Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade.

The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from BRAF-mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2-11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20-35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.

Transient TCR-based T cell therapy in a patient with advanced treatment-resistant MSI-high colorectal cancer.

We previously demonstrated the antitumor effectiveness of transiently T cell receptor (TCR)-redirected T cells recognizing a frameshift mutation in transforming growth factor beta receptor 2. We here describe a clinical protocol using mRNA TCR-modified T cells to treat a patient with progressive, treatment-resistant metastatic microsatellite instability-high (MSI-H) colorectal cancer. Following 12 escalating doses of autologous T cells electroporated with in-vitro-transcribed Radium-1 TCR mRNA, we assessed T cell cytotoxicity, phenotype, and cytokine production. Tumor markers and growth on computed tomography scans were evaluated and immune cell tumor infiltrate at diagnosis assessed. At diagnosis, tumor-infiltrating CD8+ T cells had minimal expression of exhaustion markers, except for PD-1. Injected Radium-1 T cells were mainly naive and effector memory T cells with low expression of exhaustion markers, except for TIGIT. We confirmed cytotoxicity of transfected Radium-1 T cells against target cells and found key cytokines involved in tumor metastasis, growth, and angiogenesis to fluctuate during treatment. The treatment was well tolerated, and despite his advanced cancer, the patient obtained a stable disease with 6 months survival post-treatment. We conclude that treatment of metastatic MSI-H colorectal cancer with autologous T cells electroporated with Radium-1 TCR mRNA is feasible, safe, and well tolerated and that it warrants further investigation in a phase 1/2 study.

First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer-the randomised METIMMOX trial.

BACKGROUND: We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. METHODS: Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. RESULTS: Eighty patients were randomised and 38 in each group received treatment. PFS was comparable-control group: median 9.2 months (95% confidence interval (CI), 6.3-12.7); experimental group: median 9.2 months (95% CI, 4.5-15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04-0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8-23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. CONCLUSIONS: The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03388190 (02/01/2018).

PALLiative care in ONcology (PALLiON): A cluster-randomised trial investigating the effect of palliative care on the use of anticancer treatment at the end of life.

BACKGROUND: Effects on anticancer therapy following the integration of palliative care and oncology are rarely investigated. Thus, its potential effect is unknown. AIM: To investigate the effects of the complex intervention PALLiON versus usual care on end-of-life anticancer therapy. DESIGN: Cluster-randomised controlled trial (RCT), registered at ClinicalTrials.gov (No. NCT01362816). The complex intervention consisted of a physician education program enhancing theoretical, clinical and communication skills, a patient-centred care pathway and patient symptom reporting prior to all consultations. Primary outcome was overall use, start and cessation of anticancer therapy in the last 3 months before death. Secondary outcomes were patient-reported outcomes. Mixed effects logistic regression models and Cox proportional hazard were used. SETTING: A total of 12 Norwegian hospitals (03/2017-02/2021). PARTICIPANTS: Patients ⩾18 years, advanced stage solid tumour, starting last line of anticancer therapy, estimated life expectancy ⩽12 months. RESULTS: A total of 616 (93%) patients were included (intervention: 309/control:307); 63% males, median age 69, 77% had gastrointestinal cancers. Median survival time from inclusion was 8 (IQR 3-14) and 7 months (IQR 3-12), and days between anticancer therapy start and death were 204 (90-378) and 168 (69-351) (intervention/control). Overall, 78 patients (13%) received anticancer therapy in the last month (intervention: 33 [11%]/control: 45 [15%]). No differences were found in patient-reported outcomes. CONCLUSION: We found no significant differences in the probability of receiving end-of-life anticancer therapy. The intervention did not have the desired effect. It was probably too general and too focussed on communication skills to exert a substantial influence on conventional clinical practice.

Chemotherapy reduces long-term quality of life in recurrence-free colon cancer survivors (LaTE study)-a nationwide inverse probability of treatment-weighted registry-based cohort study and survey.

AIM: Stage III colon cancer is routinely treated with adjuvant chemotherapy, which causes significant short-term morbidity. Its effect on long-term quality of life (QoL) is poorly investigated. The aim of this study was to investigate long-term QoL after curative treatment for colon cancer and explore the impact of chemotherapy on general and disease-specific QoL. METHOD: All patients aged under 75 years operated on for colon cancer between 30 September 2007 and 1 October 2019 were identified by the Cancer Registry of Norway. Exclusion criteria were distant metastasis, recurrence, dementia and rectal/rectosigmoid cancer operation. The primary outcome measure was Gastrointestinal Quality of Life Index (GIQLI). Secondary outcome measures included the Short Form Health Survey (SF-36). To achieve balanced groups when assessing differences in outcome measures the analyses were weighted by inverse probability weights based on a multiple logistic regression model with prechosen confounders. RESULTS: A total of 8627 patients were invited and 3109 responded (36% response rate). After exclusions 3025 patients were included, of whom 1148 (38%) had received adjuvant chemotherapy and 1877 (62%) had surgery alone, with mean follow-up of 75.5 versus 74.5 months, respectively. The GIQLI differed significantly between the groups [mean 111.0 (SD 18.4) vs. 115.6 (SD 17.8), respectively; mean difference: -4.6 (95% CI -5.9; -3.2); p < 0.001]. Those with the highest neurotoxicity exhibited the lowest GIQLI. The adjuvant chemotherapy group scored significantly lower in six of eight SF-36 domains compared with the surgery alone group. The main differences were found in social, physical and emotional function. CONCLUSION: Long-term QoL was significantly lower in patients who received adjuvant chemotherapy than in patients who did not. Neurotoxicity was closely related to reduced QoL in these patients. The low response rate limits the generalizability of the results.

Early radiologic signal of responsiveness to immune checkpoint blockade in microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer.

BACKGROUND: Immune checkpoint blockade (ICB) results in radiologic tumour response dynamics that differ from chemotherapy efficacy measures and require an early signal of clinical utility. METHODS: Previously untreated, unresectable microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) patients were randomly assigned to the oxaliplatin-based Nordic FLOX regimen (control arm) or repeat sequential two FLOX cycles and two ICB cycles (experimental arm). The radiologic response was assessed every 8 weeks. In this post hoc analysis, we explored early target lesion (TL) dynamics as indicator of ICB responsiveness. Progression-free survival (PFS) was the primary endpoint. RESULTS: Using a landmark analysis approach, we categorised experimental-arm patients into ≥10% (N = 19) or <10% (N = 16) TL reduction at the first post-baseline response assessment. Median PFS for the groups was 16.0 (95% confidence interval (CI), 12.3-19.7) and 3.9 months (95% CI, 2.3-5.5), respectively, superior and inferior (both P < 0.01) to the median PFS of 9.8 months (95% CI, 4.9-14.7) for control arm patients (N = 31). CONCLUSIONS: Radiologic TL reduction of ≥10% at the first post-baseline response assessment identified patients with ICB-responsive metastatic MSS/pMMR-CRC. This pragmatic measure may be used to monitor patients in investigational ICB schedules, enabling early treatment adaptation for unresponsive cases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03388190 (02/01/2018).

Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway.

BACKGROUND: Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. METHODS: In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient's tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like 'admissible' monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system. DISCUSSION: Precision oncology means to stratify treatment based on specific patient characteristics and the molecular profile of the tumor. Use of targeted drugs is currently restricted to specific biomarker-defined subgroups of patients according to their market authorization. However, other cancer patients might also benefit of treatment with these drugs if the same biomarker is present. The emerging technologies in molecular diagnostics are now being implemented in Norway and it is publicly reimbursed, thus more cancer patients will have a more comprehensive genomic profiling of their tumour. Patients with actionable genomic alterations in their tumour may have the possibility to try precision cancer drugs through IMPRESS-Norway, if standard treatment is no longer an option, and the drugs are available in the study. This might benefit some patients. In addition, it is a good example of a public-private collaboration to establish a national infrastructure for precision oncology. Trial registrations EudraCT: 2020-004414-35, registered 02/19/2021; ClinicalTrial.gov: NCT04817956, registered 03/26/2021.

Treatment and survival of patients with pancreatic ductal adenocarcinoma: 15-year national cohort.

BACKGROUND: Improvement in survival from pancreatic ductal adenocarcinoma (PDAC) has been reported in trial settings but is less explored in unselected cohorts. The aim of this study was to assess trends in provision of treatments and survival in Norway over a 15-year period following the implementation of hepato-pancreato-biliary (HPB) multidisciplinary teams, centralization of surgery, and implementation of modern chemotherapy (CTx) regimens. METHODS: A population-based observational study was conducted by analysing all patients diagnosed with PDAC between 2004 and 2018 using coupled data from the Cancer Registry of Norway and the National Patient Registry. RESULTS: A total of 10 630 patients were identified, of whom 1492 (14.0 per cent) underwent surgical resection. The resection rate, median age of those resected, and provision of perioperative CTx all increased over time. Median overall survival after resection improved from 16.0 months in the period 2004 to 2008 to 25.1 months in the period 2014 to 2018 (P < 0.001). For non-resected patients there was a rise in the provision of palliative chemotherapy, but little survival gain over time (median overall survival for 2004 to 2008 was 3.2 months versus 4.2 months for 2014 to 2018; P < 0.001). The rate of patients who did not receive any tumour-directed treatment (neither CTx nor surgery) was 44.3 per cent (2481 of 5603 patients) and decreased from 52.9 per cent in 2010 to 37.9 per cent in 2018 (P < 0.001). The median overall survival for all patients with PDAC increased from 3.7 months for 2004 to 2008 to 5.8 months for 2014 to 2018 (P < 0.001). CONCLUSION: Survival after resection increased substantially, as did national resection rates. Little development in the provision of CTx or survival was observed for non-resected patients.

PALLiON - PALLiative care Integrated in ONcology: study protocol for a Norwegian national cluster-randomized control trial with a complex intervention of early integration of palliative care.

BACKGROUND: Several publications have addressed the need for a systematic integration of oncological care focused on the tumor and palliative care (PC) focused on the patient with cancer. The exponential increase in anticancer treatments and the high number of patients living longer with advanced disease have accentuated this. Internationally, there is now a persuasive argument that introducing PC early during anticancer treatment in patients with advanced disease has beneficial effects on symptoms, psychological distress, and survival. METHODS: This is a national cluster-randomized trial (C-RCT) in 12 Norwegian hospitals. The trial investigates effects of early, systematic integration of oncology and specialized PC in patients with advanced cancer in six intervention hospitals compared with conventional care in six. Hospitals are stratified on the size of local catchment areas before randomization. In the intervention hospitals, a three-part complex intervention will be implemented. The backbone of the intervention is the development and implementation of patient-centered care pathways that contain early, compulsory referral to PC and regular and systematic registrations of symptoms. An educational program must be completed before patient inclusion. A total of 680 patients with advanced cancer and one caregiver per patient are included when patients come for start of last line of chemotherapy, defined according to national treatment guidelines. Data registration, clinical variables, and patient- and caregiver-reported outcomes take place every 2 months for 1 year or until death. The primary outcome is use of chemotherapy in the last 3 months of life by comparing the proportion of patients who receive this in the intervention and control groups. Primary outcome is use of chemotherapy in the last 3 months before death, i.e. number of patients. Secondary outcomes are initiation, discontinuation and number of cycles, last 3 months of life, administration of other medical interventions in the last month of life, symptom burden, quality of life (QoL), satisfaction with information and follow-up, and caregiver health, QoL, and satisfaction with care. DISCUSSION: Results from this C-RCT will be used to raise the awareness about the positive outcomes of early provision of specialized palliative care using pathways for patients with advanced cancer receiving medical anticancer treatment. The long-term clinical objective is to integrate these patient-centered pathways in Norwegian cancer care. The specific focus on the patient and family and the organization of a predictable care trajectory is consistent with current Norwegian strategies for cancer care. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03088202. Registered on 23 March 2017.

Adverse Health Outcomes and Associations with Self-Reported General Health in Childhood Lymphoma Survivors.

BACKGROUND: The increased incidence of physical and psychosocial adverse health outcomes (AHOs) in childhood lymphoma survivors (CLSs) is well known, but these AHOs' association with self-reported general health is rarely described. AIM: We explored this association among long-term CLSs. METHODS: In 124 CLSs (Hodgkin: 81; non-Hodgkin: 43; median age: 33 years), physical AHOs were graded based on slightly modified common toxicity criteria for adverse effects (CTCAE)-4 recommendations (Grade 0-3). Psychosocial AHOs (pain, work inability, fatigue, and mental distress) were mainly assessed by validated patient-reported questionnaires (Grade 0-2). The results were related to contemporary self-reported general health. Statistical significance: p < 0.01. RESULTS: At least one physical AHO was found in 120 CLSs, being of Grades 1, 2, and 3, respectively, in 43, 43, and 34 survivors. The prevalence of psychosocial AHOs (Grades 1 or 2) was 63%, being Grade 2 in 62 CLSs. The CLSs described their general health as significantly reduced compared with controls, with the greatest reduction for survivors in whom physical AHOs were combined with moderate to severe psychosocial AHOs. CONCLUSION: Psychosocial more than physical AHOs impact on CLSs' current self-reported general health. Clinicians responsible for follow-up of CLSs should be aware of the strong reduction of contemporary general health by Grade 2 psychosocial AHOs. The study challenges the use of the physician-assessed CTCAE-4 categories in long-term cancer survivors and emphasizes the need to develop instruments, which reflect both physical and psychosocial AHOs in these individuals.

Feasibility of a physical activity intervention during and shortly after chemotherapy for testicular cancer.

BACKGROUND: Given the risk of developing acute and long-term adverse effects in patients receiving cisplatin-based chemotherapy for testicular cancer (TC), risk-reducing interventions, such as physical activity (PA), may be relevant. Limited knowledge is available on the challenges met when conducting PA intervention trials in patients with TC during and shortly after chemotherapy. The aims of the present feasibility study are therefore to determine patient recruitment, compliance and adherence to a PA intervention. RESULTS: Patients with metastatic TC referred to cisplatin-based chemotherapy were eligible. They followed an individual low-threshold PA intervention, including counseling from a personal coach during and 3 months after chemotherapy. Outcomes were recruitment rate, compliance rate and adherence to the intervention including preferences for type of PA and barriers for PA. During 8 months 12 of 18 eligible patients were invited, all consented, but three dropped out. Walking and low intensity activities were preferred and nausea and feeling unwell were the most often reported barriers towards PA. DISCUSSION: In order to achieve adequate recruitment, compliance and complete data in future PA intervention trials, close cooperation with treating physicians, individual PA plans and availability of personalized coaching are required. Trial registration NCT01749774, November 2012, ClinicalTrials.gov.

Utility of Global Longitudinal Strain by Echocardiography to Detect Left Ventricular Dysfunction in Long-Term Adult Survivors of Childhood Lymphoma and Acute Lymphoblastic Leukemia.

Measuring left ventricular (LV) global longitudinal strain (GLS) is recommended in screening of long-term cancer survivors for cardiotoxicity. However, there are limited data on GLS in this setting, in particular in survivors with apparently normal LV function without risk factors of impaired GLS. In the present study, we measured GLS in 191 adult survivors of childhood lymphoma or acute lymphoblastic leukemia, with normal LV ejection fraction and fractional shortening (FS) and without known hypertension, diabetes mellitus, myocardial infarction, or stroke. We compared GLS in the survivors with 180 controls. Mean GLS was -19.0 ± 2.2% in the survivor group and -21.4 ± 2.0% in the controls (p <0.001). Impaired GLS, defined as mean - 1.96 SDs in the control group, occurred in 53 of 191 survivors (28%). We included survivors with impaired LV ejection fraction and/or FS or traditional risk factors (n = 231 in all) in multiple regression analyses to explore associations with previous cancer treatment. Survivors treated with mediastinal radiotherapy had an odds ratio of impaired GLS of 5.2 (95% confidence interval 2.2 to 12) compared with other survivors. Survivors treated with cumulative anthracycline doses >300 mg/m(2) had an odds ratio of 4.8 (95% confidence interval 1.7 to 14) of impaired GLS. In conclusion, this study demonstrates a high proportion of LV dysfunction assessed by GLS in apparently healthy adult survivors of childhood cancer. Impaired GLS was associated with previous exposure to mediastinal radiotherapy and high doses of anthracyclines. The prognostic role of measuring GLS in this specific patient population should be examined in prospective studies.

Right ventricular function in long-term adult survivors of childhood lymphoma and acute lymphoblastic leukaemia.

AIMS: Little is known about right ventricular (RV) function in survivors of childhood cancer, although both anthracyclines and radiotherapy represent potentially cardiotoxic treatment. We hypothesized that adult survivors of childhood malignant lymphoma or acute lymphoblastic leukaemia would have impaired RV function. METHODS AND RESULTS: We examined RV dimensions and function by echocardiography in 246 survivors, mean 21.7 years after diagnosis, and in 211 matched controls. Of the survivors, 84% had been exposed to anthracyclines, mediastinal radiotherapy, or both. Compared with controls, all mean measures of RV function were lower in the survivor group: fractional area change (44.5 vs. 48.6%, P < 0.001), tricuspid annular plane systolic excursion (2.24 vs. 2.49 cm, P < 0.001), peak systolic tricuspid annular velocity (12.1 vs. 13.0 cm/s, P < 0.001), and free wall strain (-26.5 vs. -28.4%, P < 0.001). In contrast, there were little differences in RV diastolic dimensions. Lower measures of RV function were found in all survivor subgroups having received cardiotoxic treatment, but not in the 16% of survivors unexposed to anthracyclines or mediastinal radiotherapy. Signs of RV systolic dysfunction were found in 30% of the survivors, and more than 3 times more often in survivors with left ventricular dysfunction. CONCLUSION: Long-term survivors of childhood lymphoma or acute lymphoblastic leukaemia frequently have impaired RV function compared with controls. As this is associated with increased risk of heart failure and death in many other conditions, we recommend increased attention to RV function in childhood survivors. Whether RV dysfunction impairs prognosis in this patient group should be examined in longitudinal studies.

"Natural course" of disease in patients with metastatic castrate-resistant prostate cancer: Survival and prognostic factors without life-prolonging treatment.

OBJECTIVE: The aim of this study was to determine survival and prognostic factors in unselected patients with metastatic castrate-resistant prostate cancer (mCRPC), who never received life-prolonging treatment. MATERIALS AND METHODS: The study was a retrospective analysis of a consecutive sample of patients with mCRPC seen at the urological unit of a local hospital from 2000 to 2005, their mCRPC diagnosis based on rising prostate-specific antigen (PSA) during androgen depletion treatment (ADT). RESULTS: Median overall survival was 12.3 months (range 0.2-108 months), the 3 year survival was 16.9% (95% confidence interval 0.11-0.24) and two patients were alive at the end of follow-up. Compared to a PSA nadir of greater than 11 µg/l during ADT, a PSA nadir of less than 1 µg/l significantly decreased the risk of death by 71%. A PSA doubling time less than 1.6 months during the early phase of mCRCP almost tripled the risk of death compared to a PSA doubling time longer than 3 months. Alkaline phosphatase serum levels and hemoglobin levels within the normal range indicated a favorable prognosis. CONCLUSIONS: The "natural course" of mCRPC varies without life-prolonging treatment along with PSA nadir during ADT, PSA doubling time, alkaline phosphatase and hemoglobin level at mCRPC diagnosis. 3-year survival or longer is observed in 16.9% of patients. In clinical intervention trials among mCRPC patients, all known prognostic factors should be taken into account during the randomization process and during survival analyses.

Providing information about late effects after childhood cancer: lymphoma survivors' preferences for what, how and when.

OBJECTIVE: Childhood cancer survivors need information about risks of late effects to manage their health. We studied how and when adult, long-term survivors prefer to receive information about late effects. METHODS: Five focus-groups with adult survivors of childhood lymphomas who had completed routine follow-up care and participated in a preceding follow-up study (n = 34, 19 females, mean age = 39). We used thematic analysis to identify themes regarding providing late effects information. RESULTS: The survivors wanted information about late effects (symptoms, prevention and treatment), lifestyle and social security rights. Information should be tailored, carefully timed, given "face-to-face" and in written format. Many expressed ambivalence regarding receiving information as adolescents, but it was seen as essential "to know" once a late effect occurred. A "re-information" consultation about late effects around age 25 was suggested as beneficial. CONCLUSION: Although ambivalent, all survivors wanted information about late effects. They preferred individualized information, disclosed "step-by-step" and in a "re-information consultation" when reaching young adulthood. PRACTICE IMPLICATIONS: Providing information about late effects should be an on-going process across the cancer care trajectory. (Re-)Informing survivors when older would enhance their understanding of their health risks and could aid better health self-management beyond completion of follow-up care.

Left ventricular function in long-term survivors of childhood lymphoma.

Survivors of childhood lymphoma (CL) have markedly increased risk of developing heart failure. Echocardiographic studies after cardiotoxic treatment have primarily demonstrated left ventricular (LV) systolic dysfunction. In the present study, we hypothesized that longer follow-up and a more comprehensive echocardiographic examination would reveal more cardiac abnormalities. We conducted a cross-sectional study with echocardiography 20.4 ± 8.6 years after diagnosis in 125 survivors of CL, grouped according to treatment methods, and compared with matched controls. Treatment included mediastinal radiotherapy (median 40.0 Gy) in 66 and anthracyclines (median dose 160 mg/m(2)) in 92 survivors of CL. Abnormal LV function, left-sided valve dysfunction, or both occurred in 62 patients (50%). Diastolic dysfunction occurred in 29%. Compared with control subjects, mitral annular early diastolic velocities (e') were reduced in patients (septal e' 0.09 ± 0.03 vs 0.12 ± 0.03 m/s, p <0.001), and the E/e' ratio was increased, particularly after mediastinal radiotherapy (10.6 ± 6.4 vs 5.6 ± 1.3, p <0.001). Survivors of CL had lower fractional shortening than control subjects (32 ± 6 vs 36 ± 7, p <0.001), but mean ejection fraction was equal and overt systolic dysfunction was infrequent. After mediastinal radiotherapy alone, global longitudinal myocardial strain was lower (p <0.05) compared with other treatment groups. Left-sided valvular dysfunction occurred in 55% of patients after mediastinal radiotherapy. In conclusion, survivors of CL had reduced LV diastolic function assessed by tissue Doppler imaging. This was more pronounced after mediastinal radiotherapy, which also frequently led to valvular disease. Systolic function was normal in most survivors of CL.

Chronic fatigue in adult survivors of childhood cancer: associated symptoms, neuroendocrine markers, and autonomic cardiovascular responses.

BACKGROUND: Chronic fatigue (CF) is a common late effect after childhood cancer. OBJECTIVE: Based on findings among patients with the chronic fatigue syndrome (CFS), this study explored symptoms, neuroendocrine markers, and autonomic cardiovascular responses associated with CFS in childhood cancer survivors. METHODS: Long-term survivors of childhood lymphoma and acute lymphoblastic leukemia reporting CF were compared with survivors without CF. Data included patient-reported outcomes, clinical examination, head-up tilt test, and neuroendocrine markers in the blood and the urine. RESULTS: Of 102 included survivors, 15 were excluded from comparative analyses because of significant co-morbidity or pregnancy. Of the remaining 87 participants (median age 33.0 years, follow-up time 25.2 years), 35 had CF and 52 did not have CF. Compared with non-CF controls, CF cases reported a significantly (P < 0.01) higher frequency of symptoms typical of the CFS (muscle or joint pain or both and feeling confused/disoriented) and symptoms of autonomic dysfunction (palpitations, feeling intermittently heat and cold, and watery diarrhea). CF cases and controls did not differ regarding autonomic cardiovascular responses to orthostatic stress, but the CF group had lower levels of plasma adrenocorticotrophic hormone (P = 0.002) and higher levels of urine norepinephrine (P = 0.017). CONCLUSIONS: Survivors with CF reported a high symptom-burden compared with controls. There were few differences between both the groups regarding biomarkers, but slight alterations of the hypothalamus-pituitary-adrenal axis and sympathetic nervous activity were detected. CF in cancer survivors has features in common with the CFS, but further efforts are required to clarify the pathophysiology.

Chronic fatigue in long-term survivors of childhood lymphomas and leukemia: persistence and associated clinical factors.

BACKGROUND: Chronic fatigue (CF) is an important late effect after childhood malignancies. Our aim was to assess CF persistence over time, concurrent comorbidities, and associations with clinical symptoms. PROCEDURE: A total of 102 long-term survivors of childhood lymphomas and acute lymphoblastic leukemia, 53 and 49 reporting CF and no CF, respectively, at time point (TP)1, were evaluated for CF at a second TP after a median interval of 2.7 years. At TP2 a survey, including self-reported and objectively measured variables, assessed depressive symptoms, pain, and physical activity. RESULTS: A total of 32 of the 53 reported CF cases at both TPs and 40/49 survivors had no CF at both TPs, whereas 30 had changed their fatigue status between first and second assessment (converters). Major somatic comorbidities were equally distributed among the groups. After exclusion of converters and survivors with major comorbidity/pregnancy, 27 persistent CF (PCF) cases and 35 controls were compared. PCF cases reported significantly more depression, sleeping problems, anxiety, pain, and reduced physical function. Further, they were less physically active than controls (steps/d; P=0.009). In a multiple regression analysis, depressive symptoms remained the only significant predictor of PCF. CONCLUSIONS: Long-term survivors of childhood cancer with PCF are characterized by more depressive symptoms, anxiety, pain, insomnia, and less physical activity.