A. Marín

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).

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.

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.

Statistical analysis of dose‐volume and dose‐wall histograms for rectal toxicity following 3D‐CRT in prostate cancer

The purpose of this paper is to determine the correlation between dose-volume histogram (DVH) and dose wall-histogram (DWH) in the evaluation of rectal complications for prostate cancer patients treated with three-dimensional conformal radiotherapy (3D-CRT). A retrospective analysis of DVHs and DWHs of a subset of 25 prostate cancer patients treated with 3D-CRT was performed. For every patient the rectum and the rectal wall (inner and outer surface) were contoured. Median ICRU radiation dose of 79.4Gy was administered. Correlation between DVHs and DWHs parameters was investigated by the nonparametric Spearman test and by linear regression analysis. The results showed a statistically significant linear correlation between pairs of DVH and DWH dosimetric parameters with Spearman correlation values (S) bigger than 0.8, with p values better than 0.0005 (two-sided) when the emptied rectum is considered. The variation of S and linear fit slope values [b(1)] showed a very similar functional shape with a minimum at 91% ICRU dose [S=0.83,b(1)=0.65]. The present study confirms a high correlation (>80%) between DVH and DWH of the rectum following 3D-CRT for prostate cancer. The derived advantage is that the contouring of inner surface of rectum could be obviated in almost 90% of patients when performing predictive models for rectal complications based on dosimetric variables under the standard treatment conditions specified in this study.

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.