Francesc Casas

Primary small cell carcinoma of the esophagus

Few studies of patients with esophageal small cell carcinoma (SCC) have been conducted. Choice of treatment remains controversial.

High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial

BACKGROUND The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation was superior to short-term androgen deprivation when combined with high-dose radiotherapy. METHODS In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c-T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175212. FINDINGS Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short-term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% [95% CI 87-92] vs 81% [78-85]; hazard ratio [HR] 1·88 [95% CI 1·12-3·15]; p=0·01). 5-year overall survival (95% [95% CI 93-97] vs 86% [83-89]; HR 2·48 [95% CI 1·31-4·68]; p=0·009) and 5-year metastasis-free survival (94% [95% CI 92-96] vs 83% [80-86]; HR 2·31 [95% CI 1·23-3·85]; p=0·01) were also significantly better in the long-term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3-4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported. INTERPRETATION Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation. FUNDING Spanish National Health Investigation Fund, AstraZeneca.

Variations in Target Volume Definition for Postoperative Radiotherapy in Stage III Non–Small-Cell Lung Cancer: Analysis of an International Contouring Study

PURPOSE Postoperative radiotherapy (PORT) in patients with completely resected non-small-cell lung cancer with mediastinal involvement is controversial because of the failure of earlier trials to demonstrate a survival benefit. Improved techniques may reduce toxicity, but the treatment fields used in routine practice have not been well studied. We studied routine target volumes used by international experts and evaluated the impact of a contouring protocol developed for a new prospective study, the Lung Adjuvant Radiotherapy Trial (Lung ART). METHODS AND MATERIALS Seventeen thoracic radiation oncologists were invited to contour their routine clinical target volumes (CTV) for 2 representative patients using a validated CD-ROM-based contouring program. Subsequently, the Lung ART study protocol was provided, and both cases were contoured again. Variations in target volumes and their dosimetric impact were analyzed. RESULTS Routine CTVs were received for each case from 10 clinicians, whereas six provided both routine and protocol CTVs for each case. Routine CTVs varied up to threefold between clinicians, but use of the Lung ART protocol significantly decreased variations. Routine CTVs in a postlobectomy patient resulted in V(20) values ranging from 12.7% to 54.0%, and Lung ART protocol CTVs resulted in values of 20.6% to 29.2%. Similar results were seen for other toxicity parameters and in the postpneumectomy patient. With the exception of upper paratracheal nodes, protocol contouring improved coverage of the required nodal stations. CONCLUSION Even among experts, significant interclinician variations are observed in PORT fields. Inasmuch as contouring variations can confound the interpretation of PORT results, mandatory quality assurance procedures have been incorporated into the current Lung ART study.

Acoustic analysis after radiotherapy in T1 vocal cord carcinoma: a new approach to the analysis of voice quality

PURPOSE The study of acoustic voice parameters (fundamental frequency, jitter, shimmer, and harmonics-to-noise ratio) in extended vowel production, oral reading of a standard paragraph, spontaneous speech and a song in irradiated patients for Tis-T1 vocal cord carcinoma. METHODS AND MATERIALS Eighteen male patients irradiated for Tis-T1 vocal cord carcinoma and a control group of 31 nonirradiated subjects of the same age were included in a study of acoustic voice analysis. The control group had been rigorously selected for voice quality and the irradiated group had previous history of smoking in two-thirds of the cases and a vocal cord biopsy. Radiotherapy patients were treated with a 6MV Linac receiving a total dose of 66 Gy, 2 Gy/day, with median treatment areas of 28 cm(2). Acoustic voice analysis was performed 1 year after radiotherapy, the voice of patients in extended vowel production, oral reading of a standard paragraph, spontaneous speech, and in a song was tape registered and analyzed by a Kay Elemetrics Computerized Speech Lab (model CSL# 4300). Fundamental frequency, jitter, shimmer, and harmonics-to-noise ratio were obtained in each case. Mann Whitney analysis was used for statistical tests. RESULTS The irradiated group presented higher values of fundamental frequency, jitter, shimmer, and harmonics-to-noise ratio. Mann-Whitney analysis showed significant differences for fundamental frequency and jitter in vowel production, oral reading, spontaneous speech, and song. Shimmer only showed differences in vowel production and harmonics-to-noise ratio in oral reading and song. CONCLUSIONS In our study only fundamental frequency and jitter showed significant increased values to the control group in all the acoustic situations. Sustained vowel production showed the worst values of the acoustic parameters in comparison with the other acoustic situations. This study seems to suggest that more work should be done in this field.

Improvement in performance status after erythropoietin treatment in lung cancer patients undergoing concurrent chemoradiotherapy.

PURPOSE A prospective Phase II trial was carried out to evaluate the effectiveness of erythropoietin in improving or maintaining performance status as determined by the Karnofsky performance status (KPS) score and hemoglobin (Hb) levels in lung cancer patients treated with concurrent chemoradiation (CH-RT). METHODS AND MATERIALS A total of 51 patients with lung cancer (11 with small-cell, limited stage and 40 with non-small-cell disease, 17 with Stage IIIA and 23 with Stage IIIB), who underwent three different concurrent CH-RT protocols were enrolled. Baseline Hb and KPS values were recorded, as were the nadir Hb and KPS values before concurrent CH-RT. The final Hb and KPS values were recorded the last week of concurrent CH-RT. An Hb level of <or=11 g/dL before concurrent CH-RT was required before receiving erythropoietin. Prognostic factors for KPS improvement and survival were assessed by univariate and multivariate studies. RESULTS Of the 51 patients, 47 (92.3%) were men (mean age 63.6 years, range 40-75). The median baseline KPS score was 80, and the mean baseline Hb was 12.2 +/- 1.76 g/dL (range 9-16.9). The mean nadir and final Hb value was 9.98 +/- 0.67 g/dL (range 8.6-11) and 11.33 +/- 1.59 g/dL (range 6.9-14.4), respectively. A significant increase was seen in the Hb and KPS score (p <0.05) in the final measurements. Differences were found between the final and nadir Hb in the predictive value for differences in performance status (p = 0.001). On univariate study, pathologic findings (p = 0.0234), weight loss (p = 0.0049), baseline Hb (p = 0.0057), and final Hb improvement (p = 0.0237) were prognostic factors for survival. Nadir Hb (p = 0.027), final Hb improvement (p = 0.0069), pathologic findings (p = 0.0006), and weight loss (p = 0.0001) had significant prognostic value for survival in multivariate analysis. CONCLUSION In this study, erythropoietin appears to have a significant, beneficial impact on the KPS and Hb of patients undergoing concurrent CH-RT.

Radiation oncology in Spain : Historical notes for the radiology centennial

Cancer started to forge as a visible disease in the first third of this century (1). This means that it began to be considered as a conceivable illness by society, and above all, a concern for doctors. They were the social agents to persuade public and states of cancer curability. The lay reality was colonized by medical discourse, and individuals were assigned to be the assistants of doctors in the ideal frame of an industrial healthy society (2). This new medical mentality about cancer was a result of the professional commitment with social change, the improvement of surgery, and the perception of radioactive remedies as innovative therapeutical hopes. The process was linked to medical profession dynamics directed at the autonomization of radiotherapy as a new medical discipline. In western societies the concern about cancer and the rise of radiotherapy as a medical speciality was a process with common steps in its devolopment (3). In Spain, the therapeutic use of x-rays and radium was incorporated with a similar celerity to other countries. In the 30s the presence of radiological devices and instruments was significant in private practice medicine. According to the Spanish Medical Catalog (Anuario Medico de Espafia), from 1927 to 1931 the number of radiologists tripled (from 223 to 571) (4). This extraordinary increase did not mean a specialized type of radiological practice. Several medical specialists (surgeons, gynecologists, dermatologists) used radiological apparatus, particularly radium, due to its simple manipulation in clinics as an auxiliary therapy or, above all, as diagnostic methods. The practice of Radiotherapy as it is defined today lasted to be generalized, and for decades radiological medicine combined the practice of diagnostic and therapeutic use of this technology. In 1936, with the beginning of the Spanish Civil War, there was no regulation of the radiology practice, although in 1935 (Primer Congreso Promedico Espafiol) it was decided to name a Commission to study the legal implications and present a regulatory proposal to the health authorities. It was not until the 1930s when the health authorities of the Spanish government had a project to fight against cancer. Until then, some benefit cancer institutions, including individuals of the medical and social elite together with members of the government, were helped occasionally with financial support. These initiatives defined their objectives with the criteria of the doctors involved and in general were directed more toward the adquisition of radioactive material and its instrumentation requirements, more than to solve public education on the incurable problem. In 1909, the ComitC Central Contra el Cancer [Central Committee Against Cancer] and the Asociacion National Contra el CXncer were founded. Also the main proposals of campaigning were discussed, but following foreign experiences, difficult to carry on. The unique achievements for this period were the national enquiries (1902 and 1909) to know clinical cancer incidence, etiology, medical services available, and doctors knowledge about the disease. But the reply obtained was insignificant: 2O.ooO enquiries and 298 replies (1902) (5). The decline of international initiatives due to the war had a negative effect on Spanish institutions. In fact, except for the creation of a modest laboratory for cancer research at the Instituto Rubio (Madrid, 1909) and the discussion about radiumtherapy in the cancer campaign, nothing more was done In 1914 the Sociedad Benefica Radium-Barcelona arose, as a nonprofit institution. to provide radium to pri-

Combination of radiotherapy and chemotherapy in locally advanced NSCLC.

The combination of radiotherapy and chemotherapy is considered to be a standard approach for patients with locally advanced, stage III non-small-cell lung cancer. The current state of the art of combined radiochemotherapy supported by evidence-based data is presented. As shown in the meta-analyses, the concurrent radiochemotherapy gives a superior outcome in terms of survival compared with sequential delivery of both modalities. This is obtained at the expense of higher toxicity, which makes further intensification of radiochemotherapy challenging. Eligibility of patients with non-small-cell lung cancer for such an approach is limited. The new methods to improve treatment results, such as selection of proper strategies, incorporation of molecular agents into combined treatment and radiotherapy technique modifications are discussed.

Radiochemotherapy in the elderly with lung cancer.

Lung cancer is the leading cause of cancer mortality with the median age of incidence being 69 years in males and 67 years in females. Radiochemotherapy (RT–CHT) is indicated in locally advanced non-small-cell lung cancer and limited-stage small-cell lung cancer; however, a significant under-representation of the elderly has been observed in patient recruitment in cancer treatment trials. In the last decades of the 20th Century, studies showed that elderly patients achieved the best quality-adjusted survival with radiotherapy alone, but recent trials have found that fit elderly patients benefit from concurrent RT-CHT, although with more short-term toxicity. Age alone should not exclude fit patients and deprive them of the standard treatment. Using tools, such as comprehensive geriatric assessment, a patient’s tolerance to therapy can be assessed and monitoring can be performed. This review will focus on RT–CHT treatment in elderly patients with nonoperable stage III non-small-cell lung cancer and limited-stage small-cell lung cancer exclusively.

Uroncor consensus statement: Management of biochemical recurrence after radical radiotherapy for prostate cancer: From biochemical failure to castration resistance.

Management of patients who experience biochemical failure after radical radiotherapy with or without hormonal therapy is highly challenging. The clinician must not only choose the type of treatment, but also the timing and optimal sequence of treatment administration. When biochemical failure occurs, numerous treatment scenarios are possible, thus making it more difficult to select the optimal approach. Moreover, rapid and ongoing advances in treatment options require that physicians make decisions that could impact both survival and quality of life. The aim of the present consensus statement, developed by the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR), is to provide cancer specialists with the latest, evidence-based information needed to make the best decisions for the patient under all possible treatment scenarios. The structure of this consensus statement follows the typical development of disease progression after biochemical failure, with the most appropriate treatment recommendations given for each stage. The consensus statement is organized into three separate chapters, as follows: biochemical failure with or without local recurrence and/or metastasis; progression after salvage therapy; and treatment of castration-resistant patients.

Single Nucleotide Polymorphisms in Tobacco Metabolism and DNA Repair Genes and Prognosis in Resected Non-Small-Cell Lung Cancer

BACKGROUND If tobacco-related carcinogens are not inactivated or extruded from the cell, they can damage the DNA. Single nucleotide polymorphisms (SNPs) in genes involved in tobacco metabolism, DNA repair, and multidrug resistance have been related to lung cancer susceptibility. We examined 13 SNPs in 10 of these genes and correlated the results with time to progression (TTP) and overall survival (OS) in 71 smoker or former smoker patients with resected non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS DNA was obtained from paraffin-embedded tumor. SNP analysis of the candidate genes was performed by allelic discrimination assay. Log-rank test, Kaplan-Meier plots, and Cox multivariate analysis were used to evaluate the association of TTP and survival with the SNPs evaluated. RESULTS Patients with wild-type (wt) XPC rs2228001, wt CYP2C8 rs10509681, or non-wt NAT2 rs1799930 had a longer TTP. Patients with wt ERCC1 showed a nonsignificant trend towards longer TTP. No other relation between SNPs and TTP were observed. Patients harboring at least two unfavorable genotypes in these four genes had a shorter TTP and OS than patients with either one or no unfavorable genotypes. In the multivariate analysis, non-wt XPC rs2228001 and the presence of at least two unfavorable genotypes emerged as independent markers for shorter TTP. CONCLUSIONS SNPs in tobacco metabolism and DNA repair genes may influence the clinical outcome of resected NSCLC.