Influence of the microbiome on radiotherapy-induced oral mucositis and its management: A comprehensive review.

Radiation-induced mucositis is the most common, debilitating and painful acute toxicity associated with active treatment in head and neck cancer area, severely affecting more than 65% of patients. Oral microbiota significantly changes during cancer therapy and appears to be involved on its pathophysiology. This review aims to present a comprehensive update of new etiopathogenic factors and treatments that may decrease the incidence of mucositis, mainly modifications of dietary interventions to modify microbiome. Despite advances in recent years, its management is mainly symptomatic opioid-based with variable results on different substances analyzed for its prevention. Immunonutrition seems to play a significant role, particularly the supplementation of compounds such as fatty acids, polyphenols or selected probiotics have shown to promote commensal bacteria diversity and reduced incidence of ulcerative mucositis. Modification of the microbiome is a promising preventive treatment for mucositis although its evidence is still scarce. Large studies are needed to demonstrate the efficacy of interventions on microbiome and its clinical impact on radiation-induced mucositis.

Development and psychometric properties of the Stressors in Breast Cancer Scale.

Background: A diagnosis of breast cancer generates psychological stress, due not only to treatment and its side effects but also to the impact on different areas of the patient's daily life. Although there are instruments for measuring psychological stress in the cancer context, there is currently no tool for assessing stressors specific to breast cancer. Aims: The aim of this study was to develop the Stressors in Breast Cancer Scale (SBCS). Method: A panel of experts evaluated the clarity and relevance of scale items, providing validity evidence based on test content. Psychometric properties of the scale were then analyzed. Results: Validity evidence based on the internal structure of the SBCS was obtained through exploratory factor analysis (EFA) and confirmatory factor analysis (CFA), following a cross-validation strategy. The CFA supported a second-order factor model with five dimensions: physical appearance and sex strains, health and daily difficulties, interpersonal relationship strains, healthcare strains, and worries and concerns about the future. This structure was invariant across two groups distinguished by time from cancer diagnosis (less than 3 and 3 years or more from diagnosis). Reliability, based on McDonald's omega and Cronbach's alpha coefficients, ranged from 0.83 to 0.89 for factor scores, and reached 0.95 for total scores. Validity evidence was also provided by correlations with depression, anxiety, perceived stress, and perceived health and quality of life. Discussion: The results support the use of the SBCS for measuring stress as a stimulus in the breast cancer context. Implications for clinical practice and research are discussed.

Relationships of Gut Microbiota Composition, Short-Chain Fatty Acids and Polyamines with the Pathological Response to Neoadjuvant Radiochemotherapy in Colorectal Cancer Patients.

Emerging evidence has suggested that dysbiosis of the gut microbiota may influence the drug efficacy of colorectal cancer (CRC) patients during cancer treatment by modulating drug metabolism and the host immune response. Moreover, gut microbiota can produce metabolites that may influence tumor proliferation and therapy responsiveness. In this study we have investigated the potential contribution of the gut microbiota and microbial-derived metabolites such as short chain fatty acids and polyamines to neoadjuvant radiochemotherapy (RCT) outcome in CRC patients. First, we established a profile for healthy gut microbiota by comparing the microbial diversity and composition between CRC patients and healthy controls. Second, our metagenomic analysis revealed that the gut microbiota composition of CRC patients was relatively stable over treatment time with neoadjuvant RCT. Nevertheless, treated patients who achieved clinical benefits from RTC (responders, R) had significantly higher microbial diversity and richness compared to non-responder patients (NR). Importantly, the fecal microbiota of the R was enriched in butyrate-producing bacteria and had significantly higher levels of acetic, butyric, isobutyric, and hexanoic acids than NR. In addition, NR patients exhibited higher serum levels of spermine and acetyl polyamines (oncometabolites related to CRC) as well as zonulin (gut permeability marker), and their gut microbiota was abundant in pro-inflammatory species. Finally, we identified a baseline consortium of five bacterial species that could potentially predict CRC treatment outcome. Overall, our results suggest that the gut microbiota may have an important role in the response to cancer therapies in CRC patients.

Oligometastatic non-small cell lung cancer: Current management.

BACKGROUND: In the past decade, major developments have improved the survival of patients with oligometastatic non-small cell lung cancer (NSCLC). About 20% - 50% of patients with NSCLC present with oligometastases at diagnosis. For this group of patients, it seems that an increase in survival would justify aggressive local therapies. The development of minimally invasive surgery and advanced radiotherapy techniques like stereotactic body radiation therapy (SBRT) makes local control possible for selected patients with metastatic NSCLC. The advantage of SBRT over surgery is that it is a non-invasive technique, with minimum side effects, and is more suitable for fragile and elderly patients, non-candidates for surgery, or patients who refuse surgery. AIM: The purpose of this review is to summarize the latest scientific evidence on the management of oligometastatic NSCLC, focusing on the role of radiotherapy. RELEVANCE FOR PATIENTS: The initial treatment recommended for patients with oligometastatic NSCLC is systemic therapy. Patients should be considered for radical treatment to both the primary tumor and oligometastases. Aggressive local therapy comprises surgery and/or definitive radiotherapy such as SRS or SBRT, and may be preceded or followed by systemic treatment. Recent clinical evidence from Phase II trials reports benefits in terms of PFS in patients with good performance status and long disease-free periods, with good response to systemic therapy, especially in EGFR wild-type tumors. Phase I and II trials have shown that radiotherapy combined with immunotherapy can improve tumor response rate and possibly overall survival. The recommendation is also to include OM patients in ongoing clinical trials.

Importance of dose in palliative treatment for incurable head and neck cancer with radiotherapy.

PURPOSE: To identify predictors of palliation for head and neck cancer treated with the "Hypo Trial" hypofractionated radiation therapy regimen in a clinical setting. DESIGN/METHOD: We retrospectively assessed 106 consecutive patients with incurable cancer, treated between January 2008 and December 2018. Regimen used was 30-36Gy in 5-6 biweekly fractions of 6Gy. RESULTS: The prescription dose was 30Gy in 57 (53.8%) patients and 36Gy in 49 (46.2%) patients. 89.6% patients completed the prescribed treatment. With a median follow-up of 6.92 months, 79.2% of the patients experienced clinical palliation. Palliation was correlated with the radiation therapy dose (P = 0.05). Median overall and progression-free survival (OS, PFS) were 7 and 4.63 months, respectively. Achieving palliation was associated to OS (P = 0.01). CONCLUSIONS: This short palliative hypofractionated scheme resulted in a high rate of palliation, with excellent compliance and acceptable toxicity. Our results show that radiation dose is a predictive factor for palliation.

Gut Microbiota-Mediated Inflammation and Gut Permeability in Patients with Obesity and Colorectal Cancer.

Obesity is considered an important factor that increases the risk of colorectal cancer (CRC). So far, the association of gut microbiota with both obesity and cancer has been described independently. Nevertheless, a specific obesity-related microbial profile linked to CRC development has not been identified. The aim of this study was to determine the gut microbiota composition in fecal samples from CRC patients with (OB-CRC) and without obesity (L-CRC) compared to the microbiota profile present in non-obese healthy controls (L-HC), in order to unravel the possible relationship between gut microbiota and microbial-derived metabolite trimethylamine N-oxide (TMAO), the inflammatory status, and the intestinal permeability in the context of obesity-associated CRC. The presence of obesity does not induce significant changes in the diversity and richness of intestinal bacteria of CRC patients. Nevertheless, OB-CRC patients display a specific gut microbiota profile characterized by a reduction in butyrate-producing bacteria and an overabundance of opportunistic pathogens, which in turn could be responsible, at least in part, for the higher levels of proinflammatory cytokine IL-1ß, the deleterious bacterial metabolite TMAO, and gut permeability found in these patients. These results suggest a possible role of obesity-related gut microbiota in the development of CRC, which could give new clues for the design of new diagnostic tools for CRC prevention.

The Role of the Gut Microbiome in Colorectal Cancer Development and Therapy Response.

Colorectal cancer (CRC) is the third most common cancer worldwide and the leading cause of cancer-related deaths. Recently, several studies have demonstrated that gut microbiota can alter CRC susceptibility and progression by modulating mechanisms such as inflammation and DNA damage, and by producing metabolites involved in tumor progression or suppression. Dysbiosis of gut microbiota has been observed in patients with CRC, with a decrease in commensal bacterial species (butyrate-producing bacteria) and an enrichment of detrimental bacterial populations (pro-inflammatory opportunistic pathogens). CRC is characterized by altered production of bacterial metabolites directly involved in cancer metabolism including short-chain fatty acids and polyamines. Emerging evidence suggests that diet has an important impact on the risk of CRC development. The intake of high-fiber diets and the supplementation of diet with polyunsaturated fatty acids, polyphenols and probiotics, which are known to regulate gut microbiota, could be not only a potential mechanism for the reduction of CRC risk in a primary prevention setting, but may also be important to enhance the response to cancer therapy when used as adjuvant to conventional treatment for CRC. Therefore, a personalized modulation of the pattern of gut microbiome by diet may be a promising approach to prevent the development and progression of CRC and to improve the efficacy of antitumoral therapy.

O6-methylguanine-DNA Methyltransferase Promoter Methylation in Patients with Rectal Adenocarcinoma After Chemoradiotherapy Treatment: Clinical Implications

Aims: To analyze the clinical relevance of O6-methylguanine-DNA methyltransferase in rectal adenocarcinoma treated with chemoradiotherapy followed by surgery. Methods: Tissue samples from 29 rectal adenocarcinoma patients were obtained after chemoradiotherapy. O6-methylguanine-DNA methyltransferase promoter methylation status was established by methylation-specific polymerase chain reaction. O6-methylguanine-DNA methyltransferase protein levels were determined by immunohistochemistry. Clinicopathologic variables, including treatment regression grade, recurrence, lymph node invasion, and stage and differentiation grade of the tumor, were determined. Results: The O6-methylguanine-DNA methyltransferase gene promoter was methylated in 81.5% of samples. Most patients (88.9%) showed low O6-methylguanine-DNA methyltransferase protein expression. O6-methylguanine-DNA methyltransferase methylation status was not correlated with any of the clinicopathological variables determined in rectal adenocarcinomas selected for chemoradiotherapy. Conclusion: O6-methylguanine-DNA methyltransferase methylation status is not correlated with clinicopathologic variables examined in rectal adenocarcinoma selected for chemoradiotherapy, although its role as a biomarker awaits further investigation.

Role of radiotherapy in the treatment of metastatic head and neck cancer.

In metastatic or locally advanced head and neck tumors that present in frail patients or after chemotherapy progression, radiotherapy is normally used as a palliative treatment, with a high rate of symptom palliation and improvement in quality of life. However, there is controversy about what the optimal regimen is. Moreover, despite the poor prognosis of metastatic head and neck cancer, different retrospective studies have shown that a minority of patients with oligometastatic disease experience prolonged disease-free survival after adding curative radiotherapy treatment to the metastatic disease and/or primary tumor. Different retrospective studies have identified clinical prognostic factors that may be used to select candidate patients with metastatic head and neck cancer for a radical approach with radiotherapy. The purpose of this manuscript is to review the role of radiotherapy in metastatic and locally advanced head and neck tumors.

The Urinary Tract Microbiome in Health and Disease.

CONTEXT: The urinary tract, previously considered a sterile body niche, has emerged as the host of an array of bacteria in healthy individuals, revolutionizing the urology research field. OBJECTIVE: To review the literature on microbiome implications in the urinary tract and the usefulness of probiotics/prebiotics and diet as treatment for urologic disorders. EVIDENCE ACQUISITION: A systematic review was conducted using PubMed and Medline from inception until July 2016. The initial search identified 1419 studies and 89 were included in this systematic review. EVIDENCE SYNTHESIS: Specific bacterial communities have been found in the healthy urinary tract. Changes in this microbiome have been observed in certain urologic disorders such as urinary incontinence, urologic cancers, interstitial cystitis, neurogenic bladder dysfunction, sexually transmitted infections, and chronic prostatitis/chronic pelvic pain syndrome. The role of probiotics, prebiotics, and diet as treatment or preventive agents for urologic disorders requires further investigation. CONCLUSIONS: There is a microbiome associated with the healthy urinary tract that can change in urologic disorders. This represents a propitious context to identify new diagnostic, prognostic, and predictive microbiome-based biomarkers that could be used in clinical urology practice. In addition, probiotics, prebiotics, and diet modifications appear to represent an opportunity to regulate the urinary microbiome. PATIENT SUMMARY: We review the urinary microbiome of healthy individuals and its changes in relation to urinary disorders. The question to resolve is how we can modulate the microbiome to improve urinary tract health.

The impact of body mass index and nuclear ß-catenin on survival in locally advanced rectal cancer treated with preoperative radiochemotherapy.

BACKGROUND AND OBJECTIVE: We examined the prognostic value of obesity and nuclear ß-catenin in patients with locally advanced rectal cancer. METHODS: We prospectively recruited a total of 98 eligible patients with locally advanced cancer for preoperative radiochemotherapy followed by total mesorectal excision. Patients' height and weight were reaorded before radiochemotherapy, and the immunohistochemical expression of nuclear ß-catenin was analyzed. Disease-free survival (DFS) was analyzed using the Kaplan-Meier method and a Cox regression model was employed for the multivariate analysis. RESULTS: Obese patients were associated with a lower number of recurrences (3.6% vs. 34.3%, P = 0.001), and a higher DFS (95% vs. 53%; HR, 0.09; 95%CI, 0.01-0.64; P = 0.005) than non-obese patients. In the multivariate analysis, body mass index, nuclear ß-catenin expression, and the absence of lymph node metastases showed a significant increase in DFS. CONCLUSIONS: Obesity and nuclear ß-catenin are independent favorable prognostic factors for DFS in locally advanced cancer treated with preoperative radiochemotherapy. J. Surg. Oncol. 2017;115:301-306. © 2017 Wiley Periodicals, Inc.

Advances in the treatment of prostate cancer with radiotherapy.

INTRODUCTION: Prognosis of prostate cancer has improved as a result of the combination with androgen deprivation therapy and the increase of radiation dose. However, a high number of prostate cancer patients will develop biochemical recurrence; therefore a research effort to increase the control of the tumour in these patients is necessary. METHODS: To increase the therapeutic ratio (the index between cytotoxic effects and normal tissue complications with a certain dose of radiation), different new strategies described in the literature have been reviewed. RESULTS: There are several strategies that may increase the efficacy of radiotherapy to treat prostate cancer. First is based on physics and technology, and second based on biology. DISCUSSION: Technical advances in radiotherapy allow intensification of radiation through escalation of the dose or in combination with chemotherapy. Furthermore, targeting specific molecular dysregulated pathways in the tumour will increase the effects of radiation specifically in tumour cells. Hopefully, these strategies will result in increased rates of tumour control in all prognostic groups, especially in high risk tumours and a subgroup of patients with intermediate risk tumours, minimizing treatment morbidity and increasing the therapeutic ratio of radiotherapy.

Prognostic impact of MGMT promoter methylation and MGMT and CD133 expression in colorectal adenocarcinoma.

BACKGROUND: New biomarkers are needed for the prognosis of advanced colorectal cancer, which remains incurable by conventional treatments. O6-methylguanine DNA methyltransferase (MGMT) methylation and protein expression have been related to colorectal cancer treatment failure and tumor progression. Moreover, the presence in these tumors of cancer stem cells, which are characterized by CD133 expression, has been associated with chemoresistance, radioresistance, metastasis, and local recurrence. The objective of this study was to determine the prognostic value of CD133 and MGMT and their possible interaction in colorectal cancer patients. METHODS: MGMT and CD133 expression was analyzed by immunohistochemistry in 123 paraffin-embedded colorectal adenocarcinoma samples, obtaining the percentage staining and intensity. MGMT promoter methylation status was obtained by using bisulfite modification and methylation-specific PCR (MSP). These values were correlated with clinical data, including overall survival (OS), disease-free survival (DFS), tumor stage, and differentiation grade. RESULTS: Low MGMT expression intensity was significantly correlated with shorter OS and was a prognostic factor independently of treatment and histopathological variables. High percentage of CD133 expression was significantly correlated with shorter DFS but was not an independent factor. Patients with low-intensity MGMT expression and ≥50% CD133 expression had the poorest DFS and OS outcomes. CONCLUSIONS: Our results support the hypothesis that MGMT expression may be an OS biomarker as useful as tumor stage or differentiation grade and that CD133 expression may be a predictive biomarker of DFS. Thus, MGMT and CD133 may both be useful for determining the prognosis of colorectal cancer patients and to identify those requiring more aggressive adjuvant therapies. Future studies will be necessary to determine its clinical utility.

Preoperative chemoradiotherapy in rectal cancer induces changes in the expression of nuclear ß-catenin: prognostic significance.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is the cornerstone of treatment for locally advanced rectal cancer (LARC). Although high local control is achieved, overall rates of distant control remain suboptimal. Colorectal carcinogenesis is associated with critical alterations of the Wnt/ß-catenin pathway involved in proliferation and survival. The aim of this study was to assess whether CRT induces changes in the expression of ß-catenin/E-cadherin, and to determine whether these changes are associated with survival. METHODS: The Immunohistochemical expression of nuclear ß-catenin and membranous E-cadherin was prospectively analysed in tumour blocks from 98 stage II/III rectal cancer patients treated with preoperative CRT. Tumour samples were collected before and after CRT treatment. All patients were treated with pelvic RT (46-50 Gy in 2 Gy fractions) and 5-fluorouracil (5FU) intravenous infusion (225 mg/m2) or capecitabine (825 mg/m2) during RT treatment, followed by total mesorectal excision (TME). Disease-free survival (DFS) was analysed using the Kaplan-Meier method and a multivariate Cox regression model was employed for the Multivariate analysis. RESULTS: CRT induced significant changes in the expression of nuclear ß-catenin (49% of patients presented an increased expression after CRT, 17% a decreased expression and 34% no changes; p = 0.001). After a median follow-up of 25 months, patients that overexpressed nuclear ß-catenin after CRT showed poor survival compared with patients that experienced a decrease in nuclear ß-catenin expression (3-year DFS 92% vs. 43%, HR 0.17; 95% CI 0.03 to 0.8; p = 0.02). In the multivariate analysis for DFS, increased nuclear ß-catenin expression after CRT almost reached the cut-off for significance (p = 0.06). CONCLUSIONS: In our study, preoperative CRT for LARC induced significant changes in nuclear ß-catenin expression, which had a major impact on survival. Finding a way to decrease CRT resistance would significantly improve LARC patient survival.

Competing causes of death in patients with locoregionally advanced head and neck cancer treated with concomitant boost radiation plus concurrent weekly cisplatin.

BACKGROUND: This study analyzes the morbidity and the contribution of different causes of death to the outcome of patients with locally advanced head and- neck cancer after weekly cisplatin plus concomitant boost accelerated radiation treated in our center. MATERIALS AND METHODS: Ninety-four patients with locally advanced head and neck carcinoma were included in this phase II trial consisting of concomitant boost radiation plus concurrent weekly cisplatin. The 43 patients treated in our centered with long-term follow-up were analyzed. Patients received radiotherapy with a concomitant boost scheme (1.8 Gy on days 1-40 and 1.5 Gy boost on days 25-40 with a total dose of 72 Gy) and concurrent cisplatin, 40 mg/m(2) weekly, for the first 4 weeks. RESULTS: Most patients (93 %) received both radiation and complete chemotherapy according to protocol. Severe late toxicity presented were subcutaneous (5 %), larynx (2 %) and esophagous (5 %). Grade I-II late toxicity included mainly xerostomy (30 %), skin (16 %) and mucosal (16 %) toxicity. With a median follow-up of 95 months (9-135), the median overall survival and progression-free survival were 26 and 19 months, respectively (95 % CI 1-52; and 95 % CI 0-45); 60 % of the patients died because of head and neck cancer and 12 % of a second neoplasm, while 27 % of non-cancer patients died. CONCLUSIONS: Patients with locoregionally advanced head and neck cancer treated with concomitant boost accelerated radiation plus chemotherapy show significant risks of mortality from causes other than disease progression.

Multicenter phase II clinical trial of preoperative capecitabine with concurrent radiotherapy in patients with locally advanced rectal cancer.

INTRODUCTION: To assess pathologic complete response, sphincter preservation rates and toxicity profile of preoperative chemoradiation with capecitabine in resectable locally advanced rectal cancer. MATERIALS AND METHODS: Fifty-eight patients from six Spanish centers were included (March 2004 to June 2005) with histological/cytological diagnosis of locally advanced rectal cancer, age between 18 and 80 years, ECOG 0-2, adequate bone marrow, renal and hepatic functions. Prior chemotherapy/radiotherapy was not allowed. Preoperative treatment was capecitabine 825 mg/m(2) bid concomitant to radiotherapy (45 + 5.4 Gy boost over 5.5 weeks). Surgery was performed 4-8 weeks after completion of chemoradiotherapy. RESULTS: Fifty-eight patients were enrolled in this study: 60.3 % males, median age of 64.5 (30.9-78.7) years, 28.6 % with ECOG 0 and 71.4 % with ECOG 1. Median distance of tumor from the anal verge was 7 (1-12) cm. Fifty-two (89.6. %) patients completed preoperative chemoradiotherapy. Primary tumor and node downstaging occurred in 61.1 and 69.6 % of patients, respectively. Surgery was performed in 55 patients (94.8 %): 80 % had negative lymph nodes and 72.7 % underwent sphincter-preserving procedures. A pathologic complete response was observed in 10.5 % (95 % CI 2.5-18.5) of the patients. Main grade I-II toxicities were leucopenia (43.1 %), neutropenia (24.1 %), anemia (36.2 %), diarrhea (32.8 %) and skin disorders (5.1 %), from which diarrhea (6.9 %), leucopenia (1.7 %) and skin disorders (1.7 %) reached grade III. There were no grade IV toxicities. CONCLUSIONS: Preoperative capecitabine-based chemoradiation is a well-tolerated and effective neoadjuvant treatment for locally advanced rectal cancer that achieves encouraging rates of tumor downstaging.

Current status of IMRT in head and neck cancer.

BACKGROUND: IMRT provides highly conformal dose distributions creating non uniform spatial intensity using different segments in the beam. MATERIAL & METHODS AND RESULTS: Different retrospective studies have shown a high capability of IMRT to treat tumours close to the base of skull. Prospective studies have shown a decrease in xerostomia compared with conventional 3D conformal treatment (3DCRT). Modulation of intensity is performed by the movement of the multileaf collimator (MLC) that can deliver the radiation in different ways, such as static field segments, dynamic field segments and rotational delivery (arc therapy and tomotherapy). There are slight differences among the different techniques in terms of homogeneity, dose conformity and treatment delivery time. CONCLUSIONS: The best method to deliver IMRT will depend on multiple factors such as deliverability, practicality, user training and plan quality.

The importance of bystander effects in radiation therapy in melanoma skin-cancer cells and umbilical-cord stromal stem cells.

PURPOSE: To examine direct and bystander radiation-induced effects in normal umbilical-cord stromal stem cell (HCSSC) lines and in human cancer cells. MATERIALS AND METHODS: The UCSSC lines used in this study were obtained in our laboratory. Two cell lines (UCSSC 35 and UCSSC 37) and two human melanoma skin-cancer cells (A375 and G361) were exposed to ionizing radiation to measure acute radiation-dosage cell-survival curves and radiation-induced bystander cell-death response. Normal cells, although extremely sensitive to ionizing radiation, were resistant to the bystander effect whilst tumor cells were sensitive to irradiated cell-conditioned media, showing a dose-response relationship that became saturated at relatively low doses. We applied a biophysical model to describe bystander cell-death through the binding of a ligand to the cells. This model allowed us to calculate the maximum cell death (χ(max)) produced by the bystander effect together with its association constant (K(By)) in terms of dose equivalence (Gy). The values obtained for K(By) in A375 and G361 cells were 0.23 and 0.29 Gy, respectively. CONCLUSION: Our findings help to understand how anticancer therapy could have an additional decisive effect in that the response of sub-lethally hit tumor cells to damage might be required for therapy to be successful because the survival of cells communicating with irradiated cells is reduced.

Radiation therapy in the elderly: more side effects and complications?

Aging is associated with physiological changes and comorbid illnesses, which may affect an individual's tolerance to radiation. There is the belief that a relationship exists between age and radiation toxicity and therefore non-curative schemes are offered to older patients. Preclinical studies show that normal tissue radiation-induced toxicity differs little with age. In the clinical setting, retrospective and some prospective studies have reported that elderly patients treated with radical radiotherapy alone or in combination with chemotherapy, who do not have comorbidities and retain a good performance status, show a benefit in treatment outcomes. However, an increase in acute effects or a lowered functional tolerance has also been reported. To select candidates for radical treatments, a specific geriatric assessment should be used to stratify elderly patients as a function of the physiological status. Only specifically designed prospective studies can define the role of radiation treatment in elderly patients with different physiological status.