Cisplatin-based Concurrent Chemoradiotherapy Research Articles

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

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. 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. 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. 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.

Abstract 4025: A phase II trial of neoadjuvant gemcitabine, cisplatin plus tislelizumab followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: Clinical efficacy, safety and the biomarker analysis

Abstract Immune checkpoint inhibitors (ICIs) have been widely used in recurrent or metastatic nasopharyngeal carcinoma (NPC), but the addition of ICIs to chemoradiotherapy in locoregionally advanced (LA) NPC requires further investigation. We conducted a phase II, single-arm trial to evaluate the efficacy and safety of neoadjuvant gemcitabine, cisplatin (GP) plus tislelizumab followed by concurrent chemoradiotherapy (CCRT) in LA-NPC. All participants received 3 cycles of GP chemotherapy plus tislelizumab (200 mg) followed by 3 cycles of cisplatin-based CCRT. The primary endpoint was the clinical complete response rate (CR) after neoadjuvant chemoimmunotherapy (NAT). The secondary endpoints include pathological CR rate, progression-free survival (PFS), overall survival (OS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), etc. Pretreatment blood samples and paired (pre-/post-NAT) tissue biopsies were collected to perform full-spectrum peripheral T-cell profiling, PD-L1 and tertiary lymphoid structures (TLS) staining. Among all 63 participants, the CR rate after NAT reached 41.3% (95% CI, 28.8%-53.8%), far exceeding our hypothesized CR rate of 22%. The objective response rate (ORR) and pCR rate after NAT were 88.9% (95% CI, 80.9% to 96.9%) and 74.6% (95% CI, 62.1% to 84.7%), respectively. As of July 15th, 2023, after the median follow-up of 25 months, the 2-year PFS and OS were 98.4% and 100%. The incidence of grade 3-4 immunotherapy-related adverse events was 1.6%. The compliance of CCRT was not compromised. Patients who achieved CR had significantly more circulating CD4+ and CD8+ effector memory T cells (Tem), regulatory T cells (Treg) and follicular helper T cells (Tfh). The peripheral abundance of LAG3+ Tem and Tfh were independently predictive of NAT response. The number and maturation of TLS significantly increased after NAT in the CR group, but not in the Non-CR group. GP chemotherapy plus tislelizumab followed by CCRT was highly therapeutic and safe in treating LA-NPC, further randomized phase III studies are awaited. Citation Format: Xiao-Yun Li, Si-Yi Xie, Qiu-Yan Chen, Hai-Qiang Mai, Lin-Quan Tang. A phase II trial of neoadjuvant gemcitabine, cisplatin plus tislelizumab followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: Clinical efficacy, safety and the biomarker analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4025.

Nab-paclitaxel and cisplatin-based concurrent chemoradiotherapy for locally advanced cervical cancer: A prospective, single-arm phase II clinical trial (182)

Nab-paclitaxel and cisplatin-based concurrent chemoradiotherapy for locally advanced cervical cancer: A prospective, single-arm phase II clinical trial (182)

Induction chemotherapy plus radiotherapy alone versus cisplatin-based concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: An open-label, non-inferiority, randomized phase 3 trial.

6001 Background: Cisplatin-based concurrent chemoradiotherapy (CCRT) has long been regarded as standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) due to its favorable local control. However, concurrent platinum is associated with intolerable toxicities and ineffective in preventing distant metastasis. Since IMRT enhances the local control and induction chemotherapy (IC) decreases the risk of distant failure, it is worth exploring whether IC plus IMRT alone regimen could replace CCRT for patients with LA-NPC. Methods: This open-label, phase 3, non-inferiority clinical trial was conducted from June 12, 2015 to April 30, 2019. Patients with stage T1-4N2-3 or T3-4N0-1 M0 NPC were randomly assigned (1:1) to receive gemcitabine (1000 mg/m²) and cisplatin (80 mg/m²) IC for 2 cycles followed by IMRT alone or IMRT plus concomitant weekly cisplatin (40 mg/m²) up to 7 cycles. 2-year failure-free survival was set as primary endpoint and non-inferiority margin of 10% was established. Efficacy analysis and safety analysis were dividedly performed in the intention-to-treat and safety population. Results: A total of 249 patients were enrolled, including 124 patients in IC group and 125 patients in CCRT group. Median follow-up time was 60 months (IQR, 48-71). 2-year failure-free survival was 90.2% in IC group versus 86.3% in CCRT group, with an HR of 0.818 (95% CI, 0.479-1.397) and absolute difference of 3.9% (1-sided 95%CI, -4.2 to 11.9). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. Compared with CCRT group, fewer grade ≥3 AEs occurred in IC group (47.5% vs 61.5%, p = 0.015), including leucopenia, anemia, mucositis, nausea and dysphagia. The IC group had significantly better QoL during and short periods after IMRT, including domains of global health status, physical functioning, fatigue, nausea and vomiting, pain, and appetite loss. Conclusions: For LA-NPC, gemcitabine and cisplatin induction chemotherapy plus IMRT alone was not inferior in 2-year failure-free survival to concurrent chemoradiotherapy. Clinical trial information: NCT02460887 .

An observational comparative study of weekly and 3 weekly concurrent cisplatin-based chemoradiotherapy in locally advanced head-and-neck cancer in a peripheral medical college

An observational comparative study of weekly and 3 weekly concurrent cisplatin-based chemoradiotherapy in locally advanced head-and-neck cancer in a peripheral medical college

Efficacy and safety of weekly versus triweekly cisplatin concurrent with radiotherapy in nasopharyngeal carcinoma: A meta-analysis.

Cisplatin-based concurrent chemoradiotherapy is a standard of care for locally advanced nasopharyngeal carcinoma (NPC), and weekly and triweekly cisplatin are both alternative regimens based on the results of squamous cell carcinoma of the head and neck. However, there is a lack of direct evidence on the efficacy and safety of weekly versus triweekly cisplatin concurrent with radiotherapy in NPC alone. This meta-analysis aimed to identify which regimen is more superior between weekly and triweekly cisplatin in patients with NPC treated with concurrent chemoradiotherapy. The PubMed, Embase, and Cochrane Library were searched for eligible literatures. Clinical outcome measures including 1-year overall survival (OS), 3-year OS, 5-year OS, 5-year loco-regional failure-free survival, 5-year distant metastasis-free survial and the most common 3 grade or higher acute toxicities (hematological toxicity, mucositis and nausea and vomiting) were analyzed by RevMan 5.4 software; significance level was 0.05. Seven clinical controlled studies with 1795 patients were included in the meta-analysis. There were no significant differences between weekly and triweekly cisplatin in 1-year OS, 3-year OS, 5-year OS, 5-year loco-regional failure-free survival, and 5-year distant metastasis-free survial) (all P > .05). Grade 3 or higher mucositis and nausea and vomiting showed similar between the 2 arms. However, grade 3 or higher hematological toxicity of weekly cisplatin was significantly higher than that of triweekly cisplatin (1.55; 95% CI, 1.22-1.98, P = .0004). Weekly cisplatin resulted in similar survival benifit as triweekly cisplatin, but with higher hematological toxicity.

Cisplatin-based concurrent chemoradiotherapy improved the survival of locoregionally advanced nasopharyngeal carcinoma after induction chemotherapy by reducing early treatment failure

PurposeThe aims of this study focusing on Locoregionally advanced nasopharyngeal carcinoma (LANPC) were mainly two-fold: on the one hand, to establish a cut-off value to differentiate early and late failure based on prognosis after recurrence or metastasis; and on the other hand, to investigate the duration of concurrent cisplatin benefit over follow-up time. The results of our study have the potential to guide clinical practice and follow-up.MethodsIn total, 3123 patients with stage III-IVa NPC receiving Induction chemotherapy followed by concurrent cisplatin or not were analysed. The cut-off value of treatment failure was calculated using the minimum P-value approach. Random survival forest (RSF) model was to simulate the cumulative probabilities of treatment failure (locoregional recurrence and /or distant metastasis) over-time, as well as the monthly time-specific, event-occurring probabilities, for patients at different treatment groups.ResultsBased on subsequent prognosis, early locoregional failure (ELRF) should be defined as recurrence within 14 months (P = 1.47 × 10 − 3), and early distant failure (EDF) should be defined as recurrence within 20 months (P = 1.95 × 10 − 4). A cumulative cisplatin dose (CCD) > 200 mg/m2 independently reduced the risk of EDF (hazard ratio, 0.351; 95% confidence interval (CI), 0.169–0.732; P = 0.005). Better failure-free survival (FFS) and overall survival (OS) were observed in concurrent chemotherapy settings ([0 mg/m2 vs. 1-200 mg/m2 vs. >200 mg/m2]: FFS: 70.4% vs. 74.4% vs. 82.6%, all P < 0.03; OS: 79.5% vs. 83.8% vs. 90.8%, all P < 0.01). In the monthly analysis, treatment failure mainly occurred during the first 4 years, and the risk of distant failure in patients treated with concurrent chemotherapy never exceeded that of patients without concurrent chemotherapy.ConclusionLocoregional failure that developed within 14 months and/or distant failure within 20 months had poorer subsequent survival. Concurrent chemotherapy provides a significant FFS benefit, primarily by reducing EDF, translating into a long-term OS benefit.

ERCC1 Overexpression Increases Radioresistance in Colorectal Cancer Cells.

Simple SummaryThe 20–30% of locally advanced rectal cancer patients undergoing preoperative concurrent chemoradiotherapy had no expected efficacy, and ERCC1 overexpression was found in these tumor tissue patients. In the interest of confirming and adding details to our understanding of that correlation, The Tet-on gene expression system was used to examine ERCC1 functionality and stability. Our data from regulatable HCT116-Tet-on and COLO205-Tet-on cell lines verified the increased radioresistance in colorectal cancer cells that are associated with ERCC1 overexpression, and they confirmed a high correlation between ERCC1 levels and radiotherapeutic efficiency. Furthermore, overexpression of ERCC1 also increases cell migration under radiation exposure. Additional data from ERCC1 expression regulation in vivo confirmed that the overexpression of increased cancer radiation resistance suggests that ERCC1 expression plays a key role.Preoperative concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced rectal cancer patients, but 20–30% do not benefit from the desired therapeutic effects. Previous reports indicate that high levels of ERCC1 reduce the effectiveness of cisplatin-based CCRT; however, it remains unclear as to whether ERCC1 overexpression increases radiation resistance. To clarify the correlation between ERCC1 levels and radiation (RT) resistance, we established two cell lines (HCT116-Tet-on and COLO205-Tet-on), induced them to overexpress ERCC1, detected cell survival following exposure to radiation, established HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models, and detected tumor volume following exposure to radiation. We found that ERCC1 overexpression increased radiation resistance. After regulating ERCC1 levels and radiation exposure to verify the correlation, we noted that increased radiation resistance was dependent on ERCC1 upregulation in both cell lines. For further verification, we exposed HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models to radiation and observed that ERCC1 overexpression increased colorectal cancer tumor radioresistance in both. Combined, our results suggest that ERCC1 overexpression may serve as a suitable CCRT prognostic marker for colorectal cancer patients.

Maintenance tegafur-plus-uracil after adjuvant concurrent chemoradiotherapy may improve outcome for resected oral cavity squamous cell carcinoma with extranodal extension.

ObjectivesTo evaluate whether tegafur-uracil maintenance (UFTm) following postoperation adjuvant cisplatin-based concurrent chemoradiotherapy (CCRT) may reduce distant metastasis in patients with resected oral cavity squamous cell carcinoma (OSCC) with pathologic extranodal extension (pENE+).MethodsA retrospective comparison was conducted between two cohorts of patients with resected pENE+ OSCC who completed adjuvant CCRT between March 2015 and December 2017, including one cohort of a phase II trial using UFTm and a trial-eligible but off-protocol cohort without using UFTm (non-UFTm) after their adjuvant CCRT. The UFTm trial enrolled patients without relapse within 2 months after the end of adjuvant CCRT and administered UFT 400 mg/day for 1 year. Kaplan–Meier methods estimated the actuarial rate of distant metastasis-free (DMF), locoregional control (LRC), event-free survival (EFS), and overall survival (OS).ResultsA total of 103 patients were included in this study, 64 patients in UFTm and 39 patients in non-UFTm. Severe adverse events in UFTm included grade 3 anemia (n = 1, 1.6%) and grade 3 mucositis (n = 1, 1.6%). A total of 40 (62.5%) patients completed the full course of UFTm, while the remaining terminated UFTm earlier due to disease relapse (n = 14, 21.8%), poor compliance (n = 9, 14.1%), and adverse event (n = 1, 1.6%). The median (range) follow-up time of surviving patients was 43 (22–65) months. The outcomes compared between UFTm and non-UFTm were OS (hazard ratio [HR] 0.31 [95% CI: 0.17–0.57], p < 0·001), EFS (0.45 [0.25–0.82], 0.009), LRC (0.45 [0.19–1.05], 0.067), and DMF (0.47 [0.24–0.95], 0.035). Multivariable analysis, adjusted for UFTm, Charlson comorbidity index score 1–3, site of tongue, and number of ENE+ LN ≧4, confirmed better OS (0.29 [0.16–0.54], <0.001) and EFS (0.47 [0.26–0.85], 0.012) in favor of UFTm over non-UFTm. The 2-year DM rate was 25.8% in UFTm and 44.2% in non-UFTm. For relapsed patients in UFTm vs. non-UFTm, the rate of metastasectomy for oligometastasis was 53% vs. 6%, and the OS was 21.0 (95% CI: 17.8–24.1) months vs. 11.0 (9.1–12.8) months (p < 0.001), respectively.ConclusionsUFTm may improve the dismal outcomes of the resected pENE+ OSCC. Further investigations are needed to confirm our observations.

Concurrent chemoradiotherapy with cisplatin given once-a-week versus every-three weekly in head and neck squamous cell carcinoma: Non-inferior, equivalent, or superior?

Cisplatin-based concurrent chemoradiotherapy is the contemporary standard-of-care in curative-intent management of loco-regionally advanced head and neck squamous cell carcinoma. The most optimal dose-schedule of concurrent cisplatin remains debatable with widespread variability in clinical practice. High-quality evidence in favour of cisplatin-based chemoradiotherapy is largely based on high-dose cisplatin given as 100 mg/m2 every three-weekly for up to three cycles. However, such dosing is typically associated with high rates of significant acute hematological and renal toxicity prompting the need for alternative lesser toxic dose-schedules. Compliance to three doses of three-weekly high-dose cisplatin is reportedly suboptimal with nearly 40% of patients unable to receive the third cycle thereby achieving cumulative cisplatin dose of 200 mg/m2 which is generally regarded sufficient for beneficial anti-tumor effect. The most common alternative schedule is low-dose (20–50 mg/m2) cisplatin once-weekly during radiotherapy. Such low-dose weekly regimens have undergone less rigorous prospective evaluation versus RT alone but continue to be widely used in co-operative group trials and routine clinical practice. In the last decade, several small prospective randomized controlled trials have reported significantly lesser toxicity and comparable disease-related outcomes with low-dose weekly cisplatin. However, two recent randomized controlled trials have re-ignited the debate globally due to their contradictory results, inferences, and conclusions. Through this commentary, we critically appraise and summarize the existing evidence-base to inform contemporary clinical practice and guide future research. There is increasingly emerging evidence that chemoradiotherapy with once-weekly cisplatin is non-inferior to three-weekly cisplatin for disease-related outcomes in curative-intent management of loco-regionally advanced head and neck cancer.

A phase III randomized, controlled trial of nedaplatin versus cisplatin concurrent chemoradiotherapy in patients with cervical cancer

BackgroundWe evaluated the non-inferiority of nedaplatin-based and cisplatin-based concurrent chemoradiotherapy in cervical cancer patients.DesignPatients aged 28-82 years with pathologically diagnosed cervical cancer (stage IB-IVA) were randomly chosen for the study. Patients in both the cisplatin and nedaplatin groups received radiotherapy and weekly intravenous nedaplatin 30 mg/m2 or cisplatin 40 mg/m2 concurrently.ResultsOne hundred and sixty patients who received treatment between 10 May 2018 and 31 August 2020 were included. The 3-year overall survival in the nedaplatin group (median 30.5 months) was not significantly different from that in the cisplatin group (28.5 months; hazard ratio 0.131, 95% confidence interval 0.016-1.068; P = 0.058). No significant differences in hematological toxicity were observed between the two groups. Vomiting (40 versus 61), nausea (44 versus 67), and anorexia (52 versus 71) were more common in the cisplatin group whereas effects on liver function, including total bilirubin (7 versus 3), alanine aminotransferase (7 versus 2), and aspartate aminotransferase (6 versus 2), were more common in the nedaplatin group. Four patients in the cisplatin group had grade I creatinine elevation, whereas none in the nedaplatin group had abnormal creatinine levels. Two patients in the nedaplatin group discontinued concurrent chemotherapy because of infusion, and one patient in the cisplatin group discontinued treatment because of infusion-induced dizziness.ConclusionsOur findings suggest that nedaplatin has a milder gastrointestinal reaction but a more significant effect on liver function than cisplatin. In patients with cervical cancer, nedaplatin-based concurrent chemoradiotherapy could serve as an alternative treatment to cisplatin.

Camrelizumab in combination with concurrent chemoradiotherapy as first-line treatment for nonoperative head and neck cancer: A comparative study.

6063 Background: We hypothesized that concurrent chemoradiotherapy (CCRT) plus concurrent and adjuvant camrelizumab as first-line treatmentwas associated with improved survival compared with concurrent chemoradiotherapy alone for nonoperative locoregionally advanced head and neck squamous cell carcinoma (HNSCC). The purpose of this comparative study was to compare the efficacy and toxicity of CCRT plus concurrent and adjuvant camrelizumab versus CCRT alone in nonoperative locoregionally advanced HNSCC. Methods: One hundred and eighty patients with nonoperative locoregionally advanced HNSCC (cancer of the oral cavity, oropharyngeal cancer, hypopharyngeal cancer and laryngeal cancer) received either CCRT plus concurrent and adjuvant camrelizumab (camrelizumab + CCRT group, n = 90) or CCRT alone (CCRT alone group, n = 90). Patients in both groups received curative cisplatin-based concurrent chemoradiotherapy. The radiation dose was 70 Gy (2.0 Gy/fraction). In camrelizumab + CCRT group, concurrent camrelizumab (200mg/day on days 1, 22, 43) was added to CCRT, followed by adjuvant camrelizumab (200mg, every 3 weeks for 6 months or until disease progression, unacceptable adverse events or withdrawal of consent). Results: Compared with CCRT alone, the addition of concurrent and adjuvant camrelizumab significantly improved complete response (CR) rates (92.2% vs. 80.0%; P = 0.018), 3-year disease free survival (DFS, 72.2% vs. 56.7%; P = 0.029), locoregional recurrence-free survival (LRRFS, 76.7% vs. 61.1%; P = 0.024), and overall survival (OS, 78.9% vs. 63.3%; P = 0.033). Reactive cutaneous capillary endothelial proliferation was higher in the camrelizumab + CCRT group (6.7% vs. 0.0%; P = 0.013). No statistically significant differences in other acute (mucositis, leukopenia, thrombocytopenia, anemia, etc.) and late toxic effects (mucosal necrosis, trismus, cranial nerve palsy, etc.) were observed between the two groups. The addition of camrelizumab (CCRT plus camrelizumab vs. CCRT alone) was a significant independent prognostic factor for 3-year DFS, LRRFS and OS (P = 0.038, P = 0.032, and P = 0.048, respectively). Conclusions: Concurrent chemoradiotherapy plus concurrent and adjuvant camrelizumab as first-line treatment is associated with a considerable survival benefit, with acceptable adverse events, as compared with concurrent chemoradiotherapy alone, among patients with nonoperative locoregionally advanced head and neck squamous cell carcinoma. Our ongoing prospective clinical trial (registered with chictr.org.cn, number ChiCTR2200056298) will further investigate the efficacy of camrelizumab in combination with chemoradiotherapy for HNSCC.

Characterization of the Immune Response to PD-1 Blockade during Chemoradiotherapy for Head and Neck Squamous Cell Carcinoma.

Simple SummaryBlockade of the PD-1/L1 interaction represents a breakthrough in the treatment for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Clinical and translational research suggests that this interaction may play a role in immune evasion during chemoradiotherapy. Using an immune-competent murine model of HNSCC, we demonstrate improved efficacy of PD-1 blockade with concurrent cisplatin-based chemoradiotherapy. Taking this approach into a clinical trial evaluating the anti-PD-1 agent, pembrolizumab, combined with chemoradiotherapy in HNSCC, we characterized the peripheral blood immune response to therapy. Our findings highlight that this combination is active in the murine model and circulating PD-1+ T-cell proportions were decreased during the clinical trial. However, additional findings from the clinical trial suggest a shift towards expression of other markers of immune exhaustion. As this treatment approach is being explored in large, randomized trials, these findings provide insight into potential pathways for treatment failure.Background: Chemoradiotherapy is a standard treatment for HNSCC. Blockade of the PD-1/L1-2 interaction may represent a target to overcome immune escape during this treatment. Methods: Utilizing a HNSCC mEERL C57BL/6 mouse model, we evaluated a PD-1 blockade alone or in combination with cisplatin-based chemoradiotherapy. Next, we evaluated peripheral blood mononuclear cells (PBMCs) with relative PD-1, TIM-3, and LAG-3 expression, and myeloid-derived suppressor-like (MDSC-like) populations from a clinical trial evaluating PD-1 blockade with chemoradiotherapy in HNSCC. Finally, we analyzed the effect of therapy on human T-cell clonality through T-cell Receptor (TCR) sequencing. Results: Anti-PD-1 monotherapy induced no response in the mEERL model; however, combination with chemoradiotherapy improved tumor clearance and survival. PBMCs from patients treated with this combination therapy demonstrate a decline in circulating T-cell populations with knockdown of PD-1 expressing CD3+CD4+ and CD3+CD8+ T cells during treatment. However, TIM-3, LAG-3 expressing T-cell and MDSC-like populations concordantly rose. During treatment, the TCR repertoire demonstrates overall clonal expansion, with both unique and previously reported T-cell clones. Conclusions: Our murine HNSCC model demonstrates efficacy of PD-1 blockade during chemoradiotherapy. However, while PD-1-expressing T cells decreased with this therapy, human PBMC findings also identified an increase in populations contributing to immune exhaustion. These findings further characterize PD-1 blockade during chemoradiotherapy for HNSCC and highlight potential competing mechanisms of immune evasion.

Olanzapine 5 mg for Nausea and Vomiting in Patients with Nasopharyngeal Carcinoma Receiving Cisplatin-Based Concurrent Chemoradiotherapy.

Purpose To explore the efficacy and safety of adding olanzapine (5 mg or 10 mg) to 5-hydroxytryptamine type 3 receptor antagonists (5-HT3 RA), neurokinin-1 receptor antagonists (NK1 RA), and dexamethasone for nausea and vomiting in patients with nasopharyngeal carcinoma (NPC) receiving cisplatin-based concurrent chemoradiotherapy. Methods Patients receiving olanzapine 5 mg or 10 mg combined with 5-HT3 RA, NK1 RA, and dexamethasone during the cisplatin-based concurrent chemoradiotherapy were included. The primary endpoint was the complete response (CR) (no vomiting) rate, and the secondary endpoint was the incidence of no nausea. Results A total of 150 chemotherapy cycles were administrated for 88 patients (75 in the olanzapine 5 mg group and 75 in the olanzapine 10 mg group). The proportions of CR in the olanzapine 5 mg group were comparable to those in the olanzapine 10 mg group in acute (93.3% vs. 94.7%, P = 0.731), delayed (76% vs. 78.7%, P = 0.697), and overall phase (73.3% vs. 77.3%, P = 0.570). Moreover, no nausea rates were also comparable between the two groups in acute (76% vs. 78.7%, P = 0.697), delayed (54.7% vs. 60%, P = 0.509), and overall period (50.7% vs. 57.3%, P = 0.111). Regarding the adverse effects, the incidence of somnolence in the 10 mg group (58.6%) was significantly higher than that in the 5 mg group (41.3%) (P = 0.034), while constipation (20.0% vs. 24.0%, P = 0.554) and hiccups (9.3% vs. 10.6%, P = 0.785) rates were comparable in two groups. Conclusions Patients receiving olanzapine plus standard antiemetic therapy has excellent antiemetic effect in NPC patients receiving cisplatin-based concurrent chemoradiotherapy, and patients with olanzapine 5 mg have a similar antiemetic effect and lower adverse effects compared with those with olanzapine 10 mg.

Role of adjuvant chemotherapy after concurrent chemoradiotherapy in patients with locally advanced cervical cancer.

Aims: With the useof concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC), survival outcomes are still not optimal. This studywas designedto evaluate the efficacy and safety of adjuvant chemotherapy (ACT) for patients with LACC after treatment with CCRT. Methods: Patients diagnosed with stage IIA-IIIB LACC, were retrospectively analyzed. All patients received cisplatin-based CCRT and were divided into two groups: ACT after CCRT (CCRT+ACT group) and observation after CCRT (CCRT group). Overall survival (OS), progression-free survival (PFS) and adverse effects wererecorded and analyzed. Results: In total, 375 patients were included; 262 patients accepted ACT after CCRT while the remaining 113 patients chose observation. With a median follow-up of 40months, no significant differences were found in the OS rates for patients in theCCRT+ACT and CCRT groups at 1year, 3years and the end of follow-up. There was alsono significant discrepancy in PFS between groups. Subgroup analysis showed theInternational Federation of Gynecology and Obstetrics (FIGO) stage and age had negligible influence on both OS and PFS. Acute adverse events (grades3-4) happened more frequently in CCRT+ACT group than in the CCRT group, with significant differences in neutropenia, anemia and creatinine. Conclusion: ACT after CCRT did not show benefit in survival but did induce some adverse effects. Therefore, this regimen is not recommended unless further large-scale randomized controlled trials are executed.

Concurrent Chemoradiotherapy With Nedaplatin Versus Cisplatin in Patients With Stage IIB-IVA Cervical Cancer: A Randomized Phase III Trial.

BackgroundIn this trial, we aimed to assess the efficacy and safety of radiotherapy with nedaplatin or cisplatin in patients with locally advanced cervical cancer.MethodsWe conducted an open-label, non-inferiority, phase III, randomized, controlled trial. Eligible patients with stage IIB-IVA cervical carcinoma were randomly assigned to receive either nedaplatin or cisplatin for two cycles concurrently with radiotherapy. We reported the therapy-associated harms and survival. The study was registered with chictr.org.cn, number ChiCTR1800020527.ResultsWe randomly assigned 68 patients to nedaplatin-based or cisplatin-based concurrent chemoradiotherapy. Study treatment was stopped early after a data analysis found a higher number of patients suffered severe hematologic harms in the nedaplatin group than in the cisplatin group. Patients in the nedaplatin group had a significantly higher frequency of grade 3-4 neutropenia (19·4% vs. 13%; P < 0·001), severe thrombocytopenia (16·1% vs. 4·3%), and grade 1-2 anemia (51·6% vs. 43·5%) than patients in the cisplatin group. The 1-year PFS and OS in the nedaplatin and cisplatin groups were similar.ConclusionOur findings showed that nedaplatin-based concurrent chemoradiotherapy expressed remarkably higher severe hematologic harms which were mortal. Though the results were negative, the experiences and lessons we learned from it were important.

Effect of Concurrent Chemoradiotherapy With Nedaplatin vs Cisplatin on the Long-term Outcomes of Survival and Toxic Effects Among Patients With Stage II to IVB Nasopharyngeal Carcinoma

Nedaplatin-based concurrent chemoradiotherapy (CCRT) regimen at 2 years was noninferior to cisplatin-based regimen in patients with locoregional, stage II to IVB nasopharyngeal carcinoma (NPC) and was associated with fewer late adverse events, but longer-term outcomes and toxicity are unclear. To evaluate the 5-year outcomes and late toxicity profile of nedaplatin-based CCRT in patients with locoregional, stage II to IVB NPC. This 5-year follow-up secondary analysis of an open-label, noninferiority, multicenter randomized clinical trial enrolled patients with nonkeratinizing stage II to IVB NPC between January 16, 2012, and July 16, 2014, with a median follow-up duration of 78 months (IQR, 3-99 months). Data analysis was conducted from November 10, 2020, to July 8, 2021. Patients were randomly assigned (1:1) to receive nedaplatin (100 mg/m2)- or cisplatin (100 mg/m2)-based chemotherapy every 3 weeks for 3 cycles concurrently with intensity-modulated radiotherapy. The primary end point was progression-free survival (PFS). Secondary end points were overall survival, distant metastasis-free survival, and locoregional relapse-free survival. A total of 402 eligible participants were enrolled (median [IQR] age, 45 [18-65] years; 302 [75.1%] male). Patients were randomly assigned to receive nedaplatin- or cisplatin-based CCRT (n = 201 for each): 196 patients (97.5%) started nedaplatin-based CCRT and 197 patients (98.0%) started cisplatin-based CCRT. Intention-to-treat analysis demonstrated a 5-year progression-free survival rate of 81.4% (95% CI, 75.9%-86.9%) for the cisplatin group and 79.8% (95% CI, 74.1%-85.5%) for nedaplatin group, with a difference of 1.6% (95% CI, -6.3% to 9.5%; P = .002 for noninferiority). No significant survival differences were observed between the cisplatin and nedaplatin groups for 5-year overall survival (89.4% vs 88.8%, P = .63), distant metastasis-free survival (85.9% vs 90.4%, P = .17), and locoregional relapse-free survival (92.6% vs 89.6%, P = .17) rates. The cisplatin group had a higher incidence of grade 3 and 4 auditory toxic effects than the nedaplatin group (35 [17.7%] vs 21 [10.5%], P = .04). In this secondary analysis of a randomized clinical trial, long-term analysis confirmed that nedaplatin-based CCRT could be regarded as an alternative doublet treatment strategy to cisplatin-based CCRT in stage II to IVB NPC. ClinicalTrials.gov Identifier: NCT01540136.

Senolytic-Mediated Elimination of Head and Neck Tumor Cells Induced Into Senescence by Cisplatin.

Therapeutic outcomes achieved in head and neck squamous cell carcinoma (HNSCC) patients by concurrent cisplatin-based chemoradiotherapy initially reflect both tumor regression and tumor stasis. However, local and distant metastasis and disease relapse are common in HNSCC patients. In the current work, we demonstrate that cisplatin treatment induces senescence in both p53 wild-type HN30 and p53 mutant HN12 head and neck cancer models. We also show that tumor cells can escape from senescence both in vitro and in vivo. We further establish the effectiveness of the senolytic, ABT-263 (Navitoclax), in elimination of senescent tumor cells after cisplatin treatment. Navitoclax increased apoptosis by 3.3-fold (P ≤ 0.05) at day 7 compared with monotherapy by cisplatin. Additionally, we show that ABT-263 interferes with the interaction between B-cell lymphoma-x large (BCL-XL) and BAX, anti- and pro-apoptotic proteins, respectively, followed by BAX activation, suggesting that ABT-263-induced apoptotic cell death is mediated through BAX. Our in vivo studies also confirm senescence induction in tumor cells by cisplatin, and the promotion of apoptosis coupled with a significant delay of tumor growth after sequential treatment with ABT-263. Sequential treatment with cisplatin followed by ABT-263 extended the humane endpoint to ∼130 days compared with cisplatin alone, where mice survived ∼75 days. These results support the premise that senolytic agents could be used to eliminate residual senescent tumor cells after chemotherapy and thereby potentially delay disease recurrence in head and neck cancer patients. SIGNIFICANCE STATEMENT: Disease recurrence is the most common cause of death in head and neck cancer patients. B-cell lymphoma-x large inhibitors such as ABT-263 (Navitoclax) have the capacity to be used in combination with cisplatin in head and neck cancer patients to eliminate senescent cells and possibly prevent disease relapse.

Impact of cumulative cisplatin dose in childhood nasopharyngeal carcinoma based on neoadjuvant chemotherapy response in the intensity-modulated radiotherapy era: a real-world study

BackgroundWe aimed to comprehensively investigate the optimal cumulative cisplatin dose during concurrent chemoradiotherapy (CC-CCD) for locoregionally advanced nasopharyngeal carcinoma (CA-LANPC) with different tumor responses after neoadjuvant chemotherapy (NAC).MethodsPatients with CA-LANPC who underwent NAC followed by cisplatin-based concurrent chemoradiotherapy were retrospectively analyzed. Evaluation of tumor response in patients was conducted by Response Evaluation Criteria for Solid Tumor (RECIST) 1.1 after two to four cycles NAC. Multivariate Cox proportional hazards models were used for prognosis. Recursive partitioning analysis (RPA) was conducted to classify participates and predict disease-free survival (DFS).ResultsOne hundred and thirty-two patients with favorable response after NAC were included. The median CC-CCD was 163 mg/m2 (IQR, 145–194 mg/m2), and 160 mg/m2 was selected as the cutoff point to group patients into low and high CC-CCD groups (< 160 vs. ≥ 160 mg/m2). There was significant improvement in 5-year DFS (91.2% vs. 72.6%; P = 0.003) for patients receiving high CC-CCD compared to those receiving low CC-CCD. Multivariate analysis revealed that CC-CCD, T stage, and Epstein–Barr virus (EBV) DNA were independent prognostic factors for DFS (P < 0.05 for all). Patients were further categorized into two prognostic groups by RPA: the low-risk group (T1-3 disease with regardless of EBV DNA, and T4 disease with EBV DNA < 4000 copy/mL), and the high-risk group (T4 disease with EBV DNA ≥ 4000 copy/mL). Significant 5-year DFS improvement was observed for the high-risk group (P = 0.004) with high CC-CCD. However, DFS improvement was relatively insignificant in the low-risk group (P = 0.073).ConclusionsCC-CCD was a positive prognostic factor for responders after NAC in CA-LANPC. Furthermore, CC-CCD ≥ 160 mg/m2 could significantly improve DFS in the high-risk group with CA-LANPC, but the benefit of high CC-CCD in the low-risk group needs further study.

Value of 18F-FDG PET/CT for Assessment of Advanced Lacrimal Sac Non-Keratinizing Squamous Cell Carcinoma Successfully Treated with Concurrent Chemoradiotherapy.

Non-keratinizing squamous cell carcinoma (NKSCC) of the lacrimal apparatus is extremely rare. It is usually very aggressive in destroying local tissue and has a grave prognosis for relentless recurrence and distant failures. Though the current evidence cannot make confident recommendations regarding the best management, curative surgical excision with adjuvant radiotherapy remains the most commonly used strategy. Here, we report a 71-year-old woman presented with progressive right medial canthal swellings for six months. A transnasal endoscopic biopsy revealed NKSCC of the lacrimal sac. She then underwent a combination of magnetic resonance images (MRI) and 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) for staging purposes. Following cisplatin-based concurrent chemo-radiotherapy (CCRT), the post-treatment PET/CT illustrated the absence of an abnormal metabolic accumulation over the suspicious region as observed in post-treatment CT. A further trans-ostia re-biopsy confirmed complete tumor remission. This case demonstrates the remarkable ability of 18F-FDG PET/CT to differentiate between a persistent malignancy and post-treatment changes. Furthermore, a definite CCRT might provide comparable outcomes to traditional surgery.