Severe psychological stress associated with a cancer diagnosis

Receiving a cancer diagnosis leads to severe psychological distress. Previous studies have shown increased risk for various health consequences following a cancer diagnosis, including mental disorders, life-threatening cardiovascular events, and suicide. However, whether the severe stress response after a cancer diagnosis impacts cancer progression and healthcare use pattern for cancer patients is not clear yet. Furthermore, whether potential interventions, including beta-blocking agent treatment and shortened waiting-time during cancer diagnostic workup, could reduce such stress response and its related adverse health outcomes needs to be investigated. In study I, to investigate whether stress-related mental disorders, as indicators of a severe stress response to cancer diagnosis, were associated with an increased mortality among cancer patients, we performed a prospective cohort study including 244,261 adult cancer patients diagnosed during 2004-2009 in Sweden. Stress-related mental disorders diagnosed after cancer diagnosis were used as the primary exposure, and cancer-specific mortality was used as the main outcome of interest. In this study, an increased cancer-specific mortality was found in relation to stress-related mental disorders, especially the first-onset mental disorders. In study II, we assessed the impact of stress-related mental disorders on rate of hospital admissions after cancer diagnosis, by a prospective cohort study including 218,508 adult cancer patients diagnosed between 2004 and 2009 in Sweden. Stress-related mental disorders diagnosed from 90 days before to 90 days after cancer diagnosis were associated with an increased risk of any hospital admissions as well as hospital admissions for external injuries, infections, and cardiovascular diseases from 90 days after cancer diagnosis onward. In study III, we explored the role of beta-blocking agent treatment on the risk of severe cardiovascular events after cancer diagnosis, in a cohort study of all adult cancer patients diagnosed during 2006-2013 in Sweden. Beta-blocking agent treatment during 90 days before cancer diagnosis was not found to be associated with a decreased risk of cardiovascular death or hospital admission due cardiovascular diseases, either during the 90 days after cancer diagnosis or thereafter. In study IV, we performed a randomized clinical trial including men clinically evaluated for suspected prostate cancer, to quantify the stress experience during the diagnostic workup of prostate cancer and assess its association with waiting-time. Patients in the intervention group had a fast-track workup with the shortest possible waiting-time, whereas the control group received the usual care. We presented baseline data at randomization and follow-up data at the first urologist visit, and found that depression symptoms and self-rated sleep quality score were reduced among men in the fast-track workup group, compared to the control group. In conclusion, stress-related mental disorders diagnosed around cancer diagnosis, as indicators of the severe stress response to cancer diagnosis, were associated with an increased cancer-specific mortality and increased rate of hospital admission. Beta-blocking agent treatment was not associated with a decreased risk of severe cardiovascular events immediately following a cancer diagnosis. For men with suspected prostate cancer, a shortened waiting-time during the diagnostic workup might lead to reduced risks of depression and sleeping problem. LIST OF SCIENTIFIC PAPERS I. Zhu J, Fang F, Sjölander A, Fall K, Adami HO, Valdimarsdóttir U. Firstonset mental disorders after cancer diagnosis and cancer-specific mortality: a nationwide cohort study. Ann Oncol. 2017 Aug 1;28(8):19641969. II. Zhu J, Sjölander A, Fall K, Valdimarsdottir U, Fang F. Mental disorders around cancer diagnosis and increased hospital admission rate – a nationwide cohort study of Swedish cancer patients. BMC Cancer. 2018 Mar 27;18(1):322. III. Zhu J, Smedby KE, Valdimarsdóttir U, Sjölander A, Eloranta S, Udumyan R, Fall K, Fang F. Beta-blocking agents and risk of severe cardiovascular events following a cancer diagnosis. Manuscript. IV. Zhu J, Fang F, Chen R, Davidsson S, Carlsson J, Messing-Eriksson A, Andrén O, Andersson SO, Valdimarsdottir U, Fall K. Fast-track clinical workup for men with suspected prostate cancer: first report from a Randomized Clinical Trial. Manuscript. CONTENTS 1 BACKGROUND . 1 1.1 Psychological stress and stress response . 1 1.2 Severe stress response, healthcare use, and cancer mortality . 3 1.3 Beta-blocking agents and severe stress response to cancer diagnosis . 4 1.4 Psychological stress and stress response during the diagnostic workup of prostate cancer . 4 2 AIMS . 5 3 STUDY MATERIALS . 6 3.1 Swedish population and health registers . 6 3.2 Randomized clinical trial . 8 4 STUDY DESIGN AND METHODS . 9 4.1 First-onset mental disorders and cancer-specific mortality . 9 4.1.1 Cancer site and stage . 9 4.1.2 Stress-related mental disorders . 10 4.1.3 Cancer-specific mortality . 10 4.1.4 Statistical analysis . 11 4.2 Stress-related mental disorders around cancer diagnosis and hospital admission . 12 4.2. 1 Hospital admission after cancer diagnosis . 13 4.2. 2 Statistical analysis . 13 4.3 Beta-blocking agents and severe cardiovascular events after cancer diagnosis . 14 4.3.1 Treatment of beta-blockers shortly before cancer diagnosis . 15 4.3.2 Severe cardiovascular events after cancer diagnosis . 15 4.3. 3 Ascertainment of comorbidity . 16 4.3. 4 Statistical analysis . 16 4.4 Fast-track clinical workup for men with suspected prostate cancer . 18 4.4.1 Data collection. 18 4.4.2 Questionnaires . 18 4.4.3 Saliva cortisol . 19 4.4.4 Heart rate variability . 20 4.4. 5 Statistical analysis . 20 5 RESULTS . 22 5.1 First-onset mental disorders and cancer-specific mortality . 22 5.2 Stress-related mental disorders around cancer diagnosis and hospital admission after cancer diagnosis . 25 5.3 Beta-blocking agents and severe cardiovascular events after cancer diagnosis . 27 5.4 Fast-track clinical workup for men with suspected prostate cancer . 31 6 DISCUSSION . 35 6.1 General discussion . 35 6.1.1 Severe stress response to cancer diagnosis and its related health consequences . 35 6.1.2 Role of beta-blocking agents on modulating stress response . 37 6.1.3 Fast-track diagnostic workup and psychological stress among men with suspected prostate cancer . 38 6.2 Strength and limitations . 39 6.2. 1 Strength . 39 6.2. 2 Limitations . 40 7 CONCLUSIONS . 43 8 FUTURE PERSPECTIVES . 44 9 ACKNOWLEDGEMENT. 45 10 REFFERENCES .