To Örebro University

Background: While Real-world Evidence (RWE) has documented value for safety monitoring and disease epidemiology, its objective contribution to safety and efficacy evaluations for regulatory purposes is still unclear. Here, we aim to describe the prevalence and type of RWE considered by European Medicines Agency (EMA) as contribution to efficacy and safety-related evidence generation among approved oncology targeted therapies...

Methods: On March 10, 2023, we screened the medicines listing of EMA to identify all anti-cancer targeted therapies for solid malignancies with a decision date (initial marketing authorizations and extension of indications) between 2018-2022. We screened the European public assessment reports (EPARs) using a standardized approach to collect data on RWE. When generated pre-authorization, the RWE contribution to the final regulatory decision was classified as definitive, supportive, or non-supportive. For...

Results: Out of a total of 1976 medicines, we identified 55 oncology targeted therapies, corresponding to 75 EPARs (indications), which are described in the table. The use of RWE in regulatory deliberations occurred in 24/75 (32%) EPARs, increasing from 30% in 2018-2020, to 34% in 2021-2022. Pre-authorization RWE was described in 20/24 (83%) EPARs, among which none were definitive, 8 RWE studies (in 7 EPARs) non-supportive, and 20 RWE studies (in 15 EPARs) were supportive of the decision. Published RWE...

Conclusions: Over the past 5 years, RWE involvement in the approval of oncology targeted therapies in Europe tends to increase, with the majority being supportive for EMA regulatory decision making complementary to traditional clinical trials...

Background: The epidemiological evidence on possible relationships between coffee consumption and prostate cancer (PCa) risk by subtype of the disease (localized, advanced) and fatal PCa risk is limited.

Materials and methods: A population-based cohort of 44 613 Swedish men aged 45-79 years was followed up from January 1998 through December 2010 for incidence of localized (n = 2368), advanced (n = 918) and fatal (n = 515) PCa. We assessed the associations between coffee consumption and localized, advanced and fatal PCa risk using competing-risk regressions. We examined possible effect modification by body mass index (BMI).

Results: For localized PCa, each one cup increase in daily coffee consumption was associated with a 3% reduced risk [sub-hazard ratio (SHR) = 0.97, 95% confidence interval (CI) = 0.95-0.99]. For advanced and fatal PCa, we found a non-significant inverse association; each one cup increase was associated with a 2% reduced risk of advanced [SHR (95% CI) = 0.98 (0.95-1.02)] and fatal PCa [SHR (95% CI) = 0.98 (0.93-1.03)]. We observed evidence of effect modification by BMI for localized PCa (P-interaction = 0.03); the inverse association was stronger among overweight and obese men (BMI >= 25 kg/m(2)) compared with normal-weight men (BMI < 25 kg/m(2)).

Conclusions: We observed a clear inverse association between coffee consumption and risk of localized PCa, especially among overweight and obese men.

Background: In cancer care, contact nurses daily meet people who deal with strong, aversive emotions in relation to that they have or may have cancer where the risk of dying is constantly present. This places demands on the ability of contact nurses to master difficult conversations with strong emotional expressions. One communication method known for its regulating effects on emotions is affirmative communication, so called validation. The overall aim of the current study was to evaluate effects of a training in validating communication for contact nurses in cancer care, aimed to strengthen their ability to work in a person-centered way.

Methods: This study had a within-group design with pre-, post- and follow-up measurements (2 months). Specifically, the study aimed to evaluate whether the validation training coincided with an increase in validation and a decrease in invalidation. Contact nurses from six regions (n = 17) with a generally long work experience as a nurse participated in a digital validation training for six weeks (three training sessions plus three pre-recorded theoretical lectures). Communicative behaviors were assessed through video-recordings of interactions between the nurses and fictitious patients. The videos were encoded by independent coders and analyzed with dependent MANOVA.

Results: The contact nurses showed a significant increase in validation and a significant decrease in invalidation after the training. These effects remained at the 2-month follow-up.

Conclusions: Experienced healthcare professionals' affirmative communication skills can be improved after a brief training in validation.

Background: Neoadjuvant treatment with Trastuzumab-emtansine was associated with similar rates of pathological complete remission (pCR) as standard therapy withd ocetaxel, trastuzumab and pertuzumab in the PREDIX HER2 trial. Here, results of event-free survival (EFS), and pCR rates in key clinical-pathological subgroups and biomarkers including the abundance of stromal tumor infiltrating lymphocytes (TILs) are presented.

Methods: PREDIX HER2 is a randomized, multicenter, open-label, phase 2 study involving 9 Swedish sites. Patients with HER2 positive breast cancer, verified by ISH, T>20 mm and/or verified lymph node metastases were randomized to six three-weekly courses of either docetaxel, trastuzumab SC and pertuzumab (group A), or trastuzumab emtansine (T-DM1, group B). Switch of treatment to the opposite arm was allowed in case of lack of response or severe toxicity. Radiological evaluation included 18F-FDG PET/CT. Patients in both groups received adjuvant chemotherapy with epirubicin and cyclophosphamide. TILs were evaluated using standard methodology, median 10%.

Results: In total 197 pts. were evaluable, 99 in group A, and 98 in group B. pCR (ypT0/is ypN0) was achieved in 90 pts, 45.7%, with no significant difference between the two treatment groups. pCR rates were lower in the group of patients with hormone receptor (HR)epositive compared with HR-negative tumors but similar in both treatment groups. pCR rates did not differ between the two treatments in subgroups defined by age, menopausal status, tumor grade, T size, node status, HR-status, HER2 status and Ki67. Progressive disease was observed in 3 pts. (3%) during treatment with T-DM1, none in group A. After a median follow-up of 2.4 years 13 EFS events occurred, with no significant differences between the treatment groups. The presence of 10% TILs predicted pCR significantly (p¼0.009), similar in both treatment groups. We also found that a decrease of SUVmax by more than 80% was highly predictive of pCR. HRQoL was significantly better in pts. receiving T-DM1.

Conclusions: Our data suggest that neoadjuvant T-DM1 may be as effective as standard neoadjuvant treatment in all clinical subgroups evaluated. Both TILs and PET/CT showed potential to predict pCR.

Clinical trial identification: NCT02568839.

Background: The aim of this Delphi study was to assess current perspectives on HR+/HER2- advanced breast cancer (aBC) treatment strategies among Nordic BC oncologists, and to gain broader understanding of the uptake and implementation of novel treatments.

Methods: A modified, three round Delphi method was followed. A steering committee was appointed for study coordination, panellist selection and questionnaires development. The questionnaires covered clinically relevant topics related to HR+/HER2- aBC treatment: treatment patterns in different lines of therapy (first- (1L), second- (2L) and third-line (3L)), oligometastatic disease, de novo aBC, brain metastases, age as influential factor, visceral crisis, radiotherapy, diagnostics and clinical guidelines. Both open and closed-ended questions were included. Consensus was defined as at least 70% agreement.

Results: In total 28 panelists participated in the study. In rounds one and two, 14 and 21 questions reached consensuses, respectively. Thirteen non-consensus reaching questions were reposted in round three, where 10 reached consensus. Overall, topics that reached a high consensus level included: treatment approaches in 1L and 2L treatment setting for HR+/HER2- aBC, treatment of oligometastatic disease, visceral crisis and brain metastases, and age-related treatment considerations. No consensus was reached for aspects regarding 3L therapy and de novo aBC. Endocrine therapy (ET) combined with CDK4/6i was the treatment of choice for both 1L and 2L therapy. Regarding implementation of clinical guidelines, a discrepancy was observed between treatments recommended in guidelines and those used in clinical practice, especially in cases where novel treatments were proposed.

Conclusions: Endocrine therapy combined with a CDK4/6i is the frontline treatment choice for HR+/HER2- aBC in the Nordics. Observed discrepancies between international clinical guidelines and practice are partly due to difference in the availability of novel treatment strategies that might lead to differences in clinical experience in the Nordics. The lack of consensus might reflect limited evidence on these topics and the need for collaborative research efforts. Written on behalf of Nordic Delphi Panellist group.

In a retrospective study on node-negative breast cancer, a prognostic index consisting of a proliferation factor, S-phase fraction (SPF), progesterone receptor status (PR), and tumour size identified one-third of patients as high risk, with a sixfold increased risk of breast cancer death. This prospective multicenter cohort study was set up to validate the index. In 576 T1-2N0 patients < 60 years, prospective analyses of PR and SPF were carried out. High risk was defined as >= 2 of the following: size > 20 mm, PR-negativity, and high SPF (in the absence of SPF, Bloom-Richardson grade 3). Median follow-up was 17.8 years. Thirty-one percent were high risk. In univariate analysis, the index was prognostic for breast cancer-specific survival after 5 years [hazard ratio (HR) = 4.7, 95% confidence interval (95% CI) 2.5-8.9], 10 years (HR = 2.2, 95% CI 1.5-3.3), and 15 years (HR = 1.7, 95% CI 1.2-2.5), and remained significant after adjustment for adjuvant medical treatment and age. In the 37% of patients with no risk factors, only one patient died of breast cancer the first 5 years. This prospective study validates a prognostic index consisting of a proliferation factor, PR-status, and tumour size. The index may be helpful for prognostic considerations and for selection of patients in need of adjuvant therapy.

Background: Data are scarce on the potential change in suicidal behavior among adolescents and young adults after receiving a cancer diagnosis.

Patients and methods: We conducted a population-based cohort study including 7 860 629 Swedes at the age of >= 15 during 1987-2009. Among the cohort participants, 12 669 received a first diagnosis of primary cancer between the age of 15 and 30. We measured the relative risks (RRs) of suicidal behavior (defined as completed suicides or suicide attempts) after cancer diagnosis. We also carried out a case-crossover study nested within the cohort to adjust for unmeasured confounders.

Results: Twenty-two completed suicides (versus 14 expected) and 136 suicide attempts (versus 80 expected) were identified among the cancer patients. The RR of suicidal behavior was 1.6 [ 95% confidence interval (CI), 1.4-1.9] after a cancer diagnosis, compared with cancer-free individuals. Risk increase was greatest immediately after diagnosis; the RR was 2.5 (95% CI 1.7-3.5) during the first year after diagnosis and was 1.5 (95% CI 1.2-1.8) thereafter. This pattern was similar for completed suicide and suicide attempts. The elevated risks were evident for majority of the main cancer types, except for cancer in thyroid, testis and melanoma. The case-crossover analysis of suicidal behavior during the first year after cancer diagnosis revealed similar results.

Conclusions: Adolescents and young adults receiving a cancer diagnosis are at substantially increased risk of suicidal behavior, particularly during the first year after diagnosis. Although the absolute excess risk is modest, these findings emphasize the need to support and carefully monitor this vulnerable population.

Background: Previous studies have shown that a high level of pre-treatment C-reactive protein to albumin ratio (CAR) is associated with poor outcomes in patients with diffuse large B cell lymphoma (DLBCL). However, these were single-centre studies with a relatively small number of patients. The aim of our study was to further investigate the prognostic value of CAR in a larger cohort and whether the addition of CAR to the International Prognostic Index (IPI) would result in a better discriminatory ability.

Methods: All adult patients treated 2000–2013 with R-CHOP/CHOP-like treatment for DLBCL in four counties of Sweden were included (n=414). The study population was divided into high respectively low CAR group using the Budczies et al.’s cut-off finder. The groups were compared in terms of differences in clinical characteristics, response to treatment and survival. The prognostic ability of IPI vs IPI plus CAR was compared by receiver-operating-characteristic curve (ROC), net reclassification improvement (NRI) and the integrated discrimination improvement index (IDI).

Results: The high CAR group was associated with higher IPI score, lower performance status, high LDH, bulky disease and more advanced Ann Arbour stage. The high CAR group had a higher proportion of patients with progressive disease (24.2% vs 6.4%, p<0.001) and a lower proportion of patients with complete remission (61.5% vs 85.7%, p<0.01). The high CAR group had poorer 5-year OS (49% vs 70%; p<0.001) and EFS (45% vs 68%; p<0.001). After adjustment for BMI, bulky disease and IPI, high CAR values independently predicted poor OS (HR: 1.58, 95% CI 1.18–2.11; p=0.002) and EFS (HR: 1.57, 95% CI 1.18–2.10; p=0.002). When assessed by NRI, the addition of CAR to IPI seems to better identify patients with better prognosis compared with IPI alone. However, the area under the ROC curve and IDI did not show any significant improvement in model performance.

Conclusions: CAR seems to be a useful prognostic biomarker in patients with DLBCL. Although the addition of CAR to IPI could identify some additional patients with better prognosis, the discriminatory ability of IPI was not improved. IPI remains the standard model for risk stratification in patients with DLBCL.

Background: A growing body of real-world evidence (RWE) aims to better reflect outcomes of cancer patients treated in real-world settings. We aimed to conduct a first comprehensive mapping review of the RWE produced over the past 3 years in terms of tumor type, treatment strategies, setting, and data sources, focusing on targeted therapies (TT) in solid tumors.

Methods: We conducted a systematic review in PubMed of RWE studies published between 01/2020 and 12/2022. We identified non-interventional studies using observational data, focusing on solid tumors exposure to targeted therapies, excluding immunotherapies. Abstract and full-text screening were performed by 11 independent reviewers.

Results: A total of 7,774 publications were retrieved with 1,251 considered eligible and extracted. The number of publications per year progressively increased during this period (328 in 2020; 421 in 2021; 502 in 2022). Most studies (50%) were performed in Asia, followed by Europe (25%) and North America (17%). Only 8% of studies had patients treated in more than one country. Treatment effectiveness and safety were assessed in 71% and 42% of studies respectively. Main data sources were medical records.

Conclusions: RWE publications on TT for solid tumors are heterogeneous and mostly rely on retrospective data such as medical records. Population-based and international studies are rare. Collaborative efforts towards international representativeness and the use of routinely collected and/or standardized data sources must be encouraged to increase the relevance and future quality of publications and their potential impact on oncology practice.

Background: The prognostic value of prostate-specific antigen (PSA) kinetics in untreated prostate cancer (PCa) patients is debatable. We investigated the association between PSA doubling time (PSAdt), PSA velocity (PSAvel) and PSAvel risk count (PSAvRC) and PCa mortality in a cohort of patients with localised PCa managed on watchful waiting.

Patients and methods: Patients with clinically localised PCa managed observationally, who were randomised to and remained on placebo for minimum 18 months in the SPCG-6 study, were included. All patients survived at least 2 years and had a minimum of three PSA determinations available. The prognostic value of PSA kinetics was analysed and patients were stratified according to their PSA at consent: ≤10, 10.1-25, and >25 ng/ml. Cumulative incidences of PCa-specific mortality were estimated with the Aalen-Johansen method.

Results: Two hundred and sixty-three patients were included of which 116, 76 and 71 had a PSA at consent ≤10, 10.1-25, and >25 ng/ml, respectively. Median follow-up was 13.6 years. For patients with PSA at consent between 10.1 and 25 ng/ml, the 13-year risks of PCa mortality were associated with PSA kinetics: PSAdt ≤3 years: 62.0% versus PSAdt >3 years: 16.3% (Gray's test: P < 0.0001), PSAvel ≥2 ng/ml/year: 48.0% versus PSAvel <2 ng/ml/year: 11.0% (Gray's test: P = 0.0008), and PSAvRC 2: 45.0% versus 0-1: 3.8% (Gray's test: P = 0.001). In contrast, none of the PSA kinetics were significantly associated with changes of 13-year risks of PCa mortality in patients with PSA at consent ≤10 or >25 ng/ml.

Conclusion: We found that magnitude changes in 13-year risks of PCa mortality that can be indicated by PSA kinetics depend on PSA level in patients with localised PCa who were managed observationally. Our results question PSA kinetics as surrogate marker for PCa mortality in patients with low and high PSA values.

Background: Although palbociclib combined with endocrine therapy is a well-established treatment option in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), there is limited evidence on patterns of dose reductions in real-world setting. The Swedish Ibrance Registries Insights (SIRI) study investigated real-world dose patterns using a nationwide cohort of palbociclib-treated MBC patients...

Methods: This was a retrospective study utilizing population-based Swedish Health Data Registers. The cohort included all patients ≥ 18 years with ≥ 1 dispensation of palbociclib from January 2017 – June 2022. Minimum follow-up was 3 months. Starting dose and dose changes for the full population and for different age groups, in total and over time, was investigated...

Results: 2058 patients were identified and the median (IQR) age at treatment initiation was 68.4 (15.7) years. Patients were stratified into three age groups: <50, 50-69, ≥70 years, with the following distribution: 9.9%, 46.1%, and 44.0%, respectively. Most patients were initiated on 125 mg (82.0%), with a lower share for older patients (≥70 years; 74.4%). In total, 45.5% of patients had ≥ 1 dose reduction, with a higher frequency for older patients (≥70 years; 48.5%). Median (IQR) time to first dose...

Conclusions: Most Swedish palbociclib-treated patients were initiated on the recommended dose, but a lower starting dose and a higher frequency of dose reductions were observed for older patients. The time to dose reduction was equal across age groups, whereas the probability for dose reduction increased over time for older patients, and for patients with a start dose of 100 mg...

Background: In the 2007 World Cancer Research Fund/American Institute for Cancer Research Second Expert Report, the expert panel judged that there was strong evidence that alcoholic drinks and body fatness increased esophageal cancer risk, whereas fruits and vegetables probably decreased its risk. The judgments were mainly based on case-control studies. As part of the Continuous Update Project, we updated the scientific evidence accumulated from cohort studies in this topic.

Methods: We updated the Continuous Update Project database up to 10 January 2017 by searching in PubMed and conducted dose-response meta-analyses to estimate summary relative risks (RRs) and 95% confidence intervals (CIs) using random effects model.

Results: A total of 57 cohort studies were included in 13 meta-analyses. Esophageal adenocarcinoma risk was inversely related to vegetable intake (RR per 100 g/day: 0.89, 95% CI: 0.80-0.99, n = 3) and directly associated with body mass index (RR per 5 kg/m2: 1.47, 95% CI: 1.34-1.61, n = 9). For esophageal squamous cell carcinoma, inverse associations were observed with fruit intake (RR for 100 g/day increment: 0.84, 95% CI: 0.75-0.94, n = 3) and body mass index (RR for 5 kg/m2 increment: 0.64, 95% CI: 0.56-0.73, n = 8), and direct associations with intakes of processed meats (RR for 50 g/day increment: 1.59, 95% CI: 1.11-2.28, n = 3), processed and red meats (RR for 100 g/day increment: 1.37, 95% CI: 1.04-1.82, n = 3) and alcohol (RR for 10 g/day increment: 1.25, 95% CI: 1.12-1.41, n = 6).

Conclusions: Evidence from cohort studies suggested a protective role of vegetables and body weight control in esophageal adenocarcinomas development. For squamous cell carcinomas, higher intakes of red and processed meats and alcohol may increase the risk, whereas fruits intake may play a protective role.

Background: The diagnosis of cancer is strongly associated with the risk of mental disorders even in patients with no previous history of mental disorders. Accumulating data suggest that mental distress may accelerate tumor progression. We hypothesized therefore that mental disorders after a cancer diagnosis may increase the risk of cancer-specific mortality.

Patients and methods: We conducted a nationwide cohort study including 244 261 cancer patients diagnosed in Sweden during 2004-2009 and followed them through 2010. Through the Swedish Patient Register, we obtained clinical diagnoses of all mental disorders and focused on mood-, anxiety-, and substance abuse disorders (ICD10: F10-F16, F18-F19, F32-F33, F40-F41, and F43-45) that are commonly diagnosed among patients with cancer. We further classified the studied mental disorders into first-onset or recurrent mental disorders. We used Cox regression to estimate multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) as a measure of the association between mental disorders after cancer diagnosis and cancer-specific mortality, adjusting for age, sex, calendar period, educational level, cancer stage, and cancer type at diagnosis.

Results: After cancer diagnosis, 11 457 patients were diagnosed with mood-, anxiety-, and substance abuse disorders; of which 7236 were first-onset mental disorders. Patients with a first-onset mental disorder were at increased risk of cancer-specific mortality (HR: 1.82, 95% CI: 1.71-1.92) while patients with a recurrent mental disorder had much lower risk elevation (HR: 1.14, 95% CI: 1.05-1.24). The increased cancer-specific mortality by first-onset mental disorders was observed for almost all cancer sites/groups and the association was stronger for localized cancers (HR: 2.00, 95% CI: 1.73-2.31) than for advanced cancers (HR: 1.49, 95% CI: 1.32-1.69).

Conclusions: Patients with a first-onset common mood-, anxiety-, or substance abuse disorder after cancer diagnosis may be at increased risk of cancer-specific death.