Concurrent Regimen Research Articles

The Influence of Pelvic Bone Dose-volume Parameters on Bone Marrow Suppression During Radiation Therapy in Patients With Stage I to III Rectal Cancer Based on Real-world Data

BackgroundThe aim of this study was to evaluate the impact of pelvic bone dose-volume parameters on bone marrow suppression during radiotherapy (RT) in rectal cancer patients with stage I-III disease receiving either neoadjuvant radiotherapy (neo-RT) or curative-intent radiotherapy (cur-RT). Materials and methodsThis was a retrospective study with data mined from an electronic medical record review at a single institution. Between January 2016 and September 2022, rectal cancer patients who consecutively received neo-RT or cur-RT in our department were included. The data collected included complete baseline peripheral blood counts and hematological toxicity (HT) data collected during RT. The radiation dose-volume parameters of three pelvic bone marrow (PBM) subsites [iliac bone marrow (IBM), lumbosacral bone marrow (LSBM), and lower pelvis bone marrow (LPBM)] were collected. The primary endpoint was grade ≥ 2 HT (HT2+), including leukopenia, neutropenia, anemia, thrombocytopenia and total HTs. Logistic regression was employed to analyze the associations of HT2+ with dosimetric parameters and clinicopathologic characteristics. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were generated to verify the prediction efficacy of the pelvic bone dose-volume parameters combined with clinicopathologic indices. ResultsA total of 130 patients with stage I-III rectal cancer with complete clinical data were included. During neo-RT and cur-RT, 57 (43.8%) of these patients experienced HT2+. Multivariate analysis revealed that gender, the IBM-Dmean, the IBM-V15 and the IBM-V40 were significantly associated with Grade 2+ leukopenia (P < 0.05), and the AUC of gender combined with the IBM-Dmean, the IBM-V15 and the IBM-V40 in predicting Grade 2+ leukopenia was 0.834. The optimal cutoff values were an IBM-Dmean = 2692.75 cGy, an IBM-V15 = 86.65%, and an IBM-V40 = 20.75%. Patients who received oxaliplatin-containing concurrent chemotherapy (ChT) regimens were more likely to experience Grade 2+ thrombocytopenia (P=0.054). The AUC of concurrent ChT regimens in predicting Grade 2+ thrombocytopenia was 0.678. Female gender was significantly associated with Grade 2+ anemia and total HT2+ status. ConclusionAmong rectal cancer patients with stage I-III disease who received neo-RT or cur-RT, female patients with higher IBM-Dmean, IBM-V15 and IBM-V40 were more likely to experience Grade 2+ leukopenia, and oxaliplatin-containing concurrent ChT regimens were identified as a potential factor for increasing the incidence of Grade 2+ thrombocytopenia.

Impact of concurrent training sequence on heart rate variability, glycemic control, body composition, lipid profile, and cardiorespiratory fitness in type 2 diabetes patients with cardiac autonomic neuropathy: A randomized controlled trial

BackgroundType 2 Diabetes Mellitus (T2DM) is a global health concern, with cardiac autonomic neuropathy (CAN) being a significant complication that exacerbates cardiovascular risks. Aerobic and resistance exercises are recognized for their benefits in managing T2DM, but the optimal integration of these modalities, especially for patients with T2DM, requires further exploration. ObjectiveTo investigate the effects of the sequence of aerobic and resistance training in a concurrent training regimen on heart rate variability (HRV), glycemic control, body composition, lipid profile, and cardiorespiratory fitness (CRF) in patients with T2DM. MethodsIn this randomized controlled trial, 45 T2DM patients with CAN were allocated to three groups: a control group, an aerobic then resistance training (ART) group, and a resistance then aerobic training (RAT) group. Measurements were taken at baseline and after a 13-week intervention, assessing HRV, glycemic control, body composition, lipid profile, and CRF. ResultsBoth ART and RAT groups showed significant improvements in HRV, glycemic control, body composition, lipid profile, and CRF compared to the control group. Notably, there were no significant differences between ART and RAT groups in these outcomes, suggesting that the sequence of aerobic and resistance exercises in concurrent training does not significantly affect the health benefits attained. ConclusionConcurrent aerobic and resistance training, irrespective of the sequence, effectively improves HRV, glycemic control, body composition, lipid profile, and CRF in T2DM patients with CAN. This study supports the inclusion of concurrent training in exercise prescriptions for managing T2DM and its complications.

Concurrent epirubicin and trastuzumab use increases complete pathological response rate without additional cardiotoxicity in patients with human epidermal growth factor receptor 2-positive early breast cancer: A meta-regression analysis.

Due to cardiotoxicity concerns, the concurrent use of epirubicin and trastuzumab has not been fully studied. This study aimed to examine the cardiotoxicity and pathological complete response (pCR) rate associated with the concurrent regimens in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC). We conducted a systematic search for relevant literature in the NCBI/PubMed, the Cochrane database, and international conference abstracts for phase II or III randomized controlled trials between January 1, 2000, and February 28, 2021, focusing on the concurrent regimens in patients with HER2-positive EBC. To compare the risk of cardiotoxicity and the odds of the pCR rate, we performed linear meta-regression analyses to investigate the effects of multiple covariates. We analyzed 7 neoadjuvant trials involving the concurrent use of epirubicin and trastuzumab with 1797 patients. The median cumulative dose of epirubicin used was 300 mg/m2, with a total of 96 reported adverse cardiac events. The concurrent regimens did not result in a significant increase in cardiotoxicity compared to nonconcurrent regimens (risk ratio [RR] = 1.18, 95% confidence interval [CI] = 0.68-2.05). Compared with nonconcurrent or non-anthracycline-containing regimens, concurrent regimens were associated with a significant increase in the pCR rate (odds ratio = 1.48, 95% CI = 1.04-2.12). The linear fixed-effects meta-regression analysis indicated that in trials including more patients with hormone receptor-positive EBC, the RR of cardiotoxicity significantly increased with concurrent regimens, and the pCR rate became less significant. The combination of trastuzumab and a low dose of epirubicin positively impacted the pCR rate without a significant increase in cardiotoxicity. We recommend exploring concurrent regimens for HR-negative, HER2-positive tumors to enhance pCR rates, with caution advised for HR-positive tumors due to potential cardiotoxicity.

Addressing sequential and concurrent treatment regimens in a small n sequential, multiple assignment, randomized trial (snSMART) in the MISTIC study

ABSTRACT Multisystem Inflammatory Syndrome in children (MIS-C) is a rare and novel pediatric complication linked to COVID-19 exposure, which was first identified in April 2020. A small n, Sequential, Multiple Assignment, Randomized Trial (snSMART) was applied to the Multisystem Inflammatory Syndrome Therapies in Children Comparative Effectiveness Study (MISTIC) to efficiently evaluate multiple competing treatments. In the MISTIC snSMART study, participants are randomized to one of three interventions (steroids, infliximab or anakinra), and potentially re-randomized to the remaining two treatments depending on their response to the first randomized treatment. However, given the novelty and urgency of the MIS-C disease, in addition to patient welfare concerns, treatments were not always administered sequentially, but allowed to be administered concurrently if deemed medically necessary. We propose a pragmatic modification to the original snSMART design to address the analysis of concurrent versus sequential treatments in the MISTIC study. A modified Bayesian joint stage model is developed that can distinguish a concurrent treatment effect from a sequential treatment effect. A simulation study is conducted to demonstrate the improved accuracy and efficiency of the primary aim to estimate the first stage treatments’ response rates and the secondary aim to estimate the combined first and second stage treatments’ responses in the proposed model compared to the standard snSMART Bayesian joint stage model. We observed that the modified model has improved efficiency in terms of bias and rMSE under large sample size settings.

High viral suppression and detection of dolutegravir-resistance associated mutations in treatment-experienced Tanzanian adults living with HIV-1 in Dar es Salaam

To curb HIV infection rate in Tanzania, antiretroviral therapy (ART) has been scaled up since 2006, and in 2019, the country shifted to regimen including dolutegravir as a default first line. We assessed the success of ART and the contribution of HIV drug resistance (HIVDR) to unsuppressed viral loads. Between February and May 2023 a cross-sectional survey with random sampling was conducted in the six clinics in an urban cohort in Dar es Salaam. Patients with unsuppresed viral loads (local criteria viral load (VL) ≥ 1000 copies/mL) were tested for HIVDR mutations using the WHO adapted protocol for plasma samples. Mutations were interpreted using the Stanford HIVDR database. In total 600 individuals participated in this survey, the majority were female (76.83%), mean age (pm standard deviation) was 44.0 (pm 11.6) years. The median duration on ART (interquartile range) was 6.5 (3.9–10.2) years. Approximately 99% were receiving tenofovir + lamivudine + dolutegravir as a fixed dose combination. VL testing was successful in 99.67% (598/600) of survey patients and only 33 had VL ≥ 1000 copies/mL, resulting in a viral suppression level of 94.48% (565/598, 95% CI 92.34–96.17%). For 23 samples, protease and reverse transcriptase (RT) genotyping were successful, with 13 sequences containing RT inhibitor surveillance drug resistance mutations (SDRMs) (56.5%). No SDRM against protease inhibitors were detected. Thirty samples were successfully genotyped for integrase with 3 sequences (10.08%) containing integrase strand transfer inhibitor (INSTI) SDRMs. In samples successfully genotyped in the three genetic regions, 68.18% (16/22) had a genotypic susceptibility score (GSS) ≥ 2.5 for the concurrent regimen, implying factors beyond drug resistance caused the unsuppressed viral load. For five patients, GSS indicated that HIVDR may have caused the unsuppressed viral load. All three patients with INSTI resistance mutations were highly resistant to dolutegravir and accumulated nucleoside and non-nucleoside RT inhibitor HIVDR mutations. Although in this cohort the last 95 UNAIDS target was almost achieved, HIVDR mutations, including INSTIs resistance mutations were detected in HIV-positive individuals taking ART for at least one year. We recommend the design and implementation of high-impact interventions to prevent the increase of HIVDR, failure of dolutegravir and address the non-resistance factors in the study area.

Biologic Treatment Modification Efficacy in Concurrent Inflammatory Bowel Disease and Ankylosing Spondylitis: A Retrospective Cohort Study at a Single Tertiary Center.

The link between ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) is well-established, with concurrent prevalence estimates ranging from 5-10%. However, there are still significant gaps in our understanding, and a comprehensive treatment guideline for these co-diagnosed patients has yet to be established. Our objective was to explore patterns of treatment alterations following the diagnosis of AS in patients previously diagnosed with IBD, and vice versa. Additionally, we sought to determine how these modifications influence clinical outcomes in both conditions. This retrospective data-based cohort study included patients with coexisting IBD and AS that were diagnosed between the years 2009-2022 and were followed by the gastroenterology and the rheumatology units of the Sheba Medical Center, Israel. The data were extracted from the electronic health record and included demographic information, medication history, treatment modification at the time of second diagnosis, and the characteristics and activity of both IBD and AS at the index time and at the 3-month mark. The study included a total of 68 patients, with a male predominance (40 patients, 59%). The median age was 43 years (IQR 31-55) and 78% had Crohn's disease (CD). The median duration between the diagnosis of the first disease to the second one was 4 years (IQR 1-9.5). A significant proportion of patients (85%) underwent treatment modification at their second diagnosis. Out of the total cohort, 28% initiated biological therapy, 17.6% switched their biologic regimen, and 16.2% discontinued NSAIDS. Patients who underwent biologic modifications at time of the second diagnosis (the initiation/switch/augmentation of a concurrent regimen) experienced significantly higher rates of clinical improvement in either IBD or AS at the 90-day follow-up compared to patients who did not (68% vs. 32%, p = 0.004), and biologic modification was found to be an independent predictor for clinical improvement (OR 3.69, CI 1.08-12.58, p = 0.037). Our findings suggest that biologic therapy modification at the time of the second diagnosis was associated with a higher rate of improvement in AS/IBD at the 90-day follow-up.

High bone tumor burden to identify advanced non-small cell lung cancer patients with survival benefit upon bone targeted agents and immune checkpoint inhibitors

BackgroundBone-targeted agents (BTA), such as denosumab (DN) and zoledronic acid (ZA), have historically reduced the risk of skeletal related events in cancer patients with bone metastases (BM), with no improvement in survival outcomes. In the immunotherapy era, BM have been associated with poor prognosis upon immune-checkpoint inhibitors (ICI). Currently, the impact of bone tumor burden on survival upon BTAs in advanced non-small cell lung cancer (aNSCLC) patients treated with ICI remains unknown. MethodsData from ICI-treated aNSCLC patients with BM (4/2013-5/2022) in one institution were retrospectively collected. BTA-ICI concurrent treatment was defined as BTA administration at any time before or within 90 days from ICI start. High bone tumor burden (HBTB) was defined as ≥ 3 sites of BM. Median OS (mOS) was estimated with Kaplan-Meier. Aikaike’s information criterion (AIC) was used to select the best model for data analysis adjusted for clinical variables. ResultsOf 134 patients included, 51 (38 %) received BTA. At a mFU of 39.6 months (m), BTA-ICIs concurrent treatment did not significantly impact on mOS [8.3 m (95% CI 3.9–12.8) versus (vs) 6.8 m (95% CI 4.0–9.6) p = 0.36]; these results were confirmed after adjustment for clinical variables selected by AIC. A multivariate model showed a significant interaction between BTA use and HBTB or radiation therapy to BM. In subgroup analyses, only HBTB confirmed to be associated with significantly longer mOS [8.3 m (95% CI 2.4–14.2) vs 3.5 m (95% CI 2.9–4.1), p = 0.003] and mPFS [3.0 m (95% CI 1.6–4.4) vs 1.8 m (95% CI 1.6–2.0) p = 0.001] upon BTA-ICI concurrent treatment, with the most pronounced OS benefit observed for DN-ICI concurrent regimen [15.2 m (95% CI 0.1–30.7) vs 3.5 m (95% CI 2.9–4.1) p = 0.002]. ConclusionsIn the immunotherapy era, HBTB can identify patients experiencing survival benefit with BTA, especially with DN-ICI combination. HBTB should be included as a stratification factor in the upcoming trials assessing BTA and ICI combinations in patients with aNSCLC and BM.

Effect of Concurrent Strength and Endurance Training on Distance Running Performances in Well-Trained Athletes

Athletes competing in distance competitions have used a combination of aerobic and anaerobic training approaches to train and enhance the performance-determining elements. Nevertheless, few studies have reported data related to the effect of concurrent training on well-trained distance (3,000 m – 10,000 m) runners. Because of limited evidence available for this population, this study aimed to investigate the effect of concurrent strength and endurance training on distance running performance. A randomized study was conducted. Thirty-nine distance runners (16.62±0.71 years) were randomly assigned into the endurance training group (ETG; n=13), strength training group (STG; n=13), and concurrent training group (CTG; n=13). The 12 weeks of training in which each group trained 3 times a week. The participants were tested on 1RM squat test, push-up test, VO2 max, and 5-km time trial. Findings showed that STG significantly higher than ETG enhancements on 1RMsquat (p&lt;0.001) and push-up (p&lt;0.001) and STG significantly higher than CTG enhancements on 1RM squat (p&lt;0.001), push up (p=0.045). ETG results were significantly better than those obtained by STG on VO2 max (p=0.002) and 5-km time trial (p=0.004). Finally, the improvements obtained by CTG were significantly higher than those attained by ETG on 1RM squat (p&lt;0.001), push-up (p&lt;0.001); VO2 max (p&lt;0.001) and 5-km time trial (p=0.002). In conclusion, performing 12-week concurrent training program improves performance variables that can be obtained with strength and endurance training in long-distance running. Athletes can acquire strength and endurance adaptations by engaging in concurrent training regimens.

Trial in Progress: Adaptive RADiation Therapy with Concurrent Sacituzumab Govitecan (SG) for Bladder Preservation in Patients with MIBC (RAD-SG).

A substantial proportion of patients with muscle invasive bladder cancer do not receive curative intent therapy, especially if unfit for or refuse radical cystectomy. Concurrent chemoradiation is an effective alternative to radical cystectomy, however systemic radio-sensitizing chemotherapy may have off target side effects. A Phase I study is accruing which will investigate the concurrent administration of a bladder cancer targeted antibody drug conjugate (Sacituzumab Govitecan) with radiotherapy. This trial in progress is a Phase I study of Adaptive RADiation therapy with concurrent Sacituzumab Govitecan (SG) for bladder preservation in patients with muscle invasive bladder cancer (MIBC). Eligible patients will have localized muscle invasive bladder cancer (MIBC) confined to the bladder. The initial cohort is expected to accrue 20 patients. The primary endpoint is to establish the safety, tolerability, and feasibility of bladder preservation therapy treatment with concurrent SG and adaptive image-guided radiation therapy for patients with localized MIBC. The secondary endpoints are to determine the bladder intact event-free survival (BI-EFS) with concurrent SG and radiation therapy for MIBC and compare to historical controls with other concurrent chemoradiation regimens. BI-EFS is defined as the time from treatment to the first documented occurrence of residual/recurrent MIBC, nodal or distant metastases on imaging, radical cystectomy, or death from any cause. Sacituzumab Govitecan targets TROP-2, a surface protein expressed in urothelial cancers of the bladder. SG will be delivered IV, 10 mg/kg, 21-day cycles for 1 loading cycle prior to radiation and two subsequent cycles with concurrent adaptive radiotherapy over a period of 6 weeks (64 Gy). Correlative objectives (Supported by NCI/NIH U54) and will involve 1) elucidation of the genetic and microenvironmental mechanisms that drive efficacy and resistance to combined ADC plus radiation therapy and 2) characterization of tumor clonal dynamics, immune repertoire editing, and imaging changes following treatment with SG plus radiation. To be determined. To be determined.

Photon vs. Proton Radiotherapy in the Definitive Treatment of Nasopharyngeal Cancer: Single Institution Experience

Definitive therapy for nasopharyngeal cancer includes chemotherapy and radiation (RT). Common toxicities such as xerostomia, mucositis, and hearing loss are correlated with the RT dose delivered to associated organs at risk. We hypothesized that compared to our historical experience with IMRT, the implementation of proton therapy (PT) would reduce radiation dose to organs at risks without compromising oncologic outcomes. A retrospective review of all non-metastatic stage II-IV nasopharyngeal carcinoma (SCC, lymphoepithelioma, undifferentiated carcinomas) treated with definitive therapy at our institution from 2012-2022. Disease parameters and the mean dose to organs at risk were evaluated. Statistical comparison was made with the chi square test for categorical and Wilcoxon rank sum test for continuous variables. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS), using a log-rank test to compare IMRT and PT. PFS was defined as the time from the start of treatment to the first of either disease progression, relapse or death from any cause. PT was delivered with pencil-beam scanning in all patients. IMRT included multi-field treatment and volumetric-modulated arc therapy. A total of 80 patients were included in analyses: 48 treated with IMRT and 32 with PT. Comparing IMRT to PT cohorts, there was no difference in the median age of patients (51 vs 55 years, p = 0.73), nor the distribution by T stage (p = 0.57) or N stage (p = 0.34) or in the percentage of patients with ECOG 2/3 performance status at presentation (p = 0.11). All but one patient received concurrent systemic therapy and there was no difference in the use of concurrent cisplatin between cohorts (83% vs 78%, p = 0.57). The most common non-cisplatin concurrent regimen was weekly carboplatin and paclitaxel. Induction chemotherapy was more commonly used in patients treated with PT (10.4% vs 25%, p = 0.04) while there was no difference in the use of adjuvant chemotherapy (10.4% vs 9.4%, p = 0.88). Among 42 cases initiating treatment since the opening of our proton center, 32 (76%) have received PT. Comparing IMRT and PT dosimetry, patients treated with PT received significantly lower mean dose to the better spared parotid gland (32.8 vs 25.7 Gy, p = 0.001), lesser spared parotid gland (35.5 vs 31.1 Gy, p = 0.047), better spared cochlea (31.5 vs 25.5 Gy, p = 0.004), lesser spared cochlea (41.8 vs 33.2 Gy, p = 0.004), larynx (44.5 vs 21.7 Gy, p<0.001), and oral cavity (42.6 vs 17.0 Gy, p<0.001). After a median follow-up time of 30 months (45 mos IMRT, 23 mos PT) the estimated 2-year PFS was 63.9% with IMRT and 90.3% with PT (p = 0.047). The estimate of 2-year overall survival was 86.8% with IMRT and 96.8% with PT (p = 0.17). Comparing patients by radiation treatment modality, PT was associated with a statistically significant reduction in mean radiation dose to the parotid glands, cochlea, larynx, and oral cavity with excellent initial oncologic outcomes.

Comparison of sequential versus concurrent chemoradiation regimens in non-metastatic muscle-invasive bladder cancer.

The treatment approach for non-metastatic bladder cancer is guided by an invasion of the muscular layer of the bladder wall. Radical cystectomy is the recommended treatment for muscle-invasive disease. However, it has considerable morbidity and mortality and is not suited for many patients. Trimodality therapy consisting of chemoradiation after transurethral resection of bladder tumor offers a definitive approach with bladder-sparing potential. However, there is a lack of research defining the optimal combination of chemotherapy and radiation in this setting. We extracted patient data from the National Cancer Database to compare survival outcomes and demographic factors in 2,227 non-metastatic bladder cancer patients who were treated with chemotherapy sequential to or concurrently with radiation. Sequential treatment was defined as chemotherapy beginning >14 days before radiation, and concurrent was defined as beginning within 14 days of the first radiation. The sequential treatment group patients were younger (mean age, 74 vs. 78 years; p < 0.001) with more advanced disease. We found no difference in overall survival between patients who received chemotherapy sequential to radiation and those who received concurrent chemoradiation only (p = 0.533). Our data are concordant with a previous prospective study, and support that chemotherapy prior to radiation does not decrease survival outcomes relative to patients receiving only concurrent chemoradiation. Given that the sequential group had an overall higher stage but no difference in survival, downstaging chemotherapy prior to radiation may be helpful in these patients. Further studies including a larger, multi-institutional clinical trial are indicated to support clinical decision-making.

Concurrent chemoradiotherapy followed by adjuvant cisplatin–gemcitabine versus cisplatin–fluorouracil chemotherapy for N2–3 nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial

Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma. We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up. From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths. Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio. National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.

A meta-analysis of cardiac toxicity of concurrent epirubicin and trastuzumab in early breast cancer.

e12583 Background: The concurrent use of doxorubicin and trastuzumab has been limited due to the increased risk of cardiac toxicity. Epirubicin is a less cardiotoxic alternative to doxorubicin, and the change in ejection fraction occurs until its cumulative dose doubles that with doxorubicin. This study aims to evaluate the cardiotoxicity and pathological complete response (pCR) rate associated with concurrent usage of epirubicin and trastuzumab in patients with HER2 positive early breast cancers (EBC). Methods: A literature search was conducted on NCBI/PubMed, and Cochrane database for phase II or III randomized controlled trials of concurrent use of epirubicin and trastuzumab in HER2 positive EBC between January 1, 2000 and February 28, 2021.The definition of adverse cardiac events varied among these trials, including changes in left ventricular systolic function and clinical heart failure. To compare the risk of cardiotoxicity and the odds of pCR rate between concurrent and non-concurrent regimens, a meta-regression analysis utilizing fixed-effects and mixed-effects linear models was conducted to investigate the relationship between various covariates. Results: Seven trials containing concurrent use of epirubicin and trastuzumab involving 1797 patients were analyzed. All of them are neoadjuvant studies. The median cumulative dose of epirubicin used was 300mg/m2 and there were a total of 96 reported cardiac adverse events. The concurrent use of epirubicin and trastuzumab did not result in a statistically significant increase in cardiotoxicity compared to non-concurrent regimens (risk ratio = 1.18, 95% CI: 0.68-2.05). Meanwhile, there was a significant increase in pCR rate with the concurrent regimens (odds ratio = 1.48, 95% CI: 1.04-2.12). Mixed-effects meta-regression analysis showed that in trials with higher proportion of hormone receptor-positive EBC patients, the risk ratio of cardiotoxicity significantly increased with concurrent regimens and pathological complete response rate became less significant. Conclusions: The concurrent use of a limited dose of epirubicin and trastuzumab demonstrated a positive impact on pCR rate without a significant increase in cardiotoxicity. Further research is necessary to fully comprehend the long-term safety profile in individuals with metastatic breast cancer. [Table: see text]

A single-arm, multi-institutional, phase 2 study of a pembrolizumab-based organ preservation strategy for locally advanced larynx cancers: SMART-KEY (LACOG 0720) trial.

TPS6111 Background: Standard treatments for locally advanced larynx cancers include concurrent cisplatin/radiation therapy, or induction chemotherapy followed by radiation therapy alone, with the goal of organ preservation. Both strategies have been shown to achieve similar laryngectomy-free survival (LFS), but failed to improve overall survival (OS) compared with radiation therapy alone or surgery followed by radiation therapy. Although cisplatin given concurrently with radiation therapy is commonly used for organ preservation, there are concerns regarding long-term outcomes, such as late toxicities. Pembrolizumab with chemotherapy has been shown to improve OS in recurrent/metastatic head and neck squamous cell carcinomas (HNSCCs). Additionally, pembrolizumab combined with radiation therapy has been shown to be safe in locally advanced HNSCC. LACOG 0720 is designed to evaluate a pembrolizumab-based, cisplatin-free, and concurrent chemoradiation therapy-free regimen for larynx preservation, in an attempt to improve outcomes and avoid late toxicities. Methods: LACOG 0720 is a phase 2, single-arm, multicentric trial assessing patients with newly diagnosed squamous cell carcinoma of the larynx (glottic or supraglottic) and clinical stages III, IVA, or IVB (AJCC 8th Ed.). Patients with large volume T4 disease (invasion through the cartilage or extension &gt; 1 cm to the base of the tongue) or T1 disease are excluded. Patients receive 3 cycles of induction chemo-immunotherapy (carboplatin AUC6, paclitaxel 175 mg/m², and pembrolizumab 200 mg, IV every 21 days [q21D]), followed by concurrent radioimmunotherapy (Intensity-modulated radiation therapy with pembrolizumab 200 mg IV q21D for 3 cycles), followed by consolidation immunotherapy (pembrolizumab 200 mg IV q21D for 11 cycles). The primary endpoint is two-year LFS rate. Secondary endpoints include two-year larynx dysfunction-free survival, OS, overall response rate, short-term and long-term toxicities, causes of death, patterns of failure, and quality of life. Predictive biomarkers of response and survival will be evaluated as exploratory analysis. The sample size was calculated based on the primary endpoint. Using the Chi-square Test for One Proportion and considering a one-sided 10% significance level, 39 patients are needed to achieve 80% power to detect the difference between the null hypothesis; that the true laryngectomy-free survival at two years is 59%, and the alternative hypothesis that the laryngectomy-free survival at two years is 75%. From Feb 2022 to Feb 2023, 24 patients were enrolled in 10 Brazilian centers. Results are expected in July 2024. NCT04943445. Clinical trial information: NCT04943445 .

Final results of phase 2 trial of personal dendritic cell (DC) vaccines loaded with autologous tumor antigens (ATA) in newly diagnosed glioblastoma (GBM).

2047 Background: Standard GBM therapy is associated with early progression and poor overall survival (OS). DC-ATA AV-GBM-1, a personal vaccine consisting of autologous DC pulsed with ATA, was investigated in a multicenter trial in patients with newly diagnosed GBM. Methods: Key eligibility criteria for surgical collection of tumor were clinical suspicion of new primary GBM &amp; age 18-70 years. ATA lysate was prepared from irradiated tumor cells that were self-renewing in serum-free media. Autologous monocytes (MC) were collected by leukapheresis. Prior to initiating concurrent radiation therapy (RT) and temozolomide (TMZ), patients were enrolled with intent-to-treat (ITT) with DC-ATA after RT/TMZ. Eligibility included confirmation of primary GBM, availability of ATA &amp; MC, KPS &gt; 70 and plans for RT/TMZ. DC-ATA was manufactured during RT/TMZ. MC were differentiated into DC by culturing with IL-4 &amp; GM-CSF, then DC were incubated with ATA. DC-ATA was suspended in 500 mg GM-CSF just prior to s.c. injections at weeks 1, 2, 3, 8, 12,16, 20, &amp; 24 (8 doses). Patients were not excluded based on apparent disease progression or PFS. Standard adjuvant TMZ regimens were started after the 3 weekly injections. Primary endpoint was &gt; 75% OS 14.6 months from ITT enrollment. Secondary endpoints included median OS &amp; progression-free survival (PFS). Results: Cell line and MC collection were successful for 97% of patients. Median age of the 60 ITT enrollees was 59 years. 3 patients withdrew before starting DC-ATA; 57 received 392 injections; 68% received all 8. Most common AE attributed to DC-ATA were local injection site reactions (16%) &amp; flu-like symptoms (10%), but 33% experienced seizures. After 3 years of follow up, OS at 14.6 mos is 52.7% (95% CI 39.8,65.8), median OS 16.0 mos (95% CI 12.9,21.7) &amp; median PFS 10.4 mos (95% CI 8.6,11.6). OS rates at 1, 2, &amp; 3 years are 70.1%, 32.4%, &amp; 23.2%. Longer OS was associated with 8 DC-ATA doses (p &lt; 0.0001), on &lt; 2 mg/day dexamethasone (dex) at start of DC-ATA (p = 0.005), &gt; 6 cycles of adjuvant TMZ (p = 0.0054), &amp; KPS 90 or 100 (p = 0.010) at enrollment. Independent variables per multivariate Cox regression analysis were 8 DC-ATA doses, dex dose, IDH mutated, TMZ &gt; 6 cycles, &amp; MGMT promoter methylated. Concurrent TMZ regimens included TMZ alone (n = 28), TMZ + anti-VEGF(n = 14), &amp; TMZ + tumor treating fields (TTF) (n = 10); 8 received no concurrent TMZ. OS was longer in patients treated with concurrent TMZ alone compared to no TMZ (p = 0.0003), TMZ + anti-VEGF (p = 0.045) or TMZ + TTF (p = 0.045). The only common features among 7 patients progression-free at 3 years are 8 DC-ATA injections, age &lt; 60, &amp; &lt; 2 mg dex. Conclusions: DC-ATA was reliably produced and injections well-tolerated in combination with various TMZ-based regimens, but the primary OS objective was not achieved. PFS was encouraging, but did not translate into improved OS, perhaps because DC-ATA was limited to 8 injections. Clinical trial information: NCT03400917 .

Efficacy and safety of camrelizumab in combination with radiation and chemotherapy for recurrent or metastatic cervical cancer.

5542 Background: Cisplatin-based concurrent chemoradiation regimens have been suggested to be beneficial in recurrent or metastatic cervical cancer. Immunotherapy has also shown good therapeutic efficacy in recurrent or metastatic cervical cancer. Among them, Pembrolizumab in combination with chemotherapy has been used for first-line treatment of advanced PD-L1-positive cervical cancer. Meanwhile, Camrelizumab has shown good anti-tumor activity and manageable toxicity in patients with locally advanced cervical cancer. The primary objective of this study is to evaluate the efficacy and safety of Camrelizumab in combination with concurrent chemoradiation in patients with recurrent or metastatic cervical cancer. Methods: Patients diagnosed with recurrent or metastatic cervical cancer received Camrelizumab combined with concurrent chemoradiotherapy, radiotherapy:External beam radiotherapy (EBRT) 1.8-2.15 Gy/f, a total of 28 fractions; Brachytherapy: high-risk CTV using image guidance 28 Gy in 4 fractions (18 Gy in 3 fractions for posthysterectomy recurrent patients); chemotherapy regimen used TP regimen (paclitaxel: 175 mg/m2, cisplatin: 75 mg/m2, Q3W 6 cycles); Camrelizumab 200 mg Q3W 6 cycles. The primary endpoint of this trial was objective response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and incidence of adverse reactions. Results: From September 16, 2020 to September 30, 2022, a total of 29 patients were recruited. 27 of these patients completed 6 cycles of planned treatment. 27 patients had a median age of 53 years (33-73 years), ECOG PS 0 (n = 8), ECOG PS 1 (n = 14), ECOG PS 2 (n = 1). The ORR rate was 96.30% (26/27), including 17 patients with CR, 9 patients with PR, and 1 patient with SD Treatment-related AEs were mainly lymphocyte count decreased, anemia, and white blood cell count decreased, with overall safety manageable and no treatment-related deaths. Conclusions: Camrelizumab combined with concurrent chemoradiation in patients with recurrent or metastatic cervical cancer has good efficacy, low side effects and acceptable toxicity. Clinical trial information: NCT04884906 .

Concurrent chemoradiotherapy followed by adjuvant cisplatin-gemcitabine versus cisplatin-5-fluorouracil chemotherapy for N2-3 nasopharyngeal carcinoma: A multicentre, open-label, randomised, controlled, phase 3 trial.

6000 Background: Patients with N2-3 nasopharyngeal carcinoma have a high risk of failures, despite the current practice of concurrent adjuvant cisplatin-5-fluorouracil (PF) regime. Adjuvant PF regimen may not be adequate for tumor control of high risk patients, emphasizing the need for more effective regimen of adjuvant chemotherapy in N2-3 nasopharyngeal carcinoma. Methods: We conducted this multicentre, open-label, phase 3, randomised, controlled trial in four centers in China. Patients aged 18–65 years with stage T1–4N2–3 nasopharyngeal carcinoma were randomly assigned (1:1) to receive concurrent cisplatin (100mg/m2 intravenously) on days 1, 22, and 43 of radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously on day 1) (GP) once every 3 weeks or 5-fluorouracil (4 g/m2 in continuous intravenous infusion over 96 h) and cisplatin (80 mg/m2 on day 1 given intravenously) once every 4 weeks for three cycles. Randomisation was by a computer-generated random number code with a block size of six, stratified by treatment centre and nodal stage (N2 or N3). The primary endpoint was 3-year progression-free survival in the intention-to-treat population. This study is registered in ClinicalTrials.gov, NCT03321539. Results: From October 30, 2017 to July 9, 2020, 240 were randomly assigned to PF group (n = 120) or GP group (n = 120). After a median follow-up of 40 months (IQR: 32-48), the 3-year progression-free survival was 83.9% (95% CI 75.9–89.4) in GP group and 71.5% (62.5–78.7) in PF group (stratified HR 0.54; 95% CI, 0.32 to 0.93; p = 0.023). Significantly lower cumulative incidence of locoregional relapse (2.6% vs. 12.5%; HR 0.33; 95% CI, 0.12 to 0.90; Fine-Gray p = 0.030) and distant metastasis (10.4% vs. 20.1%; HR 0.50; 95% CI, 0.26 to 0.98; Fine-Gray p = 0.042) were also observed in GP group than PF group. However, there was no effect on early 3-year overall survival (90.7% vs. 94.0%; HR 1.12; 95% CI, 0.50 to 2.55; log-rank p = 0.779). Overall incidence of treatment-related adverse events was not significant different between the two treatment groups in the concurrent phase. In the adjuvant phase, significant higher incidence of grade 3-4 leucopenia (42 [41.2%] vs. 19 [16.8%], p &lt; 0.001), neutropenia (33 [32.0%] vs. 10 [8.9%], p = 0.001) and thrombocytopenia (9 [8.7%] vs. 2 [1.8%], p = 0.044) was observed in GP group than PF group, whereas the frequency of diarrhea (6 [5.3%] vs. 0 [0%], p = 0.030) and mucositis (21 [18.6%] vs. 7 [6.8%], p = 0.010) was higher in PF group than in GP group. Conclusions: Concurrent adjuvant GP regimen significantly improved progression-free survival in patients with N2-3 nasopharyngeal carcinoma with acceptable toxicity. Long term follow-up is needed to confirm the ultimate therapeutic ratio. Clinical trial information: NCT03321539 .

Pharmacoeconomic Appraisal of Treating Head and Neck Cancer with Various Chemotherapy and Chemoirradiation Regimens Using Branded and Jan-aushadhi Drugs in India.

According to recent studies, head and neck cancers (HNC) make up a substantial proportion of all cancers in India and are proportionately high in the lower socioeconomic people practising tobacco and alcohol. Chemotherapy is a crucial component of treating HNC, and this study was carried out to determine the Cost Minimization Analysis (CMA) by comparing the price of the high and least expensive branded drugs marketed in India. This study was performed to understand the cost difference (CD), Cost ratio (CR) and percentage of cost variation (PCV) of both individual drugs and the standard anticancer regimens. The Current Index of Medical Stores was used to determine the costs of the most and least expensive branded medications and analysed. The results indicated that Paclitaxel-Cisplatin-5 Fluoruracil chemotherapy regimen exhibited the greatest variance in cost, with the Jan Aushadhi brand of medicine costing 8.1 times and 4.3 times less than the most expensive and cheapest branded drugs, respectively. The cost of the concurrent cisplatin regimen with Jan Aushadi Medicine was Rs 1764, Rs 3489.64 with the lowest branded drug, and Rs 8477 with the most expensive branded drug. Also when compared to Jan Aushadhi medication, the cost of Ciplatin was 4.8 times higher with the most expensive branded drug and 2 times higher with the least expensive branded drug. As far as the authors are aware of this is the first study that addresses the pharmacoeconomic appraisal of treating HNC with various chemotherapy and chemoirradiation regimens. This study will help oncologists, pharmacists, and healthcare workers comprehend the financial advantages of treating breast cancer with less expensive chemotherapeutic agents instead of brand-name medications.

Local Liver Irradiation Concurrently Versus Sequentially with Cabozantinib on the Pharmacokinetics and Biodistribution in Rats.

The aim of this study was to evaluate the radiotherapy (RT)-pharmacokinetics (PK) effect of cabozantinib in concurrent or sequential regimens with external beam radiotherapy (EBRT) or stereotactic body radiation therapy (SBRT). Concurrent and sequential regimens involving RT and cabozantinib were designed. The RT-drug interactions of cabozantinib under RT were confirmed in a free-moving rat model. The drugs were separated on an Agilent ZORBAX SB-phenyl column with a mobile phase consisting of 10 mM potassium dihydrogen phosphate (KH2PO4)-methanol solution (27:73, v/v) for cabozantinib. There were no statistically significant differences in the concentration versus time curve of cabozantinib (AUCcabozantinib) between the control group and the RT2Gy×3 f'x and RT9Gy×3 f'x groups in the concurrent and the sequential regimens. However, compared to those in the control group, the Tmax, T1/2 and MRT decreased by 72.8% (p = 0.04), 49.0% (p = 0.04) and 48.5% (p = 0.04) with RT2Gy×3 f'x in the concurrent regimen, respectively. Additionally, the T1/2 and MRT decreased by 58.8% (p = 0.01) and 57.8% (p = 0.01) in the concurrent RT9Gy×3 f'x group when compared with the control group, respectively. The biodistribution of cabozantinib in the heart increased by 271.4% (p = 0.04) and 120.0% (p = 0.04) with RT2Gy×3 f'x in the concurrent and sequential regimens compared to the concurrent regimen, respectively. Additionally, the biodistribution of cabozantinib in the heart increased by 107.1% (p = 0.01) with the RT9Gy×3 f'x sequential regimen. Compared to the RT9Gy×3 f'x concurrent regimen, the RT9Gy×3 f'x sequential regimen increased the biodistribution of cabozantinib in the heart (81.3%, p = 0.02), liver (110.5%, p = 0.02), lung (125%, p = 0.004) and kidneys (87.5%, p = 0.048). No cabozantinib was detected in the brain in any of the groups. The AUC of cabozantinib is not modulated by irradiation and is not affected by treatment strategies. However, the biodistribution of cabozantinib in the heart is modulated by off-target irradiation and SBRT doses simultaneously. The impact of the biodistribution of cabozantinib with RT9Gy×3 f'x is more significant with the sequential regimen than with the concurrent regimen.

Efficacy and toxicity of three concurrent chemoradiotherapy regimens in treating nasopharyngeal carcinoma: Comparison among cisplatin, nedaplatin, and lobaplatin.

Few studies directly compare efficacy and toxicity among lobaplatin, nedaplatin and cisplatin concurrently with intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC). Totally 141 treatment-naïve NPC without distant metastasis receiving IMRT concurrent with cisplatin or nedaplatin or lobaplatin were retrospectively enrolled. Their response rate, toxicity and long-term survival were compared. Complete response (CR) rates of concurrent lobaplatin (CR-nasopharynx [CR-nx], 82.7%; CR-cervical lymph node [CR-nd], 94.2%) were lower than those of cisplatin (CR-nx, 89.3%; CR-nd, 98.2%) and nedaplatin (CR-nx, 93.9%; CR-nd, 97.0%), but statistical significance wasn't detected. Estimated five-year overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) weren't statistically significant between three groups. Multivariable analysis by COX proportional hazards model showed concurrent chemotherapy regimen wasn't an independent prognostic factor. Gastrointestinal toxicity was prevalent in platinum-based concurrent chemotherapy; cisplatin group suffered heavier (≥grade 2) than other two groups. More nephrotoxicity happened in cisplatin group (17.9%) than nedaplatin (9.1%) and lobaplatin (2.0%) groups. Incidence of dermatitis of ≥grade 2 was higher in cisplatin group (60.7%) than nedaplatin (27.3%) and lobaplatin (9.6%) groups. More patients in lobaplatin and nedaplatin groups suffered from any grade thrombocytopenia (P < .001), but incidence of severe thrombocytopenia (≥grade 3) was similar. Economic cost was significant less in lobaplatin group. Cisplatin, nedaplatin and lobaplatin are equally effective when used concurrently with IMRT in NPC. Lobaplatin and nedaplatin have potential to be alternatives to cisplatin in terms of less severe acute side-effects and economic cost.