Laura Cerezo

Bystander effects and radiotherapy

Radiation-induced bystander effects are defined as biological effects expressed after irradiation by cells whose nuclei have not been directly irradiated. These effects include DNA damage, chromosomal instability, mutation, and apoptosis. There is considerable evidence that ionizing radiation affects cells located near the site of irradiation, which respond individually and collectively as part of a large interconnected web. These bystander signals can alter the dynamic equilibrium between proliferation, apoptosis, quiescence or differentiation. The aim of this review is to examine the most important biological effects of this phenomenon with regard to areas of major interest in radiotherapy. Such aspects include radiation-induced bystander effects during the cell cycle under hypoxic conditions when administering fractionated modalities or combined radio-chemotherapy. Other relevant aspects include individual variation and genetics in toxicity of bystander factors and normal tissue collateral damage. In advanced radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), the high degree of dose conformity to the target volume reduces the dose and, therefore, the risk of complications, to normal tissues. However, significant doses can accumulate out-of-field due to photon scattering and this may impact cellular response in these regions. Protons may offer a solution to reduce out-of-field doses. The bystander effect has numerous associated phenomena, including adaptive response, genomic instability, and abscopal effects. Also, the bystander effect can influence radiation protection and oxidative stress. It is essential that we understand the mechanisms underlying the bystander effect in order to more accurately assess radiation risk and to evaluate protocols for cancer radiotherapy.

Invasive Bladder Cancer: A Single-Institution Experience With Bladder-Sparing Approach

Our objective was to assess the efficacy and safety of a selective bladder‐preserving approach by transurethral resection and sequential chemoradiotherapy in patients with muscle‐invasive bladder cancer. From 1989 through 1997, 40 patients with biopsy‐confirmed bladder cancer, clinical stages T2–4NxM0, were treated with induction by aggressive transurethral resection (TUR) and three cycles of methotrexate, cisplatin, and vinblastine (MCV) chemotherapy. Tumor response was evaluated by cystoscopy and biopsy. In complete responders, the treatment was continued by radiotherapy (60 Gy to the bladder and 50 Gy to pelvic lymph nodes). Radical cystectomy was recommended to patients with residual tumor. Clinical complete response rate to TUR and MCV chemotherapy was 70%. The 4‐year actuarial overall survival rate for the whole series was 80.5%. Among 36 patients who completed chemotherapy and radiotherapy, the 4‐year actuarial survival was 84%, with 82.6% surviving with their bladders intact. Freedom from local failure in complete responders to TUR‐chemotherapy was 84%. Multivariate analysis revealed that the extent of initial TUR and status after TUR‐chemotherapy were independent prognostic factors associated with survival and disease‐free survival. This study confirms that the combination of aggressive TUR and sequential chemoradiotherapy with bladder preservation is an alternative treatment option to primary cystectomy for selected patients with invasive bladder carcinoma. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 287–294 (2000).

Unknown primary cancer of the head and neck: a multidisciplinary approach

The management of patients with cervical lymph node metastases from an unknown primary cancer (CUP) remains a matter of controversy. Although new advanced diagnostic tools, such as positron emission tomography, have recently been introduced in oncology, the frequency of this tumour entity in clinical practice means it is still relevant. Recently introduced molecular profiling platforms may provide biological classification for the primary tissue of origin as well as insights into the pathophysiology of this clinical entity, including the characterisation of the Epstein-Barr virus and human papilloma virus genomas in the metastatic cervical nodes. Due to the lack of randomised trials, a standard therapy has not been identified yet. Although neck dissection followed by post-operative radiotherapy is the most generally accepted approach, there are other curative options that can be used in some patients: neck dissection alone, nodal excision followed by post-operative radiotherapy or radiotherapy alone. A major controversy remains in the target radiation volumes that range from ipsilateral neck irradiation to prophylactic irradiation of all potential mucosal sites and both sides of the neck. Finally, the administration of concurrent chemotherapy is currently being advised for patients with adverse prognostic factors.

Ipsilateral irradiation for well lateralized carcinomas of the oral cavity and oropharynx: results on tumor control and xerostomia.

BackgroundIn head and neck cancer, bilateral neck irradiation is the standard approach for many tumor locations and stages. Increasing knowledge on the pattern of nodal invasion leads to more precise targeting and normal tissue sparing. The aim of the present study was to evaluate the morbidity and tumor control for patients with well lateralized squamous cell carcinomas of the oral cavity and oropharynx treated with ipsilateral radiotherapy.MethodsTwenty consecutive patients with lateralized carcinomas of the oral cavity and oropharynx were treated with a prospective management approach using ipsilateral irradiation between 2000 and 2007. This included 8 radical oropharyngeal and 12 postoperative oral cavity carcinomas, with Stage T1-T2, N0-N2b disease. The actuarial freedom from contralateral nodal recurrence was determined. Late xerostomia was evaluated using the European Organization for Research and Treatment of Cancer QLQ-H&N35 questionnaire and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.ResultsAt a median follow-up of 58 months, five-year overall survival and loco-regional control rates were 82.5% and 100%, respectively. No local or contralateral nodal recurrences were observed. Mean dose to the contralateral parotid gland was 4.72 Gy and to the contralateral submandibular gland was 15.30 Gy. Mean score for dry mouth was 28.1 on the 0-100 QLQ-H&N35 scale. According to CTCAE v3 scale, 87.5% of patients had grade 0-1 and 12.5% grade 2 subjective xerostomia. The unstimulated salivary flow was > 0.2 ml/min in 81.2% of patients and 0.1-0.2 ml/min in 19%. None of the patients showed grade 3 xerostomia.ConclusionIn selected patients with early and moderate stages, well lateralized oral and oropharyngeal carcinomas, ipsilateral irradiation treatment of the primary site and ipsilateral neck spares salivary gland function without compromising loco-regional control.

Incidence of human papillomavirus-related oropharyngeal cancer and outcomes after chemoradiation in a population of heavy smokers

Incidence of human papillomavirus (HPV)‐related oropharyngeal carcinomas is increasing worldwide. The purpose of this study was to report the incidence in our region, and to determine the influence of HPV status on survival among a heavy smoking population.

Molecular alterations in the pathogenesis of endometrial adenocarcinoma. Therapeutic implications

SummaryMolecular genetic evidence indicates that endometrial carcinoma likely develops as the result of a multistep process of oncogene activation and tumor suppressor gene inactivation. These molecular alterations appear to be specific for Type I (endometrioid) and Type II (non endometrioid) cancers. Type I cancers are characterized by mutation of PTEN, KRAS2, defects in DNA mismatch repair, as evidenced by the microsatellite instability phenotype, and a near diploid karyotype. Type II cancers often contain mutations of TP53 and Her-2/neu and are usually nondiploid. The clinical value of many of these molecular markers is now being tested and it may help to refine diagnosis and establish an accurate prognosis. Furthermore, some of these tumor biomarkers constitute the targets for emerging therapies. Transtuzumab against Her-2/neu and bevacizumab against VEGF overexpressing carcinomas are among the promising novel treatments. Additional translational research is needed to identify molecular and genetic alterations with potential for therapeutic interventions.

Successful bone marrow transplantation in sensitized aplastic anemia patients using total lymphoid irradiation for conditioning: long-term follow-up

Between June 1986 and November 1994, 22 previously transfused patients with severe aplastic anemia (SAA) were treated with high‐dose cyclophosphamide (CY) (50 mg/kg over 4 consecutive days) and 7 Gy total lymphoid irradiation (TLI) in two fractions before allogeneic bone marrow transplantation (BMT) from HLA‐identical sibling. Graft‐versus‐host‐disease (GVHD) prophylaxis included the combination of methotrexate and cyclosporine A in all cases. Actuarial survival at 5 years is 73±9 per cent for the entire group and 86±13 per cent for the seven patients ⩽18 years. The incidence of graft failure was 0 per cent, and of acute GVHD and chronic GVHD was 31·5 per cent and 24 per cent respectively. Prolonged interval from diagnosis to BMT adversely influenced survival (P=0·03). No hypothyroidism or secondary malignancies have been documented in this series. Our findings indicate that survival with CY‐TLI is comparable to that obtained using preparative regimens without radiation. The changing role of radiotherapy in pretransplant immunosuppression for SAA is discussed.

Prospective clinical evaluation of transdermal fentanyl for the treatment of cancer pain

BackgroundTransdermal therapeutic systems offer potential advantages over oral or intravenous routes of drug administration. The purpose of this prospective study was to evaluate the analgesic efficacy of the new drug formulation transdermal fentanyl (TTS Fen) in the treatment of cancer pain, as well as its safety and patient acceptability.MethodsForty patients were included over a 12-month period. The dose of TTS Fen was titrated individually, increasing 25 μg/h every 72 hours, until analgesic control was adequate.ResultsPain intensity, determined by means of a numeric analog scale going from 0 to 10, decreased from a mean of 7.14 on day 1 of treatment to 3.96 on day 15, 2.40 on day 60 and 2.07 on day 90, with significant differences (p = 0.002). Treatment satisfaction was high in 89% of patients. Rescue medication with short-acting oral morphine was needed in 30% of patients during the first week of treatment with TTS Fen, but only in 26% and 15% of patients by days 15 and 60, respectively. The most frequent side effects were constipation, which occurred in 39% of patients, drowsiness in 21% and fatigue in 13%.ConclusionsTTS Fen is effective in the treatment of cancer pain and patient satisfaction is high, mainly because of ease of use. The frequency of side effects is low.ResumenFundamentoLa vía transdérmica de administración de fármacos presenta ventajas potenciales sobre las vías oral o parenteral. El objetivo de este estudio prospectivo fue evaluar la eficacia analgésica del nuevo fármaco fentanilo transdérmico (Fen TTS) en el control del dolor neoplásico, su seguridad y la satisfacción global del paciente.MétodosEn un período de 12 meses se incluyeron 40 pacientes. La dosis de Fen TTS fue ajustada individualmente, aumentando 25 μg/h cada 3 días hasta lograr un control analgésico adecuado.ResultadosLa intensidad del dolor, según una escala analógica numérica de 0 a 10, descendió de una media de 7.14 el día 1 del tratamiento a 3.96 el día 15, 2.40 el día 60 y 2.07 el día 90, siendo significativas las diferencias (p = 0,002). La satisfacción con el tratamiento fue alta en el 89% de los pacientes. El 30% de los pacientes precisó analgesia de rescate con morfina oral de liberación rápida la primera semana de tratamiento, disminuyendo al 26 y al 15% los días 15 y 60, respectivamente. Los efectos secundarios más frecuentes fueron estreñimiento, 39%, somnolencia, 21% y astenia, 13%.ConclusionesEl Fen TTS es eficaz en el tratamiento del dolor neoplásico y su aceptación por el paciente es alta, principalmente por la comodidad de administración. Los efectos secundarios son leves.

Xerostomía postradioterapia: eficacia de tratamientos tópicos basados en aceite de oliva, betaína y xilitol

espanolLa xerostomia es la complicacion mas frecuente en los pacientes que reciben radioterapia para el cancer oral. La reduccion en la tasa de flujo salival y una disminucion de su pH estan directamente relacionado con un cambio en la composicion de la saliva y el desplazamiento de la microflora oral hacia especies bacterianas cariogenicas. Por otro lado sabemos que la xerostomia se asocia a dificultad para el habla, la masticacion, la deglucion, cambios en el sabor, caries dentales, sensacion de ardor, infecciones microbianas y un deterioro de la calidad de vida. El manejo de la xerostomia incluye la prevencion, la estimulacion y el tratamiento sintomatico. La prevencion no siempre es posible a pesar de que con radioterapia de intensidad modulada (IMRT), se puede administrar dosis mas bajas de radiacion a las glandulas parotidas. Los farmacos estimuladores, como los agonistas colinergicos, han demostrado mejorar la xerostomia, sin embargo tienen efectos secundarios y estan contraindicados en algunas patologias. Hoy disponemos de una gran variedad de productos topicos para el alivio de los sintomas de la boca seca, como la goma de mascar, pastillas sin azucar, sustitutos salivales, cremas hidratantes o pastas dentales. Un trabajo previo nos indica que el uso diario de productos de boca seca topicos que contienen aceite de oliva, betaina y xilitol es seguro y eficaz en el alivio de los sintomas de xerostomia en pacientes con xerostomia inducida por farmacos. En este trabajo se revisa la eficacia de las diversas opciones de tratamiento para la hiposalivacion inducida por la radiacion y presentamos nuestros resultados con el uso de productos topicos especificos en estos pacientes. EnglishXerostomia is the most frequent complication among patients who receive radiotherapy for oral cancers. A reduction in salivary flow rate and decrease of its pH is paralleled with a change in saliva competence and shifting of oral microflora to cariogenic bacterial spices. Therefore difficulties in speech, mastication, swallowing, changes in taste, dental caries, burning sensation, microbial infections and a compromised quality of life are associated with the presence of xerostomia. Studies have led to three therapeutic approach for xerostomia treatment: prevention, stimulation and symptomatic treatment. Prevention it is not always possible, although intensity modulated radiation therapy (IMRT) technique, gives the ability to delivering lower doses of radiation to parotid glands. Stimulation agents as cholinergic agonist have all demonstrated some ability to improve xerostomia, however have side effects and are contraindicated for certain medical disorders. There are a huge variety of products for relief dry mouth symptoms as Chewing gum, sugarfree lozenges, salivary substitutes and moisturizers, toothpastes. A previous study report that the daily use of topical dry mouth products containing olive oil, betaine and xilitol is safe and effective in relieving symptoms of xerostomia in a population with polypharmacy-induced xerostomia. The objective of this study is to review efficacy of various treatment options for radiation-induced hyposalivation and present our results with the use of specific topical products in this patients.