What types of biopsies can aid in the diagnostic workup of cancer?
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CHAPTER 175 Overview of Cancer and Treatment
Jennifer Duff, MD
Merry Jennifer Markham, MD
Key Clinical Questions
What types of biopsies can aid in the diagnostic workup of cancer? How is the cancer stage determined? What are the goals of therapy in the neoadjuvant, adjuvant, and palliative setting? What are the different types of systemic therapies commonly used in the treatment of cancer?
What are the approaches to treating chemotherapy-related nausea, vomiting and mucositis?
When are modified blood products recommended for cancer patients and what are the transfusion thresholds for anemia and thrombocytopenia?
EPIDEMIOLOGY
Cancer is a group of diseases characterized by uncontrolled proliferation of abnormal cells that invade surrounding tissue and carry the potential to metastasize. Environmental
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and lifestyle risk factors and genetic susceptibility all contribute to an individual’s risk of developing cancer. In 2015, more than 1.6 million Americans will be diagnosed with cancer, and approximately 600,000 cancer-related deaths will occur. The most common cancers afflicting men and women are prostate and breast, respectively, followed by lung and colorectal. Overall, lung cancer is the leading cause of cancer-related mortality, followed by colorectal cancer. The incidence of lung and colon cancer in men is steadily declining, perhaps reflecting decreased tobacco use and emphasis on colorectal cancer screenings. Lung cancer incidence in women is finally starting to decrease after rising over the last few decades, reflecting the delayed uptake in smoking (and later, smoking cessation) by women compared to men.
DIAGNOSIS AND STAGING Biopsy of a primary and/or metastatic site of a presumed malignancy is necessary to provide histologic confirmation of a cancer diagnosis. Involving a hematologist-oncologist early in the workup of a newly diagnosed cancer patient can be helpful in guiding the appropriate testing, biopsy sites, or biopsy techniques. For example, different biopsy techniques—including fine needle aspiration (FNA), core needle biopsy, excisional biopsy, or laparotomy—may be utilized depending on the type of cancer suspected. An FNA alone is inadequate in the diagnosis of lymphomas as the morphology of the nodal tissue is crucial in determining lymphoma subtype. Core needle biopsies and excisional or incisional biopsies provide a larger volume of tissue for pathologic evaluation of morphology and for molecular or genetic analysis. When a hematologic malignancy, such as lymphoma, is suspected, sending a fresh, not fixed, specimen for comprehensive immunophenotyping using flow cytometry is important in yielding the correct diagnosis. Finally, in addition to confirming a cancer diagnosis, the biopsied tissue specimen may guide therapeutic decisions. For example, molecular biomarkers, such as HER2Neu for breast cancer and KRAS/NRAS for colon cancer, have implications for the oncologist’s choice of antineoplastic agents used during therapy.
Accurately staging patients to determine the extent of their disease is critical in determining prognosis and for guiding treatment decisions. Staging often involves radiographic imaging (such as computed tomography [CT] or positron emission tomography [PET] scans) or endoscopic or surgical visualization to determine local and distant organ involvement. Comprehensive radiologic imaging is not always necessary in the staging process when the cancer appears to be locally confined and has a low likelihood of distant involvement (eg, early stage breast cancer). Serum tumor markers have a role in the staging of some cancers, such as testicular and ovarian cancers. Bone marrow biopsy or lumbar puncture may be important in the staging of various hematologic malignancies. Decisions about type of staging studies needed for an individual patient should be made in conjunction with a consulting hematologist- oncologist.
Solid organ tumors are staged by the American Joint Committee on Cancer (AJCC) TNM classification system, where T refers to tumor size or degree of mucosal infiltration of the primary tumor, N describes lymph node involvement, and M refers to the presence or absence of metastatic disease. Lymphomas have their own unique staging systems and, as in solid tumors, prognosis and treatment options vary with stage.
Typically, early stage (stages I and II) solid tumors lack lymph node involvement and are curable. Stage III solid organ cancers are often referred to as locally advanced and
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typically involve regional lymph nodes. Metastatic, or stage IV, solid organ cancers are generally incurable but are often treatable. However, some solid tumors, including colorectal and breast cancers, and melanoma with limited metastatic sites, have curative potential with a multidisciplinary treatment approach.
TREATMENT A CASE EXAMPLE
Ms J, a 55-year-old woman, presented with intermittent rectal bleeding and difficulty passing bowel movements. A colonoscopy revealed a friable, partially circumferential mass in the rectum. Biopsy of the mass confirmed a moderately well-differentiated adenocarcinoma. Staging with contrasted CT of the chest, abdomen, and pelvis, did not show any distant metastatic disease. Further staging with endoscopic ultrasound confirmed a stage IIIA (T3N1M0) rectal cancer. She was treated with neoadjuvant chemoradiation using oral capecitabine with daily radiation therapy for 5.5 weeks. After completing neoadjuvant treatment, she underwent a low anterior resection with an end-to- end anastomosis. The surgical pathology showed moderate treatment response with down-staging of the disease and no involved lymph nodes. She completed 3 out of 4 months of curative adjuvant systemic chemotherapy with fluorouracil, leucovorin, and oxaliplatin, stopping 1 month short due to side effects. For the next 3 years, she had no radiographic or clinical evidence of recurrent disease until she developed persistent right upper quadrant abdominal pain. Computed tomography imaging demonstrated innumerable hypodensities in the liver and scattered nodules in the lungs, all concerning for metastatic disease. A core biopsy of a liver lesion confirmed metastatic colorectal adenocarcinoma. Mutational testing of the tissue confirmed wild-type KRAS and NRAS genes. She was treated with palliative chemotherapy consisting of fluorouracil, leucovorin, irinotecan, and bevacizumab with good tumor response and relief of pain symptoms. However, restaging imaging after 8 months demonstrated peritoneal carcinomatosis, consistent with progressive disease. Her treatment was switched to irinotecan plus cetuximab. She tolerated this regimen poorly with a declining performance status. After two cycles, the chemotherapy was discontinued and she was enrolled in Hospice. She lived another 2.5 months without treatment, allowing her to travel with her family prior to her death.
This case illustrates the continuum of cancer care in an initially curable cancer that ultimately relapsed and progressed, resulting in death. In this example, neoadjuvant, adjuvant, and palliative treatment regimens were utilized, each intended to accomplish a specific goal. Neoadjuvant therapy was used to improve surgical outcomes and reduce the risk of local tumor recurrence. Adjuvant therapy was used to eradicate micrometastatic disease and reduce the likelihood of systemic recurrence. Palliative chemotherapy was used to improve disease control, survival, and to relieve cancer-related symptoms.
The optimal treatment of cancer patients often requires a multidisciplinary, team-based approach, with collaboration among all health care providers involved including surgeons, radiation oncologists, medical oncologists, radiologists, pharmacists, nursing, social workers, psychologists, and nutritionists. Providing patient-centric care for cancer patients extends beyond formulating treatment plans; it involves understanding patients’ emotional well-being, their psychosocial needs, and recognition of socioeconomic barriers that may impede safe care. Early identification of depression or anxiety, inadequate support
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systems, or insufficient understanding of the diagnosis and treatment goals, is crucial in providing humanistic oncology care.
SURGERY, SYSTEMIC THERAPY, RADIATION THERAPY
Surgical resection of the tumor burden is the gold standard therapy for achieving cure in most solid-organ cancers. Lymphomas and other hematologic malignancies, small-cell lung cancer, locally advanced non–small-cell lung cancer, and prostate and cervical cancer are among those malignancies that have curative potential with chemotherapy or radiation therapy alone, or a combination of these treatment modalities. The extent of surgical resection depends on the operative risk, size and location of the primary tumor, involvement of surrounding tissues, and the degree of lymph node dissection indicated. For certain high-risk, complex surgeries, such as esophagectomy for esophageal cancer, surgeon and hospital experience and higher surgical volume yield improved outcomes for patients, and referral to an experienced surgeon in a high-volume center is important. Similarly, for the gynecologic cancers, outcomes are improved for women who have surgical resection by a gynecologic oncologist rather than a general surgeon or gynecologist.
Systemic therapy is an umbrella term encompassing a variety of cancer treatments, including chemotherapy, biologic (or targeted) therapy, immunotherapy, and hormonal therapy. Oncologists’ choice of a chemotherapy regimen is based on current evidence- based national guidelines, the goals of treatment (curative vs palliative), and patient performance status. Multiagent chemotherapy regimens are often selected in the curative setting or when maximum disease control is preferred and feasible. Single-agent chemotherapy is often selected when palliation is desired. When chemotherapy agents are combined, they are often selected due to diverse mechanisms of action and nonoverlapping side effects in order to maximize efficacy while minimizing undesirable toxicity to the patient.
Cytotoxic chemotherapy drugs lead to cancer cell death through a variety of mechanisms that interfere with the cell growth cycle. Each class of chemotherapy drugs carries its own unique set of side effects, some of which are short term and only occur transiently during treatment, while others may occur during or after treatment and result in permanent morbidity (Table 175-1). The drugs in the vinca alkaloid, platinum, and taxane classes may result in varying degrees of motor or sensory neuropathy. Anthracyclines (eg, doxorubicin) are associated with a risk of cardiac toxicity in the short and long term, including cardiomyopathy and/or arrhythmias.
TABLE 175-1 Chemotherapy Drug Classes and Usual Toxicities
Chemotherapy Class Examples of Drugs Side Effects Alkylating agents Cyclophosphamide
Ifosfamide Dacarbazine Temozolomide Chlorambucil
Myelosupression Dose-related emesis Pneumonitis Syndrome of inappropriate ADH (SIADH) Secondary leukemias
Anthracyclines Doxorubicin Myelosupression
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Daunarubicin Epirubicin
Mucositis Cardiotoxicity Vesicant
Antimetabolites 5-fluoruracil Capecitabine Pemetrexed Methotrexate
Myelosuppression Mucositis Gastrointestinal (nausea, vomiting, diarrhea)
Platinum agents Carboplatin Cisplatin Oxaliplatin
Renal Toxicity Neuropathy Nausea/vomiting Myelosuppression
Taxanes Docetaxel Paclitaxel
Myelosupression Hypersensitivity reactions Neuropathy
Topoisomerase I inhibitors
Irinotecan Diarrhea Early onset (1-6 h from infusion), due to inhibition of acetylcholinesterase; treated with atropine Later onset, from mucosal damage; treated with aggressive loperamide dosing
Topoisomerase II inhibitors
Etoposide Myelosuppression Nausea/vomiting Secondary acute myelogenous leukemia
Vinca alkaloids Vincristine Vinblastine
Vesicant Peripheral neuropathy, motor and sensory Autonomic neuropathy (such as ileus) Cranial nerve palsies SIADH Myelosuppression with vinblastine
Systemic cancer therapies are continuously evolving and novel biologics and immunotherapies have an important and growing role in the treatment of malignancy. Biologic agents, also referred to as targeted therapies, are directed toward specific intracellular characteristics or pathways of tumors. One of the first targeted therapies was imatinib, the oral drug that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal gene product of the Philadelphia chromosome in chronic myeloid leukemia. Monoclonal
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antibodies selectively target specific cell antigens found predominantly on tumor cells. For example, rituximab is an anti-CD20 monoclonal antibody which, when paired with chemotherapy, has substantially improved response rates and survival in B-cell non- Hodgkin lymphoma. Other monoclonal antibodies include bevacizumab, which binds to the vascular endothelial growth factor protein interfering with angiogenesis; cetuximab, which binds to the EGFR receptor to prevent downstream signals involved in tumor growth and proliferation; trastuzumab and pertuzumab, which work through targeting the HER2 receptor; and ado-trastuzumab (also known as T-DM1) which combines trastuzumab with a chemotherapeutic to target delivery of the cytotoxic agent specifically to cancer cells.
Immunotherapy refers to those agents aimed at stimulating the immune system to overcome the immune evasion triggered by the malignancy. For example, Sipuleucel-T, an autologous immunotherapy approved in advanced prostate cancer, primes a patient’s antigen presenting cells to promote an immune response against their disease. Newer immunotherapy agents block immune checkpoints such as the cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) and the programmed death 1 (PD-1) receptor, thus enhancing antitumor immunity. Ipilimumab used in metastatic melanoma is an antibody directed against CTLA-4, and pembrolizumab and nivolumab are anti-PD-1 antibodies both used for metastatic melanoma. Nivolumab is also approved for use in metastatic squamous cell non–small-cell lung cancer.
Hormonal, or endocrine, therapy refers to agents that modulate hormones that are a driving factor in the growth and proliferation of a tumor. They function through several mechanisms, some of which include direct hormone receptor blockade, interfering with hormone production by the pituitary and adrenal glands and ovaries, and inhibiting peripheral hormone conversion. The treatment of breast and prostate cancers frequently incorporates hormonal therapies such as antiestrogenic agents including the aromatase inhibitors (eg, anastrazole, letrozole, and exemestane) and selective estrogen receptor modulators (eg, tamoxifen) and LHRH agonists (eg, goserelin).
Radiation therapy consists of delivering high-energy x-rays or other particles to a specified body region, resulting in DNA destruction and tumor death. Common radiation therapy techniques include external beam radiation, 3-D conformational radiation therapy (3-D CRT), intensity modulated radiation therapy (IMRT), stereotactic and proton beam radiation therapy. All of these methods have varying degrees of precision in targeting the tumor to minimize the impact on surrounding healthy tissue. Internal radiation therapy, or brachytherapy, involves placing radioactive material into or near the tumor tissue; this technique is often used in the treatment of prostate or cervical cancer. Radioimmunotherapy is a method to target radiation to a tumor site using monoclonal antibodies attached to radioactive substances.
Radiation therapy may be used as a neoadjuvant, adjuvant, or palliative therapy. More than half of all cancer patients will receive radiation at some point during their treatment course. Radiation therapy can be used to shrink the tumor burden, allowing for a less extensive surgical procedure and/or improved cosmesis (eg, performing a lumpectomy instead of a mastectomy for a breast mass). It may also be used to reduce the risk of local cancer recurrence or to palliate tumor-related symptoms, such as bleeding or pain. For some cancers, such as head and neck or cervical cancer, modified doses of chemotherapy may be administered simultaneously with radiation to enhance the radiation effect.
PRACTICE POINT
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Workup and evaluation for cancer Involve a hematologist-oncologist early in the workup to advise on diagnostic studies or biopsy site/technique. A biopsy is necessary to confirm a histologic diagnosis. Consider a biopsy approach that will obtain the most tissue for diagnosis and allow for molecular analysis, if appropriate. Typically core needle biopsies are preferred over fine needle aspirates. Staging imaging should consist first of a contrasted CT chest, abdomen, pelvis. Not all stage IV malignancies are incurable. Some solid tumors, including colorectal and breast cancer with oligometastatic disease, may be cured using a multidisciplinary approach. Comprehensive cancer treatment utilizes a multidisciplinary team of physicians, often including medical oncologists, surgeons, and radiation oncologists.
INPATIENT MANAGEMENT OF COMMONLY ENCOUNTERED SCENARIOS
Cancer treatment can result in complications leading to hospitalization. Some of the commonly encountered inpatient scenarios include febrile neutropenia, nausea, vomiting, diarrhea, severe anemia or thrombocytopenia necessitating transfusion, and tumor lysis syndrome.
Nausea and vomiting
Prevention of nausea and vomiting is the most widely used supportive care measure in cancer treatment, and the development of new classes of antiemetics have had significant impact on the ability of patients to tolerate chemotherapy. Despite these efforts, nausea in the cancer patient may be encountered in the inpatient setting. It is important to consider potential reasons for nausea and vomiting other than cancer treatment, such as altered gut motility, bowel obstruction, electrolyte disturbance, brain metastases, narcotic use, or dyspepsia. Several antiemetics have been developed in the last decade that have substantially reduced the incidence of treatment-related emesis by interfering with the effect of endogenous neurotransmitters such as dopamine, histamine, and serotonin at the chemoreceptor trigger zone. The categories of available antiemetics include corticosteroids, benzodiazepines, cannabinoids, NK-1 receptor antagonists, serotonergic and dopaminergic receptors antagonists, and the atypical antipsychotic olanzapine. Antiemetics may be administered intravenously, orally, or per rectum, with rare use of intramuscular delivery due to discomfort and the risk of tissue fibrosis with repeated doses. Prior to administration of chemotherapy, one or more of these agents are administered depending on the emetogenic potential of the chemotherapy regimen. The 5HT3-receptor antagonists are among the most effective agents in preventing chemotherapy-related emesis. Benzodiazepines such as lorazepam are valuable in the prevention of anticipatory nausea triggered by the anxiety of receiving chemotherapy and are typically used simultaneously with other antiemetics. For patients who develop breakthrough nausea and vomiting despite these preventative efforts, treating with an
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antiemetic from a different class is helpful (Table 175-2) (see Chapter 97 [Nausea and Vomiting]).
TABLE 175-2 Antiemetics Used for Breakthrough Nausea and Vomiting
Antiemetic Drug Drug Class Dose/Frequency Dexamethasone Steroid 4-12 mg PO/IV daily Dronabinol Cannabinoid 5-10 mg PO 3-6 h Lorazepam Benzodiazepine 0.5-2 mg PO/IV q 6 h Metoclopramide Prokinetic 10-40 mg PO/IV q 4-6 h Olanzopine Atypical antipsychotic 2.5-5 mg PO daily Ondansetron 5-HT3 receptor
antagonist 8-24 mg PO or 8-12 mg IV (max 32 mg/d)
Prochlorperazine Phenothiazine 10 mg PO/IV q 6 h Promethazine Phenothiazine 12.5-25 mg PO/IV q 4-6 h Scopolamine Other 1 transdermal patch q 72 h
Mucositis
Another potential consequence of both chemotherapy and radiation is damage to rapidly dividing epithelial cells of the mucosa lining the oropharynx and the gastrointestinal tract leading to mucositis. Oral mucositis is defined as painful inflammation of the oral mucosa manifesting as erythema, ulcerations, and soft white patches. This particularly afflicts patients treated with 5-flurouracil, methotrexate, high-dose chemotherapy used prior to hematopoietic stem cell transplantation, or those undergoing radiation treatments to the head and neck. It typically develops within 7 to 10 days from initiation of chemotherapy and lasts several weeks. There are few remedies available to expedite recovery and supportive measures to minimize discomfort are the mainstay of treatment. Palifermin, a keratinocyte growth factor, is approved in patients receiving high-dose chemotherapy in the setting of hematopoietic stem cell transplant to decrease the incidence and duration of severe mucositis. Other management strategies include mouth rinses (avoiding alcohol based), topical anesthetics, mucosal coating agents, analgesics, and lubricants (Table 175-3). One effective regimen that is frequently prescribed is a mixture of a mucosal coating agent with a topical anesthetic. Opioids may be required for patients whose discomfort is not relieved with topical treatments.
TABLE 175-3 Mucositis Management
Bland Rinses Topical Anesthetics
Mucosal Coating
Lubricating Agents Analgesia
0.9% normal saline
Lidocaine -2% viscous Benzocaine
Milk of Magnesia Kaopectate
Artificial saliva Opioids – Patient controlled
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– Mix 1 teaspoon of table salt in 32 ounces of water
Sodium bicarbonate solution – Mix 0.5 teaspoon salt and 2 tablespoons sodium bicarbonate in 32 ounces water
Spray or gel Diphenhydramine solution
Amphojel – Cellulose film- forming agents
eg, Zilactin
analgesia [PCA] – Elixir – Transdermal patches
Anemia and thrombocytopenia
Cancer patients may be hospitalized for symptomatic anemia necessitating red cell transfusion. The anemia may be directly related to chemotherapy myelosuppression or it may be multifactorial secondary to anemia of chronic disease, nutritional deficiencies, cancer infiltrating the marrow, or impaired erythropoietin production. The hemoglobin threshold at which to initiate red cell transfusion depends on the goals of care. Transfusion guidelines recommend that cancer patients be transfused in a manner similarly to other noncardiac, hospitalized patients, for example, transfusion is considered when the hemoglobin (Hgb) is between 7 and 8 g/dL, using the minimum number of units necessary. If the Hgb is less than 9 g/dL and the patient is symptomatic from the anemia, transfusion is also reasonable. For patients with advanced cancer and anemia, transfusion may provide palliation and subjective benefit according to small observational studies. For patients who would benefit from an increased hemoglobin but decline red cell transfusion, erythropoietin stimulating agents (ESAs) and iron infusions are alternative approaches to enhancing red cell production. Because studies using both available ESAs— epoetin and darbepoetin alfa—report a potential risk of increased tumor growth and chance of death from cancer, the use of ESAs are typically reserved for patients with incurable malignancies and not generally used when the goal of treatment is cure.
The threshold at which to transfuse platelets depends on a patient’s risk of bleeding, need for invasive procedures, and whether they are critically ill versus clinically stable. Patients have been observed to be at increased risk of spontaneous bleeding with severe thrombocytopenia, defined as platelet counts less than 5000/μL. There has been no observed difference in bleeding risk between platelet counts of 10,000/μL versus 20,000/ μL in clinically stable patients. Thus, it is recommended to consider platelet transfusion for all patients with platelets less than 10,000/μL. There are some clinical scenarios where different platelet triggers are recommended. For example, in patients with coagulopathy, on anticoagulation, or if there is an anatomic lesion at risk for bleeding, transfuse platelets if the platelet count is less than 20,000/μL. One may also consider transfusing platelets to achieve a platelet count over 50,000/μL if an invasive surgical procedure is planned or
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transfusing platelets to achieve a platelet count over 100,000/μL in the case of bleeding or surgery within the central nervous system.
Certain groups of cancer patients, such as those with neutropenia or those who have received or are being considered for stem cell transplant, may require certain modifications to transfused blood products. Leukoreduction is a common modification that depletes the blood product of leukocytes, thus minimizing the risk for alloimmunization against leukocyte antigens. Leukocyte contamination of red cell products results in febrile nonhemolytic transfusion reactions (FNHTR), and leukoreduction reduces the risk of this complication. Leukoreduction also substantially decreases the risk of cytomegalovirus (CMV) transmission by blood transfusion. Most health care facilities in the United States have adopted universal leukoreduction of blood products; however, in centers that have not implemented this, leukoreduced products should be considered for patients with the following characteristics: past history of FNHTR, prior history of solid organ or hematopoietic stem cell transplant, planned solid organ or hematopoietic stem cell transplant, immunocompromised CMV negative patients, and patients requiring chronic transfusions.
Irradiated blood products are recommended for immunocompromised patients at risk for transfusion-related graft versus host disease (GVHD), a condition with high mortality. The blood products are exposed to gamma irradiation, thereby inactivating the donor lymphocytes responsible for this phenomenon. Irradiated blood products should be considered in these specific patient scenarios: current or prior treatment with chemotherapy agents in the purine analog class (eg, fludarabine, cladribine); a diagnosis of Hodgkin lymphoma (compared to other lymphomas, patients with Hodgkin lymphoma are at higher risk for developing transfusion-related GVHD); previous hematopoietic stem cell transplantation; receiving blood products from a related donor; and patients needing HLA-matched platelets. Patients with acute leukemia do not require irradiated blood products unless they are receiving conditioning therapy in preparation for allogeneic stem cell transplant. In summary, the decision to transfuse blood products should be individualized for each patient and the risks of transfusion must be carefully considered.
Venous thromboembolism prophylaxis
Cancer itself is associated with a hypercoaguable state, and treatment with chemotherapy further contributes to the risk of thrombotic complications. Deep venous thrombosis (DVT) is the most common thrombotic complication seen in patients with cancer. Compared to patients without cancer, those with cancer are at a substantially elevated risk of thrombosis after surgical procedures and extended DVT prophylaxis beyond hospital discharge is sometimes considered. It is essential to be mindful of this elevated risk and to provide appropriate DVT prophylaxis to hospitalized cancer patients (see Chapter 252 [Venous Thromboembolism Prophylaxis for Hospitalized Medical Patients]).
PRACTICE POINT
Caring for a hospitalized cancer patient Cancer produces a state of hypercoagulability. All patients should be offered deep venous thrombosis prophylaxis while hospitalized.
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Breakthrough nausea/vomiting can be controlled with a variety of medications, including antiemetics, prokinetic agents, steroids, atypical antipsychotics, and benzodiazepines. First-line treatment for supporting mucositis includes saline washes and topical agents. Opioids may be necessary for pain relief. Certain populations of cancer patients are recommended to have leukoreduced blood products to minimize the risk of febrile nonhemolytic transfusions reactions and reduce the risk of CMV transmission. Irradiated blood products are reserved for patients at risk for transfusion related graft versus host disease. For most cancer patients, transfuse the minimum number of blood products necessary to maintain a hemoglobin between 7 and 8 g/dL and a platelet count greater than 10,000/μL.
SUGGESTED READINGS Bensinger W, Schubert M, Ang KK, et al. NCCN Task Force Report: prevention and
management of mucositis in cancer care. J Natl Compr Canc Netw. 2008;6(Suppl 1):S1- S21.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual, 7th ed. New York, NY: Springer; 2010.
Gerber DE, Chan TA. Recent advances in radiation therapy. Am Fam Physician. 2008;78(11):1254-1262.
Jordan K, Sippel C, Schmoll HJ. Guidelines for antiemetic treatment of chemotherapy- induced nausea and vomiting: past, present, and future recommendations. Oncologist. 2007;12(9):1143-1150.
Szczepiorkowski ZM, Dunbar NM. Transfusion guidelines: when to transfuse. Hematology Am Soc Hematol Educ Program. 2013;638-644.