Box 22.1 RISK FACTORS FOR BREAST CANCER
Gender
Age
Higher weight/BMI (for postmenopausal women)
Personal history of breast cancer or benign breast disease
Exposure to ionizing radiation
Family history of breast cancer
Race/ethnicity
Diet
Alcohol
Prolonged postmenopausal hormone replacement therapy (HRT)
Longer exposure to and higher concentrations of endogenous estrogen (early menarche, nulliparity, older age at first birth, later menopause)
Inherited breast cancer susceptibility gene; BRCA1/2, p53, etc.
Box 22.2 MAMMOGRAM GUIDELINES, U.S. PREVENTIVE SERVICES TASK FORCE 2009
1. Screening mammograms should be done every 2 years beginning at age 50 for women at average risk of breast cancer.
2. Screening mammograms before age 50 should not be done routinely and should be based on a woman’s values regarding the risks and benefits of mammography.
3. Doctors should not teach women to do breast self-examinations.
4. There is insufficient evidence that mammogram screening is effective for women age 75 and older, so specific recommendations for this age group were not included.
NOTE: USPSTF guidelines differ from those of the American Cancer Society (ACS). The ACS mammogram guidelines for women at average risk for breast cancer recommend yearly mammogram screening beginning at age 40 and continuing as long as a woman is in good health. ACS guidelines indicate that the breast self-examination is optional in breast cancer screening. SOURCES:http:/www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm and http://www.cancer.org/healthy/findcancerearly/cancerscreeningguidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer OURCES:http:/www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm and http://www.cancer.org/healthy/findcancerearly/cancerscreeningguidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer
The vast majority (>95%) of breast cancers are epithelial in origin and are classified as carcinomas. Breast carcinomas can be divided into two distinct groups: (1) in situ carcinomas, in which cancer cells are confined inside ducts or lobules and do not invade into the surrounding stroma; and (2) invasive or infiltrating carcinomas, where cancer cells invade into the breast stroma and consequently have the potential to metastasize. There are two major histologic types of in situ carcinomas, referred to as ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). There are several different histologic types of invasive breast cancer, including invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), mixed ductal/lobular carcinoma, mucinous (colloid) carcinoma, tubular carcinoma, medullary carcinoma, and papillary carcinoma. IDC is the most common histologic subtype, accounting for approximately 75% of all invasive breast cancers.
Approximately two-thirds of all invasive breast cancers are hormone receptor-positive; that is, the cancer cells express either the estrogen receptor (ER) or the progesterone receptor (PR). Different laboratories may have different cut-off points for categorizing a cancer as “hormone receptor-positive” or “hormone receptor-negative.” Research studies have demonstrated that even cancers that have only a small percentage of cells that express hormone receptors may respond to hormonal therapy. In 20% of invasive breast cancers, the human epidermal growth factor cell surface receptor 2 (HER2) is overexpressed. The risk of recurrence is higher for hormone receptor-negative compared to hormone receptor-positive breast cancer, and for HER2-positive compared to HER2-negative breast cancer. Invasive breast cancers that express none of these three receptors (approximately 15% of all invasive breast cancers) are called “triple-negative” breast cancers and carry a poor prognosis. Inflammatory breast cancer can be of any subtype and represents a particularly aggressive locally advanced form of breast cancer with a relatively high risk for systemic disease.
Management options are summarized in table 22.1.
Table 22.1 MANAGEMENT OPTIONS FOR BREAST CANCER
| STAGES OF BREAST CANCER | MANAGEMENT OPTIONS |
Stage 0 breast cancer (carcinoma in situ) LCIS DCIS | Consider preventative tamoxifen or raloxifene. Excision of breast tissue to achieve negative margins and radiation therapy are not indicated. Mastectomy, or lumpectomy (breast-conserving therapy) with complete removal of the tumor to achieve negative margins. Radiation therapy to the breast follows lumpectomy and reduces the risk of local recurrence. Sampling of the axillary lymph nodes is not indicated for cases of pure DCIS (i.e., no evidence of invasive cancer). Both lumpectomy followed by radiation therapy and mastectomy confer a high likelihood of survival (>98%). Tamoxifen is frequently recommended after lumpectomy to reduce risk of local recurrence. |
| Stage I, II, and III breast cancer (nonmetastatic) | Cure is the goal of therapy. Surgical resection includes either mastectomy or lumpectomy with axillary nodal sampling to remove the primary cancer. Radiation therapy to the breast traditionally follows lumpectomy, and radiation therapy to the chest wall following mastectomy is occasionally recommended in higher-risk situations (e.g., if the tumor is >5 cm or axillary lymph nodes are involved). Hormone-receptor–negative breast cancers tend to recur within the first few years, whereas hormone-receptor–positive breast cancers may recur 10 or more years after diagnosis. The choice of adjuvant systemic therapy depends on the risk of recurrence and the subtype of breast cancer. The higher the risk of recurrence, the greater the potential benefit of adjuvant therapy. Adjuvant endocrine therapy is specifically indicated if a tumor is hormone-receptor positive. Adjuvant chemotherapy is typically indicated for women with hormone-receptor–negative cancers and selected higher-risk hormone-receptor–positive cancers. Gene expression analysis, e.g., OncotypeDX, can be used to determine if the addition of chemotherapy would provide reduction in the risk of recurrence. Chemotherapy for breast cancer usually involves the administration of two or three medications with minimally overlapping toxicity profiles; commonly used medications include cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, epirubicin, paclitaxel, and docetaxel. The addition of adjuvant trastuzumab to chemotherapy is indicated for most HER2+ cancers. |
| Stage IV breast cancer (metastatic) | Metastatic breast cancer is incurable. The primary goals of treatment include prolongation of survival and palliation of symptoms. Selection of systemic therapy is tailored for tumor subtype. Initial management of hormone-receptor–positive metastatic breast cancer most commonly involves the administration of an antiestrogen hormonal medication. Hormonal treatment options can include tamoxifen, a selective aromatase inhibitor (e.g., anastrozole, letrozole, or exemestane), fulvestrant, or a gonadotropin-releasing hormone (GnRH) agonist for premenopausal women. For endocrine-refractory/hormone-receptor–negative metastatic breast cancer or symptomatic metastatic disease, systemic chemotherapy is typically administered. Multiple chemotherapy medications have activity in advanced breast cancer. Anti-HER2-directed therapy, including trastuzumab, pertuzumab, T-DM1 and lapatinib, is indicated in the treatment of advanced HER2+ disease. For women who have metastatic bony deposits, the regular administration of an intravenous bisphosphonate (e.g., pamidronate or zoledronic acid) or a RANK ligand inhibitor (e.g., denosumab) helps prevent/delay the development of skeletal complications and palliates bone pain. Targeted local therapies such as surgical excision, radiation therapy, or radiofrequency ablation are sometimes indicated. |
LUNG CANCER
Lung cancer is a heterogeneous group of malignancies comprising small cell lung cancer (SCLC; 13%) and non-small cell lung cancer (NSCLC; 86%); additional rare thoracic malignancies include mesothelioma and carcinoid tumors. The single most important risk factor, smoking, accounts for approximately 85% of all lung cancers. Other associated factors include exposure to radon, asbestos, and heavy metals. Additional causative exposures include wood smoke, previous chest radiotherapy, and heavy metals such as arsenic, chromium, nickel, beryllium, and cadmium. Clinically, the respiratory symptoms of lung cancer often mimic the effects of chronic tobacco use. Many patients present with cough, worsening dyspnea, or hemoptysis, which can also be symptoms of bronchitis or pneumonia. Systemic symptoms include weight loss, chest pain, bone pain, hoarseness, or neurologic symptoms.
Paraneoplastic syndromes are most frequently seen in patients with small cell lung cancer, but can be seen in either type of lung cancer.
• Hematologic abnormalities: Leukocytosis (likely from tumor secretion of granulocyte colony-stimulating factor [G-CSF]), anemia, and thrombocytosis.
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH): Up to 10% of SCLC may secrete ADH, resulting in profound hyponatremia.
• Hypercalcemia: Hypercalcemia in malignancy may result from direct bone invasion or secretion of osteoclast-activating factors and occurs most commonly in squamous cell cancers.
• Cushing syndrome: Excess production of adrenocorticotropic hormone (ACTH) by tumor tissue can lead to Cushing syndrome: truncal obesity, hypertension, hyperglycemia, hypokalemic alkalosis, and osteoporosis.
• Pancoast syndrome: Lung tumors that arise in the superior sulcus of either lung can cause damage to the brachial plexus and the sympathetic ganglia. This results in a syndrome of shoulder/arm pain, ipsilateral Horner syndrome, bone destruction, and atrophy of the hand muscles.
• Neurological abnormalities: Eaton-Lambert syndrome (a myasthenia-like neuropathy) and anti-neuronal antibodies (e.g. “anti-Hu”).
• Thrombosis: Presenting with deep vein thrombosis and/or pulmonary embolism.
Diagnostic evaluation should include a chest radiograph—a nodule on a chest x-ray or computed tomography (CT) scan may lead to the diagnosis of lung cancer. A CT of the chest with IV contrast gives an overview of the extent of parenchymal disease and regional nodal involvement and can also demonstrate metastatic disease to the bones, liver, or adrenal glands. PET/CT scans are used frequently to further evaluate the extent of regional or metastatic disease. Bronchoscopy, increasingly in combination with endobronchial ultrasound, is most useful for proximal tumors and can yield information about a primary tumor and lymph node staging. Although the diagnosis can be made from fine-needle aspiration alone, advanced molecular testing requires more tissue in the form of a core biopsy or surgical sample. Chest radiographs have repeatedly been shown to be ineffective as a means of screening for lung cancers; recent observations have suggested a role for spiral CT scans as a screening approach for high-risk individuals with a heavy smoking history.
Management options are summarized in table 22.2.
Table 22.2 MANAGEMENT OPTIONS FOR LUNG CANCER
| TYPE OF LUNG CANCER | MANAGEMENT OPTIONS |
| Stage I–II NSCLC | Initial treatment for stage I (small tumor without lymph node involvement) and stage II (larger and more invasive tumors or hilar lymph node involvement) consists of surgical resection. For large stage Ib tumors, and for all stage II tumors, it is estimated that patients have approximately a 5% overall survival benefit to cisplatin-based doublet adjuvant chemotherapy. For small stage I tumors there is no evidence of benefit from adjuvant chemotherapy. There is no role for adjuvant radiation therapy in completely resected NSCLC. |
| Stage III NSCLC | Therapy for stage III NSCLC includes a combination of chemotherapy, radiation, and sometimes surgical resection. Stage IIIB disease is generally considered surgically unresectable and is treated with concurrent chemotherapy and high-dose radiation with curative intent (“definitive” treatment). The treatment of stage IIIA disease is less standardized and often includes surgery, preoperative and/or postoperative chemotherapy, and consideration of radiotherapy. |
| Stage IV NSCLC | The backbone of therapy for stage IV NSCLC is systemic chemotherapy. Standard first-line chemotherapy consists of platinum-based doublet chemotherapy. Most platinum-based doublets (carboplatin or cisplatin, in combination with paclitaxel, docetaxel, gemcitabine, vinorelbine, or pemetrexed) generally have equivalent impacts on survival. A number of novel agents are considered for advanced disease, including inhibitors of VEGF, EGFR, and EML4-ALK. |
| Limited-stage SCLC | Concurrent radiotherapy and concurrent full-dose chemotherapy with cisplatin and etoposide, followed by chemotherapy alone. Following chemotherapy and radiation, prophylactic cranial irradiation. |
| Extensive-stage SCLC | Extensive-stage small cell lung cancer is incurable. Patients who respond to initial therapy also have a survival benefit from prophylactic cranial irradiation. Second-line therapy is more successful in patients with a disease-free interval longer than 3 months after initial therapy (“relapsed” disease) than patients with a disease-free interval of less than 3 months (“refractory” disease). Supportive care also plays an essential role in the management of SCLC. |
GI MALIGNANCIES
The most common gastrointestinal cancers in the United States are esophageal, gastric, pancreatic, and colorectal.
Esophageal Cancer
Esophageal cancer is diagnosed in approximately 16,000 individuals in the United States annually, leading to nearly 14,000 deaths. There are two major histologic types, squamous cell carcinoma and adenocarcinoma. Other histologic types, such as melanomas, carcinoids, lymphomas, and sarcomas are rare.
Squamous cell carcinomas largely develop in the upper third and middle third of the esophagus. Adenocarcinomas primarily develop in the lower third of the esophagus and, particularly in cancers at the gastroesophageal junction, have markedly increased in frequency during the past several decades. The primary risk factors for squamous cell carcinomas are tobacco and alcohol exposure. Other conditions that lead to irritation of the esophageal mucosa and increase the risk of squamous cell carcinoma include achalasia, caustic injury to the esophagus, and esophageal diverticuli. Rare conditions that carry a very high risk of squamous cell carcinoma include nonepidermolytic palmoplantar keratoderma (tylosis), a rare autosomal dominant disorder characterized by hyperkeratosis of the palms and soles and thickening of the oral mucosa, and Plummer–Vinson syndrome, a nutritional deficiency characterized by dysphagia, iron-deficiency anemia, and esophageal webs. Adenocarcinomas of the esophagus principally develop in the setting of Barrett’s esophagus. Risk factors associated with the development of Barrett’s esophagus include gastroesophageal reflux disease and obesity.
Patients with esophageal cancer commonly present with symptoms of difficulty swallowing (dysphagia) and, less commonly, with painful swallowing (odynophagia). Prior to diagnosis, patients often have dysphagia for solids that gradually progresses to difficulty even for liquids. Patients may also present with hematemesis, unexpected weight loss, cough, aspiration pneumonia, hoarseness, or symptoms related to areas of metastases.
The treatment and prognosis of esophageal cancer reflect the stage of disease at diagnosis (table 22.3) Squamous cell carcinomas and adenocarcinomas are radiologically indistinguishable and are approached diagnostically and therapeutically in a similar fashion. Patients who are diagnosed with esophageal cancer by upper endoscopy should undergo staging evaluation including CT of the chest, abdomen, and pelvis to assess for metastases. PET/CT scans have been shown to be particularly effective in identifying spread to regional lymph nodes in such patients. The most common sites of metastases are liver, lung, lymph nodes, and bone.
Table 22.3 MANAGEMENT OPTIONS FOR GI CANCERS
| GI CANCER | MANAGEMENT OPTIONS |
| Esophageal cancer | For patients with disease that does not extend beyond the muscle layer of the esophageal wall and without evidence of lymph node involvement, immediate surgery is recommended. For those with disease that extends beyond the muscle layer or with locoregional lymph nodes, neoadjuvant therapy with chemotherapy and radiation should be considered prior to surgery. Chemoradiation therapy is given over 5–6 weeks with daily radiation and various combinations of chemotherapy agents. Following the completion of neoadjuvant therapy, restaging is recommended, followed by surgery approximately 6 weeks after the last dose of radiation. For patients with localized disease who are not surgical candidates due to concurrent medical conditions or who refuse surgery, disease is treated with chemoradiation. Patients with metastatic disease should be considered for palliative therapy. Chemotherapy can palliate symptoms relating to swallowing and can prolong overall survival. |
| Gastric cancer | For patients with nonmetastatic disease, the primary treatment modality is surgery. Following surgical resection, nonmetastatic patients whose disease extends beyond the muscle layer of the gastric wall or with positive lymph nodes should be considered for adjuvant chemoradiotherapy. For patients with metastatic disease, palliative chemotherapy is the primary treatment modality. No single regimen is considered standard. For patients with a good performance status, combination regimens that include a platinum agent are reasonable first-line choices. |
| Pancreatic cancer | For head of the pancreas lesions, a pancreaticoduodenectomy (Whipple) operation is performed with resection of part of the pancreas and duodenum, common bile duct, gallbladder, and distal stomach. For body or tail of the pancreas lesions, a distal pancreatectomy with or without splenectomy is performed. Resection of body or tail lesions is considerably less common because most such cancers are metastatic at the time of diagnosis. Following resection, adjuvant therapy with chemotherapy alone or a combination of chemotherapy and radiation is recommended. Combined-modality chemotherapy and radiation is typically pursued for locally advanced pancreatic cancer. Palliative chemotherapy is utilized for metastatic pancreatic cancer; however, benefit tends to be limited. |
| Colorectal cancer | Treatment for colorectal cancer depends on stage of disease. Surgery is considered the only curative therapy for colorectal cancers. Multiple clinical trials have demonstrated a survival benefit for adjuvant chemotherapy in stage III (lymph node–positive) colon cancer patients following surgery. For patients with metastatic disease, removal of the primary tumor still remains an important consideration to palliate and prevent symptoms due to the colorectal lesion (including bleeding and obstruction). Chemotherapy is an important component of the treatment of patients with metastatic disease as well as many patients with surgically resected tumors. The backbone of colorectal cancer treatment for the past four decades is the fluorinated pyrimidine, 5-fluorouracil (5-FU). Newer regimens can also include oxaliplatin, irinotecan, and/or targeted biological therapy. |
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