Evaluating the clinical efficacy and safety of concurrent chemoradiotherapy with cisplatin and nab-paclitaxel in postoperative early-stage cervical cancer.

OBJECTIVE: A preclinical study showed that nab-paclitaxel acted as a radiosensitizer and improved tumor radiotherapy in a supra-additive manner. In this study, we aimed to evaluate the clinical efficacy and safety of concurrent chemoradiotherapy (CCRT) with cisplatin and nab-paclitaxel in postoperative early-stage cervical cancer with an unfavorable prognosis. METHODS: Eligible patients with stage IB1-IIA2 (FIGO 2009) cervical carcinoma were recruited retrospectively between August 2018 to May 2021. Patients in both the cisplatin and nab-paclitaxel groups received postoperative radiotherapy and weekly intravenous cisplatin 40 mg/m2 or nab-paclitaxel 100 mg concurrently. An analysis of overall survival, progression-free survival, and adverse reactions was conducted. RESULTS: A total of 105 early-stage cervical cancer patients were included into our study. The median follow-up time was 38.7 months. The 3-year overall survival and progression-free survival in both group was similar. The cycles of chemotherapy in the cisplatin group were less than those in the nab-paclitaxel group (4.5 vs. 5.0; p = 0.001). Patients in the cisplatin group had a significantly higher frequency of hematological adverse events than patients in the nab-paclitaxel group (P < 0.05). Patients in the cisplatin group had a significantly higher frequency of grade 3-4 leukopenia (46.1% vs. 18.9%; P = 0.03), grade 1-2 thrombocytopenia (32.7% vs. 9.5%; P = 0.014) than patients in the nab-paclitaxel group. Gastrointestinal reactions, such as vomiting, nausea, and anorexia were significantly reduced in the nab-paclitaxel group compared with those in the cisplatin group. Regarding the effects on alopecia, the incidence rate of the nab-paclitaxel group was higher than that of the cisplatin group (P = 0.001). There were no differences between the groups in terms of other adverse reactions. CONCLUSION: The results of this study indicate that nab-paclitaxel-based concurrent radiotherapy is tolerable and effective, and can be considered an alternative to cisplatin chemotherapy.

Effects of concurrent chemoradiotherapy with or without Endostar on the regression of retropharyngeal lymph node and prognosis of patients with locally advanced nasopharyngeal carcinoma: a retrospective study.

BACKGROUND AND PURPOSE: To investigate the effect of combining Endostar with concurrent chemoradiotherapy (ECCRT) compared to concurrent chemoradiotherapy (CCRT) on the regression rate of retropharyngeal lymph nodes (RLNs) and the relationship between regression rate of RLNs and prognosis of patients with locally advanced nasopharyngeal carcinoma (LANPC). METHODS: A total of 122 LANPC patients with RLNs metastasis were included. Metastatic RLNs were delineated both before and after treatment slice by slice on the magnetic resonance images cross-section. The regression rate of RLNs, adverse effects (AE) were evaluated. The median regression rate of RLNs was taken as the cut-off value, and the patients were furtherly divided into high regression rate (HRR) group and low regression rate (LRR) group, then survival times were evaluated. RESULTS: The median regression rates of RLNs in the ECCRT and CCRT groups were 81% and 50%, respectively (P < 0.001). There was no statistically significant difference in the incidence of grade 3/4 AEs between the two groups, except for oral mucositis (ECCRT 26.23% vs. CCRT 44.26%, P = 0.037). The 3-year overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional failure-free survival (LRFFS) rates in the HRR and LRR groups were 85.48% and 86.67% (P = 0.983), 80.65% and 68.33% (P = 0.037), 83.87% and 85% (P = 0.704), 93.55% and 81.67% (P = 0.033), respectively. CONCLUSIONS: Patients in the ECCRT group had higher regression rates of RLNs and lower incidence of severe oral mucositis. Furthermore, patients in the HRR group had a better 3-year PFS and LRFFS rate than those in the LRR group.

Comparison of neoadjuvant chemotherapy or chemoradiotherapy plus immunotherapy for locally resectable esophageal squamous cell carcinoma.

Background: Neoadjuvant chemotherapy plus immunotherapy (nCT + ICIs) and neoadjuvant chemoradiotherapy plus immunotherapy (nCRT + ICIs) both induced favorable pathological response and tolerant toxicities for locally resectable esophageal squamous cell carcinoma (ESCC). However, few studies compared safety and efficacy between the two treatment strategies. Methods: This retrospective study collected clinical data of locally resectable ESCC patients who underwent nCT + ICIs or nCRT + ICIs followed by esophagectomy from November 2019 to December 2022. The incidence of adverse events, surgical outcomes, short and long-term efficacy, and treatment costs were compared. Results: A total of 206 patients were included, with a ratio of 158:48 between nCT + ICIs group and nCRT + ICIs group. The two groups exhibited well-balanced baseline characteristics. Most adverse events were grade 1-2 in both groups. The nCT + ICIs group had a longer operative time (334.00 ± 170.2 min vs 279.60 ± 88.31 min, P=0.020) than nCRT + ICIs group, but there were no differences in surgical complications. Although nCT + ICIs group had a lower pCR rate (32.3% vs 52.1%, P=0.004), the 2-year overall survival (84.42% vs 81.70%, P=0.860), 2-year disease-free survival (83.21% vs 80.47%, P=0.839), and recurrence patterns were similar to nCRT + ICIs group. In addition, nCT + ICIs group had significantly lower expenses (188796.00 ± 107704.00 RMB vs 231808.00 ± 48067.00 RMB, P=0.045). Conclusion: Overall, nCT + ICIs have comparable safety and efficacy compared to nCRT + ICIs for locally resectable ESCC, but with lower hospitalization costs.

Late coronary artery injury following chemoradiotherapy for thymic carcinoma: a case report.

INTRODUCTION: Surgery remains the primary treatment modality for thymic carcinoma, with adjuvant radiotherapy being recommended to effectively mitigate local recurrence and metastasis rates subsequent to incomplete or complete resection. Chemoradiotherapy has the potential to induce coronary artery occlusion, thereby potentially impacting patients' long-term survival rates. The existing literature currently lacks comprehensive research on the lesion characteristics of coronary artery injury resulting from chemoradiotherapy. CASE PRESENTATION: The male patient, aged 55, was admitted to the hospital due to recurrent chest tightness and pain persisting for one week. Notably, the patient had previously undergone curative resection surgery for thymic carcinoma seven years ago. After the surgical procedure, the patient underwent a course of adjuvant chemotherapy comprising docetaxel and platinum. 11 months later, imaging examination diagnosed tumor recurrence, and concurrent chemoradiotherapy was administered at a total dose of 62 Gy/31F for planning gross target volume (PGTV) and 54 Gy/31F for planning target volume (PTV) with 2 cycles of paclitaxel and cisplatin. Re-admission of the patient occurred after a 7-year interval subsequent to the completion of concurrent chemoradiotherapy, leading to a subsequent diagnosis of acute non-ST segment elevation myocardial infarction. Following administration of antiplatelet, anticoagulant, and anti-myocardial ischemia therapy, coronary angiography revealed the presence of a bifurcation lesion at the distal end of the left main trunk. Intravascular ultrasound (IVUS) examination demonstrated significant negative remodeling of both the main trunk and its branches at the bifurcation site, characterized by minimal atherosclerotic plaque components. CONCLUSIONS: Chemoradiotherapy may induce damage to endothelial cells, resulting in an inflammatory response. Negative remodeling of blood vessels is likely to occur, primarily characterized by vasoconstriction but with less atherosclerotic plaque burden. Routine stent implantation in negatively remodeled areas may lead to vascular rupture, necessitating intravascular imaging examination.

Penile-scrotal erythrodysesthesia among rectal cancer patients receiving fluoropyrimidine-based chemoradiation: a case report series.

BACKGROUND: Palmar-plantar erythrodysesthesia (PPE) is a slowly developing cutaneous reaction commonly experienced by patients treated with fluoropyrimidines. While erythrodysesthesia normally presents in a palmar-plantar distribution, it can also present with genital involvement, but this presentation is likely underreported and incorrectly attributed to an acute reaction from radiation therapy. This article aims to define erythrodysesthesia of the penis and scrotum as a rare but significant side effect of capecitabine. CASE PRESENTATION: We identified five cases of moderate to severe penis and scrotal erythrodysesthesia over a 2-year period at a large tertiary cancer center, representing an estimated incidence of 3.6% among male patients with rectal cancer who were treated with fluoropyrimidine-based chemoradiation within our institution. CONCLUSIONS: Improved understanding of erythrodysesthesia involving the penis and scrotum can facilitate early identification and treatment of symptoms, and possibly prevent the discontinuation or delay of cancer treatment in patients treated with capecitabine and similar drugs. These clinical advances would improve and prolong patient quality of life during cancer treatment and prevent complications that result in hospitalization.

Efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in the treatment of locally advanced cervical cancer.

BACKGROUND: Evaluate the efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in treating locally advanced cervical cancer (LACC). METHODS: Retrospective data was collected from LACC patients who were treated at our institution. These patients were categorized into three groups: the single-agent cisplatin (DDP) chemoradiotherapy group, the paclitaxel plus cisplatin (TP) chemoradiotherapy group, and the nanoparticle albumin-bound (nab-) paclitaxel combined with cisplatin (nPP) chemoradiotherapy group. The primary endpoints were overall survival (OS) and progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR) and incidence of adverse events (AEs). RESULTS: A total of 124 patients were enrolled (32 in the DDP group, 41 in the TP group, and 51 in the nPP group). There were differences in OS (P = 0.041, HR 0.527, 95% CI 0.314-0.884) and PFS (P = 0.003, HR 0.517, 95% CI 0.343-0.779) between the three groups. Notably, the 2-year OS rate was significantly higher in the nPP group compared to the DDP group (92.2% vs. 85.4%, P = 0.012). The 2-year PFS rates showed a marked increase in the TP group (78.0% vs. 59.4%, P = 0.048) and the nPP group (88.2% vs. 59.4%, P = 0.001) relative to the DPP group, with multiple comparisons indicating that the 2-year PFS rate was significantly superior in the nPP group versus the DDP group (88.2% vs. 59.4%, P = 0.001). Moreover, the ORR was also significantly higher in the nPP group than in the DDP group (P = 0.013); and no statistically significant differences were found in the incidence of AEs among the groups (P > 0.05). CONCLUSIONS: In LACC treatment, the two cisplatin-based doublet chemotherapy regimens are associated with better outcomes, with the nab-paclitaxel plus cisplatin regimen showing better efficacy than the paclitaxel plus cisplatin regimen. Furthermore, the AEs associated with these regimens were deemed tolerable. These findings could provide a reference for the clinical treatment of LACC. However, further prospective studies are needed to verify it.

Systemic Anti-Inflammatory Agents in the Prevention of Chemoradiation-Induced Mucositis: A Review of Randomised Controlled Trials.

Mucositis is a pathological condition characterised by inflammation and ulceration of the mucous membranes lining the alimentary canal, particularly in the mouth (oral mucositis) and the gastrointestinal tract. It is a common side effect of cancer treatments, including chemotherapy and radiotherapy, and it is sometimes responsible for treatment interruptions. Preventing mucositis throughout the alimentary tract is therefore crucial. However, current interventions mainly target either oral or gastrointestinal side effects. This review aimed to investigate the use of systemically administered anti-inflammatory agents to prevent mucositis in cancer patients undergoing cancer treatment. PubMed, Ovid, Scopus, Web of Science, WHO ICTRP and ClinicalTrials.gov were screened to identify eligible randomised controlled trials (RCTs). The published literature on anti-inflammatory agents provides mixed evidence regarding the degree of efficacy in preventing/reducing the severity of mucositis in most anticancer treatments; however, sample size continued to be a significant limitation, alongside others discussed. Our review yielded a list of several anti-inflammatory agents that exhibit potential mucositis-preventive effects in cancer patients undergoing cancer treatment, which can be used to inform clinical practice.

Effects of neoadjuvant chemotherapy vs chemoradiotherapy in the treatment of esophageal adenocarcinoma: A systematic review and meta-analysis.

BACKGROUND: Neoadjuvant therapy is an essential modality for reducing the clinical stage of esophageal cancer; however, the superiority of neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) is unclear. Therefore, a discussion of these two modalities is necessary. AIM: To investigate the benefits and complications of neoadjuvant modalities. METHODS: To address this concern, predefined criteria were established using the PICO protocol. Two independent authors performed comprehensive searches using predetermined keywords. Statistical analyses were performed to identify significant differences between groups. Potential publication bias was visualized using funnel plots. The quality of the data was evaluated using the Risk of Bias Tool 2 (RoB2) and the GRADE approach. RESULTS: Ten articles, including 1928 patients, were included for the analysis. Significant difference was detected in pathological complete response (pCR) [P < 0.001; odds ratio (OR): 0.27; 95%CI: 0.16-0.46], 30-d mortality (P = 0.015; OR: 0.4; 95%CI: 0.22-0.71) favoring the nCRT, and renal failure (P = 0.039; OR: 1.04; 95%CI: 0.66-1.64) favoring the nCT. No significant differences were observed in terms of survival, local or distal recurrence, or other clinical or surgical complications. The result of RoB2 was moderate, and that of the GRADE approach was low or very low in almost all cases. CONCLUSION: Although nCRT may have a higher pCR rate, it does not translate to greater long-term survival. Moreover, nCRT is associated with higher 30-d mortality, although the specific cause for postoperative complications could not be identified. In the case of nCT, toxic side effects are suspected, which can reduce the quality of life. Given the quality of available studies, further randomized trials are required.

Rational and design of prophylactic cranial irradiation (PCI) and brain MRI surveillance versus brain MRI surveillance alone in patients with limited-stage small cell lung cancer achieving complete remission (CR) of tumor after chemoradiotherapy: a multicenter prospective randomized study.

BACKGROUND: Prophylactic cranial irradiation (PCI) is part of standard care in limited-stage small cell lung cancer (SCLC) at present. As evidence from retrospective studies increases, the benefits of PCI for limited-stage SCLC are being challenged. METHODS: A multicenter, prospective, randomized controlled study was designed. The key inclusion criteria were: histologically or cytologically confirmed small cell carcinoma, age ≥ 18 years, KPS ≥ 80, limited-stage is defined as tumor confined to one side of the chest including ipsilateral hilar, bilateral mediastinum and supraclavicular lymph nodes, patients have received definitive thoracic radiotherapy (regardless of the dose-fractionation of radiotherapy used) and chemotherapy, evaluated as complete remission (CR) of tumor 4-6 weeks after the completion of chemo-radiotherapy. Eligible patients will be randomly assigned to two arms: (1) PCI and brain MRI surveillance arm, receiving PCI (2.5 Gy qd to a total dose of 25 Gy in two weeks) followed by brain MRI surveillance once every three months for two years; (2) brain MRI surveillance alone arm, undergoing brain MRI surveillance once every three months for two years. The primary objective is to compare the 2-year brain metastasis-free survival (BMFS) rates between the two arms. Secondary objectives include 2-year overall survival (OS) rates, intra-cranial failure patterns, 2-year progression-free survival rates and neurotoxicity. In case of brain metastasis (BM) detect during follow-up, stereotactic radiosurgery (SRS) will be recommended if patients meet the eligibility criteria. DISCUSSION: Based on our post-hoc analysis of a prospective study, we hypothesize that in limited-stage SCLC patients with CR after definitive chemoradiotherapy, and ruling out of BM by MRI, it would be feasible to use brain MRI surveillance and omit PCI in these patients. If BM is detected during follow-up, treatment with SRS or whole brain radiotherapy does not appear to have a detrimental effect on OS. Additionally, this approach may reduce potential neurotoxicity associated with PCI.

Comparisons of successful and failed Phase III trials of drugs and biologicals tested for mitigation of oral mucositis in patients being treated with radiotherapy with or without concomitant chemotherapy for cancers of the head and neck.

Oral mucositis (OM) remains a significant toxicity among patients being treated with radiotherapy (RT) alone or with concomitant chemotherapy (CRT) for cancers of the head and neck (HNC). Given its clinical significance as an unmet need and its potential commercial viability, the pharmaceutical industry has been actively pursuing an effective intervention. Despite this interest and activity, only a few agents have been studied in Phase III trials (n = 6). The objective of this study was to identify common features that differentiate successful and failed Phase III OM trials. We used the United States Patent and Trademark Office Patent Public Search database to search patents with "oral mucositis" in the claims. We then searched ClinicalTrials.gov and PubMed to determine if Phase III or Phase II trial data for identified biologics/drugs had been published. We assessed each Phase III and Phase II trial for characteristics that may be associated with trial success or failure. We considered a study as a "success" if the primary endpoint reached statistical significance, and we considered a study as "failure" if the primary endpoint did not reach statistical significance. Of the three successful Phase III trials, one investigated avasopasem manganese (Galera Therapeutics) and two examined palifermin (Amgen). The three failed trials included those evaluating dusquetide (Soligenix), iseganan hydrochloride (IntraBiotics Pharmaceuticals), and clonidine (Monopar Therapeutics). We found that differences in the level of sponsor funding, patient inclusion criteria including radiation source and concomitant chemotherapy regimen, and concordance of primary efficacy outcomes between Phase II and Phase III trials influenced outcomes. To properly design clinical trials for OM in HNC patients, it is important that researchers and sponsors take note of specific study characteristics associated with success or failure, particularly with Phase III trials where the risks and costs are the highest.

Evaluation of anorectal function using real-time tissue elastography before and after preoperative chemoradiotherapy.

PURPOSE: This study aimed to clarify the relationship between changes in elasticity and anorectal function before and after chemoradiotherapy. METHODS: This is a single-center prospective cohort study (Department of Surgical Oncology, The University of Tokyo). We established a technique to quantify internal anal sphincter hardness as elasticity using transanal ultrasonography with real-time tissue elastography. Twenty-seven patients with post-chemoradiotherapy rectal cancer during 2019-2022 were included. Real-time tissue elastography with transanal ultrasonography was performed before and after chemoradiotherapy to measure internal anal sphincter hardness as "elasticity" (hardest (0) to softest (255); decreased elasticity indicated sclerotic changes). The relationship between the increase or decrease in elasticity pre- and post-chemoradiotherapy and the maximum resting pressure, maximum squeeze pressure, and Wexner score were the outcome measures. RESULTS: A decrease in elasticity was observed in 16/27 (59.3%) patients after chemoradiotherapy. Patients with and without elasticity decrease after chemoradiotherapy comprised the internal anal sphincter sclerosis and non-sclerosis groups, respectively. The maximum resting pressure post-chemoradiotherapy was significantly high in the internal anal sphincter sclerosis group (63.0 mmHg vs. 47.0 mmHg), and a majority had a worsening Wexner score (60.0% vs. 18.2%) compared with that of the non-sclerosis group. Decreasing elasticity (internal anal sphincter sclerosis) correlated with a higher maximum resting pressure (r = 0.36); no correlation was observed between the degree of elasticity change and maximum squeeze pressure. CONCLUSION: Internal anal sphincter sclerosis due to chemoradiotherapy may correlate to anorectal dysfunction.

The safety and efficacy of Compound Kushen Injection with chemoradiotherapy for the outcomes of lung and gastrointestinal cancers: A PRIMSA-compliant meta-analysis.

BACKGROUND: Compound Kushen injection (CKI) is a mixture of natural compounds extracted from Radix Sophorae and Smilax glabra Roxb. CKI, as an antitumor preparation, plays a vital role in the clinical treatment of lung and gastrointestinal cancers. METHODS: Electronic databases such as the China National Knowledge Infrastructure, Wanfang data, PubMed, EMBASE, and Web of Science were searched for studies. The included studies were evaluated according to the Cochrane Handbook for Systematic Reviews, and meta-analyses were performed using RevMan 5.3 software. RESULTS: Twenty-four randomized controlled trials were selected for meta-analysis. The outcomes showed that CKI adjuvant therapy significantly improved complete remission (CR) and partial response (PR) compared to patients without CKI treatment in gastrointestinal cancers (CR: odds ratio [OR] = 1.76, 95% confidence interval [CI]: [1.29, 2.41], P = .0004; PR: OR = 1.64, 95% CI: [1.29, 2.07], P =.0001), and lung cancer (CR: OR = 2.18, 95% CI: [1.36, 3.51], P = .001); PR: OR = 1.81, 95% CI: [1.31, 2.50], P = .0003). CKI adjuvant therapy had a statistically significant advantage in optimizing life and health status (quality of life [QOL] for gastrointestinal cancers: MD = 1.76, 95% CI: [6.41, 13.80], P = .001, and Karnofsky performance status [KPS] for gastrointestinal cancers: MD = 4.64, 95% CI: [2.72, 6.57], P = .001; KPS for lung cancer: MD = 6.24, 95% CI [1.78, 10.71], P = .006). CKI reduced the pain in lung cancer patients (MD = -1.76, 95% CI: [-1.94, -1.58], P < .00001), increased immunity level (MD = 2.51, 95% CI: [2.17, 2.85], P < .00001), and alleviated the adverse reactions for lung and gastrointestinal cancers (MD = 0.38, 95% CI: (0.32, 0.46); P < .00001). CONCLUSION: The combination of CKI and chemoradiotherapy for treating lung and gastrointestinal cancer has positive effects on short-term and long-term outcomes and has advantages over chemoradiotherapy alone regarding safety and efficacy.

Effects of bone marrow sparing radiotherapy on acute hematologic toxicity for patients with locoregionally advanced cervical cancer: a prospective phase II randomized controlled study.

OBJECTIVE: To evaluate effects of bone marrow sparing (BMS) radiotherapy on decreasing the incidence of acute hematologic toxicity (HT) for locoregionally advanced cervical cancer (LACC) patients treated by pelvic irradiation. MATERIALS AND METHODS: LACC patients were recruited prospectively from May 2021 to May 2022 at a single center and were evenly randomized into the BMS group and the control group. All patients received pelvic irradiation with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy and BM V40 < 25% in the BMS group was additionally prescribed. Acute HT was assessed weekly. Binary logistic regression model and receiver operating characteristic (ROC) curve were used for predictive value analysis. The trial was registered with Chinese clinical trial registry (ChiCTR2200066485). RESULTS: A total of 242 patients were included in the analysis. Baseline demographic, disease and treatment characteristics were balanced between the two groups. In the intention-to-treat population, BMS was associated with a lower incidence of grade ≥ 2 and grade ≥ 3 acute HT, leukopenia and neutropenia s(72.70% v 90.90%, P < 0.001*; 16.50% vs. 65.30%, P < 0.001*; 66.10% vs. 85.10%, P = 0.001*; 13.20% vs. 54.50%, P < 0.001*; 37.20% vs. 66.10%, P < 0.001*; 10.70% vs. 43.80%, P < 0.001*). BMS also resulted in decreased dose delivered to the organs at risk (OARs) including rectum, bladder and left and right femoral head. Univariate and multivariate analyses showed that BM V40 was an independent risk factor for grade ≥ 3 acute HT (odds ratio [OR] = 2.734, 95% confidence interval [CI] = 1.959-3.815, P < 0.001*). Cutoff value was 25.036% and area under the curve (AUC) was 0.786. The nomogram was constructed, which was rigorously evaluated and internally cross-validated, showing good predictive performance. CONCLUSIONS: Receiving BMS pelvic irradiation could reduce the incidence of acute HT in LACC patients, and BM V40 < 25% may be a significant factor in reducing the risks of acute HT.

Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial.

BACKGROUND: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. METHODS: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting. FINDINGS: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1-52·3). Median event-free survival was not reached (95% CI 44·7 months-not reached) in the pembrolizumab group and 46·6 months (27·5-not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68-1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). INTERPRETATION: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Immune checkpoint inhibitors combined with concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.

Purpose: This study aims to evaluate the efficacy of immune checkpoint inhibitors (ICIs) combined with concurrent chemoradiotherapy (CCRT) versus CCRT alone in patients with locally advanced esophageal squamous cell carcinoma. Materials and methods: This retrospective cohort study included patients diagnosed with locally advanced esophageal squamous cell carcinoma who received either CCRT alone or CCRT combined with ICIs from April 2019 to February 2023. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was overall survival (OS). Results: A total of 101 patients were enrolled, with 58 undergoing CCRT alone and 43 receiving CCRT+ICI. The CCRT+ICI group demonstrated a higher complete response rate compared to the CCRT alone group (11.6% vs. 1.7%, P = 0.037). However, no significant difference was observed in 1-year PFS (58.9% vs. 55.2%; hazard ratio [HR] = 1.26, 95% confidence interval [CI]: 0.70-2.26; P = 0.445) or 1-year OS (70.8% vs. 75.9%; HR = 1.21, 95% CI: 0.58-2.53; P = 0.613) between CCRT+ICI and CCRT alone groups. The CCRT alone group experienced a higher incidence of leukopenia of any grade (93.1% vs. 76.7%, P = 0.039) but a lower incidence of pneumonitis of any grade (36.2% vs. 65.1%, P = 0.008). Conclusion: CCRT+ICI may not lead to improved survival outcomes compared to CCRT alone in patients with locally advanced esophageal squamous cell carcinoma. These findings indicate the need for further investigation into this treatment approach.

Results of Definitive (Chemo)radiotherapy Using Computed Tomography-based Brachytherapy for Cervical Cancer.

BACKGROUND/AIM: Concurrent cisplatin-based chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer. Especially, CCRT with magnetic resonance imaging (MRI) or computed tomography-based image-guided brachytherapy (CT-based 3D-IGBT) for cervical cancer has resulted in good LC rates. However, progression-free survival (PFS) and overall survival (OS) rates for locally advanced cervical cancer are still low and could be improved. The aim of the study was to evaluate treatment efficacy and late toxicity of external beam radiotherapy (EBRT) and CT-based IGBT with or without concurrent chemotherapy in patients with squamous cell carcinoma of the uterine cervix and investigate patterns of failure. PATIENTS AND METHODS: We retrospectively analyzed clinical data of cervical squamous cell carcinoma patients treated with definitive radiotherapy with or without concurrent chemotherapy at Saitama Medical University International Medical Center. Local control (LC), PFS, patterns of failure, and late toxicity were the evaluated outcomes. RESULTS: Overall, 290 patients were enrolled in the study. Median follow-up was 51.5 months. During follow-up, 74 patients developed recurrence: 10 patients with intra-pelvic failure only, 45 with extra-pelvic failure only, and 19 with both. The 3-year LC was 100% for T1b-T2a, 96.8% for T2b, 89.5% for T3b, and 88.5% for T4 disease. The 3-year PFS was 100% for stage IB-IIA, 89.0% for stage IIB, 70.7% for stage IIIB, 72.6% for stage IIIC1r, and 40.1% for stage IVA. The incidence of grade 3-4 gastrointestinal and genitourinary toxicities was 3.0% and 1.7%, respectively. CONCLUSION: Combination of EBRT and CT-based IGBT with or without concurrent chemotherapy produced favorable LC with acceptable rates of late toxicities. However, extra-pelvic failures frequently occurred and PFS was less satisfactory in patients with stage III-IVA disease, which indicated the need for additional treatment in these patients.

Radiotherapy alone versus concurrent chemoradiotherapy in patients with stage II and T3N0 nasopharyngeal carcinoma with adverse features: A propensity score-matched cohort study.

BACKGROUND AND PURPOSE: Whether concurrent chemoradiotherapy would provide survival benefits in patients with stage II and T3N0 NPC with adverse factors remains unclear in IMRT era. We aimed to assess the value of concurrent chemotherapy compared to IMRT alone in stage II and T3N0 NPC with adverse features. MATERIALS AND METHODS: 287 patients with stage II and T3N0 NPC with adverse factors were retrospectively analyzed, including 98 patients who received IMRT alone (IMRT alone group) and 189 patients who received cisplatin-based concurrent chemotherapy (CCRT group). The possible prognostic factors were balanced using propensity score matching (PSM). Kaplan-Meier analysis was used to evaluate the survival rates, and log-rank tests were employed to compare differences between groups. RESULTS: The median follow-up duration was 90.8 months (interquartile range = 75.6-114.7 months). The IMRT alone and the CCRT group were well matched; however, for all survival-related endpoints, there were no significant differences between them (5-year failure-free survival: 84.3% vs. 82.7%, P value = 0.68; 5-year overall survival: 87.3% vs. 90.6%, P value = 0.11; 5-year distant metastasis-free survival: 92.8% vs. 92.5%, P value = 0.97; 5-year locoregional relapse-free survival: 93.4% vs. 89.9%, P value = 0.30). The incidence of acute toxicities in the IMRT alone group was significantly lower than that in the CCRT group. CONCLUSION: For patients with stage II and T3N0 NPC with adverse features treated using IMRT, no improvement in survival was gained by adding concurrent chemotherapy; however, the occurrence of acute toxicities increased significantly. For those combined with non-single adverse factors, the comprehensive treatment strategy needs further exploration.

Durvalumab in combination with chemoradiotherapy in patients with head and neck squamous cell carcinoma: Results from the Phase 1 CLOVER study.

BACKGROUND: The Phase 1 CLOVER study (NCT03509012) assessed durvalumab in combination with concurrent chemoradiotherapy (cCRT) in patients with advanced solid tumors; we report results from the head and neck squamous cell carcinoma (HNSCC) cohort. METHODS: Patients with histologically/cytologically confirmed locally advanced HNSCC, eligible for definitive cCRT and not considered for primary surgery, received durvalumab plus cisplatin and concurrent external beam radiation. Objectives were to assess safety/tolerability and preliminary efficacy. RESULTS: Eight patients were enrolled. The most frequent any-cause adverse events (AEs) were nausea and radiation skin injury (each n = 5); most frequent grade 3/4 AEs were lymphopenia and stomatitis (each n = 3). No patients had dose-limiting toxicities. Objective response rate was 71.4% (5/7 patients; four complete responses, one partial response); disease control rate was 85.7% at 18 weeks and 83.3% at 48 weeks. CONCLUSIONS: Durvalumab plus cCRT was tolerable and active in patients with unresected, locally advanced HNSCC.

Radiation toxicity grading after chemoradiotherapy of canine urinary tract carcinomas: Comparing VRTOG to VRTOG_v2.0.

Radiation toxicities may be underestimated after treatment of transitional cell carcinoma in dogs' lower urinary tract. Assessing acute and late toxicities and differentiating them from progressive disease (PD) impacts further therapeutic approach. We retrospectively assessed dogs treated with definitive-intent chemoradiotherapy (12 × 3.8 Gy, various first-line chemotherapeutics). Local tumour control, radiation toxicities and survival were evaluated. We classified radiation toxicities according to the previously published radiation toxicity scheme "VRTOG" as well as the updated version, "VRTOG_v2.0". Fourteen dogs with transitional cell carcinoma of bladder ± urethra (n = 8), +prostate (n = 3) or solely urethra (n = 3), were included. Median follow-up was 298 days (range 185-1798 days), median overall survival 305 days (95%CI = 209;402) and 28.6% deaths were tumour-progression-related. Acute radiation toxicity was mild and self-limiting with both classification systems: In VRTOG, 5 dogs showed grade 1, and 1 dog grade 2 toxicity. In VRTOG_v2.0, 2 dogs showed grade 1, 3 dogs grade 2, and 3 dogs grade 3 toxicity. Late toxicity was noted in 14.2% of dogs (2/14) with the VRTOG, both with grade 3 toxicity. With VRTOG_v2.0, a larger proportion of 42.9% of dogs (6/14) showed late toxicities: Four dogs grade 3 (persistent incontinence), 2 dogs grade 5 (urethral obstructions without PD resulting in euthanasia). At time of death, 5 dogs underwent further workup and only 3 were confirmed to have PD. With the updated VRTOG_v2.0 classification system, more dogs with probable late toxicity are registered, but it is ultimately difficult to distinguish these from disease progression as restaging remains to be the most robust determinant.