RESUMEN
Radiotherapy (RT) is a modality of oncologic treatment that can be used to treat approximately 50% of all cancer patients either alone or in combination with other treatment modalities such as surgery, chemotherapy, immunotherapy, and therapeutic targeting. Despite the technological advances in RT, which allow a more precise delivery of radiation while progressively minimizing the impact on normal tissues, issues like radioresistance and tumor recurrence remain important challenges. Tumor heterogeneity is responsible for the variation in the radiation response of the different tumor subpopulations. A main factor related to radioresistance is the presence of cancer stem cells (CSC) inside tumors, which are responsible for metastases, relapses, RT failure, and a poor prognosis in cancer patients. The plasticity of CSCs, a process highly dependent on the epithelial-mesenchymal transition (EMT) and associated to cell dedifferentiation, complicates the identification and eradication of CSCs and it might be involved in disease relapse and progression after irradiation. The tumor microenvironment and the interactions of CSCs with their niches also play an important role in the response to RT. This review provides a deep insight into the characteristics and radioresistance mechanisms of CSCs and into the role of CSCs and tumor microenvironment in both the primary tumor and metastasis in response to radiation, and the radiobiological principles related to the CSC response to RT. Finally, we summarize the major advances and clinical trials on the development of CSC-based therapies combined with RT to overcome radioresistance. A better understanding of the potential therapeutic targets for CSC radiosensitization will provide safer and more efficient combination strategies, which in turn will improve the live expectancy and curability of cancer patients.
Asunto(s)
Neoplasias/radioterapia , Células Madre Neoplásicas/efectos de la radiación , Tolerancia a Radiación , Radioterapia/métodos , Animales , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Radioterapia/efectos adversos , Radioterapia/normasRESUMEN
BACKGROUND: Standard radiobiology theory of radiation response assumes a uniform innate radiosensitivity of tumors. However, experimental data show that there is significant intratumoral heterogeneity of radiosensitivity. Therefore, a model with heterogeneity was developed and tested using existing experimental data to show the potential effects from the presence of an intratumoral distribution of radiosensitivity on radiation therapy response over a protracted radiation therapy treatment course. METHODS: The standard radiation response curve was modified to account for a distribution of radiosensitivity, and for variations in the repopulation rates of the tumor cell subpopulations. Experimental data from the literature were incorporated to determine the boundaries of the model. The proposed model was then used to show the changes in radiosensitivity of the tumor during treatment, and the effects of fraction size, α/ß ratio and variation of the repopulation rates of tumor cells. RESULTS: In the presence of an intratumoral distribution of radiosensitivity, there is rapid selection of radiation-resistant cells over a course of fractionated radiation therapy. Standard treatment fractionation regimes result in the near-complete replacement of the initial population of sensitive cells with a population of more resistant cells. Further, as treatment progresses, the tumor becomes more resistant to further radiation treatment, making each fractional dose less efficacious. A wider initial distribution induces increased radiation resistance. Hypofractionation is more efficient in a heterogeneous tumor, with increased cell kill for biologically equivalent doses, while inducing less resistance. The model also shows that a higher growth rate in resistant cells can account for the accelerated repopulation that is seen during the clinical treatment of patients. CONCLUSIONS: Modeling of tumor cell survival with radiosensitivity heterogeneity alters the predicted tumor response, and explains the induction of radiation resistance by radiation treatment, the development of accelerated repopulation, and the potential beneficial effects of hypofractionation. Tumor response to treatment may be better predicted by assaying for the distribution of radiosensitivity, or the extreme of the radiosensitivity, rather than measuring the initial, general radiation sensitivity of the untreated tumor.
Asunto(s)
Fraccionamiento de la Dosis de Radiación , Modelos Biológicos , Neoplasias/radioterapia , Tolerancia a Radiación/efectos de la radiación , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Humanos , Neoplasias/patología , Radiobiología/normas , Efectividad Biológica RelativaRESUMEN
PURPOSE: To assess tumor cell proliferation and repopulation during fractionated radiotherapy and investigate the spatial concordance of cell proliferation and repopulation according to the uptake of 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT). PROCEDURES: Mice bearing A549 xenograft tumors were assigned to five irradiated groups, including 3 fraction (f)/6 days (d), 6f/12d, 9f/18d, 12f/24d, and 18f/36d with 2 Gy/f irradiations performed every other day and one non-irradiated group. Serial [18F]FLT positron emission tomography (PET) scans were performed at different time points as the groups finished the radiotherapy. The maximum of standard uptake values (SUVmax) were measured to confirm the likely time of tumor repopulation. A layer-by-layer comparison between SUVmax of PET images and Ki-67 LI of pathology images, including the thresholds at which maximum overlap occurred between FLT-segmented areas and cell proliferation areas were conducted to evaluate the spatial correlation. RESULTS: The SUVmax decreased in the 3f/6d group (P = 0.000) compared to the non-irradiated group, increased in the 6f/12d group and then gradually reduced with prolonged treatment. Proliferation changes in 6f/12d group on pathology images were also confirmed. Significant correlations were found between the SUVmax and Ki-67 LI in each in vitro tumor of cell proliferation group and accelerated repopulation group (both of the P < 0.001). Furthermore, the mean overlap region rates (ORRs) were 56.21 % and 57.82 % in the proliferation group and repopulation group, respectively. The data represented the preferable registration. CONCLUSIONS: [18F]FLT PET is a promising imaging surrogate of tumor proliferative response to fractionated radiotherapy and may help make an adaptive radiation oncology treatment plan to realize radiotherapy dose painting.
Asunto(s)
Didesoxinucleósidos/farmacocinética , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Tomografía de Emisión de Positrones , Dosificación Radioterapéutica , Células A549 , Animales , Proliferación Celular , Estudios de Factibilidad , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND AND PURPOSE: Accelerated repopulation (AR) can compromise tumor control after conventional radiotherapy for fast-growing tumors. Standard AR models assume it begins at a fixed time, with repopulation rates independent of the number of clonogens killed. We investigate the validity and significance of an alternative model where onset-time and rate of AR depend on the number of clonogens killed, and thus on dose and dose-fractionation. MATERIALS AND METHODS: We analyzed tumor control (TCP) from randomized trials for head and neck cancer (HNC, 7283 patients), featuring wide ranges of doses, times, and fractionation-schemes. We used the linear-quadratic model with the standard dose-independent AR model, or with an alternative dose-dependent model, where AR onset and rate depend on clonogen killing. RESULTS: The alternative dose-dependent model of AR provides significantly-improved descriptions of a wide range of randomized clinical data, relative to the standard dose-independent model. This preferred model predicts that, for currently-used HNC fractionation schemes, the last 5 fractions do not increase TCP, but simply compensate for increased accelerated repopulation. CONCLUSIONS: The preferred dose-dependent AR model predicts that, for standard fractionation schemes currently used to treat HNC, the final week (5 fractions) could be eliminated without compromising TCP, but resulting in significantly decreased late sequelae due to the lower overall dose.
Asunto(s)
Neoplasias de Cabeza y Cuello/radioterapia , Modelos Biológicos , Fraccionamiento de la Dosis de Radiación , Relación Dosis-Respuesta en la Radiación , Neoplasias de Cabeza y Cuello/patología , Humanos , Funciones de Verosimilitud , Modelos Lineales , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Prolonged radiation treatment time (RTT) in head and neck squamous cell carcinoma (HNSCC) is associated with inferior tumor control in patients treated with radiation therapy (RT) alone. However, the significance of prolonged RTT with concurrent chemotherapy is less clear. METHODS: We reviewed outcomes for 171 patients with primary HNSCC treated with curative intent RT and concurrent drug therapy from 2001 to 2009. The effects of RTT and other variables on local control and survival were analyzed. RESULTS: Patients with RTT >7 weeks had a significantly increased risk of local failure (hazard ratio [HR], 2.6; p = .018) and death (HR, 1.9 p = .035). These results retained significance even after adjustment for tumor stage (age was not significant). CONCLUSION: For patients treated with concurrent chemoradiotherapy (chemoRT), prolonged RTT may compromise tumor control as has been established in the setting of RT alone. Symptoms of patients with HNSCC undergoing definitive chemoRT should be managed aggressively to limit treatment interruptions.