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.     

Multidisciplinary approach to esophageal and gastric cancer

Despite marked advances in surgical therapy for patients with esophageal, esophagogastric, and gastric cancers, the overall prognosis of these patients has not markedly improved during the past decades. Multidisciplinary approaches using adjuvant postoperative and neoadjuvant preoperative therapeutic principles have received increasing attention with regard to the management of these patients. A series of randomized, prospective trials has demonstrated that adjuvant postoperative radiation or chemotherapy does not result in a convincing survival advantage after complete tumor resection in esophageal, esophagogastric junction, or gastric cancer. The available data on the role of neoadjuvant preoperative therapy are not yet conclusive. Although neoadjuvant therapy may reduce the tumor mass in many patients, several randomized, controlled trials have shown that, compared with primary resection, a multimodal approach does not result in a survival benefit in patients with locoregional, that is, potentially resectable, tumors. In contrast, in patients with locally advanced tumors, that is, patients in whom complete tumor removal with primary surgery seems unlikely, neoadjuvant therapy increases the likelihood of complete tumor resection on subsequent surgery, but only patients with objective histopathologic response to preoperative therapy seem to benefit from this approach. Consequently, in the future, improvements in the overall survival of patients with esophageal, esophagogastric junction, or gastric cancer most likely will be achieved only by tailored therapeutic strategies that are based on the individual tumor location, tumor stage, and consideration of established prognostic factors. A clear classification of the underlying tumor entity, a profound knowledge of the prognostic factors applicable, a thorough preoperative staging, and identification of parameters that allow for the prediction of response to preoperative therapy will become essential for the selection of the optimal therapeutic modality for individual patients.     

Multimodality treatment for esophageal cancer: the role of surgery and neoadjuvant therapy

Treatment of esophageal cancer has traditionally included surgery as the initial modality. Neoadjuvant chemoradiation therapy has been introduced with the goal of downstaging tumors before surgical resection; however, its role in esophageal cancer remains controversial. We report 116 patients who underwent esophagogastrectomy with reconstruction for carcinoma of the esophagus or esophagogastric junction over a 10-year period (January 1, 1990 to June 1, 2001). Forty patients underwent neoadjuvant radiation and chemotherapy followed by surgery. Hospital mortality in this group was 7.5 per cent, complete pathologic response (CPR) was 37.5 per cent, and overall 3- and 5-year survival rates were 47 and 38 per cent. Five-year survival in the 15 patients with CPR was 85 per cent. Five patients underwent neoadjuvant single-agent therapy (four chemotherapy and one radiation) followed by surgery, and none survived to 3 years. Seventy-one patients underwent surgery without neoadjuvant therapy. Hospital mortality in this group was 1.4 per cent, with 3- and 5-year survival of 21 and 17 per cent--a decreased long-term survival compared with the neoadjuvant therapy group despite the observation that patients who underwent neoadjuvant therapy had a larger tumor size on presentation (5.5 +/- 0.4 cm vs 3.8 +/- 0.2 cm; P = 0.002). Squamous cell carcinomas seemed to be more responsive to neoadjuvant radiation and chemotherapy followed by surgery than were adenocarcinomas, with a CPR of 44.4 versus 35.5 per cent; however, 5-year survival rates in these complete responders were not significantly different (100% and 78%, respectively; P = 0.97). We report that esophagogastrectomy in conjunction with neoadjuvant therapy results in increased survival compared with surgery without neoadjuvant therapy (P < 0.01), although there may be an increased perioperative mortality associated with neoadjuvant therapy. Further studies are needed to evaluate the role of preoperative chemoradiation and to better identify the pretreatment characteristics of patients with a complete pathological response.     

Survival After Neoadjuvant Therapy Compared with Surgery Alone for Resectable Esophageal Cancer in a Population-based Study

Background Esophagectomy remains the standard treatment for resectable esophageal cancer, but the cure rate is low. Neoadjuvant therapy has been tried in attempts to prolong survival and reduce tumor recurrence. The aim of this study was to assess the surgical outcomes with and without neoadjuvant treatment for resectable esophageal cancer in a population-based setting. Methods All 1,155 patients treated with esophagectomy for esophageal cancer in Sweden in 1987 through 2000 with or without neoadjuvant therapy were identified and followed up in nationwide registers up to 18 October 2004. Tumor characteristics and response to neoadjuvant treatment were obtained from histopathological reports. Hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for potential confounding factors were calculated by a Cox proportional hazards regression model. Results Overall survival was similar in the groups with and without neoadjuvant therapy (adjusted HR 0.99, 95% CI 0.86–1.16). The 3-year survival rates were 34.6% and 32.0%, respectively. Survival was better among the 27.6% of the neoadjuvant group with a complete histopathological response (HR 0.71, 95% CI 0.53–0.94) compared with the surgery only group. Patients without complete response to neoadjuvant therapy had seemingly poorer survival (HR 1.10, 95% CI 0.94–1.29). Conclusions Surgical outcomes with and without neoadjuvant therapy were equivalent. Only patients with a complete histopathological response after neoadjuvant treatment had better survival.     

Magen- und Adenokarzinome des ?sophagogastralen ��bergangs

According to the current European and German S3 guidelines, neoadjuvant chemotherapy is now an integral part of the treatment of locally advanced gastric cancer and adenocarcinoma of the esophagogastric junction. Neoadjuvant therapy seeks to achieve downsizing of the primary tumor, lowering of the T and N categories and eradication of micrometastases. As the indications for neoadjuvant treatment are based on pretherapeutic information alone, a sophisticated clinical staging plays a central role. Despite all progress made in the field of diagnostic work-up, clinical staging often fails. Despite this fact, controlled randomized trials showed that neoadjuvant chemotherapy enhances the rate of curative (R0) resections and reduces the likelihood of systemic relapse. Overall, survival can be improved by neoadjuvant chemotherapy. The current research is focused on the molecular prediction of response and early response monitoring with functional imaging. New targeted drugs are being integrated into the peri-operative treatment.     

Preoperative radiochemotherapy of esophageal carcinoma. Light at the end of the tunnel?

Studies on neoadjuvant therapy of esophageal cancer showed that not either preoperative chemotherapy or radiotherapy lead to a significant improvement of prognosis. However, two prospective studies showed a significant prognostic improvement after neoadjuvant combined radio/chemotherapy. Most treatment protocols include a radiation with 30-45 Gy and a simultaneous therapy with Cis-Platin/5-Fluorouracil. As an increase of perioperative morbidity and mortality has to be expected through this treatment, a careful selection of patients is necessary. Several studies have shown that mostly patients with good response benefit from this neoadjuvant therapy. The clinical response evaluation is difficult and response is best proved by classification of the histomorphologic regression of the tumor. For future research, predictive response analyses based on molecular biologic and immuno-histochemic techniques are of great importance and first differentiations by biomarkers have been detected.     

Pretreatment Gene Expression Profiles Can Be Used to Predict Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer

BACKGROUND: The use of neoadjuvant therapy, in particular chemoradiotherapy (CRT), in the treatment of esophageal cancer (EC) remains controversial. The ability to predict treatment response in an individual EC patient would greatly aid therapeutic planning. Gene expression profiles of EC were measured and relationship to therapeutic response assessed. METHODS: Tumor biopsy samples taken from 46 EC patients before neoadjuvant CRT were analyzed on 10.5K cDNA microarrays. Response to treatment was assessed and correlated to gene expression patterns by using a support vector machine learning algorithm. RESULTS: Complete clinical response at conclusion of CRT was achieved in 6 of 21 squamous cell carcinoma (SCC) and 11 of 25 adenocarcinoma (AC) patients. CRT response was an independent prognostic factor for survival (P < .001). A range of support vector machine models incorporating 10 to 1000 genes produced a predictive performance of tumor response to CRT peaking at 87% in SCC, but a distinct positive prediction profile was unobtainable for AC. A 32-gene classifier was produced, and by means of this classifier, 10 of 21 SCC patients could be accurately identified as having disease with an incomplete response to therapy, and thus unlikely to benefit from neoadjuvant CRT. CONCLUSIONS: Our study identifies a 32-gene classifier that can be used to predict response to neoadjuvant CRT in SCC. However, because of the molecular diversity between the two histological subtypes of EC, when considering the AC and SCC samples as a single cohort, a predictive profile could not be resolved, and a negative predictive profile was observed for AC.     

食管癌新辅助放化疗疗效预测分子标志物

局部晚期食管癌单纯手术治疗预后较差,新辅助放化疗并手术治疗的方案可明显延长食管癌患者的总体生存时间.目前,该治疗方案已成为欧美国家及我国对局部晚期食管癌进行规范化治疗的指南.然而,由于只有经新辅助放化疗后获得病理缓解的患者可从中获益,治疗无反应的患者预后可能比单纯手术更差.因此,预测食管癌新辅助放化疗的疗效,区分优势人群和耐受人群,从而实现个体化的治疗极为重要.分子标记物用于预测食管癌新辅助放化疗的疗效研究前景广阔,有望广泛应用于临床实践,指导局部晚期食管癌个体化治疗方案的决策.     

Apoptotic and proliferative indexes in esophageal cancer: predictors of response to neoadjuvant therapy [corrected].

Altered expression of the genes that control apoptosis and proliferation may influence the response of cancer cells to cytotoxic agents. The primary aim of this study was to determine the role of the novel antiapoptotic and cell cycle gene, survivin, in apoptotsis and proliferation in esophageal cancer and to evaluate whether the survivin, p53, and bcl-2 status were able to predict a patient's response to neoadjuvant therapy. A total of 104 patients with esophageal tumors were studied. Tumor tissue was immunostained for survivin, p53, and bcl-2 proteins. Proliferative and apoptotic activity was measured using ki-67 immunohistochemical analysis and the TUNEL method, respectively. Forty-eight patients whose pretreatment biopsies were analyzed received neoadjuvant chemoradiation therapy or chemotherapy followed by surgery. Outcome was graded as a complete response, a partial response, or no response according to the results of histologic examination and CT imaging. Expression of survivin was found to correlate significantly with the proliferative index but not the apoptotic index. Patients who received neoadjuvant treatment were more likely to achieve a complete response if their tumors had high proliferative activity, and p53 positive tumors were more likely to contain residual tumor after treatment. In conclusion, survivin expression appears to foster proliferative activity in esophageal cancer, and tumors with a high proliferative index or a functioning p53 gene are more responsive to neoadjuvant chemoradiation therapy.     

Multimodal Treatment of Gastrointestinal Tract Tumors: Consequences for Surgery

Formerly an exclusive business of surgery, gastrointestinal (GI) tumors are nowadays increasingly approached with multimodal strategies. Neoadjuvant concepts have had a particularly far-reaching impact on surgery and have contributed to improved survival. Modern pre-treatment staging and risk assessment provide the basis for decision on one of three general treatment concepts (1) Early cancers, confined to the mucosal/submucosal layers, are approached with primary surgery, without prior antineoplastic therapy. (2) Systemically metastasized tumors receive merely palliative treatment. (3) Locally advanced cancers are increasingly approached with neoadjuvant strategies. The benefit from these preoperative protocols is proven for diverse entities, but is evidently confined to a specific subgroup patients, i.e., the responders to neoadjuvant treatment. These are the ones benefiting most from subsequent surgical resection, which is required to ensure complete removal of the residual tumor tissue, as complete tumor regression occurs very rarely and cannot be proven without a specimen. The fact that responders will benefit and non-responders will not benefit or will even deteriorate during the neoadjuvant treatment makes early response prediction most demanding. An amazing new approach is the use of position emission tomography with fluro-desoxyglucose (FDG-PET) to assess the "metabolic response," which is possible as early as 14 days after initiation of the neoadjuvant protocol. This strategy offers the chance for modulating the surgical approach in accord i.e., with such metrobolic response termination of the protocol and proceeding to resection in the case of nonresponse.The future of GI cancer surgery is multimodal therapy in a response-based fashion and requires reponse-based trials for further evaluation.     

影像学对直肠癌新辅助治疗后分期的评估价值

局部进展期直肠癌的标准治疗方案是术前新辅助放化疗联合手术的综合治疗.高达30％的局部进展期直肠癌患者经过新辅助治疗后可以达到病理完全缓解（pCR）.研究显示,病理完全缓解的病例,局部复发率低、预后较好.故有学者提出,对新辅助治疗后达到部分或完全临床缓解（cCR）的病例,可分别采取手术局部切除术或严密随访的治疗方案,以避免根治性手术带来的风险或功能障碍.当前,影像学检查能对新辅助治疗前的直肠癌进行准确分期,但治疗所引起的肿瘤及周围组织的改变,会影响治疗后再分期的准确性,尤其是预测pCR的准确性一直比较低.如何在术前判定新辅助治疗后达到pCR,是目前人们关注的问题.本文以术后病理结果为标准,就当前常用影像学技术在直肠癌新辅助治疗后分期诊断中的价值及pCR的预测作一简要综述。     

Nutritional Support with Endoluminal Stenting During Neoadjuvant Therapy for Esophageal Malignancy

Background  

Perioperative nutrition remains a significant problem in patients undergoing neoadjuvant treatment for esophageal cancer. The aim of this study was to evaluate the effectiveness of esophageal stenting, feeding tube placement, or observation among esophageal cancer patients receiving neoadjuvant therapy.     

Apoptotic and proliferative indexes in esophageal cancer: Predictors of response to neoadjuvant therapy apoptosis and proliferation in esophageal cancer

Altered expression of the genes that control apoptosis and proliferation may influence the response of cancer cells to cytotoxic agents. The primary aim of this study was to determine the role of the novel an-tiapoptotic and cell cycle gene, survivin, in apoptotsis and proliferation in esophageal cancer and to evaluate whether the survivin, p53, and bcl-2 status were able to predict a patient’s response to neoadjuvant therapy. A total of 104 patients with esophageal tumors were studied. Tumor tissue was immunostained for survivin, p53, and bcl-2 proteins. Proliferative and apoptotic activity was measured using ki-67 immu-nohistochemical analysis and the TUNEL method, respectively. Forty-eight patients whose pretreat-ment biopsies were analyzed received neoadjuvant chemoradiation therapy or chemotherapy followed by surgery. Outcome was graded as a complete response, a partial response, or no response according to the results of histologic examination and CT imaging. Expression of survivin was found to correlate significantly with the proliferative index but not the apoptotic index. Patients who received neoadjuvant treatment were more likely to achieve a complete response if their tumors had high proliferative activity, and p53 positive tumors were more likely to contain residual tumor after treatment. In conclusion, survivin expression appears to foster proliferative activity in esophageal cancer, and tumors with a high proliferative index or a functioning p53 gene are more responsive to neoadjuvant chemoradiation therapy. Presented at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, California, May 19–22, 2002 (oral presentation). Supported by grants from the Royal College of Surgeons of England and Yorkshire Cancer Research.     

Long-term results of neoadjuvant radiochemotherapy in squamous carcinoma of the thoracic esophagus

AIM: Surgery is considered the mainstay of therapy for clinically resectable esophageal cancer, even though neoadjuvant treatments are frequently added. The aim of this study was to analyse our experience on neoadjuvant treatment of squamous cell carcinoma of the thoracic esophagus with special reference to long-term RESULTS: METHODS: The results of 66 patients who underwent neoadjuvant chemo-radiotherapy for squamous cell carcinoma of the thoracic esophagus at the 1(st) Division of General Surgery, University of Verona, from February 1995 to December 2002 were analysed statistically. The median follow-up period for the surviving patients was 65.3 months. RESULTS: The induction treatment was completed in 93.9% of cases, with a null treatment related mortality and a complication rate of 34.8%. Sixty-one out of the 66 patients (92.4%) underwent resection with a R0-resection rate of 83.9%. A major pathological response (responders) was gained in 42.6% of the cases, with a complete response (pTONO) observed in 29.5% of the cases. Overall 5-year survival for the 66 patients was 30%, while the 5-year survival rate raised to 43% in R0-patients. A better long-term survival was observed for responders with respect to 'non-responders' with a 5-year survival rate of 70% and 13%, respectively (P<0.001). CONCLUSIONS: This neoadjuvant protocol regimen represents a feasible treatment with an acceptable morbidity. The tumor efficacy in term of pathological responses was similar to literature RESULTS: An high rate of R0-resections was achieved with a possibility of cure limited to this group of patients. A better long-term survival was observed in patients with major pathological responses.     

Endoscopic ultrasound does not accurately assess pathologic stage of esophageal cancer after neoadjuvant chemoradiotherapy

The accuracy of endoscopic ultrasound (EUS) for initial staging of esophageal cancer is widely accepted. There is, however, considerable variability in the reported accuracy of EUS for restaging of esophageal neoplasms after neoadjuvant therapy. From June 1995 through December 1999, we prospectively studied a series of 26 patients who underwent neoadjuvant treatment for esophageal cancer and were subsequently restaged by EUS before resection. Twenty-four patients had adenocarcinoma (92%), and two patients had squamous cell carcinoma (8%). EUS correctly predicted tumor stage in seven of 26 patients for an overall accuracy of 27 per cent. EUS overestimated the depth of tumor penetration in 18 patients (69%) and underestimated depth of penetration in one patient (4%). Lymph nodes were correctly staged in 15 of 26 patients for an overall accuracy of 58 per cent. Levels of sensitivity for detecting N0 and N1 disease were 44 per cent and 80 per cent respectively. Patients with a complete pathologic response were staged as T4N1 (one patient), T3N1 (three patients), T3N0 (one patient), and T2N1 (two patients). EUS cannot distinguish tumor involvement of the esophageal wall and lymph nodes from the postinflammatory changes that characterize effective neoadjuvant treatment. EUS is of limited utility in guiding clinical decision making after neoadjuvant therapy.     

Death-Associated Protein Kinase (DAPK) Promoter Methylation and Response to Neoadjuvant Radiochemotherapy in Esophageal Cancer

Background  Multiple studies have shown that promoter methylation of tumor suppressor genes underlies esophageal carcinogenesis. Hypothetically, methylation resulting in tumor suppressor gene inactivation might result in tumors that are unresponsive to chemotherapy and radiation. Accordingly, our aim was to investigate if aberrant methylation of the apoptosis-related gene Death-Associated Protein Kinase (DAPK) could be used as a predictor of response to neoadjuvant therapy in locally advanced cancer of the esophagus. Methods  Tumor and normal esophageal tissues were obtained from 50 patients with locally advanced cancer of the esophagus prior to neoadjuvant radiochemotherapy. DAPK methylation analysis was performed on all samples by methylation-specific real-time polymerase chain reaction (PCR). Results  Seventeen (34%) patients showed a major and 33 (66%) a minor histomorphological response to neoadjuvant therapy. DAPK methylation was detectable in normal esophageal tissues with a frequency of 10% and in tumor tissue with a frequency of 78%. The median methylation level for DAPK was 2.7 × 10⁻³ in tumor compared with 0.1 × 10⁻³ in normal tissues (p < 0.001). DAPK methylation was not associated with response to neoadjuvant therapy or prognosis after esophagectomy. Conclusion  Aberrant DAPK methylation in tumor tissues is significantly higher compared with matching normal esophageal tissues, suggesting a fundamental role of this epigenetic alteration in the pathogenesis of this disease. The level of DAPK methylation in pretreatment biopsies of patients with locally advanced cancer of the esophagus is no marker for the prediction of histomorphological regression or prognosis following neoadjuvant chemoradiation in this disease.     

Usefulness of positron emission tomography for assessing the response of neoadjuvant chemoradiotherapy in patients with esophageal cancer

BACKGROUND: In this study, we retrospectively assessed the performance of 18-F-fluorodeoxyglucose positron emission tomography (FDG-PET) compared with computed tomography (CT) and esophagography for assessing the response of advanced esophageal squamous cell carcinoma (SCC) to neoadjuvant chemoradiotherapy. METHODS: We studied 10 patients with thoracic esophageal SCC who received neoadjuvant chemoradiotherapy followed by surgery. Tumor response was assessed by CT, endoscopy, esophagography and FDG-PET before and after neoadjuvant treatment. RESULTS: Assessment of the rate of decrease in standardized uptake value (SUV) revealed a partial response (more than 50% decrease) in 5 (50%) of the patients, and assessment of length decrease of FDG uptake showed a partial response in 9 (90%) of the patients. Comparison of the histological response and the rate of decrease of various parameters revealed significant associations between histological response and tumor length (P <0.05), SUV after neoadjuvant therapy (P <0.05), and reduction in the extent of FDG uptake (P <0.01). However histological response was not significantly correlated with the rate of reduction of SUV, for both CT and esophagography. CONCLUSIONS: FDG-PET may be of considerable value for predicting the pathologic response of esophageal SCC to neoadjuvant therapy. Despite assessment of SUV before neoadjuvant therapy, low FDG uptake after therapy and reduction in the extent of FDG uptake may provide a reliable assessment of the response to therapy.     

Multimodality treatment of esophageal cancer

Stage specific management of non-small cell lung cancer is widely accepted. The use of pretreatment disease stage to guide therapy for esophageal cancer is an intellectually appealing concept. To date, there isa relative lack of data upon which one may base stage specific treatment decisions for esophageal carcinoma. This is because thorough pretreatment TNM staging is not universally practiced. As a result, stage-specific treatment varies widely. Based upon the available data, surgery alone may be appropriate for resectable, node-negative disease. In the case of clearly un-resectable disease, definitive chemoradiation is indicated.The value of neoadjuvant or adjuvant treatment modalities in the case of clearly resectable node-negative disease (TlN0 or T2N0) is questionable;however, in the presence of lymph node involvement (N1), or in the case of a marginally resectable primary tumor (T3 or T4), neoadjuvant chemoradiation is probably indicated. Although the achievement ofa complete pathologic response following chemoradiation may obviate surgical resection, even microscopic residual cancer can result in local recurrence. To date, there is no reliable method of ascertaining a complete pathologic response before surgical resection. Therefore, when feasible, the addition of surgical resection following chemoradiation is warranted.Future treatment trials for esophageal cancer should include rigorous pretreatment staging protocols to elucidate stage-specific results of therapy.     

Präoperative Erfassung von Prognosefaktoren beim Plattenepithelkarzinom des Ösophagus

Despite substantial improvements in the surgical therapy of esophageal squamous cell cancer, the prognosis still remains poor. This is mainly due to locally advanced tumors (T3-4, N+) or systemic metastases (M1) in the majority of patients at initial presentation. It is of the utmost importance to reliably detect relevant pretherapeutic prognostic indicators for optimal individual therapeutic strategies. Pretherapeutic prognostic indicators should therefore discriminate precisely between incurable and potentially curative disease. Preoperative or definitive multimodal treatment is increasingly being offered to patients with locally advanced tumors and opens a broad field for innovative techniques such as pretherapeutic molecular response prediction or early response detection by PET scan to further individualize and optimize treatment strategies.