Hypoalbuminemia, but not derived neutrophil to lymphocyte ratio (dNLR), predicts overall survival in neuroendocrine tumours undergoing peptide receptor radionuclide therapy: A retrospective, cohort study of 557 patients.

Several inflammation scores have shown association with survival outcomes for patients with neuroendocrine tumours (NET) treated with peptide receptor radionuclide therapy (PRRT). However, whether these scores add value to established prognostic factors remains unknown. In this retrospective, cohort study of 557 NET patients undergoing PRRT in a tertiary referral centre from 2005 to 2015, we examined inflammatory markers and scores previously associated with cancer outcomes, using Cox proportional hazard models and Akaike's information criterion. Lower albumin (hazard ratio [95% confidence interval], .91 [.87-.95] per unit), as well as higher C-reactive protein (CRP; 1.02 [1.01-1.02]), Glasgow Prognostic Score (GPS; 1 vs. 0: 1.67 [1.14-2.44], 2 vs. 0 3.60 [2.24-5.79]), CRP/albumin ratio (1.84 [1.43-2.37]) and platelet count (Plt) × CRP, but not white blood cell, neutrophil and thrombocyte counts or derived neutrophil to lymphocyte ratio (dNLR), were associated with shorter median overall survival (OS) in an adjusted analysis. The addition of parameters based on albumin and CRP, but not dNLR, to a base model including age, chromogranin A, the cell proliferation marker Ki-67, performance status, tumour site and previous treatments improved the predictive accuracy of the base model. In an exploratory analysis of patients with available erythrocyte sedimentation rate (ESR) and CRP, ESR emerged as the most powerful predictor. When added to a prognostic model for OS in NET patients treated with PRRT, most inflammation scores further improved the model. Albumin was the single marker adding most value to the set of established prognostic markers, whereas dNLR did not seem to improve the model's prognostic ability.

Treatment Patterns and Efficacy of Chemotherapy After Pembrolizumab in Advanced Urothelial Cancer-a Real-World Study in the pre-Antibody-Drug Conjugate Era.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been established as a routine treatment in patients with metastatic urothelial cancer (mUC). However, there has been no standard of care after progression on ICIs. We investigated real-world treatment patterns and efficacy of chemotherapy (CHT) after pembrolizumab, in the era before introduction of maintenance avelumab and antibody-drug conjugates (ADC). PATIENTS AND METHODS: An observational, retrospective study was conducted at twelve Nordic centers. Patients with mUC were treated according to investigator´s choice of CHT after pembrolizumab. Primary endpoint was overall response (ORR) and disease control rate (DCR); secondary endpoints were progression-free (PFS) and overall survival (OS). RESULTS: In total, 102 patients were included whereof 23 patients received CHT after pembrolizumab as second line treatment (subcohort A) and 79 patients in third line (subcohort B). Platinum-gemcitabine combinations were the most common regimens in subcohort A, and vinflunine in subcohort B. The ORR and DCR were 36% and 47%, respectively. Presence of liver metastases was independently associated with lower ORR and DCR. The PFS and OS were 3.3 months and 7.7 months, respectively. Eastern Cooperative Oncology Group Performance Status (ECOG PS) and number of previous cycles of pembrolizumab were found to be independent prognostic factors associated with OS. CONCLUSION: In a real-world setting, CHT showed clinically meaningful response rates and survival in mUC patients after progression with pembrolizumab. Clinical benefit may primarily be achieved in patients with favorable ECOG PS, in patients treated with > 6 cycles pembrolizumab as well as in patients without presence of liver metastases.

Activity and safety of KEES - an oral multi-drug chemo-hormonal metronomic combination regimen in metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge and evidence for late-line treatments in real-life is limited. The present study investigates the efficacy and safety of an oral metronomic chemo-hormonal regimen including cyclophosphamide, etoposide, estramustine, ketoconazole and prednisolone (KEES) administered in a consecutive biweekly schedule. METHODS: A retrospective cohort study in two Swedish regions was conducted. Overall (OS) and progression-free survival (PFS), biochemical response rate (bRR) and toxicities were analyzed. RESULTS: One hundred and twenty-three patients treated with KEES after initial treatment with at least a taxane or an androgen-receptor targeting agents (ARTA) were identified. Of those, 95 (77%) had received both agents and were the primary analysis population. Median (95% CI) OS and PFS in the pre-treated population were 12.3 (10.1-15.0) and 4.4 (3.8-5.5) months, respectively. Biochemical response, defined as ≥ 50% prostate-specific antigen (PSA) reduction, occurred in 26 patients (29%), and any PSA reduction in 59 (65%). PFS was independent of prior treatments used, and KEES seemed to be effective in late treatment lines. The bRR was higher compared to historical data of metronomic treatments in docetaxel and ARTA pre-treated populations. In multivariable analyses, performance status (PS) ≥ 2 and increasing alkaline phosphatase (ALP) predicted for worse OS. Nausea, fatigue, thromboembolic events and bone marrow suppression were the predominant toxicities. CONCLUSIONS: KEES demonstrated meaningful efficacy in heavily pre-treated CRPC patients, especially those with PS 0-1 and lower baseline ALP, and had an acceptable toxicity profile.

Outcomes of Patients with Advanced Urothelial Carcinoma after Anti-programmed Death-(ligand) 1 Therapy by Fibroblast Growth Factor Receptor Gene Alteration Status: An Observational Study.

Background: Clinical outcomes of anti-programmed death­(ligand) 1 (anti-PD-[L]1) therapy in patients with locally advanced or metastatic urothelial carcinoma (mUC) and fibroblast growth factor receptor alterations (FGFRa+) remain unclear; recent studies have reported either comparable or poorer outcomes versus patients without FGFR alterations (FGFRa-). Objective: To analyze the outcomes of patients with mUC and any FGFRa (mutations or fusions) who received anti-PD-(L)1 therapy. Design setting and participants: In this noninterventional, retrospective, multicenter study, clinical practice data were collected from FGFRa+/- patients who received prior immunotherapy between May 2018 and July 2019. Outcome measurements and statistical analysis: Investigator­determined overall response rate (ORR), disease control rate (DCR), and overall survival (OS) were assessed in multivariate and unadjusted analyses. Results and limitations: Ninety-four patients (66% men; median age, 63 yr) with mUC and known FGFR status were included; 38 (40%) were FGFRa+ and 56 (60%) were FGFRa-. In FGFRa+ versus FGFRa- patients who received any line of anti-PD-(L)1 therapy (n = 92), ORR, DCR, and OS were 16% versus 26%, 29% versus 52% (relative risk: 1.14 [95% confidence interval {CI}, 0.92-1.40]; p = 0.3), and 8.57 versus 13.2 mo (hazard ratio [HR]: 1.33 [95% CI, 0.77-2.30]; p = 0.3), respectively. A multivariate analysis provided some evidence supporting shorter OS in FGFRa+ versus FGFRa- (any line of anti-PD-L[1] therapy; HR: 1.81 [95% CI, 0.99-3.31]; p = 0.054). Limitations include this study's retrospective nature and a potential selection bias from small sample size. Conclusions: Some evidence of lower response rates and shortened OS following anti-PD-(L)1 therapy was observed in FGFRa+ patients. The phase 3 THOR study (NCT03390504) will prospectively compare FGFRa+ patients with advanced mUC treated with erdafitinib versus pembrolizumab. Patient summary: Patients with metastatic urothelial carcinoma and prespecified fibroblast growth factor receptor alterations (FGFRa) potentially have worse clinical outcomes when treated with anti-PD-(L)1 therapy than those without FGFRa.

Treatment efficacy in a metastatic small intestinal neuroendocrine tumour grade 2 cohort.

Small intestinal neuroendocrine tumours (Si-NET) are often studied as a uniform group. Proliferation index Ki-67 influences prognosis and determines tumour grade. We hypothesized that Si-NET grade 2 (G2) tumours, which have a higher Ki-67 than G1 tumours, might benefit less from established treatments for metastatic disease. We conducted a retrospective cohort study of 212 patients with metastatic Si-NET G2 treated in two Swedish hospitals during 20 years (2000-2019). Median cancer-specific survival on first-line somatostatin analogues (SSA) was 77 months. Median progression-free survival (PFS) was 12.4 months when SSA was given as monotherapy and 19 months for all patients receiving first-line SSA. PFS after SSA dose escalation was 6 months in patients with radiological progression. Treatment efficacies of SSA and peptide receptor radionuclide treatment (PRRT) were studied separately in patients with Ki-67 of 3-5%, 5-10% and 10-20%. For SSA, PFS was significantly shorter at higher Ki-67 levels (31, 18 and 10 months, respectively), while there was only a minor difference in PFS for PRRT (29, 25 and 25 months). Median PFS for sequential treatment with interferon-alpha (IFNα), everolimus and chemotherapy was 6, 5 and 9 months. IFNα seemed to be effective in tumours with low somatostatin-receptor expression. In conclusion, established treatments appeared effective in Si-NET G2, despite their higher proliferation index compared to G1 tumours. However, efficacy of SSA but not PRRT was reduced at higher Ki-67 levels. SSA dose escalation provided limited disease stabilization.

Systemic treatment in patients with malignant pleural mesothelioma - real life experience.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural cavity linked to asbestos exposure. The combination of pemetrexed and platinum is a standard first-line therapy for malignant pleural mesothelioma. Despite some progress, almost all MPM patients experience progression after first-line therapy. The second-line treatment is still being under discussion and there are very limited data available on the second-line and subsequent treatments. METHODS: The retrospective analysis included 57 patients (16 females and 41 males) from two Polish oncological institutions treated for advanced mesothelioma between 2013 and 2019. We analysed the efficacy of first-line and second-line therapy: progression-free survival (PFS), overall survival (OS), overall response rate (ORR). RESULTS: In the first-line treatment, 55 patients received pemetrexed-based chemotherapy (PBC) and two cisplatin in monotherapy. Patients' characteristics at baseline: median age was 64.2 years, ECOG PS ≤ 1 (86.2%), epithelial histology (85.7%). Median PFS and OS were 7.6 months and 14 months, respectively. Patients with ECOG PS ≤ 1 vs > 1 had a longer median OS (14.8 months vs 9.7 months, p = 0.057). One-year OS and PFS were 60.9% and 32.0%, respectively. Disease control rate (DCR) was 82.5%. Response to first-line therapy: PFS ≥ 6 months and PFS ≥ 12 months had a significant impact on median OS. Twelve patients received second-line therapy (seven PBC and five other cytotoxic single agents: navelbine, gemcitabine, or adriamycin/vincristine/methotrexate triplet). Median PFS and OS were 3.7 months and 7.2 months, respectively. DCR was 83%. One-year OS and PFS were 37% and 16.7%, respectively. In the group receiving PBC, OS was prolonged by 4.5 months compared to the non-PBC group (6.0 months vs 10.5 months, p = 0.47). CONCLUSION: Patients who benefited from first-line therapy and had prolonged PFS at first-line and achieve PFS longer than 6 months at first-line should be offered second-line treatment. Consideration of retreatment with the same cytotoxic agent could to be a viable option when no other treatment are available.

Quality of Life in the First Year of Follow-Up in a Randomized Multicenter Trial Assessing the Role of Imaging after Radical Surgery of Stage IIB-C and III Cutaneous Melanoma (TRIM Study).

The benefit of imaging in the follow-up setting for high-risk melanoma patients is uncertain, and even less is known about the impact of intensive follow-up on the patient´s quality of life. In 2017, a Swedish prospective randomized multicenter study started, in which high-risk melanoma patients are randomly assigned 1:1 to follow-up by physical examinations +/- whole-body imaging. The first-year examinations are scheduled at 0, 6 and 12 months. The aim of this study was to investigate whether the patients´ health-related quality of life (HRQoL) and levels of anxiety and depression were affected at 1 year by imaging. Anxiety/depression and HRQoL were assessed at 0 and 12 months by the questionnaires Hospital Anxiety and Depression (HAD) scale and EORTC QLQ-C30 version 3. Expected baseline QLQ-C30 values for the patients were calculated using data from the general population. In total, 204 patients were analyzed. Mean differences in subscale scores at 1 year were not statistically significant either for HRQoL or for anxiety/depression. Baseline HRQoL did not differ from expected values in the general Swedish population. In conclusion, the patients in general coped well with the situation, and adding whole-body imaging to physical examinations did not affect the melanoma patients' HRQoL or levels of anxiety or depression.

Real-world evaluation of upfront docetaxel in metastatic castration-sensitive prostate cancer.

BACKGROUND: The majority of patients with newly diagnosed metastatic prostate cancer (PC) initially respond to androgen deprivation therapy (ADT) and are classified as metastatic castration-sensitive PC (mCSPC). Following months to years of ADT, the disease tends to become resistant to ADT. Recent randomized phase-III trials demonstrated a survival benefit with the addition of upfront docetaxel to ADT in mCSPC. Following its implementation in routine care, this combined treatment strategy requires more detailed evaluation in a real-world setting. AIM: To assess the real-world outcome and safety of upfront docetaxel treatment in mCSPC. METHODS: A multicenter retrospective cohort study in the Southeast Health Care Region of Sweden was performed. This region includes approximately 1.1 million citizens and the oncology departments of Linköping, Jönköping, and Kalmar. All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included. The primary endpoint was progression-free survival (PFS) at 12 mo, and the secondary endpoints were PFS at 24 mo, overall survival (OS), treatment intensity, adverse events, and unplanned hospitalizations. Exploratory analyses on potential prognostic parameters were performed. RESULTS: Ninety-four patients were eligible and formed the study cohort. PFS at 12 and 24 mo was 75% (95%CI: 66-84) and 58% (46-70), respectively. OS at 12 and 24 mo was 93% (87-99) and 86% (76-96). A total of 91% of patients (n = 86) were given docetaxel according to the standard protocol of 75 mg/m2 every 3 wk (6 cycles), while 9% (n = 8) received a modified protocol of 50 mg/m2 every 2 wk (9 cycles). The average overall dose intensity for those commencing standard treatment was 91%. Univariate Cox regression analyses show that baseline PSA > 180 vs < 180 and the presence of distant metastases vs locoregional lymph node metastases were only negative prognostic factors (HR 2.86, 95%CI: 1.39-5.87, P = 0.0041 and 3.36, 95%CI: 1.03-10.96, P = 0.045). Following multivariate analysis, statistical significance remained for PSA (2.51, 95%CI: 1.21-5.19, P = 0.013) but not for metastatic status (2.60, 95%CI: 0.78-8.65, P = 0.12). Febrile neutropenia was recorded in 21% (n = 20) of patients, and 26% (n = 24) had at least one episode of unplanned hospitalization under and up to 30 d after the treatment course. CONCLUSION: Results from this study support the implementation of upfront docetaxel plus ADT as part of the standard of care treatment strategy in mCSPC.

Assessment of hormonal levels as prognostic markers and of their optimal cut-offs in small intestinal neuroendocrine tumours grade 2.

PURPOSE: Small intestinal neuroendocrine tumours (siNETs) with a Ki-67 proliferation index between 3 and 20% belong to WHO grade 2. Response to treatment may be monitored by blood chromogranin A (CgA) and urine 5-hydroxyindoleacetic acid (5HIAA). The aim of this retrospective study was to investigate the prognostic value of baseline CgA and 5HIAA and of the early biochemical response to treatment, and to compare different cut-off values used in the literature. METHODS: A retrospective cohort study of 184 patients with siNET Grade 2 treated with somatostatin analogues (SSA), interferon-alpha (IFN) or peptide receptor radionuclide therapy (PRRT). RESULTS: Baseline CgA was a statistically significant prognostic marker for both cancer-specific survival (CSS) and progression-free survival (PFS). A cut-off of 5 × ULN (upper limit of normal) was best discriminative in most cases, but 2 × ULN discriminated better for SSA. Baseline 5HIAA was a prognostic marker for CSS in treatment with IFN and PRRT, but not for single SSA. Early changes of CgA and 5HIAA correlated well with CSS (HR 3.18, 95% CI 1.82-5.56 and HR 1.47, 95% CI 1.16-1.86) and PFS (HR 3.08, 95% CI 1.86-5.10 and HR 1.37, 95% CI 1.11-1.68) for SSA, but not for PRRT. CONCLUSIONS: Baseline CgA and to a lesser extent 5HIAA are associated with CSS irrespective of treatment used, and with PFS after PRRT, and 5 × ULN provides best discrimination in many, but not all, cases. Early reductions of CgA and 5HIAA are prognostic for treatment with SSA, but not PRRT.

TRIM study protocol - a prospective randomized multicenter Trial to assess the Role of Imaging during follow-up after radical surgery of stage IIB-C and III cutaneous malignant Melanoma.

BACKGROUND: The incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3 years by clinical examinations only. METHODS: The TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5 years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is > 1300. Patients are randomized to clinical examinations for 3 years +/- whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group. DISCUSSION: This is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM. RESULTS: The first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03116412 . Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412.

Predictors of antiproliferative effect of lanreotide autogel in advanced gastroenteropancreatic neuroendocrine neoplasms.

PURPOSE: The antiproliferative properties of lanreotide autogel (LAN) in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) were demonstrated in the CLARINET study. However, there is limited literature regarding factors that affect progression-free survival (PFS) in patients with GEP NENs treated with LAN. METHODS: We identified a total of 191 treatment-naive patients with advanced GEP NENs and positive SSTR uptake on imaging (Octreoscan or 68Gallium DOTATATE Positron Emission Tomography [68GaPET]) who received first-line LAN monotherapy, albeit at various starting doses (60, 90 or 120 mg/month). A group of 102 patients who initiated treatment at the standard dose of 120 mg/month were included in the study and further evaluated by univariate and multivariate analyses to identify predictors of PFS. RESULTS: The location of tumour primary was in the small bowel in 63 (62%), pancreas in 31 (30%) and colon/rectum in 8 patients (8%). The tumours were well-differentiated, and the majority were grade 1 (52%), or 2 (38%). About 60% of cases had progressive disease at the time of treatment initiation. Most patients with available pretreatment nuclear medicine imaging (Octreoscan or 68Ga PET) had a Krenning score of 3 (44%) or 4 (50%). The median PFS for the entire cohort was 19 months (95% CI 12, 26 months). The univariate analysis demonstrated that grade 2 tumours, progressive disease at baseline and metastatic liver disease were associated with a significantly shorter PFS, while other evaluated variables did not affect PFS at a statistically significant level. However, at multivariate analysis only the tumour grade remained statistically significant. CONCLUSIONS: The current study showed that, of many evaluated variables, only the tumour grade was predictive of PFS duration and this should be considered during patient selection for treatment.

Evaluation of Clinical Prognostic Factors and Further Delineation of the Effect of Mesenteric Fibrosis on Survival in Advanced Midgut Neuroendocrine Tumours.

BACKGROUND: Small intestinal neuroendocrine tumours (SI NETs) represent 30-50% of small bowel neoplasms and often present at an advanced stage. To date, there is relatively limited literature regarding prognostic factors affecting overall survival (OS) in stage IV disease. In addition, the prevalence of mesenteric fibrosis (MF) in SI NETs and its effect on OS have not been sufficiently explored in the literature. AIM: The primary aim of this study was to perform a large-scale survival analysis in an institutional cohort of 387 patients with metastatic (stage IV) SI NETs. The secondary aim was to provide epidemiological information regarding the prevalence of MF and to evaluate its effect on OS. RESULTS: The median OS was 101 months (95% CI 84, 118). Age > 65 years, mesenteric metastases with and without desmoplasia, liver metastases, carcinoid heart disease (CHD) and bone metastases were associated with a significantly shorter OS, while primary tumour resection was predictive of a longer OS. The benefit of surgical resection was limited to symptomatic patients. MF was present in approximately 50% of patients with mesenteric lymphadenopathy. Elevated urinary 5-HIAA levels correlated strongly with the presence of CHD (p < 0.001) and to a lesser extent (p = 0.02) with MF. MF and CHD did not usually co-exist, suggesting that different mechanisms are likely to be involved in the development of these fibrotic complications. CONCLUSIONS: This study has identified specific prognostic factors in a large cohort of 387 patients with advanced SI NETs and has provided useful epidemiological data regarding carcinoid-related fibrotic complications.

A Case Series of Molecular Imaging of Glucagonoma After Initial Therapy-68Ga-DOTATATE PET/CT Reveals Similar Results as in Neuroendocrine Tumors of Other Origin in Follow-up and Re-evaluation.

Glucagonoma is an extremely rare, glucagon-secreting neuroendocrine tumor of the pancreas. Only sparse data are available about the characteristics of this tumor in somatostatin receptor imaging and only for the situation of initial diagnosis. We present a series of 3 glucagonoma patients who underwent at least 1 Ga-DOTATATE PET/CT scan. All patients were diagnosed by either histology and/or elevated serum levels of glucagon. The presented cases suggest that somatostatin receptor-based imaging can probably be used for re-evaluation of disease status in patients with glucagonoma in a similar way as it is already established for neuroendocrine tumors of other origin.