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Population-based assessment of relationship between volume of practice and outcomes in head and neck… McLay, Mary 2017

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  POPULATION-BASED ASSESSMENT OF RELATIONSHIP BETWEEN VOLUME OF  PRACTICE AND OUTCOMES IN HEAD AND NECK CANCER PATIENTS    by  MARY MCLAY  B.Sc, The University of Victoria, 2012     A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF  THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE   in   THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES  (Interdisciplinary Oncology)       THE UNIVERSITY OF BRITISH COLUMBIA  (Vancouver)      April 2017   © Mary McLay, 2017  ii  Abstract  Background and Purpose: Recent literature has suggested that higher volumes of practice are associated with better survival outcomes for head and neck cancer (HNC) patients. However, these studies are limited by looking at the volume of practice on a cancer centre level (i.e. not provider level), and include jurisdictions without central coordination and specialized HNC tumor group support. The objective of this thesis was to evaluate the effect of treatment centre on the overall survival (OS) and cancer-specific survival (CSS) of HNC patients in British Columbia in a provincially coordinated program. Methods: The BC Cancer Registry (BCCR), a population-based provincial database, was used to identify all patients in BC diagnosed for the first time with a primary non-thyroid HNC and treated with radiotherapy between 2006 and 2011. Patients were categorized as residing in large, small and rural local health authorities (LHAs) using BC Stats and BC Ministry of Health information. Physician case frequency was defined as low (0-14 cases per year), medium (15-29 cases per year) and high (>30 cases per year).  There was no effect on OS or head and neck CSS when physician case frequency was treated as a continuous variable. Results: 2,330 HNC patients were included in the study. On multivariable analysis, after controlling for age, gender, cancer stage, anatomical site, treatment and physician case frequency, neither head and neck CSS (HNCSS) (HR range=0.86-1.03; p=0.54-0.99) nor OS (HR range=0.91-1.05; p=0.60-0.88) was significantly different by centre. OS was also not significantly different for patients treated by physicians with low case frequency (HR=0.96; 0.81-1.13; p=0.60) and medium case frequency (HR=1.12; 0.84-1.49; p=0.43) in reference to high case frequency.  iii  Conclusions: There was no significant difference in survival among BC cancer centres after controlling for differences in rurality, physician case volume and other potential confounding variables. This lack of difference may be in large part due to the centrally coordinated population-run program where radiation oncologists subspecialize, follow provincial guidelines, attend multidisciplinary rounds, have access to radiotherapy quality assurance, and are supported by a HNC tumor group. iv  Preface  This thesis is based on analysis of British Columbia Cancer Registry data. Chart review of cancer centre patient charts was performed by Mary McLay, Adrienne Stedford, Emily Yurkowski and Scott Matlock at the BC Cancer Agency Centre for the North. With substantial input and guidance from Dr. Robert Olson, Mary McLay conducted all statistical analyses and wrote the manuscript presented in this thesis. The research was approved by the joint University of British Columbia and BC Cancer Agency Research Ethics Board (certificate # H15-00651).                             v  Table of Contents 	Abstract .......................................................................................................................................... ii	Preface ........................................................................................................................................... iv Table of Contents .......................................................................................................................... v	List of Tables ................................................................................................................................ vi	List of Figures .............................................................................................................................. vii	List of Abbreviations .................................................................................................................. viii	Introduction ................................................................................................................................... 1	Materials and Methods ................................................................................................................. 3	Study Population ......................................................................................................................... 3	Statistical Methods ...................................................................................................................... 4	Results ............................................................................................................................................ 5	Clinical Characteristics ............................................................................................................... 5	Survival Analysis by Cancer Centre ........................................................................................... 7	Survival Analysis by LHA Population Size .............................................................................. 10	Survival Analysis by Physician Case Frequency ...................................................................... 13	Discussion ..................................................................................................................................... 16	Conclusions .................................................................................................................................. 20	References .................................................................................................................................... 21	 	 vi 	List of Tables 	Table 1. Patient, tumor and treatment characteristics by cancer centre .......................................... 6 Table 2. Multivariable analysis assessing the impact of patient, tumor and treatment characteristics on overall survival and head and neck cancer-specific survival ............................. 9 Table 3. Multivariable analysis assessing the impact of patient, tumor and treatment characteristics as well as LHA size on overall survival and head and neck cancer-specific survival .......................................................................................................................................... 12 Table 4. Multivariable analysis assessing the impact of patient, tumor and treatment characteristics on overall survival and head and neck cancer-specific survival, physician case frequency as continuous variable .................................................................................................. 15 	 	 		vii 	List of Figures  Figure 1. Kaplan-Meier estimate of overall survival by treatment centre .......................................... 7 Figure 2. Kaplan-Meier estimate of head and neck cancer-specific survival by treatment centre .. 8 Figure 3. Kaplan-Meier estimate of overall survival by local health area size ................................ 10 Figure 4. Kaplan-Meier estimate of head and neck cancer-specific survival by local health area size .............................................................................................................................................................. 11 Figure 5. Kaplan-Meier estimate of overall survival by physician case frequency ........................ 13 Figure 6. Kaplan-Meier estimate of head and neck cancer-specific survival by physician case frequency ................................................................................................................................................... 14                  viii  List of Abbreviations  BC   —  British Columbia  BCCA  — British Columbia Cancer Agency BCCR  — British Columbia Cancer Registry CAIS  — Cancer Agency Information System CSS   — Cancer-Specific Survival HN  — Head and Neck  HNC  — Head and Neck Cancer HNCSS — Head and Neck Cancer-Specific Survival HR  — Hazard Ratio IMRT  — Intensity Modulated Radiation Therapy  LHA  — Local Health Area MDT  — Multidisciplinary Team OS  — Overall Survival QA  — Quality Assurance RT  — Radiation Therapy  1  Introduction  Recent literature has suggested that higher volumes of practice are associated with better survival outcomes for head and neck cancer (HNC) patients [1-4]. Some limitations in these studies, however, include looking at the volume of practice on a cancer centre level (i.e. not a provider level) and not controlling for rurality of patient residence. Other studies have demonstrated worse outcomes for cancer patients residing in rural areas compared to urban areas [5-9]. It is therefore possible that differences found by volume of practice could alternately be associated with the rurality of patients, as large centres with large volumes predominantly see urban patients. Multiple previous studies have demonstrated that patients living in rural areas have lower socioeconomic status, higher rates of smoking status, and decreased access to health care, all of which could explain worse outcomes for these patients, rather than attributing it to the centre they received their radiotherapy.   A recent US study demonstrated that among patients treated with intensity modulated radiation therapy (IMRT), those treated by radiation oncologists with a higher practice volume had superior survival over those treated by radiation oncologists with a lower practice volume [10]. However, in the US as compared to Canada, it is more common for community radiation oncologists to practice as generalist radiation oncologists treating many, and in some cases all tumor sites without an affiliation with an academic centre [11, 12]. In other jurisdictions, such as British Columbia (BC), Canada, most radiation oncologists specialize in 1-3 tumors sites and have a strong relationship with academic centres within their province. This study therefore assessed whether the association found between practice volume and outcomes in the US was 2  transferrable to a Canadian population where radiation oncologists specialize more frequently and potentially have a larger support network.  The primary objective of this thesis was to evaluate the effect of treatment centre on the overall survival (OS) and cancer-specific survival (CSS) of HNC patients in BC between 2006 and 2011, while controlling for physician case volume and rurality. It was hypothesized that rurality and physician case volume would be associated with survival outcomes in BC, but after controlling for these and other potential confounding variables, there would be no significant difference in survival among cancer centres.               3  Materials and Methods Study Population   A retrospective cohort study was conducted using the BC Cancer Registry (BCCR), a population-based provincial database. All patients in BC newly diagnosed with a primary non-thyroid HNC and treated with radical radiotherapy between 2006 and 2011 were included. The BCCR automated dataset was supplemented with information from cancer centre patient charts using the BC Cancer Agency Information System (CAIS). A full chart review was not possible, as some patients were not referred to the BC Cancer Agency (BCCA). Patients with a prior history of HNC, a thyroid cancer, or those who only received palliative radiotherapy were excluded from the study.   The BCCA operated five regional cancer centres during the study period and provided all radiotherapy (RT) services. The province of BC was divided into 90 administrative local health areas (LHAs) using BC Stats and BC Ministry of Health information. Patients were categorized as residing in rural, small and large LHAs using this information and Canadian census data based on patients’ postal code, and outlined elsewhere [8]. An LHA was defined as rural if greater than 50% of its residents lived in a community of fewer than 10,000. A small LHA was defined by less than 50% of its population residing in communities of fewer than 10,000 and a large LHA if at least 95% of its population resided in communities over 100,000. Physician case frequency was defined as low (0-14 cases per year), medium (15-29 cases per year) and high (>30 cases per year), using similar divisions to the recent US study where the number of HNC patients treated per year (15 more and fewer) were compared to baseline [10]. 4  Statistical Methods   Descriptive statistics were performed on patient, tumor and treatment variables. The proportion of all radical courses of radiotherapy that were IMRT, by cancer centre, was calculated. Overall survival (OS) and head and neck cancer-specific survival (HNCSS) rates were estimated by the Kaplan-Meier method and survival curves. Survival was compared among different cancer centres, physician case frequencies, and LHA sizes using the log-rank test. Multivariable survival analyses were performed using Cox proportional hazard models to investigate centre and rurality differences in survival, while controlling for age, gender, cancer stage, anatomical site, treatment, including IMRT use, and physician case frequency. For survival analyses, time was calculated from date of diagnosis until death. If subjects were still alive at the end of the study period, the date of the last follow-up appointment was used for the censor time. If the last follow-up appointment was before December 31, 2014, the censor time was calculated as the time from diagnosis until December 31, 2014 since all Canadian deaths are accurate up to this date at the time of the analysis. All tests were two-sided, with a p-value less than or equal to 0.05 considered to be significant. Analyses were conducted using Statistical Package for Social Sciences software version 14.0 (SPSS, Chicago, IL).                                                                                                                                                                                                                                                                                              5  Results Clinical Characteristics  There were 2,330 patients diagnosed with HNC and treated with radiotherapy in BC between 2006 and 2011. Table 1 summarizes select patient, tumor and treatment characteristics based on cancer centre. There were significant differences in age, gender, stage, anatomical site and treatment utilization between centres (Table 1).                    6  Table 1. Patient, tumor and treatment characteristics by cancer centre                                                                                                                                  Cancer Centre                                                    Total P-value Characteristic  Vancouver (N=884) Abbotsford (N=87) Southern Interior  (N=398) Fraser Valley (N=464) Vancouver Island  (N=497)           N=2330  Median age at diagnosis in years (range)   66 (23-100) 68 (37-92) 69 (37-101) 67 (24-99) 69 (29-101) 68 (23-101) <0.001 Proportion male   639 (72%) 60 (69%) 317 (80%) 350 (75%) 376 (76%) 1742 (75%) 0.04 AJCC Staging 6th & 7th ed.  I  145 (16%)  8 (9%)  73 (18%)  74 (16%)  61 (12%)  361 (16%)  0.04  II 166 (19%) 13 (15%) 61 (15%) 83 (18%) 85 (17%) 408 (18%)   III 155 (18%) 18 (21%) 65 (16%) 85 (18%) 86 (17%) 409 (18%)   IVA 356 (40%) 35 (40%) 169 (43%) 184 (40%) 236 (48%) 980 (42%)   IVB 38 (4%) 8 (9%) 22 (6%) 26 (6%) 24 (5%) 118 (5%)   IVC 8 (1%) 1 (1%) 3 (1%) 3 (1%) 2 (<1%) 17 (1%)  Index HNC anatomical site  Nasal cavity and sinuses  33 (4%)  2 (2%)  12 (3%)  10 (2%)  11 (2%)  68 (3%)  <0.001  Oral cavity 210 (24%) 27 (31%) 91 (23%) 90 (19%) 118 (24%) 536 (23%)   Lip 4 (1%) 0  1 (<1%) 4 (1%) 10 (2%) 19 (1%)   Nasopharynx 146 (17%) 0  8 (2%) 27 (6%) 12 (2%) 193 (8%)   Oropharynx 214 (24%) 28 (32%) 108 (27%) 162 (35%) 203 (41%) 715 (31%)   Hypopharynx 35 (4%) 3 (3%) 25 (6%) 23 (5%) 27 (5%) 113 (5%)   Supraglottis 52 (6%) 11 (13%) 33 8%) 43 (9%) 38 (8%) 177 (8%)   Glottis 118 (13%) 8 (9%) 98 (25%) 77 (17%) 60 (12%) 361 (16%)   Subglottis 4 (1%) 0 1 (<1%) 2 (<1%) 2 (<1%) 9 (<1%)   Major salivary gland 67 (8%) 8 (9%) 20 (5%) 26 (6%) 16 (3%) 137 (6%)   Treatment  Radiotherapy alone  307 (35%)  30 (35%)  149 (37%)  196 (42%)  279 (56%)  961 (41%)  <0.001  Chemoradiotherapy  377 (43%) 35 (40%) 171 (43%) 160 (35%) 136 (27%) 879 (38%)   Surgery + adjuvant radiotherapy +/- chemotherapy  179 (20%)  22 (25%)  69 (17%)  101 (22%)  75 (15%)  446 (19%)    Radiotherapy + salvage surgery +/- chemotherapy 21 (2%) 0  9 (2%) 7 (2%) 7 (1%) 44 (2%)  Population size of LHA  Large  689 (78%)  53 (61%)  114 (29%)  418 (90%)  228 (46%)  1502 (65%)  <0.001  Small 95 (11%) 26 (30%) 137 (34%) 29 (6%) 235 (47%) 522 (22%)   Rural 100 (11%) 8 (9%) 147 (37%) 17 (4%) 34 (7%) 306 (13%)  7  Survival Analysis by Cancer Centre  There was no significant difference in OS or HNCSS between treatment centres after a median follow-up of 5.9 years, as shown in Figures 1 and Figure 2, respectively. The 5-year HNCSS for the Abbotsford, Fraser Valley, Southern Interior, Vancouver and Vancouver Island centres was 72%, 71%, 73%, 75% and 68%, respectively (p=0.54), while OS was 59%, 61%, 60%, 65% and 56%, respectively (p=0.06). Table 2 presents the multivariable analyses assessing the impact of treatment, physician case frequency, and other patient and tumor characteristics on survival. There was no significant difference in subjects from all five treatment centres in OS (HR range=0.91-1.05; p=0.60-0.88) or HNCSS (HR range=0.86-1.03; p=0.54-0.97).             Figure 1. Kaplan-Meier estimate of overall survival by treatment centre   8            Figure 2. Kaplan-Meier estimate of head and neck cancer-specific survival by treatment centre             9  Table 2. Multivariable analysis assessing the impact of patient, tumor and treatment characteristics on overall survival and head and neck cancer-specific survival  Characteristic   Head and Neck Cancer-Specific Survival Overall Survival   Hazard Ratio (95% CI) P-value Hazard Ratio  (95% CI) P-value Age (continuous yearly)  1.02 (1.01 – 1.03) <0.001 1.03 (1.03 – 1.04) <0.001 Gender Male 1 (reference)  1 (reference)   Female 0.91 (0.76  – 1.08) 0.28 0.89 (0.77 – 1.04)  0.14 IMRT use   0.02 0.95 (0.80 – 1.11) 0.50 Index HNC AJCC Stage I 1 (reference)  1 (reference)   II 1.60 (1.13 – 2.28) 0.01 1.76 (1.34 – 2.30) <0.001  III 2.45 (1.73 – 3.49) <0.001 2.52 (1.92 – 3.31) <0.001  IVA 3.17 (2.27 – 4.43) <0.001 2.81 (2.15 – 3.66) <0.001  IVB 6.50 (4.30 – 9.84) <0.001 5.80 (4.12 – 8.17) <0.001  IVC 9.45 (4.79 – 18.65) <0.001 7.05 (3.85 – 12.92) <0.001 Index HNC anatomical site  Oropharynx  1 (reference)   1 (reference)   Nasal Cavity and Sinuses 1.53 (0.98 – 2.36) 0.06 1.43 (0.98 – 2. 08) 0.06  Oral Cavity 2.33 (1.89 – 2.88) <0.001 1.94 (1.62 – 2.33) <0.001  Lip 0.99 (0.31 – 3.14) 0.98 0.82 (0.34 – 2.02) 0.67  Nasopharynx 1.20 (0.85 – 1.69) 0.31 1.02 (0.75 – 1.39) 0.89  Hypopharynx 2.67 (1.96– 3.64) <0.001 2.48 (1.92 – 3.21) <0.001  Supraglottis 2.01 (1.51 – 2.67) <0.001 1.98 (1.58 – 2.49) <0.001  Glottis 0.98 (0.69 – 1.38) 0.90 1.15 (0.89 – 1.49) 0.29  Subglottis 3.45 (1.26 – 9.46) 0.02 2.33 (0.95 – 5.73) 0.07  Major Salivary Gland 0.94 (0.60 – 1.46) 0.78 0.79 (0.54 – 1.16) 0.24 Treatment Radiotherapy alone 1 (reference)  1 (reference)   Radiotherapy + chemotherapy ± salvage surgery 0.73 (0.59– 0.89) 0.002 0.75 (0.63 – 0.89) 0.001  Surgery + radiotherapy  ± chemotherapy  0.85 (0.68 – 1.08) 0.19 0.82 (0.68 – 1.00) 0.05 Centre Vancouver  1 (reference)  1 (reference)   Abbotsford 0.86 (0.54 – 1.37)  0.97 0.91 (0.61 – 1.36) 0.65  Southern Interior 1.00 (0.75 – 1.33) 0.54 1.03 (0.81 – 1.30) 0.80  Fraser Valley 0.97 (0.77 – 1.23) 0.99 1.02 (0.83 – 1.24) 0.88  Vancouver Island 1.03 (0.82 – 1.29) 0.82 1.05 (0.87 – 1.28) 0.60 Physician Case Frequency (cases per year)   >30   1 (reference)     1 (reference)   15-29 1.14 (0.81 – 1.59) 0.46 1.12 (0.84 – 1.49) 0.43  0-14 0.94 (0.77 – 1.15) 0.54 0.96 (0.81 – 1.13) 0.60 10  Survival Analysis by LHA Population Size   Neither OS nor HNCSS were significantly different among subjects living in large, small and rural LHAs (Figures 3 and 4, respectively). The 5-year HNCSS survival for large, small and rural LHAs was 72%, 72% and 73%, respectively (p=0.62). The 5-year OS for large, small and rural LHAs was 62%, 59% and 61%, respectively (p=0.65). Multivariable analyses assessing the impact of patient, tumor and treatment characteristics on HNCSS and OS, using the population size of LHA instead of centre as a covariate, were also performed (Table 3). There was no significant difference in HNCSS of subjects from rural LHAs (HR=0.89; 0.68-1.16; p=0.38) or small LHAs (HR=1.10; 0.87-1.39; p=0.45) compared to subjects from large LHAs. Likewise, OS was not significantly different for subjects from rural LHAs (HR=0.97; 0.85-1.11; p=0.67) or small LHAs (HR=1.13; 0.86-1.47; p=0.38) compared to subjects from large LHAs.               Figure 3. Kaplan-Meier estimate of overall survival by local health area size  11             Figure 4. Kaplan-Meier estimate of head and neck cancer-specific survival by local health area size  12  Table 3. Multivariable analysis assessing the impact of patient, tumor and treatment characteristics as well as LHA size on overall survival and head and neck cancer-specific survival     Characteristic   Head and Neck Cancer-Specific Survival Overall Survival                                            Hazard Ratio  (95% CI) P-value Hazard Ratio  (95% CI) P-value Age (continuous yearly)  1.02 (1.01 – 1.03) <0.001 1.03 (1.03 – 1.04) <0.001 Gender Male 1 (reference)  1 (reference)   Female 0.92 (0.76  – 1.10) 0.33 0.89 (0.77  – 1.04) 0.13 Index HNC AJCC Stage I 1 (reference)  1 (reference)   II 1.66 (1.17 – 2.35) 0.01 1.77 (1.35 – 2.31) <0.001  III 2.57 (1.81 – 3.65) <0.001 2.56 (1.95 – 3.36) <0.001  IVA 3.39 (2.43 – 4.72) <0.001 2.86 (2.20 – 3.72) <0.001  IVB 6.99 (4.63 – 10.54) <0.001 5.90 (4.20 – 8.29) <0.001  IVC 9.37 (4.74 – 18.50) <0.001 7.01 (3.82 – 12.84) <0.001 Index HNC anatomical site Oropharynx 1 (reference)  1 (reference)   Oral Cavity 2.32 (1.88 – 2.86) <0.001 1.93 (1.61 – 2.31) <0.001  Lip 0.91 (0.29 – 2.89) 0.88 0.81 (0.33 – 1.99) 0.65  Nasopharynx 1.24 (0.89 – 1.74) 0.21 1.02 (0.75 – 1.37) 0.92  Nasal Cavity and Sinuses 1.59 (1.03 – 2.45) 0.04 1.43 (0.99 – 2.08) 0.06  Hypopharynx 2.62 (1.93 – 3.57) <0.001 2.45 (1.90 – 3.17) <0.001  Supraglottis 1.98 (1.49 – 2.63) <0.001 1.97 (1.56 – 2.47) <0.001  Glottis 0.91 (0.65 – 1.28) 0.58 1.12 (0.87 – 1.44) 0.37  Subglottis 3.08 (1.13 – 8.42) 0.03 2.25 (0.92 – 5.51) 0.08  Major Salivary Gland 0.91 (0.58 – 1.41) 0.66 0.78 (0.53 – 1.14) 0.19 Treatment Radiotherapy alone 1 (reference)  1 (reference)   Radiotherapy + chemotherapy ± salvage surgery 0.73 (0.60– 0.89) 0.002 0.74 (0.63 – 0.88) 0.001  Surgery + radiotherapy  ± chemotherapy  0.83 (0.66 – 1.05) 0.12 0.81 (0.67 – 0.98) 0.03 Population Size of LHA Large  1 (reference)  1 (reference)   Small  1.10 (0.87 – 1.39)  0.45 1.13 (0.86 – 1.47) 0.38  Rural  0.89 (0.68 – 1.16) 0.38 0.97 (0.85 – 1.11) 0.67 Physician Case Frequency (cases per year)   >30   1 (reference)   1 (reference)   15-29 1.16 (0.84 – 1.59) 0.38 1.01 (0.83 – 1.23) 0.91  0-14 0.96 (0.81 – 1.13) 0.59 0.96 (0.77 – 1.19) 0.72 13  Survival Analysis by Physician Case Frequency   A comparison of survival based on physician case frequency showed that OS (p=0.42) and HNCSS (p=0.76) were not significantly different for physicians with patient frequencies of 0-14, 15-29 or greater than 30 cases per year (Figures 5 and 6, respectively). On multivariable analysis, OS was not significantly different for patients treated by physicians with low case frequency (HR=0.96; 0.81-1.13; p=0.60) and middle case frequency (HR=1.12; 0.84-1.49; p=0.43) in reference to high case frequency (Table 2). HNCSS was also not significantly different for patients treated by physicians with low case frequency (HR=0.94; 0.77-1.15; p=0.54) and middle case frequency (HR=1.14; 0.81-1.59; p=0.46) in reference to high case frequency. There was no effect on OS or HNCSS when physician case frequency was treated as a continuous variable (Table 4).            Figure 5. Kaplan-Meier estimate of overall survival by physician case frequency 14              Figure 6. Kaplan-Meier estimate of head and neck cancer-specific survival by physician case frequency            15  Table 4. Multivariable analysis assessing the impact of patient, tumor and treatment characteristics on overall survival and head and neck cancer-specific survival, physician case frequency as continuous variableCharacteristic   Head and Neck Cancer-Specific Survival Overall Survival   Hazard Ratio (95% CI) P-value Hazard Ratio  (95% CI) P-value Age (continuous yearly)  1.02 (1.01 – 1.03) <0.001 1.03 (1.03 – 1.04) <0.001 Gender Male 1 (reference)  1 (reference)   Female 0.90 (0.75  – 1.08) 0.27 0.89 (0.76 – 1.04)  0.13 IMRT use  0.78 (0.64 – 0.95) 0.02 0.94 (0.80 – 1.11) 0.50 Index HNC AJCC Stage I 1 (reference)  1 (reference)   II 1.61 (1.13 – 2.28) 0.01 1.76 (1.35 – 2.30) <0.001  III 2.46 (1.73 – 3.49) <0.001 2.52 (1.92 – 3.31) <0.001  IVA 3.18 (2.27 – 4.44) <0.001 2.81 (2.15 – 3.67) <0.001  IVB 6.47 (4.28 – 9.79) <0.001 5.78 (4.10 – 8.15) <0.001  IVC 9.51 (4.82 – 18.77) <0.001 7.13 (3.89 – 13.06) <0.001 Index HNC anatomical site  Oropharynx  1 (reference)   1 (reference)   Nasal Cavity and Sinuses 1.54 (0.99 – 2.38) 0.05 1.44 (0.99 – 2. 09) 0.06  Oral Cavity 2.34 (1.89 – 2.89) <0.001 1.94 (1.62 – 2.33) <0.001  Lip 1.00 (0.31 – 3.17) 0.99 0.83 (0.34 – 2.03) 0.67  Nasopharynx 1.19 (0.84 – 1.68) 0.33 1.02 (0.75 – 1.39) 0.91  Hypopharynx 2.65 (1.94– 3.61) <0.001 2.46 (1.90 – 3.19) <0.001  Supraglottis 2.01 (1.52 – 2.68) <0.001 1.98 (1.58 – 2.49) <0.001  Glottis 0.98 (0.69 – 1.39) 0.91 1.15 (0.89 – 1.49) 0.29  Subglottis 3.42 (1.25 – 9.37) 0.02 2.29 (0.93 – 5.62) 0.07  Major Salivary Gland 0.95 (0.61 – 1.48) 0.82 0.80 (0.54 – 1.17) 0.25 Treatment Radiotherapy alone 1 (reference)  1 (reference)   Radiotherapy + chemotherapy ± salvage surgery 0.72 (0.59– 0.89) 0.002 0.75 (0.63 – 0.89) 0.001  Surgery + radiotherapy  ± chemotherapy  0.85 (0.67 – 1.08) 0.18 0.82 (0.67 – 0.99) 0.04 Centre Vancouver  1 (reference)  1 (reference)   Abbotsford 1.04 (0.76 – 1.41)  0.59 0.90 (0.61 – 1.34) 0.61  Southern Interior 0.97 (0.76 – 1.25) 0.81 1.03 (0.80 – 1.32) 0.84  Fraser Valley 0.96 (0.75 – 1.24) 0.84 1.03 (0.80 – 1.32) 0.96  Vancouver Island 1.00 (0.99 – 1.01) 0.77 1.04 (0.84 – 1.28) 0.73 Physician Case Frequency (continuous)     1.00 (0.99-1.01)  0.55    1.00 (0.99 – 1.01)  0.92 16  Discussion  The results of this population-based study suggest that overall survival and cancer-specific survival for patients with HNC and treated with radical radiotherapy do not differ significantly between the five cancer centres operating in BC, Canada, where the radiotherapy program is centrally coordinated and supported by a strong HNC tumor group. In addition, there was no association between rurality of patient residence nor physician case volume and survival in the cohort. These results differ from previous published studies that found higher volumes of practice are associated with better survival outcomes for HNC patients [1-4]. The findings in this thesis are also distinct from other studies showing cancer patients residing in urban areas [6, 7, 9] and treated by radiation oncologists with higher case frequency [2, 10] have superior outcomes.      It is hypothesized that the reason for the discrepancy between the results in BC and other published studies, with BC not seeing an association between centre volume and survival, is in large part due to the population-based provincial structure of the BCCA. In BC there is a coordinated tumor group and radiation oncologists typically specialize in treating 1-3 tumor sites. There are weekly provincial tumor board conferences where difficult patients are discussed in the presence of a multidisciplinary team (MDT) of radiologists, surgeons, pathologists, medical oncologists, radiation oncologists, and dietitians, and annual retreats where this MDT discusses challenges and future directions.  Most HNC patients are not treated with surgery, though head and neck surgeons operate near all cancer centres (except Northern BC) therefore minimizing referral of these patients to large centres such as Vancouver. There has also been a move to increase use of peer review quality assurance (QA) in radiotherapy planning in BC [13, 17  14]. Research has identified that QA of radiotherapy plans can improve the quality of the plan, and could potentially explain why outcomes in BC do not vary by volume of practice, or location of residence. However, without information on QA practices in the US, it is not possible to determine whether that explains the difference in the results in comparison to the US data published recently [13, 14]. Finally, and potentially most importantly, there are provincial systemic therapy and radiation oncology protocols that guide care at all BCCA centres. All of these factors may be responsible for the lack of difference in survival among centres that was observed.  The findings did not confirm an association between rurality and HNC outcomes within the BC population. It was hypothesized that there would be an association based on previous studies demonstrating worse outcomes for patients residing in rural areas compared to urban areas [6, 7, 9]. These studies have shown that patients living in rural areas have lower socioeconomic status, higher smoking rates, and decreased access to health care, all of which could explain worse outcomes. An association between rurality of patient residence and outcomes may not have been observed for several reasons. It is possible that a statistically significant difference in survival was not able to be detected among those living in rural versus urban areas due to the sample size. However, it is also a possibility that there is no association between rurality and HNC survival.   The findings suggest physician case volume was not associated with survival. This is in contrast to prior studies that showed superior outcomes for HNC patients treated by high-volume radiation oncologists compared to those treated by low-volume radiation oncologists [2, 10]. It was observed that patients treated by physicians with low case volume had no difference in 18  survival than those treated by medium or high case volumes. Ultra-low or high physician case volumes are not typically observed in BC as they may be in other jurisdictions. It is possible, therefore, that the volume of practice that exists in BC is too narrow to detect a difference between physician case volumes. Although it was not possible to test adequately if ultra-low volumes are detrimental to survival, it is hypothesized that the wider variability in other jurisdictions may explain why a relationship between volume of practice and outcomes was found in other studies.  IMRT use varied among the different centres and increased overall from 2006 to 2011 but there did not appear to be any association with survival outcomes. This is not surprising, given that during the study period the radiotherapy dose was consistent across BC, whether or not IMRT was used. It is anticipated that IMRT use is associated with less adverse events and better quality of life outcomes (such as less xerostomia, which was not captured with this study) rather than outcomes such as overall survival, and therefore the results are as expected [15, 16].  This study should be interpreted in the context of its strengths and limitations. As a population-based database, the BCCR captures all cases of cancer diagnosed to BC residents, including personal, demographic, diagnosis and death information. This information is relatively free from selection bias, and since most cancer patients in BC are treated at their regional cancer centre, referral bias is also minimized. The large sample size and data on provider-level rather than centre-level are additional strengths. However, as a retrospective review, the study is limited by the data already collected; several key patient demographics (e.g. marital status, comorbidities, HPV status, alcohol and smoking habits, and socioeconomic status) are not available. In 19  addition, although it is hypothesized that a difference in outcomes by physician volume was not found because of the strong support of the tumor group in a centrally run provincial radiotherapy program, without comparing these outcomes directly with a jurisdiction without this structure, this hypothesis cannot be tested. The study was also limited by short follow-up time and there may not be a large enough variation in physician volume to observe differences between volume categories.                 20  Conclusions  This population-based study demonstrates that there is no significant difference in HNC centre survival by BC cancer centre within a provincially run radiotherapy program supported by multiple functions of a provincial HN tumor group. Additionally, neither physician case volume nor rurality of patients was associated with survival outcomes. It is hypothesized that a lack of association between outcomes and centre size, physician case volume, or rurality of patient residence, may be secondary to a centrally coordinated population-run program in BC, where radiation oncologists subspecialize in 1-3 tumor sites, follow provincial guidelines, are supported by a strong tumor group, attend multidisciplinary rounds, and have access to provincial radiotherapy quality assurance. Future research should assess whether similar models exist in other jurisdictions that can improve outcomes for HNC patients who do not have access to high volume centres. Additional research should also evaluate whether ultra-low physician case volumes are associated with worse outcomes, since the cohort in this study could not assess this.       21  References 1. MacKillop W, Kong W, Zaza K, Owen T, Booth C. Volume of Practice and the Outcomes of Radiation Therapy for Head and Neck Cancer. International Journal of Radiation Oncology • Biology • Physics(1):S139. 2. Chien CR, Lin HW, Yang CH, et al. High case volume of radiation oncologists is associated with better survival of nasopharyngeal carcinoma patients treated with radiotherapy: a multifactorial cohort analysis. Clin Otolaryngol. 2011 Dec;36(6):558-65. 3. Corry J, Peters LJ, Rischin D. Impact of center size and experience on outcomes in head and neck cancer. J Clin Oncol. 2015 Jan 10;33(2):138-40. 4. Wuthrick EJ, Zhang Q, Machtay M, et al. Institutional clinical trial accrual volume and survival of patients with head and neck cancer. J Clin Oncol. 2015 Jan 10;33(2):156-64. 5. Loree JM, Javaheri KR, Lefresne SV, et al. Impact of Travel Distance and Urban-Rural Status on the Multidisciplinary Management of Rectal Cancer. The Journal of Rural Health. 2016:n/a,n/a. 6. Papa N, Lawrentschuk N, Muller D, et al. Rural residency and prostate cancer specific mortality: results from the Victorian Radical Prostatectomy Register. Aust N Z J Public Health. 2014;38(5):449-54. 7. Pozet A, Westeel V, Berion P, et al. Rurality and survival differences in lung cancer: A large population-based multivariate analysis. Lung Cancer. 2008 3;59(3):291-300. 8. Olson RA, Nichol A, Caron NR, et al. Effect of Community Population Size on Breast Cancer Screening, Stage Distribution, Treatment Use and Outcomes. Canadian Journal of Public Health / Revue Canadienne de Sante'e Publique. 2012;103(1):46-52. 9. Hallet J, Law CHL, Karanicolas PJ, Saskin R, Liu N, Singh S. Rural-urban disparities in incidence and outcomes of neuroendocrine tumors: A population-based analysis of 6271 cases. Cancer. 2015;121(13):2214-21. 10. Boero IJ, Paravati AJ, Xu B, et al. Importance of Radiation Oncologist Experience Among Patients With Head-and-Neck Cancer Treated With Intensity-Modulated Radiation Therapy. Journal of Clinical Oncology. 2016 March 01;34(7):684-90. 11. Lewis RS, Sunshine JH. Radiation Oncologists in the United States. International Journal of Radiation Oncology*Biology*Physics. 2007 10/1;69(2):518-27. 12. Smith GG, Thrall JH, Pentecost MJ, et al. Subspecialization in Radiology and Radiation Oncology. Journal of the American College of Radiology. 2009 3;6(3):147,159.e4. 22  13. Lo AC, Liu M, Chan E, et al. The impact of peer review of volume delineation in stereotactic body radiation therapy planning for primary lung cancer: a multicenter quality assurance study. J Thorac Oncol. 2014 Apr;9(4):527-33. 14. Lefresne S, Olivotto IA, Joe H, Blood PA, Olson RA. Impact of quality assurance rounds in a Canadian radiation therapy department. Int J Radiat Oncol Biol Phys. 2013 Mar 1;85(3):e117-21. 15. Ghosh-Laskar S, Yathiraj PH, Dutta D, et al. Prospective randomized controlled trial to compare 3-dimensional conformal radiotherapy to intensity-modulated radiotherapy in head and neck squamous cell carcinoma: Long-term results. Head Neck. 2015 Nov 11. 16. Song T, Fang M, Zhang XB, Zhang P, Xie RF, Wu SX. Sustained improvement of quality of life for nasopharyngeal carcinoma treated by intensity modulated radiation therapy in long-term survivors. Int J Clin Exp Med. 2015 Apr 15;8(4):5658-66.     

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