Assessment of radiation pneumonitis and predictive factors in patients with locally advanced non-small cell lung cancer treated with chemoradiotherapy.

PURPOSE: Radiation pneumonitis (RP) is a dose-limiting toxicity associated with increased mortality for patients with non-small cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT). This study aims to assess the incidence of symptomatic RP (grade 2-5), rate of recovery and associated predictive factors. MATERIAL AND METHODS: We performed a retrospective population-based study including 602 patients with NSCLC who were treated with CRT between 2002 and 2016. RP and rate of recovery were analysed using Common Terminology Criteria for Adverse Events version 4.0. Stepwise logistic regression was performed to analyse potential predictive factors for the two endpoints RP grade ≥ 2 and RP grade ≥ 3. RESULTS: A total of 136 (23%) patients developed symptomatic RP and 37 (6%) developed RP grade ≥ 3. A total of 67 (71%) recovered, whereas the remaining 27 (29%), with the major proportion of patients belonging to the RP grade ≥ 3 group, suffered from prevailing sequelae. On multivariable analysis, the selected model for predicting RP grade ≥ 2 included the factors V20, smoking status, average fractions per week and chemotherapy agent. V20 and age were selected factors for RP grade ≥ 3. INTERPRETATION: The results suggest that regardless of all proposed factors predictive for RP, the most important influenceable significant factor still is dose to the lung. The main aim should be to avoid RP grade ≥ 3, where a substantial proportion of patients suffer from prevailing sequalae. Consequently, the technical improvement and precision of radiotherapy delivery should continue to focus on lung sparing techniques also in the ongoing immunotherapy-containing schedules where the risk of pneumonitis may be increased. e factor still is dose to the lung. Consequently, the technical improvement and precision of radiotherapy delivery should continue to focus on lung sparing techniques also in the ongoing immunotherapy-containing schedules where the risk of pneumonitis may be increased.

Pulmonary Adenocarcinoma In Situ and Minimally Invasive Adenocarcinomas in European Patients Have Less KRAS and More EGFR Mutations Compared to Advanced Adenocarcinomas.

Pulmonary adenocarcinoma (ADC) is a very diverse disease, both genetically and histologically, which displays extensive intratumor heterogeneity with numerous acquired mutations. ADC is the most common type of lung cancer and is believed to arise from adenocarcinoma in situ (AIS) which then progresses to minimally invasive adenocarcinoma (MIA). In patients of European ethnicity, we analyzed genetic mutations in AIS (n = 10) and MIA (n = 18) and compared the number of genetic mutations with advanced ADC (n = 2419). Using next-generation sequencing, the number of different mutations detected in both AIS (87.5%) and MIA (94.5%) were higher (p < 0.001) than in advanced ADC (53.7%). In contrast to the high number of mutations in Kirsten rat sarcoma virus gene (KRAS) in advanced ADC (34.6%), there was only one case of AIS with KRAS G12C mutation (3.5%; p < 0.001) and no cases of MIA with KRAS mutation (p < 0.001). In contrast to the modest prevalence of epidermal growth factor receptor (EGFR) mutations in advanced ADC (15.0%), the fraction of EGFR mutant cases was higher in both in AIS (22.2%) and MIA (59.5%; p < 0.001). The EGFR exon 19 deletion mutation was more common in both MIA (50%; n = 6/12) and ADC (41%; n = 149/363), whereas p.L858R was more prevalent in AIS (75%; n = 3/4). In contrast to pulmonary advanced ADC, KRAS driver mutations are less common, whereas mutations in EGFR are more common, in detectable AIS and MIA.

Phase II trial demonstrates the efficacy and safety of individualized, dosimetry-based 177Lu-DOTATATE treatment of NET patients.

PURPOSE: Radionuclide therapy with 177Lu-DOTATATE is well established for patients with advanced somatostatin receptor-positive neuroendocrine tumors with a standard schedule of 7.4 GBq at four occasions. However, this approach does not consider individual variability affecting the tumor radiation dose or dose to organs at risk. Therefore, it is important to assess more personalized strategies. The aim of this phase II trial was to evaluate individualized 177Lu-DOTATATE for which the number of cycles varied based on renal dosimetry. METHODS: Patients were eligible if they had a progressive, somatostatin receptor-positive neuroendocrine tumor with a Ki 67 labeling index < 20%. They received cycles of 7.4 GBq of 177Lu-DOTATATE at 10 ± 2-week intervals until a predefined radiation dose to the kidneys was reached. The primary endpoint was objective tumor response (RECIST v 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity (CTCAE v. 4.0). RESULTS: Ninety-six patients who had received a median of 5 cycles (range 1-9) were evaluable for efficacy. The objective tumor response was 16% partial response, 66% stable disease, and 19% progressive disease. The median PFS and OS were 29 months and 47 months, respectively, and were significantly associated with kidney dose, performance status, and Ki 67 levels but not with tumor origin. The overall toxicity was mild, and the most common events were grade 1-2 anemia, thrombocytopenia, fatigue, nausea, and diarrhea. Grade 3-4 toxicity occurred in < 10% of patients and was mostly hematological, with no grade 3-4 renal toxicity. CONCLUSION: Individualized treatment with 177Lu-DOTATATE based on renal dosimetry is clearly feasible with low toxicity and promising efficacy, showing the potential to further improve outcome beyond the standard approach, and should be further assessed in randomized trials. TRIAL REGISTRATION: EudraCT 2011-000,240-16. NCT01456078. https://clinicaltrials.gov/ct2/show/NCT01456078.

Stereotactic radiotherapy for brain metastases in patients with lung cancer; outcome and toxicity in clinical practice.

Background: Stereotactic radiotherapy (SRT) is an established modality for treating limited brain metastases (BMs). This study aimed to assess the real-life treatment outcome and associated prognostic factors for survival in a consecutive lung cancer cohort receiving SRT for BMs. Materials and methods: A retrospective review and analysis of patients with lung cancer with BMs treated with SRT in western Sweden between 2002 and 2017 were performed. Data were collected from patient charts and the radiotherapy dose planning system. Results: One hundred nine patients corresponding to 139 lesions were assessed; the majority were treated with single-fractionated SRT with 20 Gy. The median overall survival (OS) was 6.1 months, with a 12-month survival rate of 24%. The estimated overall disease control rate (DCR) was 84% at a median time of three months. On multivariate analysis, WHO performance status (PS) (p = 0.002) and smoking status (p = 0.005) were significant predictive factors for survival. Four percent of the patients experienced possible grade III-IV toxicity, and previously administered cranial radiation therapy was a significant independent factor (p = 0.03) associated with the risk of developing acute toxicity. Conclusions: SRT due to brain metastases from lung cancer is a well-tolerated treatment. When selecting patients suitable for treatment, PS and extracranial disease progression should be considered. Smoking cessation is probably of value even in this palliative setting. The goal of SRT for BMs is not only to improve survival but also to provide symptom relief, and future studies on SRT should assess patient-reported outcomes in addition to survival.

Immune checkpoint blockade and biomarkers of clinical response in non-small cell lung cancer.

Immunotherapy with PD-1 and PD-L1 inhibitors has revolutionized the treatment for patients with NSCLC the last years with increased overall survival and in particular increased number of long-time survivors in patients with metastatic disease. It is now a treatment of choice for patients with distant metastases (stage IV) and in conjunction with chemoradiotherapy for patients with limited spread confined to the chest (stage III). PD-1 inhibition has been proven to be superior to standard chemotherapy, both as a single treatment and when combined with either chemotherapy or CTLA-4 inhibition. Despite the success of immunotherapy, the majority of patients do not respond or relapse within a short time frame. Biomarkers that would help to properly select patients with a high likelihood of clinical response to PD-1 and PD-L1 inhibitors are scarce and far from optimal, and only one (PD-L1 expression) has reached clinical practice. Thus for immunotherapy to be effective, the discovery and validation of additional biomarkers is critical for patient selection and prediction of clinical response. In this mini-review, we give an overview of current clinical management of NSCLC including treatment landscape with regard to immunotherapy, as well as discuss the current genetic and immune cell biomarker studies and their potential for introduction into clinical practice.

LINAC-based stereotactic radiosurgery versus hypofractionated stereotactic radiotherapy delivered in 3 or 5 fractions for vestibular schwannomas: comparative assessment from a single institution.

PURPOSE: The optimal treatment strategy for vestibular schwannoma (VS) is not known, and different radiation techniques and fractionation regimens are currently being used. This report aimed to assess outcomes after LINAC-based radiosurgery (SRS) and hypofractionated radiotherapy (hypo-FSRT) and identify possible differences in outcomes between hypo-FSRT delivered in 3 or 5 fractions. METHODS: From 2005 to 2017, 136 patients underwent treatment with radiotherapy for VS. Thirty-seven patients received SRS (12 Gy), and 99 received hypo-FSRT. Hypo-FSRT was delivered in 3 fractions (total 18-21 Gy, n = 39) and 5 fractions (total 25 Gy, n = 60). RESULTS: The median follow-up was 57 months. Eight patients had progression requiring surgery, corresponding to an overall local control rate of 93.4%, with no significant difference between the fractionation schedules. A correlation with borderline significance (p = 0.052) was detected between cystic tumors and local failure. A tendency toward a higher incidence of local failure was observed after 2015 when SRS treatment increased and included slightly larger tumors. Hearing preservation was observed in 35% of patients and 36% of patients experienced acute side effects, but persistent facial or trigeminal nerve toxicity was rare. CONCLUSION: SRS and hypo-FSRT with 3 or 5 fractions provided a high rate of local control with no significant differences between treatment schedules. SRS is a well-documented radiation technique for VS and is the recommendation for small- to medium-sized tumors. This report demonstrates excellent long-term outcomes after hypo-FSRT; this regimen can be delivered safely and is an alternative for selected patients.

Analysis of early respiratory-related mortality after radiation therapy of non-small-cell lung cancer: feasibility of automatic data extraction for dose-response studies.

Purpose: To examine the feasibility of automatic data extraction from clinical radiation therapy (RT) databases at four hospitals to investigate the impact of mean lung dose (MLD) and age on the risk of early respiratory-related death and early overall death for patients treated with RT for non-small-cell lung cancer (NSCLC).Material and methods: We included adult patients with NSCLC receiving curatively intended RT between 2002 and 2017 at four hospitals. A script was developed to automatically extract RT-related data. The cause of death for patients deceased within 180 days of the start of RT was retrospectively assessed. Using logistic regression, the risks of respiratory-related death and of overall death within 90 and 180 days were investigated using MLD and age as variables.Results: Altogether, 1785 patients were included in the analysis of early overall mortality and 1655 of early respiratory-related mortality. The respiratory-related mortalities within 90 and 180 days were 0.9% (15/1655) and 3.6% (60/1655). The overall mortalities within 90 and 180 days were 2.5% (45/1785) and 10.6% (190/1785). Higher MLD and older age were associated with an increased risk of respiratory-related death within 180 days and overall death within 90 and 180 days (all p<.05). For example, the risk of respiratory-related death within 180 days and their 95% confidence interval for patients aged 65 and 75 years with MLDs of 20 Gy was according to our logistic model 3.8% (2.6-5.0%) and 7.7% (5.5-10%), respectively.Conclusions: Automatic data extraction was successfully used to pool data from four hospitals. MLD and age were associated with the risk of respiratory-related death within 180 days of the start of RT and with overall death within 90 and 180 days. A model quantifying the risk of respiratory-related death within 180 days was formulated.

Assessing the prognostic value of KRAS mutation combined with tumor size in stage I-II non-small cell lung cancer: a retrospective analysis.

Background: KRAS mutation status is a well-established independent prognostic factor in advanced non-small cell lung cancer (NSCLC), yet its role in early-stage disease is unclear. Here, we investigate the prognostic value of combining survival data on KRAS mutation status and tumor size in stage I-II NSCLC. Methods: We studied the combined impact of KRAS mutational status and tumor size on overall survival (OS) in patients with stage I-II NSCLC. We performed a retrospective study including 310 diagnosed patients with early (stage I-II) NSCLCs. All molecularly assessed patients diagnosed with stage I-II NSCLC between 2016-2018 in the Västra Götaland Region of western Sweden were screened in this multi-center retrospective study. The primary study outcome was overall survival. Results: Out of 310 patients with stage I-II NSCLC, 37% harbored an activating mutation in the KRAS gene. Our study confirmed staging and tumor size as prognostic factors. However, KRAS mutational status was not found to impact OS and there was no difference in the risk of death when combining KRAS mutational status and primary tumor size. Conclusions: In our patient cohort, KRAS mutations in combination with primary tumor size did not impact prognosis in stage I-II NSCLC.

Immune checkpoint blockade improves the activation and function of circulating mucosal-associated invariant T (MAIT) cells in patients with non-small cell lung cancer.

Mucosal-associated invariant T (MAIT) cells constitute one of the most numerous unconventional T cell subsets, and are characterized by rapid release of Th1- and Th17-associated cytokines and increased cytotoxic functions following activation. MAIT cells accumulate in tumor tissue but show an exhausted phenotype. Here, we investigated if immune checkpoint blockade (ICB) with antibodies to PD-1 or PD-L1 affects the function of circulating MAIT cells from non-small cell lung cancer patients. ICB increased the proliferation and co-expression of the activation markers HLA-DR and CD38 on MAIT cells in most patients after the first treatment cycle, irrespective of treatment outcome. Furthermore, production of cytokines, especially TNF and IL-2, also increased after treatment, as did MAIT cell polyfunctionality. These results indicate that MAIT cells respond to ICB, and that MAIT cell reinvigoration may contribute to tumor regression in patients undergoing immune checkpoint therapy.

Specific Uptake in the Bone Marrow Causes High Absorbed Red Marrow Doses During [177Lu]Lu-DOTATATE Treatment.

Bone marrow suppression is a common side effect after [177Lu]Lu-DOTATATE treatment of neuroendocrine neoplasms. Neuroendocrine neoplasms share expression of somatostatin receptor type 2 with CD34-positive hematopoietic progenitor cells, potentially leading to active uptake in the radiosensitive red marrow region where these cells are located. This study aimed to identify and quantify specific red marrow uptake using SPECT/CT images collected after the first treatment cycle. Methods: Seventeen patients diagnosed with neuroendocrine neoplasms were treated with [177Lu]Lu-DOTATATE. Seven of them had confirmed bone metastases. After the first treatment cycle, each patient went through 4 SPECT/CT imaging sessions 4, 24, 48, and 168 h after administration. Monte Carlo-based reconstructions were used to quantify activity concentrations in tumors and multiple skeletal sites presumed to house red marrow: the T9-L5 vertebrae and the ilium portion of the hip bones. The activity concentration from the descending aorta was used as input in a compartment model intended to establish a pure red marrow biodistribution by separating the nonspecific blood-based contribution from the specific activity concentration in red marrow. The biodistributions from the compartment model were used to perform red marrow dosimetry at each skeletal site. Results: Increased uptake of [177Lu]Lu-DOTATATE was observed in the T9-L5 vertebrae and hip bones in all 17 patients compared with activity concentrations in the aorta. The mean specific red marrow uptake was 49% (range, 0%-93%) higher than the nonspecific uptake. The median (±SD) total absorbed dose to the red marrow was 0.056 ± 0.023 Gy/GBq and 0.043 ± 0.022 Gy/GBq for the mean of all vertebrae and hip bones, respectively. The patients with bone metastases had an absorbed dose of 0.085 ± 0.046 Gy/GBq and 0.069 ± 0.033 Gy/GBq for the vertebrae and hip bones, respectively. The red marrow elimination phase was statistically slower in patients with fast tumor elimination, which is in line with transferrin transport of 177Lu back to the red marrow. Conclusion: Our results suggest that specific red marrow uptake of [177Lu]Lu-DOTATATE is in line with observations of somatostatin receptor type 2-expressing hematopoietic progenitor cells within the bone marrow. Blood-based dosimetry methods fail to account for the prolonged elimination of specific uptake and underestimate the absorbed dose to red marrow.

Estimating the Risk for Secondary Cancer After Targeted α-Therapy with 211At Intraperitoneal Radioimmunotherapy.

Intraperitoneal 211At-based targeted α-therapy (TAT) may hold great promise as an adjuvant therapy after surgery and chemotherapy in epithelial ovarian cancer to eradicate any remaining undetectable disease. This implies that it will also be delivered to patients possibly already cured by the primary treatment. An estimate of long-term risks is therefore sought to determine whether the treatment is justified. Methods: Baseline data for risk estimates of α-particle irradiation were collected from published studies on excess cancer induction and mortality for subjects exposed to either 224Ra treatments or Thorotrast contrast agent (25% ThO2 colloid, containing 232Th). Organ dosimetry for 224Ra and Thorotrast irradiation were taken from the literature. These organ-specific risks were then applied to our previously reported dosimetry for intraperitoneal 211At-TAT patients. Results: Risk could be estimated for 10 different organ or organ groups. The calculated excess relative risk per gray (ERR/Gy) could be sorted into 2 groups. The lower-ERR/Gy group, ranging up to a value of approximately 5, included trachea, bronchus, and lung, at 0.52 (95% CI, 0.21-0.82); stomach, at 1.4 (95% CI, -5.0-7.9); lymphoid and hematopoietic system, at 2.17 (95% CI, 1.7-2.7); bone and articular cartilage, at 2.6 (95% CI, 2.0-3.3); breast, at 3.45 (95% CI, -10-17); and colon, at 4.5 (95% CI, -3.5-13). The higher-ERR/Gy group, ranging from approximately 10 to 15, included urinary bladder, at 10.1 (95% CI, 1.4-23); liver, at 14.2 (95% CI, 13-16); kidney, at 14.9 (95% CI, 3.9-26); and lip, oral cavity, and pharynx, at 15.20 (95% CI, 2.73-27.63). Applying a typical candidate patient (female, age 65 y) and correcting for the reference population mortality rate, the total estimated excess mortality for an intraperitoneal 211At-monoclonal antibody treatment amounted to 1.13 per 100 treated. More than half this excess originated from urinary bladder and kidney, 0.29 and 0.34, respectively. Depending on various adjustments in calculation and assumptions on competing risks, excess mortality could range from 0.11 to 1.84 per 100 treated. Conclusion: Published epidemiologic data on lifelong detriment after α-particle irradiation and its dosimetry allowed calculations to estimate the risk for secondary cancer after 211At-based intraperitoneal TAT. Measures to reduce dose to the urinary organs may further decrease the estimated relative low risk for secondary cancer from 211At-monoclonal antibody-based intraperitoneal TAT.

KRAS G12C Mutant Non-Small Cell Lung Cancer Linked to Female Sex and High Risk of CNS Metastasis: Population-based Demographics and Survival Data From the National Swedish Lung Cancer Registry.

BACKGROUND: Real-world data on demographics related to KRAS mutation subtypes are crucial as targeted drugs against the p.G12C variant have been approved. METHOD: We identified 6183 NSCLC patients with reported NGS-based KRAS status in the Swedish national lung cancer registry between 2016 and 2019. Following exclusion of other targetable drivers, three cohorts were studied: KRAS-G12C (n = 848), KRAS-other (n = 1161), and driver negative KRAS-wild-type (wt) (n = 3349). RESULTS: The prevalence of KRAS mutations and the p.G12C variant respectively was 38%/16% in adenocarcinoma, 28%/13% in NSCLC-NOS and 6%/2% in squamous cell carcinoma. Women were enriched in the KRAS-G12C (65%) and KRAS-other (59%) cohorts versus KRAS-wt (48%). A high proportion of KRAS-G12C patients in stage IV (28%) presented with CNS metastasis (vs. KRAS-other [19%] and KRAS-wt [18%]). No difference in survival between the mutation cohorts was seen in stage I-IIIA. In stage IV, median overall survival (mOS) from date of diagnosis was shorter for KRAS-G12C and KRAS-other (5.8 months/5.2 months) vs. KRAS wt (6.4 months). Women had better outcome in the stage IV cohorts, except in KRAS-G12C subgroup where mOS was similar between men and women. Notably, CNS metastasis did not impact survival in stage IV KRAS-G12C, but was associated with poorer survival, as expected, in KRAS-other and KRAS-wt. CONCLUSION: The KRAS p.G12C variant is a prevalent targetable driver in Sweden and significantly associated with female sex and presence of CNS metastasis. We show novel survival effects linked to KRAS p.G12C mutations in these subgroups with implications for clinical practice.

Successful Treatment with Selpercatinib for Ectopic Cushing's Syndrome Due to Medullary Thyroid Cancer.

Selpercatinib, a RET kinase inhibitor, is an effective treatment for patients with medullary thyroid cancer with RET mutations. In this paper, we present the case of a 62-year-old man with ectopic Cushing's syndrome due to medullary thyroid cancer who received treatment with selpercatinib. Six months later, all the cushingoid features had resolved, and s-calcitonin had decreased from 580 pmol/L to 3.5 pmol/L (normal < 3). After further 6 months, s-calcitonin had normalized (1.5 pmol/L), and radiological evaluation showed a profound tumour volume reduction. We are aware of two other cases where treatment with selpercatinib has also been successful. Thus, selpercatinib may be a promising treatment alternative in patients with ectopic Cushing's syndrome due to medullary thyroid cancer, especially when other treatment options are ineffective or not tolerated.

Astatine-211 based radionuclide therapy: Current clinical trial landscape.

Astatine-211 (211At) has physical properties that make it one of the top candidates for use as a radiation source for alpha particle-based radionuclide therapy, also referred to as targeted alpha therapy (TAT). Here, we summarize the main results of the completed clinical trials, further describe ongoing trials, and discuss future prospects.

KRAS Mutations Impact Clinical Outcome in Metastatic Non-Small Cell Lung Cancer.

There is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PT) and immune checkpoint blockade (ICB). Here, we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (Stage IV) non-small cell lung cancer (NSCLC). All consecutive patients molecularly assessed and diagnosed between 2016−2018 with Stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. The primary study outcome was overall survival (OS). Out of 580 Stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.478, 95% CI 1.207−1.709, p < 0.001). When treated with first-line platinum doublet (n = 195), KRASMUT was a negative factor for survival (p = 0.018), with median OS of 9 months vs. KRASWT at 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95% CI 1.124−2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1highKRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significantly (p = 0.006) better outcome than KRASWT patients, with a median OS of 23 vs. 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95% CI 0.148−0.822, p = 0.016). kRAS mutations are associated with better response to treatment with immune checkpoint blockade and worse response to platinum doublet chemotherapy as well as shorter general OS in Stage IV NSCLC.

Combinatory analysis of immune cell subsets and tumor-specific genetic variants predict clinical response to PD-1 blockade in patients with non-small cell lung cancer.

Objectives: Immunotherapy by blocking programmed death protein-1 (PD-1) or programmed death protein-ligand1 (PD-L1) with antibodies (PD-1 blockade) has revolutionized treatment options for patients with non-small cell lung cancer (NSCLC). However, the benefit of immunotherapy is limited to a subset of patients. This study aimed to investigate the value of combining immune and genetic variables analyzed within 3-4 weeks after the start of PD-1 blockade therapy to predict long-term clinical response. Materials and methodology: Blood collected from patients with NSCLC were analyzed for changes in the frequency and concentration of immune cells using a clinical flow cytometry assay. Next-generation sequencing (NGS) was performed on DNA extracted from archival tumor biopsies of the same patients. Patients were categorized as clinical responders or non-responders based on the 9 months' assessment after the start of therapy. Results: We report a significant increase in the post-treatment frequency of activated effector memory CD4+ and CD8+ T-cells compared with pre-treatment levels in the blood. Baseline frequencies of B cells but not NK cells, T cells, or regulatory T cells were associated with the clinical response to PD-1 blockade. NGS of tumor tissues identified pathogenic or likely pathogenic mutations in tumor protein P53, Kirsten rat sarcoma virus, Kelch-like ECH-associated protein 1, neurogenic locus notch homolog protein 1, and serine/threonine kinase 11, primarily in the responder group. Finally, multivariate analysis of combined immune and genetic factors but neither alone, could discriminate between responders and non-responders. Conclusion: Combined analyses of select immune cell subsets and genetic mutations could predict early clinical responses to immunotherapy in patients with NSCLC and after validation, can guide clinical precision medicine efforts.

Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale.

177Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair 177Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance 177Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with 177Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during 177Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of 177Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to 177Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of 177Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and 177Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).

Evaluation of therapeutic efficacy of 211At-labeled farletuzumab in an intraperitoneal mouse model of disseminated ovarian cancer.

INTRODUCTION: Antibodies labeled with alpha-emitter astatine-211 have previously shown effective in intraperitoneal (i.p.) treatments of ovarian cancer. In the present work we explore the use of investigational farletuzumab, aimed at the folate receptor alpha. The aim was to evaluate the biodistribution and therapeutic effect of 211At-farletuzumab in in-vitro and in-vivo experiments and, using models for radiation dosimetry, to translate the findings to expected clinical result. The activity concentration used for therapy in mice (170 kBq/mL) was chosen to be in agreement with an activity concentration that is anticipated to be clinically relevant in patients (200 MBq/L). METHODS: For biodistribution, using intravenous injections and mice carrying subcutaneous (s.c.) tumors, the animals were administered either 211At-farletuzumab (n = 16); or with a combination of 125I-farletuzumab and 211At-MX35 (n = 12). At 1, 3, 10 and 22 h, mice were euthanized and s.c.-tumors and organs weighted and measured for radioactivity. To evaluate therapeutic efficacy, mice were inoculated i.p. with 2 × 106 NIH:OVCAR-3 cells. Twelve days later, the treatments were initiated by i.p.-administration. Specific treatment was given by 211At-labeled farletuzumab (group A; n = 22, 170 kBq/mL) which is specific for OVCAR-3 cells. Control treatments were given by either 211At-labeled rituximab which is unspecific for OVCAR-3 (group B; n = 22, 170 kBq/mL), non-radiolabeled farletuzumab (group C; n = 11) or PBS only (group D; n = 8). RESULTS: The biodistribution of 211At-farletuzumab was similar to that with 125I as radiolabel, and also to that of 211At-labeled MX35 antibody. The tumor-free fraction (TFF) of the three control groups were all low (PBS 12%, unlabeled specific farletuzumab 9% and unspecific 211At-rituximab 14%). TFF following treatment with 211At-farletuzumab was 91%. CONCLUSION: The current investigation of intraperitoneal therapy with 211At-farletuzumab, delivered at clinically relevant 211At-mAb radioactivity concentrations and specific activities, showed a 6 to 10-fold increase (treated versus controls) in antitumor efficacy. This observation warrants further clinical testing.

Intraperitoneal α-Emitting Radioimmunotherapy with 211At in Relapsed Ovarian Cancer: Long-Term Follow-up with Individual Absorbed Dose Estimations.

Eliminating microscopic residual disease with α-particle radiation is theoretically appealing. After extensive preclinical work with α-particle-emitting 211At, we performed a phase I trial with intraperitoneal α-particle therapy in epithelial ovarian cancer using 211At conjugated to MX35, the antigen-binding fragments-F(ab')2-of a mouse monoclonal antibody. We now present clinical outcome data and toxicity in a long-term follow-up with individual absorbed dose estimations. Methods: Twelve patients with relapsed epithelial ovarian cancer, achieving a second complete or nearly complete response with chemotherapy, received intraperitoneal treatment with escalating (20-215 MBq/L) activity concentrations of 211At-MX35 F(ab')2.Results: The activity concentration was escalated to 215 MBq/L without any dose-limiting toxicities. Most toxicities were low-grade and likely related to the treatment procedure, not clearly linked to the α-particle irradiation, with no observed hematologic toxicity. One grade 3 fatigue and 1 grade 4 intestinal perforation during catheter implantation were observed. Four patients had a survival of more than 6 y, one of whom did not relapse. At progression, chemotherapy was given without signs of reduced tolerability. Overall median survival was 35 mo, with a 1-, 2-, 5-, and 10-y survival of 100%, 83%, 50%, and 25%, respectively. Calculations of the absorbed doses showed that a lower specific activity is associated with a lower single-cell dose, whereas a high specific activity may result in a lower central dose in microtumors. Individual differences in absorbed dose to possible microtumors were due to variations in administered activity and the specific activity. Conclusion: No apparent signs of radiation-induced toxicity or decreased tolerance to relapse therapy were observed. The dosimetric calculations show that further optimization is advisable to increase the efficacy and reduce possible long-term toxicity.

Positron emission tomography and computed tomographic (PET/CT) imaging for radiation therapy planning in anal cancer: A systematic review and meta-analysis.

To improve the accuracy of chemoradiation therapy in anal cancer patients PET/CT is frequently used in the planning of radiation therapy. A systematic review was performed to assess impact on survival, quality of life, symptom score, change in target definition and treatment intention. Systematic literature searches were conducted in Medline, EMBASE, the Cochrane Library, and Centre for Reviews and Dissemination. Ten cross-sectional studies were identified. No data were available on survival or quality of life. The summary estimate of the proportion of patients in which PET/CT had an impact on the target definition, was 23% (95% CI 16;33). The corresponding summary estimate of a change in treatment intent from curative to palliative was 3% (95% CI 2;6). Almost one in four patients had a change in target definition, which supports the use of PET/CT in radiation therapy planning, but the consequence regarding survival and quality of life is still uncertain.