THE CANCER PATIENT GUIDE
Conveying or receiving an initial diagnosis of cancer, or the knowledge that cancer has recurred, are among the most difficult of human enterprises, and no amount of either specialized training or forewarning can adequately assuage the intensity of the emotions associated with these encounters. Patients often experience a storm of feelings that may limit useful discussion immediately following the receipt of a diagnosis of cancer. Unquestionably, it is difficult for even the most well-informed patient to process the complexities of his or her individual situation, including the range of additional diagnostic tests that may be required and the potentially vast array of treatment options and potential outcomes that lie ahead. And yet, at some point prior to the initiation of treatment, the physician and the patient must discuss the diagnosis, its implications, and therapeutic alternatives. Because of the wide range of potential prognoses (from curable disseminated testicular cancer to the limited lifespan of patients with locally advanced gastric or pancreatic cancer), it is often useful for family members or close friends to be present in the consulting room when detailed discussions of the complexities of either disease or therapy are conducted, both to provide emotional support and to be another “set of ears” during the visit. It is helpful to ask patients directly: “What do you understand about your diagnosis and treatment?” Family members or close associates of the patient may also be especially helpful in developing a written or digital record of the questions posed to and answered by health care providers; many patients find such a record to be especially helpful for later reference.
If the physician is not familiar with the latest treatment options, prompt referral to a specialist, whether a surgical oncologist, radiation oncologist, or medical oncologist, is imperative. The generalist should not be a therapeutic nihilist unless he or she is intimately involved in the field and is well versed in the potential risks and benefits of currently available therapies and clinical trials.
Diagnostic possibilities are protean for the wide range of human malignancies that may be discovered either in the presence of nonspecific but foreboding symptoms or signs (severe weight loss, hematuria, jaundice) or in asymptomatic individuals (e.g., during a routine physical examination). The importance of the medical history and physical examination, however, must be emphasized whether or not a pathologic diagnosis of cancer has already been confirmed. One of the most important considerations that underlies the approach to both the diagnostic work-up and choice of cancer treatment (surgical, radiation, or systemic therapy) is the patient’s basic physiologic condition or “performance status”. For example, a past medical history of prolonged tobacco smoking is not only relevant to a possible diagnosis of lung cancer but to the ability of a patient to tolerate potentially curable multimodality treatment. Underlying evidence of excessive alcohol consumption may play a role in both the tolerance for and metabolism of systemic chemotherapeutic agents. Family histories of cancer can provide prognostic indicators as well as suggest molecularly guided treatment approaches in, for example, women with possible BRCA1-related breast or ovarian cancer. It is also critical to assess the environment of care, including all of the patient’s support systems, that may be sorely tested by the experience of a cancer diagnosis and the interventions that ensue therefrom. Finally, the physical examination will define the extent of certain sites of measurable malignancy—lymph node, splenic, or hepatic enlargement, for example—as well as the patient’s muscle strength, the presence of possible malignant effusions, and potential central or peripheral neuropathies reflective of metastatic disease or paraneoplastic syndromes. But most importantly, it provides the treating physician with an initial sense of the patient’s well-being, or lack thereof, prior to the initiation of therapy.
|KARNOFSKY PERFORMANCE STATUS SCALE|
|VALUE||LEVEL OF FUNCTIONAL CAPACITY|
|100||Normal, no complaints, no evidence of disease|
|90||Able to carry on normal activity, minor signs or symptoms of disease|
|80||Normal activity with effort, some signs or symptoms of disease|
|70||Cares for self, unable to carry on normal activity or to do active work|
|60||Requires occasional assistance but is able to care for most needs|
|50||Requires considerable assistance and frequent medical care|
|40||Disabled, requires special care and assistance|
|30||Severely disabled; hospitalization is indicated, although death is not imminent|
|20||Hospitalization is necessary; very sick, active supportive treatment necessary|
|10||Moribund; fatal processes progressing rapidly|
|EASTERN COOPERATIVE ONCOLOGY GROUP (ZUBROD) PERFORMANCE SCALE|
|1||Symptomatic; fully ambulatory|
|2||Symptomatic; in bed < 50% of day|
|3||Symptomatic; in bed > 50% of day|
A lesion that has been found on physical examination, or following radiographic studies prompted by abnormal laboratory results, will often undergo a percutaneous biopsy for pathologic evaluation. It is critical that the biopsy be representative of the entire tumor and be robust enough in size that appropriate investigations (e.g., special immunohistologic stains, flow cytometry, cytogenetics, hormone assays) can be performed before treatment is initiated. If there is a question whether the lesion is benign or malignant or about its proper classification, consideration should be given to additional biopsies, and consultation with a reference pathologist may be indicated. The recent emergence of a wide range of molecularly targeted systemic therapeutic agents active in solid tumors has focused renewed attention on obtaining sufficient tissue from patients for performance of the essential molecular studies (DNA sequencing, RNA expression analyses, FISH [fluorescence in situ hybridization]) necessary to determine treatment choice. A1 Although tumors removed by surgical resection are routinely of sufficient size to permit the full range of diagnostic examinations, active involvement of a skilled interventional radiologist or endoscopist is often required to produce both the size and number of tumor biopsies required for modern cancer therapeutic decision making. Finally, there is seldom a need for such rapid therapy that appropriate pretreatment evaluations cannot be performed. For some tumor sites such as the colon, there is one predominant histology but critical molecular features of the tumor (presence or absence of a mutant Ras oncogene) that can define therapy; in others, such as the lung, the distinction between small cell lung cancer and non–small cell lung cancer is critical for treatment. For breast cancer, the treating physician is interested in a variety of factors, such as histology, tumor grade, the presence (and its degree) or absence of estrogen and progesterone receptor proteins, and the presence of HER2/neu overexpression. The rapidly increasing sophistication of molecular diagnostics has, furthermore, begun to improve the potential to localize cancers of unknown primary origin.
Staging and Multidisciplinary Evaluation
After a tissue diagnosis has been established, staging follows to determine the extent of disease. The American Joint Committee on Cancer staging system is considered the standard in the United States and is based on the TNM (tumor, node, metastasis) system that is anatomically and pathologically based. The approach to staging from a clinical perspective depends on the type of cancer, but it commonly includes computed tomography (CT), magnetic resonance imaging (MRI), radionuclide scans, and, increasingly, positron emission tomography (PET). These studies are supplemented by routine hematologic and chemistry profiles, tumor markers (when appropriate), and in some cases, bone marrow aspiration and biopsy.
The goal of tumor staging is to define the extent of a patient’s disease. Tumor stage provides critical prognostic information that will inform the therapeutic approach that is most appropriate. Accurate staging involves delineating the magnitude of the tumor determined by imaging procedures, as well as confirming the pathologic limits of disease spread from tissues removed at surgery. In essence, for most solid tumor patients, the tumor stage will establish whether the treatment will focus on a local (usually confined to an organ), regional, or disseminated pattern of malignancy and can determine whether the expected outcome of therapy is curative or palliative. On the other hand, hematopoietic malignancies are often disseminated at diagnosis and demand their own prognostic classifiers.
The focus of the staging work-up is to identify potential sites of metastases and to establish indicator lesions with which to monitor therapy. For most solid tumors, CT scans can accomplish both goals; however, in some circumstances, other imaging modalities are more appropriate for therapeutic monitoring (e.g., MRI when central nervous system [CNS] metastases are likely [small cell lung cancer], or combined PET/CT imaging to establish that a given lesion is likely to be malignant, or in diseases where early metabolic responses to treatment can be confirmed (such as for gastrointestinal stromal tumors). In patients with established advanced disease, indicator lesions for therapeutic monitoring should be carefully chosen prior to the initiation of treatment, be well documented in the medical record, and should be evaluated with the minimum frequency of imaging procedures required for accurate follow-up, consistent with evidence-based medical practice or the clinical protocol on which the patient is entered.
The consulting medical oncologist may often be advised by a local tumor board composed of other medical, surgical, and radiation oncologists, pathologists, radiologists, and members of the cancer care team (oncology nurses, social workers, and palliative care specialists). In such a multidisciplinary environment, the patient’s overall prognosis can be reviewed and alternatives for care, including standard therapy, possible clinical trials, a second opinion, or no treatment, can be considered. The outcome of such an evaluation is usually viewed by patients and families as an important component in the coordinated development of an overall plan for either further diagnostic procedures or therapy. Finally, many oncologists actively participate in clinical trials that may make investigational drugs or other investigational procedures available for patients, or they may suggest referral to a tertiary cancer center where disease-specific clinical trials are available, as appropriate.
Intention of Treatment
Based on the multidisciplinary evaluation of an accurately staged patient, it should be possible to define whether the intent of treatment is curative or palliative. Whether or not this is done during a formal tumor board or multidisciplinary case conference, clarity must be reached regarding the specific choice of therapeutic options (and their potential risks and benefits, overall goals, and alternatives) when considered in the context of the wishes of the patient and family. This is particularly true when the side effects of treatment are substantial (such as for the multidisciplinary management of non–small cell lung cancer or esophageal cancer). For cancers amenable to surgery, resection is often an initial alternative if the patient is a suitable candidate for anesthesia and is otherwise in acceptable condition in terms of concomitant or comorbid illnesses. Determination of the patient’s performance score is a simple means of assessing functional status. If life expectancy is limited or if the patient is not a good candidate for surgery, more limited approaches to palliative radiation or systemic therapy may be appropriate. There are now substantial data suggesting that the extent of surgery required for an optimal long-term outcome may be reduced for certain solid tumors through the use of presurgical neoadjuvant chemotherapy, often as part of an “organ-sparing” approach. Concomitant and/or sequential multimodality treatments also have the potential to produce long-term disease-free remissions. When the best therapeutic outcomes require the combined skills of surgical, radiation, and medical oncologists, the need for coordination of care among a variety of specialists becomes paramount, and the use of predefined treatment regimens critical.
Therapeutic Paradigm and Therapeutic Index
The therapeutic paradigm in oncology, although still directed at improving the multidisciplinary care model, has begun to change from one focused on delivering treatments at the “maximally tolerated dose” for normal tissues, to therapy that is personalized based on both the molecular characteristics of the patient’s tumor as well as any individual germline features that could modify treatment tolerance. Based on the rapid expansion of our understanding of somatic mutations in human malignancies, and the ability to produce therapeutic molecules that can target specific deficiencies in tumoral DNA repair, growth factor signaling, or energy balance, for example, the currently developing approach to cancer therapeutics involves the employment of predictive molecular markers to guide all modalities of cancer care for the benefit of unique cancer patients. Hence, the focus of oncologists today is on the elaboration of treatments that can be administered with a high therapeutic index, defined as the comparison of the amount of treatment that is effective to the amount that causes toxicity; in this era of personalized cancer medicine, the goal of cancer therapy is to minimize normal tissue toxicity while preserving quality of life by advancing therapies or procedures that are targeted only to specific molecular dependencies in tumors.
Surgery is used to biopsy a suspected lesion, remove the primary tumor, bypass obstructions, provide palliation, and prevent cancers in patients at very high risk because of genetic predispositions or chronic inflammatory states. Surgical staging also establishes the extent of disease. For example, patients with ovarian cancer benefit from surgical “debulking” to remove all visible disease, leaving minimal residual tumor, a process that may enhance the effectiveness of systemic treatment. Placement of a venous access device at the time of surgery, if considered proactively, may eliminate the need for a second surgical anesthesia.
Surgery remains the most common method to cure localized cancers such as breast cancer, colorectal cancer, and lung cancer, but it is limited by the location of the tumor, its extension, and distant metastases. Even if a tumor cannot be removed, surgical biopsy provides confirmation of the diagnosis and additional tissue for molecular analysis. Occasionally, an obstructing lesion can be bypassed to provide palliation.
In specific circumstances when the primary tumor has been controlled, removal of a single metastasis (metastasectomy) can result in long-term survival; an example is resection of a solitary liver metastasis found at the time of colectomy for colorectal cancer. A variety of surgical techniques, such as radiofrequency ablation or cryoablation, can also be used to treat hepatic metastases in carefully selected patients. Adjuvant chemotherapy is often given after surgery in this situation to treat microscopic metastases.
The careful application of reconstructive surgery after a disfiguring procedure is critical to long-term physical and emotional well-being. Examples include postmastectomy breast reconstruction and plastic surgical procedures to correct deformities following head and neck surgery.
Ionizing radiation can be delivered using beams of high-energy rays, known as teletherapy, via a linear accelerator; by brachytherapy, through the application of sealed radioactive implants, seeds, wires, or plaques; and intravenously by using radioisotopes, either directly or attached to antibodies or other targeting molecules. Radiation interacts with water molecules to induce free radical species, including hydroxyl radicals, which damage DNA, proteins, and lipid membranes, leading to cell death. Like chemotherapy, radiation therapy is most effective against rapidly dividing cells that are well oxygenated.
The utility of radiation therapy is limited by the inapparent extension of disease outside a local treatment field, by the location of tumors next to normal structures that must be preserved, and by the presence of distant metastases. Normal tissue tolerance, which varies across different organs and tissues, often prevents the use of radiation doses that could uniformly eradicate cancers. Radiation therapy is also limited by tumor hypoxia: large, bulky tumors are frequently relatively radioresistant, whereas well-oxygenated tumors can be more effectively treated at lower doses. In addition to acute radiation-related toxicities, late effects of radiation therapy include second malignancies, such as breast cancers that may occur decades after administering thoracic radiation fields during curative treatment for Hodgkin disease.
Radiation therapy can be used as primary treatment, as part of multimodality therapy, in the adjuvant setting, and for palliation. As a single modality, radiation therapy can be curative for early-stage malignancies such as laryngeal cancer, cervical cancer, and prostate cancer. Breast-conserving surgery requires the use of radiation to treat the remaining breast. Partial irradiation techniques using three-dimensional planning with external beam radiation have recently been developed and used in selected patients with appropriately placed and sized breast cancers. For localized prostate cancer, implanted radioactive seeds of gold or palladium offer an alternative to surgery or external beam radiation therapy in certain patients.
Newer techniques, such as intensity-modulated radiation therapy (IMRT), permit more exact tailoring of the dose to the target, thereby reducing damage to the surrounding normal tissues. Stereotactic radiation therapy or gamma knife techniques allow the treatment of primary or metastatic brain tumors measuring up to 3 cm with enhanced accuracy, minimizing damage to normal brain. Particle-based treatment with protons has expanded in use, particularly for limited-stage prostate cancer, based on the potential to deliver higher radiation doses locally. However, there are no randomized studies demonstrating its superiority over other approaches using computational techniques to improve the specificity of radiation delivery (such as IMRT); it is also used for some uveal melanomas, base-of-skull tumors, and a few pediatric malignancies.
Low- to moderate-dose palliative radiation is used to ameliorate symptomatic cancer when cure is no longer the goal. For instance, radiation therapy can improve symptoms from brain metastases, relieve pain from bone lesions, relieve some obstructing lesions, and sometimes improve hemoptysis caused by lung cancer or bleeding from a gynecologic malignancy. Bone-seeking radioisotopes of samarium, strontium, or radium may relieve pain from bone metastases in prostate cancer or breast cancer.
The fundamental goal of cancer pharmacology is the development of treatments that can be matched to the intrinsic sensitivity of specific tumors, and that can be delivered in concentrations that affect the molecular target of interest with an acceptable therapeutic index. Three properties of all cancer therapeutic agents underlie their clinical utility: (1) pharmacogenetics of the drug (how the germline or somatic expression of genes alters normal tissue toxicity or antitumor efficacy); (2) action of the drug (pharmacodynamics, or what the drug does to the tumor/body); and (3) delivery of the drug (pharmacokinetics, or what the body does to the drug).
Pharmacogenetics, the study of inherited interindividual differences in drug disposition and effects, is important in cancer therapy because genetic polymorphisms in drug-metabolizing enzymes may be responsible for variations in efficacy and toxicity observed with many chemotherapeutic agents. Drugs potentially affected by polymorphisms identified to date include the thiopurines, 5-fluorouracil, irinotecan, taxanes, and the platinum agents. In patients who are heterozygous or homozygous for deficiencies in metabolizing enzymes, toxicity can be dramatically enhanced. Testing for pharmacogenetic variations that predict for altered normal tissue tolerance is currently available for thiopurines and irinotecan.
Molecular Targeting and Pharmacodynamics
Molecular diagnostic testing to predict antitumor activity for hormonal and anti-HER2 therapeutics has been part of routine oncologic practice for the past two decades, but the recent past has witnessed a remarkable increase in the use of molecular diagnostic testing in cancer drug development and a consequent increase in the number of molecularly targeted anticancer agents that are prescribed only after demonstration of specific molecular abnormalities (predictive of response) in primary or metastatic tumor tissues. Examples of such diagnostic/drug pairs include: EGFR mutations in lung adenocarcinomas and erlotinib; ALK tyrosine kinase translocations in lung adenocarcinomas and crizotinib; and BRAF V600E mutations in melanoma and vemurafenib. Recent advances in the process of cancer drug discovery, furthermore, have focused on demonstrating engagement of presumed molecular targets of drug action early in the development process (e.g., evidence of enzyme inhibition, protein dephosphorylation, or DNA damage) as the first step toward implementation of a predictive molecular test for the drug in clinical practice.
Pharmacokinetics and Drug Delivery
Dose selection in oncology is a critical issue primarily because anticancer agents have among the smallest therapeutic ratios in all of medicine. When tumors are responsive to treatment, higher doses may or may not be more effective but are likely to be more toxic to normal tissues. The clearance of a drug from both the systemic circulation and, potentially, from specific physiologic compartments (CNS, thoracic, or peritoneal effusions) is the most important determinant of the dose chosen for a particular patient. It is a composite of all the routes and mechanisms by which the drug can be eliminated from the body and thus determines dose and dose adjustments in the face of changes in drug metabolism, transport, or altered organ function. Although it is important to develop a clear understanding of drug half-lives to establish initial dosing schedules, drug clearance will be the actual determinant of the dose of drug that can be safely administered. Another aspect of drug delivery is the use of body surface area dosing versus flat dosing (using fixed amounts of a drug) in oncologic practice. Although dosing based on body surface area has a long history in oncology (unlike other areas of internal medicine), very little data support this approach; for most agents in common use, empirically determined pharmacokinetic variability from patient to patient is far greater than that which could reasonably be ameliorated by dosing based on weight or surface area.
Routes of Drug Dosing
Prior to the approval of imatinib (administered orally) for the treatment of chronic myelogenous leukemia in 2001, most anticancer agents were developed for parenteral use. However, although intravenous administration remains important, most new anticancer agents are developed for oral use; 7 of the 11 cancer drugs approved by the U.S. Food and Drug Administration (FDA) in 2012 are given by mouth. This change in the route of administration for new drugs brings to the forefront many drug delivery issues that had previously not been routinely considered in the oncology clinic, such as: treatment adherence (does the patient take his/her medication), variability in absorption due to food effects, emesis prior to drug absorption, first-pass metabolism in the liver or intestine, and difficulties in swallowing. For example, whether the orally administered anti-HER1/2 drug lapatinib is taken with food or on an empty stomach can alter its absorption by as much as 10-fold.
In addition to intravenous or oral dosing, anticancer drugs may be used: for intrathecal delivery (to overcome the blood-brain barrier) for the treatment or prevention of meningeal spread of leukemia; for intravesicle therapy of early-stage bladder cancer; for intra-arterial delivery of fluoropyrimidines or other agents to treat hepatic metastases from colon cancer or hepatocellular carcinoma; and for intraperitoneal administration of drugs such as platinum agents for ovarian cancer therapy, which provides a survival advantage for these agents compared with intravenous treatment. In almost all cases, administration of anticancer agents by other than the oral or intravenous routes requires intimate involvement of an oncologic specialist.
Clinical trials in oncology are defined by the steps in which new diagnostic approaches, therapeutic agents, or procedures are tested to determine whether they will become part of the standard care for cancer patients. During interventional (rather than observational) clinical trials, specific treatments or procedures are assigned to participants, and the effects of the interventions are measured. For trials of new oncologic drugs, the FDA recognizes several states in the drug development process. Exploratory studies of new drugs examined for the first time in humans (phase 0 trials) may be conducted in on a limited number of patients to define a drug’s mechanism of action or biodistribution and to guide subsequent dosing in larger studies. Phase 1 trials define, using a variety of dose-escalation strategies, the maximum dose that can be safely administered to humans and the most appropriate schedule for drug administration, as well as the pharmacokinetic (and more recently pharmacodynamics) profile of the drug. Phase 2 trials often enroll 50 to 150 subjects and focus on testing the drug to determine its effectiveness and side-effect profile in a specific malignancy (or for a specific cancer-related molecular abnormality). If a drug demonstrates anticancer activity in a phase 2 study, phase 3 trials are performed to compare the usefulness of an investigational treatment to a control group receiving the standard of care; patients in most phase 3 studies are randomly assigned to the new or standard treatment to avoid a biased assessment of the results of the study. Finally, after approval of a new drug by the FDA, usually based on the results of phase 3 studies, phase 4 trials may be performed to collect safety information on larger patient populations to define the prevalence of side effects that may be rare but serious.
Many drug interactions affect the toxicity profile of anticancer agents, for the most part because concomitant administration of a second drug changes the clearance of the cancer therapeutic, potentially enhancing side effects if the clearance is decreased or diminishing efficacy because of reduced drug exposure. Most often these interactions occur because one drug affects the metabolism of the other by inhibiting or enhancing the activity of cytochrome P-450 isoforms (such as CYP3A) in the liver. This is particularly true for agents administered orally, such as imatinib, crizotinib, enzalutamide, pazopanib, and lapatinib. Concomitant drug-related as well as pharmacogenetic variations in proteins that affect the transport of anticancer agents across tumor and normal cell membranes, such as efflux pumps, also affect the sensitivity or resistance of many classes of cancer drugs. For example, certain drugs that are well-known inducers of hepatic metabolism (phenytoin and rifampin) also induce the expression of drug transport proteins.
Virtually all curative chemotherapy regimens developed for hematologic malignancies or solid tumors use combinations of active agents. Combination chemotherapy is usually superior to the use of single agents in adjuvant and neoadjuvant therapy as well. The improved results achieved by combination chemotherapy can be explained in several ways. Mechanisms of resistance to any particular single agent are almost always present in the tumor genome at diagnosis, even in clinically responsive tumors. Tumors that are initially “sensitive” to systemic therapy rapidly acquire resistance to single agents, either as a result of selection of a preexisting clone of resistant tumor cells or because of a variety of potential acquired molecular changes (e.g., increased drug efflux, enhanced DNA repair, insensitivity to apoptosis) leading to clinical drug resistance. Combination therapy may address these phenomena by providing a broader range of mechanisms of drug action against initially resistant tumor cells, preventing or slowing the selection of resistant clones.
The development of combination systemic therapy regimens follows a set of principles. For standard cytotoxic agents, each drug in the combination must be active against the tumor, and all drugs must be given at an optimal dose and on an appropriate schedule. The drugs should have different mechanisms of antitumor activity as well as different toxicity profiles, and the drugs should be given at consistent intervals for the shortest possible treatment time. The use of molecularly targeted agents in combination requires that each agent engages its specific target and that dual target inhibition produces a complementary enhancement of tumor growth inhibition. Toxicities of targeted agents should be moderate to allow prolonged administration and maximum target inhibition.
|CYTOTOXIC AGENTS||MOLECULARLY TARGETED DRUGS|
|Drugs are each active against the tumor||Agent has therapeutic effect on molecular pathway in vivo|
|Drugs have different mechanisms of action||Agents have complementary effects on the same target or other targets in the same pathway or pathways that cross-talk to control tumor growth|
|Drugs have different clinical toxicities to allow full doses of each to be administered||Toxicities do not overlap with cytotoxics and are moderate to low to allow prolonged administration. Consider physiologic consequences of target engagement in relation to toxicity profile|
|Intermittent intensive therapy preferred to continuous treatment for cytoreduction and to reduce immunosuppression||Schedule chosen to maximize target inhibition|
Systemic therapy is used in a variety of settings with or without and before, during, or after surgery and radiation therapy. Considerable experimental evidence suggests that cancers are most sensitive to chemotherapy during early stages of growth because of higher growth fractions and shorter cell cycle times. Thus, a given dose of a cytotoxic drug may exert a greater therapeutic effect against a rapidly growing tumor than against a larger quiescent tumor.
|ADJUVANT THERAPY||NEOADJUVANT THERAPY||ORGAN-SPARING THERAPY||COMBINATION CHEMOTHERAPY|
|Stage I and II breast cancer||Stage III breast cancer||Anal cancer||Metastatic solid tumors *|
|Stage III colorectal cancer||Laryngeal cancer||Hematologic malignancies|
|Stage II lung cancer||Esophageal cancer|
* Usually palliative.
Neoadjuvant therapy , also called primary or induction systemic therapy, is used before surgery or radiation therapy to decrease the size of locally advanced cancers, thereby permitting a more complete surgical resection or eradicating undetectable metastases. It also affords an opportunity to evaluate the effectiveness of treatment by histologic and molecular analysis of resected tissue. This approach is most often used for locally advanced breast cancer.
Organ-sparing therapy is another use of chemotherapy, radiation therapy, or both, to salvage organs that would have been surgically removed if cure were the intended result. This technique is often effective in patients with cancers of the larynx, esophagus, and anus.
Adjuvant chemotherapy is used in patients whose primary tumor and all evidence of cancer (e.g., regional lymph nodes) have been surgically removed or treated definitively with radiation, but in whom the risk of recurrence is high because of involved lymph nodes or certain morphologic or biologic characteristics of the cancer. Common examples include cancers of the breast and colon. The typical end points of chemotherapy, such as shrinkage of measurable tumor on serial radiographic studies, are not available in this situation; instead, relapse-free survival and overall survival are the principal measures of treatment effect. For an individual patient receiving adjuvant therapy, there is no way to determine whether such therapy is beneficial; hence, decisions are generally based on evidence from clinical trials.
Assessment of Response
Assessment of the response to therapy (usually performed using RECIST [Response Evaluation Criteria in Solid Tumors]) depends largely on tumor size, determined by either direct measurement or diagnostic imaging studies, using predefined categories. The categories of response are “complete response,” with total absence of tumor and correction of tumor-associated changes measured twice at least 4 weeks apart; “partial response,” defined as 30% or greater reduction in the sum of the longest diameters of up to 5 target lesions per organ confirmed by repeat measurement 4 weeks later; “progressive disease,” characterized by either 20% or greater increase over the smallest sum of the longest diameters of target lesions or the development of new tumors; and “stable disease,” defined as meeting criteria for neither partial response nor progressive disease. Leukemias are assessed by bone marrow biopsies and molecular diagnostic tests for residual disease, and multiple myeloma is typically assessed by the measurement of monoclonal proteins, peripheral blood counts, and percentages of malignant plasma cells in bone marrow samples, as well as imaging of bone lesions. Accurate assessment of response following systemic therapy is essential because of the tight relationship between the degree of response and the duration of disease control.
Cytotoxic Agents, Targeted Small Molecules, and Antibodies
The pharmacologic properties of the most commonly used cytotoxic and molecularly targeted chemotherapeutic agents approved by the FDA are described in the following table, as well as their most common therapeutic indications. In all cases, current information from the manufacturer should be sought before therapy is initiated.
|DRUG NAME||DRUG CLASS AND MECHANISM OF ACTION||PHARMACOKINETICS AND METABOLISM||TOXICITY||INDICATIONS|
|Bendamustine (Treanda)||Alkylating agent; bifunctional, with both alkylating and purine-like antimetabolite action||Biotransformation in liver; decrease dose for hematologic toxicity||Nausea, vomiting, and bone marrow suppression||CLL and B-cell non-Hodgkin lymphoma|
|Carboplatin (Paraplatin)||Platinum coordination compound; produces intrastrand and interstrand DNA cross-links leading to introduction of DNA breaks during replication||Rapidly cleared largely unchanged by kidney; patients with decreased CrCl experience greater thrombocytopenia||Thrombocytopenia; nephrotoxicity substantially less than cisplatin||Ovarian cancer, testicular cancer, lung cancer, head and neck cancer, breast cancer|
|Chlorambucil (Leukeran)||Bifunctional alkyl forms interstrand DNA cross-links with resultant inactivation of DNA; cell cycle nonspecific acting agent||Highly orally bioavailable; hepatic biotransformation||Dose-limiting myelosuppression; mucosal toxicity mild||CLL, Waldenström macroglobulinemia, non-Hodgkin lymphomas|
|Cisplatin (Platinol)||Platinum coordination compound; produces interstrand and intrastrand DNA cross-links leading to DNA breaks; cell cycle nonspecific||Rapid distribution and DNA binding to tissues; over 90% of drug is protein bound||Nephrotoxicity is dose-limiting; significant nausea and vomiting require expert management; ototoxicity; peripheral neuropathy; hypomagnesemia and potassium wasting||Testicular cancer, other germ cell tumors, ovarian cancer, bladder cancer, lung cancer, sarcomas, cervical cancer, endometrial cancer, gastric cancer, breast cancer, head and neck cancer|
|Cyclophosphamide (Cytoxan, Neosar)||Alkylating agent; cross links DNA, decreasing macromolecular synthesis; immunosuppressive||Hepatic biotransformation of parental pro-drug to alkylating species; metabolites excreted in urine||Bone marrow suppression moderate at standard doses; alopecia; hemorrhagic cystitis, SIADH, and pulmonary fibrosis infrequent||Breast cancer, Hodgkin and non-Hodgkin lymphomas, leukemias, neuroblastoma, retinoblastoma, other sarcomas, osteogenic sarcoma, Wilms tumor|
|Ifosfamide (Ifex)||Alkylating agent; alkylated metabolites interact with DNA; cell cycle nonspecific||Hepatic biotransformation; renal elimination||Myelosuppression; hemorrhagic cystitis (requires co-administration of the uroprotector mesna); nephrotoxicity; CNS toxicity (lethargy, stupor)||Germ cell tumors, sarcomas, non-Hodgkin lymphomas|
|Melphalan (Alkeran)||Alkylating agent; forms interstrand, intrastrand, or DNA protein cross-links; cell cycle nonspecific||Unpredictable absorption by GI tract; highly protein bound; hydrolyzed in plasma; partially eliminated by kidney||Myelosuppression; vomiting when used at high dose; associated with secondary leukemias when used chronically||Multiple myeloma, rhabdomyosarcoma, bone marrow ablation for stem cell transplantation|
|Oxaliplatin (Eloxatin)||Platinum coordination compound; produces interstrand DNA cross-links; not identical to other platins||Renal elimination following active metabolism; no excretion by liver and safe to use in face of liver dysfunction||Cumulative sensory neuropathy is dose-limiting and worse in the cold; fatigue and nausea common||Colorectal cancer|
|Temozolomide (Temodar)||Nonclassic alkylating agent that is affected by DNA methylation status||Oral bioavailability good; penetrates blood-brain barrier||Myelosuppression may be cumulative; treatable nausea; fatigue||Melanoma, brain tumors|
|5-Azacitidine (Vidaza)||Antimetabolite; pyrimidine nucleoside analogue of cytidine; hypomethylates DNA, producing gene activation; directly incorporated into DNA, with cytotoxicity at higher doses||Hepatic metabolism; renal excretion||Dose-limiting myelosuppression; transient liver function abnormalities; nausea, vomiting, abdominal pain||Myelodysplastic syndrome|
|Capecitabine (Xeloda)||Pyrimidine antimetabolite; pro-drug form of 5-fluorouracil; inhibits DNA and RNA synthesis||Well absorbed after oral administration; metabolized to 5-fluorouracil in liver and in tumor||Myelosuppression, hand-foot syndrome, diarrhea, stomatitis, fatigue||Breast cancer, colorectal cancer|
|Cladribine (Leustatin), 2-chloro-2-deoxy- d -adenosine||Purine nucleoside antimetabolite; inhibits DNA synthesis and repair||Excreted primarily in urine as unchanged parent drug; excellent oral bioavailability||Bone marrow suppression, fever||Hairy cell leukemia, CLL, non-Hodgkin lymphoma|
|Clofarabine (Clofar)||Purine nucleoside antimetabolite; inhibits DNA synthesis and repair; activates apoptosis||Excreted in urine||Bone marrow suppression, hepatotoxicity, capillary leak syndrome||Relapsed acute lymphoblastic leukemia|
|Cytarabine *(Cytosar-U, Tarabine PFS)||Antimetabolite activated to cytarabine triphosphate in tissues; inhibits DNA synthesis; cell cycle specific, S phase||Deaminated in blood and tissues, with short terminal half-life||Bone marrow suppression, stomatitis, pancreatitis; with high doses, cerebral dysfunction, GI damage, hepatotoxicity, pulmonary edema, corneal damage, Ara-C syndrome||Acute myelocytic leukemia|
|Decitabine (Dacogen)||Antimetabolite that inhibits DNA methyltransferase, producing hypomethylation and gene activation||Deaminated in liver, blood, and GI tract; short half-life||Bone marrow suppression, nausea and vomiting, fatigue, abnormal liver function and blood sugar||Myelodysplastic syndrome|
|Fludarabine phosphate (Fludara)||Purine nucleotide antimetabolite; 2-fluoro-ara-ATP inhibits DNA synthesis by inhibition of ribonucleotide reductase and DNA polymerases||After IV dosing, 2-fluoro-ara-A widely taken up by tissues; drug and metabolites excreted by kidney||Neurotoxicity, including somnolence and demyelinating lesions, dose-limiting; myelosuppression (lymphopenia)||CLL; also used for low-grade non-Hodgkin lymphomas|
|Fluorouracil (5-FU, Adrucil)||Pyrimidine antimetabolite; inhibitor of thymidylate synthase; also alters RNA synthesis||Primarily metabolized by dyhydropyrimidine dehydrogenase in liver; remainder metabolized in tumor and other tissues to active species; renal excretion of remaining drug||Mucositis and diarrhea, myelosuppression; hand-foot syndrome when used as an IV infusion; rare cerebellar ataxia or cardiac ischemia||Colorectal cancer, other GI cancers, breast cancer, head and neck cancer|
|Gemcitabine (Gemzar)||Nucleoside analogue antimetabolite that inhibits ribonucleotide reductase and is incorporated into DNA following intracellular metabolism, leading to DNA synthesis inhibition||Metabolized by deamination in a variety of tissues and excreted both as parent drug and metabolites by the kidneys; elevated bilirubin requires dose reduction; increased creatinine enhances drug toxicity||Myelosuppression, nausea and vomiting, elevated transaminases, fever||Pancreatic cancer, breast cancer, non–small cell lung cancer, bladder cancer, ovarian cancer|
|Methotrexate (Folex, Mexate)||Folic acid analogue antimetabolite; inhibition of dihydrofolate reductase blocks nucleotide synthesis||Mainly renal excretion with minimal hepatic metabolism; strict attention to renal function required for dosing; third-space accumulation, including pleural effusions and ascites, with prolonged release and associated toxicity||Myelosuppression is dose-limiting; stomatitis and diarrhea common, especially if delayed excretion; renal toxicity can also be severe if drug elimination impaired||Acute leukemias, especially in children; non-Hodgkin lymphoma, breast cancer, head and neck cancer, sarcomas|
|Pemetrexed (Alimta)||Folic acid analogue antimetabolite; inhibits multiple enzymes in folate pathway, leading to altered DNA and RNA synthesis||Excreted as unchanged drug by kidney||Myelosuppression, nausea, diarrhea, rash, fatigue; must be given with folic acid and vitamin B 12to reduce toxicity||Mesothelioma, non–small cell lung cancer|
|Pralatrexate (Fotolyn)||Folic acid analogue antimetabolite||Renal excretion||Myelosuppression, mucositis, pyrexia; must be given with folic acid and vitamin B 12 to reduce toxicity||Relapsed peripheral T-cell lymphoma|
|All- trans -retinoic acid (ATRA)||Retinoid; induces cellular differentiation and/or apoptosis||Conjugated to glucuronic acid, with subsequent biliary excretion and enterohepatic circulation||Mucocutaneous, ocular, musculoskeletal, neurologic, hepatic toxicity; hyperlipidemia||Acute promyelocytic leukemia|
|Arsenic trioxide (Trisenox)||Arsenical differentiating agent||Hepatic metabolism; excreted in urine||Prolonged QT interval; acute promyelocytic leukemia differentiation syndrome (leukocytosis, fever, dyspnea, chest pain, hypoxia) that can be treated with corticosteroids; peripheral neuropathy||Acute promyelocytic leukemia|
|l -Asparaginase (Elspar)||Enzyme that hydrolyzes 1-asparagine to aspartic acid and ammonia, resulting in cellular deficiency of 1-asparagine, critical for tumor cells that lack asparagine synthetase; interferes with protein, DNA, and RNA synthesis||Metabolized in the vasculature by proteolysis||Hypersensitivity reactions; inhibitory effects on protein synthesis, with resultant decreases in hepatic synthesis of coagulation factors, pancreatitis, hyperglycemia, CNS depression, hepatotoxicity, transient renal dysfunction||Acute lymphoblastic leukemia|
DNA-ACTIVE DRUGS WITH PLEIOTROPIC MECHANISMS OF ACTION
|Bleomycin (Blenoxane)||Antitumor antibiotic; produces free radical–related DNA strand breaks||Metabolized partially by intracellular aminopeptidases; renal excretion||Dose-related pulmonary fibrosis, fever, hypersensitivity reactions, skin toxicity, including Raynaud phenomenon||Testicular cancer and other germ cell tumors, Hodgkin and non- Hodgkin lymphomas; sclerosing agent for pleural effusions|
|Carmustine (BiCNU, BCNU)||Nitrosourea-class alkylating agent; alkylates DNA and may affect carbamoylation of amino acids||Taken up by CNS; metabolized in liver and excreted by kidney||Myelosuppression may be slow in onset and cumulative; severe nausea and vomiting, renal toxicity, interstitial lung disease||Glioblastoma|
|Daunorubicin (Cerubidine)||Anthracycline antibiotic; pleiotropic effects, including free radical formation, inhibition of topoisomerase II, altered mitochondrial metabolism, activation of pro-apoptotic signal transduction||Hepatic metabolism with biliary excretion; small amount of renal excretion leads to “orange-red” urine||Myelosuppression and mucositis are dose-limiting; alopecia, cumulative dose-related cardiotoxicity, extravasation injury||Acute myelocytic leukemia, acute lymphoblastic leukemia|
|Doxorubicin (Adriamycin, Rubex)||Anthracycline antibiotic; pleiotropic effects, including free radical formation, inhibition of topoisomerase II and DNA strand breaks, altered mitochondrial metabolism, activation of pro-apoptotic signal transduction||Hepatic metabolism to both active and inactive species, with 50% biliary excretion; “orange-red” urine||Myelosuppression and mucosal injury are dose-limiting; alopecia, cumulative dose-related cardiotoxicity (cardiomyopathy), nausea and vomiting, severe extravasation injury risk, secondary AML||Acute myelocytic leukemia, acute lymphoblastic leukemia, breast cancer, small cell lung cancer, Hodgkin and non-Hodgkin lymphomas, sarcomas, endometrial cancer, Wilms tumor, neuroblastoma|
|Doxorubicin liposomal (Doxil)||Anthracycline antibiotic with pleiotropic mechanisms of action||Liver||Myelosuppression, dose-related cardiotoxicity, extravasation injury, hand-foot syndrome||Ovarian cancer, breast cancer, Kaposi sarcoma|
|Epirubicin (Ellence)||Anthracycline antibiotic with pleiotropic mechanisms of action similar to others in class||Liver||Similar to doxorubicin; modestly less cardiotoxic; extravasation||Breast cancer adjuvant therapy|
|Etoposide (VP-16, VePesid)||Epipodophyllotoxin plant alkaloid; inhibits topoisomerase II, leading to decreased DNA synthesis||Extensively protein bound; hepatic metabolism; excreted as metabolites in bile and unchanged in urine||Dose-limiting myelosuppression, nausea and vomiting, stomatitis when used at high dose, secondary AML||Small cell lung cancer, germ cell tumors, lymphomas; high-dose therapy conditioning regimens|
|Idarubicin (Idamycin)||Anthracycline antibiotic with pleiotropic mechanisms of action similar to others in class||Hepatic metabolism with biliary excretion||Similar to doxorubicin; modestly less cardiotoxic; extravasation||Acute myelocytic leukemia|
|Irinotecan (Camptosar)||Semisynthetic camptothecin analogue that poisons DNA topoisomerase I, preventing religation of replication-related single-strand breaks||Partially inactivated in plasma; metabolized by esterases to active species SN-38, which is excreted into bile; patients with elevated bilirubin have increased toxicity||Myelosuppression; early and late diarrhea may be severe; flushing, alopecia||Colorectal cancer|
|Topotecan (Hycamtin)||Semisynthetic camptothecin analogue that inhibits DNA topoisomerase I, inhibiting transcription||Excreted primarily unchanged in urine||Severe myelosuppression is dose-limiting (both granulocytes and platelets); mild nausea, fatigue, diarrhea||Relapsed ovarian and small cell lung cancer|
INHIBITORS OF MITOTIC FUNCTION
|Docetaxel (Taxotere)||Mitotic spindle poison that stabilizes tubulin polymers, leading to mitotic tumor cell death||Biliary excretion||Myelosuppression and alopecia, hypersensitivity reactions, fluid retention syndrome, peripheral sensorimotor neuropathy||Breast cancer, non–small cell lung cancer, ovarian cancer, gastric cancer, head and neck cancer|
|Eribulin mesylate (Halaven)||Semisynthetic natural product; microtubule inhibitor||Excreted primarily as unchanged parent compound in feces||Neutropenia, peripheral neuropathy, QT prolongation, fatigue, nausea||Metastatic breast cancer|
|Ixabepilone (Ixempra)||Microtubule inhibitor; analogue of epothilone B that binds to β-tubulin, suppressing function of microtubules and causing mitotic cell death||Metabolized by liver and excreted in feces; dose reduction required in face of liver dysfunction||Cumulative peripheral neuropathy, neutropenia, hypersensitivity reactions, fatigue, myalgias, stomatitis||Breast cancer|
|Paclitaxel (Taxol)||Taxane natural product; mitotic spindle poison that inhibits tubulin depolymerization||Hepatic metabolism, biliary excretion||Myelosuppression, mucositis, hypersensitivity reactions, cumulative peripheral neuromyopathy with arthralgias, cardiovascular toxicity with hypotension, arrhythmias||Non–small cell lung cancer, ovarian cancer, breast cancer, esophageal cancer, gastric cancer, head and neck cancer|
|Paclitaxel protein- bound particles (Abraxane)||Albumin nanoparticle-bound form of paclitaxel; same mechanism of action||Hepatic metabolism, biliary excretion||Hypersensitivity reactions, myelosuppression, neuropathy, arthralgias/myalgias, cardiotoxicity||Metastatic breast cancer, pancreatic cancer, non–small cell lung cancer|
|Vincristine (Oncovin)||Vinca alkaloid natural product; inhibits tubulin polymerization, arresting cells in metaphase||Hepatic metabolism, biliary excretion||Extravasation injury, dose-limiting peripheral neurotoxicity, constipation||Acute lymphocytic leukemia, neuroblastoma, Wilms tumor, Hodgkin and non-Hodgkin lymphomas, rhabdomyosarcoma|
|Vinorelbine (Navelbine)||Semisynthetic vinca alkaloid; inhibits tubulin polymerization during mitosis||Hepatic metabolism, biliary excretion||Myelosuppression, extravasation, milder neurotoxicity than other vincas||Non–small cell lung cancer, breast cancer|
|Abiraterone acetate (Zytiga)||Inhibitor of androgen biosynthesis||Parent drug and metabolites excreted in stool; systemic clearance decreased in patients with liver dysfunction||Joint swelling, edema, hepatotoxicity||Castration-resistant metastatic prostate cancer|
|Anastrozole (Arimidex)||Nonsteroidal aromatase inhibitor; inhibits conversion of adrenal androgens to estrogens||Metabolized in liver, excreted into bile and urine||Hot flashes, headache, arthralgias||Adjuvant and metastatic breast cancer in postmenopausal women|
|Bicalutamide (Casodex)||Nonsteroidal antiandrogen that binds to prostatic androgen receptor||Hepatic metabolism||Worsening bone pain, hot flashes, gynecomastia||Prostate cancer (usually in conjunction with LHRH antagonist)|
|Degarelix (Firmagon)||GnRH receptor antagonist; binds to GnRH receptors in pituitary, decreasing gonadotropin release||Biliary excretion of parent and metabolites; lesser renal excretion of unchanged parent drug||Injection site reactions, hot flashes, weight gain, increased LFTs, QT prolongation||Prostate cancer|
|Enzalutamide (Xtandi)||Nonsteroidal antiandrogen; inhibits androgen receptor-mediated signal transduction||Hepatic metabolism, eliminated primarily in urine||Fatigue, arthralgias, dizziness, bone pain||Metastatic castration-resistant prostate cancer|
|Exemestane (Aromasin)||Steroidal aromatase inhibitor; binds and irreversibly inhibits aromatase, inhibits synthesis of estrogens by preventing conversion of adrenal androgens to estrogens||Metabolized in liver||Hot flashes, fatigue, arthralgias||Metastatic breast cancer in postmenopausal women|
|Flutamide (Eulexin)||Nonsteroidal antiandrogen; inhibition of nuclear binding of androgen in target tissues; its interference with testosterone at cellular level complements “medical castration” produced by LHRH analogues||Metabolized to active and inactive metabolites in liver||Worsening bone pain, hot flashes, gynecomastia, impotence||Prostate cancer (usually in conjunction with LHRH antagonist)|
|Fulvestrant (Faslodex)||Estrogen receptor antagonist; binds to estrogen receptor, causing degradation of estrogen receptor protein||Metabolized by liver, excreted in bile||Hot flashes, nausea, peripheral edema and weight gain, fatigue, arthralgias||Recurrent breast cancer in postmenopausal women|
|Goserelin (Zoladex)||Synthetic decapeptide analogue of LHRH; suppresses pituitary gonadotropins, with fall of serum testosterone into castrate range||Slowly released from depot injection site; not extensively metabolized; urinary excretion||Worsening bone pain, hot flashes, impotence, gynecomastia, breakthrough vaginal bleeding||Prostate cancer, breast cancer|
|Letrozole (Femara)||Nonsteroidal competitive inhibitor of aromatase; inhibits estrogen synthesis by blocking conversion of adrenal androgens to estrogens||Metabolized in liver, excreted by kidney||Hot flashes, fatigue, arthralgias||Adjuvant and metastatic breast cancer in postmenopausal women|
|Leuprolide (Lupron, Lupron Depot)||Synthetic LHRH analogue; suppresses secretion of GnRH, with resultant fall in testosterone secretion, producing “medical castration”||Metabolized to inactive peptide fragments; minor renal excretion||Increased bone pain, hot flashes, gynecomastia, lethargy, thromboembolic phenomena||Prostate cancer, breast cancer|
|Octreotide (Sandostatin)||Synthetic octapeptide analogue of somatostatin; suppresses secretion of serotonin and GI peptides; blocks carcinoid flush, decreases serum 5-HIAA, and controls other symptoms associated with carcinoid syndrome||Hepatic metabolism; renal excretion following hydrolysis in plasma||Hyper/hypoglycemia, hepatic dysfunction, diarrhea||Palliative treatment of carcinoid tumors and vasoactive intestinal peptide tumors (VIPomas)|
|Tamoxifen (Nolvadex)||Nonsteroidal antiestrogen; competes with estradiol for estrogen receptor protein; also has non–estrogen receptor–dependent effects on tumor cells||Metabolized in liver but not excreted in bile or urine||Hot flashes, nausea/vomiting, vaginal bleeding or discharge, endometrial hyperplasia, thrombophlebitis, hypercalcemia, visual disturbances||Adjuvant and metastatic estrogen receptor–positive breast cancer; also approved for chemoprevention of breast cancer in high-risk individuals|
BIOLOGIC AND IMMUNOLOGIC MODIFIERS
|Aldesleukin (Human Recombinant IL-2, Proleukin)||Cytokine that supports T-cell proliferation, augments natural killer cell cytotoxicity, induces lymphokine-activated killer (LAK) cell development, and participates in activation of monocytes and B cells||Catabolized by proteolysis in many tissues; minimal renal or biliary excretion||Toxicities associated with continuous infusion (and to a lesser extent with bolus dosing) include: capillary leak syndrome, fever and chills, hypotension, edema, arrhythmias, nephrotoxicity, pulmonary edema, abnormal liver function, endocrinopathies, dermatologic complications, CNS toxicity, myelosuppression, sepsis||Renal cancer, melanoma|
|Erythropoietin (Aranesp, Epogen, Procrit) †||Hematopoietic growth factor; stimulates division and differentiation of committed erythroid progenitors in bone marrow||Proteolytically degraded in vasculature, with minimal excretion of intact peptide||Increased risk of thrombosis, stroke, myocardial infarction; headache, hypertension, and possible seizures; allergic reactions; can produce iron deficiency with prolonged use—concomitant iron dosing may enhance efficacy||Correction of anemia due to chronic renal failure or HIV-related infection, and symptomatic chemotherapy-induced anemia (however, risk of tumor progression limits use for patients being treated with chemotherapy for cure)|
|Filgrastim (G-CSF, Neupogen)||Hematopoietic growth factor; binds to specific cell surface receptors on progenitor cells to stimulate proliferation and differentiation of neutrophils||Elimination by proteolysis in vasculature and by the kidney||Pain at site of subcutaneous injection, allergic reactions, bone pain, low-grade fever, myalgia, arthralgia||Decreases incidence of infection after myelosuppressive chemotherapy; enhances myeloid engraftment after BMT; enhances peripheral progenitor cell yield prior to BMT|
|Interferon-α (Intron-A, Roferon)‡||Interferon antiviral immunostimulant with both antiproliferative and immunomodulatory properties||Catabolized in renal tubules||Fever and flulike symptoms, fatigue, myelosuppression, cardiotoxicity, depression, neurotoxicity||Hairy cell leukemia, Kaposi sarcoma|
|Ipilimumab (Yervoy)||CTLA-4-blocking monoclonal antibody that enhances the anticancer effect of activated T cells||No clear pharmacokinetic effects of altered renal or hepatic function||Fatigue, diarrhea and immune-mediated colitis, hepatitis, rash, pruritus, endocrinopathy||Metastatic melanoma|
|Sargramostim (GM-CSF, Leukine, Prokine)||Hematopoietic growth factor; binds to specific cell surface receptors to stimulate proliferation and differentiation of granulocytes and macrophages; not lineage specific||Metabolized in liver and kidney||Fever and capillary leak syndrome, pain at site of subcutaneous injection, allergic reactions, arthralgias, bone pain||Decreases incidence of infection after myelosuppressive chemotherapy; enhances myeloid engraftment after BMT; enhances peripheral progenitor cell yield|
MOLECULARLY TARGETED AGENTS
|Aflibercept (Zaltrap)||VEGF inhibitor; decoy receptor that binds circulating VEGF thus inhibiting activation of VEGFR||Metabolized by proteolysis||Hemorrhage, GI fistulas and perforation, hypertension, altered wound healing, stomatitis, fatigue, myelosuppression||Colon cancer in combination with chemotherapy|
|Axitinib (Inlyta)||Multikinase inhibitor, including VEGFR1, 2, and 3; inhibits angiogenesis||Metabolized by hepatic P-450 enzymes; excreted in feces>urine; multiple interactions with CYP 3A4/5 inducers||Hypertension, hand-foot syndrome, fatigue, asthenia, stomatitis, hypothyroidism||Advanced renal cancer|
|Bevacizumab (Avastin)||Recombinant humanized monoclonal antibody against VEGF; inhibits angiogenesis by binding to VEGF, blocking receptor binding and subsequent stimulation of blood vessel growth||Prolonged (20-day) half-life after IV infusion||Fatigue, nausea, delayed wound healing, hypertension, proteinuria, thromboembolic phenomena and hemorrhage||Metastatic colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer|
|Bortezomib (Velcade)||Reversible inhibitor of 26S proteasome; blocks breakdown of ubiquitinated intracellular proteins and disrupts ubiquitin-proteasome pathway||Undergoes oxidative metabolism (deboronation) as well as cytochrome P-450-dependent metabolism; dose reduction to 0.7 mg/m 2 required in face of moderate to severe liver dysfunction; adverse event profile unchanged in myeloma patients with CrCl < 50 mL/min||Myelosuppression, peripheral neuropathy, asthenia, diarrhea, hypotension||Multiple myeloma, non-Hodgkin lymphoma|
|Cetuximab (Erbitux)||Chimeric monoclonal antibody targeted against EGFR; blocks growth factor binding to EGFR, preventing cell signaling by tyrosine kinase phosphorylation||Half-life 5-7 days, with minimal renal or hepatic clearance||Hypersensitivity reactions (fever, dyspnea), acneiform rash, diarrhea, hypomagnesemia||Metastatic colorectal cancer (K-Ras wild-type); head and neck cancer in combination with radiation|
|Carbozantanib (Cometriq)||Multikinase inhibitor that targets RET, MET, VEGFR1-3, KIT, AXL, TIE-2, and FLT-3||Metabolized by hepatic CYP 3A4 and subject to interactions related to CYP3A4 substrates; excreted into urine and feces||Hypertension, GI perforation, diarrhea, stomatitis, hemorrhage, fatigue||Metastatic medullary thyroid cancer, prostate cancer, bone metastases|
|Crizotanib (Xalkori)||Tyrosine kinase inhibitor active against ALK, ROS, MET||Hepatic P-450-mediated metabolism; excreted in feces and urine||Hepatotoxicity, pneumonitis, QT prolongation, vision disturbance, nausea, fatigue||Non–small cell lung cancer positive for anaplastic lymphoma kinase (ALK) rearrangement|
|Dasatinib (Sprycel)||Multitargeted tyrosine kinase inhibitor; inhibits BCR-ABL, SRC, and multiple other kinases||Metabolized in liver by P-450 CYP3A4; multiple interactions with CYP3A4 inducers or inhibitors||Myelosuppression, fluid retention, diarrhea, rash, musculoskeletal pain||Resistant/refractory CML|
|Denosumab (Prolia)||IgG2 monoclonal antibody that targets RANKL, a ligand for the RANK receptor on osteoclasts, and decreases bone resorption||Prolonged elimination (>20 days) typical of monoclonal antibodies||Musculoskeletal and bone pain, arthralgias, abdominal pain, peripheral edema, hypersensitivity, hypocalcemia||Prevention of malignant bone fractures|
|Erlotinib (Tarceva)||Small molecule inhibitor of tyrosine kinase domain of EGFR||Hepatic metabolism with excretion in feces; CYP3A4 inducers and inhibitors may alter metabolism, and dose should be reduced by 50% in patients with hepatic dysfunction; renal dysfunction does not alter drug tolerability||Acneiform rash, fatigue, diarrhea, interstitial lung disease, weight gain, hepatic toxicity||Non–small cell lung cancer; pancreatic cancer in combination with gemcitabine|
|mTOR inhibitor that inhibits signal transduction through PTEN/AKT pathway||Metabolized by CYP3A4 in liver||Pneumonitis, stomatitis, renal dysfunction, myelosuppression, hyperglycemia, altered lipids||Renal cell carcinoma; hormone receptor–positive breast cancer in combination with exemestane; neuroendocrine tumors|
|Ibrutinib (Imbruvica)||Oral inhibitor of Bruton tyrosine kinase; blocks signaling through the B-cell antigen receptor important for B-cell chemotaxis and adhesion||Metabolized in the liver by CYP3A (avoid use with strong CYP3A inhibitors such as ketoconazole or grapefruit); primarily eliminated unchanged in feces||Myelosuppression, renal dysfunction, bleeding||Mantle cell lymphoma|
|Imatinib (Gleevec)||Inhibits BCR-ABL tyrosine kinase||Hepatic metabolism, excreted in feces; inhibits CYP3A4 and CYP2D6; mild hepatic dysfunction requires dose reduction to 500 mg/day; mild to moderate renal dysfunction alters kinetics but does not affect drug tolerance||Myelosuppression, hypophosphatemia, fluid retention, nausea, fatigue, hemorrhage, myelosuppression, hepatotoxicity||CML; GIST|
|Lapatinib (Tykerb)||Inhibitor of both EGFR and HER2 tyrosine kinases||Metabolized by CYP3A4 in liver||Diarrhea, hand-foot syndrome, hepatotoxicity, decreased cardiac function||HER2-positive breast cancer in combination with capecitabine|
|Lenalidomide §(Revlimid)||Immunomodulatory and antiangiogenic agent, in part through downregulation of VEGF, TNF-α, and IL-6, and T-cell and NK cell activation||Renal excretion||Neutropenia, thrombocytopenia, diarrhea, pruritus, rash, fatigue, leg cramps||Myelodysplasia, multiple myeloma|
|Nilotinib (Tasigna)||Inhibits ATP site of BCR-ABL kinase||Metabolized in liver||Prolonged QT interval, rash, fatigue, myalgias, nausea, myelosuppression||Resistant/intolerant CML|
|Ofatumumab (Arzerra)||Monoclonal antibody against CD-20||Not known if dose requires modification for patients with renal impairment||Infusion reactions, tumor lysis syndrome, myelosuppression, hepatitis B reactivation, infection||Resistant CLL|
|Pazopanib (Votrient)||Inhibits multiple tyrosine kinases including VEGFR-1, VEGFR-2, PDGFR, FGF, Kit, Lck, and cFms||Hepatic P-450 metabolism; excreted in feces||Hepatotoxicity, QT prolongation, hypertension, fatigue, nausea, decreased cardiac function||Renal cell cancer, soft tissue sarcoma|
|Panitumumab (Vectibix)||Monoclonal antibody that binds EGFR, inhibiting ligand interaction||Prolonged (7-day) half-life||Acneiform rash (may be severe), diarrhea, infusion reaction, hypomagnesemia, pulmonary fibrosis||EGFR-expressing colorectal cancer|
|Pertuzumab (Perjeta)||Monoclonal antibody against HER2; blocks HER2-mediated signaling; associated with antibody-dependent cell-mediated cytotoxicity||Prolonged half-life||Decreased cardiac ejection fraction (particularly in patients previously exposed to anthracyclines), hypersensitivity reactions, nausea, diarrhea, rash||HER2-positive metastatic breast cancer in combination with trastuzumab and docetaxel for patients without prior anti-HER2 therapy|
|Ponatinib (Iclusig)||BCR-ABL kinase inhibitor; also inhibits BCR-ABL carrying the T315I resistance mutation; also inhibits other tyrosine kinases including VEGFR, FGFR, SRC, PDGFR, and FLT3||Hepatic metabolism with fecal excretion||Significant risk of arterial thrombosis, stroke, myocardial infarction; myelosuppression, hypertension, hepatotoxicity, fatigue, rash||Because of thrombotic risk, usage limited to patients with CML resistant to or intolerant of first- or second-line BCR-ABL inhibitors|
|Romidepsin (Istodax)||Histone deacetylase inhibitor; catalyzes removal of acetyl groups from lysines on histone proteins, enhancing transcription from less condensed chromatin||Metabolized by hepatic P-450 system||Nausea and vomiting, T-wave changes and QT prolongation on ECG, diarrhea, infections, hypomagnesemia, hypotension, myelosuppression, hypersensitivity reactions||Cutaneous T-cell lymphoma|
|Rituximab (Rituxan)||Chimeric antibody targeting B-cell CD20 surface antigen on lymphocytes||Proteolysis without substantial excretion||Hypersensitivity reactions, lymphopenia||Relapsed low-grade CD20-positive non-Hodgkin lymphomas|
|Rogorafenib (Stivarga)||Multikinase inhibitor; targets VEGFR2, TIE-2; inhibits angiogenesis||Hepatic metabolism with excretion into feces>urine||Hypertension, hepatotoxicity, fatigue, abdominal pain||Colorectal cancer, GIST|
|Ruxolitinib (Jakafi)||JAK1 and 2 kinase inhibitor; blocks JAK-dependent immune and hematopoietic signal transduction pathways||Hepatic metabolism with excretion into urine >feces||Myelosuppression, bruising, headache, weight gain, liver function abnormalities||Myelofibrosis|
|Sorafenib (Nexavar)||Multikinase inhibitor; inhibits RAF kinase, as well as VEGF and PDGF receptors; antiangiogenic||Metabolized in liver, excreted in feces; patients with severe liver or kidney dysfunction do not tolerate drug well||Rash, hand-foot syndrome, fatigue, diarrhea, hair loss, hypertension, arthralgias, myelosuppression, cardiac ischemia and QT prolongation||Renal cell carcinoma, hepatocellular carcinoma, thyroid cancer|
|Sunitinib maleate (Sutent)||Multitargeted tyrosine kinase inhibitor with activity against VEGFR1-3, FLT-3, PDGFR; antiangiogenic||Metabolized by P-450’s in liver, with excretion in feces||Bleeding, decreased cardiac function, prolonged QT interval, hypertension, myelosuppression, nausea, rash, liver function abnormalities||Renal cell cancer, GIST, pancreatic neuroendocrine tumors|
|Temosirolimus (Torisel)||Inhibits mTOR kinase-dependent cell signaling||Metabolized in liver||Hypersensitivity reaction, bowel perforation, interstitial lung disease||Renal cell cancer|
|Thalidomide (Thalomid)||Immunomodulatory and antiangiogenic agent; inhibits TNF-α production; alters endothelial cell proliferation and cytokine production||Nonenzymatic hydrolysis; eliminated in urine||Teratogenicity, sedation, constipation, peripheral neuropathy, rash||Multiple myeloma|
|Trastuzumab (Herceptin)||Recombinant monoclonal antibody against HER2; downregulates expression of HER2 pathways; immune-mediated effects||Minimal renal or hepatic clearance||Hypersensitivity reactions, fever, and chills; nausea; enhances anthracycline cardiac toxicity||Metastatic or adjuvant HER2-expressing breast cancer or HER2-positive gastric cancer|
|Vemurafenib (Zelboraf)||Inhibits B-RAF kinase carrying V600E mutation||Metabolized by liver, excreted into feces||QT prolongation, liver function abnormalities, photosensitivity, alopecia, arthralgias, fever, rash, hyperkeratosis and skin papillomas||Malignant melanoma carrying B-RAF V600E mutation|
|Vismodegib (Erivedge)||Hedgehog pathway inhibitor; binds and inhibits Smoothened, a transmembrane G-protein receptor important for signal transduction in the hedgehog pathway||Hepatic metabolism, excretion in feces||Muscle spasms, fatigue, alopecia, weight loss, diarrhea||Advanced basal cell carcinoma|
|Vorinostat (Zolinza)||Histone deacetylase inhibitor; catalyzes removal of acetyl groups from lysines on histone proteins, enhancing transcription from less condensed chromatin||Metabolized in liver, eliminated in urine||Deep venous thrombosis, diarrhea, fatigue, alopecia, myelosuppression,||Cutaneous T-cell lymphoma|
|Zoledronic acid (Zometa)||Bisphosphonate inhibitor of osteoclastic bone resorption||Renal elimination||Bone pain, arthralgias and muscle pain, fever, fatigue, abnormal renal function, osteonecrosis of jaw, atypical subtrochanteric femoral fractures||Hypercalcemia of malignancy, multiple myeloma; prevention of bone fractures for patients with advanced breast and prostate cancer in concert with standard systemic therapy|
DRUGS THAT AMELIORATE CHEMOTHERAPY SIDE EFFECTS
|Dexrazoxane (Zinecard)||Anthracycline protective agent that chelates iron and protects the heart by inhibiting formation of anthracycline-induced reactive oxygen species||Hepatic metabolism, excreted in urine||Myelosuppression, nausea and vomiting, stomatitis||Reduces cumulative cardiotoxicity when administered with anthracyclines; also ameliorates anthracycline-induced extravasation injury|
|Leucovorin (folinic acid, citrovorum factor, Wellcovorin)||Water-soluble folate vitamin; increases body and tumor pool of reduced folates; enhances 5-FU metabolite-mediated inhibition of thymidylate synthase||Renal excretion||Well tolerated by itself; occasional nausea||Prophylaxis and treatment of hematopoietic side effects of folic acid antagonists; enhanced efficacy of 5-FU for colon cancer and other GI malignancies|
|Mesna (Mesnex)||Synthetic sulfhydryl compound; metabolite, mesna disulfide, reacts chemically with urotoxic ifosfamide metabolites, resulting in their detoxification||Renal||Bad taste, diarrhea||Prophylaxis of cyclophosphamide/ifosfamide-induced hemorrhagic cystitis|
AML = acute myelogenous leukemia, ATP = adenosine triphosphate; bFGF, basic fibroblast growth factor; BMT = bone marrow transplantation; CrCe = creatine clearance, CHF = congestive heart failure; CLL = chronic lymphocytic leukemia; CML = chronic myelogenous leukemia; CNS = central nervous system; CSF = colony-stimulating factor; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; EGFR = epidermal growth factor receptor; ERBB2 = HER2/neu; FDA = U.S. Food and Drug Administration; FSH = follicle-stimulating hormone; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; GI = gastrointestinal; GIST = gastrointestinal stromal tumor; GnRH = gonadotropin-releasing hormone; 5-HIAA = 5-hydroxyindolacetic acid; HIV = human immunodeficiency virus; IL = interleukin; LFT = liver function test; LH = luteinizing hormone; LHRH = luteinizing hormone–releasing hormone; MAO = monoamine oxidase; mTOR = mammalian target of rapamycin; NSAID = nonsteroidal anti-inflammatory drug; PDGF = platelet-derived growth factor; SIADH = syndrome of inappropriate secretion of antidiuretic hormone; TKI = tyrosine kinase inhibitor; TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor.
* An intrathecal formulation, DepoCyt, is used for the treatment of carcinomatous meningitis.
† Dosing differs among agents.
‡ Dosages differ among brands.
- An analogue of thalidomide, which is a severe human teratogen; restricted prescribing.
Administration of chemotherapy is best done by specifically trained individuals because of the dual acute risks of hypersensitivity reactions and extravasation. No doses or schedules are suggested in the above tables because these agents are often used in combination, and the doses of each drug may need to be reduced when the compounds are combined. The treatment of special populations, including patients with significant obesity, during pregnancy, the elderly, and those with abnormal end-organ function.
Unless otherwise specified, most cytotoxic chemotherapeutic agents are capable of producing some degree of nausea and vomiting, myelosuppression, alopecia, mucositis, and/or diarrhea after treatment; many agents are also teratogenic, mutagenic, and carcinogenic. Drugs used routinely to prevent agent-specific toxicities are also included in the above tables.
Over the past decade, several dozen small molecule anticancer agents with more precisely targeted mechanisms of action have become a standard part of oncologic practice (see the above tables). Although the molecular dependencies within tumor cells against which these drugs are targeted are broad in scope, including tyrosine kinase growth factors or their receptors, they are functionally much more specific than prior generations of systemic cancer therapies. This allows for a better appreciation of the clinical situations wherein certain drugs might be beneficial, as well as the possibility of developing agents for use in specific tumors based on their genetic susceptibilities. It is also noteworthy that the toxicity profiles of molecular targeted agents most often reflect alterations produced in biochemical pathways that control normal organ function, rather than a general pattern of toxicity consistent with injury to rapidly growing tissues, such as the bone marrow or gastrointestinal tract. Current research aims to clarify specific mutational profiles in the clinic that can be used to prospectively select patients for therapy.
The development of monoclonal antibodies directed against antigens found on cancer cells represents an additional approach to molecular targeting of systemic therapy. Examples include cetuximab (targeting the epidermal growth factor receptor), rituximab (targeting the B-cell CD20 surface antigen), and trastuzumab (which blocks HER2). These monoclonal antibodies can be used alone, or labeled with a radioactive molecule, or conjugated to another cytotoxin to enhance cell killing. Radioimmunoconjugate approaches have been most effective in the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia. The effectiveness of monoclonal antibodies in specific tumor types is not identical to small molecules developed against the same target, in part because of the induction of immunologically mediated mechanisms of tumor cell killing that are unique to antibodies.
Endocrine or hormonal therapy for cancer, the earliest form of systemic therapy, is almost entirely limited to breast cancer and prostate cancer. Many premenopausal breast cancers are thought to be under the influence of estrogens, and hormonal deprivation (ablation) may produce long-term responses in properly selected patients (those with estrogen and/or progesterone receptor positivity who have predominantly soft tissue or bone disease). The antiestrogen tamoxifen is effective against breast cancer, and it may decrease the incidence of contralateral breast cancers in both premenopausal and postmenopausal women with breast cancer. It also has an estrogen-like activity that is responsible for an increased rate of endometrial cancers. Postmenopausal women who are candidates for hormonal therapy may also respond to tamoxifen; however, aromatase inhibitors (e.g., anastrozole, letrozole, exemestane), which decrease the conversion of metabolites in fat and muscle into estrogen, have been found to be more effective than tamoxifen as first-line therapy in both the adjuvant and metastatic settings.
Prostate cancer is usually androgen dependent, and androgen deprivation can produce meaningful responses. The recent introduction of more potent inhibitors of androgen biosynthesis (abiraterone) and androgen receptor-mediated signal transduction (enzalutamide) has further enhanced the range and effectiveness of androgen deprivation therapy for this disease.
The corticosteroids, typically prednisone or dexamethasone, are widely used in the treatment of hematologic and oncologic cancers. In Hodgkin disease, the non-Hodgkin lymphomas, and multiple myeloma, corticosteroids have antitumor activity. In solid tumor patients, they are used as antiemetics and for symptomatic relief of cerebral edema in cases of CNS metastases, or as an adjunct to radiation therapy for spinal cord metastases.
Recently, several new approaches to improving cancer immunotherapy by blocking the negative effects on the immune system produced by tumors have yielded dramatic clinical benefits for patients with a variety of advanced cancers, including melanoma, kidney, and lung cancers. The survival of men and women with metastatic melanoma was significantly increased following treatment with an antibody (ipilumumab, anti-CTLA-4) that neutralizes proteins that protect tumor cells against destruction by the immune system. Additional antibodies that target other immunologic checkpoints (anti-PD-1 and anti-PD-L1) are in advanced stages of clinical investigation and are likely to provide substantive clinical benefits for patients with melanoma, renal cancer, and non–small cell lung cancer.
Drugs for Prevention of Toxicity
In addition to the hematopoietic growth factors used to reduce the adverse effects of systemic cancer therapies on the bone marrow (discussed later under Management of Complications), there are drugs that have been developed to ameliorate important side effects of cytotoxic chemotherapy. These include dexrazoxane, an iron chelating agent that can prevent the cardiac toxicity of the anthracyclines (doxorubicin and daunorubicin); leucovorin, which can diminish the hematologic side effects of folic acid antagonists; and mesna, a thiol-containing compound that blocks damage to the bladder mucosa from metabolites of cyclophosphamide.
Bone Marrow or Hematopoietic Stem Cell Transplantation
Because the major dose-limiting toxicity of most chemotherapeutic agents is myelosuppression, approaches have been developed to harvest the pluripotent stem cells found in bone marrow, peripheral blood, or, less often, cord blood before marrow-damaging chemotherapy so that the stem cells can be reinfused later. This technique is most effective for acute leukemias, relapsed lymphomas, and germ cell tumors. The effectiveness of the approach is limited more by the inability to eradicate cancer cells than by the inability to achieve engraftment. Transplants may be syngeneic (from an identical twin), autologous (from oneself), allogeneic (from a matched donor such as a sibling or parent), or from a matched unrelated donor. Nonablative hematopoietic transplants that do not completely abolish myelopoiesis reduce toxicity and allow the treatment of older and medically infirm patients.
Special Treatment Populations
Studies of practice patterns indicate that up to 40% of obese patients receive limited doses of chemotherapy that are not based on actual body weight. Concerns about toxicity or overdosing based on the use of actual body weight in obese patients with cancer are unfounded. The American Society of Clinical Oncology (ASCO) has published evidence-based practice guidelines that recommend that full cytotoxic chemotherapy doses be used to treat obese patients with cancer, especially when the goal of treatment is a cure.
Cancer during pregnancy is not uncommon, with breast, cervical, ovarian, and thyroid cancers, melanoma, and hematologic malignancies being most common. This is an emotionally charged time, and clinical decision making is complicated by ethical, moral, cultural, and religious issues. If surgery can be safely accomplished, this may be the best course, even if it is only a temporizing measure. Radiation therapy carries the very real risk of radiation exposure to the fetus, and staging is almost always suboptimal and confined to ultrasound examinations. When the disease requires chemotherapy, changes in both the mother and fetus must be taken into account; for instance, there are major changes in drug clearance during pregnancy, along with gastrointestinal absorption and placental transfer, not to mention fetal pharmacokinetics and placental excretion. Many commonly used chemotherapeutic drugs are classified by the FDA as category D (positive human fetal risk, but the benefits in pregnant women may be acceptable despite the risk) or category X (studies in humans and animal have shown fetal malformations or there is evidence of fetal risk based on human evidence). If the mother’s condition permits, it is advisable to defer chemotherapy (including anthracyclines and taxanes) during the first trimester and to treat life-threatening situations during the third trimester after extensive counseling with the parents.
An increasing proportion of cancers occur in the older population. The physiologic changes that develop with age include: decreased excretion of drugs and metabolites from the kidneys, decreased volume of distribution of water-soluble drugs, and increased susceptibility to myelosuppression, cardiomyopathy, and neuropathy, related in part to comorbid conditions. As a general rule, the suitability of an older patient for therapy can be determined by a comprehensive geriatric assessment (CGA) that evaluates the patient’s function, comorbidity, nutrition, medications, and resources. By itself, age is not a barrier to surgery; rather, the patient’s performance status and the CGA should determine the likelihood of a good recovery. Tolerance of radiation therapy seems to remain largely intact with increasing age. Chemotherapy decisions are also based on the performance status and CGA. Dosage adjustments are also made for individual glomerular filtration rates for patients aged 65 and older, where appropriate. The use of lower chemotherapy doses based on age alone is not advisable and may result in ineffective treatment.
Alterations in drug clearance play a critical role in the safe administration of anticancer agents. Over the past decade, pharmacokinetic studies have begun to detail the landscape of how specific levels of carefully defined renal or hepatic dysfunction alter the clearance and tolerance of many of the most commonly used drugs for the systemic treatment of cancer. For each new agent, prospective investigations are required to define usage parameters for each clinically defined level of organ dysfunction. It should be pointed out that alterations in pharmacokinetic parameters per se may occur with or without important changes in toxicity. Where evidence exists, applicable recommendations for chemotherapeutic drug use in the setting of renal or hepatic dysfunction are outlined in the above tables
Management of Complications
Nutrition is always a concern for patients newly diagnosed with cancer, even if they have not experienced weight loss. In fact, significant weight loss is an adverse prognostic factor for several cancers, especially lung cancer. Patients are often concerned about whether their diet contributed to development of the cancer and whether diet can influence the results of therapy. In most settings, neither of these scenarios is the case. Malnourished patients should be evaluated by a dietitian to determine whether they are ingesting sufficient calories and whether dietary supplements might be needed. Some patients, such as those with head and neck cancers or esophageal cancers, may require parenteral nutrition through a percutaneous gastrostomy tube. Total parenteral nutrition is rarely indicated. Larger-than-recommended doses of vitamins are also not helpful and may be toxic. It is important to determine whether over-the-counter and/or alternative medications are being contemplated or used by the patient because of the potential for drug interactions.
Patients with a recent cancer diagnosis have increased risks of death from cardiovascular causes, especially during the first week after diagnosis. The need for continuing psychosocial support in the face of ongoing cancer treatment, and the associated anxiety, depression, and fear experienced by many patients, is substantive and may be beyond the ability of the immediate family to fulfill. In this setting, patients often benefit from participation in support groups or from direct one-on-one counseling, and from efforts to improve communication across all levels of care and support systems.
Hematopoietic Growth Factors
Growth factors, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), speed recovery from white blood cell count depression, permitting chemotherapy to be given on schedule, without reducing the dosage in many cases. However, such therapy does not decrease hospitalizations or improve survival. It is possible to determine which individuals are at greatest risk for febrile neutropenia and to treat them in advance, based on published guidelines. Correction of anemia with erythropoiesis-stimulating agents (ESAs) (Epoetin alfa and Darbepoietin alfa), while possible, may be associated with complications of adverse cardiovascular events and even potentially tumor progression.
Prevention of Pathologic Bone Fractures
The bisphosphonates pamidronate and zoledronate are very effective not only for the treatment of tumor-induced hypercalcemia but also to reduce pathologic fractures in bones with metastatic lesions, particularly from breast cancer, prostate cancer, and myeloma. They are also used to treat osteoporosis caused by chemotherapy-induced premature menopause in young women with breast cancer. Denosumab is a human monoclonal antibody that binds to RANK ligand, a protein found on osteoclasts that is involved in bone breakdown. Some clinical trials have found denosumab to be superior to zoledronic acid for the prevention of skeletal-related events in cancer patients with bone metastases.
Effective management of symptoms is critical to successful delivery of either curative or palliative treatment and maintenance of a patient’s quality of life.
Nausea and Vomiting
Patients continue to fear chemotherapy because of the risk of nausea and vomiting. New antiemetics, used in combination, have made this side effect much less debilitating. Chemotherapeutic drugs can be ranked according to their probability of causing nausea and vomiting, with prophylactic treatment given accordingly. The availability of the serotonin 5-hydroxytryptamine type 3 (5-HT 3) receptor antagonists (dolasetron, granisetron, ondansetron) has dramatically improved our ability to completely control nausea and vomiting. More emetogenic regimens require combination therapy with a corticosteroid (usually dexamethasone), a 5-HT 3 antagonist, and a benzodiazepine (e.g., lorazepam) or the neurokinin-1 receptor antagonist, aprepitant. Aprepitant is particularly useful for the treatment/prevention of delayed nausea and vomiting. A double-blind randomized clinical trial of four combination regimens for controlling delayed nausea concluded that the addition of dexamethasone on days 2 and 3 was particularly effective.
Pain control can be accomplished with a variety of analgesics, both non-narcotic and narcotic. Oncologists use a variety of scales for the evaluation of pain and start treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and acetaminophen, progress through ibuprofen and related drugs, and then through combinations of NSAIDs and narcotics to stronger narcotics. Newer narcotics are available in both short-duration and long-duration forms; some dermal patches last 72 hours, which is ideal for patients who have severe pain and are unable to take oral medications. Oral transmucosal fentanyl is more effective than standard-release morphine in this setting. Painful oral mucositis, a common complication of intensive therapy for hematologic malignancies, can be treated with local measures or with recombinant human keratinocyte growth factor. Oral anti- Candida drugs that are absorbed or partially absorbed from the gastrointestinal tract can help prevent pain from oral candidiasis. American Pain Society standards for pain management in cancer recommend both pharmacologic and psychosocial interventions as complementary approaches. A recently published meta-analysis of randomized controlled studies of various psychosocial interventions among adult cancer patients (e.g., relaxation training, cognitive behavioral therapy, and other education- and skills-based approaches) demonstrated medium-sized effects on both pain severity and interference with daily activities.
Accumulations of fluid and malignant cells in the pleural, peritoneal, or pericardial spaces are common complications of epithelial and hematopoietic malignancies that frequently produce a significant array of symptoms, either at the time of diagnosis or accompanying tumor progression. Malignant pleural effusions are most commonly associated with cancers of the lung and breast or lymphomas, may be the result of lymphatic obstruction or direct invasion of pleural membranes, and can produce significant degrees of dyspnea, cough, or pain that require therapy. Diagnostic thoracentesis of sufficient volume (>60 mL), with cytologic analysis of the pleural effusion, has a reasonably high diagnostic yield for malignancy (60 to 90%). In patients with previously untreated lymphoma, breast cancer, or small cell lung cancer, objective response to the initiation of systemic chemotherapy may provide long-term symptomatic relief. However, in patients with recurrent lung or breast cancer, for example, pleural effusions that are confirmed to contain malignant cells may present difficult ongoing therapeutic challenges. For symptomatic patients, therapeutic thoracentesis, usually under ultrasound guidance, is required and may need to be repeated to reduce dyspnea. When frequent thoracenteses over short intervals are needed, a pleurodesis procedure is often performed, encompassing drainage of the pleural space with a chest thoracostomy and the instillation of a sclerosing compound (talc, doxycycline) that will initiate an inflammatory response of sufficient magnitude to obliterate the pleural space. Pleurodesis is at least temporarily successful in preventing fluid recurrence in most patients; when it is not, placement of an indwelling pleural catheter may provide long-term symptomatic relief of dyspnea.
Malignant ascites (peritoneal effusion) occurs most frequently in patients with intra-abdominal malignancies (gastric, ovarian, pancreatic, and primary peritoneal cancers) but can be observed as well in patients with advanced breast and lung cancers or lymphoma. Malignant ascites may be caused in part by increased permeability of the tumor vasculature that is a result of vascular endothelial growth factor overexpression, by inflammatory cytokine overproduction in the peritoneal space, or by lymphatic blockade secondary to carcinomatosis. Ultrasound-guided paracentesis provides relief of bloating, dyspnea, and the pain of abdominal distension, but will often need to be repeated, which carries the risk of dehydration, protein loss, electrolyte imbalance, bleeding, infection, and kidney dysfunction. A requirement for paracentesis at frequencies less than 1 week should prompt consideration of placement of a permanent catheter to allow self-drainage, although these devices carry a significant risk of infection.
Malignant pericardial effusions are most commonly related to direct extension or metastatic spread from lung or breast cancers, melanomas, and hematologic malignancies. As is the case for other malignant effusions, image-guided pericardiocentesis with cytologic examination of the fluid that has been evacuated will frequently provide diagnostic confirmation of malignancy; furthermore, even the removal of a relatively modest amount of fluid (<50 mL) may, at least partially, relieve the hemodynamic compromise produced by the effusion. The approach to a patient with malignant pericardial effusions is dictated by hemodynamic status (which can drive the choice between emergency pericardiocentesis or elective pericardiostomy) and by the predicted sensitivity of the inciting tumor to systemic therapy (untreated lymphoma versus chemotherapy-resistant lung cancer, for example).
Endocrine Manifestations of Cancer
Clinical syndromes associated with ectopic hormone production may pose special diagnostic dilemmas, can produce a significant degree of morbidity or even death in cancer patients, and may be difficult to treat. Management of these syndromes involves the simultaneous treatment of both the cancer and the syndrome caused by excessive hormone production. Many of the endocrine manifestations of cancer are caused by the production of small polypeptide hormones by tumors, some of which are derived from specific types of neuroendocrine cells. These cells are widely dispersed in a wide variety of organs, are often of neural crest origin, and can produce biogenic amines. The hormones produced from these tumors include adrenocorticotropic hormones (corticotropin, ACTH), calcitonin, vasoactive intestinal peptide, growth hormone–releasing hormone, corticotropin-releasing hormone (CRH), somatostatin, and other peptides. A second group of tumors, generally derived from squamous epithelium, produces parathyroid hormone–related proteins (PTHrP) and vasopressin.
SOME CLINICAL SYNDROMES OF ECTOPIC HORMONE PRODUCTION
|· Humoral hypercalcemia
o Parathyroid hormone–related protein
§ Squamous cell carcinoma
§ Breast cancer
§ Neuroendocrine tumors
§ Renal cell cancer
§ Prostate cancer
o Increased calcitriol
§ Benign conditions: sarcoid, berylliosis, tuberculosis, fungal infections
§ Small cell lung cancer
§ Pulmonary carcinoid
§ Medullary thyroid cancer
§ Islet cell tumor
o Corticotropin-releasing hormone
§ Medullary thyroid cancer
§ Prostate cancer
§ Islet cell tumors
|· Human chorionic gonadotropin
o Testicular embryonal cell carcinoma
o Sarcomas or large retroperitoneal tumors
|· Inappropriate antidiuretic hormone secretion
o Small cell lung cancer
o Squamous cell head and neck cancer
o Renal cell cancer
o Benign conditions: cerebellar hemangioblastoma, uterine fibroids
Hypercalcemia of Malignancy
Humoral hypercalcemia is one of the most common endocrine syndromes related to an underlying malignancy. There are several different underlying mechanisms related to this pathophysiologic process, including ectopic production of PTHrP with activation of the PTH receptor to increase osteoclast differentiation and bone resorption, with consequent hypercalcemia. Ectopic PTHrP (rather than PTH) production by several different types of cancer, most characteristically in squamous cell, breast, renal cell, and prostate cancer, as well as neuroendocrine tumors and melanoma, is one of the most common causes of hypercalcemia of malignancy. Increased production of calcitriol, which increases calcium absorption with suppression of serum PTH levels, is another cause of malignant hypercalcemia that is most commonly observed in patients with lymphoma. Bone metastases, particularly in patients with breast cancer and myeloma, may produce hypercalcemia due to increased local production of PTHrP or other cytokines that increase bone resorption.
The treatment of malignant hypercalcemia is similar to that caused by hyperparathyroidism in that reversal of dehydration and the initiation of a saline diuresis should begin early; patients with a serum calcium in excess of 13 mg/dL should be treated with a bisphosphonate initially, with extended use of the bisphosphonate, as described earlier, for the prevention of bone fractures and recurrence of hypercalcemia.
Other Ectopic Hormone Syndromes
Inappropriate secretion of ACTH is rare but resembles pituitary Cushing disease; tumors that produce CRH include medullary thyroid cancer, prostate cancer, and islet cell neoplasms. Ectopic ACTH syndrome may become manifest as classic Cushing syndrome, with easy bruisability, centripetal obesity, muscle wasting, hypertension, diabetes, and metabolic alkalosis, although many patients with ectopic ACTH-producing cancers progress too quickly to develop prominent cushingoid manifestation clinically. Profound hypokalemia may predominate without all the classic features of Cushing syndrome in patients with small cell lung cancer.
Tumor-associated hypoglycemia, although uncommon, may be the result of: insulin overproduction by islet cell tumors; insufficient hepatic gluconeogenesis related to loss of functional hepatic mass by metastatic disease; and overexpression of insulin-like growth factor II, which can activate the insulin receptor in patients with large retroperitoneal sarcomas or hepatocellular carcinomas. In each of these cases, treatment with frequent small feedings can be prescribed; however, successful symptomatic management of hypoglycemia may be difficult without control of the primary tumor mass or metastases.
The clinical syndrome of inappropriate secretion of antidiuretic hormone is caused by ectopic production of vasopressin, primarily in patients with small cell lung cancer or squamous cancers of the head and neck, and occasionally in those with primary brain tumors. It is characterized by hyponatremia, hypo-osmolality, excessive urine sodium excretion, an inappropriately high urine osmolality for the low serum osmolality, and normal kidney, adrenal, and thyroid function. Fluid (free water) restriction can provide adequate short-term management of symptomatic hyponatremia; however, treatment with demeclocycline, which blocks the effects of vasopressin on the kidney, provides more effective long-term therapy.
The term paraneoplasia , which means “alongside cancer,” has been commonly used to denote remote effects of cancer that cannot be attributed either to direct invasion or to distant metastases. These syndromes may be the first sign of a malignancy and affect up to 15% of patients with cancer. However, if patients with cachexia are excluded, the incidence probably drops to only a few percent. Paraneoplastic syndromes may be the initial presenting sign or symptom of an underlying malignancy. Up to two thirds of paraneoplastic syndromes arise before an associated malignancy is diagnosed. In some cases, the paraneoplastic syndrome may be associated with relatively small tumors; recognition of these associations may lead to earlier diagnosis and possibly more effective therapy. Furthermore, one of the hallmarks in defining a paraneoplastic syndrome is that the course of the syndrome generally parallels the course of the tumor. Therefore, effective treatment of the underlying malignancy is often accompanied by improvement or resolution of the syndrome. Conversely, recurrence of the cancer may be heralded by the return of systemic symptoms. The numerous neurologic paraneoplastic syndromes 12 are reviewed in.
EVALUATION AND DIAGNOSIS OF PARANEOPLASTIC SYNDROMES
|· Characterize abnormality; obtain laboratory studies and biopsy as necessary.
· Carefully elicit any additional symptoms and signs.
· Eliminate common causes.
· If there is no obvious etiology, consider a paraneoplastic syndrome.
· If findings are consistent with a known syndrome, screen for underlying malignancy.
· If signs and symptoms are consistent with a known paraneoplastic syndrome, undertake a search for an unknown primary cancer or recurrence or progression of a known primary tumor.
· Screening should include a careful physical examination with breast, gynecologic, and prostate evaluations; basic hematology, chemistry, and urine studies; chest radiograph; and mammogram.
· Computed tomography (CT) of the abdomen and pelvis or positron emission tomography (PET) scan is indicated if there are any suspicious symptoms, signs, or laboratory abnormalities.
· Antibody testing for paraneoplastic neurologic syndromes and/or skin biopsy should be performed as indicated.
· Consider treatment of cancer and/or appropriate palliative treatment, including immunosuppressive therapy for paraneoplastic symptoms when possible.
Dermatologic Paraneoplastic Syndromes
Associations between cutaneous syndromes and underlying malignancies may be difficult to confirm. Generally, the skin condition and cancer follow a parallel course, and the two diagnoses should be made at about the same time. Some skin lesions are almost always associated with malignancy. Others, however, are nonspecific and are most commonly seen with nonmalignant conditions, making it difficult or impossible to connect the skin disease with the underlying malignancy. In addition, biopsies of the skin lesion are usually nonspecific, showing features identical to those when the same lesion is seen without a malignant condition. The formation of tumor-related autoantibodies has rarely been associated with dermatologic paraneoplastic syndromes, although inflammatory cell infiltration may be seen.
Recognition of cutaneous manifestations of malignancy can be critical for the early diagnosis and successful treatment of cancer, but some syndromes are seen only with advanced, incurable disease. Cutaneous manifestations include direct involvement of the skin with tumor as well as the remote effects of cancer. Both specific and nonspecific dermatologic adverse effects are also seen with cytotoxic chemotherapeutic agents, including alkylating agents, antimetabolites, anthracyclines, and antitumor antibiotics.
One of the best-known paraneoplastic syndromes is acanthosis nigricans, the pathogenesis of which is unclear. The tumor may produce factors that activate insulin-like growth factors or the insulin receptor in skin. Many tumors are known to produce transforming growth factor-α (TGF-α), which might activate epidermal growth factor receptors in skin, causing hyperpigmentation and thickening. The skin lesions arise as velvety, verrucous hyperpigmentation of the neck, axilla, groin, and mucosal membranes, including the lips, periocular area, and anus. Although acanthosis nigricans clearly occurs as a benign entity associated with obesity and endocrinopathy, its appearance in older adults, especially when it includes mucosal lesions, has been highly associated with malignancies of the gastrointestinal tract as well as other adenocarcinomas. The lesions often regress with successful treatment of the underlying tumor.
Rheumatologic Paraneoplastic Syndromes
In patients who have rheumatic disorders with atypical clinical presentation—particularly older patients, those with coexisting systemic symptoms, and patients who respond unexpectedly poorly to usual antirheumatic treatments—the possibility of an underlying occult malignancy should be considered. Chemotherapeutic agents can also cause rheumatic adverse effects.
One of the more common and specific rheumatologic paraneoplastic syndromes is hypertrophic osteoarthropathy, which arises as an oligoarthritis or polyarthritis of the distal joints, with clubbing, tender periostitis of the distal long bones, and noninflammatory synovial effusions. Hypertrophic osteoarthropathy may affect up to 10% of patients with adenocarcinoma of the lung. It is also seen with a variety of other pulmonary malignancies, including lung metastases from other primary sites. The etiology is unknown. Laboratory studies often reveal an elevation in the erythrocyte sedimentation rate; bone radiographs show linear ossification of the distal long bones separated by a radiolucent zone from the underlying cortex. Treatment is symptomatic with anti-inflammatory agents; successful treatment of the underlying tumor may also improve the signs and symptoms of this syndrome.
Fever and Cachexia
Fever, night sweats, and cachexia are nonspecific symptoms that, when seen in the absence of infection or a known disorder, suggest the diagnosis of an underlying malignancy. Cytokines clearly play a pathogenetic role in inducing both fever and cachexia. TNF-α, interleukins (particularly IL-1 and IL-6), and interferon-γ are produced directly by the tumor or by tumor-associated host inflammatory cells, such as macrophages, which results in a catabolic state. Cytokines may produce fever directly by acting at the level of the hypothalamic thermoregulatory center. In addition to the burden of tumor and the production of cytokines, cachexia may be caused or worsened by the side effects of cancer treatment, by intestinal blockage or malabsorption caused by tumor infiltration, and by depression.
Fever is generally cyclic and may be associated with drenching night sweats. Symptoms resolve with successful treatment of the underlying tumor, and return of fever usually heralds relapse. When treatment of the tumor is not possible or is ineffective, NSAIDs or steroids given around the clock significantly improve quality of life. Although cancer-related fever is most commonly seen in association with malignant lymphoproliferative disease, renal cell carcinoma, and leukemias, it may also occur with other cancers, particularly in the face of extensive hepatic metastases.
Cachexia, or the cancer wasting syndrome, is probably the single most common paraneoplastic syndrome, eventually affecting up to 80% of patients with cancer. This syndrome is characterized by anorexia, muscle wasting, loss of subcutaneous fat, and fatigue. It appears to be caused by a combination of protein wasting, malabsorption, immune dysregulation, and increased glucose turnover in the setting of tumor-induced increases in energy expenditure. Successful treatment of the underlying tumor reverses the process; symptomatic treatment for patients with advanced disease is modestly successful at best. Megestrol acetate given in high concentrations in liquid form (400 to 800 mg/day) can improve appetite and result in weight gain, but at the cost of fluid retention.
Survivorship and Follow-Up
Approximately 4% of the United States population (≈14 million people) is living with a history of cancer; about 60% of cancer survivors are age 65 or older. Thus, there is a large and increasing number of individuals who are living longer during the period of cancer survivorship—from the end of active treatment to the point of recurrence or death from another condition. There has been a growing appreciation of the specific care needs of these patients, including: a defined program of surveillance to detect recurrence or second cancers and the late effects of cancer treatment; intervention to treat the consequences of the cancer and its treatment (such as lymphedema, fatigue, and psychosocial distress); prevention of new cancers through changes in diet, behavior, and physical activity; and the institution of a coordinated program of care for cancer survivors that may require a variety of specialty services. Long-term follow-up can be optimized by the provision of a survivorship care plan for patients that provides a comprehensive summary of all diagnostic and therapeutic procedures undergone, toxicities experienced, and therapeutic outcomes, as well as a specific program of individualized follow-up care. Although definitive follow-up regimens do not exist for most cancers, evidence-based templates for common malignancies have been developed by the American Society of Clinical Oncology and the National Comprehensive Cancer Network. Lastly, it must be remembered that issues of survivorship affect caregivers, who often experience a high degree of psychological distress, along with the patient, during and after the period of active treatment.