fewer deaths from cardiovascular causes and other cancers, leading to a trend in reduced overall mortality in the TARGIT arm (3.9%, 95% CI 2.7% to 5.8% vs. 5.3%, 95% CI 3.9% to 7.3%;p = 0.099]. Health economic analyses suggest that TARGIT was statistically significantly less costly than EBRT, produced similar quality-adjusted life-years, had a positive incremental net monetary benefit that was borderline statistically significantly different from zero and had a probability of > 90% of being cost-effective. There appears to be little uncertainty in the point estimates, based on deterministic and probabilistic sensitivity analyses. If TARGIT were given instead of EBRT in suitable patients, it might potentially reduce costs to the health-care providers in the UK by £8–9.1 million each year. This does not include environmental, patient and societal costs.LimitationsThe number of local recurrences is small but the number of events for local recurrence-free survival is not as small (TARGIT 57 vs. EBRT 59); occurrence of so few events (< 3.5%) also implies that both treatments are effective and any difference is unlikely to be large. Not all 3451 patients were followed up for 5 years; however, more than the number of patients required to answer the main trial question (n = 585) were followed up for > 5 years.ConclusionsFor patients with breast cancer (women who are aged ≥ 45 years with hormone-sensitive invasive ductal carcinoma that is up to 3.5 cm in size), TARGIT concurrent with lumpectomy within a risk-adapted approach is as effective as, safer than and less expensive than postoperative EBRT.Future workThe analyses will be repeated with longer follow-up. Although this may not change the primary result, the larger number of events may confirm the effect on overall mortality and allow more detailed subgroup analyses. The TARGeted Intraoperative radioTherapy Boost (TARGIT-B) trial is testing whether or not a tumour bed boost given intraoperatively (TARGIT) boost is superior to a tumour bed boost given as part of postoperative EBRT.Trial registrationCurrent Controlled Trials ISRCTN34086741 and ClinicalTrials.gov NCT00983684.FundingUniversity College London Hospitals (UCLH)/University College London (UCL) Comprehensive Biomedical Research Centre, UCLH Charities, Ninewells Cancer Campaign, National Health and Medical Research Council and German Federal Ministry of Education and Research (BMBF). From September 2009 this project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 73. See the NIHR Journals Library website for further project information.

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“…Meanwhile, it has been recognized that hypoxia can result in resistance to chemoradiotherapy of solid tumor [13] . The high oxygen pressure is often used in combination with the low LET radiation to treat tumors because the high oxygen pressure can consolidate the damage caused by ROS to the macromolecular substance [14] . Researchers began to doubt whether the anti-angiogenesis therapy might promote the infi ltration and metastasis of the tumors on account of the increased anoxia in tumor matrix, thus leading to a poor prognosis [15] .…”

Section: Discussionmentioning

confidence: 99%

Expression of mitochondrial transcripts in gastric MGC803 cell line subjected by hypoxia

Han

Zhou

2009

Clin. Oncol. Cancer Res.

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OBJECTIVE To determine the transcriptional expression of mitochondrial genome (mtDNA) in MGC803 cell lines subjected by various time-phase hypoxic dispositions, and further to discuss the influence of mtDNA transcripts on hypoxic resistance to irradiation. METHODS The MGC803 cells exposed to anoxic environment were divided into control group (0 h), hypoxic group (2 h, 8 h, 16 h, 24 h) and irradiated group a er exposing the hypoxia. RT-PCR was applied to detect the transcripts of cytochrome oxidase subunit I (COI), NADH dehydrogenase subunit 4 (ND4), ND5, cytochrome b (cyt-b) and ATPase6 (ATP-6) in MGC803 cell lines at various time-phases of hypoxic, and a er X-ray irradiation. Flow cytometry and colony formation assay were conducted to evaluate the cell cycle phase and survival fraction. RESULTSCOI and ND4 transcripts of MGC803 cell lines were influenced remarkably by hypoxia. COI transcripts were decreased remarkably with the elongation time of exposing the hypoxic, and reduced to one fourth of its original amount of prehypoxia 24 h after exposing the hypoxia. ND4 transcripts were increased initially, and elevated to two folds 8 h a er exposing the hypoxia, and then reduced to one second 24 h a er exposing the hypoxia. Hypoxia resulted in G 1 phase blockage, especially a er hypoxia for 16 h. The survival fraction of MGC803 cells exposing the hypoxia in irradiated group showed that as the time of exposing the hypoxic before irradiation is prolonged, the survival fraction of MGC803 cells may have an elevated tendency. CONCLUSION The tumor cells with lower expression levels of the COI and the ND4 a er exposing the hypoxic have stronger resistance to the radiation, which indicates that increasing the expression levels of the COI and the ND4 might be advantageous to enhance the sensitivity of hypoxic tumor cells to the radiotherapy.

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Effects of oxygen on intrinsic radiation sensitivity: A test of the relationship between aerobic and hypoxic linear-quadratic (LQ) model parametersa)

Cited by 126 publications

References 92 publications

A Mathematical Study to Select Fractionation Regimen Based on Physical Dose Distribution and the Linear–Quadratic Model

A Mathematical Study to Select Fractionation Regimen Based on Physical Dose Distribution and the Linear–Quadratic Model

An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with early-stage breast cancer (the TARGIT-A trial)

Expression of mitochondrial transcripts in gastric MGC803 cell line subjected by hypoxia

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