Magnesium sensing via LFA-1 regulates CD8+ T cell effector function.

The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8+ T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial.

BACKGROUND: Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs. METHODS: We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting. FINDINGS: Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]). INTERPRETATION: Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs. FUNDING: Amgen.

Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study.

BACKGROUND: Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell survival, leading to immunogenic cell death and enhanced antitumour immune response. In preclinical models of non-small-cell lung cancer, TTFields amplified the effects of chemotherapy and immune checkpoint inhibitors. We report primary results from a pivotal study of TTFields therapy in metastatic non-small-cell lung cancer. METHODS: This randomised, open-label, pivotal phase 3 study recruited patients at 130 sites in 19 countries. Participants were aged 22 years or older with metastatic non-small-cell lung cancer progressing on or after platinum-based therapy, with squamous or non-squamous histology and ECOG performance status of 2 or less. Previous platinum-based therapy was required, but no restriction was placed on the number or type of previous lines of systemic therapy. Participants were randomly assigned (1:1) to TTFields therapy and standard systemic therapy (investigator's choice of immune checkpoint inhibitor [nivolumab, pembrolizumab, or atezolizumab] or docetaxel) or standard therapy alone. Randomisation was performed centrally using variable blocked randomisation and an interactive voice-web response system, and was stratified by tumour histology, treatment, and region. Systemic therapies were dosed according to local practice guidelines. TTFields therapy (150 kHz) was delivered continuously to the thoracic region with the recommendation to achieve an average of at least 18 h/day device usage. The primary endpoint was overall survival in the intention-to-treat population. The safety population included all patients who received any study therapy and were analysed according to the actual treatment received. The study is registered with ClinicalTrials.gov, NCT02973789. FINDINGS: Between Feb 13, 2017, and Nov 19, 2021, 276 patients were enrolled and randomly assigned to receive TTFields therapy with standard therapy (n=137) or standard therapy alone (n=139). The median age was 64 years (IQR 59-70), 178 (64%) were male and 98 (36%) were female, 156 (57%) had non-squamous non-small-cell lung cancer, and 87 (32%) had received a previous immune checkpoint inhibitor. Median follow-up was 10·6 months (IQR 6·1-33·7) for patients receiving TTFields therapy with standard therapy, and 9·5 months (0·1-32·1) for patients receiving standard therapy. Overall survival was significantly longer with TTFields therapy and standard therapy than with standard therapy alone (median 13·2 months [95% CI 10·3-15·5] vs 9·9 months [8·1-11·5]; hazard ratio [HR] 0·74 [95% CI 0·56-0·98]; p=0·035). In the safety population (n=267), serious adverse events of any cause were reported in 70 (53%) of 133 patients receiving TTFields therapy plus standard therapy and 51 (38%) of 134 patients receiving standard therapy alone. The most frequent grade 3-4 adverse events were leukopenia (37 [14%] of 267), pneumonia (28 [10%]), and anaemia (21 [8%]). TTFields therapy-related adverse events were reported in 95 (71%) of 133 patients; these were mostly (81 [85%]) grade 1-2 skin and subcutaneous tissue disorders. There were three deaths related to standard therapy (two due to infections and one due to pulmonary haemorrhage) and no deaths related to TTFields therapy. INTERPRETATION: TTFields therapy added to standard therapy significantly improved overall survival compared with standard therapy alone in metastatic non-small-cell lung cancer after progression on platinum-based therapy without exacerbating systemic toxicities. These data suggest that TTFields therapy is efficacious in metastatic non-small-cell lung cancer and should be considered as a treatment option to manage the disease in this setting. FUNDING: Novocure.

Single-dose carboplatin followed by involved-node radiotherapy for stage IIA and stage IIB seminoma (SAKK 01/10): a single-arm, multicentre, phase 2 trial.

BACKGROUND: Standard treatment options for patients with stage IIA or stage IIB seminoma include either para-aortic and pelvic radiotherapy or three to four cycles of cisplatin-based combination chemotherapy. These options result in 3-year progression free survival rates of at least 90%, but bear risks for acute and late toxic effects, including secondary malignancies. We tested a novel approach combining de-escalated chemotherapy with de-escalated involved node radiotherapy, with the aim of reducing toxicity while preserving efficacy. METHODS: In the single-arm, multicentre, phase 2 SAKK 01/10 trial, patients with stage IIA or IIB classic seminoma (either at primary diagnosis or at relapse during active surveillance for stage I) were enrolled at ten centres of the Swiss Group for Clinical Cancer Research and ten centres of the German Testicular Cancer Study Group. WHO performance status 0-2, age 18 years or older, and adequate bone marrow and kidney function were required for eligibility. Treatment comprised one cycle of carboplatin (area under the curve 7) followed by involved-node radiotherapy (30 Gy in 15 fractions for stage IIA disease and 36 Gy in 18 fractions for stage IIB disease). The primary endpoint was 3-year progression-free survival. Efficacy analyses were done on the full analysis set, which comprised all patients who signed the informed consent, were registered in the trial, initiated trial treatment, and met all medically relevant inclusion or exclusion criteria. Safety was assessed in all patients who were treated at least once with one of the trial treatments. The study is ongoing but no longer recruiting, and is registered with Clinicaltrials.gov, NCT01593241. FINDINGS: Between Oct 18, 2012, and June 22, 2018, 120 patients were registered in the study. 116 patients were eligible and started treatment according to the study protocol (46 patients with stage IIA disease and 70 with stage IIB disease). After a median follow-up of 4·5 years (IQR 3·9-6·0), 3-year progression-free survival was 93·7% (90% CI 88·5-96·6). With a target progression-free survival of 95% at 3 years, the primary endpoint was not met. Acute treatment-related adverse events of any grade were noted in 58 (48%) of 116 patients, and grade 3 or 4 treatment-related adverse events occurred in the form of neutropenia in five (4%) patients, thrombocytopenia in three (3%) patients, and vomiting in one (1%) patient. No treatment-related deaths and no late treatment-related adverse events were reported. Serious adverse events were reported in five (4%) of 116 patients (one transient creatinine increase and four second primary tumours). INTERPRETATION: Despite the fact that the primary endpoint was not met, we observed favourable 3-year progression-free survival with single-dose carboplatin area under the curve 7 and involved-node radiotherapy, with minimal toxic effects. Our findings might warrant discussion with patients about the SAKK 01/10 regimen as an alternative to standard-of-care treatment, but more research on this strategy is needed. FUNDING: Swiss State Secretariat for Education, Research and Innovation and Rising Tide Foundation for Clinical Cancer Research.

SAKK 19/17: safety analysis of first-line durvalumab in patients with PD-L1 positive, advanced nonsmall cell lung cancer and a performance status of 2.

INTRODUCTION: The safety of first-line (1L) durvalumab in patients with advanced nonsmall-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (PS2) is unknown. This is an interim unplanned safety analysis of the study SAKK 19/17 for patients with metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression in ≥ 25% of tumor cells and an ECOG PS2 treated with 1L durvalumab. This safety analysis was triggered by the SAKK data and safety monitoring board due to a high mortality rate observed after the recruitment of the first 21 patients. METHODS: This single-arm phase II study recruited patients with metastatic NSCLC with PD-L1 in ≥ 25% and ECOG PS2. Patients received durvalumab 1500 mg every four weeks. The trial aims to recruit 48 patients in total. This report includes safety analyses only. Adverse events (AEs) were assessed using National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 5.0. Efficacy data including the primary endpoint overall survival at 6 months and secondary endpoints (objective response rate, progression-free survival, and quality of life) will be reported at a later time point. RESULTS: The data from 21 patients were available at this interim safety analysis. Among these, 13 deaths (13/21; 62%) were reported, including one treatment-related fatal colonic perforation at 9 months after treatment initiation (1/13; 8%). Twelve deaths were not treatment-related (12/13; 92%), and mostly attributed to tumor progression (10/13; 77%). Of note, seven deaths (7/13; 54%) occurred during the first 5 weeks (range 0.6-4.7 weeks) after treatment initiation. Four (4/7; 57%) were respiratory failures attributed to tumor progression. One of these patients (25%) had pre-existing COPD, and three (75%) had baseline dyspnea grade 2-3 related to the tumor. Grade ≥ 3 treatment-related AEs (TRAEs) included colonic perforation (grade 5), abdominal pain, and colitis (grade 3 each) in one patient, and fatigue (grade 3) in another. Other Grade ≥ 3 AEs unrelated to treatment were all of pulmonary origin: lung infections (19%), dyspnea (24%), cough (5%), and bronchial obstruction (5%). CONCLUSIONS: 1L durvalumab in patients with ECOG PS2 and metastatic NSCLC with PD-L1 expression ≥ 25% resulted in an unexpectedly high number of fatal early events due to rapid tumor progression. We recommend to avoid treatment with 1 L durvalumab of patients who are highly symptomatic from the tumor, particularly those with respiratory symptoms. The study is continuing its accrual after an amendment excluding these patients.

Preoperative chemotherapy and radiotherapy concomitant to cetuximab in resectable stage IIIB NSCLC: a multicentre phase 2 trial (SAKK 16/08).

BACKGROUND: Neoadjuvant chemotherapy (CT) followed by radiotherapy (RT) and surgery showed a median survival of 28.7 months in resectable stage IIIB non-small-cell lung cancer (NSCLC) patients (pts). Here, we evaluate the impact of concomitant cetuximab to the same neoadjuvant chemo-radiotherapy (CRT) in selected patients (pts) with NSCLC, stage IIIB. METHODS: Resectable stage IIIB NSCLC received three cycles of CT (cisplatin 100 mg/m2 and docetaxel 85 mg/m2 d1, q3w) followed by RT (44 Gy in 22 fractions) with concomitant cetuximab (250 mg/m2, q1w) and subsequent surgery. The primary endpoint was 1-year progression-free survival (PFS). RESULTS: Sixty-nine pts were included in the trial. Fifty-seven (83%) pts underwent surgery, with complete resection (R0) in 42 (74%) and postoperative 30 day mortality of 3.5%. Responses were: 57% after CT-cetuximab and 64% after CRT-cetuximab. One-year PFS was 50%. Median PFS was 12.0 months (95% CI: 9.0-15.6), median OS was 21.3 months, with a 2- and 3-yr survival of 41% and 30%, respectively. CONCLUSIONS: This is one of the largest prospective phase 2 trial to investigate the role of induction CRT and surgery in resectable stage IIIB disease, and the first adding cetuximab to the neoadjuvant strategy. This trial treatment is feasible with promising response and OS rates, supporting an aggressive approach in selected pts.

Glioblastoma in the Canton of Zurich, Switzerland revisited: 2005 to 2009.

BACKGROUND: A population-based analysis of patients with glioma diagnosed between 1980 and 1994 in the Canton of Zurich in Switzerland confirmed the overall poor prognosis of glioblastoma. To explore changes in outcome, registry data were reevaluated for patients diagnosed between 2005 and 2009. METHODS: Patients with glioblastoma who were diagnosed between 2005 and 2009 were identified by the Zurich and Zug Cancer Registry. The prognostic significance of epidemiological and clinical data, isocitrate dehydrogenase 1 (IDH1)(R132H) mutation status, and O6 methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: A total of 264 patients with glioblastoma were identified, for an annual incidence of 3.9 compared with the previous incidence of 3.7. The mean age of the patients at the time of diagnosis was 59.5 years in the current cohort compared with 61.3 years previously. The overall survival (OS) rate was 46.4% at 1 year, 22.5% at 2 years, and 14.4% at 3 years in the current study compared with 17.7% at 1 year, 3.3% at 2 years, and 1.2% at 3 years as reported previously. The median OS for all patients with glioblastoma was 11.5 months compared with 4.9 months in the former patient population. The median OS was 1.9 months for best supportive care, 6.2 months for radiotherapy alone, 6.7 months for temozolomide alone, and 17.0 months for radiotherapy plus temozolomide. Multivariate analysis revealed age, Karnofsky performance score, extent of tumor resection, first-line treatment, year of diagnosis, and MGMT promoter methylation status were associated with survival in patients with IDH1(R132H) -nonmutant glioblastoma. CONCLUSIONS: The OS of patients newly diagnosed with glioblastoma in the Canton of Zurich in Switzerland markedly improved from 1980 through 1994 to 2005 through 2009. Cancer 2016;122:2206-15. © 2016 American Cancer Society.

Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.

BACKGROUND: One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS: We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS: From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION: Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

Are Four Simple Questions Able to Predict Weight Loss in Outpatients With Metastatic Cancer? A Prospective Cohort Study Assessing the Simplified Nutritional Appetite Questionnaire.

BACKGROUND: Severe weight loss is directly responsible for up to one-fifth of all cancer deaths and has a major impact on quality of life. The simplified nutritional appetite questionnaire (SNAQ) was validated to predict weight loss within 6 mo in community-dwelling adults and nursing home residents. METHODS: We prospectively assessed the SNAQ in 133 palliative cancer outpatients. The SNAQ predictions were validated after 3 and 6 mo with the observed weight change. In addition, the treating oncologists gave their predictions concerning future weight loss according to their clinical judgment. RESULTS: A significant weight loss of 5% of the original body weight within 6 mo occurred in 20 (24%) of the 133 patients. The SNAQ predicted weight loss with a sensitivity of 0.38 and a specificity of 0.66 (P-value 0.81). The treating oncologists predicted weight loss with a sensitivity of 0.67 and a specificity of 0.7 (P-value 0.002). CONCLUSION: The SNAQ does not represent a useful tool to predict impending weight loss in palliative cancer outpatients. The predictions of the treating oncologists were more reliable than those from the SNAQ, but remain poor. Better methods to predict weight loss in this patient group are therefore required.

Multidisciplinary care in patients with prostate cancer: room for improvement.

PURPOSE: New multimodality treatment approaches for prostate cancer require multidisciplinary management of patients. We aimed to assess the current practices of multidisciplinarity and their possible implications in treatment management in Switzerland. METHODS: In a survey, urologists and medical oncologists in Switzerland were asked to include at least 25 or 15 consecutive patients with the diagnosis of prostate cancer, respectively. Information about treatment patterns and multidisciplinary parameters of these patients was collected retrospectively. RESULTS: Thirty-seven urologists and 20 oncologists from the French- and German-speaking parts of Switzerland representing 7 out of 11 non-university tertiary centres and 20/10 % of all office-based urologists/oncologists in Switzerland collected data on 1,184 patients. Sixty-five percent of the office-based (16/24 urologists; 6/10 oncologists) and 95 % of the hospital-based (10/11 urologists; 8/8 oncologists) physicians participate in multidisciplinary tumour boards (MTBs). However, only 1.5 % of patients with a new diagnosis of prostate cancer (13 of 883) are discussed at a MTB. Overall, second opinions at diagnosis are requested in 23 % of patients, mainly from radiation oncologists (8.4 %) or fellow urologists (7.4 %). Second opinions are more often requested by urologists who participate at MTBs and in case of advanced stage. CONCLUSIONS: Participation at MTBs is high among Swiss urologists and oncologists in private practice and at non-university tertiary centers. In spite of that only a small minority of patietns with prostate cancer are presented at MTBs.

Analysis of the EGFR mutation status in head and neck squamous cell carcinoma before treatment with Gefitinib.

BACKGROUND: The efficacy of chemotherapy in metastatic and recurrent squamous cell carcinomas of the head and neck (HNSCC) remains unsatisfactory. Gefitinib offers a new therapeutic option with comparable results and better tolerability than chemotherapy. We conducted this study to see if mutations in the epidermal growth factor receptor (EGFR) might predict the therapeutic benefit in HNSCC patients. PATIENTS AND METHODS: In a pilot trial, 8 patients with metastatic or recurrent HNSCC were treated palliatively with gefitinib (500 mg/day orally). Forceps biopsies were taken to confirm tumor recurrence and to perform an EGFR mutation analysis. RESULTS: The EGFR status could be determined in 6 of the 8 patients. 5 patients had no EGFR gene mutation, and 1 patient showed a silent guanine-to-adenosine mutation in position 2607. Even without any relevant mutation in the EGFR, we observed partial remission in 3 of 6 patients treated with gefitinib. We also observed that an additional 4 patients had stable disease for at least 10 weeks. The median progression-free survival was 6.25 months, and the median overall survival was 7.39 months. CONCLUSION: In HNSCC, there are tumor responses to gefitinib without protein-altering mutations in the EGFR gene.

Smartphone-Based Psychotherapeutic Interventions in Blended Care of Cancer Survivors: Nested Randomized Clinical Trial.

BACKGROUND: Cancer is related to not only physical but also mental suffering. Notably, body image disturbances are highly relevant to cancer-related changes often persisting beyond recovery from cancer. Scalable and low-barrier interventions that can be blended with face-to-face psychotherapy for cancer survivors are highly warranted. OBJECTIVE: The aim of the study is to investigate whether smartphone-based bodily interventions are more effective to improve the mood of patients with cancer than smartphone-based fairy tale interventions (control intervention). METHODS: We recruited patients with cancer in 2 Swiss hospitals and conducted daily, fully automated smartphone-based interventions 6 times a week for 5 consecutive weeks, blended with weekly face-to-face group body psychotherapy. We applied 2 types of smartphone-based interventions using a within-subject design, randomly assigning patients daily to either bodily interventions or fairy tales. Each intervention type was presented 3 times a week. For this secondary analysis, 3-level mixed models were estimated with mood assessed by the 3 Multidimensional Mood Questionnaire subscales for good-bad mood, wakefulness, and calmness as key indicators. In addition, the effects on experience of presence, vitality, and burden assessed with visual analog scales were investigated. RESULTS: Based on the data from s=732 interventions performed by 36 participants, good-bad mood improved (ß=.27; 95% CI 0.062-0.483), and participants became calmer (ß=.98; 95% CI 0.740-1.211) following smartphone-based interventions. Wakefulness did not significantly change from pre- to postsmartphone-based intervention (ß=.17; 95% CI -0.081 to 0.412). This was true for both intervention types. There was no interaction effect of intervention type with change in good-bad mood (ß=-.01; 95% CI -0.439 to 0.417), calmness (ß=.22; 95% CI -0.228 to 0.728), or wakefulness (ß=.14; 95% CI -0.354 to 0.644). Experience of presence (ß=.34; 95% CI 0.271-0.417) and vitality (ß=.35; 95% CI 0.268-0.426) increased from pre- to postsmartphone-based intervention, while experience of burden decreased (ß=-0.40; 95% CI -0.481 to 0.311). Again, these effects were present for both intervention types. There were no significant interaction effects of intervention type with pre- to postintervention changes in experience of presence (ß=.14; 95% CI -0.104 to 0.384), experience of vitality (ß=.06; 95% CI -0.152 to 0.265), and experience of burden (ß=-.16; 95% CI -0.358 to 0.017). CONCLUSIONS: Our results suggest that both smartphone-based audio-guided bodily interventions and fairy tales have the potential to improve the mood of cancer survivors. TRIAL REGISTRATION: ClinicalTrials.gov NCT03707548; https://clinicaltrials.gov/study/NCT03707548. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s40359-019-0357-1.

Group-based body psychotherapy improves appreciation of body awareness in post-treatment cancer patients: A non-randomized clinical trial.

Introduction: Cancer-related impairments often co-occur with bodily disturbances. Body psychotherapy (BPT) can improve bodily wellbeing, yet evidence in cancer survivors is scarce. Hence, we aimed to evaluate whether blended group BPT alleviates bodily disturbances in post-treatment cancer patients. Methods: We conducted a bi-center study (registered in ClinicalTrials.gov, under No. NCT03707548), applying a pre-post convergent parallel design of weekly group BPT interspersed with smartphone-based ambulatory interventions using a waiting-period comparator. We included patients with completed curatively intended treatment for malignant neoplasms, suffering from bodily disturbances. The primary outcome was body image disturbances. Secondary outcomes were experiencing and appreciating body awareness, mental wellbeing, and health-related quality of life. Results: Forty patients (mean age 51.7 years) attended group BPT. Mixed-effect linear regression models contrasting intervention with the waiting period did not show statistically significant differences regarding the primary outcome [Pre-post difference contrasts: 1.44, 95% confidence interval (CI): -1.51 to 4.93, p = 0.339]. However, patients showed greater improvements in appreciating body awareness, measured by the "Body Mindfulness Questionnaire" (BMQ), from pre- to post-intervention as compared to the waiting period (pre-post difference contrasts: 7.31 95% CI: 4.15-10.47, Bonferroni-Holm corrected q = 0.0002). Discussion: We found no evidence that blended group BPT was effective in improving body image disturbances in post-treatment cancer patients, but found indications for an increase in body awareness appreciation. Clinical trial registration: ClinicalTrials.gov, identifier NCT03707548.

Only EBUS-Guided Mediastinal Lymph Node Cryobiopsy Enabled Immunotherapy in a Patient with Non-Small Cell Lung Cancer.

Personalized treatment of metastatic non-squamous non-small cell lung cancer (NSCLC) requires detailed molecular characterization of the tumour including detection of predictive driver mutations and programmed death ligand 1 (PD-L1) expression. Complete detection is influenced by the amount of tumour cells sampled as well as their quality. Different sampling techniques may be necessary to provide sufficient tumour material for comprehensive molecular characterization. Missing the detection of targetable molecular genetic aberrations would have a serious impact on the quality of life and prognosis of a patient. This case report highlights the importance of biopsy technique in a patient with NSCLC. Several procedures-pleural puncture, transthoracic lung biopsy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)-could not provide sufficient tumour material for precise tumour characterization. Only the addition of EBUS-guided transbronchial lymph node cryobiopsy (EBUS-TBLNC) enabled complete immunohistochemical and genetic tumour characterization, demonstrating PD-L1 expression in 100% of the tumour cells in the absence of actionable genetic alterations. Based on these results, immunotherapy was initiated.

Completion and publication of clinical trials in a cooperative group: a cohort study of trials of the Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: Premature trial discontinuation and non-publication of trial results are still major issues negatively affecting reliable evidence generation. OBJECTIVES: To investigate trial completion and publication rate of cancer trials conducted within the Swiss Group for Clinical Cancer Research (SAKK). DESIGN: Cohort study of clinical trials. SETTING: Cohort of interventional cancer trials conducted in Switzerland with accrual closure between 1986 and 2021 identified from the SAKK trial management system. OUTCOMES: Premature trial discontinuation and publication in peer-reviewed journal. RESULTS: We included 261 trials; median number of recruited patients was 150.5 (range 1-8028). Most trials (67.0%) were randomised. Overall, 76 of 261 (29.1%) trials were prematurely closed for accrual. The three main reasons for premature closure were insufficient accrual in 28 trials, followed by stopping for futility in 17 or efficacy in 8 trials. We included 240 trials for the publication status (21 excluded, because 8 still in follow-up, for 10 the primary completion date was less than a year ago and for 3 the manuscript was submitted, but to accepted yet). 216 of 240 (90.0%) were published as a full article, 14 were published in other formats, leading to an overall publication rate of 95.8%. The rate of premature discontinuation declined over time, with 34.2%, 27.8% and 23.5% in trials activated before 2000, between 2000 and 2009, and since 2010, respectively. We observed an increasing publication rate in peer-reviewed journals over time: 79.2% (closed before 2000), 95.7% (closed between 2000 and 2009) and 93.2% (closed after 2010). CONCLUSION: Insufficient patient recruitment is still the major reason for premature trial discontinuation. SAKK has continuously improved its quality management of trial conduct over time leading to increased successful trial completion and publication. However, there is still room for improvement to increase the number of trials reaching their target sample size.

Effect of combined therapies including nutrition and physical exercise in advanced cancer patients: A pooled analysis.

Background and aims: Although many cancer patients suffer from malnutrition or cancer cachexia, there is no standard of care so far due to limited intervention trials. Pooled data from two combined trials were analyzed regarding nutritional status and survival time. Materials and methods: Data from two trials with advanced cancer patients were included. In both trials, patients in the intervention group received at least three times nutritional counseling and supervised training sessions. Patients in the control group continued being treated according to usual care. Nutritional status was measured using BMI, body composition and handgrip strength. Survival time was analyzed using the Cox proportional hazard model with the period between the beginning of the trial and death as underlying time scale. Results: 68 men (61.8%) and 42 women (38.2%) were randomized either to the intervention (n = 56) or the control (n = 54) group. The inter-group difference for changes in BMI and body composition was not statistically significant after 3 months. Handgrip strength improved significantly from 34.4 ± 10.2 kg to 36.3 ± 9.9 kg at 3 months in the intervention compared to 33.9 ± 9.2 kg to 34.9 ± 9.1 kg in the control group (p = 0.006). The analysis of survival time showed no inter-group difference for all patients. A detailed analysis for different diagnoses showed that in patients with lung cancer, the covariates "CRP value," "days from first diagnosis to randomization" as well as "gender" were significantly associated with survival time. Patients with higher CRP value had a shorter survival time and female patients had a shorter survival time than male patients in our analysis. In addition, patients with pancreatic cancer randomized to the control group had a 20% shorter survival time than those in the intervention group (p = 0.048). Conclusion: The pooled analysis showed a significant improvement of handgrip strength in advanced cancer patients through the implementation of a combined therapy. Handgrip strength is of prognostic significance in hospitalized patients due to its association with mortality and morbidity. However, no improvements in further tests were detected. There is great need for further investigations examining the effect of nutritional and exercise therapy on survival time with focus on different cancer diagnoses.

Predictive value of radiological response, pathological response and relapse-free survival for overall survival in neoadjuvant immunotherapy trials: pooled analysis of 29 clinical trials.

BACKGROUND: An increasing number of clinical trials are being conducted exploring the efficacy of neoadjuvant immune checkpoint inhibitors. Surrogate end-points for overall survival (OS) are urgently needed. METHODS: Phase II or III trials of neoadjuvant immunotherapy that reported data on OS and surrogate end-points were identified from January 1, 2000, to November 25, 2022. Individual patient data, and trial-level data were requested from corresponding authors or extracted from eligible trials. At the individual level, correlations between radiological and pathological response and OS were measured by the Cox model and quantified by hazard ratio (HR). C-statistic was used to quantify the predictive performance of radiological and pathological response for OS. The coefficient of determination (R2) between RFS and OS was evaluated by a bivariate survival model. RESULTS: A total of 29 trials reporting 2901 patients were included. ORR correlated with improved OS (3-year OS: 87.0% versus 70.4% for ORR versus non-ORR, respectively; HR, 0.34, 95% confidence interval [CI], 0.17-0.68). The HRs for OS in patients achieving MPR and pCR were 0.24 (95% CI, 0.12-0.46) and 0.13 (95% CI, 0.05-0.36). The survival benefit maintained after adjusting tumour type. C-statistics of ORR, MPR and pCR were 0.63, 0.63 and 0.65, respectively. The strength of association between RFS and OS was strong (R2 = 0.88, 95% CI, 0.79-0.94). CONCLUSIONS: These findings suggest that ORR, MPR, pCR and RFS are valid predictors for OS when using neoadjuvant immune checkpoint inhibitors. Moreover, MPR, pCR and RFS may be the most optimal surrogates for OS.

Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy.

PURPOSE: To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. PATIENTS AND METHODS: Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m2 intravenously (IV) day 1 with vitamin B12, folic acid, and dexamethasone or docetaxel 75 mg/m2 IV day 1 with dexamethasone every 21 days. The primary end point was overall survival. RESULTS: Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P = .105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia (40.2% v 5.3%; P < .001), febrile neutropenia (12.7% v 1.9%; P < .001), neutropenia with infections (3.3% v 0.0%; P = .004), hospitalizations for neutropenic fever (13.4% v 1.5%; P < .001), hospitalizations due to other drug related adverse events (10.5% v 6.4%; P = .092), use of granulocyte colony-stimulating factor support (19.2% v 2.6%, P < .001) and all grade alopecia (37.7% v 6.4%; P < .001) compared with patients receiving pemetrexed. CONCLUSION: Treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.

Outcome and Prognostic Factors of COVID-19 Infection in Swiss Cancer Patients: Final Results of SAKK 80/20 (CaSA).

Purpose: These are the final results of a national registry on cancer patients with COVID-19 in Switzerland. Methods: We collected data on symptomatic COVID-19-infected cancer patients from 23 Swiss sites over a one-year period starting on 1 March 2020. The main objective was to assess the outcome (i.e., mortality, rate of hospitalization, ICU admission) of COVID-19 infection in cancer patients; the main secondary objective was to define prognostic factors. Results: From 455 patients included, 205 patients (45%) had non-curative disease, 241 patients (53%) were hospitalized for COVID-19, 213 (47%) required oxygen, 43 (9%) invasive ventilation and 62 (14%) were admitted to the ICU. Death from COVID-19 infection occurred in 98 patients, resulting in a mortality rate of 21.5%. Age ≥65 years versus <65 years (OR 3.14, p = 0.003), non-curative versus curative disease (OR 2.42, p = 0.012), ICU admission (OR 4.45, p < 0.001) and oxygen requirement (OR 20.28, p < 0.001) were independently associated with increased mortality. Conclusions: We confirmed high COVID-19 severity and mortality in real-world cancer patients during the first and second wave of the pandemic in a country with a decentralized, high-quality, universal-access health care system. COVID-19-associated mortality was particularly high for those of older age in a non-curative disease setting, requiring oxygen or ICU care.

Extended resection for potentially operable patients with stage III non-small cell lung cancer after induction treatment.

OBJECTIVE: Surgical treatment of locally advanced non-small cell lung cancer including single or multilevel N2 remains a matter of debate. Several trials demonstrate that selected patients benefit from surgery if R0 resection is achieved. We aimed to assess resectability and outcome of patients with locally advanced clinical T3/T4 (American Joint Committee on Cancer 8th edition) tumors after induction treatment followed by surgery in a pooled analysis of 3 prospective multicenter trials. METHODS: A total of 197 patients with T3/T4 non-small cell lung cancer of 368 patients with stage III non-small cell lung cancer enrolled in the Swiss Group for Clinical Cancer Research 16/96, 16/00, 16/01 trials were treated with induction chemotherapy or chemoradiation therapy followed by surgery, including extended resections. Univariable and multivariable analyses were applied for analysis of outcome parameters. RESULTS: Patients' median age was 60 years, and 67% were male. A total of 38 of 197 patients were not resected for technical (81%) or medical (19%) reasons. A total of 159 resections including 36 extended resections were performed with an 80% R0 and 13.2% pathological complete response rate. The 30- and 90-day mortality were 3% and 7%, respectively, without a difference for extended resections. Morbidity was 32% with the majority (70%) of minor grading complications. The 3-, 5-, and 10-year overall survivals for extended resections were 61% (95% confidence interval, 43-75), 44% (95% confidence interval, 27-59), and 29.5% (95% confidence interval, 13-48), respectively. R0 resection was associated with improved overall survival (hazard ratio, 0.41; P < .001), but pretreatment N2 extension (177/197) showed no impact on overall survival. CONCLUSIONS: Surgery after induction treatment for advanced T3/T4 stage including single and multiple pretreatment N2 disease resulted in 80% R0 resection rate and 7% 90-day mortality. Favorable overall survival for extended and not extended resection was demonstrated to be independent of pretreatment N status.