Improved Survival with Anti-VEGF Therapy in the Treatment of Unresectable Appendiceal Epithelial Neoplasms.

BACKGROUND: Currently, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are accepted treatments for surgically resectable appendiceal epithelial neoplasms. However, for nonsurgical candidates, systemic treatment may be considered. The purpose of this analysis was to determine the benefit of biologic therapy (anti-vascular endothelial growth factor and anti-epidermal growth factor receptor) in addition to systemic chemotherapy in this select patient population. METHODS: The MD Anderson Cancer Center tumor registry was retrospectively reviewed for systemic treatment-naive appendiceal epithelial neoplasm patients registered between January 2000 to July 2007 for prior cytoreductive surgery and hyperthermic intraperitoneal chemotherapy status, histologic grade, signet ring pathology, systemic chemotherapy, biologic therapy, tumor markers (carcinoembryonic antigen, carbohydrate antigen [CA] 125, and/or CA19-9), progression-free survival (PFS), overall survival (OS), and disease control rate. Kaplan-Meier method, log-rank, and Cox proportional hazard regression models were used for statistical analysis. RESULTS: A total of 353 patients were identified; 130 patients met the inclusion criteria. Fifty-nine patients received biologic therapy. The use of the anti-vascular endothelial growth factor (VEGF) agent bevacizumab improved both OS (42 months vs. 76 months, hazard ratio 0.49 [95 % confidence interval 0.25-0.94] P = 0.03) and PFS (4 months vs. 9 months, hazard ratio 0.69 [95 % confidence interval 0.47-0.995], P = 0.047) for all histologic subtypes. Moderately differentiated tumors had an improved PFS relative to well-differentiated tumors, 9 months versus 3 months (P = 0.05). CONCLUSIONS: Bevacizumab in combination with chemotherapy appears to play a role in surgically unresectable appendiceal epithelial neoplasm patients, with an improvement in PFS and OS. Anti-VEGF agents should be strongly considered in the management of patients with higher-grade appendiceal epithelial neoplasms who are suboptimal candidates for surgical resection.

Phase II trial of imatinib mesylate in patients with metastatic melanoma.

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome.

PURPOSE: Preoperative chemoradiotherapy may increase the R0 (curative) resection rate, overall survival (OS) duration, and disease-free survival (DFS) duration. We evaluated paclitaxel-based induction chemotherapy and chemoradiotherapy in patients with localized gastric or gastroesophageal adenocarcinoma to determine its feasibility, impact on the R0 resection rate, type of pathologic response, OS, and DFS. PATIENTS AND METHODS: Patients with operable, localized gastric, or gastroesophageal adenocarcinoma were eligible. Staging included endoscopic ultrasonography (EUS) and laparoscopy. Patients received two 28-day cycles of induction chemotherapy of fluorouracil, paclitaxel, and cisplatin followed by 45 Gy of radiation and concurrent fluorouracil plus paclitaxel. The cancer was restaged and surgery was attempted. Postsurgery pathologic findings and R0 resection were correlated with OS and DFS. RESULTS: Forty-one patients were enrolled. Most carcinomas were proximal (83%) and pretreatment stage EUST3 (85%). Forty patients (98%) underwent surgery, and 78% had an R0 resection. We observed a pathologic complete response (pathCR) rate of 20% and a pathologic partial response (pathPR) rate of 15% (< 10% residual cancer cells in the resected specimen). No pretreatment parameter (sex, cancer location, baseline T stage, or baseline N stage) predicted the type of postsurgery pathologic response, OS, or DFS. However, pathCR (P = .02), pathCR + pathPR (P = .006), R0 resection (P < .001), and postsurgery T and N stages (P = .01 and P < .001, respectively) were associated with OS. Same parameters were significantly correlated with DFS. Toxicity was manageable. CONCLUSION: The type of pathologic response but not pretreatment parameters was associated with OS and DFS. Efforts to increase the rate of pathologic response and better systemic cancer control are warranted.

Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma.

PURPOSE: In the West, curative (R0) resection is achieved in approximately 50% of patients with localized gastric carcinoma, and more than 60% die of cancer following an R0 resection. A multi-institutional study of preoperative chemoradiotherapy was done to assess the R0 resection rate, pathologic complete response (pathCR) rate, safety, and survival in patients with resectable gastric carcinoma. PATIENTS AND METHODS: Operable patients with localized gastric adenocarcinoma were eligible. Staging also included a laparoscopy and endoscopic ultrasonography (EUS). Patients received up to two 28-day cycles of induction chemotherapy of fluorouracil, leucovorin, and cisplatin, followed by 45 Gy of radiation plus concurrent fluorouracil. Patients were then staged and surgery was attempted. RESULTS: Thirty-four patients were registered at three institutions. One ineligible patient was excluded. Most patients had a promixal cancer and EUST3N1 designation. Twenty-eight (85%) of 33 patients underwent surgery. The R0 resection rate was 70% and pathCR rate was 30%. A pathologic partial response (< 10% residual carcinoma in the primary) occurred in eight patients (24%). EUS T plus N and postsurgery T plus N correlation showed significant downstaging (P = <.01). The median survival time for 33 patients was 33.7 months. Patients achieving a pathCR or pathPR had a significantly longer median survival time (63.9 months) than those achieving less than pathPR (12.6 months; P =.03). There were two treatment-related deaths. CONCLUSION: Our data suggest that the three-step strategy of preoperative induction chemotherapy followed by chemoradiotherapy resulted in substantial pathologic response that resulted in durable survival time. This strategy is worthy of a direct comparison with postoperative adjuvant chemoradiotherapy.

ZD6126 inhibits orthotopic growth and peritoneal carcinomatosis in a mouse model of human gastric cancer.

The purpose of this study was to examine the effects of ZD6126, a novel vascular-targeting agent, on tumour growth and angiogenesis in an orthotopic model of gastric cancer. TMK-1 human gastric adenocarcinoma cells were injected into the gastric wall of nude mice. After the tumours were established (day 14), therapy was initiated. Mice (n=11-12/group) received (a). vehicle, (b). ZD6126 at 100 mg x kg day(-1) i.p. one time per week or (c) ZD6126 at 100 mg x kg day(-1) i.p. five times per week. Tumour mass, volume and the presence or absence of peritoneal carcinomatosis were determined at sacrifice on day 38. Tumours from each group were stained for markers of blood vessels, proliferation and apoptosis. To further define the time frame of the vascular-targeting effects of chronic therapy with ZD6126, TMK-1 cells were again injected into the gastric wall of mice in a second experiment. On day 14, a single i.p. injection of ZD6126 100 mg x kg(-1) mouse(-1) or vehicle was delivered. Groups of three mice each were killed and the tumours harvested at days 1, 3 and 5 post-ZD6126 injection. Tumours were processed and stained for endothelial and tumour cell apoptosis and proliferation. No overt toxicity was observed with ZD6126 therapy. ZD6126 led to a marked inhibition of tumour growth (82% decrease vs control (P<0.001)). ZD6126 also led to a significant decrease in the incidence of peritoneal carcinomatosis (10 out of 12 controls, vs one out of 12 ZD6126) (P<0.01). Histological analysis of tumours revealed large regions of central necrosis in the treated group, as well as a dramatic increase in tumour cell apoptosis (7.4-fold increase (P<0.001)), consistent with the vascular-targeting activity of ZD6126. Mice treated with ZD6126 demonstrated a 59% decrease in PCNA-positive cells (P< 0.02), indicating reduced tumour cell proliferation. In addition, tumours treated with ZD6126 exhibited a 40% decrease in microvessel density (P<0.05). Results from mice treated with a single injection of ZD6126 demonstrated the acute effects this agent has on the tumour vasculature. The ratio of endothelial cell apoptosis to endothelial cell proliferation was increased within 24 h of a single injection. In conclusion, ZD6126 significantly inhibited tumour growth and metastasis in an orthotopic model of human gastric adenocarcinoma, without detectable problematic adverse effects. These data suggest that ZD6126 may be worthy of investigation in the treatment of primary gastric adenocarcinoma.

Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells.

The epidermal growth factor receptor (EGF-R) pathway plays a pivotal role in the progression of human gastric cancer. The angiogenic factor vascular endothelial growth factor (VEGF) has been shown to be induced by EGF in various cancer cell lines. Neuropilin-1 (NRP-1) acts as a coreceptor for VEGF-165 and increases its affinity for VEGF receptor 2 (VEGFR-2) in endothelial cells. Furthermore, NRP-1 has been found to be expressed by tumour cells and has been shown to enhance tumour angiogenesis and growth in preclinical models. We examined the expression of NRP-1 mRNA and EGF-R protein in seven human gastric cancer cell lines. NRP-1 expression was expressed in five of seven cell lines, and EGF-R expression closely mirrored NRP-1 expression. Moreover, in EGF-R-positive NCI-N87 and ST-2 cells, EGF induced both NRP-1 and VEGF mRNA expression. C225, a monoclonal antibody to EGF-R, blocked EGF-induced NRP-1 and VEGF expression in NCI-N87 cells in a dose-dependent manner. The treatment of NCI-N87 cells with EGF resulted in increases in phosphorylation of Erk1/2, Akt, and P38. Blockade of the Erk, phosphatidylinositol-3 kinase/Akt, or P38 pathways in this cell line prevented EGF induction of NRP-1 and VEGF. These results suggest that regulation of NRP-1 expression in human gastric cancer is intimately associated with the EGF/EGF-R system. Activation of EGF-R might contribute to gastric cancer angiogenesis by a mechanism that involves upregulation of VEGF and NRP-1 expression via multiple signalling pathways.

Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model.

We hypothesised that the combination of anti-angiogenic and anti-epidermal growth factor (EFG)-receptor (R) therapies would more effectively inhibit gastric cancer growth than single-agent therapy. TMK-1 gastric cancer cells were injected into the gastric wall of nude mice to generate tumours. After 4 days, mice were randomly assigned to the following groups: control, DC101 ([vascular endothelial growth factor (VEGF)-receptor (R)-2 antibody], C225 (EGF-R antibody), or a combination of DC101 and C225. The combination therapy significantly inhibited gastric tumour growth compared with the control group, whereas the decrease in tumour growth in mice treated with DC101 or C225 alone did not reach statistical significance. All mice administered DC101 demonstrated decreased tumour vascularity and increased endothelial cell apoptosis. C225 alone did not affect angiogenesis, but inhibited tumour cell proliferation. The combination therapy led to a further decrease in tumour cell proliferation. The combination of anti-VEGF-R and anti-EGF-R therapies was effective in inhibiting gastric cancer growth. These findings support the hypothesis that inhibiting multiple biological pathways that mediate tumour growth may be an effective therapeutic strategy.

A pilot study of preoperative chemoradiotherapy for resectable gastric cancer.

BACKGROUND: The goals of this study were to assess the feasibility and toxicity of a regimen of preoperative chemoradiotherapy, surgery, and intraoperative radiotherapy in the treatment of patients with potentially resectable gastric cancer. A secondary objective was to assess pathologic response to chemoradiotherapy in the treated tumors. METHODS: Twenty-four patients were entered in the protocol. Treatment regimen consisted of 45 Gy of external beam radiotherapy with concurrent 5-FU given as a continuous infusion at a dose of 300 mg/m2. Patients were restaged 4-6 weeks after chemoradiotherapy and then underwent surgical resection and intraoperative radiotherapy to a dose of 10 Gy. RESULTS: Twenty-three patients (96%) completed chemoradiotherapy in accordance with the study protocol. Nineteen (83%) of 23 patients who completed chemoradiotherapy underwent surgical resection with D2 lymphadenectomy. Four patients (17%) had progressive disease and were not resected. The morbidity and mortality rates were 32% and 5%, respectively. Of the resected patients, two (11%) had complete pathologic responses while 12 (63%) had pathologic evidence of significant treatment effect. CONCLUSIONS: Preoperative chemoradiotherapy for gastric cancer can be delivered safely and is well tolerated. The rate of surgical complications is consistent with that of other recently reported prospective trials of gastrectomy alone. Preoperative chemoradiotherapy resulted in significant pathologic responses in the majority of treated tumors, and complete pathologic responses were achieved in some patients.

Irinotecan plus cisplatin in advanced gastric or gastroesophageal junction carcinoma.

A phase II study was conducted to assess the response rate and toxicity profile of the combination of irinotecan (CPT-11, Camptosar) and cisplatin (Platinol) administered weekly to patients with untreated advanced adeno-carcinoma of the stomach or gastroesophageal junction. Patients with histologic proof of adenocarcinoma of the stomach or gastroesophageal junction and with adequate liver, kidney, and bone marrow functions were included. Patients were treated with 65 mg/m2 of irinotecan plus 30 mg/m2 of cisplatin, both administered intravenously 1 day per week for 4 consecutive weeks, followed by a 2-week recovery period. Response rate, time to progression, survival, and toxic effects were analyzed. Thirty-six (95%) of 38 registered patients were assessable for toxicity and response. The median number of 6-week cycles per patient was 2.5 (range: 1 to 7 cycles). Four patients (11%) achieved a complete response and 17 (47%) had a partial response for an overall response rate of 58%. Median time to progression of carcinoma was 24 weeks, and median survival was 9 months (range: 1 to 23+ months). There was one treatment-related death. Major toxic effects included diarrhea, neutropenia, and fatigue. The combination of irinotecan and cisplatin is active against gastric or gastroesophageal adenocarcinoma and should undergo further study. The addition of other active drugs or radiation therapy to this regimen would be of interest.

Significance of plasma cytokine levels in melanoma patients with histologically negative sentinel lymph nodes.

INTRODUCTION: Although sentinel lymph node (SLN) status is the most powerful predictor of prognosis in patients with clinically localized melanoma, a proportion of melanoma patients with histologically negative SLNs will still recur. It is hypothesized that tumor response may be altered or mediated by specific cytokines. We therefore investigated whether levels of IL-4, IL-6, IL-10, TNF-alpha, or IFN-gamma would predict disease recurrence in melanoma patients with histologically negative SLNs. METHODS: This prospective cohort study involved 218 patients with clinically localized melanoma who underwent a histologically negative SLN biopsy. Preoperative plasma cytokine levels were determined by enzyme-linked immunosorbent assay on these patients, as well as on 90 healthy controls. Kaplan-Meier life tables were constructed, and Cox proportional hazards analyses were performed to assess predictors of disease-free survival (DFS). RESULTS: At a median follow-up of 43 months, 33 of 218 patients (15%) had suffered disease recurrence. Melanoma patients had significant elevations of IL-4, IL-6, and IL-10 compared to healthy controls; levels of IFN-gamma were less elevated in melanoma patients compared to controls. Despite this, melanoma patients with detectable IFN-gamma levels were at significantly higher risk for recurrence compared to patients with undetectable levels (5-year DFS 70% vs. 86%, P = .03). On multivariate analysis including standard melanoma prognostic factors, only tumor thickness (P = .004) and the presence of detectable IFN-gamma levels (P = .05) were significant independent prognostic factors for disease-free survival. CONCLUSIONS: Among melanoma patients with clinically localized disease who have undergone a histologically negative SLN biopsy, presence of a detectable plasma level of IFN-gamma is an independent predictor of disease recurrence. Elevated levels of IFN-gamma may identify a group of early-stage melanoma patients who are more likely to have recurrence of disease and who may benefit from adjuvant therapies, including immunotherapies.

A caution regarding lymphatic mapping in patients with colon cancer.

BACKGROUND: The value of lymphatic mapping and sentinel lymph node biopsy in the treatment of colon cancer is controversial. The purpose of this study was to determine the accuracy of lymphatic mapping in patients with colon cancer. METHODS: Forty-eight patients with colon cancer underwent lymphatic mapping and sentinel lymph node biopsy using isosulfan blue dye followed by standard surgical resection. The sentinel lymph nodes underwent thin sectioning as will as immunohistochemical staining for cytokeratin, in addition to standard hematoxylin and eosin staining. RESULTS: In 47 (98%) patients, a sentinel lymph node was identified. Sixteen patients had lymph nodes containing metastatic disease, and in 6 patients the sentinel lymph node was positive for disease. In no patient was the sentinel lymph node the only site of metastatic disease. In 10 patients the sentinel lymph node was negative for disease, whereas the nonsentinel lymph nodes contained metastatic disease (false negative rate = 38%). CONCLUSIONS: The role of lymphatic mapping and sentinel lymph node biopsy in colon cancer is not as clear as its role in other tumors. Further large prospective studies are needed to evaluate the accuracy and potential benefit of this procedure in patients with colon cancer.

How many lymph nodes are enough during sentinel lymphadenectomy for primary melanoma?

BACKGROUND: Sentinel lymph node (SLN) biopsy has been shown to reliably identify nodal metastases and the subsequent need for further surgical and adjuvant therapy in patients with cutaneous melanoma. Although SLN identification rates have improved with the addition of radioactive colloid to the blue dye technique, it remains unclear how many lymph nodes should be removed to accurately determine the histologic status of the nodal basin. The objective of this study was to determine the optimal extent of SLN biopsy in these patients. METHODS: The records of 633 consecutive patients with melanoma (765 nodal basins) whose primary treatment included SLN biopsy with the use of a combination of blue dye and technetium Tc 99 labeled sulfur colloid were reviewed. SLN biopsy consisted of the removal of all of the blue-stained nodes and all nodes with radiotracer uptake activity of at least twice background. RESULTS: SLN biopsy was successful in 765 of 772 basins (99%). A mean of 1.9 SLNs (median, 2 SLNs) per basin were excised. At least 3 SLNs were removed in 176 basins (23%). The overall histologic status of a basin was always established by the first or second SLN harvested (ie, in no patient was the third or subsequent SLN positive when 1 of the first 2 was not). Of the 124 basins containing lymphatic metastases, the SLN that contained the maximal radiotracer uptake (hottest) and/or stained blue was pathologically positive in 118 basins (95%). In only 6 of the 124 positive basins (5%) was the sole evidence of occult nodal metastases identified in an SLN that was neither blue-stained nor the hottest. All but 1 of these SLNs had counts that were at least 66% of the hottest node in the basin. CONCLUSIONS: With a combined modality approach to SLN biopsy, removal of more than 2 SLNs did not provide information that upstaged any patient with primary melanoma. Removal of additional nonblue SLN(s) that contained radioactive counts of at least twice background but lower than two thirds of the SLNs with maximal radiotracer uptake affected patient management in less than 0.2% of all cases. These findings may be helpful in minimizing the extent of surgery and perhaps in reducing the costs and resource use associated with operating room time and pathologic examination.

Significance and management of local recurrences and limited metastatic disease in the abdomen.

The management of patients with synchronous or metachronous metastatic carcinoma, sarcoma, or melanoma in the abdomen requires a knowledge of the natural history of the disease and of the available treatment options. Patients with advanced malignant disease may be of marginal performance status yet may require large surgical procedures or combined modality therapy; the most challenging therapeutic decisions involve such patients. The authors highlight the role of surgery in selected patients with metastatic or recurrent malignancy as it is practiced at The University of Texas M. D. Anderson Cancer Center.

Significance of multiple nodal basin drainage in truncal melanoma patients undergoing sentinel lymph node biopsy.

BACKGROUND: Although previous studies have demonstrated that truncal site is associated with an adverse prognosis, explanations for such risk are lacking. In addition, the number of nodal basins as well as the number of lymph nodes containing regional metastases are important prognostic factors in these patients. Because the lymphatic drainage pattern of truncal melanoma often includes more than one basin, we designed a study to evaluate (1) whether patients with multiple nodal basin drainage (MNBD) were at an increased risk of lymph node metastases identified by sentinel lymph node (SLN) biopsy, and (2) whether the histological status of an individual basin reliably predicted the status of the other draining basins in patients with MNBD. METHODS: The records of 295 consecutive truncal melanoma patients who were managed primarily with intraoperative lymphatic mapping and SLN biopsy, between 1991 and 1997, were reviewed. All patients underwent preoperative lymphoscintigraphy, which established the number and location of draining nodal basins. Univariate and multivariate analyses of relevant clinicopathological factors were performed to assess which factors may predict the presence of a pathologically positive SLN. RESULTS: At least one SLN was identified in 281 patients. MNBD was present in 86 (31%) patients, and a pathologically positive SLN was found in 56 (20%) patients. By multivariate analysis, the presence of MNBD (relative risk = 1.9; P = .03), tumor thickness (P = .007), and tumor ulceration (relative risk = 2.4; P = .01) were significant independent risk factors for the presence of at least one pathologically positive SLN. SLN pathology in one basin did not predict the histology of other basins in 19 (22%) of 86 patients with MNBD. CONCLUSIONS: MNBD is independently associated with an increased risk of nodal metastases in truncal melanoma patients. Because the histological status of an individual basin did not reliably predict the status of the other draining basins in patients with MNBD, it is important to adequately identify and completely assess all nodal basins at risk, as defined by lymphoscintigraphy, in truncal melanoma patients.

Regional nodal basin control is not compromised by previous sentinel lymph node biopsy in patients with melanoma.

BACKGROUND: Regional nodal basin control is an important goal of lymphadenectomy in the management of melanoma patients with nodal disease. The purpose of this study was to determine if previous sentinel lymph node (SLN) biopsy compromises the ultimate regional nodal control achieved by subsequent therapeutic lymph node dissection in melanoma patients with microscopic lymph node metastases. METHODS: A surgical melanoma database and hospital records were reviewed for 602 patients with primary cutaneous melanoma who underwent successful lymphatic mapping and SLN biopsy between 1991 and 1997. RESULTS: A total of 105 (17%) of 602 patients had histologically positive SLNs and were offered therapeutic lymphadenectomy; 101 (96%) underwent this procedure. Thirty-six patients (36%) developed recurrent melanoma at one or more sites. The median follow-up period was 30 months. Recurrence in the previously dissected nodal basin was observed in 10 patients (10%); none had recurrence at only that site. Nodal basin disease appeared after local/in-transit (n = 6) or distant (n = 1) failure in seven patients and, as a component of the first site of failure, simultaneously with local/in-transit (n = 2) or distant (n = 1) recurrence in three patients. CONCLUSIONS: Nodal basin failure after lymphadenectomy in patients who underwent previous biopsy of a histologically positive SLN is primarily a function of aggressive locoregional disease rather than of contamination from previous surgery. Because regional nodal control was comparable with that in other series, we conclude that SLN biopsy with selective lymphadenectomy does not compromise regional nodal basin control.

Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (> or = 4 mm) primary melanoma.

BACKGROUND: Historically, patients with thick (> or =4 mm) primary melanoma have not been considered candidates for elective lymph node dissection, because their risk for occult distant disease is significant. Sentinel lymph node (SLN) biopsy offers an alternative approach to assess disease in the regional nodal basin, but no studies have specifically addressed the role for this technique in patients with thick melanoma. Although adjuvant therapy benefits patients who develop nodal metastases, data that supports its routine use in all patients with thick melanoma is both limited and controversial. This study was performed to determine whether pathological status of the SLN is an important risk factor in this heterogeneous group and, thus, provides a rationale for SLN biopsy. METHODS: The records of 131 patients with primary cutaneous melanoma whose primary tumors were at least 4 mm thick and who underwent lymphatic mapping and SLN biopsy were reviewed. Several known prognostic factors, i.e., tumor thickness, ulceration, Clark level, location, sex, as well as SLN pathological status were analyzed with respect to disease-free and overall survival. RESULTS: Lymphatic mapping and SLN biopsy was successful in 126 (96%) of 131 patients who underwent the procedure. In 49 patients (39%), the SLN biopsy was positive by conventional histology, although it was negative in 77 patients (61%). The median follow-up was 3 years. Although presence of ulceration and SLN status were independent prognostic factors with respect to disease-free and overall survival, SLN status was the most powerful predictor of overall survival by univariate and multivariate analyses. CONCLUSIONS: Lymphatic mapping and SLN biopsy is a highly accurate method of staging lymph node basins at risk for regional metastases in patients with thick melanoma and identifies those patients who may benefit from earlier lymphadenectomy as well as patients with a more favorable prognosis. Pathological status of the SLN in these patients with clinically negative nodes is the most important prognostic factor for survival and is essential to establish stratification criteria for future adjuvant trials in this high-risk group.

Enhanced staging and all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma.

PURPOSE: Patients with local-regional gastric carcinoma have a low rate of curative resection (R0) because of the advanced stage at diagnosis and suboptimal clinical staging. This study was designed to improve clinical staging with the use of laparoscopy and endoscopic ultrasonography (EUS) and to improve R0 resection rates and tolerance by delivering all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma. PATIENTS AND METHODS: All patients with histologic proof of localized adenocarcinoma of the stomach underwent a staging laparoscopy before registration. EUS was performed when feasible. The intention was to administer up to five courses of preoperative chemotherapy consisting of fluorouracil (500 mg/m(2)/d as a continuous infusion on days 1 through 5 and as a bolus on days 12 and 19), interferon alfa-2b (3 million units subcutaneously three times a week for 3 weeks), and cisplatin (15 mg/m(2)/d as a bolus on days 1 through 5). After chemotherapy, surgery was attempted to remove the primary and regional lymph nodes. Clinical response and EUS staging were correlated with surgical pathology. The feasibility of this approach, resection rates, patient survival, and patterns of failure also were assessed. RESULTS: All 30 patients enrolled were assessed for toxicity, response, and survival. Nineteen men and 11 women were enrolled. The median number of courses delivered per patient was three (range, one to five courses). Fourteen patients (47%) received all five preoperative courses of chemotherapy. The overall clinical response rate was 34%. Twenty-nine patients (97%) underwent attempted resection. Twenty-five (83%) had an R0 resection. Two patients (7%) had no evidence of carcinoma in the surgical specimen, and three had only microscopic carcinoma (>/= 90% necrosis). Posttreatment EUS findings did not correlate well with surgical pathology. The median duration of follow-up was 30 months (range, 5 months to 65+ months). The median survival time for 30 patients, calculated by the Kaplan-Meier method, was 30 months (range, 5 months to 65+ months). There were no cases of grade 4 toxicity. CONCLUSION: It is feasible to administer prolonged preoperative therapy in patients with potentially resectable gastric carcinoma. Enhanced staging with laparoscopy and EUS helped in proper selection of patients and better characterization of the stage.