InternalMed_Harrison

InternalMed_Harrison. Angiogenesis inhibitors function by targeting the critical molecular pathways involved in EC proliferation, migration, and/or survival, many of which are unique to the activated endothelium in tumors. Inhibition of growth factor and adhesion-dependent signaling pathways can induce EC apoptosis with concomitant inhibition of tumor growth. Different types of tumors can use distinct combinations of molecular mechanisms to activate the angiogenic switch. Therefore, it is doubtful that a single antiangiogenic strategy will suffice for all human cancers; rather, a number of agents or combinations of agents will be needed, depending on distinct programs of angiogenesis used by different human cancers. Despite this, experimental data indicate that for some tumor types, blockade of a single growth factor (e.g., VEGF) may inhibit tumor-induced vascular growth. A. Normal blood vessel B. Tumor blood vessel


InternalMed_Harrison

InternalMed_Harrison. A. Normal blood vessel B. Tumor blood vessel Pericytes Tumor cells Loss of EC junction complexes Irregular or no BM Absent (or few) pericyte Increased permeability C. Treatment with bevacizumab (Early) D. Treatment with bevacizumab (Late) Pericytes Tumor cells Death of EC due to loss of VEGF survival signals (plus chemotherapy or radiotherapy) Apoptosis of tumor due to starvation and/or effects of chemotherapy.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 102e-11 Normalization of tumor blood vessels due to inhibition of VEGF signaling. A. Blood vessels in normal tissues exhibit a regular hierarchical branching pattern that delivers blood to tissues in a spatially and temporally efficient manner to meet the metabolic needs of the tissue (top). At the microscopic level, tight junctions are maintained between endothelial cells (ECs), which are adherent to a thick and evenly distributed basement membrane (BM). Pericytes form a surrounding layer that provides trophic signals to the EC and helps maintain proper vessel tone. Vascular permeability is regulated, interstitial fluid pressure is low, and oxygen tension and pH are physiologic. B. Tumors have abnormal vessels with tortuous branching and dilated, irregular interconnecting branches, causing uneven blood flow with areas of hypoxemia and acidosis. This harsh environment selects genetic events that result in resistant tumor variants, such as the loss of p53. High levels of VEGF


InternalMed_Harrison

InternalMed_Harrison. causing uneven blood flow with areas of hypoxemia and acidosis. This harsh environment selects genetic events that result in resistant tumor variants, such as the loss of p53. High levels of VEGF (secreted by tumor cells) disrupt gap junction communication, tight junctions, and adherens junctions between EC via src-mediated phosphorylation of proteins such as connexin 43, zonula occludens-1, VE-cadherin, and α/β-catenins. Tumor vessels have thin, irregular BM, and pericytes are sparse or absent. Together, these molecular abnormalities result in a vasculature that is permeable to serum macromolecules, leading to high tumor interstitial pressure, which can prevent the delivery of drugs to the tumor cells. This is made worse by the binding and activation of platelets at sites of exposed BM, with release of stored VEGF and microvessel clot formation, creating more abnormal blood flow and regions of hypoxemia. C. In experimental systems, treatment with bevacizumab or blocking antibodies to


InternalMed_Harrison

InternalMed_Harrison. release of stored VEGF and microvessel clot formation, creating more abnormal blood flow and regions of hypoxemia. C. In experimental systems, treatment with bevacizumab or blocking antibodies to VEGFR2 leads to changes in the tumor vasculature that has been termed vessel normalization. During the first week of treatment, abnormal vessels are eliminated or pruned (dotted lines), leaving a more normal branching pattern. ECs partially regain features such as cell-cell junctions, adherence to a more normal BM, and pericyte coverage. These changes lead to a decrease in vascular permeability, reduced interstitial pressure, and a transient increase in blood flow within the tumor. Note that in murine models, this normalization period lasts only for ~5–6 days. D. After continued anti-VEGF/VEGFR therapy (which is often combined with chemoor radiotherapy), ECs die, leading to tumor cell death (either due to direct effects of the chemotherapy or lack of blood flow).


InternalMed_Harrison

InternalMed_Harrison. Bevacizumab, an antibody that binds VEGF, appears to potentiate the effects of a number of different types of active chemotherapeutic regimens used to treat a variety of different tumor types including colon cancer, lung cancer, cervical cancer, and RCC. Bevacizumab is administered IV every 2–3 weeks (its half-life is nearly 20 days) and is generally well tolerated. Hypertension is the most common side effect of inhibitors of VEGF (or its receptors), but can be treated with antihypertensive agents and rarely requires discontinuation of therapy. Rare but serious potential risks include arterial thromboembolic events, including stroke and myocardial infarction, and hemorrhage. Another serious complication is bowel perforation, which has been observed in 1–3% of patients (mainly those with colon and ovarian cancers). Inhibition of wound healing is also seen.


InternalMed_Harrison

InternalMed_Harrison. Several small-molecule inhibitors (SMIs) that target VEGFR tyrosine kinase activity but are also inhibitory to other kinases have also been approved to treat certain cancers. Sunitinib (see above and Table 102e-2) has activity directed against mutant c-Kit receptors (approved for GIST), but also targets VEGFR and PDGFR, and has shown significant antitumor activity against metastatic RCC, presumably on the basis of its antiangiogenic activity. Similarly, sorafenib, originally developed as a Raf kinase inhibitor but with potent activity against VEGFR and PDGFR, has activity against RCC, thyroid cancer, and hepatocellular cancer. Other inhibitors of VEGFR approved for the treatment of RCC include axitinib and pazopanib. The success in targeting tumor angiogenesis has led to enhanced enthusiasm for the development of drugs that target other aspects of the angiogenic process; some of these therapeutic approaches are outlined in Fig. 102e-12.


InternalMed_Harrison

InternalMed_Harrison. Cancers have a number of mechanisms that allow them to evade detection and elimination by the immune system. These include down-regulation of cell surface proteins involved in immune recognition (including MHC proteins and tumor-specific antigens), expression of other cell surface proteins that inhibit immune function (including members of the B7 family of proteins such as PD-L1), secretion of proteins and other molecules that are immunosuppressive, recruitment and expansion of immunosuppressive cells such as regulatory T cells, and induction of T cell tolerance. In addition, the inflammatory effects of some of the immune mediator cells in the tumor microenvironment (especially tissue-associated macrophages and myeloid-derived suppressor cells) can suppress T cell responses to the tumor as well as stimulate inflammation that can enhance tumor growth.


InternalMed_Harrison

InternalMed_Harrison. Immunotherapy approaches to treat cancer aimed at activating the immune response against tumors using immunostimulatory molecules such as interferons, IL-2, and monoclonal antibodies have had some successes. Another approach that has shown particular clinical promise is the targeting of proteins or cells (such as regulatory T cells) involved in normal homeostatic control to prevent autoimmune damage to the host but that malignant cells and their stroma can also use to inhibit the immune response directed against them. The approach that is furthest along clinically has involved targeting CTLA-4, PD-1, and PDL-1, co-inhibitory molecules that are expressed on the surface of cancer cells, cells of the immune system, and/or stromal cells and are involved in inhibiting the immune response against cancer (Fig. 102e13). Monoclonal antibodies directed against CTLA-4 and PD-1 are approved for the treatment of melanoma, and additional antibodies


InternalMed_Harrison

InternalMed_Harrison. VEGFR2 VEGF Tie2 receptor EPH receptor Novel inhibitors Novel inhibitors Stromal cell Ang 1 Ang 2 Kinase domain Anti-integrin MoAb, RGD peptides Extracellular matrix (ECM) Specific kinase inhibitors Proliferation survival migration Enhanced binding to ECM, vessel stabilization Ephrin-B2 Nucleus Microtubules 2-Methoxy estradiol ˜v°3 ˜v°5 ˜5°1 MMPs (invasion, growth factor Anti-VEGF MoAb Endothelial cell


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 102e-12 Knowledge of the molecular events governing tumor angiogenesis has led to a number of therapeutic strategies to block tumor blood vessel formation. The successful therapeutic targeting of VEGF is described in the text. Other endothelial cell– specific receptor tyrosine kinase pathways (e.g., angiopoietin/Tie2 and ephrin/EPH) are likely targets for the future. Ligation of the αvβ3 integrin is required for endothelial cell (EC) survival. Integrins are also required for EC migration and are important regulators of matrix metalloproteinase (MMP) activity, which modulates EC movement through the extracellular matrix (ECM) as well as release of bound growth factors. Targeting of integrins includes development of blocking antibodies, small peptide inhibitors of integrin signaling, and arg-gly-asp–containing peptides that prevent integrin:ECM binding. Peptides derived from normal proteins by proteolytic cleavage, including endostatin and tumstatin, inhibit angiogenesis by


InternalMed_Harrison

InternalMed_Harrison. and arg-gly-asp–containing peptides that prevent integrin:ECM binding. Peptides derived from normal proteins by proteolytic cleavage, including endostatin and tumstatin, inhibit angiogenesis by mechanisms that include interfering with integrin function. Signal transduction pathways that are dysregulated in tumor cells indirectly regulate EC function. Inhibition of EGF-family receptors, whose signaling activity is upregulated in a number of human cancers (e.g., breast, colon, and lung cancers), results in downregulation of VEGF and IL-8, while increasing expression of the antiangiogenic protein thrombospondin-1. The Ras/MAPK, PI3K/Akt, and Src kinase pathways constitute important antitumor targets that also regulate the proliferation and survival of tumor-derived EC. The discovery that ECs from normal tissues express tissue-specific “vascular addressins” on their cell surface suggests that targeting specific EC subsets may be possible.


InternalMed_Harrison

InternalMed_Harrison. Tumor cells Elaboration of immunosuppressive cytokines TGF-˜ Interleukin-4 Interleukin-6 Interleukin-10 Induction of CTLA-4 Induction of PD-1 T cell inactivation Cell signaling disruption Degradation of T cell receptor ° chain Class I MHC loss in tumor cells STAT-3 signaling loss in T cells Generation of indoleamine 2, 3-dioxygenase Immunosuppressive immune cells FIGuRE 102e-13 Tumor-host interactions that suppress the immune response to the tumor.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 102e-13 Tumor-host interactions that suppress the immune response to the tumor. targeting PD-1 or PDL-1 have shown activity against melanoma, RCC, and lung cancer and continue to be evaluated against other malignancies as well. Combination approaches targeting more than one protein or involving other anticancer approaches (targeted agents, chemotherapy, radiation therapy) are also being explored and have shown promise in early studies. An important aspect of these approaches is balancing sufficient release of the negative control of the immune response to allow immune-mediated attack on the tumors while not allowing too much release and inducing severe autoimmune effects (such as against skin, thyroid, pituitary gland, or the gastrointestinal tract).


InternalMed_Harrison

InternalMed_Harrison. The explosion of information on tumor cell biology, metastasis, and tumor-host interactions (including angiogenesis and immune evasion by tumors) has ushered in a new era of rational targeted therapy for cancer. Furthermore, it has become clear that specific molecular factors detected in individual tumors (specific gene mutations, gene-expression profiles, microRNA expression, overexpression of specific proteins) can be used to tailor therapy and maximize antitumor effects. Robert G. Fenton contributed to this chapter in prior editions, and important material from those prior chapters has been included here.


InternalMed_Harrison

InternalMed_Harrison. Robert G. Fenton contributed to this chapter in prior editions, and important material from those prior chapters has been included here. principles of Cancer treatment Edward A. Sausville, Dan L. Longo CANCER PRESENTATION Cancer in a localized or systemic state is a frequent item in the differ-ential diagnosis of a variety of common complaints. Although not all forms of cancer are curable at diagnosis, affording patients the greatest 103e opportunity for cure or meaningful prolongation of life is greatly aided by diagnosing cancer at the earliest point possible in its natural history and defining treatments that prevent or retard its systemic spread. Indeed, certain forms of cancer, notably breast, colon, and possibly lung cancers in certain patients, can be prevented by screening appropriately selected asymptomatic patients; screening is arguably the earliest point in the spectrum of possible cancer-related interventions where cure is possible (Table 103e-1).


InternalMed_Harrison

InternalMed_Harrison. The term cancer, as used here, is synonymous with the term tumor, whose original derivation from Latin simply meant “swelling,” not otherwise specified. We now understand that the swelling that is a common physical manifestation of a tumor derives from increased interstitial fluid pressure and increased cellular and stromal mass per volume, compared to normal tissue. Tumors historically were referred to as carcinomas, or “crab-like” infiltrating tumors, or sarcomas, or “fleshy tumors,” derived from the Greek terms for “crab” and “flesh,” respectively. Leukemias are a special case of a cancer of the blood-forming tissues presenting in a disseminated form frequently without definable tumor masses. In addition to localized swelling, tumors present by altered function of the organ they afflict, such as dyspnea on exertion from the anemia caused by leukemia replacing normal hematopoietic cells, cough from lung cancers, jaundice from tumors disrupting the hepatobiliary tree, or seizures and


InternalMed_Harrison

InternalMed_Harrison. such as dyspnea on exertion from the anemia caused by leukemia replacing normal hematopoietic cells, cough from lung cancers, jaundice from tumors disrupting the hepatobiliary tree, or seizures and neurologic signs from brain tumors. Hemorrhage is also a frequent presenting sign of tumors involving hollow viscera, as are decreases in the number of platelets and inappropriate inhibition of blood coagulation. Thus, although statistically the fraction of patients with cancer underlying a particular presenting sign or symptom may be low, the implications for a patient with cancer of missing an early-stage tumor call for vigilance; therefore, persistent signs or symptoms should be evaluated as possibly coming from an early-stage tumor.


InternalMed_Harrison

InternalMed_Harrison. Evidence of a tumor’s existence can objectively be established by careful physical examination, such as enlarged lymph nodes in lymphomas or a palpable mass in a breast or soft tissue site. A mass SpeCtrum of CanCer-related InterventIonS Consideration of cancer in a differential diagnosis Physical examination, imaging, or endoscopy to define a possible tumor Diagnosis of cancer by biopsy or removal: Specialized histology: immunohistochemistry Staging the cancer: Where has it spread? During treatment: related to tumor effects on patient During treatment to counteract side effects of treatment Palliative and end of life


InternalMed_Harrison

InternalMed_Harrison. Staging the cancer: Where has it spread? During treatment: related to tumor effects on patient During treatment to counteract side effects of treatment Palliative and end of life When useful treatments are not feasible or desired may also be detected or confirmed by an imaging modality, such as 103e-1 plain x-ray, computed tomography (CT) scan, ultrasound, positron emission tomography (PET) imaging, or nuclear magnetic resonance approaches. Sensitivity of these technologies varies considerably, and the index of suspicion for a tumor should match the technology chosen. For example, low-dose helical CT scans are superior to plain chest radiographs in detecting lung cancers. Another way of initially establishing the existence of a possible tumor is through direct visualization of an afflicted organ by endoscopy.


InternalMed_Harrison

InternalMed_Harrison. Once the existence of a likely tumor is defined, unequivocally establishing the diagnosis is the next step in the spectrum of correctly addressing a patient’s needs. This is usually accomplished by a biopsy procedure and the emergence after pathologic examination of an unequivocal statement that cancer is present. The underlying principle in cancer diagnosis is to obtain as much tissue as safely as possible. Due 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 the differential diagnosis or provide information about prognosis or likely response to treatment. Efforts to


InternalMed_Harrison

InternalMed_Harrison. patterns, such as hormone receptor expression in breast cancers, that may aid in the 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. The general internist should make sure that a patient’s cancer biopsy is appropriately referred from the surgical suite for important molecular studies that can advise the best treatment (Table 103e-2).


InternalMed_Harrison

InternalMed_Harrison. Similar-appearing tumors by microscopic morphology may have very different gene expression patterns when assessed by such techniques as microarray analysis for gene expression patterns using gene dIagnoStIC bIopSy: Standard of Care moleCular and SpeCIal StudIeS Breast cancer: primary and suspected metastatic Hormone receptors: estrogen, progesterone HER2/neu oncoprotein Lung cancer: primary and suspected metastatic If nonsquamous non-small cell: epidermal growth factor receptor mutation; alk oncoprotein gene fusion Colon cancer: suspected metastatic Ki-ras mutation Gastrointestinal stromal tumor c-kit oncoprotein mutation Bcr-Abl fusion protein t(15,17) inversion 16 t(8,21) Lymphoma Immunohistochemistry for CD20, CD30, T cell markers Treatment defining chromosomal translocations: t(14,18) t(8,14)


InternalMed_Harrison

InternalMed_Harrison. Chapter 103e Principles of Cancer Treatment chips, with important differences in biology and 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. Biopsy techniques that involve cutting into tumor carry with them a risk of facilitating the spread of the tumor, and


InternalMed_Harrison

InternalMed_Harrison. cross-sectional diameter of the tumor in the biopsy to minimize sampling error. Biopsy techniques that involve cutting into tumor carry with them a risk of facilitating the spread of the tumor, and consideration of whether the biopsy might be the prelude to a curative surgery if certain diagnoses are established should inform the actual approach taken. 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. However, a negative fine-needle aspiration for a neoplastic diagnosis cannot be taken as definitive evidence that a tumor is absent or make a definitive diagnosis


InternalMed_Harrison

InternalMed_Harrison. and extensive surgical procedure. However, a negative fine-needle aspiration for a neoplastic diagnosis cannot be taken as definitive evidence that a tumor is absent or make a definitive diagnosis in someone not known to have a cancer.


InternalMed_Harrison

InternalMed_Harrison. An essential component of correct patient management in many cancer types is defining the extent of disease, because this information critically informs whether localized treatments, “combined-modality” approaches, or systemic treatments should initially be considered. 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.


InternalMed_Harrison

InternalMed_Harrison. For tumors associated with a potential “primary site,” staging systems have evolved to define a “T” component related to the size of the tumor or its invasion into local structures, an “N” component related to the number and nature of lymph node groups adjacent to the tumor with evidence of tumor spread, and an “M” component, based on the presence of local or distant metastatic sites. The various “TNM” components are then aggregated to stages, usually stage I to III or IV, depending on the anatomic site. The numerical stages reflect similar long-term survival outcomes of the aggregated TNM groupings in a numeric stage after treatment tailored to the stage. In general, stage I tumors are T1 (reflecting small size), N0 or N1 (reflecting no or minimal node spread), and M0 (no metastases). Such early-stage tumors are amenable to curative approaches with local treatments. On the other hand, stage IV tumors usually have metastasized to distant sites or locally invaded viscera in a


InternalMed_Harrison

InternalMed_Harrison. Such early-stage tumors are amenable to curative approaches with local treatments. On the other hand, stage IV tumors usually have metastasized to distant sites or locally invaded viscera in a nonresectable way and are dealt with using techniques that have palliative intent, except for those diseases with exceptional sensitivity to systemic treatments such as chemotherapy or immunotherapy. Also, the TNM staging system is not useful in diseases such as leukemia, where bone marrow infiltration is never really localized, or central nervous system tumors, where tumor histology and the extent of anatomically feasible resection are more important in driving prognosis.


InternalMed_Harrison

InternalMed_Harrison. 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 considered 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 may be quite narrow, with treatments 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.


InternalMed_Harrison

InternalMed_Harrison. Cancer treatments are divided into two main types: local and systemic. Local treatments include surgery, radiation therapy (including photodynamic therapy), and ablative approaches, including radio-frequency and cryosurgical approaches. Systemic treatments include chemotherapy (including hormonal therapy and molecularly targeted therapy) and biologic therapy (including immunotherapy). 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. Oncology, the study of tumors including treatment approaches, is a multidisciplinary effort with surgical, radiation, and internal medicine–related areas of oncologic expertise. Treatments for patients with hematologic malignancies are often shared by hematologists and medical oncologists.


InternalMed_Harrison

InternalMed_Harrison. 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 property of having (1) a population of cells actively progressing through the cell cycle with their division providing a basis for tumor growth, 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


InternalMed_Harrison

InternalMed_Harrison. 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, as they may serve as a basis for giving rise to tumor initiating or repopulating cells. The stem cell fraction may define new targets for therapies that will retard their ability to reenter the cell cycle.


InternalMed_Harrison

InternalMed_Harrison. Tumors follow a Gompertzian growth curve (Fig. 103e-1), with the apparent growth fraction of a neoplasm being high with small tumor burdens and declining until, at the time of diagnosis, with a tumor burden of 1–5 × 109 tumor cells, the growth fraction is usually 1–4% for many solid tumors. By this view, the most rapid growth rate occurs before the tumor is detectable. An alternative explanation for such growth properties may also emerge from the ability of tumors at metastatic sites to recruit circulating tumor cells from the primary tumor or other metastases. An additional 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. 102e). 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


InternalMed_Harrison

InternalMed_Harrison. barriers (Chap. 102e). 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. necessary to obtain the best outcomes. Thus, lumpectomy with 103e-3 radiation therapy is as effective as modified radical mastectomy for breast cancer, and limb-sparing surgery followed by adjuvant radia rhabdomyosarcomas and osteosarcomas. More limited surgery is also being used to spare organ function, as in larynx and bladder cancer. The magnitude of operations necessary to optimally control and cure 1012 Lethal cancer has also been diminished by technical advances; for example, the circular anastomotic stapler has allowed narrower (<2 cm) margins Tumor burden logs of cells in colon cancer without compromise of local control rates, and many patients who would have had colostomies are able to maintain normal anatomy.


InternalMed_Harrison

InternalMed_Harrison. Tumor burden logs of cells 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 can 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 autoregulatory 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.


InternalMed_Harrison

InternalMed_Harrison. Surgery is unquestionably the most effective means of treating cancer. Today at least 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. Such a resection is defined as an R0 resection. R1 and R2 resections, in contrast, are imprecisely defined pathologically as having microscopic or


InternalMed_Harrison

InternalMed_Harrison. and lymphatic spread, and minimizing operative risk. Such a resection is defined as an R0 resection. R1 and R2 resections, in contrast, are imprecisely defined pathologically as having microscopic or macroscopic tumor at resection margins. Such outcomes may be necessitated by proximity of the tumor to vital structures or recognition only in the resected specimen of the extent of tumor involvement, and may be the basis for reoperation to obtain optimal margins if feasible. Extending the procedure to resect draining lymph nodes obtains prognostic information and may, in some anatomic locations, improve survival.


InternalMed_Harrison

InternalMed_Harrison. 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 or radioisotope into the tumor site at operation and then resecting the first node to turn blue or collect label. 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 (chemotherapy given systemically after removal of all disease by operation and without evidence of active metastatic disease) and radiation therapy following surgery have permitted a substantial decrease in the extent of primary surgery cer), surgery is not the first treatment modality used. After an initial diagnostic biopsy, chemotherapy and/or radiation


InternalMed_Harrison

InternalMed_Harrison. have permitted a substantial decrease in the extent of primary surgery cer), surgery is not the first treatment modality used. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 eliminate estrogen production, and orchiectomy may reduce androgen production, hormones that drive certain breast and all prostate cancers, respectively; both procedures can have useful effects on metastatic tumor growth. If resection of the primary lesion takes place in the presence of metastases, acceleration of metastatic growth has also been described in certain cases, perhaps based on the removal of a source of angiogenesis inhibitors and mass-related


InternalMed_Harrison

InternalMed_Harrison. place in the presence of metastases, acceleration of metastatic growth has also been described in certain cases, perhaps based on the removal of a source of angiogenesis inhibitors and mass-related growth regulators in the tumor.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Surgery is used in a number of ways for palliative or supportive care of the cancer patient, not related to the goal of curing the cancer. These include insertion and care 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 rehabilitative efforts to restore health or function.


InternalMed_Harrison

InternalMed_Harrison. portals. Surgery may correct other treatment-related toxicities such as adhesions or strictures. Surgical procedures are also valuable in rehabilitative efforts to restore health or function. 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.


InternalMed_Harrison

InternalMed_Harrison. Surgery is also a tool valuable in the prevention of cancers in high-risk populations. Prophylactic mastectomy, colectomy, oophorectomy, and thyroidectomy are mainstays of prevention of genetic cancer syndromes. Resection of premalignant skin and uterine cervix lesions and colonic polyps prevents progression to frank malignancy. Chapter 103e Principles of Cancer Treatment


InternalMed_Harrison

InternalMed_Harrison. RADIATION Radiation Biology and Medicine Therapeutic radiation is ionizing; it damages any tissue in its path. The selectivity of radiation for causing cancer cell death may be due to defects in a cancer cell’s ability to repair sublethal DNA and other damage. Ionizing radiation causes breaks in DNA and generates free radicals from cell water that may damage cell membranes, proteins, and organelles. Radiation damage is augmented by oxygen; hypoxic cells are more resistant. Augmentation of oxygen presence is one basis for radiation sensitization. Sulfhydryl compounds interfere with free radical generation and may act as radiation protectors. X-rays and gamma rays are the forms of ionizing 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


InternalMed_Harrison

InternalMed_Harrison. 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 ionizing radiation using protons has also become available. Most radiation-induced cell damage is due to the formation of hydroxyl radicals from tissue water:


InternalMed_Harrison

InternalMed_Harrison. Radiation is quantitated based on the amount of radiation absorbed by the tumor in the patient; it is not based on the amount of radiation generated by the machine. The International System (SI) unit for radiation absorbed is the Gray (Gy): 1 Gy refers to 1 J/kg of tissue; 1 Gy equals 100 centigrays (cGy) of absorbed dose. A historically used unit appearing in the oncology literature, the rad (radiation absorbed dose), is defined as 100 ergs of energy absorbed per gram of tissue and is equivalent to 1 cGy. Radiation dosage is defined by the energy absorbed per mass of tissue. Radiation dose is measured by placing detectors at the body surface or based on radiating phantoms that resemble human form and substance, containing internal detectors. The features that make a particular cell more sensitive or more resistant to the biologic effects of radiation are not completely defined and critically involve DNA repair proteins that, in their physiologic role, protect against environmentally


InternalMed_Harrison

InternalMed_Harrison. sensitive or more resistant to the biologic effects of radiation are not completely defined and critically involve DNA repair proteins that, in their physiologic role, protect against environmentally related DNA damage.


InternalMed_Harrison

InternalMed_Harrison. Localized Radiation Therapy Radiation effect is influenced by three determinants: total absorbed dose, number of fractions, and time of treatment. 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 150to 200-cGy fractions.


InternalMed_Harrison

InternalMed_Harrison. A number of parameters influence the damage done to tissue (normal and tumor) by radiation. Hypoxic cells are relatively resistant. Nondividing cells are more resistant than dividing cells, and this is one rationale for delivering radiation in repeated fractions, to ultimately expose a larger number of tumor cells that have entered the division cycle. 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


InternalMed_Harrison

InternalMed_Harrison. 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 doses to small volumes of tumor, sparing normal tissue.


InternalMed_Harrison

InternalMed_Harrison. Therapeutic radiation is delivered in three ways: (1) teletherapy, with focused 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 administered, for example, intravenously but targeted by some means to a tumor site. Teletherapy with x-ray or gamma-ray photons is the most commonly used form of radiation therapy. Particulate forms of radiation are also used in certain circumstances, such as the use of proton beams. The difference between photons and protons relates to the volume in which the greatest delivery of energy occurs. Typically protons have a much narrower range of energy deposition, theoretically resulting in more precise delivery of radiation with improvement in the degree to which adjacent structures may be affected, in comparison to photons. Electron beams are a particulate form of


InternalMed_Harrison

InternalMed_Harrison. resulting in more precise delivery of radiation with improvement in the degree to which adjacent structures may be affected, in comparison to photons. Electron beams are a particulate form of radiation that, in contrast to photons and protons, have a very low tissue penetrance and are used to treat cutaneous tumors. Apart from sparing adjacent structures, particulate forms of radiation are in most applications not superior to x-rays or gamma rays in clinical studies reported thus far, but this is an active area of investigation.


InternalMed_Harrison

InternalMed_Harrison. 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 at local sites, as does hydroxyurea, another DNA synthesis inhibitor. These are important adjuncts to the local treatment of certain tumors, such as squamous head and neck, uterine cervix, and rectal cancers.


InternalMed_Harrison

InternalMed_Harrison. Toxicity of Radiation Therapy Although 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. Injured tissues release cytokines that act systemically to produce these effects. Bone is among the most radio-resistant organs, with 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Endoscopy techniques may allow the placement of stents to unblock viscera by mechanical means, palliating, for example, gastrointestinal or biliary obstructions. Radiofrequency ablation (RFA) refers to the use of focused microwave radiation to induce thermal injury within a volume of tissue. RFA can be useful in the control of metastatic lesions, particularly in liver, that may threaten biliary drainage (as one example) and threaten quality and duration of useful life in patients with otherwise unresectable disease. Cryosurgery uses extreme cold to sterilize lesions in certain sites, such as prostate and kidney, when at a very early stage, eliminating the need for modalities with more side effects such as surgery or radiation.


InternalMed_Harrison

InternalMed_Harrison. Some chemicals (porphyrins, phthalocyanines) are preferentially 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 (phototherapy) 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. Infusion of chemotherapeutic or biologic agents or radiation-bearing delivery devices such as isotope-coated glass spheres into local sites through catheters inserted into specific vascular sites such as liver or an extremity have been used in an effort to control disease limited to that site; in selected cases, prolonged control of truly localized disease has been possible.


InternalMed_Harrison

InternalMed_Harrison. The concept that systemically administered agents 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Systemic cancer treatments are of four broad types. Conventional “cytotoxic” 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 “biologics” (generally macromolecules such as antibodies or cytokines) designed and developed to interact with a defined molecular target important in maintaining the malignant state or expressed by the tumor cells. As described in Chap. 102e, 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.


InternalMed_Harrison

InternalMed_Harrison. 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 103e-5 of tumor cells or induce a host immune response to kill tumor cells. Thus, biologic therapies include not only antibodies but also cytokines and gene therapies.


InternalMed_Harrison

InternalMed_Harrison. CANCER CHEMOTHERAPY Principles 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 a tissue or cell type is governed by the differential expression of a drug’s target in the “sensitive” cell type or by differential drug accumulation into or elimination from compartments where greater or lesser toxicity is experienced, 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


InternalMed_Harrison

InternalMed_Harrison. experienced, 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.


InternalMed_Harrison

InternalMed_Harrison. Figure 103e-2 illustrates steps in cancer drug 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 of administration and schedule. Safety testing in two species on an analogous schedule of administration defines the starting dose for a phase 1 trial in humans, usually but not always in patients with cancer who have exhausted “standard” (already approved) treatments. The initial dose is 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 1 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 maximum-tolerated dose (MTD).


InternalMed_Harrison

InternalMed_Harrison. 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 maximum-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 2 trials, where 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. In a phase 3 trial, evidence of improved overall survival or improvement in the time to progression of disease on the part of the new drug is sought in comparison to an appropriate control population, which is usually receiving an acceptable “standard of care” approach. A favorable outcome of a phase 3 trial is the basis for application to a regulatory agency for approval of the new agent for commercial marketing as safe and possessing a measure


InternalMed_Harrison

InternalMed_Harrison. of care” approach. A favorable outcome of a phase 3 trial is the basis for application to a regulatory agency for approval of the new agent for commercial marketing as safe and possessing a measure of clinical effectiveness.


InternalMed_Harrison

InternalMed_Harrison. Response, defined as tumor shrinkage, is 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. 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


InternalMed_Harrison

InternalMed_Harrison. 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 Response Evaluation Criteria in Solid Tumors (RECIST), use unidimensional measurement, but the intent is similar in rigorously defining evidence for the activity of the agent in assessing its value to the patient. An active chemotherapy 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 3 trials to assess efficacy in comparison to standard or no therapy. Active efforts are being made to quantitate effects of anticancer


InternalMed_Harrison

InternalMed_Harrison. Chapter 103e Principles of Cancer Treatment Preclinical Model (e.g., mouse or rat) Rx :Time ? Phase II FIGuRE 103e-2 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 1 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 2 trials directed against specific cancer types, with rigorous quantitation of antitumor effects (middle). Phase 3 trials then may reveal activity superior to standard or no treatment (bottom).


InternalMed_Harrison

InternalMed_Harrison. agents on quality of life. Cancer drug clinical trials conventionally use a toxicity grading scale where grade 1 toxicities do not require treatment, grade 2 toxicities may require symptomatic treatment but are not life-threatening, grade 3 toxicities are potentially life-threatening if untreated, grade 4 toxicities are actually life-threatening, and grade 5 toxicities are those that result in the patient’s death.


InternalMed_Harrison

InternalMed_Harrison. Development of targeted agents may proceed quite differently. While phase 1–3 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 1 and early phase 2 trials with targeted agents.


InternalMed_Harrison

InternalMed_Harrison. Useful cancer drug treatment strategies using conventional chemotherapy agents, targeted agents, hormonal treatments, or biologics 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. A blocking in normal cellular differentiation may be a key feature in the pathogenesis of certain leukemias.


InternalMed_Harrison

InternalMed_Harrison. 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. 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 physiologic cell death responses, such as occurs in the developing organism or in the normal function of immune cells. Influencing


InternalMed_Harrison

InternalMed_Harrison. or in response to specific cell-surface receptors that mediate physiologic cell death responses, such as occurs in the developing organism or in the normal function of immune cells. Influencing 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 where 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” where proteases, nucleases, and endogenous regulators of the cell death pathway are activated (Fig. 103e-3).


InternalMed_Harrison

InternalMed_Harrison. 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 HER2/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 directed at or HER2/neu may alter the “threshold” tumors driven by these molecules may have for undergoing apoptosis without actually creating any molecular lesions such as direct DNA strand breakage or altered membrane function.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Chemotherapy agents may be used for the treatment of active, clinically apparent cancer. The goal of such treatment in some cases is cure of the cancer, that is, elimination of all clinical and pathologic evidence of cancer and return of the patient to an expected survival no different than the general population. Table 103e-3, A lists those tumors considered curable by conventionally available chemotherapeutic agents chemotherapy prior to any surgery or radia-103e-7 tion to a local tumor in an effort to enhance the effect of the local treatment. Chemotherapy is routinely used in


InternalMed_Harrison

InternalMed_Harrison. Chemotherapy is routinely used in FASR “conventional” dose regimens. In general, TRAIL-R effects, primarily consisting of transient therapy regimens are predicated on the myelosuppression with or without gastro- intestinal toxicity (usually nausea), which are readily managed. “High-dose” chemo- observation that the dose-response curve for many anticancer agents is rather steep, increased therapeutic effect, although at the cost of potentially life-threatening com- plications that require intensive support, usually in the form of hematopoietic stem Cytochrome C PIGs, etc cell support from the patient (autologous) or from donors matched for histocompatibility loci (allogeneic), or pharmacologic “rescue” strategies to repair the effect of Chapter 103e Principles of Cancer Treatment the high-dose chemotherapy on normal tissues. High-dose regimens have definite curative potential in defined clinical settings (Table 103e-3, D).


InternalMed_Harrison

InternalMed_Harrison. If cure is not possible, chemotherapyFIGuRE 103e-3 Integration of cell death responses. Cell death through an apoptotic mecha-may be undertaken with the goal of palliatnism requires active participation of the cell. In response to interruption of growth factor (GF) or ing some aspect of the tumor’s effect on thepropagation of certain cytokine death signals (e.g., tumor necrosis factor receptor [TNF-R]), there host. In this usage, value is perceived by the is activation of “upstream” cysteine aspartyl proteases (caspases), which then directly digest demonstration of improved symptom relief,cytoplasmic and nuclear proteins, resulting in activation of “downstream” caspases; these cause progression-free survival, or overall survivalactivation of nucleases, resulting in the characteristic DNA fragmentation that is a hallmark of at a certain time from the inception of treatapoptosis. Chemotherapy agents that create lesions in DNA or alter mitotic spindle function ment in the treated


InternalMed_Harrison

InternalMed_Harrison. DNA fragmentation that is a hallmark of at a certain time from the inception of treatapoptosis. Chemotherapy agents that create lesions in DNA or alter mitotic spindle function ment in the treated population, compared seem to activate aspects of this process by damage ultimately conveyed to the mitochondria, to a relevant control population established perhaps by activating the transcription of genes whose products can produce or modulate the as the result of clinical research protocol ortoxicity of free radicals. In addition, membrane damage with activation of sphingomyelinases other organized comparative study. Such results in the production of ceramides that can have a direct action at mitochondria. The anti-clinical research protocols are the basis forapoptotic protein bcl2 attenuates mitochondrial toxicity, while proapoptotic gene products such U.S. Food and Drug Administration (FDA)as bax antagonize the action of bcl2. Damaged mitochondria release cytochrome C and approval of a


InternalMed_Harrison

InternalMed_Harrison. mitochondrial toxicity, while proapoptotic gene products such U.S. Food and Drug Administration (FDA)as bax antagonize the action of bcl2. Damaged mitochondria release cytochrome C and approval of a particular cancer treatment as apoptosis-activating factor (APAF), which can directly activate caspase 9, resulting in propaga-safe and effective and are the benchmark for tion of a direct signal to other downstream caspases through protease activation. Apoptosis-an evidence-based approach to the use ofinducing factor (AIF) is also released from the mitochondrion and then can translocate to the chemotherapeutic agents. Common tumorsnucleus, bind to DNA, and generate free radicals to further damage DNA. An additional proapop-that may be meaningfully addressed by chetotic stimulus is the bad protein, which can heterodimerize with bcl2 gene family members to motherapy with palliative intent are listedantagonize apoptosis. Importantly, though, bad protein function can be retarded by its


InternalMed_Harrison

InternalMed_Harrison. protein, which can heterodimerize with bcl2 gene family members to motherapy with palliative intent are listedantagonize apoptosis. Importantly, though, bad protein function can be retarded by its seques-in Table 103e-3, E. tration as phospho-bad through the 14-3-3 adapter proteins. The phosphorylation of bad is Usually, tumor-related symptoms manimediated by the action of the AKT kinase in a way that defines how growth factors that activate fest as pain, weight loss, or some localthis kinase can retard apoptosis and promote cell survival. symptom related to the tumor’s effect on normal structures. Patients treated with palliative intent should be aware of their when used to address disseminated or metastatic cancers. If a tumor diagnosis and the limitations of the proposed treatments, have accessis localized to a single site, serious consideration of surgery or primary to supportive care, and have suitable “performance status,” accordingradiation therapy should be given, because


InternalMed_Harrison

InternalMed_Harrison. have accessis localized to a single site, serious consideration of surgery or primary to supportive care, and have suitable “performance status,” accordingradiation therapy should be given, because these treatment modalities to assessment algorithms such as the one developed by Karnofskymay be curative as local treatments. Chemotherapy may then be used (see Table 99-4) or by the Eastern Cooperative Oncology Groupafter the failure of these modalities to eradicate a local tumor or as part (ECOG) (see Table 99-5). ECOG performance status 0 (PS0) patientsof multimodality approaches to offer primary treatment to a clinically are without symptoms; PS1 patients are ambulatory but restricted inlocalized tumor. In this event, it can allow organ preservation when strenuous physical activity; PS2 patients are ambulatory but unablegiven with radiation, as in the larynx or other upper airway sites, or to work and are up and about 50% or more of the time; PS3 patientssensitize tumors to radiation


InternalMed_Harrison

InternalMed_Harrison. are ambulatory but unablegiven with radiation, as in the larynx or other upper airway sites, or to work and are up and about 50% or more of the time; PS3 patientssensitize tumors to radiation when given, e.g., to patients concur-are capable of limited self-care and are up <50% of the time; and PS4rently receiving radiation for lung or cervix cancer (Table 103e-3, B). patients are totally confined to bed or chair and incapable of self-care.Chemotherapy can be administered as an adjuvant, i.e., in addition to Only PS0, PS1, and PS2 patients are generally considered suitable forsurgery or radiation (Table 103e-3, C), even after all clinically appar-palliative (noncurative) treatment. If there is curative potential, evenent disease has been removed. This use of chemotherapy has curative poor–performance status patients may be treated, but their prognosispotential in breast and colorectal neoplasms, as it attempts to eliminate is usually inferior to that of good–performance status patients


InternalMed_Harrison

InternalMed_Harrison. status patients may be treated, but their prognosispotential in breast and colorectal neoplasms, as it attempts to eliminate is usually inferior to that of good–performance status patients treated clinically unapparent tumor that may have already disseminated. As with similar regimens.noted above, small tumors frequently have high growth fractions and An important perspective the primary care provider may bring totherefore may be intrinsically more susceptible to the action of antipro-patients and their families facing incurable cancer is that, given theliferative agents. Neoadjuvant chemotherapy refers to administration of limited value of chemotherapeutic approaches at some point in the


InternalMed_Harrison

InternalMed_Harrison. CurabIlIty of CanCerS wIth Chemotherapy A. Advanced Cancers with D. Cancers Possibly Cured with Possible Cure “High-Dose” Chemotherapy with Stem Cell Support Acute lymphoid and acute myeloid leukemia (pediatric/ Relapsed leukemias, lymphoid adult) and myeloid Hodgkin’s disease (pediatric/ Relapsed lymphomas, Hodgkin’s adult) and non-Hodgkin’s E. Cancers Responsive with Embryonal carcinoma Useful Palliation, But Not Cure, by Chemotherapy B. Advanced Cancers Possibly Islet cell neoplasms Cured by Chemotherapy and F. Tumors Poorly Responsive in Advanced Stages to Carcinoma of the uterine cervix Biliary tract neoplasms (stage III) Thyroid carcinoma Small-cell lung carcinoma Carcinoma of the vulva C. Cancers Possibly Cured with Chemotherapy as Adjuvant to Surgery Prostate carcinoma Breast carcinoma Melanoma (subsets) Colorectal carcinomaa Hepatocellular carcinoma Osteogenic sarcoma Salivary gland cancer Soft tissue sarcoma aRectum also receives radiation therapy.


InternalMed_Harrison

InternalMed_Harrison. natural history of most metastatic cancers, 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 (Chaps. 10 and 99). 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.


InternalMed_Harrison

InternalMed_Harrison. Cytotoxic Chemotherapy Agents Table 103e-4 lists commonly used cytotoxic cancer chemotherapy agents and pertinent clinical aspects of their use, with particular reference to adverse effects that might be encountered by the generalist in the care of patients. The drugs listed may be usefully grouped into two general categories: those affecting DNA and those affecting microtubules.


InternalMed_Harrison

InternalMed_Harrison. 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 where 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.


InternalMed_Harrison

InternalMed_Harrison. 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: 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.


InternalMed_Harrison

InternalMed_Harrison. 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 prevented from progressing or prevented altogether (if expected from the dose of cyclophosphamide to be used) by mesna (2-mercaptoethanesulfonate). Liver disease impairs cyclophosphamide 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 or ointment 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.


InternalMed_Harrison

InternalMed_Harrison. 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 used 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.


InternalMed_Harrison

InternalMed_Harrison. 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. Procarbazine is metabolized in the liver and possibly in tumor cells to yield a variety of free radical and alkylating species. In addition to Drug Toxicity Interactions, Issues Liver metabolism required to activate to phosphoramide mustard + acrolein Mesna protects against “high-dose” bladder damage Analogue of cyclophosphamide Must use mesna Greater activity vs testicular neoplasms and sarcomas Liver and tissue metabolism required Disulfiram-like effect with ethanol Acts as MAOI HBP after tyrosinase-rich foods Metabolic activation 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


InternalMed_Harrison

InternalMed_Harrison. 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 Reduce dose according to CrCl: to AUC of 5–7 mg/mL per min [AUC = dose/(CrCl + 25)] Acute reversible neurotoxicity; chronic sensory neurotoxicity cumulative with dose; reversible laryngopharyngeal spasm Chapter 103e Principles of Cancer Treatment Drug Toxicity Interactions, Issues Marrow (WBCs > platelet) Alopecia Hypotension Hypersensitivity (rapid IV) Nausea Mucositis (high dose) Marrow Mucositis Nausea Mild alopecia Diarrhea: “early onset” with cramping, flush ing, vomiting; “late onset” after several doses Marrow Alopecia Nausea Vomiting Pulmonary Marrow Mucositis Alopecia Cardiovascular acute/chronic Vesicant Marrow Cardiac (less than doxorubicin) Marrow Cardiac Marrow Cardiac (less than doxorubicin) Vesicant (mild) Blue urine, sclerae, nails


InternalMed_Harrison

InternalMed_Harrison. Hepatic metabolism—renal 30% Reduce doses with renal failure Schedule-dependent (5-day schedule better than 1-day) Late leukemogenic Accentuate antimetabolite action Reduce dose with renal failure No liver toxicity 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) Heparin aggregate; coadministration increases clearance Acetaminophen, BCNU increase liver toxicity Radiation recall Interacts with heparin Less alopecia, nausea than doxorubicin Radiation recall Less alopecia, nausea than doxorubicin Excretes in urine Reduce dose for renal failure Inhibits adenosine deaminase Reduce dose for renal failure Variable bioavailability Metabolize by xanthine oxidase Decrease dose with allopurinol Increased toxicity with thiopurine methyltransferase deficiency Variable bioavailability Increased toxicity with thiopurine methyltransferase deficiency


InternalMed_Harrison

InternalMed_Harrison. Metabolizes to 6-MP; therefore, reduce dose with allopurinol Increase toxicity with thiopurine methyltransferase deficiency Decrease dose with renal failure Augments antimetabolite effect Drug Toxicity Interactions, Issues Asparaginase Protein synthesis; indirect inhibition of DNA synthesis by decreased histone synthesis Clotting factors Glucose Albumin Hypersensitivity CNS Pancreatitis Hepatic Toxicity lessened by “rescue” with leucovorin Excreted in urine Decrease dose in renal failure; NSAIDs increase renal toxicity Toxicity enhanced by leucovorin by increasing “ternary complex” with thymidylate synthase; dihydropyrimidine dehydrogenase deficiency increases toxicity; metabolism in tissue Prodrug of 5FU due to intratumoral metabolism Enhances activity of alkylating agents Metabolizes in tissues by deamination but renal excretion prominent at doses >500 mg; therefore, dose reduce in “high-dose” regimens in patients with decreased CrCl


InternalMed_Harrison

InternalMed_Harrison. Metabolizes in tissues by deamination but renal excretion prominent at doses >500 mg; therefore, dose reduce in “high-dose” regimens in patients with decreased CrCl Use limited to leukemia Altered methylation of DNA alters gene expression Dose reduction with renal failure Metabolized to F-ara converted to F-ara ATP in cells by deoxycytidine kinase Chapter 103e Principles of Cancer Treatment Vincristine Vesicant Hepatic clearance Marrow Dose reduction for bilirubin >1.5 mg/dL Neurologic Prophylactic bowel regimen GI: ileus/constipation; bladder hypotoxicity; Drug Toxicity Interactions, Issues trum to other vincas) Hypertension Raynaud’s spectrum to other vincas) aCommon allkylator: alopecia, pulmonary, infertility, plus teratogenesis. Hepatic clearance Dose reduction as with vincristine Premedicate with steroids, H1 and H2 blockers Hepatic clearance Dose reduction as with vincas Premedicate with steroids, H1 and H2 blockers


InternalMed_Harrison

InternalMed_Harrison. Hepatic clearance Dose reduction as with vincristine Premedicate with steroids, H1 and H2 blockers Hepatic clearance Dose reduction as with vincas Premedicate with steroids, H1 and H2 blockers Abbreviations: ALL, acute lymphocytic leukemia; AUC, area under the curve; CHF, congestive heart failure; CNS, central nervous system; CrCl, creatinine clearance; CV, cardiovascular; GI, gastrointestinal; HBP, high blood pressure; MAOI, monoamine oxidase inhibitor; NSAID, nonsteroidal anti-inflammatory drug; SIADH, syndrome of inappropriate antidiuretic hormone secretion.


InternalMed_Harrison

InternalMed_Harrison. myelosuppression, it causes hypnotic and other CNS effects, including vivid nightmares. It can cause a disulfiram-like syndrome on ingestion of ethanol. Altretamine (formerly hexa-methylmelamine) 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.


InternalMed_Harrison

InternalMed_Harrison. Cisplatin was discovered fortuitously by observing that bacteria present in electrolysis solutions with platinum electrodes 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.


InternalMed_Harrison

InternalMed_Harrison. Cisplatin requires administration with adequate hydration, including forced diuresis with mannitol to prevent kidney damage; even with the use of hydration, 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 because the drug is exclusively cleared through the kidney, adjustment of dose for creatinine clearance must be accomplished through use of various dosing


InternalMed_Harrison

InternalMed_Harrison. myelosuppression is more frequent, and because the drug is exclusively cleared through the kidney, 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.


InternalMed_Harrison

InternalMed_Harrison. ANtitumor ANtibiotics AND topoisomerAse poisoNs 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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;


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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, other sarcomas, multiple myeloma, and ovarian cancer.


InternalMed_Harrison

InternalMed_Harrison. 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 has 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


InternalMed_Harrison

InternalMed_Harrison. 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 103e-13 usually a decline in the carbon monoxide diffusing capacity (DLco) or coughing, 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 bleomycindependent electron transport is dependent on O2, bleomycin toxicity may become apparent after exposure to transient very high fraction of inspired oxygen (Fio2). Thus, during surgical procedures, patients with prior


InternalMed_Harrison

InternalMed_Harrison. transport is dependent on O2, bleomycin toxicity may become apparent after exposure to transient very high fraction of inspired oxygen (Fio2). Thus, during surgical procedures, patients with prior exposure to bleomycin should be maintained on the lowest Fio2 consistent with maintaining adequate tissue oxygenation.


InternalMed_Harrison

InternalMed_Harrison. 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 to 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. Although 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.


InternalMed_Harrison

InternalMed_Harrison. 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.