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The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APC(Min/+)MSH2(-/-) mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuel hyperproliferation of MSH2(-/-) colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating ß-catenin activity and modulating the differentiation of transit-amplifying cells in the colon. These data thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction. PAPERCLIP:
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Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Carbohidratos de la Dieta/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Animales , Butiratos/metabolismo , Proliferación Celular , Transformación Celular Neoplásica , Pólipos del Colon/metabolismo , Pólipos del Colon/microbiología , Pólipos del Colon/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/microbiología , Reparación de la Incompatibilidad de ADN , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Inflamación/genética , Inflamación/metabolismo , Inflamación/microbiología , Ratones , Ratones Endogámicos C57BL , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/metabolismo , Organismos Libres de Patógenos Específicos , beta Catenina/metabolismoRESUMEN
BACKGROUND: There are limited preclinical orthotopic prostate cancer models due to the technical complexity of surgical engraftment and tracking the tumor growth in the mouse prostate gland. Orthotopic xenografts recapitulate the tumor microenvironment, tumor stromal interactions, and clinical behavior to a greater extent than xenografts grown at subcutaneous or intramuscular sites. METHODS: This study describes a novel micro-surgical technique for orthotopically implanting intact tumors pieces from cell line derived (transgenic adenocarcinoma mouse prostate [TRAMP]-C2) or patient derived (neuroendocrine prostate cancer [NEPC]) tumors in the mouse prostate gland and monitoring tumor growth using magnetic resonance (MR) imaging. RESULTS: The TRAMP-C2 tumors grew rapidly to a predetermined endpoint size of 10 mm within 3 weeks, whereas the NEPC tumors grew at a slower rate over 7 weeks. The tumors were readily detected by MR and confidently identified when they were approximately 2-3 mm in size. The tumors were less well-defined on CT. The TRAMP-C2 tumors were characterized by amorphous sheets of poorly differentiated cells similar to a high-grade prostatic adenocarcinoma and frequent macroscopic peritoneal and lymph node metastases. In contrast, the NEPC's displayed a neuroendocrine morphology with polygonal cells arranged in nests and solid sheets and high count. There was a local invasion of the bladder and other adjacent tissues but no identifiable metastases. The TRAMP-C2 tumors were more hypoxic than the NEPC tumors. CONCLUSIONS: This novel preclinical orthotopic prostate cancer mouse model is suitable for either syngeneic or patient derived tumors and will be effective in developing and advancing the current selection of treatments for patients with prostate cancer.
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Adenocarcinoma , Modelos Animales de Enfermedad , Neoplasias de la Próstata , Animales , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/diagnóstico por imagen , Ratones , Humanos , Adenocarcinoma/patología , Adenocarcinoma/terapia , Línea Celular Tumoral , Ratones Transgénicos , Trasplante de Neoplasias/métodos , Imagen por Resonancia Magnética , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/diagnóstico por imagen , Carcinoma Neuroendocrino/terapiaRESUMEN
BACKGROUND: Sexual health is an important survivorship issue in cervical cancer. We assessed patient-reported sexual health outcomes and correlations with oncologist-assessed vaginal toxicity (VT). METHODS: This was a prospective, cross-sectional study of stage IB-IVA cervical cancer patients treated with definitive chemoradiation, who completed a socio-demographic questionnaire and the following patient-reported-outcomes (PROs): Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), Menopause Rating Scale (MRS), Hospital Anxiety and Depression Scale (HADS). VT was assessed using the CTCAE v4.0. Sociodemographic, clinical data, PROs and VT were summarized using descriptive statistics; correlations were evaluated using linear regression analyses. RESULTS: Between August 2018 and April 2022, 73 patients were analyzed. Median age was 49 (range 25-81), 57.5% had vaginal involvement at diagnosis and 76.9% were partnered. Sexual dysfunction (FSFI score ≤ 26), sexual distress (FSDS-R ≥ 11), severe menopausal symptoms (MRS ≥ 17), anxiety (HAD-Anxiety >7) and depression (HAS-Depression >7) were reported in 86.3%, 54.5%, 36.2%, 46.6% and 24.7%, respectively. Grade 2+ VT was reported in 27.4%. No significant associations were found between PROs and VT. On multivariable analysis, non-partnered status, use of hormone replacement therapy, and International Commission on Radiation Units and Measurements - rectovaginal dose (ICRU-RV) >65Gy were associated with worse sexual health (p < 0.005). CONCLUSION: Cervical cancer patients self-report high rates of sexual distress, dysfunction and menopause symptoms. Discordance between oncologist-assessed VT and PROs highlights the importance of evaluating the patient's experience. Proactive treatment of menopausal symptoms and attention to radiotherapy doses to the vagina should be considered.
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OBJECTIVE: Wee1 kinase is a crucial regulator of the G2/M checkpoint which prevents entry of damaged DNA into mitosis. Adavosertib (AZD1775), a selective inhibitor of Wee1, induces G2 escape and increases cytotoxicity when combined with DNA damaging agents. We aimed to evaluate the safety and efficacy of adavosertib in combination with definitive pelvic radiotherapy and concurrent cisplatin in patients with gynecological cancers. METHODS: A multi-institutional, open-label phase I trial was designed to assess dose escalation (3+3 design) of adavosertib in combination with standard chemoradiation. Eligible patients with locally advanced cervical, endometrial or vaginal tumors were treated with a 5-week course of pelvic external beam radiation 45-50 Gy in 1.8-2 Gy daily fractions plus concurrent weekly cisplatin 40 mg/m2 and adavosertib 100 mg/m2 on days 1, 3 and 5 of each week during chemoradiation. The primary endpoint was to determine the recommended phase II dose of adavosertib. Secondary endpoints included toxicity profile and preliminary efficacy. RESULTS: Ten patients were enrolled (nine locally advanced cervical and one endometrial cancer). Two patients experienced a dose-limiting toxicity at dose level 1 (adavosertib 100 mg by mouth daily on days 1, 3 and 5), including one patient with grade 4 thrombocytopenia, and one with treatment hold >1 week due to grade 1 creatinine elevation and grade 1 thrombocytopenia. At dose level -1 (adavosertib 100 mg by mouth daily on days 3 and 5), one out of five patients enrolled had a dose-limiting toxicity in the form of persistent grade 3 diarrhea. The overall response rate at 4 months was 71.4%, including four complete responses. At 2 years follow-up, 86% of patients were alive and progression-free. CONCLUSION: The recommended phase II dose could not be determined due to clinical toxicity and early trial closure. Preliminary efficacy appears promising, yet selecting the adequate dose/schedule in combination chemoradiation warrants further investigation to limit overlapping toxicities.
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Antineoplásicos , Trombocitopenia , Neoplasias del Cuello Uterino , Femenino , Humanos , Cisplatino/uso terapéutico , Antineoplásicos/uso terapéutico , Inhibidores de Proteínas Quinasas , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Primary vaginal cancer is a rare cancer and clinical evidence to support recommendations on its optimal management is insufficient. Because primary vaginal cancer resembles cervical cancer in many aspects, treatment strategies are mainly adopted from evidence in locally advanced cervical cancer. To date, the organ-sparing treatment of choice is definitive radiotherapy, consisting of external beam radiotherapy and brachytherapy, combined with concurrent chemotherapy. Brachytherapy is an important component of the treatment and its steep dose gradient enables the delivery of high doses of radiation to the primary tumour, while simultaneously sparing the surrounding organs at risk. The introduction of volumetric CT or MRI image-guided adaptive brachytherapy in cervical cancer has led to better pelvic control and survival, with decreased morbidity, than brachytherapy based on x-ray radiographs. MRI-based image-guided adaptive brachytherapy with superior soft-tissue contrast has also been adopted sporadically for primary vaginal cancer. This therapy has had promising results and is considered to be the state-of-the-art treatment for primary vaginal cancer in standard practice.
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Braquiterapia , Imagen por Resonancia Magnética , Dosis de Radiación , Radioterapia Guiada por Imagen/métodos , Tomografía Computarizada por Rayos X , Neoplasias Vaginales/radioterapia , Braquiterapia/efectos adversos , Braquiterapia/mortalidad , Quimioradioterapia , Femenino , Humanos , Tratamientos Conservadores del Órgano , Valor Predictivo de las Pruebas , Radioterapia Guiada por Imagen/efectos adversos , Radioterapia Guiada por Imagen/mortalidad , Factores de Riesgo , Resultado del Tratamiento , Neoplasias Vaginales/diagnóstico por imagen , Neoplasias Vaginales/mortalidad , Neoplasias Vaginales/patologíaRESUMEN
Vulvar squamous cell carcinomas (VSCC) represent the most common carcinoma of the female external genitalia, with increasing incidence. Although high-risk human papillomavirus (HPV) infection has long been implicated in the majority of cervical and anal squamous cell carcinomas, there is uncertainty about its prevalence and prognostic impact in VSCC. In this study, we conducted a retrospective integrated morphologic and multimodal HPV analysis of a cohort of 114 VSCC cases treated at the Princess Margaret Cancer Centre/University Health Network, Toronto, Canada between 2000 and 2010. VSCC histology was reviewed. We analyzed the cohort for HPV using polymerase chain reaction based method, and tissue microarray DNA and RNA in situ hybridization (ISH), and p16 immunohistochemistry. Among the 114 cases (age 70±16 yr), 36.7% of cases were classified as having histomorphology of HPV infection. HPV was detected in 31.9% (polymerase chain reaction), 14.0% (DNA ISH), and 27.3% (RNA ISH) of cases. p16 immunohistochemistry was positive in 37.8% of cases. On univariate analysis, HPV morphology (P=0.009), p16+ (P=0.00013), DNA ISH+ (P=0.021), and RNA ISH+ (P=0.00061) were associated with better 5-yr progression-free survival. DNA ISH+ (P=0.049) was associated with better 5-yr overall survival. On multivariate analysis, HPV morphology (P=0.033), p16+ (P=0.01), and RNA ISH+ (P=0.035) were associated with better 5-yr progression-free survival. In conclusion, a subset of VSCC is associated with HPV, which correlates with better outcome. Relatively inexpensive tests such as histomorphologic evaluation, p16 immunohistochemistry, and HPV RNA ISH can be used to predict outcome in VSCC. Therefore, routine reporting of HPV status in VSCC is recommended.
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Carcinoma de Células Escamosas/diagnóstico , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/diagnóstico , Neoplasias de la Vulva/diagnóstico , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/patología , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Hibridación in Situ , Persona de Mediana Edad , Ontario/epidemiología , Papillomaviridae/genética , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/patología , Reacción en Cadena de la Polimerasa , Pronóstico , Supervivencia sin Progresión , ARN Viral/genética , Estudios Retrospectivos , Neoplasias de la Vulva/epidemiología , Neoplasias de la Vulva/patologíaRESUMEN
BACKGROUND: Radiotherapy is standard of care for cervical cancer, but major global gaps in access exist, particularly in low-income and middle-income countries. We modelled the health and economic benefits of a 20-year radiotherapy scale-up to estimate the long-term demand for treatment in the context of human papillomavirus (HPV) vaccination. METHODS: We applied the Global Task Force on Radiotherapy for Cancer Control investment framework to model the health and economic benefits of scaling up external-beam radiotherapy and brachytherapy for cervical cancer in upper-middle-income, lower-middle-income, and low-income countries between 2015 and 2035. We estimated the unique costs of external-beam radiotherapy and brachytherapy and included a specific valuation of women's caregiving contributions. Model outcomes life-years gained and the human capital and full income net present value of investment. We estimated the effects of stage at diagnosis, radiotherapy delivery system, and simultaneous HPV vaccination (75% coverage) up to a time horizon set at 2072. FINDINGS: For the period from 2015 to 2035, we estimated that 9·4 million women in low-income and middle-income countries required treatment with external-beam radiotherapy, of which 7·0 million also required treatment with brachytherapy. Incremental scale-up of radiotherapy in these countries from 2015 to meet optimal radiotherapy demand by 2035 yielded 11·4 million life-years gained, $59·3 billion in human capital net present value (-$1·5 billion in low-income, $19·9 billion in lower-middle-income, and $40·9 billion in upper-middle-income countries), and $151·5 billion in full income net present value ($1·5 billion in low-income countries, $53·6 billion in lower-middle-income countries, and $96·4 billion in upper-middle-income countries). Benefits increased with advanced stage of cervical cancer and more efficient scale up of radiotherapy. Bivalent HPV vaccination of 12-year-old girls resulted in a 3·9% reduction in incident cases from 2015-2035. By 2072, when the first vaccinated cohort of girls reaches 70 years of age, vaccination yielded a 22·9% reduction in cervical cancer incidence, with 38·4 million requiring external-beam radiotherapy and 28·8 million requiring brachytherapy. INTERPRETATION: Effective cervical cancer control requires a comprehensive strategy. Even with HPV vaccination, radiotherapy treatment scale-up remains essential and produces large health benefits and a strong return on investment to countries at different levels of development. FUNDING: None.
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Costos de la Atención en Salud , Necesidades y Demandas de Servicios de Salud , Modelos Económicos , Infecciones por Papillomavirus/economía , Infecciones por Papillomavirus/radioterapia , Neoplasias del Cuello Uterino/economía , Neoplasias del Cuello Uterino/radioterapia , Anciano , Niño , Países en Desarrollo , Femenino , Humanos , Renta , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus , Pobreza , Radioterapia/economía , Radioterapia/estadística & datos numéricos , Neoplasias del Cuello Uterino/virologíaRESUMEN
BACKGROUND: The CXCL12/CXCR4 chemokine pathway is involved in cervical cancer pathogenesis and radiation treatment (RT) response. We previously reported that radiochemotherapy (RTCT) and concurrent administration of the CXCR4 inhibitor plerixafor improved primary tumour response. The aims of this study were to determine optimal sequencing of RTCT and plerixafor, the mechanisms responsible for improved response and the effect of plerixafor on late intestinal toxicity. METHODS: Orthotopic cervical cancer xenografts were treated with RTCT (30 Gy in 2 Gy fractions and cisplatin) with or without concurrent, adjuvant or continuous plerixafor. The endpoints were growth delay and molecular and immune cell changes at the end of treatment. Late intestinal toxicity was assessed by histologic examination of the rectum 90 days after a single 20 Gy fraction. RESULTS: RTCT increased CXCL12/CXCR4 signalling and the intratumoral accumulation of myeloid cells; the addition of plerixafor mitigated these effects. All of the RTCT and plerixafor arms showed prolonged tumour growth delay compared to RTCT alone, with the adjuvant arm showing the greatest improvement. Plerixafor also reduced late intestinal toxicity. CONCLUSION: Adding Plerixafor to RTCT blunts treatment-induced increases in CXCL12/CXCR4 signalling, improves primary tumour response and reduces intestinal side effects. This combination warrants testing in future clinical trials.
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Quimiocina CXCL12/antagonistas & inhibidores , Quimioradioterapia , Compuestos Heterocíclicos/uso terapéutico , Células Mieloides/efectos de los fármacos , Receptores CXCR4/antagonistas & inhibidores , Neoplasias del Cuello Uterino/terapia , Animales , Bencilaminas , Quimiocina CXCL12/fisiología , Quimioradioterapia/efectos adversos , Ciclamas , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Células Mieloides/fisiología , Receptores CXCR4/fisiología , Transducción de Señal/efectos de los fármacosRESUMEN
Since the publication of this paper, the authors have reported that an incorrect version of Figure 1 was presented. The correct version of Figure 1 is provided.An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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The practice of radiation oncology is primarily based on precise technical delivery of highly conformal, image-guided external beam radiotherapy or brachytherapy. However, systematic research efforts are being made to facilitate individualised radiation dose prescriptions on the basis of gene-expressssion profiles that reflect the radiosensitivity of tumour and normal tissue. This advance in precision radiotherapy should complement those benefits made in precision cancer medicine that use molecularly targeted agents and immunotherapies. The personalisation of cancer therapy, predicated largely on genomic interrogation, is facilitating the selection of therapies that are directed against driver mutations, aberrant cell signalling, tumour microenvironments, and genetic susceptibilities. With the increasing technical power of radiotherapy to safely increase local tumour control for many solid tumours, it is an opportune time to rigorously explore the potential benefits of combining radiotherapy with molecular targeted agents and immunotherapies to increase cancer survival outcomes. This theme provides the basis and foundation for this American Society for Radiation Oncology guideline on combining radiotherapy with molecular targeting and immunotherapy agents.
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Antineoplásicos/uso terapéutico , Quimioradioterapia/normas , Factores Inmunológicos/uso terapéutico , Inmunoterapia/normas , Terapia Molecular Dirigida/normas , Neoplasias/terapia , Medicina de Precisión/normas , Oncología por Radiación/normas , Animales , Antineoplásicos/efectos adversos , Quimioradioterapia/efectos adversos , Consenso , Regulación Neoplásica de la Expresión Génica , Humanos , Factores Inmunológicos/efectos adversos , Inmunoterapia/efectos adversos , Terapia Molecular Dirigida/efectos adversos , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Medicina de Precisión/efectos adversos , Tolerancia a Radiación/genética , Resultado del TratamientoRESUMEN
Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer death in women worldwide. Approximately half of cervical cancer patients present with locally advanced disease, for which surgery is not an option. These cases are nonetheless potentially curable with radiotherapy and cisplatin chemotherapy. Unfortunately, some tumours are resistant to treatment, and lymph node and distant recurrences are major problems in patients with advanced disease at diagnosis. New targeted treatments that can overcome treatment resistance and reduce metastases are urgently needed. The CXCL12/CXCR4 chemokine pathway is ubiquitously expressed in many normal tissues and cancers, including cervical cancer. Emerging evidence indicates that it plays a central role in cervical cancer pathogenesis, malignant progression, the development of metastases and radiation treatment response. Pre-clinical studies of standard-of-care fractionated radiotherapy and concurrent weekly cisplatin plus the CXCR4 inhibitor Plerixafor (AMD3100) in patient-derived orthotopic cervical cancer xenografts have shown improved primary tumour response and reduced lymph node metastases with no increase in early or late side effects. These studies have pointed the way forward to future clinical trials of radiotherapy/cisplatin plus Plerixafor or other newly emerging CXCL12 or CXCR4 inhibitors in women with cervical cancer.
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Quimiocina CXCL12/antagonistas & inhibidores , Células Mieloides/patología , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Receptores CXCR4/antagonistas & inhibidores , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Antineoplásicos/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células Mieloides/efectos de los fármacos , Células Mieloides/efectos de la radiación , Radioterapia , Neoplasias del Cuello Uterino/patologíaRESUMEN
With the increasing complexity of cancer treatment and the emergence of technologies that offer individualized therapy options for people being treated for the disease, cancer care professionals are facing greater demands for knowledge exchange and information input. The Canadian Partnership for Quality Radiotherapy was established in 2010 in response to such demands and has used both bottom-up and top-down approaches to successfully support improved program planning, treatment delivery, and patient care within the Canadian radiation treatment community. Focusing on shared priorities using this bilateral engagement is a lesson that can be applied broadly across the cancer system.
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Neoplasias/radioterapia , Calidad de la Atención de Salud , Canadá , Prioridades en Salud , Humanos , Cultura Organizacional , Participación del Paciente , Guías de Práctica Clínica como Asunto , Indicadores de Calidad de la Atención de Salud , Calidad de la Atención de Salud/organización & administración , Oncología por Radiación/normasRESUMEN
BACKGROUND: The Hedgehog (Hh) pathway is upregulated in cervical cancer and associated with poor outcome. We explored the effects of Hh pathway inhibition in combination with RTCT in a patient derived orthotopic cervical cancer xenograft model (OCICx). METHODS: 5E1, a monoclonal antibody for SHH, or Sonidegib (LDE225), a clinical SMO inhibitor (Novartis) were added to RTCT. We investigated tumour growth delay, metastasis and GI toxicity using orthotopic cervical cancer xenografts models. The xenografts were treated with radiotherapy (15 × 2 Gy daily fractions over 3 weeks) and weekly cisplatin 4 mg kg-1 concurrently, with or without 5E1 or Sonidegib (LDE225). The Hh inhibitors were administered by subcutaneous injection (5E1; 20 mg kg-1 weekly for 3 weeks), or by oral gavage (Sonidegib; 60 mg kg-1 daily for 3 weeks). RESULTS: We observed that both Hh inhibitors administered with RTCT were well tolerated and showed increased tumour growth delay, and reduced metastasis, with no increase in acute GI-toxicity relative to RTCT alone. CONCLUSIONS: Our data suggest Hh can be a valid therapeutic target in cervical cancer and supports data suggesting a potential therapeutic role for targeting Hh in patients undergoing RTCT. This warrants further investigation in clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Proteínas Hedgehog/antagonistas & inhibidores , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Animales , Anticuerpos Monoclonales/administración & dosificación , Compuestos de Bifenilo/administración & dosificación , Sinergismo Farmacológico , Femenino , Proteínas Hedgehog/inmunología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Piridinas/administración & dosificación , Trasplante Heterólogo , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: A high rate of glycolysis leading to elevated lactate content has been linked to poor clinical outcomes in patients with head and neck and cervical cancer treated with radiotherapy. Although the biological explanation for this relationship between lactate and treatment response remains unclear, there is a continued interest in evaluating strategies of targeting metabolism to enhance the effectiveness of radiotherapy. The goal of this study was to investigate the effect of metabolic-targeting through HIF-1α inhibition and the associated changes in glycolysis, oxygen consumption and response on the efficacy of high-dose single-fraction radiotherapy (HD-SFRT). METHODS: HIF-1α wild-type and HIF-1α knockdown FaDu and ME180 xenograft tumors were grown in the hind leg of mice that were placed in an environmental chamber and exposed to different oxygen conditions (air-breathing and hypoxia). Ex vivo bioluminescence microscopy was used to measure lactate and ATP levels and the hypoxic fraction was measured using EF5 immunohistochemical staining. The oxygen consumption rate (OCR) in each cell line in response to in vitro hypoxia was measured using an extracellular flux analyzer. Tumor growth delay in vivo was measured following HD-SFRT irradiation of 20 Gy. RESULTS: Targeting HIF-1α reduced lactate content, and increased both oxygen consumption and hypoxic fraction in these tumors after exposure to short-term continuous hypoxia. Tumors with intact HIF-1α subjected to HD-SFRT immediately following hypoxia exposure were less responsive to treatment than tumors without functional HIF-1α, and tumors irradiated under air breathing conditions regardless of HIF-1α status. CONCLUSIONS: Blocking the HIF1 response during transient hypoxic stress increased hypoxia, reduced lactate levels and enhanced response to HD-SFRT. This strategy of combining hypofractionated radiotherapy with metabolic reprogramming to inhibit anaerobic metabolism may increase the efficacy of HD-SFRT through increased oxygen consumption and complementary killing of radiosensitive and hypoxic, radioresistant cells.
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Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Hipoxia/metabolismo , Ácido Láctico/metabolismo , Neoplasias/metabolismo , Consumo de Oxígeno , Adenosina Trifosfato/metabolismo , Animales , Biomarcadores , Línea Celular Tumoral , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de la radiación , Femenino , Técnicas de Silenciamiento del Gen , Glucólisis , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , Neoplasias/patología , Neoplasias/radioterapia , Neovascularización Patológica , Dosis de Radiación , Carga Tumoral/efectos de la radiación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV). METHODS: Patients were treated with veliparib, 40-400mg orally BID on days 1-21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor material and quality of life were serially assessed. RESULTS: 32pts were treated. Median follow-up was 45months (10-50). The most common treatment-related grade 3 and 4 toxicities were lymphopenia (59%), anemia (9%), thrombocytopenia (12%), neutropenia (6%), leukopenia (6%), nausea (6%), diarrhea (6%), anorexia (6%), vomiting (6%) and fatigue (6%). The maximum tolerated dose was determined to be 250mg PO BID. Median PFS was 3.6months and median OS was 9.1months. In OV patients, OS was longer for platinum-sensitive patients (10.9mo) compared to platinum-resistant patients (5.8mo). QoL decreased for all groups during treatment. Germline BRCA status was known for 14/18 patients with OV cancers, 5 of whom were BRCA mutation carriers. One objective response (3%) was observed. CONCLUSION: ABT-888 plus LDFWAR is tolerable with gastrointestinal symptoms, fatigue and myelosuppression as the most common toxicities. The single observed objective response was in a germline BRCA mutated, platinum-sensitive patient.
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Bencimidazoles/administración & dosificación , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/radioterapia , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/radioterapia , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Anciano , Bencimidazoles/efectos adversos , Quimioradioterapia , Fraccionamiento de la Dosis de Radiación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversosRESUMEN
Elevated neutrophil-lymphocyte ratio (NLR) may predict worse outcomes in cancer, including glioblastoma (GBM). This study assessed whether change in NLR during focal radiotherapy and concomitant temozolomide (RT-TMZ) provides further prognostic information. This was a retrospective review of patients treated with RT-TMZ for histologically confirmed GBM from January 2004 to September 2010. Variables assessed included age, ECOG performance status (PS), dexamethasone use and extent of surgery. Hematological results were collected at baseline, during and 4 weeks post RT-TMZ. Kaplan-Meier method was used to calculate overall survival (OS). Multivariable analysis (MVA) assessed for joint effect of covariates on OS and Pearson Correlation Coefficients assessed for association between dexamethasone dose and NLR change. With a median age of 55 (range 18-70), 369 patients were included. Median follow up was 15.1 month (range 1.6-134.6). The OS was 66.1% (95% CI 61.2-70.6) and 31.4 (95% CI 26.8-36.1) at 1 and 2 years, respectively. On univariate analysis, both decrease in NLR post RT-TMZ (HR 0.641, p < 0.0001) and baseline NLR < 7.5 (HR 0.628, p < 0.0001) were associated with longer OS. On MVA decrease in NLR (HR 0.727, 95% CI 0.578-0.915), age (HR 1.025, 95% CI 1.012-1.038), baseline neutrophil (<8) (HR 0.689, 95% CI 0.532-0.891), total TMZ cycles (HR 0.89, 95% CI 0.867-0.913) and PS (HR 0.476, 95% CI 0.332-0.683) were independent predictors of OS. These findings suggest that a decrease in NLR during RT-TMZ, accounting for known prognostic factors, is an independent prognostic factor for survival in GBM.
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Neoplasias Encefálicas/patología , Glioblastoma/patología , Linfocitos/patología , Neutrófilos/patología , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/mortalidad , Quimioradioterapia , Femenino , Glioblastoma/mortalidad , Humanos , Estimación de Kaplan-Meier , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: The role of hormone therapy (HT) with dose-escalated external-beam radiotherapy (DE-EBRT) in the treatment of intermediate-risk prostate cancer (IRPC) remains controversial. The authors report the long-term outcome of a phase 3 study of DE-EBRT with or without HT for patients with localized prostate cancer (LPC). METHODS: From 1999 to 2006, 252 of an intended 338 patients with LPC were randomized to receive DE-EBRT with or without 5 months of neoadjuvant and concurrent bicalutamide 150 mg once daily. The study was closed early because of contemporary concerns surrounding bicalutamide. The primary outcome was biochemical failure (BF) incidence, and the secondary endpoints were overall survival (OS), local control (LC), and quality of life. The BF and OS rates were estimated using the cumulative incidence function and Kaplan-Meier methods and were compared using the Gray test and the log-rank test. RESULTS: Eleven patients were excluded from analysis. Characteristics were well balanced in each treatment arm. Ninety-five percent of patients had IRPC. The prescribed dose increased from 75.6 grays (Gy) in 42 fractions to 78 Gy in 39 fractions over the period. At a median follow-up of 9.1 years, 98 BFs occurred, with no significant effect of HT versus no HT on the BF rate (40% vs 47%; P = .32), the OS rate (82% vs 86%; P = .37), the LC rate (52% vs 48 %; P = .32) or quality of life, in the patients who completed the questionnaires. Dose escalation to 75.6 Gy versus >75.6 Gy reduced the BF rate by 26% (P = .004). CONCLUSIONS: For patients who predominantly have IRPC, the addition of HT to DE-EBRT did not significantly affect BF, OS, or LC. Bicalutamide appeared to be well tolerated. The conclusions from the study are limited by incomplete recruitment. Cancer 2016;122:2595-603. © 2016 American Cancer Society.
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Antagonistas de Andrógenos/uso terapéutico , Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Braquiterapia , Nitrilos/uso terapéutico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Compuestos de Tosilo/uso terapéutico , Anciano , Antagonistas de Andrógenos/efectos adversos , Anilidas/efectos adversos , Antineoplásicos/efectos adversos , Braquiterapia/efectos adversos , Braquiterapia/métodos , Terapia Combinada , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Nitrilos/efectos adversos , Neoplasias de la Próstata/mortalidad , Calidad de Vida , Compuestos de Tosilo/efectos adversos , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
PURPOSE: To investigate whether volumetrically derived apparent diffusion coefficient (ADC) from pretreatment diffusion-weighted (DW) magnetic resonance (MR) imaging is associated with disease recurrence in women with locally advanced cervical cancer treated with chemotherapy and radiation therapy. MATERIALS AND METHODS: An ethics board-approved, retrospective study was conducted in 85 women with stage IB-IVA cervical cancer treated with chemo- and radiation therapy in 2009-2013. All patients underwent MR imaging for staging, including T2-weighted and DW MR imaging series, by using a 1.5- or 3.0-T imager. The mean, median, 75th, 90th, and 95th percentile ADCs (ADCmean, ADC50, ADC75, ADC90, and ADC95, respectively) of all voxels that comprised each tumor were extracted and normalized to the mean urine ADC (nADCmean, nADC50, nADC75, nADC90, and nADC95, respectively) to reduce variability. The primary outcome was disease-free survival (DFS). Uni- and multivariable Cox regression analyses were used to evaluate the association of ADC parameters and relevant clinical variables with DFS. RESULTS: Of the 85 women included, 62 were free of disease at last follow-up. Median follow-up was 37 months (range, 5-68 months). Significant variables at univariable analysis included T2-weighted derived tumor diameter, para-aortic nodal involvement, advanced stage, ADC90 and ADC95, nADC75, nADC90, and nADC95. Normalized parameters were more highly associated (hazard ratio per 0.01 increase in normalized ADC, 0.91-0.94; P < .04). Because nADC75, nADC90, and nADC95 were highly correlated, only nADC95 (which had the lowest P value) was included in multivariable analysis. At multivariable analysis, absolute and normalized ADC95 remained associated with DFS (hazard ratio, 0.90-0.98; P < .05). CONCLUSION: The volumetric ADC95 may be a useful imaging metric to predict treatment failure in patients with locally advanced cervical cancer treated with chemo- and radiation therapy.
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Imagen de Difusión por Resonancia Magnética/métodos , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias del Cuello Uterino/patología , Terapia Combinada , Femenino , Humanos , Imagen por Resonancia Magnética Intervencional , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care. For many of the most common cancers in low-income and middle-income countries, radiotherapy is essential for effective treatment. In high-income countries, radiotherapy is used in more than half of all cases of cancer to cure localised disease, palliate symptoms, and control disease in incurable cancers. Yet, in planning and building treatment capacity for cancer, radiotherapy is frequently the last resource to be considered. Consequently, worldwide access to radiotherapy is unacceptably low. We present a new body of evidence that quantifies the worldwide coverage of radiotherapy services by country. We show the shortfall in access to radiotherapy by country and globally for 2015-35 based on current and projected need, and show substantial health and economic benefits to investing in radiotherapy. The cost of scaling up radiotherapy in the nominal model in 2015-35 is US$26·6 billion in low-income countries, $62·6 billion in lower-middle-income countries, and $94·8 billion in upper-middle-income countries, which amounts to $184·0 billion across all low-income and middle-income countries. In the efficiency model the costs were lower: $14·1 billion in low-income, $33·3 billion in lower-middle-income, and $49·4 billion in upper-middle-income countries-a total of $96·8 billion. Scale-up of radiotherapy capacity in 2015-35 from current levels could lead to saving of 26·9 million life-years in low-income and middle-income countries over the lifetime of the patients who received treatment. The economic benefits of investment in radiotherapy are very substantial. Using the nominal cost model could produce a net benefit of $278·1 billion in 2015-35 ($265·2 million in low-income countries, $38·5 billion in lower-middle-income countries, and $239·3 billion in upper-middle-income countries). Investment in the efficiency model would produce in the same period an even greater total benefit of $365·4 billion ($12·8 billion in low-income countries, $67·7 billion in lower-middle-income countries, and $284·7 billion in upper-middle-income countries). The returns, by the human-capital approach, are projected to be less with the nominal cost model, amounting to $16·9 billion in 2015-35 (-$14·9 billion in low-income countries; -$18·7 billion in lower-middle-income countries, and $50·5 billion in upper-middle-income countries). The returns with the efficiency model were projected to be greater, however, amounting to $104·2 billion (-$2·4 billion in low-income countries, $10·7 billion in lower-middle-income countries, and $95·9 billion in upper-middle-income countries). Our results provide compelling evidence that investment in radiotherapy not only enables treatment of large numbers of cancer cases to save lives, but also brings positive economic benefits.
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Países en Desarrollo/economía , Salud Global/economía , Costos de la Atención en Salud , Accesibilidad a los Servicios de Salud/economía , Disparidades en Atención de Salud/economía , Programas Nacionales de Salud/economía , Neoplasias/economía , Neoplasias/radioterapia , Análisis Costo-Beneficio , Difusión de Innovaciones , Predicción , Salud Global/tendencias , Costos de la Atención en Salud/tendencias , Accesibilidad a los Servicios de Salud/tendencias , Disparidades en Atención de Salud/tendencias , Humanos , Modelos Económicos , Programas Nacionales de Salud/tendencias , Neoplasias/diagnóstico , Neoplasias/mortalidad , Radioterapia/economía , Factores Socioeconómicos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The objective of this study was to investigate the prognostic value of the pretreatment circulating neutrophil count (CNC), circulating monocyte count (CMC), and circulating lymphocyte count (CLC) in human papillomavirus (HPV)-related (HPV+) and HPV-unrelated (HPV-) oropharyngeal cancer (OPC). METHODS: All p16-confirmed HPV+ and HPV- OPC cases treated with chemoradiotherapy from 2000 to 2010 were included. Overall survival (OS) and recurrence-free survival (RFS) were compared for high and low CNCs, CMCs, and CLCs (dichotomized by median values). A multivariate analysis (MVA) confirmed their prognostic value in HPV+ and HPV- tumors, respectively. RESULTS: Five hundred ten HPV+ OPC cases and 192 HPV- OPC cases were included. The HPV+ cohort had lower CNC and CMC values but a CLC similar to that of the HPV- patients (P < .01). The median follow-up was 4.8 years. In the HPV+ cohort, a high CNC or CMC correlated with reduced OS and RFS in comparison with a low CNC or CMC (P < .01 for all), but no difference was evident in OS (P = .30) or RFS (P = .10) with the CLC. MVA confirmed that a higher CNC or CMC independently predicted lower OS (hazard ratio [HR] for CNC, 1.14, P < .01; HR for CMC, 2.95, P < .01) and lower RFS (HR for CNC, 1.11, P < .01; HR for CMC, 3.39, P < .01), whereas a higher CLC was associated with higher RFS (HR, 0.66, P = .03) and marginally higher OS (HR, 0.80, P = .08). In the HPV- cohort, CNC, CMC, and CLC were not predictive of OS (P = .16, P = .86, and P = .14) or RFS (P = .61, P = .59, and P = .62). CONCLUSIONS: This relatively large cohort study demonstrates that a high CNC and a high CMC independently predict inferior OS and RFS, whereas a high CLC predicts better RFS and marginally better OS in HPV+ OPC patients. This association was not apparent in HPV- patients.