20 Medical Management of Malignant Disease - Bài viết - Bệnh Học
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20 Medical Management of Malignant Disease

Cho điểm
Medical Management of Malignant Disease
Mike Naughton
Approach to the Cancer Patient
General Principles
Before treatment of a cancer patient is initiated, all patients should have a diagnosis of cancer based on tissue pathology, and, if possible, a clinical, biochemical, or radiographic marker of disease should be identified to assess the results of therapy.
Stage is a clinical or pathologic assessment of tumor spread. The major role of staging is to define the optimal therapy and prognosis in subsets of patients. Treatment plans are generally determined by the stage of the tumor. The role of local therapies, surgery, and radiation are determined by regional spread of disease. The role of systemic therapy, or chemotherapy, is also dependent on the stage of the tumor. In general, the probability of survival correlates well with tumor stage.
The grade of a tumor defines its retention of characteristics compared to the cell of origin. It is designated as low, moderate, or high as the tissue loses its normal appearance. Although grade is important in determining prognosis for many tumors, it is not used as commonly as stage in defining treatment plans.
Performance status is a gauge of a patient's overall functional status. Two scales are commonly used: the Karnofsky performance status scale and the Eastern Cooperative Oncology Group scale (Table 20-1). Performance status is an essential component of the evaluation of cancer patients, as it helps predict response to treatment, duration of response, and survival. For most solid tumors, patients with poor performance status are unlikely to derive significant benefit from systemic chemotherapy. However, patients with tumors that respond dramatically to chemotherapy may benefit from this treatment, even if they have poor performance status.
Cancers are broadly characterized as “liquid” or “solid” malignancies.
Leukemias and lymphomas comprise the “liquid” group. The treatment of liquid tumors is usually chemotherapy or radiation therapy, or both.
The “solid” tumors include tumors that arise from any solid organ or tissue. Solid tumors are treated with surgery, radiation therapy, chemotherapy, or some combination of these modalities.
Therapy. Cancer is in general treated with surgery, radiation, systemic chemotherapy, or a combination of these modalities.
Chemotherapy is administered in several different settings. Specific mechanisms of action and toxicities will be discussed in detail below.
Induction chemotherapy is used to achieve a complete remission.
Consolidation chemotherapy is administered to patients who initially respond to treatment.
TABLE 20-1 Performance Status
Karnofsky performance status scale
ECOG performance status scale
Normal; no complaints; no symptoms of disease
Fully active, able to carry on all predisease activity without restriction
Able to carry on normal activity; minor signs or symptoms of disease
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature
Normal activity with effort; some signs or symptoms of disease

Able to care for self; unable to carry on normal activity or to do active work
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about >50% of waking hours
Requires occasional care for most needs
Capable of only limited self-care; confined to bed or chair >50% of waking hours
Requires considerable assistance and frequent medical care

Disabled; requires special care and assistance
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
Severely disabled; hospitalization is indicated, although death is not imminent

Very sick; hospitalization necessary; active supportive treatment necessary
Moribund; fatal process progressing rapidly
ECOG, Eastern Cooperative Oncology Group.
Maintenance therapy refers to low-dose, outpatient treatment used to prolong remissions; its use has proved effective in a few malignancies.
Adjuvant chemotherapy is given after complete surgical or radiologic eradication of a primary malignancy to eliminate any unmeasurable metastatic disease.
Neoadjuvant chemotherapy is given in the presence of local disease, before planned local therapy.
Survival data are often reported in terms of median survival and 5-year survival, and cause confusion among patients with newly diagnosed malignancies; these data must be conveyed to the patient with caution by the treating oncologist who can help interpret these data.
Median survival equates to the period of time during which 50% of studied subjects are alive and 50% are dead.
Five-year survival means the percentage of patients studied who are alive at 5 years.
Therapy of Selected Solid Tumors
Guidelines for treatment of selected tumors are provided below.
Breast cancer is the most common cause of cancer in women outside of nonmelanoma skin cancer.
Approach to an undiagnosed lump in the breast. Breast cancer develops in approximately 11% of women during their lifetime in the United States.
A breast lump in a premenopausal woman is less likely to be cancerous than a breast lump in a postmenopausal woman.
In a younger woman, a mass should be observed for 1 month to identify any cyclic changes that suggest benign disease.
If the mass is still present, bilateral mammography should be performed. The accuracy of mammography to diagnose cancer in pre- and postmenopausal women is approximately 90%. Nevertheless, a woman with a clinically suspicious lump and negative mammograms should undergo biopsy.
Surgical options. Treatment is focused on local control and the risk of systemic spread.
Local control with tylectomy (lumpectomy and axillary lymph node dissection) is as effective as a modified radical mastectomy. An axillary lymph node dissection should be included because it provides prognostic information and is of therapeutic value.
Sentinel lymph node mapping and dissection allow many women to be spared full axillary dissection. In this procedure, blue dye, a radiotracer, or both are injected around the tumor bed. The lymph node(s) that pick up the dye/tracer are excised. If no cancer cells are seen in these lymph nodes, further axillary dissection can be avoided.
Radiation therapy is indicated for patients treated with tylectomy and for some individuals with axillary lymph node involvement. It can also be used for palliation of painful or obstructing metastatic lesions.
Systemic therapy. Systemic therapy is given for two reasons in the treatment of breast cancer:
Adjuvant therapy is given to a woman who has had surgery to completely remove her tumor to reduce recurrence risk.
Palliative therapy is given to women with metastatic breast cancer to slow the progression of their disease and to extend their lives.
Hormone therapy is used for women with estrogen receptor (ER)÷ and/or progesterone receptor (PR)÷positive disease.
Trastuzumab (Herceptin) is appropriate for women with her-2-neu÷positive breast cancer.
Anthracycline-based chemotherapy is potentially useful in all subtypes.
Adjuvant therapy. The presence or absence of axillary lymph node metastases is the most important prognostic factor in breast cancer. All women with axillary nodal involvement should receive adjuvant therapy.
Women with node-negative breast cancer should also be considered for adjuvant therapy if the tumor is >1 cm, is ER negative, or has overexpression of her-2.
Chemotherapy should be considered in patients who are premenopausal, have cancers that are ER negative, or overexpress her-2.
Tamoxifen, 20 mg PO daily for 5 years, is recommended for all ER-positive breast cancers1 in premenopausal women.
In postmenopausal women, the aromatase inhibitors anastrozole, letrozole, and exemestane have generally replaced tamoxifen for adjuvant hormone therapy.
Trastuzumab has been found to be effective in the adjuvant treatment of women with her-2-neu÷positive disease.2
Metastatic disease. Menopausal status, hormone receptor status, her-2-neu expression, and sites of metastatic disease dictate initial treatment.
ER-negative breast cancer, lymphangitic lung disease, and liver metastasis
seldom respond to hormonal manipulation and should be treated with chemotherapy.
ER-positive disease is treated with hormonal manipulation.
 Premenopausal women are initially treated with tamoxifen and a luteinizing hormone÷releasing hormone (LHRH) agonist; postmenopausal women should receive a hormonal agent such as tamoxifen or an aromatase inhibitor. If the disease responds to hormonal therapy, subsequent disease progression may respond to other hormonal agents.
Chemotherapy should be considered if there is no response to initial hormonal therapy or if progression occurs during subsequent hormonal manipulations.
 In her-2÷overexpressing cancers, the addition of trastuzumab to first-line chemotherapy produced an improvement in survival compared to chemotherapy alone.3
 In women with more than one osteolytic metastasis, the monthly administration of zoledronic acid, 4 mg IV, produces an improvement in quality of life, greater response to therapy, fewer extravertebral fractures, and possibly a prolongation in survival.4
Inflammatory and unresectable cancers. Inflammatory breast cancer manifests as “peau d'orange” changes or erythema involving more than one-third of the chest wall. Because of the high likelihood of metastases at diagnosis, these patients and those with inoperable primary breast cancers are initially treated with chemotherapy. Subsequently, surgery and radiation therapies are used for maximal local control.
Lung cancer is the most common cause of cancer death in the United States and is the most preventable given its relationship to cigarette smoking.
Treatment is based on the histology and stage of the disease.
Small-cell and non÷small-cell lung cancers are treated according to whether disease is limited (confined to one hemithorax and ipsilateral regional lymph nodes) or extensive stage.
Whenever possible, surgical resection should be attempted for non÷small-cell lung cancer because it affords the best chance of cure.
Small-cell lung cancer is often responsible for a variety of paraneoplastic syndromes in addition to local symptoms.
For limited disease, combination chemotherapy and radiation therapy result in an 85%÷90% response rate, a median survival of 12÷18 months, and a cure in 5%÷15% of patients.
With extensive disease, the median survival is 8÷9 months, and cures are rare. For patients who achieve a complete remission with chemotherapy, prophylactic whole-brain radiation therapy has been shown to decrease the risk of central nervous system (CNS) metastases.5 Radiation therapy to the chest as consolidation therapy may improve survival in limited disease but is not recommended in extensive disease except for palliation of local symptoms.
Non÷small-cell lung cancer (NSCLC) survival rates after resection are improved with adjuvant chemotherapy with without radiation therapy.
For unresectable disease confined to the lung and regional lymph nodes, radiation therapy in combination with chemotherapy is the conventional treatment.
In patients with metastatic disease, cisplatin-based combination chemotherapy may modestly improve survival. Erlotinib, a tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor (EGFR), is approved for NSCLC.
Gastrointestinal (GI) malignancies commonly present with vague symptoms and are often advanced at the time of diagnosis.
Esophageal cancers are either squamous cell (associated with cigarette smoking and alcohol use) or adenocarcinoma (arising in Barrett's esophagus).
Surgical resection of the esophagus is recommended in small primary tumors and in selected patients after chemoradiation.
Local control of unresectable cancers can be achieved with combined chemotherapy and radiation therapy.6
Palliation of obstructive symptoms can be accomplished by radiation therapy, dilation, prosthetic tube placement, or laser therapy.
Gastric cancer is usually adenocarcinoma and can be cured with surgery in the rare patient with localized disease.
Adjuvant chemotherapy and concurrent radiation have been shown to improve outcomes in surgically resected gastric cancer.7
Locally advanced but unresectable cancers may benefit from concomitant chemotherapy and radiation therapy. Chemotherapy may offer palliation for metastatic disease.
Colon and rectal adenocarcinomas are primarily treated by surgical resection.
In all patients who are undergoing surgical resection of colon or rectal cancer, a preoperative carcinoembryonic antigen level should be measured and followed. A persistently elevated or increasing level may indicate residual or recurrent tumor.
A prolonged survival in patients with colon cancer and regional lymph node involvement is seen with administration of postoperative 5-fluorouracil (FU) and levamisole for 12 months or FU and leucovorin (LV) for 6 months.8
The addition of oxaliplatin to the traditional FU and leucovorin improves risk reduction in stages II and III colon cancer.9
Rectal cancer that arises below the peritoneal reflection commonly recurs locally after surgery alone; postoperative radiation therapy and FU are recommended.
A number of chemotherapy agents are available for the treatment of metastatic colorectal cancer. These include FU, irinotecan, capecitabine, and oxaliplatin. In metastatic disease, the addition of irinotecan to FU/LV produces a higher likelihood of response and possible survival advantage.10
Three monoclonal antibodies have been approved for the treatment of metastatic colon cancer. Bevacizumab targets vascular endothelial growth factor (VEGF). Both cetuximab and panitumumab target EGFR.
Selected patients with metastases confined to the liver may be candidates for liver resection.11
Anal cancer. Chemotherapy with concurrent radiation therapy appears to result in a higher cure rate than surgical resection and usually preserves the anal sphincter and fecal continence.12 Surgical resection should be used only as salvage therapy.
Genitourinary malignancies
Bladder cancer in the United States is usually a transitional cell carcinoma. A variety of chemical carcinogens, including those in cigarette smoke, have been implicated.
Unifocal tumors confined to the mucosa should be managed with cystoscopy and transurethral resection or fulguration, repeated at approximately 3-month intervals; multifocal mucosal disease is treated with intravesicular bacillus Calmette-Guérin, thiotepa, or mitomycin-C.
Locally invasive cancers should be resected.
Adjuvant chemotherapy improves survival when regional lymph node involvement is confirmed in the cystectomy specimen.
In metastatic or recurrent disease, the highest response rates are seen with cisplatin-containing regimens.
Prostate cancer is the most common cancer in men besides nonmelanoma skin cancer.
Prostate-specific antigen is useful as a marker for recurrence, bulk of disease, and response to therapy and may detect asymptomatic early-stage disease.
Local control of the primary lesion can be achieved with either prostatectomy or radiation therapy.
In patients with metastatic disease, bilateral orchiectomy and LHRH analogs with or without an antiandrogen produce tumor regression in approximately 85% of patients for a median of 18÷24 months.
Disease that has relapsed after hormonal therapy may respond to withdrawal of that antiandrogen.13
Anthracyclines, taxanes, vinblastine, and estramustine may be of palliative value in hormone-refractory disease.
Anemia and bone pain dominate the advanced phases of this disease and are best relieved with transfusions, growth factors, and palliative radiation therapy.
Renal cell cancer is treated by surgical resection, which may be curative if disease is localized; no effective adjuvant therapy is available.
Chemotherapy, interferon-α, and interleukin-2 have reported response rates of 15%÷30%.
Two new agents, sunitinib and sorafanib, have been approved for the treatment of metastatic renal cell cancer. Both agents are multitargeted TKIs. Both appear more active and better tolerated than previously available agents.
Testicular cancer is considered one of the most curable malignancies and should be treated aggressively. A patient suspected of having cancer of the testis should only have tissue obtained through an inguinal orchiectomy because a transscrotal incision facilitates tumor spread to the inguinal lymph nodes.
The initial evaluation should include serum α-fetoprotein and β-human chorionic gonadotropin levels and a computed tomography (CT) scan of the abdomen and pelvis.
Most patients with seminoma should be treated with radiation therapy.
In nonseminomatous germ cell cancer, a retroperitoneal lymph node dissection should be performed for staging, except in the instance of bulky abdominal disease or pulmonary metastasis.
If microscopic disease is identified at surgery, two alternatives are acceptable: two cycles of postoperative chemotherapy or observation until relapse occurs followed by institution of chemotherapy.
With gross metastatic disease, cisplatin-based chemotherapy is curative for most germ cell cancers. If tumor markers normalize after chemotherapy but a radiographic mass persists, exploratory surgery should be performed. The lesion proves to be residual cancer in approximately one third of the patients. Patients with residual cancer should receive additional chemotherapy.14
Gynecologic malignancies
Cervical cancer. The recognized risk factors are multiparity, multiple sexual partners, and infection with human papillomavirus (HPV).
Carcinoma in situ and superficial disease can be treated by endocervical cone biopsy.
Microinvasive disease is treated with an abdominal hysterectomy.
Advanced local disease (invasion of the cervix or local extension) is initially treated with surgery or radiation therapy, or both. The addition of chemotherapy to radiation therapy postoperatively is associated with improved survival.15
Inoperable cancer can be controlled with radiation therapy; metastatic disease is treated with cisplatin-based chemotherapy.
A vaccine for HPV has recently been approved and is being administered to young women in hopes of reducing the rates of cervical carcinoma.
Ovarian cancer is primarily a disease of postmenopausal women.
Because symptoms are uncommon with localized disease, most patients present with advanced local disease, malignant ascites, or peritoneal metastases.
Surgical staging and treatment include an abdominal hysterectomy, bilateral oophorectomy, lymph node sampling, omentectomy, peritoneal cytology, and removal of all gross tumor. If the tumor is localized to the ovary, the surgery may be curative and further treatment is not routinely recommended. However, if microscopic foci of cancer are identified, chemotherapy is administered postoperatively.
The serum marker CA-125, although not specific, is elevated in more than 80% of women with epithelial ovarian cancer and is a sensitive indicator of response.
After a response is achieved, a “second-look laparotomy” is performed to restage and remove residual tumor. Approximately one-third of the patients who are in pathologic complete remission after a second-look laparotomy are cured. Those patients who have residual cancer should receive additional chemotherapy.
Endometrial cancer risks include obesity, nulliparity, polycystic ovaries, and the use of unopposed estrogens (including tamoxifen). Patients generally present with vaginal bleeding. Surgery and radiation therapy are often curative.
Head and neck cancer is usually a squamous cell cancer. It may arise in a variety of sites, each of which has a different natural history.
Early lesions can be cured with surgery, radiation therapy, or both.
Despite aggressive surgical and radiation therapy, approximately 65% of patients with head and neck cancer have uncontrolled local disease.
The addition of chemotherapy to radiation therapy improves the survival in patients with nasopharyngeal cancers and selected patients with other primary disease sites.16
Malignant melanoma should be considered in any changing or enlarging nevus, and suspicious lesions should be removed by excisional biopsy. Subsequently, a wide local excision is performed to remove possible vertical and radial spread of tumor.
Deeper invasion is associated with a worse prognosis.
High-dose interferon prolongs the survival of selected high-risk resected patients.17 Systemic disease may respond to dacarbazine, interferon-α, or interleu- kin-2 in 10%÷30% of patients.
Sarcomas are tumors arising from mesenchymal tissue and occur most commonly in soft tissue or bone. Initial evaluation should include a CT scan of the chest, as hematogenous spread to the lungs is common.
Prognosis for soft tissue sarcoma is primarily determined by tumor grade and not by the cell of origin.
Surgical resection should be performed when feasible and may be curative.
In low-grade tumors, local and regional recurrence is most common, and adjuvant radiation therapy may be of benefit. High-grade tumors often recur systemically, but no advantage to the routine use of adjuvant chemotherapy has been demonstrated.
In metastatic disease, doxorubicin, ifosfamide, and dacarbazine produce responses in 40%÷55% of patients.
Osteogenic sarcomas are treated with surgical resection followed by adjuvant chemotherapy for 1 year. Treatment of isolated pulmonary metastasis by surgical resection is associated with long-term survival.
Kaposi sarcoma in an immunocompetent patient is generally a low-grade lesion of the lower extremities that is readily treated with local radiation therapy or vinblastine. When Kaposi sarcoma complicates organ transplantation or AIDS, it is more aggressive and may arise in visceral sites. Liposomal doxorubicin alone is as effective as combination chemotherapy for palliation.18
Cancer with an unknown primary site. Approximately 5% of cancer patients present with symptoms of metastatic disease, but no primary tumor site is identifiable on physical examination, routine laboratory studies, or chest radiography.
The histopathologic cell type and the site of the metastasis should direct a search for the primary lesion. Immunohistochemical stains may identify specific tissue antigens that help to define the origin of the tumor and guide subsequent therapy.
Cervical adenopathy suggests cancer of the lung, breast, head and neck, or lymphoma. In this case, initial evaluation usually includes panendoscopy (nasendoscopy, laryngopharyngoscopy, bronchoscopy, and esophagoscopy) and biopsy of any suspicious lesion before excision of the lymph node. If squamous cell carcinoma is identified, the patient is presumed to have primary head and neck cancer, and radiation therapy may be curative.
Midline mass in the mediastinum or retroperitoneum. In both sexes, a midline mass in the mediastinum or retroperitoneum may be an extragonadal germ cell cancer. Elevations in α-fetoprotein or β-human chorionic gonadotropin further suggest this diagnosis. This neoplasm is potentially curable.
Therapy of Selected Lymphomas/Leukemias
Lymphoma is usually diagnosed by biopsy of an enlarged lymph node.
Staging of Hodgkin's disease and non-Hodgkin's lymphoma is organized into four categories.
Stage I is disease localized to a single lymph node or group.
Stage II is disease involving more than one lymph node group but confined to one side of the diaphragm.
Stage III is disease in the lymph nodes or the spleen and occurs on both sides of the diaphragm.
Stage IV is disease involving the liver, lung, skin, or bone marrow.
B symptoms include fever above 38.5°C, night sweats that require a change in clothes, or a 10% weight loss over 6 months. These symptoms suggest bulky disease and a worse prognosis.
Hodgkin's disease usually presents with cervical adenopathy and spreads in a predictable manner along lymph node groups.
Treatment is based on the presenting stage of the disease; the cell type is relatively unimportant in the natural history and prognosis.
Initial evaluation includes a CT scan of the chest, abdomen, and pelvis, and bilateral bone marrow biopsies to determine the clinical stage of the disease.
Exploratory laparotomy with splenectomy and liver biopsy is performed only if the findings will change the disease stage and treatment.
Stages I and IIA are treated with radiation therapy or a combination of chemotherapy and radiation.
Stage IIIA disease can be treated either by radiation therapy or chemotherapy, whereas all stage IV patients should receive combination chemotherapy.
When B symptoms are present, chemotherapy is recommended regardless of the stage.
Non-Hodgkin's lymphoma is classified as low, intermediate, or high grade based on the histologic type. Staging evaluation is the same as for Hodgkin's disease, but non-Hodgkin's lymphoma has a less predictable pattern of spread. Advanced-stage disease (stage III or IV) is very common and can usually be diagnosed by CT scan or bone marrow biopsy; exploratory laparotomy and lymphangiography are rarely necessary.
Low-grade lymphoma often involves the bone marrow at diagnosis, but the disease has an indolent course. Because this tumor is not curable with standard chemotherapy, treatment can be delayed until the patient is symptomatic (“watch and wait”).
Radiation therapy or an alkylating agent (e.g., cyclophosphamide) can be used to ameliorate symptoms. Radiation therapy may produce a long-term complete remission in stage I or II disease.
Rituximab produces an objective response in approximately 50% of patients with follicular lymphoma without the usual toxicities of chemotherapy.
Intermediate-grade lymphoma has a more aggressive course, usually does not involve the bone marrow at diagnosis, and can be cured with chemotherapy. Complete response rates exceed 80%.
Features associated with a lower likelihood of cure include an elevated lactate dehydrogenase level, stage III/IV disease, age older than 60 years, more than one extranodal site, and poor performance status.
High-grade lymphoma (Burkitt's, lymphoblastic) includes the most aggressive subtypes and has a high frequency of CNS and bone marrow involvement.
Cerebrospinal fluid (CSF) cytology should be included as part of the initial evaluation.
Combination chemotherapy is the mainstay of treatment and should include CNS prophylaxis if the CSF is cytologically free of tumor. If tumor cells are seen in the CSF, additional therapy may be indicated.
Prophylaxis to prevent tumor lysis syndrome should be initiated before induction chemotherapy.
Acute leukemias may present with manifestations of cytopenias, including fatigue and dyspnea (anemia), cutaneous or mucosal hemorrhage (thrombocytopenia), and
fever/infection (neutropenia). Patients may also present with leukemic infiltration of organs, manifested as lymphadenopathy, splenomegaly (more common in acute lymphocytic leukemia), gingival hyperplasia, and skin nodules (more common in acute myeloid leukemia).
Leukemic blasts are usually present in the blood.
Bone marrow aspiration/biopsy is performed to establish the diagnosis and often shows nearly complete replacement by blasts.
Flow cytometry and cytogenetics must be performed on the bone marrow aspirate for classification and to provide prognostic information.
Acute myeloid leukemia constitutes approximately 80% of adult acute leukemia.
Approximately 50%÷80% of patients achieve complete remission with induction chemotherapy that includes cytarabine (cytosine arabinoside [ara-C]) and daunorubicin.
Consolidation is given with at least one additional cycle of chemotherapy, which is typically ara-C at a dose of 10÷30 times that used for induction (high-dose ara-C). High-dose ara-C consolidation results in cure in approximately 30%÷40% of patients younger than 60 years.
Pretreatment factors associated with a low (<10%) chance for cure include preceding myelodysplastic syndrome; prior exposure to radiation, benzene, or chemotherapy; and adverse cytogenetic abnormalities.
For these high-risk patients, allogeneic stem cell transplant in first remission increases the likelihood of cure.
Acute promyelocytic leukemia is characterized by a chromosomal translocation (t[15;17]) that results in a hybrid protein (pml-rar).
Treatment with oral tretinoin (all-trans retinoic acid) results in complete remission in >90% of patients. After consolidation chemotherapy, approximately 75% of patients are cured.
Acute lymphocytic leukemia is predominantly a disease of childhood, with only 25% of all cases occurring in patients older than the age of 15 years.
For adults, induction and consolidation involve treatment with multiple chemotherapeutic agents over a period of approximately 6 months followed by at least 18 months of lower-dose maintenance chemotherapy.
To prevent CNS relapse, patients receive intrathecal (IT) chemotherapy and either cranial radiation or CNS penetrating chemotherapy.
Approximately 60%÷80% of adults achieve complete remission, with about 30%÷40% being cured; increasing age, higher white blood cell (WBC) count, and longer time to remission are associated with reduced survival.
Cytogenetics are crucial in determining prognosis, and allogeneic stem cell transplantation during the first remission should be considered in patients with a poor prognosis.
Chronic lymphocytic leukemia (CLL) usually presents with lymphocytosis, lymph-adenopathy, and splenomegaly. Malignant cells resemble mature lymphocytes.
Treatment is similar to that for low-grade lymphoma except that fludarabine appears to be more active than alkylating agents.
Median survival is approximately 6÷8 years; anemia and thrombocytopenia are associated with shortened survival. As in low-grade lymphoma, patients are treated for control of symptoms or cytopenias.
Because CLL is accompanied by immunodeficiency, life-threatening infections may occur. Therefore, febrile patients must be evaluated carefully.
Immune hemolytic anemia or immune thrombocytopenia may develop as complications of CLL. Treatment of these conditions is with glucocorticoids (e.g., prednisone, 1 mg/kg PO daily) or chemotherapy, or both. CLL may transform to an intermediate- or high-grade lymphoma (Richter transformation).
Chronic myelogenous leukemia (CML) presents with leukocytosis and a left shift, as well as splenomegaly. Thrombocytosis, basophilia, and eosinophilia are also common.
The diagnosis is confirmed by demonstration of the Philadelphia chromosome (t9:22), which results in production of a hybrid protein (bcr-abl).
During the stable phase of the disease, leukocytosis, thrombocytosis, and splenomegaly can be controlled for several years with oral hydroxyurea, and most patients are asymptomatic.
Acute leukemic transformation (blast phase) is inevitable and unpredictable, with a median time to transformation of 5÷7 years. Blast phase is highly resistant to treatment and is usually fatal.
For younger patients (40÷50 years old) with HLA-identical siblings, allogeneic stem cell transplantation performed in stable phase within 1 year of diagnosis is the treatment of choice, resulting in a 50%÷70% likelihood of cure.
For older patients and for those without an HLA-identical sibling, options include unrelated donor transplant or therapy with interferon-α. The latter agent delays blast phase in some patients.
Imatinib is an orally administered medication designed specifically to inhibit the bcr-abl tyrosine kinase. Because imatinib is more active and has far fewer toxicities than interferon, it is currently the first-line therapy for this disease. Even blast-phase CML or Philadelphia chromosome÷positive acute leukemia may respond to imatinib. Responses in this setting are generally of relatively short duration.
Hairy-cell leukemia represents 2%÷3% of all adult leukemias. Clinical presentation includes splenomegaly, pancytopenia, and infection.
Patients are at increased risk for bacterial, viral, and fungal infections and have a unique susceptibility to atypical mycobacterial infections.
Bone marrow biopsy reveals infiltration by cells that have prominent cytoplasmic projections.
A single 7-day course of chlorodeoxyadenosine produces remission in more than 90% of patients. Although this drug is not curative, 5-year progression-free survival exceeds 50%.
Multiple myeloma is a malignant plasma cell disorder that is usually accompanied by a serum or urine paraprotein, or both. Presenting manifestations may include hypercalcemia, anemia, lytic bone lesions with bone pain, and acute renal failure.
The initial evaluation should include a radiographic bone survey, bone marrow aspiration and biopsy, serum and urine protein electrophoresis, β2-microglobulin, and quantitative immunoglobulins.
Treatment generally includes a combination of an oral alkylating agent (i.e., melphalan) and prednisone or vincristine/doxorubicin/dexamethasone.
Local radiation therapy can be used to relieve painful bone lesions, and zoledronic acid, 4 mg IV every month, decreases skeletal complications.
Thalidomide, an immunomodulatory agent, has been shown to be effective in multiple myeloma. Because thalidomide can cause severe fetal malformations, prescribing this medication requires participation in a prescriber program. Combinations of dexamethasone and thalidomide are also active in the treatment of multiple myeloma.
Bortezomib (Velcade), a proteasome inhibitor that degrades ubiquitinated proteins, has recently been approved for the treatment of multiple myeloma that has progressed despite two previous treatments. Toxicities of bortezomib are primarily thrombocytopenia and neuropathy.
After induction chemotherapy, consolidation with high-dose therapy and autologous stem cell transplant improves survival.
Hematopoietic Stem Cell Transplantation
General Principles
Hematopoietic stem cell transplantation involves IV infusion of either hematopoietic progenitors (collected from the bone marrow by aspiration from the iliac crests) or peripheral blood stem cells (collected by apheresis after treatment of the donor with granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]).
Allogeneic stem cells are collected from another person (the donor), whereas autologous stem cells are collected from the patient. For autologous transplant, peripheral blood stem cells have largely replaced bone marrow as the source of progenitors because hematologic recovery is more rapid.
Allogeneic stem cell transplant. HLA-matched siblings are the most common donors, but matched unrelated donors can be identified for many patients through the National Bone Marrow Donor Registry.
Allogeneic transplants can be performed to restore normal hematopoiesis or immune function in patients with aplastic anemia, immunodeficiency, or hemoglobinopathies and are also used to treat resistant leukemia and lymphoma. For patients with resistant acute leukemia, allogeneic transplant is generally favored, whereas for those with resistant lymphoma, autologous transplant is usually preferred.
The “preparative regimen” is given immediately before transplant and includes chemotherapy with or without total body irradiation. For patients with nonmalignant conditions, the preparative regimen provides immunosuppression, which is needed for engraftment. For patients with resistant malignancy, the preparative regimen is designed to promote engraftment and to kill tumor cells.
Unlike autologous transplant, allogeneic transplants may be accompanied by a graft versus tumor effect, which appears to be a very important part of curing leukemia or lymphoma.
Autologous stem cell transplantation. Eradication of malignancy is entirely the result of the preparative regimen, because no graft versus tumor effect can occur.
The major advantage of autologous transplant is that graft versus host disease (GVHD) does not occur; therefore, the risk of death from transplant-related complications is <5%.
Most autologous transplants are performed for relapsed lymphoma. In patients with relapsed large-cell lymphoma who achieve at least a partial response to salvage chemotherapy, cure can be achieved in 30%÷50%.
Autologous transplant also prolongs the survival of patients with multiple myeloma and is a viable option for individuals with acute leukemia in first remission who lack a compatible sibling donor.
Complications of transplantation may be the result of high-dose therapy, pancytopenia, immunodeficiency, or GVHD.
Infections. After the preparative regimen, 7÷10 days of profound pancytopenia (absolute neutrophil count <100, platelets <10,000) develops in all patients. During this time nearly all patients experience fever and require empiric broad-spectrum antibiotic therapy.
Patients who are seropositive for herpes simplex virus should also receive acyclovir prophylaxis until neutrophil recovery.
G-CSF or GM-CSF is usually given starting on the day after transplant until neutrophil recovery.
Patients who have undergone autologous transplant recover immune function within 3÷6 months. However, patients who undergo allogeneic transplant have profound and prolonged impairment of humoral and cell-mediated immunity that persists until GVHD resolves. Therefore, patients who are febrile after allogeneic transplant should be cultured and immediately receive IV broad-spectrum antibiotics even if they are not neutropenic.
After allogeneic transplant, patients receive long-term prophylaxis for varicella-zoster virus with acyclovir and for Pneumocystis with trimethoprim/sulfamethoxazole. Patients are also at risk for reactivation and systemic infection with cytomegalovirus (CMV). One strategy for preventing overt infection is to perform shell vial cultures or polymerase chain reaction assays on blood
weekly or biweekly during the period of maximal risk (1÷6 months posttransplant).
Ganciclovir or foscarnet is given if testing is positive for CMV. Patients who have undergone allogeneic transplant require reimmunization.
GVHD is an immunologic response by the donor to recipient antigens and is the major complication of allogeneic transplantation. Overall, GVHD accounts for most of the 20%÷30% mortality that accompanies matched sibling transplant, with death usually resulting from infection.
GVHD within the first 100 days of transplant (acute GVHD) produces a skin rash, diarrhea, and liver dysfunction. Despite prophylaxis with cyclosporine and methotrexate, significant acute GVHD occurs in 30%÷50% of transplants from matched sibling donors.
Chronic GVHD occurs more than 100 days after transplant and resembles an autoimmune disorder with protean manifestations, including keratoconjunctivitis sicca, lichenoid changes of the buccal mucosa, and sclerodermatous skin changes.
After allogeneic transplant, donor T cells can mediate immunologic destruction of residual tumor cells. This “graft versus tumor effect” is unique to allogeneic transplant and plays a key role in eradicating residual malignancy.
Veno-occlusive disease (VOD) occurs in 1%÷5% of patients, usually within 21 days of treatment. Risk factors include extensive prior therapy and elevated transaminase values before transplant.
Manifestations include hyperbilirubinemia, ascites, tender hepatomegaly, and fluid retention.
In its severe form, VOD is almost uniformly fatal. Treatment options are limited.
Pulmonary complications. CMV pneumonia usually occurs within 6 months of allogeneic transplant in patients who are seropositive or who receive transplants from seropositive donors. It is uncommon after autologous transplant. Treatment is with ganciclovir or foscarnet.
Interstitial pneumonitis may complicate total body radiation or high-dose chemotherapy and is manifested by cough, dyspnea, and interstitial infiltrates that present 1÷3 months after transplant. Prior chest radiotherapy is a risk factor; treatment with prednisone usually results in rapid and long-term improvement.
Complications of Cancer
Complications related to tumor mass
Brain metastasis. Patients with parenchymal brain metastasis may present with headache, mental status changes, weakness, or focal neurologic deficits. Papilledema is observed in only 25% of patients.
In individuals with malignancy, a CT scan of the head showing one or more round, contrast-enhancing lesions surrounded by edema is usually sufficient for the diagnosis. If cancer has not been diagnosed previously, tissue should be obtained from the brain lesion or a more accessible site before radiation therapy is initiated.
Therapy with dexamethasone, 10 mg IV or PO, should be initiated to decrease cerebral edema and should be continued at a dosage of 4÷6 mg PO q6h throughout the course of radiation therapy, or longer if symptoms related to edema persist.
Subsequent therapy depends on the number and location of the brain lesions as well as the prognosis of the underlying cancer.
Patients with a chemotherapy-responsive neoplasm and a solitary accessible lesion should be considered for surgical resection. All patients who have not received prior radiation therapy should be given whole-brain radiation therapy.
Meningeal carcinomatosis should be suspected in a cancer patient with headache or cranial neuropathies. This pattern of spread is most often seen with lung or breast cancer, melanoma, or lymphoma; the diagnosis is confirmed by cytology of the CSF.
A CT scan of the head should be performed to rule out parenchymal metastases or hydrocephalus before a lumbar puncture is performed.
Local radiation therapy or IT chemotherapy may provide temporary relief of symptoms. Meningeal lymphoma may respond to IV ara-C.
Spinal cord compression is most commonly caused by hematogenous spread of cancer to the vertebral bodies followed by expansion into the spinal canal or ischemia of the spinal cord.
The most common malignancies causing spinal cord compression are breast, lung, and prostate cancer, but the diagnosis should be considered in any patient with cancer who complains of back pain.
Treatment involves urgent neurosurgical and radiation oncology consultation in addition to high-dose corticosteroid therapy. MRI is the imaging modality of choice to assess for acute cord compression.
Superior vena cava obstruction is most commonly caused by cancers that arise in or spread to the mediastinum, such as lymphoma or lung cancer. The compressed superior vena cava leads to swelling of the face or trunk, chest pain, cough, and shortness of breath. Dilated superficial veins of the chest, neck, or sublingual area suggest an engorged collateral circulation. The presence of a mass on chest radiograph or CT scan usually confirms the diagnosis.
A mediastinal mass may compromise the airway. If the histologic origin of the obstruction is unknown, tissue can be obtained for diagnosis via bronchoscopy or mediastinoscopy. Therapy is directed at the underlying disease.
Chemotherapy should be administered through a vein that is not obstructed by the lesion.
Neoplasms that are not responsive to chemotherapy are treated with radiation therapy.19
Malignant effusions
Malignant pericardial effusions most commonly result from cancer of the breast or lung. Initial presentations range from dyspnea to acute cardiovascular collapse from cardiac tamponade requiring emergency pericardiocentesis.
After cardiovascular stabilization, some patients may improve with treatment if the tumor is chemotherapy sensitive.
When the pericardial effusion is a complication of uncontrolled disease, palliation can be achieved by pericardiocentesis with sclerosis; the effusion should be completely drained, followed by instillation of 30÷60 mg bleomycin through the drainage catheter, which is subsequently clamped for 10 minutes and then withdrawn.
Subxiphoid pericardiotomy can be performed in patients whose effusions do not respond to other treatment.
Malignant pleural effusions develop as a result of pleural invasion by tumor or obstruction of lymphatic drainage.
When systemic control is impossible and reaccumulation of fluid occurs rapidly after drainage, removal of the fluid followed by instillation of a sclerosing agent into the pleural space is recommended. Resistant effusions can be controlled with pleurectomy or placement of an indwelling pleural catheter, which can drain pleural fluid as needed.
Malignant ascites is most commonly caused by peritoneal carcinomatosis and is best controlled by systemic chemotherapy. Therapeutic paracenteses can provide symptomatic relief. Intraperitoneal instillation of chemotherapy has been used but is not routinely recommended.
Bone metastases may result in spontaneous fracture. Prophylactic surgical pinning and radiation therapy may be indicated. Bisphosphonates may also protect against skeletal complications from myeloma and breast cancer.20
Paraneoplastic syndromes are complications of malignancy that are not directly caused by a tumor mass effect and are presumed to be mediated by either secreted tumor products or the development of autoantibodies. Paraneoplastic syndromes can affect virtually every organ system, and in most cases, successful treatment of the underlying malignancy eliminates these effects.
Metabolic complications
Hypercalcemia is the most common metabolic complication in malignancy and can cause mental status changes, GI discomfort, arrhythmias, and constipation (see Chapter 3, Fluid and Electrolyte Management).
Syndrome of inappropriate antidiuretic hormone (SIADH) should be considered in a euvolemic cancer patient with unexplained hyponatremia. Although a variety of neoplasms have been described in association with SIADH, small-cell lung cancer is most often responsible. If chemotherapy is ineffective, radiation therapy may decrease the tumor mass and relieve symptoms.
Cancer anorexia and cachexia refers to the clinical syndrome of anorexia, distortion of taste perception, and loss of muscle mass. The asthenic appearance of patients is more often related to tumor type than to tumor burden. Megestrol acetate, 160 mg PO daily, has been used as an appetite stimulant and results in weight gain in some patients.21 Other appetite stimulants include corticosteroids, cannabinoids, and promotility agents such as metoclopramide.
Neuromuscular complications
Polymyositis and dermatomyositis. Dermatomyositis, more often than polymyositis, has been associated with a variety of malignancies, including non÷small-cell lung cancer and colon, ovarian, and prostate cancers. In some patients, successful treatment of the underlying malignancy has resulted in resolution of the symptoms. An exhaustive search for a malignancy is not recommended because a primary malignancy is found in <20% of patients.22
Lambert-Eaton myasthenic syndrome is characterized by proximal muscle weakness, decreased or absent deep tendon reflexes, and autonomic dysfunction. Electromyography using high-frequency nerve stimulation may show posttetanic potentiation.
Small-cell lung cancer is most often associated with this syndrome, and effective chemotherapy may result in improvement. Worsening symptoms have been reported with the use of calcium channel antagonists; these agents are contraindicated in this syndrome.23
Hematologic complications. Although cytopenias occur more often as a complication of treatment or marrow involvement with cancer, elevated counts may be explained by paraneoplastic syndromes.
Erythrocytosis is a rare complication of hepatoma, renal cell cancer, and benign tumors of the kidney, uterus, and cerebellum. Debulking the tumor with surgery or radiation therapy generally results in resolution of the erythrocytosis. Occasionally, therapeutic phlebotomy is indicated.
Granulocytosis (leukemoid reaction) in the absence of infection occurs in cancer that arises in the stomach, lung, pancreas, brain, and lymphoma. Because the neutrophils are mature and seldom exceed 100,000/mm3, complications are rare and intervention is generally unnecessary.
Thrombocytosis in patients with cancer may be caused by splenectomy, iron deficiency, acute hemorrhage, or inflammation; treatment is usually not necessary.
Thromboembolic complications. Mucin-secreting adenocarcinomas of the GI tract and lung cancer have been associated with a “hypercoagulable state,” resulting in recurrent venous and arterial thromboembolism.
Nonbacterial thrombotic (marantic) endocarditis, usually involving the mitral valve, may also occur.
Heparin anticoagulation or low molecular weight heparin should be instituted, as well as treatment of the underlying cancer. Long-term warfarin with a target international normalized ratio of 2÷3 or daily low molecular weight heparin is recommended to prevent subsequent thrombi.24
Glomerular injury resulting in renal failure has been observed as a paraneoplastic syndrome. Minimal change disease is often associated with lymphoma, especially Hodgkin's disease; membranous glomerulonephritis is more often seen with solid tumors. The process can be reversed with treatment of the underlying cancer.
Clubbing of the fingers and hypertrophic osteoarthropathy (polyarthritis and periostitis of long bones) are most often observed in non÷small-cell lung cancer but are also
seen with lesions that are metastatic to the mediastinum. Some improvement in the osteoarthropathy can be achieved with nonsteroidal anti-inflammatory drugs, but definitive therapy requires treatment of the underlying malignancy.
Fever may accompany lymphoma, renal cell cancer, and hepatic metastasis. Once an infectious etiology for the fever has been excluded, nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, 400 mg PO q6h, or indomethacin, 25÷50 mg PO tid) may provide symptomatic relief.
Principles of Chemotherapy
Administration of chemotherapeutic drugs. The advice of an oncologist and precise adherence to a treatment plan are mandatory because of the low therapeutic index of chemotherapeutic agents.
The dosage of chemotherapy is usually based on body surface area; for some agents, dosage is determined by body weight and should be adjusted when changes in body weight occur.
An assessment of the patient disease status, determination of side effects from the previous treatment, and a CBC should be obtained before each cycle of chemotherapy.
Drug dosages usually must be adjusted for the following conditions: (a) neutropenia, (b) thrombocytopenia, (c) stomatitis, (d) diarrhea, or (e) limited metabolic capacity for the drug.
Route of administration
Oral drug administration may be accompanied by nausea and vomiting and may require antiemetic therapy. For some agents, oral absorption is erratic and parenteral administration is preferred.
IV drug administration should be performed by experienced personnel. Care should be taken to ensure free flow of fluid to the vein, and adequate blood return should be verified before instillation of chemotherapy. Infusions should be through a large-caliber, upper extremity vein. When possible, veins of the antecubital fossa, wrist, dorsum of the hand, and arm ipsilateral to an axillary lymph node dissection should be avoided.
In patients with poor peripheral venous access or those who require many doses of chemotherapy, indwelling venous catheter devices should be consid- ered.
Intrathecal chemotherapy is administered for the treatment of meningeal carcinomatosis or as CNS prophylaxis. Side effects include acute arachnoiditis, subacute motor dysfunction, and progressive neurologic deterioration (leukoencephalopathy). Impaired cognitive function and leukoencephalopathy occur more often when IT chemotherapy is combined with whole-brain radiation.
Methotrexate, 10÷12 mg, is diluted in 5 mL preservative-free nonbacteriostatic isotonic solution. Before administration, 5÷10 mL CSF should be allowed to drain; methotrexate is then injected into the spinal canal over 5÷10 minutes.
To decrease the risk of arachnoiditis, patients should remain in a supine position for 15 minutes after the infusion is completed.
Slow-release cytarabine, 50 mg, or ara-C, 50÷100 mg in 5÷10 mL diluent, can be administered in a similar manner.25
Intracavitary instillation of chemotherapy may be useful in some circumstances. Thiotepa, 30÷60 mg, is commonly instilled in the bladder for the treatment of bladder carcinoma. Doxorubicin and cisplatin have been given through an implanted peritoneal catheter for the treatment of peritoneal metastasis.
Intra-arterial chemotherapy is advocated as a method of achieving high drug concentrations at specific tumor sites. Although it is of theoretical advantage, there are no absolute indications for chemotherapy administered by this route.
Chemotherapeutic Medications
Chemotherapeutic agents. Class-specific or unique side effects are described here.
Antimetabolites exert antitumor activity by acting as pseudosubstrates for essential enzymatic reactions. Their greatest toxicity occurs in tissues that are actively replicating (e.g., GI mucosa, hematopoietic cells).
Ara-C is an analog of deoxycytidine that is most useful in hematologic neoplasms. In standard doses, myelosuppression and GI toxicity are dose limiting. In high doses, conjunctivitis is common, and prophylaxis with dexamethasone eye drops, two drops in each eye tid, should be administered. Cerebellar ataxia, pancreatitis, and hepatitis may also develop. If cerebellar dysfunction occurs during treatment, ara-C must be discontinued.
FU is a pyrimidine analog that is administered as an injection or as a continuous infusion.
When it is administered as a bolus injection, myelosuppression is dose limiting.
With infusion, stomatitis and diarrhea are dose limiting. Cerebellar ataxia has been reported with both schedules and requires discontinuation of the drug.
Chest pain ascribed to coronary artery vasospasm may occur with infusions and, if suspected, should be treated with a calcium channel antagonist (e.g., nifedipine) or by discontinuing the chemotherapy.26
FU can be administered over 6÷8 weeks and is limited by the development of a palmar÷plantar dermatologic toxicity (the hand÷foot syndrome can be palliated with vitamin B6, 150 mg/d). LV can be coadministered with FU to potentiate cytotoxicity; diarrhea is dose limiting.27
Methotrexate is an inhibitor of dihydrofolate reductase and has numerous toxicities. Mucositis is dose limiting.
Prolonged reabsorption. Methotrexate is polyglutamated, and these metabolites accumulate in effusions to produce substantial toxicity. Patients with effusions should either have the fluid drained before receiving methotrexate or have the dosage drastically reduced.
Interstitial pneumonitis, unrelated to cumulative dose and associated with a peripheral eosinophilia, may occur. It should be treated with glucocorticoids (e.g., prednisone, 1 mg/kg PO daily or equivalent) and precludes additional use of methotrexate.
Hepatitis may occur with long-term oral administration but may also occur after a single high dose.
High-dose methotrexate may be associated with crystalline nephropathy and renal failure. Urine alkalinization with sodium bicarbonate should be maintained to minimize this risk. LV is used to “rescue” normal tissue after high-dose methotrexate. The dose depends on the amount of methotrexate used, but the usual dosage is 5÷25 mg IV or PO q6h for 8÷12 doses, or until the serum methotrexate concentration is <50 nM.
6-Mercaptopurine is a purine analog that is partially metabolized by xanthine oxidase. To avoid increased toxicity, the dose of 6-mercaptopurine should be decreased by 75% in patients taking allopurinol. Hepatic cholestasis has also been observed.
Fludarabine is an adenosine monophosphate analog that produces myelosup- pression.28
Cladribine (2-chlorodeoxyadenosine) is a purine substrate analog that is resistant to degradation by adenosine deaminase. Myelosuppression is predictable.29
Gemcitabine is a nucleoside analog that may produce fever, edema, flulike symptoms, and rash. Pneumonitis is an uncommon complication.
Alkylating agents are useful in a wide variety of malignancies. These drugs cause DNA cross linking and strand breaks. Most alkylating agents are cytotoxic to resting and dividing cells. Patients should be counseled that irreversible sterility may develop after treatment with alkylating agents. Chlorambucil, cyclophosphamide, melphalan, and mechlorethamine have been implicated in the development of acute myeloid leukemia and myelodysplasia 3÷10 years after treatment.
Busulfan can cause interstitial pneumonitis and gynecomastia. A reversible syndrome resembling Addison disease may develop with long-term daily oral administration.
Chlorambucil is a well-tolerated orally administered drug. Myelosuppression is dose limiting and usually readily reversible.
Cyclophosphamide can cause hemorrhagic cystitis; therefore, adequate hydration to maintain urine output is required during treatment. Oral cyclophosphamide should be given early in the day to ensure adequate hydration. High-dose cyclophosphamide is used as a preparative agent before stem cell transplantation; at these doses a hemorrhagic myocarditis can occur.
Dacarbazine can produce a flulike syndrome consisting of fever, myalgias, facial flushing, malaise, and marked elevations of hepatic enzymes.
Ifosfamide is chemically similar to cyclophosphamide, but the incidence of hemorrhagic cystitis is much higher (occurring in 20%÷30% of treated patients). Administration of 2-mercaptoethanesulfonate (mesna) is recommended to lower the incidence of cystitis. Ifosfamide can also cause neurologic toxicity, including seizures.
Mechlorethamine (nitrogen mustard) is a skin irritant; protective gloves and eyewear must be used during drug preparation and administration. Development of a drug rash does not prevent further use of this agent.
Melphalan is available in oral and injectable forms. An idiosyncratic interstitial pneumonitis may occur, and, although usually reversible, it precludes further use of the drug.
Nitrosoureas (carmustine [BCNU] and lomustine [CCNU]) are lipid soluble and penetrate the blood-brain barrier. BCNU is usually administered in an ethanol solution, and toxicity from the vehicle, including giddiness, flushing, and phlebitis, may occur. Because delayed myelosuppression occurs 6÷8 weeks after treatment and may be cumulative, these agents are commonly given at 8-week intervals.
Temozolomide is an oral alkylating agent with activity in primary and metastatic brain tumors.
Thiotepa can be administered IV with bone marrow rescue. When used intra-vesically, 60÷90 mg is administered in 60÷100 mL of water and instilled over 2 hours.
Antitumor antibiotics intercalate adjacent DNA nucleotides, interrupting replication and transcription to cause strand breaks; they are cell cycle nonspecific.
Anthracycline antibiotics are associated with a cardiomyopathy consisting of intractable CHF and dysrhythmias. With doxorubicin, this complication is seen in approximately 2% of patients who receive a cumulative lifetime dose of 550 mg/m2. The incidence increases dramatically at higher cumulative doses. Concomitant cyclophosphamide or previous chest irradiation may potentiate this toxicity. As the cumulative dose approaches 450÷550 mg/m2, serial radionuclide ventriculography should be performed, and the anthracycline should be discontinued if LV function is compromised. Myocardial damage is related to peak serum concentrations and cumulative dosage; longer (96-hour) infusions have allowed for higher cumulative dosages.
The cardioprotectant dexrazoxane has been shown to decrease the incidence and severity of the cardiomyopathy associated with doxorubicin.30
Daunorubicin is used in the treatment of acute leukemia. Bone marrow suppression is expected, and the dose-limiting toxicity is usually mucositis. Red urine may be caused by the drug and its metabolites.
Doxorubicin toxicity is similar to that of daunorubicin,
although this drug has a broader spectrum of activity. Liposomal doxorubicin is indicated for Kaposi sarcoma and has similar toxicities.
Mitoxantrone is structurally similar to doxorubicin and daunorubicin but is associated with less cardiac toxicity. Mucositis and myelosuppression are dose limiting; a bluish discoloration of the urine and sclera may occur.
Idarubicin is more rapidly taken up in cells than other anthracyclines. Toxicity is similar to that of daunorubicin.
Bleomycin is useful in combination chemotherapy because it is rarely myelosuppressive. A test dose, 1÷2 mg SC, should be administered before full doses are instituted because severe allergic reactions with hypotension may occur, especially in patients with lymphoma. Interstitial pneumonitis, which occasionally results in irreversible pulmonary fibrosis, is more common in patients with underlying pulmonary disease or previous lung irradiation or those who received a cumulative dose of 200 mg/m2. Pulmonary symptoms and chest radiographs should be monitored.
Mitomycin-C is associated with delayed myelosuppression that worsens with repeated use of the drug. Interstitial pneumonitis has also been observed. The hemolytic÷uremic syndrome has been reported, is exacerbated by red blood cell (RBC) transfusions, and should be suspected in patients with sudden onset of a microangiopathic hemolytic anemia and renal failure.
2-Deoxycoformycin (Pentostatin) is isolated from Streptomyces and acts as an inhibitor of adenosine deaminase. Myelosuppression is the chief toxicity.
Plant alkaloids are naturally occurring nitrogenous bases. Most inhibit cell division through inhibition of mitotic spindle formation.
Vincristine often causes a dose-limiting neuropathy. Paresthesias followed by loss of deep tendon reflexes are the usual manifestations. Neuritic pain, jaw pain, diplopia, constipation, abdominal pain, and an adynamic ileus occur less often. Other adverse effects include SIADH and Raynaud phenomenon.
Vinblastine is less neurotoxic than vincristine; dosage is usually limited by myelosuppression. At high doses, myalgias, obstipation, and transient hepatitis may occur.
Etoposide (VP-16). The major dose-limiting toxicity is myelosuppression.
Teniposide (VM-26) is a semisynthetic derivative of podophyllotoxin. Toxicities include myelosuppression, hypersensitivity reactions, alopecia, and hypotension.
Paclitaxel (Taxol) has a unique antitubulin mechanism that disrupts microtubule assembly. Because paclitaxel is dissolved in Cremophor, anaphylactoid reactions may occur and are partially related to the rate of infusion.
All patients should be premedicated with dexamethasone and histamine-1 (H1) and H2 blockers. In addition, myelosuppression, arthralgias, neuropathy, and arrhythmias may occur. An albumin-bound nanoparticle formulation of pac-litaxel is now available (Abraxane). The albumin binding allows the drug to be delivered without the Cremophor solvent and reduces solvent-related toxicities.
Docetaxel (Taxotere) can be administered more rapidly than paclitaxel without anaphylactoid reactions. Dexamethasone, 8 mg bid for 3 days beginning the day before chemotherapy, is administered to prevent third-space fluid collections.
Navelbine may produce pain in the IV injection site.
Platinum-containing agents act as intercalators, causing single- and double-strand breaks in DNA.
Cisplatin produces severe nausea and vomiting; aggressive antiemetic therapy is mandatory (see Table 20-3). The patient should be aggressively volume expanded with 1 L isotonic saline administered over 4÷6 hours before and after chemotherapy to prevent renal toxicity. The dosage of cisplatin should be reduced for patients with renal insufficiency and should be withheld if the serum creatinine is >3 mg/dL.
Other toxicities include hypomagnesemia and ototoxicity.
Pretreatment with amifostine may reduce the cumulative hematologic, renal, and neurologic toxicities.31
Carboplatin is a cisplatin analog with less neurotoxicity, ototoxicity, and nephrotoxicity than cisplatin; myelosuppression is the dose-limiting toxicity.
Oxaliplatin is a recently approved platinum-containing agent with activity in colorectal cancer. It is associated with a sensory neuropathy.
Other agents
Hydroxyurea, an oral agent that inhibits ribonucleotide reductase, is used in the management of the chronic phase of CML and other myeloproliferative diseases.
The dosage is adjusted according to the peripheral blood neutrophil and platelet count.
L-Asparaginase hydrolyzes asparagine, depleting cells of an essential substrate in protein synthesis. Allergic or anaphylactic reactions may occur. Other toxicities include hemorrhagic pancreatitis, hepatic failure with depression of clotting factors, and encephalopathy.
Procarbazine is an oral agent that inhibits DNA, RNA, and protein synthesis. It is a monoamine oxidase inhibitor, and therefore tricyclic antidepressants, sympathomimetic agents, and tyramine-containing foods should be avoided. Procarbazine has a disulfiramlike effect, and therefore ethanol should not be ingested while this medication is being administered.
Topotecan is a topoisomerase I inhibitor. Myelosuppression is dose limiting.
Irinotecan has a similar mechanism of action to topotecan. It can produce severe diarrhea, which can be treated with atropine and loperamide.
Hormonal agents lack direct cytotoxicity. In general, they have few serious adverse effects. In disseminated disease, eventual resistance to hormonal agents should be anticipated.
Tamoxifen is a selective ER modulator. It acts as an ER antagonist in some tissues including breast and as an ER agonist on others. The usual dosage is 10 mg PO bid.
After 7÷14 days of treatment, a hormone flare (increasing bone pain, erythema, and hypercalcemia) occurs in approximately 5% of women with ER-positive breast cancer and bone metastases. The symptoms abate over 7÷10 days, and 75% of these patients respond to tamoxifen; therefore, palliation of pain, control of hypercalcemia, and continuation of the drug are recommended.
Long-term administration of tamoxifen is not associated with a systemic anties-trogen effect (vaginal atrophy, osteoporosis, or increased risk of heart disease) but is related to some estrogen effects (endometrial cancer and deep vein thrombosis).
Aromatase inhibitors. Third-generation aromatase inhibitors have become available for the treatment of postmenopausal women with hormone-responsive breast cancer. Two nonsteroidal agents, anastrazole (Arimidex, 1 mg/d) and letrozole (Femara, 2.5 mg/d), and one steroidal agent, exemestane (Aromasin, 25 mg/d), are available. All three agents have been found to be active in hormone-sensitive breast cancer.32 The most common side effects of aromatase inhibitors are hot flashes and night sweats.
Gonadotropin agonists. Two LHRH agonists are used in the treatment of metastatic prostate cancer. Leuprolide acetate and goserelin acetate can be given as monthly SC depot injections, and leuprolide acetate is also available in a daily injection form. The first weeks of treatment may be associated with an initial flare in tumor symptoms, bone pain, fluid retention, hot flashes, sweats, and impotence. One should monitor for signs of neurologic dysfunction or urinary obstruction.
Progestational agents. Megestrol acetate, 40 mg PO four times daily, and me-droxyprogesterone, 10 mg PO daily, have been used in the treatment of a variety of neoplasms. Principal toxicities include weight gain, fluid retention, hot flashes, and vaginal bleeding with discontinuation of therapy. Both agents also have been used in the treatment of cachexia associated with cancer and AIDS.
Antiandrogens. Flutamide and bicalutamide may produce nausea, vomiting, gynecomastia, and breast tenderness.33 In advanced prostate cancer, withdrawal of flutamide results in tumor regression in 25% of patients.34
Targeted therapies in the form of monoclonal antibodies and TKIs are now available.
Trastuzumab (4 mg/kg over 90 minutes week 1, then 2 mg/kg over 30 minutes weekly) should be added to the first-line chemotherapy in patients with metastatic breast cancer whose cancers overexpress her-2 as measured by gene amplification or protein expression. Its use is associated with an improved survival. As a single agent, it has modest activity and a different mechanism of action than chemotherapy.35
Rituximab, an unconjugated antibody targeted to CD20, is administered weekly for 1 month for treatment of low-grade non-Hodgkin lymphomas that are CD20 positive. Toxicities include chills and fevers during administration and rare hypersensitivity reactions.36
Alemtuzumab is a humanized antibody to CD52 (present on normal B and T cells) and has been used to treat CLL. Because of a high incidence of opportunistic infections from resulting immunodeficiency, prophylactic antifungals and antivirals are recommended.37
Bevacizumab targets VEGF and is approved for the treatment of colon cancer, and has activity in breast and lung cancer. Common toxicities include hypertension and proteinuria. It has infrequently been associated with serious bleeding or clotting events and gastrointestinal perforations.
Cetuximab and panitumumab target EGFR and have been approved for the treatment of colon cancer. Toxicities include infusion reactions, rash, and diarrhea.
Gemtuzumab is directed against CD33 and is indicated in myeloid leukemias.
Ibritumomab and iodine 131 tositumomab are radiolabeled antibodies indicated for the treatment of non-Hodgkin lymphoma.
Imatinib is a TKI targeting the BCR-ABL fusion protein in CML, as well as c-kit in gastrointestinal stromal tumors (GISTs). It has activity in a number of less common disorders.
Erlotinib is a TKI-targeting EGFR approved in NSCLC and with activity in pancreatic cancer as well. Toxicities include diarrhea and rash.
Sunitinib and sorafenib are multitargeted TKIs approved for the treatment of renal cell carcinoma.
Nonspecific immunotherapy
Interferon-α is used for hairy-cell leukemia, CML, and melanoma. Toxicity includes nausea and vomiting, flulike symptoms, and headaches. Acute toxicity may respond to acetaminophen; with continued administration these symptoms subside.
Aldesleukin (interleukin-2) can produce responses in melanoma or renal cell carcinoma; some of these remissions are durable. At high doses this agent is toxic, producing increased vascular permeability with fluid overload, hypotension, prerenal azotemia, and elevation of liver enzymes.
Chemopreventive agents
Retinoids have been used as therapeutic and chemopreventive agents. Isotretinoin (13-cis-retinoic acid), 50÷100 mg/m2 PO daily for 12 months, has been shown to lower the incidence of second primary tumors in patients who were previously treated for head and neck cancer.38 Common toxicities include dry skin, cheilitis, hyperlipidemia, and elevation of transaminases.39
Tamoxifen, 20 mg PO daily administered for 5 years, has been shown to decrease the incidence of breast cancer in women with a high risk of developing breast cancer.40 Raloxifene has been found to have similar risk reduction benefit with a lower risk of endometrial cancer and blood clots.
Complications of Treatment
Chemotherapy often causes serious or life-threatening toxicity. The most common and predictable toxicities are to the rapidly proliferating cells of hematopoietic and mucosal tissue. Because repair of these tissues cannot be accelerated, palliation during the healing process is the primary goal.
Radiation therapy toxicity is related to the location of the therapy, total dose delivered, and rates of delivery. Large-dose fractions of radiation are associated with greater toxicity to the normal tissues encompassed in the radiation field.
Acute toxicity develops within the first 3 months of therapy and is characterized by an inflammatory reaction in the tissue receiving radiation. Such toxicity may respond to anti-inflammatory agents such as glucocorticoids. Local irritations or burns in the treatment field generally resolve with time. Close observation and treatment of any
infections and palliation of symptoms such as pain, dysphagia, dysuria, or diarrhea (depending on the site of treatment) are the mainstays of supportive care until healing has occurred.
Subacute toxicities between 3 and 6 months of therapy and chronic toxicity after 6 months are less amenable to therapy, as fibrosis and scarring are present. Daily amifostine before head and neck radiation therapy decreases the incidence of xerostomia.41
Specific Complications: Tumor Lysis Syndrome
General Principles
Tumor lysis syndrome occurs in patients with rapidly proliferating neoplasms that are highly sensitive to chemotherapy. Rapid tumor cell death releases intracellular contents and causes hyperkalemia, hyperphosphatemia, and hyperuricemia. Although reported in the treatment of a variety of malignancies, it is usually associated with high-grade non-Hodgkin's lymphoma and acute leukemia.
The diagnosis of tumor lysis syndrome is based on susceptibility, clinical suspicion, and close monitoring of laboratory data in patients at risk. Rapidly progressive hyperkalemia, hyperphosphatemia, and hyperuricemia as well as acutely worsening renal failure are the hallmarks.
Prophylaxis and Treatment
Prophylaxis and pretreatment are paramount in preventing tumor lysis syndrome.
During induction chemotherapy for tumor lysis syndrome, prophylactic measures should include allopurinol, 300÷600 mg PO daily, and aggressive IV volume expansion (e.g., 3,000 mL/m2/d). The addition of sodium bicarbonate, 50 mEq/1,000 mL IV fluid, to alkalinize the urine above a pH of 7 may prevent uric acid nephropathy and acute renal failure.
When hyperphosphatemia accompanies hyperuricemia, urine alkalinization should be avoided because calcium phosphate precipitation may result in renal failure.
Rasburicase is a recombinant urate oxidase enzyme that catalyzes the oxidation of uric acid into allantoin, a soluble metabolite. It can be used prophylactically or in the treatment of hyperuricemia. It can be administered as a daily dose of 0.15÷0.20 mg/kg/d for up to 5 days.
Despite these preventive measures, hemodialysis may be needed for hyperkalemia, hyperphosphatemia, acute renal failure, or fluid overload.
Specific Complications: Hematologic
Myelosuppression/Febrile Neutropenia
General Principles
The risk of infection increases dramatically with neutropenia (defined as an absolute neutrophil count of <500/mm3) and is directly related to the duration of the neutropenia. Fever is defined as a single core temperature reading of >38.3°C or two readings of >38.0°C spanning 1 hour. Other clinical signs of infection must be considered in this evaluation, because the inflammatory response may be muted in the absence of neutrophils. A febrile neutropenic patient should be presumed to be infected and must be evaluated and treated promptly.
Physical Examination
A complete physical examination should be performed to locate potential sites of infection, with particular attention to indwelling catheter sites, sinuses, and the oral and perirectal areas.
Digital rectal examination should be avoided to prevent bacterial translocation.
Laboratory Studies
Cultures of blood, urine, stool, sputum, and other foci that are susceptible to bacterial infections (e.g., fluid collections) should be collected.
A chest radiograph should be obtained to check for infection.
To guard against infection, empiric antimicrobial treatment should be initiated immediately after cultures are obtained. In the absence of any obvious source, the antimicrobials should provide broad coverage for Gram-negative bacilli (including Pseudomonas aeruginosa) and Gram-positive cocci (including α-hemolytic Streptococcus species). In choosing a regimen, local susceptibility patterns should also be considered. Empiric therapy may consist of an aminoglycoside and semisynthetic penicillin or a single agent such as cefepime. Antimicrobials are continued until the neutrophil count is >500/mm3.
Vancomycin should not be included in initial empiric regimens unless the patient is clinically unstable or has had a recent oxacillin-resistant Staphylococcus aureus infection.
Low-risk patients (afebrile after institution of antibiotics, negative cultures, and anticipated to recover from myelosuppression in <1 week) can be discharged on an oral broad-spectrum agent such as a fluoroquinolone or trimethoprim/sulfamethoxazole.
Modification of the antimicrobial regimen according to the culture data or clinical picture may become necessary. Additional agents to treat Staphylococcus epidermidis, Clostridium difficile, or anaerobic infections are commonly necessary based on physical examination findings and suspected foci of infection.
Persistent fever, in the absence of other data, usually does not warrant an empiric change in the antibacterial therapy.
Empiric antifungal therapy with amphotericin B (starting at 0.5 mg/kg and advanced to 1.0 mg/kg qd) should be added if the fever continues for longer than 72 hours.
Growth factors include many cytokines that may ameliorate the myelosuppression associated with cytotoxic chemotherapy. They act on hematopoietic cells, stimulating proliferation, differentiation, commitment, and some functional activation. Because they can increase myelosuppression, they should not be given within 24 hours of chemotherapy or radiation.
G-CSF, given at an initial dose of 5 mcg/kg SC or IV beginning the day after the last dose of cytotoxic chemotherapy, may reduce the incidence of febrile neutropenic events. Blood counts should be monitored twice a week during therapy. Bone pain is a common toxicity that can be managed with nonnarcotic analgesics. A pegylated form of G-CSF is now available, allowing for single-dose/cycle administration at a dose of 6 mg.
GM-CSF, given subcutaneously at a dose of 250 mcg/m2/d beginning the day after the last dose of cytotoxic chemotherapy, shortens the period of neutropenia after stem cell transplant.
Neutropenic patients should be maintained in modified reverse isolation. Those who enter the room should wash their hands thoroughly with antiseptic soap or an alcohol-based hand-cleaning solution. Visitors with colds should wear a mask, and those with fevers should not enter. Due to the risk of fungal infection, live plants should not be allowed in the room.
Anemia is a common side effect of multiple chemotherapeutic agents. Symptoms include fatigue, dyspnea, or lethargy. RBC transfusions are indicated for patients who have symptoms of anemia, active bleeding, or a hemoglobin concentration below 7÷8 g/dL. Because of anecdotal reports of GVHD associated with transfusions, radiation of all blood products is generally recommended for immunosuppressed marrow transplant patients.
Recombinant erythropoietin given at a starting dose of 150 units/kg SC three times a week has been shown to improve anemia and decrease transfusion requirements in cancer patients, particularly those in whom the anemia is predominantly caused by cytotoxic chemotherapy.42 Hematocrit should be monitored weekly during therapy, and the dosage should be adjusted accordingly.
Darbepoetin alfa is a recombinant erythropoietin with a longer half-life. It is indicated for the treatment of chemotherapy-induced anemia in patients with solid tumors and can be dosed every 2 weeks.43
Thrombocytopenia is another common side effect of chemotherapeutic agents toxic to the bone marrow. Symptoms include easy bruising and bleeding, including epistaxis and gingival bleeding.
Thrombocytopenia below 10,000/mm3 that is the result of chemotherapy should be treated with platelet transfusions to minimize the risk of spontaneous hemorrhage.
Interleukin-11 was approved to reduce the duration and severity of thrombocytopenia after chemotherapy. However, limited efficacy and significant toxicity (fluid retention and atrial arrhythmias) have limited its use.
When prolonged thrombocytopenia is anticipated, histocompatibility testing should be performed before therapy so that HLA-matched single-donor platelets can be provided when alloimmunization makes the patient refractory to random-donor platelets.
Specific Complications: Extravasation
Extravasation of certain chemotherapeutic agents from venous infusion sites may lead to severe local tissue injury. Offending agents are identified as vesicants. Initial symptoms of pain or erythema may appear within hours or may be delayed for up to 1÷2 weeks. When extravasation occurs, the steps described below should be taken.
Stop the chemotherapy infusion. With the venous catheter still in place, approximately 5 mL of blood should be aspirated to remove any residual drug.
Certain drugs require hot or cold compresses and may be neutralized by instillation of agents locally through the catheter and subcutaneously into the nearby tissue (Table 20-2).
Observe the area closely for signs of tissue breakdown; surgical intervention for debridement or skin grafting may be necessary. Because extravasation injuries usually result in severe pain, adequate analgesia should be supplied.44
Specific Complications: Gastrointestinal
Stomatitis is an unpleasant consequence of many chemotherapeutic agents and is commonly the dose-limiting toxicity of methotrexate and FU. With simultaneous administration of radiation therapy, the toxicity is more severe. Healing generally occurs within 7÷10 days of the development of symptoms. The severity of stomatitis ranges from mild (oral discomfort) to severe (ulceration, impaired oral intake, and hemorrhage).
In mild cases of stomatitis, oral rinses (chlorhexidine, 15÷30 mL swish and spit tid, or the combination of equal parts diphenhydramine elixir, saline, and 3% hydrogen peroxide) may provide relief. Polyvinylpyrrolidone-sodium hyalonurate gel can also be used.
Palifermin, a keratinocyte growth factor analog, has been approved for use in chemotherapy-induced stomatitis.45
In severe cases, IV morphine is appropriate.
IV fluids should be used to supplement oral intake as needed.
Aspiration may develop in patients with moderate or severe stomatitis; precautions should include elevation of the head of the bed and availability of a handheld suction apparatus.
In severe or prolonged episodes, superinfection with Candida or herpes simplex is possible and requires appropriate diagnosis and antimicrobial intervention.
Diarrhea is the result of cytotoxicity to proliferating cells of the intestinal mucosa.
In some cases of diarrhea, IV fluids are necessary to avoid intravascular volume depletion. The use of oral opioid agents as antidiarrheals is commonly limited by abdominal cramping. Severe diarrhea associated with FU and LV has been reported to respond to octreotide, 150÷500 mcg SC tid. Diarrhea secondary to irinotecan can be treated with loperamide, 4 mg PO then 2 mg q2h while awake, and 4 mg q4h during the night.
Nausea and vomiting may develop in varying degrees and frequency. Suggestions for antiemetic agent(s) are listed in Table 20-3.
Specific Complications: Other
Interstitial pneumonitis may develop as a dose-related, cumulative toxicity or as an idiosyncratic reaction. The implicated agent should be discontinued.
With interstitial pneumonitis, the institution of glucocorticoids (e.g., prednisone, 1 mg/kg PO daily or equivalent) may be of some benefit. The long-term outcome, however, is unpredictable.
Hemorrhagic cystitis may develop with either cyclophosphamide or ifosfamide.
Hemorrhagic cystitis is best anticipated and treated with prophylactic mesna at a dosage of at least 0.6 mg mesna to 1 mg ifosfamide. Treatment consists of continuous bladder irrigation with isotonic saline and should continue until the hematuria resolves.
Palliative Care
Palliative care and pain management. Patients with cancer experience a multitude of symptoms. Studies have revealed that individuals with advanced cancer often experience
ten or more symptoms, including pain, nausea, fatigue, weakness, constipation, and dyspnea. In addition to physical symptoms, patients also suffer emotionally and spiritually. Individuals with early-stage cancer experience similar symptoms, but with less frequency. The optimal management of cancer patients includes a careful assessment of symptomatology and appropriate management of these symptoms.
Pain is present at diagnosis in 5%÷10% of patients with localized cancer and 60%÷90% of individuals with metastases. Improved oral analgesics, use of indwelling venous access devices, development of home nursing care agencies, and public acceptance of the hospice philosophy now allow patients to receive a large portion of their palliative treatment out of the hospital. Successful treatment of the underlying disease usually provides relief of pain. Painful foci of disease that are refractory to systemic intervention can be controlled with local radiation therapy, regional nerve block, or an ablative surgical procedure. In many situations, however, analgesics are necessary (see Chapter 1, Patient Care in Internal Medicine).
Mild or moderate cancer pain may respond to nonopioid analgesics such as ace-taminophen or nonsteroidal anti-inflammatory drugs. Moderate to severe pain almost always requires an opioid analgesic to attain significant relief. Medication administered on a prescribed schedule is more effective in maintaining analgesia than that taken intermittently once pain has developed. Several potent opioids are available in sustained-release formulations, including morphine, oxycodone hydrochloride, and fentanyl. Methadone has a long half-life and can be used as a long-lasting pain medication. Most patients with cancer pain have some combination of chronic and intermittent pain.
Optimal pain management includes a long-lasting pain medication with PRN dosing for breakthrough pain. Occasionally, infusions of morphine, 3÷5 mg/hr IV, increased by 2÷4 mg/hr as needed, are necessary. Under supervision, morphine drips can be used in the home setting. Morphine, as well as most other parenteral opioids, can also be
administered subcutaneously. This reduces the difficulty of delivering these medications, especially in the home setting. Although tolerance and physical dependency can develop with long-term narcotic administration, drug abuse and psychological dependency seldom occur in the setting of chronic pain from cancer. These concerns should not compromise the patient's ability to achieve adequate analgesia.
Nonopioid adjuvant pain medications. Acetaminophen and nonsteroidal anti-inflammatory drugs may offer some relief even in the setting of severe pain, allowing a lower dose of opioid to be used. Other adjuvant pain medications include tricyclic antidepressants and antiseizure medications, which may be especially useful for neuropathic pain. The bisphosphonates may improve the treatment of bone pain.
Palliative care is defined by the World Health Organization as “the active total care of the patient whose disease is not responsive to curative intent.” Palliative care focuses on the relief of symptoms and coping with the implications of advanced cancer, as most patients with advanced cancer die from their disease. Control of pain and other symptoms, as well as addressing psychological, social, and spiritual problems, is paramount (World Health Organization, Technical Report 804, 1990). A detailed overview of palliative care is beyond the scope of this chapter. The basic principles include a multidisciplinary approach to patient assessment and management. A careful and detailed assessment of symptoms, physical as well as psychological, is essential to this process, as is an assessment of the disease and patient status. This allows for realistic expectations regarding the disease process and prognosis to be determined, which in turn allows for informed decision making to formulate a plan of care.
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