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PURPOSE To derive the isodose line R relative to the prescription dose below which irradiated normal tissue (NT) regions benefit from a hypofractionated schedule with an isoeffective dose to the tumor. To apply the formalism to clinical case examples. METHODS From the standard biologically effective dose (BED) equation based on the linear-quadratic (LQ) model, the BED of an NT that receives a relative proportion r of the prescribed dose per fraction for a given α/β-ratio of the tumor, (α/β)T , and NT, (α/β)NT , is derived for different treatment schedules while keeping the BED to the tumor constant. Based on this, the "break-even" isodose line R is then derived. The BED of NT regions that receive doses below R decreases for more hypofractionated treatment schedules, and hence a lower risk for NT injury is predicted in these regions. To assess the impact of a linear behavior of BED for high doses per fraction (>6 Gy), we evaluated BED also using the LQ-linear (LQ-L) model. RESULTS The formalism provides the equations to derive the BED of an NT as function of dose per fraction for an isoeffective dose to the tumor and the corresponding break-even isodose line R. For generic α/β-ratios of (α/β)T = 10 Gy and (α/β)NT = 3 Gy and homogeneous dose in the target, R is 30%. R is doubling for stereotactic treatments for which tumor control correlates with the maximum dose of 100% instead of the encompassing isodose line of 50%. When using the LQ-L model, the notion of a break-even dose level R remains valid up to about 20 Gy per fraction for generic α/β-ratios and DT=2(α/β) . CONCLUSIONS The formalism may be used to estimate below which relative isodose line R there will be a differential sparing of NT when increasing hypofractionation. More generally, it allows to assess changes of the therapeutic index for sets of isoeffective treatment schedules at different relative dose levels compared to a reference schedule in a compact manner.

PURPOSE This study compares the effectiveness of three fractionation schemes of equal fraction size, comprising five fractions of SBRT over 5 days, 10 days, or 15 days, respectively. METHOD This comparative study is based on two tumor-control-probability (TCP) models that take into account tumor cell re-sensitization and repopulation during treatment; the Zaider-Minerbo-Stavreva (ZMS) and the Ruggieri-Nahum (RN) models. The ZMS model is further modified to include also re-sensitization according to the β mechanism of the linear-quadratic (LQ) model of cell killing. The modified version of the ZMS model is verified through fitting to the experimental data set of Fisher and Moulder. The study applies an idea used in a plan ranking methodology developed for the case when the specific values of the model parameters are not known. RESULTS The TCPs of the compared regimens are calculated for various values of the model parameters and for two different values of the dose per fraction. The TCPs are presented as 2-D functions of two of the model parameters for each model correspondingly. The differences between the TCPs of each of the prolonged regimens and the TCP of the every week day regimen are also calculated for each model. CONCLUSIONS Both models predict that the prolonged regimens are superior in terms of TCP to the every week-day one for most of the studied cases; however this is shown to exist to a different degree by the two models. It is shown again to a different degree that reversed situations where the every week day schedule is better than the prolonged regimens are also possible. It is concluded that a 30% TCP difference observed in a clinical study in favor of the fifteen-day regimen is theoretically possible. However, the fifteen-day regimen is outperformed in terms of TCP by the every week day regimen in more cases than the regimen lasting ten days. Therefore the choice of a prolongation in time must be made with care.

PURPOSE To assess the role of reoxygenation of hypoxic tumor cells in hypofractionated radiotherapy of prostate cancer. METHODS The considered radiobiological model is based on the assumption of two populations (compartments) of cells: oxygenated (aerobic) cells and hypoxic cells. After each fraction of radiation, some of the hypoxic cells reoxygenate while a fraction of initially aerobic cells becomes hypoxic. The kinetics of this process between successive treatments is described by coupled, first-order differential equations. To determine the effect of reoxygenation on cell kill in the treatment target, we utilize the linear-quadratic (LQ) model assuming different radiosensitivities for the aerobic and hypoxic cells. RESULTS Analytical solutions for the number of surviving malignant cells are obtained for special cases of slow and fast reoxygenation. The radiobiological effect of reoxygenation for different fractionation regimens is also evaluated numerically. CONCLUSIONS In this study, a radiobiological model for kinetics of reoxygenation in tumors is used to evaluate different fractionation schedules in radiotherapy of prostate cancer. The obtained results indicate that in the case of low alpha/beta ratio for malignant cells (e.g., α/β = 1.5 Gy), treatment schedule with 4-10 fractions and dose per fraction >4-5 Gy can result in increased cell kill in the treatment target at the same level of rectal toxicity as compared to conventional fractionation. The findings of this study also suggest that radiotherapy of the prostate with 1-3 fractions can be radiobiologically inferior to treatments with greater number of fractions.

PURPOSE To evaluate three different formulae for calculating the biologically effective dose (BED) by use of a multipopulation reaction-diffusion simulation to determine whether these formulae produce equivalent effects for different treatment regimes. METHODS The standard BED formula, BEDs , was updated to account both for spacial nonuniformity in dose and for cellular regrowth between fractions, by creating two new formulae: BEDϕ and BEDϕT . These BED formulae were used to calculate dose per fraction values for two, three, and five fraction treatments and to compare the tumor volumes of those treatments to those of a single fraction. A spherical tumor model based on the reaction-diffusion equation was used to calculate the final volume of each tumor 185 days after the delivery of the first fraction. The percent difference in volume between single-fraction and multiple-fraction treatments was used as a measure to test the accuracy of each BED formula. RESULTS Percent differences in volume between single- and multiple-fraction treatment regimes varied up to approximately 18.5% if the dose per fraction was calculated using BEDs but the delivered dose was nonuniform. Proper application of spacial nonuniformity in dose and tumor regrowth correction factors modified the dose per fraction values by no more than 5%, but resulted in the improvement of simulated tumor volumes down to around 2% or lower difference in volume. CONCLUSIONS Treatment regimes with the same BED value should have the same effect. However, small changes in the dose per fraction delivered in multiple-fraction treatments can have a large effect on the tumor volume of a treatment when the dose is delivered nonuniformly or when tumor regrowth between fractions is ignored. Inclusion of these correction factors is important for the underlying assumption that treatments with equal BED will have equal effects on the clinically observed tumor volume.

Aim/objectives/background To standardize the practice of stereotactic body radiation therapy (SBRT), the American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO) cooperatively developed the practice parameter for SBRT. SBRT is a treatment technique that delivers radiation dose to a well-defined extracranial target in 5 fractions or less and usually employs a higher dose per fraction than used in conventional radiation. Methods The ACR-ASTRO Practice Parameter for the Performance of Stereotactic Body Radiation Therapy was revised according to the process described on the ACR website ("The Process for Developing ACR Practice Parameters and Technical Standards," www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the ASTRO. Both societies then reviewed and approved the document. Results Given the complexities of SBRT, a separate document was created to develop a technical standard for the medical physics of SBRT (ACR-AAPM Technical Standard for Medical Physics Performance Monitoring of Stereotactic Body Radiation Therapy). Workflow, qualifications and responsibilities of personnel, specifications, documentation, quality control/safety/improvement, simulation/treatment, and follow-up were addressed in this practice parameter. Conclusions This practice parameter assists practitioners in providing safe and appropriate SBRT treatment and care for patients when clinically indicated. As technologies and techniques continue to evolve, this document will be reviewed, revised and renewed accordingly to a 5 year or sooner timeline specified by the ACR.

The main method of treating rare mesenchymal tumors PEComas is surgical removal of the tumor and external-beam radiation therapy has historically been considered ineffective. However, the individual cases in the foreign literature as well as this article authors’ experience in the form of the clinical case provided in it shows the possibility of achieving some anti-tumor effect due to the use of aggressive variants of radiation therapy. The use of variations of stereotactic radiotherapy with high dose per fraction and sum dose as an neoadjuvant and definitive treatment looks promising.

Simple Summary Brain metastases are one of the most frequent complications for cancer patients. Stereotactic radiosurgery is considered a cornerstone treatment for patients with limited brain metastases and the ideal dose and fractionation schedule still remain unknown. The aim of this literature review is to discuss the dose-effect relation in brain metastases treated by stereotactic radiosurgery, accounting for fractionation and technical considerations. Abstract For more than two decades, stereotactic radiosurgery has been considered a cornerstone treatment for patients with limited brain metastases. Historically, radiosurgery in a single fraction has been the standard of care but recent technical advances have also enabled the delivery of hypofractionated stereotactic radiotherapy for dedicated situations. Only few studies have investigated the efficacy and toxicity profile of different hypofractionated schedules but, to date, the ideal dose and fractionation schedule still remains unknown. Moreover, the linear-quadratic model is being debated regarding high dose per fraction. Recent studies shown the radiation schedule is a critical factor in the immunomodulatory responses. The aim of this literature review was to discuss the dose–effect relation in brain metastases treated by stereotactic radiosurgery accounting for fractionation and technical considerations. Efficacy and toxicity data were analyzed in the light of recent published data. Only retrospective and heterogeneous data were available. We attempted to present the relevant data with caution. A BED10 of 40 to 50 Gy seems associated with a 12-month local control rate >70%. A BED10 of 50 to 60 Gy seems to achieve a 12-month local control rate at least of 80% at 12 months. In the brain metastases radiosurgery series, for single-fraction schedule, a V12 Gy < 5 to 10 cc was associated to 7.1–22.5% radionecrosis rate. For three-fractions schedule, V18 Gy < 26–30 cc, V21 Gy < 21 cc and V23 Gy < 5–7 cc were associated with about 0–14% radionecrosis rate. For five-fractions schedule, V30 Gy < 10–30 cc, V 28.8 Gy < 3–7 cc and V25 Gy < 16 cc were associated with about 2–14% symptomatic radionecrosis rate. There are still no prospective trials comparing radiosurgery to fractionated stereotactic irradiation.

Purpose\ud A graphical user interface (GUI) was developed to aid in the assessment of changes in the radiation tolerance of spinal cord/similar central nervous system tissues with time between two individual treatment courses.\ud \ud Methods\ud The GUI allows any combination of photons, protons (or ions) to be used as the initial, or retreatment, radiotherapy courses. Allowances for clinical circumstances, of reduced tolerance, can also be made. The radiobiological model was published previously and has been incorporated with additional checks and safety features, to be as safe to use as possible. The proton option includes use of a fixed RBE of 1.1 (set as the default), or a variable RBE, the latter depending on the proton linear energy transfer (LET) for organs at risk. This second LET-based approach can also be used for ions, by changing the LET parameters.\ud \ud Results\ud GUI screenshots are used to show the input and output parameters for different clinical situations used in worked examples. The results from the GUI are in agreement with manual calculations, but the results are now rapidly available without tedious and error-prone manual computations. The software outputs provide a maximum dose limit boundary, which should not be exceeded. Clinicians may also choose to further lower the number of treatment fractions, whilst using the same dose per fraction (or conversely a lower dose per fraction but with the same number of fractions) in order to achieve the intended clinical benefit as safely as possible.\ud \ud Conclusions\ud The new GUI will allow scientific-based estimations of time related radiation tolerance changes in the spinal cord and similar central nervous tissues (optic chiasm, brainstem), which can be used to guide the choice of retreatment dose fractionation schedules, with either photons, protons or ions.

Background The aim of the study was to update our experience treating patients with glottic carcinoma in situ (CIS) with curative radiotherapy (RT). Methods Fifty patients received continuous-course RT using once-daily fractionation. Twenty-eight (56%) had recurrent or persistent CIS after resection. Median total dose was 63.0 Gy; median dose per fraction was 2.25 Gy. Median follow-up was 9.6 years for all patients and 8.4 years for survivors. Results After RT, 5 patients (10%) recurred locally; salvage surgery was performed in 4 (1 refused). Five-year outcomes were as follows: local control, 91%; ultimate local control (including patients successfully salvaged after local recurrence), 100%; ultimate local control with larynx preservation, 93%; local-regional control, 91%; ultimate local-regional control, 100%; distant metastases-free survival, 100%; cause-specific survival, 100%; and overall survival, 81%. No patient experienced a severe complication. Conclusion RT is an excellent treatment for patients with CIS recurrent after transoral excision and those with previously untreated CIS who are unsuitable for partial laryngectomy.

Purpose: To report the outcomes of sinonasal tumors treated with proton beam therapy (PBT) on the Proton Collaborative Group registry study. Methods and Materials: Sixty-nine patients with sinonasal tumors underwent curative intent PBT between 2010 and 2016. Patients who received de novo irradiation (42 patients) were analyzed separately from those who received reirradiation (27 patients) (re-RT). Median age was 53.1 years (range, 15.7-82.1; de novo) and 57.4 years (range, 31.3-88.0; re-RT). The most common histology was squamous cell carcinoma in both groups. Median PBT dose was 58.5 Gy (RBE) (range, 12-78.3; de novo) and 60.0 Gy (RBE) (range 18.2-72.3; re-RT), and median dose per fraction was 2.0 Gy (RBE) for both cohorts. Survival estimates for patients who received de novo irradiation and those who received re-RT were calculated using the Kaplan-Meier method. Results: Median follow-up for surviving patients was 26.4 months (range, 3.5-220.5). The 3-year overall survival (OS), freedom from distant metastasis, freedom from disease progression, and freedom from locoregional recurrence (FFLR) for de novo irradiation were 100%, 84.0%, 77.3%, and 92.9%, respectively. With re-RT, the 3-year OS, freedom from distant metastasis, FFDP, and FFLR were 76.2%, 47.4%, 32.1%, and 33.8%, respectively. In addition, 12 patients (17.4%) experienced recurrent disease. Re-RT was associated with inferior FFLR (P = .04). On univariate analysis, squamous cell carcinoma was associated with inferior OS (P

Purpose In our department, for high dose-per-fraction treatments such as stereotactic body radiation therapy, we require a physician to perform the pretreatment on-board imaging match. The purpose of this study was to determine whether patient-matching positioning performed by radiation therapists (RTTs) is as accurate as that performed by physicians. Methods and Materials Sixteen RTTs and 5 physicians participated in this study. Data were collected from 113 patients, totaling 324 measurements. A total of 60 patients were treated for bone lesions and 53 for soft-tissue lesions, such as lung and liver. Matching was performed using kV-kV imaging for bones and cone beam computed tomography for soft tissue. All treatments were delivered on Varian linear accelerators. The initial match was performed by the RTTs, and the shifts were noted. Subsequently, the match was reset, and the physician performed an independent match blinded to the RTT match. Physician shifts were applied for treatment. We used the Wilcoxon rank sum test to determine the statistical significance between RTT and physician shifts. Results The differences in patient shifts between physicians and RTTs were calculated in 3 translational 1 one rotational axis. The average vector shift was 0.88 ± 0.57 cm versus 0.91 ± 0.57 cm for RTTs versus physicians, respectively. Neither the average vector nor the individual axis shifts were statistically significantly different ( P > .2). There was no significant difference when testing for bony or soft lesion matches separately. Conclusions RTT on-board imaging matching is as accurate as physician matching for both bone and soft tissue lesions. On the basis of these results, RTTs are as qualified as physicians to perform a pretreatment match. Thus, it may be feasible for the RTTs to perform the match and the physician to review it offline after treatment without being present at the machine during treatment. Our results show that this approach does not compromise patient safety.

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.

External beam radiotherapy cancer treatment aims to deliver dose fractions to slowly destroy a tumor while avoiding severe side effects in surrounding healthy tissues. To automate the dose fraction schedules, this paper investigates how deep reinforcement learning approaches (based on deep Q network and deep deterministic policy gradient) can learn from a model of a mixture of tumor and healthy cells. A 2D tumor growth simulation is used to simulate radiation effects on tissues and thus training an agent to automatically optimize dose fractionation. Results show that initiating treatment with large dose per fraction, and then gradually reducing it, is preferred to the standard approach of using a constant dose per fraction.

Aims To evaluate survival outcomes and toxicology profiles in oligometastatic/oligoprogressive patients treated with SBRT for adrenal metastases. Methods We retrospectively analyzed 25 metastatic adrenal lesions in 24 oligometastatic/oligoprogressive patients undergoing ablative Stereotactic Body Radiation Therapy (SBRT) between February 2010 and November 2019 in our department. The primary endpoint was overall survival (OS). Secondary endpoints were local overall response rate (ORR), acute and late toxicities. Results The most common primary tumor was non-small cell lung cancer (54%). Twenty-one patients received chemo or immuno-therapy. The median planning target volume (PTV) was 41.7 cm3. Median SBRT dose was 36 Gy. Median dose per fraction was 15 Gy. Median survival was 35-months with OS outcomes ranging from 6-months (100%), 1-year (87.5%) and 2-years (66.7%). ORR based on RECIST criteria was 66.5%. 12 patients experienced acute toxicities, mostly grade 1-2 (8 patients, 32%). Conclusions SBRT for oligometastatic/oligoprogressive patients with adrenal metastases showed acceptable survival outcomes and a safe toxicity profile.

The linear-quadratic (LQ) model utilizes the terms α (single-hit kill) and β (two-hit kill) which correlate with low-dose killing and high-dose killing, respectively. Fractionation experiments with normal tissues (Chap. 23) for survival and functional tissue endpoints and tumor survival have allowed calculation of α/β ratios. These α/β ratios along with dose per fraction and total dose can be used to calculate biologically equivalent doses (BEDs) based on fraction size and total dose for various tissues and tumors compared to standard single fractions of no more than 2 Gy once a day, 5 days per week.

Strahlentherapie und Onkologie 196(8), 679 - 682 (2020). doi:10.1007/s00066-020-01635-7, Published by Springer Medizin, Heidelberg

Background/aim Radiotherapy is widely accepted as the treatment of choice for early glottic squamous cell carcinoma (EGSCC), although it varies greatly with respect to dose, dose per fraction, and treatment techniques. The study aim was to evaluate the use of accelerated fractionation strategy (AFS) for EGSCC in standard clinical practice. Patients and methods Patients treated with definitive radiotherapy for EGSCC between 2008 and 2019 were retrospectively identified and received either conventional fractionation, hypofractionation, or hyperfractionation. Results One hundred six patients were analyzed, and 19, 71, and 16 patients underwent conventional fractionation, hypofractionation, and hyperfractionation, respectively. The median follow-up was 56 months. The 5-year local control and overall survival rates were 79% and 83%; 78% and 79%; and 87% and 77%, respectively, and no significant difference was observed between the fractionation schedules. Conclusion Our findings confirmed the utility of AFS in standard clinical practice and support its use for patients with EGSCC.

Purpose To develop a novel biological dosimetric margin (BDM) and to create a biological conversion factor (BCF) that compensates for the difference between physical dosimetric margin (PDM) and BDM, which provides a novel scheme of a direct estimation of the BDM from the physical dose (PD) distribution. Methods The offset to isocenter was applied in 1-mm steps along left-right (LR), anterior-posterior (AP), and cranio-caudal (CC) directions for 10 treatment plans of lung stereotactic body radiation therapy (SBRT) with a prescribed dose of 48 Gy. These plans were recalculated to biological equivalent dose (BED) by the linear-quadratic model for the dose per fraction (DPF) of d = 3-20 Gy/fr and α / β = 3 - 10 . BDM and PDM were defined so that the region that satisfied that the dose covering 95% (or 98%) of the clinical target volume was greater than or equal to the 90% of the prescribed PD and BED, respectively. An empirical formula of the BCF was created as a function of the DPF. Results There was no significant difference between LR and AP directions for neither the PDM nor BDM. On the other hand, BDM and PDM in the CC direction were significantly larger than in the other directions. BCFs of D95% and D98% were derived for the transverse (LR and AP) and longitudinal (CC) directions. Conclusions A novel scheme to directly estimate the BDM using the BCF was developed. This technique is expected to enable the BED-based SBRT treatment planning using PD-based treatment planning systems.

Radiotherapy (RT) has been developed with remarkable technological advances in recent years. The accuracy of RT is dramatically improved and accordingly high dose radiation of the tumors could be precisely projected. Stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), are rapidly becoming the accepted practice in treating solid small sized tumors. Compared with the conventional fractionation external beam radiotherapy (EBRT), SABR with very high dose per fraction and hypo-fractionated irradiation yields convincing and satisfied therapeutic effects with low toxicity, since tumor cells could be directly ablated like radiofrequency ablation (RFA). The impressive clinical efficacy of SABR is greater than expected by the linear quadratic model and the conventional radiobiological principles, i.e., 4 Rs of radiobiology (reoxygenation, repair, redistribution, and repopulation), which may no longer be suitable for the explanation of SABR's ablation effects. Based on 4 Rs of radiobiology, 5 Rs of radiobiology emphasizes the intrinsic radiosensitivity of tumor cells, which may correlate with the responsiveness of SABR. Meanwhile, SABR induced the radiobiological alteration including vascular endothelial injury and the immune activation, which has been indicated by literature reported to play a crucial role in tumor control. However, a comprehensive review involving these advances in SABR is lacking. In this review, advances in radiobiology of SABR including the role of the 4 Rs of radiobiology and potential radiobiological factors for SABR will be comprehensively reviewed and discussed.

Purpose: The aim of the study was to exploit the feasibility of thermoluminescent dosimeters (TLDs) in radiation therapy techniques in which high dose per fraction is involved. Methods: Dose–response of TLD-100 (LiF: Mg, Ti) was investigated in both 6-MV photon and 6-MeV electron beams. The element correction factor (ECF) generation method was applied to check the variability of the TLDs response. Two batches of 50 TLDs were divided into groups and exposed in the dose range 0 to 30 Gy. Regression analysis was performed with both linear and quadratic models. For each irradiation beam, the calibration curves were obtained in 3 dose range 0 to 8 Gy, 0 to 10 Gy, and 0 to 30 Gy. The best-fitting model was assessed by the Akaike Information Criterion test. Results: The ECF process resulted a useful tool to reduce the coefficients of variation from original values higher than 5% to about 3.5%, for all the batches exposed. The results confirm the linearity of dose–response curve below the dose level of 10 Gy for photon and electron beam and the supralinear trend above. Conclusion: The TLDs are suitable dosimeters for dose monitoring and verification in radiation treatment involving dose up to 30 Gy in a single fraction.

Purpose More than a decade of randomized controlled trials in prostate cancer has established a positive radiation dose response at moderate doses and a consistently low α/β ratio in the linear quadratic model for moderate hypofractionation. The recently published large randomized trial of ultrahypofractionated prostate cancer radiation therapy adds substantially to our current knowledge of dose response and fractionation sensitivity. Methods and Materials Randomized trials of dose escalation and hypofractionation of radiation therapy were meta-analyzed to yield the overall best estimate of the α/β ratio. Additionally, a putative saturation of dose effect previously reported at approximately 80 Gy EQD2 was investigated by mapping the relative effectiveness assessed at 5 years onto a single reference dose-response curve. Results Meta-analysis of 14 randomized trials including 13,384 patients yielded a best estimate of α/β = 1.6 Gy (95% confidence interval, 1.3-2.0 Gy) but with highly significant heterogeneity (I2 = 70%, P = .0005). Further analysis indicated an association between increasing dose per fraction in the experimental arm and increasing α/β ratio (slope, 0.6 Gy increase in α/β per Gy increase in fraction size; P = .017). This deviation from the linear quadratic model could, however, also be explained by biochemical control maxing out at doses above approximately 80 Gy. Conclusions Biochemical control data from randomized controlled trials of dose-per-fraction escalation in prostate cancer radiation therapy are inconsistent with the presence of a constant fractionation sensitivity in the linear-quadratic model and/or a monotonic dose response for biochemical control beyond 80 Gy equivalent dose. These observations have a potential effect on the optimal doses in future trials and the interpretation of ongoing trials of ultrahypofractionation.

Successful anticancer strategies require a differential response between tumor and normal tissue (i.e., a therapeutic ratio). In fact, improving the effectiveness of a cancer therapeutic is of no clinical value in the absence of a significant increase in the differential response between tumor and normal tissue. Although radiation dose escalation with the use of intensity modulated radiation therapy has permitted the maximum tolerable dose for most locally advanced cancers, improvements in tumor control without damaging normal adjacent tissues are needed. As a means of increasing the therapeutic ratio, several new approaches are under development. Drugs targeting signal transduction pathways in cancer progression and more recently, immunotherapeutics targeting specific immune cell subsets have entered the clinic with promising early results. Radiobiological research is underway to address pressing questions as to the dose per fraction, irradiated tumor volume and time sequence of the drug administration. To exploit these exciting novel strategies, a better understanding is needed of the cellular and molecular pathways responsible for both cancer and normal tissue and organ response, including the role of radiation-induced accelerated senescence. This review will highlight the current understanding of promising biologically targeted therapies to enhance the radiation therapeutic ratio.

Several studies have reported changes in dose distribution and delivery time based on the value of specific planning parameters [field width (FW), pitch, and modulation factor (MF)] in tomotherapy. However, the variation in the parameters between different facilities is unknown. The purpose of this study was to determine standard values of the above parameters for cases of head and neck cancer (HNC) and prostate cancer (PC) in Japan. In this survey, a web-based questionnaire was sent to 48 facilities performing radiation therapy with tomotherapy in March 2016. The deadline for data submission was April 2016. In the questionnaire, the values of the planning parameters usually used were requested and 23 responses were received, representing a response rate of 48% (23/48). The FW selected was 2.5 cm in most facilities, and facilities with a tomoEDGE license used dynamic FW rather than fixed FW. Facilities changed the pitch based on FW, dose per fraction, or target offset more frequently in HNC than in PC. In contrast, >50% of the facilities used the magic number proposed by Kissick et al. Median preset MFs (range, min to max) in HNC and PC were 2.4 (1.8-2.8) and 2.0 (1.8-3.0), respectively, and MF values showed large variations between the facilities. Our results are likely to be useful to several facilities designing treatment plans in tomotherapy.

Stereotactic treatments are today the reference techniques for the irradiation of brain metastases in radiotherapy. The dose per fraction is very high, and delivered in small volumes (diameter1 cm). As part of these treatments, effective detection and precise segmentation of lesions are imperative. Many methods based on deep-learning approaches have been developed for the automatic segmentation of gliomas, but very little for that of brain metastases. We adapted an existing 3D convolutional neural network (DeepMedic) to detect and segment brain metastases on MRI. At first, we sought to adapt the network parameters to brain metastases. We then explored the single or combined use of different MRI modalities, by evaluating network performance in terms of detection and segmentation. We also studied the interest of increasing the database with virtual patients or of using an additional database in which the active parts of the metastases are separated from the necrotic parts. Our results indicated that a deep network approach is promising for the detection and the segmentation of brain metastases on multimodal MRI.

Purpose: To investigate the feasibility of applying ANOVA newly proposed by Yukinori to verify the setup errors, PTV (Planning Target Volume) margins, DVH for lung cancer with SBRT. Methods: 20 patients receiving SBRT to 50 Gy in 5 fractions with a Varian iX linear acceleration were selected. Each patient was scanned with kV-CBCT before the daily treatment to verify the setup position. Two other error calculation methods raised by Van Herk and Remeijer were also compared to discover the statistical difference in systematic errors (Σ), random errors (σ), PTV margins and DVH. Results: Utilizing two PTV margin calculation formulas (Stroom, Van Herk), PTV calculated by Yukinori method in three directions were (5.89 and 3.95), (5.54 and 3.55), (3.24 and 0.78) mm; Van Herk method were (6.10 and 4.25), (5.73 and 3.83), (3.51 and 1.13) mm; Remeijer method were (6.39 and 4.57), (5.98 and 4.10), (3.69 and 1.33) mm. The volumes of PTV using Yukinori method were significantly smaller (P 0.05) among three methods. Conclusions: In lung SBRT treatment, due to fraction reduction and high level of dose per fraction, ANOVA was able to offset the effect of random factors in systematic errors, reducing the PTV margins and volumes. However, no distinct dose distribution improvement was founded in target volume and organs at risk.

The purpose of this study is to evaluate the effect of nonrigid and fractionation-corrected dose summation on total doses in radiotherapy and to demonstrate the benefits of such dose summation on clinical decision-making for planning of retreatments. Dose summation of organs at risk (OARs) was investigated for 3 clinical cases with need of retreatment to the same site: head and neck, brain, and mediastinum. Three different summation methods over old and new radiotherapy treatment plans are presented and compared: (1) rigid raw sum with rigid registration of the planning images and direct dose summing; (2) deformable raw sum with deformable image registration and direct dose summing; and (3) deformable biological sum with deformable registration and takes into account the dose per fraction in biological manner in certain critical organs. In 2 cases, a user-defined dose downscaling is applied to take into account the time between the treatments and the healing from the radiation-induced effects. Of the 3 summation methods presented, the deformable biological sum was considered to offer the most biologically plausible account of the treatment. There were remarkable differences between near-maximum doses (D0.1cc) and dose-volume histogram (DVH) curves for OARs between different summation methods. The differences between deformable raw sum and rigid raw sum D0.1cc doses are in the range from −8 Gy to 2 Gy. Similarly, the deviation was from −14 Gy to 5 Gy for the deformable biological sum compared with the rigid raw sum. These differences come from incorrect summation of doses in the rigid raw sum case, and from the dose per fraction effect in biological summation. We conclude that computing the 3-dimensional deformable biological summation could be a valuable tool for treating patients with complex retreatments. It has the potential to assist the oncologist in refining plans for maximally curative doses while respecting appropriate tissue tolerances.

The objective of this paper is to evaluate the clinical impact of biological uncertainties in small field proton therapy due to the assumption of using a constant relative biological effectiveness (RBE) value of 1.1 (RBE-fixed) compared to a variable RBE (RBE-weighted). In this context the impact of the applied range margin was investigated. Eight patients with arteriovenous malformation (AVM) treated with proton radiosurgery were selected due to the small target volume. Dose distributions were compared for RBE-weighted and RBE-fixed. The impact of RBE was assessed using Monte Carlo (MC) dose calculations for stereotactic doses and doses of 2 Gy(RBE). Four different α/β ratios were investigated. Additionally, dose distributions were recalculated with reduced range margins. Applying variable RBE values for stereotactic doses resulted in an increase in the mean dose of 1.6% for a low α/β of 2 Gy, but a decrease of 2.6% for an α/β of 10 Gy. However, the mean dose increased to 17.1% and 2.1% for doses of 2 Gy(RBE) and α/β of 2 Gy and 10 Gy, respectively. Reducing range margins from 3.5% + 1 mm to 2.5% + 1 mm resulted in negligible difference in the mean RBE within the target, or 0.1% for stereotactic doses and 0.3% for doses of 2 Gy(RBE). Larger differences were seen for a range reduction to 0% + 1 mm, i.e. 1.1% and 3.0% for stereotactic doses and doses of 2 Gy(RBE), respectively. Because potential RBE effects are typically more pronounced in the distal part of a field, a bigger clinical impact of RBE uncertainties in small fields is expected. Our study shows that this could be significant for tissues with low α/β and a small dose per fraction. The uncertainty in RBE due to the uncertainty associated with the α/β ratio seems larger than the impact of the applied range uncertainty margin on RBE.

Flattening filter free (FFF) beams are now commonly available with new standard linear accelerators. These beams have recognised clinical advantages in certain circumstances, most notably the reduced beam-on times for high dose per fraction stereotactic treatments. Therefore FFF techniques are quickly being introduced into clinical use. The purpose of this report is to provide practical implementation advice and references for centres implementing FFF beams clinically. In particular UK-specific guidance is given for reference dosimetry and radiation protection.

Granulocytic sarcomas, also referred to as chloromas or myeloid sarcomas, are extramedullary neoplasms that are composed of immature myeloid cells. This uncommon disease is known to be radiosensitive. However, the total dose and dose per fraction are not standardized. In addition, during the course of radiation therapy, significant reduction of the tumor is usually obtained. Thus, target volume reduction may require an intermediate radiotherapy plan evaluation for an adaptive treatment. A second plan at mid-dose is highly recommended.

Purpose The purpose of this study is to evaluate the treatment outcomes of adjuvant radiotherapy using vaginal brachytherapy (VB) with a lower dose per fraction and/or external beam radiotherapy (EBRT) following surgery for patients with stage I endometrial carcinoma. Materials and methods The subjects were 43 patients with the International Federation of Gynecology and Obstetrics (FIGO) stage I endometrial cancer who underwent adjuvant radiotherapy following surgery between March 2000 and April 2014. Of these, 25 received postoperative VB alone, while 18 received postoperative EBRT to the whole pelvis; 3 of these were treated with EBRT plus VB. The median EBRT dose was 50.0 Gy (45.0-50.4 Gy) and the VB dose was 24 Gy in 6 fractions. Tumor dose was prescribed at a depth of 5 mm from the cylinder surface and delivered twice per week. Results The median follow-up period for all patients was 57 months (range, 9 to 188 months). Five-year disease-free survival (DFS) and overall survival (OS) for all patients were 92.5% and 95.3%, respectively. Adjuvant radiotherapy was performed according to risk factors and stage IB, grade 3 and lymphovascular invasion were observed more frequently in the EBRT group. Five-year DFS for EBRT and VB alone were 88.1% and 96.0%, respectively (p = 0.42), and 5-year OS for EBRT and VB alone were 94.4% and 96%, respectively (p = 0.38). There was no locoregional recurrence in any patient. Two patients who received EBRT and 1 patient who received VB alone developed distant metastatic disease. Two patients who received EBRT had severe complications, one each of grade 3 gastrointestinal complication and pelvic bone insufficiency fracture. Conclusion Adjuvant radiotherapy achieved high DFS and OS with acceptable toxicity in stage I endometrial cancer. VB (with a lower dose per fraction) may be a viable option for selected patients with early-stage endometrial cancer following surgery.

The aim of the current study is to develop a radiobiological model which describes the effect of linear energy transfer (LET) on cell survival and relative biological effectiveness (RBE) of megavoltage protons. By assuming the existence of critical sites within a cell, analytical expression for cell survival S as a function of LET is derived. The obtained results indicate that in cases where dose per fraction is small, [Formula: see text] is a linear-quadratic (LQ) function of dose while both alpha and beta radio-sensitivities are non-linearly dependent on LET. In particular, in the current model alpha increases with increasing LET while beta decreases. Conversely, in the case of large dose per fraction, the LQ dependence of [Formula: see text] on dose is invalid. The proposed radiobiological model predicts cell survival probability and RBE which, in general, deviate from the results obtained by using conventional LQ formalism. The differences between the LQ model and that described in the current study are reflected in the calculated RBE of protons.

Purpose To compare dosimetric characteristics with multiparametric magnetic resonance imaging–identified imaging tumor volume (gross tumor volume, GTV), prostate clinical target volume and planning target volume, and organs at risk (OARs) for 2 treatment techniques representing 2 arms of an institutional phase 3 randomized trial of hypofractionated external beam image guided highly targeted radiation therapy. Methods and Materials Group 1 (n=20) patients were treated before the trial inception with the standard dose prescription. Each patient had an additional treatment plan generated per the experimental arm. A total of 40 treatment plans were compared (20 plans for each technique). Group 2 (n=15) consists of patients currently accrued to the hypofractionated external beam image guided highly targeted radiation therapy trial. Plans were created as per the treatment arm, with additional plans for 5 of the group 2 experimental arm with a 3-mm expansion in the imaging GTV. Results For all plans in both patient groups, planning target volume coverage ranged from 95% to 100%; GTV coverage of 89.3 Gy for the experimental treatment plans ranged from 95.2% to 99.8%. For both groups 1 and 2, the percent volumes of rectum/anus and bladder receiving 40 Gy, 65 Gy, and 80 Gy were smaller in the experimental plans than in the standard plans. The percent volume at 1 Gy per fraction and 1.625 Gy per fraction were compared between the standard and the experimental arms, and these were found to be equivalent. Conclusions The dose per fraction to the OARs can be made equal even when giving a large simultaneous integrated boost to the GTV. The data suggest that a GTV margin may be added without significant dose effects on the OARs.

339 Background: Stereotactic Body Radiotherapy (SBRT) delivers high dose per fraction radiotherapy to targets with high precision. Such hypofractionated RT appears to act as an immune adjuvant, altering the tumor infiltrating immune landscape and enriching it for lymphocytes as numerous preclinical investigations would suggest. Based on this hypothesis, hundreds of ongoing trials listed in clinicaltrials.gov currently test the combination of RT (largely SBRT) with various immunotherapies. However, studies directly measuring the representation of infiltrating immune cells after SBRT in patients are few and far between and none exist in the context of prostate cancer. We therefore sought to interrogate the tumor-immune interface after prostate SBRT using fresh tissue in patients. Methods: Fresh prostate tissue from patients (N=10) enrolled in a clinical trial of prostate SBRT (three fractions of 8 Gy directed to the prostate and seminal vesicles) in the neoadjuvant setting two weeks prior to radical prostatectomy was subjected to multicolor flow cytometry and compared to that of Gleason Grade and T stage matched controls who did not undergo neoadjuvant therapy. Results: With a threshold of significance level of 0.05 for unadjusted p-values, using two-sided two-sample t-test, myeloid cells and particularly CD14+/hiCD16+DR+ intermediate monocytes/macrophages were enriched, while lymphocytes, including T cells and CD56+16− NK cells were decreased in SBRT-treated prostates as compared to unirradiated controls. Conclusions: The immune infiltrates in prostates two weeks after SBRT demonstrates a significant lymphoid to myeloid shift consistent with a tumor microenvironment after SBRT that is likely immunosuppressive beyond what can be targeted through the PD-1/L1 or CTLA-4 axis alone. This may have implications for the design of immunotherapy trials, especially in prostate cancer, that test SBRT in combination with immunotherapies.

For prostate cancer radiation therapy, daily sessions spanning approximately 2 months has been considered the standard of care for patients managed with curative intent. In recent years, data has emerged which supports the use of higher dose per fraction schemes leading to a reduced duration of treatment. This form of radiation—generally termed moderate hypofractionation or stereotactic body radiation therapy—increasingly appears to be a safe and effective alternative to the conventional course. This review summarizes salient data from the literature on outcomes, toxicities, and future directions for this innovative strategy of care.

Objective: To evaluate the outcomes of radical intent radiation therapy in early glottic carcinoma (EGC), including local control rate (LCR), disease-free survival (DFS), death specific free survival (DSFS), and overall survival (OS) rates, in Saudi patients treated at a single institution. Materials and methods: This is an institutional review board (IRB) approved, retrospective study of 27 patients with T1-2 N0 M0, early glottic carcinoma (EGC) who were treated from 2010 to 2015 at our institution with different radiotherapy (RT) fractionation regimens. The regimens included six different fractionation schedules of radiotherapy (RT): 50 Gy (20 x 2.5 Gy) dose prescribed to 95% isodose line, 52.4 Gy (20 x 2.52 Gy), 63 Gy (28 x 2.25 Gy), 66 Gy (33 x 2 Gy), and 70 Gy (35 x 2 Gy). The cohort was stratified into two groups, ≤ 52.5 Gy (n=15) and > 52.5 Gy (n=12). The median follow-up of all patients was 31.7 months (range 7-82). Results: The mean age of the cohort was 64.5 years (median 65, range: 41-83). Eleven patients (40.7%) had a history of smoking. The majority of the cohort was with T1a EGC (70.4%, n=19), and anterior commissure invasion was seen in three patients (11.1%). The mean RT doses were 55.6 Gy (range: 50-70). The five-year LCR, DFS, DSFS, and OS rates were 83.1%, 80.0%, 96.2%, and 92.6%, respectively. The LCR rates for those receiving a dose of 52.5 Gy or less were 61.3 months compared to 89.5 months for those who received more than 52.5 Gy (p=0.994). Non-smokers and patients with an unknown smoking history achieved a five-year LCR of 100%, while patients with a positive smoking history achieved a five-year LCR of 60.6% (p=0.044). Conclusion: Radiation therapy for EGC in our patients showed reasonable five-year LCR with larynx preservation at 83.1%, DFS 80.0%, five-year OS rate 92.6%, and DSFS rate 96.2%. We found that smoking had a significant correlation with LCR. However, large prospective trials are warranted to evaluate the efficacy of overall treatment time, dose per fraction of above 2 Gy, and smoking effect.

In intensity modulated radiation therapy (IMRT), the dose in each voxel of the organs at risk (OAR) can be strongly reduced compared to conformal radiation therapy (RT). Due to the sensitivity of late side-effects to fraction size, a smaller dose per fraction in the normal tissues represent an increased tolerance to RT. This expected reduction in biological effect may then be used as an additional degree of freedom during IMRT optimization. In this study, the comparison between plans optimized with and without a voxel-based fractionation correction was made. Four patients diagnosed with a head and neck (HN), a breast, a lung or a prostate tumor were used as test cases. Voxel-based fractionation corrections were incorporated into the optimization algorithm by converting the dose in each normal tissue voxel to EQD2 (equivalent dose delivered at 2 Gy per fraction). The maximum gain in the probability of tumor control (PB), due to the incorporation of the correction for fractionation in each voxel, was 1.3% with a 0.1% increase in the probability of complications (PI) for the HN tumor case. However, in plan optimization and evaluation, when tolerance doses were compared with the respective planned EQD2 (calculated from the 3-dimensional dose distribution), PB increased by 19.3% in the HN, 12.5% in the lung, 6.2% in the breast and 2.7% in the prostate tumor case, respectively. The corresponding increases in PI were 2.3%, 6.2%, 1.0% and 0.7%, respectively. Incorporating voxel-based fractionation corrections in plan optimization is important to be able to show the clinical quality of a given plan against established tolerance constraints. To properly compare different plans, their dose distributions should be converted to a common fractionation scheme (e.g. 2 Gy per fraction) for which the doses have been associated with clinical outcomes.

With the current UK expansion of proton therapy there is a great opportunity for clinical oncologists to develop a translational interest in the associated scientific base and clinical results. In particular, the underpinning controversy regarding the conversion of photon dose to proton dose by the relative biological effectiveness (RBE) must be understood, including its important implications. At the present time, the proton prescribed dose includes an RBE of 1.1 regardless of tissue, tumour and dose fractionation. A body of data has emerged against this pragmatic approach, including a critique of the existing evidence base, due to choice of dose, use of only acute-reacting in vivo assays, analysis methods and the reference radiations used to determine the RBE. Modelling systems, based on the best available scientific evidence, and which include the clinically useful biological effective dose (BED) concept, have also been developed to estimate proton RBEs for different dose and linear energy transfer (LET) values. The latter reflect ionisation density, which progressively increases along each proton track. Late-reacting tissues, such as the brain, where α/β = 2 Gy, show a higher RBE than 1.1 at a low dose per fraction (1.2–1.8 Gy) at LET values used to cover conventional target volumes and can be much higher. RBE changes with tissue depth seem to vary depending on the method of beam delivery used. To reduce unexpected toxicity, which does occasionally follow proton therapy, a more rational approach to RBE allocation, using a variable RBE that depends on dose per fraction and the tissue and tumour radiobiological characteristics such as α/β, is proposed.

Purpose: The aim of this publication is to compile available literature data and expert experience regarding skin brachytherapy (BT) in order to produce general recommendations on behalf of the GEC-ESTRO Group. Methods: We have done an exhaustive review of published articles to look for general recommendations. Results: Randomized controlled trials, systemic reviews and meta-analysis are lacking in literature and there is wide variety of prescription techniques successfully used across the radiotherapy centers. BT can be delivered as superficial application (also called contact BT or plesiotherapy) or as interstitial for tumours thicker than 5 mm within any surface, including very irregular. In selected cases, particularly in tumours located within curved surfaces, BT can be advantageous modality from dosimetric and planning point of view when compared to external beam radiotherapy. The general rule in skin BT is that the smaller the target volume, the highest dose per fraction and the shortest overall length of treatment can be used. Conclusion: Skin cancer incidence is rising worldwide. BT offers an effective non-invasive or minimally invasive and relative short treatment that particularly appeals to elder and frail population. (C) 2018 The Authors. Published by Elsevier B.V.

Purpose Aim of the work is to model biochemical free survival at five year (5 y BCFS), based on literature clinical outcome data available until now and to evaluate parameters describing dose-fractionation radiosensitivity and repopulation. Methods Twenty-six data sets published in literature reporting the 5 y BCFS, dose scheduling, androgen deprivation therapy (ADT) and clinical variables, have been considered for a total of 17949 prostate cancer patients treated with external beam radiation therapy (EBRT), with and without ADT with dose per fraction from 1.80 Gy/fr to 7.25 Gy/fr and overall treatment time (OTT) from 1 week to 10 weeks. Fifteen patients groups have been built considering the risk class and the use of ADT. At first, for each group, D50 and g50 parameters were calculated. Then, dprolif, Tprolif and α / β parameters have been evaluated considering three hypothesis: dependence and not on OTT and dependence only on OTTs difference. Results The median values of D50 and g50 were 57 Gy and 1.7 for low risk patients, 61 Gy and 1.8 for intermediate risk patients and 68 Gy and 1.9 for high risk patients. For intermediate and high risk patients, a reduction of 4 Gy for D50 and 0.5 for g50 for ADT respect to no ADT treated patients was found. Not considering OTT dependence, the median α / β value parameter was in the range 0.8 Gy–2.6 Gy for the groups analysed. Median value of the dprolif was in the range 0.0 Gy/d–0.3 Gy/d while a median value of Tprolif parameter greater than 20 days was obtained. Conclusions Low α / β values have been confirmed for each risk class and the use of ADT seems to reduce median α / β values for intermediate and high risk patients. α / β values lower than values for late normal tissue morbidity increase and support the interest of hypofractionated radiotherapy schedules for all risk groups.

Breast cancer (ВС) is a common malignant disease of the female reproductive system. Currently we have many treatment strategies given location depending on the clinical data. Radiation therapy is an important component in a comprehensive program of treatment for ВС. Despite the fact that often use a single dose fractionation regime 1.8–2 Gy daily fractions to a total of 50 Gy in 5 weeks, do not run out to try to find new modes of fractionation. According to published research results hypofractionated regimes, we can conclude that the approaches to the value of the dose per fraction, the number of fractions and the time of treatment differ. Dose per fraction ranged from 2.66 to 3.2 Gy, and more recently have been tested modes with a single dose of 6 Gy. Empirical data from these studies are important, but must also be aware of the possibility of applying mathematical methods for computing the probability of cure of the tumor and the occurrence of radiation complications. It is necessary for an individual approach to each patient, picking up for some clinical cases the optimal mode of fractionation. In addition, the search continues and improvement fractionation regimes, and the results of clinical trials can tell a lot about how good the chosen model. In work the opportunity of application of the synthesized mathematical model (SM model), intended for description of NTCP, to the description of probability of local treatment of early stages of the ВС.

The purpose of the study was to evaluate a treatment dose using planning computed tomography (pCT) that was deformed to pre-treatment cone beam computed tomography (CBCT) for lung stereotactic body radiation therapy (SBRT) treatment. Five lung SBRT patients were retrospectively selected, and their daily CBCTs were employed in this study. Dosimetric comparison was performed between the original and recalculated plans from the deformed pCT (dose per fraction) by comparing a target coverage and organs at risk. Dose summation of five fractions was computed and compared to the original plan. A phantom study was conducted to evaluate the dosimetric accuracy for the dose per fraction. In the phantom study, the difference between the mean Hounsfield Unit (HU) values of the original and deformed pCTs is less than 0.5%. In patient study, the mean HU deviation of the five deformed pCTs compared to that of the original pCT was within ±5%, which is dosimetrically insignificant. While the internal target volume (ITV) shrank by 17% on average among the five patients, mean lung dose (MLD) increased by up to 7%, and D95% of PTV decreased slightly but stayed within 5%. Results showed that MLD might be a better indicative metric of normal lung dose than V20Gy as the ITV volume decreases. This study showed a feasibility to use a deformed pCT for evaluation of the dose per fraction and for a possible plan adaptation in lung SBRT cases. Readers should be cautious in selecting patients before clinical application due to the image quality of CBCT.

Radiation therapy delivered with hypofractionation, which involves the delivery of a higher dose per fraction in fewer fractions (generally with a lower total nominal dose) over a shorter overall treatment time, is an established therapeutic option at least for a selected group of early breast cancer patients after breast-conserving surgery. Optimal delivery of the tumor bed boost dose in terms of timing, fractionation, and total dose whenever a hypofractionated schedule is employed has yet to be established. We herein present a review of the current evidence on the role of boost integration in whole breast radiotherapy.

The recommended radio-therapeutic treatment for cervix cancer consists of a first phase of external beam radiotherapy (EBRT) plus a second phase of brachytherapy (BT), the combined treatment being delivered within 8 weeks. In order to assess a comprehensive dosimetry of the whole treatment, it is necessary to take into account that these two phases are characterized by different spatial and temporal dosimetric distributions, which complicates the task of the summation of the two contributions, EBRT and BT. Radiobiology allows to tackle this issue pragmatically by means of the LQ model and, in fact, this is the usual tool currently in use for this matter. In this work, we describe the rationale behind the summation of the dosimetric contributions of the two phases of the treatment, EBRT and BT, for cervix cancer, as carried out with the LQ model. Besides, we address, from a radiobiological point of view, several important considerations regarding the use of the LQ model for this task. One of them is the analysis of the effect of the overall treatment time in the result of the global treatment. Another important question considered is related to the fact that the capacity of LQ to predict the treatment outcomes is deteriorated when the dose per fraction of the radiotherapic scheme exceeds 6–10 Gy, which is a typical brachytherapy fractionation. Finally, we analyze the influence of the uncertainty and the variability of the main parameters utilized in the LQ model formulation in the assessment of the global dosimetry.