Research Item (126)
Colon cancer (CC) is the third most common cancer diagnosed in the United States and the incidence has been rising among young adults. We and others have shown a relationship between the immune infiltrate and prognosis, with improved disease-free survival (DFS) being associated with a higher expression of CD8⁺ T cells. We hypothesized that a microbial signature might be associated with intratumoral immune cells as well as DFS. We found that the relative abundance of one Operational Taxonomic Unit (OTU), OTU_104, was significantly associated with recurrence even after applying false discovery correction (HR 1.21, CI 1.08 to 1.36). The final multivariable model showed that DFS was influenced by three parameters: N-stage, CD8⁺ labeling, as well as this OTU_104 belonging to the order Clostridiales. Not only were CD8⁺ labeling and OTU_104 significant contributors in the final DFS model, but they were also inversely correlated to each other (p=0.022). Interestingly, CD8⁺ was also significantly associated with the microbiota composition in the tumor: CD8⁺ T cells was inversely correlated with alpha diversity (p=0.027) and significantly associated with the beta diversity. This study is the first to demonstrate an association among the intratumoral microbiome, CD8⁺ T cells, and recurrence in CC. An increased relative abundance of a specific OTU_104 was inversely associated with CD8⁺ T cells and directly associated with CC recurrence. The link between this microbe, CD8⁺ T cells, and DFS has not been previously shown.
Background: The association between tumor mismatch repair status and obesity in colon cancer is not well understood. The authors of this study hypothesized that mismatch repair deficiency in colon cancer may be associated with a lower Body Mass Index (BMI) and improved patient outcome due to an enhanced tumor immune microenvironment. Methods: For this study, 70 patients were randomly selected from a prospective trial evaluating nodal ultrastaging for colon cancer. The mismatch repair status of tumors and immunomarker expression were correlated with clinicopathologic characteristics and evaluated for disease-free survival. Results: Patients with mismatch repair-deficient tumors (n = 11) had a lower mean BMI than those with mismatch repair-proficient tumors (n = 59) (22.16 vs. 26.30 kg/m2, respectively; p = 0.029).The findings showed that CD3+T cells were inversely associated with mismatch repair proficiency (p = 0.048). Mismatch repair-proficient tumors in nonobese patients (BMI < 30 kg/m2) versus obese patients had a higher density of CD8+(p = 0.008) and FOXP3+(p = 0.005) T cells. Multivariable analysis linked CD4+(hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.35-0.76), CD8+(HR 0.67; 95% CI 0.50-0.89), and number of tumor-positive lymph nodes (HR 1.19; 95% CI 1.03-1.36) to disease-free survival for patients with mismatch repair-proficient tumors. Conclusions: Tumor mismatch repair status and obesity are correlated in patients with colon cancer. Increased intratumoral T cells in nonobese patients suggests an unexplored link between tumor mismatch repair and immunoprofile.
Background: An initiative was established to improve value-based care for pancreatic surgery in a large non-profit health system. Cost data was presented bimonthly to a hepatobiliary (HPB) clinical performance group (CPG) via a videoconference. Study design: The direct costs were calculated for all patients undergoing distal pancreatectomy (DP) and pancreaticoduodenectomy (PD) between January 2014 and July 2017. Median length of stay (LOS), 30, 90-day mortality, readmission rate, and costs were stratified by surgeon volume, utilizing two published criteria: "Volume Pledge" criteria (≥5 PDs/year) and Leapfrog criteria (≥11 PDs/year). Results: There were 270 DPs and 526 PDs performed in 14 hospitals spanning four states. Median PD costs were less for HVS (≥5 PDs/year), $21026 vs. $24706 (p=0.005). HVS had shorter LOS (9 days vs. 11 days, p<0.001) for PD and DP (6 days vs. 7 days, p=0.001). Increased costs for LVS included operative/anesthesia costs ($7321 vs. $6325, p=0.03), room and board ($5828 vs. $4580, p=0.01), and intensive care costs ($4464 vs. $3113, p=0.04). Operating time was increased for HVS for DP and PD (p<0.001). There was no difference in 30-day or 90-day mortality or readmissions for DP or PD when stratified by Volume Pledge criteria. There was no difference in total costs for DP or PD when stratified by Leapfrog criteria. Conclusions: There was a significant cost reduction for PD but not DP when the threshold of 5 PDs was used as a definition of HVS. The sharing of detailed financial data with HPB surgeons on a regular basis provides opportunity to evaluate practice patterns and thereby reduce direct costs.
The survival benefit of an extended versus standard lymphadenectomy for gastric cancer (GC) is often attributed to upstaging when more lymph nodes (LNs) are removed, i.e., stage migration. An extended lymphadenectomy is defined as 30 or more LNs examined, a surrogate for a D2 dissection. The aim of this study is to examine whether the survival benefit of extended lymphadenectomy persists when stage migration is not possible. The National Cancer Data Base was queried to identify patients with pathologic N3 (pN3, 7 positive LNs) gastric adenocarcinoma. Overall survival (OS) was compared by extent of lymphadenectomy (7-14, 15-29, and 30 LN) and stratified by Tstage. Of 2101 pN3 patients, 419 (19.9%) had 7 to 14 LNs examined, 1164 (55.4%) had 15 to 29 LNs examined, and 518 (24.7%) had 30 LNs examined. Unadjusted three-year OS in the entire cohort was 24.6, 27.3, 30.5 per cent for 7 to 14 LNs, 15 to 29 LNs, and 30 LNs, respectively (P 5 0.003). On adjusted survival analysis by stage for patients with pT1-T2N3 disease, removing 30 LNs significantly improved OS compared with removing 7 to 14 LNs (hazard ratio [HR] 2.45, 95% confidence interval5 1.25-4.82, P50.009). Extended lymphadenectomy may confer a survival benefit in select patients with pT1N3 and pT2N3 GC, highlighting the importance of the number of LNs examined rather than stage migration on survival. For the majority of the N3 population, pT3-pT4, the extent of lymphadenectomy did not significantly improve the OS.
- Sep 2017
Background: In 2016, the National Comprehensive Cancer Network included neoadjuvant chemotherapy as a treatment option for patients with clinical T4b colon cancer. However, there is little published data on the survival impact of neoadjuvant chemotherapy for locally advanced colon cancer. Methods: Adult patients with non-metastatic clinically staged T3 or T4 colon cancer who underwent surgical resection were identified from the National Cancer Data Base between 2006 and 2014. Treatment was categorized as neoadjuvant chemotherapy followed by surgery and surgery followed by adjuvant chemotherapy. Overall survival was compared between the two groups using propensity score matching. Results: Of 27,575 patients that met inclusion criteria, 26,654 (97%) were treated with surgery followed by adjuvant chemotherapy and 921 (3%) received neoadjuvant chemotherapy followed by surgery. After propensity score matching, patients with T4b colon cancer treated with neoadjuvant chemotherapy had a 23% lower risk of death at 3 years compared to patients that had adjuvant chemotherapy (HR 0.77, 95% CI 0.60-0.98; p = 0.04). However, neoadjuvant chemotherapy did not demonstrate a similar significant benefit for patients with T3 and T4a disease. Conclusions: Patients with clinical T4b colon cancer treated with neoadjuvant chemotherapy may have an improved survival compared to those who receive adjuvant chemotherapy. Further prospective investigation is warranted.
Introduction: There is no consensus on the relationship between patient sex and the location, stage and oncologic outcome of colon cancer (CC). We hypothesized a sex-specific difference in the biology and management of CC. Study design: Our cohort was drawn from a database of patients enrolled in international trials of nodal ultrastaging for non-metastatic CC. These trials required strict adherence to surgical and pathological quality measures. Postoperative follow-up included colonoscopy at 1 and 4 years and annual CT scans. Sex-specific differences in tumor biology, location, stage and recurrence were evaluated by Chi-squared, Fischer's exact, and independent t-tests. Results: The cohort included 435 males (median age 69 years) and 423 females (median age 70 years). Females had more right-sided (p=0.03) and earlier T stage (p=0.05) tumors, but there was no sex-based difference in pathologic grade, total lymph nodes retrieved, nodal positivity (p=0.47) or lymphovascular invasion (p=0.45). The overall 4-year disease-free survival (DFS) was comparable in females and males (77.9% and 77.5%, respectively). By multivariate analysis only nodal positivity and cancer recurrence impacted overall survival (OS) (p=0.008). Neither sex nor primary tumor affected disease-free survival (DFS) or OS. Conclusion: This is the first prospective study to demonstrate sex-specific differences in location and T stage of CC when surgical and pathological management adhered to strict quality standards. The predominance of right-sided CC in females suggests that flexible sigmoidoscopy may be inadequate for screening/surveillance. Interestingly, earlier stage and right-sided location did not confer a DFS or OS advantage for women. Further studies are needed to determine why females have a higher propensity for right-sided lesions and a potential difference in CC biology.
Importance: Systemic therapy for metastatic melanoma has evolved rapidly during the last decade, and patient treatment has become more complex. Objective: To evaluate the survival benefit achieved through surgical resection of melanoma metastatic to the abdominal viscera in patients treated in the modern treatment environment. Design, setting, and participants: This retrospective review of the institutional melanoma database from the John Wayne Cancer Institute at Providence St Johns Health Center, a tertiary-level melanoma referral center, included 1623 patients with melanoma diagnosed as having potentially resectable abdominal metastases before (1969-2003) and after (2004-2014) advances in systemic therapy. Main outcomes and measures: Overall survival (OS). Results: Of the 1623 patients identified in the database with abdominal melanoma metastases, 1097 were men (67.6%), and the mean (SD) age was 54.6 (14.6) years. Of the patients with metastatic melanoma, 1623 (320 [19.7%] in the 2004-2014 period) had abdominal metastases, including 336 (20.7%) with metastases in the gastrointestinal tract, 697 (42.9%) in the liver, 138 (8.5%) in the adrenal glands, 38 (2.3%) in the pancreas, 109 (6.7%) in the spleen, and 305 (18.8%) with multiple sites. Median OS was superior in surgical (n = 392; 18.0 months) vs nonsurgical (n = 1231; 7.0 months) patients (P < .001). The most favorable 1-year and 2-year OS was seen after surgery for gastrointestinal tract (52% and 41%) and liver (51% and 38%) metastases, respectively. Multivariable analysis found increasing age (hazard ratio [HR], 1.01; 95% CI, 1.00-1.01; P = .02) and the presence of ulceration (HR, 1.21; 95% CI, 1.01-1.45; P = .04) were associated with a worse OS. Alternatively, treatment with metastasectomy (HR, 0.59; 95% CI, 0.46-0.74; P < .001) and metastases involving the gastrointestinal tract (HR, 0.65; 95% CI, 0.48-0.87; P = .004) were associated with a better OS. The systemic treatment era did not significantly affect outcomes (HR, 0.82; 95% CI, 0.67-1.02; P = .15). Overall, patients with gastrointestinal tract metastases undergoing complete, curative resection derived the greatest benefit, with a median OS of 64 months. Conclusions and relevance: To our knowledge, this series is the largest single-institution experience with abdominal melanoma metastases, demonstrating that surgical resection remains an important treatment consideration even in the systemic treatment era.
- Oct 2016
IntroductionStage II–III rectal cancer requires multidisciplinary cancer care, and adolescents and young adults (AYA, ages 15–39 years) often do not receive optimal cancer therapy. Methods Overall, 3295 AYAs with clinical stage II–III rectal cancer were identified in the National Cancer Database. Factors associated with the receipt of adjuvant and surgical therapies, as well as overall survival (OS), were examined. ResultsThe majority of patients were non-Hispanic White (72.0 %), male (57.5 %), and without comorbidities (93.8 %). A greater proportion of Black and Hispanic patients did not receive radiation (24.5 and 27.1 %, respectively, vs. 16.5 % for non-Hispanic White patients), surgery (22.4 % and 21.6 vs. 12.3 %), or chemotherapy (21.5 % and 24.1 vs. 14.7 %) compared with non-Hispanic White patients (all p < 0.05). After controlling for competing factors, Black (odds ratio [OR] 0.7, 95 % confidence interval [CI] 0.5–0.9) and Hispanic patients (OR 0.6, 95 % CI 0.4–0.9) were less likely to receive neoadjuvant chemoradiation compared with non-Hispanic White patients. Females, the uninsured, and those treated at a community cancer center were also less likely to receive neoadjuvant therapy. Having government insurance (OR 0.22, 95 % CI 010–0.49) was a predictor for not receiving surgery. Although 5-year OS was lower (p < 0.05) in Black (59.8 %) and Hispanic patients (65.9 %) compared with non-Hispanic White patients (74.9 %), on multivariate analysis race did not impact mortality. Not having surgery (hazard ratio [HR] 7.1, 95 % CI 2.8–18.2) had the greatest influence on mortality, followed by poorly differentiated histology (HR 3.0, 95 % CI 1.3–6.5), nodal positivity (HR 2.6, 95 % CI 1.9–3.6), no chemotherapy (HR 1.9, 95 % CI 1.03–3.6), no insurance (HR 1.7, 95 % CI 1.1–2.7), and male sex (HR 1.5, 95 % CI 1.1–2.0). Conclusion There are racial and socioeconomic disparities in the treatment of stage II–III rectal cancer in AYAs, many of which impact OS. Interventions that can address and mitigate these differences may lead to improvements in OS for some patients.
- Aug 2016
Background: Studies on perioperative outcomes of octogenarians with gastric cancer are limited by small sample size. Our aim was to determine the outcomes of gastrectomy and the variation of treatments associated with advanced age (≥80 y). Methods: The National Surgical Quality Improvement Program database was queried from 2005 to 2011. Patients who underwent gastrectomy for malignancy were identified using International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes. Results: Of 2591 cases, 487 patients were octogenarians (≥80) and 2104 were nonoctogenarians (<80). Overall, 4.9% of patients had disseminated cancer. Octogenarians had higher 30-d mortality (7.2% versus 2.5%, P < 0.01) and more major complications (31.4% versus 25.5%, P < 0.01), though fewer octogenarians underwent total gastrectomy (24.0% versus 43.2%, P < 0.01) and extended lymphadenectomy (10.1% versus 17.4%, P < 0.01) than the nonoctogenarian cohort. On multivariate analysis, age ≥80 y was associated with major complications (OR, 1.3; 95% CI, 1.03-1.6; P = 0.03) and increased mortality (OR, 3.0; 95% CI, 1.9-4.9; P < 0.01). Conclusions: Advanced age (≥80 y) was associated with worse outcomes in patients undergoing gastrectomy for malignancy. Therefore, careful staging is necessary to reduce unnecessary operations in this population. Furthermore, surgeons must place greater attention on optimizing the octogenarian population before surgery.
- Jun 2016
Background Various mechanisms, including somatic and visceral nociceptive stimulation, have been suggested as a cause for pain after laparoscopic cholecystectomy (LC). We therefore conducted a prospective randomized controlled trial (PRCT) to evaluate whether somatovisceral pain blockade reduces pain after LC. Hypothesis Analgesic efficacy of multimodal analgesia is superior to standard analgesia for patients undergoing elective LC for symptomatic cholelithiasis. Specifically, topical cystic plate and port-site injection with 0.25 % bupivacaine significantly reduces pain after LC. Design This study was designed as single-blinded PRCT. Setting This study was conducted in an academic medical center. Patients and methods Between February and May 2010 we randomly assigned 63 patients with symptomatic cholelithiasis in a 1:1 ratio to non-opioid/opioid analgesic combinations (Control Group, n = 32) and non-opioid/opioid analgesic combinations plus topical 0.25 % bupivacaine onto the cystic plate and local 0.25 % bupivacaine port-site injection, post-LC (Study Group, n = 31). Primary endpoint was patient-reported pain 1, 4, 6, 12, 24 h and 1 week post-LC using the Visual Analog Scale (VAS 0–10). Results Study groups were comparable clinicopathologically. There were no adverse events. A statistically significant reduction in mean pain score was apparent in Study Group patients in comparison with Control Group (mean VAS 4.83 ± 2.33 vs. 6.80 ± 1.87; p < 0.001) at all early (1–6 h) post-operative time points following LC. Conclusion This PRCT shows significantly improved pain control with somatovisceral pain blockade over non-opioid/opioid analgesic combinations following LC for symptomatic cholelithiasis. For centers not utilizing adjunctive local anesthetic for LC, this topical use of bupivacaine may improve patient comfort during recovery. This trial was registered on www. ClinicalTrials. gov NCT# 01972620.
- May 2016
Background: The incidence of colorectal cancer (CRC) in the adolescent and young adult (AYA) population (aged 15-39 y) is rising. Materials and methods: We used the Surveillance, Epidemiology, and End Results Database to study CRC in the AYA population. We studied clinical and socioeconomic factors associated with survival. Results: Of the 11,071 cases of CRC, the most common site of the primary tumor was the rectum (25%), whereas 66.6% of the diseases were left sided. Most of the patients (72%) presented with regional or metastatic disease. However, the disease-specific survival (DSS) and the overall survival of the AYA population were comparable to those of the general population (DSS; 5- and 10-y: 64.8%, 57.3%; overall survival; 5- and 10-y: 61.5% and 52.4%). On multivariate analysis, disease stage at the time of the diagnosis was the strongest predictor of mortality. After controlling for disease stage, male gender, black race, and higher grade tumors were associated with worse survival. Conclusions: The AYA population presents with advanced distal CRC but have similar survival compared with the general population.
- Mar 2016
Background: Retrospective data indicate that immunoprofiling of T cell markers can be prognostic in colon cancer. Prospective T cell immunoprofiling of colon cancer has not been well defined for patients whose lymph nodes are ultrastaged. Study design: A prospective cohort was selected from patients enrolled in an ongoing phase II multicenter trial of nodal ultrastaging for colon cancer. Primary tumor specimens from 89 patients were analyzed by immunohistochemistry for the T cells CD3(+), CD4(+), CD8(+), and FOXP3(+). Lymphocyte populations were quantified with digital image analysis. Results were examined for their association with 5-year disease-free survival along with TNM stage and clinicopathologic variables. Results: Longer disease-free survival was associated with higher CD3(+) counts at the invasive margin (IM) (p = 0.005), higher CD8(+) counts at the tumor center (TC) and IM (p = 0.002), a lower CD4(+)/CD8(+) ratio at the TC+IM (p = 0.027), and a higher CD8(+)/FOXP3(+) ratio at the TC+IM (p = 0.020). After multivariable analysis, CD8(+) at the TC+IM (p = 0.002), the CD8(+)/FOXP3(+) ratio at the TC+IM (p = 0.004), and the number of tumor-positive lymph nodes (p = 0.003) remained significant. Conclusions: This is the first prospective demonstration of the prognostic utility of immunoprofiling in colon cancer after nodal ultrastaging. Staging based on tumor immunoprofile can augment TNM staging and provide targets for specific immunotherapies.
Surgical resection of metastases to the adrenal gland can improve overall survival of patients with stage IV melanoma, but its relative value with respect to current nonsurgical therapies is unknown. We hypothesized that surgery remains an optimal first-line treatment approach for resectable adrenal metastases. A search of our institution’s prospectively collected melanoma database identified stage IV patients treated for adrenal metastases between January 1, 2000, and August 11, 2014. The 91 study patients had a mean age of 60.3 years at diagnosis of adrenal metastasis and 24 had undergone adrenalectomy. Improved survival was associated with an unknown primary lesion, surgical resection, and nonsurgical therapies. Median overall survival from diagnosis of adrenal metastases was 29.2 months with adrenalectomy versus 9.4 months with nonoperative treatment. Adrenalectomy, either as complete metastasectomy or targeted to lesions resistant to systemic therapy, is associated with improved long-term survival in metastatic melanoma.
- Aug 2015
Survival from gastric cancer in the USA still lags behind Asia. Genetic, environmental, and tumor biology differences, along with extent of surgery have been implicated. Our aim was to evaluate survival outcomes in Asian-American gastric cancer patients undergoing surgical resection by comparing place of birth and clinicopathologic characteristics (including evaluation of 15 lymph nodes).The Surveillance, Epidemiology, and End Results database was queried to identify patients treated surgically for gastric cancer with curative intent in the USA (2000-2010). US-born versus foreign-born Asian-American patients were analyzed for survival. Secondary comparison was made to non-Asian patients. Stage IV and non-surgical patients were excluded. Of 10,089 patients identified, 1467 patients were Asian: 271 were born in the USA, and 1196 were born outside the USA. Median survival was 32 months for non-Asians and 29 months for US-born Asians versus 61 months for Asian immigrants (p < 0.001). On multivariable analysis of overall survival in Asian patients, only US birthplace, older age, and higher stage yielded a significantly poorer outcome. Asian-American patients have a worse prognosis if born in the USA. Anatomic and surgical differences do not explain this disparity; environmental factors may be responsible.
- Jun 2015
With the first qualifying examination administered September 15, 2014, complex general surgical oncology (CGSO) is now a board-certified specialty. We aimed to assess the attitudes and perceptions of current and future surgical oncology fellows regarding the recently instituted Accreditation Council for Graduate Medical Education (ACGME) accreditation. A 29-question anonymous survey was distributed to fellows in surgical oncology fellowship programs and applicants interviewing at our fellowship program. There were 110 responses (79 fellows and 31 candidates). The response rate for the first- and second-year fellows was 66 %. Ninety-percent of the respondents were aware that completing an ACGME-accredited fellowship leads to board eligibility in CGSO. However, the majority (80 %) of the respondents stated that their decision to specialize in surgical oncology was not influenced by the ACGME accreditation. The fellows in training were concerned about the cost of the exam (90 %) and expressed anxiety in preparing for another board exam (83 %). However, the majority of the respondents believed that CGSO board certification will be helpful (79 %) in obtaining their future career goals. Interestingly, candidate fellows appeared more focused on a career in general complex surgical oncology (p = 0.004), highlighting the impact that fellowship training may have on organ-specific subspecialization. The majority of the surveyed surgical oncology fellows and candidates believe that obtaining board certification in CGSO is important and will help them pursue their career goals. However, the decision to specialize in surgical oncology does not appear to be motivated by ACGME accreditation or the new board certification.
- May 2015
We recently reported, in a prospective randomized trial, that ultra-staging of patients with colon cancer is associated with significantly improved disease-free survival (DFS) compared with conventional staging. That trial did not control for lymph node (LN) number or adjuvant chemotherapy use. The current international prospective multicenter cooperative group trial (ClinicalTrials.gov identifier NCT00949312; "Ultra-staging in Early Colon Cancer") evaluates the 12-LN quality measure and nodal ultra-staging impact on DFS in patients not receiving adjuvant chemotherapy. Eligibility criteria included biopsy-proven colon adenocarcinoma; absence of metastatic disease; >12 LNs staged pathologically; pan-cytokeratin immunohistochemistry (IHC) of hematoxylin and eosin (H&E)-negative LNs; and no adjuvant chemotherapy. Of 445 patients screened, 203 patients were eligible. The majority of patients had intermediate grade (57.7%) and T3 tumors (64.9%). At a mean follow-up of 36.8 ± 22.1 months (range 0 to 97 months), 94.3% remain disease free. Recurrence was least likely in patients with ≥12 LNs, H&E-negative LNs, and IHC-negative LNs (pN0i-): 2.6% vs 16.7% in the pN0i+ group (p < 0.0001). This is the first prospective report to demonstrate that patients with optimally staged node-negative colon cancer (≥12 LNs, pN0i-) are unlikely to benefit from adjuvant chemotherapy; 97% remain disease free after primary tumor resection. Both surgical and pathologic quality measures are imperative in planning clinical trials in nonmetastatic colon cancer. Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.
Long-acting somatostatin analogues (S-LAR) improve recurrence-free survival in patients with metastatic neuroendocrine tumor (NET) from gastrointestinal (GI) primary, but their impact on overall survival when combined with aggressive cytoreductive surgery is unclear. We reviewed our institutional cancer database to identify patients who underwent cytoreductive surgery for metastatic NET from GI primary between December 1997 and June 2013. Additionally, a cohort selected from 3,384 metastatic neuroendocrine cases in the SEER-Medicare database (January 2003 to December 2009) was used to verify and expand on our results. Most of the 49 patients from our institution had primary lesions in the small intestine (22 of 49 [44.9%]) or pancreas (14 of 49 [28.6%]); 37 patients (75.5%) had metastatic disease at initial diagnosis. These patients underwent 1 (32 of 49 [65.3%]), 2 (11 of 49 [22.4%]), or at least 3 (6 of 49 [12.3%]) surgical procedures; 33 patients (67.3%) underwent resection plus ablation, 19 (38.7%) underwent major hepatectomy, and 34 (69.4%) received S-LAR (29.4% administered preoperatively). Median follow-up was 112 months. Rates of 1-, 5-, 10-, and 15-year disease-specific survival (DSS) were 94%, 78%, 64%, and 31%, respectively, in the 34 patients undergoing aggressive cytoreductive surgery plus S-LAR. Of the SEER-Medicare population, 1,741 patients met inclusion criteria. The DSS for the 104 patients treated with combination therapy was 68.3% at 5 years and 60.6% at 10 years, as compared with 54.7% and 51.8%, respectively, for the 202 patients receiving surgery alone, and 50.0% and 36.0%, respectively, for the 342 patients receiving S-LAR alone (p < 0.0001). The group receiving neither treatment (n = 1,093) had 5-year and 10-year DSS of 34.3% and 26.3%, respectively. Long-acting somatostatin analogues combined with aggressive cytoreductive surgery improves the long-term survival of select patients with metastatic NET from GI primary. Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.
- Mar 2015
Gastric adenocarcinoma studies show improved survival for Asians but have not reported stage-specific overall survival (OS) or disease-specific survival (DSS) by race. The Surveillance, Epidemiology and End Results database was queried for cases of gastric adenocarcinoma between 1998 and 2008. We evaluated OS and DSS by race and stage. Number of assessed lymph nodes was compared among surgical patients. Of 49,058 patients with complete staging data, 35,300 were white, 7709 were Asian, and 6049 were black. Asians had significantly better OS for all stages (P < 0.001) and significantly better DSS for Stages I (P < 0.0001) and II (P = 0.0006). As compared with blacks, whites had significantly better DSS for Stages I (P < 0.0001), II (P = 0.0055), III (P = 0.0165), and IV (P < 0.0001). Among the 28,133 (57%) surgical patients, average number of evaluated lymph nodes was highest for Asians (P < 0.0001). Among surgical patients with 15 or more nodes evaluated, DSS was worse in blacks with Stage I disease (P < 0.05). Blacks with gastric adenocarcinoma have a worse DSS, which disappears when surgical treatment includes adequate lymphadenectomy. Race-associated survival differences for gastric adenocarcinoma might simply reflect variations in surgical staging techniques and socioeconomic factors.
- Oct 2014
Background The staging of gastric cancer has become increasingly complex. With an emerging 15-node quality measure and a revised American Joint Committee on Cancer (AJCC) staging system, we evaluated the need for more intricate staging systems to predict survival outcomes in gastric cancer. Methods The Surveillance, Epidemiology and End Results Program (SEER) database was used to identify 124,972 patients with gastric cancer between 2000 and 2010. Primary endpoints were 5-year disease-specific survival (DSS) and overall survival (OS). Analysis was performed on patients with ≥15 nodes evaluated. Multivariable regression with/without the inclusion of lymph node (LN) assessment and LN ratio were compared using the Akaike information criterion. Results The number of patients included in the final analysis was 12,096. The proportion of patients with an adequate lymphadenectomy increased markedly from 27 % in 2000 to 52 % in 2010. Overall 5-year DSS and OS was 61.9 and 48.8 %, respectively, for patients with ≥15 nodes examined, versus 57.7 and 39.9 %, respectively, for those with
Background The purpose of this study was to determine if gene signatures are informative in colon cancer (CC) when National Quality Standards (NQS) are adhered to. Several studies have demonstrated the prognostic potential of gene signatures in primary CC. This has never been evaluated prospectively with adherence to NQS. Methods This was a prospective, international, multicenter trial. Eligibility criteria were: no distant metastasis, ≥12 lymph nodes (LNs), and no adjuvant chemotherapy for LN-negative CC. RNA from frozen tumor samples was considered reliable if RNA Integrity Number >9. Using an Agilent whole human genome array, 44,000 genes were analyzed in primary tumors for differential gene expression (DGE). ANOVA applied at 2-fold expression level was performed in at least 8 experiments to obtain the DGEs. Results Molecular analysis was completed in 113 of 128 patients. With median follow-up of 27 months, 11.5 % recurred within 3 years after surgery. Significant DGE was identified in recurrent tumors reflected by upregulation (UR) in cellular proliferation and by downregulation (DR) in prodifferentiating panel of 9 genes, independent of T or N classification. By multivariate analysis 3-year disease-free survival was 12.5 % in the UR/DR group versus 93.4 % in the non-UR/DR group (p
- Jul 2014
Background: Melanoma liver metastasis is most often fatal, with a 4- to 6-month median overall survival (OS). Over the past 20 years, surgical techniques have improved in parallel with more effective systemic therapies. We reviewed our institutional experience of hepatic melanoma metastases. Study design: Overall and disease-specific survivals were calculated from hepatic metastasis diagnosis. Potential prognostic factors including primary tumor type, depth, medical treatment response, location, and surgical approach were evaluated. Results: Among 1,078 patients with melanoma liver metastases treated at our institution since 1991, 58 (5.4%) received surgical therapy (resection with or without ablation). Median and 5-year OS were 8 months and 6.6 %, respectively, for 1,016 nonsurgical patients vs 24.8 months and 30%, respectively, for surgical patients (p < 0.001). Median OS was similar among patients undergoing ablation (with or without resection) relative to those undergoing surgery alone. On multivariate analysis of surgical patients, completeness of surgical therapy (hazard ratio [HR] 3.4, 95% CI 1.4 to 8.1, p = 0.007) and stabilization of melanoma on therapy before surgery (HR 0.38, 95% CI 0.19 to 0.78, p = 0.008) predicted OS. Conclusions: In this largest single-institution experience, patients selected for surgical therapy experienced markedly improved survival relative to those receiving only medical therapy. Patients whose disease stabilized on medical therapy enjoyed particularly favorable results, regardless of the number or size of their metastases. The advent of more effective systemic therapy in melanoma may substantially increase the fraction of patients who are eligible for surgical intervention, and this combination of treatment modalities should be considered whenever it is feasible in the context of a multidisciplinary team.
- Sep 2013
Although staging for colon cancer has become more complex over time, it is not clear that this complexity has improved prognostic assessment. Even with revisions in the 7th edition of the AJCC staging system, a clear rank order of prognosis from substage to substage has not been established. Improved staging models will need to be developed, and attempts at further identifying those high-risk patients within each stage may be clinically useful. Through improved quality measures with lymph node yield, advances in colon cancer staging accuracy have been made over the last decade. Determining how to incorporate ultrastaging and molecular techniques will be the challenge for future staging models.
- Jun 2013
Background: The 7th edition of the AJCC Cancer Staging Manual (AJCC-7) includes substantial changes for colon cancer (CC), which are particularly complex in patients with stage II and III disease. We used a national cancer database to determine if these changes improved prediction of survival. Study design: The database of the Surveillance, Epidemiology and End Results Program was queried to identify patients with pathologically confirmed stage I to III CC diagnosed between 1988 and 2008. Colon cancer was staged by the 6(th) edition of the AJCC Cancer Staging Manual (AJCC-6) and then restaged by AJCC-7. Five-year disease-specific survival and overall survival were compared. Results: After all exclusion criteria were applied, AJCC-6 and AJCC-7 staging was possible in 157,588 patients (68.9%). Bowker's test of symmetry showed that the number of patients per substage was different for AJCC-6 and AJCC-7 (p < 0.001). The Akaike information criteria comparison showed superior fit with the AJCC-7 model (p < 0.001). However, although AJCC-7 staging yielded a progressive decrease in disease-specific survival and overall survival of patients with stage IIA (86.3% and 72.4%, respectively), IIB (79.4% and 63.2%, respectively), and IIC (64.9% and 54.6%, respectively) CC, disease-specific survival and overall survival of patients with stage IIIA disease increased (89% and 79%, respectively). Subset analysis of patients with >12 lymph nodes examined did not affect this observation. Conclusions: The AJCC-7 staging of CC does not address all survival discrepancies, regardless of the number of lymph nodes examined. Consideration of other prognostic factors is critical for decisions about therapy, particularly for patients with stage II CC.
- Apr 2012
Background: Although carcinoembryonic antigen (CEA) is the most frequently used marker for colon cancer, it is elevated in only 70% of patients with advanced disease and in even fewer patients with earlier stages of disease. We previously identified a 90-kDa glycoprotein, TA90, which is present in serum in the form of circulating immune complexes. TA90 is found in a variety of solid neoplasms but rarely in healthy controls (3.2%). We hypothesized that this new tumor-associated antigen may be a useful marker for colon cancer. Methods: Serum samples from 59 patients with known colon adenocarcinoma were analyzed for the presence of CEA and TA90. Fifty-one (86%) patients had distant metastases; the remaining patients had clinically localized primary colon cancer. A murine monoclonal antibody-based enzyme-linked immunosorbent assay was used to measure concentrations of TA90-specific circulating immune complexes (TA90-IC). A positive value was defined as an optical density of more than 0.410 at 405 nm. Forty-seven (80%) of the 59 patients had serum samples for TA90 and CEA drawn at the same time. Results: TA90-IC concentrations were elevated more frequently than CEA concentrations (82.9% vs. 70.2%; P 5.134). The combination of both markers identified more patients with colon carcinoma than did either marker alone (93.6%; P,.001). Conclusions: Concomitant use of TA90-IC and CEA identified 93.6% of patients with advanced colon cancer. The role of TA90-IC in screening and monitoring progression of earlier disease deserves further investigation.
- Jun 2010
- Minimally Invasive Cancer Management
It is likely that every solid neoplasm drains to an initial lymph node (sentinel lymph node – SLN) before spreading to regional nodes or systemically. Focused evaluation of the SLN as originally described by Morton et al. in 1990  has improved staging accuracy in melanoma and breast cancer and has been applied to other solid neoplasms with the purpose of minimizing the morbidity of lymph node dissections and/or to increase the accuracy of staging. Until the development of this technique, there was significant controversy and difficulty in the selection of patients needing full lymph node dissections in the setting of clinically negative nodes. The incidence of complications, most prominently lymphedema, had to be balanced against the possible additional staging information gleaned by complete nodal evaluation.
- Mar 2010
The relationship between primary colon cancer and occult nodal metastases (OMs) detected by cytokeratin immunohistochemistry (CK-IHC) is unknown. We sought to investigate the correlation of clinicopathologic features of colon cancer with OMs and to identify predictors of OM. Patients with colon cancer from 5 tertiary referral cancer centers enrolled in a prospective trial of staging had standard pathologic analysis performed on all resected lymph nodes (using hematoxylin and eosin staining [H&E]). Nodes negative on H&E underwent CK-IHC to detect OMs, which were defined as micrometastases (N1mic) or isolated tumor cells (N0i+). Patients who were negative on both H&E and CK-IHC were defined as node negative (NN), and those positive on H&E were node positive (NP). The relationships between tumor characteristics and OMs were analyzed using the Kruskal-Wallis and the Fisher exact test. OMs were identified in 23.4% (25/107) of patients. No significant differences were found in demographics, tumor location, tumor size, and number of nodes examined between groups. Compared with the NN group, patients with OMs had more tumors that were T3/T4 (72% vs 57%; P < .001), had tumors of higher grade (28% vs 12%; P = .022), and had tumors with lymphovascular invasion (16% vs 3%; P < .001). Adverse primary pathologic colon cancer characteristics correlate with OMs. In patients with negative nodes on H&E and stage T3/T4 colon cancer, lymphovascular invasion, or high tumor grade, consideration should be given to performing CK-IHC. The detection of OMs in this subset may influence decisions regarding adjuvant chemotherapy and risk stratification.
- Mar 2009
- From Local Invasion to Metastatic Cancer
Sentinel lymph node (SLN) mapping has been widely applied in the staging of solid neoplasms including colon and rectal cancer. Since the first reported feasibility study in 1997, there have been numerous publications validating SLN mapping as a highly accurate and powerful upstaging technique for colon and rectal cancer. In addition to refining the technical aspects of this procedure, these studies have investigated the use of other tracers and operative techniques, while determining the indications, limitations, and pitfalls of SLN mapping in patients with colorectal cancers. This chapter reviews the rationale for performing SLN mapping for the accurate staging of colon and rectal cancers, and provides a brief review of the historical background of the development of the procedure. We will focus on the technical details of the procedure, and on the pathological evaluation of the specimen and the SLNs. The various tracers and techniques of SLN mapping in colon and rectal cancer will be discussed. We have performed SLN mapping in more than 600 consecutive patients over the past 10 years. The success rates for identifying at least one SLN for colon and rectal cancer were 99.2 and 92%, respectively. The accuracy rates were 93.1 and 95.2%, respectively. In terms of upstaging, 24.2% of the colon cancer patients with nodal metastases and 25.9% of rectal patients with nodal metastases were upstaged by the detection of micrometastases found in the SLNs only.
Nodal micrometastasis and circulating tumor cells detected by multimarker quantitative real-time reverse transcription-PCR (qRT-PCR) may have prognostic importance in patients with colorectal cancer. Paraffin-embedded sentinel lymph nodes from 67 patients and blood from 34 of these patients were evaluated in a prospective multicenter trial of sentinel lymph node mapping in colorectal cancer. Sentinel lymph nodes were examined by H&E staining and cytokeratin immunohistochemistry. Sentinel lymph nodes and blood were examined by a four-marker qRT-PCR assay (c-MET, melanoma antigen gene-A3 family, beta1-->4-N-acetylgalactosaminyltransferase, and cytokeratin-20); qRT-PCR results were correlated with disease stage and outcome. In H&E-negative sentinel lymph node patients that recurred, cytokeratin immunohistochemistry and qRT-PCR detected metastasis in 30% and 60% of patients, respectively. Disease-free survival differed significantly by multimarker qRT-PCR upstaged sentinel lymph node (P = 0.014). qRT-PCR analysis of blood for circulating tumor cells correlated with overall survival (P = 0.040). Molecular assessment for micrometastasis in sentinel lymph node and blood specimens may help identify patients at high risk for recurrent colorectal cancer, who could benefit from adjuvant therapy.
Despite recent advances in the medical treatment of metastatic colorectal cancer (mCRC), which include irinotecan- and oxaliplatin-based first-line regimens, the concept of planned sequential therapy involving three active agents during the course of a patient's treatment and the increasing use of targeted monoclonal antibodies, 5-year survival rates for patients with advanced CRC remain unacceptably low. For patients with CRC liver metastases, liver resection remains the only chance of cure, with 5-year survival rates ranging from 25% to 40%. However, 80% to 85% of patients with stage IV CRC have liver disease which is considered unresectable at presentation. The rapid expansion in the use of improved combination chemotherapy regimens plus or minus biologics, to render initially unresectable metastases resectable has increased the percentage of patients eligible for potentially curative surgery. However, the current staging criteria for CRC patients with metastatic disease do not reflect these recent changes or the fact that there is also a large variation in the survival of patients with stage IV CRC. For example the survival for a patient with a solitary, resectable liver metastasis is better than that for a patient with stage III disease. A new staging system is therefore needed that acknowledges both the improvements that have been made in surgical techniques for resectable metastases and the impact of modern chemotherapy on rendering initially unresectable CRC liver metastases resectable, while at the same time distinguishing between patients with a chance of cure at presentation and those for whom only palliative treatment is possible.
- Jul 2008
through LNR4 were defined as \1/14, 1/14 to 25%, 25% to 50%, and 50% to 100%, respectively. This study confirms the prognostic implications of LNR suggested in smaller retrospective studies 2 and complements the reported correlation between more extensive nodal dissection and improved survival of
adjuvant therapy are largely based on nodal status. Chemotherapy is not routine for node-negative CC because its toxicity and expense exceed its limited benefit in patients without evidence of nodal involvement. However, 25% of patients with nodenegative CC will develop disease recurrence after surgical resection alone. This suggests that either the tumor staging system or the staging technique is inadequate. The sentinel lymph node (SLN) procedure is a selective sampling technique that can be used to ultrastage regional nodes. The SLN is the first node or nodes to receive lymphatic drainage from a primary tumor and thus the most likely nodal site of metastasis. Mapping, dissection, and focused examination of SLNs can identify occult nodal metastases that may increase the risk of recurrence. The tumor status of the SLN does not change the extent of resection because en bloc resection of the primary CC includes regional lymph nodes; however, results of SLN-based nodal ultrastaging can improve identification of candidates for adjuvant therapy of CC. In this issue, Lim et al. 2 present a prospective phase 2 cohort study of SLN evaluation in 120 CC patients. Although SLNs were identified in 99% of patients undergoing colectomy for cancer, 17% of patients with nodal metastasis had SLNs that were tumor negative by hematoxylin and eosin (HE) staining of a single 2- to 3-mm section. The reported sensitivity of SLN analysis by routine or thin-section HE was 59% and the false-negative rate was 24% .O f 119 patients, 16 (13%) had SLNs that were negative on HE but positive by immunohistochemistry (IHC). These patients were not included in the sensitivity analysis because the authors did not consider IHCpositive nodes to have clinical significance. As evidence of the significance of IHC nodes, an analysis of overall survival found no difference in patients with nodes found to be positive by IHC versus nodes
- Jan 2008
The national recommendation for the management of localized T2 gallbladder cancer (GBCA) is radical cholecystectomy. Although reported survival for localized T2 disease has been poor, groups have documented improvement with radical resection. We hypothesized that a discrepancy exists between national recommendations and current practice patterns. Patients diagnosed with localized T2 GBCA between 1988 and 2002 were identified from the Surveillance, Epidemiology, and End Results registry. Age, sex, race, ethnicity, extent of surgery, and overall survival were assessed. Surgical procedure was categorized as cholecystectomy alone (CS), cholecystectomy plus lymph node dissection (CS+LN), radical cholecystectomy (RCS), or other. Survival calculations were made using the Kaplan-Meier method and compared with the log-rank test. Of 382 patients with pathologically confirmed T2 GBCA, 280 were women. The median patient age was 75 years. A total of 238 patients underwent CS, 76 underwent CS+LN, and 14 underwent RCS. The remaining 54 patients underwent a lesser or no procedure and were excluded from comparative analysis. The median survival was 14 months for all patients and 14, 14, and 8 months for subgroups treated with CS, CS+LN, and RCS, respectively. Rates of 5-year survival were 23%, 24%, and 36% for CS, CS+LN, and RCS subgroups, respectively. There was no significant difference in survival rates between RCS and CS+LN, or between RCS and CS. The majority of patients with T2 GBCA in the United States are not managed according to current national recommendations.
The 2007 Santa Monica Conference on Assessing and Treating Early-Stage Colon and Rectal Cancer, a multidisciplinary meeting of leaders in surgery, medical and radiation oncology, and pathology, was convened on January 12 to 13, 2007. The purpose of the meeting was to assess current data and issues in the field and to develop recommendations for advancing patient care and clinical research. Topics included pathologic assessment and staging, transanal versus laparoscopic versus open resection, adjuvant therapy, genetic testing and counseling, cooperative group strategies, and the use of biological therapies and novel agents. A review of the key issues discussed, as well as conclusions and recommendations considered significant to the field, is summarized below and presented at greater length in the individual manuscripts and accompanying discussion that comprise the full conference proceedings. Although the management of early-stage colon and rectal cancers remains a challenge for all of us, the development and use of new technologies and methods of assessment and treatment over the past several decades is yielding encouraging results. A variety of opportunities to further improve outcomes were addressed in this forum, including recommendations that specific protocols be adopted regarding surgical and pathologic dissection and reporting, particularly for stage II disease; the corollary need to increase active multidisciplinary collaboration; and the development of comprehensive consensus guidelines and recommendations to standardize care in early-stage colorectal cancer.
- Dec 2007
Overexpression of cyclooxygenase-2 (COX-2) in gastric cancer has been shown to enhance tumor progression. We investigated whether silencing by promoter region hypermethylation of the COX-2 gene contributes to disease outcome in gastric cancer. COX-2 methylation status was initially assessed by capillary array electrophoresis methylation-specific polymerase chain reaction (CAE-MSP) and COX-2 protein expression by immunohistochemistry (IHC) in 40 primary gastric cancer tissues in a pilot study. Prognostic end points of correlative studies of COX-2 methylation status were time to recurrence, overall survival, and standard clinicopathologic features. CAE-MSP analysis was then validated in a second independent gastric cancer population (n = 137). COX-2 methylation was detected in 23% and 28% of the pilot and validation patient groups, respectively. COX-2 expression (IHC) in gastric tumors inversely correlated with COX-2 gene methylation status in the pilot study (P = .02). COX-2 methylation in tumors was significantly associated with lower T, N, and TNM stage in the validation patient group (P = .02, P = .006, and P = .008, respectively). Patients with COX-2 methylated tumors had significantly longer time to recurrence and improved overall survival in a multivariate analysis in the validation patient group (hazard ratio[HR], 0.49; 95% CI, 0.24% to 0.99%; HR, 0.62; 95% CI, 0.38% to 0.99%, respectively). Hypermethylation of COX-2 gene promoter was identified as an independent prognostic factor in gastric cancer patients. The results suggest promoter hypermethylation to be an important regulatory mechanism of COX-2 expression in gastric cancer and an important prognostic biomarker.
The 25% rate of recurrence after complete resection of stage II colon cancer (CC) suggests the presence of occult nodal metastases not identified by hematoxylin and eosin staining (H&E). Interim data from our ongoing prospective multicenter trial of sentinel node (SN) biopsy indicate a 29.6% rate of micrometastases (MM) identified by immunohistochemical staining (IHC) of H&E-negative SNs in CC. We hypothesized that these MM have prognostic importance. Between March 2001 and August 2006, 152 patients with resectable colorectal cancer were enrolled in the trial. IHC and quantitative RT-PCR (qRT) assay were performed on H&E-negative SNs. Results were correlated with disease-free survival. The sensitivity of lymphatic mapping was significantly better in CC (75%) than rectal cancer (36%), P<0.05. Of 92 node-negative CC patients 7 (8%) were upstaged to N1 and 18 (22%) had IHC MM. Four patients negative by H&E and IHC were positive by qRT. At a mean follow-up of 25 months, 15 patients had died from noncancer-related causes, 12 had developed recurrence, 5 had died of CC (2 with macrometastases, 3 with MM), and 7 were alive with disease. The 12 recurrences included 4 patients with SN macrometastases and 6 with SN MM (2 by IHC, 4 by qRT). One of the 2 SN-negative recurrences had other positive lymph nodes by H&E. All patients with CC recurrences had a positive SN by either H&E/IHC or qRT. No CC patient with a negative SN by H&E and qRT has recurred (P=0.002). This is the first prospective evaluation of the prognostic impact of MM in colorectal cancer. These results indicate that the detection of MM may be clinically relevant in CC and may improve the selection of patients for adjuvant systemic chemotherapy. Patients with CC who are node negative by cumulative detection methods (H&E/IHC and qRT) are likely to be cured by surgery alone.
- Aug 2007
Patients with gut-based metastatic neuroendocrine tumors (NET) often present late in the course of their slowly progressive disease, when cancer has extended beyond the point of reasonable expectation for surgical cure. At this stage of disease, the tumor's overwhelming hormonal production often significantly impairs the patient's quality of life. Unlike patients with other malignancies that might involve a heavy burden of hepatic metastatic disease, many patients with metastatic NET continue to live for a long time despite escalating hormone-related symptoms. This establishes the justification and rationale for cytoreduction, a noncurative surgical intervention that reduces tumor burden and hormonal burden and thereby can significantly increase symptom-free survival in the setting of an often slow but inevitable disease progression.
Multimodal treatment consisting of repeated hepatectomy and adjuvant systemic chemotherapy for liver-confined recurrence of colorectal cancer can yield long-term survival comparable with that associated with primary hepatectomy. Retrospective analysis. A prospective database at a tertiary referral cancer center. Review of 274 consecutive liver resections identified 64 patients who underwent resection of hepatic colorectal metastases without ablation followed by adjuvant irinotecan hydrochloride- or oxaliplatin-based systemic chemotherapy. Median and 5-year overall and disease-free survival after primary and repeated hepatectomy. At median follow-up of 40 months, median and 5-year overall survival after hepatectomy were 60 months and 53%, respectively; median and 5-year disease-free survival were 33 months and 25%, respectively. Multivariate analysis showed that less than 1 year between colectomy and liver resection (P = .001), more than 3 metastases (P = .001), no repeated hepatectomy (P = .01), and lymph node-positive primary colon cancer (P = .02) were independently predictive of worse survival. Of 28 patients (44%) with liver-confined recurrence, 19 (30%) underwent repeated hepatectomy; at median follow-up of 38 months, median and 5-year overall survival after repeated hepatectomy were 48 months and 44%, respectively. No risk factors were identified in multivariate analysis. In patients with recurrence, median and 5-year overall survival measured from primary hepatectomy were 70 months and 73%, respectively, with repeated hepatectomy vs 43 months and 43%, respectively, without repeated hepatectomy (P = .03). Multimodal treatment of recurrent colorectal cancer confined to the liver should begin with consideration of repeated hepatectomy.
- Nov 2006
To determine whether analyzing more lymph nodes in colon cancer specimens improves survival. Increasing the number of lymph nodes analyzed has been reported to correlate with improved survival in patients with node-negative colon cancer. The Surveillance, Epidemiology, and End Results database was queried for all patients undergoing resection for histologically confirmed colon cancer between the years 1988 and 2000. Patients were excluded for distant metastases or if an unknown number of nodes was sampled. The number of nodes sampled was categorized into 0, 1 to 7, 8 to 14, and > or =15 nodes. Survival curves constructed using the Kaplan-Meier method were compared using log rank testing. A Cox proportional hazard model was created to adjust for year of diagnosis, age, race, gender, tumor grade, tumor size, TNM stage, and percent of nodes positive for tumor. The median number of lymph nodes sampled for all 82,896 patients was 9. For all stages examined, increasing nodal sampling was associated with improved survival. Multivariate regression demonstrated that patients who had at least 15 nodes sampled as compared with 1 to 7 nodes experienced a 20.6% reduction in mortality independent of other patient and tumor characteristics. Adequate lymphadenectomy, as measured by analysis of at least 15 lymph nodes, correlates with improved survival, independent of stage, patient demographics, and tumor characteristics. Currently, most procedures do not meet this guideline. Future trials of adjuvant therapy should include extent of lymphadenectomy as a stratification factor.
Treatment of colorectal metastatic disease has changed dramatically over the past 10 years. Liver resection has been the only accepted curative treat- ment option for patients with metastatic colon can- cer, but the introduction of better imaging, newer ablative techniques, improved systemic therapies and improved patient selection has increased the number of patients eligible for consideration for this goal. To date, there have been only modest prospective clinical trial efforts in this population to evaluate long-term benefits in relapse-free and overall survival, as well as, in patients who have undergone resection. This con- sensus conference is timely in bringing together leaders in the field in an effort to consolidate current approaches to this disease. This effort is laudable, focusing the discussion on the current standards for care of colorectal liver metastases (CLM), while highlighting the areas of controversy and the unan- swered questions. Like all good academic endeavors, it raises as many questions as it answers.
Second-generation radiofrequency ablation (RFA) probes and their successors have more power, shorter ablation times, and an increased area of ablation compared with the first-generation probes used before 2000. We examined whether the use of the newer probes has improved the clinical outcome of RFA for hepatic metastases of colorectal cancer at our tertiary cancer center. Of 160 patients who underwent RFA between 1997 and 2003, 52 had metastases confined to the liver: 21 patients underwent 46 ablations with the first-generation probes and 31 patients underwent 58 ablations with the newer probes. The two groups had similar demographic characteristics. At a median follow-up of 26.2 months, patients treated with the newer probes had a longer median disease-free survival (16 months vs 8 months, P < 0.01) and a lower rate of margin recurrence (5.2% vs 17.4%); eight patients had no evidence of disease and one patient was alive with disease. By contrast, of the 46 patients treated with the first-generation probes, 2 patients had no evidence of disease and 1 patient was alive with disease. Newer-generation probes are associated with lower rates of margin recurrence and higher rates of disease-free survival after RFA of hepatic metastases from colorectal cancer.
Although Hispanics demonstrate a low overall incidence of rectal cancer, mortality rates have not decreased relative to non-Hispanic whites. To determine if this was in part due to racial disparities in care, we compared rates of neoadjuvant therapy and sphincter-preserving surgery between Hispanics and non-Hispanic whites diagnosed with rectal cancer using the Surveillance, Epidemiology, and End Results (SEER) database. The study population was comprised of 2,573 Hispanics (55.4% male) and 28,395 non-Hispanic whites (56.6% male). Rates of neoadjuvant radiation were 13.5 per cent for Hispanics compared with 10.4 per cent for non-Hispanic whites (P < 0.001). In a Cox proportional hazards model adjusting for nodal status, tumor size, and T stage, non-Hispanic whites were significantly less likely to have received neoadjuvant therapy (hazard ratio, 0.72; P < 0.001; 95% confidence interval 0.63-0.83). Rates of sphincter preservation were 67 per cent for Hispanics and 70 per cent for non-Hispanic whites (P = 0.003). Non-Hispanic whites were significantly more likely to have received a sphincter-preserving operation than Hispanics (hazard ratio, 1.076; P = 0.019; 95% confidence interval 1.02-1.27). We conclude that Hispanics are significantly more likely to receive neoadjuvant therapy but are less likely to receive sphincter-sparing operations for rectal cancer compared with non-Hispanic whites. Further studies are required to assess the impact of these treatment disparities on patient outcome.
- Sep 2006
Since the introduction of sentinel node biopsy in 1990 as a minimally invasive surgical technique for the diagnosis of melanoma lymphatic metastases, the number of applications has expanded. We review applications and the current status of sentinel node biopsy in melanoma, breast, colon, gastric, esophageal, head and neck, thyroid, and lung cancer. Variations on techniques specific to each organ are explained, and the current role of sentinel node biopsy in diagnosis and treatment is discussed.
- Aug 2006
To determine the role of chemokine receptor (CR) expression in patients with melanoma and colorectal cancer (CRC) liver metastases. Murine and in vitro models have identified CR as potential factors in organ-specific metastasis of multiple cancers. Chemokines via their respective receptors have been shown to promote cell migration to distant organs. Patients who underwent hepatic surgery for melanoma or CRC liver metastases were assessed. Screening cDNA microarrays of melanoma/CRC cell lines and tumor specimens were analyzed to identify CR. Microarray data were validated by quantitative real-time RT-PCR (qRT) in paraffin-embedded liver metastases. Migration assays and immunohistochemistry were performed to verify CR function and confirm CR expression, respectively. Microarray analysis identified CXCR4 as the most common CR expressed by both cancers. qRT demonstrated CXCR4 expression in 24 of 27 (89%) melanoma and 28 of 29 (97%) CRC liver metastases. In vitro treatment of melanoma or CRC cells with CXCL12, the ligand for CXCR4, significantly increased cell migration (P < 0.001). Low versus high CXCR4 expression in CRC liver metastases correlated with a significant difference in overall survival (median 27 months vs. 10 months, respectively; P = 0.036). In melanoma, low versus high CXCR4 expression in liver metastases demonstrated no difference in overall survival (median 11 months vs. 8 months, respectively; P = not significant). CXCR4 is expressed and functional on melanoma and CRC cells. The ligand for CXCR4 is highly expressed in liver and may specifically attract melanoma and CRC CXCR4 (+) cells. Quantitative analysis of CXCR4 gene expression in patients with liver metastases has prognostic significance for disease outcome.
Lymph node evaluation is an important prognostic factor in colorectal cancer (CRC). A 25% recurrence rate in patients with node-negative CRC suggests that current staging practices are inadequate. Focused analysis of the sentinel node (SN) by multiple sectioning and immunohistochemistry improves staging accuracy. Prospective phase 2 multicenter trial. Tertiary referral cancer centers. Between March 2001 and June 2005, 132 patients were enrolled with clinical stage I and II CRC in a prospective multicenter trial (R01-CA90484). During a standard oncologic resection, lymphatic mapping was performed and the SN identified either by the surgeon or the pathologist. Hematoxylin-eosin staining was performed on all lymph nodes and immunohistochemistry, on lymph nodes negative by hematoxylin-eosin staining. Micrometastases greater than 0.2 mm but less than 2 mm and isolated tumor cells less than 0.2 mm were defined according to the sixth edition of the American Joint Committee on Cancer Cancer Staging Manual. The 63 men and 69 women had a median age of 74 years. Sixty-eight patients (52%) underwent a right hemicolectomy; 3 (2.3%), a transverse colectomy; 9 (7%), a left colectomy; 15 (11%), a sigmoid colectomy; 34 (26%), a low anterior resection; 1 (1%), an abdominal perineal resection; and 2 (2%), a total colectomy. Of the 111 evaluable primary tumors, 19 (17%) were T1 lesions; 17 (15%), T2; 72 (65%), T3; and 3 (2.7%), T4 tumors. Thirty-three patients (30%) were classified as stage I; 46 (41%), stage II, and 32 (29%), stage III. The SN was identified by the surgeon in 127 patients (96%) and by the pathologist in 5 patients (4%). The median number of SNs and total lymph nodes examined were 3 and 14.5, respectively. The sensitivity of lymphatic mapping and SN analysis was 88.2% and the false-negative rate, 7.4% (6/81). Of the 6 false-negative results, 4 were attributed to lymphatic channels obliterated by tumor. Upstaging occurred in 28 patients (23.6%). In a multicenter trial, ultrastaging of colon cancer is feasible and accurate. In stage II CRC, 24% of patients had nodal carcinoma cells not detected by conventional staging methods. Surgical technique (adequate lymph node retrieval) and focused pathological analysis may improve staging accuracy and the selection of patients for chemotherapy. The unnecessary toxicity and expense of chemotherapy may be avoided in those patients who are truly node negative.
Radiofrequency ablation (RFA) may improve survival of high-risk patients with unresectable and refractory tumors. Retrospective analysis of a prospective database. A tertiary referral cancer center. Between November 1, 1997, and January 31, 2005, we performed 219 RFA procedures to ablate 521 hepatic tumors in 181 patients. Of the 181 patients, 52% were male and 48% were female, and the mean age was 61.3 years (age range, 27-91 years). Radiofrequency ablation was performed via celiotomy (n = 135), via laparoscopy (n = 48), or percutaneously (n = 36). In 106 patients (79%), RFA was used in combination with surgical resection. The most common tumors included colorectal cancer (40.9%), hepatocellular carcinoma (14.9%), carcinoid tumor (13.8%), melanoma (9.4%), and breast cancer (5.0%). The average number of tumors per patient was 3.3 tumors. The average number of RFA-treated lesions per procedure was 2.38 lesions; the mean lesion size was 3.56 cm (lesion size range, 0.8-9.0 cm). At a mean follow-up of 33.2 months (follow-up range, 12-91 months), overall survival was 48.3 months for carcinoid tumors, 25.2 months for hepatocellular carcinoma, 18.5 months for melanoma, 29.7 months for colorectal cancer, and 30.1 months for breast cancer. Seventy-eight patients (43%) developed recurrences. Of 521 tumors that were treated, 125 (24%) recurred; the incidence of local recurrence was 28% for tumors larger than 3 cm vs 18% for tumors 3 cm or smaller (P = .04). Twenty-nine patients underwent serial ablations. Seventy-one patients (39%) were disease free at last follow-up. A significant number of patients whose hepatic malignancies are unresectable or refractory to chemotherapy may be considered for RFA as part of a multimodality therapeutic regimen. In these patients, RFA is safe and may prolong survival.
Precise evaluation of lymph node status is one of the most important factors in determining clinical outcome in treating gastro-intestinal (GI) cancer. Sentinel lymph node (SLN) mapping clearly has become highly feasible and accurate in staging GI cancer. The lunchtime symposium focused on the present status of SLN mapping for GI cancer. Dr. Kitigawa proposed a new strategy using sentinel node biopsy for esophageal cancer patients with clinically early stage disease. Dr. Uenosono reported on whether the SLN concept is applicable for gastric cancer through his analysis of more than 180 patients with cT1-2, N0 tumors. The detection rate was 95%, the false negative rate of lymph node metastasis including micro-metastasis was 4%, and accuracy was 99% in gastric cancer patients with cT1N0. Dr. Bilchik recommended the best technique for identifying SLNs in colorectal cancer: a combination of radiotracer and blue dye method, emphasizing that this technique will become increasingly popular because of the SLN concept, with improvement in staging accuracy. He stressed that this novel procedure offers the potential for significant upstaging of GI cancer. Dr. Saha emphasized that SLN mapping for colorectal cancer is highly successful and accurate in predicting the presence or absence of nodal disease with a relatively low incidence of skip metastases. It provided the "right nodes" to the pathologists for detailed analysis for appropriate staging and treatment with adjuvant chemotherapy. Although more evidence from large-scale multicenter clinical trials is required, SLN mapping may be very useful for individualizing multi-modal treatment for esophageal cancer and might be widely acceptable even for GI cancer.
Its prevalence, long premalignant course, and favorable response to early intervention make colorectal cancer an ideal target for screening regimens. The success of these regimens depends on accurate assessment of risk factors, patient compliance with scheduled visits and tests, and physician knowledge of screening strategies. We review the current recommendations for colorectal cancer screening in general and at-risk populations, comment on surveillance methods in high-risk patients, and examine current trends that will likely influence screening regimens in the future.
- Jun 2006
Cell-free DNA circulating in blood is a candidate biomarker for malignant tumors. Unlike uniformly truncated DNA released from apoptotic nondiseased cells, DNA released from dead cancer cells varies in size. We developed a novel method to measure the ratio of longer to shorter DNA fragments (DNA integrity) in serum as a potential biomarker for patients with colorectal cancer (CRC) or periampullary cancers (PACs). Sera from 32 patients with CRC (3 stage I, 14 stage II, 6 stage III, and 9 stage IV patients), 19 patients with PACs (2 stage I, 9 stage II, 1 stage III, and 7 stage IV patients), and 51 healthy volunteers were assessed by quantitative real-time PCR of ALU repeats (ALU-qPCR) with 2 sets of primers (115 and 247 bp) amplifying different lengths of DNA. We used serum directly as a template for ALU-qPCR without DNA purification. DNA integrity was determined as ratio of qPCR results of 247-bp ALU over 115-bp ALU. ALU-qPCR had a detection limit of 0.01 pg of DNA. Eliminating DNA purification reduced technical artifacts and reagent/labor costs. Serum DNA integrity was significantly increased for stage I/II and III/IV CRC and stage I/II and III/IV PACs (P = 0.002, P = 0.006, P = 0.022, and P <0.0001, respectively). ROC curves for detecting CRC and PACs had areas under the curves of 0.78 and 0.80, respectively. Direct ALU-qPCR is a robust, highly sensitive, and high-throughput method to measure serum DNA integrity. DNA integrity is a potential serum biomarker for detection and evaluation of CRC and PACs.
The MAGEA gene family that encodes cancer testis antigens is differentially expressed in many cancers. Though MAGEA3 expression has been detected in gastrointestinal malignancies, its role in pancreatic ductal adenocarcinoma (PDAC) has not been well established. We assessed 57 patients who underwent intent-to-cure surgery for PDAC. Total RNA from paraffin-embedded pancreatic tumors was extracted and assessed for MAGEA3 gene expression by an optimized probe-based quantitative real-time RT-PCR (qRT) assay. MAGEA3 gene expression was detected by qRT in 25 (44%) patients. For the entire cohort, detection of MAGEA3 expression was associated with significantly decreased overall survival (median, 16 vs 33 months; log-rank, p = 0.032). When clinicopathologic factors, including age, gender, stage, tumor extent, lymph node metastasis, tumor grade, perineural invasion and lymphovascular invasion were assessed by univariate analysis, MAGEA3 gene expression and tumor grade were significant prognostic factors for poor survival (HR 2.1, 95% CI: 1.0-4.4, p = 0.041; and HR 3.7, 95% CI: 1.8-7.6, p = 0.0004, respectively). Immunohistochemistry (IHC) was performed and confirmed MAGEA3 protein in PDAC specimens. In conclusion, MAGEA3 is differentially expressed in patients with PDAC; its expression correlates with significantly worse survival. Molecular assessment for MAGEA3 should be considered to improve prognostic evaluation and to identify eligible patients for potential immune-based therapy.
- Feb 2006
Hepatic metastases from breast cancer signal a dismal prognosis, with a median survival of 9.5 months. Twenty breast cancer patients with liver metastases underwent hepatic resection, biopsy, or ablation between 1995 and 2004. Hormone receptor status and Her-2/neu expression of primary and metastatic tumors were correlated with overall survival. At a mean follow-up of 39 months after hepatic resection, median survival was 32 months. Patients undergoing anatomic resection with or without ablation lived significantly longer than those undergoing more limited resections (46 vs. 25 months, P = .016). Survival was significantly greater in patients with estrogen receptor (ER)-positive primary (P = .02) and metastatic (P < .004) tumors, Her-2/neu-positive metastases (P = .02), </=2 hepatic metastases (P < .002), and age >50 years at metastasectomy (P = .02). The ER status of the primary tumor and ER and Her-2/neu status of hepatic metastases, in addition to other clinical factors, may help select patients who would benefit from hepatic metastasectomy.
- Apr 2005
Liver metastasis is the predominant cause of colorectal cancer (CRC) related mortality. Chemokines, soluble factors that orchestrate hematopoetic cell movement, have been implicated in directing cancer metastasis, although their clinical relevance in CRC has not been defined. Our hypothesis was that the chemokine receptor CXCR4 expressed by CRC is a prognostic factor for poor disease outcome. CRC cell lines (n = 6) and tumor specimens (n = 139) from patients with different American Joint Committee on Cancer (AJCC) stages of CRC were assessed. Microarray screening of select specimens and cell lines identified CXCR4 as a prominent chemokine receptor. CXCR4 expression in tumor and benign specimens was assessed by quantitative real-time reverse transcription polymerase chain reaction and correlated with disease recurrence and overall survival. High CXCR4 expression in tumor specimens (n = 57) from AJCC stage I/II patients was associated with increased risk for local recurrence and/or distant metastasis (risk ratio, 1.35; 95% CI, 1.09 to 1.68; P = .0065). High CXCR4 expression in primary tumor specimens (n = 35) from AJCC stage IV patients correlated with worse overall median survival (9 months v 23 months; RR, 2.53; 95% CI, 1.19 to 5.40; P = .016). CXCR4 expression was significantly higher in liver metastases (n = 39) compared with primary CRC tumors (n = 100; P < .0001). CXCR4, a well-characterized chemokine receptor for T-cells, is differentially expressed in CRC. CXCR4 gene expression in primary CRC demonstrated significant associations with recurrence, survival, and liver metastasis. The CXCR4-CXCL12 signaling mechanism may be clinically relevant for patients with CRC and represents a potential novel target for disease-directed therapy.
- Feb 2005
Accurate staging of colon cancer is prognostically and therapeutically important. By identifying those patients who would most benefit from adjuvant chemotherapy, accurate staging should decrease recurrence rates and improve overall survival. Lymphatic mapping and sentinel node analysis allow for a focused review of the lymph nodes, which are most likely to harbor a metastasis and may make ultrastaging techniques, such as immunohistochemistry and reverse-transcriptase polymerase chain reaction, more practical. The prognostic significance of micrometastatic disease detected via ultrastaging techniques remains controversial.
- Dec 2004
ID4 gene is a member of the inhibitor of DNA binding (ID) family proteins that inhibit DNA binding of basic helix-loop-helix transcription factors. The epigenetic inactivation of ID4 gene on colorectal cancer (CRC) development and its clinical significance was assessed. In CRC cell lines, ID4 methylation status of the promoter region was assessed by methylation-specific PCR and bisulfite sequencing. The mRNA expression level was assessed by quantitative real-time reverse transcription-PCR. The methylation status of 9 normal epithelia, 13 adenomas, 92 primary CRCs, and 26 liver metastases was assessed by methylation-specific PCR. ID4 protein expression was assessed by immunohistochemistry analysis of tissue specimen. CRC cell lines were shown to be hypermethylated, and mRNA expression was suppressed and could be restored by 5-aza-cytidine treatment. In clinical specimens from normal epithelia, adenomas, primary CRCs, and liver metastases, the frequency of ID4 hypermethylation was 0 of 9 (0%), 0 of 13 (0%), 49 of 92 (53%), and 19 of 26 (73%), respectively, with a significant elevation according to CRC pathological progression. Methylation status of primary CRCs significantly correlated with histopathological tumor grade (P = 0.028). Immunohistochemistry analysis showed ID4 expression of normal colon epithelia, adenomas, and unmethylated primary CRCs but not hypermethylated CRC specimens. Among 76 American Joint Committee on Cancer stage I to IV patients who had undergone curative surgical resection, overall survival was significantly poorer in patients with hypermethylated ID4 bearing tumors (P = 0.0066). ID4 gene is a potential tumor suppressor gene for which methylation status may play an important role in the CRC progression.
APAF-1 gene, located at chromosome locus 12q23, is a key factor in the mitochondrial apoptotic pathway downstream of p53, and is a potential tumor suppressor gene. We hypothesized that APAF-1 gene dysfunction due to allelic imbalance (AI) contributes to the development and progression of colorectal carcinoma (CRC). AI at APAF-1 locus and microsatellite instability (MIN) in CRCs and adenomas were assessed by multiple microsatellite markers. The frequency of AI significantly increased with tumor progression; 0 of 33 (0%) adenomas, 14 of 49 (29%) primary CRCs, and 18 of 34 (53%) liver metastases had AI. A total of 12 metastases were matched with corresponding primary CRCs; in 11 of 12 (92%) pairs, the metastasis had same AI status as the corresponding primary tumor. APAF-1 mRNA transcription level was significantly decreased with AI in liver metastases (P=0.009). Promoter hypermethylation was found in three of 35 (9%) primary CRCs and one of 15 (7%) liver metastases by methylation-specific PCR but was not correlated with AI. MIN was observed in 11 of 49 (23%) primary CRCs and was a favorable prognostic factor. Our results suggest that APAF-1 gene haploinsufficiency caused by AI increases with tumor progression, and relates to hepatic metastasis.
- Sep 2004
Inaccurate staging of colorectal cancer (CRC) has been attributed to the failure to detect lymph node metastases by conventional pathology. We have previously reported the use of lymphatic mapping to accurately identify those lymph nodes most likely to harbor micrometastatic disease and permit focused pathologic examination. Mutation of K-ras allele at codons 12 or 13 occurs frequently in early stages of CRC development. The purpose of our study was to assess sentinel lymph nodes (SLN) for occult CRC micrometastases using a unique peptide nucleic acid (PNA) clamp PCR assay specific for K-ras mutations. Seventy-two paraffin-embedded primary CRC and paired SLN were evaluated by PNA clamp PCR for K-ras mutations. Thirty primary tumors (42%) were positive for K-ras mutations, and in 5 of these cases the SLN were positive for metastases by Hematoxylin and Eosin staining. PNA clamp PCR identified occult metastases in an additional 6 patients, upstaging 24% of K-ras positive primary CRCs (p = 0.014). No K-ras mutations were detected among the 20 noncancer lymph nodes assessed. This study demonstrates the utility, specificity and sensitivity of PNA clamp PCR assay in identifying occult micrometastases in the SLN of CRC patients by single-base mutation analysis.
- Apr 2004
The advent of sentinel lymph node mapping (SLNM) has had a profound impact on the surgical management of breast cancer and melanoma over the past decade. However, SLNM in gastrointestinal malignancies is still in its infancy. The role of SLNM in gastrointestinal malignancies is to increase staging accuracy and to reduce the understaging associated with standard surgical and pathological techniques. Numerous authors have described the successful use of SLNM in colon, rectal, gastric, esophageal, and anal canal malignancies, with a high degree of accuracy and upstaging by detailed pathological analysis of the sentinel nodes. Over the past 2 years, research and publications related to gastrointestinal lymphatic mapping have dramatically increased worldwide.
- Jan 2004
- Radiofrequency Ablation for Cancer
Radiofrequency ablation is a technology that has demonstrated promise for cytoreduction of many primary and metastatic hepatic malignancies that cannot be resected. This new technology can be applied at laparotomy, laparoscopy, or via a percutaneous approach. Because the largest laparoscopic series does not report complications,24 documented complications of laparoscopic RFA are few. While the benefits of RFA are great, complications have been noted to occur, and perioperative measures in addition to intraoperative vigilance may help minimize risk. Knowledge of potential pitfalls is required to perform the procedure in a safe and effective manner. It is thus crucial that institutions utilizing RFA continually monitor their outcomes. Complications, attempts to minimize risk, long-term results, and mortalities are all end points that must be monitored to ensure safe application of this technology.
Although the expression of thymidylate synthase (TS) in metastatic colorectal cancer (CRC) may be a better predictor of response to 5-fluorouracil chemotherapy than TS expression in primary CRC, this enzyme has not been well studied in tumor-draining regional lymph nodes. We retrospectively examined TS expression in 12 primary CRC lesions (pT3) and matched sentinel lymph nodes. Of the 8 primary tumors that were TS-positive, 50 per cent (4/8) had tumor-positive lymph nodes and 50 per cent (4/8) had tumor-negative nodes. Of the 4 primary tumors that were TS-negative, 75 per cent (3/4) had tumor-positive nodes and 25 per cent (1/4) had tumor-negative nodes [kappa = -0.1386, 95 per cent confidence interval: (-0.4820, 0.2048), P = 0.4284]. Of the 8 TS-positive primaries, 25 per cent (2/8) had TS-positive nodes and 75 per cent (6/8) had TS-negative nodes. Of the 4 TS-negative primaries, 50 per cent (2/4) had TS-positive nodes and 50 per cent (2/4) had TS-negative nodes [kappa = -0.0131, 95 per cent confidence interval: (-0.2958, 0.2696), P = 0.9274]. Two of the three TS-negative primaries that had metastasized to regional lymph nodes were associated with TS-positive lymph nodes. Our findings indicate that expression of TS by a primary CRC does not correlate with nodal metastases or nodal TS expression. Nodal expression of TS may be important in predicting response to 5-fluorouracil when a primary CRC is TS-negative.
Lymphatic mapping and sentinel lymphadenectomy (LM/SL) have been applied to virtually all solid neoplasms since our original description of LM/SL for melanoma. Our objectives were to determine the diagnostic and therapeutic utility of LM/SL, investigate carbon dye for mapping the microanatomy of lymphatic flow within the sentinel node (SN), and determine the prognostic accuracy of molecular assessment of the SN. Since 1985, 1599 patients with AJCC Stage I/II melanoma have been treated by LM/SL at our institution and 4590 have been treated by wide excision (WE) without nodal staging. We examined the incidence of clinical nodal recurrence after WE alone, the incidence of subclinical nodal metastases found by LM/SL, and the incidence of nodal recurrence in basins with histopathology-negative SNs. In 1514 LM/SL patients with a primary of known Breslow thickness, the incidence of metastasis in nodes claimed to be sentinel was 7.3%, 19.7%, 33.2%, and 39.7% for primary lesions </=1.0, 1.01-2.0, 2.01-4.0, and >4.0 mm, respectively. In 3652 WE-only patients, the corresponding rates of nodal recurrence were 12.0%, 32.0%, 34.4%, and 30.1%. Thus, LM/SL detected only 60% of expected nodal metastases from primary melanomas <2.01 mm. Forty of 1599 (3.1%) patients developed recurrence in basins with immunohistochemistry (IH)-negative SNs. To determine whether nonrandom intranodal distribution of tumor cells could explain missed SN metastases, we coinjected carbon particles and blue dye during LM/SL in 166 patients: 25 (16%) patients had nodal metastases, all of which were found only in nodal subsectors containing carbon particles. When paraffin-embedded SNs from a subset of 162 IH-negative patients were re-examined by quantitative multimarker reverse-transcriptase polymerase chain reaction (qRT) assay, 49 (30%) gave positive signals. These patients had a significantly higher risk of disease recurrence and death than did patients whose IH and qRT results were negative (p < 0.0001). Comparison of 287 prognostically matched pairs of patients who underwent immediate (after LM/SL) versus delayed (after observation) dissection of nodal metastases revealed 5-, 10-, and 15-year survival rates of 73%, 69%, and 69% versus 51%, 37%, and 32%, respectively (P < or = 0.001). SN assessment based on intranodal compartmentalization of lymphatic flow (carbon dye mapping) should increase the accuracy of IH and, in combination with multimarker qRT assessment, will allow confident identification of most patients for whom surgery alone is curative. Our data suggest a significant therapeutic benefit for immediate dissection based on identification of a tumor-involved SN.
- Jun 2003
Nodal staging accuracy is important for prognosis and selection of patients for chemotherapy. Sentinel lymph node (SLN) mapping improves staging accuracy in breast cancer and melanoma and is being investigated for colorectal carcinoma. To assess pathologic aspects of SLN staging for colon cancer. Sentinel lymph nodes were identified with a dual surgeon-pathologist technique in 51 colorectal carcinomas and 12 adenomas. The frequency of cytokeratin (CK)-positive cells in mesenteric lymph nodes, both SLN and non-SLN, was determined along with their immunohistochemical characteristics. The median number of SLNs was 3; the median number of total nodes was 14. The CK-positive cell clusters were detected in the SLNs of 10 (29%) of 34 SLN-negative patients. Adjusted per patient, SLNs were significantly more likely to contain CK-positive cells than non-SLNs (P <.001). Cell clusters, cytologic atypia, and/or coexpression of tumor and epithelial markers p53 and E-cadherin were supportive of carcinoma cells. Single CK-positive cells only, however, could not be definitively characterized as isolated tumor cells; these cells generally lacked malignant cytologic features and coexpression of tumor and epithelial markers and in 2 cases represented mesothelial cells with calretinin immunoreactivity. Colorectal adenomas were associated with a rare SLN CK-positive cell in 1 (8%) of 12 cases. Sentinel lymph node staging with CK-immunohistochemical analysis for colorectal carcinomas is highly sensitive for detection of nodal tumor cells. Cohesive cell clusters can be reliably reported as isolated tumor cells. Single CK-positive cells should be interpreted with caution, because they may occasionally represent benign epithelial or mesothelial cells.
- Mar 2003
Nodal metastasis is the single most important prognostic factor in early colorectal cancer (CRC). Lymphatic mapping can identify sentinel nodes for focused histopathologic examination and thereby improve the nodal staging of CRC; however, the optimal technique for identifying sentinel nodes in CRC is unclear. We hypothesized that a combination of radiotracer and blue dye would more accurately identify tumor-positive sentinel nodes than blue dye alone. Lymphatic mapping was performed in 48 consecutive patients undergoing resection for CRC and in two original patients who underwent sentinel node mapping in 1996. Prior to resection, 1% vital blue dye and radiotracer were injected around the tumor in the subserosal layer. Nodes were designated as sentinel by blue coloration and/or radioactivity. Lymphatic mapping identified at least one sentinel node in 49 patients. Focused examination of multiple sentinel node sections by means of hematoxylin and eosin and immunohistochemical analysis showed that sentinel nodes accurately predicted the status of the nodal basin in 93.8% (46 of 49) of patients. Of the 19 patients with nodal metastases, 11 had macrometastases (>.2 mm), three had micrometastases (between 2 mm and 0.2 mm), and five had isolated tumor cells or clusters (<.2 mm) identified by immunohistochemical analysis only. Patients had significantly fewer blue/radioactive ("hot") nodes than blue-only nodes (1.38 vs. 2.48 per patient; P = 0.0001). It is important to note that nodal metastases were more common in blue/hot nodes than in blue-only nodes (27.3% [19 of 68] vs. 8.8% [11 of 124]; P = 0.005). Dual-agent lymphatic mapping more accurately identifies sentinel node metastases than blue dye alone. In addition, this technique allows a more focused histopathologic examination of these nodes, in conjunction with the revised American Joint Committee on Cancer guidelines, and thereby offers the potential for significant upstaging of CRC.
Regional hepatic chemotherapy with FUDR significantly improves local recurrence rates and may impact overall survival in patients with hepatic colorectal metastases. The results of prospective randomized trials confirm that careful patient selection, a thorough knowledge of intricate hepatic arterial anatomy, and an understanding of the pharmacokinetics and delivery of FUDR optimize treatment efficacy. A multimodality approach that includes adjuvant therapy in addition to cytoreductive surgery offers promise for the treatment of unresectable hepatic metastases. Because many tumors recur in extrahepatic sites, the addition of novel systemic agents such as CPT-11 may further reduce recurrences. Molecular analysis of the tumor may ultimately help select patients who are good candidates for regional chemotherapy.
Sensitive detection methods and accurate reporting are necessary to determine the prognostic significance of micrometastases (MM) and isolated tumor cells (ITCs) in lymph nodes that drain colorectal cancers (CRCs). This study examined the role of lymphatic mapping (LM) in the application of the new tumor-node-metastasis (TNM) classification for MM and ITC. All patients at the John Wayne Cancer Institute underwent LM immediately before standard resection of primary CRC between 1996 and 2001. Sentinel nodes (SNs) were identified using blue dye and/or radiotracer and were examined by hematoxylin-eosin (H&E) staining, cytokeratin immunohistochemistry, and multilevel sectioning. The comparison group comprised 370 patients whose primary CRCs were resected without LM during the same period at the same institution. LM was successfully performed in 115 of 120 (96%) patients and correctly predicted the tumor status of the nodal basin in 110 of 115 (96%) patients. Thirty-seven patients (32%) were lymph node-positive by H&E, ITC and MM were found in 23 patients (29.4%) whose lymph nodes were negative by H&E. Tumor deposits were found in the SN only in 29 patients (50%). Nodal involvement was identified for 14.3%, 30%, 74.6%, and 83.3% of T1, T2, T3, and T4 tumors, respectively, in the study group, and for 6.8%, 8.5%, 49.3%, and 41.8% of T1, T2, T3, and T4 tumors, respectively, in the comparison group. The study group had a higher percentage of nodal metastases (53% v 36%; P <.01) and a higher incidence of MM and ITC (29.4% v 1.9%; P <.0001). The mean number of lymph nodes found in the study group (14) was also significantly more than the number found in the comparison group (10; P <.00001). Conventional examination of lymph nodes for CRC is inadequate for the detection of MM and ITC as described in the new TNM classification. Thus, LM and focused SN analysis should be considered to fully stage CRC.
Irinotecan is a first-line chemotherapeutic agent for patients with metastatic colorectal cancer (CRC). Response rates of less than 40% underscore the problem of treating CRC with irinotecan. Our studies have shown that chemosensitization correlates with high levels of ceramide, whereas resistance correlates with high levels of glucosylceramide (GlcCer). The purpose of this study was to characterize the role of ceramide in irinotecan-mediated CRC cell death. We used four human CRC cell lines to assess ceramide metabolism, cell viability, and apoptosis after treatment with irinotecan. Fumonisin B(1) (FB(1)) and 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) were used to inhibit de novo ceramide synthesis and GlcCer production, respectively. L-threo-dihydrosphingosine (safingol) was used to inhibit secondary proliferative pathways mediated by an atypical protein kinase C that is activated by ceramide. Irinotecan elicited dose- and time-dependent increases in ceramide, which preceded apoptosis. When FB(1) was added to irinotecan, CRC cell death was significantly decreased. A significant increase in intracellular levels of GlcCer also was noted after treatment with irinotecan. When GlcCer production was blocked by treating cells with PPMP in addition to irinotecan, ceramide levels increased to 228% of control values and cell death increased by 88%, compared to irinotecan alone. When irinotecan was combined with both PPMP and safingol, cell death was increased by 225% to 325%, compared to irinotecan lone. CRC cell death due to irinotecan is mediated, at least in part, by the de novo synthesis of ceramide. Blocking further metabolism of ceramide can enhance this cytotoxicity. Targeting ceramide pathways is a novel strategy for the treatment of patients with CRC.
Radiofrequency ablation (RFA) is a promising technique for unresectable hepatic malignancies. We reviewed our RFA experience to identify variables affecting local recurrence. Patients undergoing RFA between 1997 and 2001 were reviewed for demographics, tumor size, pathology, diagnosis, recurrence, procedures, survival, and complications. The 447 unresectable liver tumors were ablated in 198 procedures. The 153 patients averaged 61.9 years of age and 1.25 RFA procedures per patient. Follow-up averaged 11 months. Serial ablations were performed in 28 patients, 8 of whom are without evidence of disease. Tumors were most commonly carcinomas of colorectal, hepatocellular, breast, and melanoma histologies. Colorectal carcinomas and hepatomas individually recurred more frequently than all other tumor types combined in univariate analyses (P =.009 and P =.008, respectively). Patients with multiple tumors ablated recurred significantly more frequently (P =.001). Size was also significant in univariate and multivariate analyses (P =.0032 and <.0001, respectively). Eighteen patients experienced 36 complications. Size has the highest correlation with local recurrence, but multiple tumors and pathology may also predict local recurrence risk. Large, complex lesions can be safely serially ablated, but because of morbidity and recurrence, RFA should not replace resection as the primary treatment of resectable liver tumors.
Approximately one third of node-negative colorectal cancers (CRCs) recur, suggesting the failure to detect occult disease. Lymphatic mapping followed by focused analysis of the sentinel node is highly accurate in identifying micrometastases. Because aberrant genetic changes occur early in tumor progression and are associated with lymphatic metastases, we hypothesized that the molecular profiling of specific tumor markers in the primary tumor might predict that tumor's metastatic potential. A prospective patient series. Forty consecutive patients with early CRC underwent lymphatic mapping after subserosal injection of 1 mL of isosulfan blue dye. All lymph nodes were examined by hematoxylin-eosin (HE) staining, and multiple sections of each sentinel node were examined by HE and cytokeratin immunohistochemistry (CK-IHC) staining. Primary tumors were analyzed for p53 expression using IHC staining and for beta-human chorionic gonadotropin (beta-hCG), hepatocyte growth factor receptor (c-Met), and universal melanoma antigen (uMAGE) messenger RNA expression using reverse-transcriptase polymerase chain reaction and electrochemiluminescence. Nine patients (23%) had positive nodes by routine HE staining. Of the remaining 31 patients with negative nodes on HE staining, 8 tumors (26%) were upstaged by CK-IHC identification of occult micrometastases. There was a direct correlation between the number of markers and the T stage (P =.001). The expression of p53, beta-hCG, c-Met, and uMAGE in primary tumors was significantly higher in the presence of nodal micrometastases vs no metastases (P =.03). Sentinel lymphatic mapping is an accurate method of detecting micrometastases in CRC. Molecular profiling of primary CRC tumors, similar to that used for breast cancer, may be important in predicting metastatic potential and determining which patients may benefit from adjuvant therapy.
- Nov 2002
Laparoscopic colectomy for colorectal cancer (CRC) has been criticized because of the potential for inadequate nodal dissection and incomplete staging. Lymphatic mapping (LM) and sentinel lymph node (SLN) analysis can improve the accuracy of staging in open colectomy, but its utility during laparoscopic colectomy is unknown. Between 1996 and 2002, 30 patients with clinically localized colorectal neoplasms or premalignant polyps underwent subserosal or submucosal injection of isosulfan blue dye via a colonoscope, via a percutaneously inserted spinal needle, or through a hand port. Blue-stained lymphatics were visualized through the laparoscope and followed to the SLN, which was tagged. The colectomy was completed in standard fashion. All lymph nodes were stained by hematoxylin and eosin, and multiple sections of each SLN were examined by immunohistochemical (IHC) staining using cytokeratin antibody. An SLN was identified laparoscopically in all patients. The SLN accurately predicted the tumor status of the nodal basin in 93% of cases. In 8 cases (29%), an unexpected lymphatic drainage pattern altered the extent of mesenteric resection, and in 4 cases (14%), tumor deposits were identified only by IHC and limited to the SLN. This study, which updates a preliminary report (Am Surg. 2002;68:561-565) confirms that SLN mapping during laparoscopic colon resection can alter the margins of resection and may improve staging by allowing a focused pathologic examination of the SLN, although direct comparison with the "gold standard" of open CRC with adequate lymphadenectomy will be required. Better ultrastaging of CRC lymph nodes may more accurately assign patients to prospective protocols to assess the significance of nodal micrometastases or isolated tumor cells.