dosing of anticancer agents in adults.pdf

Official reprint from UpToDatewww.uptodate.com 2016 UpToDate

AuthorsKeith D Eaton, MD, PhDGary H Lyman, MD, MPH, FASCO,FACP, FRCP (Edin)

Section EditorPaul J Hesketh, MD

Deputy EditorSadhna R Vora, MD

Disclosures: Keith D Eaton, MD, PhD Nothing to disclose. Gary H Lyman, MD, MPH, FASCO, FACP, FRCP (Edin) Nothing to disclose.Paul J Hesketh, MD Nothing to disclose. Sadhna R Vora, MD Nothing to disclose.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a

Dosing of anticancer agents in adults

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Dec 2015. | This topic last updated: Jul 08, 2015.INTRODUCTION Most anticancer agents have a steep dose response relationship and a narrow therapeutic index.Small variations in the administered dose can lead to severe and life-threatening toxicity in some individuals andunderdosing in others, which may compromise cancer outcomes. Proper dose selection is of great importance,particularly in individuals with potentially curable diseases such as lymphoma or testicular cancer, and in the setting ofadjuvant treatment (eg, breast and colon cancer). Selection of the right dose is complicated by the fact that individualshave a highly variable capacity to metabolize and eliminate drugs.

The most relevant pharmacokinetic parameter for drug exposure is the area under the curve (AUC) of plasmaconcentration x time following a single dose. During drug development, drug level sampling at multiple time points helpsdefine the relationship between drug administration and the AUC. The AUC is influenced by external factors such asdrug dose and schedule, as well as patient-specific factors such as age, gender, height, weight, concomitantmedications and habits, genetics (inherited variations in drug metabolizing enzymes, drug transporters, and/or drugtargets), and clearance (which depends upon renal and hepatic function). As a result, there is much interindividualvariation in the AUC following a single dose of a drug [1]. For most anticancer agents, attempts to minimizeinterindividual variation have been limited to normalizing doses based on body size (weight, body surface area [BSA]).This topic will address issues related to dosing of anticancer agents in adults, including BSA-based dosing, which isused for most cytotoxic agents, weight-based dosing (eg, as is done for some cytotoxic agents such as melphalan andseveral therapeutic monoclonal antibodies), fixed dose prescribing (as is done for oral targeted agents such as tyrosinekinase inhibitors [TKIs]), AUC-based dosing (as is done for carboplatin), and pharmacogenetic as well aspharmacokinetic-guided dosing, including therapeutic drug monitoring. Dosing of anticancer agents in patients with renalor hepatic failure, and issues pertinent to dosing in the elderly are discussed in detail elsewhere. (See "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency" and "Chemotherapy hepatotoxicity anddose modification in patients with liver disease" and "Systemic chemotherapy for cancer in elderly persons".)DEFINING OPTIMAL DOSE

Conventional cytotoxic agents Appropriate dosing for cytotoxic anticancer agents has been largely determinedfrom prospective and retrospective studies in which the goal was to maximize efficacy and minimize toxicity. Thestarting dose for conventional cytotoxic agents in phase I studies has generally been based upon animal studies, wheredoses are usually escalated until the LD10 is reached (the dose that results in lethality in 10 percent of the treatedanimals). By convention, in human phase I studies, the first dose employed has been one-tenth of the LD10.Based upon the theory and intuitive belief that larger patients have a larger volume of distribution and a highermetabolizing capacity, it has been assumed that they require more drug to induce the same effects. In an attempt tominimize interindividual variation, dosing for most anticancer agents has generally been normalized using mg of drug perm of body surface area (BSA), which is calculated using a patient's height and weight.However, normalization of doses based upon BSA does not account for most of the interindividual variation in drug

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exposure. For cytotoxic agents, interindividual variability in drug clearance based upon the area under the curve (AUC)is expressed as the percent coefficient of variation (which is the standard deviation divided by the mean, times 100).Values of 25 to 70 percent are very common despite the use of BSA for individual dose calculation. (See 'Body surfacearea (BSA)-based dosing' below.)

Importance of dose intensity Historical data on optimal dosing for most existing cytotoxic agents have beengenerated using dose considerations that are derived from the maximum tolerated dose concept, irrespective of anindividuals genetic constitution. The concept is that cytotoxic chemotherapy agents are administered at the maximumdose that an individual can tolerate before the onset of severe and even life-threatening toxicity. This dose, which isderived from phase I trials, is one dose level below that associated with dose-limiting toxicity and is termed themaximum tolerated dose. This dose is used for subsequent phase II and III trials testing antitumor efficacy.

This approach is supported by a series of retrospective analyses indicating that the greater the dose intensity of anindividual drug, the better the outcome. Dose intensity, defined as the amount of chemotherapy delivered per unit time,has been recognized as an important determinant of efficacy of cytotoxic chemotherapy in theoretical models, in vitrostudies, and clinical trials [2,3]. The clinical data are strongest for breast cancer, in which prospective studies havedemonstrated inferior outcomes for patients who receive lower than intended dose intensity [4-7] and better outcomeswith dose-dense as compared with non dose-dense therapy [8]. (See "Adjuvant chemotherapy for hormone receptor-positive or negative, HER2-negative breast cancer", section on 'Importance of chemotherapy schedule'.)Another line of evidence supporting the importance of dose intensity in oncologic outcomes is derived from the use ofhematologic toxicity as a surrogate marker for efficacy and the delivery of effective chemotherapy doses.Retrospective analyses of clinical trials in lung [9], breast [7], and ovarian [10] cancer demonstrate inferior outcomes inpatients who lack significant hematologic toxicity from myelosuppressive chemotherapy. The practice of giving higherdrug doses to individuals who lack significant treatment-related toxicity seems logical given the correlation between lackof toxicity and low drug concentrations [11-14]. However, despite its logical appeal, there have been limited trialstesting this concept, and it has not been widely adopted or endorsed in clinical practice. In contrast, the practice ofreducing doses based upon excess hematologic or other toxicity (eg, neurologic, gastrointestinal, or dermatologic) iswidely accepted. In general, dose reduction for individual agents has been based upon criteria that were used in clinicaltrials, often an arbitrarily selected percentage of the initial starting dose.

Given the limited amount of high-quality evidence in this area, additional prospective trials are needed to assesswhether drug dosing guided by the occurrence of toxic effects (pharmacodynamics) could improve efficacy of standardcytotoxic regimens.

Newer targeted therapies There has been a paradigm shift in oncologic treatment away from the development ofclassic intravenously administered cytotoxic chemotherapy drugs toward so-called targeted therapies such as kinaseinhibitors that are often administered orally on an ongoing daily basis, and therapeutic monoclonal antibodies, which aredosed parenterally. Dose-limiting toxicities for targeted therapies are often markedly different from those of cytotoxicchemotherapy agents. In addition, when compared with classic cytotoxic agents, these novel agents show differentrelationships between levels of exposure, particularly exposure over time, and pharmacologic effects on the moleculardrug target. Finally, these agents are characterized by unique mechanisms of action, and many are highly specific forsingle or multiple key cellular biological pathways implicated in carcinogenesis. Anticancer activity levels for therapiestargeted against defined cellular and molecular markers significantly improve if patient pool enrichment is carried outbased upon the presence of that specific marker in tumor tissue. Examples include tumor HER2 expression to select fortreatment with trastuzumab, and the use of imatinib for patients with chronic myelogenous leukemia (CML) harboring anoncogenic BCR-ABL translocation. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on'HER2-directed therapy' and "Cellular and molecular biology of chronic myeloid leukemia", section on 'The BCR-ABL1fusion protein'.)

More recently, given the trajectory towards personalized medicine, pharmacogenetic andpharmacokinetic-based dosing strategies have received more attention, though these approaches are not yet inwidespread use. (See 'Pharmacogenetics, pharmacokinetics, and therapeutic drug monitoring (TDM)' below and"Treatment of adrenocortical carcinoma", section on 'Suggested regimen'.)


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Whether the maximum tolerated dose paradigm is valid for anticancer agents with an apparent selectivity for acancer-specific target (targeted therapies) is unclear. For these drugs, multiple approaches are being explored todevelop alternative strategies for the identification of an optimal dose as opposed to the maximum tolerated dose[15]. At present, all of the orally active kinase inhibitors (most of which are tyrosine kinase inhibitors [TKIs]), as well asvemurafenib, dabrafenib, and trametinib (inhibitors of the BRAF serine/threonine protein kinase), are dosed using afixed dose schedule for all patients regardless of weight or BSA. In contrast, some therapeutic monoclonal antibodiesare dosed using a fixed dose schedule (eg, alemtuzumab, ofatumumab, pertuzumab), while others are dosed on amg/kg basis (ipilimumab, bevacizumab, trastuzumab, panitumumab, brentuximab, ramucirumab), and still others aredosed according to BSA (rituximab, cetuximab). (See 'Fixed-dose prescribing' below and 'Weight-based dosing' belowand 'Orally active small molecule kinase inhibitors' below.)Although these drugs offer specific important advantages over conventional cytotoxic agents, they are still afflicted bysome of the same problems, including extensive interindividual variability in clearance (figure 1) [16] and a narrowtherapeutic window. Although it is imperative to ensure that sufficiently high local drug concentrations are reached so asto maximize efficacy without exacerbating toxicity, the optimal way to achieve this goal is not yet apparent [15]. Forsome drugs, biologic activity at the intended target can be used to select an appropriate dose. As an example, with theinvestigational PARP [Poly (ADP)-Ribose Polymerase] inhibitor olaparib, biologic activity can be demonstrated byinhibition of the enzyme in tumor tissue. In phase I studies, biologic activity of olaparib was demonstrated withcontinuous twice daily dosing at dose levels above approximately 100 mg; a dose of 200 mg twice daily was chosen forphase II testing, although the maximum tolerated dose of 600 mg twice daily was much higher [17,18]. Dosecomparison studies are underway to select the optimal dose for pivotal trials.

For other drugs in which a biomarker of activity is not available or easily accessible, the best way to optimize dosing isnot established. Therapeutic drug monitoring has not been widely studied or endorsed, though this might be changing[19,20]. (See 'Therapeutic drug monitoring' below.)A major problem is the lack of dose comparison studies, which do not fit into the current framework of clinical drugtesting (ie, phase I, II, and III trials). At least partly in response to the emergence of these novel treatment strategies,the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have enabled the execution ofso-called phase 0 studies, one type of which is a clinical trial to study pharmacologically relevant doses to explore thepharmacologic effects of a test molecule or the pharmacodynamic effect of a new drug that is expected to correlatewith its clinical activity [21].BODY SURFACE AREA (BSA)-BASED DOSING In an attempt to minimize the amount of interindividual variation indrug exposure in the calculation of effective drug doses, various methods have been developed, primarily based uponbody size descriptors. BSA-based dosing has been widely adopted for most cytotoxic agents and some therapeuticmonoclonal antibodies (rituximab, cetuximab), despite the lack of rigorous validation and even though its ability toreduce interindividual variation in drug clearance is limited. No superior dosing scheme has been demonstrated, with theexception of AUC-based dosing for carboplatin. (See 'AUC-based dosing' below.)In the 1950s, investigators originally proposed normalizing doses of chemotherapeutic agents by using BSA, which hadbeen noted to explain the variation in metabolic rates of animals across a range of species, including humans, and tocorrelate linearly with blood volume [22-24]. In an early retrospective study conducted in the 1950s, doses ofmechlorethamine and methotrexate per unit of body weight were higher for smaller animals than for larger animals, andfor children than in adults, while doses per unit of body surface area were nearly similar for all species and for humansof all ages [25]. Subsequently, despite the lack of rigorous validation (and an increasing number of publications thatquestion the validity of BSA-based dosing for a number of conventional cytotoxic agents [26-36]), BSA-basedchemotherapy dosing has become a de facto standard for determining chemotherapy dosing for most cytotoxic agents[37-39] and some therapeutic monoclonal antibodies (rituximab, cetuximab).Unfortunately, for many anticancer agents, normalizing doses according to the BSA has only a limited ability to reduceinterindividual variability in drug clearance after a single dose of an anticancer agent [22]. In a study of 1012 adultpatients with cancer receiving one of six different cytotoxic chemotherapy drugs (cisplatin, docetaxel, paclitaxel,doxorubicin, topotecan, and irinotecan), clearance of all six drugs was poorly correlated with BSA (figure 2) [40]. The


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correlation coefficients (r values) of the regression curves representing the contribution of BSA to interindividualvariation in clearance ranged from 0.17 to 0.44 (r = 0.03 to 0.19). However, the precision for reaching the target AUCwas significantly better for BSA dosing compared with fixed dosing for four of the six drugs.

No method has eliminated or even significantly reduced interindividual variation in drug clearance when dosing drugsaccording to BSA. Many oncologists have a false sense of precision based upon BSA dosing when, in fact,interindividual variation for most drugs (both conventional cytotoxic, as well as novel oral agents) exceeds 30 percent(figure 1) [16], and the range of clearance among individuals can vary 4- to 10-fold [11].No alternate body-size measures (including lean body mass [LBM], ideal body weight, body mass index [BMI]) havereliably performed better than the BSA in reducing the interindividual variability [41,42]. One study found that for avariety of therapeutic drugs, LBM was the best size descriptor for clearance of chronically dosed drugs [43]. The LBMhas also been proposed as a potentially superior body size measure for anticancer agents [44], but a proper scientificrationale for the use of LBM or any other body size measure other than BSA is lacking [22,45].Algorithms for calculating BSA In 1916, the first formula (the Du Bois method) for estimating BSA in humans waspublished [46]. Despite only nine subjects being studied, this formula is relatively accurate for normal weight individualsand is still in use (calculator 1).Various formulae have subsequently been developed to estimate BSA using height and weight. These are listed in thetable (table 1), and compared graphically in the figure (figure 3). The Mosteller formula is the easiest to remember andcalculate (calculator 2) [47].Over the range of typical weights and heights, commonly used BSA formulae do not vary significantly from each other(figure 3). As an example, even for overweight patients, the Mosteller and Du Bois formulae differ by only 3 percent[48]. Given this fact, and the absence of trial data suggesting superiority of any specific formula, an expert panelconvened by the American Society of Clinical Oncology (ASCO) concluded that any of the formulae is acceptable whencalculating doses of anticancer agents according to BSA [49].Notably, individuals with very high body mass index (BMI) have been poorly represented in the cohorts used togenerate these formulae. Despite the limited data, the BSA estimates from these formulae seem to differ moresubstantially in obese (BMI >30 kg/m ) and morbidly obese (BMI >40 kg/m ) individuals. In one study that included anobese cohort, all common formulas underestimated BSA for obese individuals [50]For persons >80 kg, the Livingstonequation had a 0.83 0.92 percent error in estimating BSA, whereas the Du Bois equation had a 12.27 1.23 percenterror, and the Gehan equation had a -6.53 0.99 percent error. Although this study is arguably the only estimator forBSA derived from a cohort of obese individuals, it has not been used to estimate the variance in chemotherapy dosesthat would result from use of each of the BSA formulas in obese individuals. Although a firm recommendation cannot bemade for any of the formulae for calculating a BSA-based dose of anticancer agents in obese patients, the Mostellerformula is the easiest to calculate and remember and provides estimates approximately in the middle of otherestimates. It is also the most commonly used formula in practice and in clinical trials. (See 'Overweight/obese patients'below.)

Overweight/obese patients Obesity is associated with worse cancer outcomes, which may be due, in part, tounderdosing through the practice of using less than actual body weight to calculate BSA or capping doses of cytotoxicchemotherapy agents. There are no data to suggest that obese patients dosed based on their actual body weight haveincreased toxicity, while there are data indicating that underdosing is associated with inferior outcomes. In keeping withguidelines from the ASCO, we recommend that actual body weight be used for the BSA calculation when dosingcytotoxic chemotherapy drugs based on BSA, especially when the intent of therapy is cure [49]. Otherrecommendations for chemotherapy treatment in obese patients from the ASCO expert panel are outlined in the table(table 2).Over the past several decades, the obesity epidemic has made its impact in oncology. Overweight and obeseindividuals (as defined according to BMI (calculator 3)) have higher rates of both cancer incidence and cancer-relatedmortality [51]. The reasons for this are multifactorial, but one likely contributor to the higher mortality rates described inoverweight/obese patients with cancer is the systematic underdosing of anticancer agents, with a substantial proportion

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of obese patients receiving reduced doses because of the use of ideal or adjusted ideal body weight or capped dosesrather than doses calculated according to actual weight [52-57]. As the prevalence of obesity has increased (accordingto projections from the World Health Organization [WHO], by 2015 more than 700 million adults worldwide will beobese [58]), awareness of this problem has grown, as reflected in practice guidelines addressing this issue [49,59,60].Overweight and obese patients often receive chemotherapy doses that are less than recommended because drugdoses are based upon a weight that is below their actual body weight [56]. A nationwide survey of chemotherapydosing in Australia found that only 6 percent of respondents routinely used actual body weight in BSA calculations forobese patients, with the majority capping the dose or using ideal body weight [54].The adverse impact of such underdosing on cancer outcomes can be illustrated by the following studies:

However, it is not clear that the inferior outcomes associated with obesity can be entirely explained by lowerchemotherapy doses. In a study of National Surgical Adjuvant Breast and Bowel Project (NSABP) colon cancer trials,obese individuals (BMI >35 kg/m ) had a poorer overall survival (HR 1.28, 95% CI 1.04-1.57) [67]. Dose capping at aBSA of 2.0 m was common, with 55 percent of the obese and 73 percent of the very obese patients having a cappeddose compared with 7 percent of normal weight patients. However, dose capping did not explain the association of highBMI with worse outcome.

One concern is that dosing of obese patients according to actual body weight might lead to excessive toxicity. Thisissue was addressed in a systematic review and meta-analysis of all studies that compared toxicity and efficacy of fullweight-based chemotherapy in obese and normal weight cancer patients [68]. Hematologic treatment-related toxicitywas significantly less in obese as compared with normal weight patients (odds ratio [OR] 0.73, 95% CI 0.55-0.98)while nonhematologic toxicity was similar (OR 0.98, 95% CI 0.76-1.26). Survival was not adversely affected whenobese patients were dosed according to actual body weight.

Given the mounting data correlating underdosing with inferior outcomes in obese patients, ASCO convened an expertpanel to study the appropriate dosing of anticancer agents [49]. The expert panel recommended using actual bodyweight for BSA calculations in obese patients receiving cytotoxic chemotherapy, particularly when the goal of treatmentis cure. They recommended that clinicians follow the same recommendations for dose reduction regardless of obesitystatus for all patients and that consideration be given to resuming full weight-based doses in subsequent cycles,particularly if a possible cause of the toxicity (eg, renal or hepatic insufficiency) is identified. The panel alsorecommended the use of fixed dosing only with selected cytotoxic agents (ie, bleomycin and carboplatin), and thatdoses of vincristine be capped at 2 mg when used as a part of the CHOP (cyclophosphamide, doxorubicin, vincristine,prednisone) and CVP (cyclophosphamide, vincristine, prednisone) regimens, primarily because of neurotoxicityconcerns. These and other key recommendations of the expert panel are outlined in the table (table 2).Limitations of the guidelines are that data were specific to certain cancers (breast, ovarian, colon, and lung) and werederived from retrospective studies. However, the conclusions of the review were consistent across studies. Therecommendations did not address dosing for novel targeted agents such as tyrosine kinase inhibitors (TKIs),immunotherapies, or monoclonal antibodies.

Underweight patients Although less data are available than in the setting of obesity, we suggest using actualbody weight for calculation of chemotherapy doses for underweight patients. However, among patients with weight lossand/or sarcopenia, organ function and performance status should be taken into consideration when dosing cytotoxicchemotherapy.

Underweight patients are relatively rare in the general population but are over-represented in the cancer population.

An analysis of the effect of BMI on survival in operable breast cancer found that BMI >30 kg/m adverselyimpacted overall survival (hazard ratio [HR] 1.25, p

Weight loss is a hallmark of cancer-associated cachexia, which is common among patients with advanced disease.(See "Pathogenesis, clinical features, and assessment of cancer cachexia".)Weight loss is associated with a worse prognosis in many malignancies including colon, breast, and lung cancer:

An underappreciated problem is that sarcopenia (defined as loss of skeletal muscle mass) is common among cancerpatients even with normal- or obese-range BMI. In some cases, sarcopenia is treatment-related (eg, fluoropyrimidines,sorafenib, androgen-deprivation therapy). As an example, in a study of 55 women with metastatic breast cancer whowere undergoing capecitabine treatment, 25 percent were sarcopenic by CT criteria [70]. Whereas most people withcachexia are sarcopenic, most sarcopenic individuals are not considered cachectic.

Sarcopenia is also associated with higher rates of treatment-related toxicity and inferior outcomes [70-73]. Asexamples:

Because sarcopenia is an adverse prognostic feature in the absence of treatment, it is difficult to separate out theadverse impact of chemotherapy doses on outcomes.

In contrast to the situation for obese patients, there are few data on the optimal weight that should be used for dosingcalculations. Proposals to prospectively use anthropomorphic measurements, electric impedance, and/or CT scans tomeasure body composition and chemotherapy dosing have not been rigorously studied. Lean body mass (LBM), whenused as a scalar for dosing chemotherapy, is typically not measured but inferred from formulae, which may not berepresentative of the population of persons with cancer. Body composition is likely more important than BMI, but usingLBM formulae derived from individuals without cancer may lead to erroneous conclusions.

In the absence of data for alternate dosing, our recommendation is to use actual body weight. Using the ideal bodyweight would result in a higher dose and would likely result in excess toxicity. However, among patients with weight lossand/or sarcopenia, organ function and performance status should be taken into consideration when dosing cytotoxicchemotherapy.

WEIGHT-BASED DOSING In addition to some therapeutic monoclonal antibodies, weight-based dosing is used fora few cytotoxic agents, including cladribine, melphalan, and arsenic. In the absence of data suggesting increasedtoxicity for underweight or obese individuals receiving weight-based dosing, doses should be based upon actual bodyweight.

Although uncommon, certain cytotoxic drugs are calculated based on weight rather than body surface area (BSA) inadult patients with cancer. This is largely based on how the drugs were initially developed. Examples include:

One study assessed gastrointestinal and lung cancer patients for cachexia by several methods (history of weightloss, muscle index, and computed tomography [CT] assessment) and found that cachexia was an adverseprognostic factor regardless of BMI [69].

Another study of 141 underweight patients (BMI

In addition, several therapeutic monoclonal antibodies are also dosed according to weight, including ipilimumab,bevacizumab, trastuzumab, panitumumab, brentuximab, and ramucirumab.

Rationale For conventional cytotoxics, there is no rationale for weight-based dosing other than historical precedent.For therapeutic monoclonal antibodies, however, there is rationale.

For large proteins (>100,000 Daltons), the US Food and Drug Administration (FDA) recommends that starting dose becalculated by weight and not BSA [74], as these drugs are not cleared through the normal renal or hepatic mechanismsbut through intracellular catabolism with nonlinear clearance. Allometric scaling models based upon body size have notgenerally been successful in predicting clearance of high molecular weight proteins in humans. At least some datasuggest that fixed dosing and weight-based dosing perform similarly across a range of therapeutic monoclonalantibodies, with fixed dosing being better for some antibodies, and weight-based dosing better for others [75]. Theseauthors suggest that first in human studies be performed using fixed doses with a full assessment of body size effect onpharmacokinetic and pharmacodynamic variability thereafter to determine the optimal dose for phase III trials.

Dosing for extremes There are no data suggesting increased toxicity for underweight or obese individuals receivingweight-based oncologic therapeutics dosed by their actual weight. Thus, in the absence of data for harm, doses shouldbe based on actual body weight.

FIXED-DOSE PRESCRIBING Fixed-dose prescribing does not take body size into account. While this is normativefor non-oncologic drugs, it is rarely used in cytotoxic chemotherapy:

On the other hand, fixed-dose prescribing is the usual method of dosing for oral targeted therapy.

Orally active small molecule kinase inhibitors For anticancer agents with an apparent selectivity for a cancer-specific target (such as tyrosine kinase inhibitors [TKIs]; BRAF serine threonine kinase inhibitors such as vemurafenib,dabrafenib, and trametinib; and inhibitors of the mammalian Target of Rapamycin [mTOR]), the best way to determinethe optimal dose is unclear. At present, fixed doses are used for all patients regardless of weight or BSA, even thoughthis approach is associated with a wide spread of plasma concentrations following standard dose regimens andsubstantial interindividual variability at the end of the dosing interval (trough concentration).Given the lack of reduction of interindividual variation with weight- or BSA-based dosing and high interindividual variationin early clinical studies, as well as the convenience and simplicity of fixed dosing, all orally active targeted therapies,including TKIs, other kinase inhibitors, and mTOR inhibitors, have used fixed-dosing schemes. However, these standarddosing regimens rarely result in comparable circulating concentrations of the active drug in all patients. It is increasinglyapparent that variability in response to newer targeted drugs is influenced not only by genetic heterogeneity of drugtargets that determine tumor sensitivity, but also by the pharmacokinetic background of the patient (eg, cytochromeP450 enzymes, oral absorption, and environmental factors that influence pharmacokinetics), as well as adherence tothe regimen [76]. The vast majority of targeted drugs are characterized by a wide spread of plasma concentrationsfollowing standard dose regimens, with interindividual variability at the end of the dosing interval (trough concentration)

internationally

Melphalan both weight-based and BSA-based dosing are used for the treatment of patients with multiplemyeloma

Vincristine is typically dosed at 1.4 mg/m but may be capped at 2 mg to avoid neurotoxicity; for most adultpatients, this amounts to a fixed dose. The 2012 American Society of Clinical Oncology (ASCO) expert panelrecommended that vincristine doses be capped at 2 mg when used as part of the CHOP (cyclophosphamide,doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) regimens [49]. (See"Treatment protocols for lymphoma".)

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Bleomycin is dosed according to body surface area (BSA) in regimens used to treat Hodgkin lymphoma, butdosed at a fixed level in testicular cancer due to concern about pulmonary toxicity. (See "Overview of thetreatment of testicular germ cell tumors" and "Treatment protocols for germ cell tumors" and "Bleomycin-inducedlung injury".)


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of up to 23-fold [19]. It is estimated that as many as 45 percent of patients are underdosed [77], yet there is noaccepted a priori way to assign an optimized dose to an individual patient.

Adherence to treatment and bioavailability are major issues:

There are also data to suggest that limited dosing options (due to pill sizes, which force large dose reductions fortoxicity) have affected outcomes of comparative clinical trials and also compromise efficacy of TKIs in clinical practice[87], although in many cases the reduced dose levels have remained above the threshold of biologic activity for the drug[88,89].Investigators have experimented with titrating doses to toxicity, building upon the observation that patients with target-related toxicity from TKIs, such as skin rash for epidermal growth factor receptor (EGFR) TKIs and hypertension forvascular endothelial growth factor (VEGF) TKIs, might have improved outcomes. Despite the rationale for this inpatients treated with some EGFR inhibitors such as the anti-EGFR therapeutic monoclonal antibody cetuximab formetastatic colorectal cancer, trials suggest that this dosing strategy does not significantly improve outcomes with othertargeted drugs, such as anti-EGFR TKIs (eg, erlotinib [90-92]) or TKIs targeting the vascular endothelial growth factor,compared with historical controls. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinicaltrials", section on 'Cutaneous toxicity' and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovasculareffects", section on 'Association with antitumor efficacy'.)AUC-BASED DOSING As described above, the area under the curve (AUC) of plasma concentration versus time isthe most relevant measure of drug exposure. AUC-based dosing is applicable for drugs that are cleared throughglomerular filtration, like carboplatin, because there is a strong correlation between carboplatin clearance and creatinineclearance [93-95]. AUC-based dosing is not applicable to most other anticancer agents (with the possible exception ofpemetrexed) because there are no characteristics (either alone or in combination) that can be used to predict drugclearance because elimination of the drug involves several pathways [96,97].Carboplatin The importance of glomerular filtration to the metabolism and excretion of carboplatin is emphasized byits usual dosing schema, which is based upon an estimate of the glomerular filtration rate (GFR) and the desired levelof drug exposure, according to the AUC of concentration x time (AUC, mg/mL x min).Using the desired target AUC (which typically varies between 5 and 7 mg/mL x min) and the estimated GFR, the doseof carboplatin is then calculated by use of the Calvert formula: Total carboplatin dose, mg = Target AUC x (estimatedcreatinine clearance + 25). Because of potential changes in weight or renal function, this calculation should be repeatedprior to each administered course of carboplatin.

Given the poor correlation between GFR and body surface area (BSA) [98], AUC-based dosing for carboplatinrepresented a significant success in reducing interindividual variation. This dosing scheme was developed eight years

Although oral administration provides the convenience of self-administration at home, the evidence suggests thatadherence to oral cancer therapies is far from optimal, putting patients at risk for adverse outcomes [78-81]. Asan example, for patients with chronic myelogenous leukemia who are treated with imatinib for several years, pooradherence is associated with a poor response, and it may be the predominant reason for an inadequate molecularresponse [80,81].

The solubility of many TKIs is pH-dependent, and an elevated gastric pH may decrease bioavailability. Stronginteractions are noted with antacids and other drugs that alter the pH of the stomach (particularly for pazopanib,dasatinib, and nilotinib).

Drugs with low water solubility and high cell membrane permeability, such as TKIs, are particularly susceptible tofood effects, especially when a high fat meal (HF) is consumed. The most striking example is lapatinib, which hasa 150 percent increase in exposure (area under the curve [AUC]) with food [82,83]. Other kinase inhibitors withsignificant food effects include erlotinib, pazopanib, and nilotinib [84-86]. The US Food and Drug Administration(FDA)-approved manufacturers product information recommends that these drugs be taken on an emptystomach.


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after the introduction of carboplatin, and in this study, the r = 0.886 (r = 0.785) was much better than previousBSA-based dosing schemes, representing a true advancement in reducing interindividual variability for this drug [93,99].The Calvert formula was developed based upon accurate measurement of GFR using the clearance of 51-Chromium-labeled EDTA (51-Cr EDTA) [93]. In most cases, GFR is estimated using the serum creatinine, and calculatedaccording to the Cockcroft-Gault equation (calculator 4). However, others suggest use of the Chronic Kidney DiseaseEpidemiology Collaboration (CKD-EPI) equation due to greater accuracy [100], although this has not been seen in allstudies [101,102]. (See "Assessment of kidney function", section on 'Estimation equations'.)Some clinicians (particularly in the field of gynecologic oncology) have preferred to estimate the creatinine clearanceusing the Jelliffe formula, which is not based upon weight or BSA [103-106]. This is because carboplatin dosing wasbased upon the Jelliffe formula in many of the trials that established carboplatin treatment for gynecologic cancers.However, in February 2011, the Gynecologic Oncology Group (GOG) changed their policies for carboplatin dosecalculation to recommend that estimated creatinine clearance be calculated by the Cockcroft-Gault method in allpatients. A more extensive discussion of GFR estimation equations is provided elsewhere. (See "Assessment of kidneyfunction", section on 'Estimation equations'.)The following issues are relevant to the carboplatin dose calculation:

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Total carboplatin dose is calculated in mg, not mg/m . 2

Maximum GFR The accuracy of dosing using a calculated rather than a directly measured GFR has beenquestioned [107]. Nevertheless, this is a standard approach.

When using an estimate instead of direct measurement of the GFR to calculate the carboplatin dose using theCalvert formula, calibration of the creatinine assay may impact dosing. In the United States, as of the end of2010, all laboratories must use a creatinine method that has calibration that is traceable to an Isotope DilutionMass Spectrometry (IDMS) reference measurement procedure [108]. However, this gives lower creatinine resultsthan the older measurement procedures used to derive the Calvert formula and, hence, higher estimates of theGFR. This could result in higher calculated carboplatin doses and may potentially result in increased toxicities.

The GOG now recommends that creatinine clearance be estimated using a minimum value for serum creatinine of0.7 mg/dL. Furthermore, if an estimated GFR based upon measured serum creatinine is used in the Calvertformula, the US Food and Drug Administration (FDA) recommends limiting the maximal GFR for the calculation to125 mL/min [109]. This recommendation does not apply if the GFR is directly measured. The GOG has nowmandated a similar cap for patients on their carboplatin trials (including trials conducted in the setting of potentiallycurable disease).For practical purposes, this means that maximal allowed doses of carboplatin are:

AUC 6 = 900 mg

AUC 5 = 750 mg

AUC 4 = 600 mg

Obese patients Another point of unresolved controversy is the appropriate weight to use when calculating theestimated GFR [110,111]. The original Cockcroft-Gault formula to estimate GFR used actual body weight, butnone of the patients was obese. Most clinicians use actual body weight in the Cockcroft-Gault formula fornon-obese patients, although institutional practice varies. However, the use of actual body weight in theCockcroft-Gault calculation can result in an overestimate of the GFR and a higher than needed carboplatin dose inobese individuals [111].

Among the methods suggested to calculate the appropriate dose of carboplatin in obese patients are the use ofadjusted rather than actual body weight to calculate the GFR (as recommended by the GOG) [110,112], use ofthe Jelliffe formula (which is not based upon weight or BSA), and the use of a flat dosing strategy based upon an


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PHARMACOGENETICS, PHARMACOKINETICS, AND THERAPEUTIC DRUG MONITORING (TDM) Thecombined use of therapeutic drug monitoring (as a phenotypic approach) and genotyping of drug metabolic capacity iscurrently considered to be the most sophisticated way to individualize dosage for drugs in which the clinical effects aredifficult to evaluate, such as anticancer agents. However, the use of pharmacogenetic testing to select initial doses hasnot been widely endorsed or adopted, and at present, the only cytotoxic agent for which pharmacokinetic-guided dosingis in widespread use is mitotane. (See 'Therapeutic drug monitoring' below.)Variation in body size does not adequately explain the majority of interindividual pharmacokinetic variability for mostanticancer agents. The term pharmacokinetics (PK) refers to the processes by which a drug is handled by the body,which are grouped into the following phases known as ADME:

The most relevant pharmacokinetic parameter used to characterize drug exposure is the area under the curve (AUC) ofplasma concentration x time, which can be estimated from drug level sampling at multiple time points. Although TDM isan accepted way to guide dosing of several agents with large interindividual pharmacokinetic variation in the noncancersetting (notably, antibiotics such as aminoglycosides and vancomycin, anticonvulsants, immunosuppressant drugs,lithium), this approach has not been established in general oncology practice (with the only exception being high-dosemethotrexate, and even then, TDM is used to manage toxicity and not individualize drug doses). (See 'Therapeutic drugmonitoring' below and "Therapeutic use and toxicity of high-dose methotrexate", section on 'Leucovorin administration'.)Drug clearance is inversely proportional to the AUC and may be influenced by the following factors:

Pharmacogenetics The rationale for pharmacogenetic studies is to investigate genes that can predictresponsiveness to a specific drug so as to increase the number of responders and decrease the number of subjectsaffected by adverse drug reactions. Despite known polymorphisms in both drug metabolizing and transporting proteinsthat influence drug exposure and pharmacokinetics in patients receiving anticancer agents, and the availability of testingfor many of these polymorphisms, genotyping has not become widespread or widely accepted for any of these drugclasses. The causes are multifactorial and include the relative rarity of these conditions, the fact that factors other than

estimate of the population carboplatin clearance (140 mL/min) for overweight patients with normal renal function[110]. As an example, if a carboplatin AUC of 5 mg min/mL is desired, an appropriate dose would be 5 x 140 =700 mg.

The optimal weight to use for calculating carboplatin by the Calvert formula was not addressed in the AmericanSociety of Clinical Oncology (ASCO) guideline [49]. The GOG recommends that actual weight be used forestimation of the GFR when using the Cockcroft-Gault equation as long as patients have a body mass index(BMI) of

inheritance of high-risk polymorphisms affect variability in drug response, the cost and inconvenience of testing, andmost importantly, a lack of data from clinical trials demonstrating a convincing difference in outcomes from the use ofpharmacogenetic testing.

Drug metabolism Several inherited polymorphisms in drug metabolizing enzymes that impact oncologictherapeutics have been identified, as described below. However, to date, the translation of pharmacogeneticparameters into clinical practice of medical oncology has been surprisingly disappointing, and none of these tests iswidely endorsed or used.

Fluoropyrimidines, DPD, and TYMS variants To avoid the risk of severe and potentially fatal reactions, themanufacturers of both fluorouracil (FU) and capecitabine recommend that the drugs are contraindicated in patients withknown deficiency in the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). A test (TheraGuide 5-FU) iscommercially available to detect the most common high-risk polymorphisms in DPD, as well as polymorphisms in asecond enzyme associated with fluoropyrimidine toxicity, thymidylate synthase (TYMS). (See "Enterotoxicity ofchemotherapeutic agents", section on 'Predictive markers'.)Use of the TheraGuide 5-FU assay is appropriate in any patient experiencing severe toxicity after receiving afluoropyrimidine-containing regimen. However, given the low frequency of finding a predictive allele and the fact thatpatients who lack one of these high-risk variants may still suffer grade 3 or 4 FU-related toxicity, preemptive genetictesting of all patients due to receiving a fluoropyrimidine in order to identify those with DPD deficiency is controversialand not widely practiced. This assay is only useful to stratify patients into categories of risk for severe toxicity, andthere are no data to suggest that it is of benefit in selecting the appropriate initial dose of a fluoropyrimidine. (See"Enterotoxicity of chemotherapeutic agents", section on 'Pharmacogenetic testing for DPYD and TYMS variants'.)

UGT1A1 polymorphisms and irinotecan Individuals who are homozygous for the UGT1A1*28 allele are atincreased risk for neutropenia and diarrhea following treatment with irinotecan. Genetic testing for the presence of theUGT1A1*28 allele is available (the Invader UGT1A1 Molecular Assay), and the US Food and Drug Administration(FDA)-approved label recommends testing, with reduced initial irinotecan doses in those who are homozygous forUGT1A1*28 to reduce the likelihood of dose-limiting neutropenia. However, routine preemptive use of this assay in allpatients who are to receive irinotecan is not widely accepted. Whether initial dose reduction improves outcomes forUGT1A1*28 homozygotes and the precise dose reduction that is warranted in this patient population remaincontroversial areas; in addition, inheritance of UGT1A1*28 polymorphisms seems to account for only a fraction of theobserved variability in irinotecan toxicity. (See "Systemic chemotherapy for metastatic colorectal cancer: Completedclinical trials", section on 'Pharmacokinetic variability'.)Several authors have concluded that body surface area (BSA) is unrelated to irinotecan clearance and metabolism [31],and the development of alternative dosing strategies has been recommended to reduce the marked interindividualvariation in drug exposure that results when the drug is dosed according to BSA [113,114].The active form of irinotecan (SN-38) is metabolized by the polymorphic enzyme UGT1A1. Intratumoral enzymaticactivity is reduced in individuals who inherit genetic polymorphisms such as the UGT1A1*28 allele (also known as TAindel or UGT1A1 7/7). Approximately 10 percent of the North American population is homozygous for the UGT1A1*28allele (which is responsible for Gilbert's syndrome); an additional 40 percent are heterozygotes [115-117]. (See "Gilbertsyndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction", section on 'Pathogenesis'.)Initial reports suggested that UGT1A1*28 homozygotes (and heterozygotes to a lesser degree) were at high risk foririnotecan-related gastrointestinal (GI) toxicity and neutropenia [116,118-122]. However, more data indicate that themagnitude of the problem (particularly the association with worse diarrhea) was not as great as initially suspected[117,119,123-125].Early studies and a meta-analysis suggested that the effect was dose dependent and not seen in patients receiving lowdoses of irinotecan (100 to 125 mg/m weekly [124]); however, a later meta-analysis concluded that inheritance ofUGT1A1*28 was associated with an increased risk of neutropenia at all doses [126]. However, the relative risk (RR) forneutropenia at doses 250 mg/m was significantly higher (RR 7.0, 95% CI 3.10-16.78) than that for lower doses (80to 145 mg/m weekly, RR 2.43, 95% CI 1.34 to 4.39).

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2

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In 2005, the FDA recommended modification of the irinotecan drug labeling to specify that individuals who arehomozygous for the UGT1A1*28 allele are at increased risk for neutropenia following treatment with irinotecan. Genetictesting for the presence of the UGT1A1*28 allele is available, and the FDA-approved label recommends testing. Themanufacturer also recommends reducing the initial irinotecan dose in those who are homozygous for UGT1A1*28 toreduce the likelihood of dose-limiting neutropenia.

However, routine use of this assay to select the appropriate dose of the drug in all patients who are to receiveirinotecan for treatment of metastatic disease has not been widely accepted for several reasons [127]:

For all of these reasons, the clinical utility of pretreatment testing for the UGT1A1*28 allele remains uncertain, at leastwhen irinotecan doses are based upon BSA. A proof of principle study has demonstrated that UGT1A1 genotype canbe used to individualize irinotecan dosing as an alternative to BSA-based dosing [113]. However, it is not yet clear howthis will affect clinical practice.

The subject of irinotecan dosing is discussed further elsewhere. (See "Systemic chemotherapy for metastatic colorectalcancer: Completed clinical trials", section on 'UGT1A1 polymorphisms'.)

TPMT and thiopurines Thiopurine S-methyltransferase (TPMT) is responsible for the metabolism ofthiopurines, which includes 6-mercaptopurine [6-MP]. Polymorphisms in the TPMT gene can result in functionalinactivation or markedly decreased activity of the enzyme, and an increased risk of treatment-related leukopenia. Over24 low-functioning genetic variants have been identified, but the two most common (TPMT*2 and *3) account for morethan 95 percent of defective TPMT.

TPMT testing is not specifically recommended by the FDA prior to treatment with 6-MP. Although dose reductions of upto 90 percent may be needed in individuals with low or absent TPMT activity, many clinicians treating acute leukemiawith 6-MP only perform TPMT genotyping if there is unexpectedly severe or prolonged myelosuppression. This subject

As noted above, the clinical relevance of identifying homozygotes is unclear. Only about 1 in 10 patients will beidentified as being homozygous, and the excess risk of severe neutropenia that is attributable to the inheritance ofthis polymorphism seems to be small, particularly at doses

is discussed in more detail elsewhere. (See "Overview of pharmacogenomics", section on 'Thiopurinemethyltransferase'.)

Drug transport

Therapeutic drug monitoring TDM, which involves sampling of plasma or serum drug levels to determine optimaldrug dosing, is theoretically appealing. This technique is in widespread use for a number of therapeutic areas includingantiepileptic drugs, antibiotics, and immunosuppressive drugs. These classes of drugs all employ continuous dosingwhereas cytotoxics are generally dosed cyclically, making TDM logistically more difficult as it would typically requiresampling at multiple time points. Furthermore, as chemotherapy regimens are commonly based on combinations ofdrugs, determination of AUC values for specific drugs would require multiple blood samples to be drawn. Otherchallenges are that TDM is expensive and labor intensive, and most clinical practices do not have the technicalinfrastructure to adequately and rapidly process blood samples for clinical pharmacokinetic analysis.

Given these logistic and economic challenges, the only cytotoxic agent for which pharmacokinetic-guided dosing is inwidespread use is mitotane. Plasma monitoring is recommended to maintain plasma levels between 14 and 20 mg/L;levels 14 mg/L are associated with better outcomes, and a significant increase in neurotoxicity is reported when levelsexceed 20 mg/L. (See "Treatment of adrenocortical carcinoma", section on 'Suggested regimen'.)TDM is also used for patients receiving high-dose methotrexate; but in that case it is not used to select drug dose, butinstead to guide the use of leucovorin rescue to mitigate excess toxicity. (See "Therapeutic use and toxicity of high-dosemethotrexate".)TDM may be emerging as a valid alternative to current strategies for dosing of some drugs:

Methotrexate pharmacokinetics and toxicity are influenced by polymorphisms in transporter proteins includingsolute carrier organic anion transporter 1B1 (SLCO1B1) and organic anion transporter protein 1B1 (OATP1B1).(See "Overview of pharmacogenomics", section on 'Drug transport'.)

Sunitinib toxicity has been correlated with specific haplotypes of efflux transporter genes ATP-binding cassette(ABC)B1 and ABCB2. (See "Overview of pharmacogenomics", section on 'Drug transport'.)

Infusional FU Infusional FU is the sole anticancer agent for which TDM has been validated as a method toimprove the therapeutic index in more than one randomized trial [141,142]. However, validation of the benefits ofTDM in randomized trials for commonly used FU-containing regimens (particularly in the setting of metastaticcolorectal cancer) is needed. Until such data are available, it is premature to conclude that pharmacokinetically-guided dosing should be integrated into clinical practice.

Like most other cytotoxic drugs, FU dosing is based upon BSA. However, a complete lack of association betweenBSA and FU clearance has been shown by two independent groups [143,144]. Pharmacokinetically-guided dosingmight improve the therapeutic index [142,145,146]:

In an early trial, 122 patients with head and neck cancer undergoing induction chemotherapy with cisplatinplus FU were randomly assigned to standard FU dose (4 g/m by 96 hour continuous infusion) or at a doseadjusted according to the FU AUC after the first dose [142]. FU doses were significantly less during cycles 2and 3 in the TDM arm, and toxicity (myelosuppression, mucositis) was also less; objective response rateswere similar (82 versus 77 percent in the standard dose arm).

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In a later trial, 208 patients with metastatic colorectal cancer received 1500 mg/m FU over eight hours withleucovorin and were then randomly assigned to continue weekly BSA-based fixed dosing or individualizeddosing based upon a single measurement of the FU plasma concentration at steady state, calculated toachieve an AUC of 20 to 25mg/mL x hour [141]. Patients receiving AUC-based FU dosing had significantlyhigher response rates, longer median survival, and less toxicity, including diarrhea.

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While these data are intriguing, the FU/leucovorin (LV) regimen used in this trial is not typical for any disease.There are no published data on the benefits of pharmacokinetically-based dosing in patients receiving modern


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SUMMARY AND RECOMMENDATIONS

FU-containing combination regimens, such as those containing oxaliplatin or irinotecan, although one early reportsuggests promise [147]. Validation of the benefits of TDM in randomized trials for commonly used FU-containingregimens is needed. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatmentrecommendations".)Tyrosine kinase inhibitors The majority of new orally administered targeted therapies are once- or twice-dailyfixed-dose drugs. The efficacy and toxicity of many tyrosine kinase inhibitors (TKIs) have been shown to correlatewith trough levels [19]. Even in tumors with driver mutations (eg, chronic myeloid leukemia [CML] and epidermalgrowth factor receptor [EGFR]-mutant lung cancer), which are very sensitive to TKIs, there is a minimumthreshold below which the drug is inactive. Furthermore, underdosing may lead to ineffective treatment oracquired resistance. Although TDM is not yet in general clinical use, it may be a rational step for improving theefficacy of TKI therapies.

The data for TDM are most compelling for imatinib, where specific trough concentration values have beenproposed for CML and gastrointestinal stromal tumors based on clinical efficacy data [148,149]. Patients with thelikeliest benefit for TDM include those with suboptimal response or treatment failure, adverse events, suspecteddrug interactions, or nonadherence to therapy [148,150]. (See "Tyrosine kinase inhibitor therapy for advancedgastrointestinal stromal tumors".)

Most anticancer drugs have a steep dose response relationship and a narrow therapeutic index. Small variationsin the administered dose can lead to severe and life-threatening toxicity in some individuals and underdosing inothers, which may compromise cancer outcomes. Proper dose selection is of great importance, particularly inindividuals with potentially curable diseases such as lymphoma or testicular carcinoma, and in the setting ofadjuvant treatment (eg, breast and colon cancer). However, individuals have a highly variable capacity tometabolize and eliminate drugs, leading to a substantial degree of interindividual variation in drug exposure. (See'Introduction' above.)

In an attempt to minimize the amount of interindividual variation in drug exposure in the calculation of effective drugdoses, various methods have been developed, primarily based upon body size descriptors. Body surface area(BSA)-based dosing has been widely adopted for most cytotoxic agents and some therapeutic monoclonalantibodies (rituximab, cetuximab), despite the lack of rigorous validation and even though its ability to reduceinterindividual variation in drug clearance is limited. No superior dosing scheme has been demonstrated, with theexception of area under the curve (AUC)-based dosing for carboplatin. (See 'Body surface area (BSA)-baseddosing' above.)

Over the range of typical weights and heights, commonly used BSA formulae do not vary from each othersignificantly (figure 3). Given this fact, and the absence of trial data suggesting superiority of any specific formula,an expert panel convened by the American Society of Clinical Oncology (ASCO) concluded that any of theformulae is acceptable [49]. (See 'Algorithms for calculating BSA' above.)There are no data to suggest that obese patients dosed based on their actual body weight have increasedtoxicity, while there are data from retrospective studies that underdosing is associated with inferior outcomes. Inkeeping with guidelines from ASCO, we recommend that actual body weight be used for the BSA calculationwhen dosing cytotoxic chemotherapy drugs based on BSA, especially when the intent of therapy is cure (Grade1B) [49]. Other recommendations for chemotherapy treatment in obese patients from the ASCO expert panel areoutlined in the table (table 2). (See 'Overweight/obese patients' above.)Although less data are available, for patients who are seriously underweight, we also suggest using actual bodyweight for calculation of chemotherapy doses (Grade 2C). However, among patients with weight loss and/orsarcopenia, organ function and performance status should be taken into consideration when dosing cytotoxicchemotherapy. (See 'Underweight patients' above.)The only cytotoxic agents for which fixed dose prescribing is used are vincristine (for which a 2 mg capped dose


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may be recommended because of neurotoxicity), and bleomycin in patients with testicular germ cell tumorsbecause of pulmonary toxicity. (See 'Fixed-dose prescribing' above.)For anticancer agents with an apparent selectivity for a cancer-specific target (targeted therapies), the best wayto determine the optimal dose is unclear. Multiple approaches are being explored to develop alternative strategiesfor the identification of an optimal dose as opposed to the maximum tolerated dose, as is used for cytotoxicagents. (See 'Newer targeted therapies' above.)

At present, fixed doses are used for all patients receiving tyrosine kinase inhibitors (TKIs), BRAF serine threoninekinase inhibitors (vemurafenib, dabrafenib, and trametinib), and inhibitors of the mammalian Target of Rapamycin(mTOR), regardless of weight or BSA, even though this approach is associated with a wide spread of plasmaconcentrations following standard dose regimens, and substantial interindividual variability at the end of the dosinginterval (trough concentration). (See 'Orally active small molecule kinase inhibitors' above.)In contrast, some therapeutic monoclonal antibodies are dosed using a fixed dose schedule (eg, alemtuzumab,ofatumumab, pertuzumab), while others are dosed on a mg/kg basis (ipilimumab, bevacizumab, trastuzumab,panitumumab, brentuximab, ramucirumab) and still others are based upon BSA (rituximab, cetuximab). (See'Weight-based dosing' above.)In addition to some therapeutic monoclonal antibodies, weight-based dosing is used for a few cytotoxic agents,including cladribine, melphalan, and arsenic. In the absence of data suggesting increased toxicity for underweightor obese individuals receiving weight-based dosing, doses should be based upon actual body weight. (See'Weight-based dosing' above.)

For most patients, carboplatin dosing uses the Calvert formula, which is based upon desired exposure (AUC ofconcentration x time) and the glomerular filtration rate (GFR). When the GFR is estimated based upon measuredserum creatinine, we suggest limiting the maximal GFR to 125 mL/min for this calculation (Grade 2C). Thissuggestion does not apply if the GFR is directly measured. (See 'Carboplatin' above.)

When calculating carboplatin doses, the appropriate weight to use is controversial. Guidelines from theGynecologic Oncology Group (GOG) suggest that actual weight should be used for estimation of the GFR by theCockcroft-Gault equation as long as patients have a body mass index of

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