M Guerrero

How low is the α/β ratio for prostate cancer?

Purpose: It has been suggested recently that the / ratio for human prostate cancer is low (around 1.5 Gy), and much debate on the evidence for such a low value is ongoing. Analyses reported so far ignored the contribution of tumor repopulation. Extremely low values and unrealistic cell numbers of tumor clonogens are found in these studies. In this paper, we present a comprehensive analysis of the updated clinical data to derive a self-consistent set of parameters for the linear-quadratic (LQ) model. Methods and Materials: The generalized LQ model, considering the effects of dose rate, sublethal damage repair, and clonogenic proliferation, was used to analyze the recently reported clinical data for prostate cancer using either external-beam radiotherapy or brachytherapy. Three LQ parameters, , /, and the repair time, were determined based on the clinical finding that the external-beam radiotherapy and the 125 I and 103 Pd permanent implants are biologically equivalent. The tumor control probability model was used also to analyze the clinical data to obtain an independent relationship of / vs. and to estimate clonogenic cell numbers for patients in different risk groups. Results: Based on the analysis of clinical data and a consideration of repopulation effect, we have derived a self-consistent set of LQ parameters for prostate cancer: 0.15 0.04 Gy 1 , / 3.1 0.5 Gy. Our analysis indicates the half-time of sublethal damage repair to be in the range from 0 to 90 min with a best estimate of 16 min. The best estimate of clonogenic cell numbers in prostate tumors is found to range from 10 6 to 10 7 according to the patient risk level. These values are more realistic than those derived previously (only 10 ‐100). Conclusions: The effect of tumor repopulation is not negligible in determining the LQ parameters for prostate cancer, especially for the low-dose-rate permanent implants. Analysis of clinical data for prostate cancer with corrections for damage repair and repopulation effects results in a low / ratio of 3.1 Gy. Unrealistic clonogenic cell numbers and extremely small values of reported in the literature can be resolved by correcting for repopulation effect. The LQ parameters derived presently from the clinical data are consistent with reports of intrinsic radiosensitivity in vitro.

Extending the linear-quadratic model for large fraction doses pertinent to stereotactic radiotherapy.

Ongoing clinical trials designed to explore the use of extracranial stereotactic radiosurgery (ESR) for different tumour sites use large doses per fraction (15, 20, 30 Gy or even larger). The question of whether the linear-quadratic (LQ) model is appropriate to describe radiation response for such large fraction doses has been raised and has not been answered definitively. It has been proposed that mechanism-based models, such as the lethal-potentially lethal (LPL) model, could be more appropriate for such large fraction/acute doses. However, such models are not well characterized with clinical data and they are generally not easy to use. The purpose of this work is to modify the LQ model to more accurately describe radiation response for high fraction/acute doses. A new parameter is introduced in the modified LQ (MLQ) model. The new parameter introduced is characterized based both on in vitro cell survival data of several human tumour cell lines and in vivo animal iso-effect curves. The MLQ model produces a better fit to the iso-effect data than the LQ model. For a high single dose irradiation, the prediction of the MLQ is consistent with that from the LPL model. Unlike the LPL model, the MLQ model retains the simplicity of the LQ model and uses the well-characterized alpha and beta parameters. This work indicates that the standard LQ model can lead to erroneous results when used to calculate iso-effects with large fraction doses, such as those used for ESR. We present a solution to this problem.

Comparison of in vitro and in vivo α/β ratios for prostate cancer

A soft gelatin capsule with a filling including lysine clonixinate as an active ingredient and in a hydrophilic matrix and with a shell comprising gelatin, a plasticizer and sorbitol, wherein the plasticizer in many instances will be glycerol but may comprise the sorbitol alone. The presence of sorbitol in the gelatin capsule of a lysine clonixinate dosage form imparts unexpectedly good drug release and stability thereto.

Deformable planning CT to cone‐beam CT image registration in head‐and‐neck cancer

PURPOSE The purpose of this work was to implement and validate a deformable CT to cone-beam computed tomography (CBCT) image registration method in head-and-neck cancer to eventually facilitate automatic target delineation on CBCT. METHODS Twelve head-and-neck cancer patients underwent a planning CT and weekly CBCT during the 5-7 week treatment period. The 12 planning CT images (moving images) of these patients were registered to their weekly CBCT images (fixed images) via the symmetric force Demons algorithm and using a multiresolution scheme. Histogram matching was used to compensate for the intensity difference between the two types of images. Using nine known anatomic points as registration targets, the accuracy of the registration was evaluated using the target registration error (TRE). In addition, region-of-interest (ROI) contours drawn on the planning CT were morphed to the CBCT images and the volume overlap index (VOI) between registered contours and manually delineated contours was evaluated. RESULTS The mean TRE value of the nine target points was less than 3.0 mm, the slice thickness of the planning CT. Of the 369 target points evaluated for registration accuracy, the average TRE value was 2.6 +/- 0.6 mm. The mean TRE for bony tissue targets was 2.4 +/- 0.2 mm, while the mean TRE for soft tissue targets was 2.8 +/- 0.2 mm. The average VOI between the registered and manually delineated ROI contours was 76.2 +/- 4.6%, which is consistent with that reported in previous studies. CONCLUSIONS The authors have implemented and validated a deformable image registration method to register planning CT images to weekly CBCT images in head-and-neck cancer cases. The accuracy of the TRE values suggests that they can be used as a promising tool for automatic target delineation on CBCT.

Analysis of a large number of clinical studies for breast cancer radiotherapy: estimation of radiobiological parameters for treatment planning

Numerous studies of early-stage breast cancer treated with breast conserving surgery (BCS) and radiotherapy (RT) have been published in recent years. Both external beam radiotherapy (EBRT) and/or brachytherapy (BT) with different fractionation schemes are currently used. The present RT practice is largely based on empirical experience and it lacks a reliable modelling tool to compare different RT modalities or to design new treatment strategies. The purpose of this work is to derive a plausible set of radiobiological parameters that can be used for RT treatment planning. The derivation is based on existing clinical data and is consistent with the analysis of a large number of published clinical studies on early-stage breast cancer. A large number of published clinical studies on the treatment of early breast cancer with BCS plus RT (including whole breast EBRT with or without a boost to the tumour bed, whole breast EBRT alone, brachytherapy alone) and RT alone are compiled and analysed. The linear quadratic (LQ) model is used in the analysis. Three of these clinical studies are selected to derive a plausible set of LQ parameters. The potential doubling time is set a priori in the derivation according to in vitro measurements from the literature. The impact of considering lower or higher T(pot) is investigated. The effects of inhomogeneous dose distributions are considered using clinically representative dose volume histograms. The derived LQ parameters are used to compare a large number of clinical studies using different regimes (e.g., RT modality and/or different fractionation schemes with different prescribed dose) in order to validate their applicability. The values of the equivalent uniform dose (EUD) and biologically effective dose (BED) are used as a common metric to compare the biological effectiveness of each treatment regime. We have obtained a plausible set of radiobiological parameters for breast cancer: alpha = 0.3 Gy(-1), alpha/beta = 10 Gy and sub-lethal damage repair time T(rep) = 1 h (mono-exponential behaviour is assumed). This set of parameters is consistent with in vitro experiments and with previously reported analyses. Using this set of parameters, we have found that most of the studies, using BCS plus whole breast RT and a boost to the tumour bed, have EUDs ranging from 60-70 Gy. No correlation is found between BED and the local recurrence rate. The treatments of BCS plus brachytherapy alone have a wide range of EUD (30-50 Gy), which is significantly lower than the treatments with whole breast EBRT plus a boost of the tumour bed. The studies with different fractionation schemes for whole breast EBRT also show a significant variation of EUD. Carefully designed clinical studies with large numbers of patients are required to determine clinically the relative effectiveness of these treatment variations. The derived LQ parameter set based on clinical data is consistent with in vitro experiments and previous studies. As demonstrated in the present work, these radiobiological parameters can be potentially useful in radiotherapy treatment planning for early breast cancer, e.g., in comparing biological effectiveness of different radiotherapy modalities, different fractionation schemes and in designing new treatment strategies.

Equivalence of the linear–quadratic and two-lesion kinetic models

Double strand breaks (DSBs) are widely accepted as the main type of DNA damage responsible for cell killing in the range of doses and dose rates relevant to radiation therapy. Although the standard linear-quadratic (LQ) model with one first-order repair term often suffices to explain the results of some radiobiological experiments, converging lines of evidence suggest that DSBs are rejoined at two or more distinct rates. A two-lesion kinetic (TLK) model has been proposed to provide a direct link between biochemical processing of the DSBs and cell killing. A defining feature of the TLK model is that the family of all possible DSBs is subdivided into simple and complex DSBs, and each kind may have its own unique repair characteristics. Break-ends associated with both kinds of DSB are allowed to interact in pairwise fashion to form irreversible lethal and non-lethal chromosome aberrations. This paper examines the theoretical and practical linkages between the TLK and LQ models. The TLK formalism is used to derive an LQ formula with two first-order repair terms (dose protraction factors) and to relate the intrinsic radiosensitivity parameters used in one model to the parameters used in the other. Two extensive radiobiological datasets, one for CHO 10B2 cells and one for C3H 10T1/2 cells, are analysed using the TLK and LQ models. The LQ with two repair terms and the TLK are equally capable of explaining the CHO 10B2 and C3H 10T1/2 cell survival data. For the doses and dose rates most relevant to radiation therapy, tests of model equivalence indicate that an LQ formula with two first-order repair terms is an excellent approximation to the TLK model. We find the LQ and TLK models useful complementary tools for the analysis and prediction of radiobiological effects.

Mechanistic formulation of a lineal‐quadratic‐linear (LQL) model: Split‐dose experiments and exponentially decaying sources

PURPOSE In recent years, several models were proposed that modify the standard linear-quadratic (LQ) model to make the predicted survival curve linear at high doses. Most of these models are purely phenomenological and can only be applied in the particular case of acute doses per fraction. The authors consider a mechanistic formulation of a linear-quadratic-linear (LQL) model in the case of split-dose experiments and exponentially decaying sources. This model provides a comprehensive description of radiation response for arbitrary dose rate and fractionation with only one additional parameter. METHODS The authors use a compartmental formulation of the LQL model from the literature. They analytically solve the models differential equations for the case of a split-dose experiment and for an exponentially decaying source. They compare the solutions of the survival fraction with the standard LQ equations and with the lethal-potentially lethal (LPL) model. RESULTS In the case of the split-dose experiment, the LQL model predicts a recovery ratio as a function of dose per fraction that deviates from the square law of the standard LQ. The survival fraction as a function of time between fractions follows a similar exponential law as the LQ but adds a multiplicative factor to the LQ parameter beta. The LQL solution for the split-dose experiment is very close to the LPL prediction. For the decaying source, the differences between the LQL and the LQ solutions are negligible when the half-life of the source is much larger than the characteristic repair time, which is the clinically relevant case. CONCLUSIONS The compartmental formulation of the LQL model can be used for arbitrary dose rates and provides a comprehensive description of dose response. When the survival fraction for acute doses is linear for high dose, a deviation of the square law formula of the recovery ratio for split doses is also predicted.

Halftime for repair of sublethal damage in normal bladder and rectum: an analysis of clinical data from cervix brachytherapy.

The halftime for repair of sub-lethal damage is an important radiobiological parameter in analysing radiation responses and in designing new treatments involving different dose rates. This work is to resolve an inconsistency existing in the repair halftime for the bladder and rectum, two of the most dose limiting critical structures for pelvic irradiation. Both long (1.5–2 h) and short (0.3–1 h) repair halftimes have been reported previously. In this work, by reconciling clinical data from cervical brachytherapy of different dose rates and by introducing a sparing factor to consider the dose sparing occurring for critical structures, we have estimated that the most likely value of the repair halftime for bladder and rectum is short, 0.2–0.4 h if assuming α/β = 2–4 Gy. The present analysis does not support the long repair halftimes reported previously for the bladder and rectum and for other normal structures.

A technique to sharpen the beam penumbra for Gamma Knife radiosurgery

In stereotactic radiosurgery, a narrow beam penumbra is often desired for producing steep dose fall-off between the target volume and adjacent critical structures. Due to limited source sizes and the scattering effects, the physical penumbra of the Gamma Knife (GK) is often restricted to a width of 1-2 mm. In this work, we developed a technique to further reduce the beam penumbra and improve the dose profile for the Gamma Knife delivery. Under this technique, a conic filter is inserted into an individual plug collimator of a GK helmet to flatten the beam profile. Monte Carlo calculations were carried out to simulate the GK geometry of the individual plug collimator and to optimize the physical shapes of the filters. The calculations were performed for a series of filter shapes with different collimator sizes. Our results show that a proper filter significantly reduces the single GK beam penumbra width (defined as the distance from the 90% to 50% isodose lines) by 30-60%. The beam intensity is reduced by about 20-50% when the filter is used. A treatment plan was developed for a trigeminal neuralgia case by commissioning the filtered beam profile for Leksell Gamma Plan (version 5.31). Compared with the conventional treatment plan, a significant improvement was found on the critical structure sparing and on the target dose uniformity. In conclusion, the proposed technique is feasible and effective in sharpening the beam penumbra for Gamma Knife beam profiles.

Response assessment in locally advanced head and neck cancer based on RECIST and volume measurements using cone beam CT images.

The purpose of this work was to find potential trends in RECIST measurements and volume regressions obtained from weekly cone-beam computed tomography images and to evaluate their relationship to clinical outcomes in locally advanced head and neck cancer. We examined thirty head and neck cancer patients who underwent a pre-treatment planning CT and weekly cone-beam computed tomography (CBCT) during the 5-7 week treatment period. The gross tumor volume (GTV) and lymph nodes were manually contoured on the treatment planning CT. The regions of interest enclosed by delineated contours were converted to binary masks and warped to weekly CBCT images using the 3D deformation field obtained by deformable image registration. The RECIST diameters and volumes were measured from these warped masks. Different predictor variables based on these measurements were calculated and correlated with clinical outcomes, based on a clinical exam and a PET imaging study. We found that there was substantial regression of the gross tumor volume over the treatment course (average gross tumor volume regression of 25%). Among the gross tumor volume predicators, it was found that the early regression of gross tumor volume showed a marginal statistical significance (p = 0.045) with complete response and non-complete response treatment outcomes. RECIST diameter measurements during treatment varied very little and did not correlate with clinical outcomes. We concluded that regression of the gross tumor volume obtained from weekly CBCT images is a promising predictor of clinical outcomes for head and neck patients. A larger sample is needed to confirm its statistical significance.