Principles of Surgery, Companion Handbook

Chapter 9 Oncology

Principles of Surgery Companion Handbook

Approximately 90 percent of patients with malignancy undergo surgical therapy for diagnosis, primary treatment, or management of complications related to cancer. Resection is the initial curative treatment for about 75 percent of patients because cancer is assumed to be a localized disease for an interval, allowing cure after adequate surgical removal. The surgeon is responsible for the initial diagnosis and management of many types of cancer. Accurate diagnosis and staging with adequate operative removal of localized disease and palliation of symptoms when possible are the guiding principles of surgical treatment of cancer.

Management of the cancer patient is a multidisciplinary effort requiring collaboration among surgical oncologists, radiation oncologists, medical oncologists, reconstructive surgeons, and other oncologic specialists. Combinations of surgery, radiation therapy, chemotherapy, hormone therapy, and immunotherapy significantly improve cure rates above those achieved with any single therapeutic modality. As the primary coordinator in cancer management, the surgeon must fully understand the indications, risks, and benefits of surgery, adjuvant chemotherapy, hormonal therapy, and radiation therapy and the importance of reconstructive surgery.

Determining a treatment plan requires the integration of information from four areas: (1) natural history of the disease by histologic type, (2) clinical staging, (3) goals of specific treatments, and (4) indications and risks for each treatment (or combination of treatments) based on results of experience and clinical trials.

EPIDEMIOLOGY

Cancer is the most frequent cause of death in the United States, accounting for 24 percent (approximately 520,000) of deaths each year. The five leading causes of cancer death among males in the United States are lung, 32 percent; prostate, 14 percent; colon and rectum, 9 percent; leukemia and lymphoma, 9 percent; and pancreas, 5 percent. Among females, the leading causes of cancer deaths are lung, 25 percent; breast, 17 percent; colon and rectum, 10 percent; leukemia and lymphoma, 8 percent; and ovary, 6 percent. Prostate cancer is the most frequent life-threatening cancer in men, and breast cancer is the most frequent in women.

The incidence rate of cancer is defined by the number of new cancer cases that develop in a population of individuals at risk during a specific interval. These rates should be distinguished from prevalence (the number of affected persons within a population). Rates can be crude, category-specific (e.g., age, gender, or race), or adjusted (e.g., accounting for mortality from other causes). Herein resides the value of population-based registries and of high-risk registries in which persons at risk can be concentrated for study and treatment.

Vastly different incidence rates for site-specific cancers have been found. Cancer of the stomach remains a leading cause of death in Asia and eastern Europe. When natives of Japan, where gastric cancer is frequent and colorectal cancer uncommon, emigrated to Hawaii, over one generation the frequency of these cancers was reversed, a change attributed to adoption of the Western diet. Given that diet and nutrition may be characterized as an environmental factor, these differences incriminate environment-induced molecular events in human carcinogenesis. The more frequent occurrence of cancer in older persons may reflect accumulation of environmentally based genetic events as well as molecular events associated with senescence.

Recognition of internal and external environmental interactions in human carcinogenesis provides the means for risk reduction and the development of prevention strategies. Elimination of exposure to asbestos or radiation, avoidance of occupational carcinogens, and reduction of cigarette smoking remove certain carcinogens from the environment and reduce risk. Sunscreens block the carcinogenic wavelength of ultraviolet light.

BIOLOGY OF MALIGNANT TRANSFORMATION

Cellular Homeostasis To achieve homeostasis in tissues, renewable cell populations must perform four related functions; they must (1) proliferate with proper timing and fidelity of DNA content, (2) differentiate in a pattern consistent with normal function of the tissue, (3) involute in a manner such that the proliferation and involution rates are balanced, and (4) repair any damages to their DNA resulting from exposure to mutagens such as radiation, toxins, and transforming viruses. A defect in any of these functions can result in tumor formation.

Carcinogenesis Cancer results from a deregulation of critical aspects of cellular function. Without the proper constraints on these processes, neoplastic cells reproduce in great numbers, invade adjacent structures, and develop metastases. Tumor initiation is defined as the exposure of cells to agents that induce an inheritable genetic change, i.e., agents that are genotoxic or induce critical mutations by binding of electrophilic carcinogenic metabolites to DNA. Tumor promotion is the exposure of initiated cells to agents that induce their proliferation. This proliferation may allow other spontaneous mutations to occur that culminate in expression of malignant phenotype. Tumor progression describes successive development of increased local growth, invasion, and metastasis by transformed cells.

CANCER PHENOTYPE

Progression of a tissue to malignancy disturbs host homeostatic mechanisms, as characterized by (1) unresponsiveness to normal growth regulators, (2) invasive phenotype, and (3) evasion of immune-mediated tumor destruction. Tumors are thought to be clonal in origin (i.e., all the cells within a tumor arise from a single progenitor cell whose growth regulation has become deranged). Despite their possible clonal origin, cancers, particularly the solid tumors, are heterogeneous in character. A cancer mass includes tumor cells and their supporting blood vessels and stroma. As regions of tumor outstrip their blood supply, areas of inflammation and necrosis further contribute to tumor heterogeneity. As a result of loss of the fidelity of DNA replication, changes in the malignant cell population occur throughout the course of tumor progression. This is best demonstrated by a change in differentiation state or tumor antigen expression between primary tumors and their metastatic foci.

Progression of a tissue to malignancy involves several stages. The earliest visible evidence of neoplastic transformation is dysplasia, a condition in which epithelial tissues exhibit altered size, shape, and organization. Dysplasia is a common reaction of tissue to chronic inflammation or exposure to environmental toxins or irritants. Because dysplastic cells retain a measure of control over cellular proliferation, dysplasia is generally reversible once the inciting factor is removed. In most tissues, however, severe dysplasia is associated with progression to carcinoma if left without intervention.

The hallmark of a solid-tumor carcinoma is the ability to invade the basement membrane and spread without regard to normal tissue boundaries. Local disease is the term used to refer to invasive tumor that is confined to the tissue of origin. Once the basement membrane has been breached, the next barrier to tumor dissemination is the network of draining lymph nodes. Tumor spread to the lymph nodes draining the tissue of origin is termed regional disease. The final stage of tumor progression is metastasis, whereby independent colonies of tumor are established in distant sites favorable to tumor growth. This type of tumor is commonly referred to as distant disease.

Physical Carcinogens Physical agents can induce tumor induction by two mechanisms: (1) induction of cell proliferation over an extended period of time, which increases the opportunity for events leading to transformation, and (2) exposure to physical agents that induce damage or changes in DNA. The best known agent of physical carcinogenesis is radiation. Ionizing radiation includes x-rays and gamma rays, whereas the most common form of non-ionizing radiation is ultraviolet radiation. Both types of radiation are associated with human cancers.

Chemical Carcinogens Epidemiologic studies reveal that a substantial number of compounds are associated with chemical carcinogenesis. Tobacco products remain the source of most chemically induced human cancers. Most carcinogenic chemicals are a complex mixture of molecules rather than a single pure agent. There are several main classes of chemical carcinogens, including organic and inorganic substances. Polycyclic hydrocarbons are organic carcinogens that undergo metabolism in the host to an active form. Benzo[a]pyrene, a component of cigarette smoke and smoked foods, is probably the most extensively studied polycyclic hydrocarbon. This substance is converted to its toxic metabolites through the action of the hepatic enzymes cyclooxygenase and cytochrome P-450. Inorganic carcinogens include heavy metal products of fossil fuel combustion such as nickel, cadmium, chromium, arsenic, and lead.

Viral Carcinogens Viruses can insert their genetic material into host cells and induce changes morphologically consistent with neoplastic transformation. It is now recognized that both RNA and DNA viruses are capable of inducing tumors in humans, although only a small proportion of individuals infected with a cancer-associated virus actually develop tumors. Virus-associated cancers arise after an incubation period of years to decades, suggesting that other genetic or environmental factors contribute to virally induced carcinogenesis. The contribution of oncogenic viruses to carcinogenesis may lie in the inactivation of the proteins that are essential for regulation of the cell cycle. The most common tumor viruses are listed in Table 9-1.

TABLE 9-1 TUMOR-ASSOCIATED VIRUSES

IMMUNODEFICIENCY AND CANCER

The theory of immunologic surveillance against cancer is that immune effector cells can eliminate cells that undergo malignant transformation. According to this theory, the development of a tumor is a failure of immune surveillance in maintaining tissue homeostasis. Despite advances in the understanding of carcinogenesis, the nature of immune surveillance and the role of the immune response cells in the progression of malignancy are unclear.

States of immunosuppression are associated with an increased risk of cancer. Patients receiving long-term immunosuppressive medication for prevention of allograft rejection have an increased incidence of skin cancers and lymphoid malignancies. The coincidence of virally induced tumor formation and states of immunosuppression provides strong evidence that a normally functioning immune system acts to suppress carcinogenesis. For example, the acquired immune-deficiency syndrome (AIDS) is associated with Kaposi's sarcoma, non-Hodgkin's lymphoma, and squamous cell carcinoma.

GENETIC ALTERATIONS

The Multistep Hypothesis Cancer is fundamentally an alteration in the genes that control cellular function. Cancer susceptibility genes can be inherited at conception as germline defects. These genes affect the cell's ability to detect and repair genetic damage, alter immune surveillance for tumors, modify cellular metabolism of carcinogens, or regulate the growth of specific cell types. Carcinogenesis seems to require the successive accumulation of genetic defects that result in the altered cellular growth and differentiation characteristic of a malignant phenotype. Such genetic changes are known as the multistep hypothesis of cancer and have been identified in the development of colorectal cancer.

Oncogenes Oncogenes are genes that promote the transformation of normal cells into tumor cells. They are usually designated by three-letter names derived from the tumors or the cell line in which the oncogene was first identified. Oncogenes derived from viral genomes are labeled with the prefix v (e.g., v-src), whereas cellular oncogenes are labeled with c (e.g., c-src). Oncogenes encode proteins, sometimes termed oncoproteins, that alter cell cycle regulation, resulting in tumor formation. Oncogenes are divided into categories depending on the role their proteins play in cellular function. These include growth factors, growth factor receptors, cytoplasmic protein kinases, guanosine triphosphate (GTP)–binding proteins, nuclear transcription factors, and cell cycle regulators (Table 9-2).

TABLE 9-2 ONCOGENES

Tumor Suppressor Genes and the Inherited Cancer Predisposition Syndromes Tumor suppressor genes keep cellular growth in check. The loss of function of one of these genes leads to tumor formation. Loss of RB1 gene function requires mutation of both copies of the gene. In familial retinoblastoma, affected individuals inherit one defunctionalizing germline mutation. Expression of the RB1 mutation phenotype requires loss of the second allele by somatic mutation, a concept known as Knudson's “two-hit” hypothesis. Most of the inherited cancer predisposition syndromes described to date involve inheritance of one mutant and one normal allele of a tumor suppressor gene.

p53 has been recognized as a tumor suppressor gene and identified as a germline mutation associated with Li-Fraumeni syndrome, a familial clustering of breast cancer, soft tissue sarcomas, brain tumors, osteosarcoma, leukemia, and adrenocortical carcinoma. Affected individuals develop cancer by age 70 through somatic loss of the wild-type p53 allele. Inactivation of the p53 gene is one of the most detectable genetic defects in tumors. The p53 protein plays a crucial role in preserving the integrity of the cell's genome by temporarily halting the cell cycle in response to damage, allowing adequate time for DNA repair prior to replication. In instances of severe damage, the p53 protein is capable of triggering programmed cell death, consequently eliminating damaged cells before replication can occur. Given its importance in preventing replication of a damaged genome, p53 has been labeled the “guardian of the genome”; intact p53 function is crucial for tumor prevention. Other diseases that have been linked to defective tumor suppressor genes include familial adenomatous polyposis, hereditary malignant melanoma, multiple endocrine neoplasia, and familial breast and ovarian cancer.

FUNCTIONAL ALTERATIONS IN CARCINOGENESIS

Tumor progression involves acquisition of several abilities by the malignant colony. These cells must be able to (1) invade the basement membrane and surrounding tissues through the production of proteases, (2) recruit blood vessels to support the growth of the tumor mass, (3) avoid destruction by effector cells of immune surveillance, such as natural killer (NK) cells, (4) move through tissues, a process that requires production and recruitment of cell adhesion molecules and chemotactic cytokines, and (5) travel to distant sites, adhere, and establish a new tumor colony. There are many parallels between fetal development and malignant transformation. The process of tumorigenesis involves the disruption of normal developmental programs.

RELATIONSHIPS BETWEEN TUMORS AND NORMAL HOST TISSUES LOCAL INVASION

In order to become invasive carcinoma, tumor cells must cross the basement membrane and enter the surrounding stromal tissue. Tumor invasion must involve partial destruction of a barrier of collagen, glycoproteins, and proteoglycins. The process of local tumor invasion includes tumor cell adhesion, matrix dissolution, and migration.

Tumor Cell Adhesion Cell-cell adhesion is an important process for growth of normal tissues. Cells that lose contact with each other undergo involution. During carcinogenesis, the requirement for cell-cell adhesion is lost, and single cells can infiltrate local tissue. Adhesion of cells and growth regulation are mediated by cell adhesion molecules (CAMs), which are complex glycoproteins present on the surfaces of both epithelial and stromal cells. CAMs are divided into four main classes according to their structure and general function. These include the cadherins, the integrins, the selectins, and the immunoglobulin superfamily receptors. Following tumor cell adhesion, the process of infiltration requires matrix dissolution. Matrix lysis occurs in experimental models of tumor infiltration from 2–8 hours after adhesion. Enzymes belong to a family known as the metalloproteinases (MMPs) and are responsible for matrix lysis. These enzymes include interstitial collagenases, Type IV collagenases, and stromelysins. Natural protease inhibitors, known as tissue inhibitors of metalloproteinases (TIMPs), produced either by the host or by the tumor itself, can counteract this process. Once the basement membrane barrier is lysed, tumor cells are free to migrate into the surrounding stromal tissues.

Migration The third step of invasion is migration. Tumor cell motility involves both fixed cell surface interactions and soluble factors. Tumor cell movement is characterized by ameba-like pseudopod extension. This movement requires coordination of multiple steps, including cellular protrusion and new adhesion formation at the leading edge, as well as release of old adhesive interactions at the trailing edge. A number of cytokines stimulate motile responses in tumor cells. These include tumor cell–derived cytokines, such as autocrine motility factor, autotaxin, and scatter factor. Many adhesion molecules, particularly those found in the extracellular matrix, such as laminin, collagen, fibronectin, and thrombospondin, serve as tumor cell attractants in motility assays.

Angiogenesis Angiogenesis, or the formation of new blood vessels, is important for all phases of tumor progression. Without new vessel growth, tumors would quickly outstrip their local nutrient supply and would be unable to form new colonies after metastasis. Endothelial cells in vessels near a tumor site are stimulated by angiogenesis factors to degrade the extracellular matrix. This allows migration of endothelial cells into the stroma, initiating a capillary sprout. Growth of a tumor colony beyond 1 cm³ in size requires vascularization through angiogenesis. The locally secreted factors of angiogenesis include basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor (PD-ECGF), transforming growth factors alpha and beta (TGF-a and -b), angiogenin, tumor necrosis factor alpha (TNF-a) and interleukin-8 (IL-8).

The development of angiogenic potential in a tumor may be an important indicator of its biologic behavior. For example, the presence of increased vascularity in early breast cancer specimens indicates a higher chance of tumor recurrence as well as increased presence of lymph node metastasis. These observations raise the possibility that antiangiogenesis agents, such as analogues of the fungus-derived angiogenesis inhibitor fumagillin, might prove beneficial in the treatment of malignancy.

Metastasis Metastatic tumors develop as clones arising from a heterogeneous primary tumor. Tumor cell metastases require multiple host-tumor interactions that probably begin early in the growth of the primary tumor. The metastatic cell must be able to break away from the original tumor population, invade through the basement membrane into a blood vessel, travel and adhere to a distant site, and induce angiogenesis. These activities require coordinating the processes of proteolysis, motility, adhesion, growth factor responsiveness, and angiogenic activity. Since all these processes are naturally occurring functions of growth and development, the basic defect of metastasis must lie in the aberrant regulation of these processes.

Metastasizing tumors have a predilection for selected organ sites. In human beings, colon tumors frequently metastasize to the liver, renal cell carcinoma to the lung, melanoma to the lung and brain, prostate cancer to bone, and ocular melanoma to the liver. Selection of a metastatic site by a particular tumor is probably governed by the adhesion and growth factor characteristics of the metastatic site and the requirements of the metastatic tumor.

The role of the regional lymphatics in the spread of cancer is controversial. It is now thought that the properties of the tumor cells themselves, rather than the filtration capacity of the lymph nodes, determine whether neoplastic cells are trapped within nodes or allowed to disseminate. The regional nodes also may be involved in the initiation of systemic immunity to tumors. For example, adoptive transfer of lymphoid cell populations derived from regional lymph nodes has been shown to induce tumor allograft immunity in normal animals.

Metastasis is a multistage process in which tumor cells acquire more and more autonomy regarding growth factor and adhesion requirements. A complex process with no universally applicable mechanism, metastasis depends on the characteristics of the tumor (the “seed”) and the microenvironment of its implantation site (the “soil”).

INTRACELLULAR SIGNAL TRANSDUCTION

Binding of a ligand to a cell surface receptor results in an intricate cascade of intracellular reactions ultimately inducing transcription of appropriate cellular genes. This complex process is known as intracellular signal transduction. Most oncogenes or tumor suppressor genes encode proteins essential for intracellular signal transduction. Oncogenes can be roughly divided into groups according to their cellular function, e.g., the cytoplasmic protein kinases, transcriptional regulators, GTP-binding proteins, and regulators of programmed cell death (apoptosis).

Growth factor receptors are also known as tyrosine kinases. Binding of a growth factor on the extracellular domain results in phosphorylation of the intracellular portion of the receptor. This triggers recruitment of intracellular substrates, which trigger a cascade of kinase activity and cytoplasmic enzymes. These kinases mediate the reactions that bridge the gap between the cell membrane and the nucleus, resulting in induction of transcription in stimulation of the cells that progress from G₁ to S phase.

Cell Cycle Control Cells take their cues for proliferation and differentiation not only from external sources such as growth factor receptors but also according to an internal program. The cell cycle encompasses the progression from G₁ phase through mitosis and is coordinated by nuclear proteins called cyclins. The passage of a cell through the cell cycle is tightly regulated by a network of controls that act on the transcription of cyclin genes, the degradation of cyclin proteins, and the modification of cyclin-dependent kinases by phosphorylation. It is now recognized that the cell cycle is a dynamic process that includes periods of arrest of cell proliferation when DNA damage occurs, presumably to allow time for DNA repair to occur. Provisions are made within the cell cycle program for apoptosis in circumstances in which the cell's genome has undergone irreparable damage. Cyclin-dependent kinases (CDKs) coordinate the cell cycle. Multiple CDKs have been described that govern progression of the cells from G₁ to mitosis.

Defects in the cell cycle control points are known to be associated with carcinogenesis. At the transition of G₁ to S phase, the Rb protein is an important control point. Loss of function of the Rb protein leads to unregulated entry of a cell into S phase. The p53 gene product is also known to be a regulator of cell cycle activity. The protein product of p53 gene activates p21, a protein that inhibits all the cyclin-CDK complexes. A cell with deficient p53 will enter S phase without sufficient DNA repair and will replicate uncorrected mutations.

Regulation of Apoptosis In order for tissues to maintain a normal state, cells subject to renewal must involute so that the proliferation and involution rates are balanced. This programmed cell death is known as apoptosis. Defects resulting in loss of normal apoptosis are associated with tumor formation. The bcl-2 oncogene was identified in follicular lymphomas and found to promote cell survival rather than proliferation. BAX, a protein identified by its association with the bc-2 gene product, counteracts the survival-promoting effects of bcl-2. Most mechanisms that induce apoptosis involve the BAX/bcl-2 interchange. Transcription of BAX protein is inducible by p53. Other regulators of apoptosis include TNF-R1 and insulin-like growth factor-1 (IGF-1).

SURGICAL MANAGEMENT OF PRIMARY TUMORS

General Considerations Some types of cancer involve some role for the surgeon, either by diagnosis, clinical staging, operative resection, pathologic staging, palliation, or management of medical conditions. Knowledge of clinical and pathologic staging is important, and accurate diagnosis and assessment of the extent of tumors are essential to appropriate treatment. Surgical resectability is determined by the tumor's relation to and degree of invasion into and around vital structures. Invasive and noninvasive radiologic studies are extremely helpful in outlining the goals of operative management and defining the operative approach. Studies to preclude metastases are indicated when they are cost-effective and would substantially alter surgical treatment.

The surgeon has a major role in disease prevention and patient/family counseling. The extent of an operation may be related to the presence of additional precancerous lesions or to a strong family history of site-specific cancers.

An important but often underemphasized goal of cancer management is restoring the patient's physical, emotional, social, and employment status. The rehabilitation for a woman with breast cancer might be directed toward minimizing scarring and swelling of the tissues in the chest and arm, regaining strength and mobility of the shoulder after axillary lymphadenectomy, and restoring contour and symmetry of the breast. For some women, an external prosthesis is satisfactory; other women significantly benefit from breast reconstructive surgery.

Clinical Diagnosis A complete history and physical examination are indispensable before further judgments can be made. Symptoms generally correspond to the sites involved, but nonspecific symptoms, such as night sweats and weight loss, may be the initial manifestations of an underlying neoplastic tumor.

The patient's past medical history often lends clues to the diagnosis. Diethylstilbestrol (DES) use by the patient's mother during pregnancy, thymic irradiation for asthma, skin irradiation for acne in childhood, and a history of chronic inflammatory bowel disease are historical factors known to be associated with the development of cancer. Smoking, alcohol ingestion, and exposure to asbestos or aniline dyes can be related to tumor development.

Inquiry into family history may reveal findings that support an initial diagnosis or influence the extent of surgical treatment. Without a thorough history, genetically influenced diseases may be missed.

Laboratory and Radiologic Studies Complete blood count, coagulation profile, serum biochemistry profile, and chest x-ray are baseline studies that are useful in determining the prognosis in patients with malignant disease. Serum markers such as carcinoembryonic antigen (CEA), CA19-9, beta-human chorionic gonadotropin (b-HCG), and alpha-fetoprotein (AFP) are useful in the management of patients with specific tumors. Elevated plasma levels are correlated with increasing tumor size, stage, and the extent of positive lymph node metastases in patients with large-bowel cancer.

Surgical Pathology Accurate pathologic diagnosis is extremely important in the proper surgical treatment of cancer patients. Determinations of the presence of cancer, the histologic grade, the site of the primary or metastatic foci, and surgical resection margins provide critical information.

Fine-needle aspiration cytology is a valuable technique for diagnosis of palpable masses in the breast and thryoid, as well as palpable suspicious nodes in the neck, axilla, or groin. Aspiration cytology cannot be completely depended on for grading of solid tumors, for subdividing types of lymphoma, or for accurate diagnosis after radiation treatment, but a positive diagnosis greatly facilitates diagnostic and treatment planning.

When an accurate diagnosis of tumor type and grade is necessary, an incisional or excisional biopsy is required. Care should be taken in the planning of a surgical biopsy so as not to jeopardize later surgical extirpation. In general, large soft tissue masses that are deeper than the superficial fascia are best sampled by incisional biopsy. Small (<2 cm) superficial lesions can be managed by excisional biopsy with a view toward further treatment depending on tumor size, grade, and depth of invasion.

Decision for Operation A decision for curative operation presupposes that the tumor is localized or confined regionally, that the area of the tumor can be encompassed by regional excision, that evidence of distant metastases cannot be found, and that the tumor is appropriately treated by operation. In principle, an en bloc resection should be performed, encompassing the primary tumor, regional lymph nodes, and intervening lymphatic channels. This principle is best illustrated by operations for large bowel cancer, in which the regional lymphatics of the colon course in one direction with the major arteries and veins.

The extent of various operations for cancer is undergoing change. The theraputic value of regional lymph node dissection has been questioned by many. Performed properly, a lymph node dissection is of clear prognostic value and can establish the database for precise staging for other adjuvant treatments.

Some surgical procedures may be performed solely for staging purposes. Examples include staging laparotomy for Hodgkin's disease. Other operations are performed solely for palliative treatment, such as bypasses around obstructed viscera. Cytoreductive surgery is controversial. This approach may be most relevant in ovarian cancer and some childhood tumors, such as neuroblastoma. Rarely is cytoreductive surgery applicable in other circumstances.

Cancer Operations

Local Resection Wide local resection that removes an adequate margin of normal tissue with the tumor mass may be adequate for certain low-grade neoplasms that do not metastasize to regional nodes or widely infiltrate adjacent tissues. Basal cell carcinomas, thin melanomas, and mixed tumors of the parotid gland are examples of such neoplasms. Some normal tissue surrounding the tumor should be excised to prevent local recurrence.

Radical Local Resection Neoplasms, such as soft tissue sarcomas and esophageal and gastric carcinomas, may spread widely by infiltration into adjacent tissues. In such cases it is necessary to remove a wide margin of normal tissue with the neoplasm. The greater the width of normal tissues between the plane of dissection and the tumor, the greater is the likelihood of a complete local excision.

If an incisional biopsy procedure was performed previously, a segment of skin and the underlying muscles, fat, and fascia must be removed far beyond the limits of the original incision because tumor cells may have been implanted in the incision during the initial operation.

Malignant neoplasms are not well encapsulated. A pseudocapsule composed of a compression zone of neoplastic cells may surround the tumor. This apparent encapsulation offers a great temptation for simple enucleation, because the tumor may be easily dislodged from its bed. The surgeon must cut through normal tissue at all times and should never disrupt the neoplasm during its removal. Dissection should proceed with meticulous care to avoid tumor cell spill. The surgeon should resect as far as possible from the gross extent of the tumor on all sides, including the deep aspect. Skin, subcutaneous fat, and some muscles may have to be sacrificed, but usually this causes little functional loss. Sacrifice of tumor-involved major vessels, nerves, joints, or bones may be necessary to obtain a curative result.

Radical Resection with En Bloc Excision of Lymphatics Since many neoplasms commonly metastasize by way of the lymphatics, operations have been designed to remove the primary neoplasm and the regional lymph nodes draining that area in continuity with all the intervening tissues. Conditions are best suited for this type of operation when the collecting nodes of the lymphatic channels draining the neoplasm lie adjacent to the primary site or when there is a single avenue of lymphatic drainage that can be removed without sacrificing vital structures. Modified radical mastectomy and radical total gastrectomy are examples of en bloc regional lymph node dissection. En bloc removal of the involved nodes offers the best chance for cure and provides significant palliation and local control.

Lymphadenectomy General principles common to lymph node dissection (LND) at various anatomic sites include the following: (1) The surgeon must thoroughly understand the anatomy of the lymph nodes in each area of the body as well as lymphatic drainage. (2) Goals of LND must be clearly defined as cure, control of local disease, or staging. (3) Incomplete LNDs generally are not acceptable, except when the goal of surgery is strictly palliative. (4) The incision providing access to regional lymph nodes should be placed to minimize the risk of dividing lymphatic vessels that contain malignant cells. (5) Closed-suction drains are important for evacuation of blood and serum and for minimizing the risk of seroma formation. The incidence of wound infection increases if drains are kept in longer than 10 days.

Elective Lymph Node Dissection Removal of regional lymph nodes without clinical evidence of metastasis is designated elective lymph node dissection. It is not clear whether cure rates are improved if lymph nodes are removed before they become palpable. Nonetheless, knowledge of tumor and regional lymph nodes affects staging, treatment, and prognosis. Breast and melanoma patients frequently have significant alterations in therapy depending on the status of regional lymph nodes. Furthermore, a comparison of experimental results from different institutions depends on accurate staging when therapy is initiated.

Selective Lymph Node Dissection Morton and colleagues recently described a promising technique for detection of the regional draining lymph nodes most likely to contain metastatic tumor cells spreading from a primary cutaneous melanoma. Their technique of intraoperative lymphatic mapping and selective sentinel LND is currently under investigation in a phase III multicenter trial for melanoma and is also being applied to breast carcinoma and other neoplasms. Initially, the technique relied on injection of a vital blue dye at the tumor site and visual tracking of this dye along the lymphatics to the nodal basin. Sentinel node mapping has been facilitated by adding a radiolabeled isotope to the dye and monitoring its path by a handheld gamma probe.

RADIATION THERAPY

Ionizing radiation is effective in the management of a wide variety of malignant tumors and is part of the treatment for 50–60 percent of patients with cancer. The radiation oncologist should be involved in the selection of patients and their evaluation before, during, and after treatment.

With radiation, tumors can be destroyed while anatomy is preserved. Often function and cosmesis can be preserved if the anatomy is intact before treatment. Concurrent medical problems have less influence on radiation therapy than on surgical or chemotherapy.

The differential effect of radiation therapy on tumors and normal tissues results in a favorable therapeutic ratio in most clinical situations. Radiation can, however, have immediate and delayed side effects on normal tissues. The incidence and severity of late sequelae, which may progress over many years, are highly dependent on treatment technique. The appearance of late sequelae may be the unfortunate consequence of treatment techniques long abandoned.

Physical Basis Ionizing radiations are characterized by their capacity to ionize atoms and molecules in an absorber such as tissue. Electromagnetic radiations can be produced artificially in kilovoltage radiation therapy units and linear accelerators by impinging energetic electrons on a target. The energy of the resulting x-rays is related to the energy of the accelerated electrons as they reach the target material. According to quantum physics, x-rays and gamma rays also can be represented as particles called photons. Other types of particulate radiations (e.g., protons, neutrons, pi mesons, and helium ions) are produced by very powerful linear accelerators, or cyclotrons, and have been used therapeutically, primarily in investigative settings. Because the basic physical mechanisms of action of all ionizing radiations are the same, the different effects observed with equal physical doses result from differences in spatial or temporal distributions.

Clinical specification of radiation doses is derived from direct measurements of absorbed doses within the patient (using thermoluminescent dosimeters) or from doses calculated within a tissue phantom that simulates the human being. Phantom measurements are adapted for precise clinical application through the use of computer programs. Recent technological advances have made it possible to correct for tissue inhomogeneities (air cavities and bone) within the treatment volume using computed tomography (CT)–based treatment planning. Doses of radiation are quantified in gray units (Gy), with 1 Gy = 100 rad = 1 joule per kilogram of the absorber and 1 cGy = 1 rad.

In some clinical situations, brachytherapy, or the direct placement of radioactive sources within tissue, may permit delivery of tumor doses higher than those achievable with external-beam radiation therapy. Because the dose delivered is inversely proportional to the square of the distance from the source, very high doses can be delivered to tissues immediately adjacent to the implant with relative sparing of surrounding normal tissues. High-dose-rate (HDR) remote afterloaded brachytherapy, a new delivery technique that is gaining greater clinical acceptance, involves the delivery of several grays in minutes. Low-dose-rate (LDR) brachytherapy may require several days of hospitalization, but HDR brachytherapy can be delivered in a fractionated manner as an outpatient procedure. In HDR remote afterloading, a high-activity source is driven to a predetermined series of positions for specified periods. Because of the small source size, smaller-diameter catheters can be applied to interstitial and intraluminal sites, such as the bronchus, esophagus, and bile duct, which previously could not be easily treated with LDR techniques. This computer-operated remote afterloading technique optimizes the dose distribution. These brachytherapy techniques have led the radiation oncologist into the operating room and into closer cooperation with the surgeon.

Biologic Basis Radiosensitivity is the susceptibility of cells to injury by ionizing radiation. This injury may cause reproductive cell death by interrupting the cell's capacity to replicate indefinitely. Radiation can kill cells by interfering with critical cell functions unassociated with cell replication. Differences in the rapidity and completeness of response of human tumors and normal tissues must be based on factors such as the capacity to repair sublethal damage, tissue oxygenation, cell cycle time and distribution, and repopulation.

Radiocurability is the ability of radiation to control a tumor permanently, allowing survival of the host. Tumor type, size, and site have a greater influence on radiocurability than cellular radiosensitivity. Radioresponsiveness, or the rapidity of a tumor's response to radiation, may not correlate well with radiocurability. Epidermoid carcinomas of the oral cavity and adenocarcinomas of the breast and prostate may be radiocurable despite relatively slow responses to radiation. Undifferentiated carcinomas tend to respond rapidly to radiation treatment but usually are not cured because of widespread tumor dissemination.

Normal tissues have a greater capacity to repair injury than do tumor cells. Fractionation, or the division of a radiation dose into multiple smaller doses, allows recovery of this damage between radiation fractions. Because of their greater repair capacity, slowly dividing normal tissues usually are spared more than tumor cells by the use of relatively small fraction sizes, but rapidly dividing stem cell populations, such as bone marrow and mucosal surfaces, have less capacity for repair. Clinicians have been investigating the use of altered, hyperfractionated schedules that use two or three small fractions per day in an effort to further decrease late normal tissue complications without increasing the overall duration of treatment.

Radiation-induced cell killing can be modified in other ways. Because molecular oxygen must be present for maximal cell killing by ionizing radiation, tumor cellular hypoxia can decrease the effectiveness of radiation therapy by as much as a factor of 3. This “oxygen effect” may explain the postirradiation persistence of tumor cells when there is necrosis or fibrosis.The intrinsic radiosensitivity of cells can be increased by altering the target DNA, such as by replacing thymidine with halogenated pyrimidine analogues during cell replication. Unfortunately, such methods are not selective for tumor cells and may not improve the therapeutic ratio.

Clinical Basis Irradiation may be the only anticipated treatment for some cancers or may be combined with surgery and/or chemotherapy for others. The intent of treatment may be curative or palliative. It is important that all such specialists are involved before initiation of therapy. Close cooperation from the beginning of therapy often can improve treatment outcome significantly. For example, careful marking of the margins of a tumor during surgery can help the radiation oncologist define a more accurate target volume and decrease the morbidity of therapy. Awkward placement of a surgical incision can dramatically increase the volume, complexity, and morbidity of subsequent irradiation. In some cases, the radiation oncologist can obtain valuable information by observing the operative field. The potential for local and regional tumor control with radiation is closely related to tumor size and the primary site. In most cases, radiation dose is limited by the tolerance of surrounding normal tissues. Surgical tumor debulking procedures that leave gross residual disease are sometimes necessary to relieve tumor-related symptoms; however, they may increase tumor hypoxia and decrease the tolerance of adjacent normal tissues.

The primary tumor site predicts biologic behavior and dictates which normal tissues will be affected by treatment. Small tumors of the glottic larynx, for example, rarely spread to regional lymph nodes, and more than 90 percent of these tumors are cured with moderate doses of radiation to a small local field. Large tumors of the cervix can be controlled locally with minimal risk of serious morbidity because of the high radiation tolerance of the uterus and vagina and the ability to deliver high doses with intracavitary therapy. By contrast, carcinomas of similar size in the upper abdomen are rarely controllable with radiation therapy alone because surrounding normal tissues such as liver, kidney, bowel, and spinal cord limit the deliverable doses of external-beam radiotherapy. Intraoperative radiotherapy (the delivery of external-beam radiotherapy directly to a tumor exposed during an operation) is currently being investigated as a possible means of increasing the radiation dose that can be delivered in such situations.

Combination Modalities Radiation therapy alone is curative in many clinical situations. Aggressive local or regional treatment yields high cure rates in many types of head and neck cancer, gynecologic malignancies, anal cancer, prostate cancer, Hodgkin's disease, and other neoplasms. In other cases, radiation is used in combination with surgery or chemotherapy. Radiation and surgery may be directed to the same site, e.g., when resection of a cancer of the hypopharynx is followed by irradiation or when irradiation of a soft tissue sarcoma in an extremity is followed by surgery. Combined modalities may decrease the morbidity associated with either modality alone. Local tumor excision plus radiation therapy is an alternative to mastectomy for breast cancer. Treatment of soft tissue sarcomas with wide local excision and preoperative or postoperative irradiation achieves local control rates comparable to amputation but with preservation of the limb.

Postoperative radiation improves local and regional control rates in most postoperative situations. Even when the survival benefit of postoperative radiation is uncertain, treatment may be indicated to prevent local recurrence.

Side Effects Any effective anticancer therapy can produce undesirable and occasionally dangerous side effects. Acute radiation-induced side effects can be distressing but usually can be managed conservatively and are almost always self-limited. The nature of these effects depends on the tissues included within the target volume. The clinically important late sequelae of radiation therapy may not be apparent until months or even years after completion of treatment. The risk of second malignancies induced by ionizing radiation is small. In studies of more than 2000 patients with head and neck cancer and 2000 patients with cancer of the breast, no increase in the incidence of second cancers could be demonstrated in patients treated with radiotherapy.

MANAGEMENT OF CANCER AT DISTANT SITES

General Principles of Treatment The treatment of a patient with advanced cancer depends on the number and sites of metastases, their rate of growth, types of and responses to previous treatment, and the patient's age, overall condition, and desires. For example, vigorous treatment might be appropriate for a slowly growing solitary metastasis, but only symptomatic treatment or none at all might be used in a debilitated patient with multiple metastases. The option of no treatment is particularly important in patients who are asymptomatic, terminally ill, or very old. Quality of life is maintained in this instance, and treatment can be instituted when the patient develops symptoms.

The number of organs or tissues containing metastases is the most significant factor predicting survival in patients with distant disease. For example, the median survival is 7 months for melanoma patients with metastasis to one site, 4 months for those with metastases to two sites, and only 2 months for those with metastatic disease at three or more sites. The locations of the metastases is also important.

Defining the Goals, Benefits, and Risks of Treatment The first goal of treatment is relief of symptoms. Treatment to relieve symptoms is worthwhile, especially when the benefit of symptom relief exceeds the risk of toxic effects and morbidity. Its efficacy can be monitored by subjective and objective assessments of the symptoms caused by the metastases.The second goal of treatment is to prolong life. This has not been achieved in most patients with metastatic cancer.

Surgery

In selected patients with slowly growing neoplasms, curative resection of metastatic lesions may be indicated, especially if the metastasis is solitary. Observation for several weeks or months sometimes provides relevant information about the rate of tumor growth and the possibility of metastases emerging at other sites. All patients considered for curative resection must undergo an extensive workup to rule out metastatic spread. Magnetic resonance imaging (MRI) of head, CT of the chest, abdomen, and pelvis, and a bone scan may be applicable. Newer whole-body imaging studies, such as positron emission tomographic (PET) scanning, eventually may replace conventional radiologic techniques.

Surgical procedures are sometimes indicated for palliative benefits, to relieve symptoms or reduce the severity of disease, or to prolong a comfortable life without attempting cure. A palliative operation that improves quality of life is justified when it can be done safely without great discomfort to the patient. Surgery that only prolongs a miserable existence does not benefit the patient. Some examples of palliative surgical procedures are colostomy and gastrojejunostomy to relieve obstruction, chordotomy to control pain, cystectomy for infected, bleeding tumors of the bladder, amputation for painful infected tumors in the extremities, and simple mastectomy for carcinoma of the breast, even in the presence of distant metastases.

Radiation Therapy

Irradiation has a role in the treatment of patients with advanced cancer, particularly those with symptomatic lesions. It is used as palliative treatment for patients with bone or brain metastases and for symptomatic lesions located in the skin, subcutaneous tissues, or lymph nodes. Radiation therapy using high-energy beams relieves the pain of bone metastases, often within 1 week.

Chemotherapy

Chemotherapy is the systemic or regional delivery of defusible pharmocologic agents that can destroy or arrest tumor cells capable of proliferation. Currently available drugs are not selected for tumor cells; they affect all dividing and some quiescent cells. Chemotherapy attempts maximal tumor cell kill with minimal and acceptable toxicity to normal host tissues. Cells and tissues with the highest growth fraction will be most affected.

Anticancer drugs may kill tumor cells, but the majority act by preventing cell division and cell proliferation. Most drugs affect one or more components of the cell cycle. DNA synthesis can be prevented by blocking the availability of purine and pyrimidine nucleotide precursors. DNA may be damaged by cross-linking with unstable alkyl groups. DNA transcription can be prevented by direct binding of drug to DNA. Mitosis can be arrested through binding of tubulin and prevention of mitotic spindle formation. Drug combinations often are based on the complementary effects of phase-specific agents on rapidly dividing cells and non-cell-cycle-specific agents on dividing and nondividing cells.

Alkylating Agents Alkylating agents are non-cell-cycle-specific drugs that contribute an unstable alkyl group to cross-link nucleic acids (primarily DNA). The major effect is on cells in G₁ or mitosis. Cyclophosphamide, cisplatin, dacarbazine, and ifosfamide are examples of clinically useful alkylating agents. Nitrosoureas are a subgroup of alkylating agents with increased lipid solubility and better CNS penetration.

Antimetabolites These agents interfere with DNA and RNA synthesis and are phase specific for the synthesis phase of the cell cycle. An exception is 5-fluorouracil, which is phase specific and cell cycle specific. These drugs are most active in rapidly proliferating tumors such as the hematologic malignancies but also have wide applicability in many solid tumors. Some antimetabolites bind to rate-limiting enzymes and the synthesis pathways. For example, leucovorin (folinic acid) potentiates the antitumor effect of 5-fluorouracil by stabilizing the covalent bond of 5-FdUMP to the enzyme thymidylate synthase.

Plant Alkaloids These agents inhibit mytosis by binding microtubules and causing arrest in metaphase. They include the derivatives of the periwinkle plant, e.g. vinblastine, vincristine, and vindesine. These alkaloids have antitumor activity against Hodgkin's and non-Hodgkin's lymphomas, acute leukemias, and a variety of solid tumors.

Antibiotics These drugs are isolated from mircoorganisms and appear to interfere with the synthesis and/or function of nucleic acids. Examples include doxorubicin, bleomycin, mitomycin C, and dactinomycin.

Dose and Timing To achieve maximal tumor cell kill, the highest tolerated dose is given over the shortest possible time. The dosage is based on the maximal tolerated dose (MTD) derived from clinical studies and must be tailored to a patient's performance status, medical illness, or organ dysfunction.

Drug dosing is most reliably calculated in terms of body surface area, milligrams per square meter (mg/m²). A dose in milligrams per kilogram can be converted to yield the milligrams per square meter dose by multiplying by a factor of 40.

The interval between doses depends on a drug's toxicity. For most chemotherapeutic agents with bone marrow toxicity, leukopenia and thrombocytopenia become evident on a complete blood count by day 9 or 10 and are most pronounced between days 14 and 18. Recovery usually begins by day 21 and is approximately 90 percent by day 28. This provides the rationale for a 28-day course or cycle of marrow-suppressive agents.

Induction chemotherapy is the use of chemotherapy as the sole form of treatment for advanced disease. These patients usually are not candidates for surgery or radiation. Adjuvant chemotherapy is the use of regional or systemic chemotherapy after locoregional tumor elimination by surgery or radiation therapy. Adjuvant therapy attempts to eliminate residual micrometastatic disease and usually is limited to patients at moderate to high risk for local or distant recurrence. Responses can only be evaluated by monitoring rates of recurrence, disease-free survival, and overall survival. Neoadjuvant or primary chemotherapy is the use of chemotherapy as the first treatment for localized solid tumors such as breast, gastrointestinal, and extremity sarcomas. It has several advantages. First, it may reduce the size of large or locally advanced tumors, allowing a safer resection that spares surrounding normal tissues, as in breast-conservation surgery, anal sphincter preservation with middle to low rectal tumors, and limb preservation with extremity sarcomas. Second, tumor responsiveness to chemotherapy can be determined while grossly or radiologically visible tumor is still present; agents that produce an initial complete or major partial response will be continued postoperatively. On the other hand, unsuccessful neoadjuvant chemotherapy can delay locoregional interventions, and tumor progression during this time may preclude safe resection or require sacrifice of additional normal surrounding structures to obtain adequate resection margins. Preoperative chemotherapy may confuse pathologic staging of resected tissues, complicating future treatment decisions and prognosis.

The clinical response to chemotherapy for visible, palpable, or radiologically measurable tumors is determined by the change in tumor mass. A partial response is generally 50 percent greater reduction in summed measurable tumor mass. Each tumor mass is measured as the product of the two greatest perpendicular diameters. A partial response is occasionally subdivided into minor responses (less than 50 percent size reduction) and major responses (more than 50 percent size reduction but less than a complete response). A complete response requires total disappearance of tumor on physical examination and radiologic studies for at least 4 weeks. A complete clinical response is likely to be followed by early relapse if chemotherapy is not continued long enough to eliminate any micrometastatic disease. Tumor progression is defined as a greater than 50 percent increase in summed measurable tumor mass. Stable disease indicates no change in tumor mass, size reduction less than a partial response, or any increase in size less than progression.

Side Effects and Toxicity Some degree of drug toxicity during the administration of chemotherapy is not only expected but often is desirable because it indicates a cellular damage response. The maximal tolerated dose of most chemotherapeutic agents is sought to achieve the highest tumor cell kill. Patterns of organ toxicity have been well described for the different classes of drugs. The degree of toxicity depends on drug concentration, duration of exposure, and host response. Anticipated drug toxicity is based on the nonspecific damage caused by most chemotherapeutic agents to rapidly proliferating normal tissues such as bone marrow.

Biologic Therapy

Biologic therapy is the administration of any biologic molecule or multimolecular complex and includes immunotherapy and gene therapy. Immunotherapy assumes that cancer progression results from failure of the host immune defenses to recognize and reject the tumor. Biologic agents augment the immune response with the goal of blunting tumor progression. Theoretically, the immune system may be activated or reactivated to attack and destroy tumor specifically, leaving normal tissue largely unaffected. Implicit in the ability of the immune system to recognize and attack neoplastic cells is the existence of immunogenic tumor-associated antigens. Evidence that human tumors are immunogenic comes primarily from investigations using melanoma, which is one of the most immunogenic solid tumors. Blood from melanoma patients contains antibodies against tumor antigens as well as cytotoxic T cells (CTLs) that can destroy tumor cells in vitro. Clinical studies indicate that approximately 3–15 percent of all cutaneous melanomas are first diagnosed as lymphatic or visceral metastases without evidence of a primary tumor, which suggests that the immune system has caused complete regression of the primary melanoma. T-lymphocytes play a critical role in the rejection of solid tumors in these models. In addition to the adoptive specific immunity afforded by T-lymphocytes, natural killer (NK) cells can lyse a wide variety of tumor and virus-infected cells without the antigen-specific receptors used by T or B cells. Rapidly emerging advances in the basic mechanisms of cell-mediated immunity provide new strategies for biologic therapy based on the prospect that the host immune system may be manipulated either in vivo or ex vivo to reject neoplastic outgrowth. Molecular biology and cell cloning enable investigation of a new level of the biology of host-tumor relationships and development of biologic agents to administer to cancer patients.

Recombinant Cytokines Several cytokines are currently in use for biotherapy of cancer. Trials using recombinant interferon-alpha (IFN-a) for metastatic melanoma show a major response rate of about 23 percent (range 14–28 percent). Interleukin-2 (IL-2), the T-cell growth factor, induces a major response, particularly in patients with metastatic melanoma and metastatic renal cell carcinoma, but not in patients with breast cancer, colon cancer, or lymphoma. The treatment of melanoma was significantly changed when Kirkwood and associates reported that high-dose IFN-a-2b significantly prolonged both relapse-free and overall survival rates after surgical resection of high-risk primary melanoma [American Joint Committee on Cancer (AJCC) Stage IIB] or regional lymph node metastases (AJCC Stage III). This important study was the first randomized, controlled trial to show a significant benefit of adjuvant therapy in prolonging relapse-free and overall survival of high-risk melanoma patients. On the basis of the results of the study, the Food and Drug Administration approved IFN-a-2b for postoperative adjuvant therapy in melanoma patients at high risk of systemic recurrence. The intravenous administration of the cytokines is not without significant toxicity, however, and it is clear that they trigger a cascade of effects that results in other lymphocyte activities as well as the direct effects of IL-2 on other tissues. Some of the side effects are similar to those seen with septic shock. Concern over the toxicity of intravenously administered cytokines has promoted the development of methods to target cytokines and reduce systemic effects. Cytokines are administered aggressively and frequently because of their short half-life in the blood. Combination biologic therapy is now in clinical trials for treatment of most major human cancers. The multiagent concept is plausible because (1) multiple immune abnormalities are most likely to occur in cancer patients, (2) there is heterogeneity in immune response (nature of lymphocytes, role of antibody, presence of macrophages) relative to the site of the metastases, and (3) combinations of agents with different mechanisms of action are more likely to augment individual aspects of immune response additively or synergistically in a diverse population of cancer patients. For example, combinations of IL-2 and IFN-a elicit a higher rate and more durable response time for metastatic melanoma than either cytokine alone. Combinations of tumor antigen, lymphokines, and cyclophosphamides are intended to activate tumor-specific immunity, promote effector T-cell proliferation, and downregulate suppressor T cells. Biochemotherapy uses cytokines such as IL-2 and IFN-a in combination with chemotherapeutic agents such as 5-fluorouracil with the goal of enhancing antitumor activity. Various biochemotherapeutic regimens are being examined in patients with metastatic colorectal cancer, lung cancer, renal cell carcinoma, and melanoma. Cytokines also have been used as supportive therapy to allow higher doses of chemotherapy. For example, granulocyte-macrophage colony-stimulating factor (GM-CSF) has been administered with erythropoietin to allow acceleration and dose escalation of chemotherapy with cyclophosphamide, epidoxorubicin, and 5-fluorouracil in patients with advanced breast cancer.

Immunotherapy Immunotherapy is a logical adjunct for the treatment of subclinical microscopic disease after definitive cancer surgery, radiation therapy, or chemotherapy for the following reasons: (1) patients who have only small foci of cancer cells remaining after destruction of the major tumor bulk are the most likely to benefit from immunotherapy because the tumor mass that must be destroyed is smallest at that time, (2) the specificity of the immune response provides a possible therapeutic tool that has selectivity for small numbers of cancer cells not possible with any other therapeutic modality, (3) patients with disease in earlier stages are more likely to respond to immunotherapeutic maneuvers because the cancer patient's general immune competence is greatest when the disease is localized and is often impaired after metastasis, and (4) immunotherapy should complement rather than interfere with currently available methods of cancer therapy. Because both irradiation and chemotherapy are immunosuppressive, the use of immunotherapy in combination with these therapeutic modalities must be controlled carefully.

Active Specific Immunotherapy (Cancer Vaccines) The clinical use of cancer vaccines was initiated at the turn of the century, prompted by the success of vaccines against infectious disease. Unlike vaccines against infectious disease, which are administered prophylactically, cancer vaccines are generally administered after the advent of disease. Both types of vaccine use attenuated whole cells, cell walls, specific antigens, or nonpathogenic strains of living organisms to stimulate the patient's immune system to fight the disease. The specific goals of active immunotherapy with cancer vaccines are to overcome the immunosuppression produced by tumor-derived factors, to stimulate specific immunity that will destroy tumor cells, and to enhance the immunogenicity of tumor-associated antigens (TAAs). Several observations support the potential value of active specific immunotherapy for the treatment of cancer. These include (1) vaccine-induced immunity against cancer in animal models, (2) the regression and eradication of tumors injected directly with immunostimulants, (3) occasional regression of noninjected tumors after the intralesional injection of bacille Calmette-Guérin (BCG), and (4) the development of antitumor antibodies.

Adoptive Immunotherapy In adoptive immunotherapy, immune lymphoid cells are transferred to a recipient to mediate tumor destruction. Rosenberg and colleagues pioneered the study of adoptive immunotherapy using lymphokine-activated killer (LAK) cells, which are cytolytic lymphocytes generated in the presence of IL-2. These cytolytic cells can kill a wide range of fresh and cultured human cancer cells but not normal cells. Clinical trials using autologous LAK cells and systemically administered IL-2 produced clear, objective responses in some patients with bulky metastatic cancer. Some evidence suggests that LAK cells may be more important in renal cell carcinoma than in melanoma. Subsequently, the method was developed for isolating tumor-infiltrating lymphocytes (TILs) from human melanoma and renal cell carcinoma; after proliferation ex vivo in the presence of IL-2, the TILs were returned to the patients and IL-2 therapy administered concurrently. In preliminary studies, response rates of up to 40 percent were obtained. TIL-based immunotherapy is an active area of research, and TILs also are being investigated in conjunction with gene therapy.

Nonspecific Immunotherapy Certain substances, such as mixed bacterial toxins and fractions of the tubercle bacillus, nonspecifically enhance host resistance to most viral, fungal, and bacterial agents. Although the exact mechanism is unknown, these agents appear to stimulate immune response to a wide variety of antigens, including tumor antigens. Interest in a nonspecific immunotherapy was revived more than 20 years ago using attenuated bovine tuberculosis bacillus (bacille Calmette-Guérin, BCG). Some tumor regressions were observed, but consistent responses in any one treatment group were difficult to achieve. Other nonspecific agents include Corynebacterium parvum, Bordetella pertussis, MTP-PE, methanol-extractable residue of BCG, bacterial endotoxins, and polynucleotides. Another form of nonspecific immunotherapy involves the use of agents capable of restoring depressed immune responses. Several agents have been proposed, including thymic hormones, such as thymosin, and the antihelmintic drug levamisole.

Passive Immunotherapy The systemic use of tumor-specific antiserum is laden with theoretical and practical problems. Passive immunotherapy is effective only in suppressing small numbers of tumor cells and must work in concert with host effectors (e.g., complement, macrophages, antigen-dependent cellular cytotoxicity) to effect a cytotoxic action on target cells. In addition, only antibodies of certain classes and subclasses can interact effectively with certain cellular effectors. Most of the better characterized human tumor-specific antisera are murine monoclonal antibodies that, because of their antigenicity, have limited applications in human beings. Immunotoxins are tumor-specific antibodies that are attached to toxic molecules. This concept uses the antibody molecule to preferentially localize anticancer agents in the vicinity of tumors. It obviates the need for the host to supply effector cells or complement to mediate tumor destruction. Monoclonal antibodies are preferred to heterologous antiserum because they permit the use of homogeneous purified antibodies of defined specificity. A wide range of toxic molecules has been tested in vitro and includes radioactive isotopes, traditional cancer drugs, and plant and bacterial toxins.

Gene Therapy Gene cloning has introduced a new era of biologic therapy that will have an impact on human clinical trials in the coming years. A novel approach is transfection of human TILs with genes for producing cytokines, such as tumor necrosis factor (TNF). The ability to transfect cytokine genes into human TILs suggests adaptive cellular therapy with genetically transfected cells capable of producing high concentrations of tumor necrosis factor or other lymphokines at the tumor site. This would deliver high concentrations of cytokine to the tumor site while sparing the vascular compartment of the otherwise deleterious effects of high-dose, systemic cytokine. Gene transfection also may be used to augment the immunogenicity of tumor vaccines. Other approaches to gene therapy of cancer are antisense oncogene and tumor suppressor gene therapy, which attempt to correct genetic disorders of cancer by suppressing the abnormal expression of proliferative genes.

Management of Distant Metastases at Specific Sites

Lung, Pleura, and Mediastinum Two of the most common initial sites of metastasis are the lungs and pleura. A standard chest x-ray is sufficiently sensitive and cost-effective for screening all cancer patients and frequently will reveal hilar and mediastinal adenopathy in those with pulmonary metastases. Although pulmonary tomograms or CT scans have too low a yield and too high a cost to be justified when the chest x-ray is normal, they are of value in evaluating suspicious chest lesions or in determining whether the metastatic disease seen on the chest x-ray is present elsewhere in the chest. CT scan can identify lesions as small as 3 mm, but it is not indicated unless the presence of pulmonary metastases would alter the treatment plan or unless a better definition of lesions is required for entry into a research protocol. Bronchoscopy with biopsy may be considered when the etiology of a pulmonary lesion is in doubt. A scalene lymph node biopsy is indicated for palpable nodes. Mediastinoscopy is indicated if the chest x-ray or CT scan reveals abnormal mediastinal nodes that are accessible through the instrument. Thoracentesis or pleural biopsies may be helpful when evaluating effusions. Fine-needle biopsy of a pulmonary lesion under CT scan guidance may be useful in selected instances to establish the histologic diagnosis. Video-assisted thoracoscopy is increasingly used both diagnostically and therapeutically in the staging and treatment of lung cancer. This technique permits visualization of the entire visceral, parietal, and mediastinal pleural surfaces and excisional or incisional biopsy for establishing diagnosis. If the diagnosis remains in doubt, an exploratory thoracotomy may be necessary, especially for a solitary lesion, because some patients will have potentially curable primary lung cancer. The treatment approach is determined by the location and number of thoracic metastases and by the patient's overall status. Criteria for resection include absence of metastases at other sites, control of the primary tumor, potential for complete resection, and a long tumor doubling time. CT scans should be obtained preoperatively because the number of lesions demonstrated by CT scanning is often greater than that shown by chest x-ray. Lung parenchyma should be conserved during resection. Most metastases occur just below the pleura, and a wedge of tissue removed by segmental resection suffices. Stapling, electrocautery, and laser surgery can be useful. Lobectomy and pneumonectomy usually are not indicated. Patients who are ineligible for surgery, such as those with multiple slowly growing tumors, might be monitored but receive no treatment while they are asymptomatic.

Tumor Doubling Time The growth rate of a tumor can be expressed by the time the tumor doubles in volume. The tumor doubling time (TDT) is an accurate and reproducible measure of biologic aggressiveness that can be used to determine the indications for surgical resection. TDT represents the balance between the intrinsic proliferative rate of the tumor cell and the patient's immune defense mechanisms. TDT measurement is especially useful in treating patients with pulmonary metastases because neoplasms tend to be peripherally located and discretely identified on chest radiographs. It is quite easy to obtain accurate serial chest x-rays that can be used to measure the changing diameters of the lesion. The greater and lesser diameters are averaged and then plotted against time on semilogarithmic paper. The slope of the line drawn between any two points represents the rate of tumor growth. The horizontal distance between any two doubling points represents the TDT in days. TDT may vary from 8–600 days, but most tumors double in 20–100 days. Patients with a short TDT have aggressive, fast-growing metastatic lesions; patients with a long TDT might have nonaggressive lesions that would be responsive to surgery. TDT is an important prognostic tool for selecting surgical candidates. Patients with pulmonary metastases can be divided into three survival groups according to TDT. Those patients with TDTs of less than 20 days are not recommended for surgery; it is likely to be ineffective and will not result in long-term survival. Patients with a TDT of 20–40 days are not ineligible for surgery, particularly if a slowing of TDT is observed after preoperative chemotherapy; their long-term survival rates are not much improved by surgery alone. Patients with a TDT of 40 days or more can have long-term survival after resection of the pulmonary lesion. Sarcoma patients with a TDT of more than 40 days were found to have significant palliation from pulmonary resection and remained free of disease for as long as 5 years; patients with a TDT of less than 20 days did not significantly benefit from resection of metastatic lesions.

Liver, Biliary Tract, and Spleen Hepatic metastases can occur in many patients with metastatic disease, especially those with gastrointestinal malignancies and breast cancer. There are no reliable and accurate tests for early detection of liver metastasis and no common symptoms and physical signs. The patient might experience decreased appetite with loss of weight followed within weeks by general lassitude and debility. A history and physical examination and serum liver chemistries with appropriate tumor markers are the most cost-effective screening tests. Elevated levels of lactate dehydrogenase or alkaline phosphatase in the presence of normal or only slightly elevated levels of serum glutamic-oxaloacetic transaminase or bilirubin suggest liver metastasis. Suspected liver metastasis should be confirmed by ultrasonography or dynamic CT scan. Radionuclide liver scanning and hepatic arteriography are used less frequently. Abdominal CT scans are more accurate and reliable than ultrasonography and radionuclide liver scans for evaluation of liver masses. PET scans also are increasingly useful in detecting metastatic disease. Hepatic metastases are not detected by radiologic tests until they are more than 1 cm in diameter. Angiography is used only when the differential diagnosis cannot be established by noninvasive techniques, when the information gained would affect the treatment decision, or when hepatic resection is contemplated. Biopsy usually is not necessary to confirm the diagnosis of liver metastasis. In the few instances in which biopsy confirmation is essential to treatment decisions, a needle biopsy can be performed percutaneously with CT or ultrasound guidance or by laparoscopy or during laparotomy. Some patients with isolated liver metastases from colorectal cancers can benefit from surgical resection. Those patients with a solitary metastasis or metastases located in one lobe are often treated successfully with resection, and approximately 25 percent will survive for 5 years. Most liver metastases are not amenable to surgical excision. Systemic chemotherapy or hepatic arterial chemotherapy is the most common intervention for patients with nonresectable hepatic metastasis, and response rates vary. Cryosurgery might offer effective palliative treatment for patients with nonresectable primary or metastatic hepatic malignancies; in certain cases, extended survival has been reported with the potential for cure. Other treatments include hepatic artery embolization, chemoembolization, radiation therapy, and alcohol injection.

Brain and Spinal Cord Many cancers, particularly breast cancer, lung cancer, and melanoma, metastasize to the brain, a common cause of death. Headache and mental deficits are the most common symptoms of brain metastasis. The most common physical sign of brain metastasis is a focal neurologic deficit; seizures are common. The best tests for diagnosing intracerebral metastasis are MRI and CT with contrast enhancement. MRI, a technique that depends on the intrinsic paramagnetic properties of biologic tissue, is generally the preferred test to detect and stage brain and spinal metastases. The accuracy and sensitivity of these scans make it unnecessary, in most cases, to perform a radionuclide brain scan or electroencephalogram unless there are some equivocal findings. The mainstay of initial treatment is corticosteroids, the most effective of which is dexamethasone (up to 100 mg/day). Dexamethasone reduces edema around the tumor and temporarily helps to relieve symptoms in the majority of patients. Chemotherapy is not usually effective for brain metastasis. Surgical excision followed by cranial irradiation is the treatment of choice for a solitary, surgically accessible metastasis. Tumor excision by means of a craniotomy is safe and may be considered in some patients who have disease at other sites plus symptomatic brain metastases because their estimated life span can exceed 3 months, and their neurologic status usually improves. Patients treated with open brain surgery and fractionated radiotherapy have a better outcome than those treated with radiation alone, but many patients do not have surgically accessible cerebral metastases. In these patients, stereotactic radiosurgery using the “gamma knife” may offer the best chance of prolonged survival.

Bone Bone metastases are common in patients with advanced breast or prostate cancer but infrequent in patients with gastrointestinal cancers. They are medullary in location and destructive in nature. The pain from bony metastases is typically nocturnal at first, becoming persistent, progressive, and localized, and it can become quite severe. Bone metastases are frequently diagnosed in symptomatic patients, but occasionally they are seen incidentally on radiographs (e.g., rib metastases on routine chest x-ray) or a bone scan prompted by an elevated serum alkaline phosphatase level in the absence of liver metastasis. They are generally osteolytic in appearance on radiography and provoke little if any bone formation, but some patients with prostate cancer have osteoblastic bone metastases. The radionuclide bone scan is the initial test for evaluating suspected bone metastases. Its sensitivity is reportedly 50–80 percent greater than radiographs alone, but bone scan abnormalities are nonspecific and must be correlated with radiographic study (e.g., x-ray or CT scan) and patient history (e.g., fractures, trauma, arthritis, etc.) to distinguish between benign and malignant causes. A bone biopsy might be necessary to establish the diagnosis before instituting treatment. The treatment of bone metastases depends on the degree of symptoms, the location and magnitude of the lesions, and the patient's life expectancy. The goals of therapy are to relieve pain and maximize ambulation. Symptomatic metastases frequently involve non-weight-bearing bones, particularly the spine and ribs. In these cases, irradiation of the lesions usually provides relief. The radiation fields should be restricted to those lesions responsible for the symptoms. Symptomatic bone lesions only occasionally respond to systemic chemotherapy, but bone metastases from breast cancer sometimes respond well to hormonal therapy. Symptomatic metastases in weight-bearing bones (e.g., the femur) require special consideration. If the lesion is large, and if there is evidence of cortical destruction, prophylactic stabilization and irradiation are sometimes used when the patient's life expectancy is at least 2 months. Alternatively, the lesion might be treated with radiation alone, but the patient must be closely monitored for evidence of pathologic fracture. Unless the surgical risk is high or the patient's expected life span is short, pathologic fracture of a weight-bearing bone should be stabilized. Patients with fractures of the vertebrae that have compressed the spinal cord require prompt treatment to avert paralysis. The treatment may require decompressive laminectomy and postoperative irradiation or irradiation alone depending on the extent of the disease and the patient's overall medical condition.

PSYCHOLOGICAL MANAGEMENT AND REHABILITATION

The physician can ease the cancer patient's fear of the disease by free and open communication. Psychological support and education are necessary for the patient to deal with any disability that can result from therapy. Examples include training in the care of a stoma following curative surgery for colonic and rectal cancer and referral to lay groups associated with the American Cancer Society for counseling the anxious patient with an altered body image resulting from mastectomy. It is impossible to predict the exact course of any malignant tumor. Patients with a poor prognosis are occasionally cured by aggressive therapy, and spontaneous regressions are sometimes observed in patients with metastases. In contrast, some patients with apparently localized disease can die of disseminated cancer in a few months. Uncertainty about the future is one of the most difficult adjustments that cancer patients and their families face. It is reassuring to emphasize that the chances for cure improve each month after successful treatment of the primary neoplasm, particularly for tumors such as squamous cell carcinoma of the lung or oropharynx. Other, more slowly growing neoplasms, such as carcinoma of the breast and malignant melanoma, can recur after disease-free intervals of 10–20 years, although the chances of recurrence also decrease with time. Recognition that cancer is a chronic disease is an important aspect of management. Long-term, consistent follow-up provides opportunities for reassurance and usually can ensure detection of recurrence at an early stage. Some patients suspect the worst but do not want to hear the truth from their physician. However, a lie is never appropriate, even if requested by the family. Untruths often create barriers between patients and their families that can lead to psychological isolation of patients, who are unable to discuss their fears and anxieties with those they need most. Gentle and optimistic truth is generally the best approach, even when primary cancer therapy has failed and the patient is judged incurable. Realistic and consistent support is actually more important to the patient and family at this stage of the disease than earlier. There is increasing evidence that patients tolerate the process of dying much better when sustained by the physician's continuing concern and active support. Some incurable patients are unable to accept the realities of the situation. In this case, it is essential that a responsible family member be informed. The duration of the incurable patient's life is so uncertain that predictions should be avoided. If, as frequently happens, the relatives insist on some estimate, a combined minimum-maximum prognosis, such as from 6 months to 2 years, will help the family accept this uncertainty. The basic aim in caring for the patient with advanced cancer is to prolong useful life, but not useless suffering. The patient should be permitted to die with dignity when active therapy can no longer be of benefit.

For a more detailed discussion, see Daly JM, Bertagnolli M, DeCosse JJ, and Morton DL: Oncology, chap. 9 in Principles of Surgery, 7th ed.

Books@Ovid

Copyright © 1998 McGraw-Hill

Seymour I. Schwartz

Principles of Surgery Companion Handbook