Development of a Treatment Plan For cancers amenable to surgery, resection is usually the best alternative if the patient is a suitable candidate for anesthesia (Chapter 457) and otherwise is in acceptable condition in terms of concomitant or comorbid illnesses. A joint discussion among the internist, oncologist, surgeon, and anesthesiologist is often very useful in this regard. Determination of the patient's performance score (Table 192-1) is a simple means of assessing functional status. If life expectancy is limited or the patient is not a good candidate for surgery, radiation therapy is usually considered as the next “local therapy,” with chemotherapy reserved for patients whose disease is too extensive or metastatic. The increasing effectiveness of chemotherapy has resulted in its incorporation into therapy earlier, often as part of an “organ-sparing” approach. The ideal discussion with the patient should include a multidisciplinary approach, with clarification of diagnosis, prognosis, treatment goals, alternatives, side effects, and risks and benefits. Surgical Therapy Surgery is used to biopsy a suspected lesion, to remove the primary tumor, to bypass obstructions, and to provide palliation. A preoperative discussion may establish the need for placement of a venous access device at the time of surgery, thus eliminating a second procedure. Surgery remains the most common method to cure localized cancers, such as breast cancer (Chapter 208), colorectal cancer (Chapter 203), and lung cancer (Chapter 201), but it is limited by the location of the tumor, its extension, and distant metastases. Even if a tumor cannot be removed, a biopsy provides confirmation of the diagnosis. Occasionally, an obstructing lesion can be bypassed to provide palliation. Surgical staging also establishes the extent of the disease. For ovarian cancer (Chapter 209) surgical “debulking” aims to remove all visible disease, leaving minimal residual disease, to enhance chemotherapy. In rare circumstances when the primary tumor is controlled, removal of a single metastasis (“metastastectomy”) can result in long-term survival; an example is resection of a single liver metastasis found at the time of colectomy for colorectal cancer. A variety of surgical techniques, such as radiofrequency ablation or cryoablation, can treat hepatic metastases in carefully selected patients. “Adjuvant” chemotherapy is often given after surgery in this situation to treat microscopic metastases. Reconstruction after a disfiguring procedure is critical to long-term physical and emotional functioning. Examples include postmastectomy breast reconstruction (Chapter 208) and plastic surgery procedures to correct deformities after head and neck surgery (Chapter 200). Radiation Therapy Ionizing radiation (Chapter 18) can be delivered using high-energy rays, known as teletherapy, via a linear accelerator; by brachytherapy, through the application of radioactive implants, seeds, wires, or plaques; and intravenously by using radioisotopes. Radiation interacts with molecular oxygen, inducing the formation of superoxide, hydrogen peroxide, or hydroxyl radicals that damage DNA, leading to cell death. Like chemotherapy, radiation therapy is most effective against rapidly dividing cells. As “local therapies,” both surgery and radiation therapy are limited in their effectiveness by inapparent extension of disease, the location of tumors next to normal structures that must be preserved, and the presence of distant metastases. Normal tissue tolerance, which varies among the various organs and tissues, often prevents the use of doses that could uniformly eradicate cancers. Radiation therapy is also limited by tumor hypoxia: large, bulky tumors are frequently relatively “radioresistant,” whereas well-oxygenated tumors can be more effectively treated at lower doses. Radiation therapy can be used as the primary treatment, as part of multimodality therapy, in the adjuvant setting, and for palliation. As a single modality, radiation therapy can be curative for early-stage malignancies such as laryngeal cancer (Chapter 200), cervical cancer (Chapter 209), and prostate cancer (Chapter 211). Breast-conserving surgery (Chapter 208) requires the use of radiation to treat the remaining breast. Partial irradiation techniques using three-dimensional planning with external beam radiation or with a balloon catheter have recently been developed and used for selected patients with appropriately placed breast cancers. For localized prostate cancer (Chapter 211), implanted radioactive seeds of gold or palladium offer an alternative to surgery or external beam radiation therapy, again in carefully selected patients. It is important to note that the combination of chemotherapy and radiation therapy may result in synergistic toxicities, such as esophagitis (Chapter 140) in the treatment of lung cancer (Chapter 201) or mucositis in the treatment of head and neck cancer (Chapter 200). Newer techniques, such as intensity-modulated radiation therapy, permit more exact tailoring of the dose to the target and therefore reduce damage to surrounding normal tissues. Stereotactic radiation therapy or “gamma knife” techniques allow treatment of primary or metastatic brain tumors (Chapter 199) of up to 3 cm with pinpoint accuracy, thereby minimizing damage to normal brain. Low- to moderate-dose palliative radiation is used to ameliorate symptomatic cancer when cure is no longer the goal. For instance, radiotherapy can improve brain metastases (Chapter 199); relieve pain from bone lesions (Chapter 212); relieve obstructing lesions; and sometimes relieve hemoptysis caused by a lung cancer (Chapter 201) or bleeding from a gynecologic malignancy (Chapter 209). Bone-seeking radioisotopes such as samarium or strontium may relieve pain from bone metastases in prostate cancer (Chapter 211) or breast cancer (Chapter 208). Systemic Therapy Chemotherapy Pharmacogenomics, the study of inherited differences in interindividual drug disposition and effects, is becoming important in cancer therapy because genetic polymorphisms in drug-metabolizing enzymes are often responsible for the variations in efficacy and toxicity observed with many chemotherapeutic agents. Drugs potentially affected by polymorphisms identified to date include the thiopurines, 5-fluorouracil, irinotecan, and the platinum agents. In patients who are heterozygous or homozygous for metabolizing enzymes, toxicity can be dramatically enhanced. Currently available tests do not reliably permit assessment of the likelihood of response to therapy, so treatment is largely empirical and based on predictive factors from the tumor itself. Gene expression microarrays currently under development may predict responses reliably in the future. Assessing Treatment Assessment of the response to therapy depends largely on tumor size, determined either by direct measurement or from diagnostic imaging studies. The categories of response are complete response, with total absence of the tumor and correction of tumor-associated changes; partial response, defined as greater than 50% reduction of tumor size; stable disease, defined as greater than 25% but less than 50% reduction in tumor size; and progressive disease, characterized by either tumor growth or the development of new tumors. Leukemias can be assessed by bone marrow aspirates, and multiple myeloma is typically assessed by measurement of monoclonal proteins, peripheral blood counts, and percentages of malignant plasma cells in bone marrow samples, as well as radiographs of bone lesions. Chemotherapy is now used in a variety of settings without, before, with, and after surgery and radiation therapy (Table 192-2). Considerable experimental evidence suggests that cancers are most sensitive to chemotherapy during the early stages of growth, as a result of the high growth fraction and shorter cell cycle times, so that a given dose of drug will exert a greater therapeutic effect against a rapidly growing tumor than against a larger, quiescent tumor. Neoadjuvant Chemotherapy Neoadjuvant therapy, also called primary or induction chemotherapy, is used before surgery or radiation therapy to decrease the size of locally advanced cancers, thereby permitting better surgical resection, and to eradicate undetectable metastases. It also affords an opportunity to evaluate the effectiveness of treatment by histologic analysis of resected tissue. This approach is most often used for locally advanced breast cancer (Chapter 208), although other primary tumors can be targeted. Disadvantages result from the initially incomplete pathologic staging and the possibility that ineffective chemotherapy will permit the tumor to grow beyond the point of resection. Organ-sparing therapy is the use of chemotherapy, radiation therapy, or both to permit salvage of organs that otherwise would have been surgically removed if cure were the intended result. This technique is often effective in patients with cancers of the larynx (Chapter 200), esophagus (Chapter 140), bladder (Chapter 207), and anus (Chapter 203). Adjuvant Therapy Adjuvant chemotherapy is the use of chemotherapy in patients in whom the primary tumor and all evidence of cancer (e.g., regional lymph nodes), have been surgically removed or treated definitively with radiation but the risk of recurrence is thought to be high because of the presence of involved lymph nodes or certain morphologic or biologic characteristics of the cancer. Common examples include cancers of the breast (Chapter 208) and colon (Chapter 203). The typical end points of clinical chemotherapy, such as shrinkage of measurable tumor on serial radiographic studies, are not available in this situation; instead, relapse-free survival and overall survival are the principal measures of treatment effect. For an individual patient receiving adjuvant therapy, there is no means to determine whether the toxicity and expense of the therapy were beneficial or necessary, so decisions are generally based on evidence from clinical trials. Adjuvant therapy has been used in a wide variety of tumors with variable success. In the cases of breast cancer (Chapter 208) and colon cancer (Chapter 203), the number of lives saved by the use of adjuvant therapy is significant because of the large number of affected patients, despite the modest absolute differences seen between treated and control patients with current treatment programs. Resectable lung cancer (Chapter 201) has recently been added to this list. Palliative Chemotherapy Chemotherapy rarely cures cancers that remain after surgical or radiation treatment or that recur after such therapy. Pancreatic cancer (Chapter 204) is perhaps the best example of this scenario, because few patients are deemed eligible for surgery, and most have recurrent cancer after surgery. Most adult patients with recurrent or metastatic disease are considered for palliative therapy if there is no realistic chance of cure, but the potential for prolongation of useful life and/or relief of tumor-related symptoms makes such therapy reasonable. Combination Chemotherapy Virtually all the curative chemotherapy regimens developed for hematologic malignancies or solid tumors use combinations of active agents. Combination chemotherapy is also usually superior to the use of single agents in adjuvant and neoadjuvant therapy. The improved results achieved by combination chemotherapy can be explained in several ways. Resistance to any given single agent is almost always present at diagnosis, even in clinically responsive tumors. Tumors that are initially “sensitive” to chemotherapy rapidly acquire resistance to single agents, either as a result of selection of a preexisting clone of resistant tumor cells or because of an increased rate of mutation leading to drug resistance. Combination chemotherapy theoretically addresses both phenomena by providing a broader range of coverage against initially resistant clones of cells and preventing or slowing the development of resistant clones. Combination chemotherapy follows a set of principles. All drugs must be active against the tumor. All drugs must be given at an optimal dose and schedule. The drugs should have different mechanisms of antitumor activity as well as differing toxicity profiles, and the drugs should be given at consistent intervals for the shortest possible treatment time. Hormonal Therapy Endocrine or hormonal therapy for cancer, the earliest form of systemic therapy, is almost entirely limited to breast cancer (Table 192-3) and prostate cancer (Chapter 211). Many premenopausal breast cancers are thought to be under the influence of estrogens, and hormonal deprivation (ablation) may produce long-term responses in properly selected patients (those with estrogen and/or progesterone receptor positivity who have predominantly soft tissue or bone disease). This hormonal ablation may take the form of surgical removal of the ovaries, ablative radiation therapy, or the use of luteinizing hormone–releasing hormone (LHRH) antagonists. The antiestrogen, tamoxifen, is effective against breast cancer, and it may decrease the incidence of contralateral breast cancers in both premenopausal and postmenopausal women with breast cancer. It also has an estrogen-like activity that is responsible for an increased rate of endometrial cancers. Somewhat paradoxically, postmenopausal women who are candidates for hormonal therapy may also respond to tamoxifen. Aromatase Inhibitors Patients who have experienced a prolonged objective response or stable disease with hormonal therapy may be candidates for second, third-, or fourth-line hormonal therapy. However, such responses tend to become less frequent and shorter, and many patients eventually need chemotherapy. Recently, aromatase inhibitors (e.g., anastrazole, letrozole, exemestane), which decrease the conversion of metabolites in fat and muscle into estrogen, have been found to be more effective than tamoxifen as first-line therapy in both the adjuvant and metastatic settings, although the optimal schedule for tamoxifen and the aromatase inhibitors in the adjuvant setting is still under study (Chapter 208). Prostate cancer is androgen dependent, and androgen deprivation though castration or antiandrogens can produce meaningful responses. Estrogen therapy now is used infrequently because of its cardiovascular side effects and the availability of better alternatives. Once prostate cancer becomes androgen independent, second-line hormonal therapy rarely produces useful responses. Corticosteroids The corticosteroids, typically prednisone or dexamethasone, are widely used in the treatment of hematologic and oncologic cancers. In Hodgkin's disease (Chapter 197), the non-Hodgkin's lymphomas (Chapter 196), and multiple myeloma (Chapter 198), corticosteroids have antitumor activity. In solid tumors, they are used as antiemetics, rarely for the treatment of hypercalcemia of cancer (Chapter 266), and for symptomatic relief of cerebral edema in cases of central nervous system metastases (Chapter 199) or as an adjunct to radiation therapy for spinal cord metastases. Medroxyprogesterone acetate (Megace) is often used in an attempt to relieve anorexia, which is common among cancer patients. Immunotherapy Two cancers that are characterized by often unpredictable clinical behavior, melanoma (Chapter 214) and renal cell carcinoma (Chapter 207), are treated with interferon or interleukin-2 or both (Table 192-4). Dramatic responses are uncommon, and immunotherapy is only a minor component of cancer therapy. Molecularly Targeted Agents Targeted agents (Table 192-5) are drugs directed at a specific molecular point, such as a protein tyrosine kinase, or at the presence of a specific antigen on a tumor cell. Tyrosine kinase inhibitors include imatinib and erlotinib. The current best example of the success of tyrosine kinase inhibitor therapy is the dramatic response of chronic myelogenous leukemia (CML; see Chapter 195) to imatinib (Gleevec). Imatinib also has activity against gastrointestinal stromal cell tumors (Chapter 202). Erlotinib, directed against the epidermal growth factor receptor (EGFR), has antitumor effects in patients whose non–small cell lung cancers (Chapter 201) have EGFR mutations. Current research aims to identify the specific types of mutations so that patients can be prospectively selected for therapy, analogous to the measurement of estrogen receptors to select breast cancer patients for hormonal therapy. The vascular endothelial growth factor receptor (VEGFR) inhibits the formation of new blood vessels that are critical for tumor growth. Anti-VEGFR agents, such as the monoclonal antibody bevacizumab, prevent VEGF from inducing its signal in endothelial cells, thereby preventing their division. Bevacizumab has antitumor effects in metastatic colorectal cancer, non–small cell lung cancer, and breast cancer. Thalidomide inhibits angiogenesis through an unknown mechanism and is used against multiple myeloma (Chapter 198). Bortezomib (Velcade), a unique drug, is a reversible inhibitor of the proteasome pathway that normally regulates the intracellular concentration of specific proteins, thus controlling homeostasis. It has been effective in the treatment of refractory multiple myeloma (Chapter 198) and non-Hodgkin's lymphomas (Chapter 196). The development of monoclonal antibodies directed against antigens found on cancer cells represents an additional treatment modality, often complementary to conventional chemotherapy. Examples include alemtuzumab, cetuximab, rituximab, and trastuzumab. Trastuzumab has recently been shown to add significantly to disease-free survival time in patients positive for ERBB2 who receive adjuvant therapy for early-stage breast cancer (Chapter 208). These monoclonal antibodies can be used alone (“naked”) or, in some cases, labeled with a radioactive molecule to enhance cell killing. This radioimmunoconjugate approach has been most effective in the treatment of non-Hodgkin's lymphomas (Chapter 196) and chronic lymphocytic leukemia (Chapter 195). The effectiveness of monoclonal antibodies is limited by changes in the antigenic composition of neoplastic cells, called “antigenic drift.” Bone Marrow/Stem Cell Transplantation Because the major dose-limiting toxicity of most chemotherapeutic agents is myelosuppression, approaches have been developed to harvest the pluripotent stem cells found in bone marrow, peripheral blood, or, less often, cord blood before marrow-damaging chemotherapy, so that the stem cells can be reinfused later (Chapter 184). This technique is most effective for acute leukemias (Chapter 194), relapsed lymphomas (Chapter 196), and germ cell tumors (Chapter 210). The effectiveness of this approach is limited more by inability to eradicate cancer cells than by the inability to achieve engraftment. Transplants may be syngeneic (from identical twin), autologous (from self), allogeneic (from a matched donor, such as a sibling or parent), or from matched unrelated donors (MUD). Nonablative hematopoietic transplants that do not completely abolish myelopoiesis reduce toxicity and allow treatment of older and medically infirm patients. Individual Agents A general list of the currently most commonly used chemotherapeutic agents (Table 192-6) can help in understanding the key issues each raises. In all cases, the most current information from the manufacturer should be sought before therapy is initiated. The number of new drugs continues to increase, and some older drugs, now less commonly used, have been omitted. The administration of chemotherapy is best done by specifically trained individuals because of the dual risks of hypersensitivity reactions and extravasation. No doses or schedules are suggested, because these agents are often used in combination, and the doses must be reduced in many cases. End-organ function also affects dosing. The administration of chemotherapy during pregnancy (Chapter 258) is an especially difficult circumstance and requires a particularly high level of expertise. Unless otherwise specified, all chemotherapeutic agents are capable of producing some degree of nausea/vomiting, myelosuppression, alopecia, mucositis, and/or diarrhea after treatment. Most agents are also teratogenic, mutagenic, and carcinogenic, so these toxicities are not repeated for each agent. Drugs used routinely to offset agent-specific toxicities are also included in Table 192-6. Management of Complications Supportive Care Nutrition is always a concern for patients newly diagnosed with cancer, even if they have not experienced weight loss. In fact, significant weight loss is an adverse prognostic factor for several cancers, especially lung cancer. Patients are often concerned with whether their diet could have contributed to the development of the cancer (Chapter 185) and whether diet can influence the results of therapy. In most settings, neither of these scenarios is the case. Malnourished patients should be evaluated by a dietitian to determine whether they are ingesting sufficient calories and to suggest dietary supplements (Chapters 235 and 237). Some patients, such as those with head and neck cancers (Chapter 200) or esophageal cancers (Chapter 140), may require parenteral nutrition through a percutaneous endoscopic gastrostomy (PEG) tube. Total parenteral nutrition (Chapter 236) is rarely indicated, is not particularly helpful, and is likely to produce an ethical dilemma when therapy has failed and a decision to discontinue it is discussed. Corticosteroids increase appetite but have many undesirable side effects. Megestrol acetate (Megace) at a dose of 800 mg daily improves appetite and allows weight gain in many patients; it is expensive, although the suspension is less expensive than the tablets. The synthetic cannabinoid dronabinol (Marinol) stimulates appetite and reduces nausea in some patients, but it can produce dysphoria, particularly in older patients. A multiple vitamin with zinc may help with abnormal taste and provide trace minerals. Larger than recommended doses of vitamins are not helpful and may be toxic. It is always useful to inquire what over-the-counter and “alternative” medications (Chapter 36) are being contemplated or used by the patient. Symptom Management Symptom management is key to successful treatment and a patient's quality of life. Pain control (Chapter 28) can be accomplished with a variety of analgesics, both non-narcotic and narcotic. Oncologists use a 10-point scale for evaluating pain control (Fig. 192-1), and start with nonsteroidal analgesics (NSAIDs) such as aspirin and acetaminophen, progressing through ibuprofen and related drugs, through combinations of NSAIDs and narcotics to stronger narcotics. Newer narcotics are available in both short-duration and long-duration forms, with patches that last 72 hours, which are ideal for patients who have severe pain and are unable to take oral medication. Oral transmucosal fentanyl is more effective than standard release morphine in this setting.[1] Oral mucositis, a common complication of intensive therapy for hematologic malignancies, may be treated with local measures or, potentially, with recombinant human keratinocyte growth factor.[2,][3] Oral anti-Candida drugs that are absorbed or partially absorbed from the gastrointestinal tract can help prevent oral candidiasis.[4] Many patients still fear chemotherapy because of the risk of nausea and vomiting. New antiemetics, used in combination, have made this side effect much less common. Chemotherapeutic drugs can be ranked according to their probability of causing nausea and vomiting, with prophylactic treatment given accordingly. The availability of the serotonin 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists (dolasetron, granisetron, ondansetron) has dramatically improved the rate of complete control of nausea and vomiting. Although prochlorperazine may be adequate for mildly emetogenic chemotherapy, more emetogenic regimens require combination therapy with a corticosteroid (usually dexamethasone), a 5-HT3 antagonist, and a benzodiazepine (e.g., lorazepam). A newer antiemetic, aprepitant, is particularly useful for the treatment of delayed nausea and vomiting. Treating patients before the development of nausea and vomiting is much more effective and helps patients adhere to their treatment schedule. Growth factors, such as granulocyte-colony stimulating factor (G-CSF) and granulocyte-monocyte colony stimulating factor (GM-CSF), permit more rapid recovery of white blood cell nadirs, thus permitting chemotherapy to be given on schedule, without reducing doses in many cases. However, such therapy does not reduce hospitalizations or improve survival.[5] It is possible to determine which individuals are at greatest risk for febrile neutropenia (Chapter 173) and treat them in advance,[6,][7] based on published guidelines. Anemia induced by chemotherapy can be alleviated, and the need for transfusions and quality of life improved, by the use of either erythropoietin (Procrit) or darbepoetin (Aranesp). A meta-analysis of randomized trials showed, however, that recombinant human erythropoiesis-stimulating agents increased the risk of death in patients with cancer by 6% to 17%.[7A] The bisphosphonates (Chapter 264), pamidronate (Aredia) or zoledronate (Zometa), are very effective, not only to treat tumor-induced hypercalcemia, but also to reduce pathologic fractures in bones with metastatic lesions, particularly from breast cancer (Chapter 208) or prostate cancer (Chapter 211) and myeloma (Chapter 198). They are also used to treat osteoporosis caused by chemotherapy-induced premature menopause in young women with breast cancer. Hematologic malignancies and chemosensitive solid tumors should be treated with prophylactic allopurinol to prevent gout and renal colic from hyperuricemia. The effects of the acute tumor lysis syndrome (hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia) may be minimized by the use of allopurinol, vigorous hydration, and careful assessment of serum electrolytes. |
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