Gain In Tumor Control Probability Research Articles

Robust dose-painting-by-numbers vs. nonselective dose escalation for non-small cell lung cancer patients.

PurposeTheoretical studies have shown that dose‐painting‐by‐numbers (DPBN) could lead to large gains in tumor control probability (TCP) compared to conventional dose distributions. However, these gains may vary considerably among patients due to (a) variations in the overall radiosensitivity of the tumor, (b) variations in the 3D distribution of intra‐tumor radiosensitivity within the tumor in combination with patient anatomy, (c) uncertainties of the 3D radiosensitivity maps, (d) geometrical uncertainties, and (e) temporal changes in radiosensitivity. The goal of this study was to investigate how much of the theoretical gains of DPBN remain when accounting for these factors. DPBN was compared to both a homogeneous reference dose distribution and to nonselective dose escalation (NSDE), that uses the same dose constraints as DPBN, but does not require 3D radiosensitivity maps.MethodsA fully automated DPBN treatment planning strategy was developed and implemented in our in‐house developed treatment planning system (TPS) that is robust to uncertainties in radiosensitivity and patient positioning. The method optimized the expected TCP based on 3D maps of intra‐tumor radiosensitivity, while accounting for normal tissue constraints, uncertainties in radiosensitivity, and setup uncertainties. Based on FDG‐PETCT scans of 12 non‐small cell lung cancer (NSCLC) patients, data of 324 virtual patients were created synthetically with large variations in the aforementioned parameters. DPBN was compared to both a uniform dose distribution of 60 Gy, and NSDE. In total, 360 DPBN and 24 NSDE treatment plans were optimized.ResultsThe average gain in TCP over all patients and radiosensitivity maps of DPBN was 0.54 ± 0.20 (range 0–0.97) compared to the 60 Gy uniform reference dose distribution, but only 0.03 ± 0.03 (range 0–0.22) compared to NSDE. The gains varied per patient depending on the radiosensitivity of the entire tumor and the 3D radiosensitivity maps. Uncertainty in radiosensitivity led to a considerable loss in TCP gain, which could be recovered almost completely by accounting for the uncertainty directly in the optimization.ConclusionsOur results suggest that the gains of DPBN can be considerable compared to a 60 Gy uniform reference dose distribution, but small compared to NSDE for most patients. Using the robust DPBN treatment planning system developed in this work, the optimal DPBN treatment plan could be derived for any patient for whom 3D intra‐tumor radiosensitivity maps are known, and can be used to select patients that might benefit from DPBN. NSDE could be an effective strategy to increase TCP without requiring biological information of the tumor.

Review and performance of the Dose Profiler, a particle therapy treatments online monitor

Particle therapy (PT) can exploit heavy ions (such as He, C or O) to enhance the treatment efficacy, profiting from the increased Relative Biological Effectiveness and Oxygen Enhancement Ratio of these projectiles with respect to proton beams. To maximise the gain in tumor control probability a precise online monitoring of the dose release is needed, avoiding unnecessary large safety margins surroundings the tumor volume accounting for possible patient mispositioning or morphological changes with respect to the initial CT scan. The Dose Profiler (DP) detector, presented in this manuscript, is a scintillating fibres tracker of charged secondary particles (mainly protons) that will be operating during the treatment, allowing for an online range monitoring. Such monitoring technique is particularly promising in the context of heavy ions PT, in which the precision achievable by other techniques based on secondary photons detection is limited by the environmental background during the beam delivery. Developed and built at the SBAI department of “La Sapienza”, within the INSIDE collaboration and as part of a Centro Fermi flagship project, the DP is a tracker detector specifically designed and planned for clinical applications inside a PT treatment room. The DP operation in clinical like conditions has been tested with the proton and carbon ions beams of Trento proton-therapy center and of the CNAO facility. In this contribution the detector performances are presented, in the context of the carbon ions monitoring clinical trial that is about to start at the CNAO centre.

WE‐AB‐207B‐11: Optimizing Tumor Control Probability in Radiation Therapy Treatment ‐ Application to HDR Cervical Cancer

Purpose:The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor‐control‐probability(TCP) with an acceptable normal‐tissue‐complication probability(NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. We design treatment plans that optimize TCP directly and contrast them with the clinical dose‐based plans. PET image is incorporated to evaluate gain in TCP for dose escalation.Methods:We build a nonlinear mixed integer programming optimization model that maximizes TCP directly while satisfying the dose requirements on the targeted organ and healthy tissues. The solution strategy first fits the TCP function with a piecewise‐linear approximation, then solves the problem that maximizes the piecewise linear approximation of TCP, and finally performs a local neighborhood search to improve the TCP value. To gauge the feasibility, characteristics, and potential benefit of PET‐image guided dose escalation, initial validation consists of fifteen cervical cancer HDR patient cases. These patients have all received prior 45Gy of external radiation dose. For both escalated strategies, we consider 35Gy PTV‐dose, and two variations (37Gy‐boost to BTV vs 40Gy‐boost) to PET‐image‐pockets.Results:TCP for standard clinical plans range from 59.4% ‐ 63.6%. TCP for dose‐based PET‐guided escalated‐dose‐plan ranges from 63.8%–98.6% for all patients; whereas TCP‐optimized plans achieves over 91% for all patients. There is marginal difference in TCP among those with 37Gy‐boosted vs 40Gy‐boosted. There is no increase in rectum and bladder dose among all plans.Conclusion:Optimizing TCP directly results in highly conformed treatment plans. The TCP‐optimized plan is individualized based on the biological PET‐image of the patients. The TCP‐optimization framework is generalizable and has been applied successfully to other external‐beam delivery modalities. A clinical trial is on‐going to gauge the clinical significance.Partially supported by the National Science Foundation.

Using spatial information about recurrence risk for robust optimization of dose‐painting prescription functions

To develop a robust method for deriving dose-painting prescription functions using spatial information about the risk for disease recurrence. Spatial distributions of radiobiological model parameters are derived from distributions of recurrence risk after uniform irradiation. These model parameters are then used to derive optimal dose-painting prescription functions given a constant mean biologically effective dose. An estimate for the optimal dose distribution can be derived based on spatial information about recurrence risk. Dose painting based on imaging markers that are moderately or poorly correlated with recurrence risk are predicted to potentially result in inferior disease control when compared the same mean biologically effective dose delivered uniformly. A robust optimization approach may partially mitigate this issue. The methods described here can be used to derive an estimate for a robust, patient-specific prescription function for use in dose painting. Two approximate scaling relationships were observed: First, the optimal choice for the maximum dose differential when using either a linear or two-compartment prescription function is proportional to R, where R is the Pearson correlation coefficient between a given imaging marker and recurrence risk after uniform irradiation. Second, the predicted maximum possible gain in tumor control probability for any robust optimization technique is nearly proportional to the square of R.

Stereotactic body radiation therapy and 3-dimensional conformal radiotherapy for stage I non-small cell lung cancer: A pooled analysis of biological equivalent dose and local control

PurposeTo determine the relationship between tumor control probability (TCP) and biological effective dose (BED) for radiation therapy in medically inoperable stage I non-small cell lung cancer (NSCLC). Methods and MaterialsForty-two studies on 3-dimensional conformal radiation therapy (3D-CRT) and SBRT for stage I NSCLC were reviewed for tumor control (TC), defined as crude local control ≥ 2 years, as a function of BED. For each dose-fractionation schedule, BED was calculated at isocenter using the linear quadratic (LQ) and universal survival curve (USC) models. A scatter plot of TC versus BED was generated and fitted to the standard TCP equation for both models. ResultsA total of 2696 patients were included in this study (SBRT: 1640; 3D-CRT: 1056). Daily fraction size was 1.2-4 Gy (total dose: 48-102.9) with 3D-CRT and 6-26 (total dose: 20-66) with SBRT. Median BED was 118.6 Gy (range, 68.5-320.3) and 95.6 Gy (range, 46.1-178.1) for the LQ and USC models, respectively. According to the LQ model, BED to achieve 50% TC (TCD50) was 61 Gy (95% confidence interval, 50.2-71.1). TCP as a function of BED was sigmoidal, with TCP ≥ 90% achieved with BED ≥ 159 Gy and 124 Gy for the LQ and USC models, respectively. ConclusionsDose-escalation beyond a BED 159 by LQ model likely translates into clinically insignificant gain in TCP but may result in clinically significant toxicity. When delivered with SBRT, BED of 159 Gy corresponds to a total dose of 53 Gy in 3 fractions at the isocenter.

Improvement in tumour control probability with active breathing control and dose escalation: A modelling study

Introduction The prognosis from non-small cell lung cancer remains poor, even in those patients suitable for radical radiotherapy. The ability of radiotherapy to achieve local control is hampered by the sensitivity of normal structures to irradiation at the high tumour doses needed. This study aimed to look at the potential gain in tumour control probability from dose escalation facilitated by moderate deep inspiration breath-hold. Method The data from 28 patients, recruited into two separate studies were used. These patients underwent planning with and without the use of moderate deep inspiration breath-hold with an active breathing control (ABC) device. Whilst maintaining the mean lung dose (MLD) at the level of the conventional plan, the ABC plan dose was theoretically escalated to a maximum of 84 Gy, constrained by usual normal tissue tolerances. Calculations were performed using data for both lungs and for the ipsilateral lung only. Resulting local progression-free survival at 30 months was calculated using a standard logistic model. Results The prescription dose could be escalated from 64 Gy to a mean of 73.7 ± 6.5 Gy without margin reduction, which represents a statistically significant increase in tumour control probability from 0.15 ± 0.01 to 0.29 ± 0.11 ( p < 0.0001). The results were not statistically different whether both lungs or just the ipsilateral lung was used for calculations. Conclusion A near-doubling of tumour control probability is possible with modest dose escalation, which can be achieved with no extra increase in lung dose if deep inspiration breath-hold techniques are used.

The impact of hypofractionation on simultaneous dose‐boosting to hypoxic tumor subvolumes

In a previous study, the dependence of the therapeutic ratio on the number of fractions (n), including both acute and chronic hypoxia, was investigated for homogeneously irradiated tumors. The present study further develops the model to include simultaneous dose-boosting to the hypoxic tumour subvolumes. The acutely hypoxic (ah) tumor subvolume was partitioned into a large number (10(2)-10(3)) of oxygenation subvolumes, modelled through rectangular pO2(t) waves all with the same frequency and fractional time spent below the hypoxic threshold, but with randomly distributed phases. Three quite different assumptions were considered for the effect of prolonged hypoxia on the radiosensitivity (alpha) of the chronically hypoxic (ch) clonogens, ranging from equal radiosensitivity to that of the ah-cells to an even greater radiosensitivity than that of the well-oxygenated (ox) cells. The linear-quadratic model, including tumor repopulation, intertumor alpha-heterogeneity, and dependence of the oxygen enhancement ratio on the dose per fraction, was adopted for tumor control probability (TCP) computation. To include a consideration of therapeutic ratio, lung irradiation was considered and the mean normalized total lung dose (NTD(L)) was used as a risk indicator. For those 1(fr/d) x 5(d/w) schedules yielding 50% TCP with homogeneous irradiation (our reference benchmark), we estimated the gain in TCP and the corresponding NTD(L) from dose boosting only the ch-subvolume, both the ah- and the ch-subvolumes, or 50% of the pretreatment tumor volume without specific targeting to tumor hypoxia. For two of the three assumptions for the radiosensitivity of the ch-clonogens, dose-boosting the ch-subvolume was associated with a substantial gain in TCP, and with a trend including minima in NTD(L), for severely hypofractionated schedules only, whereas when dose-boosting both the ah- and the ch-subvolumes a substantial gain in TCP was always obtained for multifractionated schedules. By contrast, the "blind" dose-boosting strategy was generally inferior, although an appreciable gain in TCP for severely hypofractionated schedules was obtained. In conclusion, a strategy of dose-boosting tumor hypoxia, guided by nuclear medicine techniques that substantially map chronic hypoxia, is expected to yield optimal gains in TCP via severely hypofractionated delivery.

Evaluation of image-guided radiation therapy (IGRT) technologies and their impact on the outcomes of hypofractionated prostate cancer treatments: A radiobiologic analysis

To quantify the mitigation of geometric uncertainties achieved with the application of various patient setup techniques during the delivery of hypofractionated prostate cancer treatments, using tumor control probability (TCP) and normal tissue complication probability. Five prostate cancer patients with approximately 16 treatment CT studies, taken during the course of their radiation therapy (77 total), were analyzed. All patients were planned twice with an 18 MV six-field conformal technique, with 10- and 5-mm margin sizes, with various hypofractionation schedules (5 to 35 fractions). Subsequently, four clinically relevant patient setup techniques (laser guided and image guided) were simulated to deliver such schedules. As hypothesized, the impact of geometric uncertainties on clinical outcomes increased with more hypofractionated schedules. However, the absolute gain in TCP due to hypofractionation (up to 21.8% increase) was significantly higher compared with the losses due to geometric uncertainties (up to 8.6% decrease). The results of this study suggest that, although the impact of geometric uncertainties on the treatment outcomes increases as the number of fractions decrease, the reduction in TCP due to the uncertainties does not significantly offset the expected theoretical gain in TCP by hypofractionation.

An audit of delays before and during radical radiotherapy for cervical cancer--effect on tumour cure probability.

To evaluate the potential impact of time delay before and during radical radiotherapy for cervical carcinoma at Addenbrooke's Hospital. An audit was undertaken which recorded the number of gaps during external beam radiotherapy (EBRT), overall treatment time, and delay between first oncology consultation to start of radiotherapy, for patients receiving primary radical radiotherapy for cervical cancer in 1996, 1998 and 2001. Radiobiological modelling was used to calculate the tumour control probability (TCP). A questionnaire survey of 62 oncology departments in the U.K. was carried out for comparison. The percentage of patients completing EBRT without any interruptions was 22, 67 and 94% in 1996, 1998, and 2001, respectively (P = 0.0009). The median overall treatment time was 49, 42 and 39 days in 1996, 1998 and 2001, respectively (P = 0.001). However, the median waiting time to start of radiotherapy increased from 14 days in 1996 to 18 days in 1998 and 35 days in 2001 (P = 0.007). The results from the national survey showed that this pattern of improved overall treatment times accompanied by deterioration in waiting times was also seen in most other U.K. centres. Radiobiological modelling showed that any potential gain in TCP resulting from shorter overall treatment times could be offset entirely by the adverse effect of increasing waiting times. The calculations suggest that the tumours most likely to be adversely affected by long waiting times are those with shorter volume doubling times or a medium chance of tumour control at the outset of treatment. A system of patient triage, and prioritization of patients deemed most likely to benefit from a reduced waiting time, may be necessary in the current climate of limited radiotherapy resources.

Inverse and forward optimization of one- and two-dimensional intensity-modulated radiation therapy-based treatment of concave-shaped planning target volumes: the case of prostate cancer.

Intensity-modulated radiation therapy (IMRT) was suggested as a suitable technique to protect the rectal wall, while maintaining a satisfactory planning target volume (PTV) irradiation in the case of high-dose radiotherapy of prostate cancer. However, up to now, few investigations tried to estimate the expected benefit with respect to conventional three-dimensional (3D) conformal radiotherapy (CRT). Estimating the expected clinical gain coming from both 1D and 2D IMRT against 3DCRT, in the case of prostate cancer by mean of radiobiological models. In order to enhance the impact of IMRT, the case of concave-shaped PTV including prostate and seminal vesicles (P+SV) was considered. Five patients with concave-shaped PTV including P+SV were selected. Two different sets of constraints were applied during planning: in the first one a quite large inhomogeneity of the dose distribution within the PTV was accepted (set (a)); in the other set (set (b)) a greater homogeneity was required. Tumor control probability (TCP) and normal tissue control probability (NTCP) indices were calculated through the Webb-Nahum and the Lyman-Kutcher models, respectively. Considering a dose interval from 64.8 to 100.8 Gy, the value giving a 5% NTCP for the rectum was found (D(NTCP(rectum)=5%)) using two different methods, and the corresponding TCP(NTCP(rectum)=5%) and NTCP(NTCP(rectum)=5%) for the other critical structures were derived. With the first method, the inverse optimization of the plans was performed just at a fixed 75.6 Gy ICRU dose; with the second method (applied to 2/5 patients) inverse treatment plannings were re-optimized at many dose levels (from 64.8 to 108 Gy with 3.6 Gy intervals). In this case, three different values of alpha/beta (10, 3, 1.5)were used for TCP calculation. The 3DCRT plan consisted of a 3-fields technique; in the IMRT plans, five equi-spaced beams were applied. The Helios Inverse Planning software from Varian was used for both the 2D IMRT and the 1D IMRT inverse optimization, the last one being performed fixing only one available pair of leaves for modulation. A previously proposed forward 1D IMRT 'class solution' technique was also considered, keeping the same irradiation geometry of the inversely optimized IMRT techniques. With the first method, the average gains in TCP(NTCP(rectum)=5%) of the 2D IMRT technique, with respect 3DCRT, were 10.3 and 7.8%, depending on the choice of the DVHs constraints during the inverse optimization procedure (set (a) and set (b), respectively). The average gain (DeltaTCP(NTCP(rectum)=5%)) coming from the inverse 1D IMRT optimization was 5.0%, when fixing the set (b) DVHs constraints. Concerning the forward 1D IMRT optimization, the average gain in TCP(NTCP(rectum)=5%) was 4.5%. The gain was found to be correlated with the degree of overlapping between rectum and PTV. When comparing 2D IMRT and 1D IMRT, in the case of the more realistic set (b) constraints, DeltaTCP(NTCP(rectum)=5%) was always less than 3%, excepting one patient with a very large overlap region. Basing our choice on this result, the second method was applied to this patient and one of the remaining. Through the inverse re-optimization of the treatment plans at each dose level, the gain in TCP(NTCP(rectum)=5%) of the inverse 2D technique was significantly higher than the ones obtained by applying the first method (concerning the two patients: +6.1% and +2.4%), while no significant benefit was found for inverse 1D. The impact of changing the alpha/beta ratio was less evident in the patient with the lower gain in TCP(NTCP(rectum)=5%). The expected benefit due to IMRT with respect to 3DCRT seems to be relevant when the overlap between PTV and rectum is high. Moreover, the difference between the inverse 2D and the simpler inverse or forward 1D IMRT techniques resulted in being relatively modest, with the exception of one patient, having a very large overlap between rectum and PTV. Optimizing the inverse planning at each dose level to find TCP(NTCP(rectum)=5%)e level to find TCP(NTCP(rectum)=5%) can improve the performances of inverse 2D IMRT, against a significant increase of the time for planning. These results suggest the importance of selecting the patients that could have significant benefit from the application of IMRT.

The required number of treatment imaging days for an effective off-line correction of systematic errors in conformal radiotherapy of prostate cancer — a radiobiological analysis

Background and purpose: To use radiobiological modelling to estimate the number of initial days of treatment imaging required to gain most of the benefit from off-line correction of systematic errors in the conformal radiation therapy of prostate cancer. Materials and methods: Treatment plans based on the anatomical information of a representative patient were generated assuming that the patient is treated with a multi leaf collimator (MLC) four-field technique and a total isocentre dose of 72 Gy delivered in 36 daily fractions. Target position variations between fractions were simulated from standard deviations of measured data found in the literature. Off-line correction of systematic errors was assumed to be performed only once based on the measured errors during the initial days of treatment. The tumour control probability (TCP) was calculated using the Webb and Nahum model. Results: Simulation of daily variations in the target position predicted a marked reduction in TCP if the planning target volume (PTV) margin was smaller than 4 mm (TCP decreased by 3.4% for 2 mm margin). The systematic components of target position variations had greater effect on the TCP than the random components. Off-line correction of estimated systematic errors reduced the decrease in TCP due to target daily displacements, nevertheless, the resulting TCP levels for small margins were still less than the TCP level obtained with the use of an adequate PTV margin of ∼10 mm. The magnitude of gain in TCP expected from the correction depended on the number of treatment imaging days used for the correction and the PTV margin applied. Gains of 2.5% in TCP were estimated from correction of systematic errors performed after 6 initial days of treatment imaging for a 2 mm PTV margin. The effect of various possible magnitudes of systematic and random components on the gain in TCP expected from correction and on the number of imaging days required was also investigated. Conclusions: Daily variations of target position markedly reduced the TCP if small margins were used. Off-line correction of systematic errors can only partly compensate for these TCP reductions. The adequate number of treatment imaging days required for systematic error correction depends on the magnitude of the random component compared with the systematic component, and on the size of PTV margin used. For random components equal to or smaller than the systematic component, 3 consecutive treatment imaging days are estimated to be sufficient to gain most of the benefit from correction for current clinically used margins (6–10 mm); otherwise more days are required.

Individualization of dose prescription based on normal-tissue dose–volume and radiosensitivity data

Purpose: The aim of this paper is to illustrate the potential gain in tumor control probability (TCP) of prostate cancer patients by individualizing the prescription dose according to both normal-tissue (N-T) dose–volume and radiosensitivity data. Methods and Materials: Two exercises have been carried out. Firstly, patients’ dose prescriptions were individualised on the basis of N-T dose–volume histograms (DVHs) alone and secondly modeling potential differences in N-T sensitivity as well. In both cases, the change in tumor control that may be achieved by individualizing patients’ dose was estimated assuming that after the dose adjustments, every patient had ( 1) the same value of normal tissue complication probability (NTCP) (5%) and ( 2) NTCP equal to the average NTCP before individualization (i.e., without increasing the average NTCP). The Lyman-Kutcher-Burman NTCP model was used to predict the N-T response curves with two different sets of parameters. The first exercise, based only on individual NT DVHs (i.e., assuming all patient equally radiosensitive), was over a real population of 50 prostate cancer patients. The second exercise modeled a 10,000-prostate-cancer patient population with varying NT dose–volume distributions and radiosensitivity (through allowing TD 50 to vary). Results: A gain of more than 9% in TCP was predicted when doses were individualized based only on DVHs so that every patient had 5% NTCP after dose adjustments. By adding the estimate of radiosensitivity, the gain increased to more than 15%. When the individualisation was performed without increasing the mean NTCP, then the potential gain in TCP was almost 5% (for adjustment based on DVH distribution solely) increasing to 7% with the additional consideration of radiosensitivity. Conclusions: There is a potential gain (increase in local tumor control) from dose individualisation strategies based on both N-T dose–volume data and radiosensitivity (assuming that this is available). Dose prescription individualization based only on dose-volume data can be exploited provided that reliable N-T response models are available. There will be additional gains if some estimate of N-T radiosensitivity is available to allow further patient stratification, identification of patients with high radiosensitivity being particularly important.

Conformal irradiation of concave-shaped PTVs in the treatment of prostate cancer by simple 1D intensity-modulated beams

Background: In the case of concave-shaped PTVs including prostate (P) and seminal vesicles (SV), intensity-modulated radiation therapy (IMRT) should improve the therapeutic ratio of the treatment of prostate cancer. Purpose: Comparing IMRT by simple 1D modulations with conventional 3D conformal therapy (i.e. non-IMRT) in the treatment of concave-shaped PTVs including P+SV. Materials and methods: For five patients having a concave-shaped PTV (P+SV) previously treated at our Institute with conformal radiotherapy, conventional 3- and 4-fields conformal plans were compared with IMRT plans in terms of biological indices. IMRT plans were generated by using five equi-spaced beams with a partial shielding of the rectum obtainable with our single-absorber modulation technique (Fiorino C, Lev A, Fusca M, Cattaneo GM, Rudello F, Calandrino R. Dynamic beam modulation by using a single dynamic absorber. Phys. Med. Biol. 1995;40:221–240). The modulation was one-dimensional and the shape of the beams was at single minimum in correspondence with the ‘core’ of the rectum; the beam intensity in the minimum was set equal to 20 or 40% of the open beam intensity. All plans were simulated on the CADPLAN TPS using a pencil-beam based algorithm (with 18 MV X-rays). Tumour control probability (TCP) and normal tissue complication probabilities (NTCPs) (for rectum, bladder and femoral head) were calculated for all situations when varying the isocentre dose from 60 to 90 Gy. Dose distributions were corrected taking dose fractionation into account through the linear-quadratic model; for the TCP/NTCP estimations the Webb–Nahum and the Lyman–Kutcher models were respectively applied. Three different scores were considered: (a) increase of TCP while keeping rectum NTCP equal to 5% (TCP(5%)); (b) increase of the uncomplicated tumour control probability (P+); (c) increase of the biological-based scoring function (S+), developed by Mohan et al. (Mohan R, Mageras GS, Baldwin B, Clinically relevant optimization of 3D conformal treatments. Med. Phys. 1992;19:933–944). The impact of the uncertainty in the knowledge of the parameters of the biological models was investigated for TCP(5%). Results: (a) The average gain in TCP(5%) when considering IMRT against non-IMRT conformal plans was 7.3% (range 5.0–13.5%); (b) the average increase of P+ was 3.4% (range: 1.0–8.5%); and (c) the average increase of S+ was 5.4% (range 2.9–12.4%). The largest gain was found for one patient (patient 5) showing a significantly larger overlapping between PTV and rectum. Conclusions: Simple 1D-IMRT may clearly improve the therapeutic ratio in the treatment of concave-shaped PTVs including P and SV. In the range of clinically suitable values, the impact of the uncertainty of the parameters n and σ α does not significantly alter the main results concerning the gain in TCP(5%). The reported gain in terms of P+ and S+ should be considered with great caution because of the intrinsic uncertainties of the model's parameters and, for bladder, because the ‘true’ DVH (considering variations of the shape and dimension due to variable filling) may be very different from the DVH calculated on a single CT scan. Further investigations should consider inversely-optimised 1D and 2D-IMRT plan in order to compare them in terms of cost-benefit.

Optimization of coplanar six-field techniques for conformal radiotherapy of the prostate

Purpose: To determine the optimal coplanar treatment technique for six-field conformal radiotherapy of prostate only (PO) or prostate plus seminal vesicles (PSV). Methods and Materials: A series of 6-MV six-field coplanar treatment plans were created for PO and PSV volumes in 10 patients prescribed to both 64 and 74 Gy. All plans consisted of laterally-symmetric anterior oblique, lateral, and posterior oblique fields. The posterior oblique fields were varied through 20–45° relative to the lateral fields, and for each of these angles, the anterior oblique fields were varied through 25–65° relative to lateral. The plans were compared by means of rectal volumes irradiated to 80% or more of the prescribed dose (V 80); normal tissue complication probability (NTCP) for rectum, bladder, and femoral heads; and tumor control probability (TCP). Femoral head tolerance was designated as 52 Gy to no more than 10% volume. Results: For the PO group, anterior oblique fields at 50° from lateral and posterior oblique fields at 25° from lateral produced the lowest V 80,together with femoral head doses which were appropriate for most patients (V 80 = 24.4 ± 5.3% [1 SD]). Compared to a commonly-used six-field (reference) plan with both anterior and posterior oblique fields at 35° from lateral (V 80 = 26.3 ± 5.9%), this represented an improvement ( p = 0.001). For the PSV group, the optimal anterior and posterior oblique fields were at 65° and 30° from lateral, respectively (V 80 = 47.5 ± 6.3%). Relative to the reference plan (V 80= 49.4 ± 5.6%), this was a marginal improvement ( p = 0.07). Conclusion: The optimized six-field plans provide increased rectal sparing at both standard and escalated doses. Moreover, the gain in TCP resulting from dose escalation can be achieved with a smaller increase in rectal NTCP using the optimized six-field plans.

The modelled benefits of individualizing radiotherapy patients’ dose using cellular radiosensitivity assays with inherent variability

Objective: To model the increases in local tumour control that may be achieved, without increasing normal tissue complications, by prescribing a patient’s dose based on cellular radiosensitivity measured using an assay possessing inherent variability. Method: Patient populations with varying radiosensitivity were simulated, based on measured distributions among cancer patients of the surviving fraction of their fibroblasts given a dose of 2 Gy in vitro (SF 2). The dose-response curve for complications in the population was assessed using a formula relating SF 2 to normal tissue complication probability (NTCP), by summing the data for the individuals. This curve was similar to clinically-derived dose-response curves. The effect of individualizing the patients’ doses was explored, based on individual radiosensitivities measured by SF 2, so that every patient had the same low (5%) value of NTCP. Results: It was found that a significant gain (up to around 30%) in tumour control probability (TCP) was predicted for the population when the doses were individualized using a predictive assay result strongly correlated with NTCP. A greater gain in TCP was predicted when each of the individuals were assumed to have a higher sensitivity and the distribution of radiosensitivity in the population was widened to compensate. The gain in TCP was less (around 20%) when considering less-sensitive patients and a narrower distribution of radiosensitivities. The effect of assay variability and other factors that could affect the predictive power of the assay was simulated. Assay variability and an imperfect correlation between in vitro cell survival and tissue complications, rapidly increased the NTCP for the population when treated with individualized doses. However the individualized doses could be reduced so that NTCP declined to an acceptable level, but in this case the TCP for the population also declined. For example, when the assay variability was half the true variability in SF 2, the gain in TCP was reduced to around 6%. Also, the predicted gains in population TCP were higher if tumour and normal tissue radiosensitivity were assumed to be correlated. In this case, and in the absence of assay variability, increases in population TCP of about 50% and 30% were predicted, depending on the assumed relative sensitivities of the individual patients compared with that of the population average. For practical application, the division of the patient population simply into three groups of high, average and low radiosensitivity was also examined. The three groups were treated with different doses and the NTCP for the population was kept below 5%. Although the gain in population TCP was less than that predicted with the full individualization, considerable gains of up to 20% were still predicted. This method of dividing the population was more resilient to assay variability and other factors that may affect complications in patients. The modelling suggests that small improvements in TCP (5–10%) may still be achievable even if the correlation between SF 2 and late complications is lower at around −0.4 to −0.6, as reported in some clinical series. Conclusion: Modelling based on measured distributions of fibroblast radiosensitivity shows that improvements in tumour control rates may be achievable through the individualization of radiotherapy dose prescriptions of cancer patients, when assay variability is less than about 50% of the true variability in radiosensitivity, and with greater benefits if tumour and normal tissue radiosensitivity are correlated. Tripartite stratification of the population proved to be less sensitive to assay uncertainty, and can provide most of the benefits of the full individualization.

A comparison of proton and megavoltage X-ray treatment planning for prostate cancer

Conformal photon and proton therapy plans for prostate cancer have been compared in an attempt to quantify the potential advantages of using protons. Two X-ray plans (3-field, 6-field) and a 2-field proton plan were made and compared for each of 20 T3 prostate patients with the aid of the 3D planning system VOXELPLAN. Dose distributions were analysed in terms of dose-volume histograms (DVH). Tumour control probability (TCP) and normal tissue complication probability (NTCP) were computed using our own and the Lyman-Kutcher-Burman models, respectively. The study shows that on average the proton technique results in the best dose distribution, giving the lowest rectal complication probability, and also that the 3-field X-ray technique is more effective than the 6-field X-ray technique in sparing the rectum. At 5% rectal NTCP, the predicted proton average TCP for the 20 patients is 2% (in absolute terms) greater than that obtained using 3-field X-ray therapy. For 7 of the patients the gain in TCP is more than 3%. For the same rectal NTCP as the 3-field X-ray plan with a 64 Gy mean target dose, the use of protons increases the TCP by 2% on average, but for 5 of the patients the increases are greater than 4%. The result is in general positive towards the use of protons but a few patients do not benefit from it and this indicates the importance of patient selection for maximum clinical benefit.

A comparison of proton and megavoltage X-ray treatment planning for prostate cancer

Conformal photon and proton therapy plans for prostate cancer have been compared in an attempt to quantify the potential advantages of using protons. Two X-ray plans (3-field, 6-field) and a 2-field proton plan were made and compared for each of 20 T3 prostate patients with the aid of the 3D planning system VOXELPLAN. Dose distributions were analysed in terms of dose-volume histograms (DVH). Tumour control probability (TCP) and normal tissue complication probability (NTCP) were computed using our own and the Lyman-Kutcher-Burman models, respectively. The study shows that on average the proton technique results in the best dose distribution, giving the lowest rectal complication probability, and also that the 3-field X-ray technique is more effective than the 6-field X-ray technique in sparing the rectum. At 5% rectal NTCP, the predicted proton average TCP for the 20 patients is 2% (in absolute terms) greater than that obtained using 3-field X-ray therapy. For 7 of the patients the gain in TCP is more than 3%. For the same rectal NTCP as the 3-field X-ray plan with a 64 Gy mean target dose, the use of protons increases the TCP by 2% on average, but for 5 of the patients the increases are greater than 4%. The result is in general positive towards the use of protons but a few patients do not benefit from it and this indicates the importance of patient selection for maximum clinical benefit.

Strategies for treating possible tumor extension: Some theoretical considerations

When there is a small possibility of cancer having extended to a region some distance from the main bulk of disease, it may be unclear whether to include that region in the target volume and, if so, what dose should be delivered to it. We have constructed a theoretical model that includes dose and volume relationships for both diseased and normal tissue. With this model one can calculate the change in tumor control probability (TCP) when varying doses are delivered to the regions of known and suspected disease. Values of TCP as a function of dose to the region of suspected disease have been calculated for a wide range of the variables on which the model depends. We conclude that the strategy of treating the region of suspected disease to about 70% of the dose delivered to the region of known disease is almost always better than not treating it at all, or treating both regions to a uniform but reduced dose designed to keep the probability of complication the same. The gain in TCP could be from 5 to 15% for situations of clinical interest.