Development of Best Practices of Peer Review for Lung Radiation Therapy.

PURPOSE: Peer review (PR) is an important component in ensuring high-quality lung radiotherapy (RT) plans. However, there are inconsistencies in the extent, timing, and minimum requirements for PR. We sought to develop guidelines of best practices for PR in curative lung RT through an expert consensus process. METHODS: A modified Delphi process was conducted that consisted of an initial review by a dedicated steering committee followed by a pan-Canadian, multidisciplinary Delphi panel with 3 rounds (premeeting survey, face-to-face meeting, and postmeeting ratification survey). Candidate PR elements were ranked by importance and stratified by treatment of locally advanced (LA) disease with conventional RT or stereotactic ablative body RT (SABR) for early-stage disease. RESULTS: For the LA case, 6 elements (indications for RT, gross tumor volume [GTV], clinical target volume [CTV], internal target volume [ITV], dose/fractionation, and normal lung dosimetry) were considered as essential PR elements. Of these, 90%-100% of the panel endorsed them to be important to PR, and 80% believed that the PR should be done by a second radiation oncologist (RO). In the SABR case, 6 PR elements (indications for RT, GTV, CTV/ITV, organs at risk contours, dose/fractionation, and composite plan review) were deemed essential. Of these, 90%-100% of panel members believed these elements to be important to PR and unanimously agreed that PR should be done by a second RO. CONCLUSION: A suite of PR elements for lung RT has been developed and endorsed with high consensus. This suite should serve as a basis to help to harmonize PR practices across centers and to help to develop novel PR approaches going forward.

External beam radiation dose escalation for high grade glioma.

BACKGROUND: This is an updated version of the original Cochrane Review published in Issue 8, 2016. High grade glioma (HGG) is a rapidly growing brain tumour in the supporting cells of the nervous system, with several subtypes such as glioblastoma (grade IV astrocytoma), anaplastic (grade III) astrocytoma and anaplastic (grade III) oligodendroglioma. Studies have investigated the best strategy to give radiation to people with HGG. Conventional fractionated radiotherapy involves giving a daily radiation dose (called a fraction) of 180 cGy to 200 cGy. Hypofractionated radiotherapy uses higher daily doses, which reduces the overall number of fractions and treatment time. Hyperfractionated radiotherapy which uses a lower daily dose with a greater number of fractions and multiple fractions per day to deliver a total dose at least equivalent to external beam daily conventionally fractionated radiotherapy in the same time frame. The aim is to reduce the potential for late toxicity. Accelerated radiotherapy (dose escalation) refers to the delivery of multiple fractions per day using daily doses of radiation consistent with external beam daily conventionally fractionated radiotherapy doses. The aim is to reduce the overall treatment time; typically, two or three fractions per day may be delivered with a six to eight hour gap between fractions. OBJECTIVES: To assess the effects of postoperative external beam radiation dose escalation in adults with HGG. SEARCH METHODS: We searched CENTRAL, MEDLINE Ovid and Embase Ovid to August 2019 for relevant randomised phase III trials. SELECTION CRITERIA: We included adults with a pathological diagnosis of HGG randomised to the following external beam radiation regimens: daily conventionally fractionated radiotherapy versus no radiotherapy; hypofractionated radiotherapy versus daily conventionally fractionated radiotherapy; hyperfractionated radiotherapy versus daily conventionally fractionated radiotherapy or accelerated radiotherapy versus daily conventionally fractionated radiotherapy. DATA COLLECTION AND ANALYSIS: The primary outcomes were overall survival and adverse effects. The secondary outcomes were progression free survival and quality of life. We used the standard methodological procedures expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Since the last version of this review, we identified no new relevant trials for inclusion. We included 11 randomised controlled trials (RCTs) with 2062 participants and 1537 in the relevant arms for this review. There was an overall survival benefit for people with HGG receiving postoperative radiotherapy compared to the participants receiving postoperative supportive care. For the four pooled RCTs (397 participants), the overall hazard ratio (HR) for survival was 2.01 favouring postoperative radiotherapy (95% confidence interval (CI) 1.58 to 2.55; P < 0.00001; moderate-certainty evidence). Although these trials may not have completely reported adverse effects, they did not note any significant toxicity attributable to radiation. Progression free survival and quality of life could not be pooled due to lack of data. Overall survival was similar between hypofractionated and conventional radiotherapy in five trials (943 participants), where the HR was 0.95 (95% CI 0.78 to 1.17; P = 0.63; very low-certainty evidence. The trials reported that hypofractionated and conventional radiotherapy were well tolerated with mild acute adverse effects. These trials only reported one participant in the hypofractionated arm developing symptomatic radiation necrosis that required surgery. Progression free survival and quality of life could not be pooled due to the lack of data. Overall survival was similar between hypofractionated and conventional radiotherapy in the subset of two trials (293 participants) which included participants aged 60 years and older with glioblastoma. For this category, the HR was 1.16 (95% CI 0.92 to 1.46; P = 0.21; high-certainty evidence). There were two trials which compared hyperfractionated radiotherapy versus conventional radiation and one trial which compared accelerated radiotherapy versus conventional radiation. However, the results could not be pooled. The conventionally fractionated radiotherapy regimens were 4500 cGy to 6000 cGy given in 180 cGy to 200 cGy daily fractions, over five to six weeks. All trials generally included participants with World Health Organization (WHO) performance status from 0 to 2 and Karnofsky performance status of 50 and higher. The risk of selection bias was generally low among these RCTs. The number of participants lost to follow-up for the outcome of overall survival was low. Attrition, performance, detection and reporting bias for the outcome of overall survival was low. There was unclear attrition, performance, detection and reporting bias relating to the outcomes of adverse effects, progression free survival and quality of life. AUTHORS' CONCLUSIONS: Postoperative conventional daily radiotherapy probably improves survival for adults with good performance status and HGG compared to no postoperative radiotherapy. Hypofractionated radiotherapy has similar efficacy for survival compared to conventional radiotherapy, particularly for individuals aged 60 years and older with glioblastoma. There are insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy) and for accelerated radiation versus conventionally fractionated radiation (without chemotherapy). There are HGG subsets who have poor prognosis even with treatment (e.g. glioblastoma histology, older age and poor performance status). These HGG individuals with poor prognosis have generally been excluded from randomised trials based on poor performance status. No randomised trial has compared comfort measures or best supportive care with an active intervention using radiotherapy or chemotherapy in these people with poor prognosis. Since the last version of this review, we found no new relevant studies. The search identified three new trials, but all were excluded as none had a conventionally fractionated radiotherapy arm.

External beam radiation dose escalation for high grade glioma.

BACKGROUND: The incidence of high grade glioma (HGG) is approximately 5 per 100,000 person-years in Europe and North America. OBJECTIVES: To assess the effects of postoperative external beam radiation dose escalation in adults with HGG. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 9), MEDLINE (1977 to October 2015) and Embase (1980 to end October 2015) for relevant randomised phase III trials. SELECTION CRITERIA: We included adults with a pathological diagnosis of HGG randomised to the following external beam radiation regimens.1. Daily conventionally fractionated radiation therapy versus no radiation therapy.2. Hypofractionated radiation therapy versus daily conventionally fractionated radiation therapy.3. Hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy.4. Accelerated radiation therapy versus daily conventionally fractionated radiation therapy. DATA COLLECTION AND ANALYSIS: The primary outcomes were overall survival and adverse effects. The secondary outcomes were progression-free survival and quality of life. We used the standard methodological procedures expected by Cochrane. We used the GRADE approach, as outlined by Cochrane, to interpret the overall quality of the evidence from included studies. MAIN RESULTS: We included 11 randomised controlled trials (RCTs) with a total of 2062 participants and 1537 in the relevant arms for this review. There was an overall survival benefit for HGG participants receiving postoperative radiotherapy compared to the participants receiving postoperative supportive care. For the four pooled RCTs (397 participants), the overall hazard ratio (HR) for survival was 2.01 (95% confidence interval (CI) 1.58 to 2.55, P < 0.00001), moderate GRADE quality evidence favouring postoperative radiotherapy. Although these trials may not have completely reported adverse effects, they did not note any significant toxicity attributable to radiation. Progression free survival and quality of life could not be pooled due to lack of data.Overall survival was similar between hypofractionated versus conventional radiotherapy in five trials (943 participants), where the HR was 0.95 (95% CI 0.78 to 1.17, P = 0.63), very low GRADE quality evidence. The trials reported that hypofractionated and conventional radiotherapy were well tolerated with mild acute adverse effects. These trials only reported one patient in the hypofractionated arm developing symptomatic radiation necrosis that required surgery. Progression free survival and quality of life could not be pooled due to the lack of data.Overall survival was also similar between hypofractionated versus conventional radiotherapy in the subset of two trials (293 participants) which included 60 years and older participants with glioblastoma. For this category, the HR was 1.16 (95% CI 0.92 to 1.46, P = 0.21), high GRADE quality evidence.There were two trials which compared hyperfractionated radiation therapy versus conventional radiation and one trial which compared accelerated radiation therapy versus conventional radiation. However, the results could not be pooled.The conventionally fractionated radiation therapy regimens were 4500 to 6000 cGy given in 180 to 200 cGy daily fractions, over 5 to 6 weeks.All these trials generally included participants with World Health Organization (WHO) performance status from 0 to 2 and Karnofsky performance status of 50 and higher.The risk of selection bias was generally low among these randomized trials. The number of participants lost to follow-up for the outcome of overall survival was low. Attrition, performance, detection and reporting bias for the outcome of overall survival was low. There was unclear attrition, performance, detection and reporting bias relating to the outcomes of adverse effects, progression free survival and quality of life. AUTHORS' CONCLUSIONS: Postoperative conventional daily radiotherapy improves survival for adults with good performance status and HGG as compared to no postoperative radiotherapy.Hypofractionated radiation therapy has similar efficacy for survival as compared to conventional radiotherapy, particularly for individuals aged 60 and older with glioblastoma.There is insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy) and for accelerated radiation versus conventionally fractionated radiation (without chemotherapy).There are HGG subsets who have poor prognosis even with treatment (e.g. glioblastoma histology, older age and poor performance status). These poor prognosis HGG individuals have generally been excluded from the randomised trials based on poor performance status. No randomised trial has compared comfort measures or best supportive care with an active intervention using radiotherapy or chemotherapy in these poor prognosis patients.

Investigation of Dose Falloff for Intact Brain Metastases and Surgical Cavities Using Hypofractionated Volumetric Modulated Arc Radiotherapy.

INTRODUCTION: Intact brain metastases tend to be small and spherical compared to postsurgery brain cavities, which tend to be large and irregular shaped and, as a result, a challenge with respect to treatment planning. The purpose of the present study is to develop guidelines for normal brain tissue dose and to investigate whether there is a dependence on target type for patients treated with hypofractionated volumetric modulated arc radiotherapy (HF-VMAT). METHODS: Treatment plans from a total of 100 patients and 136 targets (55 cavity and 81 intact) were retrospectively reviewed. All targets were treated with HF-VMAT with total doses ranging between 20 and 30 gray (Gy) in 5 fractions. All plans met institutional objectives for organ-at-risk constraints and were clinically delivered. Dose falloff was quantified using gradient index (GI) and distance between the 100% and 50% isodose lines (R50). Additionally, the dose to normal brain tissue (brain contour excluding all gross tumor or clinical target volumes) was assessed using volume receiving specific doses (Vx) where x ranged from 5 to 30 Gy. Best-fit curves using power law relationships of the form y = ax(b) were generated for GI, R50, and Vx (normal brain tissue) versus target volume. RESULTS: There was a statistically significant difference in planning target volume (PTV) for cavities versus intact metastases with mean volumes of 37.8 cm(3) and 9.5 cm(3), respectively (P < .0001). The GI and R50 were statistically different: 3.4 and 9.8 mm for cavities versus 4.6 and 8.3 mm for intact metastases (P < .0001). The R50 increased with PTV with power law coefficients (a, b) = (6.3, 0.12) and (5.9, 0.15) for cavities and intact, respectively. GI decreased with PTV with coefficients (a, b) = (5.9, -0.18) and (5.7, -0.14) for cavities and intact, respectively. The normal brain tissue Vx also exhibited power law relationships with PTV for x = 20 to 28.8 Gy. In conclusion, target volume is the main predictor of dose falloff. The results of the present study can be used for determining target volume-based thresholds for dose falloff and normal brain tissue dose-volume constraints.

Prophylactic dexamethasone effectively reduces the incidence of pain flare following spine stereotactic body radiotherapy (SBRT): a prospective observational study.

PURPOSE: The purpose of this study was to determine the incidence of pain flare (PF) in patients receiving spine stereotactic body radiotherapy (SBRT) treated with prophylactic oral dexamethasone (DEX) 1 h before and for 4 days following SBRT. METHODS: Forty-seven patients were accrued on this prospective observational study. The first cohort of 24 patients was treated with 4 mg, while a second cohort of 23 patients treated with 8 mg of DEX. The Brief Pain Inventory (BPI) was used to score pain and functional interference each day during SBRT and for 10 days following. Comparisons between the 4 and 8 mg cohorts, in addition to our previously reported steroid naïve patients post SBRT (n = 41), were also performed. RESULTS: The total incidence of PF was 19 % (9/47). The incidence in the 4 and 8 mg cohorts was 25 % (6/24) and 13 % (3/23), respectively, and the difference was not statistically significant (p = 0.46). Comparing functional interference, the 4 mg cohort had better profile in walking ability (p < 0.005) and relationships with others (p < 0.035) compared to the 8 mg cohort. Compared to our previously reported steroid naïve cohort, prophylactic DEX significantly reduced the incidence of PF (68 vs. 19 %, p < 0.0001, respectively), patients had lower worst pain scores, and improved general activity interference outcome. CONCLUSION: We recommend prophylactic DEX for patients treated with spine SBRT. Our current practice is based on the 4 mg protocol primarily due to the improved functional interference outcomes. A randomized trial is required to finalize the optimal regimen and schedule.

Role of stereotactic body radiotherapy for symptom control in head and neck cancer patients.

PURPOSE: Our aim was to determine the efficacy and quality of life outcomes of head and neck (HN) stereotactic body radiotherapy (SBRT) in a palliative population with significant proportions of de novo HN tumors not amenable to surgery or protracted course of curative radiotherapy (RT). METHODS: A retrospective review of a prospective database identified 21 patients with 24 sites that were treated. Patients were treated with intensity modulated RT (IMRT), usually 7-9 static fields with a 2-3-mm margin from gross tumor volume to planning target volume only with no microscopic margin added. Electronic patient records and treatment plans were reviewed. Basic demographic information was collected. The EORTC QLQ-H&N35 questionnaire was the tool used to collect QOL data both pre- and on-treatment fraction 5. Univariate analysis was performed for predictors of local control (LC) and prognostic factors for overall survival (OS). RESULTS: A total of 21 patients had 24 sites that were treated. The median age was 87 (range 25-103) and median KPS was 70. The most common histology was squamous cell carcinoma (SCC) 19/24 (79 %), basal cell carcinoma (BCC) 3/24 (16 %), and melanoma (4 %). The median maximal diameter was 3.7 cm (range 1-10 cm). The most commonly treated site was lymph nodes in the neck 13/24 (54 %), skin 8/24 (33 %), 4/24 (16 %) other HN mucosal primary sites. Of the 24 lesions, 17 (71 %) were de novo, without prior treatment and 7/24 (29 %) were recurrent. The most commonly used dose/fraction (fx) was 40 Gy/5 (fx) (range 35/5fx-48/6fx). Of the 24 lesions, 6 (25 %) had complete response, 16/24 (67 %) had partial response, and 2/24 (8 %) had no response. Control was defined as no further progression after treatment. For the entire cohort, LC at 3, 6, and 9 months were 66, 50, and 33 %, respectively. In the de novo group, 2/16 (12.5 %) had local failures with the LC rate of 94, 94, and 87 % at 3 months, 6 months, and 1 year, respectively. In the recurrent group, 4/8 (50 %) had failure with LC rates of 87. 5, 62.5, and 50 % at 3 months, 6 months, and 1 year, respectively. Of the 21 patients, 10 died during follow up, with the OS rate at 3 months, 6 months, and 1 year of 90, 70, and 60 %, respectively. Being defined "de novo" showed a trend toward statistical significance p = 0.046 for local failure. Overall survival did not show significant difference between de novo and recurrent with a p value of 0.267. No significant prognostic variables for OS were found. Pre-treatment QOL scores for the entire cohort were 53/130 versus 38/130 (lower scores indicating better QOL) scores with a trend toward statistical significance p = 0.05. CONCLUSIONS: SBRT is efficacious with improved quality of life within this elderly frail population in the treatment of de novo and recurrent tumors of the head and neck with promising quality of life scores.

A single institution experience of extranodal natural killer/T cell lymphoma of nasal type.

Extranodal natural killer/T cell lymphoma (ENKTL) nasal type is a rare form of non-Hodgkin lymphoma that is more commonly seen in Asia and Latin America than in North America or Europe. The purpose of this study was to determine the treatment outcomes with a combined modality approach and whether treatment outcomes varied according to ethnicity in patients with ENKTL, nasal type in Toronto, Canada. Patients presenting with ENKTL, nasal type, between 1994 and 2011 were retrospectively reviewed. Patient characteristics, including the patient's ethnic origin, treatment details and outcomes were recorded and analyzed for significant differences between Asian and Caucasian patients. A total of 34 patients were identified: 16 Asian, 16 Caucasian, one Aboriginal and one Hispanic. All patients had nasal cavity involvement. The majority had localized disease: stage I (n = 22), stage II (n = 6); and stage IV in six patients. Combined radiotherapy (RT) and chemotherapy was intended for 32 of the 34 patients, with two receiving RT alone. Median RT dose was 45 Gy (range: 35-50.4 Gy). Response to initial treatment was observed in 44% of patients. Two-year disease-free survival was 17.8% (Asian patients: 18.8%, Caucasians: 20%, p = 0.82), and overall survival 39.2% (Asian patients: 30%, Caucasians: 42%, p = 0.52). There were no significant differences in clinical outcomes in terms of patient ethnicity. A combined modality approach (with cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP] chemotherapy administered initially) is of limited effectiveness. We have now adopted the use of RT as the initial treatment approach, followed by multiagent chemotherapy.

Fatigue scores in patients with brain metastases receiving whole brain radiotherapy.

PURPOSE: Whole brain radiotherapy (WBRT) is a treatment strategy used commonly to relieve burdensome symptoms and improve quality of life (QOL) in patients with multiple brain metastases. The purpose of this study is to determine changes in fatigue score following WBRT as it is a common symptom experienced in this population. METHODS: Fatigue and overall QOL scores were collected prospectively in patients for up to 3 months post-WBRT by several questionnaires at different times including the following: Edmonton Symptom Assessment System (ESAS), Brain Symptom and Impact Questionnaire (BASIQ), Spitzer Questionnaire, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), EORTC brain module (EORTC QLQ-BN20+2), EORTC QLQ-C15-PAL, and Functional Assessment of Cancer Therapy-General (FACT-G). Questionnaires were grouped for analysis by Wilcoxon Signed Rank test according to the scale of ranking into 0-10, 1-4, and 0-4. RESULTS: Thirty-six patients were interviewed with the ESAS or BASIQ. The median age was 65 years old, and median Karnofsky Performance Status (KPS) was 70. There was a significant increase in fatigue score from baseline to month 1 (p=0.02), and months 2 and 3 had no significant change. There was a significant correlation between fatigue and overall QOL score at baseline and month 1 (p=0.01, p<0.0001), respectively. Two hundred and twenty-eight patients were surveyed with Spitzer, C15-PAL, BN20+2, QLQ-C30, or FACT-G. Median age was 64 years old and median KPS was 80. Compared to baseline, fatigue score was significantly higher at month 1 (p<0.0001) and month 2 (p=0.001), with no significant change at month 3. Significant correlation was found between fatigue and overall QOL at baseline, months 1, 2 (p<0.0001), and 3 (p=0.0009). For all groups, there was no significant change in fatigue score between patients with or without dexamethasone (Dx), except for the fatigue changed score of the group with scale 0-4. CONCLUSIONS: Fatigue was significantly increased from baseline to month 1 in all patients, and most patients experienced no difference in fatigue if they were receiving Dx. Increased fatigue was significantly related with decreased overall QOL.

Symptom clusters using the Spitzer quality of life index in patients with brain metastases--a reanalysis comparing different statistical methods.

PURPOSE: The purpose of this paper is to determine whether the use of three different statistical methods influences the composition of symptom clusters derived from patients with brain metastases. MATERIALS AND METHODS: The dataset previously compiled from 129 brain metastases patients who completed the Spitzer Quality of Life Index (SQLI) and an additional study-designed 17-item symptom questionnaire was employed in this study. Symptom clusters extracted using principal component analysis in our previous study were compared to clusters determined using hierarchical cluster analysis and exploratory factor analysis. Clusters were identified using the three statistical methods at baseline, and at 1, 2, and 3 months following whole brain radiotherapy. RESULTS: The number and composition of symptom clusters at each time point varied based on the statistical method employed, despite the use of an identical dataset. However, some domains consistently clustered together, such as activity and daily living from the SQLI items. Of the 17 additional symptoms, memory loss, confusion, and trouble concentrating were always present in the same cluster. Nausea and vomiting also occurred in conjunction regardless of the analytical method employed. CONCLUSION: Symptom clusters vary with respect to occurrence, quantity, and composition based on the statistical method utilized to extract them. Further studies should be conducted to determine an ideal statistical method in order to select the optimal method to employ. The use of a single analytical method is essential for consistency and comparison purposes in future symptom cluster research.

Recommendations for CTV margins in radiotherapy planning for non melanoma skin cancer.

PURPOSE: To provide practice guidelines for delineating clinical target volume (CTV) for radiotherapy planning of non melanoma (NMSC) skin cancers. METHODS AND MATERIALS: A prospective, single arm, study. Preoperatively, a radiation oncologist outlined the boundary of a gross lesion, and drew 5-mm incremental marks in four directions from the delineated border. Under local anesthesia, the lesion was excised, and resection margins were assessed microscopically by frozen section. Once resection margins were clear, the microscopic tumor extent was calculated using the presurgical incremental markings as references. A potential relationship between the distance of microscopic tumor extension and other variables was analyzed. RESULTS: A total of 159 lesions in 150 consecutive patients, selected for surgical excision with frozen section assisted assessment of resection margins, were accrued. The distance of microscopic tumor extension beyond a gross lesion varied from 1mm to 15 mm, with a mean of 5.3mm. The microscopic tumor extent was positively correlated with the size of gross lesion, histology and number of surgical attempts required to obtain a clear margin. To provide a 95% or greater chance of covering microscopic disease we make the following recommendations for CTV margins; 10mm for BCC less than 2 cm, 13 mm for BCC greater than 2 cm, 11 mm for SCC less than 2 cm, and 14 mm for SCC greater than 2 cm. CONCLUSIONS: Tumors greater than 2 cm and SCC histology required larger margins to adequately cover the microscopic extent of disease. This information is crucial in radiation planning of NMSC. Clinicians should be cautioned, as these guidelines may not offer optimum treatment for patients with extremely large or small lesions.

Radiotherapy for metastatic merkel cell carcinoma: a review of the literature.

Introduction. Merkel cell carcinoma is a rare form of non-melanoma skin cancer of neuroendocrine origin. Optimal management of patients is controversial and the role of radiotherapy is unclear. Purpose. The purpose of this study was to review the efficacy of RT in the treatment of both local and distant metastatic disease from MCC. Methods. A literature search was conducted in MEDLINE (1946-January Week 1 2012) and Embase (1980-2012 Week 2). Articles of interest analyze the efficacy of radiotherapy for treatment of metastatic MCC and did not exclude case reports. Results. All articles except one focusing on the role of radiotherapy were of retrospective origin or case series. Significant limitations applied in all studies due to limited sample sizes and the retrospective nature of these studies. Radiotherapy improves locoregional control in the adjuvant setting, and many series suggest an improvement in overall survival. In cases where surgery is not possible, definitive radiotherapy may be an as-efficacious alternative. The radiosensitive nature of MCC coupled with existing reports suggests that treatment via current protocols for other primary tumors is adequate. Conclusion. Further studies should be conducted prospectively to clarify the true role of radiotherapy in metastatic MCC.

Symptom clusters in patients with advanced cancer: a reanalysis comparing different statistical methods.

CONTEXT: The clinical relevance of symptom cluster research remains questionable if inconsistencies, partially attributable to the varying statistical analyses used, exist. OBJECTIVES: To investigate whether symptom clusters identified were consistent using three different statistical methods and to observe the temporal pattern of clusters. A secondary objective was to compare symptom clustering in responders and nonresponders to radiotherapy over time. METHODS: Reanalysis of an existing data set compiled from 1296 patients with advanced cancer was performed using hierarchical cluster analysis (HCA) and exploratory factor analysis (EFA) to extract symptom clusters at baseline, 1-, 2-, 4-, 8-, and 12-week follow-up time points. Findings were compared with results obtained using principal component analysis (PCA) in our previously published study. The original sample was further divided into two subgroups: responders and nonresponders. The symptom clusters present in each subgroup were examined using PCA, HCA, and EFA at the same time points as mentioned above. RESULTS: The symptom cluster findings of HCA and PCA correlated more frequently with each other than either did with the results of EFA. Complete consensus in all three statistical methods was never reached at any assessment time point in the present study. Increasingly diverging patterns of symptom cluster development over time were observed in the responder vs. nonresponder subgroups. Symptom pairs comprising anxiety and depression or fatigue and drowsiness consistently presented in the same cluster despite the shifting of other symptoms in the cluster over time. CONCLUSION: The presence and composition of symptom clusters identified varied depending on which statistical analysis method was used. A key step in achieving consistency in symptom cluster research involves the utilization of a common analytical method.

Symptom clusters in patients with bone metastases--a reanalysis comparing different statistical methods.

PURPOSE: The aims of this study were to determine whether symptom clusters in patients with bone metastases varied when derived using three different statistical methods and to compare the presentation of symptom clusters over time in responders and nonresponders to palliative radiation treatment (RT). METHODS: Secondary analysis of a previously reported data set compiled using the brief pain inventory from 348 patients with bone metastases. Hierarchical cluster analysis (HCA) and exploratory factor analysis (EFA) were performed to identify symptom clusters at baseline, 1, 2, and 3 months following radiation treatment. Clusters derived were compared with the findings obtained using principal component analysis (PCA) in our previous study. The total patient sample was further separated into two subgroups: responders and nonresponders to RT. PCA, HCA, and EFA identified symptom clusters experienced by each subgroup at the same time points as before. RESULTS: Little correlation was observed in the symptom cluster findings of PCA, EFA, and HCA in the total patient sample. Absolute consensus among all three statistical methods was never reached at any assessment time point in the present study. Varying patterns of symptom cluster presentation over time were observed in the responders versus nonresponders subgroups regardless of the analytical method employed. A core cluster of symptoms composed of worst pain, general activity, walking ability, normal work, and enjoyment of life frequently presented in the same cluster. CONCLUSION: The presence and composition of symptom clusters derived varied depending on which statistical analysis method was employed. A key step in attaining consistency in symptom cluster research necessitates the utilization of a common method.

Prophylaxis of radiation-induced nausea and vomiting using 5-hydroxytryptamine-3 serotonin receptor antagonists: a systematic review of randomized trials.

PURPOSE: To systematically review the effectiveness and safety of 5-hydroxytryptamine-3 receptor antagonists (5-HT3 RAs) compared with other antiemetic medication or placebo for prophylaxis of radiation-induced nausea and vomiting. METHODS AND MATERIALS: We searched the following electronic databases: MEDLINE, Embase, the Cochrane Central Register of Controlled Clinical Trials, and Web of Science. We also hand-searched reference lists of included studies. Randomized, controlled trials that compared a 5-HT3 RA with another antiemetic medication or placebo for preventing radiation-induced nausea and vomiting were included. We excluded studies recruiting patients receiving concomitant chemotherapy. When appropriate, meta-analysis was conducted using Review Manager (v5) software. Relative risks were calculated using inverse variance as the statistical method under a random-effects model. We assessed the quality of evidence by outcome using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: Eligibility screening of 47 articles resulted in 9 included in the review. The overall methodologic quality was moderate. Meta-analysis of 5-HT3 RAs vs. placebo showed significant benefit for 5-HT3 RAs (relative risk [RR] 0.70; 95% confidence interval [CI] 0.57-0.86 for emesis; RR 0.84, 95% CI 0.73-0.96 for nausea). Meta-analysis comparing 5-HT3 RAs vs. metoclopramide showed a significant benefit of the 5-HT3 RAs for emetic control (RR 0.27, 95% CI 0.15-0.47). CONCLUSION: 5-Hydroxytryptamine-3 RAs are superior to placebo and other antiemetics for prevention of emesis, but little benefit was identified for nausea prevention. 5-Hydroxytryptamine-3 RAs are suggested for prevention of emesis. Limited evidence was found regarding delayed emesis, adverse events, quality of life, or need for rescue medication. Future randomized, controlled trials should evaluate different 5-HT3 antiemetics and new agents with novel mechanisms of action such at the NK(1) receptor antagonists to determine the most effective drug. Delayed nausea and vomiting should be a focus of future study, perhaps concentrating on the palliative cancer population.

Comparing baseline symptom severity and demographics over two time periods in an outpatient palliative radiotherapy clinic.

PURPOSE: The primary objective of this study was to compare the symptom severity in two different patient populations assessed in an outpatient palliative radiotherapy clinic over two time periods spanning 10 years. The secondary objective was to assess any changes in the baseline demographics of these patients. METHODS: Data were collected from 1999 to 2009. Upon initial presentation to the clinic, the Edmonton Symptom Assessment Scale (ESAS) was administered to patients to capture symptom severity. This validated assessment tool asks patients to score their level of pain, tiredness, nausea, depression, anxiety, drowsiness, loss of appetite, well-being, and dyspnea on an 11-point Likert scale. Differences between the two patient groups were assessed using chi-squared analysis and Wilcoxon rank-sum tests. A p value of <0.05 was considered significant. RESULTS: A total of 1,439 patients completed the ESAS from 1999 to 2009. Patients were divided into two time periods 1999-2002 (n = 689) and 2006-2009 (n = 750). Pain, depression, nausea, fatigue, anxiety, drowsiness, and dyspnea were significantly better in 2006-2009 (p < 0.0001). Loss of appetite was not statistically different between the two time periods (p = 0.236). Significantly more patients with genitourinary cancers (p = 0.03) or a referral for a mass (p < 0.0001) were seen in 2006-2009. More patients with breast cancer (p = 0.04) and bone pain (p = 0.0002) were seen in 1999-2002. The median age was significantly higher (70 years vs. 68 years, p = 0.03) for patients seen in 2006-2009. No significant differences were seen in performance status or gender between the two groups. CONCLUSION: There have been statistically significant lower scores in the severity of the majority of symptoms as scored by the latter patient cohort; however, whether this difference in magnitude is clinically significant is debatable. The reason for referral and demographics in patients sent for palliative radiotherapy has changed over a 10-year period. This may be a reflection of the changes in systemic therapies and improvements in supportive care for patients with advanced cancer.

Comparison of pain response and functional interference outcomes between spinal and non-spinal bone metastases treated with palliative radiotherapy.

PURPOSE: The purpose of this study was to compare functional interference and pain response outcomes using the Brief Pain Inventory (BPI) for patients treated with palliative radiotherapy to spine versus non-spine bones and determine if dose fractionation was associated with each group's respective response. MATERIALS AND METHODS: Patients treated for painful bone metastases with palliative radiotherapy during May 2003 to June 2007 were analyzed. The BPI was utilized at baseline and monthly for 6 months post-radiation. Pain response was determined using International Bone Metastases Consensus response definitions. Wilcoxon rank-sum test (for continuous variable), Fisher exact test (for categorical value), and two-way analysis of variance were used for comparisons, and a p value of ≤ 0.05 was considered statistically significant. RESULTS: Three hundred eighty-six patients were analyzed, 62% were treated with a single fraction, 38% with multiple fractions. Pain and functional interference scores significantly improved over time in both spine and non-spine sites. At 3 months, 42% of all patients had a partial response, and 25% had a complete response. Location of bone metastases and radiotherapy dose were not predictive factors for pain response nor functional interference following radiation treatment. CONCLUSION: Spine and non-spine bone metastases exhibited similar pain and functional interference improvements over a period of 6 months post-radiotherapy. There were, however, high attrition rates as expected with palliative studies, with approximately half the patients remaining in this study by 3 months and a fifth by 6 months. A single 8 Gy resulted in equal benefits in terms of both pain response and improvement in function.

Symptom clusters in patients with advanced cancer: sub-analysis of patients reporting exclusively non-zero ESAS scores.

BACKGROUND: Advanced cancer patients often experience multiple concurrent symptoms, which can have prognostic effects on patients' quality of life. Including patients who did not experience all of the symptoms measured by an assessment tool may interfere with accurate symptom cluster identification. Varying statistical methods may also contribute to inconsistencies of cluster results. AIMS: To compare symptom clusters in a subgroup of patients reporting exclusively non-zero ESAS scores with those in the total patient sample. To examine whether using different statistical methods results in varied symptom clusters. DESIGN: Principal Component Analysis (PCA), Hierarchical Cluster Analysis (HCA) and Exploratory Factor Analysis (EFA) were performed on the 'non-zero' subgroup and the total patient sample to identify symptom clusters at baseline and weeks 1, 2, 4, 8 and 12 following palliative radiotherapy. SETTING/PARTICIPANTS: A previous single-centre study used Principal Component Analysis to explore symptom clusters in 1296 advanced cancer patients. The present study analyzed this previously reported data set. RESULTS: Notably different symptom clusters were extracted between the two patient groups regardless of the statistical method at baseline, with the exception of a cluster composed of drowsiness, fatigue and dyspnea using Principal Component Analysis and Hierarchical Cluster Analysis. At follow-ups, different statistical methods yielded significantly varied symptom clusters. Only anxiety, depression and well-being consistently occurred in the same cluster across methods and over time. CONCLUSIONS: The composition of symptom clusters varied depending on if patients with non-zero scores were excluded at baseline and on the statistical method employed. Identifying valid clusters may prove useful for bettering symptom diagnosis and management for cancer patients.

Symptom Clusters in Patients With Bone Metastases: A Sub-Analysis of Patients Reporting Exclusively Non-Zero BPI Scores.

BACKGROUND: The use of different statistical methods and inclusion criteria when deriving symptom clusters in cancer patients are contributing factors in cluster inconsistencies across studies. Primary objective was to extract symptom clusters in a subgroup of patients reporting non-zero Brief Pain Inventory (BPI) scores at baseline, and to compare clusters with those identified in the total patient sample. METHODS: Principal Component Analysis (PCA), Hierarchical Cluster Analysis (HCA) and Exploratory Factor Analysis (EFA) were performed on the non-zero subgroup and total patient sample to identify symptom clusters at baseline and 1, 2 and 3 months following radiotherapy. RESULTS: At baseline, different symptom clusters were derived from the non-zero subgroup and the total patient population. Only PCA identified identical clusters. Over time, clusters extracted using the three statistical methods varied, with a few exceptions where the same clusters were extracted using two different methods at a specific time point. A complete consensus between all three methods was not noted at any time. The BPI, which is a short assessment tool, may lead to the extraction of oversimplified clusters. In addition, since this study analyzed results in the non-zero subgroup, clusters derived may be reflective of patients with poorer prognosis as these patients experienced all symptoms. CONCLUSION: Analyzing data compiled from all eligible consenting patients may not provide clinically relevant clustering among all symptoms in the assessment tool. The composition of symptom clusters varied with the inclusion of patients with zero symptom severity scores and with the statistical method employed.

Symptom Clusters Using the Edmonton Symptom Assessment System in Patients With Bone Metastases: A Reanalysis Comparing Different Statistical Methods.

BACKGROUND: To determine whether symptom clusters in patients with bone metastases vary when extracted using three different statistical methods. To compare the temporal composition of symptom clusters in responders versus non-responders to palliative radiation treatment. METHODS: A previous dataset of 518 bone metastases patients who completed the Edmonton Symptom Assessment System (ESAS) was used in this study. Clusters derived using Principal Component Analysis (PCA) in our previous study were compared to symptom clusters extracted using Hierarchical Cluster Analysis (HCA) and Exploratory Factor Analysis (EFA). Clusters were derived at baseline, and 1, 2, 4, 8 and 12 weeks after radiation treatment. The patient sample was further divided into responders versus non-responders to radiotherapy. The three statistical methods were performed to identify clusters in the subgroups at each time point. RESULTS: A complete consensus between HCA, EFA and PCA for the number and composition of symptom clusters was not reached at any time point. Furthermore, little correlation in clusters was found between the three statistical methods despite the use of an identical data set. As expected, different symptom clusters were observed in the responders and non-responders with all three statistical methods. In addition, clusters varied at each time point within each subgroup. Depression and anxiety were consistently found in the same cluster. CONCLUSION: The quantity, composition, and occurrence of symptom clusters varied based on which statistical method was employed. The use of a common analytical method is necessary for consistency and comparison purposes in future symptom cluster research.

Patients' and Health Care Providers' Evaluation of Quality of Life Issues in Advanced Cancer Using Functional Assessment of Chronic Illness Therapy - Palliative Care Module (FACIT-Pal) Scale.

BACKGROUND: To examine the agreement of Health Care Providers (HCPs) and patients' evaluation of quality of life on the Functional Assessment of Chronic Illness therapy - Palliative care module (FACIT-Pal) scale. METHODS: Sixty advanced cancer patients and fifty-six health care providers involved in their care at Sunnybrook Health Sciences Centre completed a modified version of the FACIT- Pal. In the survey, patients and HCPs indicated the 10 top issues affecting the quality of life of patients with advanced cancer most profoundly. The percentage of participants selecting each item as one of their 10 most relevant items was calculated in HCPs and patients. RESULTS: There were differences in relative rankings of QOL issues among patients and HCPs. Among the top 10 items which were identified from both patients and HCPs, there were differences in the rankings. Patients ranked emotional support from family (40.9%) as most important followed by pain (38.6%), lack of energy (31.8%) and able to enjoy life (29.6%). HCPs ranked in the following order: pain (73.2%), lack of energy (63.4%), nausea (51.2%) and dyspnea (51.2%) whereas patients rated nausea at 18.2 % and dyspnea at 9.09%. CONCLUSION: There is a discrepancy between scores of patients and HCPs as they may prioritize differently. HCPs tended to put more emphasis on physical symptoms, whereas patients had emotional and global issues as priorities.