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Title: Stochastic Predictions of Cell Kill During Stereotactic Ablative Radiation Therapy: Do Hypoxia and Reoxygenation Really Matter?

Abstract

Purpose: To simulate stereotactic ablative radiation therapy on hypoxic and well-oxygenated in silico tumors, incorporating probabilistic parameter distributions and linear-quadratic versus linear-quadratic-cubic methodology and the evaluation of optimal fractionation schemes using biological effective dose (BED{sub α/β=10} {sub or} {sub 3}) comparisons. Methods and Materials: A temporal tumor growth and radiation therapy algorithm simulated high-dose external beam radiation therapy using stochastic methods. Realistic biological proliferative cellular hierarchy and pO{sub 2} histograms were incorporated into the 10{sup 8}-cell tumor model, with randomized radiation therapy applied during continual cell proliferation and volume-based gradual tumor reoxygenation. Dose fractions ranged from 6-35 Gy, with predictive outcomes presented in terms of the total doses (converted to BED) required to eliminate all cells that could potentially regenerate the tumor. Results: Well-oxygenated tumor control BED{sub 10} outcomes were not significantly different for high-dose versus conventional radiation therapy (BED{sub 10}: 79-84 Gy; Equivalent Dose in 2 Gy fractions with α/β of 10: 66-70 Gy); however, total treatment times decreased from 7 down to 1-3 weeks. For hypoxic tumors, an additional 28 Gy (51 Gy BED{sub 10}) was required, with BED{sub 10} increasing with dose per fraction due to wasted dose in the final fraction. Fractions of 9 Gy compromised well for total treatment time and BED, withmore » BED{sub 10}:BED{sub 3} of 84:176 Gy for oxic and 132:278 Gy for non-reoxygenating hypoxic tumors. Initial doses of 12 Gy followed by 6 Gy further increased the therapeutic ratio. When delivering ≥9 Gy per fraction, applying reoxygenation and/or linear-quadratic-cubic cell survival both affected tumor control doses by a significant 1-2 fractions. Conclusions: The complex temporal dynamics of tumor oxygenation combined with probabilistic cell kinetics in the modeling of radiation therapy requires sophisticated stochastic modeling to predict tumor cell kill. For stereotactic ablative radiation therapy, high doses in the first week followed by doses that are more moderate may be beneficial because a high percentage of hypoxic cells could be eradicated early while keeping the required BED{sub 10} relatively low and BED{sub 3} toxicity to tolerable levels.« less

Authors:
 [1];  [2];  [3];  [2];  [2];  [4];  [2]
  1. Department of Medical Physics, Royal Adelaide Hospital, Adelaide, South Australia (Australia)
  2. (Australia)
  3. School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia (Australia)
  4. Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide, South Australia (Australia)
Publication Date:
OSTI Identifier:
22648748
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 95; Journal Issue: 4; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CELL PROLIFERATION; DOSE EQUIVALENTS; EXTERNAL BEAM RADIATION THERAPY; FORECASTING; NEOPLASMS; PROBABILISTIC ESTIMATION; SIMULATION; STOCHASTIC PROCESSES; TUMOR CELLS

Citation Formats

Harriss-Phillips, Wendy M., E-mail: wharrphil@gmail.com, School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia, Bezak, Eva, International Centre for Allied Health Evidence, University of South Australia, Adelaide, South Australia, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Potter, Andrew, and Adelaide Radiotherapy Centre, Genesis CancerCare, Adelaide, South Australia. Stochastic Predictions of Cell Kill During Stereotactic Ablative Radiation Therapy: Do Hypoxia and Reoxygenation Really Matter?. United States: N. p., 2016. Web. doi:10.1016/J.IJROBP.2016.03.014.
Harriss-Phillips, Wendy M., E-mail: wharrphil@gmail.com, School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia, Bezak, Eva, International Centre for Allied Health Evidence, University of South Australia, Adelaide, South Australia, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Potter, Andrew, & Adelaide Radiotherapy Centre, Genesis CancerCare, Adelaide, South Australia. Stochastic Predictions of Cell Kill During Stereotactic Ablative Radiation Therapy: Do Hypoxia and Reoxygenation Really Matter?. United States. doi:10.1016/J.IJROBP.2016.03.014.
Harriss-Phillips, Wendy M., E-mail: wharrphil@gmail.com, School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia, Bezak, Eva, International Centre for Allied Health Evidence, University of South Australia, Adelaide, South Australia, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Potter, Andrew, and Adelaide Radiotherapy Centre, Genesis CancerCare, Adelaide, South Australia. 2016. "Stochastic Predictions of Cell Kill During Stereotactic Ablative Radiation Therapy: Do Hypoxia and Reoxygenation Really Matter?". United States. doi:10.1016/J.IJROBP.2016.03.014.
@article{osti_22648748,
title = {Stochastic Predictions of Cell Kill During Stereotactic Ablative Radiation Therapy: Do Hypoxia and Reoxygenation Really Matter?},
author = {Harriss-Phillips, Wendy M., E-mail: wharrphil@gmail.com and School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia and Bezak, Eva and International Centre for Allied Health Evidence, University of South Australia, Adelaide, South Australia and Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia and Potter, Andrew and Adelaide Radiotherapy Centre, Genesis CancerCare, Adelaide, South Australia},
abstractNote = {Purpose: To simulate stereotactic ablative radiation therapy on hypoxic and well-oxygenated in silico tumors, incorporating probabilistic parameter distributions and linear-quadratic versus linear-quadratic-cubic methodology and the evaluation of optimal fractionation schemes using biological effective dose (BED{sub α/β=10} {sub or} {sub 3}) comparisons. Methods and Materials: A temporal tumor growth and radiation therapy algorithm simulated high-dose external beam radiation therapy using stochastic methods. Realistic biological proliferative cellular hierarchy and pO{sub 2} histograms were incorporated into the 10{sup 8}-cell tumor model, with randomized radiation therapy applied during continual cell proliferation and volume-based gradual tumor reoxygenation. Dose fractions ranged from 6-35 Gy, with predictive outcomes presented in terms of the total doses (converted to BED) required to eliminate all cells that could potentially regenerate the tumor. Results: Well-oxygenated tumor control BED{sub 10} outcomes were not significantly different for high-dose versus conventional radiation therapy (BED{sub 10}: 79-84 Gy; Equivalent Dose in 2 Gy fractions with α/β of 10: 66-70 Gy); however, total treatment times decreased from 7 down to 1-3 weeks. For hypoxic tumors, an additional 28 Gy (51 Gy BED{sub 10}) was required, with BED{sub 10} increasing with dose per fraction due to wasted dose in the final fraction. Fractions of 9 Gy compromised well for total treatment time and BED, with BED{sub 10}:BED{sub 3} of 84:176 Gy for oxic and 132:278 Gy for non-reoxygenating hypoxic tumors. Initial doses of 12 Gy followed by 6 Gy further increased the therapeutic ratio. When delivering ≥9 Gy per fraction, applying reoxygenation and/or linear-quadratic-cubic cell survival both affected tumor control doses by a significant 1-2 fractions. Conclusions: The complex temporal dynamics of tumor oxygenation combined with probabilistic cell kinetics in the modeling of radiation therapy requires sophisticated stochastic modeling to predict tumor cell kill. For stereotactic ablative radiation therapy, high doses in the first week followed by doses that are more moderate may be beneficial because a high percentage of hypoxic cells could be eradicated early while keeping the required BED{sub 10} relatively low and BED{sub 3} toxicity to tolerable levels.},
doi = {10.1016/J.IJROBP.2016.03.014},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 4,
volume = 95,
place = {United States},
year = 2016,
month = 7
}
  • Purpose: To assess the association between colorectal cancer (CRC) histology, dose, and local failure (LF) after stereotactic ablative radiation therapy (SABR) for pulmonary metastases, and to describe subsequent cancer progression, change of systemic therapy (CST), survival, and their association with treatment indications. Methods and Materials: From a prospective SABR cohort, 180 pulmonary metastases in 120 patients were identified. Treatment indications were single metastasis, oligometastases, oligoprogression, and dominant areas of progression. Doses of 48 to 52 Gy/4 to 5 fractions were delivered. Since 2010 the dose for peripheral CRC metastases was increased to 60 Gy/4 fractions. Cumulative incidence function (CIF) was used tomore » report LF, progression probability, and CST. The Kaplan-Meier method estimated overall survival (OS). Univariate and multivariable analyses to assess variable associations were conducted. Results: Median follow-up was 22 months (interquartile range, 14-33 months). At 24 months, the CIF of LF was 23.6% (95% confidence interval [CI] 15.1%-33.3%) and 8.3% (95% CI 2.6%-18.6%), respectively, for CRC and non-CRC metastases (P<.001). This association remained significant after adjusting for confounders (subdistribution hazard ratio [SHR] 13.6, 95% CI 4.2-44.1, P<.001). Among CRC metastases, 56 and 45 received <60 Gy and 60 Gy, respectively. Delivering 60 Gy was independently associated with a lower hazard of LF (SHR 0.271, 95% CI 0.078-0.940, P=.040). At 12 months the CIF of progression was 41.67% (95% CI 21.69%-60.56%), 42.51% (95% CI 29.09%-55.29%), 62.96% (95% CI 41.25%-78.53%), and 78.57% (95% CI 42.20%-93.48%), respectively, for patients treated for single metastasis, oligometastases, oligoprogression, and dominant area of progression (P<.001). A CST was observed, respectively, in 4 (17%), 17 (31%), 12 (44%), and 10 (71%) patients with a median time of 13.1, 11.1, 8.4, and 8.4 months. Conclusion: Colorectal cancer lung metastases are associated with a higher hazard of LF and require higher SABR doses. Outcomes for patients with oligometastases and oligoprogression treated with SABR seem favorable. Prospective clinical trials are needed to confirm these benefits.« less
  • Purpose: To retrospectively investigate treatment outcomes of stereotactic ablative body radiation therapy (SABR) for octogenarians with non-small cell lung cancer (NSCLC). Methods and Materials: Between 2005 and 2012, 109 patients aged ≥80 years with T1-2N0M0 NSCLC were treated with SABR: 47 patients had histology-unproven lung cancer; 62 patients had pathologically proven NSCLC. The prescribed doses were either 50 Gy/5 fractions for peripheral tumors or 40 Gy/5 fractions for centrally located tumors. The treatment outcomes, toxicities, and the correlating factors for overall survival (OS) were evaluated. Results: The median follow-up duration after SABR was 24.2 (range, 3.0-64.6) months. Only limited toxicitiesmore » were observed, except for 1 grade 5 radiation pneumonitis. The 3-year local, regional, and distant metastasis-free survival rates were 82.3%, 90.1%, and 76.8%, respectively. The OS and lung cancer-specific survival rates were 53.7% and 70.8%, respectively. Multivariate analysis revealed that medically inoperable, low body mass index, high T stage, and high C-reactive protein were the predictors for short OS. The OS for the operable octogenarians was significantly better than that for inoperable (P<.01). Conclusions: Stereotactic ablative body radiation therapy for octogenarians was feasible, with excellent OS. Multivariate analysis revealed that operability was one of the predictors for OS. For medically operable octogenarians with early-stage NSCLC, SABR should be prospectively compared with resection.« less
  • Purpose: Pencil beam (PB) and collapsed cone convolution (CCC) dose calculation algorithms differ significantly when used in the thorax. However, such differences have seldom been previously directly correlated with outcomes of lung stereotactic ablative body radiation (SABR). Methods and Materials: Data for 201 non-small cell lung cancer patients treated with SABR were analyzed retrospectively. All patients were treated with 50 Gy in 5 fractions of 10 Gy each. The radiation prescription mandated that 95% of the planning target volume (PTV) receive the prescribed dose. One hundred sixteen patients were planned with BrainLab treatment planning software (TPS) with the PB algorithm and treatedmore » on a Novalis unit. The other 85 were planned on the Pinnacle TPS with the CCC algorithm and treated on a Varian linac. Treatment planning objectives were numerically identical for both groups. The median follow-up times were 24 and 17 months for the PB and CCC groups, respectively. The primary endpoint was local/marginal control of the irradiated lesion. Gray's competing risk method was used to determine the statistical differences in local/marginal control rates between the PB and CCC groups. Results: Twenty-five patients planned with PB and 4 patients planned with the CCC algorithms to the same nominal doses experienced local recurrence. There was a statistically significant difference in recurrence rates between the PB and CCC groups (hazard ratio 3.4 [95% confidence interval: 1.18-9.83], Gray's test P=.019). The differences (Δ) between the 2 algorithms for target coverage were as follows: ΔD99{sub GITV} = 7.4 Gy, ΔD99{sub PTV} = 10.4 Gy, ΔV90{sub GITV} = 13.7%, ΔV90{sub PTV} = 37.6%, ΔD95{sub PTV} = 9.8 Gy, and ΔD{sub ISO} = 3.4 Gy. GITV = gross internal tumor volume. Conclusions: Local control in patients receiving who were planned to the same nominal dose with PB and CCC algorithms were statistically significantly different. Possible alternative explanations are described in the report, although they are not thought likely to explain the difference. We conclude that the difference is due to relative dosimetric underdosing of tumors with the PB algorithm.« less
  • Purpose: We extended our previous experience with stereotactic ablative radiation therapy (SABR; 50 Gy in 4 fractions) for centrally located non-small cell lung cancer (NSCLC); explored the use of 70 Gy in 10 fractions for cases in which dose-volume constraints could not be met with the previous regimen; and suggested modified dose-volume constraints. Methods and Materials: Four-dimensional computed tomography (4DCT)-based volumetric image-guided SABR was used for 100 patients with biopsy-proven, central T1-T2N0M0 (n=81) or isolated parenchymal recurrence of NSCLC (n=19). All disease was staged with positron emission tomography/CT; all tumors were within 2 cm of the bronchial tree, trachea, major vessels, esophagus, heart,more » pericardium, brachial plexus, or vertebral body. Endpoints were toxicity, overall survival (OS), local and regional control, and distant metastasis. Results: At a median follow-up time of 30.6 months, median OS time was 55.6 months, and the 3-year OS rate was 70.5%. Three-year cumulative actuarial local, regional, and distant control rates were 96.5%, 87.9%, and 77.2%, respectively. The most common toxicities were chest-wall pain (18% grade 1, 13% grade 2) and radiation pneumonitis (11% grade 2 and 1% grade 3). No patient experienced grade 4 or 5 toxicity. Among the 82 patients receiving 50 Gy in 4 fractions, multivariate analyses showed mean total lung dose >6 Gy, V{sub 20} >12%, or ipsilateral lung V{sub 30} >15% to independently predict radiation pneumonitis; and 3 of 9 patients with brachial plexus D{sub max} >35 Gy experienced brachial neuropathy versus none of 73 patients with brachial D{sub max} <35 Gy (P=.001). Other toxicities were analyzed and new dose-volume constraints are proposed. Conclusions: SABR for centrally located lesions produces clinical outcomes similar to those for peripheral lesions when normal tissue constraints are respected.« less
  • Purpose: For inoperable stage I (T1-T2N0) small cell lung cancer (SCLC), national guidelines recommend chemotherapy with or without conventionally fractionated radiation therapy. The present multi-institutional cohort study investigated the role of stereotactic ablative radiation therapy (SABR) for this population. Methods and Materials: The clinical and treatment characteristics, toxicities, outcomes, and patterns of failure were assessed in patients with histologically confirmed stage T1-T2N0M0 SCLC. Kaplan-Meier analysis was used to evaluate the survival outcomes. Univariate and multivariate analyses identified predictors of outcomes. Results: From 24 institutions, 76 lesions were treated in 74 patients (median follow-up 18 months). The median age and tumor sizemore » was 72 years and 2.5 cm, respectively. Chemotherapy and prophylactic cranial irradiation were delivered in 56% and 23% of cases, respectively. The median SABR dose and fractionation was 50 Gy and 5 fractions. The 1- and 3-year local control rate was 97.4% and 96.1%, respectively. The median disease-free survival (DFS) duration was 49.7 months. The DFS rate was 58.3% and 53.2% at 1 and 3 years, respectively. The median, 1-year, and 3-year disease-specific survival was 52.3 months, 84.5%, and 64.4%, respectively. The median, 1-year, and 3-year overall survival (OS) was 17.8 months, 69.9%, and 34.0% respectively. Patients receiving chemotherapy experienced an increased median DFS (61.3 vs 9.0 months; P=.02) and OS (31.4 vs 14.3 months; P=.02). The receipt of chemotherapy independently predicted better outcomes for DFS/OS on multivariate analysis (P=.01). Toxicities were uncommon; 5.2% experienced grade ≥2 pneumonitis. Post-treatment failure was most commonly distant (45.8% of recurrence), followed by nodal (25.0%) and “elsewhere lung” (20.8%). The median time to each was 5 to 7 months. Conclusions: From the findings of the largest report of SABR for stage T1-T2N0 SCLC to date, SABR (≥50 Gy) with chemotherapy should be considered a standard option.« less