Dosing of Anticancer Agents in Adults PDF

Dosing of anticancer agents in adults
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http://www.uptodate.com/contents/dosing-of-anticancer-agents-in-adults?...
Official reprint from UpToDate

www.uptodate.com 2016 UpToDate

Authors
Keith D Eaton, MD, PhD
Gary H Lyman, MD, MPH, FASCO,
FACP, FRCP (Edin)
Section Editor
Paul J Hesketh, MD
Deputy Editor
Sadhna 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
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 and
underdosing 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 of
adjuvant treatment (eg, breast and colon cancer). Selection of the right dose is complicated by the fact that individuals
have 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 plasma
concentration x time following a single dose. During drug development, drug level sampling at multiple time points helps
define the relationship between drug administration and the AUC. The AUC is influenced by external factors such as
drug dose and schedule, as well as patient-specific factors such as age, gender, height, weight, concomitant
medications and habits, genetics (inherited variations in drug metabolizing enzymes, drug transporters, and/or drug
targets), and clearance (which depends upon renal and hepatic function). As a result, there is much interindividual
variation in the AUC following a single dose of a drug [1]. For most anticancer agents, attempts to minimize
interindividual 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 is
used for most cytotoxic agents, weight-based dosing (eg, as is done for some cytotoxic agents such as melphalan and
several therapeutic monoclonal antibodies), fixed dose prescribing (as is done for oral targeted agents such as tyrosine
kinase inhibitors [TKIs]), AUC-based dosing (as is done for carboplatin), and pharmacogenetic as well as
pharmacokinetic-guided dosing, including therapeutic drug monitoring. Dosing of anticancer agents in patients with renal
or hepatic failure, and issues pertinent to dosing in the elderly are discussed in detail elsewhere. (See "Chemotherapyrelated nephrotoxicity and dose modification in patients with renal insufficiency" and "Chemotherapy hepatotoxicity and
dose 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 determined
from prospective and retrospective studies in which the goal was to maximize efficacy and minimize toxicity. The
starting dose for conventional cytotoxic agents in phase I studies has generally been based upon animal studies, where
doses are usually escalated until the LD10 is reached (the dose that results in lethality in 10 percent of the treated
animals). 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 higher
metabolizing capacity, it has been assumed that they require more drug to induce the same effects. In an attempt to
minimize interindividual variation, dosing for most anticancer agents has generally been normalized using mg of drug per
m2 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 surface
area (BSA)-based dosing' below.)
More recently, given the trajectory towards personalized medicine, pharmacogenetic and
pharmacokinetic-based dosing strategies have received more attention, though these approaches are not yet in
widespread use. (See 'Pharmacogenetics, pharmacokinetics, and therapeutic drug monitoring (TDM)' below and
"Treatment of adrenocortical carcinoma", section on 'Suggested regimen'.)
Importance of dose intensity Historical data on optimal dosing for most existing cytotoxic agents have been
generated using dose considerations that are derived from the maximum tolerated dose concept, irrespective of an
individuals genetic constitution. The concept is that cytotoxic chemotherapy agents are administered at the maximum
dose that an individual can tolerate before the onset of severe and even life-threatening toxicity. This dose, which is
derived from phase I trials, is one dose level below that associated with dose-limiting toxicity and is termed the
maximum 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 an
individual 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 vitro
studies, and clinical trials [2,3]. The clinical data are strongest for breast cancer, in which prospective studies have
demonstrated inferior outcomes for patients who receive lower than intended dose intensity [4-7] and better outcomes
with dose-dense as compared with non dose-dense therapy [8]. (See "Adjuvant chemotherapy for hormone receptorpositive 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 of
hematologic 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 in
patients who lack significant hematologic toxicity from myelosuppressive chemotherapy. The practice of giving higher
drug doses to individuals who lack significant treatment-related toxicity seems logical given the correlation between lack
of toxicity and low drug concentrations [11-14]. However, despite its logical appeal, there have been limited trials
testing this concept, and it has not been widely adopted or endorsed in clinical practice. In contrast, the practice of
reducing doses based upon excess hematologic or other toxicity (eg, neurologic, gastrointestinal, or dermatologic) is
widely accepted. In general, dose reduction for individual agents has been based upon criteria that were used in clinical
trials, 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 assess
whether drug dosing guided by the occurrence of toxic effects (pharmacodynamics) could improve efficacy of standard
cytotoxic regimens.
Newer targeted therapies There has been a paradigm shift in oncologic treatment away from the development of
classic intravenously administered cytotoxic chemotherapy drugs toward so-called targeted therapies such as kinase
inhibitors that are often administered orally on an ongoing daily basis, and therapeutic monoclonal antibodies, which are
dosed parenterally. Dose-limiting toxicities for targeted therapies are often markedly different from those of cytotoxic
chemotherapy agents. In addition, when compared with classic cytotoxic agents, these novel agents show different
relationships between levels of exposure, particularly exposure over time, and pharmacologic effects on the molecular
drug target. Finally, these agents are characterized by unique mechanisms of action, and many are highly specific for
single or multiple key cellular biological pathways implicated in carcinogenesis. Anticancer activity levels for therapies
targeted against defined cellular and molecular markers significantly improve if patient pool enrichment is carried out
based upon the presence of that specific marker in tumor tissue. Examples include tumor HER2 expression to select for
treatment with trastuzumab, and the use of imatinib for patients with chronic myelogenous leukemia (CML) harboring an
oncogenic 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-ABL1
fusion protein'.)
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Whether the maximum tolerated dose paradigm is valid for anticancer agents with an apparent selectivity for a
cancer-specific target (targeted therapies) is unclear. For these drugs, multiple approaches are being explored to
develop 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 as
vemurafenib, dabrafenib, and trametinib (inhibitors of the BRAF serine/threonine protein kinase), are dosed using a
fixed dose schedule for all patients regardless of weight or BSA. 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
dosed according to BSA (rituximab, cetuximab). (See 'Fixed-dose prescribing' below and 'Weight-based dosing' below
and 'Orally active small molecule kinase inhibitors' below.)
Although these drugs offer specific important advantages over conventional cytotoxic agents, they are still afflicted by
some of the same problems, including extensive interindividual variability in clearance (figure 1) [16] and a narrow
therapeutic window. Although it is imperative to ensure that sufficiently high local drug concentrations are reached so as
to maximize efficacy without exacerbating toxicity, the optimal way to achieve this goal is not yet apparent [15]. For
some drugs, biologic activity at the intended target can be used to select an appropriate dose. As an example, with the
investigational PARP [Poly (ADP)-Ribose Polymerase] inhibitor olaparib, biologic activity can be demonstrated by
inhibition of the enzyme in tumor tissue. In phase I studies, biologic activity of olaparib was demonstrated with
continuous twice daily dosing at dose levels above approximately 100 mg; a dose of 200 mg twice daily was chosen for
phase II testing, although the maximum tolerated dose of 600 mg twice daily was much higher [17,18]. Dose
comparison 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 is
not 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 drug
testing (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 of
so-called phase 0 studies, one type of which is a clinical trial to study pharmacologically relevant doses to explore the
pharmacologic effects of a test molecule or the pharmacodynamic effect of a new drug that is expected to correlate
with its clinical activity [21].
BODY SURFACE AREA (BSA)-BASED DOSING In an attempt to minimize the amount of interindividual variation in
drug exposure in the calculation of effective drug doses, various methods have been developed, primarily based upon
body size descriptors. BSA-based dosing has been widely adopted for most cytotoxic agents and some therapeutic
monoclonal antibodies (rituximab, cetuximab), despite the lack of rigorous validation and even though its ability to
reduce interindividual variation in drug clearance is limited. No superior dosing scheme has been demonstrated, with the
exception 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 had
been noted to explain the variation in metabolic rates of animals across a range of species, including humans, and to
correlate linearly with blood volume [22-24]. In an early retrospective study conducted in the 1950s, doses of
mechlorethamine and methotrexate per unit of body weight were higher for smaller animals than for larger animals, and
for children than in adults, while doses per unit of body surface area were nearly similar for all species and for humans
of all ages [25]. Subsequently, despite the lack of rigorous validation (and an increasing number of publications that
question the validity of BSA-based dosing for a number of conventional cytotoxic agents [26-36]), BSA-based
chemotherapy 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 reduce
interindividual variability in drug clearance after a single dose of an anticancer agent [22]. In a study of 1012 adult
patients 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 interindividual
variation in clearance ranged from 0.17 to 0.44 (r2 = 0.03 to 0.19). However, the precision for reaching the target AUC
was 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 drugs
according 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]) have
reliably performed better than the BSA in reducing the interindividual variability [41,42]. One study found that for a
variety of therapeutic drugs, LBM was the best size descriptor for clearance of chronically dosed drugs [43]. The LBM
has also been proposed as a potentially superior body size measure for anticancer agents [44], but a proper scientific
rationale 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 was
published [46]. Despite only nine subjects being studied, this formula is relatively accurate for normal weight individuals
and is still in use (calculator 1).
Various formulae have subsequently been developed to estimate BSA using height and weight. These are listed in the
table (table 1), and compared graphically in the figure (figure 3). The Mosteller formula is the easiest to remember and
calculate (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 panel
convened by the American Society of Clinical Oncology (ASCO) concluded that any of the formulae is acceptable when
calculating 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 to
generate these formulae. Despite the limited data, the BSA estimates from these formulae seem to differ more
substantially in obese (BMI >30 kg/m2) and morbidly obese (BMI >40 kg/m2) individuals. In one study that included an
obese cohort, all common formulas underestimated BSA for obese individuals [50]For persons >80 kg, the Livingston
equation had a 0.83 0.92 percent error in estimating BSA, whereas the Du Bois equation had a 12.27 1.23 percent
error, and the Gehan equation had a -6.53 0.99 percent error. Although this study is arguably the only estimator for
BSA derived from a cohort of obese individuals, it has not been used to estimate the variance in chemotherapy doses
that would result from use of each of the BSA formulas in obese individuals. Although a firm recommendation cannot be
made for any of the formulae for calculating a BSA-based dose of anticancer agents in obese patients, the Mosteller
formula is the easiest to calculate and remember and provides estimates approximately in the middle of other
estimates. 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, to
underdosing through the practice of using less than actual body weight to calculate BSA or capping doses of cytotoxic
chemotherapy agents. There are no data to suggest that obese patients dosed based on their actual body weight have
increased toxicity, while there are data indicating that underdosing is associated with inferior outcomes. In keeping with
guidelines from the ASCO, we recommend that actual body weight be used for the BSA calculation when dosing
cytotoxic chemotherapy drugs based on BSA, especially when the intent of therapy is cure [49]. Other
recommendations 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 obese
individuals (as defined according to BMI (calculator 3)) have higher rates of both cancer incidence and cancer-related
mortality [51]. The reasons for this are multifactorial, but one likely contributor to the higher mortality rates described in
overweight/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 doses
rather than doses calculated according to actual weight [52-57]. As the prevalence of obesity has increased (according
to projections from the World Health Organization [WHO], by 2015 more than 700 million adults worldwide will be
obese [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 drug
doses are based upon a weight that is below their actual body weight [56]. A nationwide survey of chemotherapy
dosing in Australia found that only 6 percent of respondents routinely used actual body weight in BSA calculations for
obese 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:
An analysis of the effect of BMI on survival in operable breast cancer found that BMI >30 kg/m2 adversely
impacted overall survival (hazard ratio [HR] 1.25, p<0.01) [61]. Among obese patients, 96 percent had BSA
calculated based on ideal weight, resulting in an average 12 percent reduction in chemotherapy dose.
Retrospective analyses of other breast and ovarian cancer clinical trials have also demonstrated inferior clinical
outcomes in patients who received arbitrarily reduced chemotherapy doses because of obesity [62-66].
However, it is not clear that the inferior outcomes associated with obesity can be entirely explained by lower
chemotherapy doses. In a study of National Surgical Adjuvant Breast and Bowel Project (NSABP) colon cancer trials,
obese individuals (BMI >35 kg/m2) had a poorer overall survival (HR 1.28, 95% CI 1.04-1.57) [67]. Dose capping at a
BSA of 2.0 m2 was common, with 55 percent of the obese and 73 percent of the very obese patients having a capped
dose compared with 7 percent of normal weight patients. However, dose capping did not explain the association of high
BMI with worse outcome.
One concern is that dosing of obese patients according to actual body weight might lead to excessive toxicity. This
issue was addressed in a systematic review and meta-analysis of all studies that compared toxicity and efficacy of full
weight-based chemotherapy in obese and normal weight cancer patients [68]. Hematologic treatment-related toxicity
was 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 when
obese patients were dosed according to actual body weight.
Given the mounting data correlating underdosing with inferior outcomes in obese patients, ASCO convened an expert
panel to study the appropriate dosing of anticancer agents [49]. The expert panel recommended using actual body
weight for BSA calculations in obese patients receiving cytotoxic chemotherapy, particularly when the goal of treatment
is cure. They recommended that clinicians follow the same recommendations for dose reduction regardless of obesity
status 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 also
recommended the use of fixed dosing only with selected cytotoxic agents (ie, bleomycin and carboplatin), and that
doses 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 neurotoxicity
concerns. 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 were
derived from retrospective studies. However, the conclusions of the review were consistent across studies. The
recommendations 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 actual
body weight for calculation of chemotherapy doses for underweight patients. However, among patients with weight loss
and/or sarcopenia, organ function and performance status should be taken into consideration when dosing cytotoxic
chemotherapy.
Underweight patients are relatively rare in the general population but are over-represented in the cancer population.
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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:
One study assessed gastrointestinal and lung cancer patients for cachexia by several methods (history of weight
loss, muscle index, and computed tomography [CT] assessment) and found that cachexia was an adverse
prognostic factor regardless of BMI [69].
Another study of 141 underweight patients (BMI <18.5 kg/m2) from a cohort of 4288 patients treated in adjuvant
colon cancer NSABP trials found excess non relapse-related mortality compared with normal weight patients (HR
2.23, 95% CI 1.50-3.31.) [67].
An underappreciated problem is that sarcopenia (defined as loss of skeletal muscle mass) is common among cancer
patients 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 who
were undergoing capecitabine treatment, 25 percent were sarcopenic by CT criteria [70]. Whereas most people with
cachexia 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]. As
examples:
In the previously noted study of breast cancer patients receiving capecitabine, patients with sarcopenia were
significantly more likely to have dose-limiting toxicity (sarcopenia was a significant predictor of dose-limiting
toxicity (50 versus 20 percent, p = 0.04) and a shorter time to tumor progression [70].
Another study of 55 patients with renal cancer treated with standard dose sorafenib also noted that rates of
dose-limiting toxicity were highest in subjects with sarcopenia and a BMI <25 kg/m2, and lowest in individuals who
were not sarcopenic and/or overweight or obese (41 versus 13 percent) [71].
Because sarcopenia is an adverse prognostic feature in the absence of treatment, it is difficult to separate out the
adverse 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 dosing
calculations. Proposals to prospectively use anthropomorphic measurements, electric impedance, and/or CT scans to
measure body composition and chemotherapy dosing have not been rigorously studied. Lean body mass (LBM), when
used as a scalar for dosing chemotherapy, is typically not measured but inferred from formulae, which may not be
representative of the population of persons with cancer. Body composition is likely more important than BMI, but using
LBM 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 body
weight would result in a higher dose and would likely result in excess toxicity. However, among patients with weight loss
and/or sarcopenia, organ function and performance status should be taken into consideration when dosing cytotoxic
chemotherapy.
WEIGHT-BASED DOSING 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 underweight or obese individuals receiving weight-based dosing, doses should be based upon actual body
weight.
Although uncommon, certain cytotoxic drugs are calculated based on weight rather than body surface area (BSA) in
adult patients with cancer. This is largely based on how the drugs were initially developed. Examples include:
Cladribine dosed by weight in chronic lymphocytic leukemia and hairy cell leukemia, and dosed by BSA for other
indications
Arsenic dosing in China was originally a flat dose, changed to weight-based dosing when developed
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internationally
Melphalan both weight-based and BSA-based dosing are used for the treatment of patients with multiple
myeloma
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 be
calculated by weight and not BSA [74], as these drugs are not cleared through the normal renal or hepatic mechanisms
but through intracellular catabolism with nonlinear clearance. Allometric scaling models based upon body size have not
generally been successful in predicting clearance of high molecular weight proteins in humans. At least some data
suggest that fixed dosing and weight-based dosing perform similarly across a range of therapeutic monoclonal
antibodies, with fixed dosing being better for some antibodies, and weight-based dosing better for others [75]. These
authors suggest that first in human studies be performed using fixed doses with a full assessment of body size effect on
pharmacokinetic 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 receiving
weight-based oncologic therapeutics dosed by their actual weight. Thus, in the absence of data for harm, doses should
be based on actual body weight.
FIXED-DOSE PRESCRIBING Fixed-dose prescribing does not take body size into account. While this is normative
for non-oncologic drugs, it is rarely used in cytotoxic chemotherapy:
Vincristine is typically dosed at 1.4 mg/m2 but may be capped at 2 mg to avoid neurotoxicity; for most adult
patients, this amounts to a fixed dose. The 2012 American Society of Clinical Oncology (ASCO) expert panel
recommended 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".)
Bleomycin is dosed according to body surface area (BSA) in regimens used to treat Hodgkin lymphoma, but
dosed at a fixed level in testicular cancer due to concern about pulmonary toxicity. (See "Overview of the
treatment of testicular germ cell tumors" and "Treatment protocols for germ cell tumors" and "Bleomycin-induced
lung injury".)
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 cancerspecific 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 determine
the optimal dose is unclear. At present, fixed doses are used for all patients regardless of weight or BSA, even though
this approach is associated with a wide spread of plasma concentrations following standard dose regimens and
substantial 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 variation
in 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 standard
dosing regimens rarely result in comparable circulating concentrations of the active drug in all patients. It is increasingly
apparent that variability in response to newer targeted drugs is influenced not only by genetic heterogeneity of drug
targets that determine tumor sensitivity, but also by the pharmacokinetic background of the patient (eg, cytochrome
P450 enzymes, oral absorption, and environmental factors that influence pharmacokinetics), as well as adherence to
the regimen [76]. The vast majority of targeted drugs are characterized by a wide spread of plasma concentrations
following standard dose regimens, with interindividual variability at the end of the dosing interval (trough concentration)
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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 no
accepted a priori way to assign an optimized dose to an individual patient.
Adherence to treatment and bioavailability are major issues:
Although oral administration provides the convenience of self-administration at home, the evidence suggests that
adherence to oral cancer therapies is far from optimal, putting patients at risk for adverse outcomes [78-81]. As
an example, for patients with chronic myelogenous leukemia who are treated with imatinib for several years, poor
adherence is associated with a poor response, and it may be the predominant reason for an inadequate molecular
response [80,81].
The solubility of many TKIs is pH-dependent, and an elevated gastric pH may decrease bioavailability. Strong
interactions 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 to
food effects, especially when a high fat meal (HF) is consumed. The most striking example is lapatinib, which has
a 150 percent increase in exposure (area under the curve [AUC]) with food [82,83]. Other kinase inhibitors with
significant 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 empty
stomach.
There are also data to suggest that limited dosing options (due to pill sizes, which force large dose reductions for
toxicity) 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 targetrelated toxicity from TKIs, such as skin rash for epidermal growth factor receptor (EGFR) TKIs and hypertension for
vascular endothelial growth factor (VEGF) TKIs, might have improved outcomes. Despite the rationale for this in
patients treated with some EGFR inhibitors such as the anti-EGFR therapeutic monoclonal antibody cetuximab for
metastatic colorectal cancer, trials suggest that this dosing strategy does not significantly improve outcomes with other
targeted 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 clinical
trials", section on 'Cutaneous toxicity' and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular
effects", section on 'Association with antitumor efficacy'.)
AUC-BASED DOSING As described above, the area under the curve (AUC) of plasma concentration versus time is
the most relevant measure of drug exposure. AUC-based dosing is applicable for drugs that are cleared through
glomerular filtration, like carboplatin, because there is a strong correlation between carboplatin clearance and creatinine
clearance [93-95]. AUC-based dosing is not applicable to most other anticancer agents (with the possible exception of
pemetrexed) because there are no characteristics (either alone or in combination) that can be used to predict drug
clearance 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 by
its usual dosing schema, which is based upon an estimate of the glomerular filtration rate (GFR) and the desired level
of 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 dose
of carboplatin is then calculated by use of the Calvert formula: Total carboplatin dose, mg = Target AUC x (estimated
creatinine clearance + 25). Because of potential changes in weight or renal function, this calculation should be repeated
prior to each administered course of carboplatin.
Given the poor correlation between GFR and body surface area (BSA) [98], AUC-based dosing for carboplatin
represented a significant success in reducing interindividual variation. This dosing scheme was developed eight years
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after the introduction of carboplatin, and in this study, the r = 0.886 (r2 = 0.785) was much better than previous
BSA-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-Chromiumlabeled EDTA (51-Cr EDTA) [93]. In most cases, GFR is estimated using the serum creatinine, and calculated
according to the Cockcroft-Gault equation (calculator 4). However, others suggest use of the Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) equation due to greater accuracy [100], although this has not been seen in all
studies [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 clearance
using the Jelliffe formula, which is not based upon weight or BSA [103-106]. This is because carboplatin dosing was
based 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 dose
calculation to recommend that estimated creatinine clearance be calculated by the Cockcroft-Gault method in all
patients. A more extensive discussion of GFR estimation equations is provided elsewhere. (See "Assessment of kidney
function", section on 'Estimation equations'.)
The following issues are relevant to the carboplatin dose calculation:
Total carboplatin dose is calculated in mg, not mg/m2.
Maximum GFR The accuracy of dosing using a calculated rather than a directly measured GFR has been
questioned [107]. Nevertheless, this is a standard approach.
When using an estimate instead of direct measurement of the GFR to calculate the carboplatin dose using the
Calvert formula, calibration of the creatinine assay may impact dosing. In the United States, as of the end of
2010, all laboratories must use a creatinine method that has calibration that is traceable to an Isotope Dilution
Mass Spectrometry (IDMS) reference measurement procedure [108]. However, this gives lower creatinine results
than the older measurement procedures used to derive the Calvert formula and, hence, higher estimates of the
GFR. 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 of
0.7 mg/dL. Furthermore, if an estimated GFR based upon measured serum creatinine is used in the Calvert
formula, the US Food and Drug Administration (FDA) recommends limiting the maximal GFR for the calculation to
125 mL/min [109]. This recommendation does not apply if the GFR is directly measured. The GOG has now
mandated a similar cap for patients on their carboplatin trials (including trials conducted in the setting of potentially
curable 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 the
estimated GFR [110,111]. The original Cockcroft-Gault formula to estimate GFR used actual body weight, but
none of the patients was obese. Most clinicians use actual body weight in the Cockcroft-Gault formula for
non-obese patients, although institutional practice varies. However, the use of actual body weight in the
Cockcroft-Gault calculation can result in an overestimate of the GFR and a higher than needed carboplatin dose in
obese individuals [111].
Among the methods suggested to calculate the appropriate dose of carboplatin in obese patients are the use of
adjusted rather than actual body weight to calculate the GFR (as recommended by the GOG) [110,112], use of
the 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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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 American
Society of Clinical Oncology (ASCO) guideline [49]. The GOG recommends that actual weight be used for
estimation of the GFR when using the Cockcroft-Gault equation as long as patients have a body mass index
(BMI) of <25 kg/m2 (calculator 5). For other patients, use of an adjusted weight is suggested (adjusted weight
[kg] = [(actual weight - ideal weight) x 0.40] + ideal weight). A calculator for ideal body weight is available
(calculator 6).
PHARMACOGENETICS, PHARMACOKINETICS, AND THERAPEUTIC DRUG MONITORING (TDM) The
combined use of therapeutic drug monitoring (as a phenotypic approach) and genotyping of drug metabolic capacity is
currently considered to be the most sophisticated way to individualize dosage for drugs in which the clinical effects are
difficult to evaluate, such as anticancer agents. However, the use of pharmacogenetic testing to select initial doses has
not been widely endorsed or adopted, and at present, the only cytotoxic agent for which pharmacokinetic-guided dosing
is 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 most
anticancer 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:
Absorption (for oral drugs)
Distribution (to different organs/body compartment)
Metabolism (activation/inactivation by enzymes)
Elimination (renal, hepatic)
The most relevant pharmacokinetic parameter used to characterize drug exposure is the area under the curve (AUC) of
plasma concentration x time, which can be estimated from drug level sampling at multiple time points. Although TDM is
an accepted way to guide dosing of several agents with large interindividual pharmacokinetic variation in the noncancer
setting (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-dose
methotrexate, and even then, TDM is used to manage toxicity and not individualize drug doses). (See 'Therapeutic drug
monitoring' 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:
Renal clearance is glomerular filtration rate (GFR) + secretion absorption. As GFR can be easily estimated,
dose selection for drugs that are cleared only by glomerular filtration, such as carboplatin, is possible. (See
'AUC-based dosing' above.)
The effect of varying hepatic function is less clearly quantifiable, as the pathways of hepatic transformation and
elimination are substrate dependent, and easily-measurable liver function tests cannot be used to quantitatively
characterize function. (See "Drugs and the liver: Metabolism and mechanisms of injury".)
Inherited variations in drug metabolizing enzymes, drug transport proteins, and drug targets can substantially alter
drug exposure. The term pharmacogenetics (used interchangeably with the term pharmacogenomics) refers to
the study of how germline (inherited) genetic polymorphisms affect the pharmacokinetics of drug exposure.
Pharmacogenetics The rationale for pharmacogenetic studies is to investigate genes that can predict
responsiveness to a specific drug so as to increase the number of responders and decrease the number of subjects
affected by adverse drug reactions. Despite known polymorphisms in both drug metabolizing and transporting proteins
that influence drug exposure and pharmacokinetics in patients receiving anticancer agents, and the availability of testing
for many of these polymorphisms, genotyping has not become widespread or widely accepted for any of these drug
classes. The causes are multifactorial and include the relative rarity of these conditions, the fact that factors other than
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inheritance of high-risk polymorphisms affect variability in drug response, the cost and inconvenience of testing, and
most importantly, a lack of data from clinical trials demonstrating a convincing difference in outcomes from the use of
pharmacogenetic testing.
Drug metabolism Several inherited polymorphisms in drug metabolizing enzymes that impact oncologic
therapeutics have been identified, as described below. However, to date, the translation of pharmacogenetic
parameters into clinical practice of medical oncology has been surprisingly disappointing, and none of these tests is
widely endorsed or used.
Fluoropyrimidines, DPD, and TYMS variants To avoid the risk of severe and potentially fatal reactions, the
manufacturers of both fluorouracil (FU) and capecitabine recommend that the drugs are contraindicated in patients with
known deficiency in the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). A test (TheraGuide 5-FU) is
commercially available to detect the most common high-risk polymorphisms in DPD, as well as polymorphisms in a
second enzyme associated with fluoropyrimidine toxicity, thymidylate synthase (TYMS). (See "Enterotoxicity of
chemotherapeutic agents", section on 'Predictive markers'.)
Use of the TheraGuide 5-FU assay is appropriate in any patient experiencing severe toxicity after receiving a
fluoropyrimidine-containing regimen. However, given the low frequency of finding a predictive allele and the fact that
patients who lack one of these high-risk variants may still suffer grade 3 or 4 FU-related toxicity, preemptive genetic
testing of all patients due to receiving a fluoropyrimidine in order to identify those with DPD deficiency is controversial
and not widely practiced. This assay is only useful to stratify patients into categories of risk for severe toxicity, and
there 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 at
increased risk for neutropenia and diarrhea following treatment with irinotecan. Genetic testing for the presence of the
UGT1A1*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 for
UGT1A1*28 to reduce the likelihood of dose-limiting neutropenia. However, routine preemptive use of this assay in all
patients who are to receive irinotecan is not widely accepted. Whether initial dose reduction improves outcomes for
UGT1A1*28 homozygotes and the precise dose reduction that is warranted in this patient population remain
controversial areas; in addition, inheritance of UGT1A1*28 polymorphisms seems to account for only a fraction of the
observed variability in irinotecan toxicity. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed
clinical 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 interindividual
variation 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 enzymatic
activity is reduced in individuals who inherit genetic polymorphisms such as the UGT1A1*28 allele (also known as TA
indel or UGT1A1 7/7). Approximately 10 percent of the North American population is homozygous for the UGT1A1*28
allele (which is responsible for Gilbert's syndrome); an additional 40 percent are heterozygotes [115-117]. (See "Gilbert
syndrome 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 for
irinotecan-related gastrointestinal (GI) toxicity and neutropenia [116,118-122]. However, more data indicate that the
magnitude 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 low
doses of irinotecan (100 to 125 mg/m2 weekly [124]); however, a later meta-analysis concluded that inheritance of
UGT1A1*28 was associated with an increased risk of neutropenia at all doses [126]. However, the relative risk (RR) for
neutropenia at doses 250 mg/m2 was significantly higher (RR 7.0, 95% CI 3.10-16.78) than that for lower doses (80
to 145 mg/m2 weekly, RR 2.43, 95% CI 1.34 to 4.39).
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In 2005, the FDA recommended modification of the irinotecan drug labeling to specify that individuals who are
homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following treatment with irinotecan. Genetic
testing for the presence of the UGT1A1*28 allele is available, and the FDA-approved label recommends testing. The
manufacturer also recommends reducing the initial irinotecan dose in those who are homozygous for UGT1A1*28 to
reduce 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 receive
irinotecan for treatment of metastatic disease has not been widely accepted for several reasons [127]:
As noted above, the clinical relevance of identifying homozygotes is unclear. Only about 1 in 10 patients will be
identified as being homozygous, and the excess risk of severe neutropenia that is attributable to the inheritance of
this polymorphism seems to be small, particularly at doses <150 mg/m2 per week [124]. As an example, the risk
of severe neutropenia with the first course of irinotecan in one study was 14 versus 2 percent in those with the
UGT1A1*28 and wild-type allele, respectively [119].
However, others report a much higher rate of grade 3 or 4 hematologic toxicity over an entire course of treatment
in patients receiving irinotecan doses <150 mg/m2 weekly who inherit the 7/7 variant as compared with carriers of
the 6/7 or 6/6 allele (48 versus 10 and 8 percent, respectively), a higher rate of hospitalization during therapy, and
greater short-term death rate, as well [128]. Whether outcomes would have been altered by upfront identification
of 7/7 carriers and initial dose modification is unclear.
Whether initial dose reduction is needed for UGT1A1*28 homozygotes who are receiving irinotecan dosed on a
mg/m2 basis and how much to reduce the dose remain unresolved issues [122,129]. Some have recommended an
initial 20 percent dose reduction [130], but there is no consensus on this point. Others have suggested that
patients without the *28/*28 genotype can tolerate much higher doses of irinotecan than are contained in standard
regimens such as FOLFIRI (table 3) [131]. However, whether the risk to benefit ratio can be improved by
selecting the irinotecan dose based on genotype will require prospective genotype-driven trials.
Inheritance of UGT1A1*28 polymorphisms seems to account for only a fraction of the observed variability in
irinotecan toxicity [113,132,133]. It is likely that both inherited (eg, alternative UGT1A haplotypes or
polymorphisms in other genes involved in irinotecan disposition [132-135]) and nongenetic factors (eg,
pretreatment bilirubin levels, gender, smoking, co-medications [132,136-139]) contribute to a patient's risk of
irinotecan-related toxicity. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical
trials", section on 'Pharmacokinetic variability'.)
The cost-effectiveness of pharmacogenetic testing for UGT1A1 before irinotecan administration remains uncertain
[140].
For all of these reasons, the clinical utility of pretreatment testing for the UGT1A1*28 allele remains uncertain, at least
when irinotecan doses are based upon BSA. A proof of principle study has demonstrated that UGT1A1 genotype can
be used to individualize irinotecan dosing as an alternative to BSA-based dosing [113]. However, it is not yet clear how
this will affect clinical practice.
The subject of irinotecan dosing is discussed further elsewhere. (See "Systemic chemotherapy for metastatic colorectal
cancer: Completed clinical trials", section on 'UGT1A1 polymorphisms'.)
TPMT and thiopurines Thiopurine S-methyltransferase (TPMT) is responsible for the metabolism of
thiopurines, which includes 6-mercaptopurine [6-MP]. Polymorphisms in the TPMT gene can result in functional
inactivation or markedly decreased activity of the enzyme, and an increased risk of treatment-related leukopenia. Over
24 low-functioning genetic variants have been identified, but the two most common (TPMT*2 and *3) account for more
than 95 percent of defective TPMT.
TPMT testing is not specifically recommended by the FDA prior to treatment with 6-MP. Although dose reductions of up
to 90 percent may be needed in individuals with low or absent TPMT activity, many clinicians treating acute leukemia
with 6-MP only perform TPMT genotyping if there is unexpectedly severe or prolonged myelosuppression. This subject
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is discussed in more detail elsewhere. (See "Overview of pharmacogenomics", section on 'Thiopurine

methyltransferase'.)
Drug transport
Methotrexate pharmacokinetics and toxicity are influenced by polymorphisms in transporter proteins including
solute 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'.)
Therapeutic drug monitoring TDM, which involves sampling of plasma or serum drug levels to determine optimal
drug dosing, is theoretically appealing. This technique is in widespread use for a number of therapeutic areas including
antiepileptic drugs, antibiotics, and immunosuppressive drugs. These classes of drugs all employ continuous dosing
whereas cytotoxics are generally dosed cyclically, making TDM logistically more difficult as it would typically require
sampling at multiple time points. Furthermore, as chemotherapy regimens are commonly based on combinations of
drugs, determination of AUC values for specific drugs would require multiple blood samples to be drawn. Other
challenges are that TDM is expensive and labor intensive, and most clinical practices do not have the technical
infrastructure 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 in
widespread 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 levels
exceed 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, but
instead to guide the use of leucovorin rescue to mitigate excess toxicity. (See "Therapeutic use and toxicity of high-dose
methotrexate".)
TDM may be emerging as a valid alternative to current strategies for dosing of some drugs:
Infusional FU Infusional FU is the sole anticancer agent for which TDM has been validated as a method to
improve the therapeutic index in more than one randomized trial [141,142]. However, validation of the benefits of
TDM in randomized trials for commonly used FU-containing regimens (particularly in the setting of metastatic
colorectal cancer) is needed. Until such data are available, it is premature to conclude that pharmacokineticallyguided dosing should be integrated into clinical practice.
Like most other cytotoxic drugs, FU dosing is based upon BSA. However, a complete lack of association between
BSA and FU clearance has been shown by two independent groups [143,144]. Pharmacokinetically-guided dosing
might improve the therapeutic index [142,145,146]:
In an early trial, 122 patients with head and neck cancer undergoing induction chemotherapy with cisplatin
plus FU were randomly assigned to standard FU dose (4 g/m2 by 96 hour continuous infusion) or at a dose
adjusted according to the FU AUC after the first dose [142]. FU doses were significantly less during cycles 2
and 3 in the TDM arm, and toxicity (myelosuppression, mucositis) was also less; objective response rates
were similar (82 versus 77 percent in the standard dose arm).
In a later trial, 208 patients with metastatic colorectal cancer received 1500 mg/m2 FU over eight hours with
leucovorin and were then randomly assigned to continue weekly BSA-based fixed dosing or individualized
dosing based upon a single measurement of the FU plasma concentration at steady state, calculated to
achieve an AUC of 20 to 25mg/mL x hour [141]. Patients receiving AUC-based FU dosing had significantly
higher response rates, longer median survival, and less toxicity, including diarrhea.
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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FU-containing combination regimens, such as those containing oxaliplatin or irinotecan, although one early report
suggests promise [147]. Validation of the benefits of TDM in randomized trials for commonly used FU-containing
regimens is needed. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment
recommendations".)
Tyrosine kinase inhibitors The majority of new orally administered targeted therapies are once- or twice-daily
fixed-dose drugs. The efficacy and toxicity of many tyrosine kinase inhibitors (TKIs) have been shown to correlate
with trough levels [19]. Even in tumors with driver mutations (eg, chronic myeloid leukemia [CML] and epidermal
growth factor receptor [EGFR]-mutant lung cancer), which are very sensitive to TKIs, there is a minimum
threshold below which the drug is inactive. Furthermore, underdosing may lead to ineffective treatment or
acquired resistance. Although TDM is not yet in general clinical use, it may be a rational step for improving the
efficacy of TKI therapies.
The data for TDM are most compelling for imatinib, where specific trough concentration values have been
proposed for CML and gastrointestinal stromal tumors based on clinical efficacy data [148,149]. Patients with the
likeliest benefit for TDM include those with suboptimal response or treatment failure, adverse events, suspected
drug interactions, or nonadherence to therapy [148,150]. (See "Tyrosine kinase inhibitor therapy for advanced
gastrointestinal stromal tumors".)
SUMMARY AND RECOMMENDATIONS
Most anticancer drugs 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 and underdosing 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 carcinoma, and in the setting of
adjuvant treatment (eg, breast and colon cancer). However, individuals have a highly variable capacity to
metabolize 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 drug
doses, 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 monoclonal
antibodies (rituximab, cetuximab), despite the lack of rigorous validation and even though its ability to reduce
interindividual variation in drug clearance is limited. No superior dosing scheme has been demonstrated, with the
exception of area under the curve (AUC)-based dosing for carboplatin. (See 'Body surface area (BSA)-based
dosing' above.)
Over the range of typical weights and heights, commonly used BSA formulae do not vary from each other
significantly (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 the
formulae 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 increased
toxicity, while there are data from retrospective studies that underdosing is associated with inferior outcomes. In
keeping with guidelines from ASCO, we recommend that actual body weight be used for the BSA calculation
when dosing cytotoxic chemotherapy drugs based on BSA, especially when the intent of therapy is cure (Grade
1B) [49]. Other recommendations for chemotherapy treatment in obese patients from the ASCO expert panel are
outlined 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 body
weight for calculation of chemotherapy doses (Grade 2C). However, among patients with weight loss and/or
sarcopenia, organ function and performance status should be taken into consideration when dosing cytotoxic
chemotherapy. (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 tumors
because of pulmonary toxicity. (See 'Fixed-dose prescribing' above.)
For anticancer agents with an apparent selectivity for a cancer-specific target (targeted therapies), the best way
to determine the optimal dose is unclear. Multiple approaches are being explored to develop alternative strategies
for the identification of an optimal dose as opposed to the maximum tolerated dose, as is used for cytotoxic
agents. (See 'Newer targeted therapies' above.)
At present, fixed doses are used for all patients receiving tyrosine kinase inhibitors (TKIs), BRAF serine threonine
kinase 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 plasma
concentrations following standard dose regimens, and substantial interindividual variability at the end of the dosing
interval (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 underweight
or 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 of
concentration x time) and the glomerular filtration rate (GFR). When the GFR is estimated based upon measured
serum creatinine, we suggest limiting the maximal GFR to 125 mL/min for this calculation (Grade 2C). This
suggestion 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 the
Gynecologic Oncology Group (GOG) suggest that actual weight should be used for estimation of the GFR by the
Cockcroft-Gault equation as long as patients have a body mass index of <25 kg/m2 (calculator 5). For other
patients, use of an adjusted weight is suggested (adjusted weight [kg] = [(actual weight - ideal weight) x 0.40] +
ideal weight). A calculator for ideal body weight is available (calculator 6).
Even when doses are normalized according to body size, individuals have a highly variable capacity to metabolize
and eliminate drugs, which is due to a combination of physiologic variables, intrinsic (genetic) characteristics, and
environmental factors (including drug-drug interactions and food intake). In general, the combined use of classical
therapeutic drug monitoring (as a phenotypic approach) and genotyping of drug metabolizing capacity is
considered to be the most sophisticated way to individualize the dosage of drugs like anticancer agents, for which
the clinical effects are difficult to evaluate. However, the use of preemptive pharmacogenetic testing has not been
widely endorsed or adopted, and at present, the only cytotoxic agent for which pharmacokinetic-guided dosing is
in widespread use is mitotane. (See 'Pharmacogenetics, pharmacokinetics, and therapeutic drug monitoring
(TDM)' above.)
Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia and diarrhea
following treatment with irinotecan. Genetic testing for the presence of the UGT1A1*28 allele is available
(the Invader UGT1A1 Molecular Assay), and the US Food and Drug Administration (FDA)-approved label
recommends testing and reduced initial irinotecan doses in those who are homozygous for UGT1A1*28 to
reduce the likelihood of dose-limiting neutropenia. However, routine preemptive use of this assay in all
patients who are to receive irinotecan is not widely accepted. Whether initial dose reduction improves
outcomes for UGT1A1*28 homozygotes and the precise dose reduction that is warranted in this patient
population remain controversial areas; in addition, inheritance of UGT1A1*28 polymorphisms seems to
account for only a fraction of the observed variability in irinotecan toxicity. (See 'UGT1A1 polymorphisms and
irinotecan' above.)
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Thiopurine S-methyltransferase (TPMT) is responsible for the metabolism of thiopurines like

6-mercaptopurine (6-MP). Polymorphisms in the TPMT gene can result in functional inactivation or markedly
decreased enzyme activity, and an increased risk of treatment-related leukopenia. TPMT testing is not
specifically recommended by the FDA prior to treatment with 6-MP. Although dose reductions of up to 90
percent may be needed in individuals with low or absent TPMT activity, many clinicians treating acute
leukemia with 6-MP only perform TPMT genotyping if there is unexpectedly severe or prolonged
myelosuppression. (See 'TPMT and thiopurines' above.)
Therapeutic drug monitoring (TDM), which involves sampling of plasma or serum drug levels to determine optimal
drug dosing, is not yet integrated into clinical practice, with the single exception of mitotane. Infusional fluorouracil
(FU) is the sole anticancer agent for which TDM has been validated as a method to improve the therapeutic index
in more than one randomized trial [141,142]. However, validation of the benefits of TDM in randomized trials for
commonly used FU-containing regimens (particularly in the setting of metastatic colorectal cancer) is needed
before it can be concluded that pharmacokinetically-guided dosing should be integrated into clinical practice. (See
'Therapeutic drug monitoring' above.)
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