Safety, efficacy, and biological data of T cell-enabling oncolytic adenovirus TILT-123 in advanced solid cancers from the TUNIMO monotherapy phase I trial.

PURPOSE: TILT-123 (igrelimogene litadenorepvec) is an oncolytic adenovirus armed with tumor necrosis factor alpha and interleukin-2, designed to induce T-cell infiltration and cytotoxicity in solid tumors. PATIENTS AND METHODS: TUNIMO (NCT04695327) was a single-arm, multicenter phase I dose escalation trial designed to assess safety of TILT-123 in advanced solid cancers refractory to standard therapy. Patients received intravenous and intratumoral TILT-123. The primary endpoint was safety by adverse events (AEs), laboratory values, vital signs, and electrocardiograms. Secondary endpoints included tumor response, pharmacokinetics, and predictive biomarkers. RESULTS: 20 patients were enrolled, with median age of 58 years. Most prevalent cancer types included sarcomas (35%), melanomas (15%) and ovarian cancers (15%). No dose-limiting toxicities were observed. The most frequent treatment related AEs included fever (16.7%), chills (13.0%) and fatigue (9.3%). 10 patients were evaluable for response on day 78 with RECIST 1.1, iRECIST or PET-based evaluation. The disease control rate by PET was 6/10 (60% of evaluable patients) and 2/10 by RECIST 1.1 and iRECIST (20% of evaluable patients). Tumor size reductions occurred in both injected and non-injected lesions. TILT-123 was detected in injected and non-injected tumors, and virus was observed in blood after intravenous and intratumoral injections. Treatment resulted in reduction of lymphocytes in blood, with concurrent lymphocyte increases in tumors, findings compatible with trafficking. CONCLUSIONS: TILT-123 was safe and able to produce anti-tumor effects in local and distant lesions in heavily pre-treated patients. Good tolerability of TILT-123 facilitates combination studies, several of which are ongoing (NCT04217473, NCT05271318, NCT05222932, NCT06125197).

Radium-223 dichloride treatment in metastatic castration-resistant prostate cancer in Finland: A real-world evidence multicenter study.

BACKGROUND: Radium-233 dichloride is an alpha emitter that specifically targets bone metastases in prostate cancer. Results of a previously reported phase III randomized trial showed survival benefit for radium-223 compared to best supportive care in castration-resistant prostate cancer (CRPC) with bone metastases. However, real-world data are also needed with wider inclusion criteria. METHODS: We report results of a retrospective multicenter study including all patients with metastatic CRPC treated with radium-223 in all five university hospitals in Finland since the introduction of the treatment. We identified 160 patients who had received radium-223 in Finland in 2014-2019. RESULTS: The median overall survival (OS) was 13.8 months (range 0.5-57 months), and the median real-world progression-free survival (rwPFS) was 4.9 months (range 0.5-29.8 months). Alkaline phosphatase (ALP) values within the normal range before and during the radium-223 treatment or the reduction of elevated ALP to normal range during treatment were associated with better OS when compared to elevated ALP values before and during treatment (p < 0.0001). High prostate-specific antigen (PSA) level (≥100 µg/L) before radium-223 treatment was associated with poor OS compared to low PSA level (<20 µg/L) (p = 0.0001). Most patients (57%) experienced pain relief. Pain relief indicated better OS (p = 0.002). Radium-223 treatment was well tolerated. Toxicity was mostly low grade. Only 12.5% of the patients had grade III-IV adverse events, most commonly anemia, neutropenia, leucopenia, and thrombocytopenia. CONCLUSION: Radium-223 was well tolerated in routine clinical practice, and most patients achieved pain relief. Pain relief, ALP normalization, lower baseline PSA, and PSA decrease during radium-223 treatment were prognostic for better survival. The efficacy of radium-223 in mCRPC as estimated using OS was comparable to earlier randomized trial in this retrospective real-world study. Our results support using radium-223 for mCRPC patients with symptomatic bone metastases even in the era of new-generation androgen receptor-targeted agents.

2-weekly versus 3-weekly docetaxel for metastatic castration-resistant prostate cancer: complete quality of life results from the randomised, phase-III PROSTY trial.

INTRODUCTION: Treatment with 2-weekly docetaxel 50 mg/m2 was shown to improve overall survival and was better tolerated than the standard 75 mg/m2 3-weekly regimen in men with metastatic castration-resistant prostate cancer (mCRPC) in the original randomised PROSTY trial. The aim of this study was to investigate, whether quality of life (QoL) effects would differ between the 2-weekly docetaxel 50 mg/m2 regimen from the standard 3-weekly 75 mg/m2 treatment. MATERIALS AND METHODS: QoL data were collected with the Functional Assessment of Cancer Therapy - Prostate (FACT-P) and Functional Assessment of Cancer Therapy Advanced Prostate Symptom Index - 8 Item version (FAPSI-8). Pain was measured using the Visual Analogue Scale (VAS). A total of 743 forms from 163 patients were analysed in Arm A (2-weekly docetaxel), and 704 forms from 173 patients were analysed in Arm B (3-weekly docetaxel). The data were analysed using both the Wilcoxon signed rank test (with Holm-Bonferroni adjustment) and Mann-Whitney U models. RESULTS: No major differences were found in total QoL. Total QoL was higher at month 8 in Arm B (p = .020), but this was reversed in the following month (p = .043), and no statistically significant differences were found during other months. Compared to Arm A, participants in Arm B had longer-lasting deterioration in FAPSI-8 scores and emotional well-being subdomain at the beginning of treatment (p < .05). Various one-month differences were found in FACT-P subdomains (except for functional well-being), and these favoured participants in Arm A, except for the prostate-cancer subdomain. There were no differences in pain. CONCLUSION: Based on our results, 2-weekly docetaxel was not inferior to 3-weekly docetaxel in terms of total health-related QoL and seemed to be superior at least in terms of the FAPSI-8 and emotional well-being subdomain in the first three to four months of treatment. More research on the topic is suggested to confirm the results.

Health-related Quality of Life in Intermediate- or High-risk Patients Treated With Radical External Radiotherapy and Adjuvant Docetaxel for Localized Prostate Cancer: A Randomized, Phase III SPCG-13 Study.

BACKGROUND/AIM: The goal of this study was to investigate whether health-related quality of life (HRQoL) was affected in patients with high- or intermediate-risk localized prostate cancer treated with docetaxel following radiation therapy (RT). PATIENTS AND METHODS: A total of 376 patients treated with RT and androgen deprivation were randomized to receive 6 cycles of docetaxel 75 mg/m2 (N=188, Arm A) or surveillance (N=188, Arm B). FACT-P HRQoL questionnaires were gathered at baseline, six months and 1, 2 and 4 years after randomization. The data were analysed using analysis of covariance. RESULTS: FACT-P scores decreased in Arm A at the end of treatment and remained unchanged in Arm B (p<0.0001). The HRQoL scores in Arm A matched Arm B in the 1-year follow-up (p=0.0528) and remained similar in further follow-up. CONCLUSION: Docetaxel transiently decreased HRQoL during chemotherapy but not after treatment for up to four years of follow-up.

Workplace Diesel Exhausts and Gasoline Exposure and Risk of Colorectal Cancer in Four Nordic Countries.

BACKGROUND: Evidence on associations between occupational diesel exhaust and gasoline exposure and colorectal cancer is limited. We aimed to assess the effect of workplace exposure to diesel exhaust and gasoline on the risk of colorectal cancer. METHODS: This case-control study included 181,709 colon cancer and 109,227 rectal cancer cases diagnosed between 1961 and 2005 in Finland, Iceland, Norway, and Sweden. Cases and controls were identified from the Nordic Occupational Cancer Study cohort and matched for country, birth year, and sex. Diesel exhaust and gasoline exposure values were assigned by country-specific job-exposure matrices. Odds ratios and 95% confidence intervals were calculated by using conditional logistic regression models. The results were adjusted for physical strain at work and occupational exposure to benzene, formaldehyde, ionizing radiation, chlorinated hydrocarbons, chromium, and wood dust. RESULTS: Diesel exhaust exposure was associated with a small increase in the risk of rectal cancer (odds ratio = 1.05, 95% confidence interval 1.02-1.08). Gasoline exposure was not associated with colorectal cancer risk. CONCLUSION: This study showed a small risk increase for rectal cancer after workplace diesel exhaust exposure. However, this finding could be due to chance, given the limitations of the study.

Perceived Physical Strain at Work and Incidence of Prostate Cancer ­ a Case-Control Study in Sweden and Finland

The evidence that prostate cancer is associated to physical inactivity is inconsistent. We studied the association of perceived physical workload (PPWL) at work and incidence of prostate cancer in a case-control setting. We used data from the Nordic Occupational Cancer study from Finland and Sweden. Five population controls were selected for each prostate cancer patient, matched on age and country. We had 239,835 cases and 1,199,175 controls in our study. For each case and control we estimated cumulative PPWL based on probability, level and duration of PPWL using the NOCCA Job Exposure Matrix. We then stratified individuals as having no exposure (reference category), low physical activity (below 50th percentile of the exposed), moderate exposure (50th-90th percentile) and high exposure (90th percentile and higher). The hazard ratios for prostate cancer from the lowest to highest cumulative PPWL levels were 0.90 (95% confidence interval 0.89-0.91), 0.88 (0.87-0.89) and 0.93 (0.92-0.95). There was no statistically significant dose response effect of PPWL on prostate cancer incidence. Inclusion of socioeconomic status in the model did not substantially change the result. The results were similar before Prostate Specific Antigen (PSA) testing and during the years of PSA testing in these countries. In summary, individuals with physical strain at work had a lower risk of invasive prostate cancer as compared to individuals without physical strain at work.

Benzene exposure at workplace and risk of colorectal cancer in four Nordic countries.

OBJECTIVE: The aim of this case-control study was to assess the effect of occupational benzene exposure on the risk of colorectal cancer, including its subtypes. METHODS: The study included 181,709 colon cancer and 109,227 rectal cancer cases diagnosed between 1961 and 2005 in Finland, Iceland, Norway and Sweden. Cases were identified from the Nordic Occupational Cancer Study (NOCCA) cohort. Five controls per case were selected from the same cohort, matched for country, birth year, and sex. Occupational benzene exposure for each study participant was estimated by linking their job titles to country specific job-exposure matrices. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by using conditional logistic regression models. The results were adjusted for physical strain at work, formaldehyde, ionizing radiation and wood dust. RESULTS: Increased risk was observed for all colorectal cancer (OR = 1.12, 95% CI 1.05-1.18) for the high decile of cumulative benzene exposure, indicating a statistically significant dose-response relationship. This excess risk was mainly seen in ascending colon (OR = 1.27, 95% CI 1.13-1.43), and transversal colon (OR = 1.21, 95% CI 1.01-1.41). The ORs in the highest exposure category were markedly higher in women than in men in all subsites of colon and rectum. CONCLUSION: This study showed an association between workplace benzene exposure and colorectal cancer. The risk was restricted to ascending and transversal colon, and was the strongest among women.

Cohort profile: a nationwide cohort of Finnish military recruits born in 1958 to study the impact of lifestyle factors in early adulthood on disease outcomes.

PURPOSE: The cohort was set up to study the impact of lifestyle factors in early adulthood on disease outcomes, with a focus on assessing the influence of body composition and physical performance in early adulthood on subsequent cancer risk. PARTICIPANTS: Men born in 1958 who performed their military service between the ages of 17 and 30 years were included in this study (n=31 158). They were eligible for military service if they were healthy or had only minor health problems diagnosed at the beginning of their service. Men with chronic illnesses requiring regular medication or treatment were not eligible for service. Comprehensive health data including diagnosed illnesses, anthropometric measures and health behaviour were collected at the beginning and at the end of military service, including data from medical check-ups. FINDINGS TO DATE: During the follow-up, 1124 new cancer cases were diagnosed between baseline (ie, end of the military service for each individual) and end of the year 2014. In the end of the follow-up, 91% of the study participants were still alive. Overweight (body mass index (BMI) ≥25 kg/m2) and obesity (BMI ≥30 kg/m2) were associated with an overall increased risk of cancer. A good or excellent physical condition significantly reduced cancer risk. FUTURE PLANS: The dataset offers the possibility of linkage with other databases, such as the Finnish Cancer Registry (eg, primary site of the tumour, morphology, time of detection, spreading and primary treatment), vital statistics (date of emigration or deaths), censuses (socioeconomic indicators), hospital discharge data (comorbidity) and population surveys (life habits).

Perceived physical strain at work and incidence of colorectal cancer: A nested case-control study.

The evidence for a relationship between colon cancer incidence and physical activity is not fully convincing, and the association between physical activity and rectal cancer is also unclear. We studied the association between perceived physical workload (PPWL) at work and colorectal cancer, stratified by subsite, in a nested case-control setting in the Nordic Occupational Cancer (NOCCA) data from Finland, Iceland, Norway and Sweden. Five population controls were selected for each cancer patient. PPWL showed a bigger protective effect on colon cancer for males (odds ratio [OR] 0.74 in the highest PPWL decile as compared with the lowest PPWL category, 95% confidence interval [95% CI]: 0.72-0.77) than for females (OR 0.87, 95% CI: 0.81-0.95), with a significant trend for different levels of PPWL for both males and females. In males, the OR of cancer in the descending colon for the highest PPWL decile of males was 0.61 (95% CI: 0.54-0.69). For females the protective effect was most notable in the transversal part of the colon (OR 0.83, 95% CI: 0.67-1.03). The OR for rectal cancer in the highest PPWL decile for males was 0.87 (95% CI: 0.85-0.90) and for females 0.93 (95% CI: 0.83-1.04). Inclusion of further agents in multivariate analyses did not alter the ORs for PPWL. The incidence of colon cancer and, to a lesser extent, rectal cancer is lowest in professions with the highest PPWL. The association is clearer in males than in females. The biggest protective effect appears to be in the descending colon in males.

Lifetime physical activity and cancer incidence--a cohort study of male former elite athletes in Finland.

OBJECTIVES: Physical activity has been shown to decrease the risk of certain cancers. Objective of this study was to assess the effect of physical activity on cancer incidence in former male athletes in older age. DESIGN: A cohort of 2448 elite male athletes and 1712 referents was followed-up for cancer incidence during 1986-2010 through the Finnish Cancer Registry. METHODS: Standardised incidence ratios were calculated with the general male population as the reference. Self-reported questionnaire-based data on covariates were used in Cox regression analyses comparing the risk of cancer in athletes and referents. RESULTS: The overall cancer incidence was lower in athletes than in the general population, standardised incidence ratio 0.89 (95% confidence interval 0.81-0.97). It was lowest among middle-distance runners (standardised incidence ratio 0.51, 95% confidence interval 0.22-1.01), long-distance runners (standardised incidence ratio 0.57, 95% confidence interval 0.35-0.88) and jumpers (standardised incidence ratio 0.60, 95% confidence interval 0.37-0.92). The standardised incidence ratio of lung cancer among athletes was 0.40 (95% confidence interval 0.27-0.55) and that of kidney cancer 0.23 (95% confidence interval 0.06-0.57). The hazard ratio for lung cancer between athletes and referents increased from the unadjusted ratio of 0.29 (95% confidence interval: 0.18-0.48) to 0.61 (95% confidence interval: 0.30-1.26) after adjustment for smoking status and pack-years of smoking. CONCLUSIONS: Former male elite athletes evidently have less cancer than men on the average. The lesser risk can be attributed to lifestyle factors, notably less frequent smoking among the athletes.