In the West in particular, the vast majority of gastric cancer (GC) patients present with advanced-stage disease. Although combination chemotherapy is still the most important component of treatment for these patients, it confers a modest survival advantage. Recently, increased knowledge of the key molecular signaling pathways involved in gastric carcinogenesis has led to the discovery of specific molecular-targeted therapeutic agents. Some of these agents such as trastuzumab and ramucirumab have changed the treatment paradigm for this disease. In this paper, we will summarize the current clinical status of targeted drug therapy in the management of GC.
Gastric cancer; Targeted therapy; Angiogenesis; Epidermal growth factor; Treatment
Colorectal cancer remains one of the most commonly diagnosed cancers with almost one-fourth of patients presenting with metastatic disease at the time of diagnosis. As the repertoire of anticancer agents has expanded to treat colorectal patients with metastatic disease, life expectancies have increased and patients are remaining on therapy for longer periods of time. The exact way in which to combine chemotherapeutic and targeted agents remains a therapeutic challenge in an attempt to preserve efficacy while minimizing toxicity. A crucial need exists for reliable and reproducible biomarkers that can assist in personalizing the most advantageous therapy for patients based on the biology of their tumor that will prevent undue side effects and result in the longest duration of tumor stability. In this review, we discuss the completed studies for each agent currently approved for the treatment of metastatic colon cancer and emphasize a need for further prospective studies to solidify the use of biomarkers in this disease.
metastatic colorectal cancer; biomarkers; 5-fluorouracil; irinotecan; oxaliplatin; bevacizumab; EGFR inhibitors
A paucity of data exists on pharmacokinetically guided 5 fluorouracil (5-FU) dosing in the community setting. This multicenter study demonstrated the practicality of using a simple methodology to guide 5-FU dosing in the community setting and resulted in significantly fewer underdosed patients and less gastrointestinal toxicity.
Pharmacokinetically guided (PK-guided) versus body surface area-based 5-fluorouracil (5-FU) dosing results in higher response rates and better tolerability. A paucity of data exists on PK-guided 5-FU dosing in the community setting.
Patients and Methods.
Seventy colorectal cancer patients, from one academic and five community cancer centers, received the mFOLFOX6 regimen (5-FU 2,400 mg/m2 over 46 hours every 2 weeks) with or without bevacizumab at cycle 1. The 5-FU continuous-infusion dose was adjusted for cycles 2–4 using a PK-guided algorithm to achieve a literature-based target area under the concentration-time curve (AUC). The primary objective was to demonstrate that PK-guided 5-FU dosing improves the ability to achieve a target AUC within four cycles of therapy. The secondary objective was to demonstrate reduced incidence of 5-FU-related toxicities.
At cycles 1 and 4, 27.7% and 46.8% of patients achieved the target AUC (20–25 mg × hour/L), respectively (odds ratio [OR]: 2.20; p = .046). Significantly more patients were within range at cycle 4 compared with a literature rate of 20% (p < .0001). Patients had significantly higher odds of not being underdosed at cycle 4 versus cycle 1 (OR: 2.29; p = .037). The odds of a patient being within range increased by 30% at each subsequent cycle (OR: 1.30; p = .03). Less grade 3/4 mucositis and diarrhea were observed compared with historical data (1.9% vs 16% and 5.6% vs 12%, respectively); however, rates of grade 3/4 neutropenia were similar (33% vs 25%–50%).
PK-guided 5-FU dosing resulted in significantly fewer underdosed patients and less gastrointestinal toxicity and allows for the application of personalized colorectal cancer therapy in the community setting.
Fluorouracil; Pharmacokinetic; Dosing; Colorectal; Community; Personalized
This phase I study investigated the safety, dose limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered 1) in combination with 5-fluourouracil with leucovorin (5-FU/LV), 2) with mFOLFOX6 (5-FU/LV + Oxaliplatin), and 3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors.
Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in sub-trial B.
Thirty six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in Level 6A. In sub-trial B, 2/3 patients experienced DLT on Level 1B and subsequent patients were enrolled on Level 1B-1 without DLT. 3/6 patients in cohort 2B-1 experienced Grade 3 mucositis and further study of the combination of everolimus, mFOLFOX6, and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45% of patients remaining on treatment with stable disease for at least three months.
While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role in which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.
everolimus; 5-fluorouracil; oxaliplatin; panitumumab; metastatic colorectal cancer
Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We therefore conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors.
Patients received bortezomib, 0.9-1.5 mg/m2, on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m2, on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and to investigate pharmacokinetic and pharmacodynamic interactions of the combination.
A total of 37 patients with 4 median prior therapies were treated. Frequent grade 1-2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia, constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1/6 patients receiving bortezomib at 1.2 mg/m2, and grade 3 nausea, vomiting, and diarrhea in 1/6 patients receiving bortezomib at 1.5 mg/m2. Grade 3 toxicities in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m2 levels, bortezomib at 1.3 mg/m2 and PLD at 30 mg/m2 are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit. Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs.
A regimen of bortezomib, 1.3 mg/m2 on days 1, 4, 8, and 11 with PLD, 30 mg/m2, on day 4 of a 21-day cycle, was safe in this study, and merits further investigation.
phase I; proteasome inhibition; bortezomib; pegylated liposomal doxorubicin; breast cancer
It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease.
Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m2 weekly for 4 weeks with 90Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2–4). In the first part of the study, 19 patients received escalating weekly 90Y doses of 6.5 mCi/m2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2.
Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses.
Fractionated radioimmunotherapy with 90Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma.
combination therapy; gemcitabine; ductal pancreatic cancer; radioimmunotherapy; clivatuzumab tetraxetan; 90Y
Pazopanib is a potent, multi-targeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics (PK). The objective of this study was to establish the maximum tolerated dose (MTD) and PK profile of pazopanib in patients with varying degrees of hepatic dysfunction.
Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used.
Ninety eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and AUC(0–24) in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower MTD in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites.
In patients with mild liver dysfunction, pazopanib is well tolerated at the FDA-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.
Gemcitabine is a potent radiosensitizer. When combined with standard radiotherapy (XRT) the gemcitabine dose must be reduced to about 10% of its conventional dose. Oxaliplatin and erlotinib also have radiosensitizing properties. In vitro, oxaliplatin and gemcitabine have demonstrated synergy. We aimed to determine the maximum tolerated dose of oxaliplatin and gemcitabine with concurrent XRT, then oxaliplatin, gemcitaibine and erlotinib with XRT in the treatment of locally advanced and low volume metastatic pancreatic or biliary cancer.
A modified 3 + 3 dose escalation design was employed testing 4 dose levels of oxaliplatin and gemcitabine given once weekly for a maximum of 6 weeks with daily XRT in fractions of 1.8 Gy to a total dose of 50.4 Gy. Dose limiting toxicity (DLT) was defined as any grade 4 toxicity or grade 3 toxicity resulting in treatment delay greater than one week. Additionally, dose reduction in two of three patients in a given cohort was counted as a DLT in dose escalation-deescalation rule in the modified 3 + 3 design.
Eighteen patients were enrolled, all with pancreatic cancer. Grade 4 transaminitis in a patient in cohort 3 resulted in cohort expansion. Cohort 4, the highest planned dose cohort, had no DLTs. The recommended phase II dose (RPTD) is oxaliplatin 50 mg/m2/wk with gemcitabine 200 mg/m2/wk and 50.4 Gy XRT The most prevalent grade 3 toxicities were nausea (22%), elevated transaminases (17%), leucopenia (17%) and hyperglycemia (17%). Median progression free survival was 7.1 months (95% CI, 4.6–11.1 months) and median overall survival was 10.8 months (95% CI, 7.1–16.7 months). The addition of erlotinib was poorly tolerated at the first planned dose level, but full study of the combination was hindered by early closure of the study.
Weekly oxaliplatin 50 mg/m2/wk combined with gemcitabine 200 mg/m2/wk and XRT for pancreatic cancer has acceptable toxicity and interesting activity.
Proangiogenic cytokines such as vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor may play crucial roles in the treatment of hepatocellular carcinoma. Recent clinical and preclinical data along with ongoing studies are discussed in this review.
Hepatocellular carcinoma (HCC) is a significant cause of death worldwide. HCC is a highly vascular tumor, and proangiogenic cytokines such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor may play crucial roles in this disease. Sorafenib, a multikinase inhibitor that blocks VEGF and PDGF signaling, was the first systemic therapy to demonstrate improved survival in patients with advanced HCC. Several other drugs targeting VEGF are in development. Because of the anticipation of eventual resistance to anti-VEGF therapies, drugs that also target alternative proangiogenic pathways are being investigated. Recent clinical and preclinical data along with ongoing studies are reviewed.
Hepatocellular carcinoma; Vascular endothelial growth factor; VEGF; FGF; Angiogenesis
Epidermal growth factor receptor (EGFR) inhibition may overcome chemotherapy resistance by inhibiting important anti-apoptotic signals that are constitutively activated by an overstimulated EGFR pathway.
This phase I dose escalation trial assessed the safety and efficacy of vinflunine, a novel vinca alkaloid microtubule inhibitor, with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with refractory solid tumors.
Seventeen patients were treated, 10 with continuous erlotinib, and 7 with intermittent erlotinib. At dose level 1, vinflunine 280 mg/m2 IV day 1 and erlotinib 75 mg PO days 2–21 (“continuous erlotinib”) in 21 day cycles, two of four patients experienced DLTs. At dose level -1 (vinflunine 250 mg/m2 every 21 days and erlotinib 75 mg/day), two of six patients experienced DLTs. The study was amended to enroll to “intermittent erlotinib” dosing: vinflunine day 1 and erlotinib days 2–15 of a 21 day cycle. Two of seven experienced DLTs and the study was terminated. One patient with breast cancer had a partial response; three had stable disease ≥6 cycles. All were treated in the continuous erlotinib group.
Given the marked toxicity in our patient population, the combination of vinflunine and erlotinib cannot be recommended for further study with these dosing schemas.
Influnine; Erlotinib; Phase I; Safety and toxicity
Rectal cancer is often clinically resistant to radiotherapy and there would be value to identifying molecular markers to define the biological basis for this phenomenon. NF-κB is a potentially anti-apoptotic transcription factor that has been associated with resistance to radiotherapy in model systems. This study was designed to evaluate NF- κB activation in rectal cancers being treated with chemoradiation to determine whether NF- κB activity correlates with outcome in rectal cancer
Methods and Materials
22 patients were biopsied at multiple time points in a prospective study, and another 50 were analyzed retrospectively. Pre-treatment tumor tissue was analyzed for multiple NF- κB subunits by immunohistochemistry (IHC). Serial tumor biopsies were analyzed for NF- κB-regulated gene expression by RT-PCR and for NF-κB subunit nuclear localization by IHC.
Several NF- κB target genes (Bcl-2, cIAP-2, IL-8 and TRAF1) were significantly upregulated by a single fraction of radiotherapy at 24 hours demonstrating for the first time that NF-κB is activated by radiotherapy in human rectal tumors. Baseline NF-κB p50 nuclear expression did not correlate with pathologic response to radiotherapy, but increasing baseline p50 was prognostic for overall survival (HR 2.15, p = 0.040).
NF-κB nuclear expression at baseline in rectal cancer is prognostic for overall survival but not predictive of response to radiotherapy. Larger patient numbers would be needed to assess the effect of NF-κB target gene upregulation on response to RT. Our results suggest that NF-κB may play an important role in tumor metastasis as opposed to resistance to chemoradiotherapy.
Hepatocellular carcinoma (HCC) is a common and deadly malignancy with few systemic therapy options. The RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is activated in approximately 50% to 60% of HCCs and represents a potential target for therapy. Selumetinib is an orally available inhibitor of MEK tyrosine kinase activity.
Patients and Methods
Patients with locally advanced or metastatic HCC who had not been treated with prior systemic therapy were enrolled on to the study. Patients were treated with selumetinib at its recommended phase II dose of 100 mg twice per day continuously. Cycle length was 21 days. Imaging was performed every two cycles. Biopsies were obtained at baseline and at steady-state in a subset of patients, and pharmacokinetic (PK) analysis was performed on all patients.
Nineteen patients were enrolled, 17 of whom were evaluable for response. Most (82%) had Child-Pugh A cirrhosis. Toxicity was in line with other studies of selumetinib in noncirrhotic patients. PK parameters were also comparable to those in noncirrhotic patients. No radiographic response was observed in this group, and the study was stopped at the interim analysis. Of 11 patients with elevated α-fetoprotein, three (27%) had decreases of 50% or more. Median time to progression was 8 weeks. Inhibition of ERK phosphorylation was demonstrated by Western blotting.
In this study of selumetinib for patients with HCC, no radiographic responses were seen and time to progression was short, which suggests minimal single-agent activity despite evidence of suppression of target activation.
Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC.
Patients and Methods
This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations.
Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response.
Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.
Aurora A kinase is critical in assembly and function of the mitotic spindle. It is overexpressed in various tumor types and implicated in oncogenesis and tumor progression. This trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MLN8054, a selective small-molecule inhibitor of Aurora A kinase.
In this first-in-human, dose-escalation study, MLN8054 was given orally for 7, 14, or 21 days followed by a 14-day treatment-free period. Escalating cohorts of 3–6 patients with advanced solid tumors were treated until DLT was seen in ≥2 patients in a cohort. Serial blood samples were collected for pharmacokinetics and skin biopsies were collected for pharmacodynamics.
Sixty-one patients received 5, 10, 20, 30 or 40 mg once daily for 7 days; 25, 35, 45 or 55 mg/day in four divided doses (QID) for 7 days; or 55, 60, 70 or 80 mg/day plus methylphenidate or modafinil with daytime doses (QID/M) for 7–21 days. DLTs of reversible grade 3 benzodiazepine-like effects defined the estimated MTD of 60 mg QID/M for 14 days. MLN8054 was absorbed rapidly, exposure was dose-proportional, and terminal half-life was 30-40 hours. Three patients had stable disease for >6 cycles.
MLN8054 dosing for up to 14 days of a 28-day cycle was feasible. Reversible somnolence was dose limiting and prevented achievement of plasma concentrations predicted necessary for target modulation. A recommended dose for investigation in phase 2 trials was not established. A second-generation Aurora A kinase inhibitor is in development.
MLN8054; Aurora A kinase; dose-limiting toxicity; pharmacokinetics; pharmacodynamics
Hepatocelluar carcinoma (HCC) has rarely been associated with familial adenomatosis polyposis (FAP). Between 1950 and 2011, only a few cases of HCC associated with classic FAP have been reported in the medical literature. Here, we report the first case to our knowledge of HCC associated with attenuated FAP (aFAP). The patient possessed a single nucleotide mutation in the noncoding region after exon 4, which is rarely observed in attenuated FAP, and not previously reported in classic FAP–associated HCC. Our patient underwent liver transplantation for a 22-cm-large HCC (in China), however, her HCC recurred 1.5 years after the transplantation. Here we review the medical literature on FAP and HCC, with a particular focus on the role of the Wnt/APC/β-catenin pathway toward a better understanding of HCC pathogenesis.
Familial adenomatosis polyposis; Hepatocelluar carcinoma
Vinflunine is a novel vinca alkaloid with promising single agent clinical activity. Pemetrexed has at least additive activity with other vincas. A phase I trial was undertaken to assess the safety of vinflunine and pemetrexed in patients with refractory solid tumors.
A standard 3-patient cohort dose escalation scheme was used to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the vinflunine/pemetrexed combination. Pemetrexed 500 mg/m2 was given with vinflunine 280 mg/m2 (cohort 1), 300 mg/m2 (cohort 2) or 320 mg/m2 (cohort 3) on day 1 of a 21-day cycle.
19 patients were enrolled, median age 58 years (range 32 to 77) and had a median of 3 (range 1–6) prior therapies. DLT occured 1 of 6 pts in cohort 1 (thrombocytopenia, hyponatremia), 2 of 10 pts in cohort 2 (febrile neutropenia, hyponatremia, hyperbilirubinema; febrile neutropenia), and 2 of 3 pts in cohort 3 (febrile neutropenia, hypokalemia; febrile neutropenia). 1 pt in cohort 2 died prior to completion of cycle 1 likely from disease progression. Most common grade 3/4 adverse events were neutropenia (7), leukopenia (5). Febrile neutropenia occurred in 4 patients (21%). No objective responses were seen. Two patients (breast and lung) had prolonged stable disease for 25 and 20 cycles respectively.
Based on this experience we recommend vinflunine 300 mg/m2 and pemetrexed 500 mg/m2 in combination every 3 weeks for future study. At these doses, the combination of vinflunine and pemetrexed was tolerable in this heavily pretreated population. Hematologic toxicity, including febrile neutropenia, was prominent.
Phase I; Vinflunine; Pemetrexed; Vinca alkaloid
Resistance to 5-fluorouracil (5-FU) represents a major contributor to cancer-related mortality in advanced colorectal cancer patients. Genetic variations and expression alterations in genes involved in 5-FU metabolism and effect have been shown to modulate 5-FU sensitivity in vitro, however these alterations do not fully explain clinical resistance to 5-FU-based chemotherapy. To determine if alterations of DNA copy number in genes involved in 5-FU metabolism impacted clinical resistance to 5-FU-based chemotherapy, we assessed thymidylate synthetase (TYMS) and thymidine phosphorylase (TYMP) copy number in colorectal liver metastases. DNA copy number of TYMS and TYMP was evaluated using real time quantitative PCR in frozen colorectal liver metastases procured from 62 patients who were pretreated with 5-FU-based chemotherapy prior to surgical resection (5-FU exposed) and from 51 patients who received no pretreatment (unexposed). Gain of TYMS DNA copy number was observed in 18% of the 5-FU exposed metastases, while only 4% of the unexposed metastases exhibited TYMS copy gain (p=0.036). No significant differences were noted in TYMP copy number alterations between 5-FU exposed and unexposed metastases. Median survival time was similar in 5-FU exposed patients with metastases containing TYMS amplification and those with no amplification. However, TYMS amplification was associated with shorter median survival in patients receiving post-resection chemotherapy (hazard ratio = 2.7, 95% confidence interval = 1.1 to 6.6; p=0.027). These results suggest amplification of TYMS amplification as a putative mechanism for clinical resistance to 5-FU-based chemotherapy and may have important ramifications for the post-resection chemotherapy choices for metastatic colorectal cancer.
Colorectal Neoplasms; Neoplasm Metastasis; DNA Copy Number Variation; Fluorouracil; Thymidylate Synthase; Thymidine Phosphorylase
KRAS mutations may predict poor response to radiotherapy. Downstream events from KRAS, such as activation of BRAF, AKT and ERK, may also confer prognostic information but have not been tested in rectal cancer (RC). Our objective was to explore the relationships of KRAS and BRAF mutation status with p-AKT and p-ERK and outcomes in RC.
Pre-radiotherapy RC tumor biopsies were evaluated. KRAS and BRAF mutations were assessed by pyrosequencing; p-AKT and p-ERK expression by immunohistochemistry.
Of 70 patients, mean age was 58; 36% stage II, 56% stage III, and 9% stage IV. Responses to neoadjuvant chemoradiotherapy: 64% limited, 19% major, and 17% pathologic complete response. 64% were KRAS WT, 95% were BRAF WT. High p-ERK levels were associated with improved OS but not for p-AKT. High levels of p-AKT and p-ERK expression were associated with better responses. KRAS WT correlated with lower p-AKT expression but not p-ERK expression. No differences in OS, residual disease, or tumor downstaging were detected by KRAS status.
KRAS mutation was not associated with lesser response to chemoradiotherapy or worse OS. High p-ERK expression was associated with better OS and response. Higher p-AKT expression was correlated with better response but not OS.
Rectal cancer; KRAS analysis; phosphoERK; phosphoAKT; radiation response
Patients with portal vein thrombosis (PVT) and hepatocellular carcinoma (HCC) have limited treatment options due to increased disease burden and diminished hepatic perfusion. 90Y-microspheres may be better tolerated than chemoembolization in these patients. Here we review the safety and efficacy of 90Y-microsphere use for HCC with major PVT.
Materials and Methods
A retrospective review of HCC with main (n=10) or first (n=12) branch PVT treated with 90Y-microspheres (n=22) was conducted. CLIP scores ranged from 2 to 5 with 18% scoring 4 or greater. Response was determined 8-12 weeks following treatment using magnetic resonance or computed tomography and RECIST criteria. Overall survival was estimated by the Kaplan-Meier method.
32 treatments (26 glass, 6 resin) were administered to 22 patients. Common grade 1–2 toxicities included abdominal pain (38%), nausea (28%), fatigue (22%). Four post-therapy hospitalizations occurred, all <48hrs in duration. 1 death occurred 10 days following therapy Response data: 2 partial responses, progressive disease 42%, stable disease 50% of treatments. Median overall survival (OS) was 7 months from time of initial 90Y-microsphere treatment. Child-Pugh A patients had a median OS of 7.7 months; B and C = 2.7 months (p = 0.01). Median OS for CLIP scores 2–3 was 7 months versus 1.3 months for scores 4–5 (p = 0.04).
90Y-microspheres are tolerated in patients with HCC and major PVT. Compared with chemoembolization, rates of severe adverse events appear low. Radiographic response rates are low. Median OS of 7 months is promising and warrants further study versus systemic therapy.
Hepatocelluar carcinoma (HCC) is the most common primary malignancy of the liver in adults and the third most common cause of cancer death worldwide. The incidence of HCC in the United States is rising steadily because of the prevalence of hepatitis C viral infection and other causes of hepatic cirrhosis. The majority of patients have underlying hepatic dysfunction, which complicates patient management and the search for safe and effective therapies. The Clinical Trials Planning Meeting (CTPM) in HCC was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to identify the key knowledge gaps in HCC and define clinical research priorities. The CTPM structured its review according to current evidence-based treatment modalities in HCC and prioritized the recommendations on the basis of the patient populations representing the greatest unmet medical need.
NF-κB is an antiapoptotic transcription factor that has been shown to be a mediator of treatment resistance. Bcl-3 is a regulator of NF-κB that may play a role in oncogenesis. The goal of this study was to correlate the activation status of NF-κB and Bcl-3 with clinical outcome in a group of patients with metastatic colorectal cancer (CRC).
A retrospective study of 23 patients who underwent surgical resection of CRC at the University of North Carolina (UNC). Activation of NF-κB was defined by nuclear expression of select components of NF-κB (p50, p52, p65) and Bcl-3. Tissue microarrays were created from cores of normal mucosa, primary tumor, lymph node metastases and liver metastases in triplicate from disparate areas of the blocks, and an intensity score was generated by multiplying intensity (0–3+) by percent of positive tumor cells. Generalized estimating equations were used to note differences in intensity scores among normal mucosa and nonnormal tissues. Cox regression models were fit to see if scores were significantly associated with overall survival.
p65 NE was significantly higher in primary tumor and liver metastases than normal mucosa (both p < 0.01). p50 nuclear expression was significantly higher for all tumor sites than for normal mucosa (primary tumor and lymph node metastases p < 0.0001, liver metastases p < 0.01). Bcl-3 nuclear expression did not differ significantly between normal mucosa and tumor; however, nuclear expression in primary tumor for each of these components was strongly associated with survival: the increase in hazard for each 50-point increase in nuclear expression was 91% for Bcl-3, 66% for p65, and 52% for p50 (all p < 0.05).
Activation of canonical NF-κB subunits p50 and p65 as measured by nuclear expression is strongly associated with survival suggesting NF-κB as a prognostic factor in this disease. Primary tumor nuclear expression appears to be as good as, or better than, metastatic sites at predicting prognosis. Bcl-3 nuclear expression is also negatively associated with survival and deserves further study in CRC.
NF-κB; P65; P50; Colorectal carcinoma
Hepatocellular carcinoma (HCC) is frequently resistant to chemotherapy. However, epidermal growth factor receptor (EGFR) inhibition has demonstrated activity in HCC and overcomes chemotherapy resistance in other settings. We studied the efficacy of combining the anti-EGFR antibody cetuximab with capecitabine and oxaliplatin in advanced HCC.
Patients who had chemotherapy-naive advanced/unresectable HCC and any Childs-Pugh–class chronic liver disease (provided bilirubin was <3 mg/dl) received capecitabine 850 mg/m2 bid days 1–14, oxaliplatin 130 mg/m2 day 1, and cetuximab 400 mg/m2 day 1 then 250 mg/m2 weekly for each 21 day cycle.
Twenty-nine patients received any protocol therapy, but 24 completed at least one cycle. Of the 24 patients evaluable for response, 3 had a partial response (12.5%, 95% confidence interval [CI], 3–32%) and 17 had stable disease (71%), for a disease control rate of 83%. Of patients with an elevated AFP, 57% had a >50% reduction in AFP. Median time to progression was 4.5 months (95% CI, 3.2–6.4), and overall survival was 4.4 months (95% CI, 2.4–7.3). Most common toxicities included diarrhea (13 patients, 45%), fatigue (12 patients, 41%), and hypomagnesemia (12 patients, 41%). Fatigue (6 patients) and diarrhea (5 patients) were the most common grade 3–4 toxicities. Three patients died within the first 30 days of treatment (one of toxicity, two of liver failure presumed to be related to disease progression).
The capecitabine/oxaliplatin/cetuximab combination was tolerable, though diarrhea was pronounced, in this population. The combination was associated with a modest response rate, but a high rate of AFP response and radiographic stable disease. Time to progression and overall survival were shorter than would be expected for treatment with sorafenib.
Subcutaneous metastasis from a visceral malignancy is rare with an incidence of 5.3%. Skin involvement as the presenting sign of a silent internal malignancy is an even rarer event occurring in approximately 0.8%. We report a case of a patient who presented to her dermatologist complaining of rapidly developing subcutaneous nodules which subsequently proved to be metastatic colon cancer, and we provide a review of the literature.
Colorectal cancer; Subcutaneous metastasis; Cutaneous metastasis
Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of EGFR and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC.
A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of < 10% and detect a true response rate of ≥30% was utilized. The dose of lapatinib was 1,500 mg/d administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins.
Twenty-six patients with HCC enrolled on this study. 19% had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%) and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease (SD) as their best response including 6 (23%) with SD lasting > 120 days. Median progression-free-survival was 1.9 months and median overall survival 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on >90% of patients. No somatic mutations in EGFR (exons 18–21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT and P70S6K expression did not correlate with survival.
Lapatinib is well-tolerated but appears to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined.
Standard therapy for stage II/III rectal cancer consists of a fluoropyrimidine and radiation therapy followed by surgery. Preclinical data demonstrated that bortezomib functions as a radiosensitizer in colorectal cancer models. The purpose of this study was to determine the maximum tolerated dose (MTD) of bortezomib in combination with chemotherapy and radiation.
Patients and Methods
Patients with locally advanced rectal adenocarcinomas, as staged by endoscopic ultrasound, were eligible. Bortezomib was administered on days 1, 4, 8, and 11 every 21 days for 2 cycles with 5-fluorouracil at 225 mg/m2/day continuously and 50.4 Gy of radiation. Dose escalation of bortezomib was conducted via a standard 3 + 3 dose escalation design. A subset of patients underwent serial tumor biopsies for correlative studies.
Nine patients in 2 dose cohorts were enrolled. Diarrhea was the principal dose-limiting toxicity and occurred at the 1.0-mg/m2 dose level. There was no clear evidence of suppression of nuclear factor-κB target gene expression in biopsy samples.
The MTD of bortezomib in combination with chemotherapy and radiation may be below a clinically relevant dose, limiting the clinical applicability of this combination. Performing biopsies before and during irradiation for determining gene expression in response to radiation therapy is feasible.
Maximum tolerated dose; NF-κB; PS-341; Proteasome inhibitors