17.5.1 The Concept of Therapeutic Index
In addition to their antitumor effects, all anticancer drugs are toxic at some level to normal tissues, and it is this toxicity that limits the dose of drugs that can be administered to patients. The relationship between the probability of a biological effect of a drug and the administered dose is usually described by a sigmoid curve (Fig. 17–9), although it is possible that for targeted agents there is an optimal dose where the target is completely inhibited and using higher doses only augments the toxicity. If the drug is to be useful, the curve describing the probability of antitumor effect (eg, complete clinical remission) must be displaced toward lower doses as compared with the curve describing the probability of major toxicity to normal tissues (eg, myelosuppression leading to infection). The therapeutic index (or therapeutic ratio) may be defined from such curves as the ratio of the dose required to produce a given probability of toxicity and the dose required to give a defined effect against the tumor. The therapeutic index in Figure 17–9 might be represented by the ratio of the drug dose required for a 5% level of probability of severe toxicity (sometimes referred to as toxic dose 05 [TD05]) to that required for 50% probability of antitumor effect (ie, effective dose 50 [ED50]). Any stated levels of probability might be used. The appropriate end points of tumor response and toxicity will depend on the limiting toxicity of the drug and the intent of treatment (ie, cure versus palliation). Improvement in the therapeutic index is the goal of systemic treatment. However, although dose–response curves similar to those of Figure 17–9 have been defined in animals, they have rarely been obtained for drug effects in humans. They emphasize the important concept that any modification in treatment that leads to increased killing of tumor cells in tissue culture or animals must be assessed for its effects on critical normal tissues prior to therapeutic trials.
Concept of Therapeutic Index. Schematic relationship between dose of a drug and the probability of a given measure of antitumor effect (curve a), and the probability of a given measure of normal-tissue toxicity (curve b). Heterogeneity among tumors often leads to a shallower slope of the line representing tumors, as shown in red. The therapeutic index might be defined as the ratio of doses to give 50% probabilities of normal-tissue damage and antitumor effects. However, if the end point for toxicity is severe (eg, sepsis as a result of bone marrow suppression), it would be more appropriate to define the therapeutic index at a lower probability of toxicity (eg, toxic dose [TD05]/effective dose [ED50]).
Toxicity to normal tissues limits both the dose and frequency of drug administration. Many drugs cause toxicity because of their preferential activity against rapidly proliferating cells, and this is especially true for chemotherapy, but also for some targeted agents—normal adult tissues that maintain a high rate of cellular proliferation include the bone marrow, intestinal mucosa, hair follicles, and gonads (see Chap. 12, Sec. 12.1.3). Nausea, vomiting, fatigue, and carcinogenic effects are also common side effects of many drugs. In addition, several drug-specific toxicities to other tissues of the body may be observed. The biological basis for toxic damage to normal tissues that may occur through a common mechanism is discussed below, whereas toxic effects specific for individual drugs are described in Chapter 18. Targeted agents, in particular, may cause a variety of side effects that are not specific to rapidly proliferating tissues.
17.5.2 Toxicity to Bone Marrow and Scheduling of Treatment
Within the bone marrow there is evidence for a pluripotent stem cell that under normal conditions proliferates slowly to replenish cells in the myelocytic, erythroid, and megakaryocytic lineages (Fig. 17–10A). Lineage-specific precursors proliferate more rapidly than stem cells, whereas the morphologically recognizable but immature precursor cells (eg, myeloblasts) have a very rapid rate of cell proliferation. Beyond a certain stage of maturation, proliferation ceases and the cells mature into circulating blood cells. The relationship between proliferation and maturation in bone marrow precursor cells provides a plausible explanation for the observed fall and recovery of blood granulocytes (and more rarely of platelets) that follows treatment with most chemotherapy drugs (Fig. 17–10B). Proliferation-dependent cytotoxic drugs, including most types of chemotherapy, deplete the rapidly proliferating cells in the earlier part of the maturation series, with minimal effects against the more mature nonproliferating cells and against slowly proliferating stem cells. Blood counts may remain in the normal range while the more mature surviving cells continue to differentiate but will then fall rapidly at a time when the cells depleted earlier would normally have completed maturation. A substantial decrease in the number of mature cells is common for granulocytes because their lifetime is only 1 to 2 days, less common for platelets (lifetime of a few days), and rare for red blood cells (mean lifetime of approximately 120 days), but it may also be influenced by differences in the intrinsic sensitivities of their precursor cells for different drugs. The number of mature granulocytes usually decreases at 8 to 10 days after treatment with drugs such as cyclophosphamide, doxorubicin, or paclitaxel, but may do so earlier for other drugs (eg, vinblastine). The variation in time from treatment to the fall in peripheral blood counts for different drugs probably reflects their different effects on the rate of cell maturation. When the peripheral granulocyte count falls, proliferation of stem cells is mediated by release of growth factors, with subsequent recovery of the entire bone marrow population. Administration of growth factors (eg, granulocyte colony-stimulating factor [G-CSF]) after chemotherapy can accelerate the reappearance of mature cells in the peripheral blood and decrease the possibility of infection that can occur in the absence of mature granulocytes. For many drugs (eg, cyclophosphamide, doxorubicin, taxanes), recovery of peripheral blood counts is complete at approximately 3 weeks after therapy (or at ~2 weeks if growth factors are given), and further treatment may be given with little or no evidence of residual damage to bone marrow.
Pattern of proliferation in bone marrow and explanation of scheduling. A) Schematic of the differentiation of hematopoietic precursor cells in the bone marrow, leading to the production of red blood cells, platelets, granulocytes, and monocytes. CFU, colony-forming unit; BFU, blast-forming unit; E, erythroid; MEG, megakaryocytic; G, granulocytic; M, monocytic. Various cells are stimulated to proliferate and/or differentiate by the growth factors interleukin (IL)-3 and -6, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), monocyte colony-stimulating factor (M-CSF), erythropoietin (EPO), stem cell factors (eg, Sox2, Klf4, Nanog), and others; only their main target cells are indicated here. Under normal conditions, the early precursor cells proliferate slowly, intermediate precursors proliferate rapidly (in the megakaryocytic series there is nuclear replication without cell division) to expand the population, and later precursors of the functional cells differentiate without further cell division. B) Fall and recovery of the peripheral granulocyte count after chemotherapy. For most drugs the count falls to a nadir at 10 to 14 days after treatment, with complete recovery by 3 to 4 weeks.
Following treatment with some drugs, such as melphalan, or with wide-field radiation to a high proportion of the bone marrow, recovery of mature granulocytes and platelets to normal levels is slower, usually requiring approximately 6 weeks after treatment. Drugs that produce prolonged myelosuppression cause direct damage to slowly or nonproliferating stem cells. Thus recovery is delayed because of repopulation from a smaller number of bone marrow stem cells, and some damage may be permanent because of incomplete repopulation of the stem cell pool.
Recovery of blood counts after treatment with anticancer drugs is the usual determinant of the interval between courses of chemotherapy. If myelosuppressive drugs are given when peripheral blood counts are low, they will not only delay recovery and increase the chance of infection and bleeding, but will also have a higher chance of depleting the stem cell population, because it is likely to be proliferating rapidly. Drug administration can be repeated up to 1 week after initial treatment, before the decrease in mature granulocytes and platelets is observed; this schedule has been incorporated into several drug regimens where anticancer drugs are given on days 1 and 8 of a 21- or 28-day cycle. Some drugs (eg, bleomycin, vincristine, and many of the newer targeted agents) cause only minimal toxicity to bone marrow, probably because of intrinsic resistance of the precursor cells; they can be given when peripheral granulocyte and platelet counts are low following the use of myelosuppressive agents.
Red blood cells have a long lifetime, which usually prevents the rapid development of anemia following initiation of chemotherapy. However, repeated courses of chemotherapy cause repeated interruptions of red blood cell production so that the serum level of hemoglobin tends to decrease slowly, leading to anemia and contributing to fatigue. This effect can occur with all types of drug therapy, but occurs more rapidly following the use of some drugs, such as cisplatin. Injection of erythroid-stimulating agents, which are analogs of the growth factor erythropoietin, can be used to stimulate production of red blood cells, thus minimizing the effects of chemotherapy to cause anemia and reducing the associated fatigue. However, these agents must be used with caution, as some tumor cells may also express the erythropoietin receptor and be stimulated by these agents, and they have also been shown to induce thrombosis in people with near-normal levels of hemoglobin, which may be life-threatening (Hadland and Longmore, 2009).
Chemotherapy is scheduled most often using intermittent large doses, but there is evidence that continuous daily administration of low doses of drugs (known as metronomic therapy) can give superior effects in animal models, perhaps because of superior effects against tumor blood vessels (Kerbel and Kamen, 2004). Although such schedules can have activity (and low toxicity) against some human tumors, there is no evidence as yet that they provide better long-term outcomes.
Many of the molecular-targeted agents described in Section 17.3 require chronic administration to provide sustained inhibition of their target receptor or pathway. Monoclonal antibodies such as trastuzumab or cetuximab have long half-lives in the circulation, and sustained levels can be achieved by dosing at weekly intervals or less often. However, most inhibitors of receptor tyrosine kinases are small molecules that are given orally (eg, everolimus, an inhibitor of mTOR) and these agents are most often given on a continuous daily schedule. Many of these agents inhibit pathways that stimulate proliferation of cancer (and other cells) and although when used alone they do not usually lead to myelosuppression, they can add substantially to this and other toxicities when used in combination with chemotherapy, and a dose reduction of both agents is then generally required.
17.5.3 Toxicity of Drugs to Other Proliferative Tissues
Ulceration of the mucosa in the mouth, throat, esophagus, or intestine may also occur after treatment with antiproliferative drugs, and can lead to soreness, intestinal bleeding, and diarrhea. It is caused by interruption of the production of new cells that normally replace the mature cells continually being sloughed into the intestine (see Chap. 12, Fig. 12–4). Damage to bone marrow is more commonly dose-limiting in humans, but mucosal ulceration may occur after treatment with several drugs, including methotrexate, 5-fluorouracil, bleomycin, and cytosine arabinoside; it may also occur after treatment with several targeted agents, including sunitinib and sorafenib, presumably because they inhibit proliferation and maturation in mucosal epithelium. Mucosal damage usually begins approximately 5 days after treatment, and its duration increases with the severity. Full recovery is usually possible if the patient can be supported through this period; recovery is analogous to that in the bone marrow, with repopulation from slowly proliferating stem cells.
Partial or complete hair loss is common after treatment with many anticancer drugs and is a result of lethal effects of drugs against proliferating cells in hair follicles; this usually begins approximately 2 weeks after treatment. Full recovery usually occurs after cessation of treatment, suggesting the presence of slowly proliferating precursor cells. In some patients, regrowth of hair is observed despite continued treatment with the agent that initially caused its loss. Regrowth of hair might reflect a compensating proliferative process that increases the number of stem cells, or may represent the development of drug resistance in a normal tissue akin to that which occurs in tumors.
Spermatogenesis in men and formation of ovarian follicles in women both involve rapid cellular proliferation and are susceptible to the toxic effects of many anticancer drugs. Men who receive chemotherapy often have decreased production of sperm and consequent infertility. Testicular biopsy usually demonstrates a loss of germinal cells within the seminiferous tubules, presumably because of drug effects against these rapidly proliferating cells. Antispermatogenic effects may be reversible after lower doses of chemotherapy, but some men remain permanently infertile; it is now usual to recommend sperm banking for young men who undergo intensive chemotherapy for potentially curable malignancies such as Hodgkin disease or testicular cancer. Chemotherapy given to premenopausal women often leads to temporary or permanent cessation of menstrual periods and to menopausal symptoms, and is accompanied by a fall in serum levels of estrogen. Reversibility of this effect depends on age, the types of drug used, and the duration and intensity of chemotherapy. Biopsies taken from the ovaries have shown failure of formation of ovarian follicles, sometimes with ovarian fibrosis. The pathological findings are consistent with a primary effect of drugs against the proliferating germinal epithelium.
17.5.4 Nausea, Vomiting, and Other Common Toxicities
Nausea and vomiting are frequent during the first few hours after treatment with many types of chemotherapy, but occur rarely after use of targeted agents. Drug-induced vomiting may occur because of direct stimulation of chemoreceptors in the brainstem, which then emit signals via connecting nerves to the neighboring vomiting center, thus eliciting the vomiting reflex. Major evidence for this mechanism comes from studies in animals, where induction of vomiting by chemotherapy is prevented by removal of the chemoreceptor zone. In addition to a central mechanism, some chemotherapeutic agents exert direct effects on the gastrointestinal tract that may contribute to nausea and vomiting. Several neurotransmitters, such as serotonin (5-HT3) and substance P are involved in transmitting signals involved in producing nausea and vomiting. Medications have been developed that inhibit nausea and vomiting after chemotherapy. The most effective of these are the serotonin antagonists (such as ondansetron, tropisetron, and granisetron), which block 5-HT3 receptors, and the neurokinin 1 (NK1) receptor antagonists (such as aprepitant), which block substance P.
Some drugs can produce diarrhea without directly damaging the intestinal mucosa. For example, irinotecan can produce diarrhea soon after administration as a consequence of a direct cholinergic effect on the cells of the intestinal mucosa. This type of diarrhea may be prevented through the use of anticholinergic drugs. A second form of diarrhea, secretory in nature, may occur several days following administration of irinotecan, and may be a result of damage to the mucosa coupled with cytokine release causing fluid secretion (see Chap. 18, Sec. 18.4.1).
Fatigue is a common side effect of both the presence of cancer and its treatment, and several types of chemotherapy (eg, taxanes) and targeted agents that inhibit multiple receptors (eg, sunitinib, sorafenib, and pazopanib) can cause profound fatigue. Unfortunately there are no pharmacological treatments that have been found to relieve fatigue, and the only strategy of proven benefit is exercise, possible only for select patients with metastatic cancer.
The hand-foot syndrome (or palmar-plantar erythrodysesthesia) may occur during treatment with several types of chemotherapy (eg, capecitabine) and with targeted agents such as sunitinib and sorafenib (Lipworth et al, 2009). Patients have redness and pain on the palms of the hands and soles of the feet, sometimes with blistering and desquamation, which can be quite disabling. The condition responds to reduction of dose of the anticancer drug. The cause of this condition is uncertain, although it might relate in part to sensitivity of proliferating cells in the basal layer of the skin in these sites.
Subtle cognitive dysfunction has also been identified as a side effect of chemotherapy, especially in women who are receiving adjuvant chemotherapy for breast cancer (Ahles et al, 2007; Vardy et al, 2007). The mechanisms underlying these effects are unknown; they may be mediated in part by changes in the levels of sex hormones and induction of menopausal symptoms, but are probably also a result of direct effects of anticancer drugs on the brain.
17.5.5 Drugs as Carcinogens
Many anticancer drugs cause toxic damage through effects on DNA; they can also cause mutations and chromosomal damage. These properties are shared with known carcinogens (see Chap. 4), and patients who are long-term survivors of such chemotherapy may be at an increased risk for developing a second malignancy. This effect has become apparent only under conditions where chemotherapy has resulted in long-term survival for some patients with drug-sensitive diseases (eg, Hodgkin disease, other lymphomas, testicular cancer) or where it is used as an adjuvant to decrease the probability of recurrence of disease following local treatment (eg, breast cancer). Many of the second malignancies are acute leukemias, and their most common time of presentation is 2 to 6 years after initiation of chemotherapy. Increased incidence of solid tumors may also be observed after longer periods of follow up. Alkylating agents are the drugs most commonly implicated as the cause of second malignancy, and there is increased risk if patients also receive radiation. It is often difficult to separate an increase in the probability of second malignancy that may be associated with the primary neoplasm (eg, in a patient with lymphoma) or with a shared etiological factor, either environmental or as a result of genetic predisposition, from that associated with treatment.
Comparisons of the incidence of leukemia and other malignancies in clinical trials that randomize patients to receive adjuvant chemotherapy or no chemotherapy after primary treatment have given conclusive evidence of the carcinogenic potential of some drugs. The relative risk of leukemia in drug-treated, as compared with control patients, was increased in women receiving adjuvant therapy for breast cancer that included an alkylating agent (especially when melphalan was used) but for modern regimens that include conventional dose cyclophosphamide there is no significant increase in relative risk (Curtis et al, 1992). There is a 2- to 3-fold increased relative risk of endometrial cancer following use of tamoxifen, but the absolute risk is below 1% and most are curable by surgery (Matesich and Shapiro, 2003). Drugs that target topoisomerase II (eg, doxorubicin, epirubicin, mitoxantrone, and etoposide; see Chap. 18, Sec. 18.4) have also been identified as causes of treatment-related leukemia, with a relative risk of approximately 1.5 compared to those not receiving this treatment (Patt et al, 2007). Leukemias that occur following treatment with these drugs have a limited number of characteristic chromosomal translocations that distinguishes them from those that occur following alkylating agents, and they tend to occur after a shorter latent period of 1 to 3 years after treatment of their primary cancer (Mistry et al, 2005).
The risk of second solid tumors following treatment with chemotherapy is far lower than that of leukemia. Nonetheless, a 4.5-fold increase in the risk of transitional cell carcinoma of the urothelium has been demonstrated in patients who had received cyclophosphamide for the treatment of non-Hodgkin lymphoma (Travis et al, 1995), and there is an increased risk of breast and other cancers in patients who are treated for Hodgkin lymphoma with radiotherapy or chemotherapy, and especially in those receiving both treatments. The absolute risk of second malignancy is small compared with the potential benefits in treating curable cancers but care is needed in using carcinogenic drugs as adjuvant chemotherapy for malignancies where benefit is minimal.
17.5.6 Determinants of Normal-Tissue Toxicity
When chemotherapy is given to a patient, a drug dose is selected on the basis of early phase clinical trials that have determined the average dose (usually per unit of body surface area) that gives some toxicity, but at an acceptable level. At this dose, there may be a small proportion of patients, who experience severe, potentially lethal toxicity. Multiple factors influence the distribution of drugs to tissues in the body (see Chap. 18, Sec. 18.1) and the response of normal cells to these drugs. Some patients have genetically determined traits that influence drug metabolism or excretion, and the study of genetically determined factors that influence the probability of drug toxicity is known as pharmacogenetics (see Chap. 3, Sec. 3.6.2 and Chap. 18, Sec. 18.3.1). For example, patients who lack the enzyme dihydropyrimidine dehydrogenase (DPD), which catabolizes 5-fluorouracil show extreme sensitivity to this drug (see Chap. 18, Sec. 18.3.2; Milano et al, 1999). Genetic abnormalities that give rise to the DPD-deficient phenotype have been identified, and screening tests can identify susceptible individuals. Changes in the activity of enzymes that metabolize other drugs, either genetically determined or induced by concomitant medications, may also have a profound effect on drug-induced toxicity.
Because lethal damage caused by chemotherapy results most often from interaction of drugs with DNA, patients with deficiencies in DNA repair (see Chap. 5, Sec. 5.5) are very sensitive to anticancer drugs, as they are to radiation. People who are heterozygous for such gene mutations (eg, xeroderma pigmentosum or ataxia telangiectasia) may also be at high risk for severe toxicity if treated by chemotherapy. Predictive assays, based on assessing chromosomal damage in lymphocytes, are being developed that could allow identification of individuals who may exhibit extreme radio- (and possibly chemo-) sensitivity (Pfuhler et al, 2011). However, the clinical utility of such tests will need to be evaluated carefully, given the low prevalence of the abnormalities being tested, although such individuals may be overrepresented among cancer patients (see also Chap. 5, Table 5–1).