Faculty Publications

Purpose The volume-outcomes relationship has led many to advocate centralization of cancer procedures at high volume hospitals (HVH). We hypothesized that in response cancer surgery has become increasingly centralized and that this centralization has resulted in increased travel burden for patients. Patients and Methods Using 1996 to 2006 discharge data from NY, NJ, PA, all patients >= 18 years old treated with extirpative surgery for colorectal, esophageal, or pancreatic cancer were examined. Patients and hospitals were geocoded. Annual hospital procedure volume for each tumor site was examined, and multiple quantile and logistic regressions were used to compare changes in centralization and distance traveled. Results Five thousand two hundred seventy-three esophageal, 13,472 pancreatic, 202,879 colon, and 51,262 rectal procedures were included. A shift to HVH occurred to varying degrees for all tumor types. The odds of surgery at a low volume hospital decreased for esophagus, pancreas and colon: per year odds ratios (ORs) were 0.87 (95% CI, 0.85 to 0.90), 0.85 (95% CI, 0.84 to 0.87), and 0.97 (95% CI, 0.97 to 0.98). Median travel distance increased for all sites: esophagus 72%, pancreas 40%, colon 17%, and rectum 28% (P < .0001). Travel distance was proportional to procedure volume (P < .0001). The majority of the increase in distance was attributable to centralization. Conclusion There has been extensive centralization of complex cancer surgery over the past decade. While this process should result in population-level improvements in cancer outcomes, centralization is increasing patient travel. For some subsets of the population, increasing travel requirements may pose a significant barrier to access to quality cancer care.

BACKGROUND: We report local recurrence (LR) after breast-conserving surgery and radiation (BCS + RT) for ductal carcinoma in situ (DCIS) to determine outcomes for patients aged &lt;or=40 years compared with older women. METHODS: The study included 440 women with DCIS treated from 1978 to 2007. All patients received whole-breast radiotherapy with a boost in 95% of cases. Demographics, characteristics, surgical, and adjuvant treatments were analyzed for an effect on LR. RESULTS: Median age was 56.5 years with 24 patients aged &lt;or=40. Median DCIS size was 0.8 cm. Re-excision was required in 62% of patients, and in 75% of those aged &lt;or=40. Tamoxifen was used in 22%, but only one patient aged &lt;or=40. Median follow-up was 6.8 years. Actuarial LR was 7% (95% confidence interval of 4-11%) at 10 years and 8% (5-14%) at 15 years. There was no difference in LR by age (P = 0.76). CONCLUSIONS: The long-term risk of LR after BCS + RT for DCIS is low, even in patients &lt;or=40 years. This may be due to patient selection for small size, high utilization of re-excision, and radiation boost. Young age may be a smaller contributor to LR risk in DCIS than previously suggested.

Purpose: To correlate changes in 2-deoxy-2-[18F]fluoro-D-glucose (18-FDG) positron emission tomography (PET) (18-FDG-PET) uptake with response and disease-free survival with combined modality neoadjuvant therapy in patients with locally advanced rectal cancer. Methods and Materials: Charts were reviewed for consecutive patients with ultrasound-staged T3x to T4Nx or TxN1 rectal adenocarcinoma who underwent preoperative chemoradiation therapy at Fox Chase Cancer Center (FCCC) or Robert H. Lurie Comprehensive Cancer Center of Northwestern University with 18-FDG-PET scanning before and after combined-modality neoadjuvant chemoradiation therapy. The maximum standardized uptake value (SUV) was measured from the tumor before and 3 to 4 weeks after completion of chemoradiation therapy preoperatively. Logistic regression was used to analyze the association of pretreatment SUV, posttreatment SUV, and % SUV decrease on pathologic complete response (pCR), and a Cox model was fitted to analyze disease-free survival. Results: A total of 53 patients (FCCC, n = 41, RLCCC, n = 12) underwent pre- and postchemoradiation PET scanning between September 2000 and June 2006. The pCR rate was 31 %. Univariate analysis revealed that % SUV decrease showed a marginally trend in predicting pCR (p = 0.08). In the multivariable analysis, posttreatment SUV was Shown a predictor of pCR (p = 0.07), but the test results did not reach statistical significance. None of the investigated variables were predictive of disease-free survival. Conclusions: A trend was observed for % SUV decrease and posttreatment SUV predicting pCR in patients with rectal cancer treated with preoperative chemoradiation therapy. Further prospective study with a larger sample size is warranted to better characterize the role of 18-FDG-PET for response prediction in patients with rectal cancer. (C) 2009 Elsevier Inc.

Purpose: Oxaliplatin is a platinum analog and radiosensitizer active in colorectal cancer. We performed a Phase I trial to test the safety and preliminary efficacy of adding oxaliplatin to standard preoperative chemoradiation therapy for rectal cancer. Methods and Materials: Eligible patients had T3 to T4 rectal adenocarcinoma. Patients received standard-dose radiation (50.4 Gy for 5.5 weeks) with concurrent infused 5-fluorouracil (5-FU) at 200 mg/m(2) per day, 7 days per week. Oxaliplatin was given three times at 14-day intervals at 55,70, or 85 mg/m(2) during the 5.5-week radiation period, before resection. Adjuvant therapy consisted of four cycles of 5-FU (500 mg/m(2) per week) with leucovorin (500 mg/m(2) per week) given every 6 weeks. The main goals were to identify the maximum tolerated dose of oxaliplatin and the dose-limiting toxicities when given with 5-FU and RT. Secondary goals were to determine resectability, pathologic response, sphincter preservation, and overall survival rates. Results: Twenty-one patients were enrolled, 5 at the 55 mg/m(2) oxaliplatin dose level, 5 at 70 mg/m(2), and 11 at 85 mg/m(2). All patients were able to complete the preoperative chemoradiation regimen with no dose adjustments. No dose-limiting toxicities or differences in the type or extent of toxicity were noted among the groups. Nineteen patients underwent surgery (three abdominopelvic resections and 16 low anterior resections), for an 84% sphincter preservation rate. The pathologic complete response rate was 26% (5 patients), and minimal microscopic residual tumor was found in 21% (4 additional patients). Conclusions: Oxaliplatin was well tolerated at 85 mg/m(2) given every 2 weeks in combination with standard preoperative chemoradiation for rectal cancer. The rates of major pathologic response and sphincter preservation are promising. (C) 2008 Elsevier Inc.

PURPOSE: Adequate lymph node evaluation is important to stage colon cancers and make adjuvant treatment decisions. Studies have demonstrated improved survival when >= 12 nodes are examined. Our objective was to assess differences in the adequacy of nodal evaluation for right vs. left colon cancers. METHODS: From the National Cancer Data Base (1998-2004), 142,009 N0M0 colon cancer patients were identified. Logistic regression was used to evaluate the number of nodes examined for right vs. left colectomies. Multivariable modeling was used to determine the impact of examining >= 12 nodes on survival. RESULTS: Of 142,009 patients, 79,444 (56 percent) had right colectomies, and 62,565 (44 percent) patients had left colectomies. More nodes were examined during right colectomies than left (median 12 vs. 8, Pe < 0.0001). When adjusted for patient, tumor, and hospital factors, patients undergoing left colectomy were less likely to have >= 12 nodes identified (P < 0.0001). Patients were more likely to have >= 12 nodes identified for right and left colon cancers at high-volume hospitals. Survival was better with examination of >= 12 nodes for right and left colon cancers (P < 0.0001). CONCLUSIONS: Evaluating >= 12 nodes for right and left colon cancers is a feasible, clinically relevant, and modifiable factor that will likely improve patient outcomes.

BACKGROUND. Sentinel lymph node (SN) biopsy is standard for breast cancer staging, but SN dye gradients and their significance have never been characterized. If predictive of SN metastasis location, their use for focused pathology examination might improve intraoperative imprint cytology sensitivity. METHODS. This prospective trial enrolled clinically lymph node-negative patients with invasive breast cancer not undergoing neoadjuvant chemotherapy. Surgeons marked SN gradients at their bluest end. Nodal halves were examined separately by imprint cytology, and the marked SN half was correlated to metastasis location. Demographic, pathologic, and prognostic features were recorded. RESULTS. Mean patient age and tumor size for the 102 patients was 59.6 years and 2.2 cm, respectively. Of 169 SNs, 159 (94.1%) had dye gradients, which varied by tumor quadrant, but not by histology, diagnosis method, grade, or stage. Among 41 marked SNs with metastases, 92.7% were present in the halves marked by the surgeon. Fourteen were confined to I nodal half, with 11 on the marked side and 3 on the unmarked side (P = .029). Metastases were smaller when confined to 1 versus both SN halves (0.14 vs 0.75 cm; P = .005), and smaller (0.87 vs 0.13 cm; P < .0001) when missed intraoperatively. CONCLUSIONS. Dye gradients occur in most SNs and predict metastasis location. The smallest metastases are hardest to detect intraoperatively and are usually confined to the marked SN half. This suggests that marking an SN's bluest half warrants further study to explore whether its correlation to metastasis location may be exploited to focus pathologic examination and decrease the reoperative axillary dissection rate. Cancer 2008; 113:3100-7. (C) 2008 American Cancer Society.

Adoptive immunotherapy of cancer patients with cytolytic T lymphocytes (CTL) has been hampered by the inability of the CTL to home into tumors in vivo. Chemokines can attract T lymphocytes to the tumor site, as demonstrated in animal models, but the role of chemokines in T-lymphocyte trafficking toward human tumor cells is relatively unexplored. In the present study, the role of chemokines and their receptors in the migration of a colon carcinoma (CC) patient's CTL toward autologous tumor cells has been studied in a novel three-dimensional organotypic CC culture. CTL migration was mediated by chemokine receptor CXCR3 expressed by the CTL and CXCL11 chemokine secreted by the tumor cells. Excess CXCL11 or antibodies to CXCL11 or CXCR3 inhibited migration of CTL to tumor cells. T cell and tumor cell analyses for CXCR3 and CXCL11 expression, respectively, in ten additional CC samples, may suggest their involvement in other CC patients. Our studies, together with previous studies indicating angiostatic activity of CXCL11, suggest that CXCL11 may be useful as an immunotherapeutic agent for cancer patients when transduced into tumor cells or fused to tumor antigen-specific Ab.

AIMS: Sentinel lymph node biopsy (SLNB) has been adopted in the surgical treatment of melanoma to reduce morbidity and enhance staging. Positron emission tomography with computerised tomography (PET/CT) has been utilised in the staging of patients with malignancy though the role of this imaging modality in early stage melanoma is unclear. This study examined the preoperative value of PET/CT in patients undergoing SLNB for malignant melanoma. METHODS: Patients presenting with primary melanoma without evidence of either locoregional or systemic metastasis were considered candidates for SLNB. Selected patients underwent preoperative PET/CT followed by definitive surgical therapy including SLNB with regional lymphadenectomy, where indicated. RESULTS: During a 12-month period 83 patients were identified as having undergone SLNB for melanoma, of which 37 (45%) had preoperative PET/CT. Mean melanoma thickness 1.9 mm and 2.4 mm (PET/CT vs. no PET/CT, p>0.05). 13 (15.6%) patients were found to have lymphatic metastasis at SLNB; nine of these patients underwent PET/CT, only two of these scans were suggestive of lymphatic metastasis (positive predictive value 24%, negative predictive value 76%). PET/CT revealed no unheralded metastatic disease but did identify a second occult malignancy in 4 (10.8%) patients undergoing therapy for melanoma. CONCLUSIONS: The results of this study do not support the use of PET/CT in patients undergoing SLNB for melanoma. SLNB appears to be a more sensitive staging modality in the detection of lymphatic metastasis; however PET/CT may have a future role as a screening tool for malignancy.

PURPOSE: Standard radiation for early breast cancer requires daily treatment for 6 to 7 weeks. This is an inconvenience to many women, and for some a barrier for breast conservation. We present the acute toxicity of a 4-week course of hypofractionated radiation. METHODS AND MATERIALS: A total of 75 patients completed radiation on a Phase II trial approved by the hospital institutional review board. Eligibility criteria were broad to include any patient normally eligible for standard radiation: age >/=18 years, invasive or in situ cancer, American Joint Committee on Cancer Stage 0 to II, breast-conserving surgery, and any systemic therapy not given concurrently. The median age was 52 years (range, 31-81 years). Of the patients, 15% had ductal carcinoma in situ, 67% T1, and 19% T2; 71% were N0, 17% N1, and 12% NX. Chemotherapy was given before radiation in 44%. Using photon intensity-modulated radiation therapy and incorporated electron beam boost, the whole breast received 45 Gy and the lumpectomy bed 56 Gy in 20 treatments over 4 weeks. RESULTS: The maximum acute skin toxicity by the end of treatment was Grade 0 in 9 patients (12%), Grade 1 in 49 (65%) and Grade 2 in 17 (23%). There was no Grade 3 or higher skin toxicity. After radiation, all Grade 2 toxicity had resolved by 6 weeks. Hematologic toxicity was Grade 0 in most patients except for Grade 1 neutropenia in 2 patients, and Grade 1 anemia in 11 patients. There were no significant differences in baseline vs. 6-week posttreatment patient-reported or physician-reported cosmetic scores. CONCLUSIONS: This 4-week course of postoperative radiation using intensity-modulated radiation therapy is feasible and is associated with acceptable acute skin toxicity and quality of life. Long-term follow-up data are needed. This radiation schedule may represent an alternative both to longer 6-week to 7-week standard whole-breast radiation and more radically shortened 1-week, partial-breast treatment schedules.

Liver cancer, whether primary or metastatic, is a major cause of death throughout the world. The surgical management of these diseases varies according to the extent of disease and the overall health of the patient. Surgical resection of hepatic disease remains the only chance for cure. However, a large proportion of patients with liver cancer are unable to undergo a complete surgical resection. These patients are often treated with liver-directed therapies. Although not as effective as surgical resection, these approaches can help to improve the survival of patients. In patients with primary liver cancer, underlying liver disease often prohibits surgical intervention. However, survival advantages have been gained with the application of percutaneous alcohol injection and radiofrequency ablation (RFA). In patients with hepatic metastases, the number of metastases is often what prevents surgical resection. In these patients, RFA, cryoablation, and hepatic artery infusional therapy have all aided in prolonging survival. As chemotherapeutic agents improve and targeted therapies are developed, more patients will be able to undergo surgical management of their liver cancer, primary or metastatic.

Purpose: The purpose of this phase II study was to prospectively determine the efficacy of preoperative chemoradiation with a hyperfractionated (Hfx) RT boost to 61.8 Gy in locally advanced rectal cancer. Methods: Eligibility stipulated that the primary lesion had to be either T4; or T3 and > 4 cm or 40% of the bowel circumference. Radiation (RT) consisted of 45 Gy to the pelvis (1.8 Gy per fraction) followed by 1.2 Gy twice daily (to the gross tumor volume) to a total RT dose of 61.8 Gy. There was 5-FU infused at 1 g/m(2)/24 hours for 4 days during the 1st and 6th weeks of RT (concurrent with the Hfx boost). Surgical resection was planned 4 to 6 weeks later. Adjuvant chemotherapy (bolus 5-FU/leucovorin) was scheduled for 4 cycles at 28-day intervals. Results: There were 22 patients, ages 22 to 81 years (median, 64) enrolled in the study. Of the 20 patients evaluable for response, 10 (50%) had evidence of clinical downstaging and 5 patients (25%) had >= 90% fibrosis in the resected specimen. With a median flu of 40 months (7-158), the 4 years actuarial rate for all patients (n=22) of OS was 64%, of DFS 62%, and of LC 84%. 3/21 patients (14%) had positive margins, all of whom developed a local failure (P < 0.001). Conclusion: This regimen of high dose preoperative chemoRT with a Hfx RT boost (to 61.8 Gy) in patients with bulky, locally advanced rectal cancer results in clinical downstaging in half of the patients with significant fibrosis in the operative specimen.

Purpose Hepatic metastases derive most of their blood supply from the hepatic artery; therefore, for patients with hepatic metastases from colorectal cancer, hepatic arterial infusion (HAI) of chemotherapy may improve outcome. Methods In a multi-institutional trial, 135 patients were randomly assigned to receive HAI versus systemic bolus fluorouracil and leucovorin. The primary end point was survival; secondary end points were response, recurrence, toxicity, quality of life, cost, and the influence of molecular markers. Results Overall survival was significantly longer for HAI versus systemic treatment (median, 24.4 v 20 months; P = .0034), as were response rates (47% and 24%; P = .012) and time to hepatic progression (THP; 9.8 v 7.3 months; P = .034). Time to extrahepatic progression (7.7 v 14.8 months; P = .029) was significantly shorter in the HAI group. Quality-of-life measurements showed improved physical functioning in the HAI group at the 3- and 6-month follow-up assessments. Toxicity included grade >= 3 neutropenia (2% and 45%; P < .01), stomatitis (0% and 24%; P < .01), and bilirubin elevation (18.6% and 0; P < .01) in the HAI and systemic treatment groups, respectively. A greater proportion of men versus women receiving HAI experienced biliary toxicity (37% and 15%, respectively; P = .05). For HAI patients with thymidylate synthase levels in tumor less than or >= 4, the median survival was 24 and 14 months, respectively (P = .17). Conclusion HAI therapy increased overall survival, response rate, THP, and was associated with better physical functioning compared with systemic therapy. Additional studies need to address the overall benefit and cost of new chemotherapy agents versus HAI alone or the combination of HAI with new agents.