A Pathologic Complete Response to Preoperative Chemoradiation Is Associated With Lower Local Recurrence and Improved Survival in Rectal Cancer Patients Treated by Mesorectal Excision

PURPOSE: Preoperative chemoradiation reduces tumor size and nodal metastasis in patients with rectal cancer. Tumor downstaging has been associated with an increased probability of a sphincter-saving procedure and with improved local control. However, pathologic complete response to chemoradiation has not been correlated with local control and patient survival. We studied the prognostic value of pathologic complete response to preoperative chemoradiation in rectal cancer patients. METHODS: We have prospectively followed up 168 consecutive patients with ultrasound Stages II (46) and III (122) rectal cancer treated by preoperative chemoradiation followed by radical resection with mesorectal excision; 161 had a curative resection. Recurrence and survival were compared with tumor characteristics and pathologic complete response. Average follow-up was 37 months. RESULTS: Tumor downstaging occurred in 97 (58 percent) patients, including 21 (13 percent) patients who had a pathologic complete response. None of the clinical or pathologic variables was associated with pathologic complete response. The estimated 5-year rate of local recurrence was 5 percent; of distant metastasis, 14 percent. None of the patients with pathologic complete response has developed disease recurrence. We found no difference in survival among patients with pathologic Stages I, II, or III tumors. CONCLUSIONS: A pathologic complete response to preoperative chemoradiation is associated with improved local control and patient survival. For patients without pathologic complete response, the pathology stage does not have prognostic significance.     

Preoperative Radiotherapy Combined With Intraoperative Radiotherapy Improve Results of Total Mesorectal Excision in Patients With T3 Rectal Cancer

PURPOSE: The survival advantage of preoperative radiotherapy in patients with rectal cancer is still a matter of debate, because its incremental benefit in the total mesorectal excision setting is unclear. This study was designed to evaluate early and long-term results of preoperative radiotherapy plus intraoperative radiotherapy in a homogeneous population of T₃ middle and lower rectal cancer patients submitted to total mesorectal excision. METHODS: A series of 113 patients with middle and lower T₃ rectal cancer consecutively submitted to total mesorectal excision at a single surgical unit from 1991 to 1997 were divided into two groups according to type of neoadjuvant treatment: preoperative radiotherapy (38 Gy) plus intraoperative radiotherapy (10 Gy; n = 69), and no preoperative treatment (total mesorectal excision; n = 44). Standard statistical analyses were used to evaluate early (downstaging, intraoperative factors, hospital morbidity, and mortality rates) and long-term results (recurrence and survival). RESULTS: Overall, 68.2 percent of patients were downstaged by the preoperative regimens (T₀ specimens in 3 cases). Postoperative complications were comparable in the two groups. Five-year, disease-specific survival was 81.4 and 58.1 percent in preoperative radiotherapy plus intraoperative radiotherapy group and total mesorectal excision group, respectively (P = 0.052). Corresponding figures for disease-free survival were 73.1 and 57.2 percent in the two groups, respectively (P = 0.096). The rates of local recurrence at five years were 6.6 and 23.2 percent in preoperative radiotherapy plus intraoperative radiotherapy and total mesorectal excision groups, respectively (P = 0.017). CONCLUSIONS: Preoperative radiotherapy plus intraoperative radiotherapy associated with total mesorectal excision reduce local recurrence rate and improve survival in T₃ rectal cancer compared with total mesorectal excision alone.     

Lymph Node Count After Preoperative Radiotherapy Is an Independently Prognostic Factor For Pathologically Lymph Node-Negative Patients With Rectal Cancer

Recent studies indicated that preoperative radiotherapy significantly reduces the lymph nodes (LNs) harvest from patients with rectal cancer. This may weaken the prognostic value of current standard of LNs retrieval (≥12 LNs). This study investigates the prognostic impact of the LN counts on pathologically LN-negative (ypN0) after preoperative radiotherapy for patients with rectal cancer.Surveillance, Epidemiology and End Results (SEER) registered nonmetastatic rectal cancer patients diagnosed between 1998 and 2005 were included in this study. Optimal cutoff value for number of LNs retrieved was determined by X-tile program. Log-rank tests were adopted to compare the rectal cause specific survival (RCSS) for ypN0 patients using separated cutoff value of LN counting from 2 to 20. Correlation between LN count and tumor regression was investigated in an additional 221 patients from Fudan University Shanghai Cancer Center (FUSCC).The results showed that there were fewer number of LNs examined in patients with preoperative radiotherapy than those without (8.9 vs 10.9, P < 0.001). X-tile program identified the difference in survival was most significant (maximum of χ² log-rank values) for the number 4. And 5-year RCSS increased accordingly with the cutoff values ranging from 4 to 15, which were confirmed as optimal cutoff and validated as independent prognostic factors in multivariate regression analysis (χ² = 50.65, P < 0.001). Patients in FUSCC set were found to have fewer LNs retrieval in group of good tumor regression than in that of poor one (P = 0.01).These results confirmed the reduced number of LN retrieval in patients with rectal cancer treated with preop-RT. LN count is still an independently prognostic factor for ypN0 rectal cancer.     

Preoperative Plasma Vascular Endothelial Growth Factor But Not Nitrite Is a Useful Complementary Tumor Marker in Patients With Colorectal Cancer

Purpose Vascular endothelial growth factor and nitric oxide are both related to tumor progression. This study was designed to measure preoperative plasma vascular endothelial growth factor and nitrite levels in patients with colorectal cancer to evaluate their clinical applications as tumor markers. Methods In total, 279 patients with primary colorectal cancer and 20 patients with hemorrhoids (as a control) were included in this study. Plasma vascular endothelial growth factor was measured by quantitative, solid-phase, enzyme-linked immunosorbent assay (R&D Systems), whereas nitrite was measured by a high-performance liquid chromatographic method. Results The vascular endothelial growth factor (mean, 220.6 pg/ml, P < 0.005) and nitrite (mean, 29.4 μM, P = 0.043) levels of patients with cancer were significantly higher than those of controls (mean vascular endothelial growth factor, 67 pg/ml; mean nitrite, 23 μM). Preoperative plasma vascular endothelial growth factor levels were positively correlated with tumor stage, T class, M class, and tumor size (Spearman correlation, P < 0.01), but were not associated with gender, N class, tumor location, histology type, or grade. There were no statistical differences in nitrite levels among different groups of patients with cancer. Higher vascular endothelial growth factor levels also were correlated with leukocytosis, elevated carcinoembryonic antigen, and a higher platelet count. The positive rates of vascular endothelial growth factor elevation (>148.6 pg/ml) compared with carcinoembryonic antigen elevation were 36.9 to 14.6 percent in Stage I, 60.9 to 33 percent in Stage II, 62.9 to 48.7 percent in Stage III, and 86 to 70.2 percent in Stage IV, respectively. The overall positive rate of vascular endothelial growth factor elevation also was higher than that of carcinoembryonic antigen elevation (63 percent for vascular endothelial growth factor vs. 42.5 percent for carcinoembryonic antigen, P = 0.016). More than one-half of the patients without carcinoembryonic antigen elevation still had elevated vascular endothelial growth factor levels. The combined assessment using vascular endothelial growth factor and carcinoembryonic antigen was superior to individual assessment using vascular endothelial growth factor or carcinoembryonic antigen. In node-negative tumor, the patients with vascular endothelial growth factor elevation had worse disease-free survival than those without vascular endothelial growth factor elevation (P = 0.0367). There was no association of vascular endothelial growth factor elevation with survival in patients with node-positive tumor. Conclusions Plasma vascular endothelial growth factor is a useful complementary tumor marker; however, synchronous measurement of white blood cells, platelets, and carcinoembryonic antigen is suggested in the clinical application of vascular endothelial growth factor to colorectal cancer. Supported by the National Science Council of the Republic of China, Taiwan (NSC89-2314-B-182A-168); No. 106, HoPing E. Road, Sec.2, Taipei 106, Taiwan (R.O.C.). Presented in part at the congress of the Asian Federation of Coloproctology, Seoul, Korea, November 27 to 28, 2003.     

Complete Pathologic Response Following Preoperative Chemoradiation Therapy for Middle to Lower Rectal Cancer Is Not a Prognostic Factor for a Better Outcome

PURPOSE The aim of this study was to evaluate factors associated with pathologic tumor response following preoperative chemoradiation therapy, and the prognostic impact of pathologic response on overall and disease-free survival.METHODS Between 1994 and 2002, 132 patients underwent chemoradiation therapy followed by surgery for middle to lower rectal cancer. After excluding 26 cases (metastatic cancer, n = 13; nonradical surgery, n = 6; local excision procedure, n = 4; non-5-fluorouracil-based chemotherapy, n = 2; incomplete data on preoperative chemoradiation therapy regimen used, n = 1), the remaining 106 patients were included in the study. Variables considered were the following: age, gender, tumor location, pretreatment T and N stage, modality of 5-fluorouracil administration, total radiotherapy dose delivered, chemoradiation therapy regimen used (Regimen A: chemotherapy (bolus of 5-fluorouracil and leucovorin, days 1–5 and 29–33) + radiotherapy (45 Gy/25 F/1.8 Gy/F); Regimen B: chemotherapy (5-fluorouracil continuous venous infusion ± weekly bolus of carboplatin or oxaliplatin) + radiotherapy (50.4 Gy/28 F/1.8 Gy/F)), time interval between completion of chemoradiation therapy and surgery, postoperative chemotherapy administration, surgical procedures, pT, pN, and pTNM stage, and response to chemoradiation therapy defined as tumor regression grade, scored from 1 (no tumor on surgical specimen) to 5 (absence of regressive changes). Statistical analysis was performed by means of logistic regression analysis (Coxs model for overall and disease-free survival).RESULTS Median age of the 106 patients was 60 (range, 31–79) years and the male:female ratio, 66:40. Median distance of tumor from the anal verge was 6 (range, 1–11) cm. Pretreatment TNM stage, available in 104 patients, was cT3–T4N0, n = 41; cT2N1, n = 9; cT3N1, n = 39; and cT4N1, n = 17. The median radiotherapy dose delivered was 50.4 (range, 40–56) Gy; 58 patients received 5-fluorouracil by continuous venous infusion, and carboplatin with oxaliplatin was added to the chemotherapy schedule in 71 cases. Patients were given Regimen A in 47 cases and Regimen B in 59. The median interval between chemoradiation therapy and surgery was 42.5 (range, 19–136) days, and 94 patients underwent a sphincter-saving procedure. Tumor regression grade, available in 104 cases, was 1, n = 19; 2, n = 18; 3, n = 15; 4, n = 13; and 5, n = 39. At a median follow-up of 42 (range, 1–110) months, 11 patients had died, and 95 were alive. None of the patients had local recurrences, but 13 had distant recurrences. At logistic regression analysis, the chemoradiation therapy regimen used was the only independent predictor of tumor response following preoperative chemoradiation therapy (odds ratio = 0.29, 95% confidence interval = 0.13–0.67, P = 0.003). At Coxs regression analysis, pretreatment T stage was the only independent prognostic factor for both disease-free survival (relative risk = 7.13, 95% confidence interval = 2.3–21.8, P = 0.001) and overall survival (relative risk = 4.83, 95% confidence interval = 1.1–19.9, P = 0.029).CONCLUSIONS Tumor response following preoperative chemoradiation therapy is mainly related to the preoperative regimen used. For patients receiving preoperative chemoradiation therapy, pretreatment T stage, but not tumor response to preoperative chemoradiation therapy, is prognostic for outcome (both disease-free and overall survival).Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, New Orleans, Louisiana, June 21 to 26, 2003.     

Neoadjuvant Therapy for Rectal Cancer: Improved Tumor Response, Local Recurrence, and Overall Survival in Nonanemic Patients

INTRODUCTION Preoperative, long-course chemoradiotherapy is recommended for rectal cancers involving or threatening the mesorectal resection margin, but tumor response is variable. Some highly radiosensitive cancers completely regress, leading to reduced local recurrence and improved survival. This study was designed to evaluate the influence of anemia during chemoradiotherapy on tumor response, local and distant recurrence, and overall survival.METHODS Mean hemoglobins during chemoradiotherapy of consecutive patients with rectal cancer undergoing chemoradiotherapy and surgery were calculated and ranked. Anemia was defined as lowest quartile for males and females. Tumor response was histologically quantified using rectal cancer regression grade.RESULTS Of 100 patients, 5 females and 20 males were anemic. Nonanemic patients achieved better tumor response (54 percent regression Grade 1) than anemic patients (28 percent, P = 0.028). There were more locally advanced cancers in anemic (48 percent T4) compared with nonanemic patients (21 percent T4), but radiologic T stage did not influence tumor response (50 percent T3 vs. 43 percent T4 regression Grade 1, P = 0.53) or overall survival. Mesorectal margin positivity was less in nonanemic (15 percent) compared with anemic patients (36 percent, P = 0.021). At median follow-up of 39 months, nonanemic patients (7 percent) suffered less local recurrence than anemic patients did (38 percent, P = 0.003). Overall survival at two years was improved in nonanemic (91 percent) compared with anemic patients (64 percent, P = 0.021), but was similar for T3 and T4 patients.CONCLUSIONS Patients with normal hemoglobin during chemoradiotherapy achieved better tumor response, less local recurrence, and improved overall survival compared with anemic patients, independent of radiologic T stage. Correcting anemia before chemoradiotherapy might improve tumor response and oncologic outcomes.Reprints are not available.Presented at the meeting of the Association of Coloproctolgy of Great Britain and Ireland, Edinburgh, United Kingdom, July 7 to 10, 2003.     

Gas Volume Analysis and Postoperative Bowel Functional Disorders in Patients Who Received Anterior Resection for Rectal Cancer

PURPOSE: Colon gas analysis using abdominal radiography has been reported as a reliable method for assessing functional bowel disorders. The aim of this study was to clarify the relevance of colon gas distribution in postoperative disorders such as constipation and feelings of incomplete evacuation following rectal cancer operation. METHODS: Colon gas volume score was calculated using plain abdominal radiographs and evaluated in 50 patients who had received low anterior resections. Twenty-one constipated patients who required laxatives and 29 patients who did not were compared in terms of colon gas distribution. In addition, 32 patients with postoperative feelings of incomplete evacuation and 18 patients without such feelings were assessed in similar fashion. RESULTS: Left colon gas scores in patients who required laxatives were significantly higher (2.82 ± 3.23 percent) than in nonusers (1.21 ± 0.96 percent; P < 0.01). Patients with feelings of incomplete evacuation displayed significantly higher left side colon gas scores (2.51 ± 2.66 percent) than those without such feelings (0.77 ± 0.81 percent; P < 0.0001). CONCLUSION: Patients with postoperative functional bowel disorders such as constipation or feelings of incomplete evacuation may experience relatively high volumes of gas in the left colon.     

Absence of Cyclooxygenase-2 Protein Expression is a Predictor of Tumor Regression in Rectal Cancer Treated with Preoperative Short-Term Chemoradiotherapy

Purpose Neoadjuvant chemoradiotherapy followed by total mesorectal excision has become the standard of care for patients with locally advanced rectal cancer. This study was designed to determine whether pretreatment cyclooxygenase-2 and p53 protein expression were predictors of histopathologic response in patients with rectal cancer treated with preoperative short-term chemoradiotherapy. Methods Fifty-two patients with low rectal cancer received short-term preoperative chemoradiotherapy (20 Gy given in 5 daily doses of 4 Gy and concurrent administration of Tegafur/Uracil 400 mg/day), followed by total mesorectal excision. Cyclooxygenase-2 and p53 protein expression were measured by immunohistochemistry before and at the time of resection. Tumor regression grading was evaluated according to the criteria by Rodel (Grade 4, complete regression; Grade 3, regression >50 percent; Grade 2, 25–50 percent; Grade 1,<25 percent; and Grade 0, no regression). Results Two patients had a pathologic complete response. Good response (Grade 3 + 4) was found in 57.7 percent of the resected specimens. Cyclooxygenase-2 was expressed in 80.8 percent of patients before chemoradiotherapy and in 100 percent after chemoradiotherapy. The rates of good response (Grade 3 + 4) were significantly associated with lack of cyclooxygenase-2 expression before chemoradiotherapy (P = 0.021). However, there was no correlation between p53 protein expression and tumor regression grading. Conclusions Patients with tumor lacking cyclooxygenase-2 expression before chemoradiotherapy are more likely to demonstrate good response to treatment. Cyclooxygenase-2 protein expression may be a marker for response to chemoradiotherapy in patients with rectal cancer. Read at the meeting of the American Society of Clinical Oncology, Atlanta, Georgia, June 2 to 6, 2006.     

Modified Tumor Classification With Inclusion of Tumor Characteristics Improves Discrimination and Prediction Accuracy in Oral and Hypopharyngeal Cancer Patients Who Underwent Surgery

Several histopathological characteristics have a significant prognostic impact on recurrence and survival rates in head and neck squamous cell carcinoma (HNSCC). We conducted a retrospective study on patients with HNSCC to compare traditional pathological T (pT) classification to a new T classification system that incorporates these histopathological characteristics.Newly diagnosed patients with HNSCC (n = 349) post major surgery were identified from the cancer registry database between 2004 and 2013. The pT and new T classification systems were compared with respect to recurrence-free survival (RFS), disease-specific survival (DSS), and survival rates using the Cox proportional hazards model with adjustments. The discriminatory ability of these 2 classification systems was evaluated using the adjusted hazard ratio (HR) and Akaike information criterion (AIC) in a multivariate regression model. The prediction accuracy was assessed using Harrell''s C-statistic.The new T classification, which incorporated tumor size, extent, and location with histopathological features had better discriminatory ability and monotonicity of gradients than did pT classification. The new T4 classification yielded a higher adjusted HR in RFS (HR, 4.11; 95% confidence interval [CI], 7.75–9.65) and in DSS (HR, 4.39; 95% CI, 1.6–12.03), and a lower AIC in recurrence (927 vs 969) and survival rates (791 vs 833).The new T classification system had better discriminatory ability in RFS and DSS compared with the routinely used American Joint Committee on Cancer (AJCC) pT classification system. Therefore, this new T classification system, which includes tumor size, location, extent, and histopathological features, could be used as an alternative to AJCC pT classification for patients with HNSCC.     

Microarray Gene Expression Profiling for Predicting Complete Response to Preoperative Chemoradiotherapy in Patients with Advanced Rectal Cancer

Purpose Preoperative chemoradiotherapy is widely used to improve local control and sphincter preservation in patients with locally advanced rectal cancer. In the present study, we investigated whether microarray gene expression analysis could predict complete response to preoperative chemoradiotherapy in rectal cancer. Methods Tumor tissues were obtained from 46 patients with rectal cancer (31 for training and 15 for validation testing). All patients underwent preoperative chemoradiotherapy involving 50.4 gray radiotherapy, followed by surgical excision 6 weeks later. Response to chemoradiotherapy was evaluated according to Dworak’s tumor regression grade. Tumor regression Grades 1, 2, and 3 were considered partial responses, and tumor regression Grade 4 was considered a complete response. By using the 31 training samples, genes differentially expressed between partial response and complete response were identified, and clustering analysis was performed. Prediction analysis of response to chemoradiotherapy was performed on the 31 training samples by using a selected set of 95 “predictor” genes. Those findings were validated by independent analysis of the 15 test samples. Results The 31 training samples comprised 20 partial response and 11 complete response cases. A primary set of 261 genes was identified as differentiating between partial response and complete response. By supervised clustering using these 261 genes, 30 of 31 training samples were clustered correctly according to tumor response. A gene set comprising the top-ranked 95 genes displaying differential expression between partial response and complete response was applied to predict response to chemoradiotherapy. Complete response and partial response were accurately predicted in 84 percent (26/31) of training samples and 87 percent (13/15) of validation samples. Conclusions Microarray gene expression analysis was successfully used to predict complete responses to preoperative chemoradiotherapy in patients with advanced rectal cancer. Supported by a research grant from the National Cancer Center, Korea, and the BK21 project for Medicine, Dentistry, and Pharmacy. Presented in part and awarded the AACR-ITO EN, Ltd, Scholar-In-Training Award at the meeting of the American Association for Cancer Research, Washington, DC, April 1 to 5, 2006. I-J Kim and S-B Lim contributed equally to this article. Reprints are not available.     

Surgical Technique and Survival in Patients Having a Curative Resection for Colon Cancer

PURPOSE: This study was performed to determine whether the adoption of a standardized technique for resection of colon cancer, based on mobilization along anatomic planes, resulted in improved survival after adjustment for other known prognostic factors. METHODS: Patients undergoing a potentially curative, elective colonic resection at Concord Hospital from 1971 to 1995 were included. None received adjuvant therapy. Data were recorded prospectively. Overall survival and colon-cancer–specific survival were examined by the Kaplan-Meier method and proportional-hazards regression in relation to patient and tumor characteristics and the introduction of a standardized surgical technique in 1980. RESULTS: Overall five-year survival rose from 48.1 percent before 1980 to 63.7 percent after 1980 (P < 0.0001); cancer-specific survival rose from 66.4 percent to 76.6 percent (P = 0.002). Factors that did not change significantly before and after 1980 were patient age and gender, tumor site, stage, grade, serosal surface involvement, and apical node metastases. The proportion of tumors 5 cm in diameter decreased after 1980 (61.9 to 49.2 percent, P = 0.001) but survival was unrelated to size. Venous invasion rose after 1980 (9 to 15.8 percent, P = 0.014). Multiple regression with adjustment for age, stage, grade, venous invasion, serosal surface involvement, and apical node metastases showed significantly shorter overall survival before the introduction of the standardized technique (hazard ratio, 1.5; 95 percent confidence interval, 1.2–1.8) and significantly shorter colon-cancer–specific survival (hazard ratio, 1.7; 95 percent confidence interval, 1.3–2.2). The proportion of patients having a noncurative operation because of residual tumor in a line of resection (excluded from the survival analyses) fell from 10.6 percent (confidence interval, 7–15.3 percent) before 1980 to 3.2 percent (confidence interval, 2–4.9 percent) after 1980. CONCLUSION: As in rectal cancer surgery, mobilization of the colon along anatomic planes is an important principle that influences outcome and needs to be emphasized.     

Oncologic Impact of Fewer Than 12 Lymph Nodes in Patients Who Underwent Neoadjuvant Chemoradiation Followed by Total Mesorectal Excision for Locally Advanced Rectal Cancer

A minimum of 12 harvested lymph nodes (hLNs) are recommended in colorectal cancer. However, a paucity of hLNs is frequently presented after preoperative chemoradiation (pCRT) in rectal cancer and the significance of this is still uncertain. The aim of this study is to analyze the impact of hLNs on long-term oncologic outcomes.A total of 302 patients with locally advanced rectal cancer who underwent pCRT and curative resection between 1989 and 2009 were reviewed. Patients were categorized into 2 groups according to the number of hLNs: <12 versus ≥12 LN. The 2 groups were compared with respect to 5-year disease-free and overall survival. The optimal number or ratio of hLNs was investigated in subgroup analysis according to LN status.The median follow-up was 57 months. Patient characteristics other than age did not differ between the 2 groups. The group with <12 LNs had more favorable ypTNM and ypN stage than those with ≥12 LNs. However, the long-term oncologic outcomes were not significantly different between the 2 groups. In subgroup analysis of ypN(−), the group with <5 hLNs had the most favorable oncologic outcomes. In ypN(+) cases, a higher LN ratio tended to be associated with poorer 5-year overall survival.The paucity of hLNs in locally advanced rectal cancer after chemoradiation did not imply poor oncologic outcomes in this study. In addition, <5 hLNs in ypN(−) patients could reflect a good tumor response rather than suboptimal radicality.     

Preoperative Serum Vascular Endothelial Growth Factor Is Not a Marker for Subsequent Recurrence During Long-Term Follow-Up of Colorectal Cancer Patients

BACKGROUND Serum vascular endothelial growth factor has been associated with stage of disease in colorectal cancer patients. We investigated whether preoperative serum vascular endothelial growth factor can provide any relevant clinical prognostic information during long-term follow-up of colorectal cancer patients.METHODS Preoperative serum samples of 79 colorectal cancer patients and serum of 28 healthy controls were stored at –80°C until later vascular endothelial growth factor analysis by enzyme-linked immunosorbent assay technique and carcinoembryogenic antigen concentration measurement were performed. There were three patient groups for comparison: 21 patients with overt liver metastases, 18 patients who developed recurrent disease after initial curative surgery, and 40 patients who remained disease-free for at least five years.RESULTS We could not demonstrate any significant difference in serum vascular endothelial growth factor values between the patient groups and controls, nor between the three patient groups (Mann-Whitney U test). There was no relevant correlation between serum vascular endothelial growth factor and carcinoembryogenic antigen concentrations (Pearson r = 0.2; P = 0.07).CONCLUSION Although vascular endothelial growth factor has been shown in previous studies to be a potent inducer of angiogenesis and metastases formation, the present data demonstrate that preoperative serum vascular endothelial growth factor concentration does not provide any relevant individual prognostic information in patients with colorectal cancer.Reprints are not available.     

p53, Deleted in Colorectal Cancer Gene,and Thymidylate Synthase as Predictors of Histopathologic Response and Survival in Low,Locally Advanced Rectal Cancer Treated With Preoperative Adjuvant Therapy

PURPOSE: Adjuvant therapy, either preoperatively or postoperatively, and modifications of surgery have been used to try to improve outcome of surgery for rectal cancer in regard to both local recurrence and survival. Assessment of prognosis in patients after resection is currently primarily based on clinicopathologic factors. These predict the subsequent behavior of the tumor only imperfectly. The aim of this study was to evaluate three potential molecular genetic markers of prognosis (p53, deleted in colorectal cancer gene, and thymidylate synthase) in Dukes Stage B and C low rectal tumors treated with adjuvant therapy and to determine whether they correlate with survival, local recurrence, or the pathologic response to adjuvant therapy (assessed by extent of tumor regression and tumor down-staging). METHODS: Sixty locally advanced low rectal tumors resected after preoperative chemoradiotherapy or radiotherapy alone were studied by immunohistochemical staining for p53, deleted in colorectal cancer gene, and thymidylate synthase. In addition, p53 gene mutations were sought by polymerase chain reaction–single-strand conformation polymorphism analysis. These results were correlated with survival, local recurrence, and pathologic response to adjuvant therapy. RESULTS: Lack of thymidylate synthase staining by immunohistochemistry was associated with tumor down-staging after preoperative chemoradiotherapy but not after radiotherapy or for these two combined groups. There was no correlation between p53, deleted in colorectal cancer gene, or thymidylate synthase immunohistochemical staining or between p53 polymerase chain reaction–single-strand conformation polymorphism and local recurrence or survival in locally advanced low rectal cancers treated with preoperative adjuvant therapies. CONCLUSION: Prediction of prognosis in patients with locally advanced low rectal cancers treated with preoperative adjuvant therapies continues to be problematic. Thymidylate synthase immunohistochemistry appears to be the most promising factor of those assessed in predicting tumor down-staging after preoperative chemoradiotherapy for locally advanced low rectal cancers.     

Signet Ring Cell Histology Is Not an Independent Predictor of Poor Prognosis After Curative Resection for Gastric Cancer: A Propensity Analysis by the KLASS Group

Whether signet ring cell (SRC) histology carries a worse prognosis than other forms of gastric adenocarcinoma has been questioned. The present study investigated the differences in clinicopathologic features and survival between SRC and non-SRC adenocarcinoma. The prospectively collected data of 2643 patients who had undergone curative gastrectomy between 1998 and 2005 by 10 surgeons were reviewed. Additionally, we employed analysis of covariance, propensity-score risk adjustment, and propensity-based matching to account for possible selection bias. The baseline characteristics of prematched patients with SRC or non-SRC adenocarcinoma histology differed: SRC presented in younger patients and less often in men, was more likely found in the middle stomach, and was more likely to be Stage I. After applying the propensity-score strata and propensity-score matching, there was no difference in the baseline characteristics, and SRC was not an independent risk factor for mortality in the same stage. SRC is not an independent predictor of poor prognosis after curative resection for gastric cancer in Korea.     

Tumor Hypoxia Detected by Positron Emission Tomography with <Superscript>60</Superscript>Cu-ATSM as a Predictor of Response and Survival in Patients Undergoing Neoadjuvant Chemoradiotherapy for Rectal Carcinoma: A Pilot Study

PURPOSE  The response of rectal cancers to neoadjuvant chemoradiotherapy is variable. Tumor hypoxia reduces the effectiveness of both radiation therapy and chemotherapy and is a well-known risk factor for tumor radioresistence. We hypothesized that imaging with the novel hypoxia-detecting agent, ⁶⁰Cu-diacetyl-bis (N⁴-methylthiosemicarbazone) (⁶⁰Cu-ATSM), previously validated in cervical and lung cancers, would predict the response of rectal cancers to neoadjuvant chemoradiotherapy and prognosis. METHODS  Patients with locally invasive (T2–4) primary or node-positive rectal cancer located <12 cm from the anal verge were recruited for this pilot study. Pretreatment tumor size and stage were determined by endorectal ultrasonography, CT, and magnetic resonance imaging. Eleven patients also underwent clinical positron emission tomography with ¹⁸F-fluorodeoxyglucose at the discretion of the treating clinician. The primary tumor was imaged by positron emission tomography with ⁶⁰Cu-ATSM, and accumulation of the tracer was measured semiquantitatively by determining the tumor-to-muscle activity ratio. Neoadjuvant chemoradiotherapy was then administered (within 2 weeks of ⁶⁰Cu-ATSM-positron emission tomography) and consisted of 45 Gy given in 25 fractions to the pelvis with continuous intravenous infusion of 5-fluorouracil (225 mg/m²/day). Proctectomy was performed six to eight weeks after neoadjuvant chemoradiotherapy and the tumor submitted to pathology for size measurement and staging. Tumor-to-muscle activity ratios were compared with tumor ¹⁸F-fluorodeoxyglucose uptake, tumor response to neoadjuvant chemoradiotherapy, and with patient survival. RESULTS  Nineteen patients were enrolled in the study, two of whom were excluded from final analysis (1 death during neoadjuvant chemoradiotherapy and 1 tumor perforation during neoadjuvant chemoradiotherapy requiring emergent surgery). Of the 17 remaining patients, 14 had a reduction in tumor size and 13 were downstaged. The median tumor-to-muscle activity ratio of 2.6 discriminated those with worse prognosis from those with better prognosis. Both overall and progression-free survivals were worse with hypoxic tumors (tumor-to-muscle activity ratio >2.6) than with nonhypoxic tumors (tumor-to-muscle activity ratio ≤2.6; both P < 0.05). In addition, 2 of the 3 tumors with no change in size had tumor-to-muscle activity ratios >2.6 (positive predictive value 66 percent), whereas 6 of 14 with decreased size had tumor-to-muscle activity ratios >2.6 (negative predictive value 57 percent). Three of the 4 tumors not downstaged had tumor-to-muscle activity ratios >2.6 (positive predictive value 75 percent), whereas 5 of 13 downstaged tumors had tumor-to-muscle activity ratios >2.6 (negative predictive value 62 percent). The mean tumor-to-muscle activity ratio for downstaged tumors (2.2) was significantly lower than that of nondownstaged tumors (3.3) (P = 0.03). The difference in mean tumor-to-muscle activity ratio between downsized (2.3) and nondownsized (2.9) tumors did not reach statistical significance (P = 0.36). Tumor ¹⁸F-fluorodeoxyglucose uptake (n = 11) did not correlate with ⁶⁰Cu-ATSM uptake (r = 0.4; P = 0.9) and there was no significant difference in mean tumor ¹⁸F-fluorodeoxyglucose uptake between patients with hypoxic tumors and those with normoxic tumors (P = 0.3). CONCLUSIONS  The results of this small pilot study suggest that ⁶⁰Cu-ATSM-PET may be predictive of survival and, possibly, tumor response to neoadjuvant chemoradiotherapy in patients with rectal cancer. A larger Phase II study is warranted to validate these results. Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, St. Louis, Missouri, June 2 to 6, 2007. Supported by an American Cancer Society Institutional Research Grant (ACS-IRG #58–010–46).     

Soft Tissue Necrosis in Head and Neck Cancer Patients After Transoral Robotic Surgery or Wide Excision With Primary Closure Followed by Radiation Therapy

Risk factors were evaluated for surgical bed soft tissue necrosis (STN) in head and neck cancer patients treated with postoperative radiation therapy (PORT) after transoral robotic surgery (TORS) or wide excision with primary closure. Sixty-seven patients were evaluated. STN was defined as ulceration and necrosis of the surgical bed or persistently unhealed high-grade acute mucositis with pain after PORT. The median RT dose of primary site was 63.6 Gy (range, 45–67.15 Gy) with 2 Gy/fx (range 1.8–2.2 Gy/fx). Total 41 patients (61.2%) were treated with concurrent chemoradiotherapy. The median follow-up period was 26 months. STN was diagnosed in 13 patients (19.4%). Most of the patients were treated with oral steroids, antibiotics, and analgesics and the lesions were eventually improved (median of 6 months after PORT). STN did not influence local control. A depth of invasion (DOI > 1.4 cm, odds ratio [OR] 14.04, p = 0.004) and maximum dose/fraction (CTV_pmax/fx > 2.3 Gy, OR 6.344, p = 0.043) and grade 3 acute mucositis (OR 6.090, p = 0.054) were related to STN. The 12 (23.5%) of 51 oropharyngeal cancer patients presented STN, and the risk factors were DOI > 1.2 cm (OR 21.499, P = 0.005), CTV_pmax/fx > 2.3 Gy (OR 12.972, P = 0.021) and grade 3 acute mucositis (OR 10.537, P = 0.052). Patients treated with TORS or WE with primary closure followed by PORT had a high risk of surgical bed STN. STN risk factors included DOI (>1.2–1.4 cm) and CTV_pmax/fx (>2.3 Gy). Radiation therapy after TORS must be carefully designed to prevent STN.