BACKGROUND:Patients with hard-to-treat or rare cancers and those not responding to standard-of-care (SoC) treatment have unmet needs. Limited access to novel drugs is an increasing additional challenge. In 2003, the Danish government adopted a Health Act to ensure that treatment of patients with life-threatening disease could be reevaluated by independent experts. The Danish Health Authority (DHA) set up an Expert Advisory Panel to provide advice on possibilities for further treatment of patients, including treatment not approved nationally. A few years later, clinical units were established that could offer unestablished treatment to patients by referral from the Panel. The treatment was first reimbursed by the Government and later by regional authorities. MATERIALS AND METHODS:We present the structure, workflow, and impact of the Health Act for 21 years for patients with cancer. Annual reports from the DHA were the primary data source. RESULTS:11 034 cases from 9603 cancer patients were evaluated by the Panel from 2003 to 2023, representing a median of 372 unique cases yearly. In 53%, the Panel advised on further treatment in Denmark, and of these, 56% were recommended nationally nonapproved treatment, 21% SoC treatment or workup, and 19% clinical trial participation. In 4.5% of cases, advice was given on treatment abroad. A significant decline in admissions to the Panel from a peak of 1167 patients in 2008 to 3-400 yearly from 2012 to 2017 followed the conversion of nonapproved treatments to SoC practice. A shift in drug reimbursement, independent of Panel advise, reduced the clinical impact and explained the further decline observed in admissions lately to only 51 patients in 2023. CONCLUSIONS:This unique national scheme provided early access to treatment for patients with no further SoC options and facilitated the introduction of new cancer treatments, initiation of clinical trials, and establishment of trial units in the country. The scheme may be adapted to other countries with a public healthcare system. Results of the current report indicate that impact is dependent on delivering clinical units and reimbursement associated with the recommended treatment.

Many studies have focused on the prognostic role of soluble programmed death ligand 1 (sPD-L1) in non-small cell lung cancer (NSCLC), but outcomes are ambiguous and further investigations are needed. We addressed the matter by studying sPD-L1 in baseline samples and in longitudinal samples taken prior to three subsequent cycles of anti-PD-1/anti-PD-L1 treatments. Eighty patients with NSCLC were enrolled. Median sPD-L1 level at baseline was 52 pg/mL [95% confidence interval (CI) 49-57]. In patients treated with pembrolizumab and nivolumab, the concentration of sPD-L1 remained rather stable throughout treatment. In contrast, sPD-L1 rose by 50-fold following the first cycle of atezolizumab therapy. We found the baseline level of sPD-L1 to be related to overall survival (OS) after two years of follow-up in simple Cox analysis (p = 0.006) and multiple Cox Regression, hazard ratio 1.02 (95% CI 1.00-1.03) (p = 0.033). There was no association between sPD-L1 and tissue PD-L1 expression, overall response rate, or progression free survival. In conclusion, sPD-L1 measured in baseline serum samples may be associated with OS in NSCLC patients receiving anti-PD1/anti-PD-L1 treatment. Importantly, the results signify that further research is warranted to explore the clinical utility of sPD-L1 in patients treated with anti-PD-L1.

Aim: Clinical utility of the dynamics of ctDNA is sparse. This study aimed at evaluating the prognostic impact of early ctDNA dynamics in patients with metastatic cancer treated with chemotherapy. Materials & methods: The ctDNA dynamics were evaluated in 595 patients with metastatic cancer using droplet digital PCR. Results: Patients with an increase in ctDNA after one treatment cycle (n = 73; 12.2%) had an overall survival of 5.6 months compared with 8.6 months in patients with stable or decreasing ctDNA (n = 328; 55.1%) and 21.0 months in patients with undetectable ctDNA (p < 0.001; hazard ratio: 0.47; 95% CI: 0.41-0.53). Conclusion: Early ctDNA dynamics hold important prognostic information and have great implications for evaluation with the perspective of a more individualized treatment strategy.

International Journal of CancerVolume 153, Issue 7 p. 1423-1424 LETTER TO THE EDITOR Comments on “The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020” Anders K. M. Jakobsen, Anders K. M. Jakobsen Department of Oncology, Vejle University Hospital, Institute of Regional Health Services, University of Southern Denmark, Vejle Hospital, Vejle, DenmarkSearch for more papers by this authorKaren-Lise Garm Spindler, Corresponding Author Karen-Lise Garm Spindler [email protected] orcid.org/0000-0001-8781-3212 @GarmLise Experimental Clinical Oncology, Department of Oncology, Aarhus University Hospital, Aarhus University, Aarhus N, Denmark Correspondence Karen-Lise Garm Spindler, Experimental Clinical Oncology, Department of Oncology, Aarhus University Hospital, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. Email: [email protected]Search for more papers by this author Anders K. M. Jakobsen, Anders K. M. Jakobsen Department of Oncology, Vejle University Hospital, Institute of Regional Health Services, University of Southern Denmark, Vejle Hospital, Vejle, DenmarkSearch for more papers by this authorKaren-Lise Garm Spindler, Corresponding Author Karen-Lise Garm Spindler [email protected] orcid.org/0000-0001-8781-3212 @GarmLise Experimental Clinical Oncology, Department of Oncology, Aarhus University Hospital, Aarhus University, Aarhus N, Denmark Correspondence Karen-Lise Garm Spindler, Experimental Clinical Oncology, Department of Oncology, Aarhus University Hospital, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. Email: [email protected]Search for more papers by this author First published: 08 July 2023 https://doi.org/10.1002/ijc.34627Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1Gloy V, Schmitt AM, Düblin P, et al. The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020. Int J Cancer. 2023; 152: 2474-2484. 2 FederalRegister.gov. eCFR::21 CFR 314.126: Adequate and well controlled studies. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-D/section-314.1261. Accessed July 5, 2023. 3 Web site. https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-cancer-accelerated-approvals. Accessed July 5, 2023. 4Tie J, Cohen JD, Lahouel K, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med. 2022; 386: 2261-2272. 5Jakobsen A, Andersen RF, Hansen TF, et al. Early ctDNA response to chemotherapy. A potential surrogate marker for overall survival. Eur J Cancer. 2021; 149: 128-133. 6Faaborg L, Andersen RF, Waldstrøm M, et al. Prognostic impact of circulating methylated homeobox A9 DNA in patients undergoing treatment for recurrent ovarian cancer. Cancers (Basel). 2022; 14: 1766. 7Jakobsen AKM, Spindler KLG. ctDNAresponse evaluation criteria in solid tumors—a new measure in medical oncology. Eur J Cancer. 2023; 180: 180-183. 8Buyse M, Molenberghs G. Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics. 1998; 54: 1014-1029. Volume153, Issue71 October 2023Pages 1423-1424 ReferencesRelatedInformation

BACKGROUND There is an urgent need for early detection of lung cancer. Screening with low-dose computed tomography (LDCT) is now implemented in the US. Supplementary use of a lung cancer biomarker with high specificity is desirable. OBJECTIVE To assess the diagnostic properties of a biomarker panel consisting of cytokeratin 19 fragment (CYFRA 21-1), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125). METHODS A cohort of 250 high-risk patients was investigated on suspicion of lung cancer. Ahead of diagnostic work-up, blood samples taken. Cross-validated prediction models were computed to assess lung cancer detection properties. RESULTS In total 32% (79/250) of patients were diagnosed with lung cancer. Area under the curve (AUC) for the three biomarkers was of 0.795, with sensitivity/specificity of 57%/93% and negative predictive value of 83%. When combining the biomarkers with US screening criteria, the AUC was 0.809, while applying only US screening criteria on the cohort, yielded an AUC of 0.62. The ability of the biomarkers to detect stage I-II lung cancer was substantially lower; AUC 0.54. CONCLUSIONS In a high-risk cohort, the detection properties of the three biomarkers were acceptable compared to current LDCT screening criteria. However, the ability to detect early stage lung cancer was low.

Background PD-1/PD-L1 inhibitors have improved survival for patients with non-small cell lung cancer (NSCLC). We evaluated natural killer cell activity (NKA) and methylated HOXA9 circulating tumor DNA (ctDNA) as prognostic biomarkers in NSCLC patients treated with PD-1/PD-L1 inhibitors. Methods Plasma was prospectively collected from 71 NSCLC patients before treatment with PD-1/PD-L1 inhibitors and before cycles 2–4. We used the NK Vue ® assay to measure the level of interferon gamma (IFNγ) as a surrogate for NKA. Methylated HOXA9 was measured by droplet digital PCR. Results A score combining NKA and ctDNA status measured after one treatment cycle had a strong prognostic impact. Group 1 had IFNγ < 250 pg/ml and detectable ctDNA ( n = 27), group 2 consisted of patients with either low levels of IFNγ and undetectable ctDNA or high levels of IFNγ and detectable ctDNA ( n = 29), group 3 had IFNγ ≥250 pg/ml and undetectable ctDNA ( n = 15). Median OS was 221 days (95% CI 121–539 days), 419 days (95% CI 235–650 days), and 1158 days (95% CI 250 days—not reached), respectively ( P = 0.002). Group 1 had a poor prognosis with a hazard ratio of 5.560 (95% CI 2.359–13.101, n = 71, P < 0.001) adjusting for PD-L1 status, histology, and performance status. Conclusions Combining NKA and ctDNA status after one cycle of treatment was prognostic in patients with NSCLC treated with PD-1/PD-L1 inhibitors.

Interest in the measurement of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) has increased during the past decade. The analysis of quantitative ctDNA changes as a general response evaluation criterion during systemic treatment is a scientific approach with high clinical potential, and results can be transferred to a pan-cancer concept if relevantly investigated. The purpose of this overview is to discuss the current evidence for ctDNA as a marker of response in metastatic CRC (mCRC) and to propose criteria for definitions of response to systemic therapies applicable in prospective clinical trials. We discuss the literature, which supports a new definition of ctDNA Response Evaluation Criteria in Solid Tumors. Finally, we discuss the challenges in preparations of the optimal trial design to establish the true clinical utility of ctDNA.

Background: Patients with detectable ctDNA after radical-intent treatment of metastatic spread from colorectal cancer (mCRC) have a very high risk of recurrence, which may be prevented with intensified adjuvant chemotherapy (aCTh). In the OPTIMISE study, we investigate ctDNA-guided aCTh after radical-intent treatment of mCRC. Here we present results from the preplanned interim analysis.Material and methods: The study is an open-label 1:1 randomized clinical trial comparing ctDNA-guided aCTh against standard of care (SOC), with a run-in phase investigating feasibility measures. Key inclusion criteria; radical-intent treatment for mCRC and clinically eligible for triple-agent chemotherapy. Patients underwent a PET-CT scan before randomization. ctDNA analyses of plasma samples were done by ddPCR, detecting CRC-specific mutations and methylation of the NPY gene. In the ctDNA-guided arm, ctDNA positivity led to an escalation strategy with triple-agent chemotherapy, and conversely ctDNA negativity led to a de-escalation strategy by shared-decision making. Patients randomized to the standard arm were treated according to SOC. Feasibility measures for the run-in phase were; the inclusion of 30 patients over 12 months in two Danish hospitals, compliance with randomization >80%, rate of PET-CT-positive findings <20%, and eligibility for triple-agent chemotherapy >80%.Results: Thirty-two patients were included. The rate of PET-CT-positive cases was 22% (n = 7/32). Ninety-seven percent of the patients were randomized. Fourteen patients were randomly assigned to SOC and sixteen to ctDNA-guided adjuvant treatment and follow-up. All analyses of baseline plasma samples in the ctDNA-guided arm passed the quality control, and 19% were ctDNA positive. The median time to result was three working days. All ctDNA-positive patients were eligible for triple-agent chemotherapy.Conclusion: The study was proven to be feasible and continues in the planned large-scale phase II trial. Results from the OPTIMISE study will potentially optimize the adjuvant treatment of patients undergoing radical-intent treatment of mCRC, thereby improving survival and reducing chemotherapy-related toxicity.

e15514 Background: Metastatic colorectal cancer (mCRC) remains a therapeutic challenge and new markers hold high priority. Natural Killer (NK) cells are immune cells with potent antitumor properties. The association between neoplastic development and level of effector functions of this cell type is well known. Moreover, it is recognized that NK cells are subject to tumor-mediated immune suppression. The present study aimed at elucidating a potential relationship between NK cell activity (NKA) and response to folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) in mCRC. Methods: NKA was analyzed in patients enrolled in a randomized trial of mCRC receiving FOLFOXIRI and either tocotrienol or placebo as first-line treatment. Blood (1 mL) was sampled into NK Vue tubes at baseline and before treatment cycles 2-3, placed at 37°C for 24 hours, and after incubation, the level of interferon-γ (IFNγ) in the plasma was a surrogate measure for NKA. A cutoff of 250 pg/mL IFNγ distinguished normal and low NKA. The endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: A total of 70 patients were enrolled in the randomized clinical trial. The results showed that tocotrienol had no effect on either RR (p = 0.62), PFS (p = 0.52), or OS (p = 0.80). Patients were classified into two groups according to the dynamics of NKA measured at the available time points. Patients that dropped from a normal to a low level of NKA in samples taken between baseline and before cycle 3 and patients with continuous low NKA (IFNγ < 250 pg/mL) were categorized as NKA-low. The NKA-high group included patients that increased from an abnormal to a normal level of NKA and patients that remained within the normal range (IFNγ > 250pg/mL) in all available samples. The RR in the two groups were 38% (8/21) and 69% (24/35), respectively (p = 0.0496). The median PFS was 186 days (95% confidence interval (CI) 136-225 days, n = 23) for the NKA-low group and 252 days (95% CI 223-305 days, n = 37) for NKA-high (p = 0.0005). The hazard ratio (HR) was 2.65 (95% CI 1.28-5.50). After adjusting for age, performance status (PS), and tumor location, NKA remained an independent prognostic factor for PFS (HR = 3.32, 95% CI 1.67-6.61, p = 0.001). Median OS was 408 days (95% CI 219-679 days, n = 23) and 1051 days (95% CI 645-1225 days, n = 37), respectively (p = 0.0034). For OS, the NKA-low group also showed a poor prognosis, HR 2.23 (95% CI 1.17-4.25). NKA dynamics remained an independent prognostic marker for OS after adjusting for age, PS, and tumor location (HR = 2.74, 95% CI 1.50-5.03, p = 0.001). Conclusions: The results suggest that NKA dynamics within the first two cycles of treatment may hold relevant prognostic information in first-line treatment of mCRC. The possible causative relationship between NKA and treatment effect needs further elucidation, but calls for experimental trials combining chemotherapy with NK cell therapy in mCRC.

Patients with detectable ctDNA after radical intent treatment of metastatic spread from colorectal cancer (mCRC) have a very high risk of recurrence, which might be prevented with intensified adjuvant chemotherapy (aCTh). In low-stage CRC, a ctDNA-guided approach for aCTh resulted in less use of chemotherapy without compromising outcome. In OPTIMISE, we investigate ctDNA-guided aCTh after radical intent treatment of mCRC. The preplanned interim analysis aimed at testing feasibility at an early time, with the possibility of optimizing study and laboratory setup and sample size calculations, if needed, before continuing in a large-scale phase II, multicenter, randomized controlled trial. OPTIMISE is an open-label 1:1 randomized trial comparing ctDNA-guided aCTh against standard of care (SOC), with a run-in phase investigating feasibility measures. Analyses of plasma samples for ctDNA were done by ddPCR, detecting CRC-specific mutations and methylation of the NPY gene. Key inclusion criteria were radical intent treatment for mCRC and clinically eligible for triple-agent chemotherapy. All included patients underwent a PET/CT scan before randomization. Patients randomized to the standard arm were treated according to SOC. In the ctDNA-guided arm, ctDNA positivity led to an escalation strategy with triple-agent chemotherapy, and ctDNA negativity led to a de-escalation strategy by shared-decision making. Feasibility measures for the run-in phase were; inclusion of 30 patients over 12 months in two Danish hospitals, compliance with randomization >80%, rate of unexpected PET-CT-positive cases 80%. Thirty-two patients were included. The rate of PET-CT-positive cases was 22% (n=7/32). Five of the PET-CT-positive cases underwent radical intent treatment and hereafter randomization. One patient awaits randomization due to ongoing treatment of residual disease. 97% of the patients were randomized (n=30/31). Fourteen patients were randomly assigned to SOC and sixteen to ctDNA-guided adjuvant treatment and follow-up. All analyses of the baseline plasma samples in the ctDNA-guided arm passed the quality control process. The median time to result was 3 working days. 19% (n=3/16) had a ctDNA-positive baseline plasma sample. All ctDNA-positive patients were eligible for triple-agent chemotherapy. The median time from inclusion until the start of aCTh was 22 days. The delay from inclusion to the start of aCTh was primarily due to the study-specific PET/CT scan. To the best of our knowledge, this is the first randomized clinical trial evaluating ctDNA-guided adjuvant treatment after radical intent treatment for mCRC. Hence, there were significant reservations when planning the study, so it was of utmost importance to test feasibility early. When taking into account the low number of patients and the consequent uncertainty in the estimates, the feasibility measures were complied with. Furthermore, the median time to result and the quality of analyses were adequate. A minor modification of the study flow has been made to reduce the delay from inclusion to the start of aCTh; solely ctDNA-positive patients in the experimental arm will undergo a PET/CT scan. In conclusion, the study has proven feasible and continues with an optimized study flow in the planned large-scale phase II, multicenter, randomized controlled trial.

Neoadjuvant treatment of breast cancer is applied to an increasing extent, but treatment response varies and side effects pose a challenge. The vitamin E isoform delta-tocotrienol might enhance the efficacy of chemotherapy and reduce the risk of side effects. The aim of this study was to investigate the clinical effect of delta-tocotrienol combined with standard neoadjuvant treatment and the possible association between detectable circulating tumor DNA (ctDNA) during and after neoadjuvant treatment with pathological treatment response. This open-label, randomized phase II trial included 80 women with newly diagnosed, histologically verified breast cancer randomized to standard neoadjuvant treatment alone or in combination with delta-tocotrienol. There was no difference in the response rate or frequency of serious adverse events between the two arms. We developed a multiplex digital droplet polymerase chain reaction (ddPCR) assay for the detection of ctDNA in breast cancer patients that targets a combination of two methylations specific for breast tissue (LMX1B and ZNF296) and one cancer specific methylation (HOXA9). The sensitivity of the assay increased when the cancer specific marker was combined with the ones specific to breast tissue (p < 0.001). The results did not show any association between ctDNA status and pathological treatment response, neither at midterm nor before surgery.

Louise Bach Callesen , Torben Frøstrup Hansen, Rikke Fredslund Andersen, Niels Pallisgaard, Stine Kramer, Sven Schlander, Søren Rafael Rafaelsen, Anders Kindberg Boysen, Lars Henrik Jensen, Anders Jakobsen and Karen-Lise Garm Spindler Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark; Department of Biochemistry and Immunology, Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark; Department of Pathology, Zealand University Hospital, Roskilde, Denmark; Department of Nuclear Medicine & PET-Centre, Aarhus University Hospital, Aarhus, Denmark; Department of Radiology, Aarhus University Hospital, Aarhus, Denmark; Department of Radiology, Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark

AbstractSkullremodeling surgery (SR-surgery) includes removing bone from the skull to enhance TTFields. In our phase 1 trial (NCT02893137) we tested multiple SR-configurations (craniectomy, burrholes, and skull thinning) with TTFields concluding it to be safe. To examine the efficacy, we recently initiated an investigator-initiated, randomized, comparative, multi-center phase 2 trial (NCT04223999).To ensure uniformity, SR-surgery will be standardized to 5 burrholes of 15 mm diameter placed cross-diagonally in a 45×45 mm square above the tumor. The configuration was chosen as a combination of maximizing the overall cm3 while not compromising patient safety.To create a standard operating procedure for the trial, we wanted to examine how the electric field was affected by this SR-surgery configuration, its location, and the electrode array placement. We created E-field simulations based on a computational head model, that mimicked a trial patient’s tumor resection cavity, residual tumor, and SR-surgery. SR-surgery was virtually applied at several locations with different electrode positions to investigate the impact on the electric field in the residual tumor tissue, resection cavity, and grey- and white matter. The electrode arrays were moved by 15-degree stepwise rotation around a central craniocaudal axis in the same horizontal plane, corresponding to 0–180 degrees for a total of 13 different positions. Control simulations without SR-surgery were also performed.In general, we found that SR-surgery increased the electric field strength significantly in the residual tumor and resection cavity with minimal effect on the healthy white and grey matter tissue. The highest electric field values were observed in the residual tumor and resection cavity when the burrholes were placed directly above the pathological tissue and the edge electrodes of both pairs were placed on top or close to the burrholes with the reference electrode directly opposite on the head.

Squamous cell carcinoma of the anus (SCCA) is primarily treated with radiotherapy (RT). Treatment failure is predominantly locoregional within the pelvic area. Information on the pattern of failure is important when optimizing treatment strategies. The aim of this study was to evaluated pattern of failure and outcome after radiotherapy for SCCA. A single center, retrospective study was conducted, including patients with histopathological proven SCCA diagnosed between 1998 and 2018 and treated with RT with curative intention. Data was collected from medical records and included patient-, disease-, and treatment characteristics, and outcome data. Disease stage was reclassified according to the 8th edition of the TNM staging system. Locoregional failure (LRF) was defined as failure within the pelvis, and distant failure (DF) as failure outside the pelvis. Survival data were estimated using the Kaplan-Meier method. In total 420 patients treated with curative RT were identified. Median age was 60 years (range 28-89), 75.0% were female, 68.8% had T1-T2 tumors, and 30.9% were diagnosed with lymph node (LN) positive disease. All patients received RT, RT only (79.8%) or with concomitant chemotherapy (19.3%), further 30.7% received induction chemotherapy. Treatment planning was done with IMRT/VMAT in 76.4% of cases, and median prescribed dose to tumor was 64Gy (range 45-64), 64Gy (range 50-64) to pathological LN and 51.2Gy (range 39-54) to the elective nodal areas. Median follow-up (FU) time was 6.1 years (range 0.05-23.6). Overall survival for all stages at 3- and 5 years was 84.0% and 75.5%, respectively and disease-free survival was 73.2% and 69.9% at 3 and 5 years. 85.9% (n=361) achieved complete response (CR) after RT whereas 13.8% (n=58) was diagnosed with progressive or persistent disease, of whom 94.8% had salvage surgery performed. Of patients with CR after RT 19.1% (n=69) experienced treatment failure during FU. As first site of recurrence 13.0% had LRF (n=47), 5.0% had DF (n=18), and 1.1% had both LRF and DF (n=4). When combining both persistent disease and later recurrence 30.2% experience treatment failure. In general, few regional LN recurrences were observed (1.7% of first failures including 0.6% with LN only failures). Recurrence in regional LN was located to the mesorectal LN (n=2), inguinal LN (n=3) or iliac LN (n=1). DF as first site of failure was seen in 22 cases (6.1%) located to either the lung (n=11), liver (n=7) distant LN (n=8), bone (n=1), brain (n=1) or other (n=2) with 8 patients having failure to more than one site. When looking at subsequent failures DF was seen in further 14 cases with a total DF rate of 8.6%. Recurrences to regional LN and DF were low, and the majority of recurrences were thus located within the standard irradiated area. Consequently, it is highly relevant to investigate the exact anatomical location and its relation to specific treatment dose. A dose-mapping study is therefore ongoing.

Introduction: Early detection of lung cancer is of great importance. A blood-based biomarker with the ability to detect lung cancer would be a valid alternative to low-dose CT screening. Methods: A high-risk cohort based on GP suspicion of lung cancer holding 250 participants was formed. Prior to lung cancer investigation, tobacco history was obtained and a blood sample was analysed for the protein carcinoembryonic antigen. Based on these results, a cross-validated prediction model was computed to assess to the diagnostic properties. Results: In the cohort, 79 participants were diagnosed with lung cancer, the remaining 171 served as controls. The ROC curve using a combination of tobacco pack years and carcinoembryonic antigen yielded an AUC value of 0.80. This corresponds to a sensitivity of 0.54 [0.43-0.65] and specificity of 0.87 [0.81-0.92]. The negative predictive value was 81%. Conclusions: In a high-risk cohort, the combination of tobacco history and carcinoembryonic antigen for detection of lung cancer yields acceptable lung cancer detection abilities. However, they are not a the level of low-dose CT screening results.

This commentary attempts to discuss the required standardization of circulating tumor DNA (ctDNA) analyses and thereby improve the clinical validity of ctDNA monitoring in the metastatic setting of solid tumors.

Definitive therapy for squamous cell carcinoma of the anus with synchronous metastases – a report from the Danish Anal Cancer Group

Objective Natural killer (NK) cells play an essential role in the immune response against cancer. However, immune escape mechanisms may cause inferior NK cell activity (NKA) in patients with cancer. This prospective study examined the relationship between NKA and lung cancer in a high-risk cohort. Methods In a cohort study, 250 participants referred by their general practitioner for suspicion of lung cancer were included. Before clinical investigation, blood was collected into NK Vue tubes, and the level of interferon gamma after 24 hours served as a surrogate marker for NKA. Results Among 250 patients, 79 were diagnosed with lung cancer. No difference in NKA was found between patients with lung cancer and control participants in which lung cancer was ruled out (median 226 pg/mL vs. 450 pg/mL). However, there was a significant difference in NKA between patients with late-stage lung cancer and controls (median 161 pg/mL vs. 450 pg/mL). A linear regression model showed that NKA was not influenced by age, sex or smoking status. Conclusions The significantly lower NKA in patients with late-stage lung cancer warrants further investigation combining NKA with other biomarkers and examining the potential role of NKA as a marker of disseminated disease.

The treatment of locally advanced rectal cancer (LARC) has evolved during the last decades, but recurrence remains a problem. Circulating tumor DNA (ctDNA) may result in an individualized treatment approach with improved survival and quality of life, but diverging results impede further development. In this systematic review, we addressed the quality of reporting and its impact on the interpretation of ctDNA results. We performed a systematic literature search using subject headings and search terms related to ctDNA and rectal cancer. The Quality of Prognostic Studies (QUIPS) tool was used to assess bias. Nine studies, with substantial heterogeneity, were included in the analysis. Three out of nine articles had moderate or high risk of bias. No association was found between treatment response and ctDNA status at baseline. There was a negative association between ctDNA positivity at baseline, before and after surgery and survival. The ctDNA status may be of importance to the long-term prognosis, but the area of research is new and is short of dedicated studies. There is an obvious need for standardization in ctDNA research, and the issue should be addressed in future research.