Biomarkers for predicting the response of esophageal squamous cell carcinoma to neoadjuvant chemoradiation therapy

This review summarizes and evaluates the literature regarding the biomarkers for predicting the response and/or prognosis of esophageal squamous cell carcinoma (ESCC) patients treated with neoadjuvant chemoradiation therapy (CRT). There are seven categories of molecules known to correlate with the response and/or prognosis: tumor suppressors (p53, p21), cell cycle regulators (Cyclin D1, CDC25B, 14-3-3sigma), DNA repair molecules (p53R2, ERCC1), drug resistance proteins [metallothionein (MT)], angiogenic factors (VEGF), molecules involved in cell proliferation/invasion/metastasis (Ki-67, COX-2) and hedgehog signaling molecules (Gli-1). Of the above molecules, the tumor suppressor p53 is expected to be a representative biomarker for predicting the response and prognosis. The cell cycle markers CDC25B and 14-3-3sigma have potential as response biomarkers independent of the p53 status. The DNA repair markers, p53R2 or ERCC1, angiogenic molecule (VEGF), and hedgehog signaling pathway factor Gli-1 also have potential to predict the response and prognosis of ESCC. However, there are still many unanswered questions with regard to predicting the clinical effects of neoadjuvant CRT.     

早期和浅表性食管鳞状细胞癌内镜治疗现状

食管癌目前已成为我国主要恶性肿瘤之一,其发病率和病死率逐年增加,发病原因多而复杂。早期食管鳞状细胞癌是指局限于食管黏膜层的鳞状细胞癌,而侵犯到黏膜下层的鳞状细胞癌属于浅表性食管癌。随着内镜检查的普及和技术的进步,早期和浅表性食管鳞状细胞癌的诊断率不断提高,目前内镜下治疗的方法主要有内镜下切除和非切除治疗,其中内镜下切除治疗主要有内镜下黏膜切除术、内镜下黏膜剥离术等,相对于手术治疗,内镜下切除治疗具有安全、创伤小、操作简单、并发症少等优点,提高了患者的生存质量。但对于淋巴结转移风险较大的患者,若行内镜下治疗后,建议术后密切随访。随着针对较大病变的内镜下隧道式黏膜下剥离术等技术的开展,内镜下治疗将会为早期食管肿瘤的患者提供更好的治疗方案。     

Endoscopic ultrasonography in the diagnosis of esophageal carcinoma

Summary In selection for esophageal cancer treatment, it is necessary to evaluate the tumor stage. We have used endoscopic ultrasonography (EUS) for diagnosis of the depth of cancer invasion and the presence of lymph node metastasis since 1983. The EUS image of the normal esophageal wall showed 5 layers. In all, 222 cases of esophageal cancer were examined with EUS, and a radical operation was performed on 139. In 78 of those cases, the scope was passed beyond the cancer site, and total observation was achieved (56%). The extent of cancer invasion was correctly determined in these 78 cases (84%). Thoracic lymph nodes that could be detected by EUS were located in the posterior mediastinum and measured more than 3 mm in diameter. Diagnostic criteria for lymph node metastasis were designated as follows: (1) spherical shape, (2) a distinct border, and (3) heterogenous echo spots within the nodes. The above criteria yielded a sensitivity of 87%, a specificity of 90%, and an overall accuracy of 89% according to the histological examination of the removed lymph nodes.     

Endoscopic ultrasonography in the diagnosis of esophageal carcinoma

In selection for esophageal cancer treatment, it is necessary to evaluate the tumor stage. We have used endoscopic ultrasonography (EUS) for diagnosis of the depth of cancer invasion and the presence of lymph node metastasis since 1983. The EUS image of the normal esophageal wall showed 5 layers. In all, 222 cases of esophageal cancer were examined with EUS, and a radical operation was performed on 139. In 78 of those cases, the scope was passed beyond the cancer site, and total observation was achieved (56%). The extent of cancer invasion was correctly determined in these 78 cases (84%). Thoracic lymph nodes that could be detected by EUS were located in the posterior mediastinum and measured more than 3 mm in diameter. Diagnostic criteria for lymph node metastasis were designated as follows: (1) spherical shape, (2) a distinct border, and (3) heterogenous echo spots within the nodes. The above criteria yielded a sensitivity of 87%, a specificity of 90%, and an overall accuracy of 89% according to the histological examination of the removed lymph nodes.     

The postoperative platelet distribution width is useful for predicting the prognosis in patients with esophageal squamous cell carcinoma

Surgery Today - The platelet distribution width (PDW) is reportedly useful as a prognostic indicator for some cancers. However, its prognostic significance in esophageal squamous cell carcinoma...     

Postoperative therapy of recurrent esophageal squamous cell carcinoma

Some 218 resected cases and 43 autopsied cases after resection during the last 13 years were analyzed with regard to the mode of recurrence and survival. Several factors were investigated with the following results. 1) Extensive clearance of upper mediastinal lymph nodes during radical surgery may reduce the incidence of tumor recurrence. It is preferable to remove the cervical lymph node, however, after positive metastasis to cervical lymph node. 2) Beginning in 1981, interstitial brachytherapy of 192Ir seed assemblies using afterloading techniques was administered to two patients with esophageal carcinoma infiltrating the aorta and four patients infiltrating the trachea and main bronchus which were not completely resected in either case due to invasion of adjacent organs. No significant difference in life-prolongation was observed, but it may have been effective for prevention of localized recurrence in cases with aortic infiltration and with infiltration of the trachea and bronchus. 3) From 1984, eleven patients with recurrent squamous cell esophageal carcinoma were treated with combination chemotherapy sandwiched with irradiation (CDDP/5FU-RT-CDDP/5FU). Eight patients (73%) had complete or partial response, and six patients survived over one year after combination chemotherapy sandwiched with irradiation. Combination chemotherapy sandwiched with irradiation appears to be effective in the treatment of patients with recurrent squamous cell carcinoma of the esophagus. Toxic effects are moderate and manageable.     

Bronchoscopic ultrasonography for staging supracarinal esophageal squamous cell carcinoma: impact on outcome

The precise, accurate diagnosis of malignant airway invasion is essential to determine the likelihood of complete resection and survival of patients with invasive carcinoma of the upper esophagus. The usefulness of ultrasonic scanning of the tracheobronchial wall by bronchoscopic ultrasonography (BUS) was studied, and results were compared with those of computed tomography (CT). Sixty-six consecutive patients with advanced squamous cell carcinoma of the upper esophagus treated from 1997 to 2000 were studied. The presence of tracheobronchial invasion was diagnosed by BUS based on an interruption in the most external hyperechoic layer of the tracheobronchus (corresponding to its adventitia). BUS was completed without any complication in all patients. The accuracy of diagnosis was validated intraoperatively, and it was better for BUS (90%) than for CT (62%) ( p = 0.001). Of the 26 patients diagnosed as being invasion-free by BUS, only 2 had invasion, compared to 7 of 22 patients who had invasion after CT scans had suggested they did not. Survival was worse for patients diagnosed as having invasion than not having it based on CT scans ( p = 0.0071), but the difference was more significant with BUS ( p < 0.0001). BUS is a safe, reliable staging modality for cancer in the upper esophagus. When surgery is considered, BUS is essential for determining whether a curative resection is possible.     

Neoadjuvant therapy of esophageal squamous cell carcinoma: response evaluation by positron emission tomography

OBJECTIVE: To evaluate the use of positron emission tomography using [(18)F]-fluorodeoxyglucose (FDG-PET) to assess the response to neoadjuvant radiotherapy and chemotherapy in patients with locally advanced esophageal cancer. SUMMARY BACKGROUND DATA: Imaging modalities, including endoscopy, endoscopic ultrasound, computed tomography, and magnetic resonance imaging, currently used to evaluate response to neoadjuvant treatment in esophageal cancer do not reliably differentiate between responders and nonresponders. METHODS: Twenty-seven patients with histopathologically proven squamous cell carcinoma of the esophagus, located at or above the tracheal bifurcation, underwent neoadjuvant therapy consisting of external-beam radiotherapy and 5-fluorouracil as a continuous infusion. FDG-PET was performed before and 3 weeks after the end of radiotherapy and chemotherapy (before surgery). Quantitative measurements of tumor FDG uptake were correlated with histopathologic response and patient survival. RESULTS: After neoadjuvant therapy, 24 patients underwent surgery. Histopathologic evaluation revealed less than 10% viable tumor cells in 13 patients (responders) and more than 10% viable tumor cells in 11 patients (nonresponders). In responders, FDG uptake decreased by 72% +/- 11%; in nonresponders, it decreased by only 42% +/- 22%. At a threshold of 52% decrease of FDG uptake compared with baseline, sensitivity to detect response was 100%, with a corresponding specificity of 55%. The positive and negative predictive values were 72% and 100%. Nonresponders to PET scanning had a significantly worse survival after resection than responders. CONCLUSION: FDG-PET is a valuable tool for the noninvasive assessment of histopathologic tumor response after neoadjuvant radiotherapy and chemotherapy.     

Current status of and perspectives regarding neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma

The significance of neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) remains controversial with regard to the pathological response and long-term survival. We herein review the current status of and future perspectives regarding NACRT followed by esophagectomy for locally advanced ESCC. Some studies have suggested that a pathological complete response with NACRT is more common in patients with ESCC than in those with adenocarcinoma and that NACRT provided a survival benefit limited to patients with ESCC. However, NACRT may increase the risk of postoperative complications after esophagectomy. It is obvious that a favorable pathological response is the most important factor for obtaining a survival benefit, although no established parameters have been implemented clinically to predict the response to NACRT. Prospective clinical studies and basic research studies to identify predictive biomarkers for the response to NACRT are needed to aid in the development of NACRT treatment strategies for patients with ESCC.     

食管癌术前放化疗后临床再分期的评价

目的探讨食管癌患者术前放化疗（pre-CRT）后采用影像学和内镜检查进行临床再分期的临床价值。方法对27例局部晚期食管鳞癌患者,在接受CRT治疗前采用颈部和胸部及腹部CT、食管超声内镜（EUS）、电子气管镜及PET-CT等检查进行临床分期;完成pre-CRT后再次进行分期。临床疗效评价采用RECIST标准,放化疗后3～6周施行手术,将术后病理结果与术前分期进行对照研究。对常规病理学检测为pT0和pN0病例的组织切片,采用免疫组织化学（免疫组化）染色检测原发灶及淋巴结中的微小肿瘤残留灶。结果全组pre．CRT后,CT对T及N分期的准确率分别为40．9％（9／22）和68．2％（15／22）,总的分期准确率为40．9％（9／22）;EUS对T及N分期的准确率分别为38．5％（5／13）和69．2％（9／13）,总的分期准确率为38．5％（5／13）。联合CT和EUS总的分期准确率为46．2％（6／13）。CRT结束后临床评价完全缓解（CR）5例,部分缓解（PR）14例,无缓解（SD）8例。5例临床评价cR者术后病理证实3例CR,1例pT3N1,1例虽经苏木精．伊红染色为pT0N0,但经免疫组化检测发现淋巴结存在微小肿瘤病灶残留。而术后病理结果pCR的5例患者中,除3例术前评价为CR外。另2例术前临床评价为PR。在15例N0的病例中,免疫组化检测有2例3个淋巴结仍可见食管癌细胞分布于其周边。结论目前常用的临床检查分期手段（食管吞钡、CT、EUS、内镜下病理活检等）和临床疗效评价手段（RECIST标准）对食管癌放化疗后的肿瘤组织反应评价准确率不高。建议CRT后临床评价食管癌CR的患者。仍应接受手术治疗。     

Molecular biomarkers as predictors of response to neoadjuvant chemoradiation therapy in rectal cancer

The standard management of locally advanced rectal cancer includes neoadjuvant chemoradiation therapy (CRT) with 5-fluorouracil (5-FU) and concurrent pelvic irradiation (RT) to 45–50.4 Gy. This regimen results in downstaging in approximately 60% of patients and a pathological complete response (pCR) in 20%. Response to CRT is associated with improved rates of survival, local control, and sphincter preservation. However, some tumors are completely resistant to CRT; thus, non-responding patients experience only the toxicity of this treatment without any of its benefits. The ability to predict an individual patient’s response to CRT would enable delivery of more effective treatment: patients predicted to respond would be directed to undergo CRT, while those predicted not to respond would be guided to alternative therapies or primary surgical resection. Molecular biomarkers have significant potential for predicting tumor regression. Furthermore, they may represent novel targets for therapeutic agents. Many studies have yielded promising results; to date, however, they have often lacked reproducibility. This review aims to summarize our current understanding of molecular biomarkers that may be used to predict response to CRT in rectal cancer.     

Swallowing dysfunction after chemoradiation for advanced squamous cell carcinoma of the head and neck

BACKGROUND: Swallowing dysfunction is a common side effect of chemoradiation. METHODS: Twelve patients with stage III or IV squamous cell carcinoma of the head and neck were enrolled. Videofluorographic swallowing studies were performed before initiation of chemoradiation to provide baseline swallowing function data. Postchemoradiation videofluorographic swallowing studies were performed from 1 to 14 weeks after the completion of treatment (mean, 8 weeks). RESULTS: Changes in swallowing physiology after treatment included decreased base of tongue to posterior pharyngeal wall contact (p =.0010) and reduced pharyngeal contraction (p =.0313), resulting in impaired bolus transport through the pharynx. In addition, decreased laryngeal elevation (p =.0039), decreased laryngeal vestibule closure (p =.0078), and laryngeal penetration (p =.0078) were present. Bolus volume did not have a significant effect on swallowing ability. Aspiration was observed in four patients. CONCLUSIONS: Organ preservation treatment impairs movement of structures essential for normal swallowing. Prophylactic swallowing exercises may benefit these patients.     

关于食管鳞状细胞癌免疫治疗的几点思考

近几年免疫治疗食管鳞状细胞癌取得了很大的进展.但是对于胸外科医生而言,免疫治疗还是个新生事物,缺乏足够的经验.因此,本文试图就一些免疫治疗的热点问题进行探讨,包括免疫治疗的适应证、不良反应、疗效以及疗效的判定等,以期引起胸外科医生的重视.     

Endoscopic ultrasonography in the staging of esophageal carcinoma after preoperative radiotherapy and chemotherapy.

BACKGROUND: In past years multimodal neoadjuvant treatment for carcinoma of the esophagus has been used with increased frequency. Staging of the neoplasm still remains fundamental in evaluating the response to therapy and in planning operation. The aim of the present study was to assess the accuracy of endoscopic ultrasonography (EUS) in a group of patients with squamous cell carcinoma of the thoracic esophagus after undergoing radiotherapy and chemotherapy. METHODS: Among a group of 111 patients with squamous cell carcinoma of the thoracic esophagus and treated with preoperative radiotherapy and chemotherapy, 87 were operated. In these patients it was possible to compare the results of EUS, with regard to depth of invasion of esophageal wall (T) and lymph node involvement (N), with the results of operation and histopathologic study. RESULTS: Feasibility of EUS before and after neoadjuvant treatment was 71.2% and 83.9%, respectively. The overall accuracy of EUS regarding the wall invasion was 47.9%. The more frequent error was overstaging, especially in patients with complete response and in patients with minimal residual disease. In the assessment of lymph node involvement, EUS showed an overall accuracy of 71.2% with a moderate kappa value. Sensitivity for N1 and NO was 73.7% and 68.6%, respectively. CONCLUSIONS: Endoscopic ultrasonography was feasible in most patients after preoperative radiotherapy and chemotherapy, but our study documented a worsening of accuracy of EUS in the evaluation of T attributable to the confounding presence of radiation fibrosis and soft tissue reaction after radiotherapy and chemotherapy.