Nancy E. Kemeny

Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry

PURPOSE To establish evidence of activity, or lack thereof, of cetuximab-based therapy in patients with refractory colorectal cancer with tumors that do not demonstrate epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC). PATIENTS AND METHODS Pharmacy computer records were reviewed to identify all patients who received cetuximab at Memorial Sloan-Kettering Cancer Center in a nonstudy setting during the first 3 months of cetuximabs commercial availability. Medical records of these patients were then reviewed to identify colorectal cancer patients who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by IHC. Pathology slides from these patients were reviewed by a reference pathologist to confirm EGFR negativity, and computed tomography scans during cetuximab-based therapy were reviewed by a reference radiologist. Response rates were reported using WHO criteria. RESULTS Sixteen chemotherapy-refractory, EGFR-negative colorectal cancer patients who received cetuximab in a nonstudy setting were identified. Fourteen of these patients received cetuximab plus irinotecan, and two received cetuximab monotherapy. In the 16 patients, four major objective responses were seen (response rate, 25%; 95% CI, 4% to 46%). CONCLUSION Colorectal cancer patients with EGFR-negative tumors have the potential to respond to cetuximab-based therapies. EGFR analysis by current IHC techniques does not seem to have predictive value, and selection or exclusion of patients for cetuximab therapy on the basis of currently available EGFR IHC does not seem warranted.

Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer.

BACKGROUND Two years after undergoing resection of liver metastases from colorectal cancer, about 65 percent of patients are alive and 25 percent are free of detectable disease. We tried to improve these outcomes by treating patients with hepatic arterial infusion of floxuridine plus systemic fluorouracil after liver resection. METHODS We randomly assigned 156 patients at the time of resection of hepatic metastases from colorectal cancer to receive six cycles of hepatic arterial infusion with floxuridine and dexamethasone plus intravenous fluorouracil, with or without leucovorin, or six weeks of similar systemic therapy alone. Patients were stratified according to previous treatment and the number of liver metastases identified at operation. The study end points were overall survival, survival without recurrence of hepatic metastases, and survival without any metastases at two years. RESULTS The actuarial rate of overall survival at two years was 86 percent in the group treated with local plus systemic chemotherapy and 72 percent in the group given systemic therapy alone (P=0.03). The median survival was 72.2 months in the combined-therapy group and 59.3 months in the monotherapy group, with a median follow-up of 62.7 months. After two years, the rates of survival free of hepatic recurrence were 90 percent in the monotherapy group and 60 percent in the monotherapy group (P<0.001), and the respective rates of progression-free survival were 57 percent and 42 percent (P=0.07). At two years, the risk ratio for death was 2.34 among patients treated with systemic therapy alone, as compared with patients who received combined therapy (95 percent confidence interval, 1.10 to 4.98; P=0.027), after adjustment for important variables. The rates of adverse effects of at least moderate severity were similar in the two groups, except for a higher frequency of diarrhea and hepatic effects in the combined-therapy group. CONCLUSIONS For patients who undergo resection of liver metastases from colorectal cancer, postoperative treatment with a combination of hepatic arterial infusion of floxuridine and intravenous fluorouracil improves the outcome at two years.

CD133 expression is not restricted to stem cells, and both CD133+ and CD133– metastatic colon cancer cells initiate tumors

Colon cancer stem cells are believed to originate from a rare population of putative CD133+ intestinal stem cells. Recent publications suggest that a small subset of colon cancer cells expresses CD133, and that only these CD133+ cancer cells are capable of tumor initiation. However, the precise contribution of CD133+ tumor-initiating cells in mediating colon cancer metastasis remains unknown. Therefore, to temporally and spatially track the expression of CD133 in adult mice and during tumorigenesis, we generated a knockin lacZ reporter mouse (CD133lacZ/+), in which the expression of lacZ is driven by the endogenous CD133 promoters. Using this model and immunostaining, we discovered that CD133 expression in colon is not restricted to stem cells; on the contrary, CD133 is ubiquitously expressed on differentiated colonic epithelium in both adult mice and humans. Using Il10-/-CD133lacZ mice, in which chronic inflammation in colon leads to adenocarcinomas, we demonstrated that CD133 is expressed on a full gamut of colonic tumor cells, which express epithelial cell adhesion molecule (EpCAM). Similarly, CD133 is widely expressed by human primary colon cancer epithelial cells, whereas the CD133- population is composed mostly of stromal and inflammatory cells. Conversely, CD133 expression does not identify the entire population of epithelial and tumor-initiating cells in human metastatic colon cancer. Indeed, both CD133+ and CD133- metastatic tumor subpopulations formed colonospheres in in vitro cultures and were capable of long-term tumorigenesis in a NOD/SCID serial xenotransplantation model. Moreover, metastatic CD133- cells form more aggressive tumors and express typical phenotypic markers of cancer-initiating cells, including CD44 (CD44+CD24-), whereas the CD133+ fraction is composed of CD44lowCD24+ cells. Collectively, our data suggest that CD133 expression is not restricted to intestinal stem or cancer-initiating cells, and during the metastatic transition, CD133+ tumor cells might give rise to the more aggressive CD133(- )subset, which is also capable of tumor initiation in NOD/SCID mice.

Actual 10-Year Survival After Resection of Colorectal Liver Metastases Defines Cure

PURPOSE Resection of colorectal liver metastases (CLM) in selected patients has evolved as the standard of care during the last 20 years. In the absence of prospective randomized clinical trials, a survival benefit has been deduced relative to historical controls based on actuarial data. There is now sufficient follow-up on a significant number of patients to address the curative intent of resecting CLM. METHODS Retrospective review of a prospectively maintained database was performed on patients who underwent resection of CLM from 1985 to 1994. Postoperative deaths were excluded. Disease-specific survival (DSS) was calculated from the time of hepatectomy using the Kaplan-Meier method. RESULTS There were 612 consecutive patients identified with 10-year follow-up. Median DSS was 44 months. There were 102 actual 10-year survivors. Ninety-nine (97%) of the 102 were disease free at last follow-up. Only one patient experienced a disease-specific death after 10 years of survival. In contrast, 34% of the 5-year survivors suffered a cancer-related death. Previously identified poor prognostic factors found among the 102 actual 10-year survivors included 7% synchronous disease, 36% disease-free interval less than 12 months, 25% bilobar metastases, 50% node-positive primary, 39% more than one metastasis, and 35% tumor size more than 5 cm. CONCLUSION Patients who survive 10 years appear to be cured of their disease, whereas approximately one third of actual 5-year survivors succumb to a cancer-related death. In well-selected patients, there is at least a one in six chance of cure after hepatectomy for CLM. The presence of poor prognostic factors does not preclude the possibility of long-term survival and cure.

Intrahepatic or Systemic Infusion of Fluorodeoxyuridine in Patients with Liver Metastases from Colorectal Carcinoma: A Randomized Trial

OBJECTIVE To compare the efficacy of direct hepatic arterial chemotherapy with systemic chemotherapy in patients with liver metastases from colorectal carcinoma. DESIGN Randomized trial with crossover allowed from systemic to intrahepatic therapy if tumor progression occurred on systemic therapy. SETTING Academic medical center, referral-based clinic. PATIENTS One hundred sixty-two patients with hepatic metastases from colorectal carcinoma agreed to be randomly assigned to treatment groups. At laparotomy, 63 were excluded from the study: 25 had hepatic resection; 33, extrahepatic disease; 1, infection; and 4, no tumor. INTERVENTION Fourteen-day continuous infusion of fluorodeoxyuridine each month using an infusaid pump (0.3 and 0.15 mg/kg body weight X d in the intrahepatic and systemic arms, respectively). MAIN RESULTS Intrahepatic therapy produced a significantly higher complete and partial response rate, 50%, compared with 20% for systemic therapy (p = 0.001). After tumor progression, 60% of the systemic patients crossed over to intrahepatic therapy; 25% then had a partial response, and 33% a minor response or stabilization of disease on intrahepatic therapy. Toxicity included ulcer disease (17%) and biliary sclerosis (8%) in patients receiving intrahepatic therapy and diarrhea (70%) in patients receiving systemic therapy. Extrahepatic disease occurred in 56% and 37% of the patients in the intrahepatic and systemic groups, respectively (p = 0.092). The median survivals were 17 and 12 months, for the intrahepatic and systemic groups, respectively. CONCLUSION When compared with systemic therapy, hepatic arterial chemotherapy significantly increases response rate for hepatic metastases from colorectal carcinoma and appears to be a more effective treatment.

Randomized Phase II Trial of Cetuximab, Bevacizumab, and Irinotecan Compared With Cetuximab and Bevacizumab Alone in Irinotecan-Refractory Colorectal Cancer: The BOND-2 Study

PURPOSE We evaluated the safety and efficacy of concurrent administration of two monoclonal antibodies, cetuximab and bevacizumab, in patients with metastatic colorectal cancer. PATIENTS AND METHODS This was a randomized phase II study in patients with irinotecan-refractory colorectal cancer. All patients were naïve to both bevacizumab and cetuximab. Patients in arm A received irinotecan at the same dose and schedule as last received before study entry, plus cetuximab 400 mg/m2 loading dose, then weekly cetuximab 250 mg/m2, plus bevacizumab 5 mg/kg administered every other week. Patients in arm B received the same cetuximab and bevacizumab as those in arm A but without irinotecan. RESULTS Forty-three patients received cetuximab, bevacizumab, and irinotecan (CBI) and 40 patients received cetuximab and bevacizumab alone (CB). Toxicities were as would have been expected from the single agents. For the CBI arm, time to tumor progression (TTP) was 7.3 months and the response rate was 37%; for the CB arm, TTP was 4.9 months and the response rate was 20%. The overall survival for the CBI arm was 14.5 months and the overall survival for the CB-alone arm was 11.4 months. CONCLUSION Cetuximab and bevacizumab can be administered concurrently, with a toxicity pattern that seems to be similar to that which would be expected from the two agents alone. This combination plus irinotecan also seems to be feasible. The activity seen with the addition of bevacizumab to cetuximab, or to cetuximab plus irinotecan, seems to be favorable when compared with historical controls of cetuximab or cetuximab/irinotecan in patients who are naïve to bevacizumab.

Outcome of Primary Tumor in Patients With Synchronous Stage IV Colorectal Cancer Receiving Combination Chemotherapy Without Surgery As Initial Treatment

CRA4030 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. [Table: see text].PURPOSE The purpose of this study was to describe the frequency of interventions necessary to palliate the intact primary tumor in patients who present with synchronous, stage IV colorectal cancer (CRC) and who receive up-front modern combination chemotherapy without prophylactic surgery. PATIENTS AND METHODS By using a prospective institutional database, we identified 233 consecutive patients from 2000 through 2006 with synchronous metastatic CRC and an unresected primary tumor who received oxaliplatin- or irinotecan-based, triple-drug chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin; bolus fluorouracil, leucovorin, and irinotecan; or fluorouracil, leucovorin, and irinotecan) with or without bevacizumab as their initial treatment. The incidence of subsequent use of surgery, radiotherapy, and/or endoluminal stenting to manage primary tumor complications was recorded. RESULTS Of 233 patients, 217 (93%) never required surgical palliation of their primary tumor. Sixteen patients (7%) required emergent surgery for primary tumor obstruction or perforation, 10 patients (4%) required nonoperative intervention (ie, stent or radiotherapy), and 213 (89%) never required any direct symptomatic management for their intact primary tumor. Of those 213 patients, 47 patients (20%) ultimately underwent elective colon resection at the time of metastasectomy, and eight patients (3%) underwent this resection during laparotomy for hepatic artery infusion pump placement. Use of bevacizumab, location of the primary tumor in the rectum, and metastatic disease burden were not associated with increased intervention rate. CONCLUSION Most patients with synchronous, stage IV CRC who receive up-front modern combination chemotherapy never require palliative surgery for their intact primary tumor. These data support the use of chemotherapy, without routine prophylactic resection, as the appropriate standard practice for patients with neither obstructed nor hemorrhaging primary colorectal tumors in the setting of metastatic disease.

Importance of response to neoadjuvant chemotherapy in patients undergoing resection of synchronous colorectal liver metastases

The purpose of this study was to compare the treatment and outcome in patients referred for staged re section of synchronous colorectal liver metastases. The records of patients who had undergone colon or rectal resection and were then referred for evaluation of clinically resectable synchronous liver metastases between January 1995 and January 2000 were reviewed. Comparisons were made between patients who did not receive neoadjuvant chemotherapy and had exploratory operations after recovery from colon re section and patients who did receive chemotherapy before liver resection. A total of 106 patients were treated during the 5-year period. Neoadjuvant chemotherapy was given to 52 of the patients; in 29 of them the disease did not progress, but in 17 patients the disease progressed while they were receiving treatment. Median follow-up was 30 months. Patient- and tumor-related variables were similar between groups. Five-year survival was statistically similar between patients who did and those who did not receive neoadjuvant chemotherapy (43% vs. 35%, P = 0.49). Patients within the neoadjuvant group whose dis ease did not progress while they were receiving chemotherapy experienced significantly improved sur vival as compared to patients who did not receive chemotherapy (85% vs. 35%, P = 0.03). In the setting of synchronous colorectal liver metastases, the response to neoadjuvant chemotherapy may be a prognos tic indicator of survival and may assist in the selection of patients for conventional or experimental adju vant therapies.

Neoadjuvant Chemotherapy Before Liver Resection for Patients With Unresectable Liver Metastases From Colorectal Carcinoma

Colorectal carcinoma is one of the most common cancers in the world, and more than 50% of these patients develop liver metastases. Despite recent advances, systemic chemotherapy for metastatic disease without the use of surgery is considered palliative, as there are rarely long-term survivors. However, patients who are candidates for surgical resection of their liver metastases can have a prolonged survival or possibly a cure. Consensus guidelines on criteria for resection and prognostic scores help facilitate patient selection, yet only 25% of patients with liver metastases are considered to have resectable metastases. Neoadjuvant chemotherapy has been explored in an attempt to render more patients candidates for resection. First reports using neoadjuvant systemic chemotherapy in patients with unresectable disease found that 13% to 16% of patients could be rendered resectable. Efforts to increase response rates using hepatic arterial infusion or biologic agents may increase resection rates. This review summarizes the current data on neoadjuvant chemotherapy, the rationale for this approach, potential complications, and future prospects.

Utility of 18F-FDG positron emission tomography scanning on selection of patients for resection of hepatic colorectal metastases

BACKGROUND Hepatectomy represents a standard and potentially curative therapy for hepatic colorectal metastases. However, up to two thirds of patients explored for resection are found to have unsuspected disease, which precludes resection. METHODS In order to determine if 18F-FDG positron emission tomography (PET) scanning may prevent unnecessary surgery, a group of 40 patients being considered for hepatic resection but at high risk for unresectable disease by clinical criteria were subjected to whole body 18F-FDG-PET scanning. Effect on clinical outcome was evaluated. In addition, PET findings in the 25 patients who underwent resection of hepatic metastases were directly compared with the resected specimen to determine the sensitivity of 18F-FDG PET scanning in the liver. RESULTS Findings on 18F-FDG-PET scanning influenced the clinical management in 16 patients (40%) and directly altered management in 9 cases (23%). Six patients were spared laparotomy, and 3 others had PET-directed surgery that found extrahepatic tumor and spared the patient unwarranted liver resection. In 3 cases PET missed peritoneal metastases found on laparotomy. In these cases all missed tumors were less than 1 cm in size. Out of 52 resected hepatic lesions, 18F-FDG-PET detected 37. Within the liver, sensitivity of detection was also related to size. Only 25% of hepatic lesions smaller than 1 cm were detected by PET, while 85% of lesions larger than 1 cm were detected. CONCLUSIONS FDG-PET is best for detecting extrahepatic disease. There are few false positives, and surgeons should carefully evaluate and biopsy extrahepatic positive sites. This test should be used for patients at high risk for extrahepatic disease and should be evaluated prospectively for all patients under consideration for liver resection.