Feasibility of Image-Guided Radiotherapy for Elderly Patients with Locally Advanced Rectal Cancer

PURPOSE: The study aims to assess the tolerance of elderly patients (70 years or older) with locally advanced rectal cancers to image-guided radiotherapy (IGRT). A retrospective review of 13 elderly patients with locally advanced rectal cancer who underwent preoperative chemoradiation using IGRT was performed. Grade 3-4 acute toxicities, survival, and long-term complications were compared to 17 younger patients (<70 years) with the same disease stage. RESULTS: Grade 3-4 hematologic toxicities occurred in 7.6% and 0% (p = 0.4) and gastrointestinal toxicities, and, in 15.2% and 5% (p = 0.5), of elderly and younger patients, respectively. Surgery was aborted in three patients, two in the elderly group and one in the younger group. One patient in the elderly group died after surgery from cardiac arrhythmia. After a median follow-up of 34 months, five patients had died, two in the elderly and three in the younger group. The 3-year survival was 90.9% and 87.5% (p = 0.7) for the elderly and younger group respectively. Two patients in the younger group developed ischemic colitis and fecal incontinence. There was no statistically significant difference in acute and late toxicities as well as survival between the two groups. CONCLUSIONS AND CLINICAL RELEVANCE: Elderly patients with locally advanced rectal cancers may tolerate preoperative chemoradiation with IGRT as well as younger patients. Further prospective studies should be performed to investigate the potential of IGRT for possible cure in elderly patients with locally advanced rectal cancer

Microenvironmental Influence on Pre-Clinical Activity of Polo-Like Kinase Inhibition in Multiple Myeloma: Implications for Clinical Translation

Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers

Expert-guided approaches to complementary interventions for common side effects of cancer therapies: a practice-based perspective from integrative oncology centers in Baden-Württemberg, Germany

IntroductionCancer patients commonly suffer from substantial side effects of oncological therapies. Therefore, the Oncology Working Group of the Competence Network for Integrative Medicine in Baden-Württemberg, Germany (KIM-BW) developed practice-oriented recommendations for the integrative treatment of chemotherapy-induced mucositis (CIM), nausea and vomiting (CINV), and cancer-related fatigue (CRF).MethodsTwo expert groups of physicians and nurses developed therapeutic recommendations using an interdisciplinary expert consensus process oriented on a Delphi-methodology with a standardized scoring matrix, considering training, feasibility, time intensity, clinical effectiveness, contraindications, and interactions. The consensus process was complemented by a targeted, non-systematic literature search conducted across the AWMF S3 Guideline on Complementary Medicine in Oncology, the KOKON knowledge database, the Working Group on Integrative Care in Oncology, and PubMed/Medline.ResultsThe expert panel consisted of 21 professionals (14 physicians, 7 nurses), all conventionally trained with additional qualifications in integrative disciplines. We evaluated 83 interventions. Top recommendations were identified for each symptom. For CIM: sage tea mouth rinses, ice cubes, sea buckthorn oil mouth rinses, frozen pineapple cubes, and herbal oral balm. For CRF: movement therapy, yarrow liver compresses, viscum album therapy, sleep hygiene with regular circadian rhythms, and hydrotherapy. For CINV: acupressure, ginger, aromatherapy, bitter botanicals such as gentian root, and homeopathic preparation nux vomica.ConclusionsIntegrative treatment recommendations developed by the KIM Oncology Working Group provide pragmatic, clinically grounded guidance for integrative management of common treatment-related symptoms in oncology. Prospective evaluation of safety, effectiveness, and implementation across settings is warranted

Discordant identification of pediatric severe sepsis by research and clinical definitions in the SPROUT international point prevalence study

Introduction: Consensus criteria for pediatric severe sepsis have standardized enrollment for research studies. However, the extent to which critically ill children identified by consensus criteria reflect physician diagnosis of severe sepsis, which underlies external validity for pediatric sepsis research, is not known. We sought to determine the agreement between physician diagnosis and consensus criteria to identify pediatric patients with severe sepsis across a network of international pediatric intensive care units (PICUs). Methods: We conducted a point prevalence study involving 128 PICUs in 26 countries across 6 continents. Over the course of 5 study days, 6925 PICU patients <18 years of age were screened, and 706 with severe sepsis defined either by physician diagnosis or on the basis of 2005 International Pediatric Sepsis Consensus Conference consensus criteria were enrolled. The primary endpoint was agreement of pediatric severe sepsis between physician diagnosis and consensus criteria as measured using Cohen's κ. Secondary endpoints included characteristics and clinical outcomes for patients identified using physician diagnosis versus consensus criteria. Results: Of the 706 patients, 301 (42.6 %) met both definitions. The inter-rater agreement (κ ± SE) between physician diagnosis and consensus criteria was 0.57 ± 0.02. Of the 438 patients with a physician's diagnosis of severe sepsis, only 69 % (301 of 438) would have been eligible to participate in a clinical trial of pediatric severe sepsis that enrolled patients based on consensus criteria. Patients with physician-diagnosed severe sepsis who did not meet consensus criteria were younger and had lower severity of illness and lower PICU mortality than those meeting consensus criteria or both definitions. After controlling for age, severity of illness, number of comorbid conditions, and treatment in developed versus resource-limited regions, patients identified with severe sepsis by physician diagnosis alone or by consensus criteria alone did not have PICU mortality significantly different from that of patients identified by both physician diagnosis and consensus criteria. Conclusions: Physician diagnosis of pediatric severe sepsis achieved only moderate agreement with consensus criteria, with physicians diagnosing severe sepsis more broadly. Consequently, the results of a research study based on consensus criteria may have limited generalizability to nearly one-third of PICU patients diagnosed with severe sepsis

Capecitabine (cape)-associated hand-foot skin reaction (HFS) as a clinical predictor of improved survival in patients (pts) with colorectal cancer.

3541 Background: HFS is frequently observed during treatment with cape. Post hoc analyses of the X-ACT trial suggested that HFS may be associated with improved prognosis in cape recipients in stage III colon cancer. In the present analysis we evaluated the potential association of HFS and survival in pts with metastatic colorectal cancer and locally advanced rectal cancer. Methods: Pts receiving cape within AIO KRK-0104 and Mannheim rectal cancer trials were analyzed. HFS was graded according to NCI-CTC. Time to first occurrence of HFS was described per cycle and HFS developing during cycles 1 and 2 was defined as “early HFS”. Baseline characteristics in the groups of pts with or without HFS were compared using standard tests. Toxicities observed in both groups were compared with Fisher’s exact test. Progression-free (PFS) or disease-free (DFS) and overall survival (OS) data from both trials were pooled and the HFS group was compared to the non-HFS using Kaplan-Meier analysis. Results: A total of 374 pts are included, of whom 29.3% developed HFS. Of these, 70.9% had “early HFS”. Baseline characteristics were comparable between the HFS and the non-HFS groups concerning age, gender, ECOG status and UICC stage. On multivariate analysis none of these factors had influence on the occurrence of HFS. The percentage of all-grade hematological toxicities did not differ between both groups. Contrarily, patients in the HFS group had a significantly higher rate of all grade (but not grade 3-4) diarrhea, stomatitis/mucositis and fatigue (p&lt;0.01 resp.). Moreover, pts in the HFS group had improved PFS/DFS (29.0 vs. 11.4 months; p=0.015, HR 0.69) and OS (75.8 vs. 41.0 months; p=0.001, HR=0.56). Within the HFS group the PFS/DFS and OS were comparable between pts in the “early” and the “late HFS” groups. Conclusions: This analysis provides further evidence for the association of HFS and survival in patients with colorectal cancer. Baseline characteristics and the time of occurrence of HFS had no impact on survival. Patients developing HFS had a higher probability of developing any-grade gastrointestinal toxicity and fatigue while no correlation with hematological toxicity was noticed. </jats:p