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CHAPTER 28: PRINCIPLES OF CANCER TREATMENT
Edward A. Sausville; Dan L. Longo
Sausville EA, Longo DL. Sausville E.A., & Longo D.L. Sausville, Edward A., and Dan L. Longo.PRINCIPLES OF CANCER TREATMENT. In: Longo DL. Longo D.L.(Ed.),Ed. Dan L. Longo.eds. Harrison's Hematology and Oncology, 2e. McGraw Hill; 2013. Accessed January 28, 2023. https://hemonc.mhmedical.com/content.aspx?bookid=1826&sectionid=126654869
Sausville EA, Longo DL. Sausville E.A., & Longo D.L. Sausville, Edward A., and Dan L. Longo. (2013). Principles of cancer treatment. Longo DL. Longo D.L.(Ed.),Ed. Dan L. Longo. Harrison's Hematology and Oncology, 2e. McGraw Hill. https://hemonc.mhmedical.com/content.aspx?bookid=1826&sectionid=126654869
Sausville EA, Longo DL. Sausville E.A., & Longo D.L. Sausville, Edward A., and Dan L. Longo. "PRINCIPLES OF CANCER TREATMENT." Harrison's Hematology and Oncology, 2e Longo DL. Longo D.L.(Ed.),Ed. Dan L. Longo. McGraw Hill, 2013, https://hemonc.mhmedical.com/content.aspx?bookid=1826&sectionid=126654869.
PRINCIPLES OF CANCER SURGERY
PRINCIPLES OF RADIATION THERAPY
PRINCIPLES OF CHEMOTHERAPY
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The goal of cancer treatment is first to eradicate the cancer. If this primary goal cannot be accomplished, the goal of cancer treatment shifts to palliation, the amelioration of symptoms, and preservation of quality of life while striving to extend life. The dictum primum non nocere may not always be the guiding principle of cancer therapy. When cure of cancer is possible, cancer treatments may be undertaken despite the certainty of severe and perhaps life-threatening toxicities. Every cancer treatment has the potential to cause harm, and treatment may be given that produces toxicity with no benefit. The therapeutic index of many interventions is quite narrow, and most treatments are given to the point of toxicity. Conversely, when the clinical goal is palliation, careful attention to minimizing the toxicity of potentially toxic treatments becomes a significant goal. Irrespective of the clinical scenario, the guiding principle of cancer treatment should be primum succerrere, "first hasten to help." Radical surgical procedures, large-field hyperfractionated radiation therapy, high-dose chemotherapy, and maximum tolerable doses of cytokines such as interleukin (IL) 2 are all used in certain settings where 100% of the patients will experience toxicity and side effects from the intervention and only a fraction of the patients will experience benefit. One of the challenges of cancer treatment is to use the various treatment modalities alone and together in a fashion that maximizes the chances for patient benefit.
Cancer treatments are divided into four main types: surgery, radiation therapy (including photodynamic therapy), chemotherapy (including hormonal therapy and molecularly targeted therapy), and biologic therapy (including immunotherapy and gene therapy). The modalities are often used in combination, and agents in one category can act by several mechanisms. For example, cancer chemotherapy agents can induce differentiation, and antibodies (a form of immunotherapy) can be used to deliver radiation therapy. Surgery and radiation therapy are considered local treatments, though their effects can influence the behavior of tumor at remote sites. Chemotherapy and biologic therapy are usually systemic treatments. Oncology, the study of tumors, including treatment approaches, is a multidisciplinary effort with surgical-, radiotherapy-, and internal medicine–related areas of expertise. Treatments for patients with hematologic malignancies are often shared by hematologists and medical oncologists.
In many ways, cancer mimics an organ attempting to regulate its own growth. However, cancers have not set an appropriate limit on how much growth should be permitted. Normal organs and cancers share the properties of having (1) a population of cells in cycle and actively renewing and (2) a population of cells not in cycle. In cancers, cells that are not dividing are heterogeneous; some have sustained too much genetic damage to replicate but have defects in their death pathways that permit their survival, some are starving for nutrients and oxygen, and some are out of cycle but poised to be recruited back into cycle and expand if needed (i.e., reversibly growth-arrested). Severely damaged and starving cells are unlikely to kill the patient. The problem is that the cells that are reversibly not in cycle are capable of replenishing tumor cells physically removed or damaged by radiation and chemotherapy. These include cancer stem cells, whose properties are being elucidated. The stem cell fraction may define new targets for therapies that will retard their ability to reenter the cell cycle.
Tumors follow a Gompertzian growth curve (Fig. 28-1); the growth fraction of a neoplasm starts at 100% with the first transformed cell and declines exponentially over time until at the time of diagnosis, with a tumor burden of 1–5 × 109 tumor cells, the growth fraction is usually 1–4%. Thus, the peak growth rate occurs before the tumor is detectable. A key feature of a successful tumor is the ability to stimulate the development of a new supporting stroma through angiogenesis and production of proteases to allow invasion through basement membranes and normal tissue barriers (Chap. 25). Specific cellular mechanisms promote entry or withdrawal of tumor cells from the cell cycle. For example, when a tumor recurs after surgery or chemotherapy, frequently its growth is accelerated, and the growth fraction of the tumor is increased. This pattern is similar to that seen in regenerating organs. Partial resection of the liver results in the recruitment of cells into the cell cycle, and the resected liver volume is replaced. Similarly, chemotherapy-damaged bone marrow increases its growth to replace cells killed by chemotherapy. However, cancers do not recognize a limit on their expansion. Monoclonal gammopathy of uncertain significance may be an example of a clonal neoplasm with intrinsic features that stop its growth before a lethal tumor burden is reached. A fraction of patients with this disorder go on to develop fatal multiple myeloma, but probably this occurs because of the accumulation of additional genetic lesions. Elucidation of the mechanisms that regulate this "organ-like" behavior of tumors may provide additional clues to cancer control and treatment.
FIGURE 28-1
Gompertzian tumor growth. The growth fraction of a tumor declines exponentially over time (top). The growth rate of a tumor peaks before it is clinically detectable (middle). Tumor size increases slowly, goes through an exponential phase, and slows again as the tumor reaches the size at which limitation of nutrients or auto- or host regulatory influences can occur. The maximum growth rate occurs at 1/e, the point at which the tumor is about 37% of its maximum size (marked with an X). Tumor becomes detectable at a burden of about 109 (1 cm3) cells and kills the patient at a tumor cell burden of about 1012 (1 kg). Efforts to treat the tumor and reduce its size can result in an increase in the growth fraction and an increase in growth rate.
Surgery is used in cancer prevention, diagnosis, staging, treatment (for both localized and metastatic disease), palliation, and rehabilitation.
Cancer can be prevented by surgery in people who have premalignant lesions resected (e.g., premalignant lesions of skin, colon, cervix) and in those who are at increased risk of cancer from an underlying disease (colectomy in those with pancolonic involvement with ulcerative colitis), the presence of genetic lesions (colectomy for familial polyposis, thyroidectomy for multiple endocrine neoplasia type 2, bilateral mastectomy or oophorectomy for familial breast or ovarian cancer syndromes), or a developmental anomaly (orchiectomy in those with an undescended testis). In some cases, prophylactic surgery is more radical than the surgical procedures used to treat the cancer after it develops. The assessment of risk involves many factors and should be undertaken with care before advising a patient to undergo such a major procedure. For breast cancer prevention, many experts use a 20% risk of developing breast cancer over the next 5 years as a threshold. However, patient fears play a major role in defining candidates for cancer prevention surgery. Counseling and education may not be enough to allay the fears of someone who has lost close family members to a malignancy.
The underlying principle in cancer diagnosis is to obtain as much tissue as safely possible. Owing to tumor heterogeneity, pathologists are better able to make the diagnosis when they have more tissue to examine. In addition to light-microscopic inspection of a tumor for pattern of growth, degree of cellular atypia, invasiveness, and morphologic features that aid in the differential diagnosis, sufficient tissue is of value in searching for genetic abnormalities and protein expression patterns, such as hormone receptor expression in breast cancers, that may aid in differential diagnosis or provide information about prognosis or likely response to treatment. Efforts to define "personalized" information from the biology of each patient's tumor and pertinent to each patient's treatment plan are becoming increasingly important in selecting treatment options. Histologically similar tumors may have very different gene expression patterns when assessed by such techniques as microarray analysis using gene chips, with important differences in response to treatment. Such testing requires that the tissue be handled properly (e.g., immunologic detection of proteins is more effective in fresh-frozen tissue rather than in formalin-fixed tissue). Coordination among the surgeon, pathologist, and primary care physician is essential to ensure that the amount of information learned from the biopsy material is maximized.
These goals are best met by an excisional biopsy in which the entire tumor mass is removed with a small margin of normal tissue surrounding it. If an excisional biopsy cannot be performed, incisional biopsy is the procedure of second choice. A wedge of tissue is removed, and an effort is made to include the majority of the cross-sectional diameter of the tumor in the biopsy to minimize sampling error. The biopsy techniques that involve cutting into tumor carry with them a risk of facilitating the spread of the tumor. Core-needle biopsy usually obtains considerably less tissue, but this procedure often provides enough information to plan a definitive surgical procedure. Fine-needle aspiration generally obtains only a suspension of cells from within a mass. This procedure is minimally invasive, and if positive for cancer, it may allow inception of systemic treatment when metastatic disease is evident, or it can provide a basis for planning a more meticulous and extensive surgical procedure.
As noted in Chap. 26 an important component of patient management is defining the extent of disease. Radiographic and other imaging tests can be helpful in defining the clinical stage; however, pathologic staging requires defining the extent of involvement by documenting the histologic presence of tumor in tissue biopsies obtained through a surgical procedure. Axillary lymph node sampling in breast cancer and lymph node sampling at laparotomy for testicular, colon, and other intraabdominal cancers may provide crucial information for treatment planning and may determine the extent and nature of primary cancer treatment.
Surgery is the most effective means of treating cancer. Today about 40% of cancer patients are cured by surgery. Unfortunately, a large fraction of patients with solid tumors (perhaps 60%) have metastatic disease that is not accessible for removal. However, even when the disease is not curable by surgery alone, the removal of tumor can obtain important benefits, including local control of tumor, preservation of organ function, debulking that permits subsequent therapy to work better, and staging information on extent of involvement. Cancer surgery aiming for cure is usually planned to excise the tumor completely with an adequate margin of normal tissue (the margin varies with the tumor and the anatomy), touching the tumor as little as possible to prevent vascular and lymphatic spread, and minimizing operative risk. Extending the procedure to resect draining lymph nodes obtains prognostic information, but such resections alone generally do not improve survival.
Increasingly, laparoscopic approaches are being used to address primary abdominal and pelvic tumors. Lymph node spread may be assessed using the sentinel node approach in which the first draining lymph node a spreading tumor would encounter is defined by injecting a dye into the tumor site at operation and then resecting the first node to turn blue. The sentinel node assessment is continuing to undergo clinical evaluation but appears to provide reliable information without the risks (lymphedema, lymphangiosarcoma) associated with resection of all the regional nodes. Advances in adjuvant chemotherapy and radiation therapy following surgery have permitted a substantial decrease in the extent of primary surgery necessary to obtain the best outcomes. Thus, lumpectomy with radiation therapy is as effective as modified radical mastectomy for breast cancer, and limb-sparing surgery followed by adjuvant radiation therapy and chemotherapy has replaced radical primary surgical procedures involving amputation and disarticulation for childhood rhabdomyosarcomas. More limited surgery is also being employed to spare organ function, as in larynx and bladder cancer. The magnitude of operations necessary to optimally control and cure cancer has also been diminished by technical advances; for example, the circular anastomotic stapler has allowed narrower (<2-cm) margins in colon cancer without compromise of local control rates, and many patients who would have had colostomies are able to maintain normal anatomy.
In some settings—e.g., bulky testicular cancer or stage III breast cancer—surgery is not the first treatment modality employed. After an initial diagnostic biopsy, chemotherapy and/or radiation therapy is delivered to reduce the size of the tumor and clinically control undetected metastatic disease. Such therapy is followed by a surgical procedure to remove residual masses; this is called neoadjuvant therapy. Because the sequence of treatment is critical to success and is different from the standard surgery-first approach, coordination among the surgical oncologist, radiation oncologist, and medical oncologist is crucial.
Surgery may be curative in a subset of patients with metastatic disease. Patients with lung metastases from osteosarcoma may be cured by resection of the lung lesions. In patients with colon cancer who have fewer than five liver metastases restricted to one lobe and no extrahepatic metastases, hepatic lobectomy may produce long-term disease-free survival in 25% of selected patients. Surgery can also be associated with systemic antitumor effects. In the setting of hormonally responsive tumors, oophorectomy and/or adrenalectomy may control estrogen production, and orchiectomy may reduce androgen production; both have effects on metastatic tumor growth. If resection of the primary lesion takes place in the presence of metastases, acceleration of metastatic growth may occur, perhaps based on the removal of a source of angiogenesis inhibitors and mass-related growth regulators in the tumor.
In selecting a surgeon or center for primary cancer treatment, consideration must be given to the volume of cancer surgeries undertaken by the site. Studies in a variety of cancers have shown that increased annual procedure volume appears to correlate with outcome. In addition, facilities with extensive support systems—e.g., for joint thoracic and abdominal surgical teams with cardiopulmonary bypass, if needed—may allow resection of certain tumors that would otherwise not be possible.
Surgery is employed in a number of ways for supportive care, including insertion of central venous catheters, control of pleural and pericardial effusions and ascites, caval interruption for recurrent pulmonary emboli, stabilization of cancer-weakened weight-bearing bones, and control of hemorrhage, among others. Surgical bypass of gastrointestinal, urinary tract, or biliary tree obstruction can alleviate symptoms and prolong survival. Surgical procedures may provide relief of otherwise intractable pain or reverse neurologic dysfunction (cord decompression). Splenectomy may relieve symptoms and reverse hypersplenism. Intrathecal or intrahepatic therapy relies on surgical placement of appropriate infusion portals. Surgery may correct other treatment-related toxicities such as adhesions or strictures.
Surgical procedures are also valuable in restoring a cancer patient to full health. Orthopedic procedures may be necessary to ensure proper ambulation. Breast reconstruction can make an enormous impact on the patient's perception of successful therapy. Plastic and reconstructive surgery can correct the effects of disfiguring primary treatment.
PHYSICAL PROPERTIES AND BIOLOGIC EFFECTS
Radiation is a physical form of treatment that damages any tissue in its path; its selectivity for cancer cells may be due to defects in a cancer cell's ability to repair sublethal DNA and other damage. Radiation causes breaks in DNA and generates free radicals from cell water that may damage cell membranes, proteins, and organelles. Radiation damage is augmented dependent on only oxygen; hypoxemic cells are more resistant. Augmentation of oxygen is the basis for radiation sensitization. Sulfhydryl compounds interfere with free radical generation and may act as radiation protectors.
Most radiation-induced cell damage is due to the formation of hydroxyl radicals:
The dose-response curve for cells has both linear and exponential components. The linear component is from double-strand DNA breaks produced by single hits. The exponential component represents breaks produced by multiple hits. Plotting the fraction of surviving cells against doses of x-rays or gamma radiation, the curve has a shoulder that reflects the cell's repair of sublethal damage followed by a linear portion reflecting greater cell kill with larger doses. The features that make a particular cell more sensitive or more resistant to the biologic effects of radiation are not completely defined.
Therapeutic radiation is delivered in three ways: (1) teletherapy, with beams of radiation generated at a distance and aimed at the tumor within the patient; (2) brachytherapy, with encapsulated sources of radiation implanted directly into or adjacent to tumor tissues; and (3) systemic therapy, with radionuclides targeted in some fashion to a site of tumor. Teletherapy is the most commonly used form of radiation therapy.
X-rays and gamma rays are the forms of radiation most commonly used to treat cancer. They are both electromagnetic, nonparticulate waves that cause the ejection of an orbital electron when absorbed. This orbital electron ejection is called ionization. X-rays are generated by linear accelerators; gamma rays are generated from decay of atomic nuclei in radioisotopes such as cobalt and radium. These waves behave biologically as packets of energy, called photons. Particulate forms of radiation are also used in certain circumstances. Electron beams have a very low tissue penetrance and are used to treat skin conditions such as mycosis fungoides. Proton beams are becoming more widely available and may be more able to delimit dose to tumor in certain anatomic locations. However, aside from these specialized uses, particulate forms of radiation such as neutrons, protons, and negative mesons, which should do more tissue damage because of their higher linear energy transfer and lesser dependence on oxygen, are in most applications not superior to X- or gamma rays in clinical studies reported thus far.
A number of parameters influence the damage done to tissue by radiation. Hypoxemic cells are relatively resistant. Nondividing cells are more resistant than dividing cells. In addition to these biologic parameters, physical parameters of the radiation are also crucial. The energy of the radiation determines its ability to penetrate tissue. Low-energy orthovoltage beams (150–400 kV) scatter when they strike the body, much like light diffuses when it strikes particles in the air. Such beams result in more damage to adjacent normal tissues and less radiation delivered to the tumor. Megavoltage radiation (>1 MeV) has very low lateral scatter; this produces a skin-sparing effect, more homogeneous distribution of the radiation energy, and greater deposit of the energy in the tumor, or target volume. The tissues that the beam passes through to get to the tumor are called the transit volume. The maximum dose in the target volume is often the cause of complications to tissues in the transit volume, and the minimum dose in the target volume influences the likelihood of tumor recurrence. Dose homogeneity in the target volume is the goal. Computational approaches and delivery of many beams to converge on a target lesion are the basis for "gamma knife" and related approaches to deliver high dose to small volumes of tumor, sparing normal tissue.
Radiation is quantitated on the basis of the amount of radiation absorbed in the patient; it is not based on the amount of radiation generated by the machine. The rad (radiation absorbed dose) is defined as 100 ergs of energy per gram of tissue. The International System (SI) unit for rad is the Gray (Gy); 1 Gy = 100 rad. Radiation dose is measured by placing detectors at the body surface or calculating the dose based on radiating phantoms that resemble human form and substance. Radiation dose has three determinants: total absorbed dose, number of fractions, and time. A frequent error is to omit the number of fractions and the duration of treatment. This is analogous to saying that a runner completed a race in 20 s; without knowing how far he or she ran, the result is difficult to interpret. The time could be very good for a 200-m race or very poor for a 100-m race. Thus, a typical course of radiation therapy should be described as 4500 cGy delivered to a particular target (e.g., mediastinum) over 5 weeks in 180-cGy fractions. Most curative radiation treatment programs are delivered once a day, 5 days a week in 150- to 200-cGy fractions.
Certain drugs used in cancer treatment may also act as radiation sensitizers. For example, compounds that incorporate into DNA and alter its stereochemistry (e.g., halogenated pyrimidines, cisplatin) augment radiation effects, as does hydroxyurea, another DNA synthesis inhibitor.
APPLICATION TO PATIENTS
Radiation therapy can be used alone or together with chemotherapy to produce cure of localized tumors and control of the primary site of disease in tumors that have disseminated. Therapy is planned based on the use of a simulator with the treatment field or fields designed to accommodate an individual patient's anatomic features. Individualized treatment planning employs lead shielding tailored to shape the field and limit the radiation exposure of normal tissue. Often the radiation is delivered from two or three different positions. Conformal three-dimensional treatment planning permits the delivery of higher doses of radiation to the target volume without increasing complications in the transit volume.
Radiation therapy is a component of curative therapy for a number of diseases, including breast cancer, Hodgkin's disease, head and neck cancer, prostate cancer, and gynecologic cancers. Radiation therapy can also palliate disease symptoms in a variety of settings, including relief of bone pain from metastatic disease, control of brain metastases, reversal of spinal cord compression and superior vena caval obstruction, shrinkage of painful masses, and opening of threatened airways. In high-risk settings, radiation therapy can prevent the development of leptomeningeal disease and brain metastases in acute leukemia and lung cancer.
Brachytherapy
Brachytherapy involves placing a sealed source of radiation into or adjacent to the tumor and withdrawing the radiation source after a period of time precisely calculated to deliver a chosen dose of radiation to the tumor. This approach is often used to treat prostate tumors and cervical cancer. The difficulty with brachytherapy is the short range of radiation effects (the inverse square law) and the inability to shape the radiation to fit the target volume. Normal tissue may receive toxic exposure to the radiation, with attendant radiation enteritis or cystitis in cervix cancer or brain injury in brain tumors.
Radionuclides and radioimmunotherapy
Nuclear medicine physicians and radiation oncologists may administer radionuclides with therapeutic effects. Iodine 131 is used to treat thyroid cancer since iodine is naturally taken up preferentially by the thyroid; it emits gamma rays that destroy the normal thyroid as well as the tumor. Strontium 89 and samarium 153 are two radionuclides that are preferentially taken up in bone, particularly sites of new bone formation. Both are capable of controlling bone metastases and the pain associated with them, but the dose-limiting toxicity is myelosuppression.
Monoclonal antibodies and other ligands can be attached to radioisotopes by conjugation (for nonmetal isotopes) or by chelation (for metal isotopes), and the targeting moiety can result in the accumulation of the radionuclide preferentially in tumor. Iodine 131–labeled anti-CD20 and yttrium 90–labeled anti-CD20 are active in B cell lymphoma, and other labeled antibodies are being evaluated. Thyroid uptake of labeled iodine is blocked by cold iodine. Dose-limiting toxicity is myelosuppression.
Some chemical structures (porphyrins, phthalocyanines) are selectively taken up by cancer cells by mechanisms not fully defined. When light, usually delivered by a laser, is shone on cells containing these compounds, free radicals are generated, and the cells die. Hematoporphyrins and light are being used with increasing frequency to treat skin cancer; ovarian cancer; and cancers of the lung, colon, rectum, and esophagus. Palliation of recurrent locally advanced disease can sometimes be dramatic and last many months.
Though radiation therapy is most often administered to a local region, systemic effects, including fatigue, anorexia, nausea, and vomiting, may develop that are related in part to the volume of tissue irradiated, dose fractionation, radiation fields, and individual susceptibility. Bone is among the most radioresistant organs, radiation effects being manifested mainly in children through premature fusion of the epiphyseal growth plate. By contrast, the male testis, female ovary, and bone marrow are the most sensitive organs. Any bone marrow in a radiation field will be eradicated by therapeutic irradiation. Organs with less need for cell renewal, such as heart, skeletal muscle, and nerves, are more resistant to radiation effects. In radiation-resistant organs, the vascular endothelium is the most sensitive component. Organs with more self-renewal as a part of normal homeostasis, such as the hematopoietic system and mucosal lining of the intestinal tract, are more sensitive. Acute toxicities include mucositis, skin erythema (ulceration in severe cases), and bone marrow toxicity. Often these can be alleviated by interruption of treatment.
Chronic toxicities are more serious. Radiation of the head and neck region often produces thyroid failure. Cataracts and retinal damage can lead to blindness. Salivary glands stop making saliva, which leads to dental caries and poor dentition. Taste and smell can be affected. Mediastinal irradiation leads to a threefold increased risk of fatal myocardial infarction. Other late vascular effects include chronic constrictive pericarditis, lung fibrosis, viscus stricture, spinal cord transection, and radiation enteritis. A serious late toxicity is the development of second solid tumors in or adjacent to the radiation fields. Such tumors can develop in any organ or tissue and occur at a rate of about 1% per year beginning in the second decade after treatment. Some organs vary in susceptibility to radiation carcinogenesis. A woman who receives mantle field radiation therapy for Hodgkin's disease at age 25 years has a 30% risk of developing breast cancer by age 55 years. This is comparable in magnitude to genetic breast cancer syndromes. Women treated after age 30 years have little or no increased risk of breast cancer. No data suggest that a threshold dose of therapeutic radiation exists below which the incidence of second cancers is decreased. High rates of second tumors occur in people who receive as little as 1000 cGy.
Medical oncology is the subspecialty of internal medicine that cares for and designs treatment approaches to patients with cancer in conjunction with surgical and radiation oncologists. The core skills of the medical oncologist include the use of drugs that may have a beneficial effect on the natural history of the patient's illness or favorably influence the patient's quality of life.
ENDPOINTS OF DRUG ACTION
The concept that systemically administered drugs may have a useful effect on cancers was historically derived from three sets of observations. Paul Ehrlich in the nineteenth century observed that different dyes reacted with different cell and tissue components. He hypothesized the existence of compounds that would be "magic bullets" that might bind to tumors, owing to the affinity of the agent for the tumor. A second observation was the toxic effects of certain mustard gas derivatives on the bone marrow during World War I, leading to the idea that smaller doses of these agents might be used to treat tumors of marrow-derived cells. Finally, the observation that certain tumors from hormone-responsive tissues, e.g. breast tumors, could shrink after oophorectomy led to the idea that endogenous substances promoting the growth of a tumor might be antagonized. Chemicals achieving each of the goals are actually or intellectually the forbearers of the currently used cancer chemotherapy agents.
Chemotherapy agents may be used for the treatment of active, clinically apparent cancer. Table 28-1, A lists tumors considered curable by conventionally available chemotherapeutic agents when used to address disseminated or metastatic cancers. If a tumor is localized to a single site, serious consideration of surgery or primary radiation therapy should be given, as these treatment modalities may be curative as local treatments. Chemotherapy may be employed after the failure of these modalities to eradicate a local tumor or as part of multimodality approaches to offer primary treatment to a clinically localized tumor. In this event, it can allow organ preservation when given with radiation, as in the larynx or other upper airway sites, or sensitize tumors to radiation when given, e.g., to patients concurrently receiving radiation for lung or cervix cancer (Table 28-1, B). Chemotherapy can be administered as an adjuvant, i.e., in addition to surgery (Table 28-1, C) or radiation after all clinically apparent disease has been removed. This use of chemotherapy may have curative potential in breast and colorectal neoplasms, as it attempts to eliminate clinically unapparent tumor that may have already disseminated. As noted earlier, small tumors frequently have high growth fractions and therefore may be intrinsically more susceptible to the action of antiproliferative agents. Chemotherapy is routinely used in "conventional" dose regimens. In general, these doses produce reversible acute side effects, primarily consisting of transient myelosuppression with or without gastrointestinal toxicity (usually nausea), which are readily managed. High-dose chemotherapy regimens are predicated on the observation that the dose-response curve for many anticancer agents is rather steep, and increased doses can produce markedly increased therapeutic effect, although at the cost of potentially life-threatening complications that require intensive support, usually in the form of hematopoietic stem cell support from the patient (autologous) or from donors matched for histocompatibility loci (allogeneic). High-dose regimens have definite curative potential in defined clinical settings (Table 28-1, D).
Table Graphic Jump Location
TABLE 28-1CURABILITY OF CANCERS WITH CHEMOTHERAPY
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Advanced Cancers with Possible Cure
Acute lymphoid and acute myeloid leukemia (pediatric/adult)
Hodgkin's disease (pediatric/adult)
Lymphomas—certain types (pediatric/adult)
Germ cell neoplasms
Embryonal carcinoma
Teratocarcinoma
Seminoma or dysgerminoma
Choriocarcinoma
Gestational trophoblastic neoplasia
Pediatric neoplasms
Wilms' tumor
Embryonal rhabdomyosarcoma
Ewing's sarcoma
Peripheral neuroepithelioma
Small cell lung carcinoma
Ovarian carcinoma
Advanced Cancers Possibly Cured by Chemotherapy and Radiation
Squamous carcinoma (head and neck)
Squamous carcinoma (anus)
Breast carcinoma
Carcinoma of the uterine cervix
Non-small cell lung carcinoma (stage III)
Cancers Possibly Cured With Chemotherapy as Adjuvant to Surgery
Colorectal carcinomaa
Cancers Possibly Cured with "High-Dose" Chemotherapy With Stem Cell Support
Relapsed leukemias, lymphoid and myeloid
Relapsed lymphomas, Hodgkin's and non-Hodgkin's
Chronic myeloid leukemia
Cancers Responsive With Useful Palliation, But Not Cure, by Chemotherapy
Bladder carcinoma
Hairy cell leukemia
Lymphoma—certain types
Gastric carcinoma
Cervix carcinoma
Endometrial carcinoma
Adrenocortical carcinoma
Islet-cell neoplasms
Colorectal carcinoma
Renal carcinoma
Tumor Poorly Responsive in Advanced Stages to Chemotherapy
Pancreatic carcinoma
Biliary tract neoplasms
Thyroid carcinoma
Carcinoma of the vulva
Non-small cell lung carcinoma
Prostate carcinoma
Salivary gland cancer
aRectum also receives radiation therapy.
Karnofsky was among the first to champion the evaluation of a chemotherapeutic agent's benefit by carefully quantitating its effect on tumor size and using these measurements to objectively decide the basis for further treatment of a particular patient or further clinical evaluation of a drug's potential. A partial response (PR) is defined conventionally as a decrease by at least 50% in a tumor's bidimensional area, a complete response (CR) connotes disappearance of all tumor, progression of disease signifies an increase in size of existing lesions by >25% from baseline or best response or development of new lesions, and "stable" disease fits into none of the above categories. Newer evaluation systems such as RECIST (Response Evaluation Criteria In Solid Tumors) utilize unidimensional measurement, but the intent is similar in rigorously defining evidence for the activity of the agent in assessing its value to the patient.
If cure is not possible, chemotherapy may be undertaken with the goal of palliating some aspect of the tumor's effect on the host. Common tumors that may be meaningfully addressed with palliative intent are listed in Table 28-1, E. Usually, tumor-related symptoms may manifest as pain, weight loss, or some local symptom related to the tumor's effect on normal structures. Patients treated with palliative intent should be aware of their diagnosis and the limitations of the proposed treatments, have access to supportive care, and have suitable "performance status," according to assessment algorithms such as the one developed by Karnofsky or by the Eastern Cooperative Oncology Group (ECOG). ECOG performance status 0 (PS0) patients are without symptoms, PS1 patients are ambulatory but restricted in strenuous physical activity, PS2 patients are ambulatory but unable to work and are up and about 50% or more of the time, PS3 patients are capable of limited self-care and are up <50% of the time, and PS4 patients are totally confined to bed or chair and incapable of self-care. Only PS0, PS1, and PS2 patients are generally considered suitable for palliative (noncurative) treatment. If there is curative potential, even poor–performance status patients may be treated, but their prognosis is usually inferior to that of good–performance status patients treated with similar regimens.
An important perspective the primary care provider may bring to patients and their families facing incurable cancer is that, given the limited value of chemotherapeutic approaches at some point in the natural history, palliative care or hospice-based approaches, with meticulous and ongoing attention to symptom relief and with family, psychological, and spiritual support, should receive prominent attention as a valuable therapeutic plan. (Chap. 32). Optimizing the quality of life rather than attempting to extend it becomes a valued intervention. Patients facing the impending progression of disease in a life-threatening way frequently choose to undertake toxic treatments of little to no potential value, and support provided by the primary caregiver in accessing palliative and hospice-based options in contrast to receiving toxic and ineffective regimen can be critical in providing a basis for patients to make sensible choices.
CANCER DRUGS: OVERVIEW AND PRINCIPLES FOR USE
Cancer drug treatments are of four broad types. Conventional chemotherapy agents were historically derived by the empirical observation that these "small molecules" (generally with molecular mass <1500 Da) could cause major regression of experimental tumors growing in animals. These agents mainly target DNA structure or segregation of DNA as chromosomes in mitosis. Targeted agents refer to small molecules or "biologicals" (generally macromolecules such as antibodies or cytokines) designed and developed to interact with a defined molecular target important in either maintaining the malignant state or selectively expressed by the tumor cells. As described in Chap. 25, successful tumors have activated biochemical pathways that lead to uncontrolled proliferation through the action of, e.g., oncogene products, loss of cell cycle inhibitors, or loss of cell death regulation, and have acquired the capacity to replicate chromosomes indefinitely, invade, metastasize, and evade the immune system. Targeted therapies seek to capitalize on the biology behind the aberrant cellular behavior as a basis for therapeutic effects. Hormonal therapies (the first form of targeted therapy) capitalize on the biochemical pathways underlying estrogen and androgen function and action as a therapeutic basis for approaching patients with tumors of breast, prostate, uterus, and ovarian origin. Biologic therapies are often macromolecules that have a particular target (e.g., antigrowth factor or cytokine antibodies) or may have the capacity to regulate growth of tumor cells or induce a host immune response to kill tumor cells. Thus, biologic therapies include not only antibodies but cytokines and gene therapies.
The usefulness of any drug is governed by the extent to which a given dose causes a useful result (therapeutic effect; in the case of anticancer agents, toxicity to tumor cells) as opposed to a toxic effect to the host. The therapeutic index is the degree of separation between toxic and therapeutic doses. Really useful drugs have large therapeutic indices, and this usually occurs when the drug target is expressed in the disease-causing compartment as opposed to the normal compartment. Classically, selective toxicity of an agent for an organ is governed by the expression of an agent's target or by differential accumulation into or elimination from compartments where toxicity is experienced or ameliorated, respectively. Currently used chemotherapeutic agents have the unfortunate property that their targets are present in both normal and tumor tissues. Therefore, they have relatively narrow therapeutic indices.
Figure 28-2 illustrates steps in cancer drug discovery and development. Following demonstration of antitumor activity in animal models, potentially useful anticancer agents are further evaluated to define an optimal schedule of administration and arrive at a drug formulation designed for a given route and schedule. Safety testing in two species on an analogous schedule of administration defines the starting dose for a phase I trial in humans. This is established as a fraction, usually one-sixth to one-tenth, of the dose just causing easily reversible toxicity in the more sensitive animal species. Escalating doses of the drug are then given during the human phase I trial until reversible toxicity is observed. Dose-limiting toxicity (DLT) defines a dose that conveys greater toxicity than would be acceptable in routine practice, allowing definition of a lower maximal tolerated dose (MTD). The occurrence of toxicity is, if possible, correlated with plasma drug concentrations. The MTD or a dose just lower than the MTD is usually the dose suitable for phase II trials, in which a fixed dose is administered to a relatively homogeneous set of patients with a particular tumor type in an effort to define whether the drug causes regression of tumors. An "active" agent conventionally has PR rates of at least 20–25% with reversible non-life-threatening side effects, and it may then be suitable for study in phase III trials to assess efficacy compared with standard or no therapy.
Steps in cancer drug discovery and development. Preclinical activity (top) in animal models of cancers may be used as evidence to support the entry of the drug candidate into phase I trials in humans to define a correct dose and observe any clinical antitumor effect that may occur. The drug may then be advanced to phase II trials directed against specific cancer types, with rigorous quantitation of antitumor effects (middle). Phase III trials then may reveal activity superior to standard or no treatment (lowest panel).
Response, defined as tumor shrinkage, is but the most immediate indicator of drug effect. To be clinically valuable, responses must translate into clinical benefit. This is conventionally established by a beneficial effect on overall survival, or at least an increased time to further progression of disease. Active efforts are being made to quantitate effects of anticancer agents on quality of life. Cancer drug clinical trials conventionally use a toxicity grading scale in which grade I toxicities do not require treatment, grade II often require symptomatic treatment but are not life-threatening, grade III toxicities are potentially life-threatening if untreated, grade IV toxicities are actually life-threatening, and grade V toxicities are those that result in the patient's death.
Development of "targeted agents" may proceed quite differently. While phase I–III trials are still conducted, molecular analysis of human tumors may allow the precise definition of target expression in a patient's tumor that is necessary for or relevant to the drug's action. This information might then allow selection of patients expressing the drug target for participation in all trial phases. These patients may then have a greater chance of developing a useful response to the drug by virtue of expressing the target in the tumor. Clinical trials may be designed to incorporate an assessment of the behavior of the target in relation to the drug (pharmacodynamic studies). Ideally, the plasma concentration that affects the drug target is known, so escalation to MTD may not be necessary. Rather, the correlation of host toxicity while achieving an "optimal biologic dose" becomes a more relevant endpoint for phase I and early phase II trials with targeted agents.
Useful cancer drug treatment strategies using conventional chemotherapy agents, targeted agents, hormonal treatments, or biologicals have one of two valuable outcomes. They can induce cancer cell death, resulting in tumor shrinkage with corresponding improvement in patient survival or increase the time until the disease progresses. Another potential outcome is to induce cancer cell differentiation or dormancy with loss of tumor cell replicative potential and reacquisition of phenotypic properties resembling normal cells. Blocking tumor cell differentiation may be a key feature in the pathogenesis of certain leukemias.
Cell death is a closely regulated process. Necrosis refers to cell death induced, for example, by physical damage with the hallmarks of cell swelling and membrane disruption. Apoptosis, or programmed cell death, refers to a highly ordered process whereby cells respond to defined stimuli by dying, and it recapitulates the necessary cell death observed during the ontogeny of the organism. Anoikis refers to the death of epithelial cells after removal from the normal milieu of substrate, particularly from cell-to-cell contact. Cancer chemotherapeutic agents can cause both necrosis and apoptosis. Apoptosis is characterized by chromatin condensation (giving rise to "apoptotic bodies"); cell shrinkage; and, in living animals, phagocytosis by surrounding stromal cells without evidence of inflammation. This process is regulated either by signal transduction systems that promote a cell's demise after a certain level of insult is achieved or in response to specific cell-surface receptors that mediate cell death signals. Modulation of apoptosis by manipulation of signal transduction pathways has emerged as a basis for understanding the actions of drugs and designing new strategies to improve their use. Autophagy is a cellular response to injury in which the cell does not initially die but catabolizes itself in a way that can lead to loss of replicative potential.
A general view of how cancer treatments work is that the interaction of a chemotherapeutic drug with its target induces a "cascade" of further signaling steps. These signals ultimately lead to cell death by triggering an "execution phase" in which proteases, nucleases, and endogenous regulators of the cell death pathway are activated (Fig. 28-3).
Integration of cell death responses. Cell death through an apoptotic mechanism requires active participation of the cell. In response to interruption of growth factor (GF) or propagation of certain cytokine death signals (e.g., tumor necrosis factor receptor, TNF-R), there is activation of "upstream" cysteine aspartyl proteases (caspases), which then directly digest cytoplasmic and nuclear proteins, resulting in activation of "downstream" caspases; these cause activation of nucleases, resulting in the characteristic DNA fragmentation that is a hallmark of apoptosis. Chemotherapy agents that create lesions in DNA or alter mitotic spindle function seem to activate aspects of this process by damage ultimately conveyed to the mitochondria, perhaps by activating the transcription of genes whose products can produce or modulate the toxicity of free radicals. In addition, membrane damage with activation of sphingomyelinases results in the production of ceramides that can have a direct action at mitochondria. The antiapoptotic protein bcl2 attenuates mitochondrial toxicity, while proapoptotic gene products such as bax antagonize the action of bcl2. Damaged mitochondria release cytochrome C and apoptosis-activating factor (APAF), which can directly activate caspase 9, resulting in propagation of a direct signal to other downstream caspases through protease activation. Apoptosis-inducing factor (AIF) is also released from the mitochondrion and then can translocate to the nucleus, bind to DNA, and generate free radicals to further damage DNA. An additional proapoptotic stimulus is the bad protein, which can heterodimerize with bcl2 gene family members to antagonize apoptosis. Importantly, though, bad protein function can be retarded by its sequestration as phospho-bad through the 14-3-3 adapter proteins. The phosphorylation of bad is mediated by the action of the AKT kinase in a way that defines how growth factors that activate this kinase can retard apoptosis and promote cell survival.
Targeted agents differ from chemotherapy agents in that they do not indiscriminately cause macromolecular lesions but regulate the action of particular pathways. For example, the p210bcr-abl fusion protein tyrosine kinase drives chronic myeloid leukemia (CML), and HER-2/neu stimulates the proliferation of certain breast cancers. The tumor has been described as "addicted" to the function of these molecules in the sense that without the pathway's continued action, the tumor cell cannot survive. In this way, targeted agents may alter the "threshold" tumors have for undergoing apoptosis without actually creating any molecular lesions such as direct DNA strand breakage or altered membrane function.
While apoptotic mechanisms are important in regulating cellular proliferation and the behavior of tumor cells in vitro, in vivo it is unclear whether all of the actions of chemotherapeutic agents to cause cell death can be attributed to apoptotic mechanisms. However, changes in molecules that regulate apoptosis are correlated with clinical outcomes (e.g., bcl2 overexpression in certain lymphomas conveys poor prognosis; proapoptotic bax expression is associated with a better outcome after chemotherapy for ovarian carcinoma). A better understanding of the relationship of cell death and cell survival mechanisms is needed.
Resistance to chemotherapy drugs has been postulated to arise either from cells not being in the appropriate phase of the cell cycle to allow drug lethality or from decreased uptake, increased efflux, metabolism of the drug, or alteration of the target, e.g., by mutation or overexpression. Indeed, p170PGP (p170 P-glycoprotein; mdr gene product) was recognized from experiments with cells growing in tissue culture as mediating the efflux of chemotherapeutic agents in resistant cells. Certain neoplasms, particularly hematopoietic tumors, have an adverse prognosis if they express high levels of p170PGP, and modulation of this protein's function has been attempted by a variety of strategies.
"Combination chemotherapy" refers to the use of regimens in which different drugs are combined with the goal of achieving at least an additive and hopefully supra-additive effect. The component drugs in such regimens ideally have distinct, nonoverlapping toxicities to the host, are each individually active to some degree, and have been shown in a clinical trial to be tolerable and convey clinical value in contrast to the use of single agents.
CHEMOTHERAPEUTIC AGENTS USED FOR CANCER TREATMENT
Table 28-2 lists commonly used cancer chemotherapy agents and pertinent clinical aspects of their use. The drugs and schedules listed are examples that have proved tolerable and useful; the specific doses that may be used in a particular patient may vary somewhat with the particular protocol, or plan, of treatment. Significant variation from these dose ranges should be carefully verified to avoid or anticipate toxicity. Not included in Table 28-2 are hormone receptor–directed agents, as the side effects are generally those expected from the interruption or augmentation of hormonal effect, and doses used in most cases are those that adequately saturate the intended hormone receptor. The drugs listed may be usefully grouped into three general categories: those affecting DNA, those affecting microtubules, and molecularly targeted agents.
TABLE 28-2COMMONLY USED CANCER CHEMOTHERAPY AGENTS
EXAMPLES OF USUAL DOSES
INTERACTIONS, ISSUES
Direct DNA-Interacting Agents
Alkylators
400–2000 mg/m2 IV
100 mg/m2 PO qd
Marrow (relative platelet sparing)
Common alkylatora
Cardiac (high dose)
Liver metabolism required to activate to phosphoramide mustard + acrolein
Mesna protects against "high-dose" bladder damage
Mechlorethamine 6 mg/m2 IV day 1 and day 8
Vesicant
Topical use in cutaneous lymphoma
Chlorambucil 1–3 mg/m2 qd PO
Melphalan 8 mg/m2 qd × 5, PO
Marrow (delayed nadir)
GI (high dose)
Decreased renal function delays clearance
Carmustine (BCNU)
200 mg/m2 IV
150 mg/m2 PO
GI, liver (high dose)
Lomustine (CCNU) 100–300 mg/m2 PO Marrow (delayed nadir)
Ifosfamide 1.2 g/m2 per day qd × 5 + mesna
Myelosuppressive
Neurologic
Metabolic acidosis
Isomeric analogue of cyclophosphamide
More lipid soluble
Greater activity vs testicular neoplasms and sarcomas
Must use mesna
Procarbazine 100 mg/m2 per day qd × 14
Liver and tissue metabolism required
Disulfiram-like effect with ethanol
Acts as MAOI
HBP after tyrosinase-rich foods
Dacarbazine (DTIC) 375 mg/m2 IV day 1 and day 15
Flulike
Metabolic activation
150–200 mg/m2 qd × 5 q28d or
75 mg/m2 qd × 6–7 weeks
Headache/fatigue
Infrequent myelosuppression
Altretamine (formerly hexamethylmelamine) 260 mg/m2 per day qd × 14–21 as 4 divided oral doses
Neurologic (mood swing)
Marrow (less)
Liver activation
Barbiturates enhance/cimetidine diminishes
20 mg/m2 qd × 5 IV 1 q3–4 weeks or
100–200 mg/m2 per dose IV q3–4 weeks
Marrow platelets > WBCs
Renal Mg2+, Ca2+
Maintain high urine flow; osmotic diuresis, monitor intake/output K+, Mg2+
Emetogenic—prophylaxis needed
Full dose if CrCl > 60 mL/min and tolerate fluid push
Carboplatin 365 mg/m2 IV q3–4 weeks as adjusted for CrCl
Renal (high dose)
Reduce dose according to CrCl: to AUC of 5–7 mg/mL per min [AUC = dose/(CrCl + 25)]
130 mg/m2 q3 weeks over 2 h or
85 mg/m2 q2 weeks
Acute reversible neurotoxicity; chronic sensory neurotoxicity cumulative with dose; reversible laryngopharyngeal spasm
Antitumor Antibiotics and Topoisomerase Poisons
Bleomycin 15–25 mg/d qd × 5 IV bolus or continuous IV
Skin effects
Inactivate by bleomycin hydrolase (decreased in lung/skin)
O2 enhances pulmonary toxicity
Cisplatin-induced decrease in CrCl may increase skin/lung toxicity
Reduce dose if CrCl < 60 mL/min
Actinomycin D 10–15 μg/kg per day qd × 5 IV bolus
Mucositis
Radiation recall
Etoposide (VP16-213)
100–150 mg/m2 IV qd × 3–5d
or 50 mg/m2 PO qd × 21 d
or up to 1500 mg/m2 per dose (high dose with stem cell support)
Marrow (WBCs > platelet)
Hypersensitivity (rapid IV)
Mucositis (high dose)
Hepatic metabolism—renal 30%
Reduce doses with renal failure
Schedule-dependent (5 day better than 1 day)
Late leukemogenic
Accentuate antimetabolite action
20 mg/m2 IV q3–4 weeks over 30 min
or 1.5–3 mg/m2 q3–4 weeks over 24 h
or 0.5 mg/m2 per day over 21 days
Mild alopecia
Reduce dose with renal failure
No liver toxicity
Irinotecan (CPT II)
100–150 mg/m2 IV over 90 min q3–4 weeks
or 30 mg/m2 per day over 120 h
Diarrhea: "early onset" with cramping, flushing, vomiting; "late onset" after several doses
Prodrug requires enzymatic clearance to active drug "SN 38"
Early diarrhea likely due to biliary excretion
Late diarrhea, use "high-dose" loperamide (2 mg q2–4 h)
Doxorubicin and daunorubicin
45–60 mg/m2 dose q3–4 weeks
or 10–30 mg/m2 dose q week
or continuous-infusion regimen
Cardiovascular acute/chronic
Heparin aggregate; coadministration increases clearance
Acetaminophen, BCNU increase liver toxicity
Idarubicin
10–15 mg/m2 IV q 3 weeks
or 10 mg/m2 IV qd × 3
Cardiac (less than doxorubicin)
None established
Epirubicin 150 mg/m2 IV q3 weeks
Mitoxantrone
12 mg/m2 qd × 3
or 12–14 mg/m2 q3 weeks
Vesicant (mild)
Blue urine, sclerae, nails
Interacts with heparin
Less alopecia, nausea than doxorubicin
Indirect DNA-Interacting Agents
Antimetabolites
Deoxycoformycin 4 mg/m2 IV every other week
Excretes in urine
Reduce dose for renal failure
Inhibits adenosine deaminase
6-Mercaptopurine
75 mg/m2 PO
or up to 500 mg/m2 PO (high dose)
Variable bioavailability
Metabolize by xanthine oxidase
Decrease dose with allopurinol
Increased toxicity with thiopurine methyltransferase deficiency
6-Thioguanine 2–3 mg/kg per day for up to 3–4 weeks
Azathioprine 1–5 mg/kg per day
Metabolizes to 6MP; therefore, reduce dose with allopurinol
2-Chlorodeoxyadenosine 0.09 mg/kg per day qd × 7 as continuous infusion
Notable use in hairy cell leukemia
Hydroxyurea
20–50 mg/kg (lean body weight)
PO qd
or 1–3 g/d
Rare renal, liver, lung,
Decrease dose with renal failure
Augments antimetabolite effect
15–30 mg PO or IM qd × 3–5
or 30 mg IV days 1 and 8
or 1.5–12g/m2 per day (with leucovorin)
Liver/lung
Renal tubular
Rescue with leucovorin
Excreted in urine
Decrease dose in renal failure
NSAIDs increase renal toxicity
5-Fluorouracil (5FU)
375 mg/m2 IV qd × 5
or 600 mg/m2 IV days 1 and 8
Toxicity enhanced by leucovorin
Dihydropyrimidine dehydrogenase deficiency increases toxicity
Metabolizes in tissues
665 mg/m2 bid continuous; 1250 mg/m2
bid 2 weeks on / 1 off; 829 mg/m2
bid 2 weeks on / 1 off + 60 mg/d leucovorin
Hand–foot syndrome
Prodrug of 5FU due to intratumoral metabolism
Cytosine arabinoside
100 mg/m2 per day qd × 7 by continuous infusion
or 1–3 g/m2 dose IV bolus
Neurologic (high dose)
Conjunctivitis (high dose)
Noncardiogenic pulmonary edema
Enhances activity of alkylating agents
Metabolizes in tissues by deamination
Azacytidine
750 mg/m2 per week or 75–200 mg/m2 per day × 5–10 (bolus)
or (continuous IV or subcutaneous)
Use limited to leukemia
Altered methylation of DNA alters gene expression
Gemcitabine 1000 mg/m2 IV weekly × 7
Hepatic
Fever/"flu syndrome"
Fludarabine phosphate 25 mg/m2 IV qd × 5
Dose reduction with renal failure
Metabolized to F-ara converted to F-ara ATP in cells by deoxycytidine kinase
25,000 IU/m2 q3–4 weeks
or 6000 IU/m2 per day qod for 3–4 weeks
or 1000–2000 IU/m2 for 10–20 days
Clotting factors
Blocks methotrexate action
Pemetrexed 200 mg/m2 q3 weeks
Supplement folate/B12
Caution in renal failure
Antimitotic Agents
Vincristine 1–1.4 mg/m2 per week (frequently cap at 2 mg total dose)
GI: ileus/constipation; bladder hypotoxicity; SIADH
Hepatic clearance
Dose reduction for bilirubin >1.5 mg/dL
Prophylactic bowel regimen
Vinblastine 6–8 mg/m2 per week
Neurologic (less common but similar spectrum to other vincas)
Dose reduction as with vincristine
Vinorelbine 15–30 mg/m2 per week
Allergic/bronchospasm (immediate)
Dyspnea/cough (subacute)
Neurologic (less prominent but similar spectrum to other vincas)
135–175 mg/m2 per 24-h infusion
or 175 mg/m2 per 3-h infusion
or 140 mg/m2 per 96-h infusion
or 250 mg/m2 per 24-h infusion plus
G-CSF
Sensory neuropathy
CV conduction disturbance
Nausea—infrequent
Premedicate with steroids, H1 and H2 blockers
Dose reduction as with vincas
Docetaxel 100 mg/m2 per 1-h infusion q3 weeks
Fluid retention syndrome
Dermatologic
Nausea infrequent
Some stomatitis
Estramustine phosphate
14 mg/kg per day in 3–4 divided doses with water >2 h after meals
Avoid Ca2+-rich foods
Nab-paclitaxel (protein bound) 260 mg/m2 q3 weeks
Caution in hepatic insufficiency
Ixabepilone 40 mg/m2 q3 weeks
Myelosuppression
Molecularly Targeted Agents
Tretinoin 45 mg/m2 per day until complete response + anthracycline-based regimen in APL
Teratogenic
APL differentiation syndrome: pulmonary dysfunction/infiltrate, pleural/pericardial effusion, fever
Bexarotene 300–400 mg/m2 per day, continuous
Hypercholesterolemia
Central hypothyroidism
Targeted Toxins
Denileukin diftitox 9–18 μg/kg per day × 5 d q3 weeks
Chills/fever
Asthenia
Acute hypersensitivity: hypotension, vasodilation, rash, chest tightness
Vascular leak: hypotension, edema, hypoalbuminemia, thrombotic events (MI, DVT, CVA)
Tyrosine Kinase Inhibitors
Imatinib 400 mg/d, continuous
Periorbital edema
Myelosuppression not frequent in solid tumor indications
Gefitinib 250 mg PO per day
In U.S., only with prior documented benefit
Erlotinib 150 mg PO per day
1 h before, 2 h after meals
Dasatinib 70 mg PO bid; 100 mg PO per day
Liver changes
Sorafenib 400 mg PO bid
Other rash
Sunitinib 50 mg PO qd for 4 of 6 weeks
Proteosome Inhibitors
Bortezomib 1.3 mg/m2 day 1,4
Histone Deacetylase Inhibitors
Vorinostat 400 mg/day
Embolism
Romidepsin 14 mg/m2 day 1, 8, 15
Cytopenias
Cardiac conduction
mTOR Inhibitors
Temsirolimus 25 mg weekly
Anorexia, fatigue
Metabolic (glucose, lipid)
Everolimus 10 mg daily
Arsenic trioxide 0.16 mg/kg per day up to 50 days in APL
↑ QTc
APL differentiation syndrome (see under tretinoin)
aCommon alkylator: alopecia, pulmonary, infertility, plus teratogenesis.
Abbreviations: APL, acute promyelocytic leukemia; ATP, adenosine triphosphate; AUC, area under the curve; bid, twice a day; CHF, congestive heart failure; CNS, central nervous system; CrCl, creatinine clearance; CV, cardiovascular; CVA, cerebrovascular accident; DVT, deep-vein thrombosis; G-CSF, granulocyte colony-stimulating factor; GI, gastrointestinal; HBP, high blood pressure; IV, intravenous; MAOI, monoamine oxidase inhibitors; MI, myocardial infarction; 6MP, 6-mercaptopurine; mTOR, mammalian target of rapamycin; NSAID, nonsteroidal anti-inflammatory drug; PO, oral; qd, every day; SIADH, syndrome of inappropriate antidiuretic hormone; WBC, white blood cell.
Direct DNA-interactive agents
DNA replication occurs during the synthesis or S-phase of the cell cycle, with chromosome segregation of the replicated DNA occurring in the M, or mitosis, phase. The G1 and G2 "gap phases" precede S and M, respectively. Historically, chemotherapeutic agents have been divided into "phase-nonspecific" agents, which can act in any phase of the cell cycle, and "phase-specific" agents, which require the cell to be at a particular cell cycle phase to cause greatest effect. Once the agent has acted, cells may progress to "checkpoints" in the cell cycle in which the drug-related damage may be assessed and either repaired or allowed to initiate apoptosis. An important function of certain tumor-suppressor genes such as p53 may be to modulate checkpoint function.
Formation of covalent DNA adducts
Alkylating agents as a class are cell cycle phase–nonspecific agents. They break down, either spontaneously or after normal organ or tumor cell metabolism, to reactive intermediates that covalently modify bases in DNA. This leads to cross-linkage of DNA strands or the appearance of breaks in DNA as a result of repair efforts. "Broken" or cross-linked DNA is intrinsically unable to complete normal replication or cell division; in addition, it is a potent activator of cell cycle checkpoints and further activates cell-signaling pathways that can precipitate apoptosis. As a class, alkylating agents share similar toxicities, including myelosuppression, alopecia, gonadal dysfunction, mucositis, and pulmonary fibrosis. They differ greatly in a spectrum of normal organ toxicities. As a class they share the capacity to cause "second" neoplasms, particularly leukemia, many years after use, particularly when used in low doses for protracted periods.
Cyclophosphamide is inactive unless metabolized by the liver to 4-hydroxy-cyclophosphamide, which decomposes into an alkylating species, as well as to chloroacetaldehyde and acrolein. The latter causes chemical cystitis; therefore, excellent hydration must be maintained while using cyclophosphamide. If severe, the cystitis may be effectively treated by mesna (2-mercaptoethanesulfonate). Liver disease impairs drug activation. Sporadic interstitial pneumonitis leading to pulmonary fibrosis can accompany the use of cyclophosphamide, and high doses used in conditioning regimens for bone marrow transplant can cause cardiac dysfunction. Ifosfamide is a cyclophosphamide analogue also activated in the liver, but more slowly, and it requires coadministration of mesna to prevent bladder injury. Central nervous system (CNS) effects, including somnolence, confusion, and psychosis, can follow ifosfamide use; the incidence appears related to low body surface area or decreased creatinine clearance.
Several alkylating agents are less commonly used. Nitrogen mustard (mechlorethamine) is the prototypic agent of this class, decomposing rapidly in aqueous solution to potentially yield a bifunctional carbonium ion. It must be administered shortly after preparation into a rapidly flowing intravenous line. It is a powerful vesicant, and infiltration may be symptomatically ameliorated by infiltration of the affected site with 1/6 M thiosulfate. Even without infiltration, aseptic thrombophlebitis is frequent. It can be used topically as a dilute solution in cutaneous lymphomas, with a notable incidence of hypersensitivity reactions. It causes moderate nausea after intravenous administration. Bendamustine is a nitrogen mustard derivative with evidence of activity in chronic lymphocytic leukemia and certain lymphomas.
Chlorambucil causes predictable myelosuppression, azoospermia, nausea, and pulmonary side effects. Busulfan can cause profound myelosuppression, alopecia, and pulmonary toxicity but is relatively "lymphocyte sparing." Its routine use in treatment of CML has been curtailed in favor of imatinib (Gleevec) or dasatinib, but it is still employed in transplant preparation regimens. Melphalan shows variable oral bioavailability and undergoes extensive binding to albumin and α1-acidic glycoprotein. Mucositis appears more prominently; however, it has prominent activity in multiple myeloma.
Nitrosoureas break down to carbamylating species that not only cause a distinct pattern of DNA base pair–directed toxicity but also can covalently modify proteins. They share the feature of causing relatively delayed bone marrow toxicity, which can be cumulative and long-lasting. Methyl CCNU (lomustine) causes direct glomerular as well as tubular damage, cumulatively related to dose and time of exposure.
Procarbazine is metabolized in the liver and possibly in tumor cells to yield a variety of free radical and alkylating species. In addition to myelosuppression, it causes hypnotic and other CNS effects, including vivid nightmares. It can cause a disulfiram-like syndrome on ingestion of ethanol. Altretamine (formerly hexamethylmelamine) and thiotepa can chemically give rise to alkylating species, although the nature of the DNA damage has not been well characterized in either case. Dacarbazine (DTIC) is activated in the liver to yield the highly reactive methyl diazonium cation. It causes only modest myelosuppression 21–25 days after a dose but causes prominent nausea on day 1. Temozolomide is structurally related to dacarbazine but was designed to be activated by nonenzymatic hydrolysis in tumors and is bioavailable orally.
Cisplatin was discovered fortuitously by observing that bacteria present in electrolysis solutions could not divide. Only the cis diamine configuration is active as an antitumor agent. It is hypothesized that in the intracellular environment, a chloride is lost from each position, being replaced by a water molecule. The resulting positively charged species is an efficient bifunctional interactor with DNA, forming Pt-based cross-links. Cisplatin requires administration with adequate hydration, including forced diuresis with mannitol to prevent kidney damage; even with the use of hydration, a gradual decrease in kidney function is common, along with noteworthy anemia. Hypomagnesemia frequently attends cisplatin use and can lead to hypocalcemia and tetany. Other common toxicities include neurotoxocity with stocking-and-glove sensorimotor neuropathy. Hearing loss occurs in 50% of patients treated with conventional doses. Cisplatin is intensely emetogenic, requiring prophylactic antiemetics. Myelosuppression is less evident than with other alkylating agents. Chronic vascular toxicity (Raynaud's phenomenon, coronary artery disease) is a more unusual toxicity. Carboplatin displays less nephro-, oto-, and neurotoxicity. However, myelosuppression is more frequent, and as the drug is exclusively cleared through the kidneys, adjustment of dose for creatinine clearance must be accomplished through use of various dosing nomograms. Oxaliplatin is a platinum analogue with noteworthy activity in colon cancers refractory to other treatments. It is prominently neurotoxic.
Antitumor antibiotics are substances produced by bacteria that in nature appear to provide a chemical defense against other hostile microorganisms. As a class they bind to DNA directly and can frequently undergo electron transfer reactions to generate free radicals in close proximity to DNA, leading to DNA damage in the form of single-strand breaks or cross-links. Topoisomerase poisons include natural products or semisynthetic species derived ultimately from plants, and they modify enzymes that regulate the capacity of DNA to unwind to allow normal replication or transcription. These include topoisomerase I, which creates single-strand breaks that then rejoin following the passage of the other DNA strand through the break. Topoisomerase II creates double-strand breaks through which another segment of DNA duplex passes before rejoining. DNA damage from these agents can occur in any cell cycle phase, but cells tend to arrest in S-phase or G2 of the cell cycle in cells with p53 and Rb pathway lesions as the result of defective checkpoint mechanisms in cancer cells. Owing to the role of topoisomerase I in the procession of the replication fork, topoisomerase I poisons cause lethality if the topoisomerase I–induced lesions are made in S-phase.
Doxorubicin can intercalate into DNA, thereby altering DNA structure, replication, and topoisomerase II function. It can also undergo reduction reactions by accepting electrons into its quinone ring system, with the capacity to undergo reoxidation to form reactive oxygen radicals after reoxidation. It causes predictable myelosuppression, alopecia, nausea, and mucositis. In addition, it causes acute cardiotoxicity in the form of atrial and ventricular dysrhythmias, but these are rarely of clinical significance. In contrast, cumulative doses >550 mg/m2 are associated with a 10% incidence of chronic cardiomyopathy. The incidence of cardiomyopathy appears to be related to schedule (peak serum concentration), with low-dose, frequent treatment or continuous infusions better tolerated than intermittent higher-dose exposures. Cardiotoxicity has been related to iron-catalyzed oxidation and reduction of doxorubicin, and not to topoisomerase action. Cardiotoxicity is related to peak plasma dose; thus, lower doses and continuous infusions are less likely to cause heart damage. Doxorubicin's cardiotoxicity is increased when given together with trastuzumab (Herceptin), the anti-HER2/neu antibody. Radiation recall or interaction with concomitantly administered radiation to cause local site complications is frequent. The drug is a powerful vesicant, with necrosis of tissue apparent 4–7 days after an extravasation; therefore, it should be administered into a rapidly flowing intravenous line. Dexrazoxane is an antidote to doxorubicin-induced extravasation. Doxorubicin is metabolized by the liver, so doses must be reduced by 50–75% in the presence of liver dysfunction. Daunorubicin is closely related to doxorubicin and was actually introduced first into leukemia treatment, where it remains part of curative regimens and has been shown preferable to doxorubicin owing to less mucositis and colonic damage. Idarubicin is also used in acute myeloid leukemia treatment and may be preferable to daunorubicin in activity. Encapsulation of daunorubicin into a liposomal formulation has attenuated cardiac toxicity and antitumor activity in Kaposi's sarcoma and ovarian cancer.
Bleomycin refers to a mixture of glycopeptides that have the unique feature of forming complexes with Fe2+ while also bound to DNA. It remains an important component of curative regimens for Hodgkin's disease and germ cell neoplasms. Oxidation of Fe2+ gives rise to superoxide and hydroxyl radicals. The drug causes little, if any, myelosuppression. The drug is cleared rapidly, but augmented skin and pulmonary toxicity in the presence of renal failure have led to the recommendation that doses be reduced by 50–75% in the face of a creatinine clearance <25 mL/min. Bleomycin is not a vesicant and can be administered intravenously, intramuscularly, or subcutaneously. Common side effects include fever and chills, facial flush, and Raynaud's phenomenon. Hypertension can follow rapid intravenous administration, and the incidence of anaphylaxis with early preparations of the drug has led to the practice of administering a test dose of 0.5–1 unit before the rest of the dose. The most feared complication of bleomycin treatment is pulmonary fibrosis, which increases in incidence at >300 cumulative units administered and is minimally responsive to treatment (e.g., glucocorticoids). The earliest indicator of an adverse effect is a decline in the carbon monoxide diffusing capacity (DLCO), although cessation of drug immediately upon documentation of a decrease in DLCO may not prevent further decline in pulmonary function. Bleomycin is inactivated by a bleomycin hydrolase, whose concentration is diminished in skin and lung. Because bleomycin-dependent electron transport is dependent on O2, bleomycin toxicity may become apparent after exposure to transient very high PIO2. Thus, during surgical procedures, patients with prior exposure to bleomycin should be maintained on the lowest PIO2 consistent with maintaining adequate tissue oxygenation.
Mitoxantrone is a synthetic compound that was designed to recapitulate features of doxorubicin but with less cardiotoxicity. It is quantitatively less cardiotoxic (comparing the ratio of cardiotoxic with therapeutically effective doses) but is still associated with a 10% incidence of cardiotoxicity at cumulative doses of >150 mg/m2. It also causes alopecia. Cases of acute promyelocytic leukemia (APL) have arisen shortly after exposure of patients to mitoxantrone, particularly in the adjuvant treatment of breast cancer. While chemotherapy-associated leukemia is generally of the acute myeloid type, APL arising in the setting of prior mitoxantrone treatment had the typical t(15;17) chromosome translocation associated with APL, but the breakpoints of the translocation appeared to be at topoisomerase II sites that would be preferred sites of mitoxantrone action, clearly linking the action of the drug to the generation of the leukemia.
Etoposide was synthetically derived from the plant product podophyllotoxin; it binds directly to topoisomerase II and DNA in a reversible ternary complex. It stabilizes the covalent intermediate in the enzyme's action where the enzyme is covalently linked to DNA. This "alkali-labile" DNA bond was historically a first hint that an enzyme such as a topoisomerase might exist. The drug therefore causes a prominent G2 arrest, reflecting the action of a DNA damage checkpoint. Prominent clinical effects include myelosuppression, nausea, and transient hypotension related to the speed of administration of the agent. Etoposide is a mild vesicant but is relatively free from other large-organ toxicities. When given at high doses or very frequently, topoisomerase II inhibitors may cause acute leukemia associated with chromosome 11q23 abnormalities in up to 1% of exposed patients.
Camptothecin was isolated from extracts of a Chinese tree and had notable antileukemia activity in preclinical mouse models. Early human clinical studies with the sodium salt of the hydrolyzed camptothecin lactone showed evidence of toxicity with little antitumor activity. Identification of topoisomerase I as the target of camptothecins and the need to preserve lactone structure allowed additional efforts to identify active members of this series. Topoisomerase I is responsible for unwinding the DNA strand by introducing single-strand breaks and allowing rotation of one strand about the other. In S-phase, topoisomerase I–induced breaks that are not promptly resealed lead to progress of the replication fork off the end of a DNA strand. The DNA damage is a potent signal for induction of apoptosis. Camptothecins promote the stabilization of the DNA linked to the enzyme in a so-called cleavable complex, analogous to the action of etoposide with topoisomerase II. Topotecan is a camptothecin derivative approved for use in gynecologic tumors and small cell lung cancer. Toxicity is limited to myelosuppression and mucositis. CPT-11, or irinotecan, is a camptothecin with evidence of activity in colon carcinoma. In addition to myelosuppression, it causes a secretory diarrhea related to the toxicity of a metabolite called SN-38. The diarrhea can be treated effectively with loperamide or octreotide.
Indirect effectors of DNA function: antimetabolites
A broad definition of antimetabolites would include compounds with structural similarity to precursors of purines or pyrimidines, or compounds that interfere with purine or pyrimidine synthesis. Antimetabolites can cause DNA damage indirectly, through misincorporation into DNA, abnormal timing or progression through DNA synthesis, or altered function of pyrimidine and purine biosynthetic enzymes. They tend to convey greatest toxicity to cells in S-phase, and the degree of toxicity increases with duration of exposure. Common toxic manifestations include stomatitis, diarrhea, and myelosuppression. Second malignancies are not associated with their use.
Methotrexate inhibits dihydrofolate reductase, which regenerates reduced folates from the oxidized folates produced when thymidine monophosphate is formed from deoxyuridine monophosphate. Without reduced folates, cells die a "thymine-less" death. N5-tetrahydrofolate or N5-formyltetrahydrofolate (leucovorin) can bypass this block and rescue cells from methotrexate, which is maintained in cells by polyglutamylation. The drug and other reduced folates are transported into cells by the folate carrier, and high concentrations of drug can bypass this carrier and allow diffusion of drug directly into cells. These properties have suggested the design of "high-dose" methotrexate regimens with leucovorin rescue of normal marrow and mucosa as part of curative approaches to osteosarcoma in the adjuvant setting and hematopoietic neoplasms of children and adults. Methotrexate is cleared by the kidney via both glomerular filtration and tubular secretion, and toxicity is augmented by renal dysfunction and drugs such as salicylates, probenecid, and nonsteroidal anti-inflammatory drugs (NSAIDs) that undergo tubular secretion. With normal renal function, 15 mg/m2 of leucovorin will rescue 10–8 to 10–6 M methotrexate in three to four doses. However, with decreased creatinine clearance, doses of 50–100 mg/m2 are continued until methotrexate levels are <5 × 10–8 M. In addition to bone marrow suppression and mucosal irritation, methotrexate can cause renal failure itself at high doses owing to crystallization in renal tubules; therefore, high-dose regimens require alkalinization of urine with increased flow by hydration. Methotrexate can be sequestered in third-space collections and leach back into the general circulation, causing prolonged myelosuppression. Less frequent adverse effects include reversible increases in transaminases and hypersensitivity-like pulmonary syndrome. Chronic low-dose methotrexate can cause hepatic fibrosis. When administered to the intrathecal space, methotrexate can cause chemical arachnoiditis and CNS dysfunction.
Pemetrexed is a novel folate-directed antimetabolite. It is "multitargeted" in that it inhibits the activity of several enzymes, including thymidylate synthetase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, thereby affecting the synthesis of both purine and pyrimidine nucleic acid precursors. To avoid significant toxicity to the normal tissues, patients receiving pemetrexed should also receive low-dose folate and vitamin B12 supplementation. Pemetrexed has notable activity against certain lung cancers and, in combination with cisplatin, also against mesotheliomas. Palatrexate is an antifolate approved for use in T cell lymphoma that is very efficiently transported into cancer cells.
5-Fluorouracil (5FU) represents an early example of "rational" drug design in that it originated from the observation that tumor cells incorporate radiolabeled uracil more efficiently into DNA than normal cells, especially gut. 5FU is metabolized in cells to 5′FdUMP, which inhibits thymidylate synthetase (TS). In addition, misincorporation can lead to single-strand breaks, and RNA can aberrantly incorporate FUMP. 5FU is metabolized by dihydropyrimidine dehydrogenase, and deficiency of this enzyme can lead to excessive toxicity from 5FU. Oral bioavailability varies unreliably, but orally administered analogues of 5FU such as capecitabine have been developed that allow at least equivalent activity to many parenteral 5FU-based approaches. Intravenous administration of 5FU leads to bone marrow suppression after short infusions but to stomatitis after prolonged infusions. Leucovorin augments the activity of 5FU by promoting formation of the ternary covalent complex of 5FU, the reduced folate, and TS. Less frequent toxicities include CNS dysfunction, with prominent cerebellar signs, and endothelial toxicity manifested by thrombosis, including pulmonary embolus and myocardial infarction.
Cytosine arabinoside (ara-C) is incorporated into DNA after formation of ara-CTP, resulting in S-phase–related toxicity. Continuous infusion schedules allow maximal efficiency, with uptake maximal at 5–7 μM. Ara-C can be administered intrathecally. Adverse effects include nausea, diarrhea, stomatitis, chemical conjunctivitis, and cerebellar ataxia. Gemcitabine is a cytosine derivative that is similar to ara-C in that it is incorporated into DNA after anabolism to the triphosphate, rendering DNA susceptible to breakage and repair synthesis, which differs from that in ara-C in that gemcitabine-induced lesions are very inefficiently removed. In contrast to ara-C, gemcitabine appears to have useful activity in a variety of solid tumors, with limited nonmyelosuppressive toxicities. 6-Thioguanine and 6-mercaptopurine (6MP) are used in the treatment of acute lymphoid leukemia. Although administered orally, they display variable bioavailability. 6MP is metabolized by xanthine oxidase and therefore requires dose reduction when used with allopurinol.
Fludarabine phosphate is a prodrug of F-adenine arabinoside (F-ara-A), which in turn was designed to diminish the susceptibility of ara-A to adenosine deaminase. F-ara-A is incorporated into DNA and can cause delayed cytotoxicity even in cells with low growth fraction, including chronic lymphocytic leukemia and follicular B cell lymphoma. CNS and peripheral nerve dysfunction and T cell depletion leading to opportunistic infections can occur in addition to myelosuppression. 2-Chlorodeoxyadenosine is a similar compound with activity in hairy cell leukemia. 2-Deoxycoformycin inhibits adenosine deaminase, with resulting increase in dATP levels. This causes inhibition of ribonucleotide reductase as well as augmented susceptibility to apoptosis, particularly in T cells. Renal failure and CNS dysfunction are notable toxicities in addition to immunosuppression. Hydroxyurea inhibits ribonucleotide reductase, resulting in S-phase block. It is orally bioavailable and useful for the acute management of myeloproliferative states.
Asparaginase is a bacterial enzyme that causes breakdown of extracellular asparagine required for protein synthesis in certain leukemic cells. This effectively stops tumor cell DNA synthesis, as DNA synthesis requires concurrent protein synthesis. The outcome of asparaginase action is therefore very similar to the result of the small-molecule antimetabolites. As asparaginase is a foreign protein, hypersensitivity reactions are common, as are effects on organs such as pancreas and liver that normally require continuing protein synthesis. This may result in decreased insulin secretion with hyperglycemia, with or without hyperamylasemia and clotting function abnormalities. Close monitoring of clotting functions should accompany use of asparaginase. Paradoxically, owing to depletion of rapidly turning over anticoagulant factors, thromboses particularly affecting the CNS may also be seen with asparaginase.
Mitotic spindle inhibitors
Microtubules are cellular structures that form the mitotic spindle, and in interphase cells they are responsible for the cellular "scaffolding" along which various motile and secretory processes occur. Microtubules are composed of repeating noncovalent multimers of a heterodimer of α and β isoform of the protein tubulin. Vincristine binds to the tubulin dimer with the result that microtubules are disaggregated. This results in the block of growing cells in M-phase; however, toxic effects in G1 and S-phase are also evident, reflecting effects on normal cellular activities of microtubules. Vincristine is metabolized by the liver, and dose adjustment in the presence of hepatic dysfunction is required. It is a powerful vesicant, and infiltration can be treated by local heat and infiltration of hyaluronidase. At clinically used intravenous doses, neurotoxicity in the form of glove-and-stocking neuropathy is frequent. Acute neuropathic effects include jaw pain, paralytic ileus, urinary retention, and the syndrome of inappropriate antidiuretic hormone secretion. Myelosuppression is not seen. Vinblastine is similar to vincristine, except that it tends to be more myelotoxic, with more frequent thrombocytopenia and also mucositis and stomatitis. Vinorelbine is a vinca alkaloid that appears to have differences in resistance patterns in comparison to vincristine and vinblastine; it may be administered orally.
The taxanes include paclitaxel and docetaxel. These agents differ from the vinca alkaloids in that the taxanes stabilize microtubules against depolymerization. The "stabilized" microtubules function abnormally and are not able to undergo the normal dynamic changes of microtubule structure and function necessary for cell cycle completion. Taxanes are among the most broadly active antineoplastic agents for use in solid tumors, with evidence of activity in ovarian cancer, breast cancer, Kaposi's sarcoma, and lung tumors. They are administered intravenously, and paclitaxel requires use of a Cremophor-containing vehicle that can cause hypersensitivity reactions. Premedication with dexamethasone (8–16 mg orally or intravenously 12 and 6 h before treatment) and diphenhydramine (50 mg) and cimetidine (300 mg), both 30 min before treatment, decreases but does not eliminate the risk of hypersensitivity reactions to the paclitaxel vehicle. Docetaxel uses a polysorbate 80 formulation, which can cause fluid retention in addition to hypersensitivity reactions, and dexamethasone premedication with or without antihistamines is frequently used. A protein-bound formulation of paclitaxel (called nab-paclitaxel) has at least equivalent antineoplastic activity and decreased risk of hypersensitivity reactions. Paclitaxel may also cause hypersensitivity reactions, myelosuppression, neurotoxicity in the form of glove-and-stocking numbness, and paresthesia. Cardiac rhythm disturbances were observed in phase I and II trials, most commonly asymptomatic bradycardia but also, much more rarely, varying degrees of heart block. These have not emerged as clinically significant in the majority of patients. Docetaxel causes comparable degrees of myelosuppression and neuropathy. Hypersensitivity reactions, including bronchospasm, dyspnea, and hypotension, are less frequent but occur to some degree in up to 25% of patients. Fluid retention appears to result from a vascular leak syndrome that can aggravate preexisting effusions. Rash can complicate docetaxel administration, appearing prominently as a pruritic maculopapular rash affecting the forearms, but it has also been associated with fingernail ridging, breakdown, and skin discoloration. Stomatitis appears to be somewhat more frequent than with paclitaxel.
Resistance to taxanes has been related to the emergence of efficient efflux of taxanes from tumor cells through the p170 P-glycoprotein (mdr gene product) or the presence of variant or mutant forms of tubulin. Epothilones represent a class of novel microtubule-stabilizing agents that have been conscientiously optimized for activity in taxane-resistant tumors. Ixabepilone has clear evidence of activity in breast cancers resistant to taxanes and anthracyclines such as doxorubicin. It retains acceptable expected side effects, including myelosuppression, and can also cause peripheral sensory neuropathy.
Estramustine was originally synthesized as a mustard derivative that might be useful in neoplasms that possessed estrogen receptors. However, no evidence of interaction with DNA was observed. Surprisingly, the drug caused metaphase arrest, and subsequent study revealed that it binds to microtubule-associated proteins, resulting in abnormal microtubule function. Estramustine binds to estramustine-binding proteins (EMBPs), which are notably present in prostate tumor tissue. The drug is used in patients with prostate cancer. Gastrointestinal and cardiovascular adverse effects related to the estrogen moiety occur in up to 10% of patients, including worsened heart failure and thromboembolic phenomena. Gynecomastia and nipple tenderness can also occur.
Hormonal agents
Steroid hormone receptor–related molecules have emerged as prominent targets for small molecules useful in cancer treatment. When bound to their cognate ligands, these receptors can alter gene transcription and, in certain tissues, induce apoptosis. The pharmacologic effect is a mirror or parody of the normal effects of the agents acting on nontransformed normal tissues, although the effects on tumors are mediated by indirect effects in some cases.
Glucocorticoids are generally given in "pulsed" high doses in leukemias and lymphomas, where they induce apoptosis in tumor cells. Cushing's syndrome or inadvertent adrenal suppression on withdrawal from high-dose glucocorticoids can be significant complications, along with infections common in immunosuppressed patients, in particular Pneumocystis pneumonia, which classically appears a few days after completing a course of high-dose glucocorticoids.
Tamoxifen is a partial estrogen receptor antagonist; it has a tenfold greater antitumor activity in breast cancer patients whose tumors express estrogen receptors than in those who have low or no levels of expression. It might be considered the prototypic "molecularly targeted" agent. Owing to its agonistic activities in vascular and uterine tissue, side effects include a somewhat increased risk of cardiovascular complications, such as thromboembolic phenomena, and a small increased incidence of endometrial carcinoma, which appears after chronic use (usually >5 years). Progestational agents—including medroxyprogesterone acetate, androgens including fluoxymesterone (Halotestin), and, paradoxically, estrogens—have approximately the same degree of activity in primary hormonal treatment of breast cancers that have elevated expression of estrogen receptor protein. Estrogen itself is not used often owing to prominent cardiovascular and uterotropic activity.
Aromatase refers to a family of enzymes that catalyze the formation of estrogen in various tissues, including the ovary and peripheral adipose tissue and some tumor cells. Aromatase inhibitors are of two types, the irreversible steroid analogues such as exemestane and the reversible inhibitors such as anastrozole or letrozole. Anastrozole is superior to tamoxifen in the adjuvant treatment of breast cancer in postmenopausal patients with estrogen receptor–positive tumors. Letrozole treatment affords benefit following tamoxifen treatment. Adverse effects of aromatase inhibitors may include an increased risk of osteoporosis.
Prostate cancer is classically treated by androgen deprivation. Diethylstilbestrol (DES) acting as an estrogen at the level of the hypothalamus to downregulate hypothalamic luteinizing hormone (LH) production results in decreased elaboration of testosterone by the testicle. For this reason, orchiectomy is equally as effective as moderate-dose DES, inducing responses in 80% of previously untreated patients with prostate cancer but without the prominent cardiovascular side effects of DES, including thrombosis and exacerbation of coronary artery disease. In the event that orchiectomy is not accepted by the patient, testicular androgen suppression can also be effected by luteinizing hormone–releasing hormone (LHRH) agonists such as leuprolide and goserelin. These agents cause tonic stimulation of the LHRH receptor, with the loss of its normal pulsatile activation resulting in decreased output of LH by the anterior pituitary. Therefore, as primary hormonal manipulation in prostate cancer, one can choose orchiectomy or leuprolide but not both. The addition of androgen receptor blockers, including flutamide or bicalutamide, is of uncertain additional benefit in extending overall response duration; the combined use of orchiectomy or leuprolide plus flutamide is referred to as total androgen blockade.
Tumors that respond to a primary hormonal manipulation may frequently respond to second and third hormonal manipulations. Thus, breast tumors that had previously responded to tamoxifen have, on relapse, notable response rates to withdrawal of tamoxifen itself or to subsequent addition of an aromatase inhibitor or progestin. Likewise, initial treatment of prostate cancers with leuprolide plus flutamide may be followed after disease progression by response to withdrawal of flutamide. These responses may result from the removal of antagonists from mutant steroid hormone receptors that have come to depend on the presence of the antagonist as a growth-promoting influence.
Additional strategies to treat refractory breast and prostate cancers that possess steroid hormone receptors may also address adrenal capacity to produce androgens and estrogens, even after orchiectomy or oophorectomy, respectively. Thus, aminoglutethimide or ketoconazole can be used to block adrenal synthesis by interfering with the enzymes of steroid hormone metabolism. Administration of these agents requires concomitant hydrocortisone replacement and additional glucocorticoid doses administered in the event of physiologic stress.
Humoral mechanisms can also result in complications from an underlying malignancy producing the hormone. Adrenocortical carcinomas can cause Cushing's syndrome as well as syndromes of androgen or estrogen excess. Mitotane can counteract these by decreasing synthesis of steroid hormones. Islet cell neoplasms can cause debilitating diarrhea, treated with the somatostatin analogue octreotide. Prolactin-secreting tumors can be effectively managed by the dopaminergic agonist bromocriptine.
TARGETED THERAPIES
A better understanding of cancer cell biology has suggested many new targets for cancer drug discovery and development. These include the products of oncogenes and tumor-suppressor genes, regulators of cell death pathways, mediators of cellular immortality such as telomerase, and molecules responsible for microenvironmental molding such as proteases or angiogenic factors. The essential difference in the development of agents that would target these processes is that the basis for discovery of the candidate drug is the a priori importance of the target in the biology of the tumor, rather than the initial detection of drug candidates based on the phenomenon of tumor cell regression in tissue culture or in animals. The following examples reflect the rapidly evolving clinical research activity in this area. Figure 28-4 summarizes how Food and Drug Administration (FDA)–approved targeted agents act.
Site of action of targeted agents. Signals proceeding from growth factor–related receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGF-R), erbB2, or c-kit can be interrupted by lapatinib, erlotinib, gefitinib, and imatinib, acting at the adenosine triphosphate (ATP) binding site; or by cetuximab, trastuzumab, or panitumumab acting at the receptor. Tyrosine kinases (TKs) that are not directly stimulated by growth factors such as p210 bcr-abl or src can be inhibited by imatinib, dasatinib, or nilotinib. Signals projected downstream from growth factor receptors can be affected by the multitargeted kinase inhibitor sorafenib, acting on c-raf, and, upon arrival at the nucleus, affect gene expression, which can be affected by the targeted transcriptional modulators vorinostat (targeting histone deacetylase), azacytidine derivatives (targeting DNA methyltransferase), or retinoid receptor modulators all-trans-retinoic acid (ATRA) or bexarotene. Cytokine receptors (CkRs) are one stimulus for degradation of the inhibitory subunit of the NFκB transcription factor by the proteosome. Bortezomib inhibits this process and can prevent activation of NFκB-dependent genes, among other growth-related effects. Sorafenib and sunitinib, acting as inhibitors of vascular endothelial growth factor (VEGF) receptors, can modulate tumor blood vessel function through their action on endothelial cells, while bevacizumab targets the same process by combining with VEGF itself.
Hematopoietic neoplasms
Imatinib targets the adenosine triphosphate (ATP) binding site of the p210bcr-abl protein tyrosine kinase that is formed as the result of the chromosome 9,22 translocation producing the Philadelphia chromosome in CML. Imatinib is superior to interferon plus chemotherapy in the initial treatment of the chronic phase of this disorder. It has lesser activity in the blast phase of CML, where the cells may have acquired additional mutations in p210bcr-abl itself or other genetic lesions. Its side effects are relatively tolerable in most patients and include hepatic dysfunction, diarrhea, and fluid retention. Rarely, patients receiving imatinib have decreased cardiac function, which may persist after discontinuation of the drug. The quality of response to imatinib enters into the decision about when to refer patients with CML for consideration of transplant approaches. Nilotinib is a tyrosine protein kinase inhibitor with a similar spectrum of activity to imatinib but with increased potency and perhaps better tolerance by certain patients. Dasatinib, another inhibitor of the p210bcr-abl oncoproteins, is active in certain mutant variants of p210bcr-abl that are refractory to imatinib and arise during therapy with imatinib or are present de novo. Dasatinib also has inhibitory action against kinases belonging to the src tyrosine protein kinase family; this activity may contribute to its effects in hematopoietic tumors and suggest a role in solid tumors where src kinases are active. Only the T315I mutant is resistant to dasatinib; a new class of inhibitors called aurora kinase inhibitors is in development to address this problem.
All-trans-retinoic acid (ATRA) targets the PML-retinoic acid receptor (RAR) α fusion protein, which is the result of the chromosome 15,17 translocation pathogenic for most forms of APL. Administered orally, it causes differentiation of the neoplastic promyelocytes to mature granulocytes and attenuates the rate of hemorrhagic complications. Adverse effects include headache with or without pseudotumor cerebri and gastrointestinal and cutaneous toxicities. Another active retinoid is the synthetic retinoid X receptor ligand bexarotene, which has activity in cutaneous T cell lymphoma.
Bortezomib is an inhibitor of the proteasome, the multisubunit assembly of protease activities responsible for the selective degradation of proteins important in regulating activation of transcription factors, including NF-κB and proteins regulating cell cycle progression. It has activity in multiple myeloma and certain lymphomas. Adverse effects include neuropathy, orthostatic hypotension with or without hyponatremia, and reversible thrombocytopenia.
Vorinostat is an inhibitor of histone deacetylases, responsible for maintaining the proper orientation of histones on DNA, with resulting capacity for transcriptional readiness. Acetylated histones allow entry of transcription factors and therefore increased expression of genes that are selectively repressed in tumors. The result can be differentiation with the emergence of a more normal cellular phenotype or cell-cycle arrest with expression of endogenous regulators of cell cycle progression. Vorinostat is approved for clinical use in cutaneous T cell lymphoma, with dramatic skin clearing and very few side effects. Romidepsin is a distinct molecular class of histone deacetylase inhibitor also active in cutaneous T cell lymphoma.
DNA methyltransferase inhibitors, including 5-aza-cytidine and 2′-deoxy-5-azacytidine (decitabine), can also increase transcription of genes "silenced" during the pathogenesis of a tumor by causing demethylation of the methylated cytosines that are acquired as an "epigenetic" (i.e., after the DNA is replicated) modification of DNA. These drugs were originally considered antimetabolites but have clinical value in myelodysplastic syndromes and certain leukemias when administered at low doses. Combinations of DNA methyltransferase inhibitors and histone deacetylase inhibitors may offer new approaches to regulate chromatin function.
Targeted toxins utilize macromolecules such as antibodies or cytokines with high affinity for defined tumor cell-surface molecules, such as a leukemia differentiation antigen, to which a therapeutic antibody can deliver a covalently linked potent cytotoxin or a growth factor such as IL-2 to deliver a toxin (in the form of diphtheria toxin in denileukin diftitox) to cells bearing the IL-2 receptor. The value of such targeted approaches is that in addition to maximizing the therapeutic index by differential expression of the target in tumor (as opposed to nonrenewable normal cells), selection of patients for clinical use can capitalize on assessing the target in the tumor.
Small-molecule epidermal growth factor (EGF) antagonists act at the ATP binding site of the EGF receptor tyrosine kinase. In early clinical trials, gefitinib showed evidence of responses in a small fraction of patients with non-small cell lung cancer (NSCLC). Side effects were generally acceptable, consisting mostly of rash and diarrhea. Subsequent analysis of responding patients revealed a high frequency of activating mutations in the EGF receptor. Often patients who developed resistance to gefitinib have acquired additional mutations in the enzyme, similar to what was seen in imatinib-resistant CML. Erlotinib is another EGF receptor tyrosine kinase antagonist with somewhat superior outcome in clinical trials in NSCLC. Even patients with wild-type EGF receptors may benefit from erlotinib treatment. Lapatinib is a combined EGF receptor and erbB2 tyrosine kinase antagonist with activity in breast cancers refractory to anti-erbB2 antibodies.
In addition to the p210bcr-abl kinase, imatinib also has activity against the c-kit tyrosine kinase, activated in gastrointestinal stromal sarcoma, and the platelet-derived growth factor receptor (PDGF-R), activated by translocation in certain sarcomas. Imatinib has found clinical utility in these neoplasms previously refractory to chemotherapeutic approaches.
"Multitargeted" kinase antagonists are small-molecule ATP site-directed antagonists that inhibit more than one protein kinase. Drugs of this type with prominent activity against the vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase have activity in renal cell carcinoma. Sorafenib is a VEGF-R antagonist with activity against the raf serine-threonine protein kinase as well. Sunitinib has anti-VEGF-R as well as anti-PDGF-R and anti-c-kit activity. It causes prominent responses as well as stabilization of disease in renal cell cancers and gastrointestinal stromal tumors. Side effects for both agents are mostly acceptable, with fatigue and diarrhea encountered with both agents. The "hand–foot syndrome" with erythema and desquamation of the distal extremities, in some cases requiring dose modification, may be seen with sorafenib. Temsirolimus and everolimus are mammalian target of rapamycin (mTOR) inhibitors with activity in renal cancers. They produce stomatitis, fatigue, and some hyperlipidemia (10%), myelosuppression (10%), and rare lung toxicity.
Personalized cancer treatment
The recognition that targeted therapies may benefit subsets of patients with an identical histologic diagnosis, but whose tumor is dependent for viability on the target's function, has spurred research to define molecular diagnostic approaches to define potentially responding patients. In addition, a patient's germ-line DNA may contain indicators of differential capacity to metabolize cancer chemotherapy agents and thus be susceptible to drug-induced toxicity. While efforts in this area are still a focus of both clinical and basic research, the following conclusions can be drawn and are applicable to patients being initially managed in the primary care setting.
All patients undergoing initial diagnostic evaluation for breast cancer should have their tumors tested for the expression of the estrogen receptor (ER), progesterone receptor (PR), and the c-erbB2 (HER2; HER2/neu) oncoprotein by immunohistochemistry or fluorescence in situ hybridization (FISH). Patients expressing the ER and/or PR are candidates for adjuvant hormone receptor–directed therapies. Patients with evidence of abundant HER2 expression or HER2 gene amplification will likely derive benefit from trastuzumab. In addition, Oncotype Dx is a 21-gene expression test that has been approved by the FDA for defining patients without lymph node involvement but with ER+ tumors who may have the greatest chance of benefiting from adjuvant chemotherapy added to adjuvant estrogen therapy. The MammaPrint test is similar in intent for node-negative patients but without reference to ER expression status.
The value of characterizing the mutational status of the EGF receptor pathway in patients with lung cancer is also a matter of current clinical investigations. While the tyrosine kinase inhibitor erlotinib is approved for use in all patients with NSCLC who have had progression of disease despite treatment with platinum-based chemotherapy, subsets of patients, such as female Asian nonsmokers, have a high evidence of EGF-R mutations, resulting in marked sensitivity to erlotinib. And it is possible that in the larger population of patients with NSCLC, such testing may allow selection of patients in whom initial use of erlotinib may also be considered. Conversely, a mutated K-ras oncogene in patients with lung adenocarcinoma is associated with no benefit from erlotinib treatment.
In patients with colon cancer, a mutated K-ras oncogene is clearly associated with no benefit to the use of the EGF-R–directed antibody cetuximab, and characterization of K-ras mutational status should be undertaken as part of the routine diagnostic evaluation of patients with newly diagnosed metastatic or newly recurrent colon cancer. Patients undergoing diagnostic evaluation for initial treatment of metastatic colon cancer might usefully undergo evaluation of their germ-line uridine diphosphate glucuronosyl transferase (UGT) 1A1 allele status, as the expression of variant alleles at that locus influences susceptibility to irinotecan-induced hematologic toxicity. Patients with known Gilbert's disease should receive irinotecan very cautiously or perhaps not at all.
ACUTE COMPLICATIONS OF CANCER CHEMOTHERAPY
The common cytotoxic chemotherapeutic agents almost invariably affect bone marrow function. Titration of this effect determines the MTD of the agent on a given schedule. The normal kinetics of blood cell turnover influences the sequence and sensitivity of each of the formed elements. Polymorphonuclear leukocytes (PMNs; t1/2 = 6–8 h), platelets (t1/2 = 5–7 days), and red blood cells (RBCs; t1/2 = 120 days), respectively, have most, less, and least susceptibility to usually administered cytotoxic agents. The nadir count of each cell type in response to classes of agents is characteristic. Maximal neutropenia occurs 6–14 days after conventional doses of anthracyclines, antifolates, and antimetabolites. Alkylating agents differ from each other in the timing of cytopenias. Nitrosoureas, DTIC, and procarbazine can display delayed marrow toxicity, first appearing 6 weeks after dosing.
Complications of myelosuppression result from the predictable sequelae of the missing cells' function. Febrile neutropenia refers to the clinical presentation of fever (one temperature ≥38.5°C or three readings ≥38°C but ≤38.5°C per 24 h) in a neutropenic patient with an uncontrolled neoplasm involving the bone marrow or, more usually, in a patient undergoing treatment with cytotoxic agents. Mortality from uncontrolled infection varies inversely with the neutrophil count. If the nadir neutrophil count is >1000/μL, there is little risk; if <500/μL, risk of death is markedly increased. Management of febrile neutropenia has conventionally included empirical coverage with antibiotics for the duration of neutropenia (Chap. 29). Selection of antibiotics is governed by the expected association of infections with certain underlying neoplasms; careful physical examination (with scrutiny of catheter sites, dentition, mucosal surfaces, and perirectal and genital orifices by gentle palpation); chest radiography; and Gram stain and culture of blood, urine, and sputum (if any) to define a putative site of infection. In the absence of any originating site, a broadly acting β-lactam with anti-Pseudomonas activity, such as ceftazidime, is begun empirically. The addition of vancomycin to cover potential cutaneous sites of origin (until these are ruled out or shown to originate from methicillin-sensitive organisms) or metronidazole or imipenem for abdominal or other sites favoring anaerobes reflects modifications tailored to individual patient presentations. The coexistence of pulmonary compromise raises a distinct set of potential pathogens, including Legionella, Pneumocystis, and fungal agents that may require further diagnostic evaluations, such as bronchoscopy with bronchoalveolar lavage. Febrile neutropenic patients can be stratified broadly into two prognostic groups. The first, with expected short duration of neutropenia and no evidence of hypotension or abdominal or other localizing symptoms, may be expected to do well even with oral regimens, e.g., ciprofloxacin or moxifloxacin, or amoxicillin plus clavulanic acid. A less favorable prognostic group is patients with expected prolonged neutropenia, evidence of sepsis, and end-organ compromise, particularly pneumonia. These patients require tailoring of their antibiotic regimen to their underlying presentation, with frequent empirical addition of antifungal agents if fever persists for 7 days without identification of an adequately treated organism or site.
Transfusion of granulocytes has no role in the management of febrile neutropenia, owing to their exceedingly short half-life, mechanical fragility, and clinical syndromes of pulmonary compromise with leukostasis after their use. Instead, colony-stimulating factors (CSFs) are used to augment bone marrow production of PMNs. Early-acting factors such as IL-1, IL-3, and stem cell factor have not been as useful clinically as late-acting, lineage-specific factors such as G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte-macrophage colony-stimulating factor), erythropoietin (EPO), thrombopoietin, IL-6, and IL-11. CSFs may easily become overused in oncology practice. The settings in which their use has been proved effective are limited. G-CSF, GM-CSF, EPO, and IL-11 are currently approved for use. The American Society of Clinical Oncology has developed practice guidelines for the use of G-CSF and GM-CSF (Table 28-3).
TABLE 28-3INDICATIONS FOR THE CLINICAL USE OF G-CSF OR GM-CSF
Preventive Uses
With the first cycle of chemotherapy (so-called primary CSF administration)
Not needed on a routine basis
Use if the probability of febrile neutropenia is ≥20%
Use if patient has preexisting neutropenia or active infection
Age >65 years treated for lymphoma with curative intent or other tumor treated by similar regimens
Poor performance status
Extensive prior chemotherapy
Dose-dense regimens in a clinical trial or with strong evidence of benefit
With subsequent cycles if febrile neutropenia has previously occurred (so-called secondary CSF administration)
Not needed after short-duration neutropenia without fever
Use if patient had febrile neutropenia in previous cycle
Use if prolonged neutropenia (even without fever) delays therapy
Afebrile neutropenic patients
No evidence of benefit
Febrile neutropenic patients
May feel compelled to use in the face of clinical deterioration from sepsis, pneumonia, or fungal infection, but benefit unclear
In bone marrow or peripheral blood stem cell transplantation
Use to mobilize stem cells from marrow
Use to hasten myeloid recovery
In acute myeloid leukemia
G-CSF of minor or no benefit
GM-CSF of no benefit and may be harmful
In myelodysplastic syndromes
Not routinely beneficial
Use intermittently in subset with neutropenia and recurrent infection
What Dose and Schedule Should Be Used?
G-CSF: 5 mg/kg per day subcutaneously
GM-CSF: 250 mg/m2 per day subcutaneously
Peg-filgrastim: one dose of 6 mg 24 h after chemotherapy
When Should Therapy Begin and End?
When indicated, start 24–72 h after chemotherapy
Continue until absolute neutrophil count is 10,000/μL
Do not use concurrently with chemotherapy or radiation therapy
Abbreviations: G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor.
Source: From the American Society of Clinical Oncology: J Clin Oncol 24:3187, 2006.
Primary prophylaxis (i.e., shortly after completing chemotherapy to reduce the nadir) administers G-CSF to patients receiving cytotoxic regimens associated with a 20% incidence of febrile neutropenia. "Dose-dense" regimens, in which cycling of chemotherapy is intended to be completed without delay of administered doses, may also benefit, but such patients should be on a clinical trial. Administration of G-CSF in these circumstances has reduced the incidence of febrile neutropenia in several studies by about 50%. Most patients, however, receive regimens that do not have such a high risk of expected febrile neutropenia, and therefore most patients initially should not receive G-CSF or GM-CSF. Special circumstances—such as a documented history of febrile neutropenia with the regimen in a particular patient or categories of patients at increased risk, such as patients older than age 65 years with aggressive lymphoma treated with curative chemotherapy regimens; extensive compromise of marrow by prior radiation or chemotherapy; or active, open wounds or deep-seated infection may support primary treatment with G-CSF or GM-CSF. Administration of G-CSF or GM-CSF to afebrile neutropenic patients or to patients with low-risk febrile neutropenia is not recommended, and patients receiving concomitant chemoradiation treatment, particularly those with thoracic neoplasms, likewise are not generally recommended for treatment. In contrast, administration of G-CSF to high-risk patients with febrile neutropenia and evidence of organ compromise, including sepsis syndrome, invasive fungal infection, concurrent hospitalization at the time fever develops, pneumonia, profound neutropenia (<0.1 × 109/L), or age >65 years, is reasonable.
Secondary prophylaxis refers to the administration of CSFs in patients who have experienced a neutropenic complication from a prior cycle of chemotherapy; dose reduction or delay may be a reasonably considered alternative. G-CSF or GM-CSF is conventionally started 24–72 h after completion of chemotherapy and continued until a PMN count of 10,000/μL is achieved unless a "depot" preparation of G-CSF such as pegfilgrastim is used, in which one dose is administered at least 14 days before the next scheduled administration of chemotherapy. Also, patients with myeloid leukemias undergoing induction therapy may have a slight reduction in the duration of neutropenia if G-CSF is commenced after completion of therapy and may be of particular value in elderly patients, but the influence on long-term outcome has not been defined. GM-CSF probably has a more restricted utility than G-CSF, with its use currently limited to patients after autologous bone marrow transplants, although proper head-to-head comparisons with G-CSF have not been conducted in most instances. GM-CSF may be associated with more systemic side effects.
Dangerous degrees of thrombocytopenia do not frequently complicate the management of patients with solid tumors receiving cytotoxic chemotherapy (with the possible exception of certain carboplatin-containing regimens), but they are frequent in patients with certain hematologic neoplasms in whom marrow is infiltrated with tumor. Severe bleeding related to thrombocytopenia occurs with increased frequency at platelet counts <20,000/μL and is very prevalent at counts <5000/μL.
The precise "trigger" point at which to transfuse patients is being evaluated in a randomized study. This issue is important not only because of the costs of frequent transfusion, but unnecessary platelet transfusions expose the patient to the risks of allosensitization and loss of value from subsequent transfusion owing to rapid platelet clearance, as well as the infectious and hypersensitivity risks inherent in any transfusion. Prophylactic transfusions to keep platelets >20,000/μL are reasonable in patients with leukemia who are stressed by fever or concomitant medical conditions (the threshold for transfusion is 10,000/μL in patients with solid tumors and no other bleeding diathesis or physiologic stressors such as fever or hypotension, a level that might also be reasonably considered for leukemia patients who are thrombocytopenic but not stressed or bleeding). In contrast, patients with myeloproliferative states may have functionally altered platelets despite normal platelet counts, and transfusion with normal donor platelets should be considered for evidence of bleeding in these patients. Careful review of medication lists to prevent exposure to NSAIDs and maintenance of clotting factor levels adequate to support near-normal prothrombin and partial thromboplastin time test results are important in minimizing the risk of bleeding in the thrombocytopenic patient.
Certain cytokines in clinical investigation have shown an ability to increase platelets (e.g., IL-6, IL-1, thrombopoietin), but clinical benefit and safety are not yet proven. IL-11 (oprelvekin) is approved for use in the setting of expected thrombocytopenia, but its effects on platelet counts are small, and it is associated with side effects such as headache, fever, malaise, syncope, cardiac arrhythmias, and fluid retention.
Anemia associated with chemotherapy can be managed by transfusion of packed RBCs. Transfusion is not undertaken until the hemoglobin falls to <80 g/L (8 g/dL) or if compromise of end-organ function occurs, or an underlying condition (e.g., coronary artery disease) calls for maintenance of hemoglobin >90 g/L (9 g/dL). Patients who are to receive therapy for >2 months on a "stable" regimen and who are likely to require continuing transfusions are also candidates for EPO. Randomized trials in certain tumors have raised the possibility that EPO use may promote tumor-related adverse events. This information should be considered in the care of individual patients. In the event EPO treatment is undertaken, maintenance of hemoglobin of 90–100 g/L (9–10 g/dL) should be the target. In the setting of adequate iron stores and serum EPO levels <100 ng/mL, EPO, 150 U three times a week, can produce a slow increase in hemoglobin over about 2 months of administration. Depot formulations can be administered less frequently. It is unclear whether higher hemoglobin levels, up to 110–120 g/L (11–12 g/dL), are associated with improved quality of life to a degree that justifies the more intensive EPO use. Efforts to achieve levels at or above 120 g/L (12 g/dL) have been associated with increased thromboses and mortality rates. EPO may rescue hypoxemic cells from death and contribute to tumor radioresistance.
The most common side effect of chemotherapy administration is nausea, with or without vomiting. Nausea may be acute (within 24 h of chemotherapy), delayed (>24 h), or anticipatory of the receipt of chemotherapy. Patients may be likewise stratified for their risk of susceptibility to nausea and vomiting, with increased risk in young, female, heavily pretreated patients without a history of alcohol or drug use but with a history of motion or morning sickness. Antineoplastic agents vary in their capacity to cause nausea and vomiting. Highly emetogenic drugs (>90%) include mechlorethamine, streptozotocin, DTIC, cyclophosphamide at >1500 mg/m2, and cisplatin; moderately emetogenic drugs (30–90% risk) include carboplatin, cytosine arabinoside (>1 mg/m2), ifosfamide, conventional-dose cyclophosphamide, and anthracyclines; low-risk (10–30%) agents include fluorouracil, taxanes, etoposide, and bortezomib, with minimal risk (<10%) afforded by treatment with antibodies, bleomycin, busulfan, fludarabine, and vinca alkaloids. Emesis is a reflex caused by stimulation of the vomiting center in the medulla. Input to the vomiting center comes from the chemoreceptor trigger zone (CTZ) and afferents from the peripheral gastrointestinal tract, cerebral cortex, and heart. The different emesis "syndromes" require distinct management approaches. In addition, a conditioned reflex may contribute to anticipatory nausea arising after repeated cycles of chemotherapy. Accordingly, antiemetic agents differ in their locus and timing of action. Combining agents from different classes or the sequential use of different classes of agent is the cornerstone of successful management of chemotherapy-induced nausea and vomiting. Of great importance are the prophylactic administration of agents and such psychological techniques as the maintenance of a supportive milieu, counseling, and relaxation to augment the action of antiemetic agents.
Serotonin antagonists (5-HT3) and neurokine (NK1) receptor antagonists are useful in "high-risk" chemotherapy regimens. The combination acts at both peripheral gastrointestinal as well as CNS sites that control nausea and vomiting. For example, the 5-HT3 blocker dolasetron (Anzamet), 100 mg intravenously or orally; dexamethasone, 12 mg; and the NK1 antagonist aprepitant, 125 mg orally, are combined on the day of administration of severely emetogenic regimens, with repetition of dexamethasone (8 mg) and aprepitant (80 mg) on days 2 and 3 for delayed nausea. Alternate 5-HT3 antagonists include ondansetron (Zofran), given as 0.15 mg/kg intravenously for three doses just before and at 4 and 8 h after chemotherapy; palonosetron (Aloxi) at 0.25 mg over 30 s, 30 min prechemotherapy; and granisetron (Kytril), given as a single dose of 0.01 mg/kg just before chemotherapy. Emesis from moderately emetic chemotherapy regimens may be prevented with a 5-HT3 antagonist and dexamethasone alone for patients not receiving doxorubicin and cyclophosphamide combinations; the latter combination requires the 5-HT3/dexamethasone/aprepitant on day 1 but aprepitant alone on days 2 and 3. Emesis from low-emetic-risk regimens may be prevented with 8 mg of dexamethasone alone, or with non-5-HT3, non-NK1 antagonist approaches including the following.
Antidopaminergic phenothiazines act directly at the CTZ and include prochlorperazine (Compazine), 10 mg intramuscularly or intravenously, 10–25 mg orally or 25 mg per rectum every 4–6 h for up to four doses, and thiethylperazine (Torecan), 10 mg by potentially all the above routes every 6 h. Haloperidol (Haldol) is a butyrophenone dopamine antagonist given at 1.0 to 1 mg intramuscularly or orally every 8 h. Antihistamines such as diphenhydramine (Benadryl) have little intrinsic antiemetic capacity but are frequently given to prevent or treat dystonic reactions that can complicate use of the antidopaminergic agents. Lorazepam (Ativan) is a short-acting benzodiazepine that provides an anxiolytic effect to augment the effectiveness of a variety of agents when used at 1–2 mg intramuscularly, intravenously, or orally every 4–6 h. Metoclopramide (Reglan) acts on peripheral dopamine receptors to augment gastric emptying and is used in high doses for highly emetogenic regimens (1–2 mg/kg intravenously 30 min before chemotherapy and every 2 h for up to three additional doses as needed); intravenous doses of 10–20 mg every 4–6 h as needed or 50 mg orally 4 h before and 8 and 12 h after chemotherapy are used for moderately emetogenic regimens. 5-9-Tetrahydrocannabinol (Marinol) is a rather weak antiemetic compared with other available agents, but it may be useful for persisting nausea and is used orally at 10 mg every 3–4 h as needed.
Regimens that include fluorouracil infusions and/or irinotecan may produce severe diarrhea. Similar to the vomiting syndromes, chemotherapy-induced diarrhea may be immediate or can occur in a delayed fashion up to 48–72 h after the drugs. Careful attention to maintained hydration and electrolyte repletion, intravenously if necessary, along with antimotility treatments such as "high-dose" loperamide, commenced with 4 mg at the first occurrence of diarrhea, with 2 mg repeated every 2 h until 12 h without loose stools, not to exceed a total daily dose of 16 mg. Octreotide (100–150 μg), a somatostatin analogue, or opiate-based preparations may be considered for patients not responding to loperamide.
Irritation and inflammation of the mucous membranes particularly afflicting the oral and anal mucosa, but potentially involving the gastrointestinal tract, may accompany cytotoxic chemotherapy. Mucositis is due to damage to the proliferating cells at the base of the mucosal squamous epithelia or in the intestinal crypts. Topical therapies, including anesthetics and barrier-creating preparations, may provide symptomatic relief in mild cases. Palifermin or keratinocyte growth factor, a member of the fibroblast growth factor family, is effective in preventing severe mucositis in the setting of high-dose chemotherapy with stem cell transplantation for hematologic malignancies. It may also prevent or ameliorate mucositis from radiation.
Chemotherapeutic agents vary widely in causing alopecia, with anthracyclines, alkylating agents, and topoisomerase inhibitors reliably causing near-total alopecia when given at therapeutic doses. Antimetabolites are more variably associated with alopecia. Psychological support and the use of cosmetic resources are to be encouraged, and "chemo caps" that reduce scalp temperature to decrease the degree of alopecia should be discouraged, particularly during treatment with curative intent of neoplasms, such as leukemia or lymphoma, or in adjuvant breast cancer therapy. The richly vascularized scalp can certainly harbor micrometastatic or disseminated disease.
Gonadal dysfunction and pregnancy
Cessation of ovulation and azoospermia reliably result from alkylating agent– and topoisomerase poison–containing regimens. The duration of these effects varies with age and sex. Males treated for Hodgkin's disease with mechlorethamine- and procarbazine-containing regimens are effectively sterile, whereas fertility usually returns after regimens that include cisplatin, vinblastine, or etoposide and after bleomycin for testicular cancer. Sperm banking before treatment may be considered to support patients likely to be sterilized by treatment. Females experience amenorrhea with anovulation after alkylating agent therapy; they are likely to recover normal menses if treatment is completed before age 30 years but unlikely to recover menses after age 35 years. Even those who regain menses usually experience premature menopause. As the magnitude and extent of decreased fertility can be difficult to predict, patients should be counseled to maintain effective contraception, preferably by barrier means, during and after therapy. Resumption of efforts to conceive should be considered in the context of the patient's likely prognosis. Hormone replacement therapy should be undertaken in women who do not have a hormonally responsive tumor. For patients who have had a hormone-sensitive tumor primarily treated by a local modality, conventional practice would counsel against hormone replacement, but this issue is under investigation.
Chemotherapy agents have variable effects on the success of pregnancy. All agents tend to have increased risk of adverse outcomes when administered during the first trimester, and strategies to delay chemotherapy, if possible, until after this milestone should be considered if the pregnancy is to continue to term. Patients in their second or third trimester can be treated with most regimens for the common neoplasms affecting women in their childbearing years, with the exception of antimetabolites, particularly antifolates, which have notable teratogenic or fetotoxic effects throughout pregnancy. The need for anticancer chemotherapy per se is infrequently a clear basis to recommend termination of a concurrent pregnancy, although each treatment strategy in this circumstance must be tailored to the individual needs of the patient. Chronic effects of cancer treatment are reviewed in Chap. 55.
The goal of biologic therapy is to manipulate the host–tumor interaction in favor of the host, potentially at an optimum biologic dose that might be different than an MTD. As a class, biologic therapies may be distinguished from molecularly targeted agents in that many biologic therapies require an active response (e.g., reexpression of silenced genes, or antigen expression) on the part of the tumor cell or on the part of the host (e.g., immunologic effects) to allow therapeutic effect. This may be contrasted with the more narrowly defined antiproliferative or apoptotic response that is the ultimate goal of molecularly targeted agents discussed above. However, there is much commonality in the strategies to evaluate and use molecularly targeted and biologic therapies.
IMMUNE MEDIATORS OF ANTITUMOR EFFECTS
Tumors have a variety of means of avoiding the immune system: (1) they are often only subtly different from their normal counterparts; (2) they are capable of downregulating their major histocompatibility complex antigens, effectively masking them from recognition by T cells; (3) they are inefficient at presenting antigens to the immune system; (4) they can cloak themselves in a protective shell of fibrin to minimize contact with surveillance mechanisms; and (5) they can produce a range of soluble molecules, including potential immune targets, that can distract the immune system from recognizing the tumor cell or can kill the immune effector cells. Some of the cell products initially polarize the immune response away from cellular immunity (shifting from TH1 to TH2 responses) and ultimately lead to defects in T cells that prevent their activation and cytotoxic activity. Cancer treatment further suppresses host immunity. A variety of strategies are being tested to overcome these barriers.
Cell-mediated immunity
The strongest evidence that the immune system can exert clinically meaningful antitumor effects comes from allogeneic bone marrow transplantation. Adoptively transferred T cells from the donor expand in the tumor-bearing host, recognize the tumor as being foreign, and can mediate impressive antitumor effects (graft-versus-tumor effects). Three types of experimental interventions are being developed to take advantage of the ability of T cells to kill tumor cells.
Allogeneic T cells are transferred to cancer-bearing hosts in three major settings: in the form of allogeneic bone marrow transplantation, as pure lymphocyte transfusions following bone marrow recovery after allogeneic bone marrow transplantation, and as pure lymphocyte transfusions following immunosuppressive (but not myeloablative) therapy (so-called minitransplants). In each of these settings, the effector cells are donor T cells that recognize the tumor as being foreign, probably through minor histocompatibility differences. The main risk of such therapy is the development of graft-versus-host disease because of the minimal difference between the cancer and the normal host cells. This approach has been highly effective in certain hematologic cancers.
Autologous T cells are removed from the tumor-bearing host, manipulated in several ways in vitro, and given back to the patient. The two major classes of autologous T cell manipulation are (a) to develop tumor antigen–specific T cells and expand them to large numbers over many weeks ex vivo before administration and (b) to activate the cells with polyclonal stimulators such as anti-CD3 and anti-CD28 after a short period ex vivo and try to expand them in the host after adoptive transfer with stimulation by IL-2, for example. Short periods removed from the patient permit the cells to overcome the tumor-induced T cell defects, and such cells traffic and home to sites of disease better than cells that have been in culture for many weeks.
Tumor vaccines are aimed at boosting T cell immunity. The finding that mutant oncogenes that are expressed only intracellularly can be recognized as targets of T cell killing greatly expanded the possibilities for tumor vaccine development. No longer is it difficult to find something different about tumor cells. However, major difficulties remain in getting the tumor-specific peptides presented in a fashion to prime the T cells. Tumors themselves are very poor at presenting their own antigens to T cells at the first antigen exposure (priming). Priming is best accomplished by professional antigen-presenting cells (dendritic cells). Thus, a number of experimental strategies are aimed at priming host T cells against tumor-associated peptides. Vaccine adjuvants such as GM-CSF appear capable of attracting antigen-presenting cells to a skin site containing a tumor antigen. Such an approach has been documented to eradicate microscopic residual disease in follicular lymphoma and give rise to tumor-specific T cells. Purified antigen-presenting cells can be pulsed with tumor, its membranes, or particular tumor antigens and delivered as a vaccine. One such vaccine, Sipuleucel-T, is approved for use in patients with hormone-independent prostate cancer. In this approach, the patient undergoes leukapheresis, wherein mononuclear cells (that include antigen-presenting cells) are removed from the patient's blood. The cells are pulsed in a laboratory with an antigenic fusion protein comprising a protein frequently expressed by prostate cancer cells, prostate acid phosphatase, fused to GM-CSF, and matured to increase their capacity to present the antigen to immune effector cells. The cells are then returned to the patient, in a well-tolerated treatment. While no objective tumor response was documented, median survival was increased about 4 months. Tumor cells can also be transfected with genes that attract antigen-presenting cells. Vaccines against viruses that cause cancers are safe and effective. Hepatitis B vaccine prevents hepatocellular carcinoma, and a tetravalent human papilloma virus vaccine prevents infection by virus types currently accounting for 70% of cervical cancer. These vaccines are ineffective at treating patients who have developed a virus-induced cancer.
In general, antibodies are not very effective at killing cancer cells. Because the tumor seems to influence the host toward making antibodies rather than generating cellular immunity, it is inferred that antibodies are easier for the tumor to fend off. Many patients can be shown to have serum antibodies directed at their tumors, but these do not appear to influence disease progression. However, the ability to grow very large quantities of high-affinity antibody directed at a tumor by the hybridoma technique has led to the application of antibodies to the treatment of cancer.
Clinical antitumor efficacy has been obtained using antibodies in which the antigen-combining regions are grafted onto human immunoglobulin gene products (chimerized or humanized) or derive de novo from mice bearing human immunoglobulin gene loci. Such humanized antibodies against the CD20 molecule expressed on B cell lymphomas (rituximab) and against the HER-2/neu receptor overexpressed on epithelial cancers, especially breast cancer (trastuzumab), have become reliable tools in the oncologist's armamentarium. Each used alone can cause tumor regression (rituximab more than trastuzumab), and both appear to potentiate the effects of combination chemotherapy given just after antibody administration. Antibodies to CD52 are active in chronic lymphoid leukemia and T cell malignancies. EGF-R–directed antibodies (such as cetuximab and panitumumab) have activity in colorectal cancer refractory to chemotherapy, particularly when utilized to augment the activity of an additional chemotherapy program, and in the primary treatment of head and neck cancers treated with radiation therapy. The mechanism of action is unclear. Direct effects on the tumor may mediate an antiproliferative effect as well as stimulate the participation of host mechanisms involving immune cell or complement-mediated response to tumor cell–bound antibody. Alternatively, the antibody may alter the release of paracrine factors promoting tumor cell survival.
The anti-VEGF antibody bevacizumab shows little evidence of antitumor effect when used alone, but when combined with chemotherapeutic agents it improves the magnitude of tumor shrinkage and time to disease progression in colorectal, lung, and breast cancer. The mechanism for the effect is unclear and may relate to the capacity of the antibody to alter delivery and tumor uptake of the active chemotherapeutic agent.
Side effects include infusion-related hypersensitivity reactions, usually limited to the first infusion, which can be managed with glucocorticoid and/or antihistamine prophylaxis. In addition, distinct syndromes have emerged with different antibodies. Anti-EGF-R antibodies produce an acneiform rash that poorly responds to steroid cream treatment. Trastuzumab (anti-HER2) can inhibit cardiac function, particularly in those patients with prior exposure to anthracyclines. Bevacizumab has a number of side effects of medical significance, including hypertension, thrombosis, proteinuria, hemorrhage, and gastrointestinal perforations with or without prior surgeries.
Conjugation of antibodies to drugs and toxins is discussed above; conjugates of antibodies with isotopes, photodynamic agents, and other killing moieties may also be effective. Radioconjugates targeting CD20 on lymphomas have been approved for use [ibritumomab tiuxetan (Zevalin), using yttrium-90 or 131I-tositumomab]. Other conjugates are associated with problems that have not yet been solved (e.g., antigenicity, instability, poor tumor penetration).
There are >70 separate proteins and glycoproteins with biologic effects in humans: interferon (IFN) α, β, γ; IL-1 through -29 (so far); the tumor necrosis factor (TNF) family (including lymphotoxin, TNF-related apoptosis-inducing ligand [TRAIL], CD40 ligand, and others); and the chemokine family. Only a fraction of these has been tested against cancer; only IFN-α and IL-2 are in routine clinical use.
About 20 different genes encode IFN-α, and their biologic effects are indistinguishable. Interferon induces the expression of many genes, inhibits protein synthesis, and exerts a number of different effects on diverse cellular processes. The two recombinant forms that are commercially available are IFN-α2a and -α2b. Interferon is not curative for any tumor but can induce partial responses in follicular lymphoma, hairy cell leukemia, CML, melanoma, and Kaposi's sarcoma. It has been used in the adjuvant setting in stage II melanoma, multiple myeloma, and follicular lymphoma, with uncertain effects on survival. It produces fever, fatigue, a flulike syndrome, malaise, myelosuppression, and depression and can induce clinically significant autoimmune disease.
IL-2 must exert its antitumor effects indirectly through augmentation of immune function. Its biologic activity is to promote the growth and activity of T cells and natural killer cells. High doses of IL-2 can produce tumor regression in certain patients with metastatic melanoma and renal cell cancer. About 2–5% of patients may experience complete remissions that are durable, unlike any other treatment for these tumors. IL-2 is associated with myriad clinical side effects, including intravascular volume depletion, capillary leak syndrome, adult respiratory distress syndrome, hypotension, fever, chills, skin rash, and impaired renal and liver function. Patients may require blood pressure support and intensive care to manage the toxicity. However, when the agent is stopped, most of the toxicities reverse completely within 3–6 days.
No gene therapy has been approved for routine clinical use. Several strategies are under evaluation, including the use of viruses that cannot replicate to express genes that can allow the action of drugs or directly inhibit cancer cell growth, viruses that can actually replicate but only in the context of the tumor cell, or viruses that can express antigens in the context of the tumor and therefore provoke a host-mediated immune response. Key issues in the success of these approaches will be in defining safe viral vector systems that escape host immune function and effectively target the tumor or tumor cell milieu. Other gene therapy strategies would utilize therapeutic oligonucleotides to target the expression of genes important in the maintenance of tumor cell viability.
Stephen M. Hahn, MD, and Eli Glatstein, MD, contributed a chapter on radiation therapy in a prior edition of Harrison's Principles of Internal Medicine, and some of their material has been incorporated into this chapter.