Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. METHODS: This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized. DISCUSSION: The multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. TRIAL REGISTRATION: Clinical Trials: NCT04927780. Registered June 16, 2021.

Serum sex hormone-binding globulin levels are reduced and inversely associated with intrahepatic lipid content and saturated fatty acid fraction in adult patients with glycogen storage disease type 1a.

PURPOSE: De novo lipogenesis has been inversely associated with serum sex hormone-binding globulin (SHBG) levels. However, the directionality of this association has remained uncertain. We, therefore, studied individuals with glycogen storage disease type 1a (GSD1a), who are characterized by a genetic defect in glucose-6-phosphatase resulting in increased rates of de novo lipogenesis, to assess the downstream effect on serum SHBG levels. METHODS: A case-control study comparing serum SHBG levels in patients with GSD1a (n = 10) and controls matched for age, sex, and BMI (n = 10). Intrahepatic lipid content and saturated fatty acid fraction were quantified by proton magnetic resonance spectroscopy. RESULTS: Serum SHBG levels were statistically significantly lower in patients with GSD1a compared to the controls (p = 0.041), while intrahepatic lipid content and intrahepatic saturated fatty acid fraction-a marker of de novo lipogenesis-were significantly higher in patients with GSD1a (p = 0.001 and p = 0.019, respectively). In addition, there was a statistically significant, inverse association of intrahepatic lipid content and saturated fatty acid fraction with serum SHBG levels in patients and controls combined (ß: - 0.28, 95% CI: - 0.47;- 0.09 and ß: - 0.02, 95% CI: - 0.04;- 0.01, respectively). CONCLUSION: Patients with GSD1a, who are characterized by genetically determined higher rates of de novo lipogenesis, have lower serum SHBG levels than controls.

89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer.

BACKGROUND: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment. PATIENTS AND METHODS: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUVmax) and expressed as geometric mean. Normal organ uptake was calculated as SUVmean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1. RESULTS: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUVmax did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUVmean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation. CONCLUSION: 89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.

Radiofrequency ablation and chemotherapy versus chemotherapy alone for locally advanced pancreatic cancer (PELICAN): study protocol for a randomized controlled trial.

BACKGROUND: Approximately 80% of patients with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy, of whom approximately 10% undergo a resection. Cohort studies investigating local tumor ablation with radiofrequency ablation (RFA) have reported a promising overall survival of 26-34 months when given in a multimodal setting. However, randomized controlled trials (RCTs) investigating the effect of RFA in combination with chemotherapy in patients with LAPC are lacking. METHODS: The "Pancreatic Locally Advanced Unresectable Cancer Ablation" (PELICAN) trial is an international multicenter superiority RCT, initiated by the Dutch Pancreatic Cancer Group (DPCG). All patients with LAPC according to DPCG criteria, who start with FOLFIRINOX or (nab-paclitaxel/)gemcitabine, are screened for eligibility. Restaging is performed after completion of four cycles of FOLFIRINOX or two cycles of (nab-paclitaxel/)gemcitabine (i.e., 2 months of treatment), and the results are assessed within a nationwide online expert panel. Eligible patients with RECIST stable disease or objective response, in whom resection is not feasible, are randomized to RFA followed by chemotherapy or chemotherapy alone. In total, 228 patients will be included in 16 centers in The Netherlands and four other European centers. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, RECIST response, CA 19.9 and CEA response, toxicity, quality of life, pain, costs, and immunomodulatory effects of RFA. DISCUSSION: The PELICAN RCT aims to assess whether the combination of chemotherapy and RFA improves the overall survival when compared to chemotherapy alone, in patients with LAPC with no progression of disease following 2 months of systemic treatment. TRIAL REGISTRATION: Dutch Trial Registry NL4997 . Registered on December 29, 2015. ClinicalTrials.gov NCT03690323 . Retrospectively registered on October 1, 2018.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Metformin Hydrochloride.

Data are examined regarding possible waiver of in vivo bioequivalence testing (i.e. biowaiver) for approval of metformin hydrochloride (metformin) immediate-release solid oral dosage forms. Data include metformin's Biopharmaceutics Classification System (BCS) properties, including potential excipient interactions. Metformin is a prototypical transporter-mediated drug and is highly soluble, but only 50% of an orally administered dose is absorbed from the gut. Therefore, metformin is a BCS Class III substance. A BCS-based approval approach for major changes to marketed products and new generics is admissible if test and reference dosage forms have the identical active pharmaceutical ingredient and if in vitro dissolution from both are very rapid (i.e. at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Recent International Council for Harmonisation BCS guidance indicates all excipients for Class III biowaivers are recommended to be qualitatively the same and quantitatively similar (except for preservatives, flavor agents, colorant, or capsule shell or film coating excipients). However, despite metformin being a prototypical transporter-mediated drug, there is no evidence that commonly used excipients impact metformin absorption, such that this restriction on excipients for BCS III drugs merits regulatory relief. Commonly used excipients in usual amounts are not likely to impact metformin absorption.

The treatment and survival of elderly patients with locally advanced pancreatic cancer: A post-hoc analysis of a multicenter registry.

BACKGROUND: The treatment options for patients with locally advanced pancreatic cancer (LAPC) have improved in recent years and consequently survival has increased. It is unknown, however, if elderly patients benefit from these improvements in therapy. With the ongoing aging of the patient population and an increasing incidence of pancreatic cancer, this patient group becomes more relevant. This study aims to clarify the association between increasing age, treatment and overall survival in patients with LAPC. METHODS: Post-hoc analysis of a multicenter registry including consecutive patients with LAPC, who were registered in 14 centers of the Dutch Pancreatic Cancer Group (April 2015-December 2017). Patients were divided in three groups according to age (<65, 65-74 and ≥75 years). Primary outcome was overall survival stratified by primary treatment strategy. Multivariable regression analyses were performed to adjust for possible confounders. RESULTS: Overall, 422 patients with LAPC were included; 162 patients (38%) aged <65 years, 182 patients (43%) aged 65-74 and 78 patients (19%) aged ≥75 years. Chemotherapy was administered in 86%, 81% and 50% of the patients in the different age groups (p<0.01). Median overall survival was 12, 11 and 7 months for the different age groups (p<0.01).Patients treated with chemotherapy showed comparable median overall survival of 13, 14 and 10 months for the different age groups (p=0.11). When adjusted for confounders, age was not associated with overall survival. CONCLUSION: Elderly patients are less likely to be treated with chemotherapy, but when treated with chemotherapy, their survival is comparable to younger patients.

Impact of nationwide enhanced implementation of best practices in pancreatic cancer care (PACAP-1): a multicenter stepped-wedge cluster randomized controlled trial.

BACKGROUND: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. METHODS/DESIGN: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. DISCUSSION: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018.

The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs.

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.

Long-term results of an intensive cognitive behavioral pain management program for patients with chronic low back pain: a concise report of an extended cohort with a minimum of 5-year follow-up.

PURPOSE: Treatment options for chronic low back pain (CLBP) include cognitive behavioral interventions. Most of these interventions only have small and short-lived effects. Using strict inclusion criteria for participation in an intensive combined physical and psychological program, encouraging effects were reported at 1-year follow-up. This study evaluates the long-term follow-up results of the same program. The hypothesis is that previously reported results are maintained. METHODS: Structured interviews were conducted in a prospective extended cohort with a minimum of 5-year follow-up in a similar fashion as in the 1-year follow-up report. The median follow-up in this cohort was 6.5 years. The extended cohort consisted of 277 patients (85% response). RESULTS: Outcomes include daily functioning, quality of life, current pain intensity, pain disturbance in daily activities and indicators of the use of pain medication and healthcare services. The previously reported positive 1-year follow-up results were maintained at a minimum of 5-year follow-up. Disability as measured with the Oswestry disability index (ODIv2.1a) decreased from 40 to 27 in the first year. This positive result was maintained at the 6.5-year follow-up with an ODI of 28. Pain intensity (NRS 0-100) improved from 60 to 39 in the first year, and at 6.5 years, this had further improved to 33. Improvement in quality of life (SF 36) at 1-year follow-up was maintained at 6.5-year follow-up, and healthcare consumption had decreased substantially as measured with doctor visits and analgesics used for CLBP. CONCLUSION: Selected and motivated patients with longstanding CLBP improve fast after an intensive combined physical and psychological program in daily functioning, pain and quality of life. Positive 1-year results are maintained, and healthcare utilization was still reduced at a minimum of 5-year follow-up. These slides can be retrieved under Electronic Supplementary Material.

Web-based personalised information and support for patients with a neuroendocrine tumour: randomised controlled trial.

BACKGROUND: Patients with a neuroendocrine tumour (NET) frequently have physical and psychosocial complaints. Aim of this study is to determine whether a web-based, personalised information and support system (WINS) reduces distress and/or improves patients' perception of and satisfaction with information received. METHODS: Patients with NET, stratified for those newly diagnosed (< 6 months, n = 28) and with a longer history of disease (n = 74), were randomised between standard care (n = 49) and intervention, consisting of access to WINS (n = 53). Primary outcome was change of distress and satisfaction with perceived information measured with the distress thermometer and problem list and the QoL questionnaire (QLQ)-INFO25. The intervention group also completed a questionnaire based on the technical acceptance model (TAM). RESULTS: We observed no difference in distress slope and slope of median global score on perceived information and satisfaction between the intervention and control group. Interestingly, 55% of patients wished to receive more information at baseline. CONCLUSIONS: In a population of NET patients, access to WINS did not improve indicators for distress, perception of information and satisfaction with information received, more than standard care only. Despite the need for more information, the WINS does not have added value to the information and care provided by health care professionals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02472678 ). Registered 6th Jan 2015. Retrospectively registered 1st May 2017.

Neoadjuvant chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: a feasibility and safety study.

BACKGROUND: Standard treatment for colorectal peritoneal carcinomatosis typically involves cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and if possible, postoperative adjuvant chemotherapy. However, a substantial percentage of patients never receive adjuvant chemotherapy because of postoperative complications. Neoadjuvant chemotherapy could be beneficial in this setting, so we assessed its feasibility and safety when used before cytoreductive surgery and HIPEC. METHODS: In this non-randomized, single-center, observational feasibility study, patients were scheduled to receive six cycles of capecitabine and oxaliplatin before cytoreductive surgery and HIPEC. Computed tomography was performed after the third and sixth chemotherapy cycles to evaluate tumor response, and patients underwent cytoreductive surgery and HIPEC if there were no pulmonary and/or hepatic metastases. Postoperative complications, graded according to the Clavien-Dindo classification, were compared with those of a historic control group that received postoperative adjuvant chemotherapy. RESULTS: Of the 14 patients included in the study, 4 and 3 had to terminate neoadjuvant chemotherapy early because of toxicity and tumor progression, respectively. Cytoreductive surgery and HIPEC were performed in eight patients, and the timing and severity of complications were comparable to those of patients in the historic control group treated without neoadjuvant chemotherapy. CONCLUSION: Patients with peritoneal metastases due to colorectal carcinoma can be treated safely with neoadjuvant chemotherapy before definitive therapy with cytoreductive surgery and HIPEC. TRIAL REGISTRATION NUMBER: NTR 3905, registered on 20th march, 2013, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3905.

The antibody-drug conjugate target landscape across a broad range of tumour types.

BACKGROUND: Antibody-drug conjugates (ADCs), consisting of an antibody designed against a specific target at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Because ADC tumour cell targets do not have to be drivers of tumour growth, ADCs are potentially relevant for a wide range of tumours currently lacking clear oncogenic drivers. Therefore, we aimed to define the landscape of ADC targets in a broad range of tumours. MATERIALS AND METHODS: PubMed and ClinicalTrials.gov were searched for ADCs that are or were evaluated in clinical trials. Gene expression profiles of 18 055 patient-derived tumour samples representing 60 tumour (sub)types and 3520 healthy tissue samples were collected from the public domain. Next, we applied Functional Genomic mRNA-profiling to predict per tumour type the overexpression rate at the protein level of ADC targets with healthy tissue samples as a reference. RESULTS: We identified 87 ADCs directed against 59 unique targets. A predicted overexpression rate of ≥ 10% of samples for multiple ADC targets was observed for high-incidence tumour types like breast cancer (n = 31 with n = 23 in triple negative breast cancer), colorectal cancer (n = 18), lung adenocarcinoma (n = 18), squamous cell lung cancer (n = 16) and prostate cancer (n = 5). In rare tumour types we observed, amongst others, a predicted overexpression rate of 55% of samples for CD22 and 55% for ENPP3 in adrenocortical carcinomas, 81% for CD74 and 81% for FGFR3 in osteosarcomas, and 95% for c-MET in uveal melanomas. CONCLUSION: This study provides a data-driven prioritization of clinically available ADCs directed against 59 unique targets across 60 tumour (sub)types. This comprehensive ADC target landscape can guide clinicians and drug developers which ADC is of potential interest for further evaluation in which tumour (sub)type.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Folic Acid.

This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate-release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the highest dose strength on the World Health Organization Essential Medicines List, the dose/solubility ratio calculated from solubility studies was higher than 250 mL, corresponding to a classification as "not highly soluble." Small, physiological doses of folic acid (≤320 µg) seem to be absorbed completely via active transport, but permeability data for higher doses of 1-5 mg are inconclusive. Following a conservative approach, folic acid is classified as a Biopharmaceutics Classification System class IV compound until more reliable data become available. Commensurate with its solubility characteristics, the results of dissolution studies indicated that none of the folic acid products evaluated showed rapid dissolution in media at pH 1.2 or 4.5. Therefore, according to the current criteria of the Biopharmaceutics Classification System, the biowaiver approval procedure cannot be recommended for immediate-release solid oral dosage forms containing folic acid.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate-release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme inhibitor enalaprilat. Enalapril as the maleate salt is shown to be highly soluble, but only 60%-70% of an orally administered dose of enalapril is absorbed from the gastrointestinal tract into the enterocytes. Consequently, enalapril maleate is a Biopharmaceutics Classification System class III substance. Because in situ conversion of the maleate salt to the sodium salt is sometimes used in production of the finished drug product, not every enalapril maleate-labeled finished product actually contains the maleate salt. Enalapril is not considered to have a narrow therapeutic index. With this background, a biowaiver-based approval procedure for new generic products or after major revisions to existing products is deemed acceptable, provided the in vitro dissolution of both test and reference preparation is very rapid (at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Additionally, the test and reference product must contain the identical active drug ingredient.

Effect of Extending the Original Eligibility Criteria for the CROSS Neoadjuvant Chemoradiotherapy on Toxicity and Survival in Esophageal Cancer.

BACKGROUND: Patients with curable esophageal cancer (EC) who proceed beyond the original Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) eligibility criteria are also treated with neoadjuvant chemoradiotherapy (nCRT). This study assessed the effect that extending the CROSS eligibility criteria for nCRT has on treatment-related toxicity and overall survival (OS) in EC. METHODS: The study enrolled 161 patients with locally advanced EC (T1N1-3/T2-4aN0-3/M0) treated with the CROSS schedule followed by esophagectomy. Group 1 consisted of 89 patients who met the CROSS criteria, and group 2 consisted of 72 patients who met the extended eligibility criteria, i.e. a tumor length greater than 8 cm (n = 24), more than 10% weight loss (n = 35), more than 2-4 cm extension in the stomach (n = 21), celiac lymph node metastasis (n = 13), and/or age over 75 years (n = 2). The study assessed the differences in nCRT-associated toxicity [National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3] and 90-day postoperative mortality. Moreover, the prognostic value for OS was assessed with multivariate Cox regression analysis. RESULTS: No difference was found in nCRT-associated toxicity (P = 0.117), postoperative complications (P = 0.783), and 90-day mortality (P = 0.492). The OS differed significantly (P = 0.004), with a median of 37.3 months [95% confidence interval (CI), 10.4-64.2 months] for group 1 and 17.2 months (95% CI 13.8-20.7 months) for group 2. Pathologic N stage (P = 0.023), pathologic T stage (P = 0.043), and group 2 (P = 0.008) were independent prognostic factors for OS. CONCLUSIONS: Extension of the CROSS study eligibility criteria for nCRT did not affect nCRT-associated toxicity, postoperative complications, and postoperative mortality, but was prognostic for OS.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ribavirin.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing ribavirin are reviewed. Ribavirin is highly soluble, but its permeability characteristics are not well defined. Therefore according to the Biopharmaceutical Classification System, and taking a "worst case" approach, ribavirin should be assigned to class III. As ribavirin is transported across the brush border membrane of the human jejunum by hCNT2, it shows saturable uptake in the intestine. However, no common excipients have been shown to compete for ribavirin absorption, nor have problems with BE of immediate release ribavirin formulations containing different excipients and produced by different manufacturing methods been reported in the open literature. So the risk of bioinequivalence caused by these factors appears to be low. Ribavirin is considered a narrow therapeutic index drug, as judged by comparing the minimum effective concentration and minimum toxic concentrations in blood. Although ribavirin would not be eligible for approval via a Biopharmaceutical Classification System-based biowaiver procedure according to today's guidances due to its narrow therapeutic index, the risks of biowaiving should be weighed against the considerable risks associated with studying BE of ribavirin products in healthy subjects.

Rectal and colon cancer: Not just a different anatomic site.

Due to differences in anatomy, primary rectal and colon cancer require different staging procedures, different neo-adjuvant treatment and different surgical approaches. For example, neoadjuvant radiotherapy or chemoradiotherapy is administered solely for rectal cancer. Neoadjuvant therapy and total mesorectal excision for rectal cancer might be responsible in part for the differing effect of adjuvant systemic treatment on overall survival, which is more evident in colon cancer than in rectal cancer. Apart from anatomic divergences, rectal and colon cancer also differ in their embryological origin and metastatic patterns. Moreover, they harbor a different composition of drug targets, such as v-raf murine sarcoma viral oncogene homolog B (BRAF), which is preferentially mutated in proximal colon cancers, and the epidermal growth factor receptor (EGFR), which is prevalently amplified or overexpressed in distal colorectal cancers. Despite their differences in metastatic pattern, composition of drug targets and earlier local treatment, metastatic rectal and colon cancer are, however, commonly regarded as one entity and are treated alike. In this review, we focused on rectal cancer and its biological and clinical differences and similarities relative to colon cancer. These aspects are crucial because they influence the current staging and treatment of these cancers, and might influence the design of future trials with targeted drugs.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Nifedipine.

Literature data relevant to the biopharmaceutical properties of the active pharmaceutical ingredient (API) nifedipine are reviewed to evaluate whether a waiver of in vivo bioequivalence (BE) testing of immediate-release (IR) dosage forms formulated as tablets and soft gelatin capsules is warranted. Nifedipine's solubility and permeability, its therapeutic use and index, pharmacokinetics, food drug interactions, and any reported BE/bioavailability problems were all taken into consideration. Solubility and BA data indicate conclusively that nifedipine is a class II substance of biopharmaceutics classification system (BCS) and that the formulation of drug product plays a key role on the dissolution characteristics of the API. Therefore, a BCS biowaiver-based approval of nifedipine containing IR oral dosage forms cannot be recommended for reformulated/new multisource drug products or for major scale-up and postapproval changes to the existing drug products.