Cancer survival statistics for patients and healthcare professionals - a tutorial of real-world data analysis.

Monitoring survival of cancer patients using data collected by population-based cancer registries is an important component of cancer control. In this setting, patient survival is often summarized using net survival, that is survival from cancer if there were no other possible causes of death. Although net survival is the gold standard for comparing survival between groups or over time, it is less relevant for understanding the anticipated real-world prognosis of patients. In this review, we explain statistical concepts targeted towards patients, clinicians and healthcare professionals that summarize cancer patient survival under the assumption that other causes of death exist. Specifically, we explain the appropriate use, interpretation and assumptions behind statistical methods for competing risks, loss in life expectancy due to cancer and conditional survival. These concepts are relevant when producing statistics for risk communication between physicians and patients, planning for use of healthcare resources, or other applications when consideration of both cancer outcomes and the competing risks of death is required. To reinforce the concepts, we use Swedish population-based data of patients diagnosed with cancer of the breast, prostate, colon and chronic myeloid leukaemia. We conclude that when choosing between summary measures of survival it is critical to characterize the purpose of the study and to determine the nature of the hypothesis under investigation. The choice of terminology and style of reporting should be carefully adapted to the target audience and may range from summaries for specialist readers of scientific publications to interactive online tools aimed towards lay persons.

Myocardial infarction in diffuse large B-cell lymphoma patients - a population-based matched cohort study.

BACKGROUND: The outcome for diffuse large B-cell lymphoma (DLBCL) patients has improved with the immunochemotherapy combination R-CHOP. An increased rate of heart failure is well documented following this treatment, whereas incidence and outcome of other cardiac complications, for example myocardial infarction, are less well known. METHOD: We identified 3548 curatively treated DLBCL patients in Sweden diagnosed between 2007 and 2014, and 35474 matched lymphoma-free general population comparators. The incidence, characteristics and outcome of acute myocardial infarctions (AMIs) were assessed using population-based registers up to 11 years after diagnosis. The rate of AMI was estimated using flexible parametric models. RESULTS: Overall, a 33% excess rate of AMI was observed among DLBCL patients compared with the general population (HR: 1.33, 95% CI: 1.14-1.55). The excess rate was highest during the first year after diagnosis and diminished after 2 years. High age, male sex and comorbidity were the strongest risk factors for AMI. Older patients (>70 years) with mild comorbidities (i.e. hypertension or diabetes) had a 61% higher AMI rate than comparators (HR: 1.61, 95% CI: 1.10-2.35), whereas the corresponding excess rate was 28% for patients with severe comorbidities (HR: 1.28, 95% CI: 1.01-1.64). Among younger patients (≤70), a short-term excess rate of AMI was limited to those with severe comorbidities. There was no difference in AMI characteristics, pharmacological treatment or 30-day survival among patients and comparators. CONCLUSION: DLBCL patients have an increased risk of AMI, especially during the first 2 years, which calls for improved cardiac monitoring guided by age and comorbidities. Importantly, DLBCL was not associated with differential AMI management or survival.

Impact of modern systemic therapies and clinical markers on treatment outcome for metastatic melanoma in a real-world setting.

BACKGROUND: The survival in metastatic melanoma has dramatically improved after the introduction of immune checkpoint- (ICIs) and MAPKinase inhibitors (MAPKis). OBJECTIVE: Our aim was to describe therapy response and survival in a real-world population as well as to assess the associations between clinical variables and therapy outcome for patients with metastatic melanoma receiving first-line ICIs or MAPKis. METHODS: A total of 252 patients with metastatic (stage IV) melanoma were prospectively followed between 1 January 2010 and 3 December 2017 with follow-up until 31 March 2019, at the Karolinska University Hospital, Sweden. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were analysed with Cox regression, and logistic regression was used to estimate odds ratios (ORs) for therapy response. RESULTS: Patients receiving ICIs (n = 138) experienced longer PFS compared to patients that received MAPKis (n = 114; median PFS for ICIs was 6.8 months, and median PFS for MAPKis was 5.3 months). In the multivariable analyses of clinical markers, increasing M-stage (OR 0.65; 95% CI 0.45-0.94; P = 0.022) and male sex (OR 0.41; 95% CI 0.19-0.90; P = 0.027) were significantly associated with lower response to ICIs. Lower baseline albumin levels (OR 0.90; 95% CI 0.83-0.98; P = 0.019) and male sex (OR 0.33; 95% CI 0.12-0.93; P = 0.036) were related with lower response to MAPKis. For ICIs, increasing M-stage (HR 1.34; 95% CI 1.07-1.68; P = 0.010), increasing LDH (HR 1.73; 95% CI 1.19-2.50; P = 0.004) and decreasing albumin (HR 1.06; 95% CI 1.01-1.10; P = 0.011) were significantly associated lower PFS in the adjusted model. The corresponding markers for MAPKis were increasing LDH (HR 1.44; 95% CI 1.08-1.92; P = 0.013) and decreasing albumin (HR 1.05; 95% CI 1.02-1.09; P = 0.005) for PFS. CONCLUSION: ICIs and MAPKis were effective in this real-world population, and we could confirm the importance of previously reported clinical prognostic markers. Albumin values may be associated with therapy outcome but need further validation.

Family history of colorectal cancer and survival: a Swedish population-based study.

OBJECTIVES: A family history of colorectal cancer (CRC) is an established risk factor for developing CRC, whilst the impact of family history on prognosis is unclear. The present study assessed the association between family history and prognosis and, based on current evidence, explored whether this association was modified by age at diagnosis. METHODS: Using data from the Swedish Colorectal Cancer Registry (SCRCR) linked with the Multigeneration Register and the National Cancer Register, we identified 31 801 patients with a CRC diagnosed between 2007 and 2016. The SCRCR is a clinically rich database which includes information on the cancer stage, grade, location, treatment, complications and postoperative follow-up. RESULTS: We estimated excess mortality rate ratios (EMRR) for relative survival and hazard ratios (HR) for disease-free survival with 95% confidence intervals (CIs) using flexible parametric models. We found no association between family history and relative survival (EMRR = 0.96, 95% CIs: 0.89-1.03, P = 0.21) or disease-free survival (HR = 0.98, 95% CIs: 0.91-1.06, P = 0.64). However, age was found to modify the impact of family history on prognosis. Young patients (<50 at diagnosis) with a positive family history had less advanced (i.e. stages I and II) cancers than those with no family history (OR = 0.71, 95% CI: 0.56-0.89, P = 0.004) and lower excess mortality even after adjusting for cancer stage (EMMR = 0.63, 95% CIs: 0.47-0.84, P = 0.002). CONCLUSIONS: Our results suggest that young individuals with a family history of CRC may have greater health awareness, attend opportunistic screening and adopt lifestyle changes, leading to earlier diagnosis and better prognosis.

Population-based study of patients with primary Sjögren's syndrome and lymphoma: lymphoma subtypes, clinical characteristics, and gender differences.

Objective: To examine lymphoma subtypes, clinical characteristics, and gender differences in patients with primary Sjögren's syndrome (pSS) and lymphoma in a population-based setting.Method: Patients with Sjögren's syndrome and lymphoma diagnoses were identified by linkage of the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007. Clinical data were collected from medical records and lymphoma tissues were re-examined. The lymphoma subtype distribution was compared with the Swedish Lymphoma Register.Results: We identified 105 pSS patients with lymphoma. Diffuse large B-cell lymphoma (DLBCL) (32%) and marginal zone lymphoma [MZL including mucosa-associated lymphoid tissue (MALT) lymphoma] (31%) were the most common lymphoma subtypes. The proportion of DLBCL was not increased compared to the general population reference (32%, p = 1), in contrast to MZL (general population 5%, p < 0.0001). Compared to DLBCL, MALT lymphoma was diagnosed at a younger age (55 vs 67 years, p = 0.0001), and earlier after patient-reported sicca onset (7 vs 18 years, p = 0.0001) and pSS diagnosis (2 vs 9 years, p = 0.0005). Sixteen of the pSS-lymphoma cases were men (15%), twice the proportion in general pSS populations. Compared to women, men had a shorter median time from pSS diagnosis to lymphoma diagnosis (1 vs 8 years, p = 0.0003) and more often had lymphoma in the salivary glands (56% vs 29%, p = 0.04).Conclusion: DLBCL and MZL are common in pSS patients, but only MZL/MALT lymphoma occurs at an increased relative frequency in pSS compared to the general population. The study supports increased awareness of signs of lymphoma in men in the first years after pSS diagnosis.

Impact of comorbidity on disease characteristics, treatment intent and outcome in diffuse large B-cell lymphoma: a Swedish lymphoma register study.

BACKGROUND: Comorbidity impacts overall survival amongst patients with diffuse large B-cell lymphoma (DLBCL). However, associations of comorbidity with lymphoma characteristics, treatment selection and lymphoma-specific mortality are less well known. OBJECTIVE: To examine the impact of comorbidity on DLBCL characteristics, treatment intent and cause of death. METHODS: We identified 3905 adult patients diagnosed with DLBCL 2007-2013 through the Swedish Lymphoma Register. We assessed comorbid disease history according to the Charlson comorbidity index (CCI). Comorbidity data and causes of death were collected through register linkage. Associations were estimated using multinomial regression and flexible parametric survival models. RESULTS: Overall, 45% of the patients (n = 1737) had a history of at least one comorbidity at DLBCL diagnosis (cardiovascular disease, diabetes and solid cancer were most frequent), and 997 (26%) had a CCI score of ≥2. The relative probability of presenting with poor performance status (PS > 2) was higher amongst comorbid patients [Relative Risk Ratio (RRR)PS>2 : 2.02, 95% CI: 1.63-2.51]. Comorbid patients had a substantially lower relative probability of receiving curative treatment (RRR: 0.48, 95% CI: 0.38-0.61). Amongst all patients, CCI ≥ 1 was associated with a significantly increased risk of all-cause and lymphoma-specific death after adjustments. Amongst patients selected for curative treatment, comorbidity was associated with an increased risk of all-cause death (HRCCI>1 : 1.54, 95% CI: 1.32-1.80), but not with lymphoma-specific death (HRCCI>1 : 1.05, 95% CI: 0.86-1.28). CONCLUSION: Comorbidity is associated with inferior DLBCL outcome, mainly due to a lower likelihood of receiving treatment with curative intent. Possibly, more comorbid DLBCL patients could be treated with curative intent if comorbid conditions were optimized in parallel.

Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome.

OBJECTIVE: In the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome (pSS), pre-existing lymphoma is not an exclusion criterion for pSS diagnosis, as in earlier criteria. We aimed to explore whether there are differences between pSS patients with and without pre-existing lymphoma at pSS diagnosis. METHOD: Patients with ICD-7-10 codes for Sjögren's syndrome (SS) and a diagnosis of malignant lymphoma before or after SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n = 224). Clinical data were collected from medical records. Lymphoma diagnoses were evaluated by tissue review. Characteristics of pSS patients with and without pre-existing lymphoma were compared. RESULTS: We identified 107 patients with pSS as the reason for an SS diagnosis code and a verified lymphoma. Of these, 18 (17%) had a pre-existing lymphoma at pSS diagnosis, defined as lymphoma diagnosed before or within 6 months of pSS diagnosis. Male gender (39% vs 10%, p = 0.006), enlarged lymph nodes during the pSS disease (61% vs 27%, p = 0.01), mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs 22%, p = 0.02), and salivary gland lymphoma (61% vs 26%, p = 0.006) were more common in patients with a pre-existing lymphoma at pSS diagnosis. Other pSS characteristics were similar. CONCLUSION: In a substantial proportion of patients, particularly in men, pSS remains undiagnosed until after lymphoma diagnosis. The study highlights the importance of pSS investigation in patients with lymphoma, especially MALT lymphoma, in the salivary glands.

Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma. There is no biomarker to indicate future lymphoma risk in RA and it is not known whether factors associated with an increased risk of RA also confer an increased risk of lymphoma. We investigated whether anti-cyclic citrullinated peptide (CCP) antibodies, other autoantibodies, and smoking, are associated with lymphoma development in RA. METHOD: From two population-based case-control studies, the Scandinavian Lymphoma Etiology (SCALE) study and the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) I study, we identified lymphoma cases with a validated RA diagnosis (n = 50), to whom we matched study participants with RA but no lymphoma (n = 261), lymphoma but no RA (n = 257), and neither RA nor lymphoma (n = 233). Lymphomas were classified according to the WHO classification. Blood samples were analysed for immunoglobulin G (IgG), IgM, and IgA isotypes and IgG1-4 subclasses of anti-CCP antibodies and for 15 antinuclear antibody (ANA)-associated specific autoantibodies. Relative risks were estimated as crude and adjusted odds ratios (adjOR) with 95% confidence intervals (CIs) using logistic regression. RESULTS: We found no association between anti-CCP IgG ≥ 25 units/mL (adjOR 1.4, 95% CI 0.7-2.7), anti-CCP IgG ≥ 500 units/mL (adjOR 1.4, 95% CI 0.7-3.0), anti-CCP Ig of other isotypes, other autoantibodies (adjOR any vs none 0.6, 95% CI 0.3-1.2), or cigarette smoking (adjOR ever vs never 1.1, 95% CI 0.5-2.2) and lymphoma risk among patients with RA. CONCLUSION: In this study, neither anti-CCP antibodies (IgG, IgG1-4, IgM, or IgA), nor other common autoantibodies, nor smoking predicted lymphoma risk in RA.

The aetiology of B-cell lymphoid malignancies with a focus on chronic inflammation and infections.

B-cell malignancies are a heterogeneous group of lymphoproliferative disorders with different molecular characteristics and clinical course. It is increasingly recognized that the group displays considerable heterogeneity also regarding aetiologic factors. Here, we summarize the latest developments in the aetiology of B-cell lymphoid malignancy subtypes focusing on immune perturbation. Severe immune suppression constitutes a strong and well-established risk factor for aggressive subtypes (e.g. diffuse large B-cell and Burkitt lymphoma), but appears unrelated to risk of common low-grade subtypes (e.g. follicular and mantle cell lymphoma). Inflammation and infections are known co-factors amongst the immunosuppressed; however, immune stimulation is now recognized as a crucial determinant of lymphomagenesis also amongst immunocompetent individuals. This is best exemplified in marginal zone lymphomas where local chronic inflammation and infection in the stomach, ocular adnexa and salivary glands have been directly linked with the development of oligoclonal and monoclonal malignant B-cell populations. Aggressive subtypes (e.g. diffuse large B-cell lymphoma) are increasingly linked with features of systemic immune stimulation including autoimmune/inflammatory disease and subclinical cytokine elevations. Lifestyle factors (e.g. high body mass index, cigarette smoking) are associated with risk of diffuse large B-cell and follicular lymphoma, respectively, possibly mediated through inflammation. Recent genome-wide association studies further underline the importance of immune function by linking several subtypes to variations in the human leucocyte antigen (HLA) class genes. In the future, improved knowledge of mechanistic pathways of inflammation/infections in lymphoma development may translate to active measures of prevention or treatment, as is already the case for some low-grade lymphoma subtypes.

Risk of second primary cancer in patients treated with radiotherapy for rectal cancer.

BACKGROUND: Many patients with rectal cancer receive radiotherapy (RT) to reduce the risk of local recurrence. Radiation may give rise to adverse effects, including second primary cancers. In view of the divergent results of previous studies, the present study evaluated the risk of second primary cancer following RT in all randomized RT rectal cancer trials conducted in Sweden and in the Swedish ColoRectal Cancer Registry (SCRCR). METHODS: Patients included in five randomized trials and the SCRCR were linked to the Swedish Cancer Registry. Cox regression models estimated the hazard ratio (HR) of second primary cancer among patients who received RT compared with those who did not. RESULTS: A total of 13 457 patients were included in this study; 7024 (52·2 per cent) received RT and 6433 (47·8 per cent) had surgery alone. Overall, no increased risk of second primary cancer was observed with RT (HR 1·03; 95 per cent c.i. 0·92 to 1·15), independently of follow-up time and location within or outside of the irradiated volume. In the randomized trials, with longer follow-up (maximum 31 years), a slight increase was observed outside of (HR 1·33, 1·01 to 1·74) but not within (HR 1·11, 0·73 to 1·67) the irradiated volume. Irradiated men had a lower risk of prostate cancer than those treated with surgery alone (HR 0·68, 0·51 to 0·91). CONCLUSION: Overall, there was no increased risk of second primary cancer following RT for rectal cancer within or outside of the irradiated volume up to 20 years of follow-up. Men with rectal cancer who received RT had a reduced risk of prostate cancer.

Prevalence of paediatric inflammatory bowel disease in Sweden: a nationwide population-based register study.

BACKGROUND: We evaluated the impact of different case definition algorithms on the prevalence of paediatric inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) and to compare the occurrence of certain diseases compared to matched controls. METHODS: Paediatric patients (<18 years) were identified via ICD codes for UC and CD in Swedish registers between 1993 and 2010 (n = 1432). Prevalence was defined as ≥2 IBD-related visits. Prevalence of treated children in 2010 was defined as ≥2 IBD-related visits with one visit and ≥1 dispensed IBD-related drug prescription in 2010. To test the robustness of the estimates, prevalence was also calculated according to alternative case definitions. The presence of rheumatic, hepatobiliary, pancreatic, and dermatologic diseases were compared with age-/sex-/county-of-residence-matched general population controls. RESULTS: The IBD prevalence was 75/100,000 (CD: 29/100,000; UC: 30/100,000; patients with IBD-U: 16/100,000). Prevalence of treated disease in 2010 was 62/100,000 (CD: 23/100,000; UC: 25/100,000; patients with IBD-U: 13/100,000). When age restrictions were employed, the prevalence estimate decreased (<17y: 61/100,000, <16y: 49/100,000 and <15y: 38/100,000). Compared to general population controls (n = 8583), children with IBD had a higher prevalence of dermatologic (4.7% vs. 0.6%), hepatobiliary (including primary sclerosing cholangitis) (5.5% vs. 0.1%), pancreatic (1.7% vs. 0%) and rheumatic diseases (7.2% vs. 1.2%; all P < 0.01). CONCLUSIONS: The overall prevalence of paediatric IBD in Sweden was similar to that in earlier regional cohorts. IBD patients had a higher prevalence of comorbid conditions than matched general population controls.

Risk of basal cell carcinoma in Swedish organ transplant recipients: a population-based study.

BACKGROUND: Risk of basal cell carcinoma (BCC) has been reported to be several-fold increased among organ transplant recipients (OTRs). However, due to lack of reliable BCC registration, population-based risk estimates are scarce. OBJECTIVES: To characterize risk of BCC among OTRs compared with the general population, and contrast with risk of cutaneous squamous cell carcinoma (SCC). SUBJECTS AND METHODS: OTRs transplanted during 2004-2011 were identified through national healthcare registers and linked with the nationwide Swedish BCC Register initialized in 2004. Relative risk of BCC was expressed as standardized incidence ratios (SIR) with 95% confidence intervals (CI). RESULTS: Altogether, 4023 transplanted patients developed 341 BCCs during follow-up. Compared with the general population, the relative risk of BCC was increased sixfold (SIR 6·1, 95% CI 5·4-6·9). The risk was higher in kidney and heart/lung than in liver recipients (SIRkidney 7·2, 6·3-8·3; SIRheart/lung 5·8, 4·0-8·2; SIRliver 2·6, 1·7-4·0), and risk increased with time since transplantation (Ptrend < 0·01). The SCC to BCC ratio was 1 : 1·7 and BCC developed earlier after transplantation than SCC. Distribution of anatomical sites and histological types did not differ substantially between OTR- and population-BCCs. CONCLUSIONS: Risk of BCC was strikingly elevated in OTRs compared with the general population. Risk was higher in kidney recipients and increased with follow-up time. These findings support a tumour-promoting effect of immunosuppressive drugs in BCC development. The low SCC to BCC ratio was possibly attributed to short follow-up time.

Risk of disability pension in patients following rectal cancer treatment and surgery.

BACKGROUND: Aspects of survivorship, such as long-term ability to work, are increasingly relevant owing to the improved survival of patients with rectal cancer. The aim of this study was to assess risk and determinants of disability pension (DP) in this patient group. METHODS: Using Swedish national clinical and population-based registers, patients with stage I-III rectal cancer aged 18-61 years in 1995-2009 were identified at diagnosis and matched with population comparators. Prospectively registered records of DP during follow-up were retrieved up to 2013. Non-proportional and proportional hazards models were used to estimate the incidence rate ratio (IRR) for DP annually and overall. Potential variations in risk by demographic and clinical factors were calculated, with relapse as a time-varying exposure. RESULTS: A total of 2815 patients were identified and compared with 13 465 population comparators. During a median follow-up of 6·0 (range 0-10) years, 23·3 per cent of the relapse-free patients and 10·3 per cent of the population comparators received DP (IRR 2·40, 95 per cent c.i. 2·17 to 2·65). An increased annual risk of DP was evident almost every year until the tenth year of follow-up. Abdominoperineal resection was associated with an increased DP risk compared with anterior resection (IRR 1·44, 1·19 to 1·75). Surgical complications (IRR 1·33, 1·10 to 1·62) and reoperation (IRR 1·42, 1·09 to 1·84), but not radiotherapy or chemotherapy, were associated with risk of DP. CONCLUSION: Relapse-free patients with rectal cancer of working age are at risk of disability pension.

Probability, rate and timing of reconstructive surgery following colectomy for inflammatory bowel disease in Sweden: a population-based cohort study.

AIM: Many patients with inflammatory bowel disease (IBD) need colectomy, but the rate of reconstructive surgery with restoration of intestinal continuity is unknown. The aim of this study was to investigate the probability, rate and timing of reconstructive surgery after colectomy in patients with IBD in a population-based setting. METHOD: The study cohort included all patients with IBD in Sweden who underwent colectomy from 2000 to 2009. Each patient was followed from admission for colectomy to admission for reconstructive surgery, date of death, migration or 31 December 2010. Kaplan-Meier survival curves and multivariable Poisson regression models were used to describe the probability, rate and timing of reconstructive surgery. RESULTS: Out of 2818 IBD patients treated with colectomy, 61.0% were male and 78.9% had ulcerative colitis. No reconstructive surgery had been performed in 1595 (56.6%) patients by the end of follow-up. Of the remaining 1223 patients, 526 underwent primary reconstructive surgery and 697 had a secondary reconstruction following a median interval of 357 days from primary surgery in the form of colectomy. The probability of reconstructive surgery was dependent on age (55.6% and 18.1% at ages 15-29 and ≥ 59 years, respectively), and the chance of reconstructive surgery was higher in hospitals that performed more than 13 colectomies for IBD per year [incidence rate ratio and 95% confidence interval 1.27 (1.09-1.49)]. CONCLUSION: Fewer than half of the patients having a colectomy for IBD underwent subsequent reconstructive surgery. Older age and low hospital volume were risk factors for no reconstructive surgery.