Enhanced Electric Dipole Strength for the Weakly Bound States in

An enhanced low-energy electric dipole (E1) strength is identified for the weakly bound excited states of the neutron-rich isotope ^{27}Ne. The Doppler-shift lifetime measurements employing a combination of the γ-ray tracking array GRETINA, the plunger device, and the S800 spectrograph determine the lower limit of 0.030 e^{2} fm^{2} or 0.052 W.u. for the 1/2^{+}→3/2^{-} E1 transition in ^{27}Ne, representing one of the strongest E1 strengths observed among the bound discrete states in this mass region. This value is at least 30 times larger than that measured for the 3/2^{-} decay to the 3/2_{gs}^{+} ground state. A comparison of the present results to large-scale shell-model calculations points to an important role of core excitations and deformation in the observed E1 enhancement, suggesting a novel example of the electric dipole modes manifested in weakly bound deformed systems.

Alpha emitter radium-223 and survival in metastatic prostate cancer.

BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors.

BACKGROUND: Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk. METHODS: We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case-control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956-2003. RESULTS: Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97-15.46)), and increased significantly with proximity of sRT to menarche (Ptrend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35-0.85)), and increased with number of premenopausal years after treatment (Ptrend=0.003). CONCLUSION: In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk.

Acute Toxicity of Hypofractionated and Conventionally Fractionated (Chemo)Radiotherapy Regimens for Bladder Cancer: An Exploratory Analysis from the RAIDER Trial.

AIMS: Adding concurrent (chemo)therapy to radiotherapy improves outcomes for muscle-invasive bladder cancer patients. A recent meta-analysis showed superior invasive locoregional disease control for a hypofractionated 55 Gy in 20 fractions schedule compared with 64 Gy in 32 fractions. In the RAIDER clinical trial, patients undergoing 20 or 32 fractions of radical radiotherapy were randomised (1:1:2) to standard radiotherapy or to standard-dose or escalated-dose adaptive radiotherapy. Neoadjuvant chemotherapy and concomitant therapy were permitted. We report exploratory analyses of acute toxicity by concomitant therapy-fractionation schedule combination. MATERIALS AND METHODS: Participants had unifocal bladder urothelial carcinoma staged T2-T4a N0 M0. Acute toxicity was assessed (Common Terminology Criteria for Adverse Events) weekly during radiotherapy and at 10 weeks after the start of treatment. Within each fractionation cohort, non-randomised comparisons of the proportion of patients reporting treatment emergent grade 2 or worse genitourinary, gastrointestinal or other adverse events at any point in the acute period were carried out using Fisher's exact tests. RESULTS: Between September 2015 and April 2020, 345 (163 receiving 20 fractions; 182 receiving 32 fractions) patients were recruited from 46 centres. The median age was 73 years; 49% received neoadjuvant chemotherapy; 71% received concomitant therapy, with 5-fluorouracil/mitomycin C most commonly used: 44/114 (39%) receiving 20 fractions; 94/130 (72%) receiving 32 fractions. The acute grade 2+ gastrointestinal toxicity rate was higher in those receiving concomitant therapy compared with radiotherapy alone in the 20-fraction cohort [54/111 (49%) versus 7/49 (14%), P < 0.001] but not in the 32-fraction cohort (P = 0.355). Grade 2+ gastrointestinal toxicity was highest for gemcitabine, with evidence of significant differences across therapies in the 32-fraction cohort (P = 0.006), with a similar pattern but no significant differences in the 20-fraction cohort (P = 0.099). There was no evidence of differences in grade 2+ genitourinary toxicity between concomitant therapies in either the 20- or 32-fraction cohorts. CONCLUSION: Grade 2+ acute adverse events are common. The toxicity profile varied by type of concomitant therapy; the gastrointestinal toxicity rate seemed to be higher in patients receiving gemcitabine.

Forward- and Inverse-Planned Intensity-Modulated Radiotherapy in the CHHiP Trial: A Comparison of Dosimetry and Normal Tissue Toxicity.

AIMS: The CHHiP (Conventional or Hypofractionated High-dose Intensity Modulated Radiotherapy In Prostate Cancer; CRUK/06/016) trial investigated hypofractionated radiotherapy for localised prostate cancer. Forward- (FP) or inverse-planned (IP) intensity-modulated techniques were permitted. Dose-volume histogram and toxicity data were compared to explore the effects of planning method. MATERIALS AND METHODS: In total, 337 participants with intermediate-risk disease and prospectively collected toxicity data were included. Patients were matched on prostate and rectum/bladder volumes and on radiotherapy dose for toxicity comparisons. The primary outcome was grade 2 or higher Radiation Therapy Oncology Group (RTOG) bowel or bladder toxicity at 2 years. RESULTS: IP patients had smaller volumes of rectum irradiated to 50-70 Gy (P < 0.001); FP patients had smaller volumes of bladder irradiated to 74 Gy (P = 0.001). Acute grade 2 + bowel toxicity was worse with FP (27/53 [52%]; 11/53 [21%] IP; P = 0.0002); with no significant differences in acute urinary toxicity. At 2 years, RTOG grade 2 + bowel toxicity rates were FP 0/53 and IP 2/53 and RTOG grade 2 + bladder rates were FP 0/54 and IP 1/57. CONCLUSIONS: Significant differences were found between dose-volume histograms from FP and IP methods. IP may result in small reductions in acute bowel toxicity but both techniques were associated with low rates of late radiotherapy side-effects.

Accuracy and reproducibility of conformal radiotherapy using data from a randomised controlled trial of conformal radiotherapy in prostate cancer (MRC RT01, ISRCTN47772397).

AIMS: The MRC RT01 trial used conformal radiotherapy to the prostate, a method that reduces the volume of normal tissue treated by 40-50%. Because of the risk of geographical miss, the trial used portal imaging to examine whether treatment delivery was within the required accuracy. MATERIAL AND METHODS: In total, 843 patients were randomly assigned to receive 64 Gy in 32 fractions over 6.5 weeks or 74 Gy in 37 fractions over 7.5 weeks. Field displacements and corrections were recorded for all imaged fractions. Displacement trends and their association with time, disease and treatment set-up characteristics were examined using univariate and multivariate analyses. A Radiographer Trial Implementation Group (RTIG) was set up to inform the quality assurance process and to promote the development of best practice. RESULTS: Treatment isocentre positioning was within 5 mm in every direction on 6238 (83%) of the 7535 fractions imaged. In total, 532 (81%) of 695 included patients had at least one > or = 3 mm displacement and 415 (63%) had at least one > or = 5 mm displacement. Univariate, multivariate and stepwise models of > or =5 mm displacements showed an increased likelihood of displacement in weeks 1 and 2 with low melting point alloy (LMPA) blocks compared with multileaf collimators, film verification compared with electronic portal imaging (EPI) and increased number of fractions imaged. Except for LMPA, this was also seen for > or = 5 mm displacements in weeks 3-6. CONCLUSIONS: Accurate conformal treatment was delivered. The use of EPI was associated with increased reported accuracy. The RTIG was a crucial part of the quality assurance process.

Twenty Fraction Prostate Radiotherapy with Intra-prostatic Boost: Results of a Pilot Study.

AIMS: For patients with high-risk, locally bulky prostate cancer, an intra-prostatic boost to tumour volumes (dose-painting) offers a risk-adapted dose escalation. We evaluated the feasibility of hypofractionated dose-painting radiotherapy and the associated toxicity. The possibility to streamline a radiobiologically optimised planning protocol was also investigated. MATERIALS AND METHODS: Twenty-eight patients were treated using a dose-painting approach; boost volumes were identified with functional magnetic resonance imaging scans. The prostate dose outside the boost volume was 60 Gy in 20 fractions, and the maximum integrated boost dose was set to 68 Gy, provided that the dose constraints to the organs at risk could be fulfilled. Rotational intensity-modulated radiotherapy was used with daily image guidance and fiducial markers. RESULTS: The boost dose was escalated to 68 Gy for 25 patients (median dose 69 Gy, range 68-70 Gy); for three patients the boost dose was 67 Gy, due to the proximity of the urethra and/or the rectum. The mean normal tissue complication probability for rectal bleeding was 4.7% (range 3.4-5.8%) and was 3.5% for faecal incontinence (range 2.3-5.0%). At a median follow-up of 38 months (range 32-45) there was no grade 3 toxicity. Two patients developed grade 2 genitourinary toxicity (7.1%) and none developed grade 2 gastrointestinal toxicity. The mean prostate-specific antigen (PSA) for 23 patients who had stopped the adjuvant hormone therapy with a normal testosterone was 0.27 ng/ml (0.02-0.72) at follow-up; two patients have suppressed PSA and testosterone after stopping 3 year adjuvant hormone and three patients have relapsed (one pelvic node, two PSA only) at 36, 12 and 42 months, respectively. CONCLUSIONS: A hypofractionated radiotherapy schedule, 60 Gy in 20 fractions with intra-prostatic boost dose of 68 Gy, can be achieved without exceeding dose constraints for organs at risk. Hypofractionated dose-painting escalated radiotherapy has an acceptable safety profile. The same planning protocol was used in a phase II single-arm trial (BIOPROP20: ClinicalTrials.gov identifier NCT02125175) and will further be used in a large phase III randomised trial (PIVOTALboost): patients will be randomised standard radiotherapy (60 Gy in 20 fractions) with or without lymph node radiotherapy versus dose-painting radiotherapy with or without lymph node radiotherapy; the trial will be opened for recruitment in summer 2017.

Prostate Dose-painting Radiotherapy and Radiobiological Guided Optimisation Enhances the Therapeutic Ratio.

AIMS: To describe the treatment of 11 patients with radiobiologically guided dose-painting radiotherapy and report on toxicity. MATERIALS AND METHODS: Boost volumes were identified with functional magnetic resonance imaging scans in 11 patients with high-risk prostate cancer. Patients were treated using a dose-painting approach; the boost dose was limited to 86 Gy in 37 fractions, while keeping the rectal normal tissue complication probability to 5-6%. Rotational intensity-modulated radiotherapy was used with daily image guidance and fiducial markers. RESULTS: The median dose to the prostate (outside the boost volume) and urethra was 75.4 Gy/37 fractions (range 75.1-75.8 Gy), whereas the median boost dose was 83.4 Gy (range 79.0-87.4 Gy). The tumour control probability (TCP) (Marsden model) increased from 71% for the standard plans to 83.6% [76.6-86.8%] for the dose-painting boost plans. The mean (Lyman-Kutcher-Burman) normal tissue complication probability for rectal bleeding was 5.2% (range 3.3-6.2%) and 5.2% for faecal incontinence (range 3.6-7.8%). All patients tolerated the treatment well, with a low acute toxicity profile. At a median follow-up of 36 months (range 24-50) there was no grade 3 late toxicity. Two patients had grade 2 late urinary toxicity (urethral stricture, urinary frequency and urgency), one patient had grade 1 and one grade 2 late rectal toxicity. The mean prostate-specific antigen at follow-up was 0.81 ng/ml after stopping hormone therapy; one patient relapsed biochemically at 32 months (2.70 ng/ml). CONCLUSIONS: The toxicity for this radiobiological guided dose-painting protocol was low, but we have only treated a small cohort with limited follow-up time. The advantages of this treatment approach should be established in a clinical trial.

Recommendations for Radiotherapy Technique and Dose in Extra-nodal Lymphoma.

Extra-nodal sites may be involved in around 40% of patients with non-Hodgkin lymphoma. The general principles for target volume delineation in this setting are presented, together with specific examples. In general, the entire organ affected should be encompassed in the clinical target volume with an expansion of at least 10 mm, increased in some instances to account for patterns of potential lymphatic flow. Adjacent lymph nodes may be treated using standard techniques for nodal irradiation. Doses for extra-nodal lymphoma follow the same principles as nodal lymphoma, delivering 30 Gy in 15 fractions for Hodgkin and aggressive non-Hodgkin lymphoma and 24 Gy in 12 fractions for indolent lymphomas, with the exception of certain palliative situations, mycosis fungoides, central nervous system lymphoma and natural killer/T-cell lymphoma.

Long-term results of a randomised trial of involved field radiotherapy vs extended field radiotherapy in stage I and II Hodgkin lymphoma.

Involved field (IF) radiation was compared with extended field (EF) radiation in Hodgkin lymphoma (HL) to ascertain whether reduced radiation fields would reduce the late sequelae of radiation without compromising disease control and survival. A total of 603 patients with stage I or II HL were entered into this trial; laparotomy was carried out in 380 (63%) patients. Stage I or IIA disease patients were randomised to receive IF or EF comprising a mantle or inverted Y fields alone. Stage I and IIB patients were randomised between mantle or inverted Y fields and total nodal irradiation (TNI). The dose was 35 Gy to uninvolved sites and 40 Gy to involved sites. The median followup of surviving patients was 25.2 years with only 3.3% lost to follow-up. The treatment failure rate at 25 years in stage IA and IIA was 44% after EF and 54% after IF (P = 0.01); in stage I and IIB this was 80% (EF) and 82% (TNI) at 25 years. No difference in overall survival between the randomised groups was seen. The incidence of second malignancies was 21% after IF and 20% after EF with a slight excess of lung cancer in the EF group. No significant differences in the causes of death between the randomised arms have emerged. In conclusion, IF radiotherapy for stage I and IIA HL results in a 11% greater risk of relapse compared with EF but has no effect on overall survival, risk of second malignancy or cause of death at 25 years.

Primary radical therapy selection in high-risk non-metastatic prostate cancer.

As the incidence of prostate cancer rises, the detection and management of men with high-risk non-metastatic prostate cancer is becoming increasingly important. The benefits of radical treatment have been clearly shown in this group from a number of publications. The current mainstays of treatment are radical prostatectomy (with selective use of adjuvant radiation) and radical radiotherapy with concurrent androgen deprivation. The outcomes from these two approaches seem to be remarkably similar and are considered equally valid options for primary treatment. The choice of therapy is critically dependent on a number of factors, but ultimately left to the decision of the patients with advice from clinicians. Clinicians themselves, however, are known to be biased towards their particular skill set and experiences. Attempts at randomised comparisons between these two modalities have so far failed and are confounded by patient-clinician bias, the continual advances in therapy as well as the long natural history of the disease. In the lack of level 1 comparable evidence, this article explores the existing literature as to the key factors that should be considered in radical treatment selection for high-risk prostate cancer. These factors include disease aggressiveness, comorbidity and life expectancy, functional outcomes and the consequences of therapy failure with regards to salvage treatment. We propose that these factors may be useful in developing a decision guide for rationale radical therapy selection in the light of two apparently equally effective treatments. Ultimately, however, there is an urgent need for added clinical and biological markers that can provide a more precise approach to therapy selection.

Long-term follow-up of young children with brain tumors after irradiation.

PURPOSE: Young children with brain tumors are at high risk of developing late sequelae after curative radiotherapy. A retrospective study was undertaken to determine the frequency and severity of neurological deficits, endocrine dysfunction, and intellectual disabilities. METHODS AND MATERIAL: One hundred and fifty-six children age < or = 3 years were treated between 1952 and 1986 with radiotherapy. Of the 57 survivors, 47 had surgery, 12 chemotherapy and 24 children received cranio-spinal radiotherapy. Late radiation side effects were assessed with a clinical examination, blood tests and an interview. RESULTS: The median follow-up was 13 years and the actuarial survival at 5 and 10 years was 49% and 44%, respectively. No, or only a mild, handicap was noted in 24 patients, while 21 had moderately severe and 16 severe disabilities. Children with supratentorial tumors had more abnormal neurological findings compared to those with infratentorial malignancies (p < 0.001). Eighty percent of children had endocrine abnormalities, which were more marked in children with parasellar tumors (p < 0.001). Twenty-one children were mentally retarded. In a multivariate analysis epilepsy emerged as the only significant variable independently associated with poor cognitive function. CONCLUSION: Long-term morbidity was found to be disabling in 58% of the surviving children. These findings encourage the development of treatment strategies designed to reduce toxicity.

Pion conformal radiation of prostate cancer: results of a randomized study.

PURPOSE: To compare the efficacy of pion radiation therapy with conventional external beam photon therapy, for the treatment of locally advanced stage T3/4, N0, M0 adenocarcinoma of the prostate. METHODS AND MATERIALS: Two hundred seventeen eligible patients were randomly allocated to either photon or pion therapy. No adjuvant hormone therapy was used. RESULTS: Median follow-up was 42 months (range 2-90). Acute bladder toxicity was worse in the pion arm, p = 0.2, but other acute toxicity did not differ. Late grade 2 toxicity was significantly less in the pion arm (29% at 5 years versus 48%, p = 0.002), but late grade 3 or 4 toxicity did not differ. Clinical local control was not significantly different between treatment arms (64% after 5 years with photons, 56% with pions, p = 0.6). Cause-specific and overall survival also did not differ (p = 0.7). There was a significant delay in time to first failure in the photon arm, largely as a result of decreased biochemical relapse, p = 0.01. A multivariate analysis is presented. CONCLUSION: Pion therapy was well tolerated, with increased acute toxicity and significantly decreased late tissue injury. This contrasts with the late toxicity observed with higher LET particle therapy such as neutron therapy. No improvement in local control with pion therapy was observed.

Pion radiation for high grade astrocytoma: results of a randomized study.

PURPOSE: This study attempted to compare within a randomized study the outcome of pion radiation therapy vs. conventional photon irradiation for the treatment of high-grade astrocytomas. METHODS AND MATERIALS: Eighty-four patients were randomized to pion therapy (33-34.5 Gy pi), or conventional photon irradiation (60 Gy). Entry criteria included astrocytoma (modified Kernohan high Grade 3 or Grade 4), age 18-70, Karnofsky performance status (KPS) > or = 50, ability to start irradiation within 30 days of surgery, unifocal tumor, and treatment volume < 850 cc. The high-dose volume in both arms was computed tomography enhancement plus a 2-cm margin. The study was designed with the power to detect a twofold difference between arms. RESULTS: Eighty-one eligible patients were equally balanced for all known prognostic variables. Pion patients started radiation 7 days earlier on average than photon patients, but other treatment-related variables did not differ. There were no significant differences for either early or late radiation toxicity between treatment arms. Actuarial survival analysis shows no differences in terms of time to local recurrence or overall survival where median survival was 10 months in both arms (p = 0.22). The physician-assessed KPS and patient-assessed quality of life (QOL) measurements were generally maintained within 10 percentage points until shortly before tumor recurrence. There was no apparent difference in the serial KPS or QOL scores between treatment arms. CONCLUSION: In contrast to high linear energy transfer (LET) therapy for central nervous system tumors, such as neutron or neon therapy, the safety of pion therapy, which is of intermediate LET, has been reaffirmed. However, this study has demonstrated no therapeutic gain for pion therapy of glioblastoma.

High dose rate Microselectron moulds for Kaposi sarcoma of the palate.

PURPOSE: External beam radiotherapy for Kaposi sarcoma of the palate in HIV positive patients has often severe acute side-effects. As alternative treatment, a high dose Microselectron brachytherapy technique was developed. METHODS AND MATERIAL: A customised dental plate with afterloading tubes was made; from outlines, three dimensional coordinates of source positions and surface points were input to a Target 2 treatment planning computer. For the best dose-distribution on the mould surface, weighting of each source dwell position was adjusted, a plan produced, and a test run with TLD measurements performed. RESULTS: We planned and treated six patients and seven lesions with this technique. A median surface dose of 24 Gy (range 14-39.9 Gy) in 3 fractions over 3 to 10 days was prescribed. There was a complete response for all lesions with only mild mucositis. No relapse occurred in the treated areas. CONCLUSIONS: Kaposi sarcoma of the palate treated with a high dose rate Microselectron dental plate is convenient for the patient, achieves local control and has less acute toxicity compared with external beam radiotherapy.

Tolerance of nicotinamide and carbogen with radiation therapy for glioblastoma.

Nineteen patients with glioblastoma were treated with nicotinamide and carbogen and radiotherapy. Eight patients did not complete the protocol because of hepatic toxicity from phenytoin/nicotinamide drug interactions, persistent nausea or vomiting with nicotinamide, intolerance of the carbogen breathing apparatus, or other reason. In addition, early radiation neurotoxicity appeared increased.

Separating components of variation in measurement series using maximum likelihood estimation. Application to patient position data in radiotherapy.

Maximum likelihood estimation (MLE) is presented as a statistical tool to evaluate the contribution of measurement error to any measurement series where the same quantity is measured using different independent methods. The technique was tested against artificial data sets; generated for values of underlying variation in the quantity and measurement error between 0.5 mm and 3 mm. In each case the simulation parameters were determined within 0.1 mm. The technique was applied to analyzing external random positioning errors from positional audit data for 112 pelvic radiotherapy patients. Patient position offsets were measured using portal imaging analysis and external body surface measures. Using MLE to analyze all methods in parallel it was possible to ascertain the measurement error for each method and the underlying positional variation. In the (AP / Lat / SI) directions the standard deviations of the measured patient position errors from portal imaging were (3.3 mm / 2.3 mm / 1.9 mm), arising from underlying variations of (2.7 mm / 1.5 mm / 1.4 mm) and measurement uncertainties of (1.8 mm / 1.8 mm / 1.3 mm), respectively. The measurement errors agree well with published studies. MLE used in this manner could be applied to any study in which the same quantity is measured using independent methods.

Mechanistic modelling of radiotherapy-induced lung toxicity.

OBJECTIVE: This work explores the biological basis of a mechanistic model of radiation-induced lung damage; uniquely, the model makes a connection between the cellular radiobiology involved in lung irradiation and the full three-dimensional distribution of radiation dose. METHODS: Local tissue damage and loss of global organ function, in terms of radiation pneumonitis (RP), were modelled as different levels of radiation injury. Parameters relating to the former could be derived from the local dose-response function, and the latter from the volume effect of the organ. The literature was consulted to derive information on a threshold dose and volume-effect mechanisms. RESULTS: Simulations of local tissue damage supported the alveolus as a functional subunit (FSU) which can be regenerated from a single surviving stem cell. A moderate interpatient variation in stem cell radiosensitivity (15%) resulted in a great variation in tissue response between 8 and 20 Gy. The threshold of FSU inactivation within a critical functioning volume leading to RP was found to be approximately 47% and the degree of health status variation (influencing the volume effect) in a population was estimated at 25%. CONCLUSION: This work has shown that it is possible to make sense of the way the lung responds to radiation by modelling RP mechanistically, from cell death to tissue damage to loss of organ function. ADVANCES IN KNOWLEDGE: Simulations were able to provide parameter values, currently not available in the literature, related to the response of the lung to irradiation.