Dose Regimen Rationale for Panitumumab in Cancer Patients: To Be Based on Body Weight or Not.

INTRODUCTION: Body weight can affect exposure, safety and efficacy of antibody-based therapies; sometimes these effects may not be clinically relevant. Panitumumab is approved for wild-type RAS metastatic colorectal cancer, using a body weight-based dosing regimen. Recently, a report cited fixed-dose usage of panitumumab, rather than approved body weight-based dosing. The current work evaluates optimal dosing regimen scientifically based on clinical data, modeling and simulation. Herein, we assessed the effect of fixed and body weight-based dosing on panitumumab pharmacokinetics to determine which approach resulted in the least interpatient pharmacokinetic variability. PATIENTS AND METHODS: From the Vectibix program, 352 patients enrolled in three studies were evaluated; they had received panitumumab (body weight-based dose: 6 mg/kg every 2 weeks) and had pharmacokinetic (maximum serum [Cmax] and trough [Cmin] concentrations) and body weight data available. Additionally, concentration-time profiles at fixed (480 mg) and body weight-based doses (6 mg/kg) were simulated using a population pharmacokinetics model developed from 1200 patients. RESULTS: After administration of panitumumab 6 mg/kg, Cmax and Cmin increased with increasing body weight; the mean Cmax and Cmin for patients weighing <65 kg (lower quartile) were 23% and 30% lower, respectively, than for those weighing >88 kg (upper quartile). The simulated area under the concentration-time curve (AUC) data also indicated that overall panitumumab exposure increased with increasing body weight for the body weight-based regimen. When AUC was simulated for a fixed dose (480 mg), the opposite effect was observed. Over the range of body weights, interpatient variability in simulated AUC was lower for the weight-based dose (29%) than for the fixed dose (34%). CONCLUSION: Results demonstrate that the weight-based dose (6 mg/kg) reduced variability in panitumumab exposure across the range of body weights compared with the fixed-dose approach, indicating that a body weight-based approach is the recommended patient dosing strategy.

Impact of Primary Tumour Location and Early Tumour Shrinkage on Outcomes in Patients with RAS Wild-Type Metastatic Colorectal Cancer Following First-Line FOLFIRI Plus Panitumumab.

OBJECTIVE: Data from a trial of first-line panitumumab plus FOLFIRI (folinic acid, infusional 5-fluorouracil and irinotecan) in metastatic colorectal cancer were retrospectively analysed to investigate the effects of primary tumour location and early tumour shrinkage on outcomes. METHODS: Patients with RAS wild-type metastatic colorectal cancer from a single-arm, open-label phase II study (NCT00508404) were included. Tumours located from the splenic flexure to rectum and in the caecum to transverse colon were defined as left- and right-sided, respectively. Baseline characteristics were summarised by primary tumour location and the effects of primary tumour location on outcomes-including objective response rate, resection rate, depth of response, duration of response and progression-free survival-were analysed. Progression-free survival and objective response rate were analysed by early tumour shrinkage status. RESULTS: Primary tumour location was determined in 52/69 (75%) patients with RAS wild-type metastatic colorectal cancer; 45 (87%) had left-sided disease. Median progression-free survival was longer in patients with left-sided tumours (11.2 vs. 7.2 months for right-sided disease) and more of these patients experienced early tumour shrinkage ≥ 30% (53% vs. 29%). Early tumour shrinkage ≥ 30% was associated with improved progression-free survival irrespective of tumour location. More patients with early tumour shrinkage ≥ 30% achieved a partial or complete response. Objective response rate, duration of response, depth of response and resection rates were similar in patients with left- and right-sided tumours. CONCLUSIONS: This analysis has confirmed a prognostic effect of primary tumour location in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab plus FOLFIRI. Early tumour shrinkage was associated with improved progression-free survival irrespective of tumour location. In right-sided disease, early tumour shrinkage may identify a subgroup of patients who might respond to panitumumab. CLINICALTRIALS. GOV IDENTIFIER: NCT00508404.

Improved body weight and performance status and reduced serum PGE2 levels after nutritional intervention with a specific medical food in newly diagnosed patients with esophageal cancer or adenocarcinoma of the gastro-esophageal junction.

BACKGROUND: The majority of cancer patients loses weight and becomes malnourished during the course of their disease. Metabolic alterations and reduced immune competence lead to wasting and an increased risk of infectious complications. In the present study, the effect of a nutritionally complete medical food, which is high in protein and leucine and enriched with fish oil and specific oligosaccharides, was investigated on immune function, nutritional status, and inflammation in patients with esophageal cancer and compared with routine care. METHODS: In this exploratory double-blind study, 64 newly diagnosed esophageal cancer patients were randomized. All patients received dietary counselling and dietary advice. In the Active group, all patients received the specific medical food for 4 weeks before the start of anticancer therapy. In the routine care control arm, patients with <5% weight loss received a non-caloric placebo product, and patients with weight loss ≥5% received an iso-caloric control product to secure blinding of the study. The required study parameters of body weight and performance status were recorded at baseline and after 4 weeks of nutritional intervention, and patients were asked to complete quality of life questionnaires. In addition, blood samples were taken for the measurement of several immune, nutritional, and safety-parameters. RESULTS: No effect of the specific nutritional intervention could be detected on ex vivo stimulations of blood mononuclear cells. By contrast, body weight was significantly increased (P < 0.05) and ECOG performance status was improved after intervention with the specific medical food (P < 0.05). In addition, serum Prostaglandin E2 (PGE2) levels were significantly decreased in the specific medical food group and increased in the control group (P = 0.002). CONCLUSIONS: Nutritional intervention with the specific medical food significantly increased body weight and improved performance status compared with routine care in newly diagnosed esophageal cancer patients. This effect was accompanied by significantly reduced serum PGE2 levels.

Supplementation with a fish oil-enriched, high-protein medical food leads to rapid incorporation of EPA into white blood cells and modulates immune responses within one week in healthy men and women.

Immune modulatory effects of EPA and DHA are well described. However, these fatty acids must be effectively incorporated into cell membrane phospholipids to modify cell function. To address the absence of human data regarding short-term incorporation, the present study investigated the incorporation of EPA and DHA into white blood cells (WBC) at different time points during 1 wk of supplementation with a medical food, which is high in protein and leucine and enriched with fish oil and specific oligosaccharides. Additionally, the effects on ex vivo immune function were determined. In a single-arm, open label study, 12 healthy men and women consumed 2 × 200 mL of medical food providing 2.4 g EPA, 1.2 g DHA, 39.7 g protein (including 4.4 g L-leucine), and 5.6 g oligosaccharides daily. Blood samples were taken at d 0 (baseline), 1, 2, 4, and 7. Within 1 d of nutritional intervention, the percentage of EPA in phospholipids of WBC increased from 0.5% at baseline to 1.3% (P < 0.001). After 1 wk, the percentage of EPA rose to 2.8% (P < 0.001). Additionally, the production of proinflammatory cytokines in LPS-stimulated whole blood cultures was significantly increased within 1 wk. Nutritional supplementation with a fish oil-enriched medical food significantly increased the percentage of EPA in phospholipids of WBC within 1 wk. Simultaneously, ex vivo immune responsiveness to LPS increased significantly. These results hold promise for novel applications such as fast-acting nutritional interventions in cancer patients, which should be investigated in future studies.

Effects of intervention with sulindac and inulin/VSL#3 on mucosal and luminal factors in the pouch of patients with familial adenomatous polyposis.

BACKGROUND/AIM: In order to define future chemoprevention strategies for adenomas or carcinomas in the pouch of patients with familial adenomatous polyposis (FAP), a 4-weeks intervention with (1) sulindac, (2) inulin/VSL#3, and (3) sulindac/inulin/VSL#3 was performed on 17 patients with FAP in a single center intervention study. Primary endpoints were the risk parameters cell proliferation and glutathione S-transferase (GST) detoxification capacity in the pouch mucosa; secondary endpoints were the short chain fatty acid (SCFA) contents, pH, and cytotoxicity of fecal water. METHODS: Before the start and at the end of each 4-week intervention period, six biopsies of the pouch were taken and feces was collected during 24 h. Cell proliferation and GST enzyme activity was assessed in the biopsies and pH, SCFA contents, and cytotoxicity were assessed in the fecal water fraction. The three interventions (sulindac, inulin/VSL#3, sulindac/inulin/VSL#3) were compared with the Mann-Whitney U test. RESULTS: Cell proliferation was lower after sulindac or VSL#3/inulin, the combination treatment with sulindac/inulin/VSL#3 showed the opposite. GST enzyme activity was increased after sulindac or VSL#3/inulin, the combination treatment showed the opposite effect. However, no significance was reached in all these measures. Cytotoxicity, pH, and SCFA content of fecal water showed no differences at all among the three treatment groups. CONCLUSION: Our study revealed non-significant decreased cell proliferation and increased detoxification capacity after treatment with sulindac or VSL#3/inulin; however, combining both regimens did not show an additional effect.

COX-2 polymorphisms in patients with familial adenomatous polyposis.

Cyclooxygenase-2 (COX-2) is an enzyme involved in the synthesis of prostaglandins and thromboxanes, which are regulators of biologic processes such as inflammation, cell proliferation, and angiogenesis. COX-2 has been found overexpressed in (pre)malignant tissues and may be relevant to cancer development. We investigated whether functional genetic polymorphisms in COX-2 may have a risk-modifying effect on duodenal adenomatosis in patients with familial adenomatous polyposis (FAP). Blood from 85 patients with FAP and 218 age- and sex-matched healthy subjects was investigated for the presence of two functional promoter region polymorphisms (-1195G-->A and -765G-->C) in COX-2. Logistic regression analysis revealed an overrepresentation of the -1195GG genotype compared to the -1195AA genotype in patients with FAP (odds ratio = 2.81; 95% CI = 1.00-7.91, p = 0.042). No associations between single COX-2 polymorphisms or COX-2 haplotype were found when patients were evaluated according to their Spigelman stage. The predicted low COX-2 expression genotype -1195GG was found overrepresented in the patients with FAP. The COX-2 genotypes showed no association with the severity of duodenal adenomatosis.

Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas.

Primary carcinomas of the small intestine are rare and the mechanism of their pathogenesis is poorly understood. Patients with familial adenomatous polyposis (FAP) have a high risk of developing duodenal carcinomas. The aim of this study is to gain more insight into the development of duodenal carcinomas. Therefore, five FAP-related duodenal carcinomas were characterized for chromosomal and methylation alterations, which were compared to those observed in sporadic duodenal carcinomas. Comparative genomic hybridization (CGH) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was performed in 10 primary sporadic and five primary FAP-related duodenal carcinomas. In the FAP-related carcinomas, frequent gains were observed on chromosomes 8, 17 and 19, whereas in sporadic carcinomas they occurred on chromosomes 8, 12, 13 and 20. In 60% of the sporadic carcinomas, gains in the regions of chromosome 12 were observed which were absent in the FAP-related carcinomas (P=0.04). Hypermethylation was observed in the immunoglobulin superfamily genes member 4 (IGSF4), TIMP metallopeptidase inhibitor 3 (TIMP3), Estrogen receptor 1 (ESR1), adenomatous polyposis coli (APC), H-cadherin (CDH13) and paired box gene 6 (PAX6) genes. Hypermethylation of PAX6 was only observed in FAP-related carcinomas (3/5) and not in sporadic carcinomas (P=0.02). In conclusion, in contrast to sporadic duodenal carcinomas, gains on chromosome 12 were not observed in duodenal carcinomas of patients with FAP. Identification of the genes in these regions of chromosome 12 could lead to a better understanding of the carcinogenesis pathways leading to sporadic and FAP-related duodenal carcinomas. Furthermore, hypermethylation seems to be a general feature of both FAP-related duodenal carcinomas as well as sporadic duodenal carcinomas with the exception of the PAX6 gene, which is methylated only in FAP-related carcinomas.

Loss of extracellular E-cadherin in the normal mucosa of duodenum and colon of patients with familial adenomatous polyposis.

The duodenum is the main site for (pre-) malignant extracolonic manifestations in patients with familial adenomatous polyposis (FAP). Changes in the E-cadherin/beta-catenin complex play a pivotal role in the development of malignancies. Loss of E-cadherin has been described in association with loss of SMAD4. To elucidate the pathways leading to the development of duodenal adenomas in patients with FAP, the distributions of E-cadherin, SMAD4, and beta-catenin were analyzed. Furthermore, differences between the duodenum and colon were evaluated. Normal FAP duodenum (n = 13) and FAP duodenal adenomas (n = 50; total, 21 patients) were compared with non-FAP duodenal adenomas (n = 7) and normal non-FAP duodenum (n = 15) by immunohistochemical staining for extracellular and intracellular E-cadherin, beta-catenin, and SMAD4. Colonic biopsies of 10 patients with FAP were also studied, as well as non-FAP colonic adenomas (n = 26) and non-FAP normal colon (n = 12). Compared with the intracellular component of E-cadherin that was present in all cases, a significant loss of extracellular E-cadherin was observed in both duodenal and colonic adenomas and normal tissue of patients with FAP. Nuclear localization of beta-catenin was more often observed in duodenal FAP adenomas compared with non-FAP adenomas. Loss of nuclear SMAD4 was seen in the duodenum and, to a higher degree, in the colon of patients with FAP, as well as non-FAP patients. The loss of extracellular E-cadherin in the normal duodenal and colonic mucosa of patients with FAP might play a role in the high susceptibility of these tissues for (pre-) malignant transformation.

Low detoxification capacity in the ileal pouch mucosa of patients with ulcerative colitis.

BACKGROUND: An ileal pouch-anal anastomosis has become the most widely accepted procedure for surgical treatment of patients with ulcerative colitis (UC). The primary function of the ileum within the pouch changes from absorption to storage. Malignancies have been described in the pouch mucosa. The detoxifying glutathione S-transferase (GST) enzymes are involved in the mucosal protection against toxins and carcinogens. Levels of GSTs are much higher in the ileum as compared with the colon. The adaptation of the ileal pouch mucosa into a more colon-like phenotype possibly influences the activity and levels of GST. This study compares the detoxification capacity of GST of the afferent ileal limb mucosa with the ileal pouch mucosa of patients with UC. METHODS: Biopsies from normal-appearing mucosa from the ileal pouch and the ileal afferent limb were obtained from 18 patients with UC. GST isoforms were quantified by immunoblotting. GST activity was measured spectrophotometrically, and glutathione and cysteine levels were determined by high-performance liquid chromatography. RESULTS: The GST activity and GSTA1+A2 levels were significantly lower in the pouch compared with the afferent ileal limb of patients with UC, whereas the GSTP1 levels were higher in the pouch. No differences were observed in the levels of GSTM1, GSTT1, glutathione, or cysteine. CONCLUSIONS: The lower GST detoxification activity in the pouch mucosa of patients with UC may result in higher levels of toxins and carcinogens and thus partly contribute to the risk of developing malignancies in the pouch.

Expression of CD45RB functionally distinguishes intestinal T lymphocytes in inflammatory bowel disease.

The importance of CD45RB expression on T cells was already shown in mice where CD45RB(high) expression determines pathogenic potential. In this study, we analyzed the expression of CD45RA, CD45RB, and CD45RO on CD4(+) T lymphocytes in the intestinal mucosa and in the circulation of patients with inflammatory bowel disease (IBD). In addition, we studied the cytokine profile of these cells. In the circulation, virtually all CD4(+)CD45RB(high) T cells expressed the naive marker CD45RA, and circulating CD4(+)CD45RB(low) cells expressed the memory marker CD45RO in IBD patients and a control patient population. In contrast, the intestinal CD4(+) CD45RB(high) T cells are in normal controls for 90% CD45RO(+). However, in IBD, 27.7% [Crohn's disease (CD)] and 49% [ulcerative colitis (UC)] of the intestinal CD4(+) CD45RB(high) T cells are CD45RA(+). This special CD4CD45RA(+) T cell in IBD can be found in the lamina propria as well as in lymphoid follicles (confocal laser-scanning microscopy). The CD4(+)CD45RB(high) T lymphocytes produce significantly less interleukin (IL)-10 and IL-4 and produce more tumor necrosis factor alpha than CD45RB(low) T lymphocytes in control patients. CD4(+)CD45RB(low) T cells from IBD patients produced less IL-10 than CD4(+)CD45RB(low) T lymphocytes of controls, and interferon-gamma production by both T lymphocyte subsets was decreased in IBD. These data indicate that CD and UC are characterized by an influx of CD4(+)CD45RB(high) T lymphocytes. These CD4(+)CD45RB(high) T lymphocytes seem to be important in the pathogenesis of IBD, as they produce more proinflammatory cytokines and less anti-inflammatory cytokines compared with CD4(+)CD45RB(low) T lymphocytes.