西妥昔单抗联合奥沙利铂治疗头颈部鳞癌HN5裸鼠移植瘤的实验研究

目的:观察阻断EGFR的西妥昔单克隆抗体(cetuximab,C225)是否能提高奥沙利铂(OXA)对头颈部鳞癌细胞株HN5移植瘤的抗瘤效应。方法:建立裸鼠移植瘤模型50只,当裸鼠右大腿的肿瘤直径达到8.0mm(7.6~8.3mm)时开始实验。实验共分5组(每组10只),分别为对照组、单用C225组、单用OXA组、C225 OXA(6h)组和C225 OXA(24h)组。观察指标为肿瘤生长延迟时间(肿瘤从8.0mm生长至12.0mm所需时间)和肿瘤治愈的情况。结果:除C225 OXA(6h)组中有1只荷瘤裸鼠在治疗过程中死亡外,其余荷瘤裸鼠有8只肿瘤消失,其中单用C225组和单用OXA组各1只,C225 OXA(6h)组有4只,C225 OXA(24h)组有2只。余下41只的裸鼠肿瘤生长情况为:单用C225组和单用OXA组的绝对延迟时间分别为(21.4±8.2)天和(2.7±2.4)天,而C225 OXA(6h)组和C225 OXA(24h)组的绝对延迟时间则分别为(32.5±8.1)天和(30.0±10.4)天,其标准化的延迟时间分别为(11.1±8.1)天和(8.6±10.4)天,增益因子分别为4.11和3.19。结论:C225能提高OXA对头颈部鳞癌细胞株HN5移植瘤的抗瘤效应。     

Current challenges and clinical investigations of epidermal growth factor receptor (EGFR)- and ErbB family-targeted agents in the treatment of head and neck squamous cell carcinoma (HNSCC)

Overexpression of the epidermal growth factor receptor (EGFR) is a common characteristic of head and neck squamous cell carcinomas (HNSCC). Cetuximab is a chimeric anti-EGFR monoclonal antibody (mAb) with multiple approved indications in HNSCC, including with radiation therapy (RT) for locoregionally advanced disease, as monotherapy after platinum progression, and with platinum/5-fluorouracil for recurrent or metastatic disease. There remain, however, numerous unanswered questions regarding the optimal use of cetuximab in HNSCC, including patient selection, its mechanisms of action and resistance, the effect of human papillomavirus status on outcomes, its role when combined with induction chemotherapy or adjuvant radiation, and optimal management of skin toxicity and hypersensitivity reactions. In addition, a variety of other anti-EGFR agents (the multitargeted small molecule tyrosine kinase inhibitors [TKIs] lapatinib, dacomitinib, and afatinib and the anti-EGFR mAbs zalutumumab, nimotuzumab, and panitumumab) are currently under investigation in phase II and III clinical trials in different HNSCC therapeutic settings. The anti-EGFR TKI erlotinib is currently in phase III development for oral cancer prevention. Numerous other drugs are in earlier stages of development for HNSCC treatment, including novel anti-EGFR mAbs (MEHD7945A, necitumumab, and RO5083945), small-molecule TKIs (vandetanib, icotinib, and CUDC-101), EGFR antisense, various add-on therapies to radiation and chemotherapy (bevacizumab, interleukin-12, lenalidomide, alisertib, and VTX-2337), and drugs (temsirolimus, everolimus, OSI-906, dasatinib, and PX-866) intended to overcome resistance to anti-EGFR agents. Overall, a wealth of clinical trial data is expected in the coming years, with the potential to modify significantly the approach to anti-EGFR therapy for HNSCC.     

抗EGFR单抗类靶向药物在头颈部鳞癌综合治疗中的应用

头颈部肿瘤是世界上第6大常见的肿瘤。超过70%的头颈部肿瘤患者在首次确诊时即为局部晚期。尽管不断地努力改进治疗方法,但晚期病例的死亡率仍然居高不下。为了提高疗效,患者通常接受化疗、手术、放射治疗和分子靶向药物综合治疗。大量研究证实,表皮生长因子受体（epidermal growth factor receptor,EGFR）与肿瘤细胞的增殖和转移密切相关,EGFR在大多数头颈部肿瘤中高表达,对这些患者的预后有显著影响。抗EGFR单克隆抗体已经在一些国家被批准用于治疗局部晚期头颈鳞状细胞癌（head and neck squamous cell carcinoma,HNSCC）。本文综述了西妥昔单抗和尼妥珠单抗治疗HNSCC的研究进展。HNSCC的单克隆抗体靶向治疗,是选择西妥昔单抗还是尼妥珠单抗？本综述将围绕这一临床医生尤为关心的问题展开讨论。     

Phase II study of pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck

PurposePlatinum/5-fluorouracil plus cetuximab is a standard systemic treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Pemetrexed has shown activity in SCCHN. This phase II study evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic SCCHN.MethodsPatients received cetuximab 250 mg/m² (loading dose: 400 mg/m²) days 1, 8 and 15; pemetrexed 500 mg/m² + cisplatin 75 mg/m² on day 1, q3w up to six cycles and folic acid, vitamin B₁₂ and prophylactic medications. After a minimum of four cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity. Efficacy (primary end-point: progression-free survival [PFS]) and toxicity were evaluated.ResultsSixty-six patients received ?1 cycle of the triplet. Most patients were male (80.3%), with a median age of 62 years and Eastern Cooperative Oncology Group (ECOG) performance status of 1 (71.2%). Diagnoses included oropharynx (45.5%) and larynx (24.2%) cancers, with locoregional disease (51.5%) alone, or combined with distant metastases (48.5%). Median (m) PFS was 4.4 months (95% confidence interval [CI]: 3.6, 5.4); median overall survival was 9.7 months (95% CI: 6.5, 13.1). Objective response rate was 29.3%; 23 patients had stable disease (39.7%). Drug-related grade 3/4 toxicities included neutropaenia (33.3%), fatigue (24.2%), anorexia (12.1%) and infection (10.6%). Five treatment-related deaths (7.6%) occurred.ConclusionsEfficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5 months was not achieved. Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected.     

Toxicity of cetuximab versus cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell cancer (LAHNSCC)

We retrospectively reviewed acute toxicity with cetuximab and radiotherapy, comparing it with a matched cisplatin group. The cetuximab group experienced significantly more toxicity - grade ?3 oral mucositis (p = 0.014), skin dermatitis (p = 0.0004), ?10% weight loss (p = 0.03), and enteral feeding requirement (p = 0.05). This finding of enhanced toxicity is similar to recent publications.     

The emerging role of cetuximab in head and neck cancer: a 2007 perspective

The integration of targeted therapies into clinical practice constitutes the paradigm of oncology treatment in the current era. Cetuximab, a recombinant human/mouse chimeric epidermal growth factor (EGFR) monoclonal antibody is a targeted agent that has seen expanding indication in recent years. Originally approved for colorectal cancer, its role in the treatment of squamous cell carcinoma of the head and neck has augmented treatment options for patients who are refractory to or cannot tolerate platinum. This article will review the science underlying cetuximab, data supportings its use in patients with locally advanced and recurrent/metastatic disease, common toxicities of therapy, and the integration of this treatment with radiation therapy.     

头颈部鳞癌分子靶向治疗进展

当前分子靶向治疗头颈部鳞状细胞癌(SCCHN)的进展非常快.由于表皮生长因子受体(EGFR)信号传导和血管发生在SCCHN的生长中起关键作用,因此EGFR及其下游效应器与血管发生过程相关的分子及其受体就成为目前SCCHN分子靶向治疗的主要靶点.     

Successful re-challenge with panitumumab in patients who developed hypersensitivity reactions to cetuximab: report of three cases and review of literature

Introduction  Monoclonal antibodies (MAbs) targeting epidermal growth factor receptor (EGFR) are effective in treatment of metastatic colorectal cancer (mCRC). Cetuximab, a chimeric MAb targets EGFR. Even with premedication, cetuximab can cause a hypersensitivity reaction (HSR). In case of severe HSR, further therapy with cetuximab is contraindicated, thus preventing these patients from receiving potentially beneficial anti-EGFR therapy. Panitumumab is a fully human MAb also targets EGFR. To date, no human antihuman Ab have been detected, and unlike CET, HSR are infrequent, and no premedication is required. Safety of panitumumab in patients with a previous severe HSR with cetuximab is not fully known. We present three patients with GI cancers who tolerated panitumumab without HSR after experiencing severe HSR to cetuximab. Patients and methods  Three patients were challenged with standard dose of panitumumab (6 mg/kg) after experiencing grade 3 HSR to standard dose of cetuximab under strict observation and no premedication. First patient, a 58-year-old male with mCRC developed grade 3 HSR during 8th dose of cetuximab. Second patient was a 58-year-old female with mCRC developed grade 3 HSR during 12th dose of cetuximab. Third patient was a 61-year-old male with pancreatic cancer who experienced grade 3 HSR during loading dose of cetuximab. Charts were reviewed to find history of prior allergy, including H1 blocker use, drug allergy, bee sting allergy, eczema, allergic reactive airways disease, or food allergy. Results  All patients were Caucasians with an average age of 59 year with no history of prior allergy. No patient received any premedication. First patient received panitumumab for 2 months, second patient was treated for 6 months, and third patient who was rechallenged 1 week after HSR to cetuximab had a partial response following 6 months of therapy. Conclusions  HSR are serious complications associated with MAbs. Thanks to hybridoma technology that newer generations of MAbs contain less or no mouse-specific protein sequences, hence reducing the risk of HSR. Identification of individuals likely to develop severe and sometimes life-threatening HSR is challenging. Our report of three patients successfully treated with panitumumab after they had severe HSR to cetuximab warrant further investigation.     

Serum hepatocyte growth factor as a marker of tumor activity in head and neck squamous cell carcinoma

Hepatocyte growth factor (HGF) has previously been reported to be elevated in the serum of patients with malignancy, including breast, colorectal and gastric cancers. Here, we evaluated the correlation between serum HGF and the progression of head and neck squamous cell carcinoma (HNSCC). The mean serum HGF levels in 71 healthy control subjects, 78 patients with primary HNSCC, and eight patients with recurrent HNSCC were 0.538 ± 0.163, 0.701 ± 0.252, and 0.925 ± 0.349 ng/ml, respectively. The increase in the HGF level was significantly correlated with tumor stage progression. The HGF level had decreased to normal at 1 month after curative resection of the tumors. During follow-up for several months, the HGF level significantly increased in recurrent HNSCC patients, whereas there was no increase in nonrecurrent patients. Our data suggest that serum HGF is significantly corrected with tumor progression and may be a strong predictor of recurrence in HNSCC.     

Cetuximab in combination with cisplatin and 5-Fluorouracil induces dramatic response in metastatic refractory squamous cell carcinoma of the anal canal

Metastatic squamous cell carcinoma (SCC) of the anal canal is rare with limited data regarding treatment. Epidermal growth factor receptor (EGFR) expression has been observed in SCC of the anal canal and Kristen rat sarcoma vial oncogene (KRAS) mutations are rare. EGFR monoclonal antibodies, cetuximab and panitumumab, represent a potential option in this patient population. We report a metastatic SCC of the anal canal patient treated with cetuximab in combination with cisplatin plus 5-Fluorouracil (5-FU) that had a dramatic response.     

Estimating the risks and benefits before salvage surgery for recurrent head and neck squamous cell carcinoma

IntroductionThe risks associated with salvage surgery of head and neck squamous cell carcinoma (SCC) in a previously irradiated field needs to be balanced against the expected survival benefits. We want to identify preoperative predictive factors for overall and disease-specific survival (OS/DSS) and for the development of serious (Clavien-Dindo, CD≥III) complications following salvage surgery for radiorecurrent SCC to help surgeons, patients, and caregivers in the decision-making process in this setting.Materials and methodsThe records of 234 patients presenting to the Lorraine Cancer Institute with locoregional radiorecurrent SCC were reviewed. The primary endpoint was OS, secondary endpoints were DSS, OS without tracheostomy/gastrostomy, and the risk of CD≥III complications. Multivariate analyses were carried out to explore preoperative factors associated with survival and the risk of postoperative complications.ResultsWith a median follow-up time of 19 months, 5-year OS since the first salvage surgery was 28.3%, 5-year DSS was 38.9%. 2- and 5-year functional OS were 45.6% and 27.2%. rcT-rcN, and WUNHCI ≥4 were both independent significant preoperative predictors of OS and DSS. 30-days postoperative complications occurred in 44.4% of patients (28 CD I, 24 CD II, 34 CD III, 11 CD IV, 7 CD V). A salvage procedure involving T+N plus the presence of a WUHNCI ≥4 was the only independent predictor of CD≥III complications.ConclusionWhen discussing with the patients and the caregivers salvage surgery for recurrent head and neck SCC, a careful evaluation of the preoperative comorbidities by the WUHNCI tool can reliably predict the expected risks and benefits from the procedure.     

Evaluation of the combination of docetaxel/carboplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN): a Southwest Oncology Group Phase II study

Carboplatin/docetaxel chemotherapy was evaluated in advanced squamous cell carcinoma of the head and neck (SCCHN). Eligibility included patients with recurrent, persistent, or metastatic SCCHN with Zubrod performance status 0-2. Docetaxel 65 mg/m² and carboplatin (AUC of 6) were given IV in a 21-day cycle to 68 patients. Response probability was 25 percent (95%CI: 15-38). The major toxicity observed was neutropenia, with 36 patients (61 percent) experiencing Grade 3 or worse. Median progression-free survival was 3.8 months (95%CI, 3.1-4.8) Median overall survival was 7.4 months (95%CI, 6.2-8.9). The results of this study suggest this regimen is active for outpatient treatment of recurrent SCCHN patients with good performance status.     

抗EGFR单抗治疗复发/转移性头颈部鳞状细胞癌临床共识（2021年版）

头颈部鳞状细胞癌（squamous cell carcinoma of the head and neck,SCCHN）是头颈部肿瘤最为常见的一种类型,其疾病负担较重。SCCHN患者中,90%以上高表达表皮生长因子受体（epidermal growth factor receptor,EGFR）,因此通过单克隆抗体特异性地与EGFR结合,是抑制EGFR信号转导的一种重要方法。目前多种基于EGFR受体及其通路相关的靶向药物中,西妥昔单抗是唯一疗效确切的药物,已于2020年2月在中国获批用于一线治疗复发/转移性SCCHN（recurrent/metastatic SCCHN,R/M SCCHN）,随着西妥昔单抗逐步应用于临床,中国晚期SCCHN患者整体的治疗模式将不断得到优化和提升。值得注意的是,虽然靶向和免疫药物在SCCHN的治疗中取得了很大的进展,但仍然存在很多挑战,其中西妥昔单抗治疗R/M SCCHN在EGFR检测、药物应用时机、联合方案和应用剂量以及不良反应管理等方面尚未达成共识。本共识就西妥昔单抗用于R/M SCCHN一线、二线以及联合免疫治疗时的疗效和安全性,结合文献及中国临床实践进行阐述,并对相关治疗方案予以推荐,希望对西妥昔单抗规范化治疗SCCHN患者及优化临床实践提供指导。经过多轮商议和探讨,共识小组的专家汇总出以下推荐意见。在分子检测方面,R/M SCCHN患者无需常规检测EGFR以指导临床实践,抗EGFR单克隆抗体通过抑制EGFR信号转导起到抗肿瘤作用。一线治疗中,对于铂类药物耐受患者,建议6个周期的西妥昔单抗联合顺铂75 mg/m ² ,5-FU 750 mg/m ² 治疗,疾病缓解或稳定后继续接受西妥昔单抗单药维持治疗至疾病进展;对于有5-FU治疗禁忌证、持续静脉输液不方便、二氢嘧啶脱氢酶（dihydropyrimidine dehydrogenase,DPD）缺乏症及治疗依从性差的患者,建议4个周期的西妥昔单抗联合铂类药物（顺铂75 mg/m ² ,每3周1次）+多西他赛（75 mg/m ² ,每3周1次）治疗,疾病缓解或稳定后继续接受西妥昔单抗单药维持治疗至疾病进展;对于铂类药物不耐受的患者,建议西妥昔单抗联合紫杉醇每周方案治疗,直至疾病进展;对于身体状况良好的老年患者,建议西妥昔单抗+卡铂+5-FU治疗6个周期后,使用西妥昔单抗维持治疗。多个临床研究和真实世界数据均显示,西妥昔单抗联合化疗一线治疗显示出一致的高客观缓解率（objective response rate,ORR）和生存获益。二线治疗中,对于一线含铂类药物化疗方案治疗失败的患者,建议西妥昔单抗单药治疗或联合紫杉醇每周方案治疗;对于一线免疫检查点抑制剂（immune checkpoint inhibitor,ICI）治疗失败的患者,建议西妥昔单抗联合化疗方案,其中联合药物应基于之前的药物暴露加以调整。安全性方面,西妥昔单抗治疗方案相关的常见不良事件包括皮肤反应、输液反应和电解质紊乱。多数皮肤反应是轻度的,可以通过预防措施加以控制,在西妥昔单抗停药或减少剂量后,这些不良反应通常会消失而无后遗症。输液反应可通过输注前预防、输注时及输注后密切监测和及时干预加以有效控制。与单纯化疗相比,西妥昔单抗治疗相关的不良反应通常耐受性良好并且可接受。此外,西妥昔单抗联合免疫治疗或新型靶向药物的应用正在探索中,未来将为R/M SCCHN患者带来更多选择。     

抗血管生成治疗头颈部鳞状细胞癌的研究进展

目前对于复发或转移头颈部鳞状细胞癌（HNSCC）以姑息性化疗及 EGFR 靶向治疗为主,肿瘤血管的形成是肿瘤生长和远处转移的关键因素,因此,促进血管生成的因子及其受体成为靶向治疗的靶点,目前抗血管生成药物主要通过阻断 VEGF-VEGF 受体（VEGFR）通路,其在治疗 HNSCC 的临床试验中取得一定效果,为治疗 HNSCC 提供更多选择。