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OBJECTIVE: To investigate the impact of response to induction chemotherapy (IC) on survival outcomes in patients with locally advanced nasopharyngeal carcinoma (LANPC) and evaluate the efficacy of adding nimotuzumab to concurrent chemoradiotherapy (CCRT) based on different responses to IC. METHODS: We retrospectively included patients with stage III-IVA NPC who underwent IC with and without nimotuzumab during CCRT. Statistical analysis included the chi-square test, propensity score matching, Kaplan-Meier survival analysis, and Cox proportional hazards model. RESULTS: Among 383 identified patients, 216 (56.4%) received nimotuzumab during CCRT, while 167 (43.6%) did not. Following IC, 269 (70.2%) patients showed a complete response (CR) or partial response (PR), and 114 (29.8%) had stable disease (SD) or progressive disease (PD). The response to IC independently influenced disease-free survival (DFS) and overall survival (OS). Patients achieving CR/PR demonstrated significantly higher 3-year DFS (80.3% vs. 70.6%, P = 0.031) and OS (90.9% vs. 83.2%, P = 0.038) than those with SD/PD. The addition of nimotuzumab during CCRT significantly improved DFS (P = 0.006) and OS (P = 0.037) for CR/PR patients but not for those with SD/PD. CONCLUSIONS: This study emphasizes the importance of IC response in LANPC and highlights the potential benefits of nimotuzumab during CCRT for improving survival outcomes in CR/PR patients. Tailored treatment approaches for SD/PD patients warrant further investigation.
Subject(s)
Antibodies, Monoclonal, Humanized , Chemoradiotherapy , Induction Chemotherapy , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Humans , Male , Female , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Carcinoma/mortality , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/pathology , Chemoradiotherapy/methods , Induction Chemotherapy/methods , Middle Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Retrospective Studies , Nasopharyngeal Neoplasms/therapy , Nasopharyngeal Neoplasms/mortality , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/drug therapy , Adult , Aged , Neoplasm Staging , Treatment Outcome , Kaplan-Meier Estimate , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease-Free Survival , Young AdultABSTRACT
Patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) have poor survival outcomes. The real-world efficacy of nimotuzumab plus intensity modulated radiotherapy (IMRT)-based chemoradiotherapy in patients with LA-HNSCC remains unclear. A total of 25,442 HNSCC patients were screened, and 612 patients were matched by propensity score matching (PSM) (1:1). PSM was utilized to balance known confounding factors. Patients who completed at least five doses of nimotuzumab were identified as study group. The primary end point was 3-year overall survival (OS) rate. Log-rank test examined the difference between two survival curves and Cloglog transformation test was performed to compare survival at a fixed time point. The median follow-up time was 54.2 (95% confidence interval [CI]: 52.7-55.9) months. The study group was associated with improved OS (hazard ratio [HR] = 0.75, 95% CI: 0.57-0.99, p = 0.038) and progression-free survival (PFS) (HR = 0.74, 95% CI: 0.58-0.96, p = 0.021). Subgroup analysis revealed that aged 50-60 year, IV, N2, radiotherapy dose ≥ 60 Gy, without previous surgery, and neoadjuvant therapy have a trend of survival benefit with nimotuzumab. Nimotuzumab showed favorable safety, only 0.2% had nimotuzumab-related severe adverse events. Our study indicated the nimotuzumab plus chemoradiotherapy provides survival benefits and safety for LA-HNSCC patients in an IMRT era.
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Objective: Definitive chemoradiotherapy (dCRT) is the standard treatment for unresectable locally advanced esophageal cancer. However, this treatment is associated with substantial toxicity, and most malnourished or elderly patients are unable to complete this therapy. Therefore, there is a need for a more suitable radiotherapy combination regimen for this population. This study was aimed to evaluate the efficacy and safety of a combination regimen comprising chemotherapy with nimotuzumab and S-1 and concurrent radiotherapy for patients with fragile locally advanced esophageal cancer with a high Nutritional Risk Screening 2002 (NRS-2002) score. Methods: Eligible patients with unresectable esophageal carcinoma who had an NRS-2002 score of 2 or higher were enrolled. They were treated with S-1 and nimotuzumab with concurrent radiotherapy, followed by surgery or definitive radiotherapy. The primary endpoint was the locoregional control (LRC) rate. Results: A total of 55 patients who met the study criteria were enrolled. After completion of treatment, surgery was performed in 15 patients and radiotherapy was continued in 40 patients. The median follow-up period was 33.3 [95% confidence interval (95% CI), 31.4-35.1)] months. The LRC rate was 77.2% (95% CI, 66.6%-89.4%) at 1 year in the entire population. The overall survival (OS) rate and event-free survival (EFS) rate were 57.5% and 51.5% at 3 years, respectively. Surgery was associated with better LRC [hazard ratio (HR)=0.16; 95% CI, 0.04-0.70; P=0.015], OS (HR=0.19; 95% CI, 0.04-0.80; P=0.024), and EFS (HR=0.25; 95% CI, 0.08-0.75; P=0.013). Most adverse events were of grade 1 or 2, and no severe adverse events occurred. Conclusions: For malnourished or elderly patients with locally advanced esophageal cancer, radiotherapy combined with nimotuzumab and S-1 is effective and has a good safety profile.
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The overexpression of programmed death ligand 1 (PD-L1) is associated with resistance to anticancer therapies and poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Nimotuzumab, a humanized anti-epidermal growth factor receptor (EGFR) mAb, has been widely used clinically for treating several solid tumors. However, whether its anticancer effect involves a reduction in PD-L1 expression remains unclear. The current study aimed to investigate the regulatory effects and underlying mechanism of nimotuzumab on PD-L1 expression in HNSCC both in vitro and in vivo. In vitro, nimotuzumab inhibited IFN-γ-induced PD-L1 upregulation at both the transcriptional and protein levels in the HNSCC cell lines. Subsequent mechanism research revealed that nimotuzumab suppressed IFN-γ-stimulated PD-L1 upregulation mainly by inhibiting phosphorylation of EGFR/MEK/ERK pathway, which was further validated by MEK and ERK inhibitors. In a HNSCC tumor-bearing model, nimotuzumab significantly decreased PD-L1 expression during tumor progression or chemotherapy, and this reduction was accompanied by increased sensitivity of the tumor to docetaxel and atezolizumab. Additionally, nimotuzumab reversed PD-L1 upregulation when combined with Taxol + Cisplatin (TP) induction chemotherapy regimens and improved the CD4+ and CD8+ T cells infiltration in HNSCC patients. These findings provide new insights into the anticancer mechanisms of nimotuzumab in HNSCC.
Subject(s)
Antibodies, Monoclonal, Humanized , B7-H1 Antigen , Head and Neck Neoplasms , Squamous Cell Carcinoma of Head and Neck , Humans , B7-H1 Antigen/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/genetics , Cell Line, Tumor , Animals , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , ErbB Receptors/metabolism , Mice , Male , Gene Expression Regulation, Neoplastic/drug effects , Female , Mice, Nude , Mice, Inbred BALB C , MAP Kinase Signaling System/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Xenograft Model Antitumor Assays , Cisplatin/pharmacology , Cisplatin/therapeutic useABSTRACT
Objectives: To assess the efficacy and safety of nimotuzumab in combination with radiotherapy or chemoradiotherapy for locally advanced head and neck squamous cell carcinoma. Methods: Systematic searches were performed on PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, China Biomedical Medicine, Wanfang, VIP databases. Seven eligible randomized controlled trials (n = 1012) were selected through rigorous inclusion and exclusion criteria. Results: A total of 1012 cases were included. including 508 (50.2%) in the nimotuzumab combination treatment group; There were 504 cases (49.8%) in the control group. The results of meta-analysis showed that the overall survival (Hazard Ratio [HR]=0.75, 95% Confidence Interval [CI]: 0.62-0.90, P<0.05), progression-free survival (HR=0.69, 95% CI: 0.54-0.87, P<0.05), complete response rate (Risk Ratio [RR]=1.52, 95% CI: 1.24-1.86, P<0.05), and objective response rate (RR=1.32, 95% CI: 1.17-1.48, P<0.05) were significantly improved in the nimotuzumab combination treatment group compared with the control group. In terms of the incidence of adverse effects, only the incidence of rash was the nimotuzumab combination group higher than in the treatment alone group, and there was no significant difference between the remaining adverse reactions (neutropenia, anemia, nausea/vomiting, mucositis, dermatitis, dysphagia). Conclusion: Nimotuzumab combined with radiotherapy or chemoradiotherapy is more effective than radiotherapy alone or chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck, and the safety profile is controllable. Therefore, the addition of nimotuzumab to treatment is expected to be an effective treatment option for this disease. However, more prospective randomized controlled trials are needed to fully explore the effectiveness of this treatment in patients with locally advanced head and neck squamous cell carcinoma. Systematic Review Registration: identifier PROSPERO (CRD: 42022383313).
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The present systematic review evaluated the effectiveness of anti-EGFR therapy in combination with radiotherapy (RT) or with chemoradiation compared with the existing standard of care for the treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC). The PubMed, SCOPUS, EMBASE and COCHRANE databases were searched and 12 phase III randomized controlled trials were included. The effectiveness of the anti-EGFR monoclonal antibody cetuximab was evaluated in nine trials. Nimotuzumab (one trial), zalutumumab (one trial) and panitumumab (one trial) were the monoclonal antibodies evaluated in the remaining three trials. One study tested the effectiveness of adding cetuximab to radical RT and found that patients with LAHNSCC exhibited improvement in locoregional control (LRC), overall survival (OS) and progression-free survival (PFS) compared with those of patients treated with RT alone. A total of three studies tested the effectiveness of adding an anti-EGFR agent to chemoradiation. Of these, a single institution study in which patients received cisplatin at 30 mg/m2 weekly, instead of the standard doses of 100 mg/m2 every 3 weeks or 40 mg/m2 every week, reported significant improvement in PFS with the addition of nimotuzumab to chemoradiotherapy without an improvement in overall survival. However, the other two studies indicated that, when added to standard chemoradiation, the anti-EGFR monoclonal antibodies cetuximab or zalutumumab did not improve survival outcomes. Two phase III trials evaluated RT plus an anti-EGFR agent compared with chemoradiation alone. Of these, one study reported inferior outcomes with cetuximab-RT in terms of OS and LRC, whereas the other study with panitumumab plus RT failed to prove the non-inferiority. Two trials evaluated induction chemotherapy followed by cetuximab-RT compared with chemoradiotherapy and reported no benefits in terms of OS or PFS. Furthermore, one study evaluated induction chemotherapy followed by cetuximab-RT compared with induction chemotherapy followed by chemoradiotherapy and found no improvement in OS or PFS. Finally, three phase III trials tested the effectiveness of cetuximab plus RT in the treatment of human papillomavirus-positive oropharyngeal carcinoma, and found it to be inferior compared with cisplatin-RT in terms of OS, PFS and failure-free survival. Based on the aforementioned findings, it is difficult to conclude that anti-EGFR therapy in any form has an advantage over conventional chemoradiation in the treatment of LAHNSCC.
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OBJECTIVE: To evaluate the feasibility, safety and efficacy of concurrent simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with nimotuzumab in the treatment of locally advanced esophageal squamous cell cancer (ESCC). METHODS: Eligible patients were histologically proven to have locally advanced ESCC, and were unable to tolerate or refuse concurrent chemoradiotherapy (CCRT). Enrolled patients underwent concurrent SIB-IMRT in combination with nimotuzumab. SIB-IMRT: For the planning target volume of clinical target volume (PTV-C), the prescription dose was 50.4 Gy/28fractions, 1.8 Gy/fraction, 5fractions/week, concurrently, the planning target volume of gross tumor (PTV-G) undergone an integrated boost therapy, with a prescription dose of 63 Gy/28fractions, 2.25 Gy/fraction, 5 fractions/week. Nimotuzumab was administered concurrently with radiotherapy, 200 mg/time, on D1, 8, 15, 22, 29, and 36, with a total accumulation of 1200 mg through intravenous infusion. The primary endpoint of the study was the safety and efficacy of the combined treatment regimen, and the secondary endpoints were 1-year, 2-year, and 3-year local control and survival outcomes. RESULTS: (1) From December 2018 to August 2021, 35 patients with stage II-IVA ESCC were enrolled and 34 patients completed the full course of radiotherapy and the intravenous infusion of full-dose nimotuzumab. The overall completion rate of the protocol was 97.1%. (2) No grade 4-5 adverse events occurred in the entire group. The most common treatment-related toxicity was acute radiation esophagitis, with a total incidence of 68.6% (24/35). The incidence of grade 2 and 3 acute esophagitis was 25.7% (9/35) and 17.1% (6/35), respectively. The incidence of acute radiation pneumonitis was 8.6% (3/35), including one case each of Grades 1, 2, and 3 pneumonitis. Adverse events in other systems included decreased blood cells, hypoalbuminemia, electrolyte disturbances, and skin rash. Among these patients, five experienced grade 3 electrolyte disturbances during the treatment period (three with grade 3 hyponatremia and two with grade 3 hypokalemia). (3) Efficacy: The overall CR rate was 22.8%, PR rate was 71.4%, ORR rate was 94.2%, and DCR rate was 97.1%.(4) Local control and survival: The 1-, 2-, and 3-year local control (LC) rate, progression-free survival(PFS) rate, and overall survival(OS) rate for the entire group were 85.5%, 75.4%, and 64.9%; 65.7%, 54.1%, and 49.6%; and 77.1%, 62.9%, and 54.5%, respectively. CONCLUSIONS: The combination of SIB-IMRT and nimotuzumab for locally advanced esophageal cancer demonstrated good feasibility, safety and efficacy. It offered potential benefits in local control and survival. Acute radiation esophagitis was the primary treatment-related toxicity, which is clinically manageable. This comprehensive treatment approach is worthy of further clinical exploration (ChiCTR1900027936).
Subject(s)
Antibodies, Monoclonal, Humanized , Chemoradiotherapy , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Radiotherapy, Intensity-Modulated , Humans , Male , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Female , Middle Aged , Esophageal Squamous Cell Carcinoma/therapy , Esophageal Squamous Cell Carcinoma/radiotherapy , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/mortality , Radiotherapy, Intensity-Modulated/methods , Radiotherapy, Intensity-Modulated/adverse effects , Esophageal Neoplasms/radiotherapy , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Esophageal Neoplasms/mortality , Esophageal Neoplasms/drug therapy , Aged , Chemoradiotherapy/methods , Adult , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/administration & dosage , Treatment OutcomeABSTRACT
Because of the common physical condition, reduced organ function, and comorbidities, elderly patients with nasopharyngeal carcinoma (NPC) are often underrepresented in clinical trials. The optimal treatment of elderly patients with locally advanced NPC remains unclear. The purpose of this study was to evaluate the efficacy of concurrent nimotuzumab combined with intensity-modulated radiotherapy (IMRT) in elderly patients with locally advanced NPC. We conducted a single-arm, phase II trial for elderly patients with stage III-IVA NPC (according to UICC-American Joint Committee on Cancer TNM classification, 8th edition). All patients received concurrent nimotuzumab (200 mg/week, 1 week prior to IMRT) combined with IMRT. The primary end-point was complete response (CR) rate. The secondary end-points were survival, safety, and geriatric assessment. Between March 13, 2017 and November 12, 2018, 30 patients were enrolled. In total, 20 (66.7%) patients achieved CR, and objective response was observed in 30 (100.0%) patients 1 month after radiotherapy. The median follow-up time was 56.05 months (25th-75th percentile, 53.45-64.56 months). The 5-year locoregional relapse-free survival, distant metastasis-free survival, cancer-specific survival, disease-free survival, and overall survival were 89.4%, 86.4%, 85.9%, 76.5%, and 78.8%, respectively. Grade 3 mucositis occurred in 10 (33%) patients and grade 3 pneumonia in 3 (10%) patients. Concurrent nimotuzumab combined with IMRT is effective and well-tolerated for elderly patients with locally advanced NPC.
Subject(s)
Antibodies, Monoclonal, Humanized , Chemoradiotherapy , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Radiotherapy, Intensity-Modulated , Humans , Radiotherapy, Intensity-Modulated/methods , Radiotherapy, Intensity-Modulated/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Male , Female , Aged , Nasopharyngeal Carcinoma/radiotherapy , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Carcinoma/mortality , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Neoplasms/radiotherapy , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/mortality , Nasopharyngeal Neoplasms/therapy , Nasopharyngeal Neoplasms/drug therapy , Chemoradiotherapy/methods , Neoplasm Staging , Aged, 80 and over , Treatment Outcome , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/administration & dosageABSTRACT
Purpose: To investigate the survival outcomes and toxicities associated with the addition of nimotuzumab to concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal carcinoma (LANPC) patients who received induction chemotherapy (IC). Methods: Patients with stage III-IVA nasopharyngeal carcinoma who received IC and CCRT between January 2017 and October 2021 were retrospectively included. We aimed to compare the locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) between patients treated with CCRT+nimotuzumab and CCRT alone. Results: We included 411 patients in the analysis. Of these patients, 267 (65.0%) and 144 (35.0%) had CCRT+nimotuzumab and CCRT alone, respectively. Similar LRFS was found between those with and without nimotuzumab (92.9% vs. 92.6%, p = 0.855). The 3-year DMFS was 88.2% and 76.2% in those with and without nimotuzumab (p = 0.002). The 3-year DFS was 83.4% and 70.6% in those with and without nimotuzumab treatment (p = 0.003). The 3-year OS was 92.1% and 81.1% in those with and without nimotuzumab (p = 0.003). The multivariate Cox regression analysis indicated that the addition of nimotuzumab was independently associated with better DMFS (hazard ratio [HR] 0.606, p = 0.049), DFS (HR 0.613, p = 0.028), and OS (HR 0.497, p = 0.019). No significant differences in major toxicities were found between the two treatment arms, including hematologic toxicities, hepatoxicity, nephrotoxicity, gastrointestinal reactions, and mucositis (all p > 0.05). Conclusion: The addition of nimotuzumab to CCRT after IC in LANPC has shown promising results in improving treatment outcomes and acceptable toxicities.
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Sleep disorders are prevalent and debilitating symptoms in primary brain tumor patients, notably those receiving radiation therapy. Nevertheless, the relationship between sleep disorders, melatonin - a circadian rhythm regulatory hormone, and gliomas is underexplored. Melatonin exhibits various biological functions, one of them being anti-tumor activity. In the context of gliomas, often overexpressing EGFR, the humanized monoclonal antibody Nimotuzumab targets this marker. Our research discovered that variations in circadian rhythm significantly influence tumor growth in mice through impacting melatonin secretion. Harnessing proteogenomic, we identified that melatonin could inhibit the phosphorylation of EGFR and its downstream effectors, key elements in angiogenesis and tumor progression. Building on structural simulations, we propose that melatonin may amplify Nimotuzumab's anti-glioma efficacy by inhibiting EGFR TK dimerization. This proposition was validated in our in vitro and in vivo studies where melatonin synergistically augmented cytotoxicity and apoptosis in Nimotuzumab-treated glioma cells. Thus, melatonin shows promise as a beneficial addition to Nimotuzumab treatment in glioma patients.
Subject(s)
Antibodies, Monoclonal, Humanized , Apoptosis , Brain Neoplasms , ErbB Receptors , Glioblastoma , Melatonin , Xenograft Model Antitumor Assays , Animals , Humans , Mice , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Brain Neoplasms/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Synergism , ErbB Receptors/metabolism , ErbB Receptors/antagonists & inhibitors , Glioblastoma/drug therapy , Glioblastoma/pathology , Glioblastoma/metabolism , Melatonin/pharmacology , Mice, Nude , Phosphorylation , Male , Mice, Inbred BALB CABSTRACT
BACKGROUND: The present meta-analysis aimed to evaluate the efficacy and safety of adding nimotuzumab to radiotherapy (RT) or chemoradiotherapy (CRT). METHODS: Prospective randomized controlled studies at EMBASE, PubMed, and the Cochrane Library from January 1, 2010, to October 1, 2022, were searched. Data on the overall survival (OS), progress-free survival (PFS), disease-free survival (DFS), complete response rate (CRR), objective response rate (ORR), and all grade adverse events were collected from the enrolled publications. OS was the primary measurement indicator. Pooled analysis was performed with relative risks (RRs), hazard risks (HRs), and their corresponding 95% confidence intervals (CIs) in the software Stata SE 16.0. RESULTS: Six randomized controlled studies were included in the analysis of the overall pooled effect. As compared to the control group, the nimotuzumab intervention group exhibited improved OS by 21% (pooled HR=0.79,95% CI: 0.64-0.98, P=0.028), along with PFS up to 31% (HR=0.69, 95% CI: 0.55-0.86, P=0.001) and DFS up to 29% (HR=0.71, 95% CI: 0.56-0.91, P=0.006), increased CRR as 50% (RR=1.50, 95% CI:1.09-2.04; P=0.012), and ORR as 35% (RR=1.35, 95% CI:1.04-1.73; P=0.022). Regarding safety, nimotuzumab in combination with RT or CRT did not increase the incidence of all grade adverse events (pooled-RD=-1.27, 95% CI:-2.78-0.23, P=0.099). CONCLUSION: The present meta-analysis has demonstrated that nimotuzumab, in combination with RT or CRT, could provide survival benefits and increase response rates. Its safety profile has been found to be controllable.
Subject(s)
Antibodies, Monoclonal, Humanized , Chemoradiotherapy , Head and Neck Neoplasms , Humans , Chemoradiotherapy/methods , Chemoradiotherapy/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Head and Neck Neoplasms/therapy , Head and Neck Neoplasms/pathology , Randomized Controlled Trials as Topic , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/administration & dosageABSTRACT
PURPOSE: Pediatric diffuse intrinsic pontine glioma (DIPG) is a fatal disease associated with a median survival of < 1 year despite aggressive treatments. This retrospective study analyzed the treatment outcomes of patients aged < 18 years who were diagnosed with DIPG between 2012 and 2022 and who received different chemotherapy regimens. METHODS: After radiotherapy, patients with DIPG received nimotuzumab-vinorelbine combination or temozolomide-containing therapy. When nimotuzumab was unavailable, it was replaced by vincristine, etoposide, and carboplatin/cyclophosphamide (VECC). Temozolomide was administered as a single agent or a part of the combination chemotherapy comprising temozolomide, irinotecan, and bevacizumab. Furthermore, 1- and 3-year overall survival (OS), progression-free survival (PFS), and median OS and PFS were analyzed. RESULTS: The median age of 40 patients with DIPG was 97 ± 46.93 (23-213) months; the median follow-up time was 12 months. One and 3-year OS were 35.0% and 7.5%, respectively. Median OS was 12 months in all patients (n = 40), and it was 16, 10, and 11 months in those who received first-line nimotuzumab-vinorelbine combination (n = 13), temozolomide-based (n = 14), and VECC (n = 6) chemotherapy regimens, respectively (p = 0.360). One patient who received gefitinib survived for 16 months. Conversely, patients who never received radiotherapy and any antineoplastic medicamentous therapy (n = 6) had a median OS of 4 months. CONCLUSION: Nimotuzumab-vinorelbine combination therapy prolonged OS by 6 months compared with temozolomide-containing chemotherapy, although the difference was not statistically significant.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Humans , Female , Child , Male , Brain Stem Neoplasms/drug therapy , Child, Preschool , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Adolescent , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Diffuse Intrinsic Pontine Glioma/drug therapy , Temozolomide/therapeutic use , Temozolomide/administration & dosage , Vinblastine/administration & dosage , Vinblastine/therapeutic use , Vinblastine/analogs & derivatives , Infant , Treatment OutcomeABSTRACT
BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most prevalent geographically-specific head and neck cancer. Its incidence was high in the Asian population, especially in certain parts such as Southern China and South East Asia. Most patients with NPC are presented with intermediate-stage or locally advanced disease requiring chemoradiation as the primary treatment of choice. Epidermal Growth Factor Receptor (EGFR) was found overexpressed in most patients with NPC associated with poor prognosis making its inhibitor one of the most plausible treatment options in addition to chemoradiation. In EGFR-positive NPC patients, nimotuzumab, a humanized anti-EGFR monoclonal antibody will bind the extracellular domain of EGFR leading to tumor growth suppressions. This study's objective was to assess the real-world clinical efficacy of nimotuzumab for patients with intermediate-stage and locally advanced NPC when in combination with concurrent chemoradiation. METHODS: This retrospective real-world study examined a sample of intermediate-stage and locally advanced NPC patients who were treated with or without adding nimotuzumab to concurrent chemoradiation at Dr. Cipto Mangunkusumo General Hospital in Indonesia from January 2009 to December 2017. The outcomes were patients' real-world five-year overall survival (rwOS) and progression-free survival (rwPFS) compared using Kaplan-Meier analysis and Cox proportional hazard models adjusting for age, gender, comorbidities, clinical staging, staging based on Tumor status (T), staging based on Nodes status (N), and types of radiotherapy. Results: A total of 407 patients were included in the analysis, 61 patients receiving concurrent nimotuzumab and chemoradiation and 346 patients receiving chemoradiation alone. Patients receiving concurrent nimotuzumab and chemoradiation tended to have less aggressive NPC than patients receiving chemoradiation alone. Multivariate-adjusted Cox models revealed that combining nimotuzumab with chemoradiation was associated with a statistically significant longer rwOS gain (hazard ratio (HR)=0.46 (95% CI: 0.26-0.82, p=0.008)) and a trend of longer rwPFS (hazard ratio (HR)=0.67 (95% CI: 0.41-1.09, p=0.109)) in comparison to chemoradiation alone. Conclusion: In this retrospective real-world study, concurrent nimotuzumab and chemoradiation usage was associated with a significant overall survival benefit than chemoradiation alone for intermediate-stage and locally advanced NPC patients. Hence, adding nimotuzumab to patients' chemoradiation should be considered in patients with intermediate-stage and locally advanced NPC.
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PURPOSE: We aimed to investigate the efficacy and side effects of concurrent chemoradiotherapy, with or without nimotuzumab, for the treatment of locally advanced nasopharyngeal carcinoma after neoadjuvant chemotherapy. METHODS: This study retrospectively enrolled 109 patients with NPC from our hospital from July 2019 to May 2021.All patients were treated with docetaxel, cisplatin, and fluorouracil(TPF) neoadjuvant chemotherapy for 2 cycles, and concurrent chemoradiotherapy was performed 2 weeks after chemotherapy. According to whether nimotuzumab was added in concurrent chemoradiotherapy, they were divided into the nimotuzumab group and the control group, with 52 cases in the nimotuzumab group and 57 cases in the control group.The efficacy and adverse reactions of the two groups were retrospectively analyzed. RESULTS: The objective remission and complete remission rates in the nimotuzumab and control groups were 100% vs 98.2% (p = 1.000), and 92.3% vs 78.9% (p = 0.049), respectively. The 3-year distant metastasis-free survival of the nimotuzumab and control groups was 91.6% and 77.3% (p = 0.047), respectively.The 3-year progression-free survival, locoregional relapse-free survival, and overall survival of the nimotuzumab and control groups were 87.6% vs 75.5% (p = 0.110), 90.5% vs 86.9% (p = 0.566), and 94.5% vs 87.1% (p = 0.295), respectively. In the nimotuzumab group, subgroup analysis showed that patients aged < 60 years (hazard ratio [HR] = 0.350, 95% confidence interval [CI]: 0.131-0.934, p = 0.036) and those with a neutrophil-to-lymphocyte ratio (neutrophil/lymphocyte ratio) ≤ 4 (HR = 0.365, 95% CI: 0.144-0.923, p = 0.033) achieved a better result. Additionally, multivariate analysis demonstrated that neutrophil/lymphocyte ratio was an independent risk factor for disease progression (HR = 7.485, p = 0.012) and distant metastasis (HR = 17.540, p = 0.009).No grade 4 adverse reactions were observed in either group. Grade 3 oral mucosal reactions, as well as pharyngeal and esophageal reactions were slightly higher in the nimotuzumab group than in the control group, but the difference was not statistically significant. No significant differences were observed in the incidence of adverse reactions such as leukopenia, HB reduction, thrombocytopenia between the two groups (P > 0.05). CONCLUSION: The concurrent chemoradiotherapy plus nimotuzumab after neoadjuvant chemotherapy for locally advanced nasopharyngeal carcinoma achieved a higher complete remission rate and significantly improved distant metastasis-free survival compared with concurrent chemoradiotherapy alone. Additionally, an increasing trend was observed in progression-free survival, and the incidence of side effects was similar in both groups.
Subject(s)
Leukopenia , Nasopharyngeal Neoplasms , Humans , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/pathology , Retrospective Studies , Neoadjuvant Therapy/adverse effects , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Neoplasm Recurrence, Local/drug therapy , Chemoradiotherapy/adverse effects , Cisplatin/adverse effects , Leukopenia/chemically inducedABSTRACT
To investigate the clinical impact of multiple courses of irradiation on pediatric patients with progressive diffuse intrinsic pontine glioma (DIPG), we conducted a retrospective case series on three children treated at our institution from 2018 to 2022. All children were candidates to receive systemic therapy with vinorelbine and nimotuzumab. Radiotherapy was administered to a total dose of 54 Gy. At any disease progression, our local tumor board evaluated the possibility of offering a new course of radiotherapy. To determine feasibility and assess toxicity rates, all children underwent clinical and hematological evaluation both during and after the treatment. To assess efficacy, all children performed contrast-enhanced MRI almost quarterly after the end of the treatment. In all children, following any treatment course, neurological improvement (>80%) was associated with a radiological response (41.7-46%). The longest overall survival (24 months) was observed in the child who underwent three courses of radiotherapy, without experiencing significant side effects. Even though it goes beyond the understanding of conventional radiobiology, first and second reirradiation in pediatric patients with progressive DIPG may represent a feasible and safe approach, capable of increasing overall survival and disease-free survival in selected patients and improving their quality of life.
ABSTRACT
Prostate cancer (PCa) is a significant health concern affecting men worldwide. Previous studies have shown that nimotuzumab, a drug targeting the epidermal growth factor receptor (EGFR), can effectively inhibit cancer progression. Here, we aimed to explore the role of miR-199a/214 cluster in mediating the inhibitory effect of nimotuzumab on the development of PCa. In this study, we conducted an MTT assay to assess cell proliferation and utilized flow cytometry to evaluate cell apoptosis and cell cycle arrest. To investigate the molecular mechanisms underlying the effects of nimotuzumab on prostate cancer development, we focused on the miR-199a-5p and miR-214-3p miRNA clusters. The TargetScan Human database was used to predict the binding sites between miR-199a-5p or miR-214-3p and the 3'-UTR of the transducin (ß)-like 1 X-linked receptor 1 (TBL1XR1) mRNA. To confirm the direct interaction and binding between miR-199a-5p or miR-214-3p and the 3'-UTR of TBL1XR1 mRNA, we performed luciferase reporter assays. Our findings demonstrated that nimotuzumab exerted a significant dosage-dependent suppression of PCa cell proliferation and facilitated PCa cell apoptosis and cell cycle arrest. Concurrently, nimotuzumab obviously impeded the activity of Wnt/ß-catenin and EGFR signaling pathways in PCa cells. We also observed downregulation of miR-199a-5p and miR-214-3p in PCa cells. Overexpression of miR-199a/214 cluster inhibited PCa cell viability and enhanced cell apoptosis. Furthermore, we found that miR-199a/214 cluster augmented the inhibitory effect of nimotuzumab on PCa cell proliferation and promoted its ability to induce apoptosis and cell cycle arrest. This effect was reversed upon TBL1XR1 overexpression, indicating that TBL1XR1 is involved in the regulatory pathway of miR-199a/214 and nimotuzumab in PCa cells. We further revealed that TBL1XR1 was overexpressed in PCa and was identified as a downstream target of the miR-199a/214 cluster. In nimotuzumab-treated PCa cells, the overexpression of miR-199a/214 markedly inhibited Wnt/ß-catenin and EGFR signaling, and this effect was also rescued by TBL1XR1 overexpression. In summary, our data indicated that miR-199a/214 cluster play a crucial role in enhancing the inhibitory effect of nimotuzumab on PCa development by downregulating TBL1XR1 and modulating Wnt/ß-catenin and EGFR signaling pathways. These findings offer a novel therapeutic approach for the treatment of prostate cancer.
Subject(s)
MicroRNAs , Prostatic Neoplasms , Male , Humans , beta Catenin/metabolism , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , MicroRNAs/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Cell Proliferation/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolism , RNA, Messenger/genetics , Cell Line, Tumor , Repressor Proteins/genetics , Receptors, Cytoplasmic and Nuclear/geneticsABSTRACT
Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small-molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies is often ineffective in treating cancers harboring wild-type EGFR. Given the fact that EGFR possesses a kinase-independent pro-survival function, more effective inhibition of EGFR-mediated signals is therefore necessary. In this study, we investigated the effects of using a combination of low-dose nimotuzumab and theasinensin A to evaluate whether the inhibitory effect of nimotuzumab on NCI-H441 cancer cells was enhanced. Here, theasinensin A, a novel epigallocatechin-3-gallate (EGCG) derivative, was identified and its potent anticancer activity against wild-type EGFR NSCLC was demonstrated in vitro; the anticancer activity was induced through degradation of EGFR. Mechanistic studies further revealed that theasinensin A bound directly to the EGFR extracellular domain, which decreased interaction with its ligand EGF in combination with nimotuzumab. Theasinensin A significantly promoted EGFR degradation and repressed downstream survival pathways in combination with nimotuzumab. Meanwhile, treatment with theasinensin A and nimotuzumab prevented xenograft growth, whereas the single agents had limited effect. Thus, the combination therapy of theasinensin A with nimotuzumab is a powerful candidate for treatment of wild-type EGFR cancers.
ABSTRACT
The epidermal growth factor receptor (EGFR) is vital for many different types of cancer. Nimotuzumab (NmAb), an anti-EGFR monoclonal antibody (mAb), is used against some of EGFR-overexpressed cancers in various countries. It targets malignant cells and is internalized via receptor-mediated endocytosis. We hypothesized that mAb-nanoparticle conjugation would provide an enhanced therapeutic efficacy, and hence we conjugated NmAb with 27 nm spherical gold nanoparticles (AuNPs) to form AuNP-NmAb nanoconjugates. Using biophysical and spectroscopic methods, including ultraviolet-visible spectroscopy (UV-Vis), transmission electron microscopy (TEM), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and Fourier-transform infrared spectroscopy (FTIR), the AuNP-NmAb complex was characterized. Furthermore, in vitro studies were performed using a medium-level EGFR-expressing skin cancer cell (A431, EGFRmedium) and low-level EGFR-expressing lung cancer cell (A549, EGFRlow) to evaluate anti-tumor and cellular uptake efficiency via MTT assay and single-particle inductively coupled plasma mass spectrometry (spICP-MS), respectively. In comparison to NmAb monotherapy, the AuNP-NmAb treatment drastically reduced cancer cell survivability: for A431 cells, the IC50 value of AuNP-NmAb conjugate was 142.7 µg/mL, while the IC50 value of free NmAb was 561.3 µg/mL. For A549 cells, the IC50 value of the AuNP-NmAb conjugate was 163.6 µg/mL, while the IC50 value of free NmAb was 1,082.0 µg/mL. Therefore, this study highlights the unique therapeutic potential of AuNP-NmAb in EGFR+ cancers and shows the potential to develop other mAb nanoparticle complexes for a superior therapeutic efficacy.
ABSTRACT
BACKGROUND AIMS: Radiation therapy is the standard treatment for patients with nasopharyngeal carcinoma (NPC), but relapse occurs in 10% to 20% of patients. The treatment of recurrent nasopharyngeal carcinoma (rNPC) remains challenging. Chimeric antigen receptors (CAR)-T-cell therapy has achieved good outcomes in the treatment of leukemia and seems to be a promising therapeutic strategy for solid tumors. c-Met has been found to be highly expressed in multiple cancer types, and the activation of c-Met leads to the proliferation and metastasis of cancer cells. However, the expression of c-Met in rNPC tissues and whether it can be used as a target for CAR-T therapy in rNPC remain to be investigated. METHODS: We detected the expression of c-Met in 24 primary human rNPC tissues and three NPC cell lines and constructed two different antibody-derived anti-c-Met CARs, namely, Ab928z and Ab1028z. To estimate the function of these two different c-Met-targeted CAR-T cells, CD69 expression, cytotoxicity and cytokine secretion of CAR-T cells were assessed after coculture with target cells. A cell line-derived xenograft mouse model also was used to evaluate these two anti-c-Met CAR-T cells. Furthermore, we determined whether combination with an anti-EGFR antibody could promote the antitumor effect of CAR-T cells in a patient-derived xenograft mouse model. RESULTS: High c-Met expression was detected in 23 of 24 primary human rNPC tissues by immunohistochemistry staining and in three NPC cell lines by flow cytometry. Ab928z-T cells and Ab1028z-T cells showed significantly upregulated expression of CD69 after coculture with targeted cells. However, Ab1028z-T cells showed superior cytokine secretion and antitumor activity. Furthermore, Ab1028z-T cells effectively suppressed tumor growth compared with control CAR-T cells, and the combination with nimotuzumab further enhanced the tumor-clearing ability of Ab1028z-T cells. CONCLUSIONS: We found that c-Met is highly expressed in rNPC tissues and confirmed its potential as a CAR-T target for rNPC. Our study provides a new idea for the clinical treatment of rNPC.
Subject(s)
Nasopharyngeal Neoplasms , Receptors, Chimeric Antigen , Animals , Humans , Mice , Cell Line, Tumor , Cytokines/metabolism , Immunotherapy, Adoptive , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/therapy , Nasopharyngeal Neoplasms/metabolism , Receptors, Chimeric Antigen/metabolism , T-Lymphocytes , Xenograft Model Antitumor Assays , Proto-Oncogene Proteins c-met/metabolismABSTRACT
The present study aimed to evaluate the effectiveness and safety of cetuximab (CTX) or nimotuzumab (NTZ) in combination with chemotherapy for patients with recurrent and/or metastatic nasopharyngeal carcinoma (RM-NPC), and for this purpose, a single-group rate meta-analysis was performed. A systematic search of the Cochrane library, Pubmed, EMBASE, Chwina National Knowledge Infrastructure and WanFang databases for studies published until February 15, 2022 was performed. The 1-, 2-, 3- and 5-year overall survival (OS) rates were the primary endpoints. Complete response, partial response, stable disease, objective response rate, disease control rate and grade ≥3 toxicities were considered secondary endpoints. Cochran Q test and I2 statistics were performed to assess the heterogeneity among studies. A total of nine studies comprising 435 patients were included in the analysis. The pooled 1-, 2-, 3- and 5-year OS rates were 81.0% [95% confidence interval (CI): 65.0-90.7%], 49.9% (95% CI: 35.3-64.5%), 46.3% (95% CI: 31.4-61.8%) and 31.0% (95% CI: 20.8-43.4%), respectively. The pooled disease control rate and objective response rate were 88.7% (95% CI: 78.4-94.5%) and 55.6% (95% CI: 39.9-70.1%), respectively. In addition, all grade 3-4 adverse events from the included studies were gathered. In conclusion, the use of CTX or NTZ in combination with chemotherapy may be a feasible and safe option for treating RM-NPC.