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Aim: The negative impact of tumour hypoxia on cancer treatment outcome has been long-known, yet there has been little success combating it. This paper investigates the potential role of in silico modelling to help test emerging hypoxia-targeting treatments in cancer therapy. Methods: A Medline search was undertaken on the current landscape of in silico models that simulate cancer therapy and evaluate their ability to test hypoxia-targeting treatments. Techniques and treatments to combat tumour hypoxia and their current challenges are also presented. Results: Hypoxia-targeting treatments include tumour reoxygenation, hypoxic cell radiosensitization with nitroimidazoles, hypoxia-activated prodrugs and molecular targeting. Their main challenges are toxicity and not achieving adequate delivery to hypoxic regions of the tumour. There is promising research toward combining two or more of these techniques. Different types of in silico therapy models have been developed ranging from temporal to spatial and from stochastic to deterministic models. Numerous models have compared the effectiveness of different radiotherapy fractionation schedules for controlling hypoxic tumours. Similarly, models could help identify and optimize new treatments for overcoming hypoxia that utilize novel hypoxia-targeting technology. Conclusion: Current therapy models should attempt to incorporate more sophisticated modelling of tumour angiogenesis/vasculature and vessel perfusion in order to become more useful for testing hypoxia-targeting treatments, which typically rely upon the tumour vasculature for delivery of additional oxygen, (pro)drugs and nanoparticles Refereed/Peer-reviewed

Simple Summary Immunotherapy (IO) and radiotherapy (XRT) are two of the most important treatment modalities in metastatic non-small cell lung cancer. There is data to suggest that XRT can enhance the IO’s efficacy. However, little is known regarding how to best combine them. In this retrospective, single-center study, we analyze data of 453 patients who have received various combinations of XRT and IO, or IO alone, to assess the treatment parameters that correlate with longer overall survival (OS). XRT doses between 30 and 40 Gy correlated with longer overall survival, while XRT doses below 10 Gy, fractions of 4.1 to 8 Gy and XRT to the bone correlated with worse overall survival. These results require validation with prospective studies. Abstract Background: Immunotherapy (IO) provides a significant benefit for a subgroup of non-small cell lung cancer (NSCLC) patients. Radiotherapy (XRT) might enhance the efficacy of IO. We evaluated the impact of the specifics of XRT treatments on the OS of IO-treated NSCLC patients. Methods: Metastatic NSCLC patients treated with IO were retrospectively identified. Parameters included demographics, tumor characteristics, IO and XRT details. Correlation between the parameters and OS was tested with Cox regression. Results: 453 patients were included. No XRT was given to 167 (36.9%) patients, whereas XRT prior and after IO had 182 (40.2%) and 104 (22.9%) patients, respectively. XRT total doses between 30 and 40 Gy had better overall survival (OS) compared to non-irradiated patients (hazard ratio (HR) 0.5, 95% CI 0.25–1.0, p = 0.049). Worse outcome was seen with total doses ≤ 10 Gy (HR 1.67, 95% 1.13–2.5, p = 0.01), XRT fractions of 4.1–8 Gy (HR 1.48, 95% CI 1.05–2.1, p = 0.027) and XRT to the bone (HR 1.36, 95% CI 1.01–1.8, p = 0.04). Several clinical parameters correlated with OS in the univariate analysis of the IO-treated patients. While, in the multivariate analysis, only ECOG-PS, treatment line, type of IO, albumin and NLR remained statistically significant. Conclusion: Specific doses, fractions and sites of XRT correlated with the OS of IO-treated NSCLC patients in the univariate analysis, although not in the multivariate analysis.

This paper deals with the classic radiotherapy dose fractionation problem for cancer tumors concerning the following goals: To maximize the effect of radiation on the tumor, restricting the effect produced to an organ at risk (healing approach). To minimize the effect of radiation on one organ at risk, while maintaining enough effect of radiation on the tumor (palliative approach). We will assume the linear-quadratic model to characterize the radiation effect without considering the tumor repopulation between doses. The main novelty with respect to previous works concerns the presence of minimum and maximum dose fractions, to achieve the minimum effect and to avoid undesirable side effects, respectively. We have characterized in which situations is more convenient the hypofractionated protocol (deliver few fractions with high dose per fraction) and in which ones the hyperfractionated regimen (deliver a large number of lower doses of radiation) is the optimal strategy. In all cases, analytical solutions to the problem are obtained in terms of the data.

Background：Hypofractionated whole breast irradiation (HF-WBI) can achieve the same treatment effect as conventional fractionated whole breast irradiation (CF-WBI) within limits , without increasing adverse reactions. Because of its characteristics of reducing the number of radiation therapy (RT) during the COVID-19 Pandemic, it is recommended as the first choice of treatment for patients with early breast cancer after breast conserving surgery. However, the choice of RT is still under exploration. Here, we conducted a network meta-analysis to evaluate the problem comprehensively using data from new randomized trials. Methods: We analyzed data from eligible studies for published events for ipsilateral breast tumor recurrence (IBTR), distant metastasis, total deaths, and non-breast cancer-related deaths. Statistical analysis was performed using a fixed-effects or random-effects model in cases of low and high heterogeneity, respectively. Network meta-analysis was conducted using a node-splitting model for two-category data among three RTs based on a Bayesian approach.Results: 16 studies with 23,418 patients were included. For IBTR, pairwise comparison showed that CF-WBI was significantly better than PBI, and HF-WBI was similar to CF-WBI. HF-WBI was superior to PBI, but the difference was not significant. However, indirect comparison of three RTs by network meta-analysis showed that HF-WBI was significantly better than PBI (OR=0.67, CI95%: 0.46–0.95). Paired and network meta-analyses found no significant differences in other endpoints among three radiotherapies. Conclusion: This meta-analysis demonstrated PBI was associated with increased IBTR compared with HF-WBI or CF-WBI in early-stage breast cancer patients.

Introduction This study aims to analyze the patterns of care, including fractionation and utilization, of hypofractionated stereotactic ablative radiotherapy (SABR) in the treatment of hepatocellular carcinoma (HCC). Methods The National Cancer Database was queried for patients diagnosed with HCC from 2004 to 2014 and treated with SABR in three, four, or five fractions in 15-20Gy, 10-13Gy, or 6-12Gy per fraction, respectively. Patients with stage IV and Charlson-Deyo Comorbidity Index > 0 were excluded in order to avoid bias resulting from the selection of poorer prognosis patients. The patients were then stratified based on several characteristics including biologically equivalent doses (BEDs) of =/> 100 Gy and 100Gy, which was associated with a median OS of 30.8 months (95% CI 5.25-32.08). On MVA, BED =/> 100Gy was not significantly associated with improved OS (HR 0.85, 95% CI 0.64-1.14, p = 0.28). Factors that were associated with significantly worse survival were tumor size in the largest quartile (HR 2.197 CI 1.440-3.354, p < 0.0001) and T3a disease (HR 2.474 CI 1.472-4.158, p = 0.001 compared to T1). Conclusion SABR fractionation schemes vary widely, but are most commonly 10Gy x five fractions followed by 8Gy x five fractions and 15Gy x three fractions. BED of at least 100Gy is not associated with improved OS. Further studies are needed to best identify the optimal SABR dose and fractionation.

Purpose or Objective Radiotherapy is an essential treatment in the local control of breast cancer. Standard treatment is currently carried out in 15 daily sessions. At present, following the results of the phase III Fast-Foward trial and in view of the situation triggered by COVID-19, the number of sessions has been reduced to 5. The RHEMA (extreme hypofractionated radiotherapy in breast cancer) study has been initiated in Spain. It is a multi-hospital study designed to determine the evolution of the change in fractionation. The hypothesis is that the change in fractionation does not increase acute toxicity. The aim of the study was to determine whether there are differences in acute skin toxicity in breast cancer patients who receive adjuvant radiotherapy according to the different fractionation schedules applied. Materials and Methods We retrospectively analysed skin toxicity in patients treated with glandular radiotherapy at the end of treatment and one month later. Out of 75 patients treated with the ultra-hypofractionated schedule, 58 patients with a follow-up of more than 1 month were compared with 38 patients who received the standard schedule, all of whom were treated in 2020 in the Multihospital Clinical Unit of Radiation Oncology of Aragon. In the case of the ultra-hypofractionated treatment, as indicated in the GEORM (Spanish group of breast radiation oncology) guidelines at the beginning of the pandemic, was carried out in 5 sessions with a total dose of 26 Gy over the breast and 29 Gy over the tumour bed, while the standard treatment, consisted in 15 sessions with a total dose of 40.5 Gy over the breast and 48 Gy over the tumour bed. Results The median age was 61 years in the standard group and 63.4 years in the ultra-hypofractionated group. No significant differences were observed in the histological profile. Differences were found in toxicity at the end of treatment, being significantly higher in the standard group (p 0.03). On the other hand, no differences were found in toxicity one month after the end of treatment. Grade 2 toxicity appeared in 2 patients from the ultra-hypofractionated group and 4 from the standard group, with no significant difference (p 0.943). There were no differences in the development of grade 1 toxicity and no grade 3 or higher toxicity was observed. Conclusion It can be concluded that the use of the ultra-hypofractionation schedule compared to standard treatment was not associated with an increase in acute skin toxicity in our series. This is a change in fractionation that could be adopted as a routine treatment in radiation oncology departments after verifying the results with a larger number of patients and a longer follow-up.

Accurate delineation of target volumes and organs-at-risk (OAR) is important in the era of intensity-modulated radiotherapy where the dose distribution is highly conformal, yet significant variations in practice exist. Establishing international guidelines and consensus based on basic knowledge of disease behavior and clinical data can enhance global consistency and help to identify controversies. In the process of radiotherapy planning, a fine balance between dose-to-target volumes and constraints to the OAR should be attained in order to maximize the risk-to-benefit ratio. Integrating the most optimal radiotherapy fractionation and schedule is also critical in modulating radiobiological response. This chapter will give an overview of these essential concepts in radiotherapy planning and review the latest data and recommendations.

Antiangiogenic therapy is the anti-tumor treatment, that leads to the cessation of blood vessels formation and subsequent nutrient deprivation of the tumor. One of its frequently occurring effects is the transient improvement of tumor oxygenation, which lasts several days and leads to increased efficiency of successive exposure to radiation. It is followed by an escalation of hypoxia, and therefore the addition of antiangiogenic therapy to the whole course of fractionated radiotherapy has an ambiguous effect. Previously we have developed a mathematical model of such combined anti-tumor treatment. Herein we present an algorithm of optimization of radiotherapy fractionation, which aim is to find the most optimal distribution of irradiation doses in order to increase the efficiency of such combined treatment. We demonstrate an example of its work and discuss its further application.

Background and purpose. The aim of this study was to estimate a radiobiological set of parameters from the available clinical data on glioblastoma (GB).Patients and methods. A number of clinical trial outcomes from patients affected by GB and treated with surgery and adjuvant radiochemotherapy were analyzed to estimate a set of radiobiological parameters for a tumor control probability (TCP) model. The analytical/graphical method employed to fit the clinical data allowed us to estimate the intrinsic tumor radiosensitivity (alpha), repair capability (b), and repopulation doubling time (T-d) in a first phase, and subsequently the number of clonogens (N) and kick-off time for accelerated proliferation (T-k). The results were used to formulate a hypothesis for a scheduleexpected to significantly improve local control. The 95 % confidence intervals (CI95 %) of all parameters are also discussed.Results. The pooled analysis employed to estimate the parameters summarizes the data of 559 patients, while the studies selected to verify the results summarize data of 104 patients. The best estimates and the CI95 % are alpha = 0.12 Gy(-1) (0.10-0.14), b = 0.015 Gy(-2) (0.013-0.020), alpha/b = 8 Gy (5.0-10.8), T-d = 15.4 days (13.2-19.5), N = 1.10(4) (1.2.10(3)-1.10(5)), and T-k = 37 days (29-46). The dose required to offset the repopulation occurring after 1 day (D-prolif ) and starting after T-k was estimated as 0.30 Gy/day (0.22-0.39).Conclusion. The analysis confirms a high value for the alpha/b ratio. Moreover, a high intrinsic radiosensitivity together with a long kick-off time for accelerated repopulation and moderate repopulation kinetics were found. The results indicate a substantial independence of the duration of the overall treatment and an improvement in the treatment effectiveness by increasing the total dose without increasing the dose fraction.

Historically, the 4Rs and then the 5Rs of radiobiology explained the effect of radiation therapy (RT) fractionation on the treatment efficacy. These 5Rs are: Repair, Redistribution, Reoxygenation, Repopulation and, more recently, intrinsic Radiosensitivity. Advances in radiobiology have demonstrated that RT is able to modify the tumor micro environment (TME) and to induce a local and systemic (abscopal effect) immune response. Conversely, RT is able to increase some immunosuppressive barriers, which can lead to tumor radioresistance. Fractionation and dose can affect the immunomodulatory properties of RT. Here, we review how fractionation, dose and timing shape the RT-induced anti-tumor immune response and the therapeutic effect of RT. We discuss how immunomodulators targeting immune checkpoint inhibitors and the cGAS/STING (cyclic GMP-AMP Synthase/Stimulator of Interferon Genes) pathway can be successfully combined with RT. We then review current trials evaluating the RT/Immunotherapy combination efficacy and suggest new innovative associations of RT with immunotherapies currently used in clinic or in development with strategic schedule administration (fractionation, dose, and timing) to reverse immune-related radioresistance. Overall, our work will present the existing evidence supporting the claim that the reactivation of the anti-tumor immune response can be regarded as the 6th R of Radiobiology.

We address the problem of finding the optimal radiotherapy fractionation scheme, representing the response to radiation of tumour and normal tissues by the LQ model including exponential repopulation and sublethal damage due to incomplete repair. We formulate the nonlinear programming problem of maximizing the overall tumour damage, while keeping the damages to the late and early responding normal tissues within a given admissible level. The optimum is searched over a single week of treatment and its possible structures are identified. In the two simpler but important cases of absence of the incomplete repair term or of prevalent late constraint, we prove the uniqueness of the optimal solution and we characterize it in terms of model parameters. The optimal solution is found to be not necessarily uniform over the week. The theoretical results are confirmed by numerical tests and comparisons with literature fractionation schemes are presented.

Purpose: To determine conditions under which hypofractionation could be favorable for a normal tissue--even if tumor [{alpha}/{beta}] exceeds the normal tissue's [{alpha}/{beta}]. Methods: The hypofractionation sufficiency condition (HSC) for an organ is defined as a dose conformality constraint such that, if satisfied, a family of tumor control probability isoeffective fractionation schemes will show decreasing normal tissue complication probability with decreasing number of fractions. Results: In the extended equivalent uniform dose (EUD) model [obtained by replacing dose with linear quadratic (LQ) 2 Gy equivalent dose], the HSC for a normal organ is proven to be satisfied if a suitably weighted average of the relative dose [hypofractionation sufficiency index (HSI)] is less than the ratio of normal tissue to tumor [{alpha}/{beta}]. The HSI is determined solely by dose distribution and the normal tissue volume factor, ''a.'' If the HSC is satisfied for every normal tissue of concern, then there is a therapeutic gain with hypofractionation. The corresponding multifractionation sufficiency condition (therapeutic gain with increasing number of fractions) and multifractionation sufficiency index (MSI) are also derived. A sample clinical case is presented. Conclusions: Within the context of the LQ/EUD models, conformality measures (HSI and MSI) can be used to inform fractionation decisions.

The palliative radiotherapeutic management of unresectable non-small-cell lung cancer is controversial, with various fractionation (Fx) schedules available. We aimed to determine patient's choice of Fx schedule after involvement in a decision-making process using a decision board. A decision board outlining the various advantages and disadvantages apparent in the Medical Research Council study of Fx schedules (17 Gy in two fractions vs 39 Gy in 13 fractions) was discussed with patients who met Medical Research Council eligibility criteria. Patients were then asked to indicate their preferred Fx schedules, reasons and their level of satisfaction with being involved in the decision-making process. Radiation oncologists (RO) could prescribe radiotherapy schedules irrespective of patients' preferences. Of 92 patients enrolled, 55% chose the longer schedule. English-speaking patients were significantly more likely to choose the longer schedule (P = 0.02, 95% confidence interval: 1.2-7.6). Longer Fx was chosen because of longer survival (90%) and better local control (12%). Shorter Fx was chosen for shorter overall treatment duration (80%), cost (61%) and better symptom control (20%). In all, 56% of patients choosing the shorter schedule had their treatment altered by the treating RO, whereas only 4% of patients choosing longer Fx had their treatment altered (P < 0.001). Despite this, all (100%) patients were satisfied with being involved in the decision-making process. The decision board was useful in aiding decision-making, with both Fx schedules being acceptable to patients. Interestingly, despite the longer average survival associated with longer Fx, nearly half of the patients believed that this was not as important as a shorter duration of treatment and lower cost. Despite patients' preferences, there were significant alterations of preferred schedules because of RO's own biases.

Large primary breast tumours and extensive lymph node involvement are linked to a high rate of local recurrence after surgery. In 10-20% of such high-risk breast cancer patients, local relapse will occur despite postoperative radiotherapy. In the present study, we investigated whether molecular features, such as angiogenesis, cancer cell proliferation, steroid receptor expression, c-erbB-2 oncoprotein overexpression, p53 protein nuclear accumulation or bcl-2 antiapoptotic protein expression, can predict failure of local therapy. We further examined as to which subgroups of patients could benefit from altered fractionation schemes of radiotherapy. In univariate analysis, high intratumoural angiogenesis, c-erbB overexpression and mutant-p53 nuclear accumulation were significantly associated with increased relapse rate (P=0.0002, 0.009 and 0.05, respectively). In multivariate analysis, the microvessel density and the c-erbB-2 status were independent and significant factors related to local relapse (P=0.001, t-ratio 3.36 and P=0.02, t-ratio 2.26, respectively). Hypofractionated and accelerated radiotherapy supported with amifostine (HypoARC regimen) was significantly more effective than standard radiotherapy in cases with high cancer cell proliferation index, c-erbB-2 and p53 overexpression. High angiogenesis, however, was linked with local relapse regardless of the radiotherapy regimen.

Purpose: To investigate the impact of using spatiotemporal optimization, i.e., intensity modulated spatial optimization followed by fractionation schedule optimization, to select the patient-specific fractionation schedule that maximizes the tumor biologically equivalent dose (BED) under dose constraints for multiple organs-at-risk (OAR).Methods: The optimal fractionation schedule for a patient using the linear-quadratic (LQ) cell survival model depends on the tumor and OAR sensitivity to fraction size, the effective tumor doubling time (Td), and the size and location of tumor target relative to one or more OAR (dose distribution). We used a spatiotemporal optimization method to identify the optimal number of fractions N that maximizes the 3D tumor BED distribution for sixteen lung phantom cases. The 15 selection of the optimal fractionation schedule used equivalent (30-fraction) OAR constraints for the heart (Dmean 45 Gy), lungs (Dmean 20 Gy), cord (Dmax 45 Gy), esophagus (Dmax 63 Gy), and unspecifed tissues (D05 60 Gy). To assess plan quality, we compared the minimum, mean, maximum, and D95 of tumor BED, as well as the equivalent uniform dose (EUD) for optimized plans to conventional IMRT plans prescribing 60 Gy in 30 fractions. A sensitivity analysis was 20 performed to assess the effects of Td (3 to 100 days), tumor lag-time (Tk = 0 to 10 days), and the size of tumors on optimal fractionation schedule.Results: Using an alpha/beta ratio of 10 Gy, the average values of tumor max, min, mean BED, and D95 were up to 19%, 21%, 20%, and 19% larger than those from conventional prescription, depending on Td and Tk used. Tumor EUD was up to 17% larger than the conventional prescription. For fast 25 proliferating tumors with Td less than 10 days, there was no significant increase in tumor BED but the treatment course could be shortened without a loss in tumor BED. The improvement in the tumor mean BED was more pronounced with smaller tumors (p-value = 0.08).Conclusions: Spatiotemporal optimization of patient plans has the potential to significantly improve local tumor control (larger BED/EUD) of patients with a favorable geometry, such as 30 smaller tumors with larger distances between the tumor target and nearby OARs. In patients with a less favorable geometry and for fast growing tumors, plans optimized using spatiotemporal optimization and conventional (spatial-only) optimization are equivalent (negligible differences in tumor BED/EUD). However, spatiotemporal optimization yields shorter treatment courses than conventional spatial-only optimization. Personalized, spatiotemporal optimization of treatment 35 schedules can increase patient convenience and help with the efficient allocation of clinical resources. Spatiotemporal optimization can also help identify a subset of patients that might benefit from non-conventional (large dose per fraction) treatments that are ineligible for the current practice of stereotactic body radiation therapy.

Using a model of cell cycle (CelCyMUS) in which the cell population is described in terms of the cell age and position within the cell cycle typical radiotherapy strategies are simulated, and the effects compared to clinical results, showing reasonable qualitative agreement. Alternative strategies are tested on a slow and a fast-growing tumour and the strategy most likely to completely destroy the tumour is found to depend on the growth rate. This work may have important applications for the development of novel radiotherapy fractionation, for example, schedules to take advantage of hypersensitivity to small doses of radiation exhibited by some tumours, which might improve results compared to conventional dosing strategies.

Five hundred sixty-four patients with squamous cell carcinoma of the head and neck receiving definitive chemoradiation in the PET Neck phase 3 trial were randomized to either planned neck dissection or PETCT scan guided surveillance. The primary endpoint for this study has been previously reported. As the trial spanned the period of IMRT introduction in the United Kingdom, a pragmatic approach to radiotherapy fractionation and technique was adopted and thus three-dimensional conformal radiotherapy (3D-CRT) or intensity modulated radiotherapy (IMRT) were permitted as were 4, 6, or 7 week radiotherapy schedules.

A national survey of British radiotherapy schedules used in women with early breast cancer was undertaken to document variation in treatment practices and to consider its clinical significance. Although the variation is considerable, the analysis suggests that the majority of schedules in use are very similar in terms of treatment intensity when allowance is made for fraction size and overall time. Half the respondents used one of three dosage schedules, which probably differ very little in terms of late normal-tissue effects and tumour control from a conventional schedule giving 50 Gy in daily 2 Gy fractions. Eighty-two per cent of respondents were using schedules that are equivalent to a dose of between 45 Gy and 50 Gy in 2 Gy fractions. The study suggests that the protocols in use by a minority of respondents may be unduly conservative or aggressive, and it leads to the proposal that oncologists should set up trials comparing commonly used schedules as a matter of urgency.

Radiotherapy factors may play an important role in both the response and local control of patients with limited SCLC. Even with older techniques, a recently reported retrospective meta-analysis showed that long-term survival was significantly improved with the addition of thoracic radiotherapy 23 . Today, with PE regimens and more conservative volumes of radiotherapy administered in more aggressive ways, long-term survival is now attainable in patients with SCLC; 2-year survival rates approach 50% and 5-year survival is in the range of 30%. Presently, the Eastern Cooperative Oncology Group is testing fractionation in patients with limited SCLC given 4 cycles of PE. Patients are randomized to receive twice-daily radiotherapy providing 4,500 cGy administered either in 25 fractions over 33 days or in 30 fractions over 19 days, respectively). More than 400 patients have been entered into this trial, which closed in August 1992. Integrating radiotherapy with chemotherapy early in the course of treatment has the advantage of potentially eliminating resistant clones; however, results from the CALGB study imply that early radiotherapy may compromise systemic therapy. The dose-reduction rules were very cautious, though. Since the majority of SCLC deaths and failures continue to be systemic, development of new agents and new strategies for systemic therapy is certainly warranted. However, analysis of the French alternating-modality experience suggests local relapse is also a major cause of failure. Therefore, improved local management remains a worthy goal.

To compare the results obtained for tumour control probability (TCP) in protracted treatments, we used two models which apply Poisson statistics for clonogenic cell distribution and a non-Poissonian model, emphasising the conditions for the validity of Poissonian models. Previously published results on two cell lines growing as megacolonies in vitro irradiated with conventional and accelerated dose fractionation schemes were used.The expressions of TCP for three models are described and conclusions are drawn on the applicability of each model, and their usefulness for different fractionations.The fits to experimental data are shown and the parameter values for both Poissonian and non-Poissonian models are given. We also determined if differences exist in repopulation rate and other related parameters, for different protocols of treatment.Both the Poissonian models, when they satisfied the required conditions, and the non-Poissonian model, gave acceptable fits. We observed no significant differences in repopulation for different irradiation protocols.

Although it may be argued that single fraction (SF) radiotherapy (RT) should be regarded as the standard palliative treatment for pain due to uncomplicated bone metastases, its widespread clinical use is still underexploited. In this chapter, the authors discuss a number of surveys investigating doctors and patients' preferences for palliative RT schedules, discuss the possible reasons for this phenomenon, and suggest potential strategies to increase the use of SF.

Despite recent advances in multimodality management of patients with stage III-IV head and neck squamous cell carcinoma, the prognosis in these patients remains disappointing. In an attempt to improve treatment outcome, several teams recently investigated the role of altered fractionation radiotherapy in conjunction with systemic chemotherapy. The controlled trials that investigated this combined approach indicate that, although the magnitude of its effect was less marked for survival indices than for local-regional control, the addition of chemotherapy to altered fractionation regimens results in a clear improvement for these endpoints compared with hyperfractionated or accelerated regimens alone. The key challenge now is to optimize the synergism of these regimens in order to increase their therapeutic ratio in terms of both local-regional and systemic outcomes. This review is a critical appraisal of the real opportunities offered by the application of treatments aimed at increasing the dose intensity of radiotherapy delivered concurrently with cytotoxic drugs.

Aims and background In 75% of the patients with bone metastases (BM) pain is the dominant symptom. Radiotherapy (XRT) plays a major role in the palliation of pain in patients with BM. Several schedules of short and long fractionation XRT are used in clinical practice, with hypofractionated treatments being even more attractive for practical reasons. A considerable body of evidence supports the clinical use of short schedules and single-dose XRT. We retrospectively evaluated the efficacy of two short fractionated schedules of 8 Gy as a single dose and 20 Gy in 5 fractions in relieving pain in patients with multiple uncomplicated BM. Method From January to December 2001, 130 patients with 146 painful BM were treated with palliative localized XRT. There were 42 males and 88 females with a median age of 58 years (range 28–84). The commonest sites of treatment were the spine (59.6%) and pelvis (14.4%). The primary endpoint was clinically significant pain relief in the first six months of follow-up evaluated with the IAEA (International Atomic Energy Agency) pain measurement score measuring pain severity and pain frequency. Analgesic use was also recorded before and after treatment as drug frequency and drug severity. Patients with painful BM from any primary tumor site were irradiated. Treatment schedules consisted of a course of XRT with 4 Gy/fraction/day (total dose: 20 Gy/5 fractions) (group A, 59 lesions) or with a single dose of 8 Gy (group B, 87 lesions). Results There was no significant difference in complete response (CR) rates between treatment schedules: complete pain relief was achieved in 17/59 lesions (29%) in the fractionated group and in 29/87 lesions (33%) in the single-dose group. Also the overall response (complete + partial) was similar: 35/59 lesions (60%) in group A and 60/87 (69%) in group B. The minimum, maximum and median follow-up was 3, 23, and 9 months, respectively, for group A and 3, 20, and 11 months for group B. The actuarial median duration of pain relief was similar: 4.5 months in group A and 4 months in group B. No particular side effects were recorded in either group. Conclusions There were no differences between the two fractionation schedules used in our study with regard to pain relief and use of analgesics. Palliation of pain was obtained in approximately two thirds of patients with both schedules, providing further evidence of the similar efficacy between single and multiple fractions. With regard to pain response these data justify a recommendation for the use of a more simple and convenient 8 Gy single fraction for the palliation of uncomplicated BM.

External beam radiotherapy remains an important local treatment modality in both high and low grade gliomas, however its contribution to outcome remains modest. In high grade tumours this is because of their extreme clinical radioresistance, with local recurrences occurring even after doses over 70 Gy. In low grade tumours radiation does not seem to alter the overall pattern of disease progression significantly. Therefore despite use of the new technologies now available that allow radiotherapy to be delivered more accurately and to higher doses, local control of these tumours is still rarely achieved. Unfortunately these tumours have not proven sensitive to changes in radiotherapy fractionation or to the addition of radio-sensitising agents. Novel approaches to these tumours are needed, based on an improved understanding of both tumour and normal tissue response to radiation.

‘Timing’ of treatment in breast cancer may refer to intervals within a single management or between different managements. Rates of shrinkage of breast cancers in response to treatment are related to histological grade and may be used as surrogates for growth rates. Histological grade should predict appropriate timing of treatment. Four cases of locally advanced breast cancer that illustrate a number of different types of interval are presented. Two tumours of differing histological grade (II and III) had been managed by historical ‘split-course’ radiotherapy and two similar grade III tumours were managed by primary medical treatment, followed at different intervals by radiotherapy. In the grade III tumours different radiotherapy fractionation regimes and effects of varying intervals between mangements are compared. The theoretical advantage of shrinkage (leading to reoxygenation) during the gap in ‘split-course’ radiotherapy is realized only in relatively slowly growing and shrinking tumours. Grade III tumours grow rapidly. They have the potential to shrink rapidly in response to appropriate treatment, namely intensive chemotherapy or radiotherapy but not hormones. Inadequate treatment leads to growth in intervals between individual doses, whether of drugs or radiation, and to failure of local control. The advantage of surgery or primary medical treatment will be lost if the interval between managements is too long in relation to the volume doubling time. Histological grade is a good guide of this parameter; the grade III tumours are particularly vulnerable to gaps in treatment.

In the early 1920s Regaud discovered the benefits of radiation treatment fractionation—that is, splitting the dose into several treatments over several days—when he was trying to sterilise the testes of rams with radiation without necrosing the scrotal skin.1 During the 1930s radiotherapy changed from a dangerous mystery that put patients and staff at risk2 to a therapeutic modality with a scientific basis. This was an era when radiotherapy fractionation and treatment guidelines were empirically developed from clinical observation tempered by pragmatic issues such as machine availability. Since then the science of radiotherapy has advanced considerably, but suspicions that pragmatic considerations still weigh too heavily are surrounding a proposed British trial of radiotherapy fractionation in breast cancer. Early randomised clinical trials in cancer—and, therefore, in radiotherapy—reflected the management arguments of the time and addressed questions about what patients to treat with which modality. Trials of radiotherapy process—techniques, fractionation, overall treatment time—had to wait until the 1970s, when radiobiology was suggesting that these factors were crucial. In 1978 Withers showed for pig skin that acute radiotherapy reactions were worse after large numbers of small dose fractions than after a few high dose fractions, while the late reactions were worse after the latter.3 Therefore, side effects depended on total dose and fraction size. Other evidence suggested that tumour cells could repopulate a tumour rapidly during radiotherapy. Hence, prolonging treatment could be …

The major morbidity of neuraxis radiotherapy in young children is late neuropsychological retardation, which may be severe (reviewed by Gamis et al, 1991). Two recent studies suggest that the total radiation dose to the neuraxis may not be lowered safely in (? any) group of these children (Deutsch et al, 1991, SIOP medulloblastoma second trial unpublished results), and this prevents the most certain method of reducing this morbidity. An alternative method of reducing this morbidity must be desirable, but carefully weighed against a possible loss of tumour control.

Plowman and Doughty have recently described a partial transmission block technique for the treatment of children with medulloblastoma or similar tumours, who require total neuraxis radiotherapy (Plowman & Doughty, 1991). In this technique, the neuraxis radiotherapy is given in a larger number of smaller fractions, and it is proposed that this will reduce the neurological morbidity associated with the treatment without reducing tumour control rates. While we agree that late side effects are likely to be less severe, we do not accept that tumour control will be unchanged; indeed we expect that it will be significantly impaired.

Computer simulations have been made of four radiotherapy fractionation regimes either in current use or proposed for clinical trials of misonidazole. A variety of cell-survival parameters and reoxygenation patterns have been used. The models allow the relative importance of repair capacity, reoxygenation rate, and dose per fraction to be assessed for these four schedules in the presence or absence of misonidazole. Unlike hyperbaric oxygen, the dose of misonidazole and the fractionation scheme to be used are critically interdependent, because the total drug dose is limited to 12 g/m2 by its neurotoxicity, regardless of the extent to which it is fractionated. The largest sensitizing effect is always demonstrated with six fractions, each given with 2 g/m2 of misonidazole. In the absence of reoxygenation a sensitizer enhancement ratio of 1.7 is predicted, but this falls to 1.1--1.2 if extensive reoxy-generation occurs. Less sensitization is observed with 30 fractions, each with 0.4 g/m2 of drug. However, for clinical use, the important question is which treatment kills the maximum number of tumour cells. Many of the simulations predict a marked disadvantage of reducing the fraction number for X rays alone. The circumstances in which this disadvantage is offset by the large SER values with a six-fraction schedule are few. The model calculations suggest that many small fractions, each with a low drug dose, are safest unless the clinician has some prior knowledge that a change in fraction number is not disadvantageous.