Principles of Cancer Therapy

From WiserWiki

[edit] Principles of Cancer Therapy

Diane Savarese

Despite recent advances, cancer remains the second leading cause of death in the United States. Historically, resection offered the only possibility of cure, however small. This changed with the introduction of radiation therapy and combination chemotherapy in the mid-twentieth century. The modern approach to cancer therapy usually involves an integrated approach by medical, surgical, and radiation oncologists; nursing; nutrition; social work; and physical therapy.

[edit] SURGICAL MANAGEMENT

Surgery may play a role in the diagnosis, staging, primary therapy, and palliation of malignant disease. The suitability of primary surgical therapy for the treatment of a malignancy depends on the patient, the tumor type, and the extent of disease (stage). Most physicians use the American Joint Committee on Cancer (AJCC) staging system to classify tumor extent.^[1] In general, primary surgical treatment is most appropriate for early stage tumors, whereas more advanced disease implies spread beyond locoregional areas and the inability of even aggressive surgery to cure the patient. For some tumors, chemotherapy or radiation therapy is preferable for primary treatment (e.g., lymphomas, small cell lung carcinoma). In other malignancies patients who have even disseminated (stage IV) disease may be amenable to surgical intervention for cure (e.g., osteogenic sarcoma, Wilms' tumor). Surgical debulking of large tumor masses may enhance the effectiveness of subsequent radiation or chemotherapy (e.g., advanced epithelial ovarian cancer). Palliation of specific complications from local tumor growth may also require surgical intervention (e.g., diverting colostomy for bowel obstruction in advanced colorectal cancer).

[edit] RADIATION THERAPY

Irradiation destroys cancer cells because, unlike normal cells, they cannot repair the cumulative cellular deoxyribonucleic acid (DNA) damage induced by x-rays administered in multiple doses over several days (fractionated radiation therapy). There are two types of radiation therapy in clinical use: external beam and interstitial radiotherapy (brachytherapy). External beam radiation is delivered by a source outside of the patient such as an x-ray generator, cobalt unit, or linear accelerator. Interstitial therapy entails placing the radiation source within an adjacent cavity or directly into the tumor itself. Radiation therapy may be delivered with curative intent, resulting in total and permanent eradication of tumor (e.g., early laryngeal or prostate cancer, Hodgkin's disease), or palliatively to relieve symptoms or reduce tumor bulk (e.g., brain metastases, epidural spinal cord compression, pain from bone metastases) (Table 118-1).

Table 118-1 Results from Palliative Radiotherapy

There is a direct relationship between the radiation dose administered, tumor cell kill, and the likelihood of complications (Fig. 118-1). In general, the larger the tumor, the higher the dose needed to sterilize the area. Preoperative radiotherapy may be used to reduce tumor volume, making a locally advanced tumor more amenable to surgical removal (e.g., rectal cancer). More commonly, postoperative radiotherapy is used to eradicate gross or microscopic disease left behind at the time of surgery. One example is the use of breast conservation therapy for early stage breast cancers. Treatment with lumpectomy followed by radiation therapy has shown equivalent long-term results when compared with modified radical mastectomy.^[2] Postoperative radiotherapy is most useful in decreasing locoregional recurrences, but it usually has little effect on overall survival from cancer. Radiation may also be used with chemotherapy to maximize both systemic and locoregional control (e.g., Hodgkin's disease with bulky mediastinal masses and limited stage small cell lung cancer). Low-dose chemotherapy has also been used to sensitize cells to radiation therapy. This approach has been most useful for tumors of the cervix, rectum, pancreas, and head and neck.

Figure 118-1 Therapeutic index of radiation portrayed as two parallel sigmoid curves indicating the likelihood of tumor control and the likelihood of significant toxicity. A, Dose required for tumor control with minimum complications;B, dose resulting in maximum tumor control. (Adapted from DeVita FT Jr, et al, editors:Cancer: principles and practice of oncology, ed 2, Philadelphia, 1993, JB Lippincott.)

[edit] DRUG TREATMENT OF CANCER

Useful chemotherapy agents include not only classic cytotoxic drugs but also hormones, biologic response modifiers, therapeutic immunoconjugates, and other drugs that by themselves have no or limited antitumor activity but instead act to modify the activity or toxicity of other drugs.

[edit] Cytotoxic Chemotherapy Agents

Cytotoxic chemotherapy agents directly kill tumor cells by interfering with cellular mechanisms such as DNA, ribonucleic acid (RNA), and protein synthesis. The mechanism of action is generally different for different classes of antineoplastic agents (Box 118-1). Although some drugs are designed to be selectively more toxic to malignant cells (e.g., 5-fluorouracil [5-FU], methotrexate), all agents are somewhat toxic to normal cells, resulting in side effects.

The normal tissues most commonly affected by toxicity are those with the highest intrinsic turnover rate: bone marrow, hair follicles, gastrointestinal tract, and skin. Most cytotoxic drugs exhibit a dose-response relationship, a characteristic that is exploited in high-dose chemotherapy regimens that require bone marrow rescue because of limiting bone marrow toxicity (see below). In general, cytotoxic drugs are administered in combination rather than as single agents because simultaneous interference with multiple biochemical pathways may result in more tumor cell kill with a delay in the appearance of drug resistance. To diminish the likelihood of additive toxicity, drugs with non-overlapping side effects are combined. Commonly prescribed combination therapy regimens for several solid tumors are presented in Table 118-2.

Table 118-2 Commonly Used Combination Chemotherapy Regimens

[edit] Hormonal Therapy

Steroid hormones are useful for the therapy of tumors whose growth is hormone-dependent (Table 118-3). These agents are usually minimally toxic and are used most often for palliation of advanced disease, except for glucocorticoids, which may be useful for the primary treatment of hematologic malignancies.

Table 118-3 Hormone Therapy of Malignant Disease

[edit] Biologic Response Modifiers

Biologic response modifiers include an ever-expanding array of molecules that augment the natural immune-mediated host response to malignant cells. The interferons are molecules that are normally produced in vivo in response to viral infection and other antigenic stimuli but are synthesized for clinical use by recombinant DNA techniques. Interferons have shown activity in hairy-cell leukemia, Kaposi's sarcoma, chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma.^[3] Interleukins, especially IL-2, have demonstrated activity against melanoma and renal cell cancer. Multiple ongoing trials are examining the role of these and other cytokines either alone or in combination with cytotoxic chemotherapy drugs in the management of malignant disease. A new class of agents, the therapeutic immunoconjugates, has become available with the recent introduction of Rituxan, a humanized anti-CD20 monoclonal antibody directed against antigenic molecules on the surface of non-Hodgkin's lymphoma tumor cells.^[4]

[edit] Adjuncts to Therapy

Some drugs used to treat cancer do not kill tumor cells directly but instead act to enhance the activity of other drugs (e.g., levamisole and leucovorin used with 5-FU in the treatment of colorectal cancer) or to ameliorate chemotherapy-associated toxicity (e.g., leucovorin rescue after high-dose methotrexate). Cytokines, including granulocyte colony-stimulating factor (G-CSF) and granulocyte- macrophage colony-stimulating factor (GM-CSF), have also been used to mitigate neutropenia after cytotoxic chemotherapy. Erythropoietin has become a valuable adjunct to chemotherapy, resulting in a decrease in the need for red blood cell transfusions, and improving fatigue and overall quality of life.

[edit] Indications for Systemic Chemotherapy

[edit] Primary Systemic Therapy.

Chemotherapy alone as the primary treatment modality with curative intent may be useful for lymphomas, advanced testicular cancer, and small cell lung cancer.

[edit] Palliation of Advanced Disease.

Palliation represents the use of chemotherapy to achieve objective tumor shrinkage, subjective improvement in symptoms, and prolongation of life. Unfortunately, improved survival is difficult to demonstrate for most patients with solid tumors. Response rates of selected metastatic cancers to typical chemotherapy regimens are presented in Table 118-4.

Table 118-4 Results of Combination Chemotherapy for Initial Treatment of Stage IV Disease

[edit] Combined-modality Therapy.

Combined-modality therapy refers to regimens that incorporate chemotherapy and/or radiotherapy with or without surgery to achieve maximal tumor cell kill. Some tumors that are apparently localized at presentation have a high likelihood of systemic relapse despite optimal initial surgery or radiotherapy. Occult micrometastases left behind may provide a nidus for regrowth of tumor at a later time, resulting in clinically evident metastatic disease. Adjuvant therapy is systemic chemotherapy administered after primary curative therapy by other means (usually surgery) in an attempt to eradicate these micrometastases. For women with resectable breast cancer, a highly significant decrease in the rate of breast cancer recurrence and death follows the use of adjuvant chemotherapy or tamoxifen.^[5] Adjuvant treatment with 5-FU–based regimens reduces recurrence rates and mortality in patients with lymph node–positive (stage III) colon cancer. For rectal cancers, adjuvant treatment with both 5-FU and radiation therapy can decrease recurrence and mortality in patients with either stage II or III disease.

Neoadjuvant therapy refers to the use of chemotherapy with or without radiotherapy before definitive local therapy (usually surgery). This approach is used most often for head and neck cancer and esophageal or rectal tumors in an attempt to increase surgical resectability or preserve organ function (e.g., anal sphincter, larynx). Although this approach may enhance local control and preserve organ function, many controlled trials have failed to show a significant survival advantage compared with that of conventional treatment.

[edit] Experimental vs. Standard Therapy.

Some patients with cancer may be asked to participate in a clinical trial. Cancer clinical trials are no longer restricted to specialized large cancer centers; community physicians are increasingly being asked to participate. Clinical trials fall into phase I, II, and III categories. The goal of phase I studies is to determine the relationship between toxicity and dose. Phase II studies attempt to identify specific tumor types for which a new treatment may be promising. In general, patients who have failed standard therapy or for whom no standard therapy exists are appropriate for these types of studies. Phase III trials are randomized trials designed to compare standard treatment for a specific tumor or tumor-related condition with a newer treatment to determine whether the new treatment may be more efficacious and/or less toxic. These trials are usually offered to previously untreated patients. Randomized trials with concurrent control groups are necessary to definitively demonstrate the superiority of one treatment over another. The randomization procedure, which may be difficult to understand from the viewpoint of the patient, is necessary in trials of this design to prevent bias.

[edit] Evaluation of the Benefit of Chemotherapy

[edit] Risk/Benefit Ratio.

Choosing optimal cancer therapy is not always easy. Guidelines for new regimens are frequently published, and it may be difficult to recommend a potentially beneficial new program of treatment without much knowledge of the results. Usually a rough estimate of the relative benefit from chemotherapy (likelihood, quality, and duration of response) may be compared with an estimate of the likelihood and severity of the side effects involved in the therapy (risk/benefit ratio). To accurately determine the value of a given response and what constitutes acceptable risk (toxicity), each patient's values and preferences, the impact of the therapy on lifestyle, and the repercussions of therapy on the patient's family must be considered.

[edit] Definition of Response Status.

Objective response refers to measurable shrinkage of tumor masses as assessed by physical examination or radiologic studies. A complete response (CR) implies eradication of all clinically apparent tumor. CR is not necessarily synonymous with cure. Patients who have a CR may harbor residual tumor cells, and the rapidity of recurrence depends on the number of cells and how quickly they grow. Cure implies the persistent eradication of tumor for a proscribed period, the duration of which depends on differences in growth rate and biologic behavior. For example, of the patients destined to relapse after potentially curative treatment of early stage breast cancer, 65% to 85% do so within 2 years; however, the risk of relapse persists for 10 to 20 years. By contrast, over 95% of expected relapses from testicular cancer occur within 2 years of the original treatment, and late relapses are rare. In general, a CR is a necessary prerequisite for cure. Chemotherapy regimens expected to result in CR and cure should be administered aggressively, with a fair amount of toxicity accepted.

Many tumors fail to be completely eradicated with chemotherapy, representing a partial response (PR) to therapy. Treatments that result in a PR may lead to clinical improvement but may not have any meaningful impact on survival. Subjective response is a patient-reported sense of improved well-being after treatment; most subjective responses occur in the setting of objective response. Attempts to quantify this measure of improvement have included the use of quality of life scales, which assess functional status by using indirect measures such as performance status (Box 118-2), weight, and amount of analgesics or other supportive measures used by the patient.

[edit] Prognostic Factors.

In general, good performance status and low tumor burden correlate most closely with better survival and higher response rates. More specific prognostic factors, such as the panel presented for early stage breast cancer (Table 118-5), may be helpful in identifying patients with a higher risk of relapse who may benefit from further systemic chemotherapy after definitive local therapy.

Table 118-5 Prognostic Factors for Axillary Node Negative Breast Cancer

[edit] High-dose Therapy.

Most cytotoxic drugs display a dose-response relationship with higher doses resulting in greater tumor cell kill and, theoretically, better cure rates. The limiting factor in increasing drug dose is toxicity, usually bone marrow toxicity. Hematopoietic support with bone marrow and/or peripheral blood stem cell transplantation has been used in an attempt to improve cure rates by allowing administration of higher-dose chemotherapy. Unfortunately, for most solid tumors, this approach has not yet been shown to result in greater survival compared with standard-dose chemotherapy and remains experimental.^[6] It is most widely accepted for hematologic malignancies such as relapsed lymphoma and multiple myeloma.

[edit] Risks and Side Effects of Chemotherapy

All organ systems may be adversely affected by chemotherapy, with a wide variation in severity. In addition to anticipated tissue toxicity to bone marrow, hair, GI tract, and skin, other less common toxicities may be characteristic of particular drugs (Table 118-6). Chemotherapy-related toxicity, especially myelosuppression, may result in dose reduction to more tolerable levels but efficacy may be adversely affected.

Table 118-6 Hematologic and Nonhematologic Toxicity

✢Necrosis if extravasted, or phlebitis; rashes, pruritus, changes in pigmentation; alopecia.

‡Arrhythmias or congestive heart failure.

§Hypersensitivity reactions.

1. Toxicity unique to agent.

∥CNS toxicity.

¶Peripheral neuropathy.

✢✢High drug concentration infusion.

Many patients are fearful of chemotherapy. The primary physician may be able to reduce anxiety by realistically defining and quantifying the specific risks involved. Not all potential side effects occur in all patients. When toxicity does occur, it is often of limited duration and reversible.

[edit] Occurrence and Management of Chemotherapy Toxicity by Organ Site

Postchemotherapy side effects may be acute or short term and generally reversible, or they may be long-term chronic toxicities, which may be irreversible. A brief synopsis of selected adverse effects by organ system follows. An extensive discussion of the adverse effects associated with biologic response modifiers is beyond the scope of this text.^[3]

[edit] Bone Marrow

[edit] Leukocytes.

Myelotoxicity may range from clinically insignificant decreases in the formed elements of the blood to life-threatening cytopenias. The nadir count refers to the lowest absolute value of the circulating blood cells after chemotherapy. Different chemotherapy drugs result in variable degrees of myelosuppression (see Table 118-6), but it may vary depending on the dose (methotrexate) or schedule of administration (5-FU). The time to the nadir averages 9 to 12 days after chemotherapy. Some agents cause prolonged or delayed granulocyte nadirs (nitrosoureas, chlorambucil, mitomycin C, busulfan, procarbazine). Patients whose neutrophil nadir is under 1000/μl have severe myelotoxicity; fever in the presence of neutropenia (less than 500/μl) is a medical emergency, and should be managed with prompt institution of broad-spectrum antibiotics.

Prophylactic antibiotics are usually not indicated for patients who are neutropenic from standard-dose chemotherapy. While neutropenic, patients should avoid persons who are ill and should report fever immediately. When fever does occur, patients must receive parenteral broad-spectrum antibiotics until the neutropenia resolves. Visitors and medical personnel should observe strict handwashing techniques. Unnecessary instrumentation and invasive procedures should be avoided. Granulocyte transfusions are not generally used because of the high risk of complications. Recombinant colony-stimulating factors such as G-CSF and GM-CSF decrease the duration of the neutrophil nadir and the duration of empiric antibiotic use and hospitalization when administered prophylactically during the chemotherapy cycle. They have not been shown to alter the course of febrile neutropenia once it develops. Nevertheless, despite their expense, they are frequently prescribed in this scenario.

[edit] Platelets.

Some agents are relatively less toxic to platelets than to other bone marrow cells (cyclophosphamide, etoposide, vinca alkaloids, mitoxantrone). A platelet decrease to under 50,000/μl represents severe thrombocytopenia, but in general, spontaneous bleeding rarely occurs unless platelet counts fall below 5000/μl.

It is important to avoid intramuscular injections, unnecessary instrumentation, and the use of medications (such as aspirin or nonsteroidal antiinflammatory drugs) that could exacerbate a bleeding tendency. Platelet transfusions should be reserved for patients with platelet counts under 5000/μl, patients with significant bleeding, and patients in whom invasive procedures become unavoidable.

[edit] Erythrocytes.

Hypoproliferative anemia secondary to chemotherapy is less common than thrombocytopenia and leukopenia, although cisplatin and the nitrosoureas can cause refractory anemia. Cisplatin may also cause hemolytic anemia. In addition, a syndrome of microangiopathic hemolytic anemia, renal insufficiency, and thrombocytopenia has been described with mitomycin.

In the differential diagnosis for all of these myelotoxicities, one must consider tumor replacement of the marrow, autoimmune destruction, sepsis, and myelosuppression from other drugs. If cytopenias do not resolve within the expected time, it may be appropriate to perform a diagnostic aspiration and/or biopsy of the bone marrow.

[edit] Hair.

Alopecia usually begins 2 to 3 weeks after the institution of cytotoxic chemotherapy. Not all cytotoxic agents produce the same degree of hair loss (see Table 118-6). Hair usually regrows after chemotherapy discontinuation. Although hair loss from the scalp is most noticeable, it may occur from all areas of the body, including eyebrows, axillary, and pubic areas.

Patients should be forewarned of this complication; a wig may be purchased if desired. Scalp hypothermia reportedly decreases the amount of hair loss, but protection depends on the type and dosage of drug. These devices should not be used during leukemia treatment, since circulation of the drug to the scalp may be impaired.

[edit] Gastrointestinal Tract

[edit] Mucositis.

Mucositis usually presents as a burning or tingling sensation, especially in response to acid foods, and may be followed by erythema, superficial erosions, ulcerations, and sloughing of the mucosa. The oral mucosa is most commonly symptomatic. However, any mucosal area may be involved. Symptoms usually last 3 to 7 days. The worst drugs are bleomycin, doxorubicin, 5-FU, and methotrexate (see Table 118-6).

In the differential diagnosis, herpesvirus and Candida albicans mucosal infections should be considered. The patient should avoid dentures and irritating foods and rinse the mouth frequently with a salt or baking soda solution. Oratect gel, ``miracle mouthwash (mixture of viscous lidocaine, diphenhydramine elixir, and/or nystatin), and systemic pain medication may help a great deal. In severe cases the patient may require hospitalization for nutrition and fluid support.

[edit] Nausea and Vomiting.

Symptoms may range from mild nausea to intractable vomiting. Symptoms usually begin 1 to 6 hours after chemotherapy and last less than 24 hours. Cisplatin, ifosfamide, and nitrosoureas may result in protracted nausea and vomiting up to 72 hours. Psychologic factors can influence vomiting, and anticipatory nausea and vomiting may occur when patients anticipate receiving treatment.

The differential diagnosis includes tumor obstruction, ileus, metabolic abnormalities (especially hypercalcemia), and brain metastases. Prophylaxis is important in management. Mildly emetogenic drugs (see Table 118-6) may be accompanied by oral phenothiazines. Moderately emetogenic drugs may require a combination of agents, including lorazepam, phenothiazines, metoclopramide, and serotonin antagonists with steroids. More severely emetogenic drugs such as cisplatin are usually managed with a serotonin antagonist like ondansetron and granisetron plus steroids. Other effective agents include haloperidol and droperidol. Patients with anticipatory nausea and vomiting may benefit from behavioral techniques, hypnosis, or the use of lorazepam.

[edit] Heart and Lungs.

Transient dysrhythmias may occur during or shortly after the administration of amsacrine, paclitaxel, or doxorubicin. Anthracyclines and amsacrine may lead to a characteristic dose-dependent cardiomyopathy. The differential diagnosis should consider volume overload, intrinsic cardiac disease, cor pulmonale, and malignant pericardial effusion. To avoid cardiomyopathy, the total doxorubicin dosage should be limited to less than 450 mg/m². If this is exceeded or if patients have a higher than usual risk of developing cardiomyopathy, serial radionuclide ventriculograms should be followed. If congestive heart failure occurs, it is frequently irreversible but can be managed with diuretics, inotropic agents, and afterload reduction.

Pneumonitis and/or pulmonary fibrosis may be caused by bleomycin, Ara-C, paclitaxel, mitomycin C, nitrosoureas, alkylating agents, procarbazine, and methotrexate. Patients usually present with insidious onset of fever, dyspnea, and nonproductive cough. Pulmonary lymphangitic spread of tumor, adult respiratory distress syndrome (ARDS), infection, and other toxins should be considered in the differential diagnosis. Discontinuation of the offending agent and treatment with corticosteroids may help, although pulmonary fibrosis is frequently irreversible. Chest x-ray studies and single breath diffusing capacity of the lungs for carbon monoxide (DLCO) are not perfect screening tests for early bleomycin pulmonary toxicity, but they should be done periodically during therapy. Patients should inform anesthesiologists about prior bleomycin exposure, and inspired oxygen concentration should always be less than 30% (lifelong).

[edit] Kidneys.

Renal insufficiency may be the result of direct tubular damage (cisplatin, streptozocin), glomerular injury (nitrosoureas), acute tubular necrosis from drug precipitation (high-dose methotrexate), or drug-induced vasculitis (mitomycin C). Differential diagnosis includes prerenal azotemia, diabetic nephropathy, paraprotein-induced renal insufficiency, other drugs, ureteral obstruction or direct kidney invasion by cancer or amyloid, infection, tumor lysis syndrome, and paraneoplastic syndromes.

For cisplatin use prevention is best accomplished by aggressive prechemotherapy hydration with 1 to 2 L of saline over several hours. Alkaline hydration should be used for high-dose methotrexate. The use of concomitant nephrotoxins such as radiographic contrast media or aminoglycosides should be avoided if possible. If renal insufficiency develops, potentially reversible causes should be ruled out and all drugs discontinued if possible. Patients with renal insufficiency may require dose reduction of chemotherapeutic agents whose excretion is predominantly renal. Chemotherapy agents excreted by the hepatic route may need dose adjustments in the presence of hepatic insufficiency also.

[edit] Genitals.

Azoospermia and anovulation develop in the majority of patients treated with alkylating agents. Cisplatin causes temporary infertility in most patients. Reversibility depends on drug dosage, concomitant radiotherapy, and age.^[7] Children treated before puberty are most likely to recover normal sexual development and fertility. Adult women older than 25 years are least likely to recover normal fertility after treatment. Many drugs are teratogenic, especially in the first trimester, but pregnancies have been successfully completed in the second or third trimester despite treatment with chemotherapy. There appears to be little if any increase in birth defects in children born of parents who have received prior chemotherapy.

Pretreatment factors may cause anovulation (stress, weight loss, heavy exercise) or azoospermia (Hodgkin's disease). Hypothyroidism, sometimes treatment related, may be a potentially reversible cause of infertility.

Patients should be counseled before therapy. The opportunity for sperm banking should be explored if pretreatment sperm counts are adequate. Unfortunately, oocyte cryopreservation is not routinely available in this country.

Second malignancies, both hematologic and solid tumors, may occur after chemotherapy, particularly when long-term treatment with alkylating agents is combined with radiation therapy. The risk for acute leukemia peaks at about 5 years, whereas that of secondary solid tumors may peak later, at 10 years.

Other side effects may also occur with various chemotherapy drugs. A full enumeration is beyond the scope of this text. They are summarized in Table 118-6.

[edit] APPROACH TO CANCER PAIN

Pain is one of the most frequent and least well-managed aspects of cancer care. Undertreatment of pain is a common problem despite the widespread availability of effective pharmacologic agents and other nonpharmacologic means of pain control. Barriers to effective pain management are summarized in Box 118-3. An excellent recent review of cancer-related pain is available.^[8]

[edit] Assessment of Pain

The initial assessment should focus on identifying the cause of the pain, and should include a detailed history of pain intensity, character, and location. Physical examination should place emphasis on the area affected by pain and, in particular, the neurologic examination.

[edit] Management of Cancer-related Pain

Specific antineoplastic therapy should be considered to control cancer-related pain. Surgery for curative excision or palliative debulking has the potential to reduce pain; however, many painful oncologic problems are not amenable to surgery. Radiotherapy may be particularly helpful in alleviating the pain of tumor invasion or compression. Alternatively, pharmacologic or neurosurgical/anesthetic approaches may be used to control pain. The World Health Organization (WHO) pain ladder (Fig. 118-2) portrays a rational progression in the doses and types of analgesic drugs for effective pain management.Fig. 118-3 is a flow chart depicting an algorithm for cancer pain management from initial assessment of pain to the various treatment modalities, including the WHO analgesic ladder and other pharmacologic and nonpharmacologic methods.

Figure 118-2 The World Health Organization (WHO) three-step analgesic ladder. (Adapted from the World Health Organization.)

Figure 118-3 Algorithm for pain management in patients with cancer.

[edit] Pharmacologic Management of Cancer Pain.

Nonsteroidal antiinflammatory drugs (NSAIDs) are especially useful in patients with bone pain or inflammatory lesions. They may also provide additive analgesia when combined with opioids. Their usefulness is limited to mild to moderate pain, and there is a ceiling dose above which no further analgesia occurs despite increasing doses. Adverse effects include gastritis, impaired platelet function, and renal insufficiency.

Opioids are the analgesics most used in managing moderate to severe pain. Opioids are classified as full agonists, partial agonists, or mixed agonist/antagonists. Commonly used narcotic agonists include morphine, codeine, hydromorphone, oxycodone, methadone, and fentanyl. These opioids are classified as full agonists because they do not reverse or antagonize the effects of other opioids within this class; they do not have a ceiling to their analgesic effect. Mixed agonist/antagonists and partial agonists are rarely used in chronic management of cancer pain, since they may reverse opioid effects and can precipitate abstinence syndrome in patients who are opioid-dependent.

Adjuvant medications, or co-analgesics, are used to enhance the analgesic efficacy of opioids. Corticosteroids, anticonvulsants such as phenytoin and carbamazepine, antidepressants, bisphosphonates, and antihistamines may all be useful in various settings.

Side effects of opioids are numerous and may result in a failure of opioid treatment, even when managed judiciously. Opioids decrease peristalsis and GI secretions, leading to increased transit time and desiccated, difficult to pass feces. A prophylactic bowel regimen should be prescribed to elderly patients, nonambulatory patients, those with intrinsic bowel disease, and patients receiving concurrent constipating drugs. Unfortunately, tolerance usually does not occur to this side effect. Management may include stool softeners, bulk agents such as psyllium, or mild stimulant laxatives.

Over 50% of patients receiving opioids experience nausea; it is usually multifactorial in etiology; constipation, CNS effects, delayed gastric emptying, and increased vestibular sensitivity may all contribute. Treatment with phenothiazine antiemetics or prokinetic agents (e.g., metoclopramide) may help.

Sedation is a property of all opioids. Fortunately, tolerance usually develops within several days. Excess sedation may be managed by administering smaller, more frequent doses of narcotic. Mental status changes including euphoria, dysphoria, and confusion may occur, especially with the initiation of narcotic therapy. Patients receiving long-term opioid therapy usually develop tolerance to the respiratory depression effects of these agents. Occasionally, respiratory depression may occur when sedative effects of opioids are no longer opposed by the stimulatory effects of pain. If rapid reversal of opioid effect resulting from excessive respiratory depression is necessary, repetitive doses of a dilute solution of naloxone should be used.

Tolerance refers to the need to increase doses over time to maintain pain relief. Increasing dose requirements are most consistently correlated with progressive disease. Opioid tolerance and physical dependency are expected with long-term opioid treatment and should not be confused with psychologic dependency (addiction). Patients should be warned not to abruptly discontinue narcotics; when a decrease is warranted, they should be tapered gradually.

[edit] Nonpharmacologic Management of Cancer Pain.

Nonpharmacologic management may include psychosocial interventions such as relaxation and imagery and anesthetic/neurosurgical approaches. A full discussion of anesthetic techniques such as nerve blocks, intraspinal or epidural administration of narcotics or local anesthetics, and neurosurgical approaches such as rhizotomy, cordotomy, commissural myelotomy, or hypophysectomy is beyond the scope of this text.

[edit] Practice Guidelines and Recommendations.

It is common clinical practice to initiate opioid therapy with a ``weak opioid such as codeine, oxycodone, or hydrocodone. These agents are most commonly available in fixed combination with acetaminophen or aspirin. In many cases the limiting factor to obtaining adequate analgesia with these agents is ingestion of maximal doses of the co-analgesic. If pain relief is inadequate with these agents, then it is appropriate to switch to a stronger opioid. Some general principles of narcotic management are listed in Box 118-4. The oral route is safe, acceptable to patients, economical, and effective. Morphine is the drug of choice in most patients requiring long-term analgesia for severe pain. Immediate- release oral morphine has a short half-life and must be dosed every 3 to 4 hours (Table 118-7). It is especially useful for ``rescue doses, when breakthrough pain necessitates the use of an opioid with a rapid onset of action. Sustained-release oral morphine eliminates the need for frequent dosing of oral morphine. Because many patients have persistent or daily pain, it is important to use opioids on a regular schedule rather than as needed.

Table 118-7 Equianalgesic Doses of Narcotic Agonists

✢1:6 relative potency po: IM changes to 1:3 during chronic dosing.

A transdermal preparation of fentanyl, a potent narcotic absorbed through skin, is available. Advantages include convenience of dosing every 3 days and the avoidance of peaks and troughs during continuous dosing. Disadvantages include expense, poor adhesion to hairy or sweaty skin, and the long elimination half-life that results in a slow titration of effect.

Cross tolerance is not universal among the various members of the class of narcotic agonists. If one agent is not effective, another may be tried. It is important to be aware of equianalgesic doses (Table 118-7).

[edit] REFERENCES