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Long-term time trends in incidence, survival and mortality of lymphomas by subtype among adults in Manitoba, Canada: a population-based study using cancer registry data

Objective To examine 30-year time trends in incidence, survival and mortality of lymphomas by subtype in Manitoba, Canada. Methods Lymphoma cases diagnosed between 1984 and 2013 were classified according to the 2008 WHO classification system for lymphoid neoplasms. Death data (1984–2014) were obtained from the Manitoba Vital Statistics Agency. To examine time trends in incidence and mortality, we used joinpoint regression to estimate annual percentage change and average annual percentage change. Age–period–cohort modelling was conducted to measure the effects of age, period and cohort on incidence and mortality time trends. We estimated age-specific and standardised 5-year relative survival and used Poisson regression model to test time trends in relative survival. Results Total Hodgkin lymphoma (HL) incidence in men and women was stable during the study period. Age-standardised total non-Hodgkin lymphoma (NHL) incidence increased by 4% annually until around 2000, and the trend varied by sex and NHL subtype. Total HL mortality continuously declined (by 2.5% annually in men and by 2.7% annually in women), while total NHL mortality increased (by 4.4% annually in men until 1998 and by 3.2% annually in women until 2001) and then declined (by 3.6% annually in men and by 2.5% annually in women). Age-standardised 5-year relative survival for HL improved from 72.6% in 1984–1993 to 85.8% in 2004–2013, and for NHL from 57.0% in 1984–1993 to 67.5% in 2004–2013. Survival improvement was also noted for NHL subtypes, although the extent varied, with the greatest improvement for follicular lymphoma (from 65.3% in 1984–1993 to 87.6% in 2004–2013). Conclusions Time trends were generally consistent with those reported in other jurisdictions in total HL and NHL incidence, but were unique in incidence for HL and for NHL subtypes chronic/small lymphocytic leukaemia/lymphoma, diffuse large B cell lymphoma and follicular lymphoma. Survival improvements and mortality reductions were seen for HL and NHL in both sexes.

Lymphomas as a group are one of the most common cancers, but the etiology for the two main 72 types, Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), and their subtypes remain 73 unclear. Overall NHL incidence increased for several decades in industrialized countries until the 74 late 1990s 1-4 and has since slightly declined. 2,5 HL incidence is relatively stable but temporal 75 trends are less consistent across countries. 6 Due to the changes in lymphoma detection, 76 diagnosis, and classification, one challenge in interpreting the time trends is distinguishing the 77 real changes in disease occurrence from artifacts caused by changes in these factors over time. 78 The evidence for etiologic heterogeneity among lymphoma subtypes 3,7-9 supports the importance 79 of examining time trends by subtype. 80 81 HL and NHL had different temporal trends in mortality in past decades. While HL mortality has 82 declined steadily since the 1960s, 2,10,11 NHL mortality increased prior to the mid-1990s but 83 declined thereafter. 2,11-13 Relative survival, defined as the ratio between the observed survival in 84 cancer patients and the expected survival of a comparable group from the general population 85 (assumed to be free of the cancer of interest 14 ), is increasingly used in population-based cancer 86 survival analysis. 15 Unlike cause-specific mortality, relative survival does not require 87 information on cause of death as it measures the excess mortality among cancer patients, 88 irrespective of whether the excess mortality is attributable to the cancer directly or indirectly 89 (e.g., deaths due to treatment complication or suicide). Previous relative survival analyses of 90 lymphoma patients have demonstrated improvement over time [16][17][18][19][20] although the extent of 91 improvement varies by patient socio-demographics (e.g., gender, age at diagnosis, 92 and 2013 (see Supplemental Table S1). Cancer diagnoses were originally coded using earlier 116 editions of the International Classification of Disease for Oncology (ICD-O) and were converted 117 to the 3rd edition (ICD-O-3). 25 The 2008 World Health Organization (WHO) classification of 118 lymphoid neoplasms was applied to classify patients according to disease subtype. 26 Other 119 patient characteristics including sex, birthday, date of diagnosis, and residential postal code at the 120 time of diagnosis were also obtained from the MCR. Household income quintile at diagnosis was 121 determined based on dissemination area level average household income derived from Canadian 122 Census data. 27 Manitoba population counts by age, sex, and year, which was used to calculate 123 incidence and mortality rates, were obtained from the Manitoba Health Insurance Registry. Vital 124 statistics data  were obtained from the Manitoba Vital Statistics Agency. Underlying 125 causes of death were coded using ICD-10 for deaths occurring since January 1, 2000 and using 126 ICD-8/9 for deaths prior to 2000 (Supplemental Table S2). This research has been approved by 127 and mortality rates, we performed age-period-cohort (APC) analyses using the Epi package for 147 R. 29 Instead of using fixed intervals (e.g., 5-year intervals), we fitted the models using 148 continuous variables for the age, period, and cohort through the use of restricted cubic spline 149 functions, as recommended by Carstensen. 29 Matrix transformations were made to the spline 150 basis vectors for the period and cohort effects, to overcome the well-known identifiability 151 problem in APC modelling. 29 We graphically present age-specific incidence/mortality rate after 152 adjusting for the effects of cohort and period. We used rate ratio to measure cohort and period 153 effects on the age-standardized rates. The cohort rate ratio, the ratio of incidence/mortality rate in 154 a given year of birth versus the rate in a reference cohort (i.e., the central 1931 birth cohort), 155 describes the relative risk after taking into account age and period effects; whereas the period 156 rate ratio is the ratio of incidence/mortality rate in a given year of diagnosis versus the rate in a We estimated 5-year relative survival, the ratio between observed survival of the lymphoma 161 patients and the expected survival of a comparable Canadian general population, using the period 162 analysis method. 30 Expected survival was estimated according to the Ederer method using 163 Canadian age-and sex-specific mortality by year obtained from the Human Mortality Database 164 (www.mortality.org). 31 Age-specific relative survival ratios were estimated for 3 age groups (20-165 54, 55-74, 75+ years) by time period (1984-1993, 1994-2003, 2004-2013) and age-standardized 166 relative survival ratios for each time period were calculated using international standard cancer 167 population. 32 Standard errors for relative survival were estimated using the Greenwood method 168 and 95% confidence intervals were derived using a logarithmic transformation. 33 (Table 4). In joinpoint analysis of HL mortality, AAPC was -232 2.5% (95% CI -4.6 ̶ -0.3%) in males and -2.7% (95% CI -5.0 ̶ -0.3%) in females. The time 233 trends in NHL mortality (Table 5) were different from that for HL: Total NHL mortality rates 234 increased by the end of 1990s in males (EPAC=4.4%, 95% CI 2.4 ̶ 6.3%) and in females 235 (EPAC=3.2%, 95% CI 0.9 ̶ 5.6%); and declined thereafter in both males (EAPC=-3.6%, 95% CI 236 -5.3 ̶ -1.9%) and females (EPAC=-2.5%, 95% CI -4.3 ̶ -0.8%). During the peak period (1995-

Relative survival 247
In both males and females, 5-year relative survival for total HL, total NHL, and NHL subtypes 248 decreased with age except for CLL/SLL (Table 6), but it was generally higher in females. 249 Changes in relative survival over time varied by sex, age group, and subtype. For HL, the oldest 250 group (75+ years) had the best improvement. For CLL/SLL in males, relative survival has been 251 stable over time in those aged 20-54 years, but significantly improved in the older people; while 252 in females relative survival declined over time for the youngest age group. For FL, relative 253  Differential period effects were found for HL and NHL and major subtypes (Supplemental Table  264 S3). Comparing to 1984-1993, relative excess mortality risk for HL in both sexes was similar in We found that total HL incidence was relatively stable between 1984 and 2013 while total NHL 273 incidence increased until around 2000 and then plateaued. While total HL mortality rate 274 continuously declined over time, total NHL mortality rate increased prior to the end of 1990s and 275 declined thereafter. On the other hand, relative survival improved for all lymphomas although 276 Previous studies have focused on time trends in total HL incidence and total NHL incidence and 281 there were geographical variations in the trends. 14 AAPC ranged from 1.3% to 6.1% for NHL 282 incidence and from -2.8% to 2.6% for HL incidence across European countries. 38 283 Average annual increases in NHL incidence for males and females in the present study were 284 greater than that in the Netherlands. 39 HL incidence in the present study has been relatively 285 stable, but it decreased in both males (-1.0% annually) and females (-1.8% annually) in the USA 286 during 2004-2013. 40 Little is known about the time trends in incidence of lymphoma subtypes. 287 This study found that time trends in incidence of certain subtypes were different from those 288 reported in previous studies. After a continuous increasing for two decades, CLL/SLL started to 289 decline in 2005. Similar decline was found in the USA between 2004 and 2013. 40 The reduction 290 in CLL/SLL incidence may be explained by the diagnosis change, i.e., individuals who would 291 have been classified as CLL/SLL were classified as monoclonal B-cell lymphocytosis (MBL) if the 292 absolute B-cell count was < 5 X 10 9 /L. 41 For DLBCL, the incidence continuously increased during 293 1984 and 2014 (by 4% annually in males and by 2.6% annually in females). The extent of the 294 increase was in the range of changes reported in other counties. 42 Different time trends were also 295 found for FL, i.e., there were no statistically changes in either sex in the present study, while in 296 the same time period FL incidence in the USA males and females declined by 2.1% annually. 40  Increased cancer incidence could be attributed to population aging, higher prevalence of risk 303 factors, better screening/diagnosis, or improved completeness of cancer registration. In the 304 present study, we found that aging and factors associated with birth cohort and diagnosis time 305 impacted NHL incidence trends. This confirmed the findings of several previous studies. Liu 306 and colleagues found statistically significant period effects on NHL incidence in both sexes, but 307 a cohort effect among females only. 45 Viel et al's analysis suggested that NHL incidence 308 increase in Doubs, France during 1980-2005 was mostly dependent on factors associated with 309 age and time period instead of cohort. 46 In Spain, factors related to age, cohort, and period 310 contributed to the NHL incidence increase during 1973-1991. 47 The cohort effect may due to 311 physical and social environmental changes, while the period effect might be partially explained 312 by improved diagnosis, classification, and case registration. Lymphoma classification has 313 experienced many changes and might have some impact on time trends of certain subtypes, but 314 the impact on total HL and total NHL might be very limited. 6,48 An earlier study in Manitoba 315 showed a large increase in CLL/SLL incidence during 1998-2003 that was largely related to the 316 introduction of flow cytometer testing but was also due to the misclassification of CD5 positive 317 chronic lymphoproliferative disorders as CLL/SLL. 49 The changes in diagnosis, registration, and 318 known risk factors might partially explain the incidence trends in this study, but the extent of the 319 influence was not quantified. Hartge and Devesa 50 found that improved accuracy and 320 completeness of diagnosis (i.e., less NHL cases were misdiagnosed as HL cases), HIV infection, 321  Lymphoma survival in Manitoba improved over time, but generally females had better survival 326 than males, which is consistent with previous findings. 17,51,52 Improvement was greater for older 327 HL patients (>=55 years) than in younger patients, on both absolute and relative measures (i.e., 328 absolute increase in relative survival and relative ratio for relative survival). This is consistent 329 with previous study findings. In Sweden, 5-year relative survival for HL patients aged 19-35 330 years increased from 72% in 1973-79 to 96% in 2001-09 (with an absolute increase 24% and a 331 relative increase ratio 1.3), but that for patients aged 66-80 years it increased from 18% to 44% 332 (with an absolute increase 26% but a relative increase ratio 2.4). 53 Another study showed that 333 HL patients aged 75+ years had a greater improvement, compared to those aged 65-74 years. 54 334 In this analysis, 5-year relative survival for NHL improved for all age groups expect in females 335 aged 20-54 years. During 1990-2004, 5-year relative survival for total NHL in USA improved 336 across all age groups (>15 years), but the greatest improvement was seen in males aged 15-44 337 years and females aged 75+ years. 55 Similar trends were observed in Western Europe for the 338 same time period, but in Central Europe there were no improvement in older patients. 55 In 339 Germany, a greater improvement in 5-year relative survival was observed in NHL patients aged 340 85+ years, compared to those aged 65-74 years. 54 341 342 Lymphoma treatment advances over the past 3 decades include the introduction of new 343 chemotherapy drugs and monoclonal antibodies (e.g., rituximab), autologous stem cell 344 cohort and period on HL mortality and NHL mortality. 63 The effects of cohort and period on 370 NHL mortality were also identified in the present study. Those effects are likely attributable to 371 the improvement in lymphoma treatment. Lead time bias associated with better diagnostic 372 techniques e.g. flow cytometer might has also played a role. 373 374

Combination of Incidence, Survival, and Mortality 375
The three measures are interrelated and mortality is determined by incidence and survival. It is 376 thus important to interpret all three measures in combination in order to interpret overall progress 377 in cancer prevention and control. Data from U.S. Surveillance, Epidemiology, and End Results 378 (SEER) program showed a continuous increase incidence of NHL during 1975-2011, but the 379 mortality started to decline in 1997. 40 This is also reflected in the present study (Table 7): female 380 NHL mortality started to decline in 1999 although incidence increased until 2001; while male 381 NHL mortality started to decline in 1998 although the incidence started to level off since that 382 year. The SEER data also showed that mortality declines for DLBCL, CLL/SLL, and FL started 383 before the decline in incidence, 61 indicating that the mortality reduction was most likely due to 384 improved survival after diagnosis. We were not able to test the time trends in mortality for NHL 385 subtypes as our data do not contain subtype-specific death cause information. 386 387

Strengths and Limitations 388
We conducted a comprehensive analysis of incidence, mortality, and survival using 30-year 389 cancer registry and vital statistics data. Compared to the unbiased Pohar Perme method, the age-390 Age-period-cohort effects were estimated based continues variables rather than commonly used 392 5-year or 10-year intervals. 30 We have tested the time trend in five-year age-standardized relative 393 survival using Poisson-regression based period analysis. 35,36 The analysis has a few limitations. 394 Reporting delay, 65 the time elapsed before a diagnosed cancer case is reported to a cancer 395 registry, was not used to adjust for incidence rate calculations as delay adjustment data are not 396 available for this population. The delay primarily affects the estimation of incidence rates in the 397 most recent 1 to 3 years (2011-2013 in this case) and the actual incidence rates in these years 398 might have been underestimated. There have been many changes to lymphoma subtype 399 classification and this might have influenced the trends in incidence of subtypes with low 400 classification reliability (e.g., T/NK-cell lymphoma). 66 Relative survival is widely used to 401 measure net survival, i.e., cancer survival in the absence of other causes of death. However, 402 approximately 50-70% of HL and 35% of NHL patients died of competing causes (i.e., cancers 403 other than lymphoma and diseases of circulatory system). 67, 68 We don't have data on treatment 404 modalities and most prognostic factors (e.g., clinical stage, serum LDH, and performance status). 405 As mentioned above, mortality rates were calculated for total HL and total NHL but subtypes. 406 Time trends in incidence and relative survival were examined for the four most common NHL 407 subtypes but not others. 408 409

Relative survival 243
In both males and females, 5-year relative survival for total HL, total NHL, and NHL subtypes 244 decreased with age except for CLL/SLL ( Previous studies have focused on time trends in total HL incidence and total NHL incidence and 277 there were geographical variations in the trends. 14 AAPC ranged from 1.3% to 6.1% for NHL 278 incidence and from -2.8% to 2.6% for HL incidence across European countries. 38 279 Average annual increases in NHL incidence for males and females in the present study were 280 greater than that in the Netherlands. 39 HL incidence in the present study has been relatively 281 stable, but it decreased in both males (-1.0% annually) and females (-1.8% annually) in the USA 282   Increased cancer incidence could be attributed to population aging, higher prevalence of risk 299 factors, better screening/diagnosis, or improved completeness of cancer registration. In the 300 present study, we found that aging and factors associated with birth cohort and diagnosis time 301 impacted NHL incidence trends. This confirmed the findings of several previous studies. Liu 302 and colleagues found statistically significant period effects on NHL incidence in both sexes, but 303 a cohort effect among females only. 45 Viel et al's analysis suggested that NHL incidence 304 increase in Doubs, France during 1980-2005 was mostly dependent on factors associated with 305 age and time period instead of cohort. 46 In Spain, factors related to age, cohort, and period 306 contributed to the NHL incidence increase during 1973-1991. 47 The cohort effect may due to 307 physical and social environmental changes, while the period effect might be partially explained 308 by improved diagnosis, classification, and case registration. Lymphoma classification has 309 experienced many changes and might have some impact on time trends of certain subtypes, but 310 the impact on total HL and total NHL might be very limited. 6,48 An earlier study in Manitoba 311 showed a large increase in CLL/SLL incidence during 1998-2003 that was largely related to the 312 introduction of flow cytometer testing but was also due to the misclassification of CD5 positive 313 chronic lymphoproliferative disorders as CLL/SLL. 49 The changes in diagnosis, registration, and 314 known risk factors might partially explain the incidence trends in this study, but the extent of the 315 influence was not quantified. Hartge  Diverse time trends in NHL mortality have been found worldwide, 59 but the trend (i.e., increased 361 between 1984 and late 1990s and declined thereafter) in Manitoba was similar to that observed in 362 USA, Japan, and Europe. 2,11,60-62 Our data suggested an effect of birth cohort on HL mortality 363 among those born prior to 1930s, but the result need to be interpreted with caution due to the 364 small number of HL death cases in the analysis. A study from Spain showed the effects on both 365 cohort and period on HL mortality and NHL mortality. 63 The effects of cohort and period on 366 NHL mortality were also identified in the present study. Those effects are likely attributable to 367   (Table 7): female 376 NHL mortality started to decline in 1999 although incidence increased until 2001; while male 377 NHL mortality started to decline in 1998 although the incidence started to level off since that 378 year. The SEER data also showed that mortality declines for DLBCL, CLL/SLL, and FL started 379 before the decline in incidence, 61 indicating that the mortality reduction was most likely due to 380 improved survival after diagnosis. We were not able to test the time trends in mortality for NHL 381 subtypes as our data do not contain subtype-specific death cause information. 382 383

Strengths and Limitations 384
We conducted a comprehensive analysis of incidence, mortality, and survival using 30-year 385 cancer registry and vital statistics data. Compared to the unbiased Pohar Perme method, the age-386 standardized Ederer II method generates a more precise estimate for a longer term follow-up. 64 387 Age-period-cohort effects were estimated based continues variables rather than commonly used 388 5-year or 10-year intervals. 30 We have tested the time trend in five-year age-standardized relative 389 survival using Poisson-regression based period analysis. 35,36 The analysis has a few limitations. 390  Reporting delay, 65 the time elapsed before a diagnosed cancer case is reported to a cancer 391 registry, was not used to adjust for incidence rate calculations as delay adjustment data are not 392 available for this population. The delay primarily affects the estimation of incidence rates in the 393 most recent 1 to 3 years (2011-2013 in this case) and the actual incidence rates in these years 394 might have been underestimated. There have been many changes to lymphoma subtype 395 classification and this might have influenced the trends in incidence of subtypes with low 396 classification reliability (e.g., T/NK-cell lymphoma). 66 Relative survival is widely used to 397 measure net survival, i.e., cancer survival in the absence of other causes of death. However, 398 approximately 50-70% of HL and 35% of NHL patients died of competing causes (i.e., cancers 399 other than lymphoma and diseases of circulatory system). 67,68 We don't have data on treatment 400 modalities and most prognostic factors (e.g., clinical stage, serum LDH, and performance status). 401 As mentioned above, mortality rates were calculated for total HL and total NHL but subtypes. 402 Time trends in incidence and relative survival were examined for the four most common NHL 403 subtypes but not others. 404 405

Relative survival 243
In both males and females, 5-year relative survival for total HL, total NHL, and NHL subtypes 244 decreased with age except for CLL/SLL (  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  Previous studies have focused on time trends in total HL incidence and total NHL incidence and 277 there were geographical variations in the trends. 14 AAPC ranged from 1.3% to 6.1% for NHL 278 incidence and from -2.8% to 2.6% for HL incidence across European countries. 38 279 Average annual increases in NHL incidence for males and females in the present study were 280 greater than that in the Netherlands. 39 HL incidence in the present study has been relatively 281 stable, but it decreased in both males (-1.0% annually) and females (-1.8% annually) in the USA 282 during 2004-2013. 40 Little is known about the time trends in incidence of lymphoma subtypes. 283 This study found that time trends in incidence of certain subtypes were different from those 284 reported in previous studies. After a continuous increasing for two decades, CLL/SLL started to 285 decline in 2005. Similar decline was found in the USA between 2004 and 2013. 40 The reduction 286 in CLL/SLL incidence may be explained by the diagnosis change, i.e., individuals who would 287 have been classified as CLL/SLL were classified as monoclonal B-cell lymphocytosis (MBL) if the 288 absolute B-cell count was < 5 X 10 9 /L. 41 For DLBCL, the incidence continuously increased during 289 1984 and 2014 (by 4% annually in males and by 2.6% annually in females). The extent of the 290 increase was in the range of changes reported in other counties. 42 Different time trends were also 291 found for FL, i.e., there were no statistically changes in either sex in the present study, while in 292 the same time period FL incidence in the USA males and females declined by 2.1% annually. 40 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  Increased cancer incidence could be attributed to population aging, higher prevalence of risk 299 factors, better screening/diagnosis, or improved completeness of cancer registration. In the 300 present study, we found that aging and factors associated with birth cohort and diagnosis time 301 impacted NHL incidence trends. This confirmed the findings of several previous studies. Liu 302 and colleagues found statistically significant period effects on NHL incidence in both sexes, but 303 a cohort effect among females only. 45 Viel et al's analysis suggested that NHL incidence 304 increase in Doubs, France during 1980-2005 was mostly dependent on factors associated with 305 age and time period instead of cohort. 46 In Spain, factors related to age, cohort, and period 306 contributed to the NHL incidence increase during 1973-1991. 47 The cohort effect may due to 307 physical and social environmental changes, while the period effect might be partially explained 308 by improved diagnosis, classification, and case registration. Lymphoma classification has 309 experienced many changes and might have some impact on time trends of certain subtypes, but 310 the impact on total HL and total NHL might be very limited. 6,48 An earlier study in Manitoba 311 showed a large increase in CLL/SLL incidence during 1998-2003 that was largely related to the 312 introduction of flow cytometer testing but was also due to the misclassification of CD5 positive 313 chronic lymphoproliferative disorders as CLL/SLL. 49 The changes in diagnosis, registration, and 314 known risk factors might partially explain the incidence trends in this study, but the extent of the 315 influence was not quantified. Hartge 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  The three measures are interrelated and mortality is determined by incidence and survival. It is 372 thus important to interpret all three measures in combination in order to interpret overall progress 373 in cancer prevention and control. Data from U.S. Surveillance, Epidemiology, and End Results 374 (SEER) program showed a continuous increase incidence of NHL during 1975-2011, but the 375 mortality started to decline in 1997. 40 This is also reflected in the present study (Table 7): female 376 NHL mortality started to decline in 1999 although incidence increased until 2001; while male 377 NHL mortality started to decline in 1998 although the incidence started to level off since that 378 year. The SEER data also showed that mortality declines for DLBCL, CLL/SLL, and FL started 379 before the decline in incidence, 61 indicating that the mortality reduction was most likely due to 380 improved survival after diagnosis. We were not able to test the time trends in mortality for NHL 381 subtypes as our data do not contain subtype-specific death cause information. 382 383

Strengths and Limitations 384
We conducted a comprehensive analysis of incidence, mortality, and survival using 30-year 385 cancer registry and vital statistics data. Compared to the unbiased Pohar Perme method, the age-386 standardized Ederer II method generates a more precise estimate for a longer term follow-up. 64 387 Age-period-cohort effects were estimated based continues variables rather than commonly used 388 5-year or 10-year intervals. 30 We have tested the time trend in five-year age-standardized relative 389 survival using Poisson-regression based period analysis. 35,36 Findings from this study, which is 390  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y based on a high-quality population-based cancer registration data, could be generalized to other 391 provinces in Canada and other areas with a similar socioeconomic development level and a 392 publicly funded healthcare system. the The analysis has a few limitations. Reporting delay, 65 the 393 time elapsed before a diagnosed cancer case is reported to a cancer registry, was not used to 394 adjust for incidence rate calculations as delay adjustment data are not available for this 395 population. The delay primarily affects the estimation of incidence rates in the most recent 1 to 3 396 years (2011-2013 in this case) and the actual incidence rates in these years might have been 397 underestimated. There have been many changes to lymphoma subtype classification and this 398 might have influenced the trends in incidence of subtypes with low classification reliability (e.g., 399 T/NK-cell lymphoma). 66 Relative survival is widely used to measure net survival, i.e., cancer 400 survival in the absence of other causes of death. However, approximately 50-70% of HL and 401 35% of NHL patients died of competing causes (i.e., cancers other than lymphoma and diseases 402 of circulatory system). 67,68 We don't have data on treatment modalities and most prognostic 403 factors (e.g., clinical stage, serum LDH, and performance status). As mentioned above, mortality 404 rates were calculated for total HL and total NHL but subtypes. Time trends in incidence and 405 relative survival were examined for the four most common NHL subtypes but not others. 406 407