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Purpose: The objective of this study is to investigate the significance of microRNAs (miRNA) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).Experimental Design: A global miRNA profiling was done on 51 formalin-fixed archival HNSCC samples using quantitative reverse transcription-PCR approach, correlated with patients' clinical parameters. Functional characterization of HNSCC-associated miRNAs was conducted on three HNSCC cell lines. Cell viability and proliferation were investigated using MTS and clonogenic assays, respectively; cell cycle analyses were assessed using flow cytometry.Results: Thirty-eight of the 117 (33%) consistently detected miRNAs were significantly differentially expressed between malignant versus normal tissues. Concordant with previous reports, overexpression of miR-21, miR-155, let-7i, and miR-142-3p and underexpression of miR-125b and miR-375 were detected. Upregulation of miR-423, miR-106b, miR-20a, and miR-16 as well as downregulation of miR-10a were newly observed. Exogenous overexpression of miR-375 in HNSCC cell lines reduced proliferation and clonogenicity and increased cells in sub-G1. Similar cellular effects were observed in knockdown studies of the miR-106b-25 cluster but with accumulation of cells in G1 arrest. No major difference was detected in miRNA profiles among laryngeal, oropharyngeal, or hypopharyngeal cancers. miR-451 was found to be the only significantly overexpressed miRNA by 4.7-fold between nonrelapsed and relapsed patients.Conclusion: We have identified a group of aberrantly expressed miRNAs in HNSCC and showed that underexpression of miR-375 and overexpression of miR-106b-25 cluster might play oncogenic roles in this disease. Further detailed examinations of miRNAs will provide opportunities to dissect the complex molecular abnormalities driving HNSCC progression. Clin Cancer Res; 16(4); 1129–39

Purpose: Despite recent improvements in local control of head and neck cancers (HNC), distant metastasis remains a major cause of death. Hence, further understanding of HNC biology, and in particular, the genes/pathways driving metastasis is essential to improve outcome.Experimental Design: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure the expression of miR-375 and metadherin (MTDH) in HNC patient samples. Targets of miR-375 were confirmed using qRT-PCR, Western blot analysis, and luciferase assays. Phenotypic effects of miR-375 reexpression and MTDH knockdown were assessed using viability (MTS), clonogenic survival, cell migration/invasion, as well as in vivo tumor formation assays. The prognostic significance of miR-375 or MTDH in nasopharyngeal carcinoma (NPC) was determined by comparing low versus high expression groups.Results: MiR-375 expression was significantly reduced (P = 0.01), and conversely, MTDH was significantly increased (P = 0.0001) in NPC samples. qRT-PCR, Western blots, and luciferase assays corroborated MTDH as a target of miR-375. Reexpression of miR-375 and siRNA knockdown of MTDH both decreased cell viability and clonogenic survival, cell migration/invasion, as well as in vivo tumor formation. NPC patients whose tumors expressed high levels of MTDH experienced significantly lower survival and, in particular, higher distant relapse rates (5-year distant relapse rates: 26% vs. 5%; P = 0.005).Conclusions: Dysregulation of miR-375 and MTDH may represent an important oncogenic pathway driving human HNC progression, particularly distant metastases, which is now emerging as a major cause of death for HNC patients. Hence, targeting this pathway could potentially be a novel therapeutic strategy by which HNC patient outcome could be improved. Clin Cancer Res; 17(24); 7539–50. ©2011 AACR.

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Supplementary Data from Comprehensive MicroRNA Profiling for Head and Neck Squamous Cell Carcinomas

Anal adenocarcinoma is a rare clinical entity for which the optimal management is not defined.This study aimed to describe the multidisciplinary management and outcomes of patients with anal adenocarcinoma.This is a retrospective cohort study.This study was conducted at a quaternary cancer center.Men and women with anal adenocarcinoma treated between 1995 and 2016 were selected.Fifty-two patients were treated with either chemoradiotherapy or trimodality therapy including radiation therapy, chemotherapy, and surgical resection.Local failure, regional failure, and distant metastasis rates were estimated using the cumulative incidence method. The Kaplan-Meier method was used to estimate progression-free survival and overall survival. The multivariable Cox proportional hazards model was used to evaluate the clinical predictors of outcome.There was a higher 5-year rate of local failure in patients treated with chemoradiotherapy compared with trimodality therapy (53% vs 10%; p0.01). The 5-year incidence of distant metastases was 29% (trimodality therapy) versus 30% (chemoradiotherapy; p = 0.9); adjuvant chemotherapy did not reduce the incidence of distant metastases (p = 0.8). Five-year overall survival was 73% (trimodality therapy) versus 49.4% (chemoradiotherapy; p = 0.1). On multivariable analysis, factors associated with worse overall survival were treatment with chemoradiotherapy, cT3-4 category disease, and node-positive disease.This study is limited by its small sample size and retrospective nature.Although treatment may continue to be tailored to individual patients, better outcomes with a trimodality therapy approach were observed. See Video Abstract at http://links.lww.com/DCR/B708.ADENOCARCINOMA ANAL: UNA ENTIDAD POCO FRECUENTE EN NECESIDAD DE UN MANEJO MULTIDISCIPLINARIO.El adenocarcinoma anal es una entidad clínica poco frecuente por lo que aún no se define el manejo óptimo.Describir el manejo multidisciplinario y los resultados de los pacientes con adenocarcinoma anal.Estudio de cohorte retrospectivo.Centro de cáncer cuaternario.Hombres y mujeres con adenocarcinoma anal tratados entre 1995 y 2016.Cincuenta y dos pacientes fueron tratados con quimiorradioterapia o terapia trimodal que incluyó: radioterapia, quimioterapia y resección quirúrgica.Se estimaron las tasas de falla local, falla regional y metástasis a distancia mediante el método de incidencia acumulada. Se utilizó el método de Kaplan-Meier para estimar la supervivencia libre de progresión y la supervivencia global. Los riesgos proporcionales de multivariable Cox se utilizaron para evaluar los predictores clínicos de los resultados.Hubo una mayor tasa de falla local a cinco años en pacientes tratados con quimiorradioterapia en comparación con terapia trimodal (53% vs 10%; p0,01). La incidencia a cinco años de metástasis a distancia fue del 29% (terapia trimodal) versus 30% (quimiorradioterapia) (p = 0,9); la quimioterapia adyuvante no redujo la incidencia de metástasis a distancia (p = 0,8). La supervivencia global a cinco años fue del 73% (terapia trimodal) versus 49,4% (quimiorradioterapia); p = 0,1. En el análisis multivariable, los factores asociados con una peor supervivencia general fueron el tratamiento con quimiorradioterapia, enfermedad de categoría cT3-4 y enfermedad con ganglios positivos.Este estudio está limitado por su pequeño tamaño de muestra y su naturaleza retrospectiva.Aunque el tratamiento puede seguir adaptándose a pacientes individuales, se observaron mejores resultados con un enfoque TTM. Conslute Video Resumen en http://links.lww.com/DCR/B708. (Traducción- Dr. Francisco M. Abarca-Rendon).

Volumetric modulated arc therapy (VMAT) has generally been perceived as too time and resource intensive for palliative radiation therapy mainly because of the need for extensive organs at risk contouring. Dose-limiting conformity-based objectives can be automatically generated and are commonly used to conform isodoses closely around the target volumes during inverse planning. The aim of this study was to determine if conformity-based objectives can be used to create VMAT plans for lumbosacral spine palliative radiation therapy without organs at risk contours, which will improve conformity, dose homogeneity, and speed of delivery compared with standard forward planning approaches.A total of 25 patients were retrospectively replanned using three different planning techniques: (1) anterior-posterior parallel opposed pair (POP); (2) single isocenter anterior-posterior half-beam block junctioned to three fields, posterior and two laterals (JUNC); and (3) VMAT single arc. Treatment volume included L1-S5 vertebrae prescribed to 20 Gy in five fractions. Conformality index, homogeneity index, contour, planning, and treatment time were compared for each technique.Planning target volume V95 ≥95% was maintained for all 75 replans. VMAT was superior to POP and JUNC in terms of conformality (POP 2.0 vs. JUNC 1.8 vs. VMAT 1.2; P.01) and homogeneity (POP 1.1 vs. JUNC 1.1 vs. VMAT 1.0; P.01). Planning times for POP were the lowest (3.2 minutes). VMAT and POP had similar delivery times (1.5 minutes), which were approximately half the JUNC delivery time (3.2 minutes).Conformity-based VMAT was dosimetrically superior to conventional field-based planning and reduced delivery time. This reduction in normal tissue dose as well as reduced time spent on the treatment couch can potentially improve the quality of life in palliative patients receiving radiotherapy to the lumbosacral spine.

Background Locally recurrent rectal cancer (LRRC) is a complex problem requiring multidisciplinary consultation and specialized surgical care. Given the paucity of published longer-term survival data, skepticism persists regarding the benefit of major extirpative surgery. We investigated ultra-long-term (~15 years) outcomes following radical resection of LRRC and sought relevant clinicopathologic prognostic variables. Methods A cohort of 52 consecutive patients who underwent resection of LRRC at our institution between 1997 and 2005 were followed with serial exams and imaging up to the point of death, or 30/06/2019. Results Median follow-up time was 16.5 years (9.9–18.3) for patients who were alive at last follow-up; only one patient was lost to follow-up, at 9.9 years. For the entire cohort of 52 patients, disease-specific survival (DSS) at 5, 10, and 15 years following salvage surgery was 41%, 33%, and 31%, respectively. All patients who had distant metastatic disease at the time of LRRC resection (n = 6) subsequently died of cancer, at a median of 21 months (4−46). In those without distant metastases at time of salvage surgery (n = 46), DSS at 5, 10, and 15 years was 47%, 38%, and 35%, respectively, median 60 months. Negative resection margin (R0) was independently predictive of superior outcomes. In patients with M0 disease who had R0 resection (n = 37), DSS at 5, 10 and 15 years was 58%, 47%, and 44%, respectively, median 73 months. No patient developed re-recurrence after 5.5 years. Conclusions This study demonstrates exceptionally durable long-term cancer-free survival following salvage surgery for LRRC, indicating that cure is possible.

Highlights • Hyperfractionated RT with augmented dose provides durable enhanced disease control. • Late toxicity is unchanged with higher optimal doses using smaller fraction sizes. • Hyperfractionation improves overall survival but mortality profile evolves over time. • Altered fractionation should avoid unnecessary RT protraction to maximize control. • Excessive acceleration should be avoided to minimize severe normal tissue sequelae., Purpose/objective(s) To examine the therapeutic ratio and mortality profile over time in a radiotherapy randomized trial in stage III-IV larynx/pharynx cancer with long-term follow-up. Materials/methods From 1988 to 1995, 331 cases were randomized to either hyperfractionated (HF) (58 Gy/40 fractions, twice daily) or conventional (CF) (51 Gy/20 fractions, once daily) radiotherapy. Overall survival (OS), locoregional (LRC), distant control (DC), ≥Grade 3 late toxicity (LT), and relative mortality risk profile over time were compared between both arms. Results Median follow-up was 13.6 years. HF had a 10% improved OS at 5-years (40% vs 30%, p = 0.04), but the benefit diminished to 3% at 10-years (21% vs 18%). A trend towards higher LRC with HF remained (5-year: 49% vs 40%; 10-year: 49% vs 39%, p = 0.05). DC rates were unchanged (5-year: 87% vs 85%; 10-year: 87 vs 84%, p = 0.56). LT rates were similar (HF vs CF: 5-year: 9% vs 12%; 10-year: 11% vs 14%, p = 0.27). Multivariable analysis confirmed that HF reduced mortality risk by 31% [HR 0.69 (0.55–0.88), p

// Ali Hosni 1 , Kathy Han 1 , Lisa W. Le 2 , Jolie Ringash 1 , James Brierley 1 , Rebecca Wong 1 , Robert Dinniwell 1 , Anthony Brade 1 , Laura A. Dawson 1 , Bernard J. Cummings 1 , Monika K. Krzyzanowska 3 , Eric X. Chen 3 , David Hedley 3 , Jennifer Knox 3 , Alexandra M. Easson 4 , Patricia Lindsay 1 , Tim Craig 1 and John Kim 1 1 Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada 2 Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 3 Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada 4 Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada Correspondence to: John Kim, email: john.kim@rmp.uhn.ca Keywords: anal cancer; chemoradiotherapy; IMRT; pattern of failure; outcomes Received: November 11, 2017 Accepted: February 27, 2018 Published: April 17, 2018 ABSTRACT Purpose: Patterns of failure and long term outcomes were prospectively evaluated following tumor factors-stratified radiation dose for anal/perianal cancer. Methods: Between 2008–2013, patients with anal/perianal squamous cell carcinoma were accrued to an institutional REB-approved prospective study. All patients were treated with image-guided intensity-modulated radiation therapy (IG-IMRT). Radiation dose selection (27–36 Gy for elective target, and 45–63 Gy for gross target) was based on tumor clinico-pathologic features. Chemotherapy regimen was 5-fluorouracil/mitomycin-C (weeks 1&5). Local [LF], regional failure [RF], distant metastasis [DM], overall- [OS], disease-free [DFS], colostomy-free survival [CFS] and late toxicity were analyzed. Results: Overall, 101 patients were evaluated; median follow-up: 56.5 months; 49.5% male; 34.7% T3/4-category, and 35.6% N+. Median radiation dose was 63 Gy. The most common acute grade ≥3 toxicities were skin (41.6%) and hematological (30.7%). Five-year OS, DFS, CFS, LF, RF, DM rates were 83.4%, 75.7%, 74.7, 13.9%, 4.6% and 5% respectively. Five-year LF for patients with T1-2 and T3-4 disease were 0% and 39.2% respectively. All LF ( n = 14, after 63 Gy, in tumors ≥5 cm) were in the high dose volume except one marginal to the high dose volume. All RF ( n = 4) were within elective dose volume except one within the high dose volume. On multivariable analysis, T3/4-category predicted for poor DFS, CFS and OS. The overall late grade ≥3 toxicity was 36.2% (mainly anal [20%]). Conclusions: Individualized radiation dose selection using IG-IMRT resulted in good long term outcomes. However, central failures remain a problem for locally advanced tumors even with high dose radiation (63 Gy/7weeks).

Purpose We evaluated the effect of consecutive protocols on overall survival (OS) for cervical esophageal carcinoma (CEC). Methods and Materials All CEC cases that received definitive radiation therapy (RT) with or without chemotherapy from 1997 to 2013 in 3 consecutive protocols were reviewed. Protocol 1 (P1) consisted of 2-dimensional RT of 54 Gy in 20 fractions with 5-fluorouracil plus either mitomycin C or cisplatin. Protocol 2 (P2) consisted of 3-dimensional conformal RT (3DRT) of ≥60 Gy in 30 fractions plus elective nodal irradiation plus cisplatin. Protocol 3 (P3) consisted of intensity modulated RT (IMRT) of ≥60 Gy in 30 fractions plus elective nodal irradiation plus cisplatin. Multivariable analyses were used to assess the effect of the treatment protocol, RT technique, and RT dose on OS, separately. Results Of 81 cases (P1, 21; P2, 23; and P3, 37), 34 local (P1, 11 [52%]; P2, 12 [52%]; and P3, 11 [30%]), 16 regional (P1, 6 [29%]); P2, 3 [13%]; and P3, 7 [19%]), and 34 distant (P1, 10 [48%]; P2, 9 [39%]; and P3, 15 [41%]) failures were identified. After adjusting for age ( P =.49) and chemotherapy (any vs none; hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.3-0.9; P =.023), multivariable analysis showed P3 had improved OS compared with P1 (HR 0.4, 95% CI 0.2-0.8; P =.005), with a trend shown for benefit compared with P2 (HR 0.6, 95% CI 0.3-1.0; P =.061). OS between P1 and P2 did not differ ( P =.29). Analyzed as a continuous variable, higher RT doses were associated with a borderline improved OS (HR 0.97, 95% CI 0.95-1.0; P =.075). IMRT showed improved OS compared with non-IMRT (HR 0.57, 95% CI 0.3-0.8; P =.008). Conclusions The present retrospective consecutive cohort study showed improved OS with our current protocol (P3; high-dose IMRT with concurrent high-dose cisplatin) compared with historical protocols. The outcomes for patients with CEC remain poor, and novel approaches to improve the therapeutic ratio are warranted.

Purpose Locoregional recurrence is common after surgery for gastric cancer. Adjuvant therapy improves outcomes but with toxicity. This phase 1/2 study investigated infusional 5-fluorouracil (5-FU) in combination with biweekly cisplatin delivered concurrently with image guided high-precision radiation therapy. Methods and Materials Eligible patients had completely resected stage IB to IV (Union for International Cancer Control TNM 6th edition) nonmetastatic gastric adenocarcinoma. Treatment constituted 12 weeks of infusional 5-FU (200 mg/m2/day) with cisplatin added in a standard 3 + 3 dose escalation protocol (0, 20, 30, and 40 mg/m2) during weeks 1, 3, 5, and 7, and an additional week 9 dose in the final cohort. Radiation therapy (45 Gy in 25 fractions) was delivered during weeks 3 to 7. Maximum tolerated dose (MTD) was determined in phase 1 and confirmed in phase 2. Results Among the 55 patients (median age, 54 years; range 28-77 years; 55% male), the median follow-up time was 3.0 years (range, 0.3-5.3 years). Five patients in phase 1 experienced dose-limiting toxicity, and MTD was determined as 4 cycles of 40 mg/m2 cisplatin. Twenty-seven patients were treated at MTD. Acute grade 3 to 4 toxicity rate was 37.0% at MTD and 29.1% across all dose levels. No treatment-related deaths occurred. Fourteen patients experienced recurrent disease. The 2-year overall survival (OS) and relapse-free survival were 85% and 74%, respectively. Median OS has not been reached. Quality of life (QOL) was impaired during treatment, but most scores recovered by 4 weeks. Conclusion Cisplatin can be safely delivered with 5-FU–based chemoradiation therapy. Acute toxicity was acceptable, and patient-reported QOL showed the regimen was tolerable. Outcomes are encouraging and justify further study of this regimen.

Background Salivary duct carcinoma is rare, with distinct morphology and behavior. We reviewed our institutional experience with salivary duct carcinoma, aiming to characterize clinical behavior and treatment outcomes. Methods All salivary duct carcinomas treated curatively between 1999 and 2010 were reviewed. Overall survival (OS), locoregional control, distant control, and patterns of failure were analyzed. Multivariate analysis identified predictors of OS. Results Fifty-four patients with salivary duct carcinoma (parotid gland = 49; submandibular gland = 5) were included in the analysis. Fifty-three patients underwent primary surgery, and 48 (89%) received postoperative radiotherapy (RT; median dose = 60 Gy). Median follow-up was 5.7 years. The 5-year OS, locoregional control, and distant control were 43%, 70%, and 48%, respectively. Nine local (6 involving facial nerve), 10 regional, and 28 distant failures were identified. Multiple pathologic involved lymph nodes (pN2b/N2c) predicted reduced OS (hazard ratio [HR] = 3.6; p = .02). Conclusion Distant recurrence is common. Presence of pN2b/N2c disease is associated with reduced OS. Local recurrence frequently involves the facial nerves. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Although multidisciplinary cancer conferences have been reported to lead to improved patient outcomes, few studies have reported results of these for rectal cancer.The purpose of this work was to assess the quality of multidisciplinary cancer conferences, the effect of the conference on the initial treatment plan, compliance with the conference treatment recommendations, and clinical outcomes for rectal cancer.This was a prospective, longitudinal study.The study was conducted at a tertiary care academic hospital.Patients with primary rectal cancer were included in this study.The intervention was a rectal cancer-specific multidisciplinary cancer conference.The quality of the multidisciplinary cancer conference was assessed using the Cancer Care Ontario Multidisciplinary Cancer Conference standards score. A change in treatment plan was defined as a change from the initial treatment plan selected by the treating physician to an alternate treatment plan recommended at the conference.Twenty-five multidisciplinary cancer conferences were conducted over a 10-month study period. The Cancer Care Ontario Multidisciplinary Cancer Conference standards score was 7 (from a maximum score of 9). Forty-two patients with primary rectal cancer were presented, and there was a 29% (12/42) change in the initial treatment plan. A total of 42% (5/12) of these changes were attributed to reinterpretation of the MRI findings. There was 100% compliance with the conference treatment recommendations. The circumferential resection margin was positive in 5.5% (2/36).Selection bias may have led to an overestimate of effect, and there is no control group for comparison of clinical outcomes.A high-quality rectal cancer-specific multidisciplinary cancer conference led to a 29% change in the treatment plan for patients with primary rectal cancer, with almost half of these changes attributed to reinterpretation of the magnetic resonance images.

Flagellate dermatitis (FD) exhibits a striking clinical appearance similar to whiplash marks. General dermatologists are likely to encounter this clinical appearance as a more localized presentation of phytophotodermatosis. Jellyfish stings may also cause localized linear or FD. Chemotherapeutic agents such as bleomycin, doxorubicin, docetaxel, and trastuzumab are well-recognized causes of a widespread FD and it may more rarely be seen in connective tissue disease such as dermatomyositis or Still disease. In our case, this was a presentation of shiitake mushroom dermatitis.

An evolving paradigm in global outreach in radiation oncology has been the implementation of a more region-specific, needs-based approach to help close the gap in radiation services to low- and middle-income countries through the use of innovative tools in information and communication technology. This report highlights 4 information and communication technology tools in action today: (1) the NCCN Framework for Resource Stratification of NCCN guidelines, (2) ASTRO e-Contouring, (3) i.treatsafely.org, and (4) ChartRounds.com. We also render special consideration to matters related to global outreach that we believe require distinct attention to help us meet the goals established by the 2011 United Nations׳ Declaration on noncommunicable diseases: (1) trainee advancement toward careers in global health, (2) ethical challenges of international outreach, (3) critical importance of political advocacy, and (4) collaboration with Industry.

Background The purpose of this study was to discuss if the adoption of intensity-modulated radiotherapy (IMRT) for hypopharyngeal squamous cell carcinoma (SCC) has improved the outcome. Methods We compared 3-dimensional (3D) radiotherapy (RT) and IMRT in all patients with hypopharyngeal SCC treated with curative intent RT or chemoradiation therapy (CRT) from January 1, 2000, to February 28, 2010. Locoregional control, overall survival (OS), distant relapse rate, larynx preservation rate, and enteral feeding tube duration were analyzed. Results Of 181 consecutive patients, 90 received 3D-RT and 91 received IMRT. At 3 years, the IMRT group had higher locoregional control compared with the 3D-RT group (75% vs 58%; p = .003), but similar OS (50% vs 52%; p = .99), distant relapse rate (23% vs 20%; p = .79), and larynx-preservation rate (90% vs 86%; p = .16). The 2-year enteral feeding tube dependency rate was similar in both groups (19% vs 18%; p = .12). Conclusion Patients with hypopharyngeal SCC treated with IMRT showed a higher locoregional control compared with 3D-RT. However, distant-relapse rate and OS remain comparable between treatment techniques. © 2014 Wiley Periodicals, Inc. Head Neck 37: 655–661, 2015

Aims To determine the efficacy of induction gemcitabine followed by biweekly gemcitabine concurrent with radiotherapy for locally advanced pancreatic cancer. Materials and methods Between March 2001 and August 2009, 90 patients with unresectable (78) or resected (12) pancreatic cancer were treated with a standard treatment policy of induction gemcitabine (seven doses of weekly gemcitabine at 1000 mg/m 2 ) followed by concurrent radiotherapy (52.5 Gy) and biweekly gemcitabine (40 mg/m 2 ). Results After induction gemcitabine, 17.8% of patients did not proceed to chemoradiotherapy, due to either disease progression, performance status deterioration or gemcitabine toxicity. Of the patients who received chemoradiotherapy, 68.9% completed the course of 52.5 Gy, whereas 79.7% received more than 45 Gy. Chemoradiotherapy was stopped early due to treatment toxicity in 22.9% of patients. On intention to treat analysis, the median overall survival was 12.7 months in the locally advanced group and 18.2 months in the resected group. On multivariate analysis for the unresectable patients, a larger gross tumour volume was a significant poor prognostic factor for overall survival and local progression-free survival. Conclusion This large series confirms, in a standard practice setting, similar efficacy and tolerability of treatment as previously reported in our phase I–II study. The benefit to patients with a gross tumour volume >48 cm 3 may be limited.

To investigate the relationship of pre-treatment volumetric apparent diffusion coefficient (ADC) histogram parameters with post-operative histopathologic treatment response and clinical outcomes following pre-operative chemoradiation treatment (CRT) in rectal cancer. In a Health Insurance Portability and Accountability Act compliant retrospective study, 78 rectal cancer patients treated with pre-operative CRT and rectal MRI were included. MR imaging analysis was performed using OncoTREAT (software tool). Multiple volumetric ADC histogram parameters (voxel distribution across ADC ranges, kurtosis, and skewness) were assessed. Correlation was made to post-operative pathological complete response, clinical, or radiological evidence of disease progression using the Mann–Whitney test. Post CRT, 8 patients showed pathologic complete response and 13 patients showed distant disease progression. Pre-treatment mean ADC was 1.2 × 10−3 mm2/s (range 0.3–1.99 × 10−3 mm2/s). Mean kurtosis measured was 0.56 (range −1 to 6; SD 1.36). Mean skewness was 0.3 (range −1 to 2; SD 0.69). Skewness had significant correlation (p value = 0.006) with disease progression. The mean rectal tumor volume was 24cc (range 1cc–134cc). Pre-treatment MRI tumor volume showed significant correlation (p value = 0.013) with pathologic complete response. Mean ADC and percentage voxels distribution against ADC ranges had no significant correlation with treatment response or disease outcomes. Volumetric ADC histogram analysis of pre-CRT rectal cancer MRI appears promising for prediction of post-CRT complete response and disease progression.

Purpose Reduction of respiratory motion is desirable to reduce the volume of normal tissues irradiated, to improve concordance of planned and delivered doses, and to improve image guided radiation therapy (IGRT). We hypothesized that pretreatment lorazepam would lead to a measurable reduction of liver motion. Methods and Materials Thirty-three patients receiving upper abdominal IGRT were recruited to a double-blinded randomized controlled crossover trial. Patients were randomized to 1 of 2 study arms: arm 1 received lorazepam 2 mg by mouth on day 1, followed by placebo 4 to 8 days later; arm 2 received placebo on day 1, followed by lorazepam 4 to 8 days later. After tablet ingestion and daily radiation therapy, amplitude of liver motion was measured on both study days. The primary outcomes were reduction in craniocaudal (CC) liver motion using 4-dimensional kV cone beam computed tomography (CBCT) and the proportion of patients with liver motion ≤5 mm. Secondary endpoints included motion measured with cine magnetic resonance imaging and kV fluoroscopy. Results Mean relative and absolute reduction in CC amplitude with lorazepam was 21% and 2.5 mm respectively (95% confidence interval [CI] 1.1-3.9, P =.001), as assessed with CBCT. Reduction in CC amplitude to ≤5 mm residual liver motion was seen in 13% (95% CI 1%-25%) of patients receiving lorazepam (vs 10% receiving placebo, P =NS); 65% (95% CI 48%-81%) had reduction in residual CC liver motion to ≤10 mm (vs 52% with placebo, P =NS). Patients with large respiratory movement and patients who took lorazepam ≥60 minutes before imaging had greater reductions in liver CC motion. Mean reductions in liver CC amplitude on magnetic resonance imaging and fluoroscopy were nonsignificant. Conclusions Lorazepam reduces liver motion in the CC direction; however, average magnitude of reduction is small, and most patients have residual motion >5 mm.

Purpose To evaluate the feasibility and response of liver radiotherapy (RT) in improving symptoms and quality of life in patients with hepatocellular carcinoma (HCC) or liver metastases (LM). Patients and Methods Eligible patients had HCC or LM, unsuitable for or refractory to standard therapies, with an index symptom of pain, abdominal discomfort, nausea, or fatigue. The Brief Pain Inventory (BPI), Functional Assessment of Cancer Therapy–Hepatobiliary (FACT-Hep), and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) were completed by patients at baseline and each follow-up. The primary outcome was the percentage of patients with a clinically significant change at 1 month in the BPI subscale of symptom on average in the past 24 hours. Secondary outcomes were improvement in other BPI subscales and at other time points, FACT-Hep and EORTC QLQ-C30 at each follow-up, and toxicity at 1 week. Results Forty-one patients (30 men and 11 women) with HCC (n = 21) or LM (n = 20) were accrued. At 1 month, 48% had an improvement in symptom on average in the past 24 hours. Fifty-two percent of patients had improvement in symptom at its worst, 37% at its least, and 33% now. Improvements in the FACT-G and hepatobiliary subscale were seen in 23% and 29% of patients, respectively, at 1 month. There were also improvements in EORTC QLQ-C30 functional (range, 11% to 21%) and symptom (range, 11% to 50%) domains. One patient developed grade 3 nausea at 1 week. Conclusion Improvements in symptoms were observed at 1 month in a substantial proportion of patients. A phase III study of palliative liver RT is planned.

The purpose of this study was to understand and compare patient and staff perceptions of a video-based preparatory education tool for head and neck radiotherapy. Patients and staff completed a questionnaire assessing their perceptions of whether the education tool was relevant, clear, complete and reassuring. Staff rated the video's accuracy and anticipated impact on future patient information needs. Demographic information was collected. Open-ended questions were used to elicit additional feedback. Quantitative responses from 50 patients and 48 staff were very positive and not significantly different between the two groups. Content analysis of the qualitative data provided insight into the information and approaches valued by patients and staff and how these differed. Staff members were more critical of the production quality and completeness of information related to procedures and treatment side effects. Patients valued seeing procedures acted out and desired more information about what these experiences would feel like and how to engage in self-care. Although staff-driven development may be an effective method of designing the content and approach of a preparatory education video, care should be taken to consider differences between patient and staff perceptions of information needs.

Purpose To describe outcomes of prospective trials of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC). Patients and Methods Two trials of SBRT for patients with active HCC unsuitable for standard locoregional therapies were conducted from 2004 to 2010. All patients had Child-Turcotte-Pugh class A disease, with at least 700 mL of non-HCC liver. The SBRT dose range was 24 to 54 Gy in six fractions. Primary end points were toxicity and local control at 1 year (LC1y), defined as no progressive disease (PD) of irradiated HCC by RECIST (Response Evaluation Criteria in Solid Tumors). Results A total of 102 patients were evaluable (Trial 1, 2004 to 2007: n = 50; Trial 2, 2007 to 2010: n = 52). Underlying liver disease was hepatitis B in 38% of patients, hepatitis C in 38%, alcohol related in 25%, other in 14%, and none in 7%. Fifty-two percent received prior therapies (no prior sorafenib). TNM stage was III in 66%, and 61% had multiple lesions. Median gross tumor volume was 117.0 mL (range, 1.3 to 1,913.4 mL). Tumor vascular thrombosis (TVT) was present in 55%, and extrahepatic disease was present in 12%. LC1y was 87% (95% CI, 78% to 93%). SBRT dose (hazard ratio [HR] = 0.96; P = .02) and being in Trial 2 (HR = 0.38; P = .03) were associated with LC1y on univariate analysis. Toxicity ≥ grade 3 was seen in 30% of patients. In seven patients (two with TVT PD), death was possibly related to treatment (1.1 to 7.7 months after SBRT). Median overall survival was 17.0 months (95% CI, 10.4 to 21.3 months), for which only TVT (HR = 2.47; P = .01) and being in Trial 2 (HR = 0.49; P = .01) were significant on multivariate analysis. Conclusion These results provide strong rationale for studying SBRT for HCC in a randomized trial.

summary Objectives: To review outcomes and analyze the patterns of locoregional recurrence of oral cavity squamous cell carcinoma (OCSCC) treated with surgery and postoperative intensity-modulated radiation therapy (IMRT). Materials and methods: All patients with Stage I-IVB OCSCC treated with surgery and postoperative IMRT ± concurrent chemotherapy between 2005 and 2010 were evaluated. Patient survival and tumor outcomes were prospectively recorded. Outcome measures were 2 year overall survival (OS), local control (LC), regional control (RC) and distant control (DC). Locoregional recurrences were spatially localized in relation to dosimetric plans. Results: A total of 180 consecutive patients with median follow-up of 34 months were identified. Disease subsites were oral tongue (46%), floor of mouth (23%), alveolus and hard palate (12%), buccal (9%), retromolar trigone (5%), and lip (4%). The 2 year rates of OS, LC, RC, locoregional control (LRC), and DC were 65%, 87%, 83%, 78% and 83%, respectively. The 2-year estimated rates of LRC for larger subsites were: oral tongue (72%), floor of mouth (84%). Of the 180 patients, 38 (21%) had locoregional failure (LRF). Most LRFs were in-field (26, 68%) with 7 marginal and 5 out-of-field. Marginal/out-of-field failures occurred in the contralateral neck in N2b patients, at high level II/skull base, and in intentionally spared regions (near parotid) of pathologically involved necks. Conclusions: Nearly a third (12/38) of LR recurrences were marginal or out-of-field following postoperative IMRT for OCSCC. Postoperative IMRT following gross total surgical resection requires careful and comprehensive target volume delineation, and larger volumes may be needed than the primary RT setting.

Purpose: Despite recent improvements in local control of head and neck cancers (HNC), distant metastasis remains a major cause of death. Hence, further understanding of HNC biology, and in particular, the genes/pathways driving metastasis is essential to improve outcome. Experimental Design: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure the expression of miR-375 and metadherin (MTDH) in HNC patient samples. Targets of miR-375 were confirmed using qRT-PCR, Western blot analysis, and luciferase assays. Phenotypic effects of miR-375 reexpression and MTDH knockdown were assessed using viability (MTS), clonogenic survival, cell migration/invasion, as well as in vivo tumor formation assays. The prognostic significance of miR-375 or MTDH in nasopharyngeal carcinoma (NPC) was determined by comparing low versus high expression groups. Results: MiR-375 expression was significantly reduced (P = 0.01), and conversely, MTDH was significantly increased (P = 0.0001) in NPC samples. qRT-PCR, Western blots, and luciferase assays corroborated MTDH as a target of miR-375. Reexpression of miR-375 and siRNA knockdown of MTDH both decreased cell viability and clonogenic survival, cell migration/invasion, as well as in vivo tumor formation. NPC patients whose tumors expressed high levels of MTDH experienced significantly lower survival and, in particular, higher distant relapse rates (5-year distant relapse rates: 26% vs. 5%; P = 0.005). Conclusions: Dysregulation of miR-375 and MTDH may represent an important oncogenic pathway driving human HNC progression, particularly distant metastases, which is now emerging as a major cause of death for HNC patients. Hence, targeting this pathway could potentially be a novel therapeutic strategy by which HNC patient outcome could be improved. Clin Cancer Res; 17(24); 7539–50. ©2011 AACR.

To examine the patterns of care, outcomes, and prognostic factors for patients with head-and-neck cancer (HNC) treated with palliative radiotherapy (RT).An institutional HNC anthology and electronic patient records were used to identify patients with previously untreated HNC of mucosal or salivary gland origin who underwent palliative RT at our institution between July 2003 and June 2008. Overall survival was determined from the start date of RT to either the date of death or the date of last follow-up for living patients. The data were censored if the subject was either lost to follow-up or had not been seen for follow-up at our institution for ≥4 months.We identified 148 eligible patients. The median age was 72 years (range, 19-94). Of the 148 patients, 12 had Stage II-III, 39 Stage IVA, 36 Stage IVB, and 54 Stage IVC; for 7 patients, the stage was unknown. Oropharyngeal primary cancer (40) was the most common primary site. The Eastern Cooperative Oncology Group performance status was 0 in 15, 1 in 69, 2 in 40, 3 in 19, and 4 in 5 patients. The Adult Co-morbidity Evaluation-27 scale was 0 in 33, 1 in 47, 2 in 44, and 3 in 21. The median radiation dose was 50 Gy (range, 2-70), the median fraction number was 20 (range, 1-40), and the median total treatment time (including breaks) was 29 days (range, 1-80). At analysis, 108 patients (73%) had died, 20 (13.5%) were alive, and 20 (13.5%) had been censored. The median follow-up was 4.8 months, and the median survival time was 5.2 months. Information on the treatment response was available for 103 patients (70%). On multivariate analysis, the radiation dose was an independent predictor of both overall survival (hazard ratio 0.97, 95% confidence interval 0.96-0.99, p.01) and treatment response (odds ratio 1.05, 95% confidence interval 1.01-1.08, p.01).For patients considered unsuitable for curative RT, the radiation dose might be an independent predictive factor for both overall survival and treatment response. Additional research is required to more effectively select those patients who might benefit from more aggressive treatment.

Background and purpose To assess the completeness and accuracy of stage and outcome data in the Anthology of Outcomes (AOs), a prospective point-of-care physician-collected electronic data system for patients at the Princess Margaret Hospital. Material and methods A random sample of 10% of the AO cases registered between July 2003 and December 2005 was drawn. An audit was conducted of the AO data compared with chart review and cancer registry. Results The AO system was applied first to a head and neck (HN) cancer patient cohort. From 1152 HN cases, 120 were audited. TNM stage was recorded in all cases. Discrepancy was found between the AO and primary data sources in 3–13% of cases. Physician review showed a 3% error rate in overall stage recorded in the AO. Sixty-two outcomes in 43 patients were found on chart review. No outcomes were incorrectly recorded in the AO. Nineteen (31%) outcomes in 17 patients were missed in the AO. Conclusions Our experience has demonstrated the feasibility of real-time outcome recording at point-of-care. New processes needed to improve the completeness of capture of patient outcomes in the AO have more recently been introduced. This successful system has been expanded to other disease sites.

Purpose To report on the outcomes of a phase I study of stereotactic body radiotherapy (SBRT) for treatment of liver metastases. Patients and Methods Patients with liver metastases that were inoperable or medically unsuitable for resection, and who were not candidates for standard therapies, were eligible for this phase I study of individualized SBRT. Individualized radiation doses were chosen to maintain the same nominal risk of radiation-induced liver disease (RILD) for three estimated risk levels (5%, 10%, and 20%). Additional patients were treated at the maximal study dose (MSD) in an expanded cohort. Median SBRT dose was 41.8 Gy (range, 27.7 to 60 Gy) in six fractions over 2 weeks. Results Sixty-eight patients with inoperable colorectal (n = 40), breast (n = 12), or other (n = 16) liver metastases were treated. Median tumor volume was 75.2 mL (range, 1.19 to 3,090 mL). The highest RILD risk level investigated was safe, with no dose-limiting toxicity. Two grade 3 liver enzyme changes occurred, but no RILD or other grade 3 to 5 liver toxicity was seen, for a low estimated risk of serious liver toxicity (95% CI, 0 to 5.3%). Six (9%) acute grade 3 toxicities (two gastritis, two nausea, lethargy, and thrombocytopenia) and one (1%) grade 4 toxicity (thrombocytopenia) were seen. The 1-year local control rate was 71% (95 CI, 58% to 85%). The median overall survival was 17.6 months (95% CI, 10.4 to 38.1 months). Conclusion Individualized six-fraction liver metastases SBRT is safe, with sustained local control observed in the majority of patients.

Purpose The role of primary radiotherapy (RT) for laryngeal verrucous carcinoma (LVC) is controversial because of concerns about anaplastic transformation, an increased incidence of metastases, and poorer local control after RT. To address these concerns, we report our experience. Methods and Materials All patients with pathologically diagnosed LVC treated with primary RT at our institution between 1961 and 2004 were reviewed. The local control, overall survival, and disease-specific survival rate were established. The outcome after salvage treatment and the incidence of metastases and anaplastic transformation were determined. Results Of 62 LVC patients with a minimal follow-up of 2 years, 20 local and 1 nodal recurrence were identified. Salvage surgery was undertaken in 18 of the 21 patients, and disease control was achieved in 17; the eighteenth patient died of a complication after surgery. Ultimate laryngeal preservation was achieved in 50 patients (81%), including 42 after initial RT and an additional 8 after salvage surgery. Distant failure and anaplastic transformation were not observed. Second cancers after RT were identified in 4 patients, only 1 of which was a head-and-neck cancer detected 11 years later. Of the 39 deceased patients, only 3 died of LVC. The local control, overall survival, and disease-specific survival rate at 5 years was 66% (95% confidence interval, 52–77%), 87% (95% confidence interval, 75–93%), and 97% (95% confidence interval, 87–99%), respectively. Conclusion The results of our study have shown that the initial control of LVC with RT is less reliable compared with reports from surgical series; however, local recurrence was almost always salvaged successfully, resulting in disease-specific survival rates equivalent to those of surgical series. Neither anaplastic transformation nor unusual metastasis development was observed in this series.

Aims We hypothesised that accelerated fractionated radiotherapy may provide a good palliative approach for dysphagia relief in patients with incurable oesophageal cancer, significantly reducing the overall duration of treatment, while providing symptom response with an acceptable toxicity profile. A phase I/II accelerated fractionation study was conducted to evaluate the efficacy and toxicity of this approach. Materials and methods Patients with incurable oesophageal cancer, symptomatic with dysphagia, Eastern Cooperative Oncology Group performance status≤3, without fistula or oesophageal stent in situ , were eligible. Treatment consisted of 40Gy in 20 fractions, twice a day (2Gy per fraction, ≥6h apart), 5 days a week, over 2 weeks. Results Of the 39 evaluable patients, the dysphagia response rate was 69% (27/39) with a median response duration of 5.5 months. The median time to response was 4 weeks. Twenty-eight per cent (11/39) of patients had transient worsening in their dysphagia scores. Acute toxicity (weeks 1–8) occurred in 41% (16/39) of patients. An improvement in global quality of life by week 8 was seen in 42% of patients. There were no late neurological sequelae. The median overall survival was 8 (range 1.7–58+) months. Conclusion The ideal palliative regimen should be relatively short, with minimal toxicity, while offering a favourable response profile. Accelerated fractionation fulfils these criteria and is a suitable treatment alternative for the palliation of dysphagia, especially if the goal is to deliver a higher total biological dose within a shorter (2 week) period of time.

Background and Purpose Fractionation strategies delivered over 4 weeks are of clinical and radiobiological interest because treatment is completed before radiotherapy (RT) induced clonogen proliferation commences in earnest approximately 3 to 4 weeks into a course of RT. We wished to test the clinical hypothesis that an increased total dose delivered over 4 weeks with smaller than standard doses per fraction in locally advanced squamous cell carcinoma (SCC) may result in relative protection of late responding tissues and an increased tumor control compared to a conventional daily course in the same overall time. Materials and methods Between 1988 and 1995 a randomized controlled trial employing RT alone was undertaken at the Princess Margaret Hospital that included 331 eligible patients with T3 or T4 N0 or any N-positive oropharynx, hypopharynx, or larynx primary SCC. RT was randomly assigned to one of two 4 week schedules, either 51 Gy in 20 equal daily fractions, termed conventional fractionation (CF), or 58 Gy in 40 equal fractions given twice per day as a hyperfractionated (HF) experimental arm. Results The 5-year local relapse rate was reduced in the HF (41%) compared to the CF arm (49%). This difference was marginally not significant ( p =0.082) when the effect was not adjusted. When the effect of the treatment was adjusted by Cox model for clinical factors that included N-category, ECOG performance status, site of disease, T-category, age, hemoglobin, and gender the HF achieved a significant effect ( p =0.02). Survival (40% vs. 30%) was also improved with HF compared to CF arm. This difference was only marginally not significant ( p =0.069) but again achieved statistical significance when the model was adjusted for clinical factors ( p =0.01). Similar results were observed for disease free survival. Although reversible acute toxicity was increased with HF, the overall 5-year rate of grade 3 and 4 late toxicity for the CF was 10.5% compared to 7.7% in the higher dose HF arm. Conclusions HF delivered in 4 weeks permits enhanced RT doses achieving improved tumor control, without increased late toxicity, compared to daily fractionated radiotherapy in the same overall time.

Aims Intergroup study 0116 (INT-0116) showed an 11% absolute improvement in 3-year survival with post-operative radiochemotherapy for gastric cancer, but reported 33% severe acute GI toxicity using conventional simulation with large fields. We adapted the treatment using conformal radiotherapy techniques and assessed toxicity and outcome in 20 consecutive patients. Methods A conformal radiotherapy technique previously developed for gastric lymphoma was adapted to treat the target volume defined in INT-0116. The five-field plan used a large anterior field, plus asymmetrically matched upper AP:PA fields and lower lateral fields. Consecutive patients with ECOG PS 0–2 and stage IB–IV non-metastatic gastric cancer were treated with 5-FU (425mg/m 2 daily ×5 days) and leucovorin (20mg/m 2 daily ×5 days) for one cycle prior to and two cycles following concurrent radiation (45Gy/25 fractions) with identical drug dosages on the first 4 and last 3 days of radiation. Acute toxicity was prospectively recorded weekly using RTOG and NCI common toxicity criteria. Patient charts were reviewed in November 2003 and late toxicity and outcome were recorded. Results Nineteen of 20 patients completed radiotherapy and 14 completed all chemotherapy cycles. One patient died of neutropenic sepsis. Maximum acute toxicity [grade (number)] was: 5(1), 4(0), 3(4), 2(10), 1(4), 0(1). There were two grade 1 late toxicities. Two-year overall survival is 70% (95% confidence interval: 50–90). Conclusions Conformal radiotherapy may improve acute toxicity (25% grade 3 or greater toxicity as compared with 41% reported in INT-0116). Survival is comparable to that achieved in the INT-0116 treatment arm (approximately 60% at 2 years). INT-0116 results can be achieved outside a study setting; however, further efforts to improve treatment efficacy and minimize toxicity are warranted.

Purpose The Intergroup 0099 trial (INT 0099) for locally advanced nasopharyngeal cancer (NPC) has set a standard of practice. This retrospective review documents our institutional experience with this regimen. Methods and materials For all NPC patients treated between January 1998 and December 2002 with the INT 0099 regimen, compliance, toxicity, weight change, and feeding tube use were recorded. Patients were grouped by therapy completion status and by feeding tube status. Results Of 78 consecutive patients, 75 were evaluable. Compliance with radiotherapy was excellent. Only 43% and 61% of patients received all cycles of concurrent and adjuvant chemotherapy, respectively. Patients who successfully completed therapy had a higher average baseline weight and were more likely to have had a prophylactic feeding tube. Forty of 75 patients had a feeding tube inserted and were analyzed as two groups. Patients with prophylactic insertion ( n = 23) had a more gradual drop in weight, and recovered to a greater degree at 1 year (93.6% vs. 87.2%), than those with a feeding tube inserted therapeutically during treatment ( n = 17). Conclusions The INT 0099 regimen was generally delivered with modifications to the chemotherapy component, as in the original trial. The prophylactic insertion of a feeding tube may facilitate therapy completion and weight recovery in some patients.

A retrospective review has been performed to assess the outcome and toxicity of post-operative adjuvant therapy of 25 Gy/5 fractions/1 week following resection of stage II and III rectal cancer. Forty patients were treated between August 1992 and May 1995. The ages ranged from 42 to 79 (median 63); 32 were male (80%). At last follow up 32 were alive with 0.9 to 11.3 years of follow-up (median 6.6 years). The 5-year actuarial survival was 76% (95% CI: 62-91%). The local relapse free rate was 73% (95% CI: 58-88). Seven patients experienced grade 3 or 4 early toxicity. Three patients had grade 2 or 3 late toxicity. Although treatment was well tolerated, the local relapse rate observed was high. In view of the changes in surgical and pathological techniques in the last decade, further studies are required to determine the merits or otherwise of postoperative Short Course Adjuvant Radiation.

Purpose To study the relationship between body mass index (BMI) and rates of sphincter-preserving operations, overall survival, cancer recurrence, and treatment-related toxicities in patients with rectal cancer. Patients and Methods We evaluated a nested cohort of 1,688 patients with stage II and III rectal cancer participating in a randomized trial of postoperative fluorouracil-based chemotherapy and radiation therapy. Results Obese patients were more likely to undergo an abdominoperineal resection (APR) than normal-weight patients (odds ratio, 1.77; 95% CI, 1.27 to 2.46). When analyzed by sex, increasing adiposity in men was a strong predictor of having an APR (P < .0001). Obese men with rectal cancer were also more likely than normal-weight men to have a local recurrence (hazard ratio [HR], 1.61; 95% CI, 1.00 to 2.59). In contrast, obesity was not predictive of cancer recurrence in women, nor was BMI predictive of overall mortality in either men or women. Underweight patients had an increased risk of death (HR, 1.43; 95% CI, 1.08 to 1.89) compared with normal-weight patients but no increase in cancer recurrences. Among all study participants, obese patients had a significantly lower rate of grade 3 to 4 leukopenia, neutropenia, and stomatitis and a lower rate of any grade 3 or worse toxicity when compared with normal-weight individuals. Conclusion Increasing BMI in male patients with rectal cancer is associated with a decreased likelihood of sphincter preservation and a higher chance of local recurrence. For both men and women, overweight and obese patients experience less toxicity associated with adjuvant chemoradiotherapy, suggesting that actual body weight dosing of fluorouracil for obese patients is justified.

Purpose : To assess the adequacy of coverage of gross tumor volume (GTV) with traditional two dimensional (2D) radiation therapy (RT) planning in patients with nasopharyngeal cancer (NPC). Materials and methods : The study comprised 94 of 179 patients treated with definitive RT between 1993 and 1997. The inclusion requirement was the availability of a digitally archived pretreatment magnetic resonance imaging. The digital images were used to record the precise location of the GTV in the sagittal plane. As a separate procedure, sagittal dose distributions for each treatment phase were created by digitizing the simulation field parameters into treatment planning software without knowledge of the GTV. The location of the GTV and dose distribution in the sagittal plane were superimposed on each other and GTV coverage by the 50, 90 and 95% isodose lines determined for each phase of treatment. Results : The 1997 tumour node metastasis (TNM) stage distribution was: 7 (8%) stage I, 16 (16%) stage II, 30 (32%) stage III and 41 (44%) stage IV. Median follow-up was 4.4 years. Median primary dose was 66 Gy. The actuarial 5-year overall survival, disease free survival and local relapse free rates were 88, 54 and 66%, respectively. The GTV was covered by the 50, 90 and 95% isodose lines for all phases of the multiphase plan in only 53, 20 and 9% of patients, respectively. The GTV was more likely to be undercovered in the latter phases of the plan particularly in those patients with advanced T category. Conclusion : 2D RT planning has significant limitations in achieving adequate GTV coverage in NPC. We strongly recommend 3D planning using either conformal techniques of dose delivery or intensity modulated radiation therapy for the treatment of these patients.

Purpose: To investigate compliance to the prescribed dose-fractionation schedule in five randomized controlled trials of altered fractionation in radiotherapy for head-and-neck carcinoma. Methods and Materials: Individual patient data from 2566 patients participating in the European Organization for Research and Treatment of Cancer (EORTC) 22791, EORTC 22811, EORTC 22851, Princess Margaret Hospital (PMH), and continuous hyperfractionated accelerated radiotherapy (CHART) head-and-neck trials were merged in the fractionation IMPACT (Intergroup Merger of Patient data from Altered or Conventional Treatment schedules) study database. The ideal treatment time was defined as the minimum time required to deliver a prescribed schedule. Compliance to the prescribed overall treatment time was quantified as the difference between the actual and the ideal overall time. An overall measure of compliance in an individual patient, the total dose lost (TDL), was calculated as the dose lost due to prolongation of therapy (assuming a D prolif of 0.64 Gy/day) plus the difference between the prescribed and the actual dose given. Results: The time in excess of the ideal ranged up to 97 days (average 3.9 days), and 25% of the patients had delays of 6 days or more. World Health Organization (WHO) performance status and nodal stage had a significant effect on TDL. TDL was significantly higher in the conventional than in the altered arm of the EORTC 22851 and CHART trials. In the PMH trial, TDL was significantly higher in the hyperfractionation than in the conventional arm. Centers participating in the three EORTC trials varied significantly in their compliance. There was a significant improvement in compliance in patients treated more recently. Conclusions: Even in randomized controlled trials, compliance to the prescribed radiation therapy schedule may be relatively poor, especially after conventional fractionation. This affects the interpretation of the outcome of these trials.

Purpose : To examine the outcome of radiotherapy (RT) alone in patients with advanced nasopharyngeal cancer (NPC) and to compare the results with those reported by the Intergroup study 0099 (IGS) comparing RT to combined modality therapy (CMT). Materials and methods : During the period 1985–1992, 198 NPC patients presenting without distant metastatic disease were treated for cure. Of these, 172 had stage III/IV (UICC 1987, 1992). Planned RT was 2 Gy/day fraction to 60–66 Gy to the primary tumor, with 50 and 60 Gy to the node negative and to palpable nodes, respectively. Outcomes included overall survival (OS) and disease-free survival (DFS), defined from the time of registration at our institution. Results : The TNM categories and other prognostic factors were similar to the IGS, though 80% had stage IV compared to 91% in IGS. The 5 year OS and DFS for the 172 patients with stage III/IV disease were 62 and 48%, respectively, as compared to the IGS results of OS 37% and DFS 29% for RT alone, and OS 67% and DFS 58% for the CMT arm of IGS. When the distribution of adverse prognostic factors was balanced between both studies the comparative results were unchanged. Conclusions : The early results for RT alone of this single institution experience are superior to those of the IGS control arm (RT), while somewhat inferior to those reported in the chemo-radiotherapy arm. The surprisingly poor outcome of the IGS/RT control arm may have resulted by chance, suggesting the need for a confirmatory randomized trial to fully establish the role of combined chemotherapy and radiation, as used in the IGS.

PURPOSE: The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure. PATIENTS AND METHODS: All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus fluorouracil (5-FU), 5-FU and leucovorin, 5-FU and levamisole, and 5-FU, leucovorin, and levamisole. Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy. RESULTS: One thousand six hundred ninety-five patients were entered and fully assessable, with a median follow-up of 7.4 years. There was no difference in overall survival (OS) or disease-free survival (DFS) by drug regimen. DFS and OS decreased between years 5 and 7 (from 54% to 50% and 64% to 56%, respectively), although recurrence-free rates had only a small decrease. The local recurrence rate was 14% (9% in low-risk [T1 to N2+] and 18% in high-risk patients [T3N+, T4N]). Overall, 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. Males had a poorer overall survival rate than females. CONCLUSION: There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates are still high, especially in T3N+ and T4 patients, even with full adjuvant chemoradiation therapy.