Validation of simplified uptake measures against dynamic Patlak Ki for quantification of lesional 89Zr-Immuno-PET antibody uptake.

PURPOSE: Positron emission tomography imaging of zirconium-89-labelled monoclonal antibodies (89Zr-Immuno-PET) allows for visualisation and quantification of antibody uptake in tumours in vivo. Patlak linearization provides distribution volume (VT) and nett influx rate (Ki) values, representing reversible and irreversible uptake, respectively. Standardised uptake value (SUV) and tumour-to-plasma/tumour-to-blood ratio (TPR/TBR) are often used, but their validity depends on the comparability of plasma kinetics and clearances. This study assesses the validity of SUV, TPR and TBR against Patlak Ki for quantifying irreversible 89Zr-Immuno-PET uptake in tumours. METHODS: Ten patients received 37 MBq 10 mg 89Zr-anti-EGFR with 500 mg/m2 unlabelled mAbs. Five patients received two doses of 37 MBq 89Zr-anti-HER3: 8-24 mg for the first administration and 24 mg-30 mg/kg for the second. Seven tumours from four patients showed 89Zr-anti-EGFR uptake, and 18 tumours from five patients showed 89Zr-anti-HER3 uptake. SUVpeak, TPRpeak and TBRpeak values were obtained from one to six days p.i. Patlak linearization was applied to tumour time activity curves and plasma samples to obtain Ki. RESULTS: For 89Zr-anti-EGFR, there was a small variability along the linear regression line between SUV (- 0.51-0.57), TPR (- 0.06‒0.11) and TBR (- 0.13‒0.16) on day 6 versus Ki. Similar doses of 89Zr-anti-HER3 showed similar variability for SUV (- 1.3‒1.0), TPR (- 1.1‒0.53) and TBR (- 1.5‒0.72) on day 5 versus Ki. However, for the second administration of 89Zr-anti-HER3 with a large variability in administered mass doses, SUV showed a larger variability (- 1.4‒2.3) along the regression line with Ki, which improved when using TPR (- 0.38-0.32) or TBR (- 0.56‒0.46). CONCLUSION: SUV, TPR and TBR at late time points were valid for quantifying irreversible lesional 89Zr-Immuno-PET uptake when constant mass doses were administered. However, for variable mass doses, only TPR and TBR provided reliable values for irreversible uptake, but not SUV, because SUV does not take patient and mass dose-specific plasma clearance into account.

Health-Related Quality of Life in Patients With Metastatic Colorectal Cancer Undergoing Systemic Therapy With or Without Maximal Tumor Debulking.

BACKGROUND: Maintaining a sufficient health-related quality of life (HRQoL) is important in the palliative treatment of patients with metastatic colorectal cancer (mCRC). The ORCHESTRA trial (ClinicalTrials.gov identifier: NCT01792934) is designed to prospectively evaluate overall survival benefit and impact on HRQoL of tumor debulking when added to first-line palliative systemic therapy in patients with multiorgan mCRC. In the present study, we report the HRQoL associated with this combination treatment compared with standard systemic therapy. METHODS: Patients included in the ORCHESTRA trial with clinical benefit after 3 or 4 cycles of first-line palliative systemic therapy with fluoropyrimidines and oxaliplatin with or without bevacizumab were randomly assigned to maximal tumor debulking followed by systemic therapy versus systemic therapy alone. Patients completed the EORTC Quality of Life Questionnaire-Core 30 and the Multidimensional Fatigue Inventory questionnaire at prespecified time points during treatment. Between-group differences in HRQoL over time were evaluated with linear mixed model analyses. A pattern mixture approach was applied to correct for missing questionnaires due to progressive disease. RESULTS: A total of 300 patients were randomized to the intervention arm (n=148) or the standard arm (n=152). No statistically significant or clinically relevant differences in HRQoL and fatigue were observed when tumor debulking was added to systemic therapy. In patients of both study arms, HRQoL after 1 year of treatment was not significantly different from HRQoL at the time of randomization. Patients in the intervention arm experienced serious adverse events (SAEs) twice as often as patients in the standard arm (P≤.001). CONCLUSIONS: Maximal tumor debulking in combination with palliative systemic therapy in patients with multiorgan mCRC was significantly associated with more SAEs resulting from local therapy but no difference in HRQoL compared with palliative systemic therapy alone. There is a remarkable lack of association between the occurrence of SAEs and impact on HRQoL.

Safety and Feasibility of Additional Tumor Debulking to First-Line Palliative Combination Chemotherapy for Patients with Multiorgan Metastatic Colorectal Cancer.

INTRODUCTION: Local treatment of metastases is frequently performed in patients with multiorgan metastatic colorectal carcinoma (mCRC) analogous to selected patients with oligometastatic disease for whom this is standard of care. The ORCHESTRA trial (NCT01792934) was designed to prospectively evaluate overall survival benefit from tumor debulking in addition to chemotherapy in patients with multiorgan mCRC. Here, we report the preplanned safety and feasibility evaluation after inclusion of the first 100 patients. METHODS: Patients were eligible if at least 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy. In case of clinical benefit after three or four cycles of respectively 5-fluorouracil/leucovorin or capecitabine and oxaliplatin ± bevacizumab patients were randomized to tumor debulking followed by chemotherapy in the intervention arm, or standard treatment with chemotherapy. RESULTS: Twelve patients dropped out prior to randomization for various reasons. Eighty-eight patients were randomized to the standard (n = 43) or intervention arm (n = 45). No patients withdrew after randomization. Debulking was performed in 82% (n = 37). Two patients had no lesions left to treat, five had progressive disease, and one patient died prior to local treatment. In 15 patients (40%) 21 serious adverse events related to debulking were reported. Postoperative mortality was 2.7% (n = 1). After debulking chemotherapy was resumed in 89% of patients. CONCLUSION: Tumor debulking is feasible and does not prohibit administration of palliative chemotherapy in the majority of patients with multiorgan mCRC, despite the occurrence of serious adverse events related to local treatment. IMPLICATIONS FOR PRACTICE: This first prospective randomized trial on tumor debulking in addition to chemotherapy shows that local treatment of metastases is feasible in patients with multiorgan metastatic colorectal cancer and does not prohibit administration of palliative systemic therapy, despite the occurrence of serious adverse events related to local treatment. The trial continues accrual, and overall survival (OS) data and quality of life assessment are collected to determine whether the primary aim of >6 months OS benefit with preserved quality of life will be met. This will support evidence-based decision making in multidisciplinary colorectal cancer care and can be readily implemented in daily practice.

Potential mechanisms underlying the effect of walking exercise on cancer-related fatigue in cancer survivors.

PURPOSE: Cancer-related fatigue (CRF) is a common and debilitating long-term side effect of cancer and its treatment. While exercise has been shown to effectively reduce CRF, the underlying mechanisms are not fully clear. Therefore, the aim of this study was to explore the effects of a 4-month walking exercise program on fatigue severity and to explore potential underlying physiological, behavioral, and psychological mechanisms of action. METHODS: We included 27 cancer survivors (59 ± 15 years, 37% female) with variable cancer diagnoses who were at least moderately fatigued and finished treatment between 6 and 36 months ago. This study with a quasi-experimental interrupted time-series design compared a 4-month walking intervention period with a 4-month control period. Measurements of fatigue and physiological, behavioral, and psychological factors were performed, supplemented with participants' perceptions on how exercise influenced their fatigue. RESULTS: A significant and clinically relevant decrease in fatigue severity was found over time (ß = - 8.1, 95% CI = - 12.1; - 4.2), but could not be attributed directly to the walking exercise intervention. Increases in muscle strength (ß = - 0.07, 95% CI = - 0.12; - 0.02), physical activity (ß = - 0.1, 95% CI = - 0.2; - 0.04), and sleep quality (ß = 1.1, 95% CI = 0.3; 1.9), as well as decreases in muscle relaxation times (ß = 0.09, 95% CI = 0.02; 0.16) and psychological distress (ß = 1.1, 95% CI = 0.8; 1.3) were associated with reductions in fatigue severity. Resilience and physical well-being were perceived as most important constructs explaining the walking exercise effects on fatigue. CONCLUSION: Our findings reveal potential physiological, behavioral, and psychological mechanisms underlying the multidimensional effects of exercise on fatigue severity. IMPLICATIONS FOR CANCER SURVIVORS: Incorporating resistance exercise and addressing resilience and physical well-being might improve the efficacy of exercise interventions for cancer survivors.

Exploring immune status in peripheral blood and tumor tissue in association with survival in patients with multi-organ metastatic colorectal cancer.

Colorectal cancer (CRC) raises considerable clinical challenges, including a high mortality rate once the tumor spreads to distant sites. At this advanced stage, more accurate prediction of prognosis and treatment outcome is urgently needed. The role of cancer immunity in metastatic CRC (mCRC) is poorly understood. Here, we explore cellular immune cell status in patients with multi-organ mCRC. We analyzed T cell infiltration in primary tumor sections, surveyed the lymphocytic landscape of liver metastases, and assessed circulating mononuclear immune cells. Besides asking whether immune cells are associated with survival at this stage of the disease, we investigated correlations between the different tissue types; as this could indicate a dominant immune phenotype. Taken together, our analyses corroborate previous observations that higher levels of CD8+ T lymphocytes link to better survival outcomes. Our findings therefore extend evidence from earlier stages of CRC to indicate an important role for cancer immunity in disease control even after metastatic spreading to multiple organs. This finding may help to improve predicting outcome of patients with mCRC and suggests a future role for immunotherapeutic strategies.

Trastuzumab plus pertuzumab for HER2-amplified advanced colorectal cancer: Results from the drug rediscovery protocol (DRUP).

BACKGROUND: In 2-5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy confers clinical benefit (CB) in one-third of these patients, it is not approved for this indication in Europe. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for treatment-refractory patients with RAS/BRAF-wild-type HER2amplified metastatic CRC (HER2+mCRC)'. METHODS: Patients with progressive treatment-refractory RAS/BRAF-wild-type HER2+mCRC with measurable disease were included for trastuzumab plus pertuzumab treatment. Primary endpoints of DRUP are CB (defined as confirmed objective response (OR) or stable disease (SD) ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and 24 patients in stage 2 if at least 1/8 patients had CB. To identify biomarkers for response, whole genome sequencing (WGS) was performed on pre-treatment biopsies. RESULTS: CB was observed in 11/24 evaluable patients (46%) with HER2+mCRC, seven patients achieved an OR (29%). Median duration of response was 8.4 months. Patients had undergone a median of 3 prior treatment lines. Median progression-free survival and overall survival were 4.3 months (95% CI 1.9-10.3) and 8.2 months (95% CI 7.2-14.7), respectively. No unexpected toxicities were observed. WGS provided potential explanations for resistance in 3/10 patients without CB, for whom WGS was available. CONCLUSIONS: The results of this study confirm a clinically significant benefit of trastuzumab plus pertuzumab treatment in patients with HER2+mCRC.

Mutant RAS and the tumor microenvironment as dual therapeutic targets for advanced colorectal cancer.

RAS genes are the most frequently mutated oncogenes in cancer. These mutations occur in roughly half of the patients with colorectal cancer (CRC). RAS mutant tumors are resistant to therapy with anti-EGFR monoclonal antibodies. Therefore, patients with RAS mutant CRC currently have few effective therapy options. RAS mutations lead to constitutively active RAS GTPases, involved in multiple downstream signaling pathways. These alterations are associated with a tumor microenvironment (TME) that drives immune evasion and disease progression by mechanisms that remain incompletely understood. In this review, we focus on the available evidence in the literature explaining the potential effects of RAS mutations on the CRC microenvironment. Ongoing efforts to influence the TME by targeting mutant RAS and thereby sensitizing these tumors to immunotherapy will be discussed as well.

A specific microRNA profile as predictive biomarker for systemic treatment in patients with metastatic colorectal cancer.

BACKGROUND: Palliative systemic therapy is currently standard of care for patients with extensive metastatic colorectal cancer (mCRC). A biomarker predicting chemotherapy benefit which prevents toxicity from ineffective treatment is urgently needed. Therefore, a previously developed tissue-derived microRNA profile to predict clinical benefit from chemotherapy was evaluated in tissue biopsies and serum from patients with mCRC. METHODS: Samples were prospectively collected from patients (N = 132) who were treated with capecitabine or 5-FU/LV with oxaliplatin ± bevacizumab. Response evaluation was performed according to RECIST 1.1 after three or four cycles, respectively. Baseline tissue and serum miRNAs expression levels of miR-17-5p, miR-20a-5p, miR-30a-5p, miR-92a-3p, miR-92b-3p, and miR-98-5p were quantified with RT-qPCR and droplet digital PCR, respectively. Combined predictive performance of selected variables was tested using logistic regression analysis. RESULTS: From 132 patients, 81 fresh frozen tissue biopsies from metastases and 93 serum samples were available. Based on expression levels of miRNAs in tissue, progressive disease could be predicted with an AUC of 0.85 (95% CI:0.72-0.91) and response could be predicted with an AUC of 0.70 (95% CI:0.56-0.80). This did not outperform clinical parameters alone (respectively P = .14 and P = .27). Expression levels of miR-92a-3p and miR-98-5p in serum significantly improved the predictive value of clinical parameters for response to chemotherapy (AUC 0.74, 95% CI:0.64-0.84, P = .003) in this cohort. CONCLUSIONS: The additive predictive value to clinical parameters of the tissue-derived six miRNA profile for clinical benefit could not be validated in patients with mCRC treated with first-line systemic therapy. Although miR-92a-3p and miR-98-5p serum levels improved the predictive value of clinical parameters, it remained insufficient for clinical decision-making.

CD276-Positive Circulating Endothelial Cells Do Not Predict Response to Systemic Therapy in Advanced Colorectal Cancer.

CD276 can discriminate between tumor derived and normal CECs (circulating endothelial cells). We evaluated whether CD276+CEC is a clinically relevant biomarker to predict response to palliative systemic therapy in patients with metastatic colorectal cancer (mCRC). Samples were prospectively collected from patients with mCRC enrolled in the ORCHESTRA trial (NCT01792934). At baseline and after three cycles of 5-fluorouracil/leucovorin and oxaliplatin ± bevacizumab, CECs were measured by flowcytometry (CD34+CD45negCD146+DNA+; and CD276+). A clinically relevant cut-off value of (CD276+)CECs was determined as 100% sensitivity (and 80% specificity in 95% confidence interval) identifying patients with progressive disease within 6 months. There were 182 baseline samples and 133 follow up samples available for analysis. CEC and CD276+CEC counts significantly increased during treatment from 48 to 90 CEC/4 mL (p = 0.00) and from 14 to 33 CD276+CEC/4 mL (p = 0.00) at baseline and at first evaluation, respectively. CEC and CD276+CEC counts were not predictive for poor response (area under the curve (AUC) 0.53 for CEC and AUC 0.52 for CD276+CEC). Despite numerical changes during therapy, CEC and CD276+CEC counts do not adequately predict poor response to first line palliative systemic therapy in patients with mCRC.

The value of tumour debulking for patients with extensive multi-organ metastatic colorectal cancer.

Local treatment of metastases by surgical resection or other ablative therapies is technically feasible in an increasing number of patients with multi-organ metastatic cancer. This results in a growing debate on whether patients with extensive disease, that is traditionally deemed unresectable, may benefit from local treatment of metastases when added to standard palliative systemic therapy. For selected patients with oligometastatic colorectal cancer, local treatment of metastases has become the standard of care based on retrospective reports showing long-term survival rates. In addition to systemic therapy, preliminary evidence suggests that patients with extensive metastatic colorectal cancer may also benefit from local treatment. Here, we present the future perspectives based on the available literature on local treatment approaches in colorectal cancer.

Postoperative stupor and coma.

OBJECTIVES: To identify predictive factors for postoperative coma or stupor and to examine the value of neuroimaging techniques in elucidating structural brain damage. PATIENTS AND METHODS: We performed a case-control study of surgical patients admitted to a Mayo Clinic-affiliated hospital. We studied preoperative comorbidity, intraoperative hypotension, and postoperative data in patients with postoperative stupor or coma and compared the characteristics with control patients (surgical intensive care unit patients with neurologic consultations for other reasons). RESULTS: A total of 35 patients with stupor or coma after surgery and 31 control patients participated in this study. Comatose patients were older (P=.004) and had significantly more presurgical comorbidity (P<.001), cardiovascular surgical procedures (P<.001), and intraoperative hypotension (P=.03). Adjusted for age and comorbidity, intraoperative hypotension remained statistically significant but not after adjusting for cardiovascular surgery. Of the 34 computed tomograms obtained, 41% showed abnormal results; of the 12 magnetic resonance images obtained, 58% showed abnormal results. Both showed primarily infarctions. In 4 patients with normal computed tomographic results, magnetic resonance imaging showed multiple territorial infarctions. CONCLUSION: Prior comorbidity, older age, intraoperative hypotension, and cardiovascular surgery may predispose patients to postoperative coma. Widespread structural ischemic brain damage was often documented by neuroimaging. Metabolic causes for coma were uncommon.

89Zr-cetuximab PET imaging in patients with advanced colorectal cancer.

Monoclonal antibodies (mAbs) against the epidermal growth factor receptor (EGFR) are used in the treatment of advanced colorectal cancer (mCRC). Approximately 50% of patients benefit despite patient selection for RAS wild type (wt) tumors. Based on the hypothesis that tumor targeting is required for clinical benefit of anti-EGFR treatment, biodistribution and tumor uptake of (89)Zr-cetuximab by Positron Emission Tomography (PET), combining the sensitivity of PET with the specificity of cetuximab for EGFR was evaluated. Ten patients with wt K-RAS mCRC received 37 ± 1 MBq (89)Zr-cetuximab directly (<2 h) after the first therapeutic dose of cetuximab. PET-scans were performed from 1 hour to 10 days post injection (p.i.). Biodistribution was determined for blood and organs. Uptake in tumor lesions was quantified by Standardized Uptake Value (SUV) and related to response. In 6 of 10 patients (89)Zr-cetuximab uptake in tumor lesions was detected. Four of 6 patients with (89)Zr-cetuximab uptake had clinical benefit, while progressive disease was observed in 3 of 4 patients without (89)Zr-cetuximab uptake. Taken together, tumor uptake of 89Zr-cetuximab can be visualized by PET imaging. The strong relation between uptake and response warrants further clinical validation as an innovative selection method for cetuximab treatment in patients with wt RAS mCRC.