Factors Associated With Prescription of Systemic Therapy in Real-world Patients With Metastatic Renal Cell Cancer Managed in a Rural Region.

Background/Aim: Numerous new treatment options have been approved for metastatic renal cell carcinoma (mRCC) in the last decade. Nevertheless, not all patients receive systemic therapy. Certain patients present with very advanced disease, poor Eastern Cooperative Oncology Group performance status (ECOG PS), or severe comorbidity, i.e. factors that lead oncologists to prefer best supportive care (BSC) instead of systemic therapy. The aim of this quality-of-care study was to identify baseline factors (disparities) associated with receipt of systemic therapy rather than BSC. Patients and Methods: This retrospective analysis included 140 consecutive patients managed in a rural region of Norway (2007-2022). Two differently managed groups were compared in univariate tests followed by multi-nominal regression. Results: The majority of patients (n=95, 68%) had received systemic therapy. Typical patients were males in their 60s or 70s, with clear cell histology, prior nephrectomy, and intermediate prognostic features. Patients who received systemic therapy lived significantly longer than those who did not (median 30.4 versus 5.0 months, p<0.001). Survival benefit of systemic treatment was observed even in patients with ECOG PS3 or age ≥80 years. In addition to younger age (p<0.001) and better ECOG PS (p<0.001), metachronous presentation was associated with higher rates of systemic therapy utilization (p=0.03). Conclusion: Assignment to systemic therapy for mRCC was individualized in the present patient population. In all age and ECOG PS subgroups, systemic therapy was associated with better survival (doubling at least). Optimum utilization rates are difficult to determine. However, in light of the survival outcomes, a rate of 12% in patients aged 80 years or older appears rather low.

Comprehensive Analysis of Blood Test Results Predicting Prognosis in Patients Undergoing Whole-brain Radiotherapy for Brain Metastases.

BACKGROUND/AIM: Blood tests, such as those included in the validated LabBM score (laboratory parameters in patients with brain metastases) predict survival after treatment of brain metastases. The model incorporates five test results [serum lactate dehydrogenase (LDH), C-reactive protein (CRP), albumin, platelets and hemoglobin]. However, many other abnormalities, albeit less well-studied, may be present in patients with metastatic cancer. Therefore, this study aimed to examine a broader range of blood tests. PATIENTS AND METHODS: This retrospective analysis included 132 patients managed with primary whole-brain radiotherapy. Additional tests, such as liver enzymes, lymphopenia, hyponatremia, and others, were also conducted. Extracranial disease extent was also analyzed. RESULTS: According to forward conditional Cox regression analyses, blood tests (albumin, hemoglobin, lymphopenia, hyponatremia) in conjunction with the number of organs affected by extracranial metastases (at least two, such as liver and bones) provided the best prognostic model. Based on these parameters, at least four prognostic strata can be assigned (median survival between 4.6 and <1 months, p=0.0001). CONCLUSION: This initial pilot study in a limited number of patients suggests that numerous blood test results may contribute to further refinement of existing prognostic models, and provides justification for additional large-scale studies.

Survival after docetaxel for metastatic castration-resistant prostate cancer in a rural health care setting.

Introduction: The aim of this study was to evaluate overall survival of men who received systemic therapy with docetaxel for metastatic castration- resistant prostate cancer (MCRPC) in rural Nordland County, Norway. Prognostic factors related to treatment and other variables were evaluated. Material and methods: Overall, 132 pa- tients were included in this retrospective study covering the years 2009-2022. Uni- and multivariate survival analyses were performed. Results: In this elderly cohort (median age 72 years), weekly low-dose docetaxel was the preferred regimen (44%). Seventy-three percent were treated in the first line. Only 11 patients (8%) were pre-exposed to docetaxel in the hormone-sensitive phase. Median survival was 14.3 months. Prognostic factors for longer survival included higher hemoglobin, lower lactate dehydrogenase, administration of docetaxel as first-line MCRPC treatment, and use of fewer prescription drugs for comorbidity. Pre-exposure to docetaxel did not play a major role, p = 0.76. Conclusions: In this rural health care setting, survival after docetaxel was shorter than reported by other groups. Blood test results were confirmed as important prognostic factors. In the present era of evolving treatment sequences, we recommend monitoring of real-world treatment results.

Independent Validation of a Unifying Prognostic Model for Intracranial and Extracranial Metastasis-directed Radiotherapy.

BACKGROUND/AIM: The aim of this study was to analyze the validity of a unifying prognostic model, originally developed by Kowalchuk et al., because relevant variations in clinical practice and observed survival may impact on the performance of predictive tools. PATIENTS AND METHODS: Retrospectively, data from a single institution were analyzed. The study included 253 patients managed with radiotherapy for spine and/or brain metastases. The Kowalchuk et al. score [3 parameters including performance status, number of organ systems involved with disease outside of the organ system of the treatment target, and treatment of intracranial target(s)] was assigned and the resulting prognostic strata compared. RESULTS: The decision tool developed by Kowalchuk et al. performed well, e.g., in terms of 2-year survival. Complementary information could be obtained by analyses of blood test results such as hemoglobin, albumin, and C-reactive protein. CONCLUSION: The new unifying score emerged as a valid prognostic model in our external validation database.

Early death after palliative radiation treatment: 30-, 35- and 40-day mortality data and statistically robust predictors.

BACKGROUND: This study analyzed mortality after radiotherapy for bone metastases (287 courses). Endpoints such as treatment in the last month of life and death within 30, 35 and 40 days from start of radiotherapy were evaluated. METHODS: Different baseline parameters including but not limited to blood test results and patterns of metastases were assessed for association with early death. After univariate analyses, multi-nominal logistic regression was employed. RESULTS: Of 287 treatment courses, 42 (15%) took place in the last month of life. Mortality from start of radiotherapy was 13% (30-day), 15% (35-day) and 18% (40-day), respectively. We identified three significant predictors of 30-day mortality (performance status (≤ 50, 60-70, 80-100), weight loss of at least 10% within 6 months (yes/no), pleural effusion (present/absent)) and employed these to construct a predictive model with 5 strata and mortality rates of 0-75%. All predictors of 30-day mortality were also associated with both, 35- and 40-day mortality. CONCLUSION: Early death was not limited to the first 30 days after start of radiotherapy. For different cut-off points, similar predictive factors emerged. A model based on three robust predictors was developed.

Patterns of Care and Survival in Cancer Patients with Brain Metastases Receiving Immune Checkpoint Inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become a mainstay of treatment for different cancer types. The purpose of this study was to evaluate patterns of care and overall survival (OS) after diagnosis of brain metastases in patients managed with ICI as component of care. METHODS: This was a retrospective cohort study. Fifty patients were included (34 with brain metastases at first cancer diagnosis, 16 with metachronous spread). RESULTS: Depending on symptoms, lesion number and size, and other individualized criteria, multidisciplinary tumor (MDT) board discussion resulted in highly individualized treatment sequences. Selected patients received systemic treatment alone. Twenty-four patients (48%) had any stereotactic radiosurgery or neurosurgical resection at some point in time (upfront/salvage). Only 7 patients (14%) were never treated with brain irradiation or neurosurgery. Median OS was 13.0 months. Better Karnofsky performance status, absence of extracranial metastases, and time interval between cancer diagnosis and brain metastases of 0-18 months predicted for improved survival. Treatment sequence was not associated with survival. Patients without extracranial metastases had median OS of 52.2 months. CONCLUSION: Long-term survival is possible in patients managed with ICI ± brain-directed treatment. This study did not identify a clear treatment sequence of choice. MDT assessment at diagnosis and each progression is recommended to ensure favorable outcomes.

Independent Validation of a Risk Stratification Model Predicting Survival in Elderly Patients Irradiated for Bone Metastases.

BACKGROUND/AIM: Many patients with bone metastases receive palliative radiotherapy. However, treatment personalization tools are needed, due to heterogeneous survival. The aim of this study was to analyze the validity of the prognostic survival model, originally developed by Rades et al., because international variations in clinical practice and survival outcomes may impact on the performance of predictive tools. PATIENTS AND METHODS: Data from a single institution were retrospectively analyzed. The study included 305 patients managed with palliative radiotherapy for bone metastases. The Rades et al. score was assigned and the resulting 3 prognostic strata were compared. RESULTS: The median overall survival for the 3 strata was 48, 248, and 1065 days, respectively (p<0.001). However, the original break-down (17 points versus 18-25 points versus >25 points) was not in accordance with the overlapping survival curves in some of the subgroups, leading us to propose slight adjustments. The modified model also performed satisfactorily in older patients (age ≥80 years; median survival 26, 192 and 489 days, respectively, p<0.001). CONCLUSION: The original Rades et al. survival score was a valid prognostic model in our Norwegian validation database. However, inclusion of patients with 18 points into the poor prognosis group is suggested as a modification to enhance the score's performance.

Stage-dependent prognostic shift in mismatch repair-deficient tumors: Assessing patient outcomes in stage II and III colon cancer.

Introduction: Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) is associated with an improved prognosis in colon cancer stage II but poor prognosis in stage IV colon cancer. The clinical significance of dMMR in colon cancer stage III is not established. Methods: Tissue microarrays (TMAs) from 544 patients with colon cancer stage II and III with clinicopathological and survival data were stained for mismatch repair (MMR) proteins, CD3, CD8, and programmed death ligand-1 (PD-L1), and programmed death ligand- 1 (PD-L1). Patient outcomes were reviewed. Results: In stage III colon cancer, dMMR was a marker of poor disease-free survival (DFS) (Kaplan-Meier, mean survival in months: dMMR: 28.76 (95% CI 18.46-39.05) vs. pMMR 40.91 (37.20-44.63), p=0.014, multivariate Cox regression: hazard ratio (HR) 4.17 (95% CI 2.02-8.61), p<0.001). In stage II colon cancer, there was a tendency toward improved DFS for dMMR patients (dMMR: 57.14 (95% CI 54.66-59.62) vs. pMMR 53.54 (95% CI 51.48-55.60), p=0.015, multivariate Cox regression HR 0.24 (95% CI 0.06-1.04), p=0.057). CD3, CD8, and PD-L1 expression was not associated with prognosis of dMMR patients. Multivariate Cox regression analysis showed a significant interaction between the MMR phenotype and stage (p=0.001). Conclusion: dMMR is associated with an improved prognosis in stage II colon cancer but is no longer associated with a favorable prognosis in stage III colon cancer.

Independent Validation of a Risk Stratification Model Predicting Survival in Patients With Metastatic Hormone-sensitive Prostate Cancer.

BACKGROUND/AIM: The aim of this study was to analyze the survival predictions obtained from an online nomogram, originally developed in two US patient cohorts with metastatic hormone-sensitive prostate cancer, because clinical practice and survival outcomes may vary on an international level. PATIENTS AND METHODS: A retrospective single-institution study of 197 patients, managed according to Norwegian guidelines, was performed. Model-predicted survival was assessed online and compared to observed survival. RESULTS: The median overall survival was 32.7 months. The nomogram predicted 3-year survival probabilities of 3-72% and 5-year probabilities of 0-54% in individual patients. Regarding 3-year prediction, the median was 47% (observed 3-year survival: 45%). The corresponding 5-year figures were 30% (nomogram) and 25% (observed). In univariate Cox regression, predicted 3-year and 5-year likelihood of survival were associated with observed survival of the study population (both p<0.001). CONCLUSION: The survival predictions from the US nomogram were correlated with observed survival in this Norwegian validation study.

30-day mortality in patients treated for brain metastases: extracranial causes dominate.

BACKGROUND: Established prognostic models, such as the diagnosis-specific graded prognostic assessment, were not designed to specifically address very short survival. Therefore, a brain metastases-specific 30-day mortality model may be relevant. We hypothesized that in-depth evaluation of a carefully defined cohort with short survival, arbitrarily defined as a maximum of 3 months, may provide signals and insights, which facilitate the development of a 30-day mortality model. METHODS: Retrospective analysis (2011-2021) of patients treated for brain metastases with different approaches. Risk factors for 30-day mortality from radiosurgery or other primary treatment were evaluated. RESULTS: The cause of death was unrelated to brain metastases in 61%. Treatment-related death (grade 5 toxicity) did not occur. Completely unexpected death was not observed, e.g. accident, suicide or sudden cardiac death. Logistic regression analysis showed 9 factors associated with 30-day mortality (each assigned 3-6 points) and a point sum was calculated for each patient. The point sum ranged from 0 (no risk factors for death within 30 days present) to 30. The results can be grouped into 3 or 4 risk categories. Eighty-three percent of patients in the highest risk group (> 16 points) died within 30 days, and none survived for more than 2 months. However, many cases of 30-day mortality (more than half) occurred in intermediate risk categories. CONCLUSION: Extracranial tumor progression was the prevailing cause of 30-day mortality and few, if any deaths could be considered relatively unexpected when looking at the complete oncological picture. We were able to develop a multifactorial prediction model. However, the model's performance was not fully satisfactory and it is not routinely applicable at this point in time, because external validation is needed to confirm our hypothesis-generating findings.

Feasibility and efficacy of early docetaxel plus androgen deprivation therapy for metastatic hormone-sensitive prostate cancer in a rural health care setting.

AIM/BACKGROUND: The aim of this study was to evaluate the feasibility and efficacy, in terms of overall survival, of intensified upfront systemic therapy in patients with metastatic hormone-sensitive prostate cancer who lived in rural Nordland County, Norway. PATIENTS AND METHODS: Overall 117 patients were included in this retrospective study. Three cohorts were created: early docetaxel and androgen deprivation therapy (ADT; the CHAARTED regimen; n = 37), ADT only during the same time period (2014-2020; n = 33), and ADT only in the years 2009-2014 (n = 47). RESULTS: Four patients (11%) did not complete 6 cycles of docetaxel, one of these due to early progression of cancer. During follow-up, 8 patients (22%) progressed to castration-resistant disease (mCRPC), compared to 24 (73%) with ADT only and 35 (75%) in the historical cohort, p = 0.000001. Such progression occurred within 12 months in 3 patients (8%) treated with docetaxel and 9 patients (27%) treated with ADT only during the same time period, p = 0.05. Median survival was 56 months (95% CI: 40-72 months), compared to 30 months in both other cohorts. 3-year survival rates were 79%, 38% and 37%, respectively (p = 0.016). In multivariate analysis, the CHAARTED regimen was associated with significantly improved survival. CONCLUSION: In this rural health care setting, early docetaxel was feasible and effective in reducing progression to mCRPC and prolonging survival. Median survival was very close to the 58 months reported in the CHAARTED trial.

A four-microRNA classifier as a novel prognostic marker for tumor recurrence in stage II colon cancer.

About 20 percent of TNM-stage II colon cancer patients who are treated by surgical resection develop recurrence, and adjuvant chemotherapy in this group is still debated among researchers and clinicians. Currently, adverse histopathological and clinical factors are used to select patients for adjuvant chemotherapy following surgery. However, additional biomarkers to classify patients at risk of recurrence are needed. We have conducted a study using fresh frozen tumor tissue from 54 TNM-stage II colon cancer patients and performed microRNA profiling using next-generation sequencing. For the selection of the prognostic microRNAs, a LASSO Cox Regression model was employed. For the validation, we used the publically available TCGA-COAD cohort (n = 122). A prognostic panel of four micorRNAs (hsa-miR-5010-3p, hsa-miR-5100, hsa-miR-656-3p and hsa-miR-671-3p) was identified in the study cohort and validated in the TCGA-COAD cohort. The four-microRNA classifier successfully identified high-risk patients in the study cohort (P < 0.001) and the validation cohort (P = 0.005). Additionally, a number of established risk factors and the four-miRNA classifier were used to construct a nomogram to evaluate risk of recurrence. We identified a four-microRNA classifier in patients with TNM-stage II colon cancer that can be used to discriminate between patients at low- and high risk of recurrence.

Identification of a sixteen-microRNA signature as prognostic biomarker for stage II and III colon cancer.

Despite advances in colon cancer research and novel therapies, high risk of recurrence remains a major challenge. This study reports miRNA expression profiling as a biomarker for the prognosis of TNM stage II and III colon cancer. Fresh frozen biopsies from the study cohort (N=111) were analyzed for miRNA by RT-qPCR and LASSO regression analysis was used to build a classifier of miRNAs. The prognostic accuracy was tested and the classifier was validated in an independent colon cohort (TCGA-COAD, N=209). The LASSO regression analysis identified a 16-miRNA signature including miR-143-5p, miR-27a-3p, miR-31-5p, miR-181a-5p, miR-30b-5p, miR-30d-5p, miR-146a-5p, miR-23a-3p, miR-150-5p, miR-210-3p, miR-25-3p, miR-196a-5p, miR-148a-3p, miR-222-3p, miR-30c-5p and miR-223-3p. A low 16-miRNA signature was associated with better 5-year disease-free survival (DFS) in the study cohort than a high signature (93 % versus 58 %; p< 0.001). The signature was an independent prognostic factor for better 5-year DFS in multivariate analyses (HR 21.4; 95% CI: 4.21-108.7; p< 0.001). The results in the validation cohort were consistent with the study cohort in univariate (77 % versus 65 %; p= 0.045) and multivariate analyses (HR 2.0; 95% CI: 1.04-3.89; p=0.039). We identified a 16-miRNA signature as a reliable prognostic biomarker for classification of colon cancer stage II and III patients into groups with low and high risk for recurrence.

LGR5 and CD133 as prognostic and predictive markers for fluoropyrimidine-based adjuvant chemotherapy in colorectal cancer.

BACKGROUND: Expression of leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5) gene is associated with a metastatic phenotype and poor prognosis in colorectal cancer (CRC). CD133 expression is a putative cancer stem cell marker and a proposed prognostic marker in CRC, whereas the predictive value of CD133 expression for effect of adjuvant chemotherapy in CRC is unclear. MATERIAL AND METHODS: For the study of LGR5 mRNA and CD133 expression, tissue microarrays from 409 primary CRC stage II and III tumors, where patients had been randomized to adjuvant chemotherapy or surgery only, were available. LGR5 mRNA and CD133 expression were assessed by in situ hybridization (ISH) and immunohistochemistry (IHC), respectively. LGR5 mRNA and CD133 expression as prognostic and predictive markers were evaluated by univariate and multivariate analyses. RESULTS: For all CRC patients, positive LGR5 mRNA and CD133 expression were associated with classic adenocarcinoma histology type (p = 0.001 and p = 0.014, respectively). Positive LGR5 mRNA expression was also associated with smaller tumor diameter for CRC stage II (p = 0.005), but not for CRC stage III (p = 0.054). For CRC stage II, lack of LGR5 mRNA expression was associated with longer time to recurrence (TTR) in Kaplan-Meier (p = 0.045) and in multivariate Cox analysis (HR 0.27, 95% CI 0.08-0.95, p = 0.041). For colon cancer stage III patients, lack of CD133 expression was associated with better effect of adjuvant chemotherapy (p = 0.016) in Kaplan-Meier univariate analysis, but the interaction between CD133 and adjuvant chemotherapy was not statistically significant in multivariate analysis (HR 0.59, 95% CI 0.18-1.89, p = 0.374). CONCLUSION: LGR5 mRNA expression is a prognostic factor for CRC stage II patients, whereas the value of CD133 expression as prognostic and predictive biomarker is inconclusive.

CXCR4, CXCL12 and the relative CXCL12-CXCR4 expression as prognostic factors in colon cancer.

The CXCL12-CXCR4 axis is proposed to mediate metastasis formation. In this study, we examined CXCL12, CXCR4 and the relative CXCL12-CXCR4 expression as prognostic factors in two cohorts of colon cancer patients. Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to study CXCR4, CXCL12 and relative CXCL12-CXCR4 expression in tissue microarrays. Our study included totally 596 patients, 290 in cohort 1 and 306 in cohort 2. For tumour, node, metastasis (TNM) stage III, low nuclear expression of CXCR4 was a positive prognostic factor for 5-year disease-free survival (DFS) in cohort 1 (P = 0.007) and cohort 2 (P = 0.023). In multivariate analysis for stage III, nuclear expression of CXCR4 in cohort 1 was confirmed as a prognostic factor for DFS (hazard ratio (HR), 0.27; 95 % CI, 0.09 to 0.77). For TNM stage III, high cytoplasmic expression of CXCL12 was associated with better 5-year DFS in both cohorts (P = 0.006 and P = 0.006, respectively). We further validated the positive prognostic value of CXCL12 expression for 5-year DFS in stage III with ISH (P = 0.022). For TNM stage III, the relative CXCL12-CXCR4 expression (CXCL12 > CXCR4 vs CXCL12 = CXCR4 vs CXCL12 < CXCR4) was a prognostic factor for 5-year DFS in cohort 1 (92 % vs 46 % vs 31 %, respectively; P < 0.001) and cohort 2 (92 % vs 66 % vs 30 %, respectively; P = 0.006). In conclusion, CXCL12 and relative CXCL12-CXCR4 expression are independent prognostic factors for 5-year DFS in TNM stage III colon cancer.

The total number of lymph nodes in resected colon cancer specimens is affected by several factors but the lymph node ratio is independent of these.

The number of lymph nodes retrieved from the specimen may be a surrogate measure of the adequacy of extensive colon cancer surgery, but many variables may influence the total lymph node yield of any specimen. We examined which variables would be influential both for negative and positive node sampling.The combined results from 428 patients from three hospitals A to C treated in 2007-2009 with single colon cancers having R0 segmental resections were analysed. The surgical technique and pathology staining methods were slightly different between the hospitals.The mean number of lymph nodes was 15.8 (range 1-60). Twelve or more lymph nodes were harvested in 78% of the specimens. In the multivariate Poisson regression analysis of all TNM stages, the factors associated with the total lymph node harvest were age, pathology handling, tumour location and size (p < 0.001), whereas for TNM stage III alone the pathology handling (p < 0.001) and a radical operating technique (p = 0.003) were highly significant. The total number of lymph nodes was the only significant factor for the number of positive lymph nodes (Posln) according to the multivariate negative regression analysis (p = 0.02) but the analysis of the lymph node ratio (LNR) detected no statistically significant variable.Several factors, and especially the specimen processing technique, were important for the total number of harvested lymph nodes. The number of Posln varied between segments and increased with the total number of harvested lymph nodes, but for LNR no variable was important. LNR seemed to abolish the combined effect of tumour location and the total lymph node yield in prognosis assessment.