Principles of Cancer Drug Action

Genetics is a fundamental part of the study of cancer research (see Chapter 1, “Molecular Tools in Cancer Research”). The range of applications for genetics in cancer include hereditary predisposition and interactions of heredity with nonhereditary factors (see Chapter 13, “Genetic and Epigenetic Changes in Cancer”).

In cancer pharmacology, molecular targets that could be relevant to therapy have received the most intense emphasis of PG. This focus includes unique proteins coded by translocations, differences in gene expression between tumors and host tissues, and mutations in sequences. The identification of the most attractive molecular targets and the ability to monitor target engagement during therapy are cornerstones for customized treatment.

As described in the preceding chapter (“Therapeutic Targeting of Cancer Cells”) and elsewhere (e.g., Chapter 8, “Vascular and Interstitial Biology of Tumors”), our understanding of the physiology and molecular biology of tumors has provided a wealth of potential targets for anticancer therapy. Although the relative intensity has magnified, the concept of molecular targeting and linkage to diagnostics for selection and monitoring of individual patients has a long history. The selection of hormonal therapies for patients whose tumors express the estrogen receptor was among the first successful uses of molecular targeting. Among several recent successful examples in the current era of targeted cancer pharmacology, two noteworthy cases are the approval and everyday use of imatinib only in patients with chronic myelogenous leukemia (CML) that is Philadelphia chromosome–positive and trastuzumab only in patients with HER2-positive tumors.

In addition to the obvious attraction of matching drugs to the molecular characteristics of the tumor, the therapeutic index can also be improved by examining host tissues. In his last major research publication,¹ Dr. Abeloff was a leader in a large multicenter study of the PG for cyclophosphamide. The goal was to determine if the germline DNA of patients altered the toxicity profile of cyclophosphamide. A subgroup of women was found who had variant GSTP1 alleles that were associated with less susceptibility to adverse hematologic toxicity in regimens containing cyclophosphamide.

Another large cooperative group clinical study examined germline determinants of paclitaxel neurotoxicity.² Wheeler et al.² used genome-wide analyses coupled with well-characterized data from a cell bank to support a polygenic approach to understanding the variation in host tissue sensitivity to the sensory peripheral neuropathy associated with paclitaxel.

Although both studies were only hypothesis-generating, these examples illustrate the possible ways that the therapeutic index for a drug can be improved by examining the host tissues. In the section on Cancer Drug Delivery, the PG of metabolism and cellular membrane transporter cell membranes in host tissues are discussed.

Combinations of Drugs

As described in the various chapters relating to specific malignancies in Part III of this book, it is rare for a drug to be used as a single agent. The development of combinations would be an extensive topic in itself. Box 29-2 provides a set of points to consider for combinations. Within a combination chemotherapy regimen, the drugs are intended to interact at the PD level. Originally, a major strategy was to combine cancer drugs with nonoverlapping toxicities. Increasingly, more detailed knowledge regarding pathways for cancer drugs permits the design and evaluation of combination strategies that target parallel and/or sequential pathways.

Most combinations are based on a preexisting scientific rationale or by addition of a new agent to an established regimen. However, it would be presumptuous to assume that all possibilities are already understood. One tool to expand the scope of hypothesis generation is the systematic study of all cancer drugs in combination with each other, or in combination with approved agents outside oncology, or testing every investigational agent versus all approved cancer drugs.³ Although this screening approach begins as an empiric exercise, the successful combinations become challenges for explaining the underlying mechanisms of action. The focus on drugs that are already approved provides a potentially fast route to clinical implementation.

Molecular Imaging of Cancer Drug Action

With the widening availability of fluorine-18 fluorodeoxyglucose (¹⁸F-FDG), a consensus was building in the late 1990s that positron emission tomography (PET) would emerge as a complementary tool to anatomic imaging modalities.⁴ Since then, FDG has been highly successful as a general probe in many tumor types, providing additional information to help separate malignant from benign lesions and to monitor response to therapy.

FDG is now an approved drug for imaging. Its success has spurred interest in the development of other probes for PET imaging that are currently in the investigational stage of clinical evaluation, including ¹⁸F-fluorothymidine (FLT). Figure 29-1 shows the results for FLT in a patient with uterine cancer.⁵ At baseline, the FLT image shows major uptake by the tumor, indicative of active proliferation. During treatment with sunitinib, uptake of FLT in the tumor decreased, which was interpreted as reduced proliferation. The image following the withdrawal of treatment exhibited a flare, that is, intensity that rebounded above the baseline value. Anatomic imaging by computed tomography (CT) readily identified the tumor and could monitor regression if that occurred, but FLT provided the ability to follow molecular pathways in real time.

Principles of Cancer Drug Delivery

Once the appropriate drug has been chosen, the most important everyday question in clinical cancer pharmacology is the selection of an appropriate dose. The standard dose is a starting point, but what factors could make this dose too high or too low for individual patients? For many cancer drugs, evidence-based advice is not available. In some cases, guidance for dose adjustment is available based on prior treatment or age, which could be interpreted as PD factors predisposing to greater host tissue sensitivity.

Increasingly, drugs are approved with information about dosage adjustment based on renal function testing, food intake, and use of other drugs concurrently. All of these factors are related to variation in changes in the delivery of drugs. In addition to empiric data from clinical investigations for specific drugs, what are the principles that underlie these decisions based on drug delivery?

Clearance is at the top of the list for drug delivery parameters in Box 29-3 because it is the factor with the greatest impact on dose-adjustment in cancer drug delivery. As stated in Box 29-4, clearance is the summation of all mechanisms for a drug to be removed from the systemic circulation, sometimes called total body clearance. Several specific applications of clearance for dosage adjustment will be covered in the next few sections.

Bioavailability has risen sharply in its utility because of the shift toward oral therapy. This concept will be described in the section on Oral Cancer Drugs. Half-life was previously the most discussed parameter for cancer drug delivery. However, its role is primarily in the development stage, to help guide frequency of dosing. Once a drug is approved for clinical practice, oncologists do not have a frequent need to know this value. Other drug delivery parameters such as volume of distribution or protein binding can have value in specific situations, but only on rare occasions.

Dosage Adjustment Based on Clearance

Compared with other medical areas in which fixed doses are prevalent, dosing in cancer pharmacology has long been titrated on the basis of each patient’s body weight or body surface area. These measurements are intended to serve as first approximations for clearance in the absence of data, but their incremental value compared with a standard dose is unfortunately small, and most current trials have adopted fixed doses, that is, “flat dosing.”⁶

The role of clearance in dosage adjustment is summarized in Box 29-4. The premise is that the standard dose was selected on the basis of the needs of patients with average drug clearance. If a patient has lower clearance than the average, then using the standard dose will lead to higher than average systemic exposure, with the probability of higher than average toxicity. Using a dose reduction to match the lower clearance will normalize the exposure of this patient relative to the average in the population. Similarly, a patient with higher than average clearance will have lower systemic drug exposure than will patients with the average exposure for the population. Although this lower systemic drug exposure will probably reduce the frequency or severity of toxicity, it has the potentially lethal consequence of reducing the response of the tumor.

This overall strategy for dosage adjustment has been elegantly demonstrated for the first scenario in Box 29-3, namely, patients with impaired renal function. The seminal clinical study of carboplatin by Egorin et al.⁷ in patients with variable renal function remains the prototype for dosage adjustment based on impaired organ function. For the other two areas in Box 29-3 (drug-drug interactions and pharmacogenetic factors), many practical cases of dosage adjustment exist. Specific examples will be discussed in the following sections.

Drug-Drug Interactions

Many categories of drug-drug interactions exist. The anticancer drugs in a chemotherapy regimen, which are generally intended to work at the level of mechanisms of drug action, are only the tip of the iceberg for drug-drug interactions. Patients with cancer are simultaneously treated with drugs for various other conditions, including diseases of the heart, gastrointestinal (GI) tract, lungs, infections, depression, and the relief of pain. All of these permutations in polypharmacy can potentially affect the delivery of cancer drugs. As a consequence of these interactions, the standard doses of drugs may need to be either reduced or increased.

Most drug-drug interactions are manifested as safety issues because of increased exposure subsequent to reduced clearance. However, induction (increasing) of clearance can decrease toxicity. Unfortunately, although this type of interaction is “silent” in terms of enhanced toxicity, reduced exposure to drug can also generate the worst toxicity of all: decreases in efficacy.

Drug-drug metabolic interactions are possible for parenteral routes of drug delivery, but they are far more common for the oral route. Because metabolism is the primary determinant of clearance for most drugs, it is the dominant controller for changes in plasma concentrations. Following the paradigm in Box 29-4, inhibition of drug metabolism via a drug-drug interaction will produce lower clearance and thus higher systemic exposure. A reduction in dose may be necessary to avoid increased toxicity. Conversely, drugs such as phenytoin can induce the expression of certain metabolizing enzymes, which would decrease systemic concentrations for the drugs cleared via those enzymes, because the rate of their metabolism would be faster. Decreased exposure increases the probability of inadequate delivery of the cancer drug to the tumor. In the section on Oral Cancer Drugs, Table 29-1 provides some examples of the enzymatic pathways that metabolize cancer drugs.

Alternate Routes of Cancer Drug Delivery

The subcutaneous (SC) route of delivery has emerged as an occasional solution to difficulties in drug delivery. The two issues that drive consideration of the SC route are: (1) inability of a drug to reliably traverse the GI tract and avoid presystemic metabolism, and (2) impracticality of the IV route for relatively frequent dosing.

The approval of 5-azacytidine in 2004 for myelodysplastic syndromes is an ideal example to demonstrate the advantages of SC drug delivery. In addition to incompatibility with oral delivery, 5-azacytidine requires daily parenteral dosing for 7 consecutive days. SC and IV delivery were both approved. The patient population for myelodysplastic syndromes has a substantial fraction of elderly patients, for whom there would be challenges in obtaining daily IV treatment.

In 2012, the approval for bortezomib was extended from IV delivery to include the SC route. Because of the frequency of dosing, this change is expected to substantially expand the utility of this drug, which previously required IV dosing. Most patients received bortezomib twice a week for their first 4 weeks, followed by weekly doses.

The primary limitation for SC delivery is the low volume of drug solution that can be delivered. The success of chronic SC insulin delivery is driven by injection of small volumes, 1 mL or less, which eases patient acceptance of injection site issues. For 5-azacytidine, the requirement for 4 mL per injection site is more difficult, but the treatment period is not the open-ended commitment required for insulin dosing.

Regional Cancer Drug Delivery

When cancer is localized or hiding between barriers to cancer drug delivery, administering the drug directly to the region of disease is an attractive concept. Nonetheless, many investigations of regional drug delivery have failed to demonstrate increased benefit compared with systemic treatment. The choice of drug is the first consideration. Cyclophosphamide and other prodrugs that must be metabolized to their active species are not suitable for regional delivery. The potential advantage of local delivery is lost because the drug must enter the body and be metabolized and then circulate throughout the body as if it had been systemically delivered.

Intraarterial catheterization has been technically feasible for delivery of cancer drugs to a variety of places in the body. The use of an implanted pump for the intraarterial delivery of fluorodeoxyuridine is approved for the treatment of liver metastases from colorectal cancer and is the most common application of this approach.¹⁶

Intraperitoneal delivery of drugs for treatment of localized ovarian cancer and other intraperitoneal malignancies has undergone many evaluations. Three randomized phase 3 studies have shown a survival benefit for intraperitoneal delivery compared with the IV route.¹⁷ Despite this success, the lack of familiarity with the catheters, uniform distribution within the peritoneal cavity, and other factors have slowed the penetration of this modality into routine practice.

Intrathecal delivery remains a mainstay for pediatric leukemia. As previously mentioned, the transporters that constitute the blood-brain barrier tightly control the passage of drugs into the brain. Direct injection of drug into the cerebral spinal fluid produces very high local concentrations for the areas close to the tissue–cerebral spinal fluid interfaces. The major limitation of intrathecal delivery to treat solid tumors is the inability of cancer drugs to penetrate deeply into tissue to reach all of the disease.

The intravesicular route is standard care for some stages of bladder cancer. Bacillus Calmette-Guérin (BCG) is an approved drug for this indication, and several other drugs are less commonly used.

Generics Versus Brand Name

Oncologists and patients become accustomed to a brand-name drug, sometimes called the “innovator drug,” and then need to readjust to the nonproprietary generic name and to different manufacturing sources. The first marketed version is covered by patent rights and/or various incentive programs that provide the company with a period during which they have an exclusive right of sale. After these periods of exclusivity expire, the drug can be marketed by other companies as a generic, which contains the same active ingredients.

For oral cancer drugs, the company manufacturing the generic drug must also provide evidence of equivalence, which is defined as the demonstration that the original drug and the generic drug produce similar plasma concentrations of the active ingredient. The fundamental assumption is that patients should obtain similar benefits (and toxicity profiles) if the same exposure of the active ingredient is delivered. This rule is not applied solely to generic approvals; it is the same principle applied for changes in the production of brand-name drugs, including changes in suppliers of bulk ingredients, manufacturing processes, or locations for producing pills. All of these events occur throughout the marketing history of the drug but are not highly visible to oncologists and their patients. The principles for ensuring similarity or equivalence are the same for all marketed oral drugs.

For cancer drugs and a few other areas of medicine, the narrow therapeutic index sharpens the focus on the boundaries of tolerance for deviation from the current product. Regulatory authorities such as the FDA have the authority to set tighter specifications for specific cases and occasionally do so.

Shortages of Cancer Drugs

Patients and oncologists experienced an unprecedented rise in drug shortages in 2011-2012. Shortages were experience in other medical areas as well, but cancer drugs were hardest hit. These shortages were an unintended consequence of the interplay among the market share for injectable generic cancer drugs, drug distribution infrastructure, and reimbursement policies. It is easy to have simplistic views of shortages, their causes, and their fixes, but discussion of the wide ranges of opinions are beyond the scope of this chapter. It is helpful to note that the current framework for generic marketing has existed in the United States since 1984. The generic drug system worked well for decades, but it is fragile for specialized products such as injectables. In 2012, new legislation required earlier notification to the FDA of potential drug shortages. This strategy has been widely praised, but it is recognized that it is not sufficient to eliminate future shortages.

Speculation that many shortages could be bypassed by substituting drugs that are “almost as good” was dramatically dashed by the study of Metzger et al.¹⁸ Because of a lack of supply of mechlorethamine, cyclophosphamide was substituted in the multidrug regimen for children with Hodgkin lymphoma. In only 2 years, more than a doubling occurred in the number of patients who no longer had event-free survival.

Approved Indications and Off-Label Use of Drugs

The description of approved indications is included on the drug label. At the beginning of the era of cancer chemotherapy, drugs were approved (indicated) for broad use, for example, “for treatment of cancer.” As we have progressed to a period in which many treatments are already established, the approved indications for new drugs are increasingly narrowed to descriptions such as “the treatment of estrogen-receptor positive breast cancer after second relapse, following at least one regimen containing an anthracycline and one regiment with a taxane.”

On one hand, this narrowness is a precise description of the clinical studies that determined the specific subpopulations that benefit from the drug. On the other hand, with very rare exceptions (e.g., thalidomide restrictive distribution), physicians have the right to prescribe any drug for any situation in which their judgment indicates a benefit for a specific individual patient. In some sense, approval of a drug for marketing in any indication, including nononcologic disease, provides the opportunity to use that agent “for the treatment of cancer.” Of course, in addition to regulatory approvals, powerful pragmatic limits exist. Most patients face reimbursement hurdles for “off-label” use. The prescription can be written (or electronically transmitted), but it cannot be filled unless its cost is reimbursed.

For oncologists, prescribing drugs for uses off-label could create a situation of legal liability in the event of an unsuccessful or adverse outcome. In contrast, the prescribing of drugs for the indications approved by the FDA provides a major shield from liability concerns. Similarly, other evidence-based or generally accepted authoritative compendia also have influence in the areas of both reimbursement and legal liability. Companies are not permitted to advertise a drug for any use except its approved indications.

New Indications and Repurposing (Repositioning)

Terms such as “repurposing” or “repositioning” have become commonplace as researchers and companies seek new uses for approved drugs. Because the safety of the drug has already been established and the supply of clinical-grade drug is readily available, the road to evaluation in patients is accelerated. Initial approval for a drug is not the end of its clinical development.

The simplest version of this concept is to search within the same therapeutic area. Additional uses for cancer drugs are often actively sought. Once again, imatinib sets the standard. In this case, the approved indications were extended from CML to gastrointestinal stromal tumor, and again to various rare cancers.

When therapeutic boundaries are crossed, potential therapies could move from oncology to other diseases or from other diseases into oncology. Methotrexate is used in juvenile and rheumatoid arthritis. Cyclophosphamide is used in both children and adults for nephrotic syndrome. Paclitaxel is used as a coating for cardiac stents. In the other direction, cancer researchers have a recurring interest in evaluation of potential anticancer effects of marketed drugs from outside oncology. Current examples include metformin and simvastatin.

Development and Discovery of Cancer Drugs

Within the context of recent trends for new cancer drugs (Box 29-6), the processes for development and discovery need to be clearly understood. However, the actual research that comprises these phases needs to adapt to the continuous stream of new findings in cancer biology. Further, the optimal approach to information gathering during human evaluation of cancer drugs is continually reevaluated, and the relevance of preclinical models to the clinical realities is continually improved.

The lack of consistent definitions of the terms “new drug” and “investigational drug” can be a minor stumbling block in understanding the development process. In the United States, the regulatory definition for a “new drug” is an agent that is regulated under certain portions of the Food, Drug, and Cosmetic Act. All marketed cancer drugs are “new” drugs under this definition, regardless of how long they have been marketed. Outside the regulatory sphere, a compound is described as a “new” drug when it is first marketed, such as the initial approval of imatinib for the indication of treatment of patients with Philadelphia chromosome–positive CML. As discussed earlier, new indications are continually sought for cancer drugs. Thus even though imatinib was already a “new” drug approved for CML, it was simultaneously an “investigational” agent for treatment of gastrointestinal stromal tumors until it was subsequently approved for that indication.

Clinical Phases of Drug Development

As indicated in Box 29-7, the clinical stages of drug development have been divided into phases that are related to the primary goals. These stages have historical and regulatory significance, but the boundaries are always being pushed, and it is not possible to assign every compound into the same bins. For patients with cancer, this view of clinical development is continually challenged by the compelling need to provide therapeutic options when no treatments have been established. The boundaries that are calibrated for less serious diseases may be a bit more flexible in oncology, just as the definition of maximum tolerated dose is a relative term that depends on the medical scenario. Phase 1, phase 2, and phase 3 are long-established terms. Phase 4 was created by a formal change in FDA regulations. Phase 0 is a less-formal term used by some investigators to describe early explorations to seek information before making a decision to launch full-scale development.

Working backward, phase 3 clinical studies are the largest and most expensive periods of clinical development and have the highest profile in the oncology community. The results of these studies are carefully followed and are prominently featured at large national meetings. These trials are designated as potentially “practice changing” because of their potential for an immediate improvement in the standard of care for the specific stage and type of cancer. The pivotal hallmark of phase 3 trials is a randomized comparison of two or more treatment groups. These trials are undertaken based on preliminary evidence of anticancer activity, and the key question is simply stated: How does the new therapy compare with established therapy?

When phase 3 trials include an investigational agent, the data from these trials are the ordinary basis for the regulatory decision to permit an indication for marketing in the population studied in the trial. Thus these trials are sponsored by the commercial organizations that will be seeking marketing approval. If the phase 3 trial is a comparison of groups for which all of the drugs are off-patent, then the NCI is usually the only organization with the resources and the mission to support such studies. Nonprofit organizations could also serve this role, but they tend to support earlier stages of clinical studies because of the cost of phase 3.

Phase 2 clinical trials are the setting for determining if an agent or combination of agents has sufficient activity in well-defined groups of patients who have no established treatments.¹⁹ In the majority of phase 2 studies, there is only a single treatment group, but randomized designs of two or more groups have been increasingly used. The goal is to determine if the activity of the agent or combination is sufficient to move into much larger phase 3 trials with comparison to standard treatments. Unfortunately, areas within oncology remain for which no standard treatment has been established. In such cases, phase 2 studies can be sufficient for regulatory approval.

Phase 1 clinical studies have historically been the first-in-human studies for new agents or for combinations of investigational or approved drugs. In diseases other than cancer, these safety studies are generally conducted with healthy volunteers. Traditionally, phase 1 clinical studies of cancer drugs were only conducted with patients because of the potential for acute, severe toxicity, as well as longer-term issues such as carcinogenicity or mutagenicity for many classes of older cancer drugs. As the biological properties of cancer drugs have evolved, some investigational agents have adverse effect profiles that are similar to agents outside oncology. For compounds sponsored by the pharmaceutical industry, there has been a trend toward use of healthy volunteers in phase 1 clinical studies for certain classes of cancer drugs.

It is likely that both strategies will co-exist, and the approach will be customized for each investigational agent. Phase 1 studies in healthy volunteers have a track record of lower costs, as well as faster and more reliable recruitment of subjects. On the other hand, the enormous value in determination of molecular effects in tumors via biopsies or imaging is unique to the inclusion of patients in these studies.

Phase 0 clinical studies are an approach to first-in-human studies that extends the preclinical search for specific types of information into the clinic. Frequently, there are concentrations that are considered essential to activity.20,21 For oral therapy, concerns exist about the consistency of absorption.

Phase 4 was added to the process for clinical development to permit approval when sufficient demonstration of safety and efficacy has been established, but before all studies are completed.

For example, during the review of the marketing application, it could be determined that certain subpopulations were not included in the pivotal studies. In return for faster approval, the sponsor of the drug makes a commitment to conduct “postmarketing” studies to fill any gaps defined by the FDA. Situations include clinical studies of patients with impaired organ function, drug-drug interactions, or expanded studies of elderly patients.

The numerical order of the clinical phases provides a logical progression for development but should not be considered as universally linear. As previously noted, a new drug is sometimes approved on the basis of phase 2 studies, and phase 3 trials are not conducted. As another example, an unanticipated problem with dosing during a phase 2 investigation might prompt the return to phase 1 to improve characterization of doses and schedules. Precedents exist for skipping phase 2 studies and moving directly from phase 1 to phase 3. Evidence of activity in phase 1 may seem so compelling that it warrants immediate comparison with standard of care. This strategy has a high risk in terms of the resources invested in a compound without much understanding of the probable activity. Of course, the potential exists for a high reward in terms of bringing new treatments to patients, as well as financially. Of course, this strategy is only feasible if the phase 1 study is conducted in patients with cancer.

Cancer Pharmacology across the Drug Discovery/Development Process

Applications of the principles of cancer pharmacology are embedded in the continuum from early drug discovery through preclinical development, and then bridging to the preapproval stages of clinical development.

During the development phases for a cancer drug, it is essential to monitor the relative drug delivery, as assessed by systemic concentration. When comparing activity studies in murine models, safety studies in various mammals, or early clinical studies, plasma concentrations can be monitored. Variation across animal models might signal important interspecies differences in either PK (e.g., metabolism) or PD (e.g., inherent host cell sensitivity) factors.

In the same manner, when making comparisons between observations of activity in cell culture versus concentrations that can be safely achieved in vivo, it is prudent to consider reasons for any discrepancies. Skepticism is particularly appropriate if “interesting” activity is observed in vitro at concentrations much higher than are achievable in vivo.