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.

Topical amitriptyline, ketamine, and lidocaine in neuropathic pain caused by radiation skin reaction: a pilot study.

PURPOSE: The purpose of this study is to assess the effect of topical amitriptyline, ketamine, and lidocaine (AKL) on alleviation of neuropathic pain from radiation dermatitis and the feasibility of a randomized trial. MATERIALS AND METHODS: Eligible subjects had radiation dermatitis with dry or moist desquamation with neuropathic pain and were intolerant or allergic to standard intervention. AKL was applied to painful sites three times a day daily until 2 weeks post-radiotherapy. Subjects were monitored every 2-5 days during radiotherapy and at 2 and 6 weeks after completion of radiotherapy. The University of Washington Neuropathic Pain Scale was used to grade the neuropathic pain before and after use of the interventional gel. Compliance was assessed by asking subjects at each visit how frequently they were using the interventional gel. RESULTS: Over a 14-month period, 16 subjects met eligibility criteria. Eighty-two percent of subjects used the AKL as directed. Five subjects (32%) reported fatigue, and three subjects (19%) reported site irritation from the interventional gel. AKL was shown to significantly reduce (p < 0.05) pain intensity, sharpness, burning, sensitivity, itchiness, unpleasantness, deepness, and surfaceness levels on a short-term basis (i.e., between pre-treatment and 30 min post-treatment). AKL was shown to significantly reduce (p < 0.05) burning levels on a long-term basis (i.e., between pre-treatment and 2 weeks post-treatment). CONCLUSIONS: AKL was a safe intervention to use with minimal toxicity and good compliance. It significantly reduced several measures of neuropathic pain associated with radiation dermatitis. A larger-scale study would require recruitment from multiple centers.

Predictors of local recurrence in a population-based cohort of women with ductal carcinoma in situ treated with breast conserving surgery alone.

BACKGROUND: To identify prognostic indicators of local recurrence (LR) in patients with ductal carcinoma in situ (DCIS) of the breast treated with breast conserving surgery (BCS) alone. METHODS: A retrospective study was conducted of all women with pure DCIS, diagnosed 1985-1999, referred for tertiary oncologic opinion in British Columbia, treated with BCS without adjuvant radiotherapy. Kaplan-Meier local control (LC) and breast cancer specific survival (BCSS) estimates for the entire group were plotted. Stratified analyses identified subgroups with high Kaplan-Meier 10-year LR. Cox multivariate modeling was used to assess predictors of LR. Kaplan-Meier BCSS rates were compared between two cohorts: those who experienced LR and those who did not have LR. RESULTS: A total of 460 women comprised the study cohort. Median follow-up was 9.4 years. The 15-year LC and BCSS rates were 82% and 97%, respectively. Stratified analyses of LR identified comedo histology, high nuclear grade, tumor size >4 cm or indeterminate size, and positive margins to be associated with significantly higher LR risk, with 10-year LR risks approximating 15-30%. The 10-year BCSS rates for the LR group were 94% compared with 99% for the NoLR group. On Cox regression modeling, high nuclear grade, the presence of comedocarcinoma, and positive margins were significant factors for higher risk of LR. CONCLUSIONS: Women with DCIS treated with BCS alone had higher LR risk, and those with a LR were more likely to die of breast cancer. Optimal local treatment is mandatory to minimize the risk of breast cancer death for women with this curable disease.

Prognostic significance of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for advanced non-small cell lung cancer patients with high PD-L1 tumor expression receiving pembrolizumab.

BACKGROUND: We investigated the association of peripheral blood inflammatory markers with overall survival (OS) in pembrolizumab treated advanced non-small cell lung cancer (aNSCLC) patients with programmed death ligand 1 (PD-L1) expression ≥50%. Clinical risk factors for development of immune-related adverse events (irAE) were also explored. METHODS: aNSCLC patients with high PD-L1 expression receiving pembrolizumab monotherapy outside of clinical trials were identified retrospectively. All patients were treated at one of six British Columbia Cancer clinics between August 2017 and June 2019. Patients were dichotomized using baseline neutrophil-to-lymphocyte ratio (NLR,

Association of age with differences in immune related adverse events and survival of patients with advanced nonsmall cell lung cancer receiving pembrolizumab or nivolumab.

OBJECTIVES: To explore the association of age with development of immune related adverse events (irAE) and survival in patients with advanced nonsmall cell lung cancer (aNSCLC) receiving programmed cell death 1 antibodies (PD-1 Ab) outside of clinical trials. METHODS: A multicenter retrospective study of PD-1 Ab prescription for patients with aNSCLC between 06/2015-11/2018 at BC Cancer. Multivariable (MVA) logistic regression identified baseline variables associated with irAE manifested within 3 months of PD-1 Ab initiation. Overall survival (OS) analyzed in a propensity-score matched cohort and survival outcomes compared between age groups by stratified log-rank. Six-week landmark analysis was performed and OS compared between patients with interrupted versus continuous treatment by log-rank. RESULTS: Of 527 patients, 40.6% were age ≤ 64 years, 40.6% were 65-74 years, and 18.8% were ≥ 75 years. In MVA, ECOG performance status 2/3 (p = .034), squamous histology (p = .031), and nivolumab therapy (vs. pembrolizumab, p = .012) were associated with increased odds of irAE by 3 months of treatment. Across age groups no difference existed in any grade irAE (p = .98), hospitalization (p = 1.0), or corticosteroids use (p = .51). The propensity score-matched survival analysis comprised 77 patients from each age group; all covariates were balanced. OS did not differ significantly by age in the matched cohort (p = .17). Treatment interruption due to irAE at 6 weeks was more common in patient ≥75 years (vs. <75, p = .055) and correlated with lower OS (p = .002). CONCLUSION: In this cohort of patients with aNSCLC treated in routine clinical practice with PD-1 Ab, immune-toxicity and observed survival were similar amongst age groups.

Bleeding and perforation after outpatient colonoscopy and their risk factors in usual clinical practice.

BACKGROUND & AIMS: The most widely quoted complication rates for colonoscopy are from case series performed by expert endoscopists. Our objectives were to evaluate the rates of bleeding, perforation, and death associated with outpatient colonoscopy and their risk factors in a population-based study. METHODS: We identified all individuals 50 to 75 years old who underwent an outpatient colonoscopy during April 1, 2002, to March 31, 2003, in British Columbia, Alberta, Ontario, and Nova Scotia, Canada. Using administrative data, we identified all individuals who were admitted to hospital with bleeding or perforation within 30 days following the colonoscopy in each province. We calculated the pooled rates of bleeding and perforation from the 4 provinces. In Ontario, we abstracted the hospital charts of all deaths that occurred within 30 days following the procedure. We used generalized estimating equations models to evaluate factors associated with bleeding and perforation. RESULTS: We identified 97,091 persons who had an outpatient colonoscopy. The pooled rates of colonoscopy-related bleeding and perforation were 1.64/1000 and 0.85/1000, respectively. The death rate was 0.074/1000 or approximately 1/14,000. Older age, male sex, having a polypectomy, and having the colonoscopy performed by a low-volume endoscopist were associated with increased odds of bleeding or perforation. CONCLUSIONS: Although colonoscopy has established benefits for the detection of colorectal cancer and adenomatous polyps, the procedure is associated with risks of serious complications, including death. Older age, male sex, having a polypectomy, and having the procedure done by a low-volume endoscopist were independently associated with colonoscopy-related bleeding and perforation.

Local Relapse After Breast-Conserving Therapy Versus Mastectomy for Extensive Pure Ductal Carcinoma In Situ ≥4 cm.

PURPOSE: The optimal treatment for patients with extensive pure ductal carcinoma in situ (DCIS) ≥4 cm is controversial. This study evaluates local relapse according to type of local therapy: mastectomy, breast-conserving surgery (BCS) alone, and BCS + radiation therapy (RT). METHODS AND MATERIALS: Subjects were female patients who received diagnoses of pure DCIS ≥4 cm between 1989 and 2010 and were referred to British Columbia Cancer. Clinicopathologic and treatment characteristics were compared between treatment cohorts. Local relapse (LR) was estimated using competing risk analysis. Multivariable analysis was performed using Cox regression analysis. RESULTS: Patients had the following treatments: 490 mastectomy, 38 BCS alone, and 192 BCS + RT. The 10-year cumulative incidence of LR was 16% after BCS (95% confidence interval [CI], 6-29%), 8% after BCS + RT (95% CI, 4-12%), and 2% after mastectomy (95% CI, 1-4%). On multivariable analysis, estrogen receptor-negative disease (hazard ratio [HR], 3.32; 95% CI, 1.08-10.18; P = .04) and positive margins (HR, 3.55; 95% CI, 1.56-8.05; P = .002) were associated with increased LR. BCS alone (HR, 7.87; 95% CI, 2.82-21.92; P < .0001), BCS + RT + no boost (HR, 3.80; 95% CI, 1.56-9.28; P = .003), and BCS + RT + boost (HR, 5.76; 95% CI, 2.59-12.83; P < .0001) were all associated with a higher risk of relapse relative to mastectomy. CONCLUSIONS: Mastectomy remains a standard local treatment option for extensive DCIS, but BCS + RT may also be reasonably considered in selected patients with a careful discussion of the benefits, side effects, and patient preferences.

Efficacy of Nivolumab and Pembrolizumab in Patients With Advanced Non-Small-Cell Lung Cancer Needing Treatment Interruption Because of Adverse Events: A Retrospective Multicenter Analysis.

INTRODUCTION: The programmed death 1 antibodies (PD-1 Ab) nivolumab and pembrolizumab improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). We evaluated the correlation between immune-related adverse events (irAE) and treatment interruption due to irAE on clinical efficacy of PD-1 Ab in advanced NSCLC. PATIENTS AND METHODS: Advanced NSCLC patients treated with PD-1 Ab between June 2015 to November 2017 at BC Cancer were identified. Demographic, tumor, treatment details, and frequency and grade (Common Terminology Criteria for Adverse Events, version 4.0) of irAE were abstracted from chart review. Kaplan-Meier curves of OS from initiation of PD-1 Ab were generated. Multivariable analysis with 6- and 12-week landmark analysis was performed by Cox proportional hazard regression models. RESULTS: In a cohort of 271 patients, irAEs were observed in 116 patients (42.8%). Nivolumab recipients developing colitis had lower OS compared to those who did not at the 6-week landmark (P = .010) and 12-week landmark (P = .072). For the entire cohort, 56 patients (20.7%) needed treatment interruption because of an irAE. Treatment interruption correlated with lower OS at the 6-week landmark (P = .005) and 12-week landmark (P = .008). Six-week landmark multivariable analysis identified Charlson Comorbidity Index score of 3 or higher, Eastern Cooperative Oncology Group Performance Status of 2 or higher, presence of liver metastases, and irAE greater than grade 2 versus no irAE to be associated with decreased OS (each P < .05). CONCLUSION: Treatment interruption due to irAE was associated with a lower median OS compared to continuous PD-1 Ab therapy. Shorter OS seen with severe irAE might reflect the need for improved physician education in irAE treatment algorithms.

Pembrolizumab for advanced nonsmall cell lung cancer: Efficacy and safety in everyday clinical practice.

OBJECTIVES: While pembrolizumab improves overall survival (OS) in a subset of advanced nonsmall cell lung cancer (aNSCLC) patients (pts) in clinical trials, individuals with poor Eastern Cooperative Oncology Group performance status (ECOG PS) were excluded. Furthermore, some studies have identified a potential link between improved pt outcomes and development of immune related adverse events (irAE.) In a large provincial cohort, we studied the efficacy and safety of pembrolizumab for poor ECOG PS pts and whether irAE correlate with improved OS. MATERIALS AND METHODS: aNSCLC pts treated with pembrolizumab between 06/2015 and 08/2018 at BC Cancer were retrospectively identified. Kaplan-Meier curves of OS from initiation of pembrolizumab were plotted. 3-, 6-, and 9- month landmark Kaplan-Meier analysis was performed and log-rank tests used to determine an association of irAE subtypes with OS. Multivariable logistic regression identified variables associated with grade ≥3 irAE within 3 months of pembrolizumab initiation. RESULTS: Of 190 pts, 74.2% were treatment naïve and 92.6% had PD-L1 expression ≥ 50%. Median OS in the 1st line and ≥2nd line settings were 24.3 months (95% CI, 9.7-not reached, NR) and 13.4 months (95% CI, 8.1-NR), respectively. Pts with ECOG PS 2/3 had lower median OS than if ECOG PS 0/1 (5.8 months vs. 16.7 months, p < 0.0001). In multivariable analysis, the odds of grade ≥ 3 irAE within 3 months was 6.3 fold higher if ECOG PS 2/3 versus 0/1 (p = 0.05). Development of pneumonitis at the 9 month landmark weakly correlated with decreased OS (p = 0.09). CONCLUSION: In the studied cohort, ECOG PS 2/3 pts had a significantly lower OS and greater odds of experiencing high-grade irAE than if ECOG PS 0/1. Development of irAE did not result in improved OS. Randomized trials to determine benefit of pembrolizumab for poor ECOG PS pts are needed.

Gender differences in colorectal cancer incidence, mortality, hospitalizations and surgical procedures in Canada.

BACKGROUND: Over the past few decades there have been changes in incidence and mortality of colorectal cancer. OBJECTIVE: To examine gender differences in incidence, hospitalization, hospital-based procedures and mortality for colorectal cancer. METHODS: Data were derived from the Hospital Morbidity Database, Canadian Cancer Registry and the Canadian Mortality Database. RESULTS: Overall incidence and mortality rates for colorectal cancer are decreasing, but remain substantially higher for males. Absolute numbers of cases are similar for men and women. The top subsite for men was rectal cancer, which was third highest for women, whereas right colon cancer was highest for women. Male/female ratios for incidence and surgeries were highest for distal cancer and are increasing with time. CONCLUSIONS: Although overall incidence rates have shown a decline, absolute numbers of new colorectal cancer cases have increased. While men have higher colorectal cancer rates, women have similar numbers and screening should target both equally. Over the years, colorectal cancer subsites are showing a rightward shift, i.e. an increase in proximal subsites, but a leftward shift in male/female ratios, i.e. a greater decrease for the more distal subsites in females. The lower rates for women for distal cancer are compatible with a degree of hormonal protection based on oral contraceptive and hormone replacement therapy. Colorectal cancer will continue to be a considerable public health problem in the foreseeable future.

Programmatic Comparison and Dissemination of an Audit of Single-fraction Radiation Therapy Prescribing Practices for Bone Metastases is Associated with a Meaningful and Lasting Change in Practice on a Population Level.

PURPOSE: There is ample evidence that single-fraction radiation therapy (SFRT) is as efficacious as more costly and morbid multifraction regimens. We previously demonstrated that an audit-based intervention increased the use of SFRT in all regional cancer centers the following year. However, other investigators have demonstrated that interventions were only associated with a transient 1-year change in prescribing practices. We sought to determine whether our intervention resulted in a more lasting impact. METHODS AND MATERIALS: In 2012, we performed an audit of the prescribing practices of individual physicians, which was then presented to leaders and oncologists as an intervention to increase SFRT. We compared the use of SFRT between 2007 to 2011 (preintervention) and 2013 to 2016 (postintervention) in all 31,192 patients treated in our provincial program. RESULTS: The use of SFRT increased from 49.2% to 58.9% postintervention (P < .001). Rates from 2007 to 2011 were 51%, 51%, 48%, 49%, and 48%, respectively, whereas the postintervention rates from 2013 to 2016 were 60%, 62%, 59%, and 56%, respectively. Postintervention, half of the centers prescribed SFRT in a relatively narrow range (55%-58%). However, across all centers, there was still a broad range, with the lowest and highest users at 35% and 81%, respectively, although the lowest-using center still showed a significant increase (26% to 35%; P < .001). CONCLUSIONS: Our audit and education-based intervention resulted in a lasting and meaningful 10% change in practice. Our provincial rate is similar to that of a previously recommended benchmark rate of 60%, but we continue to see significant variation by center, suggesting further room for improvement in provincial standardization. With emerging evidence in support of ablative radiation therapy for select populations of patients with bone metastases, future benchmark rates of SFRT should be readdressed. However, our data suggest that programmatic comparison and dissemination of SFRT prescribing practices can achieve a population-based SFRT utilization rate near 60%.

Impact of fraction size on cardiac mortality in women treated with tangential radiotherapy for localized breast cancer.

PURPOSE: To determine whether fraction size affects the risk of cardiac mortality in women treated with adjuvant radiotherapy (RT) for left-sided breast cancer. METHODS AND MATERIALS: A population-based retrospective study of women with a diagnosis of localized breast cancer treated with adjuvant RT in British Columbia from 1984 to 2000. Cases were identified from the British Columbia Cancer Agency database. Overall and cardiac-specific survival were compared for women treated with RT for left- vs. right-sided breast cancer. We analyzed the impact of age (60 years) at diagnosis and RT fraction size (2 Gy) on risk of fatal cardiac events. RESULTS: We identified 3,781 women with left-sided and 3,666 women with right-sided breast cancer who received adjuvant RT. Median follow-up was 7.9 years. There were 52 vs. 47 breast cancer deaths in women treated for left- and right-sided breast cancer, respectively. There was no significant difference in cardiac mortality for women 60 years of age who received adjuvant RT for left-sided vs. right-sided cancer. There was no difference in cardiac mortality for women who received adjuvant RT with fraction sizes 2 Gy for left- or right-sided cancer. CONCLUSIONS: There was no evidence for increased risk of cardiac mortality in women treated with adjuvant RT after a median follow-up of 7.9 years in our cohort. Hypofractionated adjuvant RT regimens did not significantly increase the risk of cardiac mortality.

Is multibeam IMRT better than standard treatment for patients with left-sided breast cancer?

PURPOSE: When treatment intent is to include breast and internal mammary lymph nodes (IMNs) in the clinical target volume (CTV), a significant volume of the heart may receive radiation, which may result in late morbidity. The value of conformal intensity-modulated radiation therapy (IMRT) to avoid heart dose was studied. METHODS AND MATERIALS: Breast, IMNs, and normal tissues were contoured for 30 consecutive patients previously treated with RT after lumpectomy for left-sided breast cancer. Eleven-beam, conformal, inverse-planned IMRT plans were developed and compared with best standard plans. Conformity Index (CI), Homogeneity Index (HI), and doses to normal tissues were compared. RESULTS: Intensity-modulated RT significantly improved (two-sided paired t test) HI (0.95 vs. 0.74), CI (0.91 vs. 0.48), volume of the heart receiving more than 30 Gy (V30-heart) (1.7% vs. 12.5%), and volume of lung receiving more than 20-Gy (V20-left lung) (17.1% vs. 26.6%), all p < 0.001. The mean Healthy Tissue Volume (HTV = CT set - PTV) dose was similar between IMRT and best standard plans (6.0 and 6.9 Gy, respectively), but IMRT increased the volume of normal tissues receiving low-dose RT: V5-right lung (13.7% vs. 2.0%), V5-right breast (29.2% vs. 7.9%), and V5-HTV (31.7% vs. 23.6%), all p < 0.001. IMRT plans were generated in less than 60 min and treatment delivered in approximately 20 min, suggesting that this technique is clinically applicable. CONCLUSIONS: IMRT significantly improved conformity and homogeneity for plans when the breast + IMNs were in the CTV. Heart and lung volume receiving high doses were decreased, but more healthy tissue received low doses. A simple algorithm based on amount of heart included in the standard plan showed limited ability to predict the benefit from IMRT.

Effect of Referral Patterns and Treatment Type on Oncologic Outcomes for Women with Ductal Carcinoma In Situ.

OBJECTIVE: Management of ductal carcinoma in situ (DCIS) remains controversial. This study examined long-term outcomes in a population-based cohort of patients with pure DCIS treated with breast-conserving surgery (BCS) alone, BCS + radiotherapy (RT), and mastectomy. Outcomes were compared between patients referred versus not referred for oncologic assessment after definitive surgery. MATERIALS AND METHODS: Subjects were 2575 women diagnosed between 1985 and 1999. Data from several electronic databases were linked and analyzed. Outcomes were invasive local recurrence-free survival (ILRFS), mastectomy-free survival (MFS), breast cancer-specific survival (BCSS), and overall survival (OS). RESULTS: Median follow-up time was 9.8 years. Overall, 56% (n = 1448) of subjects were referred to a cancer centre. Factors associated with non-referral were older age, comorbidities, and travel distance. Ten-year MFS, BCSS, and OS were higher among referred patients (all p ≤ 0.001). In cohorts treated with BCS alone (n = 1314) vs. BCS + RT (n = 510) vs. mastectomy (n = 751), 10-year ILRFS were 93.7% vs. 96.6% vs. 97.7%, (p < 0.001) and BCSS were 97.6% vs. 99.8% vs. 98.6%, (p = 0.01). Corresponding rates of ipsilateral invasive breast relapse at 10 years were 6.3% after BCS alone, 3.4% after BCS + RT, and 2.3% after mastectomy (p < 0.001). On multivariable analysis, factors associated with improved ILRFS were older age at diagnosis, low comorbidity score, absence of comedo histology, mastectomy, and post-BCS RT. CONCLUSION: Patients with DCIS referred for oncologic assessment were more likely to undergo post-BCS RT, resulting in lower mastectomy and higher survival rates compared to non-referred patients. Patients with significant comorbidities were less likely to be referred and experienced lower ILRFS and BCSS. Referral for multidisciplinary oncologic assessment after surgery is warranted to individualize management and optimize outcomes for patients with DCIS.

Malignant Epithelial Transformation in Phyllodes Tumor: A Population-Based Case Series.

Background Phyllodes tumor (PT) of the breast is an uncommon fibroepithelial neoplasm. Malignant epithelial transformation in PT is rare. This study reports clinicopathologic characteristics and outcomes of patients with malignant epithelial transformation in PT. Methods From an institutional database of 183 patients with newly diagnosed PT referred to a Canadian provincial cancer institution between 1999 and 2014, 11 cases of PT with concomitant in situ or invasive carcinoma were identified. Descriptive analysis was performed to document the characteristics, treatment and outcomes of this cohort. Results Prevalence of malignant epithelial transformation in PT was 6.0%. Median (range) age was 54 (35-75) years. Types of carcinoma were ductal carcinoma in situ (DCIS) (n = 6), lobular carcinoma in situ (n = 4), and invasive ductal carcinoma (IDC) (n = 1). Median PT size was 5 (1-15) cm. Three PTs were classified as benign (27%), five as borderline (45%), and three as malignant (27%). Mastectomy was performed in six (55%) and breast conserving surgery in five (45%) patients. Hormonal therapy was used in two cases: one with a 1 cm, grade 2 DCIS, and one with an 11 cm, grade 1 IDC, the latter also receiving radiotherapy. Mean follow-up duration was 54 (6-175) months. None of the cases showed any evidence of disease after treatment at the time of their last follow-up. Conclusion This case series showed a higher prevalence of malignant epithelial transformation in PT than reported in previous literature. Outcomes were favourable despite the presence of either in situ or invasive carcinoma within PT.

Canadian Phase III Randomized Trial of Stereotactic Body Radiotherapy Versus Conventionally Hypofractionated Radiotherapy for Stage I, Medically Inoperable Non-Small-Cell Lung Cancer - Rationale and Protocol Design for the Ontario Clinical Oncology Group (OCOG)-LUSTRE Trial.

We describe a Canadian phase III randomized controlled trial of stereotactic body radiotherapy (SBRT) versus conventionally hypofractionated radiotherapy (CRT) for the treatment of stage I medically inoperable non-small-cell lung cancer (OCOG-LUSTRE Trial). Eligible patients are randomized in a 2:1 fashion to either SBRT (48 Gy in 4 fractions for peripherally located lesions; 60 Gy in 8 fractions for centrally located lesions) or CRT (60 Gy in 15 fractions). The primary outcome of the study is 3-year local control, which we hypothesize will improve from 75% with CRT to 87.5% with SBRT. With 85% power to detect a difference of this magnitude (hazard ratio = 0.46), a 2-sided α = 0.05 and a 2:1 randomization, we require a sample size of 324 patients (216 SBRT, 108 CRT). Important secondary outcomes include overall survival, disease-free survival, toxicity, radiation-related treatment death, quality of life, and cost-effectiveness. A robust radiation therapy quality assurance program has been established to assure consistent and high quality SBRT and CRT delivery. Despite widespread interest and adoption of SBRT, there still remains a concern regarding long-term control and risks of toxicity (particularly in patients with centrally located lesions). The OCOG-LUSTRE study is the only randomized phase III trial testing SBRT in a medically inoperable population, and the results of this trial will attempt to prove that the benefits of SBRT outweigh the potential risks.

Association of Radiotherapy Boost for Ductal Carcinoma In Situ With Local Control After Whole-Breast Radiotherapy.

IMPORTANCE: The use of a radiotherapy (RT) boost to the tumor bed after whole-breast RT (WBRT) for ductal carcinoma in situ (DCIS) is largely extrapolated from invasive cancer data, but robust evidence specific to DCIS is lacking. OBJECTIVE: To compare ipsilateral breast tumor recurrence (IBTR) in women with DCIS treated with vs without the RT boost after breast-conserving surgery and WBRT. DESIGN, SETTING, AND PARTICIPANTS: This retrospective analysis pooled deidentified patient-level data from 10 academic institutions in the United States, Canada, and France from January 1, 1980, through December 31, 2010. All patients had newly diagnosed pure DCIS (no microinvasion), underwent breast-conserving surgery, and received WBRT with or without the boost with a minimum of 5 years of follow-up required for inclusion in the analysis. Given the limited events after WBRT, an a priori power analysis was conducted to estimate the DCIS sample size needed to detect the anticipated benefit of the boost. Data were uniformly recoded at the host institution and underwent primary and secondary reviews before analysis. Sample size calculations (ratio of patients who received the boost dose to those who did not, 2:1; α = .05; power = 80%) estimated that 2982 cases were needed to detect a difference of at least 3%. The final analysis included 4131 patients (2661 in the boost group and 1470 in the no-boost group) with a median follow-up of 9 years and media boost dose of 14 Gy. Data were collected from July 2011 through February 2014 and analyzed from March 2014 through August 2015. INTERVENTIONS: Radiotherapy boost vs no boost. MAIN OUTCOMES AND MEASURES: Ipsilateral breast tumor recurrence. RESULTS: The analysis included 4131 patients (median [SD] age, 56.1 [10.9] years; range, 24-88 years). Patients with positive margins, unknown estrogen receptor status, and comedo necrosis were more likely to have received an RT boost. For the entire cohort, the boost was significantly associated with lower IBTR (hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) and with IBTR-free survival (boost vs no-boost groups) of 97.1% (95% CI, 0.96-0.98) vs 96.3% (95% CI, 0.95-0.97) at 5 years, 94.1% (95% CI, 0.93-0.95) vs 92.5% (95% CI, 0.91-0.94) at 10 years, and 91.6% (95% CI, 0.90-0.93) vs 88.0% (95% CI, 0.85-0.91) at 15 years. On multivariable analysis accounting for confounding factors, the boost remained significantly associated with reduced IBTR (HR compared with no boost, 0.68; 95% CI, 0.50-0.91; P = .01) independent of age and tamoxifen citrate use. CONCLUSIONS AND RELEVANCE: This patient-level analysis suggests that the RT boost confers a statistically significant benefit in decreasing IBTR across all DCIS age groups, similar to that seen in patients with invasive breast cancer. These findings suggest that a DCIS RT boost to the tumor bed could be considered to provide an added incremental benefit in decreasing IBTR after a shared discussion between the patient and her radiation oncologist.

Consistency in seroma contouring for partial breast radiotherapy: impact of guidelines.

PURPOSE: Inconsistencies in contouring target structures can undermine the precision of conformal radiation therapy (RT) planning and compromise the validity of clinical trial results. This study evaluated the impact of guidelines on consistency in target volume contouring for partial breast RT planning. METHODS AND MATERIALS: Guidelines for target volume definition for partial breast radiation therapy (PBRT) planning were developed by members of the steering committee for a pilot trial of PBRT using conformal external beam planning. In phase 1, delineation of the breast seroma in 5 early-stage breast cancer patients was independently performed by a "trained" cohort of four radiation oncologists who were provided with these guidelines and an "untrained" cohort of four radiation oncologists who contoured without guidelines. Using automated planning software, the seroma target volume (STV) was expanded into a clinical target volume (CTV) and planning target volume (PTV) for each oncologist. Means and standard deviations were calculated, and two-tailed t tests were used to assess differences between the "trained" and "untrained" cohorts. In phase 2, all eight radiation oncologists were provided with the same contouring guidelines, and were asked to delineate the seroma in five new cases. Data were again analyzed to evaluate consistency between the two cohorts. RESULTS: The "untrained" cohort contoured larger seroma volumes and had larger CTVs and PTVs compared with the "trained" cohort in three of five cases. When seroma contouring was performed after review of contouring guidelines, the differences in the STVs, CTVs, and PTVs were no longer statistically significant. CONCLUSION: Guidelines can improve consistency among radiation oncologists performing target volume delineation for PBRT planning.

Inverse-planned, dynamic, multi-beam, intensity-modulated radiation therapy (IMRT): a promising technique when target volume is the left breast and internal mammary lymph nodes.

The purpose of this study was to determine the optimum beam number and orientation for inverse-planned, dynamic intensity-modulated radiation therapy (IMRT) for treatment of left-sided breast cancer and internal mammary nodes (IMNs) to improve target coverage while reducing cardiac and ipsilateral lung irradiation. Computed tomography (CT) data was used from 5 patients with left-sided breast cancer in whom the heart was close to the chest wall. The planning target volume (PTV) was the full breast plus ipsilateral IMNs. Two geometric beam arrangements were investigated, 240 degrees and 190 degrees sector angles, and the number of beams was increased from 7 to 9 to 11. Dose comparison metrics included: PTV homogeneity and conformity indices (HI, CI), heart V30, left lung V20, and mean doses to surrounding structures. To assess clinical application, the IMRT plans with 11 beams equally spaced in a 190 degrees sector angle were compared to conventional plans. Treatment times were modeled. The 190 degrees IMRT plans improved PTV HI and CI and reduced mean dose to the heart, lungs, contralateral breast, and total healthy tissue (all p < 0.05) compared to a 240 degrees sector angle. The 11-beam plan significantly improved PTV HI and CI, heart V30, left lung V20, and healthy tissue V5 compared to a 7-beam plan (all p < 0.05). The 11-beam plan reduced heart V30 and left lung V20 (p < 0.05) without compromising PTV coverage, compared to a 9-beam plan. Compared to a conventional plan, the IMRT class solution significantly improved PTV HI and CI (both p < 0.01), heart V30 (p = 0.01), and marginally reduced left lung V20 (p = 0.07) but increased contralateral breast and lung mean dose (p < 0.001) and healthy tissue V5 (p < 0.001). An 11-beam 190 degrees sector angle IMRT technique as a class solution is clinically feasible.

Salvage treatment for local or local-regional recurrence after initial breast conservation treatment with radiation for ductal carcinoma in situ.

The present study evaluated the outcome of salvage treatment for women with local or local-regional recurrence after initial breast conservation treatment with radiation for mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast. The study cohort consisted of 90 women with local only first failure (n=85) or local-regional only first failure (n=5). The histology at the time of recurrence was invasive carcinoma for 53 patients (59%), non-invasive carcinoma for 34 patients (38%), angiosarcoma for one patient (1%), and unknown for two patients (2%). The median follow-up after salvage treatment was 5.5 years (mean=5.8 years; range=0.2-14.2 years). The 10-year rates of overall survival, cause-specific survival, and freedom from distant metastases after salvage treatment were 83%, 95%, and 91%, respectively. Adverse prognostic factors for the development of subsequent distant metastases after salvage treatment were invasive histology of the local recurrence and pathologically positive axillary lymph nodes. These results demonstrate that local and local-regional recurrences can be salvaged with high rates of survival and freedom from distant metastases. Close follow-up after initial breast conservation treatment with radiation is warranted for the early detection of potentially salvageable local and local-regional recurrences.