Mathematical modelling of radiotherapy strategies for early breast cancer

Enderling, Heiko; Anderson, Alexander R.A.; Chaplain, M. A. J.; Munro, Alastair J.; Vaidya, JS

doi:10.1016/j.jtbi.2005.11.015

Cited by 100 publications

(72 citation statements)

References 54 publications

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“…22,27 In fact, giving TARGIT at the time of surgery as a tumour bed boost followed by subsequent EBRT has been found to result in a very low 5-year recurrence rate of 1.73%, 27,28 with favourable toxicity and cosmetic outcome results; [29][30][31][32] furthermore, mathematical models of TARGIT have recently suggested that it could be superior in terms of local control to conventional radiotherapy. 33,34 This could be because of the radiotherapy limiting breast cancer cell proliferation normally caused by the trauma of surgery. 17 The biological, economical and technical advantages of TARGIT distinguish this trial from other trials that have since been launched with a similar aim to irradiate only the index quadrant, such as the ELectron IntraOperative radiotherapy (ELIOT) trial in Italy, 35 Thus, the TARGIT-A trial was an investigator-initiated trial that was launched in March 2000.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…Cells quiescent at the time of radiation can become proliferative again and repopulate the tumor even beyond pre-treatment cell numbers [28]. Different mathematical models of radiation response have previously considered a homogeneously radiosensitive tumor population [29,30], as well as tumor populations composed of cells with varying radiotherapeutic [31,32] and chemotherapeutic resistance [33,34,35]. Here we present a model that focuses on the understated role of stem cell pool size and stem cell repopulation during the course of treatment.…”

Section: Introductionmentioning

confidence: 99%

The Importance of Spatial Distribution of Stemness and Proliferation State in Determining Tumor Radioresponse

Enderling

Park

Hlatky

et al. 2009

Math. Model. Nat. Phenom.

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Abstract. Tumor growth and progression is a complex phenomenon dependent on the interaction of multiple intrinsic and extrinsic factors. Necessary for tumor development is a small subpopulation of potent cells, so-called cancer stem cells, that can undergo an unlimited number of cell divisions and which are proposed to divide symmetrically with a small probability to produce more cancer stem cells. We show that the majority of cells in a tumor must indeed be non-stem cancer cells with limited life span and limited replicative potential. Tumor development is dependent as well on the proliferative potential and death of these cells, and on the migratory ability of all cancer cells. With increasing number of cells in the tumor, competition for space limits tumor progression, and in agreement with in vitro observation, the majority of cancer cells become quiescent, with proliferation primarily occurring on the outer rim where space is available. We present an agent-based model of early tumor development that captures the spatial heterogeneity of stemness and proliferation status. We apply the model to simulations of radiotherapy to predict treatment outcomes for tumors with different stem cell pool sizes and different quiescence radiosensitivities. We show by first presuming homogeneous radiosensitivity throughout the tumor, and then considering the greater resistance of quiescent cells, that stem cell pool size and stem cell repopulation during treatment determine treatment success. The results for tumor cure probabilities comprise upper bounds, as there is evidence that cancer stem cells are also more radioresistant than other tumor cells. Beyond just demonstrating the influence of mass effects of stem to non-stem cell ratios and proliferating to quiescent cell ratios, we show that the spatiotemporal evolution of the developing heterogeneous population plays a pivotal role in determining radioresponse and treatment optimization.

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“…Numerical estimation of these coefficients was already made in [11] (and also in [8] values have been drawn randomly from a log-normal distribution, to avoid negative values, but keeping the immune system efficiency ( /   ) always smaller than 1. Survival factors [19,22] are also taken as random values. As initial conditions we assumed, for simplicity, that the number of tumor cells is higher than the number of lymphocytes and that both initial populations are distributed as normal random numbers.…”

Section: Simulationmentioning

confidence: 99%

Radioterapia y el papel del sistema inmunitario

Grau

Pérez

Antoranz

et al. 2014

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ResumenSe simuló computacionalmente un gran número de pacientes bajo tratamiento de radioterapia, mediante un sistema dinámico. De los resultados, se halló un método para cambiar el número de sesiones de radiación manteniendo óptimo el tratamiento. Además, se obtuvo que la relación entre la fracción sistema inmune-eficiencia tumoral para un paciente dado y la máxima probabilidad de éxito del tratamiento sigue una ley de potencias. Palabras clave: Sistemas Dinámicos, RadiobiologíaRecepción: 23-01-201223-01- Aceptación: 26-03-2012 Abstract Using a population dynamics formulation to model radiotherapy treatments a large amount of patients under treatment was mimicked. From the obtained results a method to change the number of radiation sessions while keeping the optimized treatment is found. Also a power law relating immune system -tumor effciency ratio (ISTER) for a given patient and maximum success probability of radiotherapy treatment is obtained.

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Mathematical modelling of radiotherapy strategies for early breast cancer

Cited by 100 publications

References 54 publications

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)

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)

The Importance of Spatial Distribution of Stemness and Proliferation State in Determining Tumor Radioresponse

Radioterapia y el papel del sistema inmunitario

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