RESUMEN
Synchronous bilateral breast cancers (SBBC) present a considerable issue in external beam radiotherapy because of large fields size and large target volumes. Mono-isocentric volumetric modulated arc therapy (VMAT) appears as an appropriate irradiation technique for these types of tumors. The aim of this study was to demonstrate the utility of a 3D DVH pretreatment quality assurance program in VMAT of SBBC cases. Twenty SBBC patients who underwent radiation therapy in our department were retrospectively enrolled in this study. Fifteen patients were treated exclusively to the mammary glands. Five patients benefited from a dose boost on the tumor bed (60Gy). Nine patients were irradiated on the supraclavicular nodes (50Gy). This dose was delivered in 25 fractions and integrated boost was used when appropriate. Depending on the complexity of the treatment plans; 2 or 4 arcs VMAT plans were used in a mono-isocentric technique. The patient specific quality assurance (PSQA) was evaluated using COMPASS measured data, COMPASS reconstructed (CR) and COMPASS computed (CC) dose compared to treatment planning system (TPS) dose. Clinical evaluation was based on DVH metrics for target volumes and organ at risks. The maximum average dose deviation between TPS, CC, and CR was below 3%. The paired t-test between TPS, CC, and CR shows a strong agreement (p < 0.001). The 3DVH dose distribution comparison between TPS and COMPASS were also performed with good gamma score for global analysis. COMPASS was successfully evaluated as a 3DVH pretreatment system for SBBC despite the large fields size and complex target volumes. It allows the verification of the plan in 3D patient anatomy and the evaluation of dose discrepancies.
RESUMEN
Poor local control and tumor escape are of major concern in head-and-neck cancers treated by conventional radiotherapy or hadrontherapy. Reduced glutathione (GSH) is suspected of playing an important role in mechanisms leading to radioresistance, and its depletion should enable oxidative stress insult, thereby modifying the nature of DNA lesions and the subsequent chromosomal changes that potentially lead to tumor escape.This study aimed to highlight the impact of a GSH-depletion strategy (dimethylfumarate, and L-buthionine sulfoximine association) combined with carbon ion or X-ray irradiation on types of DNA lesions (sparse or clustered) and the subsequent transmission of chromosomal changes to the progeny in a radioresistant cell line (SQ20B) expressing a high endogenous GSH content. Results are compared with those of a radiosensitive cell line (SCC61) displaying a low endogenous GSH level. DNA damage measurements (γH2AX/comet assay) demonstrated that a transient GSH depletion in resistant SQ20B cells potentiated the effects of irradiation by initially increasing sparse DNA breaks and oxidative lesions after X-ray irradiation, while carbon ion irradiation enhanced the complexity of clustered oxidative damage. Moreover, residual DNA double-strand breaks were measured whatever the radiation qualities. The nature of the initial DNA lesions and amount of residual DNA damage were similar to those observed in sensitive SCC61 cells after both types of irradiation. Misrepaired or unrepaired lesions may lead to chromosomal changes, estimated in cell progeny by the cytome assay. Both types of irradiation induced aberrations in nondepleted resistant SQ20B and sensitive SCC61 cells. The GSH-depletion strategy prevented the transmission of aberrations (complex rearrangements and chromosome break or loss) in radioresistant SQ20B only when associated with carbon ion irradiation. A GSH-depleting strategy combined with hadrontherapy may thus have considerable advantage in the care of patients, by minimizing genomic instability and improving the local control.
Asunto(s)
Carbono/química , Cromosomas Humanos/metabolismo , Daño del ADN , Glutatión/deficiencia , Neoplasias/metabolismo , Neoplasias/patología , Radiación , Butionina Sulfoximina/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de la radiación , Muerte Celular/efectos de los fármacos , Muerte Celular/efectos de la radiación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Cromatografía Líquida de Alta Presión , Células Clonales , Análisis por Conglomerados , Roturas del ADN de Doble Cadena/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de la radiación , Roturas del ADN de Cadena Simple/efectos de los fármacos , Roturas del ADN de Cadena Simple/efectos de la radiación , Dimetilfumarato , Fumaratos/farmacología , Reordenamiento Génico/efectos de los fármacos , Reordenamiento Génico/efectos de la radiación , Glutatión/metabolismo , Histonas/metabolismo , Humanos , Iones , Cinética , Pruebas de Micronúcleos , Rayos XRESUMEN
PURPOSE: We initiated studies on the mechanisms of cell death in head and neck squamous cell carcinoma cell lines (HNSCC) since recent clinical trials have shown that local treatment of HNSCC by carbon hadrontherapy is less efficient than it is in other radioresistant cancers. METHODS AND MATERIALS: Two p53-mutated HNSCC cell lines displaying opposite radiosensitivity were used. Different types of cell death were determined after exposure to carbon ions (33.6 and 184 keV/microm) or X-rays. RESULTS: Exposure to radiation with high linear energy transfer (LET) induced clonogenic cell death for SCC61 (radiosensitive) and SQ20B (radioresistant) cells, the latter systematically showing less sensitivity. Activation of an early p53-independent apoptotic process occurred in SCC61 cells after both types of irradiation, which increased with time, dose and LET. In contrast, SQ20B cells underwent G2/M arrest associated with Chk1 activation and Cdc2 phosphorylation. This inhibition was transient after X-rays, compared with a more prolonged and LET-dependent accumulation after carbon irradiation. After release, a LET-dependent increase of polyploid and multinucleated cells, both typical signs of mitotic catastrophe, was identified. However, a subpopulation of SQ20B cells was able to escape mitotic catastrophe and continue to proliferate. CONCLUSIONS: High LET irradiation induced distinct types of cell death in HNSCC cell lines and showed an increased effectiveness compared with X-rays. However, the reproliferation of SQ20B may explain the potential locoregional recurrence observed among some HNSCC patients treated by hadrontherapy. An adjuvant treatment forcing the tumor cells to enter apoptosis may therefore be necessary to improve the outcome of radiotherapy.
Asunto(s)
Carcinoma de Células Escamosas/radioterapia , Muerte Celular , Neoplasias de Cabeza y Cuello/radioterapia , Tolerancia a Radiación , Proteína Quinasa CDC2/metabolismo , Radioisótopos de Carbono/farmacología , Muerte Celular/fisiología , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Fase G2/efectos de la radiación , Genes p53/genética , Humanos , Transferencia Lineal de Energía , Mitosis/efectos de la radiación , Proteínas Quinasas/metabolismo , Tolerancia a Radiación/genética , beta-Galactosidasa/metabolismoRESUMEN
PURPOSE: To establish the radiobiologic parameters of head-and-neck squamous cell carcinomas (HNSCC) in response to ion irradiation with various linear energy transfer (LET) values and to evaluate the relevance of the local effect model (LEM) in HNSCC. METHODS AND MATERIALS: Cell survival curves were established in radiosensitive SCC61 and radioresistant SQ20B cell lines irradiated with [33.6 and 184 keV/n] carbon, [302 keV/n] argon, and X-rays. The results of ion experiments were confronted to LEM predictions. RESULTS: The relative biologic efficiency ranged from 1.5 to 4.2 for SCC61 and 2.1 to 2.8 for SQ20B cells. Fixing an arbitrary D(0) parameter, which characterized survival to X-ray at high doses (>10 Gy), gave unsatisfying LEM predictions for both cell lines. For D(0) = 10 Gy, the error on survival fraction at 2 Gy amounted to a factor of 10 for [184 keV/n] carbon in SCC61 cells. We showed that the slope (s(max)) of the survival curve at high doses was much more reliable than D(0). Fitting s(max) to 2.5 Gy(-1) gave better predictions for both cell lines. Nevertheless, LEM could not predict the responses to fast and slow ions with the same accuracy. CONCLUSIONS: The LEM could predict the main trends of these experimental data with correct orders of magnitude while s(max) was optimized. Thus the efficiency of carbon ions cannot be simply extracted from the clinical response of a patient to X-rays. LEM should help to optimize planning for hadrontherapy if a set of experimental data is available for high-LET radiations in various types of tumors.