... A Clinical Perspective Max Dahele, Johan Cuijpers, and Suresh Senan Contents ... M. Dahele (&... more ... A Clinical Perspective Max Dahele, Johan Cuijpers, and Suresh Senan Contents ... M. Dahele (&) 4 J. Cuijpers 4 S. Senan Department of Radiation Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands e-mail: [email protected] ...
International Journal of Radiation Oncology*Biology*Physics, 2014
Purpose/Objective(s): One major challenge in radiation therapy is to determine the appropriate pl... more Purpose/Objective(s): One major challenge in radiation therapy is to determine the appropriate planning target volume (PTV) margin. The ability to secure tumor coverage while reducing normal tissue toxicity is especially critical in treating prostate cancer in the modern dose-escalation era. The goal of this study is to develop a margin assessment and optimization method that takes into consideration the organ deformation, translation and rotation, and the coverage of CTV and the overlapping of organ at risk (OAR). Materials/Methods: We obtained daily mega-voltage computed tomography (MVCT) data from 20 prostate cancer patients who underwent definitive radiation therapy. Each patient received one planning computed tomography simulation scan (CTsim) and 30-38 MVCT. For all scans, one physician delineated the prostate, the seminal vesicles, the rectum and the bladder. Three off-line matching strategies (skin markers, bone, and soft tissue) were performed for the MVCT-CTsim registration, from which translation and rotation registration parameters were collected. After performing the match, contours were exported to Matlab for analysis. By combining contours of all fractions, a 3D probability density rendering for the four organs was produced for each patient and then merged with CTsim. Two margin recipes were created. The first was an isotropic margin with 2 to 10 mm expansion of either the prostate alone or prostate with seminal vesicles and the second was an anisotropic margin with modification of anterior and posterior borders. Finally, both margin recipes were tested for both CTV coverage and OAR overlapping percentage. Results: The mean isotropic margin to achieve 95% of CTV coverage in skin markers, bone, and soft tissue registration were 9.7, 5.9, and 5.8 mm, while the overlapping of rectum/bladder was 5.1/16.3, 5/6.8, and 3.7/7.1 % of total volume. In anisotropic margin, a reduced anterior/posterior margin of 3.9/9.6, 2.4/3.7, and 2/3.7 mm in skin markers, bone, and soft tissue registration can achieve comparable CTV coverage and better OARs sparing than the isotropic margin recipe. Conclusions: Daily 3D IGRT enable analysis of the inter-fractional change of organs in the presence of deformation, translation and rotation. Utilizing this data, we introduced a new margin recipe that optimizes both CTV coverage and OAR sparing. For the patient sample of this study, anisotropic margin with reduced anterior/posterior borders generates optimal PTV. By building a larger database using this technique, we can find a margin recipe that is most suitable for each patient type.
Oral Sessions / Radiotherapy the whole lungs volume The PTV included the GTV with a standard marg... more Oral Sessions / Radiotherapy the whole lungs volume The PTV included the GTV with a standard margin of 0.5 mm on axial plan and 10 mm on longitudinal direction. All patients were treated with 3 fractions of 15 Gy over 5 days. The dose was prescribed to the 80% isodose line and delivered with 6-8 noncoplanar static multiple fields The average Conformity Index according to RTOG definition was 0.65 (range 0 53-0 76). Dose-Volume Histograms (DVHs), TCP and NTCP (LKB model) were obtained and evaluated for each case RTOG toxicity scoring system was employed. Follow-up included CT scans after 45 days from treatment and then every 3 months, pulmonary function tests after 3 months, PET after 4 months Patients were considered in complete response (CR) if radiologlcally negative, in partial response (PR) if lesion axial diameter was reducted of at least 30%, in stable disease (SD) if no change, in progressive disease (PD) if increased of more than 20% Patients with radlologically evaluable lesions but with negative PET findings were also considered in CR Results: 17 out of 20 patients with primary neoplasms and 12 patients with 13 metastatic tumors were considered for analysis Three patients were excluded due to limited follow up. Median follow up time was 9.5 months (range 1.5-19). Treatment was feasible in all patients regardless the site of lesions (peripheral or central) Two patients experienced grade II subacute radiation pneumonitis, requiring steroid treatment. One was treated for 2 lesions on the same lobe, in the other one a concomitant infection was diagnosed. Local control patients was 94.05% (4 CR, 8 PR, 4 SD) in the 17 NSCLC and 100% (6 CR, 2 PR, 5 SD) in 13 metastlc tumors. Conclusions: Stereotactic radiotherapy for limited-stage primary and metastatic lung cancer is a feasible, safe and effective procedure. It promises high local control rates with a very low toxicity profile.
International Journal of Radiation Oncology Biology Physics, 2014
From 118 and 111 patients receiving conventional and hypofractionated radiation therapy (RT) at 3... more From 118 and 111 patients receiving conventional and hypofractionated radiation therapy (RT) at 3 institutions, the pre-RT and post-RT computed tomographic scans were registered to each other and to the 3-dimensional dose distributions to quantify dosedependent changes in normal lung tissue density. The frequency of changes greater than Hounsfield units (80 HU) was modeled by use of a Probit model and compared Purpose: To quantitatively assess changes in computed tomography (CT)edefined normal lung tissue density after conventional and hypofractionated radiation therapy (RT). Methods and Materials: The pre-RT and post-RT CT scans from 118 and 111 patients receiving conventional and hypofractionated RT, respectively, at 3 institutions were registered to each other and to the 3-dimensional dose distribution to quantify dose-dependent changes in normal lung tissue density. Dose-response curves (DRC) for groups of patients receiving conventional and hypofractionated RT were generated for each institution, and the frequency of density changes >80 Hounsfield Units (HU) was modeled depending on the fractionation type using a Probit model for different follow-up times. Results: For the pooled data from all institutions, there were significant differences in the DRC between the conventional and hypofractionated groups; the respective doses resulting in 50% complication risk (TD 50) were 62 Gy (95% confidence interval [CI] 57-67) versus 36 Gy (CI 33-39) at <6 months, 48 Gy (CI 46-51) versus 31 Gy (CI 28-33) at 6-12 months, and 47 Gy (CI 45-49) versus 35 Gy (32-37) at >12 months. The corresponding m values (slope of the DRC) were 0.52 (CI 0.46-0.59) versus 0.31 (CI 0.28-0.34) at <6 months, 0.46 (CI 0.42-0.51) versus 0.30 (CI 0.26-0.34) at 6-12 months, and 0.45 (CI 0.42-0.50) versus 0.31 (CI 0.27-0.35) at >12 months (P<.05 for all comparisons).
The toxicity of endobronchial brachytherapy (EB), in particular fatal haemoptysis and bronchial w... more The toxicity of endobronchial brachytherapy (EB), in particular fatal haemoptysis and bronchial wall necrosis, has been correlated with the total dose, fraction size, volume encompassed by the 100% isodose, and a proximal tumor location. We describe a CT-based planning method which, by improving target volume definition and volumetric dose information, can improve the therapeutic ratio of EB. Sixteen CT-assisted EB procedures were performed in patients who were treated with palliative high-dose rate EB. The CT data were used to analyze applicator position in relation to anatomy. An example of a three-dimensional optimized treatment plan was generated and analyzed using different types of dose-volume histograms. The procedure was well tolerated by patients and no post-procedure complications were observed. The bronchial applicator was eccentrically positioned at the level of the carina/mainstem bronchus in 12 (of 14) CT scans. A planning CT prior to EB was not found to be useful as the final target volume and/or the final applicator position were not reliably predicted before the therapeutic bronchoscopy. CT-scans performed with the applicator in situ allowed the bronchial segments in the target volume to be identified and enabled dose prescription to the bronchial mucosa. CT-assisted EB is feasible and underlines the need for using centered applicators for proximally located tumors. By enabling accurate mucosal dose prescription, CT-assisted EB may reduce the toxicity of fractionated EB in the curative setting. However, faster on-line EB treatment planning is needed for the routine clinical application of this technique.
Poster Discussions/Non-small cell lung cancer-Early disease (I-IliA) 68 5% of patients respective... more Poster Discussions/Non-small cell lung cancer-Early disease (I-IliA) 68 5% of patients respectively Using mul~variate Coo propert]onal hazards analysis, increes4ng tumour Islet macrophage density (p < 0 001) and tumour isiet/st]-omal macrephage rafio (p < 0 001)om erged as favourable Independent prognostic indicators. In contrast, increasing StTomal macrophage density was an independent predictor of reduced survlval (p 0 001) The presence of tumour islet mast cells (p-0.018) end increasing isietist]omal mast cell ratio (,o-0.032) wore also favourable independent prognce~c indicators Macrophage islet density showed the strongest effect: 5-year sun/lval was 52 99{. with an islet macrephage dens4ty >median versus 7 7% when <median (p <0 0001) In the same groups respoctN'ely, median survival was 2244 versus 334 days (p<00001) Pa'dents with a high islet macraphage density but incomplete rooectlen survived markedly longer than pafients with a low Islet macrophage density but complete resection. Conclusions: The tumeur islet CD68 + macrophage density Is a powerful pro dictor of survrval from surgically resected NSCLC. The biological ~0(plenation for this and its implications for the use of adjunclJve b-eatment requires further study. ~ Initial results of pro-operative pulmonary function testing in patients with stage I-II Non-Small Cell Lung Cancer (NSCLC) b'eated with naoadjuvant chemotherapy with gern citabine-containin g regimens
suggest this intriguing approach may be a reality in the near future (24-26). Finally, all therap... more suggest this intriguing approach may be a reality in the near future (24-26). Finally, all therapy in the setting of metastatic disease is ultimately palliative. Consequently treatment decisions should be tempered by this sobering reality.
International Journal of Radiation Oncology*Biology*Physics, 2012
Conclusions: SBRT offers inferior overall survival but similar causespecific survival and local f... more Conclusions: SBRT offers inferior overall survival but similar causespecific survival and local failure rates compared to that of surgery in patients with stage I NSCLC. Randomized trial is needed to compare the efficacy of SBRT and surgery.
International Journal of Radiation Oncology*Biology*Physics, 2009
Erlotinib has shown activity in patients with brain metastases from non-small-cell lung cancer. T... more Erlotinib has shown activity in patients with brain metastases from non-small-cell lung cancer. The present dose-escalation Phase I trial evaluated the toxicity of whole brain radiotherapy (WBRT) with concurrent and maintenance erlotinib in this patient group. Erlotinib (Cohort 1, 100 mg/d; Cohort 2, 150 mg/d) was started 1 week before, and continued during, WBRT (30 Gy in 10 fractions). Maintenance erlotinib (150 mg/d) was continued until unacceptable toxicity or disease progression. A total of 11 patients completed WBRT, 4 in Cohort 1 and 7 in Cohort 2. The median duration of erlotinib treatment was 83 days. No treatment-related neurotoxicity was observed. No treatment-related Grade 3 or greater toxicity occurred in Cohort 1. In Cohort 2, 1 patient developed a Grade 3 acneiform rash and 1 patient had Grade 3 fatigue. Two patients in Cohort 2 developed erlotinib-related interstitial lung disease, contributing to death during maintenance therapy. The median overall survival and interval to progression was 133 and 141 days, respectively. Six patients developed extracranial progression; only 1 patient had intracranial progression. In 7 patients with follow-up neuroimaging at 3 months, 5 had a partial response and 2 had stable disease. WBRT with concurrent erlotinib is well tolerated in patients with brain metastases from non-small-cell lung cancer. The suggestion of a high intracranial disease control rate warrants additional study.
International Journal of Radiation Oncology*Biology*Physics, 2011
Volumetric modulated arc therapy (RapidArc; Varian Medical Systems, Palo Alto, CA) allows fast de... more Volumetric modulated arc therapy (RapidArc; Varian Medical Systems, Palo Alto, CA) allows fast delivery of stereotactic radiotherapy for Stage I lung tumors. We investigated discrepancies between the calculated and delivered dose distributions, as well as the dosimetric impact of leaf interplay with breathing-induced tumor motion. In 20 consecutive patients with Stage I lung cancer who completed RapidArc delivery, 15 had tumor motion exceeding 5 mm on four-dimensional computed tomography scan. Static and dynamic measurements were performed with Gafchromic EBT film (International Specialty Products Inc., Wayne, NJ) in a Quasar motion phantom (Modus Medical Devices, London, Ontario, Canada). Static measurements were compared with calculated dose distributions, and dynamic measurements were compared with the convolution of static measurements with sinusoidal motion patterns. Besides clinical treatment plans, additional cases were optimized to create excessive multileaf collimator modulation and delivered on the phantom with peak-to-peak motions of up to 25 mm. γ Analysis with a 3% dose difference and 2- or 1-mm distance to agreement was used to evaluate the accuracy of delivery and the dosimetric impact of the interplay effect. In static mode film dosimetry of the two-arc delivery in the phantom showed that, on average, fewer than 3% of measurements had γ greater than 1. Dynamic measurements of clinical plans showed a high degree of agreement with the convolutions: for double-arc plans, 99.5% met the γ criterion. The degree of agreement was 98.5% for the plans with excessive multileaf collimator modulations and 25 mm of motion. Film dosimetry shows that RapidArc accurately delivers the calculated dose distribution and that interplay between leaves and tumor motion is not significant for single-fraction treatments when RapidArc is delivered with two different arcs.
International Journal of Radiation Oncology*Biology*Physics, 2007
Purpose: Changes in position or size of target volumes have been observed during radiotherapy for... more Purpose: Changes in position or size of target volumes have been observed during radiotherapy for lung cancer. The need for adaptive treatment planning during stereotactic radiotherapy of Stage I tumors was retrospectively analyzed using repeat four-dimensional computed tomography (4DCT) scans. Methods and Materials: A planning study was performed for 60 tumors in 59 patients using 4DCT scans repeated after two or more treatment fractions. Planning target volumes (PTV) encompassed all tumor mobility, and dose distributions from the initial plan were projected onto PTVs derived from the repeat 4DCT. A dosimetric and volumetric analysis was performed. Results: The repeat 4DCT scans were performed at a mean of 6.6 days (range, 2-12 days) after the first fraction of stereotactic radiotherapy. In 25% of cases the repeat PTV was larger, but the difference exceeded 1 mL in 5 patients only. The mean 3D displacement between the center of mass of both PTVs was 2.0 mm. The initial 80% prescription isodose ensured a mean coverage of 98% of repeat PTVs, and this isodose fully encompassed the repeat internal target volumes in all but 1 tumor. "Inadequate" coverage in the latter was caused by a new area of atelectasis adjacent to the tumor on the repeat 4DCT. Conclusions: Limited "time trends" were observed in PTVs generated by repeated uncoached 4DCT scans, and the dosimetric consequences proved to be minimal. Treatment based only on the initial PTV would not have resulted in major tumor underdosage, indicating that adaptive treatment planning is of limited value for fractionated stereotactic radiotherapy.
International Journal of Radiation Oncology*Biology*Physics, 2005
Single four-dimensional CT (4DCT) scans reliably capture intrafractional tumor mobility for radio... more Single four-dimensional CT (4DCT) scans reliably capture intrafractional tumor mobility for radiotherapy planning, but generating internal target volumes (ITVs) requires the contouring of gross tumor volumes (GTVs) in up to 10 phases of a 4DCT scan, as is routinely performed in our department. We investigated the use of maximum intensity projection (MIP) protocols for rapid generation of ITVs. 4DCT data from a mobile phantom and from 12 patients with Stage I lung cancer were analyzed. A single clinician contoured GTVs in all respiratory phases of a 4DCT, as well as in three consecutive phases selected for respiratory gating. MIP images were generated from both phantom and patient data, and ITVs were derived from encompassing volumes of the respective GTVs. In the phantom study, the ratio between ITVs generated from all 10 phases and those from MIP scans was 1.04. The corresponding center of mass of both ITVs differed by less than 1 mm. In scans from patients, good agreement was observed between ITVs derived from 10 and 3 (gating) phases and corresponding MIPs, with ratios of 1.07 +/- 0.05 and 0.98 +/- 0.05, respectively. In addition, the center of mass of the respective ITVs differed by only 0.4 and 0.5 mm. MIPs are a reliable clinical tool for generating ITVs from 4DCT data sets, thereby permitting rapid assessment of mobility for both gated and nongated 4D radiotherapy in lung cancer.
International Journal of Radiation Oncology*Biology*Physics, 2012
Background and purpose: Stereotactic ablative radiotherapy (SABR) has improved the survival for m... more Background and purpose: Stereotactic ablative radiotherapy (SABR) has improved the survival for medically inoperable patients with peripheral early-stage non-small cell lung cancer (NSCLC). We performed a systematic review of outcomes for central lung tumours. Material and methods: The systematic review was performed following PRISMA guidelines. Survival outcomes were evaluated for central early-stage NSCLC. Local control and toxicity outcomes were evaluated for any centrally-located lung tumour. Results: Twenty publications met the inclusion criteria, reporting outcomes for 563 central lung tumours, including 315 patients with early-stage NSCLC. There was heterogeneity in the planning, prescribing and delivery of SABR and the common toxicity criteria used to define toxicities (versions 2.0-4.0). Tumour location (central versus peripheral) did not impact overall survival. Local control rates were P85% when the prescribed biologically equivalent tumour dose was P100 Gy. Treatment-related mortality was 2.7% overall, and 1.0% when the biologically equivalent normal tissue dose was 6210 Gy. Grade 3 or 4 toxicities may be more common following SABR for central tumours, but occurred in less than 9% of patients. Conclusions: Post-SABR survival for early-stage NSCLC is not affected by tumour location. SABR achieves high local control with limited toxicity when appropriate fractionation schedules are used for central tumours.
International Journal of Radiation Oncology*Biology*Physics, 2008
Purpose: Respiration-induced organ motion is a major source of positional, or geometric, uncertai... more Purpose: Respiration-induced organ motion is a major source of positional, or geometric, uncertainty in thoracic radiotherapy. Interventions to mitigate the impact of motion include audio-coached respiration-gated radiotherapy (RGRT). To assess the impact of coaching on average tumor position during gating, we analyzed fourdimensional computed tomography (4DCT) scans performed both with and without audio-coaching. Methods and Materials: Our RGRT protocol requires that an audio-coached 4DCT scan is performed when the initial free-breathing 4DCT indicates a potential benefit with gating. We retrospectively analyzed 22 such paired scans in patients with well-circumscribed tumors. Changes in lung volume and position of internal target volumes (ITV) generated in three consecutive respiratory phases at both end-inspiration and end-expiration were analyzed. Results: Audio-coaching increased end-inspiration lung volumes by a mean of 10.2% (range, À13% to +43%) when compared with free breathing (p = 0.001). The mean three-dimensional displacement of the center of ITV was 3.6 mm (SD, 2.5; range, 0.3-9.6mm), mainly caused by displacement in the craniocaudal direction. Displacement of ITV caused by coaching was more than 5 mm in 5 patients, all of whom were in the subgroup of 9 patients showing total tumor motion of 10 mm or more during both coached and uncoached breathing. Comparable ITV displacements were observed at end-expiration phases of the 4DCT. Conclusions: Differences in ITV position exceeding 5 mm between coached and uncoached 4DCT scans were detected in up to 56% of mobile tumors. Both end-inspiration and end-expiration RGRT were susceptible to displacements. This indicates that the method of audio-coaching should remain unchanged throughout the course of treatment.
... A Clinical Perspective Max Dahele, Johan Cuijpers, and Suresh Senan Contents ... M. Dahele (&... more ... A Clinical Perspective Max Dahele, Johan Cuijpers, and Suresh Senan Contents ... M. Dahele (&amp;) 4 J. Cuijpers 4 S. Senan Department of Radiation Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands e-mail: [email protected] ...
International Journal of Radiation Oncology*Biology*Physics, 2014
Purpose/Objective(s): One major challenge in radiation therapy is to determine the appropriate pl... more Purpose/Objective(s): One major challenge in radiation therapy is to determine the appropriate planning target volume (PTV) margin. The ability to secure tumor coverage while reducing normal tissue toxicity is especially critical in treating prostate cancer in the modern dose-escalation era. The goal of this study is to develop a margin assessment and optimization method that takes into consideration the organ deformation, translation and rotation, and the coverage of CTV and the overlapping of organ at risk (OAR). Materials/Methods: We obtained daily mega-voltage computed tomography (MVCT) data from 20 prostate cancer patients who underwent definitive radiation therapy. Each patient received one planning computed tomography simulation scan (CTsim) and 30-38 MVCT. For all scans, one physician delineated the prostate, the seminal vesicles, the rectum and the bladder. Three off-line matching strategies (skin markers, bone, and soft tissue) were performed for the MVCT-CTsim registration, from which translation and rotation registration parameters were collected. After performing the match, contours were exported to Matlab for analysis. By combining contours of all fractions, a 3D probability density rendering for the four organs was produced for each patient and then merged with CTsim. Two margin recipes were created. The first was an isotropic margin with 2 to 10 mm expansion of either the prostate alone or prostate with seminal vesicles and the second was an anisotropic margin with modification of anterior and posterior borders. Finally, both margin recipes were tested for both CTV coverage and OAR overlapping percentage. Results: The mean isotropic margin to achieve 95% of CTV coverage in skin markers, bone, and soft tissue registration were 9.7, 5.9, and 5.8 mm, while the overlapping of rectum/bladder was 5.1/16.3, 5/6.8, and 3.7/7.1 % of total volume. In anisotropic margin, a reduced anterior/posterior margin of 3.9/9.6, 2.4/3.7, and 2/3.7 mm in skin markers, bone, and soft tissue registration can achieve comparable CTV coverage and better OARs sparing than the isotropic margin recipe. Conclusions: Daily 3D IGRT enable analysis of the inter-fractional change of organs in the presence of deformation, translation and rotation. Utilizing this data, we introduced a new margin recipe that optimizes both CTV coverage and OAR sparing. For the patient sample of this study, anisotropic margin with reduced anterior/posterior borders generates optimal PTV. By building a larger database using this technique, we can find a margin recipe that is most suitable for each patient type.
Oral Sessions / Radiotherapy the whole lungs volume The PTV included the GTV with a standard marg... more Oral Sessions / Radiotherapy the whole lungs volume The PTV included the GTV with a standard margin of 0.5 mm on axial plan and 10 mm on longitudinal direction. All patients were treated with 3 fractions of 15 Gy over 5 days. The dose was prescribed to the 80% isodose line and delivered with 6-8 noncoplanar static multiple fields The average Conformity Index according to RTOG definition was 0.65 (range 0 53-0 76). Dose-Volume Histograms (DVHs), TCP and NTCP (LKB model) were obtained and evaluated for each case RTOG toxicity scoring system was employed. Follow-up included CT scans after 45 days from treatment and then every 3 months, pulmonary function tests after 3 months, PET after 4 months Patients were considered in complete response (CR) if radiologlcally negative, in partial response (PR) if lesion axial diameter was reducted of at least 30%, in stable disease (SD) if no change, in progressive disease (PD) if increased of more than 20% Patients with radlologically evaluable lesions but with negative PET findings were also considered in CR Results: 17 out of 20 patients with primary neoplasms and 12 patients with 13 metastatic tumors were considered for analysis Three patients were excluded due to limited follow up. Median follow up time was 9.5 months (range 1.5-19). Treatment was feasible in all patients regardless the site of lesions (peripheral or central) Two patients experienced grade II subacute radiation pneumonitis, requiring steroid treatment. One was treated for 2 lesions on the same lobe, in the other one a concomitant infection was diagnosed. Local control patients was 94.05% (4 CR, 8 PR, 4 SD) in the 17 NSCLC and 100% (6 CR, 2 PR, 5 SD) in 13 metastlc tumors. Conclusions: Stereotactic radiotherapy for limited-stage primary and metastatic lung cancer is a feasible, safe and effective procedure. It promises high local control rates with a very low toxicity profile.
International Journal of Radiation Oncology Biology Physics, 2014
From 118 and 111 patients receiving conventional and hypofractionated radiation therapy (RT) at 3... more From 118 and 111 patients receiving conventional and hypofractionated radiation therapy (RT) at 3 institutions, the pre-RT and post-RT computed tomographic scans were registered to each other and to the 3-dimensional dose distributions to quantify dosedependent changes in normal lung tissue density. The frequency of changes greater than Hounsfield units (80 HU) was modeled by use of a Probit model and compared Purpose: To quantitatively assess changes in computed tomography (CT)edefined normal lung tissue density after conventional and hypofractionated radiation therapy (RT). Methods and Materials: The pre-RT and post-RT CT scans from 118 and 111 patients receiving conventional and hypofractionated RT, respectively, at 3 institutions were registered to each other and to the 3-dimensional dose distribution to quantify dose-dependent changes in normal lung tissue density. Dose-response curves (DRC) for groups of patients receiving conventional and hypofractionated RT were generated for each institution, and the frequency of density changes >80 Hounsfield Units (HU) was modeled depending on the fractionation type using a Probit model for different follow-up times. Results: For the pooled data from all institutions, there were significant differences in the DRC between the conventional and hypofractionated groups; the respective doses resulting in 50% complication risk (TD 50) were 62 Gy (95% confidence interval [CI] 57-67) versus 36 Gy (CI 33-39) at <6 months, 48 Gy (CI 46-51) versus 31 Gy (CI 28-33) at 6-12 months, and 47 Gy (CI 45-49) versus 35 Gy (32-37) at >12 months. The corresponding m values (slope of the DRC) were 0.52 (CI 0.46-0.59) versus 0.31 (CI 0.28-0.34) at <6 months, 0.46 (CI 0.42-0.51) versus 0.30 (CI 0.26-0.34) at 6-12 months, and 0.45 (CI 0.42-0.50) versus 0.31 (CI 0.27-0.35) at >12 months (P<.05 for all comparisons).
The toxicity of endobronchial brachytherapy (EB), in particular fatal haemoptysis and bronchial w... more The toxicity of endobronchial brachytherapy (EB), in particular fatal haemoptysis and bronchial wall necrosis, has been correlated with the total dose, fraction size, volume encompassed by the 100% isodose, and a proximal tumor location. We describe a CT-based planning method which, by improving target volume definition and volumetric dose information, can improve the therapeutic ratio of EB. Sixteen CT-assisted EB procedures were performed in patients who were treated with palliative high-dose rate EB. The CT data were used to analyze applicator position in relation to anatomy. An example of a three-dimensional optimized treatment plan was generated and analyzed using different types of dose-volume histograms. The procedure was well tolerated by patients and no post-procedure complications were observed. The bronchial applicator was eccentrically positioned at the level of the carina/mainstem bronchus in 12 (of 14) CT scans. A planning CT prior to EB was not found to be useful as the final target volume and/or the final applicator position were not reliably predicted before the therapeutic bronchoscopy. CT-scans performed with the applicator in situ allowed the bronchial segments in the target volume to be identified and enabled dose prescription to the bronchial mucosa. CT-assisted EB is feasible and underlines the need for using centered applicators for proximally located tumors. By enabling accurate mucosal dose prescription, CT-assisted EB may reduce the toxicity of fractionated EB in the curative setting. However, faster on-line EB treatment planning is needed for the routine clinical application of this technique.
Poster Discussions/Non-small cell lung cancer-Early disease (I-IliA) 68 5% of patients respective... more Poster Discussions/Non-small cell lung cancer-Early disease (I-IliA) 68 5% of patients respectively Using mul~variate Coo propert]onal hazards analysis, increes4ng tumour Islet macrophage density (p < 0 001) and tumour isiet/st]-omal macrephage rafio (p < 0 001)om erged as favourable Independent prognostic indicators. In contrast, increasing StTomal macrophage density was an independent predictor of reduced survlval (p 0 001) The presence of tumour islet mast cells (p-0.018) end increasing isietist]omal mast cell ratio (,o-0.032) wore also favourable independent prognce~c indicators Macrophage islet density showed the strongest effect: 5-year sun/lval was 52 99{. with an islet macrephage dens4ty >median versus 7 7% when <median (p <0 0001) In the same groups respoctN'ely, median survival was 2244 versus 334 days (p<00001) Pa'dents with a high islet macraphage density but incomplete rooectlen survived markedly longer than pafients with a low Islet macrophage density but complete resection. Conclusions: The tumeur islet CD68 + macrophage density Is a powerful pro dictor of survrval from surgically resected NSCLC. The biological ~0(plenation for this and its implications for the use of adjunclJve b-eatment requires further study. ~ Initial results of pro-operative pulmonary function testing in patients with stage I-II Non-Small Cell Lung Cancer (NSCLC) b'eated with naoadjuvant chemotherapy with gern citabine-containin g regimens
suggest this intriguing approach may be a reality in the near future (24-26). Finally, all therap... more suggest this intriguing approach may be a reality in the near future (24-26). Finally, all therapy in the setting of metastatic disease is ultimately palliative. Consequently treatment decisions should be tempered by this sobering reality.
International Journal of Radiation Oncology*Biology*Physics, 2012
Conclusions: SBRT offers inferior overall survival but similar causespecific survival and local f... more Conclusions: SBRT offers inferior overall survival but similar causespecific survival and local failure rates compared to that of surgery in patients with stage I NSCLC. Randomized trial is needed to compare the efficacy of SBRT and surgery.
International Journal of Radiation Oncology*Biology*Physics, 2009
Erlotinib has shown activity in patients with brain metastases from non-small-cell lung cancer. T... more Erlotinib has shown activity in patients with brain metastases from non-small-cell lung cancer. The present dose-escalation Phase I trial evaluated the toxicity of whole brain radiotherapy (WBRT) with concurrent and maintenance erlotinib in this patient group. Erlotinib (Cohort 1, 100 mg/d; Cohort 2, 150 mg/d) was started 1 week before, and continued during, WBRT (30 Gy in 10 fractions). Maintenance erlotinib (150 mg/d) was continued until unacceptable toxicity or disease progression. A total of 11 patients completed WBRT, 4 in Cohort 1 and 7 in Cohort 2. The median duration of erlotinib treatment was 83 days. No treatment-related neurotoxicity was observed. No treatment-related Grade 3 or greater toxicity occurred in Cohort 1. In Cohort 2, 1 patient developed a Grade 3 acneiform rash and 1 patient had Grade 3 fatigue. Two patients in Cohort 2 developed erlotinib-related interstitial lung disease, contributing to death during maintenance therapy. The median overall survival and interval to progression was 133 and 141 days, respectively. Six patients developed extracranial progression; only 1 patient had intracranial progression. In 7 patients with follow-up neuroimaging at 3 months, 5 had a partial response and 2 had stable disease. WBRT with concurrent erlotinib is well tolerated in patients with brain metastases from non-small-cell lung cancer. The suggestion of a high intracranial disease control rate warrants additional study.
International Journal of Radiation Oncology*Biology*Physics, 2011
Volumetric modulated arc therapy (RapidArc; Varian Medical Systems, Palo Alto, CA) allows fast de... more Volumetric modulated arc therapy (RapidArc; Varian Medical Systems, Palo Alto, CA) allows fast delivery of stereotactic radiotherapy for Stage I lung tumors. We investigated discrepancies between the calculated and delivered dose distributions, as well as the dosimetric impact of leaf interplay with breathing-induced tumor motion. In 20 consecutive patients with Stage I lung cancer who completed RapidArc delivery, 15 had tumor motion exceeding 5 mm on four-dimensional computed tomography scan. Static and dynamic measurements were performed with Gafchromic EBT film (International Specialty Products Inc., Wayne, NJ) in a Quasar motion phantom (Modus Medical Devices, London, Ontario, Canada). Static measurements were compared with calculated dose distributions, and dynamic measurements were compared with the convolution of static measurements with sinusoidal motion patterns. Besides clinical treatment plans, additional cases were optimized to create excessive multileaf collimator modulation and delivered on the phantom with peak-to-peak motions of up to 25 mm. γ Analysis with a 3% dose difference and 2- or 1-mm distance to agreement was used to evaluate the accuracy of delivery and the dosimetric impact of the interplay effect. In static mode film dosimetry of the two-arc delivery in the phantom showed that, on average, fewer than 3% of measurements had γ greater than 1. Dynamic measurements of clinical plans showed a high degree of agreement with the convolutions: for double-arc plans, 99.5% met the γ criterion. The degree of agreement was 98.5% for the plans with excessive multileaf collimator modulations and 25 mm of motion. Film dosimetry shows that RapidArc accurately delivers the calculated dose distribution and that interplay between leaves and tumor motion is not significant for single-fraction treatments when RapidArc is delivered with two different arcs.
International Journal of Radiation Oncology*Biology*Physics, 2007
Purpose: Changes in position or size of target volumes have been observed during radiotherapy for... more Purpose: Changes in position or size of target volumes have been observed during radiotherapy for lung cancer. The need for adaptive treatment planning during stereotactic radiotherapy of Stage I tumors was retrospectively analyzed using repeat four-dimensional computed tomography (4DCT) scans. Methods and Materials: A planning study was performed for 60 tumors in 59 patients using 4DCT scans repeated after two or more treatment fractions. Planning target volumes (PTV) encompassed all tumor mobility, and dose distributions from the initial plan were projected onto PTVs derived from the repeat 4DCT. A dosimetric and volumetric analysis was performed. Results: The repeat 4DCT scans were performed at a mean of 6.6 days (range, 2-12 days) after the first fraction of stereotactic radiotherapy. In 25% of cases the repeat PTV was larger, but the difference exceeded 1 mL in 5 patients only. The mean 3D displacement between the center of mass of both PTVs was 2.0 mm. The initial 80% prescription isodose ensured a mean coverage of 98% of repeat PTVs, and this isodose fully encompassed the repeat internal target volumes in all but 1 tumor. "Inadequate" coverage in the latter was caused by a new area of atelectasis adjacent to the tumor on the repeat 4DCT. Conclusions: Limited "time trends" were observed in PTVs generated by repeated uncoached 4DCT scans, and the dosimetric consequences proved to be minimal. Treatment based only on the initial PTV would not have resulted in major tumor underdosage, indicating that adaptive treatment planning is of limited value for fractionated stereotactic radiotherapy.
International Journal of Radiation Oncology*Biology*Physics, 2005
Single four-dimensional CT (4DCT) scans reliably capture intrafractional tumor mobility for radio... more Single four-dimensional CT (4DCT) scans reliably capture intrafractional tumor mobility for radiotherapy planning, but generating internal target volumes (ITVs) requires the contouring of gross tumor volumes (GTVs) in up to 10 phases of a 4DCT scan, as is routinely performed in our department. We investigated the use of maximum intensity projection (MIP) protocols for rapid generation of ITVs. 4DCT data from a mobile phantom and from 12 patients with Stage I lung cancer were analyzed. A single clinician contoured GTVs in all respiratory phases of a 4DCT, as well as in three consecutive phases selected for respiratory gating. MIP images were generated from both phantom and patient data, and ITVs were derived from encompassing volumes of the respective GTVs. In the phantom study, the ratio between ITVs generated from all 10 phases and those from MIP scans was 1.04. The corresponding center of mass of both ITVs differed by less than 1 mm. In scans from patients, good agreement was observed between ITVs derived from 10 and 3 (gating) phases and corresponding MIPs, with ratios of 1.07 +/- 0.05 and 0.98 +/- 0.05, respectively. In addition, the center of mass of the respective ITVs differed by only 0.4 and 0.5 mm. MIPs are a reliable clinical tool for generating ITVs from 4DCT data sets, thereby permitting rapid assessment of mobility for both gated and nongated 4D radiotherapy in lung cancer.
International Journal of Radiation Oncology*Biology*Physics, 2012
Background and purpose: Stereotactic ablative radiotherapy (SABR) has improved the survival for m... more Background and purpose: Stereotactic ablative radiotherapy (SABR) has improved the survival for medically inoperable patients with peripheral early-stage non-small cell lung cancer (NSCLC). We performed a systematic review of outcomes for central lung tumours. Material and methods: The systematic review was performed following PRISMA guidelines. Survival outcomes were evaluated for central early-stage NSCLC. Local control and toxicity outcomes were evaluated for any centrally-located lung tumour. Results: Twenty publications met the inclusion criteria, reporting outcomes for 563 central lung tumours, including 315 patients with early-stage NSCLC. There was heterogeneity in the planning, prescribing and delivery of SABR and the common toxicity criteria used to define toxicities (versions 2.0-4.0). Tumour location (central versus peripheral) did not impact overall survival. Local control rates were P85% when the prescribed biologically equivalent tumour dose was P100 Gy. Treatment-related mortality was 2.7% overall, and 1.0% when the biologically equivalent normal tissue dose was 6210 Gy. Grade 3 or 4 toxicities may be more common following SABR for central tumours, but occurred in less than 9% of patients. Conclusions: Post-SABR survival for early-stage NSCLC is not affected by tumour location. SABR achieves high local control with limited toxicity when appropriate fractionation schedules are used for central tumours.
International Journal of Radiation Oncology*Biology*Physics, 2008
Purpose: Respiration-induced organ motion is a major source of positional, or geometric, uncertai... more Purpose: Respiration-induced organ motion is a major source of positional, or geometric, uncertainty in thoracic radiotherapy. Interventions to mitigate the impact of motion include audio-coached respiration-gated radiotherapy (RGRT). To assess the impact of coaching on average tumor position during gating, we analyzed fourdimensional computed tomography (4DCT) scans performed both with and without audio-coaching. Methods and Materials: Our RGRT protocol requires that an audio-coached 4DCT scan is performed when the initial free-breathing 4DCT indicates a potential benefit with gating. We retrospectively analyzed 22 such paired scans in patients with well-circumscribed tumors. Changes in lung volume and position of internal target volumes (ITV) generated in three consecutive respiratory phases at both end-inspiration and end-expiration were analyzed. Results: Audio-coaching increased end-inspiration lung volumes by a mean of 10.2% (range, À13% to +43%) when compared with free breathing (p = 0.001). The mean three-dimensional displacement of the center of ITV was 3.6 mm (SD, 2.5; range, 0.3-9.6mm), mainly caused by displacement in the craniocaudal direction. Displacement of ITV caused by coaching was more than 5 mm in 5 patients, all of whom were in the subgroup of 9 patients showing total tumor motion of 10 mm or more during both coached and uncoached breathing. Comparable ITV displacements were observed at end-expiration phases of the 4DCT. Conclusions: Differences in ITV position exceeding 5 mm between coached and uncoached 4DCT scans were detected in up to 56% of mobile tumors. Both end-inspiration and end-expiration RGRT were susceptible to displacements. This indicates that the method of audio-coaching should remain unchanged throughout the course of treatment.
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Papers by Senan Senan