Chapter 44: Oncology

Over 1.6 million individuals in the United States are diagnosed with invasive cancer each year. Currently, 23% of all deaths in the United States are due to cancer, ranking second only to heart disease as the leading cause of mortality in this country. Over the past 10 years, however, cancer death rates have decreased. Death rates have continued to decline for the four top cancer sites (lung, colorectum, breast, and prostate). This reduction in overall cancer death rates translates to the avoidance of over 1 million deaths from cancer.

The surgeon is intimately involved in the care of cancer patients, since the majority will require surgical therapy at some time. Surgeons are often the first specialists to see newly diagnosed cancer patients or are often called upon to make the diagnosis in patients suspected to have cancer. As such, they will be responsible for orchestrating the patient’s care, including coordination with medical oncologists and radiation oncologists. It is imperative that they have an in-depth knowledge of the different types of cancer and the different modalities available for treatment.

Neoplasms are defined as benign or malignant according to the clinical behavior of the tumor. Benign tumors have lost normal growth regulation but tend to be surrounded by a capsule and do not invade surrounding tissues or metastasize.

Benign tumors are generally designated by adding the suffix -oma to the name of the cell of origin. Examples include lipoma and adenoma. The term cancer normally refers to malignant tumors, which can invade surrounding tissues or metastasize to distant sites in the host. The nomenclature of malignant tumors is typically based on the cell’s embryonal tissue origins. Malignant tumors derived from cells of mesenchymal origin are called sarcomas. These include cancers that derive from muscle, bone, tendon, fat, cartilage, lymphoid tissues, vessels, and connective tissue. Neoplasms of epithelial origin are called carcinomas. These may be further categorized according to the histologic appearance of the cells. Tumor cells that have glandular growth patterns are called adenocarcinomas, and those that resemble squamous epithelial cells are called squamous cell carcinomas. Cancers composed of undifferentiated cells that bear no resemblance to any tissues are designated as “poorly differentiated” or “undifferentiated” carcinomas.

Tumor Grade

Beyond the type of cancer, it is important to classify tumors by their behavior and prognosis in order to determine appropriate therapy as well as evaluate different treatment modalities. Grading of a tumor is a histologic determination and refers to the degree of cellular differentiation. Separate pathologic grading systems exist for each histologic type of cancer. Depending on the type of tumor, these systems are based on nuclear pleomorphism, cellularity, necrosis, cellular invasion, and the number of mitoses. Increasing grades generally denote increasing degrees of dedifferentiation. While the grade of the tumor typically has less prognostic value than its stage, tumor grade has great clinical significance in soft tissue sarcoma, astrocytoma, transitional cell cancers of the genitourinary tract, and Hodgkin and non-Hodgkin lymphoma.

Tumor Stage

Tumor staging establishes the extent of disease and has important prognostic and therapeutic implications in most types of cancer. Clinical staging is based on the results of a noninvasive evaluation, including physical examination and various imaging studies. Pathologic staging is based on findings in surgical tumor specimens and biopsies and allows for the evaluation of microscopic disease undetectable by imaging techniques. Pathologic staging may reveal more extensive tumor spread than the clinical evaluation and is the more reliable information. Clinicians must be careful when attempting to compare clinically and pathologically staged patients, as the two groups may have dramatically different outcomes.

As with grading, the staging systems vary with different tumor types. Two major staging systems are currently in use, one developed by the Union Internationale Contre le Cancer (UICC) and the other by the American Joint Committee on Cancer (AJCC). The UICC system is based on the TNM classification. T refers to the primary tumor and is based on the size of the tumor and invasion of surrounding structures. Tumors are characterized as T1 to T4 cancers, with the higher T stages for larger and more invasive tumors. N refers to regional lymph nodes, and classifications of N0 to N3 denote increasing degrees of lymph node involvement. Finally, M refers to distant metastatic disease, with M0 signifying no distant metastases and M1 and M2 indicating the presence of blood-borne metastatic disease. The AJCC system divides cancers into stages 0 to IV, with higher stages representing more widespread disease and a poorer prognosis. Regardless of the staging system or the tumor type, higher stages correlate with decreased survival.

Cancer Epidemiology

Cancer epidemiology is the study of the distribution of cancer and its determinants among defined populations and is used to examine cancer etiology as well as the efficacy of prevention, detection, and treatment strategies. The most basic types of epidemiologic terms describe cancer rates or cancer deaths for specific populations over a certain period of time.

While absolute numbers of cancer cases may be useful for health care planning, they do not take into account the size or nature of the underlying population at risk. For this reason, the most commonly used population-based measures of cancer are incidence and mortality. Cancer incidence rates are defined as the number of new cancer cases diagnosed during a fixed time period divided by the total population at risk. Cancer mortality rates are defined similarly, with cancer deaths replacing new cancer cases. These rates are typically expressed as the number of events per 100,000 individuals per year.

Incidence and mortality rates are compared across populations or over time to identify causes as well as the effect of screening or treatment. However, other factors among populations may contribute to observed differences, and these must be taken into account. For most cancers, age is the strongest risk factor, and so comparison of cancer incidence between two populations must consider the age distributions of the two groups. Adjustment (or standardization) is the most common method used to account for such differences. Comparing age-adjusted cancer incidence rates ensures that any observed differences are not the results of differences in age distributions between the two populations. Incidence and mortality rates are often also adjusted for gender, race, or socioeconomic status.

Cancer incidence examines only those diagnosed with the disease during that time period; it does not include patients diagnosed earlier who are living with cancer. Cancer prevalence describes the number of people with the disease either at a single point in time (point prevalence) or within a defined period of time (period prevalence). Prevalence is more relevant to the public health burden of cancer because all prevalent cases involve accessing health care. The relationship among incidence, prevalence, and mortality is influenced by the fatality of the disease. If the disease is highly fatal and the interval between presentation and death is short, mortality rates will be similar to incidence rates. The number of deaths from cancer divided by the total number people diagnosed with the cancer is known as the cancer fatality rate, although this is somewhat of a misnomer because they are not technically rates (they do not include time as a parameter).

Examining the fatality of cancer is obviously important when comparing treatments meant to improve outcome. Overall survival (OS) is the most global endpoint and is defined as the proportion of people alive at a specified period after being diagnosed with the disease. Five years is conventionally used as the time period (ie, 5-year survival). However, overall survival may not always reflect the success of treatment. Over that period of time, some patients may die of disease, but others may die of other causes. In addition, some patients may have a local or regional recurrence that is successfully treated, while some may recur with distant metastases but not succumb to them. For this reason, survival rates in cancer are often qualified by the patient’s disease status.

Disease-free survival refers to the proportion of patients alive and without disease over a specific period of time. A patient who developed metastases but is still alive would be included in the overall survival rate but not the disease-free survival rate. Disease-free survival and overall survival may provide different pictures of the success of treatment. A therapy that improves disease-free survival but not overall survival may still be important if quality of life is improved. In some cancers, local or regional recurrences can be readily treated with minimal impact on overall survival. In these cases, disease-free survival may present an overly pessimistic picture of outcome. Therefore, it may be more relevant to compare distant disease-free survival, which refers to the proportion of people alive and without distant metastases, regardless of local recurrence. In some cases, it is difficult to assess the efficacy of a treatment by looking at overall survival or disease-free survival if there are deaths from competing causes. It may be more helpful to compare disease-specific survival, which is the percentage of people who have survived a disease since diagnosis or treatment and does not count patients who died from other causes.

It is important for the surgeon to understand the different methods for describing cancer survival as well as the differences between the definitions, because the appropriateness of the comparison will vary with the biology of the disease and the clinical question being asked.

The surgeon is often the first specialist to see a patient with suspected or newly diagnosed cancer and in many cases assumes responsibility for orchestrating the overall management of the cancer patient’s care. The role of the surgeon involves not only the curative resection of the tumor but also obtaining tissue for diagnosis and staging, providing palliation for incurable patients, and preventing cancer by the prophylactic removal of organs. With improving imaging technologies, expanded use of neoadjuvant therapies, molecular staging, and increasing knowledge of the genetic predisposition to cancer, the role of the surgical oncologist is continuously evolving. It is therefore imperative for surgical oncologists to remain current on the newest approaches to cancer therapy and be prepared to adapt to the changing role of surgery.

Diagnosis & Staging

A tissue diagnosis is critical to the care of all cancer patients. Depending on the type of tumor and its location, the method of biopsy will vary. Common diagnostic techniques include needle aspiration biopsy, core needle biopsy, incisional biopsy, and excisional biopsy.

Fine-needle aspiration biopsy (FNAB) is a rapid and minimally invasive technique for the biopsy of palpable superficial tumors. Deeper, nonpalpable lesions may also be sampled by this technique when FNAB is combined with various imaging modalities, such as ultrasonography or computed tomography (CT). FNAB involves aspiration of cells from a suspicious mass, followed by cytologic examination of the stained smear. FNAB is particularly useful in the diagnosis of enlarged lymph nodes, breast lumps, thyroid masses, and lung nodules.

Advantages to FNAB include the simplicity of the procedure and the low rate of complications. However, there are limitations. FNAB cytology requires an experienced cytopathologist for accurate interpretation. Because cytology does not demonstrate architecture, it does not allow the cytopathologist to accurately grade tumors or to differentiate between in situ and invasive disease. If this information is necessary, FNAB may be inadequate. Sampling errors can lead to false-negative results, so a negative FNAB should be interpreted cautiously. In addition, though rare, false-positive results can occur, so confirmation may be needed before definitive surgical intervention. For example, a mastectomy should never be performed on the basis of an FNAB of a breast lump without confirming the diagnosis by either preoperative core biopsy or frozen section analysis at the time of surgery.

Core needle biopsy utilizes a needle that removes a sliver of tissue for analysis. This technique provides more histologic information than FNAB because it allows the pathologist to see the histologic architecture of the sample rather than just the cellular characteristics. False-positive results are extremely rare. Although less so than with FNAB, sampling errors may occur, and a negative result must be weighed against clinical judgment. Core biopsies are frequently used for prostate, breast, and liver masses. Again, ultrasound and radiographic imaging may enable the clinician to sample deep-seated or nonpalpable masses. The technique may also be used during surgery to biopsy suspicious masses encountered at operation.

When a larger tumor sample is necessary for accurate grading or staging, or a needle biopsy provided inadequate information, an incisional or excisional biopsy is required. Excisional biopsy is the surgical removal of an entire gross lesion, while incisional biopsy involves sampling a representative portion of a suspicious lesion. In general, excisional biopsy is recommended whenever it is possible to excise the entire lesion without damage to surrounding structures. Incisional biopsy should be considered whenever a core biopsy fails to make the diagnosis, but removing the tumor might compromise the subsequent operation (eg, a large [> 5 cm], deep soft tissue mass for which sarcoma is a possibility) or preclude delivery of neoadjuvant therapy.

Although biopsy techniques are usually simple, the surgeon must adhere to some specific principles when performing a biopsy for a suspected malignancy. The positioning of the needle tract or scar should be such that if further surgery is required, the biopsy site will be easily included in the excised specimen. Excisional biopsies of the breast should consider the possibility of a subsequent mastectomy, and the excision of skin or subcutaneous lesions on the extremities should be oriented in a way that allows for the following wide excision and lymphatic mapping if malignancy is discovered. Meticulous hemostasis is imperative, as the formation of a wound hematoma may make subsequent operation more difficult. The surgeon should carefully orient the pathologic specimen to allow the pathologist to evaluate margins in the context of the preresection anatomy, which may prove important in curative surgical procedures.

Once a diagnosis is made, the next step is typically to determine the extent of the cancer, or staging. This step begins with a complete history and physical examination, looking for signs or symptoms of advanced or metastatic disease. Laboratory or imaging studies may follow to determine not only the extent of the primary tumor but the presence of regional or distant metastases. Patients with signs or symptoms of metastatic disease should undergo appropriate workup of their symptoms. For some tumor types, routine staging examinations are indicated. However, for many asymptomatic patients newly diagnosed with cancer, a full battery of staging studies is not necessary and not only will increase the cost of treatment but may lead to false-positive findings, unnecessary biopsies, and inappropriate changes in therapy.

Surgeons are often called upon to perform operations that provide staging information for various types of cancer. Such procedures are necessary when the clinical extent of the disease has a direct bearing on the choice of treatment modalities. Examples include laparoscopy for gastric or pancreatic cancer, a staging laparotomy for ovarian cancer, or mediastinoscopy for lung and esophageal cancer. Staging procedures can often help to avert highly morbid procedures in cases where there is little chance for cure.

Curative Surgery

Surgical resections with curative intent can be divided into three categories: resection of a primary lesion, resection of isolated metastases, and resection of metastatic deposits. In each case, the clinician must strive to reach a balance between the chance for cure and the morbidity of the procedure. Each situation must be evaluated individually, and the patient’s wishes must be paramount.

The guiding principle of cancer surgery is to remove the entire tumor with adequate margins so as to prevent local recurrence and potentially distant recurrence. What constitutes an adequate margin varies among tumor types. Various tumors require different disease-free margins in order to achieve optimal chances for a cure. For a tumor that appears adherent or fixed to adjacent structures, en bloc resection is mandatory, and any attachment should be considered malignant in nature. Appropriate preoperative imaging of the tumor is often necessary to be prepared in the operating room for the possible resection of small or large bowel, bladder, or other adjacent organs.

It is important that the surgeon have knowledge of other modalities that may be integrated into the management plan to allow for a less extensive surgical procedure. Radiation and chemotherapy are commonly used in combination with surgery and are referred to as adjuvant therapies if used after complete resection with no demonstrable local or systemic disease. While their use has in some cases diminished the extent of resection necessary for local control (breast, sarcoma, head, and neck), it is important to note that these modalities do not compensate for inadequate margins in controlling local disease. Every attempt should be made to achieve widely negative margins surgically, even if it requires a second operation, rather than assuming radiation will “clean up” residual disease.

If these modalities are used in the preoperative setting, they are called neoadjuvant therapies. In many cases, neoadjuvant therapy has dramatically improved outcomes, as with pediatric rhabdomyosarcoma or locally advanced or inflammatory breast cancer. In some cases, neoadjuvant therapy can convert an unresectable tumor to resectable, while in other cases, it can decrease the extent of surgery necessary to obtain control or decrease the likelihood of positive margins. Neoadjuvant therapy is commonly used in the treatment of esophageal cancer, rectal cancer, pancreatic cancer, breast cancer, and sarcoma. It is important the surgeon consider the possibility of neoadjuvant therapy when performing a biopsy, staging the patient, or planning surgery.

The regional lymph nodes represent the most prevalent site of metastases for solid tumors, and in most cases involvement of the regional nodes represents the most important prognostic factor. Removal of the regional lymph nodes not only provides important prognostic information that may help guide adjuvant therapy, but provides regional control, preventing regional recurrence and the associated complications. For this reason, the removal of the regional lymph nodes is often performed at the time of resection of the primary cancer. More controversial is whether the removal of regional lymph nodes can improve survival. These controversies concern both the extent and the timing of the procedure. For example, the extent of lymphadenectomy at the time of gastrectomy for stomach cancer has been hypothesized to have an impact on improving overall survival. This has not, however, been borne out in prospective randomized trials. It may be that extended lymphadenectomy results in more accurate staging of patients at a cost of increased morbidity and minimal effect, if any, on overall survival. The relative benefit of nodal dissection may also vary with the efficacy of adjuvant therapies, such as chemotherapy or radiation therapy. How extensive a lymph node dissection to perform at the time of definitive resection varies with tumor type and in many cases remains controversial.

For many nonvisceral solid tumors, such as melanoma or breast cancer, elective node dissections were performed in clinically node negative patients at the time of their primary tumor resection. Unfortunately, this exposed many node-negative patients to the morbidity of a node dissection, and a clear survival benefit could not be demonstrated in prospective randomized studies. This practice has been replaced with lymphatic mapping and sentinel lymph node biopsy. Mapping agents (a radioactive tracer or a blue dye) are injected around the site of the tumor prior to surgery. These travel to the lymph nodes that first receive drainage from the site of the primary, and thus are the most likely to harbor cancer. Only the sentinel nodes (those nodes that are blue or radioactive) are removed, and carefully examined for micrometastases. This has dramatically improved our ability to stage the regional lymph nodes, helping to guide adjuvant therapies, while minimizing morbidity. Classically, node negative patients could safely avoid further surgery, while node positive patients underwent a completion lymph node dissection. This approach has also changed recently. In breast cancer, the American College of Surgeons Oncology Group (ACoSOG) Z0011 trial, demonstrated that a subset of breast cancer patients with positive sentinel lymph nodes did not benefit from completion lymph node dissection. A similar trial, the Multicenter Selective Lymphadenectomy Trial II (MSLT-II), is examining a similar question among sentinel lymph node positive melanoma patients.

The surgeon plays a much more limited role when the patient has metastatic disease; nonetheless, the resection of “isolated” metastases in patients with solid malignancies is sometimes a consideration when technically feasible. The selection of candidate patients for surgical resection requires a thorough evaluation of the extent of known disease, likelihood of additional metastatic disease, length of time between the primary and the distant recurrence (disease-free interval), medical status of the patient, and feasibility of resecting the metastatic site with a negative margin. Ultimately, this process identifies a small subset of patients who would be surgical candidates. Although there are no prospective randomized trials documenting the survival benefit of surgical resection of metastatic disease, there is considerable retrospective evidence indicating that this approach can result in long-term benefit. The resection of lung metastases in patients with osteogenic or soft tissue sarcomas has been associated with an approximately 20%-25% overall survival rate greater than 5 years. There is also a large body of retrospective evidence documenting the benefit of resecting colorectal metastases to the liver, resulting in a 25%-40% overall 5-year survival rate, depending on the extent of liver involvement. A similar benefit has been demonstrated in an aggressive surgical approach to metastatic melanoma. Another question in stage IV disease is when to resect the primary tumor. Typically, resection of the primary cancer when the patient already has metastatic disease was only done for palliation, or to prevent future complications. This approach is changing, however. For some cancers, such as colon cancer, resection of the primary tumor in the face of metastatic disease to prevent obstruction or bleeding, is less necessary due to the improved efficacy of systemic agents. Conversely, in some cancers, such as renal cell carcinoma and possibly breast cancer, there is evidence that resection of the primary tumor improves may improve outcome in stage IV patients. One of the roles of the surgical oncologist is to know when it is appropriate to offer this option.

Palliation

Surgical intervention is sometimes required in the patient with unresectable advanced cancer for palliative indications such as pain, bleeding, obstruction, malnutrition, or infection. The decision to operate must balance several factors, including the likelihood of adding significantly to the quality of life of the patient, the expected survival of the individual, the potential morbidity of the procedure, and whether there are alternative methods of palliation.

Malnutrition is a common problem in the cancer patient, especially one with advanced, unresectable disease. Commonly, the surgeon is involved in placement of vascular access for hyperalimentation, or if the gastrointestinal tract is functional, the placement of gastrostomy or jejunostomy tubes for enteral nutrition. Occasionally, the surgeon is involved in palliating pain due to a metastatic lesion compressing upon an organ or adjacent nerves. Examples include cutaneous or subcutaneous melanoma metastases, a large ulcerating breast cancer, or a recurrent intra-abdominal sarcoma mass. The surgeon must assess the relative risk-to-benefit ratio in resecting a symptomatic mass knowing that it will not impact the overall survival of the patient. If the quality of life of the individual can be improved at an acceptable operative risk, then the surgical intervention is warranted.

Finally, the surgeon may be called upon to manage oncologic emergencies. Acute hemorrhage and obstruction of a hollow viscus represent the most common potential oncologic emergencies. In these cases, surgeons may have to emergently intervene in the care of a cancer patient, or in some instances, use nonsurgical approaches (such as stents or angiography).

Prophylaxis

With our improved understanding of inherited genetic mutations and the identification of patients who are predisposed to cancer, surgical therapy has expanded beyond the therapy of established tumors and into the prevention of cancer. Prophylaxis is not a new concept in surgical oncology. Patients with chronic inflammatory diseases are known to be at high risk of subsequent malignant transformation. This typically prompts close surveillance and surgical resection at the first identification of premalignant changes. One of the earliest examples of this is the recommendation for total proctocolectomy for subsets of patients with chronic ulcerative colitis.

The ability to perform genetic screening for relevant mutations has allowed for prophylactic surgery to be implemented prior to the onset of symptoms or histologic changes. Familial adenomatous polyposis (FAP) syndrome, defined by the diffuse involvement of the colon and rectum with adenomatous polyps, almost always predisposes to colorectal cancer if the large intestine is left in place. With the identification of the gene responsible for FAP, the adenomatous polyposis coli (APC) gene, members of families in which an APC mutation has been identified can have genetic testing prior to polyps becoming evident and be considered for prophylactic proctocolectomy. Medullary thyroid cancer (MTC) is a well-established component of multiple endocrine neoplasia syndrome type 2A (MEN2A) or type 2B (MEN2B). Mutations in the RET protooncogene are present in almost all cases of MEN2A and 2B. Family members of MEN patients can be screened for the presence of a RET mutation, and those with the mutation should undergo total thyroidectomy at a young age (6 years for MEN2A, infancy for MEN2B). The role of prophylactic mastectomies has been greatly expanded with the identification of BRCA1 and BRCA2, which can be associated with a lifetime probability of breast cancer of between 40% and 85%. Other prophylactic operations are listed in Table 44–1. However, potential benefits of prophylactic surgeries must be weighed against quality-of-life issues and the morbidity of the surgery. A detailed discussion must be held with each patient considering prophylactic surgery regarding the risks and benefits, so today’s surgical oncologist needs a clear understanding of genetics and inherited risk.

The goal of chemotherapeutic regimens is to deliver pharmacologic agents systemically to eradicate all tumor cells. The ideal tumor drug would kill cancer cells without harming normal tissues. No such agent exists, and most drugs affect normal cells to some extent. The success of chemotherapy relies on the normal cell’s greater capacity for repair and survival relative to tumor cells.

Even a single cancer cell can potentially reproduce to form a lethal tumor. For this reason, the goal of curative chemotherapy must be the complete eradication of all tumor cells. Tumor burden is important in chemotherapy. A large cancer may harbor more than 10⁹ tumor cells. If a tolerable dose of an effective drug killed 99.99% of these cells, the tumor burden would still be 10⁵ cells. The remaining cells, while clinically undetectable, are likely to continue to grow and lead to a clinical recurrence of cancer. For this reason, most chemotherapy protocols rely on repeated administrations of drugs in order to achieve maximal cell killing. Tumor cells may avoid the cell-killing effects of a particular drug because of their stage in the cell cycle, residence in an area protected from the drug (central nervous system), or an inherent resistance to the drug.

Drug resistance plays a large role in chemotherapy failures. Several mechanisms of tumor resistance are known. The multidrug resistance (MDR) gene encodes a protein that actively pumps drugs out of tumor cells. This gene confers resistance on a variety of antitumor drugs, including the antibiotics and plant-derived compounds. Other tumor mechanisms of resistance include the alteration of target enzymes, increased production of a target enzyme to overwhelm the drug, and an increased capability for DNA repair. Tumor resistance to a given chemotherapeutic agent can often be overcome by the administration of multiple drugs.

Principles of Chemotherapy Use

A. Curative Chemotherapy

Hematologic malignancies are typically treated by chemotherapy, radiation, or both, with surgery used primarily for diagnosis and staging. On the other hand, surgery is the primary treatment for nonhematologic malignancies, although there are some exceptions. Anal cancer is cured in approximately 80% of patients with the Nigro protocol—5-FU/mitomycin-C and radiation therapy—as first-line treatment. Testicular cancer, even when metastatic, is curable with bleomycin/etoposide/cisplatin in approximately 85% of patients.

B. Adjuvant Treatment

Although all visible tumor may be removed at the time of surgery, microscopic tumor deposits may still be present locally or may have spread to distant locations. Chemotherapy is most effective against very small tumors and microscopic tumor deposits. Therefore, adjuvant chemotherapy is often given to improve the likelihood of cure after surgical resection.

The benefit gained from adjuvant chemotherapy can be thought of in terms of absolute benefit or relative benefit (Figure 44–1). For example, after colectomy for stage III colon cancer, the chance of cure is approximately 50%. This can be increased to approximately 70% by adjuvant 5-FU/leucovorin. This represents a 40% relative benefit (40% more patients are cured with chemotherapy than without chemotherapy) but a 20% absolute benefit (20% of the patients who take the chemotherapy will have altered their outcome). Another way to look at this is that with a 20% absolute benefit, 80% of patients experience the inconvenience and side effects of chemotherapy without gaining any improvement themselves. The decision to receive adjuvant chemotherapy is a balance between the expected benefit of treatment, the patient’s comorbid conditions and general health, and the patient’s wishes.

C. Neoadjuvant Treatment

Neoadjuvant chemotherapy is usually given to facilitate surgical resection by shrinking the primary tumor, or it may convert an unresectable tumor into a resectable tumor. In some cases, this treatment has been shown to prolong survival. Another advantage to neoadjuvant chemotherapy is that it allows the oncologist to observe the primary tumor to determine if it is sensitive to a particular chemotherapeutic regimen. During the course of cancer treatment, it is important to define the progress and outcomes resulting from therapy. The terms complete and partial response are often used as endpoints to evaluate the efficacy of a particular therapeutic regimen. A complete response is defined as the absence of demonstrable cancer. A partial response refers to a reduction of tumor mass by greater than 50%. The patient’s response to neoadjuvant chemotherapy can be an important predictor of outcome.

D. Chemotherapy for Metastatic Disease

The majority of patients who are receiving chemotherapy have metastatic disease that is not curable. For these patients, treatment with chemotherapy is intended to prolong survival, improve quality of life, or both. Response rates range from 20% to 75% depending on the tumor type and chemotherapy regimen. However, even a complete remission is rarely durable. Most partial or complete remissions last only months.

As with all therapies, the decision to use chemotherapy must balance the potential benefits with the risks, toxicities, and the patient’s general health and condition. There is little to be gained by treating an asymptomatic patient if no prolongation of survival is expected. A detailed discussion must be held with each individual patient; some patients are more willing than others to tolerate the side effects of chemotherapy. Since the disease is not curable, treatment with single agents, which are less toxic than combination chemotherapy, are often considered, with more willingness to reduce doses for toxicity.

Classes of Chemotherapeutic Agents

With all forms of curative chemotherapy, the goal is elimination of all tumor stem cells. Cells that are incapable of further division cannot cause progression of a tumor, and the sterilization of a tumor cell is as good as a kill. Chemotherapeutic drugs are generally classified as cell cycle-specific (CCS) drugs, which are toxic to actively proliferating cells, or cell cycle-nonspecific (CCNS) drugs, which are capable of killing cells that are not dividing during drug exposure. These two classifications are not absolute, and many drugs may overlap between the two categories.

In order to achieve maximal cell killing, most therapeutic protocols use combination chemotherapy. Agents with differing mechanisms of action and different toxic side effects are used, allowing for relatively high doses of multiple agents. This method of combining agents helps to combat tumor cell resistance and increase the tumor cell killing while avoiding the compounding of toxic effects.

A. Alkylating Agents

These agents exert their effects by the transfer of alkyl groups to various cellular components, most importantly by the alkylation of DNA. Alkylators can cause DNA strand breaks, cross-linking of DNA strands, or miscoding of DNA during replication. The alkylating agents are considered cell cycle–nonspecific agents but tend to have their greatest effect on proliferating cells. Normal cells are able to avoid many of the lethal affects of alkylating agents because of their ability to repair DNA. The alkylating agents are effective in treatment of the hematologic malignancies and in a variety of solid tumors such as breast, melanoma, lung, and endometrial cancers. Included in this class are the nitrosoureas (eg, carmustine, semustine, lomustine), cyclophosphamide, chlorambucil, mechlorethamine, dacarbazine, and procarbazine.

B. Platinum Analogues

The platinum analogs are similar to the alkylating agents. They bind DNA to form interstrand and intrastrand cross-links, leading to inhibition of DNA synthesis and transcription. The mechanisms of cancer cell resistance are also similar to those of alkylating agents: decreased cellular uptake of the drugs, increased activity of DNA repair enzymes, and increased thiol-containing proteins. In addition, resistance to both cisplatin and carboplatin has been associated with a deficiency of mismatch repair (MMR) genes. It is not known why this mechanism of resistance appears to be specific to cisplatin and carboplatin, but the efficacy of the newest platinum analog, oxaliplatin, is not affected by MMR gene deficiency.

C. Antimetabolites

Rapidly dividing cells require increased synthesis of nucleic acid precursors. This increased synthesis can be exploited pharmacologically by the antimetabolites. These drugs are analogs of nucleic acids or nucleic acid precursors. The antimetabolites may be incorporated into the nucleic acids of a cell and serve as a false messenger. Antimetabolites can shut down the cellular synthetic machinery by binding to and inhibiting enzymes important in the production of nucleic acids. Since this class of drugs affects all rapidly proliferating cells, they are relatively toxic to normal tissues that have a high rate of cell turnover. Antimetabolites are most effective in the hematologic malignancies but are also used in the treatment of solid tumors such as breast and gastrointestinal cancers. They include methotrexate, mercaptopurine, thioguanine, fluorouracil, and cytarabine.

D. Antimicrotubule Agents

A variety of antitumor drugs are derived from natural plants (and are also known as plant alkaloids). Vincristine, vinblastine, docetaxel, and paclitaxel work by binding tubulin and poisoning the assembly of microtubules in the mitotic spindle. This leads to mitotic arrest in metaphase, and these compounds are effective only on rapidly dividing cell populations. The plant alkaloids are most useful for hematologic malignancies and breast, renal, testicular, and head and neck cancers.

E. Topoisomerase Inhibitors

These plant derivatives exert their antitumor effects by binding to and inhibiting various forms of the enzyme topoisomerase. Topoisomerases are responsible for the maintenance of DNA structure and are also important in the cleavage and religation of DNA strands. Inhibition of these enzymes leads to DNA strand breakage and structural damage. The topoisomerase inhibitors are also cell cycle–specific agents and have their greatest activity against rapidly proliferating cells. Examples include etoposide, teniposide, and topotecan. These drugs are used in the treatment of hematologic malignancies and lung, bladder, prostate, and testicular cancers.

F. Antibiotics

Most of the drugs in this class are derived from the soil fungus Streptomyces. All the antibiotics exert their antitumor effects by interference with the synthesis of nucleic acids. Most of the drugs in this class intercalate in DNA, blocking DNA synthesis and inducing strand breakages. The antibiotics are considered cell cycle–nonspecific, and they have antitumor activity against a wide variety of solid tumors. Included in this class of drugs are doxorubicin, dactinomycin, plicamycin, mitomycin, and bleomycin.

Side Effects of Chemotherapy

Most side effects from chemotherapeutic regimens are the result of toxicities to rapidly dividing normal cell populations—particularly bone marrow and epithelial cells. Bone marrow suppression is an adverse effect of many of these drugs, resulting in neutropenia, thrombocytopenia, and even anemia. Mucosal ulcerations and alopecia also occur in patients treated with cell cycle–specific agents. Intractable nausea and vomiting is another common side effect that can severely affect quality of life. Testicular or ovarian failure can result from chemotherapy, leading to sterility. Many of these drugs also are powerful teratogens and should be avoided in pregnant patients. Finally, many of the alkylating agents have been implicated in the development of secondary cancers, especially hematologic malignancies.

Systemic chemotherapy is limited by toxicity to the host. Regional delivery of chemotherapeutic agents via arterial cannulation allows for high levels of drugs in the region of the primary tumor while decreasing systemic toxicity.

Isolated limb perfusion (ILP) is a technique for the delivery of chemotherapeutic agents to an extremity with locally advanced cancer and is of benefit primarily in the treatment of extremity melanoma and sarcoma. In this approach, a tourniquet is applied to the extremity to occlude venous outflow. The major artery perfusing the limb is then isolated, cannulated, and perfused with hyperthermic chemotherapeutic agents using a pump oxygenator as for cardiopulmonary bypass. The perfusion is done in the operating room and lasts for approximately 1 hour. The cannula is then removed. Most protocols involve only a single treatment. Melphalan, an alkylating agent, is the most common agent used today in the treatment of both sarcomas and melanomas. In patients with extensive in-transit melanoma confined to an extremity, isolated limb perfusion can provide regional control and palliation. In patients with unresectable extremity sarcomas, preoperative limb perfusion may shrink the tumor and allow for a limb-sparing resection. While improving regional control, this therapy has yet to show a definitive survival benefit. An alternate approach is isolated limb infusion (ILI), which involves using minimally invasive techniques to access the vessels along with a tourniquet to minimize systemic uptake.

Another approach is isolated hepatic artery infusion for the treatment of colorectal cancer metastatic to the liver. Metastatic tumors derive nearly all of their blood supply from the hepatic artery, while the normal liver parenchyma derives more than two-thirds of its blood supply from the portal system. This permits the delivery of higher doses of chemotherapeutic agents to the tumor relative to the normal hepatocytes. The drug most commonly used in this protocol is floxuridine, which is almost completely extracted on its first pass through the liver, resulting in relatively low systemic toxicity. Hepatic artery infusion requires the surgical placement of a catheter into the hepatic artery, which is connected to an implanted or external infusion pump for continuous treatment. Hepatic artery infusion has been used for unresectable colorectal metastases as well as an adjuvant to hepatic resection. While there are clearly improved tumor responses in comparison to systemic therapy, the data is less clear on overall survival benefits. Some studies, however, have suggested an improved survival and have stimulated further investigation.

An expanding knowledge of molecular biology is revolutionizing the field of oncology, truly personalizing care for each individual patient with cancer. Molecular diagnostics is increasingly allowing us to customize the selection and dosing of traditional agents to maximize benefit and minimize toxicity. Molecular oncology is changing the way we approach drug discovery and development, leading to the development of targeted therapies. One definition of targeted therapy is any drug in which there is a specific diagnostic test that must be performed before the patient can be considered eligible to receive the drug. An example is measuring Her-2/neu overexpression on breast cancer to determine if a patient is eligible for trastuzumab (Herceptin). A more oncologic definition is any drug with a focused mechanism that specifically acts on a well-defined target or biologic pathway. Inactivation of this target/pathway results in regression or destruction of the malignant cell. Targeted therapies are often considered “magic bullets.”

Several targeted therapies have been FDA approved and are in clinical use; many others are being developed. The ideal target is one that is expressed (and can be measured) on cancer cells but not significantly expressed in vital organs and tissues. It is preferably crucial to the malignant phenotype, and its inhibition results in a clinical response in patients whose tumor expresses the target. Several methods for very specific targeting are being examined. The ability of therapeutic antibodies to bind with high affinity makes them excellent candidates for targeted therapy. While antibodies may induce an immune-mediated destruction of cancer cells (and be considered immunotherapy [see section on Immunotherapy]), they can also be used to target specific cell surface receptors to interrupt that pathway. For this latter function, it is important that the target, when bound by the antibody, is internalized by endocytosis to facilitate the intracellular mechanism of pathway inhibition and cell death.

Trastuzumab is an IgG antibody that binds to the juxtamembrane portion of the extracellular domain of the Her-2/neu receptor and has become an important option for patients with Her-2/neu–positive breast cancer. Her-2/neu is an epidermal growth factor receptor (EGFR) that has a functional intracellular tyrosine kinase and when overexpressed can lead to increased proliferation, increased metastatic potential, and resistance to therapeutic agents. While the binding of trastuzumab to the Her-2/neu protein may lead to antibody-dependent cell-mediated cytotoxicity, the more important function appears to be the disruption of the downstream signaling through the intracellular tyrosine kinase.

Another way to target cancer cells is through the use of small molecules. The development of imatinib mesylate is the classic example of a small-molecule targeted therapy. Imatinib is an adenosine triphosphate-binding selective inhibitor of bcr-abl, and its use has been associated with durable, complete responses in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia as well as the treatment of gastrointestinal stromal tumors. The latter characteristically express an activating mutation in the c-kit receptor tyrosine kinase (RTK) gene.

Perhaps the most noteworthy example of the impact of targeted therapies is in the treatment of melanoma. It was discovered that 40%-60% of melanoma patients harbor a specific mutation in the BRAF gene, and 90% of these mutations involve a substitution of glutamic acid for valine at amino acid 600 (the V600E mutation). This gene codes for the protein kinase BRAF, a component of the mitogen-activated protein (MAPT) kinase pathway. Vemurafenib (Zelboraf) selectively inhibits the kinase activity of this mutated BRAF. Vemurafenib is FDA approved for the treatment of unresectable or metastatic melanoma that tests positive for the BRAF V600E mutation based on prospective randomized studies that demonstrated a dramatic improvement in progression free and overall survival. Dabrafenib also specifically targets the BRAF V600E mutation and has very promising clinical trial data. Another promising drug for melanoma patients with the BRAF mutation is trametinib, which blocks MEK, an alternate protein in the MAP kinase pathway.

Multiple other targeted therapies, both monoclonal antibodies and small molecule inhibitors, are in clinical use. Cetuximab (Erbitux) binds to the EGFR with high affinity, blocking the subsequent signal transduction events leading to cell proliferation. It enhances the antitumor effects of chemotherapy by inhibiting cell proliferation and angiogenesis and promoting apoptosis. Cetuximab has been approved for use in combination with CPT-11 for the treatment of advanced colorectal cancer. Bevacizumab (Avastin) targets the vascular endothelial growth factor (VEGF), which regulates vascular proliferation and permeability and promotes angiogenesis. Other targeted therapies in use in cancer are listed in Table 44–2.

Hormones are normally involved in the differentiation, stimulation, and control of certain tissues, including but not limited to lymphoid tissue, the uterus, the prostate, and the mammary glands. Tumors arising from these tissues may also be stimulated or inhibited by hormones, and so manipulation of the hormonal balance can be beneficial in the systemic therapy of these cancers. In some cases, hormones themselves are used as cancer therapies. For example, the administration of estrogen to a man ultimately suppresses the production of testosterone, which is a useful effect in the treatment of prostate cancer. Corticosteroids, particularly the glucocorticoids, have a powerful suppressive effect on lymphoid cells, making them useful in the treatment of acute leukemias, lymphomas, myeloma, and other myeloproliferative disorders. In most cases, however, hormonal therapy involves blocking the effects of hormones that stimulate proliferation.

Estrogen & Androgen Inhibitors

One approach to hormonal therapy is to block the hormone receptor on the cell. Selective estrogen receptor modulators (SERMs) are medications that mimic the structure of estrogen. Because the estrogen-receptor complex varies among tissue types, SERMs can have different effects on different tissues, sometimes inhibiting the actions of estrogen and sometimes behaving like estrogen. The most well-known SERM is tamoxifen (Nolvadex), which is used not only to treat estrogen-sensitive breast cancer but also to prevent breast cancer in high-risk individuals. Because it also has some proestrogen properties, side effects of tamoxifen can include an increased risk of uterine cancer and deep vein thrombosis. Raloxifene (Evista) is a newer SERM that has been approved for prevention and treatment of postmenopausal osteoporosis and is used in the chemoprevention of breast cancer for postmenopausal women.

Flutamide (Eulexin) is a testosterone antagonist used in the treatment of prostate cancer. It works by blocking translocation of the androgen receptor to the nucleus. Although hormonal therapy for prostate cancer is palliative, it can be quite effective in slowing the progression of disease. Hormonal therapy can add several years to the life expectancy of patients with unresectable or metastatic disease. Flutamide is most effective when used in combination with surgical or pharmacologic castration.

Gonadotropin-Releasing Hormone Analogues

The most definitive way to block the production of testosterone and estrogen is by surgical castration. The pharmacologic equivalent of castration can be accomplished with leuprolide, an analog of gonadotropin-releasing hormone (GnRH). Normally, GnRH leads to the production of luteinizing hormone and follicle-stimulating hormone, the physiologic stimulators of sex hormone production. Constant stimulation with leuprolide actually inhibits luteinizing hormone and follicle-stimulating hormone release and leads to decreased synthesis of the sex steroids. Leuprolide (Lupron) is commonly used to decrease testosterone levels in the treatment of unresectable prostate cancer. In premenopausal women, estrogen levels fall to postmenopausal values with leuprolide administration. For this reason, the drug can be useful in the treatment of estrogen receptor-positive breast cancers in premenopausal women.

Aromatase Inhibitors

Postmenopausal women have functionally inactive ovaries; however, estrogens are still produced to a lesser extent in extragonadal tissues, primarily the conversion of adrenal steroids in fat cells by the enzyme aromatase. Aromatase inhibitors, such as anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara), eliminate functional estrogen in this population of women and are an effective hormonal treatment of breast cancer. A number of studies have demonstrated the benefit of aromatase inhibitors in postmenopausal women with hormone receptor positive breast cancer, either as first-line therapy or after the use of tamoxifen.

Radiation therapy may be used alone or in combination with surgery and chemotherapy and may be given with curative or palliative intent. Some tumors, such as head and neck cancers, prostate cancer, and Hodgkin disease, can often be cured by irradiation alone, eliminating the need for surgical resection or chemotherapy. More commonly, locoregional control of tumors involves surgical resection combined with localized radiation. The theoretical advantage of combining these two therapies is based on the mechanisms by which they fail to achieve their purpose. Surgical failures occur at the margins of tumors, while radiation therapy fails in the center of tumors, where the malignant cells are numerous and hypoxic conditions exist. Radiation failures are rare at the periphery of tumors, where cell numbers are low and oxygenation is high. Depending on tumor histology and location, radiation therapy can be used as a surgical adjunct either preoperatively or postoperatively. Preoperative radiation can shrink tumors and increase the chances for complete surgical resection in cancers such as sarcomas, rectal cancers, and superior sulcus lung cancers.

Principles of Radiation Therapy

Ionizing radiation is defined as energy with sufficient strength to cause the ejection of an orbital electron from an atom when the radiation is absorbed. Ionizing radiation can take either an electromagnetic form, as high-energy photons, or particulate forms, such as electrons, protons, neutrons, alpha particles, or other particles. Most radiation therapies utilize either photons or electrons. Electrons interact directly with tissue, causing ionization, in contrast to photons, which affect tissues by the electrons that they eject. Electron beams deliver a high skin dose and exhibit a rapid fall-off after only a few centimeters and are therefore commonly used to treat superficial targets such as skin cancers or lymph nodes within a few centimeters of the surface of the body. More commonly, electromagnetic radiation (high-energy photons) is used to treat cancer. This consists of either gamma rays (photons created from the decay of radioactive nuclei) or x-rays (photons created by interaction of accelerated electrons with electrons and nuclei of atoms in an x-ray tube target).

To quantify the interaction of radiation on tissues, one must first measure the ionization produced in air by the beam of radiation. This quantity is known as exposure and is measured in Roentgens (R). One can then correct for the presence of soft tissue and calculate the absorbed dose: the amount of energy absorbed per unit mass. This quantity was previously measured in rads but today is typically measured as joules per kilogram, or gray (Gy) units: 100 rad = 100 cGy = 1 Gy. As photons enter tissue, the dose increases at first and then begins to fall off because radiation falls off with the square of the distance from the source (a law of physics known as the inverse-square law).

The effect on biological tissues when they encounter ionizing radiation comes from ejected electrons interacting either directly with target molecules within the cell or indirectly with water to produce free radicals (such as hydroxyl radicals) that subsequently interact with target molecules. During their brief life span, electrons and free radicals interact with molecules in a random fashion. If they interact with molecules that are not crucial to cell survival, the effect of the radiation will be harmless. If they react with biologically important molecules, the effect will be detrimental. Molecular oxygen prolongs the life of reactive radicals, increasing the likelihood that it will have a detrimental effect. This is why tumor hypoxia tends to increase resistance to radiation.

While ionizing radiation may damage many molecules with the cell, the most critical injury with respect to cell death appears to be DNA damage in the form of single-strand or double-strand breaks. Cells have relatively efficient repair mechanisms for single-strand breaks in DNA, but double-strand breaks in DNA are much more difficult for cells to repair, although not impossible. Therefore, the ability of ionizing radiation to kill cells is dependent not only on the generation of enough DNA double-strand breaks to overwhelm repair pathways but also on the time the cell has to repair those breaks prior to the next mitotic cell division.

This phenomenon is known as sublethal damage repair in which increased cell survival is observed if a dose of radiation is divided into two fractions separated by a time interval. As the time interval between the fractions increases, the surviving fraction of the cells also increases as the cells are able to repair double-strand DNA breaks. Of course, in clinical radiation therapy, the goal is to kill the cancer cells but spare the normal cells. Delivering a single large dose of radiation will have a high rate of tumor cell killing, but the concordant killing of the normal tissue cells may limit the clinical utility due to normal tissue toxicity. This has led to the development of multifraction regimens commonly used today, typically delivering daily fractions of 1.8-2.5 Gy. Fractionation of radiation dose spares normal tissues because of their greater ability to repair sublethal damage between dose fractions and repopulate with cells if the overall time is sufficiently long.

Modes of Delivery

A. Teletherapy

Radiation is administered by two methods: an external machine (teletherapy) or the implantation of radioactive sources in or around the tumor (brachytherapy). In the past, teletherapy radiation was delivered using cobalt 60, a radioisotope produced in nuclear reactors. Although cobalt machines were very reliable, their usefulness is restricted by limited penetration to deep tumors without significant skin toxicity and difficulty in confining the dose to normal tissues. Today, external radiation is most often administered using a linear accelerator capable of producing higher energy photons without the geometric disadvantages associated with cobalt 60 units.

No matter the source, the beam of radiation needs to be modified to get optimal delivery of the desired dose to the tumor while minimizing dose to the normal tissues. Typically, the beam of radiation is rectangular. Collimators are thick shielding devices made from materials with a high atomic number. Primary collimators at the head of the machine create a rectangular beam, and additional devices such as wedges, compensators, blocks, or multileaf collimators are used to further modify the beam to desired specifications. Wedges or compensators can optimize the dose distribution if the treatment surface is curved or irregular in shape. The beam can also be shaped using individually fashioned blocks custom-made for each patient’s anatomy and tumor size and shape. In modern linear accelerators, multileaf collimators have replaced handmade blocks and allow automated and precise field shaping without the use of cumbersome handmade blocks.

B. Brachytherapy

Brachytherapy involves the placement of radioactive sources into or next to the target tissue. It takes advantage of the inverse-square law, which states that the intensity of electromagnetic radiation dissipates as the inverse square of the distance from the source. Thus, if radioactive sources can be placed so that the tumor is within a centimeter of the sources, the dose received by normal tissues just 2 cm distant from the source and 1 cm distant from the tumor would be one fourth of the dose received by the tumor. This can allow delivery of a high dose to the tumor with only a modest dose to normal tissue.

There are many implantation techniques for brachytherapy. The surgical approach to the target volume may be interstitial (such as prostate seed implantation), intracavitary (such as gynecologic applicators), transluminal (such as endoscopic applications), or surface mold techniques (such as eye plaques for ocular melanoma). The implants may be permanent or temporary, and the dose may be delivered using low-, medium-, or high-dose rates. Many modern applications use afterloading techniques that place treatment applicators and subsequently load radioactive sources to reduce radiation exposure for therapy personnel.

Complications of Radiation Therapy

A. Acute Radiation Effects

Acute radiation effects are those toxicities that occur within a few weeks to months of radiation therapy. They occur mainly in self-renewing tissues that are characterized by actively proliferating stem cells producing progeny that divide and differentiate into mature functioning cells. This includes bone marrow, skin and its appendages, and mucosal surfaces of the oropharynx, esophagus, stomach, intestines, rectum, bladder, and vagina. Once the normal life span of the mature cells expires, the normal turnover and replacement with new cells does not occur because of radiation killing of the dividing stem cells. Acute toxicity is influenced by both fraction size and the time interval between fractions. The more rapidly a given dose is delivered during the overall treatment period, the more severe the acute effects will be. A decrease in fraction size or prolongation of the interval between fractions allows the cell populations to repair and repopulate, decreasing the severity of acute toxicity.

Head and neck irradiation is among the most toxic in the acute period due to significant mucositis of the oral cavity, oropharynx, larynx, and cervical esophagus. Skin and the salivary glands are also affected. Mucositis, yeast superinfection, desquamation, pain, xerostomia, odynophagia, dysphagia, dehydration, and malnutrition are all common clinical scenarios that radiation oncologists manage when delivering head and neck radiotherapy. Other common acute effects observed during radiation therapy directed at other anatomic sites include dysphagia and cough from thoracic radiation, nausea, vomiting, and diarrhea from abdominal radiation, and dysuria, proctitis, and perineal desquamation and pain from pelvic radiation.

B. Late Radiation Effects

Late effects are those toxicities that occur months to years after radiotherapy and are more commonly permanent. Mitotically inactive tissues without the capacity for self-renewal are commonly involved. The mechanism causing late effects may include direct damage to the parenchymal cells within an organ or indirect effects due to microvascular damage. Each organ is characterized by a tolerance dose, a radiation dose above which the risk of organ complications increases rapidly. These normal tissue tolerances are the true dose-limiting factors in clinical radiation therapy, because late complications can be permanent and in some cases life threatening.

The types of late complications induced by radiation can vary. For the brain, late toxicity may mean necrosis of the brain tissue, while in the kidney it may mean nephrotic syndrome and organ failure. The tolerance doses for different organs vary over a large range, from a few Gy for sterility from testicular irradiation to over 100 Gy for necrosis or perforation of the uterus. Late complications may include fibrosis, necrosis, ulceration and bleeding, chronic edema, telangiectasias and pigmentation changes, cataract formation, nerve damage, lung pneumonitis and fibrosis, pericarditis, myocardial damage, bone fracture, liver or kidney failure, sterility, intestinal obstruction, and fistula and stricture formation.

Principles of Antitumor Immune Responses

Immunotherapy refers to treatments designed to kill tumor cells through immune mechanisms. There are two broad types of antitumor immune responses: one involving the humoral arm of the immune system and the other involving the cellular arm. Humoral immunity involves antibody production by mature B lymphocytes. Cell-mediated immunity involves stimulation of cytotoxic (CD8+) T cells through a major histocompatibility complex (MHC) class I-restricted process and stimulation of helper (CD4+) T cells through an MHC class II-restricted process. The humoral and cell-mediated immune responses overlap in that the activation of a B-cell response usually requires the presence of helper T cells. Whether a humoral or a cell-mediated immune response is more important in generating antitumor immunity is still debated; however, patients who exhibit both responses appear to fare better than those who demonstrate only one type of response or no response.

Essential to the generation of an immune response through either arm of the immune system is the ability of antigen-presenting cells (APCs), such as monocytes, macrophages, B cells, and dendritic cells, to process and present tumor-related peptide antigens. Proteins are phagocytosed by APCs and partially digested into smaller polypeptides. These small peptide antigens are then bound to MHC molecules on the cell surface. These unique antigen:MHC complexes can then be recognized by naïve T lymphocytes through the T-cell receptor. When a naïve helper (CD4+) T cell recognizes the antigen being expressed on the MHC class II molecule and also recognizes costimulatory molecules present on the APC, it becomes activated, resulting in proliferation and differentiation. There are two types of helper T cells. The Th1 helper T cells produce cytokines to promote a cellular response (interleukin [IL]-2, interferon [IFN]-γ, tumor necrosis factor α, granulocyte-macrophage colony-stimulating factor). In the presence of these cytokines, naïve cytotoxic (CD8+) T cells that recognize antigen being presented on MHC class I molecules on the surface of an APC become activated. Once activated, cytolytic T cells destroy tumor cells via T-cell receptor recognition of tumor-specific antigen presented on MHC class I molecules at the tumor cell surface. Antigen-specific T cells bind to the MHC I receptor–tumor antigen complex and destroy the tumor cell via the release of granules containing granzyme B and perforin and via induction of the Fas/Fas ligand apoptosis. Cytotoxic T cells can only recognize antigen expressed on the tumor surface in the context of the MHC class I molecule.

The second type of helper T cell (Th2) secretes B-cell stimulatory cytokines (IL-4, IL-5, IL-10), which results in the proliferation and differentiation of plasma cells. As opposed to a cellular response, for an antibody response, the antigens do not have to be presented on class I MHC receptors. Tumor cells can then be killed by a variety of methods. Antibody-dependent cell-mediated cytotoxicity involves the attachment of tumor-specific antibodies to tumor cells and the subsequent destruction of the tumor cell by the natural killer (NK) cell. Complement-dependent cell-mediated cytotoxicity involves the recognition and attachment of complement-fixing antibodies to tumor-specific surface antigens followed by complement activation. A third mechanism of tumor destruction, opsonization, results when tumor-specific antibodies attach to their target antigens on tumor cell surfaces, thus marking them for engulfment by macrophages.

There are several methods by which the immune system may be incorporated into cancer therapy. Immunotherapy can be categorized as either active or passive. With passive immunotherapy, the host need not mount an immune response; the therapeutic agent will directly or indirectly mediate tumor killing. Examples of passive immunotherapy include the use of monoclonal antibodies or adoptive (cellular) immunotherapy. Active immunotherapy, on the other hand, is the delivery of materials designed to elicit an immune response by the host. This can further be broken down to nonspecific and specific active immunotherapies. Nonspecific agents are those that stimulate the immune system globally but do not recruit tumor-specific effector cells. Active specific immunotherapy is designed to elicit an immune response to one or more tumor antigens, the prime example being the use of vaccines.

Passive Immunotherapy (Monoclonal Antibodies)

The development of monoclonal antibodies with unique specificity to tumor antigens has allowed for multiple attempts to utilize them as cancer therapy. In addition to their relative selectivity and minimal toxicity, they are easily mass produced for widespread application. In some cases, monoclonal antibodies work primarily through the immune system (antibody-dependent cell-mediated cytotoxicity), while in other cases, they behave more as targeted therapies (see earlier section on Targeted Therapies). Examples of monoclonal antibodies that are primarily immunotherapies include rituximab and alemtuzumab. Rituximab (Rituxan) is an anti-CD20 monoclonal antibody that is approved for the treatment of relapsed or refractory low-grade or follicular non-Hodgkin lymphoma (NHL). Alemtuzumab (Campath) targets CD52, which is present on both B and T cells, and is used in the treatment of B-cell chronic lymphocytic leukemia (B-CLL).

Adoptive Immunotherapy

Adoptive immunotherapy is the passive administration of cells with antitumor activity to the tumor-bearing host. Tumor-infiltrating lymphocytes are lymphocytes that infiltrate growing tumors and can be isolated by growing single-cell suspensions from the tumor in the presence of IL-2. They have been isolated from virtually all types of tumors and can recognize tumor-associated antigens. These cells can also be manipulated ex vivo to increase their recognition of tumor antigen or cytolytic potential. Adoptive immunotherapy is presently under active investigation.

Nonspecific Active Immunotherapy

A. Immunostimulants

Before the mechanism by which the immune system can eradicate tumor cells was fully understood, early attempts at immunotherapy involved nonspecific stimulation of the immune system. The idea was that any increase in immune reactivity would be associated with a concomitant increase in the antitumor immune response. Probably the most widely embraced immunostimulant investigated has been the use of bacille Calmette-Guérin (BCG), a modified form of the tubercle bacillus. Initial trials suggested a possible benefit, but multiple prospective, randomized trials in various malignancies have failed to substantiate a survival benefit of BCG, either alone or in combination with other therapeutics. Local therapy with BCG in the bladder eliminates superficial bladder cancers and prevents tumor recurrences. It is one of several standard therapies for patients with bladder cancer. It is also being studied as an adjuvant to other immunotherapies, such as vaccines. Levamisole is an antihelminthic drug that was reported to have several immunomodulatory properties. Although the exact mechanism of action is unknown, it has been effective in the adjuvant therapy of colorectal cancer.

B. Cytokines

Cytokines are naturally occurring soluble proteins produced by mononuclear cells of the immune system that can affect the growth and function of cells through interaction with specific cell-surface receptors. There have been over 50 cytokines isolated to date, and several have subsequently been approved by the FDA for clinical use, including interferon-α and IL-2.

The interferons (IFN-α, IFN-β, IFN-γ) were originally described as proteins produced by virally infected cells that serve to protect against further viral infection through a variety of effects. These include the increased antigen presentation via increased expression of MHC and antigens, enhancement of NK cell function, and the enhancement of antibody-dependent cell-mediated cytotoxicity. In addition, the interferons exert direct antiangiogenic, cytotoxic, and cytostatic effects. While the anticancer effects of IFN-β and IFN-γ have been disappointing, several hematologic and solid tumors have proved responsive to IFN-α, including chronic myelogenous leukemia, cutaneous T-cell lymphoma, hairy cell leukemia, melanoma, and Kaposi sarcoma.

IL-2 was originally described as the “T-cell growth factor” because it is required for the differentiation and proliferation of activated T cells. As such, it seems like an ideal choice for immunotherapy. The major drawback of IL-2 is the significant dose-related toxicity. IL-2 leads to significant interstitial edema and vascular depletion and lymphoid infiltration into vital organs, possibly resulting in severe hypotension and ischemic damage to the heart, liver, kidneys, and bowel, which limits the use of IL-2 to patients with excellent performance status, normal pulmonary and cardiac function, and no active infections. Despite these limitations, IL-2 has proved to be an effective therapy in patients with metastatic melanoma and metastatic renal cell carcinoma.

Specific Active Immunotherapy (Vaccines)

The goal of cancer vaccines is to generate a host immune response to known or unknown tumor-associated antigens. Many different vaccine strategies are under investigation, each with advantages and disadvantages in regard to clinical feasibility, cost, the number of antigens available, and the mechanism of response (cellular, humoral, or both). Some vaccine strategies use specific peptide antigens. These are highly purified and therefore are easy to standardize, distribute, and administer. Unfortunately, immunizing a patient against a single antigen has several drawbacks that limit the potential clinical benefit. If a peptide vaccine does stimulate a response, it may not be the “right” peptide for many patients. Even commonly expressed tumor antigens are not present on all patients’ tumors, or they may be present in varying degrees. In addition, the T-cell recognition of an antigen depends on the presentation of that antigen on a specific MHC molecule. Only certain human lymphocyte antigen (HLA) phenotypes can present any given peptide to induce an immune response, so they will function only on a limited subset of patients. A classic example is that of the MART-1/Melan-A antigen in melanoma. The antigen is expressed by 80% of melanomas, but the peptide only binds to HLA-A2. Because only about 45% of Caucasians have HLA-A2, only 36% (80% of 45%) of melanoma patients given a MART-1/Melen-A vaccine would see a benefit. Finally, a cancer can escape immune recognition rather simply if a population of cells stops expressing that antigen or the MHC molecule.

For many cancers, only a few tumor-associated antigens have been defined; these may not be present on a large percentage of patients. Using the patient’s cancer as the vaccine precludes the need to identify specific antigens. Autologous tumor cell vaccines are created from cancer cells harvested from the patient, altered to be more immunogenic, and irradiated, before being returned to the patient to stimulate a tumor-specific immune response. This approach is limited to individuals with sufficient tumor to prepare a vaccine. Trials are restricted to patients with bulky nodal or accessible distant metastatic disease who have a poor overall prognosis to begin with. Furthermore, the technical complexities inherent in procuring tumor and preparing a vaccine have made it difficult to conduct multi-institutional trials to test the efficacy of these vaccines.

Since many tumor-associated antigens are shared among a large number of patients, it is possible that one could create a vaccine from cultured cell lines that would stimulate an antitumor immune response in any patient who shared some of those antigens. This is the principle behind allogeneic tumor cell vaccines. This approach offers several advantages over autologous vaccines: Allogeneic vaccines are readily available, even for patients who lack sufficient tumor to produce an autologous tumor cell vaccine, and can be standardized, preserved, and distributed in a manner akin to any other therapeutic agent.

Tumor-Induced Immunosuppression

It is becoming increasingly apparent that in addition to mechanisms to generate and propagate an immune response, the immune system has several mechanisms to limit an immune response. This immune regulatory function is necessary to prevent lymphoproliferative disorders and autoimmune diseases. Neoplasms, however, may take advantage of this, creating an immunosuppressive network within the tumor microenvironment that protects the tumor from immune attack and minimizes the efficacy of immunotherapy.

Several components of the immune system function to regulate or limit an immune response. While it was initially thought that dendritic cells were exclusively immunogenic, recent evidence suggests that they possess dual functions, and some subsets of dendritic cells possess a regulatory function. Myeloid-derived suppressor cells can also suppress the antitumor response to cancer by blocking the effects of cytotoxic T cells in the tumor microenvironment. In addition to cytotoxic and helper T cells, another T-cell population is the regulatory T cell, which also functionally suppresses immune responses. Immunosuppressive cytokines within the tumor microenvironment (IL-6, IL-10, TFG-β) may function to intensify these immunosuppressive components, augmenting tumor escape from immune recognition. It is also possible that many immunotherapies fail by augmenting not only immune stimulation but immune suppression, canceling out the effect. In some cases, these therapies may tilt the response toward immune suppression, for a detrimental effect. Newer immunotherapeutic strategies are focusing on not only increasing immune recognition of the tumor but blocking the suppressive mechanisms. These include pretreatment depletion of regulatory T cells, blocking suppressive pathways or neutralizing immunosuppressive cytokines.

Activated T lymphocytes express the molecule CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), which exerts a suppressive effect on the induction of immune response through its interactions with the B7 molecules on antigen-presenting cells. Blocking the binding of CTLA-4, through the use of monoclonal antibodies, can therefore enhance antitumor T-cell responses. Ipilimumab (Yervoy), a monoclonal antibody to CTLA-4, has been shown to cause tumor regression and improve survival in patients with metastatic melanoma. PD-L1 is often expressed on tumor cells, and when it binds to PD-1 on T cells, can prevent T-cell function and lead to anergy. The use of an anti-PD-1 monoclonal antibody in patients with a variety of advanced cancers showed promising tumor responses, and may provide a new immunotherapy for patients with PD-L1 expressing tumors.

SOFT TISSUE SARCOMA

Soft tissue sarcomas account for approximately 1% of all new cancer diagnoses. Almost half of all patients diagnosed with the disease eventually die as a result of the cancer. Soft tissue sarcomas can occur anywhere in the body, but most originate in an extremity (41%), the trunk (10%), the retroperitoneum (16%), visceral sites (21%), or the head and neck (12%). Soft tissue sarcomas originate from a wide variety of mesenchymal cell types and include malignant fibrous histiocytoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, and desmoid tumors. While the histopathology of these tumors is highly variable, with some exceptions they tend to behave in a fashion dictated by tumor grade rather than the cell of origin.

Most soft tissue sarcomas arise de novo, and rarely do they result from malignant degeneration of a benign lesion. There are several familial syndromes in which patients are genetically predisposed to the formation of soft tissue sarcomas, including Li-Fraumeni syndrome, Recklinghausen disease, and Gardner syndrome. Other proven risk factors exist that may increase the chances of sarcoma formation. External radiation therapy can increase the incidence of sarcomas by 8-fold to 50-fold. Chronic extremity lymphedema also increases the risk for lymphangiosarcoma. A classic example is the development of upper extremity lymphangiosarcomas in the lymphedematous arm of women treated for breast cancer (Stewart-Treves syndrome). Other less clear associations link chronic tissue trauma and occupational chemical exposures with an increased risk for sarcoma formation.

The major features of the staging system for soft tissue sarcomas are the grade of the tumor, its size, and the presence of metastatic disease (Table 44–3). Although the site of the tumor is not considered in staging, patients with retroperitoneal tumors tend to have a worse prognosis. Sarcomas generally metastasize by the hematogenous route, and the metastatic sites of sarcomas are related to the location of the primary tumor. The vast majority of metastases from extremity sarcomas are to the lung, while the majority of retroperitoneal tumors metastasize to the liver. Lymph node involvement is rare with most soft tissue sarcomas, although it may occur with epithelioid sarcoma, clear cell sarcoma, angiosarcoma, rhabdomyosarcoma, or synovial sarcoma.

The most important prognostic variables for patients with soft tissue sarcoma are the size and grade of the primary tumor. Since grading is based on the cellular architecture and invasive nature of the tumor, FNAB is not a typically useful biopsy technique for the initial diagnosis of a sarcoma. If a tumor is small (< 3 cm) and superficial, excisional biopsy should be performed. All extremity biopsy incisions should be oriented longitudinally, as the biopsy incision scar should be excised in a subsequent definitive resection of the tumor. Core needle biopsies may be performed for large, palpable superficial tumors. For large, deep tumors or those adjacent to vital structures, where core needle biopsy is not advised or failed, incisional biopsy should be considered. The incision should be centered over the mass, tissue flaps should not be raised, and meticulous hemostasis should be ensured, all to prevent the dissemination of tumor cells into adjacent tissue planes.

Treatment of Extremity Sarcomas

MRI is the imaging modality of choice for any suspected extremity sarcoma because it is most accurate in defining the extent of the tumor and invasion of surrounding structures. MRI is also used for follow-up imaging to assess response in patients undergoing therapy, as well as for local and regional recurrence. A chest x-ray or chest CT should be obtained in order to evaluate for pulmonary metastases in patients with high-grade tumors.

Surgery remains the primary therapy for localized extremity sarcomas, but multimodality therapy is recommended to minimize the likelihood of recurrence or the need for amputation. Historically, amputation was the only form of curative surgical therapy for large extremity sarcomas, but multimodality therapy has allowed for a high rate of limb preservation. Today, fewer than 5% of patients with extremity soft tissue sarcoma require amputation, generally reserved for patients whose tumors do not respond to preoperative therapy and cannot be resected adequately, have no evidence of metastatic disease, and have a good prognosis for rehabilitation.

A pseudocapsule composed of tumor cells surrounds sarcomas, and local invasion along fascial planes and neurovascular structures is common. It is important not to dissect along the pseudocapsule, which is associated with high local recurrence rates, but rather obtain a wide (2-cm) margin of normal tissue. This may need to be compromised in the immediate vicinity of functionally important neurovascular structures. If the tumor involves these structures, nerve grafts and arterial reconstruction with autologous or prosthetic conduits may be required. Large soft tissue defects often require the construction of myocutaneous flaps to improve function and cosmesis. Soft tissue sarcomas rarely invade bone or skin, and wide resections of these structures are infrequently necessary.

Following wide local excision, metal clips should be placed at all margins of the resection in order to guide subsequent radiotherapy. For patients with T1 tumors located superficially in an area where it is not difficult to obtain widely negative margins, postoperative radiation therapy may not be necessary. For most other lesions, postoperative radiation is almost always recommended, with either external beam radiation or brachytherapy. Radiation should be started 4-8 weeks after surgery, as delay can result in a lower local control rate. Preoperative radiotherapy may have some advantages in patients with large tumors. Lower doses can be delivered to an undisturbed tumor bed, which may also have better oxygenation, and larger tumors may decrease in size, allowing for limb-sparing procedures. Preoperative radiation is associated with an increase in short-term wound complications but a decrease in long-term tissue fibrosis and edema. The optimal mode and sequence for treatment has yet to be defined and often requires a multidisciplinary approach.

Adjuvant chemotherapy remains controversial. Chemotherapy can be given either preoperatively or postoperatively. The three drugs most effective in sarcoma are doxorubicin, dacarbazine, and ifosfamide. Preoperative chemotherapy is sometimes recommended because in addition to the early treatment of micrometastatic disease, it allows for assessment of tumor response, which helps avoid prolonged therapy in patients not responding. However, while disease-free survival may be improved, there are conflicting data on overall survival. A recent meta-analysis of randomized trials suggested there may be a small survival benefit for extremity sarcomas, and so its use has increased.

The vast majority of localized recurrences in soft tissue sarcomas occur in the first 2 years after resection, necessitating close follow-up during that period. A local recurrence is not indicative of systemic disease and, in the absence of evidence of metastases, should be treated aggressively in the same manner as a primary tumor. The resection of pulmonary metastases should be considered in patients who have fewer than four radiographically detectable lesions and who have achieved apparent local control following resection of the primary tumor. In such circumstances, disease-free survival can approach 25%-35%.

Treatment of Retroperitoneal Sarcomas

Retroperitoneal sarcomas comprise approximately 15% of all soft tissue sarcomas, with liposarcoma, malignant fibrous histiocytoma, and leiomyosarcoma the three most common types. They usually present as a large abdominal mass. Nearly half are over 20 cm in size at diagnosis. Once they compress or invade contiguous structures, they can cause symptoms such as abdominal pain or nausea and vomiting. Workup should include CT of the abdomen and pelvis to evaluate the mass as well as CT of the lung and liver to look for metastases. CT-guided core biopsy is the sampling technique of choice, with open or laparoscopic incisional biopsy reserved for inconclusive core biopsies.

As with extremity sarcomas, surgery represents the primary treatment, with the goal being en bloc resection with a rim of normal tissue. Although retroperitoneal tumors are generally large at presentation and often invade vital structures, the majority of these tumors are resectable. Retroperitoneal sarcomas rarely invade surrounding organs, but an intense desmoplastic reaction makes it difficult to assess the extent of tumor, so often these organs need to be resected rather than risk positive margins. The kidney, colon, pancreas, and spleen are the most commonly resected organs.

While adjuvant radiation therapy is standard in extremity sarcoma, evidence supporting its use in retroperitoneal sarcoma is less convincing. Because of the low tolerance to radiation of the abdominal and retroperitoneal organs, delivery of adequate radiotherapy is often difficult. There is encouraging evidence for intraoperative radiation therapy to the tumor bed, but this technique is still considered investigational and can be performed only in select centers. Although complex, preoperative radiation may be beneficial because it uses lower radiation doses, is less injurious to the small bowel, and can increase respectability by shrinking the tumor and creating a thickened capsular structure around the lesion.

MELANOMA

The incidence of melanoma is unfortunately rising. The reasons for this rise are not clear but are most likely related to an increased exposure to ultraviolet radiation from sunlight. Individuals whose first sunburn occurred at an early age, or have had three or more sunburns before age 21 have an increased incidence of melanoma, as do individuals who use tanning beds. Other risk factors include freckles, a fair complexion, reddish or blond hair, blue eyes, a first-degree relative with melanoma, and the presence of multiple or dysplastic nevi.

The best approach to melanoma is to prevent it from occurring, through sun avoidance and sun protection with sunscreens with a sun protection factor (SPF) of 30 or higher. Second to prevention, the most significant impact on melanoma comes from early recognition and diagnosis. The prognosis of melanoma is inversely and dramatically related to the depth of invasion at diagnosis (Breslow thickness), emphasizing the importance of early diagnosis of this disease. Lesions that are suspicious for melanoma can be identified by their clinical characteristics, often referred to as the ABCDs of melanoma (Table 44–4). Diagnosed early, well over 90% of primary melanomas can be cured with surgical excision alone. Patients presenting with thicker lesions or regional nodal metastases have a significantly poorer prognosis. The AJCC staging system is presented in Table 44–5.

There are several distinct categories of melanoma; the four most common are superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma.

Superficial spreading melanoma is the most common presentation, accounting for nearly 70% of all melanomas. These usually occur in sun-exposed areas of the body or in individuals with multiple dysplastic nevi. They generally arise in preexisting nevi and can occur at any age after puberty. The superficial spreading subtype tends to grow in a radial pattern during the earlier stages and converts to a vertical growth pattern during the later stages of development.

Nodular melanomas account for between 15% and 25% of all melanomas. These tend to occur in older individuals and are more common in men. Nodular melanomas generally develop de novo, not in a preexisting nevus. They usually are dome shaped with distinct borders and often resemble a blood blister. Nodular melanomas occur most commonly on the head, neck, and trunk. They lack a significant horizontal growth phase and tend to be deep at the time of diagnosis.

Lentigo maligna melanoma has less propensity to metastasize and thus has a more favorable prognosis relative to the other subtypes. However, it can be locally aggressive, with high recurrence rates after excision. These lesions account for 4%-10% of melanomas and occur in an older population. Lentigo maligna lesions almost always develop in sun-exposed areas. They have a long horizontal growth phase and often have very convoluted borders.

Acral lentiginous melanomas account for between 2% and 8% of melanomas in Caucasians but for 30%-60% of melanomas in blacks, Asians, and Hispanics. These lesions do not occur in sun-exposed areas; instead, they occur on the sole of the foot, the palm, beneath the nail beds, and in the perineal region. Acral lentiginous melanomas are often large, with an average diameter of 3 cm at the time of diagnosis. They develop relatively rapidly over the course of months to several years and tend to behave very aggressively. The clinical characteristics of these melanomas are often unmistakable, with variegations in color and convoluted borders. Ulceration of these lesions is common.

Treatment of Primary Melanoma

Any suspected melanoma should be removed by punch or excisional biopsy. Given the importance of Breslow thickness, shave or curette biopsies are contraindicated. If the biopsy specimen reveals melanoma, a formal excision with adequate margins is required. Because microscopic tumor cells frequently surround primary melanomas, excision with narrow margins is associated with an unacceptably high rate of local recurrence. The current standard for lesions less than 1 mm in depth is excision with 1-cm margins. Melanomas between 1 and 2 mm in thickness should be excised with 2-cm margins, but a smaller margin (10-15 mm) may be acceptable in areas where it is difficult to get 2 cm without the need for a skin graft or exceptionally tight closure. Melanomas deeper than 2 mm should be excised with a 2-cm margin. The resection should be carried down to the underlying fascia, although the fascia need not be excised.

Melanomas generally metastasize by the lymphatic route in a predictable and orderly fashion. Any palpable nodes must be considered suspicious for metastatic involvement, easily verified with an FNAB. About 5%-10% of patients have clinical evidence of nodal metastases upon initial presentation and should undergo a therapeutic lymph node dissection at the time of their wide excision. Many patients will have microscopic disease in the lymph nodes that will not be apparent on physical examination. In the past, substantial controversy surrounded elective lymph node dissection of the draining nodal basin for melanoma. The practice gained dramatic acceptance, however, with the advent of the sentinel lymph node biopsy, which is based on the anatomic concept that lymphatic fluid from defined regions of skin drains specifically to an initial node or nodes (“sentinel nodes”) prior to disseminating to other nodes in the same or nearby basins. Sentinel node biopsy allows for a more detailed histologic examination of the sentinel lymph nodes and helps avoid the morbidity of lymph node dissection in patients who are pathologically node negative. Patients with a negative sentinel node are over six times more likely to survive than those with a positive sentinel lymph node, making the predictive impact of sentinel node status much greater than any other prognostic factor. Evidence also suggests that early removal of micrometastatic disease from the lymph nodes, as compared with waiting for regional recurrence to perform a lymph node dissection, may improve survival.

The sentinel lymph node biopsy has become the standard of care in the staging and treatment of melanoma and should be performed at the time of the wide excision for primary melanomas thicker than 1.0 mm. It should be selectively applied for tumors between 0.75 and 1.0 mm when other worrisome features are present, such as ulceration, angiolymphatic invasion or a mitotic rate >1. Melanomas less than 0.75 mm are very unlikely to have regional metastases and do not require sentinel lymph node biopsy. The dominant drainage basins can be identified by lymphoscintigraphy, which involves intradermal injection of technetium-99m (^99mTc) sulfur colloid in the area around the tumor and a gamma camera to image the sites of lymph node drainage. In the operating room, blue dye (isosulfan or methylene) is injected in a similar fashion. Any lymph nodes that have evidence of ^99mTc uptake on a handheld gamma probe, have evidence of blue dye, or are clinically suspicious should be excised. After removal of the nodes, they are analyzed by serial thin-sectioning, routine H&E staining, and immunohistochemical staining. Using these methods of analysis, the pathologist is able to detect even minute numbers of metastatic melanoma cells in the sentinel node. Patients with a positive sentinel lymph node biopsy should undergo formal lymph node dissection of the entire drainage basin, although the benefit of this is being examined in the prospective randomized Multicenter Selective Lymphadenectomy Trial-II (MSLT-II).

Traditional chemotherapy regimens have proved largely ineffective in the treatment of melanoma; however, the cytokine IFN alpha-2b (Intron A) has been shown to improve disease-free and overall survival in high-risk patients with no evidence of systemic metastases. This treatment is not without controversy, however, as the duration of therapy is long (12 months), the toxicities are substantial, and some of the data regarding the overall survival benefit are conflicting. An alternate approach to high-dose IFN alpha-2b is pegylated interferon alpha-2b. This has a longer half-life and can be administered subcutaneously with fewer side effects, albeit for a longer period of time (5 years). Finally, another consideration for adjuvant therapy is biochemotherapy, which combines IL-2, IFN alpha-2b, cisplatin, vinblastine, and DTIC. This regimen has significant toxicity but is shorter (9 weeks) and was shown in a prospective randomized trial to improve relapse-free survival compared with high-dose interferon, although there was no improvement in overall survival. All patients with high-risk melanoma (node-positive melanoma or thick, ulcerated, node-negative melanoma) should have a balanced discussion of the potential risks and benefits of adjuvant therapy. While melanoma is relatively radioresistant, there may be some benefit to regional control after node dissection with radiation in patients with gross extracapsular extension or multiple involved lymph nodes.

Local Recurrence & In-transit Metastasis

Although rare with appropriate surgery, an isolated local recurrence can be treated with a repeat wide excision with 2-cm margins. Approximately 2%-3% of melanoma patients will develop in-transit metastasis, which is the appearance of metastasis along the path from the primary tumor to its regional nodal basin, and is lymphatic in nature. The management of in-transit metastasis is dictated by the number and the size of the lesions. If few in number, surgical excision with a margin of surrounding normal cutaneous and subcutaneous tissue is appropriate; however, this becomes unlikely with multiple lesions. Intralesional therapy with granulocyte-macrophage colony-stimulating factor can result in significant regression of melanoma deposits but requires multiple injections and is not always effective. Although melanoma is relatively radiation resistant, this therapy can provide palliation in unresectable lesions in many cases. Radiation therapy should be considered in those patients with a smaller volume of cutaneous or subcutaneous metastases.

Hyperthermic isolated limb perfusion (HILP) is a way of isolating the blood circuit to the extremity and administering chemotherapeutic agents regionally at a concentration 15-25 times higher without resulting in systemic side effects. Melphalan has been used as a standard drug for hyperthermic isolated limb perfusion secondary to its efficacy and low regional toxicity. While this has not been shown to improve survival, the use of hyperthermic isolated limb perfusion provides a significant palliation of locoregional symptoms when other options are not available. Less complicated, but also effective, is isolated limb infusion (ILI). This involves using minimally invasive techniques to access the vessels along with a tourniquet to minimize systemic uptake.

Regional and systemic recurrence of melanoma can be latent, and recurrence 10 years after the original diagnosis is not uncommon. This fact necessitates close lifelong follow-up of these patients. Patients with a past history of melanoma have a dramatically increased risk of developing a second primary lesion and require diligent screening for other lesions.

LYMPHOMA

Lymphomas are malignant neoplasms that originate from the lymphoid tissues. Two distinct categories of lymphoma exist: Hodgkin and non-Hodgkin. The two types not only have different morphologic characteristics but differ also in their clinical behavior and their response to various therapeutic regimens. It is not possible to differentiate Hodgkin and non-Hodgkin lymphoma on clinical grounds; surgical biopsy is necessary. In the diagnosis of a suspected lymphoma, excisional biopsy of the entire lymph node or nodes is imperative, as the architecture has a bearing on the diagnosis and the subsequent treatment of the tumor.

1. Hodgkin Lymphoma

Hodgkin lymphoma may occur at any age but is generally a disease of young adults. Prevalence in women peaks in the third decade and then falls, while it remains fairly constant in men after this time. The diagnosis of Hodgkin lymphoma is based on the finding of Reed-Sternberg cells in an appropriate cellular background of reactive leukocytes and fibrosis. It is the pattern of the lymphocytic infiltrate that determines the classic subtypes of Hodgkin disease (see Table 44–6). All subtypes of classical Hodgkin lymphoma are presently treated in the same way, and modern therapy has allowed for cure of over 70% of patients with this malignancy.

The cause of Hodgkin disease is not well understood; however, epidemiologic studies have revealed certain patterns of disease clustering. The incidence appears to be higher with a lower number of siblings, early birth order, siblings with Hodgkin disease, a decreased number of playmates, certain HLAs, single-family dwellings, and patients who have undergone tonsillectomy. The incidence is increased also in persons with immunodeficiencies and autoimmune disorders. This pattern suggests that an oncogenic virus may cause Hodgkin disease. Nuclear proteins of the Epstein-Barr virus have been detected in about 40% of classical Hodgkin lymphoma, and alternative lymphotropic viruses may be involved in the pathogenesis of cases negative for Epstein-Barr virus.

Most patients present with enlarged but painless lymph nodes, typically in the lower neck or supraclavicular region. On occasion, mediastinal masses are associated with cough or dyspnea or discovered on routine chest x-ray. About 25% of patients will have systemic symptoms, called B symptoms, including weight loss, pruritus, fever, and drenching night sweats.

Staging

With regard to therapy, the most important prognostic factor in Hodgkin lymphoma is the disease stage. The AJCC staging system for Hodgkin and non-Hodgkin lymphoma is shown in Table 44–7. The Ann Arbor staging system is also commonly used, which further subclassifies the stages into A and B categories: B for those with weight loss, fever, night sweats, or other constitutional symptoms, and A for those without such symptoms.

As discussed earlier, excisional lymph node biopsy is essential to the diagnosis of Hodgkin lymphoma. Once the diagnosis is made, disease staging begins with a detailed history and physical examination, with attention to all lymph node beds, B symptoms, and symptoms related to extranodal involvement. CT of the chest, abdomen, and pelvis is the major means of staging intrathoracic and intra-abdominal disease. Bone marrow biopsy is also part of the staging evaluation of patients with bony symptoms or cytopenias. Fluorodeoxyglucose F 18 (FDG-PET) scan significantly adds to the staging of Hodgkin lymphoma and has become a standard staging tool both before treatment and at completion. In the past, a staging laparotomy (splenectomy, wedge liver biopsy, and dissection of the para-aortic, iliac, splenic hilar, and hepatic portal lymph nodes) was used to determine the extent of disease in the abdomen. Given the improved imaging studies and the inclusion of chemotherapy for patients even with favorable stage I disease, staging laparotomies are rarely, if ever, performed.

Treatment

Hodgkin lymphoma has changed from a uniformly fatal disease to one that is curable in almost three-quarters of patients. Treatment is guided by both the stage of disease as well as stratification into favorable and unfavorable prognosis. This has allowed for less intensive therapy in patients with a favorable prognosis, with no compromise in outcome. The definition of favorable disease differs with different groups, but takes into account stage and extent of disease, age, ESR, and symptoms. For patients with favorable prognosis stage I-II disease, treatment typically involves a combination of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) in combination with involved field irradiation. For patients at risk of long-term complications from radiation, 4 to 6 cycles of ABVD without radiation can be considered, although there are higher recurrence rates compared with combined modality therapy. Patients with unfavorable stage I-II disease are treated with more cycles of AVBD in combination with irradiation.

While ABVD remains the standard regimen for stage III-IV Hodgkin lymphoma (advanced stage), newer regimens include escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine bleomycin, etoposide and prednisone). Consolidation radiotherapy may be considered with ABVD or BEACOPP, but is an essential component of the Stanford V protocol. The response rates, toxicity and patient comorbidities must be weighed when deciding on a regimen.

Approximately 5%-10% of patients are refractory to initial therapy, and 10%-30% will relapse after complete remission. In this case, salvage therapy typically involves an alternate chemotherapy regimen. High-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) should be considered for patients with early relapse (within 12 months), second relapse or a generalized systemic relapse, even after 12 months. For patients who fail this approach or are not candidates for high-dose chemotherapy with HCT, there are unfortunately few good treatment options.

2. Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma encompasses a wide spectrum of lymphoid-derived tumors. This heterogeneous group of diseases includes more than 10 distinct tumor subtypes with variable biologic behavior and responses to treatment. As opposed to Hodgkin lymphoma, the prevalence of non-Hodgkin lymphoma rises with age. The incidence has been rising steadily over the past 20 years by about 3%-5% per year, for unknown reasons. Several risk factors have been identified that predispose patients to the development of disease. Patients with congenital disorders such as ataxia-telangiectasia, Wiskott-Aldrich syndrome, and celiac disease have an increased incidence of lymphoma. Certain acquired conditions also predispose patients to lymphoma, including prior chemotherapy or radiotherapy, immunosuppressive therapy, Epstein-Barr infection, HIV infection, human T-cell lymphoma virus [HTLV]-1 infection, Helicobacter pylori gastritis, Hashimoto thyroiditis, and Sjögren syndrome.

Non-Hodgkin lymphoma may originate from B cells, T cells, or histiocytes. Morphologically, the tumors may appear as nodular clusters or diffuse sheets of lymphoid cells.

Classically, non-Hodgkin lymphoma presents as nontender enlargement of lymph nodes, but nearly one-third of all cases originate outside the lymph nodes. These extranodal malignancies develop in organs that normally have nests of lymphoid tissue (mucosal surfaces, bone marrow, and skin).

Staging & Classification

The goal of the staging evaluation is to distinguish patients who have localized disease from those with disseminated disease. After pathologic diagnosis, the staging evaluation for non-Hodgkin lymphoma consists of a detailed history and physical examination, routine laboratory tests, a bone marrow biopsy, and a CT scan of the neck, chest, abdomen, and pelvis. Evaluation of the cerebrospinal fluid should be considered in patients with diffuse large-cell non-Hodgkin lymphoma with bone marrow involvement, a high lactate dehydrogenase (LDH) level, or multiple extranodal sites of disease. It should also be considered in patients with high-grade lymphomas, HIV-related lymphomas, primary central nervous system lymphomas, and posttransplantation lymphoproliferative disorders. Finally, FDG-PET scans provide whole-body images that allow a comprehensive assessment of disease extent and, in conjunction with CT, provides complementary staging information. A pretreatment PET scan is often obtained so that PET can be used for monitoring of response to treatment. Normal PET at the end of therapy correlates with a highly favorable prognosis, while persistent abnormalities mandate close follow-up or biopsy to rule out residual disease.

The staging system for Hodgkin lymphoma is also used in non-Hodgkin lymphoma. Although helpful in assessing the anatomic extent of disease, the Ann Arbor system is of minimal clinical value in non-Hodgkin lymphoma. The international prognostic index (IPI) uses patient age, Ann Arbor stage, LDH level, number of extranodal sites, and ECOG performance status to categorize aggressive non-Hodgkin lymphoma. However, this system does not clearly stratify indolent lymphomas, so another prognostic factor model was devised for follicular lymphoma. The follicular lymphoma international prognostic index uses patient age, Ann Arbor stage, hemoglobin level, number of nodal areas, and serum LDH level to stage patients.

Scientists have made countless attempts to develop a universal, clinically relevant classification system for the subtypes of non-Hodgkin lymphoma, and the merits of the various classifications are an area of hot debate. The most widely accepted classification system is the Revised European-American Lymphoma/World Health Organization (REAL/WHO) classification (Table 44–8).

In determining the therapeutic approach to patients with non-Hodgkin lymphoma, a simpler classification system can be utilized. For treatment purposes, these lymphomas can be functionally divided into two groups: indolent (low-grade) and aggressive (high-grade) lymphomas. Smaller, differentiated cells characterize the indolent lymphomas, and this class tends to have a follicular architecture. Although the course of these lymphomas is not very aggressive and they have a long median survival, they are not usually curable in advanced clinical stages. The natural history of indolent lymphomas often involves progression of the tumor cells to a more aggressive subtype. This progression is sometimes heralded by the onset of B symptoms and portends a dismal prognosis.

The aggressive lymphomas behave differently from the indolent ones and demand a different therapeutic approach. Histologically, the aggressive lymphomas spread more diffusely throughout the lymph nodes and consist of larger, less differentiated cell types. This class of lymphomas demonstrates a very rapid growth rate and an increased rate of early mortality. Despite this malignant behavior, this class of non-Hodgkin lymphoma is more often curable. The extranodal lymphomas develop outside of the lymph nodes and are not amenable to conventional classifications, so they are generally regarded as a separate entity. They can involve any organ but most commonly affect the oropharynx, paranasal sinuses, thyroid, gastrointestinal tract, liver, testicles, skin, and bone marrow.

Treatment

A. Indolent Lymphoma

Patients with localized disease, although this is the minority, can be treated with radiation therapy only with curative intent. Most patients have disseminated disease, which tends to be chronic relapsing and remitting. The current therapies for systemic indolent lymphomas are rarely curative, and the goal of treatment is generally directed at palliation of symptoms. At present, a “watch and wait” approach to treatment is recommended for asymptomatic patients. After diagnosis, asymptomatic patients are followed up clinically until they progress to more aggressive disease, major symptoms, or organ dysfunction. Withholding chemotherapy does not reduce survival in patients with non-Hodgkin lymphoma, and it probably improves quality of life.

For patients who have symptoms, a combination of rituximab and alkylator chemotherapy has high response rates and can alleviate symptoms. Rituximab is a monoclonal antibody that binds to the B-cell surface antigen CD20. CD20 is a cell-surface protein involved in the development and differentiation of normal B cells. It is found on the vast majority of B-cell lymphomas. Rituximab is well tolerated and has remission rates of 40%-50% when used as single-agent therapy for relapsed indolent lymphoma. In younger patients with systemic indolent disease, or patients who had a short response to first-line treatment, high-dose chemotherapy with HCT may be considered, although the chance of cure should be balanced against the mortality of treatment, which can approach 10%.

B. Aggressive Lymphomas

Despite their aggressive nature, these lymphomas have a better chance for cure than their more indolent counterparts. The treatment is typically guided by the prognostic factors (IPI score). Patients with low-risk lymphoma respond well to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy plus rituximab. Radiotherapy may be used after chemotherapy for areas of bulky disease. Patients with high-risk lymphoma benefit from more intensive regimens of chemotherapy and rituximab and potentially high-dose therapy with HCT. This approach should also be considered for patients who relapse or fail to enter remission after induction chemotherapy. A promising immunotherapy is tositumomab, an anti-CD20 monoclonal antibody bound to ¹³¹I (Bexxar). It can kill cells by antibody-mediated cellular cytotoxicity, activation of complement-mediated tumor cell lysis, and the tumor-specific delivery of radiation. Bexxar is currently indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory non-Hodgkin lymphoma.

C. Nonlymphoid Disease

There is no consensus about the proper management of localized nonlymphoid lymphomas because large-scale studies of therapy for this disease have not been conducted. With few exceptions, nonlymphoid disease is managed somewhat in the same way as systemic aggressive lymphomas, using combination CHOP therapy.

The CHOP regimen has the disadvantage of poor penetration of the blood-brain barrier and is thus ineffective in the treatment of primary central nervous system lymphomas. These lymphomas rarely metastasize, remaining localized to the central nervous system. Current regimens utilize steroids and whole-brain radiation with some form of adjuvant chemotherapy. Methotrexate is the most common adjuvant treatment in this patient population, and it can be effective when delivered either systemically or intrathecally. This can be combined with whole brain radiation therapy. Central nervous system lymphomas have a poor prognosis, with approximately 20% 5-year survival rates in treated patients. The combined modalities, while providing modest survival benefits, have significant neurotoxicities, and as many as 50% of patients develop severe dementia. Given this morbidity, clinicians often use chemotherapy as the sole modality in the treatment of patients with primary central nervous system lymphomas. Extranodal lymphomas that have a predilection for metastases to the central nervous system, such as testicular, paranasal, and AIDS-related lymphomas, require systemic CHOP therapy combined with prophylactic intrathecal methotrexate treatments.

The treatment of gastric lymphomas has been controversial. Mucosa-associated lymphoid tissue–type gastric lymphomas (MALT-type gastric lymphomas) typically have an indolent behavior, and the most widely accepted initial therapy is the eradication of H. pylori using regimens combining antibiotics and proton pump inhibitors. For patients with MALT-type gastric lymphoma who are H. pylori negative or do not respond to antibiotic/proton pump inhibitor therapy, radiation therapy to the stomach and perigastric lymph nodes obtains high complete response rates and excellent long-term survival. While surgery had previously been used in the treatment of gastric lymphomas, there is now sufficient data to suggest nonoperative management permits a better quality of life with no impact on overall survival. When the disease has spread, the use of chemotherapy is similar to that used for other indolent, advanced lymphomas.

High-grade gastric lymphoma is treated with aggressive polychemotherapy, usually combined with rituximab. Again, surgery used to play a more prominent role but has greatly diminished. It was assumed that the increased risk of perforation and bleeding with chemotherapy could be prevented by pretreatment gastric resection, but modern series have failed to demonstrate that benefit and actually show a high degree of postsurgical complications that may delay the start of chemotherapy. Surgery is limited to patients who have complications or who cannot be managed by standard regimens.

Splenectomy in patients with lymphomatous splenic involvement has not demonstrated therapeutic benefit and should be reserved for patients with symptomatic splenomegaly, pain from recurrent splenic infarctions, and hematologic depression from hypersplenism.