Key Clinical Questions
What factors should be considered in determining treatment for a patient with cancer?
How do the outcomes of cancer clinical trials influence treatment decision making?
What treatment modalities exist and under what formats are these provided?
What are the main classes of systemic and radiation therapy?
Introduction
Cancer is a heterogeneous disease affecting all age groups, nationalities, and socioeconomic classes. Cancer patients, along with their families and friends, experience enormous social, emotional, and economic effects. In the United States, the National Cancer Institute (NCI) collects cancer-related statistics and produces the Surveillance, Epidemiology, and End Results (SEER) database (seer.cancer.gov).
It is estimated that in 2010 in the United States, 1,529,560 people will be diagnosed with and 569,490 will die of cancer. The lifetime risk of developing cancer is 1 in 2. In the United States in 2007, cancer was second to heart disease as the leading cause of death (23.2% versus 25.4%). Compared with death rates from 1975, the percentage of deaths from cardiac causes has decreased while cancer-related deaths have increased. Allowing for this, the absolute death rate among those diagnosed with cancer continues to decline. In North America, the most frequent incident cancers among men are prostate, lung, and colon and among women are breast, lung, and colon. Lung cancer is the leading cause of cancer-related deaths for both men and women. The second commonest cause of cancer deaths are prostate (males) and breast (females). Colon cancer is the third leading cause of cancer death for both sexes.
A 64-year-old woman was admitted with bowel obstruction due to metastatic rectal cancer. She has undergone many previous therapies. Some were attempts to cure the disease, and others were given with palliative intent. She was diagnosed eight years previously with stage III rectal cancer after presenting with rectal bleeding and was initially treated with curative intent consisting of 5-flurouracil and concurrent radiation therapy followed by surgery consisting of a total mesorectal resection. She then received additional chemotherapy. Three years later, her cancer recurred in the right lobe of the liver. She underwent a right hepatic lobectomy followed by further chemotherapy. She was free of disease for two years, but has recently been discovered to have peritoneal carcinomatosis and retroperitoneal lymphadenopathy. She was given radiation therapy to the lymph nodes to treat pain and followed by chemotherapy. This case demonstrates the continuum of cancer therapy intent. At initial presentation, the goal of treatment was to cure the disease. With subsequent cancer recurrences, the goals evolved. With the first recurrence, the intent was to potentially cure the patient given the isolated liver disease. Although not cured, the surgery prolonged a disease-free state and improved quality of life. Later recurrences were associated with strategies to palliate symptoms and transition to end-of-life care. This case demonstrates use of multiple treatment modalities (systemic, radiation, and surgical) used according to different principles (neoadjuvant, adjuvant, palliative). |
The approaches to management of two patients with lymphoma have been very different. The first patient was a 45-year-old man diagnosed with follicular lymphoma. His only symptoms were his finding of small lymph nodes in his right neck and left groin. While his blood cell counts were normal, a bone marrow biopsy showed the presence of clonal lymphocytes. After thorough discussions, it was decided that he would be evaluated again in three months and that therapy would be deferred. The approach was referred to as “watchful waiting.” In contrast, a 78-year-old woman presented with abdominal pain and was found to have a large mesenteric mass. A biopsy showed diffuse large B-cell lymphoma. She was treated with cyclical systemic therapy consisting of cyclophosphamide, hydroxydaunorubicin (doxorubicin or Adriamycin), vincristine (Oncovin), prednisone, and rituximab (CHOP-R). While treatment was associated with important side-effects, her oncologist now hopes that she is cured. These two cases demonstrate how prognostic determinants influence management. Both the histologic classification of the cancer (follicular versus diffuse large B-cell lymphoma) and the extent of disease (stage) are associated with unique natural histories and the abilities to alter disease courses. Management decisions will also be influenced by patient comorbidities and preferences; these cases illustrate the caveat that patient age should not independently dominate this decision-making process. |
Cancer Etiology
Four types of human cells exist: germ cells, stem cells, partially differentiated cells, and mature/specialized cells. These cells vary in their abilities to reproduce and differentiate. When cells differentiate, most eventually undergo a programmed process of cell death, referred to as apoptosis. Apoptosis is triggered by the cell surpassing a number of cell cycle divisions. Cancer is a disease in which cells have altered genetic processes as a result of mutations. Mutations lead to gain or loss of genetic functions that permit abnormal proliferation, failure to undergo apoptosis leading to cellular accumulation, or both. The etiology of mutations varies, with many being unknown. Factors contributing to genetic instability include inherited risks, viruses, chronic inflammation, chemical carcinogens (eg, tobacco, asbestos), radiation (eg, UVA/UVB), and lifestyle factors (eg, diet and obesity). The resulting abnormal genetic processes lead to special properties that permit cell transit, invasion, and growth at new sites, referred to as metastases. Increased understanding of cancer-specific genetic alterations have led to the availability of more selective therapies and the advent of the term personalized medicine.
Basic mechanism of cancer
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Classifying Cancer for Treatment and Prognosis
Cancer is a heterogeneous group of diseases. Three factors that assist classifying patient management strategies are cancer site, histology, and stage. Site refers to anatomic location (eg, breast, lung). Histology refers to pathologic cellular and tissue appearances and includes broad (eg, carcinoma, sarcoma, lymphoma) and specific (eg, squamous cell, adenocarcinoma) categorization. Histology is usually determined through pathologic evaluation of resected material or a large bore needle core biopsy. In some instances, histology can be inferred through the cytologic examination of cells obtained by fine needle aspiration (FNA). Cancers of the same site but of different histology will have different clinical behaviors, management strategies, and prognoses. Stage refers to the anatomic extent of disease, including anatomic regions involved with the primary tumor (T), lymph node involvement (N), and the presence or absence of distant metastasis (M); stage is often categorized using the TNM schema. Some diseases such as lymphoma and gynecologic cancers have separate staging classifications. In addition to facilitating determination of prognosis, stage has important implications for management as “local” therapies (ie, surgery, radiation therapy) are most applicable to patients with more limited stages of disease. Determination of site, histology, and stage require systematic diagnostic processes that include a comprehensive history and physical examination, obtaining diagnostic material and expert pathology review and appropriate laboratory and imaging investigations.
Recent understandings have permitted more sophisticated patient risk profile assessments that enhance abilities to determine prognosis and best management. Initially, risk categorizations were predominantly based on combining evaluations of standard clinically determined cancer-related factors such as histology, stage, and associated laboratory markers (eg, lactate dehydrogenase), patient-related factors such as age and comorbidity (see the proceeding section on Patient Factors and Goals when Determining Treatment) and general measures of health influenced by the combination of cancer- and patient-related factors (eg, the Eastern Cooperative Oncology Group [ECOG] or Karnofsky Performance Status Indices). More recently, prognostic and predictive biomarkers that include molecular markers (eg, HER2 in breast cancer, K-Ras in colon cancer) and gene expression signature profiles are either used or are being tested to determine best treatment.
Patient Factors and Goals When Determining Treatment
The management of individuals with cancer is highly influenced by patient-specific determinants that include their comorbidities, relative contraindications to specific treatment components, and values and preferences. As illustrated in the case descriptions at the beginning of this chapter, cancer therapy often includes the use of multiple modalities and drugs. Perhaps more than any other disease, each therapeutic component can be associated with risks of treatment-related morbidity and mortality. These risks must be balanced with the potential for benefit on a case-by-case basis. This evaluation begins with understanding global aspects of a patient’s health, their functional status (which includes capacities to address basic activities of daily living), and psychosocial and socioeconomic circumstances. Understanding the need for, and availability of, caregiver support can be essential. The evaluation then proceeds to include understanding whether special risks exist with respect to specific therapies. For instance, use of anthracycline agents such as doxorubicin may not be feasible in patients with cardiac disease, platinum agents such as cisplatin must be attenuated or avoided in patients with renal disease, and radiation treatment may need to be modified in patients with a pacemaker near a thoracic tumor.
The goals of cancer therapy are to prolong life, reduce suffering, and enhance quality of life. These goals must balance the potential benefits and harms of treatment. Increasingly, treatment policies are influenced by the economic determinants of cost effectiveness and cost utility. Central to decision making is understanding whether the potential of therapy is to cure the patient and leave them with a life-expectancy that parallels that of age- and sex-matched controls, to induce a prolonged state of freedom from obvious disease and its symptoms (ie, a remission) even if eventual disease recurrence is anticipated, or to provide a temporary reduction in the burden of disease and palliation of symptoms.
The risks of the underlying cancer and treatment toxicities must be balanced with the potential benefits of the treatment intervention. This evaluation can range from the more statistically-based paradigm in which adjuvant chemotherapy (see Treatment Modalities later in this chapter) enhances the potential for cure in patients with surgically resected cancer to the trade-offs associated with palliating the symptoms created by cancer versus introducing new symptoms associated with treatment toxicity in patients with advanced disease. Decisions vary according to patient perspectives, values, and experiences. Careful communication, usually through involvement of a multidisciplinary team, is essential.
Making treatment decisions
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Deciding Whether Therapy Has Benefits that Outweigh Harms: Clinical and Surrogate Endpoints Used in Cancer Clinical Trials
The management of cancer patients has been tightly interwoven with the conduct of clinical trials. This culture continues and often clinical trials provide opportunities for patients to access therapies that may later be confirmed efficacious and become new standards of care. However, when patient care includes participation in a clinical trial, clinicians and patients need to understand the objectives of the trial and whether the endpoints used represent potential benefit to the patient. A useful paradigm is to contrast explanatory trials, in which a trial’s objective is to determine whether an intervention is associated with a potentially efficacious causal biologic relationship (eg, treatment results in a reduction in tumor size), with pragmatic
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