Multi-centre evaluation of variation in cumulative dose assessment in reirradiation scenarios.

BACKGROUND AND PURPOSE: Safe reirradiation relies on assessment of cumulative doses to organs at risk (OARs) across multiple treatments. Different clinical pathways can result in inconsistent estimates. Here, we quantified the consistency of cumulative dose to OARs across multi-centre clinical pathways. MATERIAL AND METHODS: We provided DICOM planning CT, structures and doses for two reirradiation cases: head & neck (HN) and lung. Participants followed their standard pathway to assess the cumulative physical and EQD2 doses (with provided α/ß values), and submitted DVH metrics and a description of their pathways. Participants could also submit physical dose distributions from Course 1 mapped onto the CT of Course 2 using their best available tools. To assess isolated impact of image registrations, a single observer accumulated each submitted spatially mapped physical dose for every participating centre. RESULTS: Cumulative dose assessment was performed by 24 participants. Pathways included rigid (n = 15), or deformable (n = 5) image registration-based 3D dose summation, visual inspection of isodose line contours (n = 1), or summation of dose metrics extracted from each course (n = 3). Largest variations were observed in near-maximum cumulative doses (25.4 - 41.8 Gy for HN, 2.4 - 33.8 Gy for lung OARs), with lower variations in volume/dose metrics to large organs. A standardised process involving spatial mapping of the first course dose to the second course CT followed by summation improved consistency for most near-maximum dose metrics in both cases. CONCLUSION: Large variations highlight the uncertainty in reporting cumulative doses in reirradiation scenarios, with implications for outcome analysis and understanding of published doses. Using a standardised workflow potentially including spatially mapped doses improves consistency in determination of accumulated dose in reirradiation scenarios.

The effect of age in breast conserving therapy: a retrospective analysis on pathology and clinical outcome data.

BACKGROUND AND PROPOSE: Age is an important prognostic marker of patient outcome after breast conserving therapy; however, it is not clear how age affects the outcome. This study aimed to explore the relationship between age with the cell quantity and the radiosensitivity of microscopic disease (MSD) in relation to treatment outcome. MATERIALS AND METHODS: We employed a treatment simulation framework which contains mathematic models for describing the load and spread of MSD based on a retrospective cohort of breast pathology specimens, a surgery simulation model for estimating the remaining MSD quantity and a tumor control probability model for predicting the risk of local recurrence following radiotherapy. RESULTS: The average MSD cell quantities around the primary tumor in younger (age⩽50years) and older patients were estimated at 1.9∗10(8)cells and 8.4∗10(7)cells, respectively (P<0.01). Following surgical simulation, these numbers decreased to 2.0∗10(7)cells and 1.3∗10(7)cells (P<0.01). Younger patients had smaller average surgical resection volume (118.9cm(3)) than older patients (162.9cm(3), P<0.01) but larger estimated radiosensitivity of MSD cells (0.111Gy(-1) versus 0.071Gy(-1), P<0.01). CONCLUSION: The higher local recurrence rate in younger patients could be explained by larger clonogenic microscopic disease cell quantity, even though the microscopic disease cells were found to be more radiosensitive.

A simulation framework for modeling tumor control probability in breast conserving therapy.

BACKGROUND AND PURPOSE: Microscopic disease (MSD) left after tumorectomy is a major cause of local recurrence in breast conserving therapy (BCT). However, the effect of microscopic disease and RT dose on tumor control probability (TCP) was seldom studied quantitatively. A simulation framework was therefore constructed to explore the relationship between tumor load, radiation dose and TCP. MATERIALS AND METHODS: First, we modeled total disease load and microscopic spread with a pathology dataset. Then we estimated the remaining disease load after tumorectomy through surgery simulation. The Webb-Nahum TCP model was extended by clonogenic cell fraction to model the risk of local recurrence. The model parameters were estimated by fitting the simulated results to the observations in two clinical trials. RESULTS: Higher histopathology grade has a strong correlation with larger MSD cell quantity. On average 12.5% of the MSD cells remained in the patient's breast after surgery but varied considerably among patients (0-100%); illustrating the role of radiotherapy. A small clonogenic cell fraction was optimal in our model (one in every 2.7*10(6)cells). The mean radiosensitivity was estimated at 0.067Gy(-1) with standard deviation of 0.022Gy(-1). CONCLUSION: A relationship between radiation dose and TCP was established in a newly designed simulation framework with detailed disease load, surgery and radiotherapy models.

Combined recipe for clinical target volume and planning target volume margins.

PURPOSE: To develop a combined recipe for clinical target volume (CTV) and planning target volume (PTV) margins. METHODS AND MATERIALS: A widely accepted PTV margin recipe is M(geo) = aΣ(geo) + bσ(geo), with Σ(geo) and σ(geo) standard deviations (SDs) representing systematic and random geometric uncertainties, respectively. On the basis of histopathology data of breast and lung tumors, we suggest describing the distribution of microscopic islets around the gross tumor volume (GTV) by a half-Gaussian with SD Σ(micro), yielding as possible CTV margin recipe: M(micro) = ƒ(N(i)) × Σ(micro), with N(i) the average number of microscopic islets per patient. To determine ƒ(N(i)), a computer model was developed that simulated radiation therapy of a spherical GTV with isotropic distribution of microscopic disease in a large group of virtual patients. The minimal margin that yielded D(min) <95% in maximally 10% of patients was calculated for various Σ(micro) and N(i). Because Σ(micro) is independent of Σ(geo), we propose they should be added quadratically, yielding for a combined GTV-to-PTV margin recipe: M(GTV-PTV) = √{[aΣ(geo)](2) + [ƒ(N(i))Σ(micro)](2)} + bσ(geo). This was validated by the computer model through numerous simultaneous simulations of microscopic and geometric uncertainties. RESULTS: The margin factor ƒ(N(i)) in a relevant range of Σ(micro) and N(i) can be given by: ƒ(N(i)) = 1.4 + 0.8log(N(i)). Filling in the other factors found in our simulations (a = 2.1 and b = 0.8) yields for the combined recipe: M(GTV-PTV) = √({2.1Σ(geo)}(2) + {[1.4 + 0.8log(N(i))] × Σ(micro)}(2)) + 0.8σ(geo). The average margin difference between the simultaneous simulations and the above recipe was 0.2 ± 0.8 mm (1 SD). Calculating M(geo) and M(micro) separately and adding them linearly overestimated PTVs by on average 5 mm. Margin recipes based on tumor control probability (TCP) instead of D(min) criteria yielded similar results. CONCLUSIONS: A general recipe for GTV-to-PTV margins is proposed, which shows that CTV and PTV margins should be added in quadrature instead of linearly.

Impact of negative margin width on local recurrence in breast conserving therapy.

BACKGROUND AND PURPOSE: This study aims to explain the unexpected weak association between the width of the negative surgical margin and the risk of local recurrence in breast conserving therapy. MATERIALS AND METHODS: We utilized a classical tumor-control probability (TCP) model to estimate the risk of local recurrence, considering the heterogeneity of microscopic disease spread observed around the invasive index tumor in a pathology dataset (N=60). The estimated result was compared with the true risk observed in the EORTC boost-versus-no-boost trial (N=1616). RESULTS: The disease volume beyond any given distance from the edge of the index tumor varied considerably among patients. Adopting this disease volume variation in the TCP model accurately reproduced the local recurrence rate as function of surgical margin width in the boost-versus-no-boost trial (Pearson's correlation coefficients are 0.652 and 0.862, and significant at the 0.05 and 0.01 level for absence and presence of a radiation boost, respectively). CONCLUSIONS: The impact of a negative margin width on local recurrence is limited due to the large variation of microscopic disease that can reach large quantities beyond any given distance from the edge of the index tumor across the patient population of breast-conserving therapy.

The impact of microscopic disease on the tumor control probability in non-small-cell lung cancer.

PURPOSE: To indicate which clinical target volume (CTV) margin (if any) is needed for an adequate treatment of non-small-cell lung cancer (NSCLC) using either 3D conformal or stereotactic radiotherapy, taking the distribution of the microscopic disease extension (MDE) into account. METHODS AND MATERIALS: On the basis of the linear-quadratic biological model, a Monte-Carlo simulation was used to study the impact of MDE and setup deviations on the tumor control probability (TCP) after typical 3D conformal and stereotactic irradiation techniques. Setup deviations were properly accounted for in the planning target volume (PTV) margin. Previously measured distributions of MDE outside the macroscopic tumor in NSCLC patients were used. The dependence of the TCP on the CTV margins was quantified. RESULTS: The presence of MDE had a demonstratable influence on the TCP in both the 3D conformal and the stereotactic technique when no CTV margins were employed. The impact of MDE on the TCP values was greater in the 3D conformal scenario (67% TCP with MDE; 84% TCP without MDE) than for stereotactic radiotherapy (91% TCP with MDE; 100% TCP without MDE). Accordingly, an increase of the CTV margin had the greatest impact for the 3D conformal technique. Larger setup errors, with appropriate PTV margins, lead to an increase in TCP for both techniques, showing the interdependence of CTV and PTV margins. CONCLUSIONS: MDE may not always be eradicated by the beam penumbra or existing PTV margins using either 3D conformal or stereotactic radiotherapy. Nonetheless, TCP modeling indicates an overall local control rate above 90% for the stereotactic technique, while a non-zero CTV margin is recommended for better local control of MDE when using the 3D conformal technique.