Katrina Y. Glover

Pathologic Response to Preoperative Chemotherapy: A New Outcome End Point After Resection of Hepatic Colorectal Metastases

PURPOSE The primary goal of this study was to evaluate whether pathologic response to chemotherapy predicts patient survival after preoperative chemotherapy and resection of colorectal liver metastases (CLM). The secondary goal of the study was to identify the clinical predictors of pathologic response. PATIENTS AND METHODS A retrospective review was performed of 305 patients who underwent preoperative irinotecan- or oxaliplatin-based chemotherapy, followed by resection of CLM. Pathologic response was systematically evaluated and reported as the mean of the percentage of cancer cells remaining within each tumor. Univariate and multivariate analyses were performed to identify the predictors of pathologic response and survival. RESULTS Cumulative 5-year overall survival rates by pathologic response status were as follows: 75% complete response (no residual cancer cells), 56% major response (1% to 49% residual cancer cells), and 33% minor response (> or = 50% residual cancer cells; complete v major response, P = .037; major v minor response, P = .028). Multivariate analysis revealed that only surgical margin status (P = .050; hazard ratio [HR], 1.77) and pathologic response (major response: P = .034; HR, 4.80; minor response: P = .007; HR, 6.93) were independent predictors of survival. Multivariate analysis of the predictors of pathologic response revealed that carcinoembryonic antigen level < or = 5 ng/mL, tumor size < or = 3 cm, and chemotherapy with fluoropyrimidine plus oxaliplatin and bevacizumab were independent predictors of pathologic response. CONCLUSION Pathologic response predicts survival after preoperative chemotherapy and resection of CLM. Degree of pathologic response represents a new outcome end point for prognosis after resection of CLM.

Phase II Trial of Infusional Fluorouracil, Irinotecan, and Bevacizumab for Metastatic Colorectal Cancer: Efficacy and Circulating Angiogenic Biomarkers Associated With Therapeutic Resistance

PURPOSE We investigated the efficacy of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in a phase II trial in patients previously untreated for metastatic colorectal cancer (mCRC), and changes during treatment in plasma cytokines and angiogenic factors (CAFs) as potential markers of treatment response and therapeutic resistance. PATIENTS AND METHODS We conducted a phase II, two-institution trial of FOLFIRI + B. Each 14-day cycle consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m(2)), bolus FU (400 mg/m(2)), and leucovorin (400 mg/m(2)) followed by a 46-hour infusion of FU (2,400 mg/m(2)). Levels of 37 CAFs were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, during treatment, and at the time of progressive disease (PD). RESULTS Forty-three patients were enrolled. Median progression-free survival (PFS), the primary end point of the study, was 12.8 months. Median overall survival was 31.3 months, with a response rate of 65%. Elevated interleukin-8 at baseline was associated with a shorter PFS (11 v 15.1 months, P = .03). Before the radiographic development of PD, several CAFs associated with angiogenesis and myeloid recruitment increased compared to baseline, including basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04), and macrophage chemoattractant protein-3 (P < .001). CONCLUSION Efficacy and tolerability of FOLFIRI + B appeared favorable to historical controls in this single arm study. Before radiographic progression, there was a shift in balance of CAFs, with a rise in alternate pro-angiogenic cytokines and myeloid recruitment factors in subsets of patients that may represent mechanisms of resistance.

Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma

PURPOSE The study objective was to determine the proportion of patients with hepatocellular carcinoma (HCC) treated with the combination of bevacizumab (B) and erlotinib (E) who were alive and progression free at 16 weeks (16-week progression-free survival [PFS16]) of continuous therapy. Secondary objectives included response rate, median PFS, survival, and toxicity. PATIENTS AND METHODS Patients who had advanced HCC that was not amenable to surgical or regional therapies, up to one prior systemic treatment; Childs-Pugh score A or B liver function; Eastern Cooperative Oncology Group performance status 0, 1, or 2 received B 10 mg/kg every 14 days and E 150 mg orally daily, continuously, for 28-day cycles. Tumor response was evaluated every 2 cycles by using Response Evaluation Criteria in Solid Tumors Group criteria. A total of 40 patients were treated. RESULTS The primary end point of PFS16 was 62.5%. Ten patients achieved a partial response for a confirmed overall response rate (intent-to-treat) of 25%. The median PFSevent was 39 weeks (95% CI, 26 to 45 weeks; 9.0 months), and the median overall survival was 68 weeks (95% CI, 48 to 78 weeks; 15.65 months). Grades 3 to 4 drug-related toxicity included fatigue (n = 8; 20%), hypertension (n = 6; 15%), diarrhea (n = 4; 10%) elevated transaminases (n = 4; 10%), gastrointestinal hemorrhage (n = 5; 12.5%), wound infection (n = 2; 5%) thrombocytopenia (n = 1; 2.5%), and proteinuria, hyperbilirubinemia, back pain, hyperkalemia, and anorexia (n = 1 each). CONCLUSION The combination of B + E in patients who had advanced HCC showed significant, clinically meaningful antitumor activity. B + E warrant additional evaluation in randomized controlled trials.

Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma

Growth factor overexpression, including epidermal growth factor receptor (EGFR) expression, is common in hepatocellular cancers. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR. The primary objective of this study was to determine the proportion of hepatocellular carcinoma (HCC) patients treated with erlotinib who were alive and progression‐free (PFS) at 16 weeks of continuous treatment.

Effect of different types of smoking and synergism with hepatitis C virus on risk of hepatocellular carcinoma in American men and women: case-control study.

The International Agency for Research on Cancer has declared smoking to be a risk factor for hepatocellular carcinoma (HCC). However, passive exposure to cigarette smoke and use of noncigarette tobacco products on the risk of HCC has not been examined. Therefore, we evaluated the independent effects of different types of smoking exposure along with multiple risk factors for HCC and determined whether the magnitude of smoking was modified by other risk factors in men and women. We conducted a case‐control study at The University of Texas M. D. Anderson Cancer Center where 319 HCC patients and 1,061 healthy control subjects were personally interviewed for several HCC risk factors. Multivariate logistic regression analysis was performed to estimate the adjusted odds ratio (AOR) and 95% confidence interval (CI) for each potential risk factor. Use of smokeless tobacco (chewing tobacco and snuff), cigars, pipes and passive smoking exposure were not related to HCC among noncigarette smokers. However, regular cigarette smoking was associated with HCC in men: AOR, 1.9 (95% CI, 1.1–3.1). Heavy alcohol consumption was associated with HCC in women: AOR, 7.7 (95% CI, 2.3–25.1). Cigarette smoking interacted synergistically with chronic infection of hepatitis C virus in men: AOR, 136.3 (95% CI, 43.2–429.6) and with heavy alcohol consumption in women: AOR, 13.7 (95% CI, 3.2–57.9). We conclude that sex differences were observed in HCC relationship with cigarette smoking and alcohol consumption. Controlling for smoking exposure might be a prudent approach to the prevention of HCC, especially in patients with chronic viral hepatitis infections.

The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States.

BACKGROUND/AIMS The study aimed at addressing the connection between positive family history of liver cancer and hepatocellular carcinoma (HCC) development in the USA. METHODS At The University of Texas M.D. Anderson Cancer Center, 347 patients with pathologically confirmed HCC and 1075 healthy controls were studied. All subjects were interviewed for their family history of cancer, including the number of relatives with cancer, the type of cancer, the individuals relationship with the relative, and the age at which the relative was diagnosed. RESULTS Independently of hepatitis B virus (HBV) and hepatitis C virus (HCV), a history of liver cancer in first degree relatives was significantly associated with HCC development (AOR=4.1 [95% CI, 1.3-12.9]). Multiple relatives with liver cancer were only observed among HCC patients with chronic HBV/HCV infection. Affected siblings with liver cancer is significantly associated with HCC development with and without HBV/HCV infection; (AOR=5.7 [95% CI, 1.2-27.3]) and (AOR=4.3 [95% CI, 1.01-20.9]), respectively. Individuals with HBV/HCV and a family history of liver cancer were at higher risk for HCC (AOR=61.9 [95% CI, 6.6-579.7]). CONCLUSIONS First degree family history of liver cancer is associated with HCC development in the USA. Further research exploring the genetic-environment interactions associated with risk of HCC is warranted.

Second-Line Chemotherapy Use in Metastatic Colon Cancer Varies by Disease Responsiveness

BACKGROUND Improved survival of patients with metastatic colorectal cancer (CRC) has been shown to correlate with increased utilization of the 3 active cytotoxic chemotherapeutic agents: 5-fluorouracil (5-FU), irinotecan, and oxaliplatin, usually administered in 2 lines of therapy. However, it is unclear which patient, disease, and treatment characteristics are associated with the utilization of a second-line regimen. PATIENTS AND METHODS We performed a retrospective chart review. Patients with metastatic CRC treated with bevacizumab outside of a clinical trial and any infusional 5-FU/leucovorin (LV) regimen off-protocol (ie, 5-FU/LV/irinotecan [FOLFIRI]/bevacizumab or 5-FU/LV/oxaliplatin [FOLFOX]/bevacizumab) at the University of Texas M. D. Anderson Cancer Center between February 2004 and September 2005 were included. Prespecified characteristics of age, tumor burden, severe toxicity, and front-line regimen efficacy were compared with exploratory analyses of additional patient, disease, and treatment characteristics. RESULTS Eighty-seven sequential patients treated with the specified front-line regimens were identified. Seventy-six percent of the eligible patients were treated with a second-line regimen. Despite equal treatment durations, patients with a better response of stable disease were significantly less likely to receive a third cytotoxic agent than patients with a partial response (68% vs. 95%; odds ratio, 8.2; P = .02) due to declining performance status (86%) or patient preference (14%). This was associated with a decreased 2-year overall survival (86% vs. 55%). Neither age, tumor burden, nor development of toxicities were associated with a different utilization of a second-line regimen. CONCLUSION Failure to obtain a response to initial chemotherapy for metastatic disease appears to be associated with decreased utilization of a second-line regimen.

Current and emerging trends in the treatment of metastatic colorectal cancer

Despite current screening recommendations, colorectal cancer remains the second leading cause of death from cancer in both men and women combined and will result in an estimated 52,180 deaths in the year 20(t7 [11. Metastases are the mNor cause of death in patients with colorectal c~mcer, with 20% to 70% of patients developing liver metastases and 10% to 20% of patients developing lung metastases [2]. After several years of limited progress, many new treatment options for patients with metastatic colorectal c~mcer have been approved over the last few years with the median survival time having doubled in the last decade. Continued development and refinement of treatment options continue to be evaluated as exemplified by the consideration of neoadjuvant chemotherapy in potential resectable liver metastases. Current advances in chemotherapy regimens have also allowed resection of previously unresectable metastases in some patients [3,4]. First-line chemotherapy options for patients with metastatic colorectal cancer include 1 of 3 standard regimens: irinotecan combined with infusional 5-fluorouracil (5-FU) and leucovorin (LV), oxaliplatin combined with infusional 5-FU and I ~V, ~md for patients that may be poor candidates for irinotecan or oxaliplatin-based therapy, 5-FU and IN alone [51. ~Ihe oral fluoropyrimidine, capecitabine, has also been introduced mad has been evaluated as a potential substitute fl~r intravenous 5-FU. Capecitabine is metabolized to 5-FU with prior studies in both local and advanced colorectal cancer showing similar efficacy but improved safety profiles when compared with bolus 5-FU [6,7]. ~[t~e addition of newer targeted molecular therapies, such as bevacizumab and cetuximab, may significantly enh~mce the efficacy of conventional chemotherapy at the cost of mild increases in toxicity [8,91. Panitumumab is the most recent molecular therapeutic to receive US Food and Drug Administration (Fl)A) approval as a single agent in previously treated metastatic colorectal cancer patients [10]. Current goals for treatment of metastatic colorectal cancer are to indMdualize selection and sequencing of treatment options to achieve maximum antitumor activity while limiting toxicity. ~Ihe development and refinement of chemotherapy approaches to achieve these goals are areas of significmlt research interest. Several clinical trials have recently been conducted to evaluate the eflicacy ~md safety of new chemotherapy regimens for patients with advanced colorectal cancer. ~II~is paper reviews recent studies that have evaluated the treatment of metastatic colorectal cancer, including options available for patients with unresectable disease, with an emphasis on treatment regimens.