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Despite recent advances in the management of colorectal cancer, metastatic disease remains challenging, and patients are rarely cured. However, a better understanding of the pathways implicated in the evolution and proliferation of cancer cells has led to the development of targeted therapies, that is, agents with action directed at these pathways/features. This approach is more specific to cells within which these pathways, such as epidermal growth factor receptor (EGFR), are overactive; this is in contrast to the relatively indiscriminate mechanism by which cytotoxic chemotherapy tends to affect rapidly dividing cells, regardless of their role. Although factors unique to a given patient, such as the location of the primary tumor (sidedness) or the presence of mutations that confer resistance, may limit the utility of these agents, targeted therapies are now a part of the treatment paradigm for metastatic colorectal cancer, and survival outcomes have significantly improved. This review provides an overview of the role of targeted therapy in the management of patients with colorectal cancer metastases as well as a discussion of issues in patient selection, with a focus on inhibitors of angiogenesis, EGFR-targeted therapy, BRAF mutation-targeted therapies, and other novel strategies, including immunotherapy.

Background Although gemcitabine plus platinum chemotherapy is the established first-line regimen for advanced biliary cancer (ABC), there is no standard second-line therapy. This study evaluated current practice and outcomes for second-line chemotherapy in patients with ABC across 3 US academic medical centers. Methods Institutional registries were reviewed to identify patients who had received second-line chemotherapy for ABC from April 2010 to March 2015 along with their demographics, diagnoses and staging, treatment histories, and clinical outcomes. Overall survival from the initiation of second-line chemotherapy (OS2) was estimated with Kaplan-Meier methods. Results This study identified 198 patients with cholangiocarcinoma (intrahepatic [61.1%] or extrahepatic [14.1%]) or gallbladder carcinoma (24.8%); 52% received at least 3 lines of systemic chemotherapy. The median OS2 was 11 months (95% confidence interval [CI], 8.8-13.1 months). The median OS2 for patients with intrahepatic cholangiocarcinoma was 13.4 months (95% CI, 10.7-17.8 months), which was longer than that for patients with extrahepatic cholangiocarcinoma (6.8 months; 95% CI, 5-10.6 months) or gallbladder carcinoma (9.4 months; 95% CI, 7.2-12.3 months; P = .018). The median time to second-line treatment failure was 2.2 months (95% CI, 1.8-2.7 months), and it was similar across tumor locations (P = .60). Conclusions In this large cohort of patients with ABC treated across 3 academic medical centers after the failure of first-line chemotherapy, the time to treatment failure on standard therapies was short, although the median OS2 was longer than has been reported previously, and more than half of the patients received additional lines of treatment. This multicenter collaboration represents the largest cohort studied to date of second-line chemotherapy for ABC and provides a contemporary benchmark for future clinical trials.

BACKGROUND: Patients with advanced stage adenocarcinoma of the pancreas have a poor prognosis. The identification of prognostic and/or predictive biomarkers may help stratify patients so that therapy can be individualized. METHODS: Serum samples from patients enrolled in the Cancer and Leukemia Group B 80303 phase 3 trial, “Randomized Study of Gemcitabine With Versus Without Bevacizumab in Patients With Locally Advanced or Metastatic Adenocarcinoma of the Pancreas” were used to discover novel biomarkers. For the discovery phase, 40 sera were selected based on length of survival and type of therapy, and subjected to liquid chromatography coupled to tandem mass spectrometry analysis (LC-MS-MS). The top features (proteins) were then further selected for validation by enzyme-linked immunosorbent assay (ELISA). RESULTS: Quantification by nano–LC-MS-MS resulted in 1452 peptides mapping to 156 proteins across all 40 samples, 92 of which had 2 or more peptides. After curation of the data, the authors selected 1 putative prognostic protein, alpha 1-antichymotrypsin (AACT), and 2 putative predictive proteins, histidine-rich glycoprotein (HRG) and complement factor H (CFH), for validation by ELISA. AACT was found to be negatively correlated with overall survival (τ = −0.30 [−0.38, −0.22]; P < .00001). There was no evidence for interaction with bevacizumab and HRG, but there was some evidence for a weak positive correlation of HRG with overall survival (τ = 0.11 [0.03, 0.19]; P < .01). CFH was found to be neither a predictive nor a prognostic factor for overall survival. CONCLUSIONS: AACT may be a useful prognostic marker in patients with advanced stage pancreatic carcinoma, although additional validation studies are needed. Cancer 2011;. © 2011 American Cancer Society.

BACKGROUND. The safety and efficacy of the fully human antibody panitumumab was evaluated in patients with metastatic colorectal cancer refractory to available therapies. METHODS. This phase 2 open-label, multicenter study of panitumumab enrolled patients with metastatic colorectal cancer who had progressed on chemotherapy that included a fluoropyrimidine and irinotecan or oxaliplatin, or both. All patients had tumors with ≥10% 1+ epidermal growth factor receptor (EGFr) staining by immunohistochemistry. Patients were stratified into 2 strata (high or low staining intensity) and received intravenous panitumumab 2.5 mg/kg weekly 8 of every 9 weeks until disease progression or unacceptable toxicity. RESULTS. In all, 148 patients received panitumumab, 105 in the high EGFr stratum, 43 in the low EGFr stratum. Overall response by central review was 9% (95% confidence interval [CI], 5%–15%) and was similar between strata. An additional 29% of patients had stable disease. Median progression-free survival was 14 weeks (95% CI, 8–16) and median overall survival was 9 months (95% CI, 6–10). Toxicities were manageable, with skin toxicity reported in 95% of patients (5% grade 3 or 4). Four patients discontinued therapy because of toxicity. No antipanitumumab antibodies were detected. One patient had an infusion reaction but was able to continue therapy. CONCLUSIONS. Panitumumab given weekly was well tolerated and had single-agent activity in previously treated patients with colorectal cancer. Dermatologic toxicity was common but rarely severe. Ongoing studies will determine panitumumab activity earlier in the course of treatment for colorectal cancer and in combination with other antineoplastic agents. Cancer 2007. © 2007 American Cancer Society.

Substantial effort has focused on the development of novel targeted agents for treating patients with late-stage colorectal carcinoma. These agents are designed specifically to inhibit biochemical processes associated with pathogenesis. Numerous molecules targeting the epidermal growth factor receptor have been investigated as therapeutic agents and appear to herald a shift in the treatment paradigm for colorectal carcinoma. Cancer 2005. © 2005 American Cancer Society.

This article presents the case of a 22-year-old patient with treated Hodgkin disease (HD) who had mediastinal widening on computed tomography scan after chemotherapy. This mass was gallium avid. These findings were explained by histologically documented benign thymic hyperplasia, the first such case reported in an adult with HD, to the knowledge of the authors. The literature on thymic hyperplasia after chemotherapy is reviewed.

Background. Twenty-nine patients with metastatic renal cell carcinoma (RCC) were treated with constantinfusion floxuridine (FUdR, Roche Laboratories, Nutley, NJ). Methods. The initial dosage was 0.075 mg/kg/day for 14 days every 28 days and was increased or decreased by 0.025-mg/kg/day increments at each subsequent cycle until the maximum tolerated dose (MTD) was achieved. Results. All patients were fully assessable. One (4%) patient had a complete response, 5 (17%) had a partial response, 13 (50%) had stabilized disease, and 10 (34%) had progressive disease. The treatment-limiting toxic effect was diarrhea, and the median tolerated dosage was 0.1 mg/kg/day for 14 days every 28 days (range, 0.05–0.275 mg/kg/day). Five of the six responses occurred at a dosage of 0.1 mg/kg/day or less, which was achievable in most patients. Patients who reached their MTD without achieving a complete or partial response were switched to circadian-infusion floxuridine to determine whether an increased dose intensity could be administered and whether this would translate into additional responses. A higher median tolerated dosage of 0.15 mg/kg/day was achieved with circadian administration; however, no additional responses were observed. The median survival time was 891 days after the diagnosis of metastatic RCC and 445 days after the institution of floxuridine therapy. Conclusions. Constant-infusion floxuridine is active against metastatic RCC and produces a response rate that appears to be comparable to that of circadian administration of floxuridine.

BACKGROUND: The authors' purpose was to explore the incidence and prognostic significance of perineural invasion (PNI) in pT3N0 rectal cancer. METHODS: Pathologic materials from resected specimens of 173 patients with pT3N0 rectal cancer were retrospectively collected. PNI-positivity was categorized into 2 groups: surrounding the nerve sheath (SS-PNI) and invading through the nerve sheath (TS-PNI). The rate of PNI-positivity was compared with PNI as initially recorded in the original reports. Patients' outcome was studied in groups with different PNI status, and multivariate analysis was performed to determine its prognostic value. RESULTS: In this retrospective analysis, PNI-positivity was found in 24.3% of all cases, in which SS-PNI and TS-PNI were 11% and 13.3%, respectively, and was related to lymphovascular invasion. Only 7.5% of patients' specimens were reported as PNI-positive in the original reports. Detection of SS-PNI was likelier to be missed than TS-PNI. The rates of local recurrence, disease-free survival, and overall survival at 5 years were similar between the groups of SS-PNI and TS-PNI. The 5-year local recurrence rate was more than 2.5-fold higher in the PNI-positive group compared with the PNI-negative group (22.7% vs 7.9%, respectively; P = .017). Multivariate analysis proved that PNI-positivity was the only independent risk factor for predicting 5-year local recurrence rate, whereas only sampled lymph nodes was related to 5-year disease-free survival and overall survival. CONCLUSIONS: PNI is a common pathologic feature in rectal cancer. The definition of PNI should include SS-PNI and TS-PNI. Rectal cancer patients who are PNI-positive are at higher risk of local recurrence and should be considered for more intensive treatment. Cancer 2011. © 2010 American Cancer Society.

This article presents the case of a 22-year-old patient with treated Hodgkin disease (HD) who had mediastinal widening on computed tomography scan after chemotherapy. This mass was gallium avid. These findings were explained by histologically documented benign thymic hyperplasia, the first such case reported in an adult with HD, to the knowledge of the authors. The literature on thymic hyperplasia after chemotherapy is reviewed.

Twenty-nine patients with metastatic renal cell carcinoma (RCC) were treated with constant-infusion floxuridine (FUdR, Roche Laboratories, Nutley, NJ).The initial dosage was 0.075 mg/kg/day for 14 days every 28 days and was increased or decreased by 0.025-mg/kg/day increments at each subsequent cycle until the maximum tolerated dose (MTD) was achieved.All patients were fully assessable. One (4%) patient had a complete response, 5 (17%) had a partial response, 13 (50%) had stabilized disease, and 10 (34%) had progressive disease. The treatment-limiting toxic effect was diarrhea, and the median tolerated dosage was 0.1 mg/kg/day for 14 days every 28 days (range, 0.05-0.275 mg/kg/day). Five of the six responses occurred at a dosage of 0.1 mg/kg/day or less, which was achievable in most patients. Patients who reached their MTD without achieving a complete or partial response were switched to circadian-infusion floxuridine to determine whether an increased dose intensity could be administered and whether this would translate into additional responses. A higher median tolerated dosage of 0.15 mg/kg/day was achieved with circadian administration; however, no additional responses were observed. The median survival time was 891 days after the diagnosis of metastatic RCC and 445 days after the institution of floxuridine therapy.Constant-infusion floxuridine is active against metastatic RCC and produces a response rate that appears to be comparable to that of circadian administration of floxuridine.