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For: van Luijk P, Faber H, Schippers JM, Brandenburg S, Langendijk JA, Meertens H, Coppes RP. Bath and shower effects in the rat parotid gland explain increased relative risk of parotid gland dysfunction after intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2009;74:1002-5. [PMID: 19545785 DOI: 10.1016/j.ijrobp.2009.03.039] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2009] [Revised: 03/13/2009] [Accepted: 03/15/2009] [Indexed: 10/20/2022]

For:	van Luijk P, Faber H, Schippers JM, Brandenburg S, Langendijk JA, Meertens H, Coppes RP. Bath and shower effects in the rat parotid gland explain increased relative risk of parotid gland dysfunction after intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2009;74:1002-5. [PMID: 19545785 DOI: 10.1016/j.ijrobp.2009.03.039] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2009] [Revised: 03/13/2009] [Accepted: 03/15/2009] [Indexed: 10/20/2022]

Number

Cited by Other Article(s)

Paganetti H, Simone CB, Bosch WR, Haas-Kogan D, Kirsch DG, Li H, Liang X, Liu W, Mahajan A, Story MD, Taylor PA, Willers H, Xiao Y, Buchsbaum JC. NRG Oncology White Paper on the Relative Biological Effectiveness in Proton Therapy. Int J Radiat Oncol Biol Phys 2025;121:202-217. [PMID: 39059509 PMCID: PMC11646189 DOI: 10.1016/j.ijrobp.2024.07.2152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/17/2024] [Accepted: 07/06/2024] [Indexed: 07/28/2024]

van Rijn-Dekker MI, van der Schaaf A, Nienhuis SW, Arents-Huls AS, Ger RB, Hamming-Vrieze O, Hoebers FJP, de Ridder M, Vigorito S, Zwijnenburg EM, Langendijk JA, van Luijk P, Steenbakkers RJHM. Clinical Introduction of Stem Cell Sparing Radiotherapy to Reduce the Risk of Xerostomia in Patients with Head and Neck Cancer. Cancers (Basel) 2024;16:4283. [PMID: 39766181 PMCID: PMC11674908 DOI: 10.3390/cancers16244283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/06/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open

Affiliation(s)

Maria I. van Rijn-Dekker Department of Radiation Oncology, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (M.I.v.R.-D.); (A.v.d.S.); (S.W.N.); (J.A.L.); (P.v.L.)
Arjen van der Schaaf Department of Radiation Oncology, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (M.I.v.R.-D.); (A.v.d.S.); (S.W.N.); (J.A.L.); (P.v.L.)
Sanne W. Nienhuis Department of Radiation Oncology, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (M.I.v.R.-D.); (A.v.d.S.); (S.W.N.); (J.A.L.); (P.v.L.)
Antoinette S. Arents-Huls Department of Radiation Oncology, Radiotherapiegroep, 6815 AD Arnhem, The Netherlands;
Rachel B. Ger Radiation Oncology and Molecular Radiation Sciences, John Hopkins Medicine, Baltimore, MD 21287, USA;
Olga Hamming-Vrieze Department of Radiation Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands;
Frank J. P. Hoebers Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University, 6229 ET Maastricht, The Netherlands;
Mischa de Ridder Department of Radiation Oncology, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands;
Sabrina Vigorito Unit of Medical Physics, European Institute of Oncology IRCCS, 20141 Milan, Italy;
Ellen M. Zwijnenburg Department of Radiation Oncology, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands;
Johannes A. Langendijk Department of Radiation Oncology, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (M.I.v.R.-D.); (A.v.d.S.); (S.W.N.); (J.A.L.); (P.v.L.)
Peter van Luijk Department of Radiation Oncology, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (M.I.v.R.-D.); (A.v.d.S.); (S.W.N.); (J.A.L.); (P.v.L.)
Roel J. H. M. Steenbakkers Department of Radiation Oncology, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (M.I.v.R.-D.); (A.v.d.S.); (S.W.N.); (J.A.L.); (P.v.L.)

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van Rijn-Dekker MI, la Bastide-van Gemert S, Stokman MA, Vissink A, Coppes RP, Langendijk JA, van Luijk P, Steenbakkers RJHM. Radiation-induced Xerostomia is Related to Stem Cell Dose-dependent Reduction of Saliva Production. Int J Radiat Oncol Biol Phys 2024;120:772-782. [PMID: 38631537 DOI: 10.1016/j.ijrobp.2024.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 03/28/2024] [Accepted: 04/05/2024] [Indexed: 04/19/2024]

Abstract

PURPOSE

Previous studies have shown that the mean dose to the parotid gland stem cell rich regions (Dmean,SCR) is the strongest dosimetric predictor for the risk of patient-reported daytime xerostomia. This study aimed to test whether the relationship between patient-reported xerostomia and Dmean,SCR is explained by a dose-dependent reduction of saliva production.

METHODS AND MATERIALS

In 570 patients with head and neck cancer treated with definitive radiation therapy (RT), flow from the parotid (FLOWPAR) and submandibular/sublingual (FLOWSMSL) glands, and patient-reported daytime (XERDAY) and nighttime (XERNIGHT) xerostomia were prospectively measured before, at 6 months, and 12 months after RT. Using linear mixed effect models, the relationship of the mean dose to the parotid glands (Dmean,par), Dmean,SCR, non-SCR parotid gland tissue (Dmean,non-SCR), submandibular glands (Dmean,sub), and oral cavity (Dmean,oral) with salivary flow and xerostomia was analyzed while correcting for known confounders.

RESULTS

Dmean,SCR proved to be responsible for the effect of Dmean,par on FLOWPAR (P ≤ .03), while Dmean,non-SCR did not affect FLOWPAR (P ≥ .11). To illustrate, increasing Dmean,SCR by 10 Gy at a fixed Dmean,non-SCR reduced FLOWPAR by 0.02 mL/min (25%) after RT. However, if the opposite happened, no change in FLOWPAR was observed (0.00 mL/min [4%]). As expected, Dmean,sub was significantly associated with FLOWSMSL (P < .001). For example, increasing Dmean,sub by 10 Gy reduced FLOWSMSL by 0.07 mL/min (26%) after RT. Xerostomia scores were also affected by dose to the salivary glands. Dmean,SCR and Dmean,oral were associated with higher XERDAY scores (P ≤ .05), while Dmean,sub increased XERNIGHT scores (P = .01). For example, an increase of 10 Gy in Dmean,SCR raised XERDAY scores by 2.13 points (5%) after RT, while an additional 10 Gy in Dmean,subs increased XERNIGHT scores by 2.20 points (6%) after RT. Salivary flow was not only associated with radiation dose, but also with xerostomia scores in line with the salivary glands' functions; ie, FLOWPAR only influenced XERDAY (P < .001, 10.92 points lower XERDAY per 1 mL/min saliva), while FLOWSMSL affected XERDAY and XERNIGHT (P ≤ .004, 6.69 and 5.74 points lower XERDAY and XERNIGHT, respectively, per 1 mL/min saliva). Therefore, the observed relationships between dose and xerostomia were corrected for salivary flow. As hypothesized, Dmean,SCR only increased XERDAY scores via reducing FLOWPAR, whereas the effects of Dmean,oral on XERDAY and Dmean,sub on XERNIGHT were independent of salivary flow.

CONCLUSIONS

Higher SCR region dose reduced parotid gland saliva production, subsequently resulting in higher daytime xerostomia scores. Consequently, this study supports the clinical implementation of stem cell sparing RT to preserve salivary flow with the aim of reducing the risk of xerostomia.

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Parotid Gland Stem Cell Preservation during Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma: Dosimetric Analysis and Feasibility. JOURNAL OF ONCOLOGY 2022;2022:4922409. [PMID: 35865088 PMCID: PMC9296294 DOI: 10.1155/2022/4922409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 11/18/2022]

Abstract Objective. Parotid gland (PG) is a radiosensitive organ, and xerostomia (XS) is a key factor affecting patients’ life quality after conventional radiotherapy for head and neck tumors. In this study, dosimetry analysis was performed on PG stem cell preservation in intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). Methods. All clinical data of 80 NPC patients diagnosed pathologically in the Radiotherapy Department of Taizhou Hospital of Zhejiang Province Affiliated with Wenzhou Medical University from August 2017 to September 2019 were retrospectively analyzed. Patients were assigned to a regular group and a restricted group according to different IMRT plans, in which a dose limitation for the parotid duct was added in the restricted group in addition to the conventional plan used in the regular group to minimize the parotid duct radiation dose. The differences in planning target volume (PTV) dose distribution, organ at risk (OAR) dose, and dose to the PG and its ducts were compared between the two groups. Results. Significantly higher mean irradiation doses of the brainstem, mandible, and oral cavity were determined in the restricted group compared with the regular group (

P > 0.05

), but there was no significant difference in the mean dose of other OARs irradiated (

P > 0.05

). As compared to the irradiation of bilateral PGs, no statistical differences were found in the mean irradiation dose and V30 between regular and restricted groups (

P > 0.05

), but lower V20 and higher V45 were determined in the restricted group (

P < 0.05

). The mean irradiation dose, V15, V20, and V26 of bilateral parotid ducts were lower in the restricted group as compared to the regular group (

P < 0.05

). Conclusion. IMRT for NPC can effectively reduce the mean irradiation dose and play a PG stem cell preservation role by giving specific dose limitation conditions to the parotid duct area without affecting PTV dose distribution and OAR irradiation dose, which has certain feasibility. Collapse

Blake SW. Can dose convolution modelling explain bath and shower effects in rat spinal cord? Phys Med Biol 2022;67. [DOI: 10.1088/1361-6560/ac5c8e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 03/10/2022] [Indexed: 12/24/2022]

Abstract Abstract Objective. ‘Bath and shower’ effects were first seen in proton irradiations of rat spinal cord, where a low dose ‘bath’ reduced the smaller field ‘shower’ dose needed for limb paralysis giving the appearance of sensitisation of the cord or disproportionate response. This was difficult to reconcile with existing tissue complication models. The purpose of this investigation is to explore a different approach using a dose convolution algorithm to model the 50% isoeffect endpoint. Approach. Bath and shower dose distributions were convolved with Gaussian functions with widths specified by the σ parameter. The hypothesis was that the maximum value from the convolved distributions was constant for isoeffect across the modelled scenarios. A simpler field length dependent relative biological effectiveness (FLRBE) approach was also used for a subset of the data which gave results independent of σ. Main results. The maximum values from the convolved distributions were constant within ±17% across the bath and shower experiments for σ = 3.5 mm, whereas the maximum dose varied by a factor of four. The FLRBE results were also within ±14% confirming the validity of the dose convolution approach. Significance. A simple approach using dose convolution modelling of the 50% isotoxicity gave compelling consistency with the full range of bath and shower results, while the FLRBE approach confirmed the results for the symmetric field data. Convolution modelling and the effect of time interval were consistent with a signalling factor diffusion mechanism such as the ‘bystander effect’. The results suggest biological effectiveness is reduced for very small field sizes, requiring a higher isoeffect dose. By implication, the bath dose does not sensitise the cord to the shower dose; when biological effectiveness is accounted for, a small increase in the bath dose requires a significantly larger reduction in shower dose for isoeffect. Collapse

Steenbakkers RJHM, van Rijn-Dekker MI, Stokman MA, Kierkels RGJ, van der Schaaf A, van den Hoek JGM, Bijl HP, Kramer MCA, Coppes RP, Langendijk JA, van Luijk P. Parotid Gland Stem Cell Sparing Radiation Therapy for Patients With Head and Neck Cancer: A Double-Blind Randomized Controlled Trial. Int J Radiat Oncol Biol Phys 2022;112:306-316. [PMID: 34563635 DOI: 10.1016/j.ijrobp.2021.09.023] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/08/2021] [Accepted: 09/13/2021] [Indexed: 02/08/2023]

Abstract

PURPOSE

Radiation therapy for head and neck cancer frequently leads to salivary gland damage and subsequent xerostomia. The radiation response of the parotid glands of rats, mice, and patients critically depends on dose to parotid gland stem cells, mainly located in the gland's main ducts (stem cell rich [SCR] region). Therefore, this double-blind randomized controlled trial aimed to test the hypothesis that parotid gland stem cell sparing radiation therapy preserves parotid gland function better than currently used whole parotid gland sparing radiation therapy.

METHODS AND MATERIALS

Patients with head and neck cancer (n = 102) treated with definitive radiation therapy were randomized between standard parotid-sparing and stem cell sparing (SCS) techniques. The primary endpoint was >75% reduction in parotid gland saliva production compared with pretreatment production (FLOW12M). Secondary endpoints were several aspects of xerostomia 12 months after treatment.

RESULTS

Fifty-four patients were assigned to the standard arm and 48 to the SCS arm. Only dose to the SCR regions (contralateral 16 and 11 Gy [P = .004] and ipsilateral 26 and 16 Gy [P = .001] in the standard and SCS arm, respectively) and pretreatment patient-rated daytime xerostomia (35% and 13% [P = .01] in the standard and SCS arm, respectively) differed significantly between the arms. In the SCS arm, 1 patient (2.8%) experienced FLOW12M compared with 2 (4.9%) in the standard arm (P = 1.00). However, a trend toward better relative parotid gland salivary function in favor of SCS radiation therapy was shown. Moreover, multivariable analysis showed that mean contralateral SCR region dose was the strongest dosimetric predictor for moderate-to-severe patient-rated daytime xerostomia and grade ≥2 physician-rated xerostomia, the latter including reported alteration in diet.

CONCLUSIONS

No significantly better parotid function was observed in SCS radiation therapy. However, additional multivariable analysis showed that dose to the SCR region was more predictive of the development of parotid gland function-related xerostomia endpoints than dose to the entire parotid gland.

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Parsai S, Qiu RLJ, Qi P, Sedor G, Fuller CD, Murray E, Majkszak D, Dorio N, Koyfman S, Woody N, Joshi N, Scott JG. In vivo assessment of the safety of standard fractionation Temporally Feathered Radiation Therapy (TFRT) for head and neck squamous cell carcinoma: An R-IDEAL Stage 1/2a first-in-humans/feasibility demonstration of new technology implementation. Radiother Oncol 2021;163:39-45. [PMID: 34333086 DOI: 10.1016/j.radonc.2021.07.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 06/13/2021] [Accepted: 07/22/2021] [Indexed: 10/20/2022]

Abstract

INTRODUCTION

Prior in silico simulations of studies of Temporally Feathered Radiation Therapy (TFRT) have demonstrated potential reduction in normal tissue toxicity. This R-IDEAL Stage 1/2A study seeks to demonstrate the first-in-human implementation of TFRT in treating patients with head and neck squamous cell carcinoma (HNSCC).

MATERIALS AND METHODS

Patients with HNSCC treated with definitive radiation therapy were eligible (70 Gy in 35 fractions) were eligible. The primary endpoint was feasibility of TFRT planning as defined by radiation start within 15 business days of CT simulation. Secondary endpoints included estimates of acute grade 3-5 toxicity.

RESULTS

The study met its accrual goal of 5 patients. TFRT plans were generated in four of the five patients within 15 business days of CT simulation, therefore meeting the primary endpoint. One patient was not treated with TFRT at the physician's discretion, though the TFRT plan had been generated within sufficient time from the CT simulation. For patients who received TFRT, the median time from CT simulation to radiation start was 10 business days (range 8-15). The average time required for radiation planning was 6 business days. In all patients receiving TFRT, each subplan and every daily fraction was delivered in the correct sequence without error. The OARs feathered included: oral cavity, each submandibular gland, each parotid gland, supraglottis, and posterior pharyngeal wall (OAR pharynx). Prescription dose PTV coverage (>95%) was ensured in each TFRT subplan and the composite TFRT plan. One of five patients developed an acute grade 3 toxicity.

CONCLUSIONS

This study demonstrates the first-in-human implementation of TFRT (R-IDEAL Stage 1), proving its feasibility in the modern clinical workflow. Additionally, assessments of acute toxicities and dosimetric comparisons to a standard radiotherapy plan were described (R-IDEAL Stage 2a).

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Sari SY, Yilmaz MT, Elmali A, Yedekci FY, Yuce D, Ozyigit G, Cengiz M, Yazici G. Parotid gland stem cells: Mini yet mighty. Head Neck 2021;43:1122-1127. [PMID: 33244802 DOI: 10.1002/hed.26556] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/24/2020] [Accepted: 11/20/2020] [Indexed: 12/24/2022] Open

Hrycushko B, Medin PM. Effects From Nonuniform Dose Distribution in the Spinal Nerves of Pigs: Analysis of Normal Tissue Complication Probability Models. Int J Radiat Oncol Biol Phys 2021;109:1570-1579. [PMID: 33171201 DOI: 10.1016/j.ijrobp.2020.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 10/15/2020] [Accepted: 11/02/2020] [Indexed: 10/23/2022]

Abstract

PURPOSE

Our purpose was to evaluate normal tissue complication probability (NTCP) models for their ability to describe the increase in tolerance as the length of irradiated spinal nerve is reduced in a pig.

METHODS AND MATERIALS

Common phenomenological and semimechanistic NTCP models were fit using the maximum likelihood estimate method to dose-response data from spinal nerve irradiation studies in pigs. Statistical analysis was used to compare how well each model fit the data. Model parameters were then applied to a previously published dose distribution used for spinal cord irradiation in rats under the assumption of a similar dose-response.

RESULTS

The Lyman-Kutcher-Burman model, relative seriality, and critical volume model fit the spinal nerve data equally well, but the mean dose logistic and relative seriality models gave the best fit after penalizing for the number of model parameters. The minimum dose logistic regression model was the only model showing a lack of fit. When extrapolated to a 0.5-cm simulated square-wave-like dose distribution, the serial behaving models showed negligible increase in dose-response curve. The Lyman-Kutcher-Burman model and relative seriality models showed significant shifting of NTCP curves due to parallel behaving parameters. The critical volume model gave the closest match to the rat data.

CONCLUSIONS

Several phenomenological and semimechanistic models were observed to adequately describe the increase in the radiation tolerance of the spinal nerves when changing the irradiated length from 1.5 to 0.5 cm. Contrary to common perception, model parameters suggest parallel behaving tissue architecture. Under the assumption that the spinal nerve response to radiation is similar to that of the spinal cord, only the critical volume model was robust when extrapolating to outcome data from a 0.5-cm square-wave-like dose distribution, as was delivered in rodent spinal cord irradiation research.

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Paganetti H, Beltran C, Both S, Dong L, Flanz J, Furutani K, Grassberger C, Grosshans DR, Knopf AC, Langendijk JA, Nystrom H, Parodi K, Raaymakers BW, Richter C, Sawakuchi GO, Schippers M, Shaitelman SF, Teo BKK, Unkelbach J, Wohlfahrt P, Lomax T. Roadmap: proton therapy physics and biology. Phys Med Biol 2021;66. [DOI: 10.1088/1361-6560/abcd16] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 11/23/2020] [Indexed: 12/12/2022]

Voshart DC, Wiedemann J, van Luijk P, Barazzuol L. Regional Responses in Radiation-Induced Normal Tissue Damage. Cancers (Basel) 2021;13:cancers13030367. [PMID: 33498403 PMCID: PMC7864176 DOI: 10.3390/cancers13030367] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/16/2021] [Accepted: 01/18/2021] [Indexed: 12/16/2022] Open

Belli ML, Sarnelli A, Mezzenga E, Cesarini F, Caroli P, Di Iorio V, Strigari L, Cremonesi M, Romeo A, Nicolini S, Matteucci F, Severi S, Paganelli G. Targeted Alpha Therapy in mCRPC (Metastatic Castration-Resistant Prostate Cancer) Patients: Predictive Dosimetry and Toxicity Modeling of ²²⁵Ac-PSMA (Prostate-Specific Membrane Antigen). Front Oncol 2020;10:531660. [PMID: 33251129 PMCID: PMC7674768 DOI: 10.3389/fonc.2020.531660] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 08/20/2020] [Indexed: 01/17/2023] Open

Abstract

Radioligand therapy is a type of internal radiotherapy combining a short-range radioisotope labeled to a carrier with a high affinity for a specific receptor expressed on tumor cells. Targeted alpha therapy (TAT) combines a high-linear energy transfer (LET) emitter (²²⁵Ac) with a prostate-specific membrane antigen (PSMA) carrier, specifically binding tumor cells in patients with metastatic castration-resistant prostate cancer. Although the antitumor activity of ²²⁵Ac-PSMA is well-documented, this treatment is nowadays only used as salvage therapy because the high incidence of xerostomia limits the therapeutic window. Thus, methods to reduce salivary toxicity and models able to describe xerostomia incidence are needed. We recently studied the efficacy of salivary gland protectors administered in combination with ¹⁷⁷Lu-PSMA therapy. Starting from these data, we performed a predictive dosimetric evaluation of ²²⁵Ac-PSMA to assess the impact of salivary gland protectors in TAT. ²²⁵Ac-PSMA predictive dosimetry was performed in 13 patients treated with ¹⁷⁷Lu-PSMA. Sequential whole-body planar images were acquired 0.5–1, 16–24, 36–48, and 120 h post-injection. ¹⁷⁷Lu time-activity curves were corrected for ²²⁵Ac physical decay and assumed in equilibrium for all daughters. The OLINDA/EXM spherical model was used for dose estimation of the parotid and submandibular glands. The dose for each daughter was calculated and summed for the total dose estimation. The biologically effective dose formalism was extended to high-LET emitters. For the total biologically effective dose formalism extended to high-LET emitters, including the contribution of all daughter isotopes, the brachytherapy formalism for a mixture of radionuclides was implemented. Equivalent doses in 2 Gy/fraction (EQD2) were then calculated and compared with the normal tissue complication probability model derived from external beam radiotherapy for grade ≥2 xerostomia induction. Median predictive doses were 0.86 Bd_RBE5/MBq for parotid glands and 1.05 Bd_RBE5/MBq for submandibular glands, with a 53% reduction compared with previously published data. The results show that the radiobiological model implemented is conservative, as it overestimates the complication rate with respect to the clinical data. Our data shows the possibility of reducing salivary gland uptake in TAT with the coadministration of organ protectors, but these results should be confirmed for TAT with ²²⁵Ac-PSMA by carrying out prospective trials with defined toxicity endpoints and dosimetry procedures.

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Hrycushko B, van der Kogel AJ, Phillips L, Folkert M, Sayre JW, Vernino S, Hassan-Rezaeian N, Foster RD, Yamada Y, Timmerman R, Medin PM. Existence of a Dose-Length Effect in Spinal Nerves Receiving Single-Session Stereotactic Ablative Radiation Therapy. Int J Radiat Oncol Biol Phys 2020;106:1010-1016. [PMID: 31953062 DOI: 10.1016/j.ijrobp.2019.11.417] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/14/2019] [Accepted: 11/21/2019] [Indexed: 12/31/2022]

Abstract

PURPOSE

The spinal nerves have been observed to have a similar single-session dose tolerance to that of the spinal cord in pigs. Small-animal studies have shown that spinal cord dose tolerance depends on the length irradiated. This work aims to determine whether a dose-length effect exists for spinal nerves.

METHODS AND MATERIALS

Twenty-seven Yucatan minipigs underwent computed tomography and magnetic resonance imaging for treatment planning, followed by single-session stereotactic ablative radiation therapy. A 0.5 cm length of the left-sided C6, C7, and C8 spinal nerves was targeted. The pigs were distributed into 6 groups with prescription doses of 16 Gy (n = 5), 18 Gy (n = 5), 20 Gy (n = 5), 22 Gy (n = 5), 24 Gy (n = 5), or 36 Gy (n = 2) and corresponding maximum doses of 16.7, 19.1, 21.3, 23.1, 25.5, and 38.6 Gy, respectively. Neurologic status was assessed with a serial electrodiagnostic examination and daily observation of gait for approximately 52 weeks. A histopathologic examination of paraffin-embedded sections with Luxol fast blue/periodic acid-Schiff's staining was also performed.

RESULTS

Marked gait change was observed in 8 of 27 irradiated pigs. The latency for responding pigs was 11 to 16 weeks after irradiation. The affected animals presented with a limp in the left front limb, and 62.5% of these pigs had electrodiagnostic evidence of denervation in the C6 and C7 innervated muscles. A probit analysis showed the dose associated with a 50% incidence of gait change is 23.9 Gy (95% confidence interval, 22.5-25.8 Gy), which is 20% higher than that reported in a companion study where a 1.5 cm length was irradiated. All symptomatic pigs had demyelination and fibrosis in the irradiated nerves, but the contralateral nerves and spinal cord were normal.

CONCLUSIONS

A dose-length effect was observed for single-session irradiation of the spinal nerves in a Yucatan minipig model.

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Huang J, Kong FF, Oei RW, Zhai RP, Hu CS, Ying HM. Dosimetric predictors of temporal lobe injury after intensity-modulated radiotherapy for T4 nasopharyngeal carcinoma: a competing risk study. Radiat Oncol 2019;14:31. [PMID: 30736809 PMCID: PMC6368802 DOI: 10.1186/s13014-019-1229-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 01/23/2019] [Indexed: 03/30/2024] Open

Abstract

BACKGROUND

In patients with T4 nasopharyngeal carcinoma (NPC), death may occur prior to the occurrence of temporal lobe injury (TLI). Because such competing risk death precludes the occurrence of TLI and thus the competing risk analysis should be applied to TLI research. The aim was to investigate the incidence and predictive factors of TLI after intensity-modulated radiotherapy (IMRT) among T4 NPC patients.

METHODS

From March 2008 to December 2014, T4 NPC patients treated with full-course radical IMRT at our center were reviewed retrospectively. A nested case-control study was designed for this cohort of patients. The cases were patients with TLI diagnosed by MRI during the follow-up period, and the controls were patients without TLI after IMRT matched 1:1 to each case by gender, age at diagnosis, intercranial involvement, and follow-up time. The end point was time to TLI or death without prior TLI. We analyzed the cumulative incidence function (CIF) and performed a competing risk regression model to identify the predictors of TLI.

RESULTS

With a median follow-up of 40.1 months, 63 patients (63/506, 12.5%) developed TLI as diagnosed by MRI, and 136 deaths occurred during the period. The cumulative incidence of TLI at 5 years was 13.2%, while 26.7% died without prior TLI. The univariate analysis showed that all selected dosimetric parameters were associated with the occurrence of TLI. On multivariate analysis, D1cc and V20 remained statistically significant. Based on the area-under-the-curve (AUC) values, D1cc was considered the most predictive. The patients with D1cc > 71.14 Gy had a 7.920-fold increased risk of TLI compared with those with D1cc ≤71.14 Gy (P < 0.05). Similarly, V20 > 42.22 cc was found to result in a statistically significant higher risk of TLI (subdistribution hazard ratio [sHR] =3.123, P < 0.05).

CONCLUSIONS

TL D1cc and V20 were predictive of TLI after IMRT for T4 NPC. They should be considered as first and second priorities of dose constraints of the TL. D1cc ≤71.14 Gy and V20 ≤ 42.22 cc could be useful dose-volume constraints for reducing the occurrence of TLI during IMRT treatment planning without obviously compromising the tumor coverage.

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Xue J, Emami B, Grimm J, Kubicek GJ, Asbell SO, Lanciano R, Welsh JS, Peng L, Quon H, Laub W, Gui C, Spoleti N, Das IJ, Goldman HW, Redmond KJ, Kleinberg LR, Brady LW. Clinical evidence for dose tolerance of the central nervous system in hypofractionated radiotherapy. ACTA ACUST UNITED AC 2018. [DOI: 10.1007/s13566-018-0367-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]

Nagle PW, Hosper NA, Barazzuol L, Jellema AL, Baanstra M, van Goethem MJ, Brandenburg S, Giesen U, Langendijk JA, van Luijk P, Coppes RP. Lack of DNA Damage Response at Low Radiation Doses in Adult Stem Cells Contributes to Organ Dysfunction. Clin Cancer Res 2018;24:6583-6593. [PMID: 30135147 DOI: 10.1158/1078-0432.ccr-18-0533] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 06/08/2018] [Accepted: 08/17/2018] [Indexed: 11/16/2022]

Abstract

PURPOSE

Radiotherapy for head and neck cancer may result in serious side effects, such as hyposalivation, impairing the patient's quality of life. Modern radiotherapy techniques attempt to reduce the dose to salivary glands, which, however, results in low-dose irradiation of the tissue stem cells. Here we assess the low-dose sensitivity of tissue stem cells and the consequences for tissue function.

EXPERIMENTAL DESIGN

Postirradiation rat salivary gland secretory function was determined after pilocarpine induction. Murine and patient-derived salivary gland and thyroid gland organoids were irradiated and clonogenic survival was assessed. The DNA damage response (DDR) was analyzed in organoids and modulated using different radiation modalities, chemical inhibition, and genetic modification.

RESULTS

Relative low-dose irradiation to the high-density stem cell region of rat salivary gland disproportionally impaired function. Hyper-radiosensitivity at doses <1 Gy, followed by relative radioresistance at doses ≥1 Gy, was observed in salivary gland and thyroid gland organoid cultures. DDR modulation resulted in diminished, or even abrogated, relative radioresistance. Furthermore, inhibition of the DDR protein ATM impaired DNA repair after 1 Gy, but not 0.25 Gy. Irradiation of patient-derived salivary gland organoid cells showed similar responses, whereas a single 1 Gy dose to salivary gland-derived stem cells resulted in greater survival than clinically relevant fractionated doses of 4 × 0.25 Gy.

CONCLUSIONS

We show that murine and human glandular tissue stem cells exhibit a dose threshold in DDR activation, resulting in low-dose hyper-radiosensitivity, with clinical implications in radiotherapy treatment planning. Furthermore, our results from patient-derived organoids highlight the potential of organoids to study normal tissue responses to radiation.

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Affiliation(s)

Peter W Nagle Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.,Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Nynke A Hosper Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.,Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Lara Barazzuol Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.,Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Anne L Jellema Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.,Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Mirjam Baanstra Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.,Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Marc-Jan van Goethem Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.,KVI Center for Advanced Radiation Technology, University of Groningen, Groningen, the Netherlands
Sytze Brandenburg KVI Center for Advanced Radiation Technology, University of Groningen, Groningen, the Netherlands
Ulrich Giesen Physikalisch-Technische Bundesanstalt (PTB), Braunschweig, Germany
Johannes A Langendijk Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Peter van Luijk Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Rob P Coppes Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. .,Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Clark HD, Thomas SD, Reinsberg SA, Moiseenko VV, Hovan AJ, Wu JS. Heterogeneous radiotherapy dose-outcomes response in parotid glands. CONVERGENT SCIENCE PHYSICAL ONCOLOGY 2018. [DOI: 10.1088/2057-1739/aac8ea] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]

Hayashi Y, Mitsudo K, Sakuma K, Iida M, Iwai T, Nakashima H, Okamoto Y, Koizumi T, Oguri S, Hirota M, Kioi M, Koike I, Hata M, Tohnai I. Clinical outcomes of retrograde intra-arterial chemotherapy concurrent with radiotherapy for elderly oral squamous cell carcinoma patients aged over 80 years old. Radiat Oncol 2017;12:112. [PMID: 28673362 PMCID: PMC5496408 DOI: 10.1186/s13014-017-0847-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Accepted: 06/26/2017] [Indexed: 11/10/2022] Open

Affiliation(s)

Yuichiro Hayashi Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Kenji Mitsudo Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan.
Kaname Sakuma Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Masaki Iida Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Toshinori Iwai Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Hideyuki Nakashima Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Yoshiyuki Okamoto Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Toshiyuki Koizumi Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Senri Oguri Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Makoto Hirota Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Mitomu Kioi Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Izumi Koike Department of Radiology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Masaharu Hata Department of Radiology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
Iwai Tohnai Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan

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Lee JY, Abugharib A, Nguyen R, Eisbruch A. Impact of xerostomia and dysphagia on health-related quality of life for head and neck cancer patients. ACTA ACUST UNITED AC 2016. [DOI: 10.1080/23809000.2016.1236661] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]

Vallard A, Espenel S, Guy JB, Diao P, Xia Y, El Meddeb Hamrouni A, Ben Mrad M, Falk AT, Rodriguez-Lafrasse C, Rancoule C, Magné N. Targeting stem cells by radiation: From the biological angle to clinical aspects. World J Stem Cells 2016;8:243-250. [PMID: 27621758 PMCID: PMC4999651 DOI: 10.4252/wjsc.v8.i8.243] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 06/18/2016] [Accepted: 07/13/2016] [Indexed: 02/06/2023] Open

van Luijk P, Pringle S, Deasy JO, Moiseenko VV, Faber H, Hovan A, Baanstra M, van der Laan HP, Kierkels RGJ, van der Schaaf A, Witjes MJ, Schippers JM, Brandenburg S, Langendijk JA, Wu J, Coppes RP. Sparing the region of the salivary gland containing stem cells preserves saliva production after radiotherapy for head and neck cancer. Sci Transl Med 2016;7:305ra147. [PMID: 26378247 DOI: 10.1126/scitranslmed.aac4441] [Citation(s) in RCA: 164] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]

Affiliation(s)

Peter van Luijk Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands.
Sarah Pringle Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands. Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713AV Groningen, Netherlands
Joseph O Deasy Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA
Vitali V Moiseenko Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92093, USA
Hette Faber Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands. Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713AV Groningen, Netherlands
Allan Hovan British Columbia Cancer Agency-Vancouver Centre, Vancouver, British Columbia V5Z 4E6, Canada
Mirjam Baanstra Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands. Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713AV Groningen, Netherlands
Hans P van der Laan Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands
Roel G J Kierkels Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands
Arjen van der Schaaf Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands
Max J Witjes Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands
Jacobus M Schippers Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands. Accelerator Department, Paul Scherrer Institut, CH-5212 Villigen, Switzerland
Sytze Brandenburg KVI Center for Advanced Radiation Technology, University of Groningen, 9747 AA Groningen, Netherlands
Johannes A Langendijk Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands
Jonn Wu British Columbia Cancer Agency-Vancouver Centre, Vancouver, British Columbia V5Z 4E6, Canada
Robert P Coppes Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands. Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713AV Groningen, Netherlands.

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Validity of Current Stereotactic Body Radiation Therapy Dose Constraints for Aorta and Major Vessels. Semin Radiat Oncol 2016;26:135-9. [DOI: 10.1016/j.semradonc.2015.11.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]

Dose-Response Model for Chest Wall Tolerance of Stereotactic Body Radiation Therapy. Semin Radiat Oncol 2016;26:129-34. [DOI: 10.1016/j.semradonc.2015.11.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]

Dose-Volume Histogram Analysis of Stereotactic Body Radiotherapy Treatment of Pancreatic Cancer: A Focus on Duodenal Dose Constraints. Semin Radiat Oncol 2016;26:149-56. [DOI: 10.1016/j.semradonc.2015.12.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]

Nevens D, Nuyts S. The role of stem cells in the prevention and treatment of radiation-induced xerostomia in patients with head and neck cancer. Cancer Med 2016;5:1147-53. [PMID: 26880659 PMCID: PMC4924373 DOI: 10.1002/cam4.609] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 11/17/2015] [Accepted: 11/19/2015] [Indexed: 11/11/2022] Open

Baum BJ. Radiation-induced salivary hypofunction may become a thing of the past. Oral Dis 2016;22:81-4. [DOI: 10.1111/odi.12388] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]

Asbell SO, Grimm J, Xue J, Chew MS, LaCouture TA. Introduction and Clinical Overview of the DVH Risk Map. Semin Radiat Oncol 2015;26:89-96. [PMID: 27000504 DOI: 10.1016/j.semradonc.2015.11.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]

Clark HD, Moiseenko VV, Rackley TP, Thomas SD, Wu JS, Reinsberg SA. Development of a method for functional aspect identification in parotid using dynamic contrast-enhanced magnetic resonance imaging and concurrent stimulation. Acta Oncol 2015;54:1686-90. [PMID: 26252349 DOI: 10.3109/0284186x.2015.1067718] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]

Clark H, Hovan A, Moiseenko V, Thomas S, Wu J, Reinsberg S. Regional radiation dose susceptibility within the parotid gland: effects on salivary loss and recovery. Med Phys 2015;42:2064-71. [PMID: 25832096 DOI: 10.1118/1.4915077] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open

Abstract

PURPOSE

Xerostomia is one of the most likely late toxic effects of radiotherapy treatment in patients with head-and-neck cancers. Modern treatment techniques can incorporate knowledge of complication risk into treatment plans. To this end, the authors attempt to quantify the regional radiotherapy dose-dependence of salivary output loss and recovery in a prospective study.

METHODS

Salivary output was collected from patients undergoing radiotherapy treatment for head-and-neck cancers at the BC Cancer Agency between February 2008 and May 2013. Regional dose-dependence (i.e., dose susceptibility) of loss and recovery is quantified using nonparametric (Spearman's rank correlation coefficients, local linear regression) and parametric (least-sum of squares, least-median of squares) techniques.

RESULTS

Salivary flow recovery was seen in 79 of 102 patients considered (p < 0.0001, Wilcoxon sign rank test). Output loss was strongly correlated with left- and right parotid combined dose φ = min (DL, 45 Gy) + min (DR, 45 Gy), and can be accurately predicted. Median early loss (three months) was 72% of baseline, while median overall loss (1 yr) was 56% of baseline. Fitting an exponential model to whole parotid yields dose sensitivities A3m = 0.0604 Gy(-1) and A1y = 0.0379 Gy(-1). Recovery was not significantly associated with dose. Hints of lateral organ sub-segment dose-response dimorphism were observed.

CONCLUSIONS

Sub-segmentation appears to predict neither loss nor recovery with any greater precision than whole parotid mean dose, though it is not any worse. Sparing the parotid to a combined dose φ of <50 Gy is recommended for a patient to keep ≈40% of baseline function and thus avoid severe xerostomia at 12 months post-treatment. It seems unlikely that a population's mean recovery will exceed 20%-30% of baseline output at 1 yr after radiotherapy treatment using current (whole-organ based) clinical guidelines.

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Arcangeli S, Agolli L, Portalone L, Migliorino MR, Lopergolo MG, Monaco A, Dognini J, Pressello MC, Bracci S, Donato V. Patterns of CT lung injury and toxicity after stereotactic radiotherapy delivered with helical tomotherapy in early stage medically inoperable NSCLC. Br J Radiol 2015;88:20140728. [PMID: 25645106 PMCID: PMC4651249 DOI: 10.1259/bjr.20140728] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 01/28/2015] [Accepted: 02/02/2015] [Indexed: 12/25/2022] Open

Abstract

OBJECTIVE

To evaluate toxicity and patterns of radiologic lung injury on CT images after hypofractionated image-guided stereotactic body radiotherapy (SBRT) delivered with helical tomotherapy (HT) in medically early stage inoperable non-small-cell lung cancer (NSCLC).

METHODS

28 elderly patients (31 lesions) with compromised pulmonary reserve were deemed inoperable and enrolled to undergo SBRT. Patterns of lung injury based on CT appearance were assessed at baseline and during follow up. Acute (6 months or less) and late (more than 6 months) events were classified as radiation pneumonitis and radiation fibrosis (RF), respectively.

RESULTS

After a median follow-up of 12 months (range, 4-20 months), 31 and 25 lesions were examined for acute and late injuries, respectively. Among the former group, 25 (80.6%) patients showed no radiological changes. The CT appearance of RF revealed modified conventional, mass-like and scar-like patterns in three, four and three lesions, respectively. No evidence of late lung injury was demonstrated in 15 lesions. Five patients developed clinical pneumonitis (four patients, grade 2 and one patient, grade 3, respectively), and none of whom had CT findings at 3 months post-treatment. No instance of symptomatic RF was detected. The tumour response rate was 84% (complete response + partial response). Local control was 83% at 1 year.

CONCLUSION

Our findings show that HT-SBRT can be considered an effective treatment with a mild toxicity profile in medically inoperable patients with early stage NSCLC. No specific pattern of lung injury was demonstrated.

ADVANCES IN KNOWLEDGE

Our study is among the few showing that HT-SBRT represents a safe and effective option in patients with early stage medically inoperable NSCLC, and that it is not associated with a specific pattern of lung injury.

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Dose–Volume Relationships Associated With Temporal Lobe Radiation Necrosis After Skull Base Proton Beam Therapy. Int J Radiat Oncol Biol Phys 2015;91:261-7. [DOI: 10.1016/j.ijrobp.2014.10.011] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 09/29/2014] [Accepted: 10/06/2014] [Indexed: 11/18/2022]

Xue J, Kubicek GJ, Grimm J, LaCouture T, Chen Y, Goldman HW, Yorke E. Biological implications of whole-brain radiotherapy versus stereotactic radiosurgery of multiple brain metastases. J Neurosurg 2015;121 Suppl:60-8. [PMID: 25434938 DOI: 10.3171/2014.7.gks141229] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]

Tan W, Han G, Wei S, Hu D. Sparing functional anatomical structures during intensity-modulated radiotherapy: an old problem, a new solution. Future Oncol 2014;10:1863-72. [PMID: 23987920 DOI: 10.2217/fon.13.172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open

Vissink A, Luijk P, Langendijk JA, Coppes RP. Current ideas to reduce or salvage radiation damage to salivary glands. Oral Dis 2014;21:e1-10. [DOI: 10.1111/odi.12222] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 12/23/2013] [Accepted: 12/23/2013] [Indexed: 12/14/2022]

Head and neck intensity modulated radiotherapy parotid glands: time of re-planning. Radiol Med 2013;119:201-7. [PMID: 24337754 DOI: 10.1007/s11547-013-0326-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2012] [Accepted: 09/25/2012] [Indexed: 12/25/2022]

Paganetti H, van Luijk P. Biological considerations when comparing proton therapy with photon therapy. Semin Radiat Oncol 2013;23:77-87. [PMID: 23473684 DOI: 10.1016/j.semradonc.2012.11.002] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]

Zips D, Baumann M. Place of proton radiotherapy in future radiotherapy practice. Semin Radiat Oncol 2013;23:149-53. [PMID: 23473693 DOI: 10.1016/j.semradonc.2012.11.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]

Buettner F, Miah AB, Gulliford SL, Hall E, Harrington KJ, Webb S, Partridge M, Nutting CM. Novel approaches to improve the therapeutic index of head and neck radiotherapy: an analysis of data from the PARSPORT randomised phase III trial. Radiother Oncol 2012;103:82-7. [PMID: 22444242 DOI: 10.1016/j.radonc.2012.02.006] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Revised: 01/22/2012] [Accepted: 02/06/2012] [Indexed: 10/28/2022]

van der Schaaf A, Xu CJ, van Luijk P, Van't Veld AA, Langendijk JA, Schilstra C. Multivariate modeling of complications with data driven variable selection: guarding against overfitting and effects of data set size. Radiother Oncol 2012;105:115-21. [PMID: 22264894 DOI: 10.1016/j.radonc.2011.12.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 11/03/2011] [Accepted: 12/12/2011] [Indexed: 11/27/2022]

Abstract

PURPOSE

Multivariate modeling of complications after radiotherapy is frequently used in conjunction with data driven variable selection. This study quantifies the risk of overfitting in a data driven modeling method using bootstrapping for data with typical clinical characteristics, and estimates the minimum amount of data needed to obtain models with relatively high predictive power.

MATERIALS AND METHODS

To facilitate repeated modeling and cross-validation with independent datasets for the assessment of true predictive power, a method was developed to generate simulated data with statistical properties similar to real clinical data sets. Characteristics of three clinical data sets from radiotherapy treatment of head and neck cancer patients were used to simulate data with set sizes between 50 and 1000 patients. A logistic regression method using bootstrapping and forward variable selection was used for complication modeling, resulting for each simulated data set in a selected number of variables and an estimated predictive power. The true optimal number of variables and true predictive power were calculated using cross-validation with very large independent data sets.

RESULTS

For all simulated data set sizes the number of variables selected by the bootstrapping method was on average close to the true optimal number of variables, but showed considerable spread. Bootstrapping is more accurate in selecting the optimal number of variables than the AIC and BIC alternatives, but this did not translate into a significant difference of the true predictive power. The true predictive power asymptotically converged toward a maximum predictive power for large data sets, and the estimated predictive power converged toward the true predictive power. More than half of the potential predictive power is gained after approximately 200 samples. Our simulations demonstrated severe overfitting (a predicative power lower than that of predicting 50% probability) in a number of small data sets, in particular in data sets with a low number of events (median: 7, 95th percentile: 32). Recognizing overfitting from an inverted sign of the estimated model coefficients has a limited discriminative value.

CONCLUSIONS

Despite considerable spread around the optimal number of selected variables, the bootstrapping method is efficient and accurate for sufficiently large data sets, and guards against overfitting for all simulated cases with the exception of some data sets with a particularly low number of events. An appropriate minimum data set size to obtain a model with high predictive power is approximately 200 patients and more than 32 events. With fewer data samples the true predictive power decreases rapidly, and for larger data set sizes the benefit levels off toward an asymptotic maximum predictive power.

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Teoh M, Clark CH, Wood K, Whitaker S, Nisbet A. Volumetric modulated arc therapy: a review of current literature and clinical use in practice. Br J Radiol 2011;84:967-96. [PMID: 22011829 DOI: 10.1259/bjr/22373346] [Citation(s) in RCA: 469] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open

Beetz I, Schilstra C, van Luijk P, Christianen MEMC, Doornaert P, Bijl HP, Chouvalova O, van den Heuvel ER, Steenbakkers RJHM, Langendijk JA. External validation of three dimensional conformal radiotherapy based NTCP models for patient-rated xerostomia and sticky saliva among patients treated with intensity modulated radiotherapy. Radiother Oncol 2011;105:94-100. [PMID: 22169766 DOI: 10.1016/j.radonc.2011.11.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Revised: 11/11/2011] [Accepted: 11/16/2011] [Indexed: 10/14/2022]

Abstract

PURPOSE

The purpose of this study was to investigate the ability of predictive models for patient-rated xerostomia (XER(6M)) and sticky saliva (STIC(6M)) at 6 months after completion of primary (chemo)radiation developed in head and neck cancer patients treated with 3D-conformal radiotherapy (3D-CRT) to predict outcome in patients treated with intensity modulated radiotherapy (IMRT).

METHODS AND MATERIALS

Recently, we published the results of a prospective study on predictive models for patient-rated xerostomia and sticky saliva in head and neck cancer patients treated with 3D-CRT (3D-CRT based NTCP models). The 3D-CRT based model for XER(6M) consisted of three factors, including the mean parotid dose, age, and baseline xerostomia (none versus a bit). The 3D-CRT based model for STIC(6M) consisted of the mean submandibular dose, age, the mean sublingual dose, and baseline sticky saliva (none versus a bit). In the current study, a population consisting of 162 patients treated with IMRT was used to test the external validity of these 3D-CRT based models. External validity was described by the explained variation (R(2) Nagelkerke) and the Brier score. The discriminative abilities of the models were calculated using the area under the receiver operating curve (AUC) and calibration (i.e. the agreement between predicted and observed outcome) was assessed with the Hosmer-Lemeshow "goodness-of-fit" test.

RESULTS

Overall model performance of the 3D-CRT based predictive models for XER(6M) and STIC(6M) was significantly worse in terms of the Brier score and R(2) Nagelkerke among patients treated with IMRT. Moreover the AUC for both 3D-CRT based models in the IMRT treated patients were markedly lower. The Hosmer-Lemeshow test showed a significant disagreement for both models between predicted risk and observed outcome.

CONCLUSION

3D-CRT based models for patient-rated xerostomia and sticky saliva among head and neck cancer patients treated with primary radiotherapy or chemoradiation turned out to be less valid for patients treated with IMRT. The main message from these findings is that models developed in a population treated with a specific technique cannot be generalised and extrapolated to a population treated with another technique without external validation.

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Greubel C, Assmann W, Burgdorf C, Dollinger G, Du G, Hable V, Hapfelmeier A, Hertenberger R, Kneschaurek P, Michalski D, Molls M, Reinhardt S, Röper B, Schell S, Schmid TE, Siebenwirth C, Wenzl T, Zlobinskaya O, Wilkens JJ. Scanning irradiation device for mice in vivo with pulsed and continuous proton beams. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2011;50:339-344. [PMID: 21556847 DOI: 10.1007/s00411-011-0365-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Accepted: 04/19/2011] [Indexed: 05/30/2023]

Bortfeld T, Jeraj R. The physical basis and future of radiation therapy. Br J Radiol 2011;84:485-98. [PMID: 21606068 PMCID: PMC3473639 DOI: 10.1259/bjr/86221320] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Revised: 12/23/2010] [Accepted: 01/06/2011] [Indexed: 12/25/2022] Open

Fiorino C, Maggiulli E, Broggi S, Liberini S, Cattaneo GM, Dell'oca I, Faggiano E, Di Muzio N, Calandrino R, Rizzo G. Introducing the Jacobian-volume-histogram of deforming organs: application to parotid shrinkage evaluation. Phys Med Biol 2011;56:3301-12. [PMID: 21558590 DOI: 10.1088/0031-9155/56/11/008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]

Evidence-based review: quality of life following head and neck intensity-modulated radiotherapy. Radiother Oncol 2011;97:249-57. [PMID: 20817284 DOI: 10.1016/j.radonc.2010.08.004] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Revised: 07/07/2010] [Accepted: 08/12/2010] [Indexed: 11/23/2022]

Coppes RP, Stokman MA. Stem cells and the repair of radiation-induced salivary gland damage. Oral Dis 2010;17:143-53. [DOI: 10.1111/j.1601-0825.2010.01723.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]

Palma DA, Senan S, Haasbeek CJA, Verbakel WFAR, Vincent A, Lagerwaard F. Radiological and clinical pneumonitis after stereotactic lung radiotherapy: a matched analysis of three-dimensional conformal and volumetric-modulated arc therapy techniques. Int J Radiat Oncol Biol Phys 2010;80:506-13. [PMID: 20584582 DOI: 10.1016/j.ijrobp.2010.02.032] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2009] [Revised: 02/05/2010] [Accepted: 02/08/2010] [Indexed: 10/19/2022]

Abstract

PURPOSE

Lung fibrosis is common after stereotactic body radiotherapy (SBRT) for lung tumors, but the influence of treatment technique on rates of clinical and radiological pneumonitis is not well described. After implementing volumetric modulated arc therapy (RapidArc [RA]; Varian Medical Systems, Palo Alto, CA) for SBRT, we scored the early pulmonary changes seen with arc and conventional three-dimensional SBRT (3D-CRT).

METHODS AND MATERIALS

Twenty-five SBRT patients treated with RA were matched 1:2 with 50 SBRT patients treated with 3D-CRT. Dose fractionations were based on a risk-adapted strategy. Clinical pneumonitis was scored using Common Terminology Criteria for Adverse Events version 3.0. Acute radiological changes 3 months posttreatment were scored by three blinded observers. Relationships among treatment type, baseline factors, and outcomes were assessed using Spearman's correlation, Cochran-Mantel-Haenszel tests, and logistic regression.

RESULTS

The RA and 3D-CRT groups were well matched. Forty-three patients (57%) had radiological pneumonitis 3 months after treatment. Twenty-eight patients (37%) had computed tomography (CT) findings of patchy or diffuse consolidation, and 15 patients (20%) had ground-glass opacities only. Clinical pneumonitis was uncommon, and no differences were seen between 3D-CRT vs. RA patients in rates of grade 2/3 clinical pneumonitis (6% vs. 4%, respectively; p = 0.99), moderate/severe radiological changes (24% vs. 36%, respectively, p = 0.28), or patterns of CT changes (p = 0.47). Radiological severity scores were associated with larger planning target volumes (p = 0.09) and extended fractionation (p = 0.03).

CONCLUSIONS

Radiological changes after lung SBRT are common with both approaches, but no differences in early clinical or radiological findings were observed after RA. Longer follow-up will be required to exclude late changes.

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Xerostomia in head and neck malignancy. Oral Oncol 2010;46:460-3. [PMID: 20403723 DOI: 10.1016/j.oraloncology.2010.03.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Accepted: 03/08/2010] [Indexed: 12/11/2022]

Broggi S, Fiorino C, Dell’Oca I, Dinapoli N, Paiusco M, Muraglia A, Maggiulli E, Ricchetti F, Valentini V, Sanguineti G, Cattaneo GM, Di Muzio N, Calandrino R. A two-variable linear model of parotid shrinkage during IMRT for head and neck cancer. Radiother Oncol 2010;94:206-12. [DOI: 10.1016/j.radonc.2009.12.014] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2009] [Revised: 12/15/2009] [Accepted: 12/20/2009] [Indexed: 10/19/2022]