Early radiologic and metabolic tumour response assessment during combined chemo-radiotherapy for locally advanced NSCLC.

Background: The role of early treatment response for patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with concurrent chemo-radiotherapy (cCRT) is unclear. The study aims to investigate the predictive value of response to induction chemotherapy (iCX) and the correlation with pattern of failure (PoF). Materials and methods: Patients with LA-NSCLC treated with cCRT were included for analyses (n = 276). Target delineations were registered from radiotherapy planning PET/CT to diagnostic PET/CT, in between which patients received iCX. Volume, sphericity, and SUVpeak were extracted from each scan. First site of failure was categorised as loco-regional (LR), distant (DM), or simultaneous LR+M (LR+M). Fine and Gray models for PoF were performed: a baseline model (including performance status (PS), stage, and histology), an image model for squamous cell carcinoma (SCC), and an image model for non-SCC. Parameters included PS, volume (VOL) of tumour, VOL of lymph nodes, ΔVOL, sphericity, SUVpeak, ΔSUVpeak, and oligometastatic disease. Results: Median follow-up was 7.6 years. SCC had higher sub-distribution hazard ratio (sHR) for LRF (sHR = 2.771 [1.577:4.87], p < 0.01) and decreased sHR for DM (sHR = 0.247 [0.125:0.485], p  <  0.01). For both image models, high diagnostic SUVpeak increased risk of LRF (sHR = 1.059 [1.05:1.106], p < 0.01 for SCC, sHR = 1.12 [1.03:1.21], p < 0.01 for non-SCC). Patients with SCC and less decrease in VOL had higher sHR for DM (sHR = 1.025[1.001:1.048] pr. % increase, p = 0.038). Conclusion: Poor response in disease volume was correlated with higher sHR of DM for SCC, no other clear correlation of response and PoF was observed. Histology significantly correlated with PoF with SCC prone to LRF and non-SCC prone to DM as first site of failure. High SUVpeak at diagnosis increased the risk of LRF for both histologies.

Drug-Drug Interactions in the Treatment of Cancer-Associated Venous Thromboembolism with Direct Oral Anticoagulants.

Venous thromboembolism (VTE) is a frequent complication of cancer, and management of cancer-associated thrombosis (CAT) is challenging due to increased risks of bleeding and recurrent VTE. Recent trials have shown an acceptable efficacy and safety of direct oral anticoagulants (DOACs) in the treatment of CAT compared to low-molecular weight heparin. Although DOACs provide an effective and convenient treatment option in CAT, the need to assess the risk of drug-drug interactions (DDI) with antineoplastic therapies poses a barrier to their use in clinical practice. With the aim of supporting the assessment of CAT patients for treatment with DOAC, this review provides a comprehensive overview of the compatibility of antineoplastic therapies with the individual DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban). Using several data sources, we characterized 100 widely used antineoplastic agents with regard to their effect on p-glycoprotein and cytochrome P450, both important in the transport and elimination of DOACs. This enabled us to evaluate 400 "DOAC-antineoplastic agent"-pairs regarding their likelihood to interact (unlikely, potential, or likely), ultimately leading to clinical recommendations on the appropriateness of concomitant use for each pair. A potential or likely DDI was identified for 12% of the evaluated pairs. For nearly all antineoplastic agents, at least one DOAC was considered compatible.

Different benefits of adaptive radiotherapy for different histologies of NSCLC.

BACKGROUND: Adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the most frequent histological subtypes of non-small cell lung cancer (NSCLC). The aim of this study was to investigate how patients with AC and SCC benefit from image-guided adaptive radiotherapy (ART) with tumour match. MATERIAL AND METHODS: Consecutive patients diagnosed with AC or SCC of the lung treated with definitive chemo-radiotherapy before and after the implementation of ART and tumour match were retrospectively included for analyses. Data collection included baseline patient and treatment characteristics in addition to clinical data on radiation pneumonitis (RP), failure, and survival. Patients were divided into four categories based on their histology and treatment before (n = 173 [89 AC and 84 SCC]) and after implementation of ART (n = 240 [141 AC and 99 SCC]). RESULTS: Median follow-up was 5.7 years for AC and 6.3 years for SCC. Mean lung dose decreased for both histologies with ART, whereas mean heart dose only decreased for patients with AC. Incidences of grade 3 and 5 RP decreased for both histologies with ART. Loco-regional failure (LRF) rates decreased significantly for patients with SCC after ART (p = .04), no significant difference was observed for AC. Overall survival (OS) increased significantly for SCC after ART (p < .01): the 2-year OS increased from 31.0% (95% confidence interval [CI] [22.5-42.6]) to 54.5% (95% CI [45.6-65.3]). No significant effect on OS was observed for patients with AC. CONCLUSION: ART and tumour match in the radiotherapeutic treatment of patients with locally advanced NSCLC primarily led to decreased LRF and improved OS for patients with SCC.

ProTarget: a Danish Nationwide Clinical Trial on Targeted Cancer Treatment based on genomic profiling - a national, phase 2, prospective, multi-drug, non-randomized, open-label basket trial.

BACKGROUND: An increasing number of trials indicate that treatment outcomes in cancer patients with metastatic disease are improved when targeted treatments are matched with druggable genomic alterations in individual patients (pts). An estimated 30-80% of advanced solid tumors harbor actionable genomic alterations. However, the efficacy of personalized cancer treatment is still scarcely investigated in larger, controlled trials due to the low frequency and heterogenous distribution of druggable alterations among different histologic tumor types. Therefore, the overall effect of targeted cancer treatment on clinical outcomes still needs investigation. STUDY DESIGN/METHODS: ProTarget is a national, non-randomized, multi-drug, open-label, pan-cancer phase 2 trial aiming to investigate the anti-tumor activity and toxicity of currently 13 commercially available, EMA-approved targeted therapies outside the labeled indication for treatment of advanced malignant diseases, harboring specific actionable genomic alterations. The trial involves the Danish National Molecular Tumor Board for confirmation of drug-variant matches. Key inclusion criteria include a) measurable disease (RECIST v.1.1), b) ECOG performance status 0-2, and c) an actionable genomic alteration matching one of the study drugs. Key exclusion criteria include a) cancer type within the EMA-approved label of the selected drug, and b) genomic alterations known to confer drug resistance. Initial drug dose, schedule and dose modifications are according to the EMA-approved label. The primary endpoint is objective response or stable disease at 16 weeks. Pts are assigned to cohorts defined by the selected drug, genomic alteration, and tumor histology type. Cohorts are monitored according to a Simon's two-stage-based design. Response is assessed every 8 weeks for the first 24 weeks, then every 12 weeks. The trial is designed similar to the Dutch DRUP and the ASCO TAPUR trials and is a partner in the Nordic Precision Cancer Medicine Trial Network. In ProTarget, serial fresh tumor and liquid biopsies are mandatory and collected for extensive translational research including whole genome sequencing, array analysis, and RNA sequencing. DISCUSSION: The ProTarget trial will identify new predictive biomarkers for targeted treatments and provide new data and essential insights in molecular pathways involved in e.g., resistance mechanisms and thereby potentially evolve and expand the personalized cancer treatment strategy. PROTOCOL VERSION: 16, 09-MAY-2022. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04341181. Secondary Identifying No: ML41742. EudraCT No: 2019-004771-40.

Survival benefits for non-small cell lung cancer patients treated with adaptive radiotherapy.

INTRODUCTION: Tumor match and adaptive radiotherapy based on on-treatment imaging increases the precision of RT. This allows a reduction of treatment volume and, consequently, of the dose to organs at risk. We investigate the clinical benefits of tumor match and adaptive radiotherapy for a cohort of non-small cell lung cancer patients (NSCLC). METHODS: In 2013, tumor match and adaptive radiotherapy based on daily cone-beam CT scans was introduced to ensure adaption of the radiotherapy treatment plan for all patients with significant anatomical changes during radiotherapy. Before 2013, the daily cone-beam CT scans were matched on the vertebra and anatomical changes were not evaluated systematically. To estimate the effect of tumor match and adaptive radiotherapy, 439 consecutive NSCLC patients treated with definitive chemo-radiotherapy (50-66 Gy/25-33 fractions, 2010-2018) were investigated retrospectively. They were split in two groups, pre-ART (before tumor match and adaptive radiotherapy, 184 patients), and ART (after tumor match and adaptive radiotherapy, 255 patients) and compared with respect to clinical, treatment-specific and dosimetric variables (χ2 tests, Mann Whitney U tests), progression, survival and radiation pneumonits (CTCAEv3). Progression-free and overall survival as well as radiation pneumonitis were compared with log-rank tests. Hazard ratios were estimated from Cox proportional hazard regression. RESULTS: No significant differences in stage (p = 0.36), histology (p = 0.35), PS (p = 0.12) and GTV volumes (p = 0.24) were observed. Concomitant chemotherapy was administered more frequently in the ART group (78%) compared to preART (64%), p < 0.001. Median[range] PTV volumes decreased from 456 [71;1262] cm3 (preART) to 270 [31;1166] cm3 (ART), p < 0.001, thereby significantly reducing mean doses to lungs (median, preART 16.4 [1.9;24.7] Gy, ART 12.1 [1.7;19.4] Gy, p < 0.001) and heart (median, preART 8.0 [0.1;32.1] Gy, ART 4.4 [0.1;33.9] Gy, p < 0.001). The incidence of RP at nine months decreased significantly with ART (50% to 20% for symptomatic RP (≥G2), 21% to 7% for severe RP (≥G3), 6% to 0.4% for lethal RP (G5), all p < 0.001). The two-year progression free survival increased from 22% (preART) to 30% (ART), while the overall survival increased from 43% (preART) to 56% (ART). The median overall survival time increased from 20 (preART) to 28 months (ART). CONCLUSION: Tumor match and adaptive radiotherapy significantly decreased radiation pneumonitis, while maintaining loco-regional control. Further, we observed a significantly improved progression-free and overall survival.

Effect of stereotactic body radiotherapy on regional metabolic liver function investigated in patients by dynamic [18F]FDGal PET/CT.

PURPOSE: Stereotactic body radiotherapy (SBRT) is increasingly used for treatment of liver tumors but the effect on metabolic liver function in surrounding tissue is largely unknown. Using 2-deoxy-2-[18F]fluoro-D-galactose ([18F]FDGal) positron emission tomography (PET)/computed tomography (CT), we aimed to determine a dose-response relationship between radiation dose and metabolic liver function as well as recovery. PROCEDURES: One male subject with intrahepatic cholangiocarcinoma and five subjects (1 female, 4 male) with liver metastases from colorectal cancer (mCRC) underwent [18F]FDGal PET/CT before SBRT and after 1 and 3 months. The dose response was calculated using the data after 1 month and the relative recovery was evaluated after 3 months. All patients had normal liver function at time of inclusion. RESULTS: A linear dose-response relationship for the individual liver voxel dose was seen until approximately 30 Gy. By fitting a polynomial curve to data, a mean TD50 of 18 Gy was determined with a 95% CI from 12 to 26 Gy. After 3 months, a substantial recovery was observed except in tissue receiving more than 25 Gy. CONCLUSIONS: [18F]FDGal PET/CT makes it possible to determine a dose-response relationship between radiation dose and metabolic liver function, here with a TD50 of 18 Gy (95% CI 12-26 Gy). Moreover, the method makes it possible to estimate metabolic recovery in liver tissue.

Difference in target definition using three different methods to include respiratory motion in radiotherapy of lung cancer.

INTRODUCTION: Minimizing the planning target volume (PTV) while ensuring sufficient target coverage during the entire respiratory cycle is essential for free-breathing radiotherapy of lung cancer. Different methods are used to incorporate the respiratory motion into the PTV. MATERIAL AND METHODS: Fifteen patients were analyzed. Respiration can be included in the target delineation process creating a respiratory GTV, denoted iGTV. Alternatively, the respiratory amplitude (A) can be measured based on the 4D-CT and A can be incorporated in the margin expansion. The GTV expanded by A yielded GTV + resp, which was compared to iGTV in terms of overlap. Three methods for PTV generation were compared. PTVdel (delineated iGTV expanded to CTV plus PTV margin), PTVσ (GTV expanded to CTV and A was included as a random uncertainty in the CTV to PTV margin) and PTV∑ (GTV expanded to CTV, succeeded by CTV linear expansion by A to CTV + resp, which was finally expanded to PTV∑). RESULTS: Deformation of tumor and lymph nodes during respiration resulted in volume changes between the respiratory phases. The overlap between iGTV and GTV + resp showed that on average 7% of iGTV was outside the GTV + resp implying that GTV + resp did not capture the tumor during the full deformable respiration cycle. A comparison of the PTV volumes showed that PTVσ was smallest and PTVΣ largest for all patients. PTVσ was in mean 14% (31 cm3) smaller than PTVdel, while PTVdel was 7% (20 cm3) smaller than PTVΣ. CONCLUSIONS: PTVσ yields the smallest volumes but does not ensure coverage of tumor during the full respiratory motion due to tumor deformation. Incorporating the respiratory motion in the delineation (PTVdel) takes into account the entire respiratory cycle including deformation, but at the cost, however, of larger treatment volumes. PTVΣ should not be used, since it incorporates the disadvantages of both PTVdel and PTVσ.

Adaptation is mandatory for intensity modulated proton therapy of advanced lung cancer to ensure target coverage.

BACKGROUND AND PURPOSE: Large anatomical changes during radiotherapy are seen for a large proportion of lung cancer patients. We investigate the applicability of a decision support protocol for photon therapy in a proton therapy setting. MATERIAL AND METHODS: Twenty-three consecutive NSCLC patients treated with adaptive photon therapy were retrospectively planned using IMPT. The adaptive protocol was based on geometrical measures of target positioning and large anatomical changes as shown on daily CBCT scans. Two surveillance CT-scans were acquired during the treatment course. The consequences of anatomical changes were evaluated by recalculating the proton plans on the surveillance scans. The CTV receiving 95% of the prescribed dose was analysed. RESULTS: Fourteen (61%) patients needed adaptations when treated with protons, given that 95% of the CTV must be covered by 95% of the dose. In comparison, no patients needed adaptation when treated with photons using this criterion. The adaptive protocol was found to identify patients with large target under-dosage for proton therapy (six patients). Additionally, target under-dosage was observed for eight patients with non-rigid changes up to 15mm in the positioning of the bones. CONCLUSIONS: Proton therapy for loco-regional lung cancer demands daily imaging and therapy adaptation for a high proportion of patients.

Adaptive radiotherapy for advanced lung cancer ensures target coverage and decreases lung dose.

BACKGROUND AND PURPOSE: Advanced lung cancer patients experience anatomical changes during radiotherapy. Uncorrected, these may lead to lower tumor dose, but can be corrected for by adaptive radiotherapy (ART). MATERIAL AND METHODS: Anatomical changes in 233 patients were monitored online on cone-beam CT-scans used for daily soft-tissue matching. If systematic changes above the pre-defined trigger criteria were observed, a new CT-scan, delineations, and treatment plan were made, restoring the intended dose distribution. Dose distributions with and without adaptation were compared. The first fifty ART patients were given two surveillance CT-scans during radiotherapy. These were used to evaluate delivered dose for patients without adaptation. The first fifty-two patients treated with ART were also compared with 52 pre-ART patients to evaluate the reduction in normal tissue doses. RESULTS: Sixty-three patients (27%) were adapted. Seventy-five per cent of all adaptations correctly adjusted for a decrease in tumor dose. Eighty-seven surveillance CT-scans were obtained for the first fifty patients and in only 2% of the cases, a decrease in tumor coverage (ΔV95%CTV>1%) was observed. With ART we observed a significant decrease in lung dose (MLD reduced from 14.6Gy to 12.6Gy on average). CONCLUSIONS: Implementation of soft-tissue match combined with ART decreased the lung dose. The trigger criteria used correctly identified all but one (98%) of the patients requiring adaptation with a false positive rate of 20%.

[Detection of occult cancer in patients with idiopathic venous thrombosis]. / Udredning for uerkendt cancer hos patienter med idiopatisk venøs trombose.

Idiopathic venous thrombosis (VTE) is frequently associated with underlying malignancy. Thus, it is tempting to search for underlying cancer in these patients. However, extensive screening is cost-intensive and no survival benefit has been demonstrated. Based on a review of the literature, we recommend the performance of a thorough medical history and physical examination in addition to basic biochemical screening and a chest X-ray in patients with idiopathic VTE. Only specific symptoms or findings should lead to a more extensive work-up.

Anatomical landmarks accurately determine interfractional lymph node shifts during radiotherapy of lung cancer patients.

BACKGROUND AND PURPOSE: Low contrast in the cone-beam computed tomography (CBCT) scans hampers fast online evaluation of interfractional changes in the lymph node position on a daily basis. In this study we have investigated whether high-contrast anatomical landmarks in the vicinity of the nodes may be used as surrogates for the lymph node positions. MATERIALS AND METHODS: Forty lung cancer patients were treated with an online CBCT-based setup strategy involving soft-tissue match on the primary tumor. One hundred and sixteen lymph nodes were delineated separately on the planning-CT scans and categorized according to the lymph node stations. Five anatomical landmarks were selected as surrogate structures and assigned to the individual nodes. In addition, the carina was delineated. Registrations between the planning-CT and the daily CBCTs were performed retrospectively and positional deviations between the nodes and the surrogate structures or the carina were registered. RESULTS: The mean displacement between lymph nodes and surrogate structures was 1.6mm with systematic/random errors of 0.7/0.7mm, significantly smaller than the mean displacement between nodes and the carina. CONCLUSIONS: The position of the lymph nodes can be evaluated using selected anatomical landmarks on a daily basis using CBCT.

Stereotactic body radiotherapy for unresectable cholangiocarcinoma.

PURPOSE: To report outcomes of a single institution study of stereotactic body radiotherapy (SBRT) for unresectable cholangiocarcinoma. The dose-volume dependency of the observed gastrointestinal toxicity is explored. METHODS AND MATERIALS: Twenty-seven patients with unresectable cholangiocarcinoma (n=26 Klatskin tumours and one intrahepatic cholangiocarcinoma (IHCC)) were treated by linac-based SBRT. The dose schedule was 45Gy in three fractions prescribed to the isocenter. RESULTS: The median progression-free survival and overall survival were 6.7 and 10.6 months, respectively. With a median follow-up of 5.4 years, 6 patients had severe duodenal/pyloric ulceration and 3 patients developed duodenal stenosis. Duodenal radiation exposure was higher in patients developing moderate to high-grade gastrointestinal toxicity with the difference in mean maximum dose to 1cm(3) of duodenum reaching statistical significance. A statistically significant association between grade 2 ulceration and volume of duodenum exposed to selected dose levels was not established. CONCLUSION: The outcomes of SBRT for unresectable cholangiocarcinoma appear comparable to conventionally fractionated chemoradiotherapy with or without brachytherapy boost. The practical advantages of SBRT are of particular interest for such poor prognosis patients. Patient selection, however, is key in order to avoid compromising such practical gains with excessive gastrointestinal toxicity.