Reflections on beam configuration optimization for intensity-modulated proton therapy.

Presumably, intensity-modulated proton radiotherapy (IMPT) is the most powerful form of proton radiotherapy. In the current state of the art, IMPT beam configurations (i.e. the number of beams and their directions) are, in general, chosen subjectively based on prior experience and practicality. Beam configuration optimization (BCO) for IMPT could, in theory, significantly enhance IMPT's therapeutic potential. However, BCO is complex and highly computer resource-intensive. Some algorithms for BCO have been developed for intensity-modulated photon therapy (IMRT). They are rarely used clinically mainly because the large number of beams typically employed in IMRT renders BCO essentially unnecessary. Moreover, in the newer form of IMRT, volumetric modulated arc therapy, there are no individual static beams. BCO is of greater importance for IMPT because it typically employs a very small number of beams (2-4) and, when the number of beams is small, BCO is critical for improving plan quality. However, the unique properties and requirements of protons, particularly in IMPT, make BCO challenging. Protons are more sensitive than photons to anatomic changes, exhibit variable relative biological effectiveness along their paths, and, as recently discovered, may spare the immune system. Such factors must be considered in IMPT BCO, though doing so would make BCO more resource intensive and make it more challenging to extend BCO algorithms developed for IMRT to IMPT. A limited amount of research in IMPT BCO has been conducted; however, considerable additional work is needed for its further development to make it truly effective and computationally practical. This article aims to provide a review of existing BCO algorithms, most of which were developed for IMRT, and addresses important requirements specific to BCO for IMPT optimization that necessitate the modification of existing approaches or the development of new effective and efficient ones.

Comparison of non-coplanar optimization of static beams and arc trajectories for intensity-modulated treatments of meningioma cases.

Two methods for non-coplanar beam direction optimization, one for static beams and another for arc trajectories, were proposed for intracranial tumours. The results of the beam angle optimizations were compared with the beam directions used in the clinical plans. Ten meningioma cases already treated were selected for this retrospective planning study. Algorithms for non-coplanar beam angle optimization (BAO) and arc trajectory optimization (ATO) were used to generate the corresponding plans. A plan quality score, calculated by a graphical method for plan assessment and comparison, was used to guide the beam angle optimization process. For each patient, the clinical plans (CLIN), created with the static beam orientations used for treatment, and coplanar VMAT approximated plans (VMAT) were also generated. To make fair plan comparisons, all plan optimizations were performed in an automated multicriteria calculation engine and the dosimetric plan quality was assessed. BAO and ATO plans presented, on average, moderate global plan score improvements over VMAT and CLIN plans. Nevertheless, while BAO and CLIN plans assured a more efficient OARs sparing, the ATO and VMAT plans presented a higher coverage and conformity of the PTV. Globally, all plans presented high-quality dose distributions. No statistically significant quality differences were found, on average, between BAO, ATO and CLIN plans. However, automated plan solution optimizations (BAO or ATO) may improve plan generation efficiency and standardization. In some individual patients, plan quality improvements were achieved with ATO plans, demonstrating the possible benefits of this automated optimized delivery technique.

Clinical validation of a graphical method for radiation therapy plan quality assessment.

BACKGROUND: This work aims at clinically validating a graphical tool developed for treatment plan assessment, named SPIDERplan, by comparing the plan choices based on its scoring with the radiation oncologists (RO) clinical preferences. METHODS: SPIDERplan validation was performed for nasopharynx pathology in two steps. In the first step, three ROs from three Portuguese radiotherapy departments were asked to blindly evaluate and rank the dose distributions of twenty pairs of treatment plans. For plan ranking, the best plan from each pair was selected. For plan evaluation, the qualitative classification of 'Good', 'Admissible with minor deviations' and 'Not Admissible' were assigned to each plan. In the second step, SPIDERplan was applied to the same twenty patient cases. The tool was configured for two sets of structures groups: the local clinical set and the groups of structures suggested in international guidelines for nasopharynx cancer. Group weights, quantifying the importance of each group and incorporated in SPIDERplan, were defined according to RO clinical preferences and determined automatically by applying a mixed linear programming model for implicit elicitation of preferences. Intra- and inter-rater ROs plan selection and evaluation were assessed using Brennan-Prediger kappa coefficient. RESULTS: Two-thirds of the plans were qualitatively evaluated by the ROs as 'Good'. Concerning intra- and inter-rater variabilities of plan selection, fair agreements were obtained for most of the ROs. For plan evaluation, substantial agreements were verified in most cases. The choice of the best plan made by SPIDERplan was identical for all sets of groups and, in most cases, agreed with RO plan selection. Differences between RO choice and SPIDERplan analysis only occurred in cases for which the score differences between the plans was very low. A score difference threshold of 0.005 was defined as the value below which two plans are considered of equivalent quality. CONCLUSION: Generally, SPIDERplan response successfully reproduced the ROs plan selection. SPIDERplan assessment performance can represent clinical preferences based either on manual or automatic group weight assignment. For nasopharynx cases, SPIDERplan was robust in terms of the definitions of structure groups, being able to support different configurations without losing accuracy.

Comparison of two beam angular optimization algorithms guided by automated multicriterial IMRT.

PURPOSE: To compare two beam angle optimization (BAO) algorithms for coplanar and non-coplanar geometries in a multicriterial optimization framework. METHODS: 40 nasopharynx patients were selected for this retrospective planning study. IMRT optimized plans were produced by Erasmus-iCycle multicriterial optimization platform. Two different algorithms, based on a discrete and on a continuous exploration of the space search, algorithm i and B respectively, were used to address BAO. Plan quality evaluation and comparison were performed with SPIDERplan. Statistically significant differences between the plans were also assessed. RESULTS: For plans using only coplanar incidences, the optimized beam distribution with algorithm i is more asymmetric than with algorithm B. For non-coplanar beam optimization, larger deviations from coplanarity were obtained with algorithm i than with algorithm B. Globally, both algorithms presented near equivalent plan quality scores, with algorithm B presenting a marginally better performance than algorithm i. CONCLUSION: Almost all plans presented high quality, profiting from multicriterial and beam angular optimization. Although there were not significant differences when average results over the entire sample were considered, a case-by-case analysis revealed important differences for some patients.

Biological dose-escalated definitive radiation therapy in head and neck cancer.

OBJECTIVE: To compare treatment outcome of patients with head and neck (HN) tumours treated with definitive radiation therapy that, mainly owing to differences in the fractionation scheme used with simultaneous integrated boost techniques, resulted in a different biological dose. METHODS: 181 patients with HN cancer, prescribed to about 70.2 Gy in the primary tumour, were included in this study. Population cohort was divided into Group <70 and Group ≥70 when the mean dose converted to a 2 Gy fractionation in the primary tumour was less or higher than 70.2 Gy, respectively. The probability of local control (LC), locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) was determined for both groups. The incidence of acute and late complications was compared between the two groups. RESULTS: At 24 months for Groups <70 and ≥70, LC was 83.2% and 87.5%, LRC was 79.5% and 81.6%, DFS was 56.3% and 66.8% and OS was 63.9% and 71.5% p = ns, respectively. The incidence of acute dysphagia, odynophagia and pain, and late mucositis was significantly higher in Group ≥70 than in Group <70. The rate of xerostomia, dysphonia, radiodermatitis, alopecia, dental complications, hypoacusia and weight loss was comparable between the two groups. CONCLUSION: The biological dose escalation was safe, but an increase in the incidence of the acute side effects: dysphagia, odynophagia and pain and late mucositis, was obtained. Advances in knowledge: Despite the significant biological dose escalation, within the range of doses delivered to this cohort, no clear dose-response effect was observed.

A derivative-free multistart framework for an automated noncoplanar beam angle optimization in IMRT.

PURPOSE: The inverse planning of an intensity-modulated radiation therapy (IMRT) treatment requires decisions regarding the angles used for radiation incidence, even when arcs are used. The possibility of improving the quality of treatment plans by an optimized selection of the beam angle incidences-beam angle optimization (BAO)-is seldom done in clinical practice. The inclusion of noncoplanar beam incidences in an automated optimization routine is even more unusual. However, for some tumor sites, the advantage of considering noncoplanar beam incidences is well known. This paper presents the benefits of using a derivative-free multistart framework for the optimization of the noncoplanar BAO problem. METHODS: Multistart methods combine a global strategy for sampling the search space with a local strategy for improving the sampled solutions. The proposed global strategy allows a thorough exploration of the continuous search space of the highly nonconvex BAO problem. To avoid local entrapment, a derivative-free method is used as local procedure. Additional advantages of the derivative-free method include the reduced number of function evaluations required to converge and the ability to use multithreaded computing. Twenty nasopharyngeal clinical cases were selected to test the proposed multistart framework. The planning target volumes included the primary tumor, the high and low risk lymph nodes. Organs-at-risk included the spinal cord, brainstem, optical nerves, chiasm, parotids, oral cavity, brain, thyroid, among others. For each case, a setup with seven equispaced beams was chosen and the resulting treatment plan, using a multicriteria optimization framework, was then compared against the coplanar and noncoplanar plans using the optimal beam setups obtained by the derivative-free multistart framework. RESULTS: The optimal noncoplanar beam setup obtained by the derivative-free multistart framework leads to high quality treatment plans with better target coverage and with improved organ sparing compared to treatment plans using equispaced or optimal coplanar beam angle setups. The noncoplanar treatment plans achieved, e.g., an average reduction in the mean dose of the oral cavity of 6.1 Gy and an average reduction in the maximum-dose of the brainstem of 7 Gy when compared to the equispaced treatment plans. CONCLUSIONS: The noncoplanar BAO problem is an extremely challenging multimodal optimization problem that can be successfully addressed through a thoughtful exploration of the continuous highly nonconvex BAO search space. The proposed framework is capable of calculating high quality treatment plans and thus can be an interesting alternative toward automated noncoplanar beam selection in IMRT treatment planning which is nowadays the natural trend in treatment planning.

SPIDERplan: A tool to support decision-making in radiation therapy treatment plan assessment.

AIM: In this work, a graphical method for radiotherapy treatment plan assessment and comparison, named SPIDERplan, is proposed. It aims to support plan approval allowing independent and consistent comparisons of different treatment techniques, algorithms or treatment planning systems. BACKGROUND: Optimized plans from modern radiotherapy are not easy to evaluate and compare because of their inherent multicriterial nature. The clinical decision on the best treatment plan is mostly based on subjective options. MATERIALS AND METHODS: SPIDERplan combines a graphical analysis with a scoring index. Customized radar plots based on the categorization of structures into groups and on the determination of individual structures scores are generated. To each group and structure, an angular amplitude is assigned expressing the clinical importance defined by the radiation oncologist. Completing the graphical evaluation, a global plan score, based on the structures score and their clinical weights, is determined. After a necessary clinical validation of the group weights, SPIDERplan efficacy, to compare and rank different plans, was tested through a planning exercise where plans had been generated for a nasal cavity case using different treatment planning systems. RESULTS: SPIDERplan method was applied to the dose metrics achieved by the nasal cavity test plans. The generated diagrams and scores successfully ranked the plans according to the prescribed dose objectives and constraints and the radiation oncologist priorities, after a necessary clinical validation process. CONCLUSIONS: SPIDERplan enables a fast and consistent evaluation of plan quality considering all targets and organs at risk.

Automated fluence map optimization based on fuzzy inference systems.

PURPOSE: The planning of an intensity modulated radiation therapy treatment requires the optimization of the fluence intensities. The fluence map optimization (FMO) is many times based on a nonlinear continuous programming problem, being necessary for the planner to define a priori weights and/or lower bounds that are iteratively changed within a trial-and-error procedure until an acceptable plan is reached. In this work, the authors describe an alternative approach for FMO that releases the human planner from trial-and-error procedures, contributing for the automation of the planning process. METHODS: The FMO is represented by a voxel-based convex penalty continuous nonlinear model. This model makes use of both weights and lower/upper bounds to guide the optimization process toward interesting solutions that are able to satisfy all the constraints defined for the treatment. All the model's parameters are iteratively changed by resorting to a fuzzy inference system. This system analyzes how far the current solution is from a desirable solution, changing in a completely automated way both weights and lower/upper bounds. The fuzzy inference system is based on fuzzy reasoning that enables the use of common-sense rules within an iterative optimization process. The method is built in two stages: in a first stage, an admissible solution is calculated, trying to guarantee that all the treatment planning constraints are being satisfied. In this first stage, the algorithm tries to improve as much as possible the irradiation of the planning target volumes. In a second stage, the algorithm tries to improve organ sparing, without jeopardizing tumor coverage. RESULTS: The proposed methodology was applied to ten head-and-neck cancer cases already treated in the Portuguese Oncology Institute of Coimbra (IPOCFG) and signalized as complex cases. IMRT treatment was considered, with 7, 9, and 11 equidistant beam angles. It was possible to obtain admissible solutions for all the patients considered and with no human planner intervention. The results obtained were compared with the optimized solution using a similar optimization model but with human planner intervention. For the vast majority of cases, it was possible to improve organ sparing and at the same time to assure better tumor coverage. CONCLUSIONS: Embedding a fuzzy inference system into FMO allows human planner reasoning to be used in the guidance of the optimization process toward interesting regions in a truly automated way. The proposed methodology is capable of calculating high quality plans within reasonable computational times and can be an important contribution toward fully automated radiation therapy treatment planning.

Simulated annealing applied to IMRT beam angle optimization: A computational study.

Electing irradiation directions to use in IMRT treatments is one of the first decisions to make in treatment planning. Beam angle optimization (BAO) is a difficult problem to tackle from the mathematical optimization point of view. It is highly non-convex, and optimization approaches based on gradient descent methods will probably get trapped in one of the many local minima. Simulated Annealing (SA) is a local search probabilistic procedure that is known to be able to deal with multimodal problems. SA for BAO was retrospectively applied to ten clinical examples of treated cases of head-and neck tumors signalized as complex cases where proper target coverage and organ sparing proved difficult to achieve. The number of directions to use was considered fixed and equal to 5 or 7. It is shown that SA can lead to solutions that significantly improve organ sparing, even considering a reduced number of angles, without jeopardizing tumor coverage.

Assessment and topographic characterization of locoregional recurrences in head and neck tumours.

PURPOSE: To evaluate the differences between three methods of classification of recurrences in patients with head and neck tumours treated with Radiation Therapy (RT). MATERIALS AND METHODS: 367 patients with head and neck tumours were included in the study. Tumour recurrences were delineated in the CT images taken during patient follow-up and deformable registration was used to transfer this volume into the planning CT. The methods used to classify recurrences were: method CTV quantified the intersection volume between the recurrence and the Clinical Target Volume (CTV); method TV quantified the intersection between the Treated Volume and the recurrence (for method CTV and TV, recurrences were classified in-field if more than 95% of their volume were inside the volume of interest, marginal if the intersection was between 20-95% and outfield otherwise); and method COM was based on the position of the Centre Of Mass of the recurrence. A dose assessment in the recurrence volume was also made. RESULTS: The 2-year Kaplan-Meier locoregional recurrence incidence was 10%. Tumour recurrences occurred in 22 patients in a mean time of 16.5 ± 9.4 months resulting in 28 recurrence volumes. The percentage of in-field recurrences for methods CTV, TV and COM was 7%, 43% and 50%, respectively. Agreement between the three methods in characterizing individually in-field and marginal recurrences was found only in six cases. Methods CTV and COM agreed in 14. The percentage of outfield recurrences was 29% using all methods. For local recurrences (in-field or marginal to gross disease) the average difference between the prescribed dose and D 98% in the recurrence volume was -5.2 ± 3.5% (range: -10.1%-0.9%). CONCLUSIONS: The classification of in-field and marginal recurrences is very dependent on the method used to characterize recurrences. Using methods TV and COM the largest percentage of tumour recurrences occurred in-field in tissues irradiated with high doses.

[Secondary hypothyroidism after cervical irradiation: systematic evaluation of thyroid function in follow-up]. / Hipotiroidismo secundário à irradiação cervical: avaliação sistemática da função tiroideia no seguimento.

INTRODUCTION: Sometimes Thyroid dysfunction is an underestimated consequence of radiation exposure. The underlying mechanism is not clearly understood, but it is likely to be multifactorial. As so, the specific risk factors associated with the development of secondary radiotherapy hypothyroidism remain undefined. The direct irradiation of the thyroid gland may result more frequently in hypothyroidism. This is an irreversible condition, requiring lifelong treatment and monitoring. OBJECTIVES: To evaluate the incidence of hypothyroidism in patients with head and neck cancer who underwent neck irradiation on an intensive or adjuvant basis and determine whether it is justifiable to integrate the monitoring of parameters for evaluation of thyroid function (TSH, free fraction T3 e free fraction T4 ) in this patient group on the Institutional follow up protocol. MATERIAL AND METHODS: This is an observational, retrospective descriptive study, which comprises a group of 376 patients with head and neck cancer undergoing radiotherapy, on adjuvant or intensive basis, between the years 2007 and 2012, at Portuguese Institute of Oncology of Coimbra, E.P.E. 145 patients met all the inclusion criteria. Standardized rating scales for the definition of hypothyroidism have been used - LENT-SOMA scales (Late Effects Normal Tissues Subjective Objective Management Analysis). Grade 1 or higher was considered as a complication hypothyroidism. RESULTS: The analysis of a cohort of 145 patients was carried out. The most frequent tumor site was the larynx (26.9%). Thirty-two patients received adjuvant radiotherapy and 113 were treated with intensive schemes. The most used radiotherapy technique was intensity modulated (IMRT), performed in 86.2% patients. The overall incidence rate of hypothyroidism at 12 months was 18.6%. The diagnosis for hypothyroidism was done between 9 and 12 months after treatment radiotherapy in 51.9% of the patients with this complication. DISCUSSION: An analysis of the published literature, hypothyroidism is the most common thyroid complication after irradiation and affects a large percentage of patients undergoing cervical radiotherapy with curative intent. It has been shown that the risk of hypothyroidism increases with time after exposure, but the highest incidence appears to be in the first two years after treatment. From our analysis we obtained at 12 months, a rate of incidence of hypothyroidism of 18.6% (16.55% grade 1 and grade 2, 2.1%). CONCLUSIONS: This study found an incidence of hypothyroidism corresponding to the lowest values reported in other published studies. The short duration of follow-up considered in this analysis, may justify these results. With these results and their correlation with the available literature, the authors consider justified and recommend the inclusion of the systematic evaluation of thyroid function in the follow-up protocol of these patients.

Introdução: A disfunção tiroideia constitui uma consequência, por vezes subestimada, da exposição à radiação. O mecanismo subjacente não está claramente esclarecido, mas terá uma origem multifatorial. Os fatores de risco específicos para o desenvolvimento de hipotiroidismo secundário à radioterapia permanecem indeterminados. A irradiação direta da glândula tiroideia pode resultar, com maior frequência, em hipotiroidismo. Este é uma condição irreversível, requerendo monitorização e tratamento permanente. Objetivos: Avaliar a incidência de hipotiroidismo nos doentes portadores de neoplasias da cabeça e pescoço submetidos a irradiação cervical, a título intensivo ou adjuvante, bem como determinar se é justificável a integração no protocolo de seguimento Institucional, de parâmetros laboratoriais (TSH, T3 Livre e T4 Livre) para avaliação da função tiroideia neste grupo de doentes e qual a sua periodicidade. Material e Métodos: Este é um estudo observacional, descritivo, retrospetivo, que engloba um grupo de 376 doentes portadores de neoplasias da cabeça e pescoço, submetidos a tratamento de radioterapia, a título adjuvante ou intensivo, entre os anos de 2007 e 2012, no Instituto Português de Oncologia de Coimbra Francisco Gentil E.P.E. Cumpriram todos os critérios de inclusão 145 doentes. Foram utilizadas escalas de avaliação padronizadas para a definição de hipotiroidismo ­ LENT-SOMA scales (Late Effects Normal Tissues Subjective Objective Management Analysis). Foi considerada como complicação o hipotiroidismo Grau 1 ou superior. Resultados: Procedeu-se à análise de um grupo de 145 doentes. A localização tumoral mais frequente foi a Laringe (26,9%). Trinta e dois doentes efetuaram radioterapia adjuvante e 113 efetuaram esquemas intensivos. A técnica de radioterapia mais utilizada foi a intensidade modulada (IMRT), efetuada em 86,2% doentes. A taxa de incidência global de hipotiroidismo aos 12 meses foi de 18,6%. Em 51,9% dos doentes foi efetuado o diagnóstico de hipotiroidismo entre os 9 e os 12 meses após o tratamento de radioterapia. Discussão: Da análise da literatura publicada, o hipotiroidismo constitui a complicação tiroideia radioinduzida mais frequente e afeta uma grande percentagem de doentes submetidos a radioterapia cervical com intenção curativa. Foi demonstrado que o risco de hipotiroidismo aumenta com o tempo após a exposição, contudo a incidência mais elevada parece ser nos dois primeiros anos após o tratamento. Da nossa análise obtivemos, aos 12 meses uma taxa de incidência global de hipotiroidismo de 18,6%, (grau 1 de 16,55% e grau 2 de 2,1%). Conclusão: Neste estudo foi encontrada uma incidência de hipotiroidismo correspondente aos valores mais baixos descritos em outros estudos publicados. O curto tempo de follow-up considerado nesta análise poderá justificar os resultados obtidos. Face aos resultados obtidos, e correlacionando-os com a literatura disponível, os autores consideram justificável e recomendável a inserção da avaliação sistemática da função tiroideia no protocolo de follow-up destes doentes.

Beam angle optimization for intensity-modulated radiation therapy using a guided pattern search method.

Generally, the inverse planning of radiation therapy consists mainly of the fluence optimization. The beam angle optimization (BAO) in intensity-modulated radiation therapy (IMRT) consists of selecting appropriate radiation incidence directions and may influence the quality of the IMRT plans, both to enhance better organ sparing and to improve tumor coverage. However, in clinical practice, most of the time, beam directions continue to be manually selected by the treatment planner without objective and rigorous criteria. The goal of this paper is to introduce a novel approach that uses beam's-eye-view dose ray tracing metrics within a pattern search method framework in the optimization of the highly non-convex BAO problem. Pattern search methods are derivative-free optimization methods that require a few function evaluations to progress and converge and have the ability to better avoid local entrapment. The pattern search method framework is composed of a search step and a poll step at each iteration. The poll step performs a local search in a mesh neighborhood and ensures the convergence to a local minimizer or stationary point. The search step provides the flexibility for a global search since it allows searches away from the neighborhood of the current iterate. Beam's-eye-view dose metrics assign a score to each radiation beam direction and can be used within the pattern search framework furnishing a priori knowledge of the problem so that directions with larger dosimetric scores are tested first. A set of clinical cases of head-and-neck tumors treated at the Portuguese Institute of Oncology of Coimbra is used to discuss the potential of this approach in the optimization of the BAO problem.

Analysis of fractionation correction methodologies for multiple phase treatment plans in radiation therapy.

PURPOSE: Radiation therapy is often delivered by multiple sequential treatment plans. For an accurate radiobiological evaluation of the overall treatment, fractionation corrections to each dose distribution must be applied before summing the three-dimensional dose matrix of each plan since the simpler approach of performing the fractionation correction to the total dose-volume histograms, obtained by the arithmetical sum of the different plans, becomes inaccurate for more heterogeneous dose patterns. In this study, the differences between these two fractionation correction methods, named here as exact (corrected before) and approximate (after summation), respectively, are assessed for different cancer types. METHODS: Prostate, breast, and head and neck (HN) tumor patients were selected to quantify the differences between two fractionation correction methods (the exact vs the approximate). For each cancer type, two different treatment plans were developed using uniform (CRT) and intensity modulated beams (IMRT), respectively. The responses of the target and normal tissue were calculated using the Poisson linear-quadratic-time model and the relative seriality model, respectively. All treatments were radiobiologically evaluated and compared using the complication-free tumor control probability (P+), the biologically effective uniform dose (D) together with common dosimetric criteria. RESULTS: For the prostate cancer patient, an underestimation of around 14%-15% in P+ was obtained when the fractionation correction was applied after summation compared to the exact approach due to significant biological and dosimetric variations obtained between the two fractionation correction methods in the involved lymph nodes. For the breast cancer patient, an underestimation of around 3%-4% in the maximum dose in the heart was obtained. Despite the dosimetric differences in this organ, no significant variations were obtained in treatment outcome. For the HN tumor patient, an underestimation of about 5% in treatment outcome was obtained for the CRT plan as a result of an underestimation of the planning target volume control probability by about 10%. An underestimation of about 6% in the complication probability of the right parotid was also obtained. For all the other organs at risk, dosimetric differences of up to 4% were obtained but with no significant impact in the expected clinical outcome. However, for the IMRT plan, an overestimation in P+ of 4.3% was obtained mainly due to an underestimation of the complication probability of the left and right parotids (2.9% and 5.8%, respectively). CONCLUSIONS: The use of the exact fractionation correction method, which is applying fractionation correction on the separate dose distributions of a multiple phase treatment before their summation was found to have a significant expected clinical impact. For regions of interest that are irradiated with very heterogeneous dose distributions and significantly different doses per fraction in the different treatment phases, the exact fractionation correction method needs to be applied since a significant underestimation of the true patient outcome can be introduced otherwise.

Response-probability volume histograms and iso-probability of response charts in treatment plan evaluation.

PURPOSE: This study aims at demonstrating a new method for treatment plan evaluation and comparison based on the radiobiological response of individual voxels. This is performed by applying them on three different cancer types and treatment plans of different conformalities. Furthermore, their usefulness is examined in conjunction with traditionally applied radiobiological and dosimetric treatment plan evaluation criteria. METHODS: Three different cancer types (head and neck, breast and prostate) were selected to quantify the benefits of the proposed treatment plan evaluation method. In each case, conventional conformal radiotherapy (CRT) and intensity modulated radiotherapy (IMRT) treatment configurations were planned. Iso-probability of response charts was produced by calculating the response probability in every voxel using the linear-quadratic-Poisson model and the dose-response parameters of the corresponding structure to which this voxel belongs. The overall probabilities of target and normal tissue responses were calculated using the Poisson and the relative seriality models, respectively. The 3D dose distribution converted to a 2 Gy fractionation, D2(GY) and iso-BED distributions are also shown and compared with the proposed methodology. Response-probability volume histograms (RVH) were derived and compared with common dose volume histograms (DVH). The different dose distributions were also compared using the complication-free tumor control probability, P+, the biologically effective uniform dose, D, and common dosimetric criteria. RESULTS: 3D Iso-probability of response distributions is very useful for plan evaluation since their visual information focuses on the doses that are likely to have a larger clinical effect in that particular organ. The graphical display becomes independent of the prescription dose highlighting the local radiation therapy effect in each voxel without the loss of important spatial information. For example, due to the exponential nature of the Poisson distribution, cold spots in the target volumes or hot spots in the normal tissues are much easier to be identified. Response-volume histograms, as DVH, can also be derived and used for plan comparison. RVH are advantageous since by incorporating the radiobiological properties of each voxel they summarize the 3D distribution into 2D without the loss of relevant information. Thus, more clinically relevant radiobiological objectives and constraints could be defined and used in treatment planning optimization. These measures become increasingly important when dose distributions need to be designed according to the microscopic biological properties of tumor and normal tissues. CONCLUSIONS: The proposed methods do not aim to replace quantifiers like the probabilities of total tissue response, which ultimately are the quantities of interest to evaluate treatment success. However, iso-probability of response charts and response-probability volume histograms illustrates more clearly the difference in effectiveness between different treatment plans than the information provided by alternative dosimetric data. The use of 3D iso-probability of response distributions could serve as a good descriptor of the effectiveness of a dose distribution indicating primarily the regions in a tissue that dominate its response.

Radiobiological evaluation of forward and inverse IMRT using different fractionations for head and neck tumours.

PURPOSE: To quantify the radiobiological advantages obtained by an Improved Forward Planning technique (IFP) and two IMRT techniques using different fractionation schemes for the irradiation of head and neck tumours. The conventional radiation therapy technique (CONVT) was used here as a benchmark. METHODS: Seven patients with head and neck tumours were selected for this retrospective planning study. The PTV1 included the primary tumour, PTV2 the high risk lymph nodes and PTV3 the low risk lymph nodes. Except for the conventional technique where a maximum dose of 64.8 Gy was prescribed to the PTV1, 70.2 Gy, 59.4 Gy and 50.4 Gy were prescribed respectively to PTV1, PTV2 and PTV3. Except for IMRT2, all techniques were delivered by three sequential phases. The IFP technique used five to seven directions with a total of 15 to 21 beams. The IMRT techniques used five to nine directions and around 80 segments. The first, IMRT1, was prescribed with the conventional fractionation scheme of 1.8 Gy per fraction delivered in 39 fractions by three treatment phases. The second, IMRT2, simultaneously irradiated the PTV2 and PTV3 with 59.4 Gy and 50.4 Gy in 28 fractions, respectively, while the PTV1 was boosted with six subsequent fractions of 1.8 Gy. Tissue response was calculated using the relative seriality model and the Poisson Linear-Quadratic-Time model to simulate repopulation in the primary tumour. RESULTS: The average probability of total tumour control increased from 38% with CONVT to 80% with IFP, to 85% with IMRT1 and 89% with IMRT2. The shorter treatment time and larger dose per fraction obtained with IMRT2 resulted in an 11% increase in the probability of control in the PTV1 with respect to IFP and 7% relatively to IMRT1 (p < 0.05). The average probability of total patient complications was reduced from 80% with CONVT to 61% with IFP and 31% with IMRT. The corresponding probability of complications in the ipsilateral parotid was 63%, 42% and 20%; in the contralateral parotid it was 50%, 20% and 9%; in the oral cavity it was 2%, 15% and 4% and in the mandible it was 1%, 5% and 3%, respectively. CONCLUSIONS: A significant improvement in treatment outcome was obtained with IMRT compared to conventional radiation therapy. The practical and biological advantages of IMRT2, employing a shorter treatment time, may outweigh the small differences obtained in the organs at risk between the two IMRT techniques. This technique is therefore presently being used in the clinic for selected patients with head and neck tumours. A significant improvement in the quality of the dose distribution was obtained with IFP compared to CONVT. Thus, this beam arrangement is used in the clinical routine as an alternative to IMRT.

A graphic user interface toolkit for specification, report and comparison of dose-response relations and treatment plans using the biologically effective uniform dose.

A toolkit (BEUDcal) has been developed for evaluating the effectiveness and for predicting the outcome of treatment plans by calculating the biologically effective uniform dose (BEUD) and complication-free tumor control probability. The input for the BEUDcal is the differential dose-volume histograms of organs exported from the treatment planning system. A clinical database is built for the dose-response parameters of different tumors and normal tissues. Dose-response probabilities of all the examined organs are illustrated together with the corresponding BEUDs and the P(+) values. Furthermore, BEUDcal is able to generate a report that simultaneously presents the radiobiological evaluation together with the physical dose indices, showing the complementary relation between the physical and radiobiological treatment plan analysis performed by BEUDcal. Comparisons between treatment plans for helical tomotherapy and multileaf collimator-based intensity modulated radiotherapy of a lung patient were demonstrated to show the versatility of BEUDcal in the assessment and report of dose-response relations.

Comparison of the helical tomotherapy and MLC-based IMRT radiation modalities in treating brain and cranio-spinal tumors.

The investigation of the clinical efficacy and effectiveness of Intensity Modulated Radiotherapy (IMRT) using Multileaf Collimators (MLC) and Helical Tomotherapy (HT) has been an issue of increasing interest over the past few years. In order to assess the suitability of a treatment plan, dosimetric criteria such as dose-volume histograms (DVH), maximum, minimum, mean, and standard deviation of the dose distribution are typically used. Nevertheless, the radiobiological parameters of the different tumors and normal tissues are often not taken into account. The use of the biologically effective uniform dose (D=) together with the complication-free tumor control probability (P(+)) were applied to evaluate the two radiation modalities. Two different clinical cases of brain and cranio-spinal axis cancers have been investigated by developing a linac MLC-based step-and-shoot IMRT plan and a Helical Tomotherapy plan. The treatment plans of the MLC-based IMRT were developed on the Philips treatment planning station using the Pinnacle 7.6 software release while the dedicated Tomotherapy treatment planning station was used for the HT plan. With the use of the P(+) index and the D(=) concept as the common prescription point, the different treatment plans were compared based on radiobiological measures. The tissue response probabilities were plotted against D(=) for a range of prescription doses. The applied plan evaluation method shows that in the brain cancer, the HT treatment gives slightly better results than the MLC-based IMRT in terms of optimum expected clinical outcome (P(+) of 66.1% and 63.5% for a D(=) to the PTV of 63.0 Gy and 62.0 Gy, respectively). In the cranio-spinal axis cancer, the HT plan is significantly better compared to the MLC-based IMRT plan over the clinically useful dose prescription range (P(+) of 84.1% and 28.3% for a D(=) to the PTV of 50.6 Gy and 44.0 Gy, respectively). If a higher than 5% risk for complications could be allowed, the complication-free tumor control could be increased by almost 30% compared to the initial dose prescription. In comparison to MLC based-IMRT, HT can better encompass the often large PTV while minimizing the volume of the OARs receiving high dose. A radiobiological treatment plan evaluation can provide a closer association of the delivered treatment with the clinical outcome by taking into account the dose-response relations of the irradiated tumors and normal tissues. The use of P - (D=) diagrams can complement the traditional tools of evaluation such as DVHs, in order to compare and effectively evaluate different treatment plans.

The impact of different dose-response parameters on biologically optimized IMRT in breast cancer.

The full potential of biologically optimized radiation therapy can only be maximized with the prediction of individual patient radiosensitivity prior to treatment. Unfortunately, the available biological parameters, derived from clinical trials, reflect an average radiosensitivity of the examined populations. In the present study, a breast cancer patient of stage I-II with positive lymph nodes was chosen in order to analyse the effect of the variation of individual radiosensitivity on the optimal dose distribution. Thus, deviations from the average biological parameters, describing tumour, heart and lung response, were introduced covering the range of patient radiosensitivity reported in the literature. Two treatment configurations of three and seven biologically optimized intensity-modulated beams were employed. The different dose distributions were analysed using biological and physical parameters such as the complication-free tumour control probability (P(+)), the biologically effective uniform dose (D), dose volume histograms, mean doses, standard deviations, maximum and minimum doses. In the three-beam plan, the difference in P(+) between the optimal dose distribution (when the individual patient radiosensitivity is known) and the reference dose distribution, which is optimal for the average patient biology, ranges up to 13.9% when varying the radiosensitivity of the target volume, up to 0.9% when varying the radiosensitivity of the heart and up to 1.3% when varying the radiosensitivity of the lung. Similarly, in the seven-beam plan, the differences in P(+) are up to 13.1% for the target, up to 1.6% for the heart and up to 0.9% for the left lung. When the radiosensitivity of the most important tissues in breast cancer radiation therapy was simultaneously changed, the maximum gain in outcome was as high as 7.7%. The impact of the dose-response uncertainties on the treatment outcome was clinically insignificant for the majority of the simulated patients. However, the jump from generalized to individualized radiation therapy may significantly increase the therapeutic window for patients with extreme radio sensitivity or radioresistance, provided that these are identified. Even for radiosensitive patients a simple treatment technique is sufficient to maximize the outcome, since no significant benefits were obtained with a more complex technique using seven intensity-modulated beams portals.

Treatment plan comparison between helical tomotherapy and MLC-based IMRT using radiobiological measures.

The rapid implementation of advanced treatment planning and delivery technologies for radiation therapy has brought new challenges in evaluating the most effective treatment modality. Intensity-modulated radiotherapy (IMRT) using multi-leaf collimators (MLC) and helical tomotherapy (HT) are becoming popular modes of treatment delivery and their application and effectiveness continues to be investigated. Presently, there are several treatment planning systems (TPS) that can generate and optimize IMRT plans based on user-defined objective functions for the internal target volume (ITV) and organs at risk (OAR). However, the radiobiological parameters of the different tumours and normal tissues are typically not taken into account during dose prescription and optimization of a treatment plan or during plan evaluation. The suitability of a treatment plan is typically decided based on dosimetric criteria such as dose-volume histograms (DVH), maximum, minimum, mean and standard deviation of the dose distribution. For a more comprehensive treatment plan evaluation, the biologically effective uniform dose (D) is applied together with the complication-free tumour control probability (P(+)). Its utilization is demonstrated using three clinical cases that were planned with two different forms of IMRT. In this study, three different cancer types at different anatomical sites were investigated: head and neck, lung and prostate cancers. For each cancer type, a linac MLC-based step-and-shoot IMRT plan and a HT plan were developed. The MLC-based IMRT treatment plans were developed on the Philips treatment-planning platform, using the Pinnacle 7.6 software release. For the tomotherapy HiArt plans, the dedicated tomotherapy treatment planning station was used, running version 2.1.2. By using D as the common prescription point of the treatment plans and plotting the tissue response probabilities versus D for a range of prescription doses, a number of plan trials can be compared based on radiobiological measures. The applied plan evaluation method shows that in the head and neck cancer case the HT treatment gives better results than MLC-based IMRT in terms of expected clinical outcome P(+) of 62.2% and 46.0%, D to the ITV of 72.3 Gy and 70.7 Gy, respectively). In the lung cancer and prostate cancer cases, the MLC-based IMRT plans are better over the clinically useful dose prescription range. For the lung cancer case, the HT and MLC-based IMRT plans give a P(+) of 66.9% and 72.9%, D to the ITV of 64.0 Gy and 66.9 Gy, respectively. Similarly, for the prostate cancer case, the two radiation modalities give a P(+) of 68.7% and 72.2%, D to the ITV of 86.0 Gy and 85.9 Gy, respectively. If a higher risk of complications (higher than 5%) could be allowed, the complication-free tumour control could increase by over 40%, 2% and 30% compared to the initial dose prescription for the three cancer cases, respectively. Both MLC-based IMRT and HT can encompass the often-large ITV required while they minimize the volume of the organs at risk receiving high doses. Radiobiological evaluation of treatment plans may provide an improved correlation of the delivered treatment with the clinical outcome by taking into account the dose-response characteristics of the irradiated targets and normal tissues. There may exist clinical cases, which may look dosimetrically similar but in radiobiological terms may be quite different. In such situations, traditional dose-based evaluation tools can be complemented by the use of P(+)--D diagrams to effectively evaluate and compare treatment plans.

Effective beam directions using radiobiologically optimized IMRT of node positive breast cancer.

The purpose of this study was to investigate the optimal coplanar beam directions when treating an early breast cancer with locoregional lymphatic spread with a few radiobiologically optimized intensity modulated beams. Also to determine the increase in the probability of complication-free cure with the number of beam portals and the smallest number required to perform a close to optimal treatment for this tumour site. Four test patients with stage II left-sided breast cancer were studied with heart, lung and contralateral breast as principal organs at risk. The clinical target volume consisted of the breast tissue remaining after surgery, the axillary, the internal mammary as well as the supraclavicular lymph nodes. Through an exhaustive search of all possible beam directions the most effective coplanar beams with one to four intensity modulated photon beam portals were investigated. Comparisons with uniform beam treatment techniques and up to 12 intensity modulated beams were also made. The different plans were optimized using the probability of complication-free tumour cure, P(+), as biological objective function. When using two intensity modulated beam directions three major sets of suitable directions were identified denoted by A, P and T. A corresponds to an anterior oblique pair of beams around 25 degrees and 325 degrees , P is a perpendicular lateral pair at around 50 degrees and 130 degrees whereas T is a more conventional tangential pair at around 155 degrees and 300 degrees . Interestingly, these configurations identify simply three major effective beam directions namely at 30 degrees +/-20 degrees , 145 degrees +/-20 degrees and 310 degrees +/-15 degrees . For the three intensity modulated beam technique a combination of these three effective beam directions generally covered the global maximum of the probability of complication-free tumour control. The improvement in complication-free cure probability with two optimally selected intensity modulated beams is around 10% when compared to a uniform beam technique with three to four beam portals. This increase is mainly due to a reduction by almost 1% in the probability of injury to the heart and an increase of 6% in the probability of local tumour control. When three or four biologically optimized beam portals are used a further increase in the probability of complication-free cure of about 6% can often be obtained. This improvement is caused by a small decrease in the probability of injury to the heart, left lung and other surrounding normal tissue, as well as a slight further increase in the probability of tumour control. The increase in the treatment outcome is minimal when more than four intensity modulated beams are employed. A small increase in dose homogeneity in the target volume and a slight decrease in the normal tissue volume receiving high dose may be seen, but without appreciably improving the complication-free cure probability. For a stage II breast cancer, three and in more complex cases four optimally oriented beams are sufficient to reach close to the maximum probability of complication-free tumour control when biologically optimized intensity modulated dose delivery is used. Angle of incidence optimization may then be advantageous starting from the given most effective three beam directions.