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2.  Part 3: Pharmacogenetic Variability in Phase II Anticancer Drug Metabolism 
The Oncologist  2011;16(7):992-1005.
This third part of a four-part series on pharmacogenetics focuses on genetic variability in phase II drug-metabolizing enzymes (glutathione S-transferases, uridine diphosphoglucuronosyl transferases, methyltransferases, sulfotransferases, and N-acetyltransferases) and discusses the effects of genetic polymorphism within the genes encoding these enzymes on anticancer drug therapy outcome.
Learning Objectives
After completing this course, the reader will be able to: Identify genetic variants of glutathione S-transferase and uridine diphosphoglucuronosyl transferase that have been shown to affect clinical outcomes in patients with cancer and describe the general effects of these variants with respect to standard treatment.Describe potential treatment considerations in patients with cancer who have genetic polymorphisms that affect Phase II metabolism of anticancer drugs.
This article is available for continuing medical education credit at CME.TheOncologist.com
Equivalent drug doses may lead to wide interpatient variability in drug response to anticancer therapy. Known determinants that may affect the pharmacological response to a drug are, among others, nongenetic factors, including age, gender, use of comedication, and liver and renal function. Nonetheless, these covariates do not explain all the observed interpatient variability. Differences in genetic constitution among patients have been identified to be important factors that contribute to differences in drug response. Because genetic polymorphism may affect the expression and activity of proteins encoded, it is a key covariate that is responsible for variability in drug metabolism, drug transport, and pharmacodynamic drug effects.
We present a series of four reviews about pharmacogenetic variability. This third part in the series of reviews is focused on genetic variability in phase II drug-metabolizing enzymes (glutathione S-transferases, uridine diphosphoglucuronosyl transferases, methyltransferases, sulfotransferases, and N-acetyltransferases) and discusses the effects of genetic polymorphism within the genes encoding these enzymes on anticancer drug therapy outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are proposed.
doi:10.1634/theoncologist.2010-0260
PMCID: PMC3228134  PMID: 21659608
Pharmacogenetics; Phase II metabolism; Personalized medicine; Oncology; Anticancer drugs
3.  Part 4: Pharmacogenetic Variability in Anticancer Pharmacodynamic Drug Effects 
The Oncologist  2011;16(7):1006-1020.
This fourth part of a four-part series on pharmacogenetics focuses on pharmacodynamic variability and encompasses genetic variation in drug target genes such as those encoding thymidylate synthase, methylene tetrahydrofolate reductase, and ribonucleotide reductase. Potential implications and opportunities for patient and drug selection for genotype-driven anticancer therapy are outlined.
Learning Objectives
After completing this course, the reader will be able to: Identify genetic polymorphisms within pharmacodynamic candidate genes that are potential predictive markers for treatment outcome with anticancer drugs.Describe treatment selection considerations in patients with cancer who have genetic polymorphisms that could influence pharmacodynamic aspects of anticancer therapy.
This article is available for continuing medical education credit at CME.TheOncologist.com
Response to treatment with anticancer drugs is subject to wide interindividual variability. This variability is expressed not only as differences in severity and type of toxicity, but also as differences in effectiveness. Variability in the constitution of genes involved in the pharmacokinetic and pharmacodynamic pathways of anticancer drugs has been shown to possibly translate into differences in treatment outcome. The overall knowledge in the field of pharmacogenetics has tremendously increased over the last couple of years, and has thereby provided opportunities for patient-tailored anticancer therapy. In previous parts of this series, we described pharmacogenetic variability in anticancer phase I and phase II drug metabolism and drug transport. This fourth part of a four-part series of reviews is focused on pharmacodynamic variability and encompasses genetic variation in drug target genes such as those encoding thymidylate synthase, methylene tetrahydrofolate reductase, and ribonucleotide reductase. Furthermore, genetic variability in other pharmacodynamic candidate genes involved in response to anticancer drugs is discussed, including genes involved in DNA repair such as those encoding excision repair crosscomplementing group 1 and group 2, x-ray crosscomplementing group 1 and group 3, and breast cancer genes 1 and 2. Finally, somatic mutations in KRAS and the gene encoding epidermal growth factor receptor (EGFR) and implications for EGFR-targeted drugs are discussed. Potential implications and opportunities for patient and drug selection for genotype-driven anticancer therapy are outlined.
doi:10.1634/theoncologist.2010-0261
PMCID: PMC3228142  PMID: 21659612
Pharmacogenetics; Personalized medicine; Pharmacodynamics; Oncology; Anticancer drugs
4.  Part 2: Pharmacogenetic Variability in Drug Transport and Phase I Anticancer Drug Metabolism 
The Oncologist  2011;16(6):820-834.
This second part of a four-part series deals with pharmacogenetic variability in drug transport and anticancer phase I drug metabolism, and emphasizes opportunities for patient-tailored pharmacotherapy based on the current knowledge in the field of pharmacogenetics in oncology.
Learning Objectives
After completing this course, the reader will be able to: List currently identified candidate genes involved in phase I metabolism that are potential pharmacogenetic markers in anticancer therapy.Describe the general effect on standard treatment of allelic variants of the candidate genes and the implications for individualized treatment.
This article is available for continuing medical education credit at CME.TheOncologist.com
Equivalent drug doses in anticancer chemotherapy may lead to wide interpatient variability in drug response reflected by differences in treatment response or in severity of adverse drug reactions. Differences in the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of a drug contribute to variation in treatment outcome among patients. An important factor responsible for this variability is genetic polymorphism in genes that are involved in PK/PD processes, including drug transporters, phase I and II metabolizing enzymes, and drug targets, and other genes that interfere with drug response. In order to achieve personalized pharmacotherapy, drug dosing and treatment selection based on genotype might help to increase treatment efficacy while reducing unnecessary toxicity.
We present a series of four reviews about pharmacogenetic variability in anticancer drug treatment. This is the second review in the series and is focused on genetic variability in genes encoding drug transporters (ABCB1 and ABCG2) and phase I drug-metabolizing enzymes (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DPYD, CDA and BLMH) and their associations with anticancer drug treatment outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are presented.
doi:10.1634/theoncologist.2010-0259
PMCID: PMC3228220  PMID: 21632461
Pharmacogenetics; Drug transport; Phase I metabolism; Personalized medicine; Oncology; Anticancer drugs
5.  Part 1: Background, Methodology, and Clinical Adoption of Pharmacogenetics 
The Oncologist  2011;16(6):811-819.
This first part of a four-part series on pharmacogenetics describes the functional impact of genetic polymorphism and provides a general background to and insight into possible clinical consequences of pharmacogenetic variability.
Learning Objectives
After completing this course, the reader will be able to: Differentiate the candidate gene and genome-wide approaches to pharmacogenetic research and the impact of each on clinical study results.Describe the clinical implications of pharmacogenetic variability and its potential role in individualized treatment of patients with cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com
Equivalent drug doses may lead to wide interpatient variability with regard to drug response, reflected by differences in drug activity and normal tissue toxicity. A major factor responsible for this variability is variation among patients in their genetic constitution. Genetic polymorphism may affect the activity of proteins encoded, which in turn may lead to changes in the pharmacokinetic and pharmacodynamic behavior of a drug, observed as differences in drug transport, drug metabolism, and pharmacodynamic drug effects. Recent insights into the functional effect of polymorphism in genes that are involved in the pharmacokinetics and pharmacodynamics of anticancer drugs have provided opportunities for patient-tailored therapy in oncology. Individualized pharmacotherapy based on genotype will help to increase treatment efficacy while reducing unnecessary toxicity, especially of drugs characterized by a narrow therapeutic window, such as anticancer drugs.
We provide a series of four reviews aimed at implementing pharmacogenetic-based drug and dose prescription in the daily clinical setting for the practicing oncologist. This first part in the series describes the functional impact of genetic polymorphism and provides a general background to and insight into possible clinical consequences of pharmacogenetic variability. It also discusses different methodologies for clinical pharmacogenetic studies and provides a concise overview about the different laboratory technologies for genetic mutation analysis that are currently widely applied. Subsequently, pharmacogenetic association studies in anticancer drug transport, phase I and II drug metabolism, and pharmacodynamic drug effects are discussed in the rest of the series. Opportunities for patient-tailored pharmacotherapy are highlighted.
doi:10.1634/theoncologist.2010-0258
PMCID: PMC3228225  PMID: 21632456
Pharmacogenetics; Oncology; Anticancer drugs; Genotyping technologies
6.  Treatment of resectable gastric cancer 
Stomach cancer is one of the most common cancers worldwide, despite its declining overall incidence. Although there are differences in incidence, etiology and pathological factors, most studies do not separately analyze cardia and noncardia gastric cancer. Surgery is the only potentially curative treatment for advanced, resectable gastric cancer, but locoregional relapse rate is high with a consequently poor prognosis. To improve survival, several preoperative and postoperative treatment strategies have been investigated. Whereas perioperative chemotherapy and postoperative chemoradiation (CRT) are considered standard therapy in the Western world, in Asia postoperative monochemotherapy with S-1 is often used. Several other therapeutic options, although generally not accepted as standard treatment, are postoperative combination chemotherapy, hyperthermic intraperitoneal chemotherapy and preoperative radiotherapy and CRT. Postoperative combination chemotherapy does show a statistically significant but clinically equivocal survival advantage in several meta-analyses. Hyperthermic intraperitoneal chemotherapy is mainly performed in Asia and is associated with a higher postoperative complication rate. Based on the currently available data, the use of postoperative radiotherapy alone and the use of intraoperative radiotherapy should not be advised in the treatment of resectable gastric cancer. Western randomized trials on gastric cancer are often hampered by slow or incomplete accrual. Reduction of toxicity for preoperative and especially postoperative treatment is essential for the ongoing improvement of gastric cancer care.
doi:10.1177/1756283X11410771
PMCID: PMC3263979  PMID: 22282708
gastric cancer; surgery; chemotherapy; radiotherapy; standard of care
7.  The CARTS study: Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery 
BMC Surgery  2011;11:34.
Background
The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer.
Methods/Design
Patients with a clinical T1-3 N0 M0 rectal adenocarcinoma below 10 cm from the anal verge will receive neoadjuvant chemoradiation therapy (25 fractions of 2 Gy with concurrent capecitabine). Transanal Endoscopic Microsurgery (TEM) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response.
Primary objective is to determine the number of patients with a (near) complete pathological response after chemoradiation therapy and TEM. Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality. A three-step analysis will be performed after 20, 33 and 55 patients to ensure the feasibility of this treatment protocol.
Discussion
The CARTS-study is one of the first prospective multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision. The CARTS study is registered at clinicaltrials.gov (NCT01273051)
doi:10.1186/1471-2482-11-34
PMCID: PMC3295682  PMID: 22171697
9.  Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS) 
BMC Cancer  2011;11:329.
Background
Radical surgery is the cornerstone in the treatment of resectable gastric cancer. The Intergroup 0116 and MAGIC trials have shown benefit of postoperative chemoradiation and perioperative chemotherapy, respectively. Since these trials cannot be compared directly, both regimens are evaluated prospectively in the CRITICS trial. This study aims to obtain an improved overall survival for patients treated with preoperative chemotherapy and surgery by incorporating radiotherapy concurrently with chemotherapy postoperatively.
Methods/design
In this phase III multicentre study, patients with resectable gastric cancer are treated with three cycles of preoperative ECC (epirubicin, cisplatin and capecitabine), followed by surgery with adequate lymph node dissection, and then either another three cycles of ECC or concurrent chemoradiation (45 Gy, cisplatin and capecitabine). Surgical, pathological, and radiotherapeutic quality control is performed. The primary endpoint is overall survival, secondary endpoints are disease-free survival (DFS), toxicity, health-related quality of life (HRQL), prediction of response, and recurrence risk assessed by genomic and expression profiling. Accrual for the CRITICS trial is from the Netherlands, Sweden, and Denmark, and more countries are invited to participate.
Conclusion
Results of this study will demonstrate whether the combination of preoperative chemotherapy and postoperative chemoradiotherapy will improve the clinical outcome of the current European standard of perioperative chemotherapy, and will therefore play a key role in the future management of patients with resectable gastric cancer.
Trial registration
clinicaltrials.gov NCT00407186
doi:10.1186/1471-2407-11-329
PMCID: PMC3175221  PMID: 21810227
10.  Digestive oncologist in the gastroenterology training curriculum 
Until the late 1980s, gastroenterology (GE) was considered a subspecialty of Internal Medicine. Today, GE also incorporates Hepatology. However, Digestive Oncology training is poorly defined in the Hepatogastroenterology (HGE)-curriculum. Therefore, a Digestive Oncology curriculum should be developed and this document might be a starting point for such a curriculum. HGE-specialists are increasingly resisting the paradigm in which they play only a diagnostic and technical role in the management of digestive tumors. We suggest minimum end-points in the standard HGE-curriculum for oncology, and recommend a focus year in the Netherlands for Digestive Oncology in the HGE-curriculum. To produce well-trained digestive oncologists, an advanced Digestive Oncology training program with specific qualifications in Digestive Oncology (2 years) has been developed. The schedule in Belgium includes a period of at least 6 mo to be spent in a medical oncology department. The goal of these programs remains the production of well-trained digestive oncologists. HGE specialists are part of the multidisciplinary oncological teams, and some have been administering chemotherapy in their countries for years. In this article, we provide a road map for the organization of a proper training in Digestive Oncology. We hope that the World Gastroenterology Organisation and other (inter)national societies will support the necessary certifications for this specific training in the HGE-curriculum.
doi:10.3748/wjg.v17.i9.1109
PMCID: PMC3063902  PMID: 21556128
Gastroenterology; Training; Digestive oncologist; Curriculum; Chemotherapy; Immunotherapy; Oncology; Targeted therapy
11.  Evaluating long-term attachment of two different endoclips in the human gastrointestinal tract 
AIM: To evaluate the long-term attachment of two types of endoclips in the human gastrointestinal tract.
METHODS: In this prospective observational study, endoclips were placed and followed-up during endoscopies or using fluoroscopic images as part of a prospective feasibility study evaluating external beam radiotherapy (EBRT, wk 1-3) followed by high dose rate brachytherapy (HDRBT with an endoluminal applicator once a week for 3 wk, wk 9-11) in medically inoperable rectal cancer patients. Initially, the type and number of endoclips were chosen randomly and later refined to 1 Resolution® clip (Microvasive) proximal and 2 Quickclips® (Olympus) distal to the tumor. Nine consecutive patients, included between September 2007 and August 2008 were analyzed. Retention rates were evaluated over three different observational periods [period 1: pre-HDRBT (wk -2-8), period 2: during HDRBT (wk 9-11) and period 3: post-HDRBT (wk 12-16)].
RESULTS: In this study, a total of 44 clips were placed during endoscopy, either at the beginning or at the end of period 1. The Resolution clip had a higher overall retention rate than the Quickclip (P = 0.01). After a median period of 81 d after placement (in period 1), long-term retention rates for the Resolution clip and Quickclip clip were 67% and 35% respectively.
CONCLUSION: The Resolution clip has a high retention rate and is useful in situations where long-term attachment to the human gastrointestinal mucosa is warranted.
doi:10.4253/wjge.v2.i10.344
PMCID: PMC2998819  PMID: 21160584
Endoclip; Radiotherapy; Retention rate; Cancer; Delineation
12.  Serum proteomics and disease-specific biomarkers of patients with advanced gastric cancer 
Oncology Letters  2010;1(2):327-333.
Gastric cancer is a commonly diagnosed solid tumor which is associated with a dismal prognosis making early diagnosis essential. Thus, this study aimed to identify novel biomarkers in gastric cancer. Serum of patients with advanced gastric cancer was collected according to a predefined schedule: prior to first-line chemotherapy with epirubicin (50 mg/m2, day 1), cisplatin (60 mg/m2, day 1) and capecitabine (1,000 mg/m2, twice daily on days 1–14). The serum was collected serially before the treatment cycles and then analyzed by SELDI-TOF MS. Normal control subjects were matched according to age, gender and serum collection. Serum proteomic mass spectrometry data of all subjects were processed using the tbimass R-package and compared. We analyzed i) whether proteomic profile changes were associated with a response to chemotherapy and survival, and ii) whether changes in proteomic profiles occurring during the time period of chemotherapy were associated with tumor response. In total, 82 patients with adenocarcinoma of the stomach (mean age 57 years, males 69.5%) were treated with a mean number of five chemotherapy cycles. The overall tumor response rate, complete and partial remission combined, was 37%, median time to progression was 7 months (95% CI, 6–8) and median overall survival 11 months (95% CI, 9.5–12). By comparing 77 serum samples of patients with normal matched controls, we identified 32 proteins which discriminated the two groups. By selecting the most differentiating proteins, we built a classification model that correctly categorized 81% of the gastric cancer patients and 90% of the normal controls. Furthermore, we found a statistically significant correlation between the pre-treatment intensity of serum amyloid-α (SAA) and overall survival in gastric cancer patients, whereby a low intensity of SAA predicted a longer patient survival. A classification model, based on the 32 most discriminating proteins differentiating gastric cancer from normal controls, correctly classified subjects with relatively high sensitivity and specificity.
doi:10.3892/ol_00000058
PMCID: PMC3436443  PMID: 22966303
proteomic; profile; gastric cancer; biomarker; prognostic
13.  Detection of Colorectal Cancer by Serum and Tissue Protein Profiling: A Prospective Study in a Population at Risk 
Biomarker Insights  2008;3:375-385.
Colorectal cancer (CRC) is the second most common cause of cancer-related death in Europe and its prognosis is largely dependent on stage at diagnosis. Currently, there are no suitable tumour markers for early detection of CRC. In a retrospective study we previously found discriminative CRC serum protein profiles with surface enhanced laser desorption ionisation—time of flight mass spectrometry (SELDI-TOF MS). We now aimed at prospective validation of these profiles. Additionally, we assessed their applicability for follow-up after surgery and investigated tissue protein profiles of patients with CRC and adenomatous polyps (AP). Serum and tissue samples were collected from patients without known malignancy with an indication for colonoscopy and patients with AP and CRC during colonoscopy. Serum samples of controls (CON; n = 359), patients with AP (n = 177) and CRC (n = 73), as well as tissue samples from AP (n = 52) and CRC (n = 47) were analysed as described previously. Peak intensities were compared by non-parametric testing. Discriminative power of differentially expressed proteins was assessed with support vector machines (SVM). We confirmed the decreased serum levels of apolipoprotein C-1 in CRC in the current population. No differences were observed between CON and AP. Apolipoprotein C-I levels did not change significantly within 1 month post-surgery, although a gradual return to normal levels was observed. Several proteins differed between AP and CRC tissue, among which a peak with similar mass as apolipoprotein C-1. This peak was increased in CRC compared to AP. Although we prospectively validated the serum decrease of apolipoprotein C-1 in CRC, serum protein profiles did not yield SVM classifiers with suitable sensitivity and specificity for classification of our patient groups.
PMCID: PMC2688344  PMID: 19578519
biomarkers; colorectal cancer; SELDI-TOF MS; validation
14.  Preoperative Chemoradiotherapy with Capecitabine and Oxaliplatin in Locally Advanced Rectal Cancer. A Phase I–II Multicenter Study of the Dutch Colorectal Cancer Group 
Annals of Surgical Oncology  2007;14(10):2773-2779.
Background
We studied the maximum tolerated dose (MTD) and efficacy of oxaliplatin added to capecitabine and radiotherapy (Capox-RT) as neoadjuvant therapy for rectal cancer.
Methods
T3-4 rectal cancer patients received escalating doses of oxaliplatin (day 1 and 29) with a fixed dose of capecitabine of 1000 mg/m2 twice daily (days 1–14, 25–38) added to RT with 50.4 Gy and surgery after 6–8 weeks. The MTD, determined during phase I, was used in the subsequent phase II, in which R0 resection rate (a negative circumferential resection margin) was the primary end point.
Results
Twenty-one patients were evaluable. In the phase I part, oxaliplatin at 85 mg/m2 was established as MTD. In phase II, the main toxicity was grade III diarrhea (18%). All patients underwent surgery, and 20 patients had a resectable tumor. An R0 was achieved in 17/21 patients, downstaging to T0-2 in 7/21 and a pCR in 2/21.
Conclusion
Combination of Capox-RT has an acceptable acute toxicity profile and a high R0 resection rate of 81% in locally advanced rectal cancer. However the pCR rate was low.
doi:10.1245/s10434-007-9396-6
PMCID: PMC2039827  PMID: 17653805
Rectal cancer; Radiotherapy; Oxaliplatin; Capecitabine; Chemoradiation; Phase I–II study

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