Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis.

BACKGROUND: Bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are amongst the bone-modifying agents used as supportive treatment in women with breast cancer who do not have bone metastases. These agents aim to reduce bone loss and the risk of fractures. Bisphosphonates have demonstrated survival benefits, particularly in postmenopausal women. OBJECTIVES: To assess and compare the effects of different bone-modifying agents as supportive treatment to reduce bone mineral density loss and osteoporotic fractures in women with breast cancer without bone metastases and generate a ranking of treatment options using network meta-analyses (NMAs). SEARCH METHODS: We identified studies by electronically searching CENTRAL, MEDLINE and Embase until January 2023. We searched various trial registries and screened abstracts of conference proceedings and reference lists of identified trials. SELECTION CRITERIA: We included randomised controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for women with breast cancer without bone metastases. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias of included studies and certainty of evidence using GRADE. Outcomes were bone mineral density, quality of life, overall fractures, overall survival and adverse events. We conducted NMAs and generated treatment rankings. MAIN RESULTS: Forty-seven trials (35,163 participants) fulfilled our inclusion criteria; 34 trials (33,793 participants) could be considered in the NMA (8 different treatment options). Bone mineral density We estimated that the bone mineral density of participants with no treatment/placebo measured as total T-score was -1.34. Evidence from the NMA (9 trials; 1166 participants) suggests that treatment with ibandronate (T-score -0.77; MD 0.57, 95% CI -0.05 to 1.19) may slightly increase bone mineral density (low certainty) and treatment with zoledronic acid (T-score -0.45; MD 0.89, 95% CI 0.62 to 1.16) probably slightly increases bone mineral density compared to no treatment/placebo (moderate certainty). Risedronate (T-score -1.08; MD 0.26, 95% CI -0.32 to 0.84) may result in little to no difference compared to no treatment/placebo (low certainty). We are uncertain whether alendronate (T-score 2.36; MD 3.70, 95% CI -2.01 to 9.41) increases bone mineral density compared to no treatment/placebo (very low certainty). Quality of life No quantitative analyses could be performed for quality of life, as only three studies reported this outcome. All three studies showed only minimal differences between the respective interventions examined. Overall fracture rate We estimated that 70 of 1000 participants with no treatment/placebo had fractures. Evidence from the NMA (16 trials; 19,492 participants) indicates that treatment with clodronate or ibandronate (42 of 1000; RR 0.60, 95% CI 0.39 to 0.92; 40 of 1000; RR 0.57, 95% CI 0.38 to 0.86, respectively) decreases the number of fractures compared to no treatment/placebo (high certainty). Denosumab or zoledronic acid (51 of 1000; RR 0.73, 95% CI 0.52 to 1.01; 55 of 1000; RR 0.79, 95% CI 0.56 to 1.11, respectively) probably slightly decreases the number of fractures; and risedronate (39 of 1000; RR 0.56, 95% CI 0.15 to 2.16) probably decreases the number of fractures compared to no treatment/placebo (moderate certainty). Pamidronate (106 of 1000; RR 1.52, 95% CI 0.75 to 3.06) probably increases the number of fractures compared to no treatment/placebo (moderate certainty). Overall survival We estimated that 920 of 1000 participants with no treatment/placebo survived overall. Evidence from the NMA (17 trials; 30,991 participants) suggests that clodronate (924 of 1000; HR 0.95, 95% CI 0.77 to 1.17), denosumab (927 of 1000; HR 0.91, 95% CI 0.69 to 1.21), ibandronate (915 of 1000; HR 1.06, 95% CI 0.83 to 1.34) and zoledronic acid (925 of 1000; HR 0.93, 95% CI 0.76 to 1.14) may result in little to no difference regarding overall survival compared to no treatment/placebo (low certainty). Additionally, we are uncertain whether pamidronate (905 of 1000; HR 1.20, 95% CI 0.81 to 1.78) decreases overall survival compared to no treatment/placebo (very low certainty). Osteonecrosis of the jaw We estimated that 1 of 1000 participants with no treatment/placebo developed osteonecrosis of the jaw. Evidence from the NMA (12 trials; 23,527 participants) suggests that denosumab (25 of 1000; RR 24.70, 95% CI 9.56 to 63.83), ibandronate (6 of 1000; RR 5.77, 95% CI 2.04 to 16.35) and zoledronic acid (9 of 1000; RR 9.41, 95% CI 3.54 to 24.99) probably increases the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (moderate certainty). Additionally, clodronate (3 of 1000; RR 2.65, 95% CI 0.83 to 8.50) may increase the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (low certainty). Renal impairment We estimated that 14 of 1000 participants with no treatment/placebo developed renal impairment. Evidence from the NMA (12 trials; 22,469 participants) suggests that ibandronate (28 of 1000; RR 1.98, 95% CI 1.01 to 3.88) probably increases the occurrence of renal impairment compared to no treatment/placebo (moderate certainty). Zoledronic acid (21 of 1000; RR 1.49, 95% CI 0.87 to 2.58) probably increases the occurrence of renal impairment while clodronate (12 of 1000; RR 0.88, 95% CI 0.55 to 1.39) and denosumab (11 of 1000; RR 0.80, 95% CI 0.54 to 1.19) probably results in little to no difference regarding the occurrence of renal impairment compared to no treatment/placebo (moderate certainty). AUTHORS' CONCLUSIONS: When considering bone-modifying agents for managing bone loss in women with early or locally advanced breast cancer, one has to balance between efficacy and safety. Our findings suggest that bisphosphonates (excluding alendronate and pamidronate) or denosumab compared to no treatment or placebo likely results in increased bone mineral density and reduced fracture rates. Our survival analysis that included pre and postmenopausal women showed little to no difference regarding overall survival. These treatments may lead to more adverse events. Therefore, forming an overall judgement of the best ranked bone-modifying agent is challenging. More head-to-head comparisons, especially comparing denosumab with any bisphosphonate, are needed to address gaps and validate the findings of this review.

Impact of the COVID-19 pandemic on training conditions and education in oncologic disciplines: a survey-based analysis.

PURPOSE: The COVID-19 pandemic has led to changes in global health care. Medical societies had to update guidelines and enhance new services such as video consultations. Cancer treatment had to be modified. The aim of this study is to ensure optimal care for cancer patients with the help of high-quality training even in times of crisis. We therefore conducted a nationwide survey of physicians in training in oncological disciplines during the pandemic to assess the impact on their education. METHODS: The survey was sent to tumour centres, hospitals, specialist societies, and working and junior research groups and distributed via newsletters and homepages. Interim results and a call for participation were published as a poster (DEGRO) [26] and in the German Cancer Society (DKG) journal FORUM [42]. The survey contained 53 questions on conditions of education and training and on clinical and scientific work. Statistics were carried out with LimeSurvey and SPSS (IBM Corp., Armonk, NY, USA). RESULTS: Between February and November 2022, 450 participants answered the survey, with radio-oncologists being the largest group (28%). Most colleagues (63%) had access to digital training methods. Virtual sessions were rated as a good alternative, especially as multidisciplinary meetings (54%) as well as in-house and external training programs (48%, 47%). The time spent by training supervisors on education was rated as less than before the pandemic by 57%. Half of all participants perceived communication (54%), motivation (44%) and atmosphere (50%) in the team as bad. The participants felt strongly burdened by extra work (55%) and by a changed team atmosphere (49%). One third felt a change in the quality of training during the pandemic and rated it as negative (35%). According to 37% of the participants, this had little influence on their own quality of work. Additional subgroup analyses revealed significant differences in gender, specialty and education level. CONCLUSION: In order to improve oncology training in times of crisis, access to digital training options and meetings should be ensured. Participants wish for regular team meetings in person to enable good team spirit, compensation for overtime work and sufficient time for training supervisors for discussion and feedback.

Can triclosan-coated sutures reduce the postoperative rate of wound infection? Data from a systematic review and meta-analysis.

BACKGROUND: Wound infections are typical postoperative complications with considerable therapeutic consequences and high personnel and financial costs. Previous meta-analyses have shown that triclosan-coated sutures can reduce the risk of postoperative wound infection. This work aimed to update previous meta-analyses with a special focus on different subgroups. METHODS: A systematic review with meta-analysis was performed (registration: PROSPERO 2022 CRD42022344194). The search was independently performed in the Web of Science, PubMed, and Cochrane databases by 2 reviewers. A critical methods review of all included full texts took place. The trustworthiness of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation method. An analysis of the cost-effectiveness of the suture material was carried out. RESULTS: In this meta-analysis of 29 randomized controlled trials, the use of triclosan-coated suture material resulted in a significant reduction of postoperative wound infection rate (24%) (random-effects model; risk ratio: 0.76; 95% confidence interval: [0.67-0.87]). The effect was evident in the subgroups according to wound contamination class, underlying oncologic disease, and pure preoperative antibiotic prophylaxis. In the subgroup analysis by the operating department, the significant effect was visible only in the abdominal surgery group. CONCLUSION: Based on the randomized controlled clinical trials reviewed, triclosan-coated sutures reduced postoperative wound infection rates in the main study and most subgroups. Additional costs of up to 12 euros for the coated suture material appear to be justified to generate an economic benefit for the hospital by reducing postoperative wound infections. The additional socioeconomic benefit of reducing wound infection rates was not investigated here.

The impact of COVID-19 on the interpretation of psycho-oncological support trial results: a quasi-experimental approach using the data from the new form of care "Integrated cross-sectoral psycho-oncology (nFC-isPO)".

OBJECTIVE: In addition to the common difficulties of ongoing trials, the COVID-19 pandemic posed several challenges to scientists worldwide and created an additional burden for vulnerable patient groups. In the nFC-isPO of individualised treatment for anxiety and depression in newly diagnosed patients with cancer caregivers (e.g. psycho-oncologists) reported elevated HADS scores in newly enrolled patients after the outbreak of the COVID-19 pandemic. Accordingly, the question arises whether the pandemic affected HADS scores. Therefore, stratified analyses by the time of enrolment (T1) were performed for patients with 12 months of care (T3). METHODS: Patients with 12 months of care (N = 1,140) were analysed. A comparison within the regression discontinuity design according to the time points at which patients completed the baseline (T1) HADS questionnaire was conducted to examine differences between patients recruited before Q2/2020 (pre-pandemic) and after the coronavirus outbreak. Furthermore, mean HADS scores at T1 and T3 for all quarters during the study were compared. RESULTS: Mean T1 and T3 HADS scores of patients with cancer during the pandemic are only slightly higher than those of the pre-pandemic group. No significant treatment effect was observed in either the pre-pandemic (p = 0.5495, Late = 1.7711) or the post-pandemic group (p = 0.9098, LATE=-0.2933). In contrast, the average local treatment effect in the post-pandemic group suggests a minimal decrease in HADS score in the predefined range and thus a positive treatment effect for isPO. Comparison of mean HADS scores at T1 and T3 did not show a large increase by pandemic-related timepoints, however, a decrease of approximately 2-3 points over each quarter at 12 months compared to baseline is observed. CONCLUSION: The existing nFC-isPO care is resilient to crisis and may counteract external influences such as the Corona pandemic. Accordingly, the pandemic had little influence on the fears of patients with cancer in the nFC-isPO. This emphasises that psycho-oncology is vital for the reduction of stress, anxiety and depression in patients with cancer. TRIAL REGISTRATION: The study was registered in the German Clinical Trials Registry on 30 October 2018 under the ID "DRKS00015326".

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

BACKGROUND: Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma (RCC) has changed fundamentally. Today, combined therapies from different drug categories have a firm place in a complex first-line therapy. Due to the large number of drugs available, it is necessary to identify the most effective therapies, whilst considering their side effects and impact on quality of life (QoL). OBJECTIVES: To evaluate and compare the benefits and harms of first-line therapies for adults with advanced RCC, and to produce a clinically relevant ranking of therapies. Secondary objectives were to maintain the currency of the evidence by conducting continuous update searches, using a living systematic review approach, and to incorporate data from clinical study reports (CSRs). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings and relevant trial registries up until 9 February 2022. We searched several data platforms to identify CSRs. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating at least one targeted therapy or immunotherapy for first-line treatment of adults with advanced RCC. We excluded trials evaluating only interleukin-2 versus interferon-alpha as well as trials with an adjuvant treatment setting. We also excluded trials with adults who received prior systemic anticancer therapy if more than 10% of participants were previously treated, or if data for untreated participants were not separately extractable. DATA COLLECTION AND ANALYSIS: All necessary review steps (i.e. screening and study selection, data extraction, risk of bias and certainty assessments) were conducted independently by at least two review authors. Our outcomes were overall survival (OS), QoL, serious adverse events (SAEs), progression-free survival (PFS), adverse events (AEs), the number of participants who discontinued study treatment due to an AE, and the time to initiation of first subsequent therapy. Where possible, analyses were conducted for the different risk groups (favourable, intermediate, poor) according to the International Metastatic Renal-Cell Carcinoma Database Consortium Score (IMDC) or the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Our main comparator was sunitinib (SUN). A hazard ratio (HR) or risk ratio (RR) lower than 1.0 is in favour of the experimental arm. MAIN RESULTS: We included 36 RCTs and 15,177 participants (11,061 males and 4116 females). Risk of bias was predominantly judged as being 'high' or 'some concerns' across most trials and outcomes. This was mainly due to a lack of information about the randomisation process, the blinding of outcome assessors, and methods for outcome measurements and analyses. Additionally, study protocols and statistical analysis plans were rarely available. Here we present the results for our primary outcomes OS, QoL, and SAEs, and for all risk groups combined for contemporary treatments: pembrolizumab + axitinib (PEM+AXI), avelumab + axitinib (AVE+AXI), nivolumab + cabozantinib (NIV+CAB), lenvatinib + pembrolizumab (LEN+PEM), nivolumab + ipilimumab (NIV+IPI), CAB, and pazopanib (PAZ). Results per risk group and results for our secondary outcomes are reported in the summary of findings tables and in the full text of this review. The evidence on other treatments and comparisons can also be found in the full text. Overall survival (OS) Across risk groups, PEM+AXI (HR 0.73, 95% confidence interval (CI) 0.50 to 1.07, moderate certainty) and NIV+IPI (HR 0.69, 95% CI 0.69 to 1.00, moderate certainty) probably improve OS, compared to SUN, respectively. LEN+PEM may improve OS (HR 0.66, 95% CI 0.42 to 1.03, low certainty), compared to SUN. There is probably little or no difference in OS between PAZ and SUN (HR 0.91, 95% CI 0.64 to 1.32, moderate certainty), and we are uncertain whether CAB improves OS when compared to SUN (HR 0.84, 95% CI 0.43 to 1.64, very low certainty). The median survival is 28 months when treated with SUN. Survival may improve to 43 months with LEN+PEM, and probably improves to: 41 months with NIV+IPI, 39 months with PEM+AXI, and 31 months with PAZ. We are uncertain whether survival improves to 34 months with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. Quality of life (QoL) One RCT measured QoL using FACIT-F (score range 0 to 52; higher scores mean better QoL) and reported that the mean post-score was 9.00 points higher (9.86 lower to 27.86 higher, very low certainty) with PAZ than with SUN. Comparison data were not available for PEM+AXI, AVE+AXI, NIV+CAB, LEN+PEM, NIV+IPI, and CAB. Serious adverse events (SAEs) Across risk groups, PEM+AXI probably increases slightly the risk for SAEs (RR 1.29, 95% CI 0.90 to 1.85, moderate certainty) compared to SUN. LEN+PEM (RR 1.52, 95% CI 1.06 to 2.19, moderate certainty) and NIV+IPI (RR 1.40, 95% CI 1.00 to 1.97, moderate certainty) probably increase the risk for SAEs, compared to SUN, respectively. There is probably little or no difference in the risk for SAEs between PAZ and SUN (RR 0.99, 95% CI 0.75 to 1.31, moderate certainty). We are uncertain whether CAB reduces or increases the risk for SAEs (RR 0.92, 95% CI 0.60 to 1.43, very low certainty) when compared to SUN. People have a mean risk of 40% for experiencing SAEs when treated with SUN. The risk increases probably to: 61% with LEN+PEM, 57% with NIV+IPI, and 52% with PEM+AXI. It probably remains at 40% with PAZ. We are uncertain whether the risk reduces to 37% with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. AUTHORS' CONCLUSIONS: Findings concerning the main treatments of interest comes from direct evidence of one trial only, thus results should be interpreted with caution. More trials are needed where these interventions and combinations are compared head-to-head, rather than just to SUN. Moreover, assessing the effect of immunotherapies and targeted therapies on different subgroups is essential and studies should focus on assessing and reporting relevant subgroup data. The evidence in this review mostly applies to advanced clear cell RCC.

Potential synergy between radiotherapy and CAR T-cells - a multicentric analysis of the role of radiotherapy in the combination of CAR T cell therapy.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has improved the limited overall survival (OS) of patients with intensively pretreated diffuse large B-cell lymphoma (DLBCL). However, the potentially life-threatening toxicities of CAR T-cells and early relapses remain a challenge. As suggested by smaller monocentric analyses, radiotherapy (RT) in combination with CAR T-cells may have an immunomodulatory effect. METHOD/ RESULTS: In this multicentric retrospective analysis, we investigated potentially synergistic effects of RT and CAR T-cells. Of 78 patients from four centers who received CAR T-cell therapy for DLBCL, 37 patients underwent bridging RT or received salvage RT. RTs (median 36 gray) were well tolerated. Therapy response and disease control of CAR T-cell therapy were comparable after bridging RT or bridging systemic therapy. High-grade neurotoxicity tended to occur less frequently after bridging RT. After further disease progression, patients with localized relapses showed better outcomes, compared to those in advanced stage. In the subgroup with localized relapse, patients receiving salvage RT had an increased OS, vs. those without salvage RT (1-year OS rate 89% vs. 38%, p = 0.03). CONCLUSION: Our analysis demonstrated that RT in combination with CAR T-cells led neither to high-grade toxicities, nor to a decreased response rate. We observed better outcomes of salvage therapies in patients with localized relapses vs. those with advanced stage relapses. Especially the patients who received salvage RTs for localized relapses seem to benefit more. Further analyses are necessary to clarify whether specific synergistic effects exist, such as an enhanced anti-tumor effect of CAR T-cells from RT sensitizing.

Chemoradiation for elderly patients (≥ 65 years) with esophageal cancer: a retrospective single-center analysis.

BACKGROUND: Present studies on the efficacy and safety of curative chemoradiation therapy (CRT) with esophageal cancer reflect heterogenous results especially in elderly patients. The aim of this study was to evaluate the toxicity and efficacy of CRT in patients ≥ 65 years. In a cohort, the focus centered around treatment-related toxicity (CTCAE Grade > 3), overall survival as well as progression free survival, comparing these rates in-between patients older than 70 years to those younger than 70 years. METHODS: A total of 67 patients older than 65 years (34 (50.7%) were older than 70 years) met the inclusion criteria for retrospective analysis (period from January 2013 to October 2017). Treatment consisted of radiotherapy and chemotherapy with carboplatin/paclitaxel or fluorouracil (5-FU)/cisplatin with the intention of neoadjuvant or definite chemoradiation. A sum of 67 patients received CRT (44 (65.6%) patients in neoadjuvant, 23 (34.4%) in definite intent). Of these, 22 and 12 patients were older than 70 years (50% and 52.2% in both treatment groups, respectively). Median age was 71 years and patients had a good physical performance status (ECOG 0: 57.6%, ECOG 1: 27.3%). Median follow-up was 24 months. Most patients had advanced tumour stages (T3 stage: n = 51, 79.7%) and nodal metastasis (N1 stage: n = 54, 88.5%). A subgroup comparison was conducted between patients aged ≤ 70 years and > 70 years. RESULTS: In severe (CTCAE Grade 3-5) toxicities (acute and late), no significant differences were observed between both patient groups (< 70 years vs. > 70 years). 21% had acute grade 3 events, 4 patients (4%) had grade 4 events, and two patients (3%) had one grade 5 event. Late toxicity after CRT was grade 1 in 13 patients (22%), grade 2 in two (3%), grade 3 in two (3%), grade 4 in four (7%), and grade 5 in one (2%). Median overall survival (OS) of all patients was 30 months and median progression-free survival (PFS) was 16 months. No significant differences were seen for OS (32 months vs. 25 months; p = 0.632) and PFS (16 months vs. 12 months; p = 0.696) between older patients treated with curative intent and younger ones. Trimodal therapy significantly prolonged both OS and PFS (p = 0.005; p = 0.018), regardless of age. CONCLUSION: CRT in elderly patients (≥ 65 years) with esophageal cancer is feasible and effective. Numbers for acute and late toxicities can be compared to cohorts of younger patients (< 65 years) with EC who received the same therapies. Age at treatment initiation alone should not be the determining factor. Instead, functional status, risk of treatment-related morbidities, life expectancy and patient´s preferences should factor into the choice of therapy.

Intravenous iron versus oral iron versus no iron with or without erythropoiesis- stimulating agents (ESA) for cancer patients with anaemia: a systematic review and network meta-analysis.

BACKGROUND: Anaemia is common among cancer patients and they may require red blood cell transfusions. Erythropoiesis-stimulating agents (ESAs) and iron might help in reducing the need for red blood cell transfusions. However, it remains unclear whether the combination of both drugs is preferable compared to using one drug. OBJECTIVES: To systematically review the effect of intravenous iron, oral iron or no iron in combination with or without ESAs to prevent or alleviate anaemia in cancer patients and to generate treatment rankings using network meta-analyses (NMAs). SEARCH METHODS: We identified studies by searching bibliographic databases (CENTRAL, MEDLINE, Embase; until June 2021). We also searched various registries, conference proceedings and reference lists of identified trials. SELECTION CRITERIA: We included randomised controlled trials comparing intravenous, oral or no iron, with or without ESAs for the prevention or alleviation of anaemia resulting from chemotherapy, radiotherapy, combination therapy or the underlying malignancy in cancer patients. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. Outcomes were on-study mortality, number of patients receiving red blood cell transfusions, number of red blood cell units, haematological response, overall mortality and adverse events. We conducted NMAs and generated treatment rankings. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: Ninety-six trials (25,157 participants) fulfilled our inclusion criteria; 62 trials (24,603 participants) could be considered in the NMA (12 different treatment options). Here we present the comparisons of ESA with or without iron and iron alone versus no treatment. Further results and subgroup analyses are described in the full text. On-study mortality We estimated that 92 of 1000 participants without treatment for anaemia died up to 30 days after the active study period. Evidence from NMA (55 trials; 15,074 participants) suggests that treatment with ESA and intravenous iron (12 of 1000; risk ratio (RR) 0.13, 95% confidence interval (CI) 0.01 to 2.29; low certainty) or oral iron (34 of 1000; RR 0.37, 95% CI 0.01 to 27.38; low certainty) may decrease or increase and ESA alone (103 of 1000; RR 1.12, 95% CI 0.92 to 1.35; moderate certainty) probably slightly increases on-study mortality. Additionally, treatment with intravenous iron alone (271 of 1000; RR 2.95, 95% CI 0.71 to 12.34; low certainty) may increase and oral iron alone (24 of 1000; RR 0.26, 95% CI 0.00 to 19.73; low certainty) may increase or decrease on-study mortality. Haematological response We estimated that 90 of 1000 participants without treatment for anaemia had a haematological response. Evidence from NMA (31 trials; 6985 participants) suggests that treatment with ESA and intravenous iron (604 of 1000; RR 6.71, 95% CI 4.93 to 9.14; moderate certainty), ESA and oral iron (527 of 1000; RR 5.85, 95% CI 4.06 to 8.42; moderate certainty), and ESA alone (467 of 1000; RR 5.19, 95% CI 4.02 to 6.71; moderate certainty) probably increases haematological response. Additionally, treatment with oral iron alone may increase haematological response (153 of 1000; RR 1.70, 95% CI 0.69 to 4.20; low certainty). Red blood cell transfusions We estimated that 360 of 1000 participants without treatment for anaemia needed at least one transfusion. Evidence from NMA (69 trials; 18,684 participants) suggests that treatment with ESA and intravenous iron (158 of 1000; RR 0.44, 95% CI 0.31 to 0.63; moderate certainty), ESA and oral iron (144 of 1000; RR 0.40, 95% CI 0.24 to 0.66; moderate certainty) and ESA alone (212 of 1000; RR 0.59, 95% CI 0.51 to 0.69; moderate certainty) probably decreases the need for transfusions. Additionally, treatment with intravenous iron alone (268 of 1000; RR 0.74, 95% CI 0.43 to 1.28; low certainty) and with oral iron alone (333 of 1000; RR 0.92, 95% CI 0.54 to 1.57; low certainty) may decrease or increase the need for transfusions. Overall mortality We estimated that 347 of 1000 participants without treatment for anaemia died overall. Low-certainty evidence from NMA (71 trials; 21,576 participants) suggests that treatment with ESA and intravenous iron (507 of 1000; RR 1.46, 95% CI 0.87 to 2.43) or oral iron (482 of 1000; RR 1.39, 95% CI 0.60 to 3.22) and intravenous iron alone (521 of 1000; RR 1.50, 95% CI 0.63 to 3.56) or oral iron alone (534 of 1000; RR 1.54, 95% CI 0.66 to 3.56) may decrease or increase overall mortality. Treatment with ESA alone may lead to little or no difference in overall mortality (357 of 1000; RR 1.03, 95% CI 0.97 to 1.10; low certainty). Thromboembolic events We estimated that 36 of 1000 participants without treatment for anaemia developed thromboembolic events. Evidence from NMA (50 trials; 15,408 participants) suggests that treatment with ESA and intravenous iron (66 of 1000; RR 1.82, 95% CI 0.98 to 3.41; moderate certainty) probably slightly increases and with ESA alone (66 of 1000; RR 1.82, 95% CI 1.34 to 2.47; high certainty) slightly increases the number of thromboembolic events. None of the trials reported results on the other comparisons. Thrombocytopenia or haemorrhage We estimated that 76 of 1000 participants without treatment for anaemia developed thrombocytopenia/haemorrhage. Evidence from NMA (13 trials, 2744 participants) suggests that treatment with ESA alone probably leads to little or no difference in thrombocytopenia/haemorrhage (76 of 1000; RR 1.00, 95% CI 0.67 to 1.48; moderate certainty). None of the trials reported results on other comparisons. Hypertension We estimated that 10 of 1000 participants without treatment for anaemia developed hypertension. Evidence from NMA (24 trials; 8383 participants) suggests that treatment with ESA alone probably increases the number of hypertensions (29 of 1000; RR 2.93, 95% CI 1.19 to 7.25; moderate certainty). None of the trials reported results on the other comparisons. AUTHORS' CONCLUSIONS: When considering ESAs with iron as prevention for anaemia, one has to balance between efficacy and safety. Results suggest that treatment with ESA and iron probably decreases number of blood transfusions, but may increase mortality and the number of thromboembolic events. For most outcomes the different comparisons within the network were not fully connected, so ranking of all treatments together was not possible. More head-to-head comparisons including all evaluated treatment combinations are needed to fill the gaps and prove results of this review.

Effectiveness, immunogenicity, and safety of COVID-19 vaccines for individuals with hematological malignancies: a systematic review.

The efficacy of SARS-CoV-2 vaccination in patients with hematological malignancies (HM) appears limited due to disease and treatment-associated immune impairment. We conducted a systematic review of prospective studies published from 10/12/2021 onwards in medical databases to assess clinical efficacy parameters, humoral and cellular immunogenicity and adverse events (AE) following two doses of COVID-19 approved vaccines. In 57 eligible studies reporting 7393 patients, clinical outcomes were rarely reported and rates of SARS-CoV-2 infection (range 0-11.9%), symptomatic disease (0-2.7%), hospital admission (0-2.8%), or death (0-0.5%) were low. Seroconversion rates ranged from 38.1-99.1% across studies with the highest response rate in myeloproliferative diseases and the lowest in patients with chronic lymphocytic leukemia. Patients with B-cell depleting treatment had lower seroconversion rates as compared to other targeted treatments or chemotherapy. The vaccine-induced T-cell response was rarely and heterogeneously reported (26.5-85.9%). Similarly, AEs were rarely reported (0-50.9% ≥1 AE, 0-7.5% ≥1 serious AE). In conclusion, HM patients present impaired humoral and cellular immune response to COVID-19 vaccination with disease and treatment specific response patterns. In light of the ongoing pandemic with the easing of mitigation strategies, new approaches to avert severe infection are urgently needed for this vulnerable patient population that responds poorly to current COVID-19 vaccine regimens.

Oncologic Outcome and Immune Responses of Radiotherapy with Anti-PD-1 Treatment for Brain Metastases Regarding Timing and Benefiting Subgroups.

While immune checkpoint inhibitors (ICIs) in combination with radiotherapy (RT) are widely used for patients with brain metastasis (BM), markers that predict treatment response for combined RT and ICI (RT-ICI) and their optimal dosing and sequence for the best immunogenic effects are still under investigation. The aim of this study was to evaluate prognostic factors for therapeutic outcome and to compare effects of concurrent and non-concurrent RT-ICI. We retrospectively analyzed data of 93 patients with 319 BMs of different cancer types who received PD-1 inhibitors and RT at the University Hospital Cologne between September/2014 and November/2020. Primary study endpoints were overall survival (OS), progression-free survival (PFS), and local control (LC). We included 66.7% melanoma, 22.8% lung, and 5.5% other cancer types with a mean follow-up time of 23.8 months. Median OS time was 12.19 months. LC at 6 months was 95.3% (concurrent) vs. 69.2% (non-concurrent; p = 0.008). Univariate Cox regression analysis detected following prognostic factors for OS: neutrophil-to-lymphocyte ratio NLR favoring <3 (low; HR 2.037 (1.184−3.506), p = 0.010), lactate dehydrogenase (LDH) favoring ≤ULN (HR 1.853 (1.059−3.241), p = 0.031), absence of neurological symptoms (HR 2.114 (1.285−3.478), p = 0.003), RT concept favoring SRS (HR 1.985 (1.112−3.543), p = 0.019), RT dose favoring ≥60 Gy (HR 0.519 (0.309−0.871), p = 0.013), and prior anti-CTLA4 treatment (HR 0.498 (0.271−0.914), p = 0.024). Independent prognostic factors for OS were concurrent RT-ICI application (HR 0.539 (0.299−0.971), p = 0.024) with a median OS of 17.61 vs. 6.83 months (non-concurrent), ECOG performance status favoring 0 (HR 7.756 (1.253−6.061), p = 0.012), cancer type favoring melanoma (HR 0.516 (0.288−0.926), p = 0.026), BM volume (PTV) favoring ≤3 cm3 (HR 1.947 (1.007−3.763), p = 0.048). Subgroups with the following factors showed significantly longer OS when being treated concurrently: RT dose <60 Gy (p = 0.014), PTV > 3 cm3 (p = 0.007), other cancer types than melanoma (p = 0.006), anti-CTLA4-naïve patients (p < 0.001), low NLR (p = 0.039), steroid intake ≤4 mg (p = 0.042). Specific immune responses, such as abscopal effects (AbEs), pseudoprogression (PsP), or immune-related adverse events (IrAEs), occurred more frequently with concurrent RT-ICI and resulted in better OS. Other toxicities, including radionecrosis, were not statistically different in both groups. The concurrent application of RT and ICI, the ECOG-PS, cancer type, and PTV had an independently prognostic impact on OS. In concurrently treated patients, treatment response (LC) was delayed and specific immune responses (AbE, PsP, IrAE) occurred more frequently with longer OS rates. Our results suggest that concurrent RT-ICI application is more beneficial than sequential treatment in patients with low pretreatment inflammatory status, more and larger BMs, and with other cancer types than melanoma.

The Role of Age and Comorbidities in Esophagogastric Cancer Chemoradiation of the Frail Elderly (>70 Years): An Analysis from a Tertiary High Volume-Center

Elderly patients > 70 years of age with esophageal cancer (EC) represent a challenging group as frailty and comorbidities need to be considered. The aim of this retrospective study was to evaluate the efficacy and side effects of curative chemoradiation therapy (CRT) with regard to basic geriatric screening in elderly patients in order to elucidate prognostic factors. Thirty-four elderly patients > 70 years with EC treated at our cancer center between May 2014 and October 2018 fulfilled the selection criteria for this retrospective analysis. Treatment consisted of intravenous infusion of carboplatin/paclitaxel or fluorouracil (5-FU)/cisplatin with the intention of neoadjuvant or definite chemoradiation. Clinicopathological data including performance status (ECOG), (age-adjusted) Charlson comorbidity index (CCI), Frailty-scale by Fried, Mini Nutritional Assessment Short Form, body mass index, C-reactive protein to albumin ratio, and treatment-related toxicity (CTCAE) were assessed. Data were analyzed as predictors of overall survival (OS) and progression-free survival (PFS). All patients (ten female, 24 male) received combined CRT (22 patients in neoadjuvant, 12 patients in definite intent). Median age was 75 years and the ECOG index between 0 and 1 (52.9% vs. 35.3%); four patients were rated as ECOG 3 (11.8%). Median follow-up was 24 months. Tumors were mainly located in the lower esophagus or esophagogastric-junction with an T3 stage (n = 25; 75.8%) and N1 stage (n = 28; 90.3%). 15 patients (44.1%) had SCC, 19 patients (55.9%) AC. 26 of the patients (76.5%) were scored as prefrail and 50% were in risk for malnutrition (n = 17). In relation to the BMI, ten patients (29.4%) were ranked as overweight, and 15 patients were presented in a healthy state of weight (44.1%). Grade 3 acute toxicity (or higher) occured in nine cases (26.5%). Most of the patients did not show any late toxicities (66.7%). Trimodal therapy provides a significant prolonged OS (p = 0.049) regardless of age, but without impact on PFS. Our analysis suggests that chemoradiation therapy is feasible for elderly patients (>70 years) with tolerable toxicity. Trimodal therapy of EC shows a positive effect on OS and PFS. Further studies are needed to elucidate benefitting subgroups within the elderly. In addition to age, treatment decisions should be based on performance status, nutritional condition and multidisciplinary validated geriatric screening tools.

Antiemetics for adults for prevention of nausea and vomiting caused by moderately or highly emetogenic chemotherapy: a network meta-analysis.

BACKGROUND: About 70% to 80% of adults with cancer experience chemotherapy-induced nausea and vomiting (CINV). CINV remains one of the most distressing symptoms associated with cancer therapy and is associated with decreased adherence to chemotherapy. Combining 5-hydroxytryptamine-3 (5-HT3) receptor antagonists with corticosteroids or additionally with neurokinin-1 (NK1) receptor antagonists is effective in preventing CINV among adults receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). Various treatment options are available, but direct head-to-head comparisons do not allow comparison of all treatments versus another.  OBJECTIVES: • In adults with solid cancer or haematological malignancy receiving HEC - To compare the effects of antiemetic treatment combinations including NK1 receptor antagonists, 5-HT3 receptor antagonists, and corticosteroids on prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy-induced nausea and vomiting in network meta-analysis (NMA) - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy • In adults with solid cancer or haematological malignancy receiving MEC - To compare whether antiemetic treatment combinations including NK1 receptor antagonists, 5-HT3 receptor antagonists, and corticosteroids are superior for prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy-induced nausea and vomiting to treatment combinations including 5-HT3 receptor antagonists and corticosteroids solely, in network meta-analysis - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings, and study registries from 1988 to February 2021 for randomised controlled trials (RCTs). SELECTION CRITERIA: We included RCTs including adults with any cancer receiving HEC or MEC (according to the latest definition) and comparing combination therapies of NK1 and 5-HT3 inhibitors and corticosteroids for prevention of CINV. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We expressed treatment effects as risk ratios (RRs). Prioritised outcomes were complete control of vomiting during delayed and overall phases, complete control of nausea during the overall phase, quality of life, serious adverse events (SAEs), and on-study mortality. We assessed GRADE and developed 12 'Summary of findings' tables. We report results of most crucial outcomes in the abstract, that is, complete control of vomiting during the overall phase and SAEs. For a comprehensive illustration of results, we randomly chose aprepitant plus granisetron as exemplary reference treatment for HEC, and granisetron as exemplary reference treatment for MEC. MAIN RESULTS: Highly emetogenic chemotherapy (HEC) We included 73 studies reporting on 25,275 participants and comparing 14 treatment combinations with NK1 and 5-HT3 inhibitors. All treatment combinations included corticosteroids. Complete control of vomiting during the overall phase We estimated that 704 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with aprepitant + granisetron. Evidence from NMA (39 RCTs, 21,642 participants; 12 treatment combinations with NK1 and 5-HT3 inhibitors) suggests that the following drug combinations are more efficacious than aprepitant + granisetron for completely controlling vomiting during the overall treatment phase (one to five days): fosnetupitant + palonosetron (810 of 1000; RR 1.15, 95% confidence interval (CI) 0.97 to 1.37; moderate certainty), aprepitant + palonosetron (753 of 1000; RR 1.07, 95% CI 1.98  to 1.18; low-certainty), aprepitant + ramosetron (753 of 1000; RR 1.07, 95% CI 0.95 to 1.21; low certainty), and fosaprepitant + palonosetron (746 of 1000; RR 1.06, 95% CI 0.96 to 1.19; low certainty).  Netupitant + palonosetron (704 of 1000; RR 1.00, 95% CI 0.93 to 1.08; high-certainty) and fosaprepitant + granisetron (697 of 1000; RR 0.99, 95% CI 0.93 to 1.06; high-certainty) have little to no impact on complete control of vomiting during the overall treatment phase (one to five days) when compared to aprepitant + granisetron, respectively.  Evidence further suggests that the following drug combinations are less efficacious than aprepitant + granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): aprepitant + ondansetron (676 of 1000; RR 0.96, 95% CI 0.88 to 1.05; low certainty), fosaprepitant + ondansetron (662 of 1000; RR 0.94, 95% CI 0.85 to 1.04; low certainty), casopitant + ondansetron (634 of 1000; RR 0.90, 95% CI 0.79 to 1.03; low certainty), rolapitant + granisetron (627 of 1000; RR 0.89, 95% CI 0.78 to 1.01; moderate certainty), and rolapitant + ondansetron (598 of 1000; RR 0.85, 95% CI 0.65 to 1.12; low certainty). We could not include two treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron) in NMA for this outcome because of missing direct comparisons.  Serious adverse events We estimated that 35 of 1000 participants experience any SAEs when treated with aprepitant + granisetron. Evidence from NMA (23 RCTs, 16,065 participants; 11 treatment combinations) suggests that fewer participants may experience SAEs when treated with the following drug combinations than with aprepitant + granisetron: fosaprepitant + ondansetron (8 of 1000; RR 0.23, 95% CI 0.05 to 1.07; low certainty), casopitant + ondansetron (8 of 1000; RR 0.24, 95% CI 0.04 to 1.39; low certainty), netupitant + palonosetron (9 of 1000; RR 0.27, 95% CI 0.05 to 1.58; low certainty), fosaprepitant + granisetron (13 of 1000; RR 0.37, 95% CI 0.09 to 1.50; low certainty), and rolapitant + granisetron (20 of 1000; RR 0.57, 95% CI 0.19 to 1.70; low certainty). Evidence is very uncertain about the effects of aprepitant + ondansetron (8 of 1000; RR 0.22, 95% CI 0.04 to 1.14; very low certainty), aprepitant + ramosetron (11 of 1000; RR 0.31, 95% CI 0.05 to 1.90; very low certainty), fosaprepitant + palonosetron (12 of 1000; RR 0.35, 95% CI 0.04 to 2.95; very low certainty), fosnetupitant + palonosetron (13 of 1000; RR 0.36, 95% CI 0.06 to 2.16; very low certainty), and aprepitant + palonosetron (17 of 1000; RR 0.48, 95% CI 0.05 to 4.78; very low certainty) on the risk of SAEs when compared to aprepitant + granisetron, respectively.  We could not include three treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron, rolapitant + ondansetron) in NMA for this outcome because of missing direct comparisons.  Moderately emetogenic chemotherapy (MEC) We included 38 studies reporting on 12,038 participants and comparing 15 treatment combinations with NK1 and 5-HT3 inhibitors, or 5-HT3 inhibitors solely. All treatment combinations included corticosteroids. Complete control of vomiting during the overall phase We estimated that 555 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with granisetron. Evidence from NMA (22 RCTs, 7800 participants; 11 treatment combinations) suggests that the following drug combinations are more efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days): aprepitant + palonosetron (716 of 1000; RR 1.29, 95% CI 1.00 to 1.66; low certainty), netupitant + palonosetron (694 of 1000; RR 1.25, 95% CI 0.92 to 1.70; low certainty), and rolapitant + granisetron (660 of 1000; RR 1.19, 95% CI 1.06 to 1.33; high certainty).  Palonosetron (588 of 1000; RR 1.06, 95% CI 0.85 to 1.32; low certainty) and aprepitant + granisetron (577 of 1000; RR 1.06, 95% CI 0.85 to 1.32; low certainty) may or may not increase complete response in the overall treatment phase (one to five days) when compared to granisetron, respectively. Azasetron (560 of 1000; RR 1.01, 95% CI 0.76 to 1.34; low certainty) may result in little to no difference in complete response in the overall treatment phase (one to five days) when compared to granisetron. Evidence further suggests that the following drug combinations are less efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): fosaprepitant + ondansetron (500 of 100; RR 0.90, 95% CI 0.66 to 1.22; low certainty), aprepitant + ondansetron (477 of 1000; RR 0.86, 95% CI 0.64 to 1.17; low certainty), casopitant + ondansetron (461 of 1000; RR 0.83, 95% CI 0.62 to 1.12; low certainty), and ondansetron (433 of 1000; RR 0.78, 95% CI 0.59 to 1.04; low certainty). We could not include five treatment combinations (fosaprepitant + granisetron, azasetron, dolasetron, ramosetron, tropisetron) in NMA for this outcome because of missing direct comparisons.  Serious adverse events We estimated that 153 of 1000 participants experience any SAEs when treated with granisetron. Evidence from pair-wise comparison (1 RCT, 1344 participants) suggests that more participants may experience SAEs when treated with rolapitant + granisetron (176 of 1000; RR 1.15, 95% CI 0.88 to 1.50; low certainty). NMA was not feasible for this outcome because of missing direct comparisons.  Certainty of evidence Our main reason for downgrading was serious or very serious imprecision (e.g. due to wide 95% CIs crossing or including unity, few events leading to wide 95% CIs, or small information size). Additional reasons for downgrading some comparisons or whole networks were serious study limitations due to high risk of bias or moderate inconsistency within networks. AUTHORS' CONCLUSIONS: This field of supportive cancer care is very well researched. However, new drugs or drug combinations are continuously emerging and need to be systematically researchedand assessed. For people receiving HEC, synthesised evidence does not suggest one superior treatment for prevention and control of chemotherapy-induced nausea and vomiting.  For people receiving MEC, synthesised evidence does not suggest superiority for treatments including both NK1 and 5-HT3 inhibitors when compared to treatments including 5-HT3 inhibitors only. Rather, the results of our NMA suggest that the choice of 5-HT3 inhibitor may have an impact on treatment efficacy in preventing CINV.  When interpreting the results of this systematic review, it is important for the reader to understand that NMAs are no substitute for direct head-to-head comparisons, and that results of our NMA do not necessarily rule out differences that could be clinically relevant for some individuals.

Bisphosphonates or RANK-ligand-inhibitors for men with prostate cancer and bone metastases: a network meta-analysis.

BACKGROUND: Different bone-modifying agents like bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are used as supportive treatment in men with prostate cancer and bone metastases to prevent skeletal-related events (SREs). SREs such as pathologic fractures, spinal cord compression, surgery and radiotherapy to the bone, and hypercalcemia lead to morbidity, a poor performance status, and impaired quality of life. Efficacy and acceptability of the bone-targeted therapy is therefore of high relevance. Until now recommendations in guidelines on which bone-modifying agents should be used are rare and inconsistent. OBJECTIVES: To assess the effects of bisphosphonates and RANKL-inhibitors as supportive treatment for prostate cancer patients with bone metastases and to generate a clinically meaningful treatment ranking according to their safety and efficacy using network meta-analysis. SEARCH METHODS: We identified studies by electronically searching the bibliographic databases Cochrane Controlled Register of Trials (CENTRAL), MEDLINE, and Embase until 23 March 2020. We searched the Cochrane Library and various trial registries and screened abstracts of conference proceedings and reference lists of identified trials. SELECTION CRITERIA: We included randomized controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for men with prostate cancer and bone metastases. We included men with castration-restrictive and castration-sensitive prostate cancer and conducted subgroup analyses according to this criteria. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of trials. We defined proportion of participants with pain response and the adverse events renal impairment and osteonecrosis of the jaw (ONJ) as the primary outcomes. Secondary outcomes were SREs in total and each separately (see above), mortality, quality of life, and further adverse events such as grade 3 to 4 adverse events, hypocalcemia, fatigue, diarrhea, and nausea. We conducted network meta-analysis and generated treatment rankings for all outcomes, except quality of life due to insufficient reporting on this outcome. We compiled ranking plots to compare single outcomes of efficacy against outcomes of acceptability of the bone-modifying agents. We assessed the certainty of the evidence for the main outcomes using the GRADE approach. MAIN RESULTS: Twenty-five trials fulfilled our inclusion criteria. Twenty-one trials could be considered in the quantitative analysis, of which six bisphosphonates (zoledronic acid, risedronate, pamidronate, alendronate, etidronate, or clodronate) were compared with each other, the RANKL-inhibitor denosumab, or no treatment/placebo. By conducting network meta-analysis we were able to compare all of these reported agents directly and/or indirectly within the network for each outcome. In the abstract only the comparisons of zoledronic acid and denosumab against the main comparator (no treatment/placebo) are described for outcomes that were predefined as most relevant and that also appear in the 'Summary of findings' table. Other results, as well as results of subgroup analyses regarding castration status of participants, are displayed in the Results section of the full text. Treatment with zoledronic acid probably neither reduces nor increases the proportion of participants with pain response when compared to no treatment/placebo (risk ratio (RR) 1.46, 95% confidence interval (CI) 0.93 to 2.32; per 1000 participants 121 more (19 less to 349 more); moderate-certainty evidence; network based on 4 trials including 1013 participants). For this outcome none of the trials reported results for the comparison with denosumab. The adverse event renal impairment probably occurs more often when treated with zoledronic acid compared to treatment/placebo (RR 1.63, 95% CI 1.08 to 2.45; per 1000 participants 78 more (10 more to 180 more); moderate-certainty evidence; network based on 6 trials including 1769 participants). Results for denosumab could not be included for this outcome, since zero events cannot be considered in the network meta-analysis, therefore it does not appear in the ranking. Treatment with denosumab results in increased occurrence of the adverse event ONJ (RR 3.45, 95% CI 1.06 to 11.24; per 1000 participants 30 more (1 more to 125 more); high-certainty evidence; 4 trials, 3006 participants) compared to no treatment/placebo. When comparing zoledronic acid to no treatment/placebo, the confidence intervals include the possibility of benefit or harm, therefore treatment with zoledronic acid probably neither reduces nor increases ONJ (RR 1.88, 95% CI 0.73 to 4.87; per 1000 participants 11 more (3 less to 47 more); moderate-certainty evidence; network based on 4 trials including 3006 participants). Compared to no treatment/placebo, treatment with zoledronic acid (RR 0.84, 95% CI 0.72 to 0.97) and denosumab (RR 0.72, 95% CI 0.54 to 0.96) may result in a reduction of the total number of SREs (per 1000 participants 75 fewer (131 fewer to 14 fewer) and 131 fewer (215 fewer to 19 fewer); both low-certainty evidence; 12 trials, 5240 participants). Treatment with zoledronic acid and denosumab likely neither reduces nor increases mortality when compared to no treatment/placebo (zoledronic acid RR 0.90, 95% CI 0.80 to 1.01; per 1000 participants 48 fewer (97 fewer to 5 more); denosumab RR 0.93, 95% CI 0.77 to 1.11; per 1000 participants 34 fewer (111 fewer to 54 more); both moderate-certainty evidence; 13 trials, 5494 participants). Due to insufficient reporting, no network meta-analysis was possible for the outcome quality of life. One study with 1904 participants comparing zoledronic acid and denosumab showed that more zoledronic acid-treated participants than denosumab-treated participants experienced a greater than or equal to five-point decrease in Functional Assessment of Cancer Therapy-General total scores over a range of 18 months (average relative difference = 6.8%, range -9.4% to 14.6%) or worsening of cancer-related quality of life. AUTHORS' CONCLUSIONS: When considering bone-modifying agents as supportive treatment, one has to balance between efficacy and acceptability. Results suggest that Zoledronic acid likely increases both the proportion of participants with pain response, and the proportion of participants experiencing adverse events However, more trials with head-to-head comparisons including all potential agents are needed to draw the whole picture and proof the results of this analysis.

Cell-Free HPV-DNA as a Biomarker for Oropharyngeal Squamous Cell Carcinoma-A Step Towards Personalized Medicine?

Global incidences of oropharyngeal squamous cell carcinoma (OPSCC) are rising due to an association with high-risk human papillomavirus (HPV). Although there is an improved overall survival of HPV-related OPSCC; up to 25% of the patients develop recurrent or distant metastatic disease with a fatal outcomes. Biomarkers to monitor this disease are not established. This meta-analysis reviews the role of cell-free HPV DNA in liquid biopsy (LB) as a biomarker for HPV-related OPSCC. Pubmed, Livivo, and Cochrane Library databases were searched from inception to August, 2020. All studies were analyzed by Meta-DiSc 1.4 and Stata 16.0 statistical software. In total, 16 studies were considered for systematic review, whereas 11 studies met inclusion criteria for meta-analysis, respectively. Pooled sensitivity of cfHPV-DNA at first diagnosis and during follow-up was 0.81 (95% CI; 0.78-0.84) and 0.73 (95% CI; 0.57-0.86), while pooled specificity was 0.98 (95% CI; 0.96-0.99) and 1 (95% CI; 0.99-1). The diagnostic odds ratio (DOR) at first diagnosis was 200.60 (95% CI; 93.31-431.22) and 300.31 (95% CI; 60.94-1479.88) during follow-up. The area under the curve (AUC) of summary receiver operating characteristic (SROC) was 0.99 at first diagnosis and 1.00 during follow-up, respectively. In conclusion, cfHPV-DNA presents a potential biomarker with high specificity in patients with HPV-related OPSCC.

Addition of Radiotherapy to Immunotherapy: Effects on Outcome of Different Subgroups Using a Propensity Score Matching.

Immune checkpoint inhibition (ICI) has been established as successful modality in cancer treatment. Combination concepts are used to optimize treatment outcome, but may also induce higher toxicity rates than monotherapy. Several rationales support the combination of radiotherapy (RT) with ICI as radioimmunotherapy (RIT), but it is still unknown in which clinical situation RIT would be most beneficial. Therefore, we have conducted a retrospective matched-pair analysis of 201 patients with advanced-stage cancers and formed two groups treated with programmed cell death protein 1 (PD-1) inhibitors only (PD1i) or in combination with local RT (RIT) at our center between 2013 and 2017. We collected baseline characteristics, programmed death ligand 1 (PD-L1) status, mutational status, PD-1 inhibitor and RT treatment details, and side effects according to the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. Patients received pembrolizumab (n = 93) or nivolumab (n = 108), 153 with additional RT. For overall survival (OS) and progression-free survival (PFS), there was no significant difference between both groups. After propensity score matching (PSM), we analyzed 96 patients, 67 with additional and 29 without RT. We matched for different covariates that could have a possible influence on the treatment outcome. The RIT group displayed a trend towards a longer OS until the PD1i group reached a survival plateau. PD-L1-positive patients, smokers, patients with a BMI ≤ 25, and patients without malignant melanoma showed a longer OS when treated with RIT. Our data show that some subgroups may benefit more from RIT than others. Suitable biomarkers as well as the optimal timing and dosage must be established in order to achieve the best effect on cancer treatment outcome.

Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis.

BACKGROUND: Multiple myeloma is a bone marrow-based hematological malignancy accounting for approximately two per cent of cancers. First-line treatment for transplant-ineligible individuals consists of multiple drug combinations of bortezomib (V), lenalidomide (R), or thalidomide (T). However, access to these medicines is restricted in many countries worldwide. OBJECTIVES: To assess and compare the effectiveness and safety of multiple drug combinations of V, R, and T for adults with newly diagnosed transplant-ineligible multiple myeloma and to inform an application for the inclusion of these medicines into the World Health Organization's (WHO) list of essential medicines. SEARCH METHODS: We searched CENTRAL and MEDLINE, conference proceedings and study registries on 14 February 2019 for randomised controlled trials (RCTs) comparing multiple drug combinations of V, R and T for adults with newly diagnosed transplant-ineligible multiple myeloma. SELECTION CRITERIA: We included RCTs comparing combination therapies of V, R, and T, plus melphalan and prednisone (MP) or dexamethasone (D) for first-line treatment of adults with transplant-ineligible multiple myeloma. We excluded trials including adults with relapsed or refractory disease, trials comparing drug therapies to other types of therapy and trials including second-generation novel agents. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias of included trials. As effect measures we used hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for adverse events. An HR or RR < 1 indicates an advantage for the intervention compared to the main comparator MP. Where available, we extracted quality of life (QoL) data (scores of standardised questionnaires). Results quoted are from network meta-analysis (NMA) unless stated. MAIN RESULTS: We included 25 studies (148 references) comprising 11,403 participants and 21 treatment regimens. Treatments were differentiated between restricted treatment duration (treatment with a pre-specified amount of cycles) and continuous therapy (treatment administered until disease progression, the person becomes intolerant to the drug, or treatment given for a prolonged period). Continuous therapies are indicated with a "c". Risk of bias was generally high across studies due to the open-label study design. Overall survival (OS) Evidence suggests that treatment with RD (HR 0.63 (95% confidence interval (CI) 0.40 to 0.99), median OS 55.2 months (35.2 to 87.0)); TMP (HR 0.75 (95% CI 0.58 to 0.97), median OS: 46.4 months (35.9 to 60.0)); and VRDc (HR 0.49 (95% CI 0.26 to 0.92), median OS 71.0 months (37.8 to 133.8)) probably increases survival compared to median reported OS of 34.8 months with MP (moderate certainty). Treatment with VMP may result in a large increase in OS, compared to MP (HR 0.70 (95% CI 0.45 to 1.07), median OS 49.7 months (32.5 to 77.3)), low certainty). Progression-free survival (PFS) Treatment withRD (HR 0.65 (95% CI0.44 to 0.96), median PFS: 24.9 months (16.9 to 36.8)); TMP (HR 0.63 (95% CI 0.50 to 0.78), median PFS:25.7 months (20.8 to 32.4)); VMP (HR 0.56 (95% CI 0.35 to 0.90), median PFS: 28.9 months (18.0 to 46.3)); and VRDc (HR 0.34 (95% CI 0.20 to 0.58), median PFS: 47.6 months (27.9 to 81.0)) may result in a large increase in PFS (low certainty) compared to MP (median reported PFS: 16.2 months). Adverse events The risk of polyneuropathies may be lower with RD compared to treatment with MP (RR 0.57 (95% CI 0.16 to 1.99), risk for RD: 0.5% (0.1 to 1.8), mean reported risk for MP: 0.9% (10 of 1074 patients affected), low certainty). However, the CIs are also compatible with no difference or an increase in neuropathies. Treatment with TMP (RR 4.44 (95% CI1.77 to 11.11), risk: 4.0% (1.6 to 10.0)) and VMP (RR 88.22 (95% CI 5.36 to 1451.11), risk: 79.4% (4.8 to 1306.0)) probably results in a large increase in polyneuropathies compared to MP (moderate certainty). No study reported the amount of participants with grade ≥ 3 polyneuropathies for treatment with VRDc. VMP probably increases the proportion of participants with serious adverse events (SAEs) compared to MP (RR 1.28 (95% CI 1.06 to 1.54), risk for VMP: 46.2% (38.3 to 55.6), mean risk for MP: 36.1% (177 of 490 patients affected), moderate certainty). RD, TMP, and VRDc were not connected to MP in the network and the risk of SAEs could not be compared. Treatment with RD (RR 4.18 (95% CI 2.13 to 8.20), NMA-risk: 38.5% (19.6 to 75.4)); and TMP (RR 4.10 (95% CI 2.40 to 7.01), risk: 37.7% (22.1 to 64.5)) results in a large increase of withdrawals from the trial due to adverse events (high certainty) compared to MP (mean reported risk: 9.2% (77 of 837 patients withdrew)). The risk is probably slightly increased with VMP (RR 1.06 (95% CI 0.63 to 1.81), risk: 9.75% (5.8 to 16.7), moderate certainty), while it is much increased with VRDc (RR 8.92 (95% CI 3.82 to 20.84), risk: 82.1% (35.1 to 191.7), high certainty) compared to MP. Quality of life QoL was reported in four studies for seven different treatment regimens (MP, MPc, RD, RMP, RMPc, TMP, TMPc) and was measured with four different tools. Assessment and reporting differed between studies and could not be meta-analysed. However, all studies reported an improvement of QoL after initiation of anti-myeloma treatment for all assessed treatment regimens. AUTHORS' CONCLUSIONS: Based on our four pre-selected comparisons of interest, continuous treatment with VRD had the largest survival benefit compared with MP, while RD and TMP also probably considerably increase survival. However, treatment combinations of V, R, and T also substantially increase the incidence of AEs, and lead to a higher risk of treatment discontinuation. Their effectiveness and safety profiles may best be analysed in further randomised head-to-head trials. Further trials should focus on consistent reporting of safety outcomes and should use a standardised instrument to evaluate QoL to ensure comparability of treatment-combinations.

Ventilation in Extremely Preterm Infants and Respiratory Function at 8 Years.

BACKGROUND: Assisted ventilation for extremely preterm infants (<28 weeks of gestation) has become less invasive, but it is unclear whether such developments in care are associated with improvements in short-term or long-term lung function. We compared changes over time in the use of assisted ventilation and oxygen therapy during the newborn period and in lung function at 8 years of age in children whose birth was extremely premature. METHODS: We conducted longitudinal follow-up of all survivors of extremely preterm birth who were born in Victoria, Australia, in three periods - the years 1991 and 1992 (225 infants), 1997 (151 infants), and 2005 (170 infants). Perinatal data were collected prospectively, including data on the duration and type of assisted ventilation provided, the duration of oxygen therapy, and oxygen requirements at 36 weeks of age. Expiratory airflow was measured at 8 years of age, and values were converted to z scores for age, height, ethnic group, and sex. RESULTS: The duration of assisted ventilation rose substantially over time, with a large increase in the duration of nasal continuous positive airway pressure. Despite the increase in the use of less invasive ventilation over time, the duration of oxygen therapy and the rate of oxygen dependence at 36 weeks rose, and airflows at 8 years of age were worse in 2005 than in earlier periods. For instance, for 2005 versus 1991-1992, the mean difference in the z scores for the ratio of forced expiratory volume in 1 second to forced vital capacity was -0.75 (95% confidence interval [CI], -1.07 to -0.44; P<0.001), and for 2005 versus 1997 the mean difference was -0.53 (95% CI, -0.86 to -0.19; P=0.002). CONCLUSIONS: Despite substantial increases in the use of less invasive ventilation after birth, there was no significant decline in oxygen dependence at 36 weeks and no significant improvement in lung function in childhood over time. (Funded by the National Health and Medical Research Council of Australia and the Victorian Government's Operational Infrastructure Support Program.).

Increasing airway obstruction from 8 to 18†years in extremely preterm/low-birthweight survivors born in the surfactant era.

BACKGROUND: The evolution of airway obstruction into late adolescence of extremely preterm (gestational age <28 weeks) or extremely low-birthweight (birth weight <1000 g) survivors in the era after surfactant was introduced is unclear. OBJECTIVE: To compare changes in spirometry from 8 to 18 years of age of a geographical cohort of preterm survivors with normal birth weight controls, and to determine higher risk groups within the preterm cohort. METHODS: Of 297 extremely preterm/low-birthweight survivors born in 1991-1992 in the state of Victoria, Australia, 81% and 70% had spirometry at 8 and 18 years of age, respectively. Corresponding rates among 260 normal birth weight controls were 80% and 58%, respectively. Data were analysed using linear mixed models. RESULTS: The preterm group had substantial impairments in airflow at both ages compared with controls (eg, mean differences in z-score for FEV1; 8 years -1.02, 95% CI -1.21 to -0.82; 18 years -0.92, 95% CI -1.14 to -0.71). The preterm group had a greater increase in small airway obstruction between 8 and 18 years compared with controls. Within the preterm group, those who had bronchopulmonary dysplasia in the newborn period and those who were smokers at 18 years had airway obstruction that increased over time compared with those who did not. CONCLUSIONS: Preterm survivors born in the surfactant era had significant impairments in airflow through childhood into late adolescence that increased over time compared with controls. At-risk preterm participants include those who had bronchopulmonary dysplasia, and smokers at 18 years.

Clinicopathological Characteristics of RET Rearranged Lung Cancer in European Patients.

INTRODUCTION: Rearrangements of RET are rare oncogenic events in patients with non-small cell lung cancer (NSCLC). While the characterization of Asian patients suggests a predominance of nonsmokers of young age in this genetically defined lung cancer subgroup, little is known about the characteristics of non-Asian patients. We present the results of an analysis of a European cohort of patients with RET rearranged NSCLC. METHODS: Nine hundred ninety-seven patients with KRAS/EGFR/ALK wildtype lung adenocarcinomas were analyzed using fluorescence in situ hybridization for RET fusions. Tumor specimens were molecularly profiled and clinicopathological characteristics of the patients were collected. RESULTS: Rearrangements of RET were identified in 22 patients, with a prevalence of 2.2% in the KRAS/EGFR/ALK wildtype subgroup. Co-occurring genetic aberrations were detected in 10 patients, and the majority had mutations in TP53. The median age at diagnosis was 62 years (range, 39-80 years; mean ± SD, 61 ± 11.7 years) with a higher proportion of men (59% versus 41%). There was only a slight predominance of nonsmokers (54.5%) compared to current or former smokers (45.5%). CONCLUSIONS: Patients with RET rearranged adenocarcinomas represent a rare and heterogeneous NSCLC subgroup. In some contrast to published data, we see a high prevalence of current and former smokers in our white RET cohort. The significance of co-occurring aberrations, so far, is unclear.

Lung Clearance Index and Structural Lung Disease on Computed Tomography in Early Cystic Fibrosis.

RATIONALE: The lung clearance index is a measure of ventilation distribution derived from the multiple-breath washout technique. It has been suggested as a surrogate for chest computed tomography to detect structural lung abnormalities in individuals with cystic fibrosis (CF); however, the associations between lung clearance index and early structural lung disease are unclear. OBJECTIVES: We assessed the ability of the lung clearance index to reflect structural lung disease on the basis of chest computed tomography across the entire pediatric age range. METHODS: Lung clearance index was assessed in 42 infants (ages 0-2 yr), 39 preschool children (ages 3-6 yr), and 38 school-age children (7-16 yr) with CF before chest computed tomography and in 72 healthy control subjects. Scans were evaluated for CF-related structural lung disease using the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis quantitative outcome measure. MEASUREMENTS AND MAIN RESULTS: In infants with CF, lung clearance index is insensitive to structural disease (κ = -0.03 [95% confidence interval, -0.05 to 0.16]). In preschool children with CF, lung clearance index correlates with total disease extent. In school-age children, lung clearance index correlates with extent of total disease, bronchiectasis, and air trapping. In preschool and school-age children, lung clearance index has a good positive predictive value (83-86%) but a poor negative predictive value (50-55%) to detect the presence of bronchiectasis. CONCLUSIONS: These data suggest that lung clearance index may be a useful surveillance tool to monitor structural lung disease in preschool and school-age children with CF. However, lung clearance index cannot replace chest computed tomography to screen for bronchiectasis in this population.