More Is Not Better When It Comes to Treating Rectal Cancer With Multimodal Chemoradiation Beyond the Standard Radiation Dose of 5040 cGy.

BACKGROUND: Radiation dose schedules for neoadjuvant chemoradiation for rectal cancers differ, with the most common dose schedule using 5040 cGy in 28 fractions. OBJECTIVES: The aim of this retrospective study was to assess the benefit of higher radiation doses beyond 5040 cGy in the context of pathological response and follow-up events. SETTING: The database from a provincial tertiary cancer center in Canada was the source of information for this study. PATIENTS: Included in this study were 508 consecutive patients with rectal cancer with locally advanced disease (clinical T3/T4 or N1/N2) who received neoadjuvant chemoradiation followed by surgery. Of the 508 patients, 281 received the standard radiation dose of 4500 to 5040 cGy and 227 received a dose >5040 cGy. MAIN OUTCOME MEASURE: The postsurgical pathology, late toxicities, and follow-up outcomes were analyzed. The outcomes were evaluated in relation to the dose of radiation received. RESULTS: Data regarding the clinical outcomes were comparable between the 4500 to 5040 cGy and >5040 cGy radiation groups with pathological complete response rates of 20.9% and 15.4% (p = 0.104); distant recurrence rates of 17.4% and 19.4% (p = 0.36); local recurrence rates of 3.2% and 3.5% (p = 0.36); and the median overall survival rates of 61 and 60.5 months (p = 0.8). No statistically significant correlation of improvement in outcomes was noted with radiation doses beyond 5040 cGy. LIMITATIONS: This is a retrospective study. CONCLUSION: Our study showed that dose escalation beyond the standard dose of 4500 to 5040cGy failed to achieve meaningful clinical outcomes. See Video Abstract at http://links.lww.com/DCR/B633. MS NO ES MEJOR CUANDO SE TRATA DE TRATAR EL CNCER DE RECTO CON QUIMIORRADIACIN MULTIMODAL MS ALL DE LA DOSIS DE RADIACIN ESTNDAR DE CGY: ANTECEDENTES:En neoadyuvancia de cáncer rectal es posible encontrar muchas variaciones, en radioterapia la dosis más común que usa 5040 cGy en 28 fracciones.OBJETIVOS:El objetivo de este estudio retrospectivo fue evaluar el beneficio de dosis de radiación más altas más allá de 5040cGy en el contexto de la respuesta patológica y en su seguimiento.AJUSTE:Base de datos de un centro de cáncer terciario provincial en Canadá.PACIENTES:Se incluyeron en este estudio quinientos ocho pacientes consecutivos con cáncer de recto y enfermedad localmente avanzada (clínica T3 / T4 o N1 / N2) que recibieron quimiorradiación neoadyuvante seguida de cirugía. De los 508 pacientes, 281 recibieron la dosis de radiación estándar de 4500-5040 cGy y 227 recibieron una dosis > 5040 cGy.PRINCIPAL MEDIDA DE RESULTADO:Se analizo evolucion posquirúrgica, toxicidad tardía y seguimiento. Los resultados se evaluaron en relación con la dosis de radiación recibida.RESULTADOS:Los datos con respecto a los resultados clínicos fueron comparables entre los grupos de radiación de 4500-5040 cGy y> 5040 cGy con tasas de respuesta patológica completa de 20,9% y 15,4% respectivamente (p = 0,104); tasas de recurrencia a distancia de 17,4% y 19,4%, respectivamente (p = 0,36); tasas de recurrencia local de 3,2% y 3,5%, respectivamente (p = 0,36); y la mediana de las tasas de supervivencia global de 61 y 60,5 meses, respectivamente (p = 0,8). No se observó una correlación estadísticamente significativa de mejoría en los resultados con dosis de radiación superiores a 5040 cGy.LIMITACIONES:Este es un estudio retrospectivo.CONCLUSIONES:Nuestro estudio mostró que el aumento de la dosis más allá de la dosis estándar de 4500-5040cGy no logró resultados clínicos significativos. Consulte Video Resumen en http://links.lww.com/DCR/B633. (Traducción-Dr. Gunther Bocic).

Impact of dose-capping chemotherapy in concurrent chemoradiotherapy in rectal cancer patients.

INTRODUCTION: The study evaluated the effect of chemotherapy dose-capping on disease recurrence, toxicity and survival of rectal cancer patients treated with chemoradiotherapy (CRT). METHODS: 601 consecutive rectal cancer patients treated with concurrent CRT were retrospectively analysed. Dose-capped patients were defined as having a body surface area (BSA) ≥2.0 m2 and who received <95% full weight-based chemotherapy dose. Binary logistic regression was used to study the factors associated with the outcome variables (capped vs. uncapped). Kaplan-Meier estimation evaluated significant predictors of survival. RESULTS: The median follow-up time was 7.54 years. The rate of disease recurrence was significantly higher in dose-capped patients (35%) compared to those without dose-capping (24%, P = 0.016). The adjusted odds ratio for dose-capped patients experiencing recurrence was 1.64 compared to uncapped patients (95% CI, 1.10-2.43). Overall, dose-capped patients were less likely to experience significant toxicity requiring dose reduction and/or treatment break when compared to uncapped patients (15% and 28% respectively, P = 0.008).There was significant differences in PFS between capped and uncapped group (77% vs. 85%; P = 0.017). The 5-year OS in the capped group was 75.0%, and 80% in the uncapped group (P = 0.149). CONCLUSIONS: Rectal cancer patients treated with dose-capped CRT were at increased risk of disease recurrence. Patients dosed by actual BSA did experience excessive toxicity compared to dose-capped group. We recommend that chemotherapy dose-capping based on BSA should not be practiced in rectal cancer patients undergoing CRT.

Exercise motivation in rectal cancer patients during and after neoadjuvant chemoradiotherapy.

PURPOSE: Aerobic exercise is safe and feasible for rectal cancer patients during and after neoadjuvant chemoradiotherapy (NACRT), but their motivation to perform such exercise is unknown. Here, we explore the motivational outcomes, perceived benefits and harms, and perceived barriers to exercise during and after NACRT. METHODS: Rectal cancer patients (n = 18) participated in supervised aerobic exercise during NACRT followed by unsupervised exercise after NACRT. Using the theory of planned behavior, we assessed perceived benefits, harms, enjoyment, support, difficulty, and barriers for exercise both during and after NACRT. RESULTS: Patients reported that exercise during NACRT was more enjoyable (p = 0.003) and less difficult (p = 0.037) than initially anticipated. The most common perceived benefits of exercise during NACRT were cardiovascular endurance (75 %), quality of life (75 %), and self-esteem (65 %). After NACRT, the most common perceived benefits were physical functioning (93 %), cardiovascular endurance (86 %), and quality of life (79 %). The most common perceived harms of exercise during NACRT were fatigue (31 %), diarrhea (31 %), and skin irritation (24 %). After NACRT, the most common perceived harms were fatigue (21 %) and hand-foot-syndrome (15 %). Side effects from NACRT were the most common exercise barrier during NACRT (88 %) whereas lack of motivation was the most common barrier after NACRT (79 %). CONCLUSIONS: Rectal cancer patients reported aerobic exercise during NACRT to be more enjoyable and less difficult than anticipated despite significant barriers. This positive motivational response may facilitate recruitment and adherence in future interventions. Moreover, rectal cancer patients identified potential benefits and harms that should be closely monitored in future interventions.

A population-based analysis of the impact of 1 vs. 2 doses of mitomycin on patterns of failure of anal cancer patients treated with concurrent chemoradiotherapy.

PURPOSE: We report the impact of 1 vs. 2 doses of mitomycin-C (MMC) based chemoradiation (CRT) on patterns of treatment failure and long-term patient outcomes in anal squamous cell carcinoma (ASCC) and the predictors for locoregional failure (LRF) and distant metastasis (DM). METHODS: In this population-based study, we identified all patients with anal cancer in our province treated radically with radiation and concurrent 5-Fluorouracil (5FU) and 1 vs. 2 doses of MMC between the years 2000-2019. The primary outcomes analyzed were locoregional recurrence (LRR), disease free survival (DFS), ASCC cancer-specific survival (ASCC-CSS) and overall survival (OS). RESULTS: 451 patients were identified. 272 (60%) patients received 1 cycle of MMC (MMC1) and 179 (40%) received 2 cycles (MMC2) as part of the CRT regimen. The median follow-up was 57 (36-252) and 97 (38-239) months for MMC1 and MMC2, respectively. Cox Regression analysis showed stage IIIb and IIIc were associated with worse locoregional recurrence free survival (RFS) (HR=2.851, p=<0.001) and distant RFS (HR=3.391, p=<0.001). Similarly, stage IIIb and IIIc patients had poorer DFS (HR 3.439, p=<0.001), ASCC-SS (HR 3.729, p=<0.001) and OS (2.230, p=<0.001). The use of MMC2 showed a positive impact on improved ASCC-SS (HR 0.569, p=0.029) and distant RFS (HR 0.555, p=0.040) in patients with stage IIIb and IIIc. CONCLUSIONS: Our analysis showed that 1 vs. 2 cycles of MMC along with 5FU and radiation is associated with comparable treatment outcomes in general. However, in patients with stage IIIb and IIIc cancer, 2 doses of MMC were associated with improved ASCC-SS and distant DFS.

Effects of exercise during and after neoadjuvant chemoradiation on symptom burden and quality of life in rectal cancer patients: a phase II randomized controlled trial.

PURPOSE: We previously demonstrated that exercise during and after neoadjuvant chemoradiation (NACRT) for rectal cancer may improve the rate of pathologic complete/near complete response. Here, we report the effects of exercise on symptom management and quality of life (QoL). METHODS: Rectal cancer patients (N = 36) were randomized to a supervised high-intensity interval training program during NACRT followed by unsupervised continuous exercise after NACRT or usual care. Patient-reported outcomes were assessed at baseline, post-NACRT, and presurgery including symptom burden (M.D. Anderson Symptom Inventory) and QoL (European Organisation for Research and Treatment of Cancer QLQ- C30 and -CR29). RESULTS: During NACRT, exercise significantly worsened stool frequency (adjusted between-group difference, 25.8; 95% CI, 4.0 to 47.6; p = 0.022), role functioning (adjusted between-group difference, -21.3; 95% CI, -41.5 to -1.1; p = 0.039), emotional functioning (adjusted between-group difference, -11.7; 95% CI, -22.0 to -1.4; p = 0.028), and cognitive functioning (adjusted between-group difference, -11.6; 95% CI, -19.2 to -4.0; p = 0.004) compared to usual care. After NACRT, exercise significantly worsened diarrhea (adjusted between-group difference, 1.2; 95% CI, 0.1 to 2.3; p = 0.030) and embarrassment (adjusted between-group difference, 19.7; 95% CI, 7.4 to 32.1; p = 0.003) compared to usual care. CONCLUSIONS: Exercise exacerbated some symptoms and worsened QoL during NACRT; however, most negative effects dissipated after NACRT. Larger trials are necessary to confirm these findings. IMPLICATIONS FOR CANCER SURVIVORS: If the clinical benefit of exercise is confirmed, then the modest symptom exacerbation during NACRT may be considered tolerable. However, in the absence of any clinical benefit, exercise may be contraindicated in this clinical setting.

Effects of Exercise on Motivational Outcomes in Rectal Cancer Patients During and After Neoadjuvant Chemoradiation: A Phase II Randomized Controlled Trial.

OBJECTIVES: Understanding exercise motivation in rectal cancer patients during and after neoadjuvant chemoradiation therapy is important to improve adherence and achieve potential benefit. We report the motivational effects of exercise from the Exercise During and After Neoadjuvant Rectal Cancer Treatment trial. DATA SOURCES: We randomized 36 rectal cancer patients to supervised high-intensity interval training during neoadjuvant chemoradiation therapy followed by unsupervised moderate-to-vigorous exercise after therapy, or usual care. Using the theory of planned behavior, we assessed motivation, perceived benefits/harms, and perceived barriers for exercise during and after therapy. Supervised exercise during neoadjuvant chemoradiation therapy was experienced as meaningfully (d≥0.33) more controllable (p=0.08, d=0.60), more enjoyable (p=0.25, d=0.45), and less difficult (p=0.45, d=-0.38) than anticipated. Unsupervised exercise after therapy was experienced as meaningfully more enjoyable (p=0.047, d=0.50) and less difficult (p=0.43, d=-0.36), but also less controllable (p=0.14, d=-0.80) than anticipated. Common self-reported benefits of exercise both during and after neoadjuvant chemoradiation therapy were cardiovascular endurance, physical functioning, and quality of life. Common self-reported harms were exacerbation of treatment side effects. Frequently reported barriers to exercise during therapy were side effects of treatment, whereas exercise barriers after therapy were lack of motivation and lingering side effects. CONCLUSION: Exercise during and after therapy generally had positive effects on exercise motivation, however, perceived harms and barriers related to treatment side effects were identified. IMPLICATIONS FOR NURSING PRACTICE: Nurses can help rectal cancer patients initiate and maintain exercise during and after neoadjuvant chemoradiation by discussing the potential benefits, harms, and barriers to exercise.

Long-Term Patient-Reported Quality of Life of Anal Cancer Survivors Treated With Intensity Modulated Radiation Therapy and Concurrent Chemotherapy: Results From a Prospective Phase II Trial.

PURPOSE: Intensity modulated radiation therapy (IMRT) has confirmed its superiority in improving acute treatment-related toxicities in anal cancer, without compromising tumor control. However, the effect of IMRT on long-term quality of life (QOL) is poorly documented. The study prospectively evaluated the long-term patient-reported QOL after IMRT-based chemoradiation in anal cancer. METHODS AND MATERIALS: Fifty-eight patients treated with IMRT and concurrent 5 fluorouracil/mitomycin-C were enrolled in the study. A prespecified secondary endpoint was prospective evaluation of long-term QOL. Fifty-four patients underwent QOL evaluation at baseline, after treatment, and during follow-up until 60 months, with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) scales and the Colorectal Cancer-Specific Quality Of Life Questionnaire (QLQ-CR29) scales. The QOL scores at baseline and posttreatment periods were compared. RESULTS: For QLQ-C30, at 60 months, the mean scores of global health status, all functional scales, and all symptoms except diarrhea had improved, indicating normalization of QOL. Clinically and statistically significant improvements in the global health status (15.4; P = .003), role functioning (19.3; P = .0017), emotional functioning (18.9; P = .008), and social functioning (29.8; P ≤ .001) were observed. Diarrhea persisted as a concern over the years (P = .172). For European Organization for Research and Treatment of Cancer QLQ-CR29, rectal pain (-38.6; P = .001), mucous or blood discharge per rectum (-22.8; P = .005), and perianal soreness (-37.3; P ≤ .001) were improved both clinically and statistically. Clinically significant fecal leakage was reported by 16% of patients (5.6; P = .421). Volumes receiving 45 and 54 Gy were independent predictors for fecal incontinence. Clinically and statistically significant urinary incontinence occurred in 21% of patients (17.5; P = .014). Deterioration of dyspareunia was clinically significant (26.7; P = .099) at 60 months. CONCLUSIONS: Compared with historical data, IMRT is associated with reduced long-term effects on QOL. The majority of patients treated with IMRT experienced clinically significant recovery of function and improvement in QOL over 5 years after completion of treatment. Specific toxicities such as chronic diarrhea, fecal incontinence, and urinary and sexual dysfunction were primarily responsible for deterioration of the long-term QOL. Future research aimed at reducing such toxicities is needed to further improve long-term QOL in anal cancer.

Tumor Volume Predicts for Pathologic Complete Response in Rectal Cancer Patients Treated With Neoadjuvant Chemoradiation.

OBJECTIVES: Nonoperative management (NOM) of locally advanced rectal cancer is an emerging approach allowing patients to preserve their anal sphincter. Identifying clinical factors associated with pathologic complete response (pCR) is essential for physicians and patients considering NOM. MATERIALS AND METHODS: In total, 412 locally advanced rectal cancer patients were included in this retrospective analysis. Tumor volumes were derived from pretreatment MRI. Clinical parameters such as tumor volume, stage, and location were analyzed by univariate and multivariate analysis, against pCR. A receiver operator characteristic curve was generated to identify a tumor volume cut-off with the highest clinically relevant Youden index for predicting pCR. RESULTS: Seventy-five of 412 patients (18%) achieved pCR. A tumor volume threshold of 37.3 cm 3 was identified as predictive for pCR. On regression analysis, a tumor volume >37.3 cm 3 was associated with a greater than 78% probability of not achieving pCR. On multivariate analysis, a GTV <37.3 cm 3 [odds ratio (OR)=3.7, P <0.0001] was significantly associated with an increased pCR rate, whereas tumor length > 4.85 cm was associated with pCR on univariate (OR=3.03, P <0.01) but not on multivariate analysis (OR=1.45, P =0.261). Other clinical parameters did not impact pCR rates. CONCLUSIONS: A tumor volume threshold of 37.3 cm 3 was identified as predictive for pCR in locally advanced rectal cancer patients receiving neoadjuvant chemoradiation. Tumors above this volume threshold corresponded to a greater than 78% probability of not achieving pCR. This information will be helpful at diagnosis for clinicians who are considering potential candidates for NOM.

Feasibility, Safety, and Preliminary Efficacy of Exercise During and After Neoadjuvant Rectal Cancer Treatment: A Phase II Randomized Controlled Trial.

BACKGROUND: Neoadjuvant chemoradiation (NACRT) improves outcomes for patients with rectal cancer; however, there are dose-limiting toxicities and only a 15% to 27% pathologic complete response (pCR) rate. Exercise may help manage toxicities and improve treatment response, but feasibility and early efficacy have not been established. EXERT was a phase II trial designed to establish the feasibility and safety of exercise and provide the first evidence of efficacy. MATERIALS AND METHODS: Patients with rectal cancer scheduled to receive NACRT were randomly assigned to usual care (n = 18) or exercise (n = 18) involving supervised exercise during NACRT and unsupervised exercise after NACRT. The primary outcome was cardiorespiratory fitness (VO2 peak). Clinical outcomes included treatment toxicities, treatment completion, and treatment response. RESULTS: Median attendance at supervised exercise sessions during NACRT was 82%, and median self-reported exercise after NACRT was 90 min/wk. From baseline to post-NACRT, VO2 peak increased by 0.4 mL·kg-1·min-1 in the exercise group and decreased by 0.8 mL·kg-1·min-1 in the usual care group (P = .47). There were no significant differences between groups for grade 3/4 toxicities or treatment completion. Of 18 patients in the exercise group, 10 (56%) achieved pCR/near pCR compared with 3 of 17 (18%) in the usual care group (P = .020). CONCLUSION: Exercise during and after NACRT is feasible for many patients with rectal cancer and may improve pCR despite limited fitness improvements. Larger trials are warranted to confirm if exercise is an effective intervention for improving treatment outcomes in this clinical setting.

Dosimetric Parameters Predicting Late Small Bowel Toxicity in Patients With Rectal Cancer Receiving Neoadjuvant Chemoradiation.

PURPOSE: The aim of this study was to identify dosimetric parameters that predict late small bowel (SB) toxicity after neoadjuvant long course chemoradiation (CRT) for rectal cancer. METHODS AND MATERIALS: Four hundred eighty-six consecutive patients with locally advanced rectal cancers (clinical T3/T4 or N1/N2) who received CRT followed by surgery and had dosimetric data available for analysis were included in this study. The dose-volume relationship between small bowel irradiation and late small bowel toxicity was evaluated and a mathematical model to predict for late SB toxicity was derived. RESULTS: Among the 486 patients with a median follow-up of 60 months from completion of radiation, 36 (7.4%) patients experienced ≥ grade 2 and 21 (4.3%) developed ≥ grade 3 late SB toxicity. A statistically significant association between the development of grade ≥3 late small bowel toxicity and the volume of small bowel irradiated was found at each dose level from 5 to 40 Gy (P < .001 for all dose volumes) in 5 Gy intervals. The average SB volume for patients who experienced grade ≥2 SB toxicity was 2149.9 cm3 and the average SB volume for patients who experienced grade ≥3 SB toxicity was 2179.9 cm3. The predicted V30 for a 5% risk for grade ≥2 SB toxicity was 101.5 cm3 and for grade ≥3 SB toxicity was 201.5 cm3. The volume of small bowel receiving at least 30 Gy (V30) was most strongly associated with grade ≥3 SB toxicity. CONCLUSIONS: This study demonstrates the significant dose-volume relationship between volume of small bowel receiving 30 Gy (V30 Gy) and late grade ≥3 SB toxicity. When planning CRT for patients with rectal cancer, restricting V30 to <200 cm3 will be a useful guideline to minimize the 5 year grade ≥3 late SB toxicity to <5%.

Concomitant Use of Proton Pump Inhibitors With Capecitabine Based Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: Is it Safe?

AIM: Capecitabine (Cape) is routinely used for the neoadjuvant chemoradiation treatment (NACRT) of locally advanced rectal cancers (LARCs). Previous reports have suggested that the concomitant use of proton pump inhibitors (PPIs) may affect the efficacy of Cape, although the true effect of PPIs when used with Cape as a radiosensitizer for neoadjuvant radiation is unclear. The aim of our study was to evaluate the impact of concurrent PPI use along with fluorouracil (FU) and Cape based NACRT in terms of pathologic and oncological outcomes, in patients with LARC. METHODS: LARC patients treated at our center with NACRT from 2010 to 2016 were identified. Postoperative pathology and follow-up outcomes were examined for any differences with relation to the use of PPIs concurrently with FU and Cape based NACRT and adjuvant chemotherapy regimens. RESULTS: Three hundred four and 204 patients received treatment with FU and Cape based NACRT. No difference in pathologic complete response rate was noted between the 2 arms with the concurrent use of PPIs (25.8% and 25%, respectively, P=0.633); or with and without the use of PPIs in the Cape-NACRT arm specifically (20% and 20.7%, P=0.945). At a median follow-up of 5 years, no statistical difference in local or distant control was noted in the Cape-NACRT patients, with and without concomitant PPI use (P=0.411 and 0.264, respectively).Multivariate analysis showed no association of PPI use and NACRT with Cape, in terms of local control (hazard ratio=0.001, P=0.988) or overall survival (hazard ratio=1.179, confidence interval=0.249-5.579, P=0.835). CONCLUSIONS: Our study revealed that there was no adverse pathologic or oncological outcome with the concurrent use of PPIs along with Cape-NACRT in the treatment of LARC. We report that it may be safe to use PPIs if essential, in this clinical setting, although it would be wise to exercise caution.

Identification of a new microRNA expression profile as a potential cancer screening tool.

PURPOSE: Small non-coding microRNAs (miRNAs) are key components of cancer development and are considered as potential biomarkers for cancer diagnosis and treatment monitoring. This study investigated miRNA expression profiles of human cancer cells in order to develop a screening method for lung cancer. METHODS: A series of lung cancer related miRNAs (miR-21, miR-145, miR-155, miR-205, miR-210, miR-92, miR-17-5p, miR-143, miR-182, miR-372, let-7a) were selected as candidates for miRNA expression profiles of human lung cancer cell lines (A549, SK-mes-1). MicroRNA u6 was the endogenous control. Cancer cell lines for positive controls; breast MCF-7, prostate Du-145, and glioblastoma U118. The negative control was normal lung fibroblast cell line MRC-5. RT-PCR was performed on StepOnePlus (Applied Biosystem, USA). MiRNA expressions of malignant cells were compared with normal fibroblast cells as well as endogenous control (u6) using the thermal cycle at threshold. Assessment of miRNA expression profiles were then performed using agglomerative hierarchical cluster analysis software (SPSS13, USA). RESULTS: We demonstrated that miR-21, miR-182 and let7-5a were over-expressed, and miR-145 and miR-155 were under-expressed in all cancer cell lines. Combined with the cluster analysis we were able to clearly distinguish cell lines for normal fibroblasts, breast cancer, prostate cancer, glioblastoma, and lung cancer. CONCLUSION: There is potential utility of screening for lung cancer with miRNA expression profiles. Future work will focus on the sensitivity of such miRNA expression profiles in screening sputum for lung cancer, which can be performed in real time.

Should Stereotactic Radiosurgery Be Considered for Salvage of Intracranial Recurrence after Prophylactic Cranial Irradiation or Whole Brain Radiotherapy in Small Cell Lung Cancer? A Population-Based Analysis and Literature Review.

BACKGROUND: Prophylactic cranial irradiation (PCI) improves survival and prevents intracranial recurrence (IR) in limited stage (LS) and extensive stage (ES) small cell lung cancer (SCLC). However, despite PCI, IR affects 12%-45%, and limited data exist regarding salvage brain reirradiation (ReRT). We performed a population-based review of IR in SCLC. METHODS: Demographic, treatment, and outcome data of consecutive patients (N = 371) with SCLC assessed at a tertiary cancer centre (01/2013-12/2015) were abstracted, and summary statistics calculated. Kaplan-Meier estimates and univariate and multivariate analysis (MVA) via the Cox proportional hazard model were performed. RESULTS: Median age was 66.1 years, and 59.8% were Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Median survival was 24 months (95% CI 18.3-29.7 months) for LS (N = 103) and 7 months (95% CI 6.1-7.9 months) for ES (N = 268). 72 of 103 patients with LS and 97 of 214 of those with ES received PCI. 54 of 268 ES presented with brain metastases (BM) of whom 46 of 54 received whole brain RT (WBRT). 18.9% (32/169) recurred post-PCI (13 LS; 19 ES) and 30.4% (14/46) recurred after WBRT. Of those who recurred/progressed after cranial RT, 56.5% (26/46) had <5 BM, 39.1% had no extracranial disease, and 50% were ECOG 0-2. In retrospect, 17 of 46 would have been candidates for salvage stereotactic radiosurgery: 13 post-PCI and 4 post-WBRT. CONCLUSIONS: This cohort challenges commonly held beliefs that IR is always diffuse, associated with clinical deterioration, and synchronous with systemic failure. Approximately 1 in 3 SCLC patients with IR after PCI or WBRT appear clinically appropriate for salvage stereotactic radiosurgery.

Prognostic utility of pre- and post-treatment FDG-PET parameters in anal squamous cell carcinoma.

BACKGROUND AND PURPOSE: We prospectively assessed the contributions of PET to initial staging, early detection of treatment failures, and prognostication in patients with anal squamous cell carcinoma (ASCC). MATERIALS AND METHODS: Consecutive patients with ASCC referred for radical chemoradiotherapy (CRT) consented to undergo FDG-PET imaging pre-treatment and at 3 and 6 months post-treatment. Clinicopathologic data were collected and CT and PET imaging reviewed for contribution to staging and recurrence detection. Maximum standardized uptake value (SUVmax), peak standardized uptake value (SUVpeak), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were assessed for association with progression-free survival (PFS), cause-specific survival (CSS), and overall survival (OS) using the Kaplan-Meier and Cox regression models. RESULTS: Between 2009 and 2016, 73 patients with clinical stages I-IIIB ASCC completed curative-intent CRT. Median follow-up was 48 months. 14 patients died and 18 patients experienced disease progression. 4-year PFS, CSS, and OS were 73%, 87%, and 84%, respectively. A pre-treatment MTV >35 cm3 predicted for worse PFS (p = 0.011) and CSS (p = 0.024) on univariate and multivariate analyses, employing an MTV definition of voxels ≥25% of SUVmax. Higher 6-month post-treatment SUVmax and SUVpeak predicted for worse PFS and OS (p ≤ 0.011). Pre-treatment SUVmax, SUVpeak, and TLG, and 3-month post-treatment SUVmax and SUVpeak did not significantly correlate with survival outcomes. CONCLUSIONS: Our findings support that pre-treatment MTV provides meaningful prognostic information, with suggestion that an MTV delineation threshold of voxels ≥25% of SUVmax is appropriate in the anal region. Post treatment, the combination of clinical examination and PET effectively detected all treatment failures. Higher 6-month post-treatment SUVmax and SUVpeak predicted worse PFS and OS; however, the optimal timing of post-treatment PET imaging remains unclear.

Exercise during and after neoadjuvant rectal cancer treatment (the EXERT trial): study protocol for a randomized controlled trial.

BACKGROUND: Standard treatment for locally advanced rectal cancer includes 5-6 weeks of neoadjuvant chemoradiotherapy (NACRT) followed by total mesorectal excision 6-8 weeks later. NACRT improves local disease control and surgical outcomes but also causes side effects including fatigue, diarrhea, hand-foot syndrome, and physical deconditioning that may impede quality of life (QoL), treatment completion, treatment response, and long-term prognosis. Interventions to improve treatment outcomes and manage side effects that are safe, tolerable and low-cost are highly desirable. Exercise has been shown to improve some of these outcomes in other cancer patient groups but no study to date has examined the potential benefits (and harms) of exercise training during and after NACRT for rectal cancer. METHODS/DESIGN: The Exercise During and After Neoadjuvant Rectal Cancer Treatment (EXERT) trial is a single-center, prospective, two-armed, phase II randomized controlled trial designed to test the preliminary efficacy of exercise training in this clinical setting and to further evaluate its feasibility and safety. Participants will be 60 rectal cancer patients scheduled to receive long-course NACRT followed by total mesorectal excision. Participants will be randomly assigned to exercise training or usual care. Participants in the exercise training group will be asked to complete three supervised, high-intensity interval training sessions/week during NACRT and ≥ 150 min/week of unsupervised, moderate-to-vigorous-intensity, continuous exercise training after NACRT prior to surgery. Participants in the usual care group will be asked not to increase their exercise from baseline. Assessments will be completed pre NACRT, post NACRT, and pre surgery. The primary endpoint will be cardiorespiratory fitness (VO2 peak) at the post-NACRT time point assessed by a graded exercise test. Secondary endpoints will include functional fitness assessed by the Senior's Fitness Test, QoL assessed by the European Organisation of Research and Treatment of Cancer, and symptom management assessed by the M.D. Anderson Symptom Inventory. Exploratory clinical endpoints will include treatment toxicities, treatment completion, treatment response, and surgical complications. DISCUSSION: If the preliminary findings of EXERT are positive, additional research will be warranted to confirm whether exercise is an innovative treatment to maintain QoL, manage side effects, and/or improve treatment outcomes in rectal cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03082495 . Registered on 9 February, 2017.

Palliative chemoradiotherapy versus radiotherapy alone for dysphagia in advanced oesophageal cancer: a multicentre randomised controlled trial (TROG 03.01).

BACKGROUND: A short course of radiotherapy is commonly prescribed for palliative relief of malignant dysphagia in patients with incurable oesophageal cancer. We compared chemoradiotherapy with radiotherapy alone for dysphagia relief in the palliative setting. METHODS: This multicentre randomised controlled trial included patients with advanced or metastatic oesophageal cancer who were randomly assigned (1:1) through a computer-generated adaptive biased coin design to either palliative chemoradiotherapy or radiotherapy alone for treatment of malignant dysphagia at 22 hospitals in Australia, Canada, New Zealand, and the UK. Eligible patients had biopsy-proven oesophageal cancer that was unsuitable for curative treatment, symptomatic dysphagia, Eastern Cooperative Oncology Group performance status 0-2, and adequate haematological and renal function. Patients were stratified by hospital, dysphagia score (Mellow scale 1-4), and presence of metastases. The radiotherapy dose was 35 Gy in 15 fractions over 3 weeks for patients in Australia and New Zealand and 30 Gy in ten fractions over 2 weeks for patients in Canada and the UK. Chemotherapy consisted of one cycle of intravenous cisplatin (either 80 mg/m2 on day 1 or 20 mg/m2 per day on days 1-4 of radiotherapy at clinician's discretion) and intravenous fluorouracil 800 mg/m2 per day on days 1-4 of radiotherapy in week 1. Patients were assessed weekly during treatment. The primary endpoint was dysphagia relief (defined as ≥1 point reduction on the Mellow scale at 9 weeks and maintained 4 weeks later), and key secondary endpoints were dysphagia progression-free survival (defined as a worsening of at least 1 point on the Mellow scale from baseline or best response) and overall survival. These endpoints were analysed in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00193882. This trial is closed. FINDINGS: Between July 7, 2003, and March 21, 2012, 111 patients were randomly assigned to chemoradiotherapy and 109 patients to radiotherapy. One patient in the chemoradiotherapy group was omitted from analysis because of ineligibility. 50 (45%, 95% CI 36-55) patients in the chemoradiotherapy group and 38 (35%, 26-44) in the radiotherapy group obtained dysphagia relief (difference 10·6%, 95% CI -2 to 23; p=0·13). Median dysphagia progression-free survival was 4·1 months (95% CI 3·5-4·8) versus 3·4 months (3·1-4·3) in the chemoradiotherapy and radiotherapy groups, respectively (p=0·58), and median overall survival was 6·9 months (95% CI 5·1-8·3) versus 6·7 months (4·9-8·0), respectively (p=0·88). Of the 211 patients who commenced radiotherapy, grade 3-4 acute toxicity occurred in 38 (36%) patients in the chemoradiotherapy group and in 17 (16%) patients in the radiotherapy group (p=0·0017). Anaemia, thrombocytopenia, neutropenia, oesophagitis, diarrhoea, nausea and vomiting, and mucositis were significantly worse in patients who had chemoradiotherapy than in patients who had radiotherapy. INTERPRETATION: Palliative chemoradiotherapy showed a modest, but not statistically significant, increase in dysphagia relief compared with radiotherapy alone, with minimal improvement in dysphagia progression-free survival and overall survival with chemoradiotherapy but at a cost of increased toxicity. A short course of radiotherapy alone should be considered a safe and well tolerated treatment for malignant dysphagia in the palliative setting. FUNDING: National Health and Medical Research Council, Canadian Cancer Society Research Institute, Canadian Cancer Trials Group, Trans Tasman Radiation Oncology Group, and Cancer Australia.

Dose-escalated Hypofractionated Intensity-modulated Radiation Therapy With Concurrent Chemotherapy for Inoperable or Unresectable Non-Small Cell Lung Cancer.

PURPOSE: The local control of inoperable non-small cell lung cancer (NSCLC) using standard radiotherapy (RT) doses is inadequate. Dose escalation is a potential strategy to improve the local control for patients with NSCLC; however, the optimal dose required for local control in this setting is unknown. METHODS AND MATERIALS: Patients with unresectable or inoperable stage II/III NSCLC with ECOG≤1 received 48 Gy in 20 daily fractions using intensity-modulated radiotherapy, followed by 1 of 3 boost dose levels: 16.8 Gy/7 (cumulative 2 Gy equivalent dose [EQD2]≅76 Gy/38), 20.0 Gy/7 (EQD2≅84 Gy/42), and 22.7 Gy/7 (EQD2≅92 Gy/46). Two cycles of cisplatin/etoposide chemotherapy were given concurrent with RT. The maximum tolerated dose was defined as the dose at which ≥30% experienced dose-limiting toxicity (any NCIC Common Terminology for Adverse Events V3.0 grade 3 or higher acute toxicity). RESULTS: Twelve patients completed treatment with a median follow-up of 22 months (range, 7 to 48). The median age was 72 (range, 54 to 80) and 50% of patients had adenocarcinoma. Five, 3, and 4 patients were treated on dose levels 1, 2, and 3, respectively. No dose-limiting toxicity was observed. One-year local progression-free survival and overall survival estimates were 81% and 58%, respectively. CONCLUSIONS: Hypofractionated intensity-modulated radiotherapy was well tolerated and provided meaningful local control for patients with locally advanced inoperable NSCLC. The maximum tolerated dose of RT in this setting lies beyond an EQD2 of 92 Gy/46 and further dose escalation in this setting is warranted.

Phase I study of hypofractionated dose-escalated thoracic radiotherapy for limited-stage small-cell lung cancer.

PURPOSE: To determine the maximal tolerated dose of hypofractionated thoracic radiotherapy with concurrent chemotherapy for limited-stage small-cell lung cancer patients. METHODS AND MATERIALS: Three radiotherapy regimens were used. Radiotherapy was given in two phases: patients initially received 20 Gy in 10 fractions to gross tumor plus uninvolved mediastinal nodes, followed by a boost to gross disease of 30, 38, or 42 Gy in 15 fractions. Radiotherapy was planned with conformal techniques. All patients received four cycles of cisplatin (25 mg/m2) and etoposide (100 mg/m2) chemotherapy. Radiotherapy commenced with Day 1 of Cycle 2 of chemotherapy. All complete/near-complete responders were offered prophylactic cranial irradiation. The maximal tolerated dose of radiotherapy was based on the dose that caused unacceptably high rates of radiotherapy-related toxicity. RESULTS: Thirteen patients were accrued. All patients who commenced radiotherapy received all prescribed chemo- and radiotherapy. There were no treatment-related deaths. There was one Grade 3 acute nonhematologic toxicity in the 50-Gy group. Of the 6 patients given 58 Gy, 3 experienced acute Grade 3 esophagitis. With a median follow-up of 7 months, median overall survival was 9.5 months. CONCLUSIONS: The maximal tolerated dose of thoracic radiotherapy with concurrent chemotherapy on this trial was 50 Gy in 25 daily fractions.

A Phase I Study Examining the Feasibility and Safety of an Aerobic Exercise Intervention in Patients With Rectal Cancer During and After Neoadjuvant Chemoradiotherapy.

PURPOSE/OBJECTIVES: To assess the feasibility and safety of an aerobic exercise intervention in patients with rectal cancer during and after neoadjuvant chemoradiotherapy (NACRT).
. DESIGN: A prospective, single-group design with assessments at pre-NACRT, post-NACRT, and presurgery.
. SETTING: The Cross Cancer Institute and University of Alberta in Edmonton, Canada.
. SAMPLE: 18 patients with rectal cancer scheduled to receive long-course NACRT followed by definitive surgery. 
. METHODS: Participants received a supervised moderate-intensity aerobic exercise program three days per week during six weeks of NACRT followed by an unsupervised aerobic exercise program for 150 minutes or more per week for 6-8 weeks prior to surgery.
. MAIN RESEARCH VARIABLES: Eligibility rate, recruitment rate, follow-up rate, exercise adherence, serious adverse events, health-related fitness outcomes, and patient-reported outcomes.
. FINDINGS: Follow-up rates post-NACRT were 83% for health-related fitness outcomes and 94% for patient-reported outcomes. Patients attended a median of 83% of their supervised exercise sessions and completed a mean of 222 minutes per week (SD = 155) of their unsupervised exercise. No serious adverse events were observed or reported. Most health-related fitness outcomes and patient-reported outcomes declined during NACRT and recovered after NACRT. 
. CONCLUSIONS: Aerobic exercise is feasible and safe for patients with rectal cancer during and after NACRT.
. IMPLICATIONS FOR NURSING: Patients with rectal cancer are able to engage in moderate-intensity aerobic exercise during NACRT.

Patient reported quality of life after helical IMRT based concurrent chemoradiation of locally advanced anal cancer.

BACKGROUND AND PURPOSE: Concurrent chemoradiation (CCRT) is the standard treatment for locally advanced anal canal carcinoma, although treatment-related side effects can affect patient quality of life (QOL). The purpose was to prospectively evaluate the effects of Tomotherapy (HT) based CCRT on patient reported QOL in locally advanced anal cancer. PATIENTS AND METHODS: Fifty-four patients treated with HT and concurrent 5-fluorouracil/mitomycin-C underwent QOL evaluation at baseline, after treatment, and during follow-up with EORTC core (QLQ-C30) and colorectal (QLQ-CR29) questionnaires. The QOL scores at baseline and post-treatment were compared. RESULTS: All C30 functional symptoms, except emotional and cognitive functioning, were impaired end-of-treatment and recovered by 3months follow-up. The majority of symptom scores were worse end-of-treatment but recovered by 3months except for fecal incontinence (FI), diarrhea, urinary incontinence (UI), and dyspareunia which persisted. FI returned to baseline at 12months while diarrhea, UI, and dyspareunia persisted. CONCLUSIONS: Most impaired functions and symptoms following HT based CCRT were temporary and improved by 3months post-therapy. Late complications affecting QOL were FI, sexual function, UI, and diarrhea. Our observations support routine use of IMRT and emphasize the significance of precise evaluation of sexual, urinary, and anorectal functions before starting CCRT and routine incorporation of QOL evaluations.