Background: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This approval was based on significantly improved median overall survival compared with 5-FU/LV alone (6.1 vs 4.2 months; hazard ratio [HR], 0.67) in the global phase 3 NAPOLI-1 trial. Here, we report the final survival analysis and baseline characteristics associated with long-term survivors (survival of !1 year) in the NAPOLI-1 trial. Patients and methods: Patients with mPDAC were randomised to receive nal-IRI þ 5-FU/LV (n Z 117), nal-IRI (n Z 151), or 5-FU/LV (n Z 149) for the first 4 weeks of 6-week cycles. Baseline characteristics and efficacy in the overall population were compared with those in patients who survived !1 year. Through 16th November 2015, 382 overall survival events had occurred.

Nowadays, complementary and alternative medicine (CAM) is popular all over the world. Billions of dollars are spent in this booming business. For several reasons, young, female, educated, and higher socioeconomic class cancer patients, in particular, have shown interest in these agents. Unfortunately, besides direct (and sometimes serious) side effects, several CAM ingredients are capable of interfering with the metabolism of concurrently used drugs, which may render the therapeutic outcome of the subscribed drug unpredictable. In the case of anticancer drugs, with their usually narrow therapeutic window, this may have dramatic consequences and can lead to unacceptable toxicities in some cases or decreased therapeutic activity in others. Therefore, cancer patients should be warned for these possible interactions and be advised to discuss CAM use openly with their treating physician. The general concept that natural products are harmless should thus be changed into a more realistic and responsible attitude. A tightened legislation and regulation (including Internet advertising and sales) could play a crucial role in this awareness process. This should finally enable safe exploration of the potential advantageous aspects of CAM, while living with cancer. The Oncologist 2006;11:732-741

LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Describe how and why BSA-based dosing was implemented into oncology. 2. Discuss if flat-fixed dosing of adults has advantages over BSA-based dosing in terms of interpatient pharmacokinetic variation of anticancer drugs, efficiency, and costs. 3. Explain which alternative dosing strategies for BSA-based dosing may have potential, leading to a minimum of adverse events and superior therapeutic outcome.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTThe current practice of using body-surface area (BSA) in dosing anticancer agents was implemented in clinical oncology half a century ago. By correcting for BSA, it was generally assumed that cancer patients would receive a dose of a particular cytotoxic drug associated with an acceptable degree of toxicities without reducing the agent's therapeutic effect. More recently, doubt has arisen to this hypothesis, and for many drugs, the effects of BSA on the pharmacokinetics of these agents have therefore been studied retrospectively. In (by far) most cases, use of BSA does not reduce the interindividual variation in the pharmacokinetics of adults, and thus, a logical rationale for further use of this tool in dosing adults is lacking. As a result, alternative dosing strategies have been proposed in order to replace BSA-based dosing. Flat-fixed dosing regimens have been suggested, thereby avoiding potential dose calculation mistakes. As flat-fixed dosing does not typically lead to greater pharmacokinetic variability, it does not seem worse than using BSA-based dosing. While it provides a simplification, it can, however, be questioned whether to call this an improvement or not. Classic cytotoxic agents are known for their relatively narrow therapeutic window. This means that "low" doses of these drugs may not be effective, while "high" doses may be (very) toxic for the patient. Therefore, the optimal dose should be somewhere in between, thereby leading to the best possible treatment, which means yielding maximal therapeutic effect given tolerable and manageable toxicities. Based on the theory that large patients have a larger volume of distribution and a higher metabolizing capacity, it is assumed that those patients need to be dosed higher than smaller patients to reach equal drug concentrations. For this reason, traditionally, the administered dose is typically adjusted to the body-surface area (BSA) of the individual patient. BSA was originally calculated using a formula based on length and weight developed by DuBois and DuBois in 1916 [1] from an investigation that involved only nine individuals (Table 1) [1][2][3][4][5]. Although validation of the derived formula was not performed initially [3, 4], the use of BSA was incorporated into animal studies for the purpose of allometric scaling, and in the 1950s, BSA-based dosing was introduced into pediatric oncology [6,7]. Without further study, its use was also incorporated int...

Purpose: The ATP-binding cassette transporter ABCG2 (breast cancer resistance protein) is an efflux protein that plays a role in host detoxification of various xenobiotic substrates, including the irinotecan metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). The ABCG2 421C>A polymorphism has been associated with reduced protein expression and altered function in vitro. The aim of this study was to evaluate the ethnic distribution and potential functional consequence of the ABCG2 421C>A genotype in cancer patients treated with irinotecan.Experimental Design: ABCG2 genotyping was performed using Pyrosequencing on DNA from 88 American Caucasians, 94 African Americans, 938 Africans, and 95 Han Chinese, as well as in 84 European Caucasian patients treated with irinotecan undergoing additional blood sampling for pharmacokinetic studies.Results: Significant differences in allele frequencies were observed between the given world populations (P < 0.001), the variant allele being most common in the Han Chinese population with a frequency as high as 34%. The mean area under the curve of irinotecan and SN-38 were 19,851 and 639 ng ؋ hour/mL, respectively. The frequency of the variant allele (10.7%) was in line with results in American Caucasians. No significant changes in irinotecan pharmacokinetics were observed in relation to the ABCG2 421C>A genotype, although one of two homozygous variant allele carriers showed extensive accumulation of SN-38 and SN-38 glucuronide.Conclusions: The ABCG2 421C>A polymorphism appears to play a limited role in the disposition of irinotecan in European Caucasians. It is likely that the contribution of this genetic variant is obscured by a functional role of other polymorphic proteins.

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