Salvage surgery after definitive chemoradiotherapy for esophageal cancer

Background Definitive chemoradiotherapy has been performed as a first-line treatment for esophageal cancer, whereas salvage surgery might be the only reliable treatment for patients with recurrence after definitive chemoradiotherapy.Methods We reviewed 38 patients with squamous cell carcinoma who underwent esophagectomy and 6 patients who underwent lymphadenectomy after definitive chemoradiotherapy (≥50 Gy).Results The median survival time and 5-year survival rate after salvage esophagectomy were 16 months and 27%, respectively. Three of the 7 patients who had cervical esophageal cancer underwent cervical esophagectomy with laryngeal preservation. Two patients (5.2%) who underwent salvage esophagectomy with three-field lymphadenectomy before 1997 died of postoperative complications, but no patient died of complications thereafter. Although the overall survival after salvage esophagectomy was correlated with residual tumor (R) (P = 0.0097), the median survival time of 7 patients with residual tumors (R₂) was 7 months. Overall postoperative survival was closely correlated with the response to chemoradiotherapy (P < 0.0001) but was not associated with histologic effects on resected specimens. Survival was significantly correlated with the depth of viable tumor invasion (pT) (P = 0.0013) and with lymph node metastasis (pN) (P < 0.0001). Long-term survival was achieved in 5 of the 6 patients who underwent salvage lymphadenectomy.Conclusions Salvage surgery should be considered for patients with recurrence after definitive chemoradiotherapy. Salvage lymphadenectomy may be useful for recurrence confined to the lymph nodes whereas postoperative complications of salvage esophagectomy should be warranted.     

The significance of abdominal para‐aortic lymph node metastasis in patients with lower thoracic esophageal cancer

Para‐aortic lymph node (PALN) recurrence is often seen in patients with lower thoracic esophageal cancer treated by esophagectomy with extended lymph node dissection. However, the clinicopathological characteristics of patients with PALN metastasis and the significance of PALN dissection are unknown. A total of 283 patients with lower thoracic esophageal cancer underwent esophagectomy with lymphadenectomy at our hospital between April 1984 and March 2007. Among these 283 patients, 60 patients were enrolled in this retrospective study according to following criteria: (i) clinical T2 to T4 tumor, (ii) no clinical PALN metastasis, and (iii) received PALN dissection. PALN dissection was indicated by a tumor depth of at least T2 and no severe complications. The clinicopathological data, recurrence pattern, and overall survival were compared between patients with PALN and without PALN metastasis. The mean length of surgery was 587 min and the mean blood loss was 1383 mL. The morbidity was 33.3% and mortality was 5% in this series. Sixteen patients (26.7%) had PALN metastasis; these showed significantly more lymph node metastases (15.8 ± 13.2 vs. 3.0 ± 3.2, P < 0.0001) and significantly worse survival rates (53.3% vs. 79.9% at 1 year, 6.7% vs. 62.0% at 3 years, P < 0.0001) than patients without PALN metastasis. The incidence of lymph node recurrence (P < 0.0001) and hematogenous recurrence (P= 0.0487) was also higher in patients with PALN metastasis than in patients without PALN metastasis. Among the 16 patients with PALN metastasis, a univariate analysis revealed total number of metastatic nodes < 8 (P= 0.0325) to be a significant prognostic factor. A multivariate logistic regression analysis of the regional lymph nodes identified the invasion of the lower mediastinal nodes (hazard ratio = 6.120) and retroperitoneal nodes (hazard ratio = 15.167) to be significantly correlated with PALN metastasis. PALN metastasis is suggested to be related to the systemic spread of lymphatic metastasis even in lower thoracic esophageal cancer. PALN dissection for pathological PALN(+) patients should not be performed. It remains to be determined in future prospective studies whether patients without pathological PALN metastasis, but showing PALN micrometastasis, could achieve improved survival with PALN dissection.     

Role of surgery in the management and prognosis of limited‐stage small cell carcinoma of the esophagus

Small cell carcinoma of the esophagus (SCCE) is a rare, highly aggressive tumor characterized by early dissemination and a poor prognosis. Surgery, chemotherapy, and radiotherapy have been used alone or in combination for the treatment of this rare disease. The aim of this retrospective study was to analyze the role of surgery in the management of limited‐stage SCCE at a high‐volume center. We retrospectively evaluated 73 patients with limited‐stage SCCE who received an esophagectomy at our center from January 1994 to December 2011. The clinical characteristics, median survival times (MSTs), overall survival (OS), and relevant prognostic factors were analyzed. The overall MST was 23.0 months, and the 1‐, 2‐, 3‐, and 5‐year OS rates were 61.6%, 47.9%, 22.7%, and 10.6%, respectively. The MST for patients without lymph node involvement (33.0 months) was greater than the MST for patients with lymph node involvement (17.0 months) (P = 0.014). Similarly, patients who underwent radical resection had a greater MST (25.0 months) than patients who underwent palliative resection (7.0 months) (P = 0.004). Patients who received chemotherapy had a greater MST (27.0 months) than patients who did not receive chemotherapy (13.0 months) (P = 0.021). Survival analysis confirmed that a radical operation, chemotherapy, and lymph node involvement were independent prognostic factors. This study suggests that radical resection combined with chemotherapy should be recommended for patients with limited‐stage SCCE, especially patients with negative regional lymph nodes. A lack of lymph node metastasis was a good prognostic factor because patients without lymph node involvement had greater OS.     

Survival in patients with primary soft-tissue sarcomas treated within 6 years

Since 1988, treatment strategies for our sarcoma patients have been determined by the same team and operations performed by one surgeon. The aim of this study was to analyse prognostic data on local recurrence and survival of 101 consecutive patients who presented in our institution with the primary tumour manifestation. After a median follow-up of 35 months, the local recurrence rate was 13.5%, the mean survival time was 68 months and the 5-year survival rate was 83%. Besides positive lymph nodes (only 3 patients) the quality of resection significantly influenced local recurrences (P<0.05). Univariate predictors of mortality were tumour grade (P<0.01), tumour size (P<0.05), distant metastases (P<0.01), and resection quality (P<0.01). Multivariate predictors of mortality consisted of grade (P<0.0001), positive lymph nodes (P<0.001) and resection quality (P<0.01). In this homogeneous group of patients, excellent recurrence and survival rates could be achieved. An optimized surgical treatment not only reduces the rate of local recurrences but also augments survival time. Received: 12 March 1997 / Accepted: 14 November 1997     

Tumor length assessed by miniprobe endosonography can predict the survival of the advanced esophageal squamous cell carcinoma with stricture receiving concurrent chemoradiation

There were tumor strictures commonly encountered in the esophageal squamous cell carcinoma (ESCC) to limit the conventional echoendoscope for exact tumor staging and size measurements. This study evaluated the role of miniprobe endosonography (EUS) to predict the survival of ESCC patients after concurrent chemoradiation therapy (CCRT). This study prospectively enrolled ESCC patients to receive high‐frequency miniprobe EUS for the assessments of the tumor size and tumor–node–metastasis (TNM) stage. For the patients defined with advanced stages to receive CCRT as initial therapy, the tumor size parameters assessed by EUS were analyzed for their correlation with the treatment response and the patients' survivals. Fifty‐four patients, >96% with advanced TNM stage III or IV, were enrolled with a medium follow‐up of 320.5 days. Almost all of the 54 cases had partial or complete stricture of the esophageal lumens due to the tumor obstructions at enrollment. The overall median survival was 18.6 months, and the 1‐ and the 2‐year survival rates were 64.9 and 45.2%, respectively. Patients with initial tumor length <6 cm assessed by the pre‐CCRT EUS had a better survival than those with length ≥6 cm (median survival: >56.5 months vs. 11.5 months, P= 0.006). The patients with initial tumor length <6 cm had a higher rate of downstage than those with tumor length ≥6 cm after the first course of CCRT (80.0% vs. 16.7%, P= 0.035). Multivariate Cox regression confirmed the initial tumor length (hazard ratio [HR]= 1.21, P= 0.034) as well as the presence of distal metastasis are both independent predictors of the survival in ESCC patients receiving CCRT. For the ESCC patients, commonly with tumor stricture, the miniprobe EUS to assess tumor length before CCRT can predict the treatment response and the survivals.     

The prognostic importance of pathologically involved celiac node metastases in node‐positive patients with carcinoma of the distal esophagus or gastroesophageal junction: a surgical series from the Mayo Clinic

The management of esophageal cancer with involvement of celiac lymph nodes is controversial. The purpose of this retrospective study was to evaluate the clinical importance of metastases to celiac lymph nodes in patients with carcinoma of the distal esophagus or gastroesophageal junction (GEJ) who undergo surgical treatment with curative intent. We reviewed the medical records of 310 patients who underwent definitive esophagectomy at the Mayo Clinic, Rochester, Minnesota, between 1976 and 1999 for carcinoma of the distal esophagus or GEJ. The disease location was distal esophagus in 163 and GEJ in 147. Fifty‐two patients (17%) were found to have celiac node involvement. The survival of these patients was compared with that of 97 N0 patients and 161 N1 patients without celiac node involvement. Squamous cell carcinoma and adenocarcinomas were found in 24% and 76%, respectively. Ivor Lewis esophagectomy was the most common surgical procedure (76%), followed by transhiatal resection (14%) and modified Ivor Lewis procedure (5%). The median number of nodes resected was 15 (range, 2–45). The median survival of the entire group was 18.8 months. The median survival was 48 months (range, 1.6 months–22 years) for N0 patients and 15.9 months (range, 0.03 months–14.4 years) for N1 patients without celiac node disease (P < 0.001). The median survival was 11.7 months (range, 2.2 months–15.7 years) for celiac node–positive patients, and this difference was statistically significant when compared with survival in N0 patients (P= 0.001) but not when compared with that in N1 patients without celiac node disease (P= 0.57). Survival at 3 and 5 years was 61% and 45% for N0 patients, 21% and 9% for N1 patients without celiac node disease, and 18% and 11% for patients with celiac node disease, respectively. At 10 years, 7% of patients with celiac node involvement in their resected specimen were alive. By multivariate analysis, patients with 4 or more positive lymph nodes had the worst prognosis (risk ratio [RR], 2.63; 95% confidence interval [CI], 1.98–3.48), regardless of their location. We concluded that celiac node metastases were not an adverse prognostic indicator in patients with celiac node involvement compared with N1 patients without celiac node disease. Overall, the number of positive nodes, not their location, correlated best with survival. Although median survival was poor, a small number of patients with resected celiac node disease had long‐term survival. Patients with undetected celiac node disease at the time of surgical resection who were subsequently found to have celiac node involvement appeared to have a prognosis similar to that of patients with stage III disease. Therefore, treatment with curative intent should be considered for fit patients with celiac node disease.     

Lymph node ratio is a powerful prognostic index in patients with stage III distal rectal cancer: a Japanese multicenter study

Purpose

The present study aims to define the prognostic impact of the lymph node ratio (LNR) in patients with stage III distal rectal cancer.

Methods

We analyzed data from 501 patients who underwent curative resection (total mesorectal excision, TME) for stage III distal rectal cancer at 12 institutions between 1991 and 1998. Patients were divided into four groups according to quartiles based on LNR.

Results

Among the 501 patients, 381 underwent TME with pelvic sidewall dissection (PSD). The median numbers of lymph nodes retrieved with and without PSD were 45 and 17, respectively (P?<?0.0001). Forty-nine patients with lymph node retrieved less than 12 were excluded from further analyses. Among various clinicopathological parameters, univariate analysis identified age (P?=?0.0059), histological grade (P?<?0.0001), depth of tumor invasion (P?=?0.0003), and number of positive nodes (P?<?0.0001) and LNR (P?<?0.0001) as prognostic factors. The Cox proportional hazards model revealed that age (P?=?0.014), histological grade (P?<?0.0001), depth of tumor invasion (P?=?0.0002), and LNR (group 3, P?=?0.0012; group 4, P?<?0.0001) were independent prognostic factors. When the American Joint Committee on Cancer (AJCC) seventh staging system was added as a covariate, both AJCC stage (P?<?0.0001) and LNR (P?<?0.0001) were independent prognostic factors.

Conclusions

Adding the LNR concept to the AJCC cancer staging system will improve accuracy in evaluating the nodal status of distal rectal cancer.     

Surgical treatment for locally advanced (T4) squamous cell carcinoma of the thoracic esophagus

It is still difficult to decide on the treatment modalities for advanced esophageal carcinoma when the prognostic factors of T4 esophageal cancer are not fully understood. In this article, we report that among 71 patients with T4 thoracic esophageal cancer, 49 underwent esophagectomy, 9 had curative resection (R0 group), and 40 had palliative resection (R1/2 group). A total of 22 patients had palliative treatments: bypass in 5 (bypass group), gastrostomy or jejunostomy in 6 (stoma group), and radiochemotherapy alone in 11 (nonoperation group). Clinicopathologic characteristics were retrospectively investigated. Treatment-related deaths occurred in 7 (10%): none in R0, 3 (8%) in R1/2, 3 (60%) in bypass, and 1 (17%) in stoma group. Swallowing was improved in 50 (70%) patients: 9 (100%) in R0, 30 (75%) in R1/2, 1 (20%) in bypass, 3 (50%) in stoma, and 7 (64%) in the nonoperation group. One-, two-, and three-year overall survival rates were 56%, 22%, and 22% in the R0 group and 35%, 19% and 6% in the R1/2 group, respectively (p = 0.19). In the bypass, stoma, and nonoperation groups, none survived 1.6 years. The factors influencing the survival rate of the 49 patients undergoing esophagectomy were grade of lymph node metastasis, amount of perioperative blood transfusion, lymph vessel, and blood vessel invasion. Among these, independent prognostic factors for survival were amount of blood transfusion (≤6 units vs. ≥7 units, p < 0.0001) and grade of lymph node metastasis {none- or peritumoral [lymph nodes adjacent to the main tumor or at a nearby location (<3 cm) from the tumor] metastasis vs. more distant metastasis [lymph nodes at a distant location (> 3 cm)], p = 0.016}. Bypass and stoma operation neither prolonged the survival nor improved the difficulty of swallowing compared with radiochemotherapy alone. Esophagectomy can achieve the best improvement of swallowing and the longest survival with an acceptable mortality rate. Esophageal carcinoma patients with T4 disease and distinct metastasis in the lymph nodes at a distant location (>3 cm) from the primary tumor may not benefit from an esophageal resection.     

Neoadjuvant chemoradiotherapy followed by esophagectomy for initially resectable squamous cell carcinoma of the esophagus with multiple lymph node metastasis

Neoadjuvant chemoradiotherapy (CRT) was expected to improve surgical curability and prognosis for advanced esophageal cancer. However, the clinical efficacy of neoadjuvant CRT followed by esophagectomy with three-field lymphadenectomy (3FL) for initially resectable esophageal squamous cell carcinoma (SCC) remains unclear. Since 1998, we have defined the status of metastases to five or more nodes, or nodal metastases present in all three fields as multiple lymph node metastasis, which was previously shown to be associated with poor prognosis. Between 1998 and 2002, 83 patients with initially resectable esophageal SCC were prospectively allocated into two groups, according to the clinical status of nodal metastasis. Nineteen patients clinically accompanied by multiple lymph node metastasis initially underwent neoadjuvant CRT followed by curative esophagectomy with 3FL (CRT group). The other 64 patients clinically without multiple lymph node metastasis immediately received curative esophagectomy with 3FL (control group). Although the overall morbidity rate was significantly higher in the CRT group, no in-hospital death occurred in either group. Patients without pathologic multiple lymph node metastasis in the CRT group showed a significantly better disease-free survival rate than either patients pathologically with multiple lymph node metastasis in the control group or those in the CRT group. However, the differences in the overall survival rate among the groups were not significant. Thus, the significant survival benefit by neoadjuvant CRT in addition to esophagectomy with 3FL was not confirmed, although it may have been advantageous, without increase in mortality, to at least some patients who responded well to neoadjuvant CRT. Therefore, neoadjuvant CRT can be an initial treatment of choice for resectable esophageal SCC clinically with multiple lymph node metastasis. The prediction of response to CRT and the development of alternative treatment for hematogenous recurrence could achieve a further survival benefit of this trimodality treatment.     

Number and Size of Lymph Nodes Recovered From Dukes B Rectal Cancers: Correlation with Prognosis and Histologic Antitumor Immune Response

Purpose In rectal cancer variation in lymph node recovery influences the detection of nodal metastases and prognosis among Dukes B (Stage II) cases. However, the possible prognostic importance of node size and inherent patient/tumor characteristics in determining node recovery has not been studied. Methods We examined 269 Dukes B (Stage II) rectal tumors, with a mean of 12 nodes per case. Primary tumor characteristics were correlated with the number and size of recovered nodes. Clinical follow-up permitted determination of long-term survival. Results The five-year survival of 94 Dukes B cases with nine or fewer nodes was 69.4 percent vs. 87.6 percent in 175 cases with ten or more nodes (P = 0.001). Lymph nodes were smaller in patients dying of recurrence; among 130 Dukes B patients whose mean node diameter was <4 mm, survival was 73.3 vs. 88 percent when mean nodal diameter was ≥4 mm. The number and size of recovered nodes was related to patient age, histologic antitumor immune response, and tumor growth pattern. By combining the number and size of nodes, a poor prognosis subgroup of 98 Dukes B patients with relatively few large nodes (no more than 5 measuring ≥4 mm) was identified with a five-year survival of 65.6 percent compared with 89.6 percent for the remaining 158 Dukes B cases (P < 0.0001). Conclusions In Dukes B rectal tumors, the number and size of lymph nodes are related to inherent patient and tumor characteristics and permit the identification of Dukes B cases at increased risk of recurrence. A valid comparison of nodal sampling efficiency between centers necessitates measuring and counting harvested lymph nodes. Supported by Cancer Research Appeal Mercy Hospital, Cork, Ireland and Cancer Research, United Kingdom     

Sequential endoscopic ultrasound identifies predictive variables for relapse-free follow-up after neoadjuvant chemotherapy in gastric cancer

Background: The accuracy of endosonographic tumor staging after neoadjuvant therapy is less reliable than in primary staging. Therefore, the value of sequential endosonographic examinations after neaodjuvant chemotherapy in gastro-esophageal cancer is discussed controversially. Previous data suggest, that endoscopic ultrasound (EUS) after neoadjuvant treatment using other variables than classic uTN-criteria may identify patients with a better prognosis.

Methods: In 67 patients with locally advanced gastric cancer treated in curative intent, we performed EUS before and after neoadjuvant chemotherapy. Endosonographic yTN-stage was compared to pathohistological yTN-stage after curative resection. The uTN-stage, yuTN-stage, maximal tumor thickness and maximal lymph node diameter as well as the shift of these variables after neoadjuvant therapy were analyzed for their usefulness to predict recurrence-free follow-up.

Results: Accuracy of EUS for yTN-staging after neoadjuvant therapy was poor, especially in lower tumor stages. However, three heavily correlated variables analyzed by sequential EUS could be used for the prediction of prognosis: low endosonographic tumor stage (yuT0–2) after neoadjuvant chemotherapy, a decrease of two or more steps in uT-stage and a maximal tumor thickness of <15?mm after chemotherapy were significantly associated with recurrence-free follow-up. Endosonographic T-stage before neoadjuvant therapy, as well as lymph node variables before or after chemotherapy, were of no predictive value.

Conclusion: In spite of poor concordance between endosonographic and pathohistological TN-stage after neoadjuvant treatment, sequential EUS, performed before and after neoadjuvant therapy, possibly identify patients at risk for tumor relapse after multimodal treatment in gastric cancer. This finding should be validated in a larger patient cohort.     

Therapeutic strategy for the treatment of postoperative recurrence of esophageal squamous cell carcinoma: clinical efficacy of radiotherapy

We investigated the effectiveness of chemoradiotherapy for the treatment of lymph node recurrence and hematogenous metastasis after esophagectomy for esophageal squamous cell carcinoma. Between 2001 and 2006, 216 patients with thoracic esophageal squamous cell carcinoma had curative esophagectomy. Of those, 23 with lymph node recurrence received chemoradiotherapy (50.0–68.8 Gy). In addition, five patients had isolated recurrences in a distant organ and received chemoradiotherapy (50.0–60.0 Gy). We analyzed outcomes from the radiotherapy for recurrent esophageal cancer. The 1‐, 2‐, and 5‐year survival rates after recurrence for the 23 patients whose lymph node recurrence was treated with chemoradiotherapy were 52, 31, and 24%, respectively, and the median survival time was 13 months. Among the five patients with recurrent tumors in a distant organ, chemoradiotherapy produced a complete response in two patients, a partial response in one patient, and stable disease in two patients, giving an effectiveness rate of 60% (complete response + partial response). Chemoradiotherapy has a beneficial prognostic effect in patients with lymph node recurrence of esophageal squamous cell carcinoma. Chemoradiotherapy for a metastatic tumor in a distant organ may be the treatment of choice in cases where systemic chemotherapy has proven ineffective.     

Intra‐arterial 5‐fluorouracil/interferon combination therapy for hepatocellular carcinoma with portal vein tumor thrombosis and extrahepatic metastases

Background and Aims: We investigated the efficacy of intra‐arterial 5‐fluorouracil (5‐FU) and systemic interferon (IFN)‐α (5‐FU‐IFN) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis in the first branch or trunk (Vp3/4) and extrahepatic metastases. Methods: We examined 17 HCC patients with Vp3/4 and extrahepatic metastases (meta group) and 31 HCC patients with Vp3/4 (non‐meta group). Baseline intrahepatic tumor factors and the hepatic reserve were similar between groups. The extrahepatic metastases of the meta group were not considered prognostic factors. Following the administration of 5‐FU/IFN to all patients, we compared the survival rates, response, time to progression (TTP), and safety between groups. Results: For intrahepatic HCC, complete response, partial response, stable disease, progressive disease, and drop out were observed in no (0%), one (6%), seven (41%), nine (53%), and no (0%) patients of the meta group, and in five (16%), seven (23%), 13 (42%), five (16%) and one (3%) patient of the non‐meta group, respectively. The response rate was significantly lower in the meta group (6% vs 39%, P = 0.018). The median TTP of intrahepatic HCC and the median survival time were significantly shorter in the meta group than in the non‐meta group (1.6 vs 6.3 months, P = 0.0001, and 3.9 months vs 10.5 months, P < 0.0001, respectively). The multivariate analysis showed that the absence of extrahepatic metastases was a significant and independent determinant of both TTP of intrahepatic HCC (P < 0.001) and overall survival (P < 0.001). No patient died of extrahepatic HCC‐related disease. Conclusions: The efficacy of 5‐FU/IFN for advanced HCC with Vp3/4 and extrahepatic metastases was markedly limited.     

Prevalence and outcome of esophagogastric anastomotic leak after esophagectomy in a UK regional cancer network

The aim of this study was to determine the contemporary prevalence, outcome, and survival after esophagogastric anastomotic leakage (EGAL) following esophagectomy by a regional upper gastrointestinal cancer network and to investigate etiological factors. Two hundred forty consecutive patients underwent esophagectomy over a 10‐year period (median age 61 [31–79] years, 147 transthoracic and 93 transhiatal esophagectomy, 105 neoadjuvant chemotherapy, 49 chemoradiotherapy). The primary outcome measures were the development of EGAL and survival. Twenty patients developed EGAL (8.3%, 15 managed conservatively, 5 reoperation). Overall operative mortality was 2% (5 patients in total, 1 after EGAL). Median, 1 and 2‐year survival was 22 months, 73% and 50%, in patients after EGAL, compared with 31 months, 80% and 56%, in patients who did not suffer EGAL (P= 0.314). On multivariate analysis, low body mass indices (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.11–0.79, P= 0.016), individual surgeon (HR 1.21, 95% CI 1.02–1.43, P= 0.02), and neoadjuvant chemotherapy (HR 3.28, 95% CI 1.16–9.22, P= 0.024) were significantly associated with the development of EGAL. EGAL following esophagectomy remained common, but associated mortality was less common than reported in earlier Western series and long‐term survival was unaffected.     

Experience of 1446 rectal cancer patients in Korea and analysis of prognostic factors

In order to investigate the changing pattern of rectal cancers in Korea and to identify prognostic factors, we investigated the case histories of 1446 rectal cancer patients who had received surgical treatment. During the study period there were trends toward a decrease in the ratio of rectal cancer to colon cancer, earlier detection (more Dukes' stages A and B and fewer C), a decrease in the number of abdominoperineal resections, and an increase in the number of sphincter-preserving operations. Univariate analysis of prognostic factors showed that gender, obstruction symptoms, preoperative serum carcinoembryonic antigen (CEA) level, tumor size, depth of bowel wall invasion, lymph node metastases (presence and number), tumor differentiation, operative method, and date of operation were significant, but age, symptom duration, and tumor location were not. The use of sphincter-saving operations did not adversely affect the clinical outcome. Multivariate analysis showed lymph node metastasis factor to be the most significant factor (P<0.001); the depth of bowel wall invasion, differentiation, CEA level, and date of operation were also significant (0.001<P<0.05). This study shows that although anatomical extent of disease (depth of invasion and lymph node metastasis) is the most reliable prognostic predictor in rectal cancer, other factors such as preoperative CEA level and tumor differentiation also provide important information on the outcome and use of an anal-preserving operation does not adversely affect the patient survival. Accepted: 26 February 1999     

Reduced Survival of Rectal Cancer Patients With Increased Tumor Epidermal Growth Factor Receptor Levels

PURPOSE: The epidermal growth factor receptor and its various ligands (epidermal growth factor, transforming growth factor-alpha, amphiregulin, heparin-binding epidermal growth factor, heregulin, and betacellulin) have been implicated in growth and regeneration of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors. Although some studies have investigated levels of epidermal growth factor receptor by radioligand binding studies, none of them have further analyzed these levels in patients with rectal cancer and investigated their prognostic value. METHODS: We quantitatively determined tumor epidermal growth factor receptor levels in 38 patients with colorectal cancer compared with adjacent normal mucosa by iodine-125–labeled epidermal growth factor binding studies and Scatchard analysis. Patients were followed up for 49.5 ± 32.2 (range, 2–120) months. RESULTS: Epidermal growth factor receptor capacity was increased in invasive colorectal carcinomas according to T classification (P < 0.001), tumors with lymph node infiltration (P = 0.038), and advanced International Union Against Cancer stage (P < 0.001). Survival of colorectal cancer was reduced in patients with advanced International Union Against Cancer stage (P < 0.001), tumors with positive lymph nodes (P < 0.001), and tumors with elevated epidermal growth factor receptor levels (P = 0.024). In rectal cancer patients, poor prognosis was associated with advanced International Union Against Cancer stage (P = 0.029), tumors with lymph node infiltration (P = 0.040), and increased epidermal growth factor receptor levels (P = 0.002). Multivariate Cox regression analysis indicated that elevated levels of epidermal growth factor receptor were an independent predictor of reduced survival in patients with rectal cancer (P = 0.005). CONCLUSION: The epidermal growth factor receptor/ligand system appears to be involved in tumor development and tumor progression of colorectal carcinomas, with prognostic implication especially in patients with invasive rectal carcinomas. These patients might take advantage of therapies that specifically block epidermal growth factor receptor–mediated signal transduction.     

Expression and prognostic relevance of p21WAF1 in stage III esophageal squamous cell carcinoma

The prognostic effect of p21^WAF1 expression on esophageal squamous cell carcinoma patients is controversial. Further clarifying the effect of this protein is beneficial for optimizing the patient outcomes. In the current study, we investigated the expression of p21^WAF1 protein in 189 specimens of stage III ESCC by immunohistochemistry. As shown by the Kaplan–Meier curve, the overall survival rate of the positive‐expression group was significantly higher than that of the negative‐expression group (P < 0.05). No significant correlation was observed between p21^WAF1 expression and clinicopathological parameters in terms of gender, age, tumor location, tumor grade, pathological stage, and number of regional lymph node metastases (P > 0.05). We concluded that p21^WAF1 played an intricate role in the tumorigenesis and development of ESCC. p21^WAF1 could serve as a positive prognostic predictor for stage III ESCC patients.     

The expression of CXCR4 and its relationship with matrix metalloproteinase‐9/vascular endothelial growth factor in esophageal squamous cell cancer

Esophageal cancer (EC) is a highly aggressive neoplasm with poor prognosis. The main reason for this disappointing outcome is the strong behavior of esophageal cancer cell's invasion and metastasis. CXC chemokine receptor 4 (CXCR4) was found to be expressed in many tumors and significantly correlated with invasion, angiogenesis, metastasis, and prognosis. In the present study, we investigated the expressions of CXCR4, matrix metalloproteinase‐9 (MMP‐9), and vascular endothelial growth factor (VEGF) in esophageal squamous cell cancer (ESCC) and analyzed the relationship among the three proteins. Sections of paraffin‐embedded tissues were obtained from 127 patients with ESCC undergoing esophagectomy at Zhongshan Hospital, Fudan University in 2005. The CXCR4, MMP‐9, and VEGF expressions in EC tissues were evaluated according to the immunohistochemical staining area and intensity. The correlations between patients' prognosis and covariates were analyzed by Kaplan–Meier method (univariate analysis) and Cox regression (multivariate analysis). The overall expression rate of CXCR4, MMP‐9, and VEGF was 88.2%, 93.7%, and 79.5%, respectively. CXCR4 expression was significantly associated with tumor grade, tumor size, tumor depth, regional lymph node metastasis, and tumor, node, metastasis (TNM) stage (P < 0.05). MMP‐9 expression was significantly associated with age and tumor grade (P < 0.05). VEGF expression was significantly associated with tumor grade, tumor depth, and TNM stage (P < 0.05). CXCR4 expression was positively correlated with MMP‐9 expression (P < 0.01, r= 0.365) and VEGF expression (P < 0.01, r= 0.380). However, there was no significant correlation between MMP‐9 and VEGF expression (P > 0.05). In univariate analysis, CXCR4 expression, tumor size, tumor depth, lymph node metastasis, and TNM stage were correlated with patients' prognosis (P < 0.05); in multivariate analysis, tumor size and lymph node metastasis were the independent factors of poor prognosis. CXCR4 was highly expressed in ESCC and correlated with MMP‐9, VEGF, clinicopathological features and prognosis. We speculated CXCR4 play an important role during the progression of this disease and there might be some regulatory mechanism existing between CXCR4 and MMP‐9/VEGF in ESCC.     

Correlation Between Tumor Regression Grade and Clinicopathological Parameters in Patients With Squamous Cell Carcinoma of the Esophagus Who Received Neoadjuvant Chemoradiotherapy

The aim of this study was 2-fold: first, to assess the prognostic significance on overall survival (OS) of the 3-point tumor regression grade (TRG) in patients with esophageal squamous cell carcinoma (ESCC) who received neoadjuvant chemoradiotherapy (nCRT); second, to investigate the associations of TRG with the clinicopathological characteristics of the study patients.A total of 357 ESCC patients were retrospectively enrolled. The 3-point TRG was determined by assessing the percentage of viable residual tumor cells (VRTC) in the resected specimens as follows: TRG 1, 0% VRTC; TRG 2, 1% to 50% VRTC; and TRG 3, >50% VRTC.A TRG of 1, 2, and 3 was found in 32.2%, 38.9%, and 28.9% of the specimens, respectively. High TRG values were significantly associated with advanced pretreatment clinical stage, longer tumor length, and higher posttreatment tumor depth of invasion (yT), the presence of lymph node metastases (LNM), and lymphovascular invasion. We observed a stepwise decrease in 5-year OS rates with increasing TRG, as follows: 51% for patients with a TRG of 1, 28% for patients with a TRG of 2, and 22% for patients with a TRG of 3 (P < 0.001). TRG and LNM were independent predictors of OS in multivariate analysis. Notably, the prognostic impact of TRG on OS was greater in patients without LNM (P < 0.001) and ypT3 disease (P = 0.021).TRG is independently associated with OS in ESCC patients treated with nCRT. The interrelationships between TRG, LNM, and depth of tumor invasion may improve the prognostic stratification in esophageal cancer.