New Oral Anti-Cancer Drugs and Medication Safety
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Background: Many oral anti-cancer drugs have come onto the market in the past 20 years. For example, kinase inhibitors, such as the BCR-ABL and BRAF inhibitors, have markedly improved the treatment of chronic myeloid leukemia and melanoma. In this review, we discuss the special challenges posed by poor adherence, drug–drug interactions with other substances, and side effects, among other problems, and the ways in which these challenges can be met.
Methods: A selective search was carried out in PubMed for original and review articles on the safety of new oral anti-cancer drugs. Guidelines and current Summaries of Product Characteristics (SmPC) were also considered in the analysis.
Results: Review articles have pointed out numerous safety concerns with oral anti-cancer drugs. One of these is adherence, on which highly variable figures are available (with mean non-adherence rates ranging from 0 to 54%). The absorption of approximately half of these drugs is influenced by the patient’s diet, and that of approximately 20% by gastric pH (Caution: proton-pump inhibitors may influence bioavailability). 70% of the active substances are metabolized primarily by CYP3A4, which means that their pharmacokinetics can be altered by grapefruit juice and CYP3A4 modulators. The prevention, detection, and treatment of side effects (which can be gastrointestinal, cutaneous, cardiovascular, or other) is a highly important matter.
Conclusion: The increasing use of oral anti-cancer drugs confronts patients and treatment teams with special challenges. To optimize treatment outcomes, a multidisciplinary approach should be taken, involving physicians, pharmacists, and nurses. To improve medication safety, medication and side-effect management should be performed, and adherence should be regularly checked and systematically encouraged.
More than 50 oral anti-cancer drugs have been licensed for use in Germany over the past 20 years. These agents are used for the treatment of a broad spectrum of solid tumors and hematological diseases (Table 1a and b). The anti-cancer properties of many substances are based on the inhibition of protein kinases, which are involved in cell growth and cell differentiation (Table 1a). In Germany, the protein kinase inhibitors have the second highest volume of sales among the group of oncological drugs (e1).
Apart from the convenience of oral intake for patients, the research data for the clinical benefit of protein kinase inhibitors are—at least in part—highly convincing (1–3). However, approaches involving oral administration of anti-cancer drugs can present considerable challenges to both patient and treatment team.
With intravenous chemotherapy, the entire dose reliably reaches the patient, but with oral intake this is less certain. Inadequate adherence must be assumed in a not inconsiderable proportion of patients: mean non-adherence rates of up to 54% have been described, which may endanger the success of treatment (4–6). About 50% of all oral anti-cancer drugs come with instructions regarding intake in relation to mealtimes, as substance absorption can be increased or decreased by food (7, e2, eTable 1). The patient has a special responsibility to follow the instructions accurately.
Moreover, attention must be paid to a variety of potential drug–drug interactions. Many oral anti-cancer drugs are metabolized by CYP3A4. Inhibitors or inducers of CYP3A4 (see ) may reduce the therapeutic effect or elevate the risk of side effects. A retrospective study in the Netherlands found potential drug–drug interactions in 46% of around 900 patients treated with oral anti-cancer drugs; in 16% of patients these were classified as potentially major events (9). The potential consequences of interactions most frequently noted in this study were QT interval prolongation, gastrointestinal effects, or complications affecting the central nervous system (9). Medication errors therefore represent a serious problem in oral anti-cancer treatment (10–12).
Characteristic side effects (affecting, for example, the skin, the cardiovascular system, and the gastrointestinal system) must be anticipated whenever oral anti-cancer drugs are used. The wide variety of possible side effects means that the health care team must be experienced in their prevention and management; also, patients must be fully informed. The trend towards oral treatment often leads to less intensive contact between physician and patient and thus to fewer opportunities to observe potential side effects.
This review article summarizes the following data on new oral anti-cancer drugs licensed for use in Germany (starting from 2001, when capecitabine was approved): indications and target structures; influence of food intake and gastric pH; essential determinants of elimination (metabolism, transport, renal and hepatic function); drug–drug interactions; and typical side effects. Furthermore, we outline the areas of treatment with new orally administered anti-cancer substances where medication safety can be promoted successfully.
A selective survey of the PubMed database was carried out to identify original articles and review articles on the medication safety of new oral anti-cancer drugs (published in English or German between January 2001 and July 2019). The MeSH terms were: administration oral, protein kinase inhibitors, antineoplastic agents, neoplasms, patient safety, side effects, medication errors, drug interactions. In addition, we took account of pertinent guidelines and scrutinized the current German Summaries of Product Characteristics (SmPC) and American Prescribing Information Sheets (as of 8 July 2019).
Oral anti-cancer drugs
Table 1 provides an overview of the oral anti-cancer drugs currently licensed for use in Germany (Table 1a: kinase inhibitors; Table 1b: other oral anti-cancer drugs). The table specifies the tumor entities for which each drug is approved and the target structures via which the anti-tumor effects can be achieved (Table 1a and b). The essential mechanism of action of two thirds of the oral anti-cancer drugs is inhibition of protein kinases.
Too low exposure to the oral anti-cancer drug (due, for example, to CYP inducers or gastric acid suppressing substances) can endanger the success of treatment. Equally, factors leading to excessively high exposure (e.g., CYP inhibitors, grapefruit) should be avoided because they increase the risk of side effects.
Factors affecting absorption
The absorption of oral anti-cancer drugs is affected, sometimes greatly, by the timing of medication around food intake and also by changes in gastric pH (eTable 1). Around 50% of the substances have to be taken at particular times relative to meals. Consumption of food can reduce (e.g., afatinib) or increase exposure; for instance, plasma concentrations (area under the curve, AUC) are elevated up to tenfold for abiraterone and up to fivefold for venetoclax when they are taken with a meal (eTable 1). Attention should be paid to the recommentations in the SmPC and patients should be informed about their relevance.
The absorption of some oral anti-cancer drugs is reduced by simultaneous administration of substances that inhibit gastric acid secretion. Proton pump inhibitors are particularly important in this regard, because they are very often prescribed and in some cases can be purchased in pharmacies without a prescription. For example, simultaneous intake of dasatinib (single dose) and omeprazole leads to a 43% reduction in the plasma concentration of dasatinib (eTable 1).
Patients with cancer regularly take an average of around five different non–anti-cancer drugs (9, 13, 14). The accompanying medications may inhibit or induce metabolism of oral anti-cancer drugs. In such a case the oral anti-cancer drug is the “victim drug” (for oral anti-cancer drugs as “perpetrator drugs,” see next paragraph). Circa 70% of oral anti-cancer drugs are metabolized predominantly via CYP3A4. Simultaneous administration of CYP3A4 inhibitors (e.g., clarithromycin, azole antimycotics, HIV protease inhibitors) leads to elevated plasma concentrations of these oral anti-cancer drugs. Conversely, induction of CYP3A4 (e.g., by St. John’s wort, carbamazepine, or rifampicin) can result in reduced plasma concentrations and thus loss of anti-tumor effect (for information on further CYP3A4 inhibitors/inducers, please consult the reviews [8, 15]). The risk for drug–drug interactions is usually potentiated by the fact that oral anti-cancer drugs are often substrates of the efflux transporter P-glycoprotein and CYP3A4 inhibitors/inducers frequently inhibit/induce P-glycoprotein (; eTable 2). Since substances contained in grapefruit juice strongly reduce the intestinal expression of CYP3A4, grapefruit products should be avoided by patients taking an oral anti-cancer drug that is metabolized predominantly via CYP3A4 (eTable 2).
An oral anti-cancer drug may also function as “perpetrator,” i.e., influence the plasma concentrations and effects of simultaneously administered medications. Examples are inhibition of CYP2D6 by abiraterone (CYP2D6 substrates: e.g., metoprolol, tricyclic antidepressants; see ) and inhibition of CYP3A4 by ribociclib. Marked induction of drug-metabolizing enzymes (e.g., CYP3A4) by apalutamide und enzalutamide can lead to loss of therapeutic effect of a variety of substances when these are administered simultaneously (eTable 2).
Although these therapies are frequently referred to as “targeted”, most of the substances are not highly selective but also address so-called off-targets (16). Especially the multikinase inhibitors (e.g., pazopanib and sunitinib), which have a wide range of target structures, are associated with a broad spectrum of side effects. The inhibition of certain targets and off-targets often gives rise to characteristic side effects and class effects (eTable 3). Some side effects, e.g., fatigue, are target independent and are listed in the Summaries of Product Characteristics of around 80% of oral anticancer agents as very commonly occurring side effects.
In general, the occurrence of side effects (depending on the substance involved and the type and severity of event) merits interruption of treatment until the symptoms resolve, and possibly dose reduction. Discontinuation of treatment may be necessary if the side effects are severe or if they persist despite reduction of the dose given. In each individual case, attention should be paid to the SmPC. A recent review investigated 74 pivot studies with regard to the frequency of dose reduction and showed that the dose was lowered in circa 20% to 70% of patients, mostly owing to toxicity (17). Subgroup analyses published for two substances (afatinib and palbociclib) demonstrated clinical efficacy despite dose reduction (17). Evidence of the efficacy of a decreased dose is often not available.
Gastrointestinal side effects
Diarrhea occurs commonly or very commonly with almost all oral anti-cancer drugs, but its severity is extremely variable. Patients receiving treatment with an oral anti-cancer drug that commonly causes diarrhea (eTable 3) should be prescribed loperamide in an initial dose of 4 mg followed by 2 mg every 2 to 4 h (off-label use, see [e3]).
Oral anti-cancer drugs classified as moderately emetogenic (e3–e6) may need to be accompanied by an prophylactic anti-emetic agent, e.g., 5-HT3-receptor antagonists or either metoclopramide or domperidone. The current research data do not suffice for any evidence-based recommendations for anti-emetic prophylaxis in patients on oral anti-cancer treatment (e3).
Cutaneous side effects
Side effects affecting skin and mucous membranes are very common (>10%) (eTable 3). Serious cutaneous reactions (e.g., Stevens–Johnson syndrome) are sometimes described (eTable 3). EGFR inhibitors are known to cause an acneiform rash that may be a predictor of a good response to treatment and a favorable outcome (18, 19, e7). The EGF receptors of the epidermis are affected by the treatment, and this may lead to a typical sequence of rash, xerosis cutis, pruritus, rhagade formation, and alterations of hair and nails (20). BRAF and MEK inhibitors block the downstream signaling pathway and are associated with similar dermatological side effects (for the management of these lesions, see ). VEGFR inhibitors can cause hand–foot syndrome, the development and extent of which differ from the hand–foot syndrome triggered by classic cytostatic drugs. The procedures for prevention and treatment have to be adjusted correspondingly (21).
VEGFR inhibitors are known to cause wound healing disorders, so interruption of treatment is sometimes advisable when surgery is planned (eTable 3). However, in most cases there are no concrete recommendations for the duration of the interruption or the timing of treatment resumption. In our opinion, decisions regarding the treatment break should take into account, in each individual case, the half-life of the oral anti-cancer drug, the type of surgical intervention/the risk of bleeding, the wound healing status, and any comorbidities. Disorders of thyroid function, usually in the form of hypothyroidism, occur with almost all VEGFR inhibitors (22) (eTable 3). Monitoring of thyroid-stimulating hormone (TSH) is then required, accompanied if necessary by initiation of treatment with levothyroxine. A patient who develops fatigue syndrome should be investigated not only for anemia, but also for hypothyroidism.
A further dermatological class effect, in the form of excessive keratinocyte proliferation, occurs with BRAF inhibitors (23). This can manifest as hyperkeratosis (especially hand–foot syndrome at sites exposed to friction and load) or as a secondary malignancy (e.g., cutaneous squamous cell carcinoma) (23).
Cardiovascular side effects
A meta-analysis has shown that VEGFR inhibitors increase the risk of hypertension (relative risk 3.43), bleeding (1.94), and cardiac dysfunction (5.87) (24). It is therefore essential to identify any pre-existing cardiovascular risk factors. The patient’s blood pressure should be routinely measured and, if required, treated according to the pertinent guidelines (25). For some substances hypertension correlates with better response to treatment and is discussed as a potential biomarker (26–28).
Anti-cancer drugs directed against HER2, such as trastuzumab, are known for the occurrence of left ventricular dysfunction (29). Similar side effects have been described for lapitinib, which also acts against HER2. The left ventricular ejection fraction (LVEF) should therefore be determined before the commencement of treatment and at regular intervals during treatment. ABL kinase has a protective effect on cardiomyocytes, so BCR-ABL inhibitors may have cardiotoxic effects (29).
Many oral anti-cancer drugs have been described to cause arrhythmia and QT-interval prolongation. For some substances electrocardiography (ECG) must always be carried out before and during treatment, while for others this is recommended only in high-risk patients (eTable 3). Moreover, patients taking critical substances should have their electrolytes and thyroid function monitored and the QT-prolonging potential of their other medications should be observed.
Compared with healthy persons, cancer patients have a four- to sevenfold risk of thromboembolic events (30). In particular, it should be highlighted that the risk of thromboembolism is increased with immunomodulators (lenalidomide, pomalidomide, thalidomide). In such cases, risk-stratified prophylactic administration of low-dose acetylsalicylic acid (ASA) or low-molecular heparins is recommended (e8).
Myelosuppression and susceptibility to infection
The myelosuppression associated with most new oral anti-cancer drugs is less pronounced than with classic cytotatics. However, pancytopenia and febrile neutropenia can occur with oral anti-cancer drugs, e.g., with CDK4/6 inhibitors (eTable 3). This results in elevated susceptibility to infection. Infections with opportunistic pathogens such as Pneumocystis jirovecii pneumonia have been described in some instances, so the appropriate preventive measures are indicated. The risk of hepatitis B virus (HBV) reactivation has also been reported for some oral anti-cancer drugs and has led to a number of Dear Doctor Letters (Rote-Hand-Briefe). These communications have particularly involved the BCR-ABL kinase inhibitors, but also the immunomodulators and ibrutinib. For the substances concerned, HBV serology testing must be conducted before treatment is initiated.
Effects on liver, kidneys, and lungs
Asymptomatic elevation of liver enzymes can occur with many different oral anti-cancer drugs and may make it necessary to interrupt the treatment or lower the dose. Severe elevation of liver enzymes (grade 3 or 4) is found in up to 12% of patients taking kinase inhibitors (31). Hepatotoxic effects to the point of acute liver failure and/or fulminant hepatitis, sometimes with a fatal outcome, have been described (for, among others, abiraterone, imatinib, lapatinib, pazopanib, and sunitinib) (31; Zytiga SmPC). This is not to be confounded with the yellow coloration of the skin caused by sunitinib.
Impairment of renal function and renal failure may also occur. The inhibition of renal transporters may cause an elevated plasma creatinine concentration without worsening of filtration capacity. For the substances concerned (e.g., abemaciclib, bosutinib, imatinib, and vandetanib), determination of the glomerular filtration rate (GFR) by means of a creatinine-independent technique (e.g., cystatin C) is recommended in order to differentiate apparent worsening of the GFR from genuine renal toxicity (32).
Pulmonary toxicity, for instance the occurrence of pneumonitis or interstitial lung disease, has been decribed for many substances (eTable 3). This potentially life-threatening side effect displays wide interindividual variability with regard to time of onset, severity, and clinical course (33). The occurrence of symptoms such as cough, fever, and dyspnea should therefore prompt consideration of the presence of interstitial lung disease.
Dose adjustment for patients with renal or hepatic insufficiency
There is often specific dosing advice for patients with impaired renal or hepatic function. Instructions extracted from the corresponding SmPC are presented in eTable 4.
Difficulties in oral anti-cancer drug treatment and published data on its optimization
The plasma concentrations of oral anti-cancer drugs vary considerably even in the relatively well controlled setting of clinical studies. Imatinib, for example, shows 60-fold variability of oral clearance (34). For quite a number of oral anti-cancer drugs an association has been shown between exposure and treatment response (e.g., crizotinib, imatinib, pazopanib, and vemurafenib) or between exposure and toxicity (e.g., afatinib, gefitinib, imatinib, and sorafenib) (35, 36). Imatinib has been particularly closely investigated: several studies, for instance, have pointed to improved rates of molecular remission and complete cytogenetic response with higher exposure to the drug (target Cmin ≥ 1000 ng/mL) (35). Nevertheless, plasma concentrations of imatinib are not universally determined; measurement is recommended, for example, whenever unexplained side effects occur (e9). One major cause of variable exposure is treatment adherence (4–6, 37). A review showed high variability in rates of adherence (46% to 100%), depending on treatment regimen, patient characteristics, methods of adherence determination, and the definition of adherence (6). It can be assumed, however, that a not inconsiderable proportion of patients do not adhere to the intake recommendations in the long term: for instance, the average adherence rates for endocrine anti-cancer treatment were only around 50% after 5 years (6). Moreover, the authors of the article cited state that there are only a small number of intervention studies on the topic of improving adherence among patients being treated with oral anti-cancer drugs.
It is by no means easy for treating physicians to ensure medication safety in patients who are prescribed oral anti-cancer drugs (9, 10). These patients are taking an average of five other medications (9). It can be highly challenging to identify and avoid the myriad potential interactions among the various substances. There is a great deal of literature on the difficulty of maintaining medication safety for oral anti-cancer drugs (38), but unfortunately only a small number of high-quality randomized trials have been published that examine how medication safety can be enhanced (39, 40). Preliminary data from a randomized trial at the Comprehensive Cancer Center Erlangen–EMN, supported by German Cancer Aid and planned to continue until 2020, indicate that additional clinical pharmaceutical/pharmacological treatment support reduces the number of drug-related problems and increases patient satisfaction (e10). The data also indicate that severe side effects can be decreased by the intervention and that the number of treatment discontinuations goes down (e10).
The American Society for Clinical Oncology’s guideline “Chemotherapy Administration Safety Standards” includes advised standards for safe prescription and management of oral anti-cancer drugs (e11). The essential recommendations relate to patient training, a physician–patient contact plan adapted to the individual course of treatment, and regular medication analyses (including OTC preparations and complementary medicine products) to identify potential interactions (e11).
Our research into medication safety with regard to orally administered anti-cancer drugs (the AMBORA study) is supported by the German Cancer Aid (project no. 70112447).
The present work was performed in (partial) fulfillment of the requirements for obtaining the degree “Dr. rer. biol. hum.” from the Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU).
Conflict of interest statement
Pauline Dürr has received lecture fees and reimbursement of travel costs from Hoffmann-La Roche.
Prof. Martin F. Fromm has received consultancy fees from Boehringer Ingelheim and lecture fees from Janssen-Cilag. He has administered third-party funds provided by Boehringer Ingelheim in support of a research project of his initiation.
Prof. Frank Dörje has received consultancy fees from Lilly Deutschland and lecture fees from B. Braun Melsungen and Sanofi-Aventis Deutschland.
Katja Schlichtig declares that no conflict of interest exists.
Manuscript received on 30 April 2019, revised version accepted on 15 August 2019
Translated from the original German by David Roseveare
Prof. Dr. med. Martin F. Fromm
Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie
Fahrstr. 17, 91054 Erlangen, Germany
Cite this as:
Schlichtig K, Dürr P, Dörje F, Fromm MF: New oral anti-cancer drugs and medication safety.
Dtsch Arztebl Int 2019; 116: 775–82.
For eReferences please refer to:
Pharmacy, University Hospital Erlangen: Pauline Dürr, Prof. Dr. phil. nat. Frank Dörje
Comprehensive Cancer Center Erlangen—European Metropolitan Region of Nuremberg (EMN), Erlangen: Katja Schlichtig, Pauline Dürr, Prof. Dr. phil. nat. Frank Dörje,
Prof. Dr. med. Martin F. Fromm
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