Locally advanced and metastatic basal cell carcinoma: molecular pathways,treatment options and new targeted therapies

The hedgehog (Hh) signaling pathway has been identified as important to normal embryonic development in living organisms and it is implicated in processes including cell proliferation, differentiation and tissue patterning. Aberrant Hh pathway has been involved in the pathogenesis and chemotherapy resistance of different solid and hematologic malignancies. Basal cell carcinoma (BCC) and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Vismodegib has recently approved as the first inhibitor of one of the components of the Hh pathway (smoothened). This review attempts to provide current data on the molecular pathways involved in the development of BCC and the therapeutic options available for the treatment of locally advanced and metastatic BCC, and the new targeted therapies in development.     

Challenges and new horizons in the management of advanced basal cell carcinoma: a UK perspective

Basal cell carcinoma (BCC) is a common malignancy with a good prognosis in the majority of cases. However, some BCC patients develop a more advanced disease that poses significant management challenges. Such cases include locally advanced, recurrent or metastatic BCC, or tumours that occur in anatomical sites where surgical treatment would result in significant deformity. Until recently, treatment options for these patients have been limited, but increased understanding of the molecular basis of BCC has enabled potential therapies, such as hedgehog signalling pathway inhibitors, to be developed. A clear definition of advanced BCC as a distinct disease entity and formal management guidelines have not previously been published, presumably because of the rarity, heterogeneity and lack of treatment options available for the disease. Here we provide a UK perspective from a multidisciplinary group of experts involved in the treatment of complex cases of BCC, addressing the key challenges associated with the perceived definition and management of the disease. With new treatments on the horizon, we further propose a definition for advanced BCC that may be used as a guide for healthcare professionals involved in disease diagnosis and management.     

Using drug scheduling to manage adverse events associated with hedgehog pathway inhibitors for basal cell carcinoma

Basal cell carcinoma (BCC) is the most common malignancy and form of skin cancer worldwide; advanced BCC, either as locally advanced BCC (laBCC) or metastatic BCC (mBCC), can cause substantial tissue invasion and morbidity. Until the recent availability of the hedgehog pathway inhibitors (HHIs) sonidegib and vismodegib, treatment options for advanced BCC were limited. These agents demonstrate efficacy in patients with laBCC and mBCC; however, the adverse events (AEs) associated with these agents can lead to treatment interruption or discontinuation and reduced quality of life, all of which significantly impact long-term adherence to therapy, which might affect clinical outcome. Given that most AEs are class-related effects, switching HHIs does not appear to lead to a significantly different AE profile, underscoring the importance of maintaining patients on their first HHI. Interrupting treatment of sonidegib and vismodegib does not appear to undermine the efficacy of these agents and is therefore a practical option to manage AEs in order to maintain continued treatment and disease control.     

The safety and efficacy of nivolumab for the treatment of advanced renal cell carcinoma

Introduction: Despite a variety of therapies for advanced advanced renal cell carcinoma (RCC) including vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors, outcomes for these patients are still not optimal. Immunotherapy with checkpoint inhibitors such as nivolumab, a fully human immunoglobulin (Ig) G4 PD-1 inhibitor antibody, is a promising development in RCC and provides a new therapeutic option for patients with advanced disease.

Areas Covered: This article reviews safety and efficacy data from the phase I, II, and III clinical trials that have led to the approval of nivolumab for the treatment of patients with advanced RCC who have previously been treated with VEGF-directed therapy.

Expert Commentary: Given the overall survival advantage with nivolumab compared to previously approved therapy, nivolumab is a new standard of care in the second-line setting for patients with advanced RCC. Additional studies are underway to answer important questions including the identification of biomarkes and the use of nivolumab in treatment-naïve patients.     

Metastatic basal cell carcinoma in the era of hedgehog signaling pathway inhibitors

BACKGROUND:

Inhibition of the hedgehog signaling pathway (HHSP) for the treatment of locally advanced basal cell carcinoma (BCC) and metastatic BCC (mBCC) has produced promising results. Typically, mBCC is not taken into consideration during the workup of a patient with multifocal metastatic disease who has a history of BCC. The objective of the current review, in which the authors evaluated the time from the first BCC diagnosis to metastasis, location of disease, and radiographic features, was to contribute to the general knowledge and awareness among providers, patients, and support groups about mBCC and to provide an outlook for the future of treatments for mBCC. A literature review on mBCC and a review of records from patients with mBCC who presented to Virginia G. Piper Cancer Center Clinical Trials (an oncology clinical trials center) were conducted. The clinical and radiographic findings of 22 patients with mBCC who were evaluated at that center from the initiation of smoothened (SMO) antagonist trials were analyzed along with a review of BCC epidemiology and pathogenesis, the HHSP, and current and future treatments for this rare presentation of the most common malignancy. The results indicated that, in the last 5 years, there has been a plethora of new agents targeting SMO, a key component of the HHSP that, for the majority of patients with mBCC, may be a good match for targeting tumor genetic vulnerability. Like with other targeted therapy for uncommon malignancies, such as chronic myelogenous leukemia and gastrointestinal stromal tumors, the authors anticipate that there will be clinical development of next‐generation HHSP inhibitors to combat mBCCs that are nonresponsive to or progress on current SMO antagonists. Cancer 2012. © 2012 American Cancer Society.     

顺铂联合氟尿嘧啶与顺铂联合多西他赛治疗局部晚期食管鳞状细胞癌的临床疗效

目的探讨顺铂联合氟尿嘧啶与顺铂联合多西他赛治疗局部晚期食管鳞状细胞癌的临床疗效、不良反应及对患者生活质量的影响。方法根据治疗方法的不同将86例局部晚期食管鳞状细胞癌患者分为对照组和观察组,每组43例,观察组患者采用顺铂联合多西他赛治疗,对照组患者采用顺铂联合氟尿嘧啶治疗。化疗完成3周后,对两组患者的临床疗效、不良反应、生活质量及治疗前后的血清癌胚抗原(CEA)和鳞状上皮细胞癌抗原(SCC-Ag)水平进行比较。结果观察组患者的总有效率为81.40%,高于对照组的65.12%,差异有统计学意义(P<0.05)。治疗后观察组患者的生活质量改善率为88.37%,高于对照组的65.12%(P<0.05)。观察组患者静脉炎、骨髓抑制、恶心呕吐的发生率均低于对照组(P<0.05)。治疗后两组患者的CEA、SCC-Ag水平均低于本组治疗前,且观察组患者的CEA、SCC-Ag水平均低于对照组,差异均有统计学意义(P<0.05)。结论与顺铂联合氟尿嘧啶方案相比,顺铂联合多西他赛治疗局部晚期食管鳞状细胞癌的临床疗效较好,不良反应发生率较低,患者耐受性较高,并可在一定程度上提高患者的生活质量,是治疗局部晚期食管鳞状细胞癌的可选方案。     

尼妥珠单抗联合IMRT治疗老年局部晚期食管癌患者的疗效观察

目的:探讨尼妥珠单抗联合适型调强放射治疗（IMRT）在局部晚期老年食管癌患者中的疗效和安全性。方法:67例老年局部晚期食管癌患者随机分为试验组和对照组,试验组34例予尼妥珠单抗联合IMRT治疗,对照组33例只行IMRT治疗。结果:试验组与对照组的近期有效率（RR）分别为85.2%和63.6%,疾病控制率（DCR）分别为97.1%和81.8%,差异均有统计学意义(P＜0.05）;1、2、3年生存率虽然试验组较对照组有提高,但差异无统计学意义(P＞0.05）;2组不良反应相似,差异无统计学意义(P＞0.05）。结论:尼妥珠单抗联合IMRT可以明显提高局部晚期老年食管癌患者的RR和DCR,但未明显提高患者的1、2、3年生存率。     

Spinal metastases of basal cell carcinoma

A case of spine metastasis of basal cell carcinoma and review of the literature are presented. The treatment approach is discussed.     

奈达铂联合放疗治疗局部晚期鼻咽癌的临床观察

目的探讨奈达铂联合放疗治疗局部晚期鼻咽癌的临床疗效及毒副作用。方法入组2010年1月至2012年1月在我院诊治的60例局部晚期鼻咽癌患者,给予同期放化疗治疗,随机分为对照组（顺铂）和观察组（奈达铂）,每组各30例,对两组近期疗效、远期疗效、毒副作用进行观察和比较。结果观察组与对照组的鼻咽部肿瘤、颈部淋巴结完全缓解率（20.0%vs 16.7%;66.7%vs 60.0%）和部分缓解率（76.7%vs 76.7%;33.3%vs 40.0%）差异无统计学意义（P〉0.05）;与对照组相比,观察组骨髓抑制（23.3%vs 50.0%）、恶心呕吐（36.7%vs 76.7%）发生率显著降低,差异有统计学意义（P〈0.05）。结论奈达铂联合放疗治疗局部晚期鼻咽癌的毒副作用少,安全性相对较高,值得临床推广。     

面部基底细胞癌的手术治疗

目的:探讨面部基底细胞癌合适的手术治疗方法和美容修复方法。方法:1994年1月～2004年11月,共收治面部基底细胞癌患者26例,根据美学理论与整形美容技术,分别采用直接缝合、皮片移植、局部皮瓣转移的方法修复创面。结果:在病灶扩大切除26例患者切口愈合良好,术后外形满意。结论:面部基底细胞癌首选手术治疗,适宜的手术方式与美学结合,可取得理想的治疗效果。     

局部晚期的早期子宫颈癌综合治疗模式探讨

目的：探讨局部晚期的早期宫颈癌（IB2和IIA期）综合治疗的模式。方法：2000年1月至2002年10月,我们以新辅化疗后＋放疗后,行宫颈癌根治术,治疗宫颈肿瘤≥4cm的局部晚期的早期宫颈癌224例,术后根据盆腔淋巴结转移、宫颈间质深层浸润、脉管内癌栓、组织分化差等高危因素给予化疗和外照射治疗。回顾性分析同期收治的IB2-IIA期宫颈癌100例,作为对照组,均行术前腔内后装放疗＋宫颈癌根治术。结果：治疗组与对照组癌细胞消失率差异有显著性（P=0.006）;癌细胞浅肌层浸润率差异也有显著性（P=0.002）;深肌层浸润率差异无显著性（P=0.316）。盆腔淋巴结转移率比较：髂血管区〉闭孔区〉骶前区同时合并髂血管区。结论：新辅助化疗＋术前后装联合手术治疗是局部晚期的早期宫颈癌综合治疗的较佳模式。宫颈癌术中有必要做骶前区淋巴结清扫。     

局部晚期的早期子宫颈癌综合治疗模式探讨

目的:探讨局部晚期的早期宫颈癌(IB2和IIA期)综合治疗的模式。方法:2000年1月至2002年10月,我们以新辅化疗后 放疗后,行宫颈癌根治术,治疗宫颈肿瘤≥4cm的局部晚期的早期宫颈癌224例,术后根据盆腔淋巴结转移、宫颈间质深层浸润、脉管内癌栓、组织分化差等高危因素给予化疗和外照射治疗。回顾性分析同期收治的IB2~IIA期宫颈癌100例,作为对照组,均行术前腔内后装放疗 宫颈癌根治术。结果:治疗组与对照组癌细胞消失率差异有显著性(P=0.006);癌细胞浅肌层浸润率差异也有显著性(P=0.002);深肌层浸润率差异无显著性(P=0.316)。盆腔淋巴结转移率比较:髂血管区>闭孔区>骶前区同时合并髂血管区。结论:新辅助化疗 术前后装联合手术治疗是局部晚期的早期宫颈癌综合治疗的较佳模式。宫颈癌术中有必要做骶前区淋巴结清扫。     

阿昔替尼与索拉非尼一线治疗晚期肾癌的临床疗效

目的:比较阿昔替尼与索拉非尼一线治疗晚期肾癌的临床疗效,探讨分子靶向药物阿昔替尼能否作为一线治疗晚期肾癌的优选药物.方法:选取海口市人民医院肿瘤科60例晚期肾癌患者,以数字表法随机分为试验组和对照组,每组30例.实验组给予阿昔替尼,对照组给予索拉非尼治疗,比较两组患者的DCR、ORR、PFS、OS及不良反应的差异.结果:两组患者均能完成试验并进行结果评价.试验组和对照组的DCR分别为83.33％和80.00％、ORR分别为20.00％和20.00％,差异均无统计学意义(P＞0.05);试验组和对照组的中位PFS分别为12.8个月和10.1个月,差异有统计学意义(P＜0.05);中位OS分别为22.2个月和22.8个月,差异无统计学意义(P＞0.05).两组患者不良反应发生率相近,差异无统计学意义(P＞0.05),主要表现在高血压、全身反应、手足皮肤综合征、消化道反应、肝功能损害,未见严重不良反应.结论:分子靶向药物阿昔替尼较索拉非尼一线治疗晚期肾癌更能延长患者中位PFS,两药治疗后患者的DCR、ORR、OS及不良反应相似,阿昔替尼可以作为一线治疗晚期肾癌的优选.     

局部进展期胰腺癌的多学科综合治疗

胰腺癌是恶性程度高且预后极差的消化系统肿瘤。对可手术切除的局限性胰腺癌,因其术后局部复发儿率也较高,故建议采用以手术为主的多学科综合治疗。外放射治疗是无法手术胰腺癌的主要治疗手段。对无法切除的局部进展期肿瘤,主要采用局部外放射治疗联合全身化疗的多学科综合治疗。Ⅲ期随机临床研究结果已经证实,同期联合放化疗较单一放射治疗对患者的生存具显著优势。与放射治疗同步应用的化疗药物目前主要包括5-FU、卡培他滨与吉西他滨等。同期联合放化疗中应用多药联合化疗方案可明显增加治疗相关的不良反应,但临床研究结果并未显示多药方案对疗效及患者预后有所助益。放疗技术目前推荐三维适形放射治疗或调强放疗（IMRT）。靶区范围建议包括临床影像检查可见肿瘤外放安全边界,对未被侵及的淋巴引流区域不行预防性照射。IMRT不仅可减低周围正常组织的照射剂量,还可提高肿瘤靶区的照射剂量,实现剂量递增。     

局部晚期乳腺癌的治疗体会

目的：观察85例III期乳腺癌患者治疗的疗效,寻找提高疗效的策略。方法：2003年6月至2005年12月85例III期乳腺癌患者接受了外科手术治疗,根据是否接受新辅助化疗分为手术组（41例）和新辅助化疗组（44例）,比较两组的手术性质及治疗结果。结果：新辅助化疗组的无病生存期为59.1个月,明显高于手术组的43.1个月（P〈0.05）,新辅助化疗组的5年无病生存率为36.16%,手术组为34.14%（P〉0.05）。结论：局部晚期乳腺癌患者接受新辅助化疗后手术可提高无病生存时间,值得临床推广。     

Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE,an international,open-label trial

BackgroundThe SafeTy Events in VIsmodEgib study (STEVIE, ClinicalTrials.gov, NCT01367665), assessed safety and efficacy of vismodegib—a first-in-class Hedgehog pathway inhibitor demonstrating clinical benefit in advanced basal cell carcinoma (BCC)—in a patient population representative of clinical practice. Primary analysis data are presented.Patients and methodsPatients with locally advanced or metastatic BCC received oral vismodegib 150 mg/d until progressive disease, unacceptable toxicity, or withdrawal. Primary objective was safety. Efficacy variables were assessed as secondary end-points.ResultsEvaluable adult patients (N = 1215, 1119 locally advanced; 96 metastatic BCC) from 36 countries were treated; 147 patients (12%) remained on study at time of reporting. Median (range) treatment duration was 8.6 (0–44) months. Most patients (98%) had ≥1 treatment-emergent adverse event (TEAE). The incidence of the most common TEAEs was consistent with reports in previous analyses. No association between creatine phosphokinase (CPK) abnormalities and muscle spasm was observed. Serious TEAEs occurred in 289 patients (23.8%). Exposure ≥12 months did not lead to increased incidence or severity of new TEAEs. The majority of the most common TEAEs ongoing at time of treatment discontinuation resolved by 12 months afterwards, regardless of Gorlin syndrome status. Response rates (investigator-assessed) in patients with histologically confirmed measurable baseline disease were 68.5% (95% confidence interval (CI) 65.7–71.3) in patients with locally advanced BCC and 36.9% (95% CI 26.6–48.1) in patients with metastatic BCC.ConclusionsThe primary analysis of STEVIE demonstrates that vismodegib is tolerable in typical patients in clinical practice; safety profile is consistent with that in previous reports. Long-term exposure was not associated with worsening severity/frequency of TEAEs. Investigator-assessed response rates showed high rate of tumour control.ClinicalTrials.govNCT01367665.     

局部晚期鼻咽癌患者营养状况及其与预后相关性分析

目的:探讨局部晚期鼻咽癌患者营养状况及其与预后相关性。方法:分析2015年8月至2017年3月湖北省肿瘤医院收治的局部晚期鼻咽癌住院患者53例,联合运用患者主观整体营养评估量表(patient-generated subjective global assessment,PGSGA)、体格测量、血液学指标和放化疗不良反应,全面评估患者营养状况;采用Kaplan-Meier法及Cox风险比例回归模型对患者生存及影响因素进行分析。结果:53例患者中,94.3%(50/53)的患者出现体质量下降,下降均值为(6.89±0.54)kg,50.9%(27/53)的患者体质量下降≥10%;PG-SGA评估的患者重度营养不良发生率为84.9%(45/53);淋巴细胞计数、红细胞、血红蛋白、白蛋白与PG-SGA评分高度负相关(P<0.05),口腔黏膜炎、吞咽困难或疼痛、厌食、体质量下降百分比与PG-SGA评分高度正相关(P<0.05);单因素及多因素分析显示,TNM分期晚、治疗期间体质量下降≥10%与局部晚期鼻咽癌患者预后不良相关,而白细胞计数增加(在正常值范围内)与局部晚期鼻咽癌患者预后...     

The safety and efficacy of neoadjuvant PD-1 inhibitor with chemotherapy for locally advanced esophageal squamous cell carcinoma

BackgroundNeoadjuvant therapy followed by esophagectomy has been recognized as an effective treatment for locally advanced esophageal cancer, though still has a dismal prognosis. Antibodies against programmed death 1 (PD-1) protein improve survival in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) compared with chemotherapy in second-line therapy. However, neoadjuvant PD-1 inhibitor combined with chemotherapy has not been tested in locally advanced ESCC. We conducted this study to evaluate the efficacy and safety of pd-1 inhibitor in neoadjuvant chemotherapy.MethodsIn this study, we administered 28 adults with untreated, surgically resectable locally advanced ESCC. PD-1 inhibitor with chemotherapy [albumin paclitaxel 100 mg/m² on days 1 and 8 + carboplatin with an area under the curve (AUC) of 5 on day 1] were administered every 3 weeks intravenously, and surgery was performed approximately 3–5 weeks after the second dose. The primary purpose of the study was to evaluate the feasibility and safety of this regimen.ResultsIn all, 28 locally advanced ESCC patients were enrolled, 27 patients received surgery, 9 (33.3%) patients’ postoperative pathological specimens suggested pCR, and 11 (40.7%) patients’ primary tumor suggested complete response. Neoadjuvant PD-1 inhibitor with chemotherapy had an acceptable side-effect profile, 26 patients’ tumors were completely resected (96.3% were R0). According to the RESIST v.1.1, the response in all 27 patients was evaluated by a computed tomography (CT) scan before surgery, showing 12 patients with complete response (CR), 12 with partial response (PR), and 3 with stable disease (SD). For surgical procedures, 15 (55.6%) patients underwent minimal invasive surgery, 4 (14.8%) underwent right transthoracic open esophagectomy, and 8 (29.6%) underwent hybrid approaches.ConclusionsThe novel treatment of PD-1 inhibitor with chemotherapy in the neoadjuvant setting for locally advanced ESCC produced satisfactory outcomes: an unprecedentedly high pCR rate for neoadjuvant chemotherapy, a high R0 resection rate, and a low-toxicity profile were achieved. The long-term efficiency of this novel treatment and the validity of the present findings should be confirmed with longer follow-up and prospective comparative trials.     

Gemcitabine and cisplatin in a multimodality treatment for locally advanced non-small cell lung cancer

The role of new cytotoxic agents like gemcitabine has not yet been proven in the neoadjuvant settings. We designed a phase II study to test the feasibility of using gemcitabine and cisplatin before local treatment for stage III non-small cell lung cancer patients. Patients received three cycles of induction chemotherapy of gemcitabine (1000 mg m(-2), days 1, 8, 15) and cisplatin (90 mg m(-2), day 15) every 4 weeks before evaluation for operability. Operable patients underwent radical resection. Inoperable patients and patients who had incomplete resection received concurrent chemoradiotherapy with daily low dose cisplatin. All patients who did not progress after local treatment received three more cycles of adjuvant chemotherapy of gemcitabine and cisplatin. Fifty-two patients received induction treatment. Two patients had complete response and 31 patients had partial response (response rate 63.5%) after induction chemotherapy. Thirty-six patients (69%) were operable. Eighteen patients (35%) had their tumours completely resected. Two patients had pathological complete response. Median overall survival was 19.1 months, projected 1-year survival was 66% and 2-year survival was 34%. Three cycles of gemcitabine and cisplatin is effective and can be used as induction treatment before surgery for locally advanced non-small cell lung cancer patients.