Anton J. Bilchik

Radiofrequency ablation of 231 unresectable hepatic tumors: indications, limitations, and complications.

AbstractBackground: Radiofrequency ablation (RFA) is increasingly used for the local destruction of unresectable hepatic malignancies. There is little information on its optimal approach or potential complications. Methods: Since late 1997, we have undertaken 91 RFA procedures to ablate 231 unresectable primary or metastatic liver tumors in 84 patients. RFA was performed via celiotomy (n=39), laparoscopy (n=27), or a percutaneous approach (n=25). Patients were followed with spiral computed tomographic (CT) scans at 1 to 2 weeks postprocedure and then every 3 months for 2 years. Results: Intraoperative ultrasound (IOUS) detected intrahepatic disease not evident on the preoperative scans of 25 of 66 patients (38%) undergoing RFA via celiotomy or laparoscopy. In 38 of 84 patients (45%), RFA was combined with resection or cryosurgical ablation (CSA), or both. RFA was used to treat an average of 2.8 lesions per patient, and the median size of treated lesions was 2 cm (range, 0.3–9 cm). The average hospital stay was 3.6 days overall (1.8 days for percutaneous and laparoscopic cases). Ten patients underwent a second RFA procedure (sequential ablations) and, in one case, a third RFA procedure for large (one patient), progressive (seven patients), and/or recurrent (three patients) lesions. Seven (8%) patients had complications: one skin burn; one postoperative hemorrhage; two simple hepatic abscesses; one hepatic abscess associated with diaphragmatic heat necrosis following sequential percutaneous ablations of a large lesion; one postoperative myocardial infarction; and one liver failure. There were three deaths, one (1%) of which was directly related to the RFA procedure. Three of the complications, including one RFA-related death, occurred after percutaneous RFA. At a median follow-up of 9 months (range, 1–27 months), 15 patients (18%) had recurrences at an RFA site, and 36 patients (43%) remained clinically free of disease. Conclusions: Celiotomy or laparoscopic approaches are preferred for RFA because they allow IOUS, which may demonstrate occult hepatic disease. Operative RFA also allows concomitant resection, CSA, or placement of a hepatic artery infusion pump, and isolation of the liver from adjacent organs. Percutaneous RFA should be reserved for patients at high risk for anesthesia, those with recurrent or progressive lesions, and those with smaller lesions sufficiently isolated from adjacent organs. Complications may be minimized when these approaches are applied selectively.

Do all patients with sentinel node metastasis from breast carcinoma need complete axillary node dissection

OBJECTIVE To determine the likelihood of nonsentinel axillary metastasis in the presence of sentinel node metastasis from a primary breast carcinoma. SUMMARY BACKGROUND DATA Sentinel lymphadenectomy is a highly accurate technique for identifying axillary metastasis from a primary breast carcinoma. Our group has shown that nonsentinel axillary lymph nodes are unlikely to contain tumor cells if the axillary sentinel node is tumor-free, but as yet no study has examined the risk of nonsentinel nodal involvement when the sentinel node contains tumor cells. METHODS Between 1991 and 1997, axillary lymphadenectomy was performed in 157 women with a tumor-involved sentinel node. Fifty-three axillae (33.5%) had at least one tumor-involved nonsentinel node. The authors analyzed the incidence of nonsentinel node involvement according to clinical and tumor characteristics. RESULTS Only two variables had a significant impact on the likelihood of nonsentinel node metastasis: the size of the sentinel node metastasis and the size of the primary tumor. The rate of nonsentinel node involvement was 7% when the sentinel node had a micrometastasis (< or =2 mm), compared with 55% when the sentinel node had a macrometastasis (>2 mm). In addition, the rate of nonsentinel node tumor involvement increased with the size of the primary tumor. CONCLUSIONS If a primary breast tumor is small and if sentinel node involvement is micrometastatic, then tumor cells are unlikely to be found in other axillary lymph nodes. This suggests that axillary lymph node dissection may not be necessary in patients with sentinel node micrometastases from T1/T2 lesions, or in patients with sentinel node metastases from T1a lesions.

Improving Resectability of Hepatic Colorectal Metastases: Expert Consensus Statement

Although only10% 20% of patients with hepatic colorectal metas-tases are eligible for resection, the absolute number ofpatients amenable to resection is large and is growingwith better imaging, better surgery, and improve-ments in systemic therapies to reduce the risk of bothintrahepatic and extrahepatic recurrences.

Chemokine Receptor CXCR4 Expression in Colorectal Cancer Patients Increases the Risk for Recurrence and for Poor Survival

PURPOSE 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. METHODS 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. RESULTS 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). CONCLUSION 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.

More extensive nodal dissection improves survival for stages I to III of colon cancer: a population-based study.

Objective:To determine whether analyzing more lymph nodes in colon cancer specimens improves survival. Summary Background Data:Increasing the number of lymph nodes analyzed has been reported to correlate with improved survival in patients with node-negative colon cancer. Methods: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 ≥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. Results: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. Conclusions: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.

Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: therapeutic utility and implications of nodal microanatomy and molecular staging for improving the accuracy of detection of nodal micrometastases.

Objective: 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. Methods: 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. Results: 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 ≤ 0.001). Conclusions: 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.

Radiofrequency Ablation in 447 Complex Unresectable Liver Tumors: Lessons Learned

Background: Radiofrequency ablation (RFA) is a promising technique for unresectable hepatic malignancies. We reviewed our RFA experience to identify variables affecting local recurrence.Methods: Patients undergoing RFA between 1997 and 2001 were reviewed for demographics, tumor size, pathology, diagnosis, recurrence, procedures, survival, and complications.Results: 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.Conclusions: 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.

Molecular Staging of Early Colon Cancer on the Basis of Sentinel Node Analysis: A Multicenter Phase II Trial

PURPOSE Approximately 30% of patients with American Joint Committee on Cancer stage I or II colorectal cancer (CRC) develop systemic disease. We hypothesized that multimarker reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of sentinel lymph nodes (SNs) draining a primary CRC could detect micrometastases not detected by conventional histopathologic analysis. PATIENTS AND METHODS In a multi-institutional study, 40 patients with primary CRC underwent dye-directed lymphatic mapping at the time of colon resection. Each dye-stained SN was tagged, and the tumor and regional nodes were resected en bloc. All lymph nodes were examined by conventional hematoxylin and eosin (HE) staining. In addition, each SN was cut into multiple sections for cytokeratin immunohistochemical (CK-IHC) staining and for RT-PCR and electrochemiluminescent detection of three markers: beta-chain human chorionic gonadotropin, hepatocyte growth factor receptor, and universal melanoma-associated antigen. Whenever possible, RT-PCR assay was also performed on primary tumor tissue. The detection sensitivity of individual markers was 10(-3) to 10(-4) microg of RNA and one to five tumor cells in 10(7) lymphocytes of healthy donors. RESULTS One to three SNs were identified in each patient. An average of 15 nodes were removed from each CRC specimen. No nonsentinel (untagged) node contained evidence of tumor if all tagged (sentinel) nodes in the same specimen were histopathology tumor-negative. HE staining of SNs identified tumor in 10 patients (25%), and CK-IHC of SNs identified occult micrometastases in four patients (10%) whose SNs were negative by HE. Of the remaining 26 patients with no evidence of SN involvement by HE or CK-IHC, 12 (46%) had positive RT-PCR results. The number of markers expressed in each SN correlated (P <.04) with the T stage of the primary tumor. There was 79% concordance in marker expression for the respective pairs (n = 38) of primary tumor and histopathologically positive SNs, and 86% (12 of 14) concordance between RT-PCR positive and histopathologically positive SNs. CONCLUSION Identification and focused examination of the SN is a novel method of staging CRC. CK-IHC and RT-PCR identified occult micrometastases in 53% of patients whose SNs were negative by conventional staging techniques. These ultrasensitive assays of the SN can identify patients who may be at high risk for recurrence of CRC and therefore are more likely to benefit from systemic adjuvant therapy.

Chemokine Receptor CXCR4 Expression in Patients With Melanoma and Colorectal Cancer Liver Metastases and the Association With Disease Outcome

Objective:To determine the role of chemokine receptor (CR) expression in patients with melanoma and colorectal cancer (CRC) liver metastases. Summary Background Data: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. Methods: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. Results: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). Conclusions: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.

Neoadjuvant Chemotherapy for Metastatic Colon Cancer: A Cautionary Note

Anton J. Bilchik, John Wayne Cancer Institute at St John’s Health Center, Santa Monica, CA Graeme Poston, Royal Liverpool and Aintree University Hospitals, Liverpool, UK Steven A. Curley, The University of Texas M.D. Anderson Cancer Center, Houston, TX Steven Strasberg, Siteman Cancer Center at Washington University in St Louis, St Louis, MO Leonard Saltz, Memorial Sloan Kettering Cancer Center, New York, NY Rene Adam, Paul Brousse Hospital, Paris, France Bernard Nordlinger and Philippe Rougier, Paul Brousse Hospital, Paris, France Lee S. Rosen, John Wayne Cancer Institute at St John’s Health Center, Santa Monica, CA