Palliative radiotherapy utilization for cancer patients at end of life in British Columbia: retrospective cohort study.

BACKGROUND: The use of palliative radiotherapy (PRT) is variable in advanced cancer. Little is known about PRT utilization by end-of-life (EOL) cancer patients in Canada. This study examined the PRT utilization rates and factors associated with its use in a cohort of cancer patients who died in British Columbia (BC). METHODS: BC residents with invasive cancer who died between April 1, 2010 and March 31, 2011 were included in the study. Their cancer registry and radiotherapy treatment records were extracted from the BC Cancer Agency information systems and linked for the analysis. The PRT utilization rates by age, sex, primary cancer diagnosis, geographic region, survival time and travel time to the cancer centre were examined. Multivariable logistic regression was used to determine the factors that influenced the PRT utilization rates. RESULTS: Of the 12,300 decedents in the study 2,669 (21.7%) had received at least one course of PRT in their last year of life. The utilization rates dropped to 5.0% and 2.2% in the last 30 and 14 days of life, respectively. PRT utilization varied across diagnosis and was highest for lung cancer (45.7%) and lowest for colorectal cancer (8.9%). The rates also varied by age, survival time and travel time to the nearest radiotherapy centre. There was a greater odds of receiving PRT for those with primary lung cancer, survival time between 1.5-26 months from diagnosis or living within 2 hours from a cancer centre. The 85+ age group was least likely to receive PRT in their last year of life. CONCLUSIONS: This study found PRT utilization rates of EOL cancer decedents to be variable across the province of BC. Age, diagnosis, survival time and travel time to the nearest radiotherapy centre were found to influence the odds of PRT treatment. Further work is still needed to establish the appropriate PRT utilization rates for the EOL cancer population.

Tumor-associated autoantibodies correlate with poor outcome in prostate cancer patients treated with androgen deprivation and external beam radiation therapy.

Standard cancer treatments trigger immune responses that may influence tumor control. The nature of these responses varies depending on the tumor and the treatment modality. We previously reported that radiation and androgen-deprivation therapy (ADT) induce tumor-associated autoantibody responses in prostate cancer patients. This follow-up analysis was conducted to assess the relationship between autoantibody responses and clinical outcome. Patients with non-metastatic prostate cancer received external beam radiation therapy (EBRT) plus neoadjuvant and concurrent androgen deprivation. Treatment-induced autoantibodies were detected in almost a third of patients receiving combinatorial ADT and EBRT. Unexpectedly, patients that developed autoantibody responses to tumor antigens had a significantly lower 5-year biochemical failure-free survival (BFFS) than patients that did not develop an autoantibody response. Thus, tumor-reactive autoantibodies may be associated with increased risk of biochemical failure and immunomodulation to prevent autoantibody development may improve BFFS for select, high-risk prostate cancer patients receiving both ADT and EBRT.

Impact of quality assurance rounds in a Canadian radiation therapy department.

PURPOSE: Quality assurance (QA) programs aim to identify inconsistencies that may compromise patient care. Radiation treatment planning is a well-documented source of variation in radiation oncology, leading many organizations to recommend the implementation of QA rounds in which radiation therapy plans are peer reviewed. This study evaluates the outcome of QA rounds that have been conducted by a radiation therapy department since 2004. METHODS AND MATERIALS: Prospectively documented records of QA rounds, from 2004 to 2010, were obtained. During rounds, randomly selected radiation therapy plans were peer reviewed and assigned a grade of A (adequate), B (minor suggestions of change to a plan for a future patient), or C (significant change required before the next fraction). The proportion of plans that received each recommendation was calculated, and the relationship between recommendations for each plan, tumor site, and mean years of experience of the radiation oncologist (RO) were explored. Chart reviews were performed for each plan that received a C. RESULTS: During the study period, 1247 plans were evaluated; 6% received a B and 1% received a C. The mean RO years of experience were lower for plans graded C versus those graded A (P=.02). The tumor sites with the highest proportion of plans graded B or C were gastrointestinal (14%), lung (13%), and lymphoma (8%). The most common reasons for plans to receive a grade of C were inadequate target volume coverage (36%), suboptimal dose or fractionation (27%), errors in patient setup (27%), and overtreatment of normal tissue (9%). CONCLUSIONS: This study demonstrated that QA rounds are feasible and an important element of a radiation therapy department's QA program. Through peer review, plans that deviate from a department's expected standard can be identified and corrected. Additional benefits include identifying patterns of practice that may contribute to inconsistencies in treatment planning and the continuing education of staff members who attend.

Use of combined androgen blockade for advanced prostate cancer in British Columbia.

OBJECTIVES: Initial androgen deprivation therapy (ADT) for metastatic prostate cancer with combined androgen blockade (luteinizing-hormone releasing hormone agonist [LHRH agonist] plus antiandrogen) is not recommended in British Columbia (BC). However, this is difficult to monitor since ADT includes concurrent antiandrogen for the first month of LHRH agonist to prevent disease flare. We describe the prevalence of CAB use in BC and its financial impact. METHODS: This was a population-based, retrospective analysis. Patients started on LHRH agonist in January 2005 to December 2006 were identified from the BC Cancer Agency database. CAB was defined as greater than 1 month of antiandrogen concurrently with LHRH agonist. Incremental cost of CAB was based on an average 18 months of therapy from the pivotal CAB study. Incremental cost-effectiveness ratio (ICER) was based on life-year gained (LYG) from the Prostate Cancer Trialists' Collaborative Group meta-analysis. Estimated financial impact for 2007-2008 was based on an annual increase by 5.5% in prevalence of prostate cancer in BC. RESULTS: A total of 2751 patients were identified. CAB was used in 607 patients (22%), associated with an incremental cost of CDN$1768 and ICER of CDN$11,220/LYG per patient. Total incremental cost was CDN$1,073,176 and estimated to be CDN$1,398,644 for January 2007 to December 2008. CONCLUSION: Nearly one-quarter of patients were treated with CAB for metastatic prostate cancer even though it was not recommended in BC. Additional cost of CAB use was considerable, at CDN$1768 per patient. With increased prevalence of prostate cancer, this has important budget implication for funding agencies which do to recommend CAB.

Does neoadjuvant hormone therapy improve outcome in prostate cancer patients receiving radiotherapy after radical prostatectomy?

PURPOSE: To assess outcome and predictive factors in men with prostate cancer who receive post radical prostatectomy (RP) radiotherapy (RT) either in the adjuvant or salvage setting, with or without neoadjuvant androgen deprivation therapy (NADT). METHODS: A retrospective analysis was performed on 175 patients with clinically localized prostate cancer treated with RP who subsequently received RT (dose range 50 Gy-68 Gy). Twenty-two patients received adjuvant RT (ART), 57 received NADT + ART, 15 received salvage RT (SRT), and 81 received NADT + SRT. Outcome was assessed by biochemical disease free survival (BDFS), prostate cancer specific survival and overall survival (OS). RESULTS: Although BDFS favored patients who received NADT with 5 year rates of 67%, 80%, 27% and 62% for the ART, NADT + ART, SRT, and NADT + SRT groups respectively; this was not a significant predictor on multivariable analysis. Significant independent predictive factors of improved BDFS were pre-RT PSA < or = 0.2 ng/ml, low Gleason score and positive surgical margins. Age and Gleason score were independent predictors of OS. CONCLUSIONS: Pre-RT PSA is an important predictor of outcome. NADT appears to benefit patients who presented with a pre-RT PSA > 0.2 ng/ml, particularly for patients receiving SRT. NADT can be considered for patients receiving RT after RP who present with a high pre-RT PSA but may not be necessary for patients without. Results of ongoing randomized studies such as RADICALS will also help clarify the role of hormone therapy in conjunction with RT.

The median non-prostate cancer survival is more than 10 years for men up to age 80 years who are selected and receive curative radiation treatment for prostate cancer.

Treatment guidelines recommend that curative radiation treatment of prostate cancer be offered only to men whose life expectancy is greater than 10 years. The average life expectancy of North American males is less than 10 years after age 75, yet many men older than 75 years receive curative radiation treatment for prostate cancer. This study used the provincial cancer registry in British Columbia, Canada, to determine median non-prostate cancer survival for men who were aged 75 to 82 years at start of radiation treatment. Median survival was found to be greater than 10 years in men aged up to 80 years at the start of their radiation treatment. This finding suggests that radiation oncologists are able to appropriately select elderly men with greater than average life expectancy to receive curative radiation treatment.

Standard treatments induce antigen-specific immune responses in prostate cancer.

PURPOSE: Prostate tumors express antigens that are recognized by the immune system in a significant proportion of patients; however, little is known about the effect of standard treatments on tumor-specific immunity. Radiation therapy induces expression of inflammatory and immune-stimulatory molecules, and neoadjuvant hormone therapy causes prominent T-cell infiltration of prostate tumors. We therefore hypothesized that radiation therapy and hormone therapy may initiate tumor-specific immune responses. EXPERIMENTAL DESIGN: Pretreatment and posttreatment serum samples from 73 men with nonmetastatic prostate cancer and 50 cancer-free controls were evaluated by Western blotting and SEREX (serological identification of antigens by recombinant cDNA expression cloning) antigen arrays to examine whether autoantibody responses to tumor proteins arose during the course of standard treatment. RESULTS: Western blotting revealed the development of treatment-associated autoantibody responses in patients undergoing neoadjuvant hormone therapy (7 of 24, 29.2%), external beam radiation therapy (4 of 29, 13.8%), and brachytherapy (5 of 20, 25%), compared with 0 of 14 patients undergoing radical prostatectomy and 2 of 36 (5.6%) controls. Responses were seen within 4 to 9 months of initiation of treatment and were equally prevalent across different disease risk groups. Similarly, in the murine Shionogi tumor model, hormone therapy induced tumor-associated autoantibody responses in 5 of 10 animals. In four patients, SEREX immunoscreening of a prostate cancer cDNA expression library identified several antigens recognized by treatment-associated autoantibodies, including PARP1, ZNF707 + PTMA, CEP78, SDCCAG1, and ODF2. CONCLUSION: We show for the first time that standard treatments induce antigen-specific immune responses in prostate cancer patients. Thus, immunologic mechanisms may contribute to clinical outcomes after hormone and radiation therapy, an effect that could potentially be exploited as a practical, personalized form of immunotherapy.

Pretreatment PSA velocity as a predictor of disease outcome following radical radiation therapy.

PURPOSE: Pretreatment prostate-specific antigen velocity (PSAV) greater than 2.0 ng/mL/year has been identified as a predictor of disease-specific survival (DSS) and overall survival (OS) after radiotherapy for prostate adenocarcinoma. This study aimed to independently verify if pretreatment PSAV is associated with biochemical disease-free survival (bDFS), DSS, or OS in men undergoing radiation therapy. METHODS AND MATERIALS: A total of 473 patients treated with radiation therapy for localized prostate cancer formed the study cohort. No men received neoadjuvant or adjuvant hormones. Kaplan-Meier and Cox regression analysis were used to evaluate if PSAV predicted disease endpoints. RESULTS: Men with a PSAV greater than 2.0 ng/mL/year had a shorter bDFS compared with men with a PSAV of 2.0 ng/mL/year or less (median, bDFS 68 months vs. 97 months; p = 0.0003). However, on multivariate analysis, PSAV was no longer a significant predictor of bDFS in the entire cohort (p = 0.09). PSAV did not predict DSS or OS (p = 0.55 and p = 0.99, respectively). In patients with high-risk disease, PSAV predicted bDFS on univariate (p = 0.0002) and multivariate (p = 0.02) analysis, but not DSS or OS. CONCLUSION: Pretreatment PSAV greater than 2.0 ng/mL/year is associated with reduced bDFS. However, PSAV is an independent predictor of bDFS only in high-risk patients. PSAV does not predict survival outcomes.

The changing age distribution of prostate cancer in Canada.

BACKGROUND: Prostate cancer incidence rates are still increasing steadily; mortality rates are levelling, possibly decreasing; and hospitalization rates for many diagnoses are decreasing. Our objective is to examine changes in age distributions of prostate cancer during these times of change. METHODS: Prostate cancer cases were derived from the Canadian Cancer Registry, prostate cancer deaths from Vital Statistics, hospitalizations from the Hospital Morbidity File. Age-standardized rates were calculated based on the 1991 Canadian population. A prevalence correction for incidence rates was calculated. RESULTS: Age-specific incidence rates increased until 1995 for all ages, but a superimposed peak (1991-94) was greatest between ages 60-79. After 1995, increases in incidence continued for the under-70 age groups. Prevalence correction indicated the greatest underestimation of incidence rates for the oldest ages, but was less in Canada than in the United States. Mortality rates increased until 1994, then levelled and slowly decreased; age-specific mortality rates showed the greatest increase for the oldest ages but the earliest downturn for younger age groups. While hospitalizations dropped drastically after 1991, this drop was confined to elderly men (70+). CONCLUSIONS: Dramatic changes in age distributions of prostate cancer incidence, mortality and hospitalizations altered age profiles of men with prostate cancer. This illustrated the changing nature of prostate cancer as a public health issue and has important implications for health care provision, e.g., the increased numbers of younger new patients have different needs from the increasing numbers of elderly long-term patients who now spend less time in hospital.

Prospective evaluation of the prevalence and severity of fatigue in patients with prostate cancer undergoing radical external beam radiotherapy and neoadjuvant hormone therapy.

OBJECTIVE: To prospectively evaluate the prevalence and severity of fatigue and its impact on quality of life (QOL) during and after radical external beam radiotherapy (RT) for prostate cancer. METHOD AND MATERIALS: Twenty-eight men with prostate cancer undergoing RT over 6-8 consecutive weeks were prospectively accrued. The Brief Fatigue Inventory (BFI), a validated fatigue assessment tool, was administered at five time points: baseline (week 1), middle of RT (week 3-4), end of RT (last week of RT), and follow-up (median 6.5 weeks after RT). The BFI contained nine questions, each using 0-10 ratings to quantify fatigue severity and interference with six QOL domains. The prevalence of moderate-severe fatigue was plotted as a function of time. Mean sum and subscale scores at each time point were compared to baseline scores using Wilcoxon tests. Linear regression analyses were performed to assess associations between fatigue scores and age, tumor and treatment characteristics. RESULTS: The median age was 69 years (range 57-84), Gleason score 7 (range 6-10), and presenting PSA 9.0 ng/mL (range 2.5 ng/mL-103.0 ng/mL). Patients were treated once daily to a median dose of 74 Gy (range 60 Gy-78 Gy) over a median of 37 fractions (range 30-39). Hormone therapy was used in all patients (median duration 12.2 months). The prevalence of moderate-severe present fatigue increased from 7% at baseline to 8% at mid-RT and 32% at RT completion. Compared to baseline (mean score 11.5), fatigue increased significantly mid-RT (mean score 14.6, p = 0.03) and peaked at the end of RT (mean score 23.5, p = 0.001). Fatigue significantly interfered with walking ability, normal work, daily chores, and enjoyment of life only at the end of RT. After RT completion, fatigue improved but remained higher compared to baseline at 6.5 weeks of follow-up (mean score 15.0, p = 0.02). On linear regression analysis, age, Gleason score, PSA, T-stage, hormone therapy duration, RT dose and fractions were not significantly associated with mean fatigue scores. CONCLUSION: Patients undergoing 6-8 weeks of RT experienced significant fatigue adversely affecting QOL persisting after therapy completion. Since walking ability was not affected until the end of RT, a walking exercise intervention to combat fatigue is likely feasible and is being investigated.

Trends in prostate cancer incidence, hospital utilization and surgical procedures, Canada, 1981-2000.

BACKGROUND: Numbers of new prostate cancer cases in Canada continue to increase because of increasing prostate cancer incidence, population growth, aging of the population, and earlier detection methods such as PSA (prostate-specific antigen) testing. Concern has been expressed that PSA-related increases in incidence will make unaffordable demands on Canadian hospital resources. Our objective is to relate increases in prostate cancer incidence to trends in hospitalizations and in- patient treatment. METHODS: Hospitalizations with prostate cancer as primary diagnosis were obtained from the Hospital Morbidity Database, estimates of prostate cancer day surgery from the Discharge Abstract Database, newly diagnosed cases from the Canadian Cancer Registry, and prostate cancer deaths from the Vital Statistics Mortality Databases--all for the years 1981-2000. RESULTS: Between 1981-2000, the number of new cases rose from 7,000 to 18,500 with a transient peak, 1991-1994. Hospitalizations rose parallel to the incidence until 1991 but then fell sharply in spite of further increasing incidence. The use of radical prostatectomy (RP) increased steadily, but transurethral prostatectomy and bilateral orchiectomy decreased in the 1990s. Decreases in length of stay and in number of hospitalizations resulted in considerably decreased annual hospital days for all prostate cancer in-patient procedures except RP, which remained level since 1993. CONCLUSIONS: A net decrease in number of in-patient days occurred, despite the increasing number of new prostate cancer cases and the increasing use of radical prostatectomy. We concluded that increases in hospital utilization due to early detection programs, such as PSA testing, are unlikely to overwhelm in-patient services of Canadian hospitals.

Neoadjuvant hormone therapy and external-beam radiation for localized high-risk prostate cancer: the importance of PSA nadir before radiation.

PURPOSE: To examine the impact of various patient, disease, and treatment characteristics on outcome in patients treated with neoadjuvant hormone therapy (NAHT) and external-beam radiation therapy (EBRT) for clinically localized, high-risk prostate adenocarcinoma (initial prostate-specific antigen [PSA] level >20, Gleason score 8-10 or Stage > or = T3). METHODS AND MATERIALS: A retrospective chart review was conducted on 407 patients treated between 1991 and 2001 with NAHT and EBRT for high-risk prostate cancer. The effect of tumor (PSA level, Gleason score, and T stage) and treatment (NAHT duration, total-hormone duration, preradiation PSA) characteristics on rates of biochemical disease-free survival (bDFS), prostate cancer-specific survival, and overall survival were examined. RESULTS: Median follow-up time was 78 months (range: 5-140 months). Actuarial bDFS at 5 years was 52% (95% confidence interval [CI], 46% to 57%) for the entire group. On multivariate analysis, initial PSA level (p = 0.004), Gleason score (p = 0.005), and preradiation PSA level (p < 0.001) were predictive of bDFS, whereas age, T stage, duration of NAHT, and duration of total hormone therapy were not predictive of outcomes. Gleason score and preradiation PSA level were also predictive of prostate cancer-specific survival rates. CONCLUSION: Improved bDFS in patients with high-risk prostate cancer was associated with lower initial PSA level, lower Gleason score, and lower preradiation PSA level. The duration of NAHT did not have an impact on outcomes, but the preradiation PSA was an important predictor of bDFS in high-risk patients.

Correction of systematic setup errors in prostate radiation therapy: how many images to perform?

The purpose of this study was to develop an evidence-based off-line setup correction protocol for systematic errors in prostate radiation therapy. Daily orthogonal electronic portal images were acquired from 30 patients. Field displacements were measured in the medial-lateral (ML), superior-inferior (SI), and anterior-posterior (AP) directions for each treatment fraction. The off-line protocol corrects the mean field displacement found from n consecutive images, starting at a particular fraction of treatment, with a fixed tolerance level. Simulations were performed with the measured data to determine (1) how many images (n) should be averaged to determine the systematic error; (2) on which treatment fraction should the protocol be initiated; and (3) what tolerance level should be applied to determine whether the patient position should be corrected. Uncorrected systematic errors in the ML, SI, and AP directions were (mean position +/- 1 standard deviation [SD]): -0.7 +/- 2.2 mm, -1.5 +/- 1.3 mm, and 1.4 +/- 2.6 mm, respectively. Random errors (1 SD and range) were 1.9 mm (1.3 - 3.3), 1.5 mm (0. - 4.1), and 1.8 mm (1.0-2.6), respectively. A correction based on a single image taken on the first fraction actually increased the systematic errors in the ML and SI directions compared with no correction. More accurate correction of systematic errors was achieved with increasing number of images averaged, with only small benefit after 5 images. With fewer images averaged, delaying the start of the protocol resulted in more accurate correction because of the influence of unrepresentative positions at early fractions. The number of corrections made on patients with small (< 2 mm) systematic errors was minimized for tolerance values of 2 mm and n > or = 5 images averaged. The optimal off-line setup correction protocol would be to shift the patient by the mean displacement of the first 5 portal images of a radical course of radiation therapy. A small tolerance level should be utilized with 2 mm giving good accuracy with minimal unnecessary shifts.

Mapping the journey of cancer patients through the health care system. Part 3: An approach to staging.

This is the third in a series of articles relating results from a line of research whose intent was to construct a complete history of patient interactions with the health care system using available data sources for all patients diagnosed in 1990 with a primary breast, colorectal, or lung tumour in Manitoba. This article presents details of the development and application of methods to produce TNM staging data on the roughly 2,000 patients in this population. The operational definitions constructed for this research can be adapted for other tumour sites and data sources. Findings include methods developed to overcome the sometimes ambiguous and inconsistent available documentation, which ultimately produced reliable TNM staging data. Survival data for this population by stage of disease are given.

Mapping the journey of cancer patients through health care system. Part 1: developing the research question.

This is the first in a series of articles relating results from research which constructed a complete history of interactions with the health care system from available data sources for all patients diagnosed in 1990 with primary breast, colorectal, or lung tumours in Manitoba from one year prior to diagnosis through to two years post-diagnosis. This article presents the motivation and genesis for this line of research. The study evolved from the question of "What happens to a person who is diagnosed with cancer?" into a major research endeavour encompassing a broad spectrum of philosophic and clinical research questions. A large interdisciplinary team collaborated on developing operational methods to combine existing data sources into unified cancer patient histories.

Mapping the journey of cancer patients through the health care system. Part 2: Methodological approaches and basic findings.

This is the second in a series of articles from a line of research whose intent was to construct a complete history of interactions with the health care system. This paper provides details of the methods developed to collect and collate the scattered information regarding the event history (trajectory) that a cancer patient experiences in traveling through the Manitoba health care system from one year prior to diagnosis through to two years post-diagnosis. Survival data were obtained through 1994. Basic population data obtained from this work are also presented, including survival information through to four years post-diagnosis. Issues regarding standardized data recording and detail level of clinical events in the chart record are discussed. This part of the research demonstrates that diverse data sources in the health care system can be linked with a high degree of accuracy and completeness of data.

Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15).

PURPOSE: This multi-institutional Phase III randomized study compared 10 Gy single-fraction radiotherapy (RT) with 20 Gy in five fractions in the palliation of thoracic symptoms from lung cancer. METHODS AND MATERIALS: The primary end point was palliation of thoracic symptoms at 1 month after RT, evaluated by a patient-completed daily diary card. Secondary end points included quality of life, toxicity, and survival. RESULTS: Most (69%) of 230 patients randomized had locally advanced disease unsuitable for curative treatment. The treatment arms were well balanced with respect to the known prognostic factors. At 1 month after RT, no difference was found in symptom control between the two arms, as judged by the daily diary scores. The changes in the scores on the Lung Cancer Symptom Scale indicated that the fractionated RT (five fractions) group had greater improvement in symptoms related to lung cancer (p = 0.009), pain (p = 0.0008), ability to carry out normal activities (p = 0.037), and better global quality of life (p = 0.039). The European Organization for Research and Treatment of Cancer QLQ-C30 scores showed that patients receiving five fractions had a greater improvement in scores with respect to pain (p = 0.04). No significant difference was found in treatment-related toxicity. Patients who received five fractions survived on average 2 months longer (p = 0.0305) than patients who received one fraction. CONCLUSION: Although the two treatment strategies provided a similar degree of palliation of thoracic symptoms, the difference in survival between the two study arms was of a clinically relevant magnitude.

Incorrect biochemistry complicates prostate cancer management.

A man with a prostate specific antigen (PSA) of 6.1 ng/mL, a clinical stage T2b prostate nodule and biopsies that showed Gleason sum 6 adenocarcinoma of the prostate underwent a radical prostatectomy. The final pathology showed organ-confined disease. His postoperative PSA remained elevated at 4.0 ng/mL. The PSA was repeated several times and was in the same range. It was re-evaluated at another lab facility and was unmeasurable (<0.02 ng/mL). He has an antibody that cross-reacts with an assay reagent causing this false reading. The most likely antibody is one against mouse immunoglobulin G (IgG).