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Palliative Care in Lung Cancer^*

ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)

^* From the Division of Pulmonary, Critical Care, Allergy, Immunology, and Sleep Disorders Medicine (Dr. Kvale), Henry Ford Health System, Detroit, MI; Pulmonary Department (Dr. Selecky), Hoag Memorial Hospital, Newport Beach, CA; and Division of Thoracic Medicine (Dr. Prakash), Mayo Clinic, Rochester, MN.

Correspondence to: Paul A. Kvale, MD, FCCP, Division of Pulmonary, Critical Care, Allergy, Immunology, and Sleep Disorders Medicine, Henry Ford Health System, 2799 W Grand Blvd, Detroit, MI 48202; e-mail: pkvale1{at}hfhs.org

	Abstract

TOP Abstract Introduction Methods and Materials Results Recommendations Recommendations Recommendations Recommendations Recommendations Recommendations Recommendation Recommendations Recommendations Recommendation Recommendation Conclusion SUMMARY OF RECOMMENDATIONS References

 
Goals/objectives: To review the scientific evidence on symptoms and specific complications that are associated with lung cancer, and the methods available to palliate those symptoms and complications.

Methods: MEDLINE literature review (through March 2006) for all studies published in the English language, including case series and case reports, since 1966 using the following medical subject heading terms: bone metastases; brain metastases; cough; dyspnea; electrocautery; hemoptysis; interventional bronchoscopy; laser; pain management; pleural effusions; spinal cord metastases; superior vena cava syndrome; and tracheoesophageal fistula.

Results: Pulmonary symptoms that may require palliation in patients who have lung cancer include those caused by the primary cancer itself (dyspnea, wheezing, cough, hemoptysis, chest pain), or locoregional metastases within the thorax (superior vena cava syndrome, tracheoesophageal fistula, pleural effusions, ribs, and pleura). Respiratory symptoms can also result from complications of lung cancer treatment or from comorbid conditions. Constitutional symptoms are common and require attention and care. Symptoms referable to distant extrathoracic metastases to bone, brain, spinal cord, and liver pose additional problems that require a specific response for optimal symptom control. There are excellent scientific data regarding the management of many of these issues, with lesser evidence from case series or expert opinion on other aspects of providing palliative care for lung cancer patients.

Conclusions: Palliation of symptoms and complications in lung cancer patients is possible, and physicians who provide such care must be knowledgeable about these issues.

Key Words: bone metastases • brain metastases • cough • dyspnea • electrocautery • hemoptysis • interventional bronchoscopy • laser • pain management • pleural effusions • spinal cord metastases • superior vena cava syndrome • tracheoesophageal fistula

	Introduction

TOP Abstract Introduction Methods and Materials Results Recommendations Recommendations Recommendations Recommendations Recommendations Recommendations Recommendation Recommendations Recommendations Recommendation Recommendation Conclusion SUMMARY OF RECOMMENDATIONS References

 
The histologic type, biological behavior, and the anatomic location of lung cancer within the thoracic cage determine the type and severity of respiratory symptoms manifested by patients with lung cancer. Pulmonary symptoms that may require palliation include those caused by the primary cancer itself (dyspnea, wheezing, cough, hemoptysis, chest pain),^1234567 or locoregional metastases within the thorax (superior vena cava [SVC] syndrome, tracheoesophageal fistula [TEF], pleural effusions, ribs, and pleura).^{89101112131415161718} Respiratory symptoms can also result from complications of lung cancer treatment (such as radiation- and chemotherapy-induced lung toxicity, airway stenosis and necrosis, fistula formation, hemoptysis from neovascularization).^{131416192021222324252627} Comorbid conditions (such as COPD, heart failure, pulmonary embolism, prior lung resection, malnutrition) cause or contribute to respiratory symptoms. Constitutional symptoms (depression, fatigue, insomnia, anorexia-cachexia syndrome) are common and require attention and care. Symptoms referable to distant extrathoracic metastases to bone, brain, spinal cord and liver pose additional problems that require a specific response for optimal symptom control.

Pharmacologic (noninvasive) approaches to alleviating the above-mentioned respiratory symptoms from lung cancer are discussed in this chapter and elsewhere in the guidelines. However, a significant number of patients have respiratory symptoms as the result of mechanical (anatomic) effects of lung cancer, such as major airway obstruction, postobstructive pneumonia, fistulae between airways and other intrathoracic organs, pleural effusion, and paralysis of diaphragm and vocal cords. In such patients, pharmacologic (noninvasive) therapies may be inadequate to palliate respiratory symptoms. Several invasive techniques are available to benefit this selected group of patients and will be discussed in the appropriate section of this chapter.

	Methods and Materials

TOP Abstract Introduction Methods and Materials Results Recommendations Recommendations Recommendations Recommendations Recommendations Recommendations Recommendation Recommendations Recommendations Recommendation Recommendation Conclusion SUMMARY OF RECOMMENDATIONS References

 
The key words for various palliative care topics, as listed in above-mentioned "Key words" section, were searched using Ovid MEDLINE and PubMed from 1966 through March 1, 2006. Randomized controlled trials (RCTs) were especially sought for all such topics; where this type of study was available, it is clearly identified as such in the appropriate section of this chapter. For many of the topics, evidence is of substantially less quality, and it typically consists of case series of varying size. This has led to recommendations that are based on publications describing clinical experience with varying sizes of patient population. The sections that discuss approaches to treatment of airway obstruction and hemoptysis, as well as palliation of malignant pleural effusion are examples where the evidence-based literature pertaining to palliative therapy is limited.

	Results

TOP Abstract Introduction Methods and Materials Results Recommendations Recommendations Recommendations Recommendations Recommendations Recommendations Recommendation Recommendations Recommendations Recommendation Recommendation Conclusion SUMMARY OF RECOMMENDATIONS References

 
Pain Control
Studies reveal that adults with lung cancer have more symptoms than patients with other types of cancer.²⁸ Pain is a common symptom in lung cancer patients, yet inadequate pain management is prevalent, harmful to patients, and costly.²⁹ A comprehensive document for the management of cancer pain was developed and published in 1994 as part of a response to Public Law 101–239 (the Omnibus Reconciliation Act of 1989), under the aegis of the Agency for Health Care Policy and Research. The name subsequently was changed to the Agency for Healthcare Research and Quality.³⁰ The document on cancer pain management was updated in October 2001.³¹

In 2005, the American Pain Society revised and updated their recommendations for improving the quality of cancer pain management, and subsequently published guidelines on this topic.³² The comments in this section are adapted from these resources. The scope of these efforts is beyond what can be discussed in detail in this document, and the reader is referred to these resources for additional information. In their 2005 recommendations, the American Pain Society calls caregivers’ attention to five areas of pain management: (1) recognize and treat pain promptly; (2) involve the patients and families in the pain-management plan; (3) improve treatment patterns by eliminating inappropriate practices and providing multimodal therapy; (4) reassess and adjust the pain management plan as needed, focusing not only on pain intensity but on functional status and side effects as well; and (5) monitor the processes and outcomes of pain management, using national performance indicators.³²

The potential causes of cancer pain are multiple and can include tumor progression and related pathology (eg, nerve damage), surgery and other procedures used for treatment and diagnosis, toxic side effects of chemotherapy, and radiation. Approximately 75% of patients with advanced cancer have pain. Failure to relieve pain leads to unnecessary suffering. Decreased activity, anorexia, and sleep deprivation caused by pain can further weaken already debilitated patients.

Effective management of pain from cancer can be achieved in most patients. Clinical trials³³³⁴³⁵ indicate that patients consider pain management effective if it decreases the pain intensity 33 to 50%, such that a clinician’s goal and/or promise to the patient of "no pain" is ill founded and unnecessary. Proper management of a patient’s pain involves more than analgesia, and the program of pain control for any one patient must be individualized. Approaches that may augment analgesia include cognitive/behavioral strategies, physical modalities, palliative radiation and antineoplastic therapies, nerve blocks, and palliative and ablative surgery. Studies^13637383940 reveal that palliative chemotherapy in advanced lung cancer can have a modest increase in survival, and often has the additional benefit of improving pain and other symptoms. Any analgesic medication program should be kept as simple as possible, both with regard to the frequency and route of administration. Oral medications are preferred, because of convenience and cost-efficacy. If the patient cannot take medications by mouth, rectal and transdermal routes should be considered because they are relatively noninvasive. IM routes of administration should be avoided because of the associated pain and inconvenience, and also because of unreliable absorption.

A nonsteroidal antiinflammatory drug (NSAID) or acetaminophen should be used unless there is a contraindication (eg, increased risk of cardiovascular events and GI bleeding with NSAID medications). If pain persists or becomes worse, an opioid should be added and not substituted. Using opioids and acetaminophen or NSAIDs often provides more analgesia than can be accomplished by either class of drug alone. Further, the use of acetaminophen or NSAIDs may have a dose-sparing effect for opioids, which can provide the benefit of fewer side effects from the opioids. When pain persists despite this approach, the dose of opioids should be increased or a more potent agent chosen. The World Health Organization ladder has been shown to be an effective method to ensure the rational titration of therapy for cancer pain (Fig 1 ).

View larger version (34K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. The World Health Organization three-step analgesic ladder.

Both the cancer patient and family members may shun the use of opioids because of a fear of addiction. Physicians must educate both the patient and the family about pain and how it is to be managed as part of the treatment plan. Effective pain control begins by asking the patient about pain. An easily administered pain rating scale should be used for assessment of pain, both at the time of initial presentation and periodically at regular intervals during the course of the disease. The most common pain scales are numeric (0 to 10 pain intensity), simple descriptive in nature (no pain, mild, moderate, severe), and a visual analog scale. Quality pain management requires a comprehensive assessment of the patient’s pain, described as learning the "who", "how," and "when" of the pain.²⁹ Focusing only on pain intensity is insufficient and can lead to poor pain relief.

Analgesic medications should be administered around-the-clock with a long-acting opioid, with extra doses of an immediate-release opioid on an as-needed basis for breakthrough pain because this approach helps to prevent recurrence of pain. A written pain-management plan should be given to patients with cancer pain and their families. Constipation is a side effect of opioid medications, and should be anticipated, treated prophylactically, and monitored constantly. Mild constipation can be managed by an increase in fiber consumption and a mild laxative such as milk of magnesia. Bulk-forming laxatives such as fiber supplements should be avoided. Unless there are contraindications, cathartic agents should be administered on a regular schedule.

Ketamine is a parenteral general anesthetic that has been used in subanesthetic doses to relieve pain, particularly in opioid-tolerant patients. In the absence of large controlled trials providing recommended dosing schedules, clinicians with limited experience in using ketamine should seek expert consultation to develop an appropriate treatment and patient-monitoring plan.⁴¹

Adjuvant drugs may be used to enhance the efficacy of opioids. Corticosteroids produce effects that include mood elevation, relief of inflammation, and reduction of cerebral or spinal cord edema when there is intracranial metastasis or spinal cord compression. Anticonvulsants such as phenytoin, carbamazepine, and clonazepam are used to manage neuropathic pain. Tricyclic antidepressants are used as an adjuvant to analgesics for the management of neuropathic pain. They augment the effects of opioids and have innate analgesic properties. Their mood-elevating properties may be helpful as an adjuvant to strict analgesics. Other adjunctive pharmacologic approaches include neuroleptics such as the major tranquilizers, hydroxyzine, bisphosphonates, and calcitonin for bone metastases.

There are many different nonpharmacologic methods to manage pain, many of which are very simple, effective, and inexpensive. Nonpharmacologic methods to manage pain include cutaneous stimulation techniques (heat and cold applications), accupuncture, psychosocial methods of care, and pastoral care. For patients with intractable and persistent pain despite use of all modalities that are known and familiar to the practitioner, referral to a clinic that specializes in the management of pain should be considered. Pain-control specialists can help to select additional methods that may improve the overall palliation of pain.

	Recommendations

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1. All lung cancer patients and their families must be reassured that pain can be relieved safely and effectively. All patients should be questioned regularly about their pain, using the patient’s self-report of pain and a simple rating scale as the primary source of assessment. Grade of recommendation, 1A

2. For all patients, individualize medications that are used to control pain. Administer medications regularly and treat pain appropriately. Document the effectiveness of pain management at regular intervals during treatment. Grade of recommendation, 1A

3. For all patients with mild-to-moderate pain, manage the pain initially with acetaminophen or an NSAID, assuming there are no contraindications to their use. Use opioids when pain is more severe or when it increases. Grade of recommendation, 1B

4. For any patient, if it is anticipated that there will be a continuous need for opioid medication, meperidine is not recommended. It has a short duration of action, and its metabolite normeperidine is toxic and can cause CNS stimulation resulting in dysphoria, agitation, and seizures. Grade of recommendation, 1B

5. For patients whose pain is not controlled by pure analgesic medications, adjunctive medications such as tricyclic antidepressants, anticonvulsants, and neuroleptic agents will often augment the effects of pure analgesic medications. Grade of recommendation, 1C

6. For all patients, administer medications by mouth because of convenience and cost-effectiveness. In patients with lung cancer who cannot take pain medications by mouth, rectal and transdermal administration are recommended. Administration of analgesics by the IM route is not recommended because of pain, inconvenience, and unreliable absorption. Grade of recommendation, 1C

7. For all patients receiving opioids, because constipation is common, anticipate it, treat it prophylactically and constantly monitor it. Grade of recommendation, 1B

8. Encourage all patients to remain active and to care for themselves whenever possible. Avoid prolonged immobilization whenever possible. Grade of recommendation, 1B

9. In patients who have pain associated with muscle tension and spasm, it is recommended that complimentary methods for pain relief such as cutaneous stimulation techniques (heat and cold applications), acupuncture, psychosocial methods of care, and pastoral care be incorporated into the pain-management plan, but not as a substitute for analgesics. Grade of recommendation, 1C

10. For patients with advanced lung cancer, provide palliative radiation therapy to control pain. Palliative chemotherapy to decrease pain and other symptoms is recommended, even though the increase in survival may be only modest. Grade of recommendation, 1B

11. In patients with lung cancer who have pain unresponsive to standard methods of pain control, referral to a specialized pain clinic or palliative care consultant is recommended. Grade of recommendation, 1C

Palliation of Dyspnea
Dyspnea is the subjective experience of difficult, labored, and uncomfortable breathing. Dyspnea and cough are the most commonly reported symptoms in lung cancer, with 15% of patients having dyspnea at diagnosis and 65% at some point during their illness.⁴²⁴³ A prospective cohort study⁴⁴ of seriously ill, hospitalized adults in five teaching hospitals in the United States reported that among 939 patients with stage III or IV non-small cell lung cancer (NSCLC), severe dyspnea was recorded in 32%. Near death, 90% of patients with NSCLC have dyspnea. It is more common in men, older patients, and those with lower quality of life scores, and the incidence of dyspnea is higher when pain and anxiety are high.⁴⁵⁴⁶ Because of its frequency, clinicians should routinely assess the lung cancer patient for dyspnea. The intensity of the dyspnea can be discerned by the patient using a modified Borg scale of 0 to 10. Often patients will modify their activities to reduce the sensation of dyspnea, such that a report of intensity alone disguises the advancing dyspnea. It behooves the clinician also to ask what activities the patient has curtailed because of dyspnea.⁴⁷ The causes of dyspnea in patients with lung cancer can be classified into five broad groups: (1) the result of direct involvement of the respiratory system by lung cancer; (2) the result of indirect respiratory complications caused by lung cancer (such as postobstructive pneumonia and pleural effusion); (3) the result of specific therapies to treat lung cancer (such as radiation- and chemotherapy-induced lung toxicity, and anemia); (4) the result of respiratory complications that occur more frequently in these patients (such as pulmonary embolism and lung infections); and (5) comorbid conditions (such as COPD, heart failure, prior lung resection, and malnutrition).

Regardless of the stage of lung cancer, dyspnea usually impacts the patient’s physical, social, and psychological well being. Anxiety, fear of impending death, and pain caused by lung cancer are among the factors that contribute to the subjective symptoms of dyspnea. A prospective study of 100 terminally ill cancer patients (49 patients with lung cancer) observed that dyspnea, measured on visual analog scale, was significantly associated with anxiety (p = 0.001).⁴⁸ From the perspectives of the patient and health-care providers, dyspnea can be perceived as panic, chest congestion and tightness, and suffocation. One study⁴⁶⁴⁹ of 52 patients with lung cancer noted that both physical and emotional sensations were associated with descriptions of breathlessness, such as the feeling of being unable to get enough breath, or of panic or impending death. Increased anxiety has been connected with worse dyspnea in patients with obstructive lung disease, chronic pulmonary disease, and/or cancer.⁵⁰⁵¹⁵² One study⁴⁶ of 120 patients with stage I-IV lung cancer observed no difference in dyspnea based on cancer stage, cell type, or performance status. However, pain and anxiety scores were higher in patients with high dyspnea scores.

The treatment of dyspnea should follow a stepwise approach, starting with treatment of the specific cause of the dyspnea if it can be identified (eg, pleural effusion, obstructed major airway, SVC syndrome, pericardial effusion and/or tamponade, carcinomatous lymphangitis, congestive heart failure, pulmonary embolism, and COPD and/or asthma).⁴⁷⁵³ If the specific cause cannot be identified, or if moderate-to-severe dyspnea persists despite attempted palliation of the cause, nonpharmacologic treatments should be considered. If these are not or only partly successful, pharmacologic therapies should be added to the treatment plan.

Nonpharmacologic Treatments
Nonpharmacologic treatments start with patient self-care strategies and coping strategies. Self-care strategies are particularly helpful in the patient who has coexisting COPD, and include simple measures such as body position (eg, leaning forward with arms and shoulders supported), pursed-lip breathing, paced breathing during activity (eg, inhale at the pause on the step while climbing stairs, exhale with the next step), and diaphragmatic breathing. Coping strategies can include practicing desensitization to the symptom, learning relaxation techniques (guided imagery, self-hypnosis, meditation/prayer, music therapy), and energy conservation techniques.⁵⁴

Complementary methods for the control of dyspnea often include intervention by allied health personnel. A multicenter RCT of 119 patients with small cell lung cancer (SCLC) or NSCLC or with mesothelioma, who had completed first-line treatment and reported dyspnea, used various strategies. These included breathing control, activity pacing, relaxation techniques, and psychosocial support, in addition to standard management and treatment available for dyspnea. The group assigned to intervention by nurses improved significantly at 8 weeks in breathlessness, performance status, and physical and emotional status compared to the control group.⁵⁵⁵⁶ Similarly, using these techniques within specialist palliative care settings in a "breathlessness clinic" demonstrated a significant improvement in breathlessness, functional capacity, activity levels, and distress levels in lung cancer patients.⁵⁷

Patient and family education about dyspnea and its treatments is the foundation of successful treatment. In patients with advanced disease, families should be educated about controlling the impact of things such as ambient weather and the indoor environment and its effect on the patient’s perception of dyspnea. Patients with dyspnea at rest or with minimal activity often prefer an open and cool room with a clear line of sight to the outside. They also can receive benefit from a fan blowing on their face or a cool compress applied to the forehead, both mediated by the trigeminal nerve.⁴⁷

The American College of Chest Physicians is in the process of developing evidence-based clinical practice guidelines for the management of dyspnea in advanced lung disease, including lung cancer. The reader is referred to the American College of Chest Physicians journal CHEST for this resource currently not yet published.

Oxygen: Supplemental oxygen is perhaps the most commonly prescribed therapy to relieve dyspnea in patients with lung cancer.⁵⁸ Significant involvement of the respiratory system by lung cancer or underlying obstructive airways disease usually produces or aggravates dyspnea and hypoxemia. A limited number of studies have shown the beneficial effects of supplemental oxygen therapy. A prospective, double-blind, crossover trial⁵⁹ assessed the effects of supplemental oxygen on the intensity of dyspnea in 14 patients with advanced cancer. Patients were randomized to receive either oxygen or air delivered at 5 L/min by mask. Dyspnea was evaluated with a visual analog scale. The results showed that 12 patients consistently preferred oxygen to air; and patients reported little or no benefit from air compared with moderate to much benefit from oxygen.⁵⁹

Regardless of the oxygenation status, supplemental oxygen therapy should be considered if patients with lung cancer experience dyspnea. Multiple blood gas analyses should be avoided to justify oxygen therapy. Percutaneous oximetry should suffice to assess adequate oxygenation. Providing supernormal oxygenation in patients with lung disease has shown an increase in exercise tolerance by relieving or decreasing the sensation of dyspnea, likely by suppressing the carotid body response.⁶⁰

Pharmacologic Treatments
Pharmacologic treatments for dyspnea caused by lung cancer have included bronchodilators, corticosteroids, anxiolytics, antidepressants, and opioids. One retrospective study⁵⁸ at a medical center specializing in cancer assessed the resource utilization associated with the management of dyspnea caused by lung cancer in 45 patients. The most common therapies administered in the emergency department were oxygen (31%), ß₂-agonists (14%), antibiotics (12%), and opioids (11%).⁵⁸

Inhaled Bronchodilators and Corticosteroids: Standard bronchodilators such as ß₂-agonists, anticholinergics, and aerosolized corticosteroids are commonly prescribed to lung cancer patients who also have underlying COPD or asthma. There is no evidence that the presence of lung cancer induces bronchospastic disease. However, the onset of lung cancer in patients with underlying obstructive lung diseases usually aggravates symptoms of preexisting obstructive lung disease. There are not many studies to prove a beneficial effect of bronchodilators in patients with lung cancer. However, a prospective study⁴⁸ of 100 terminally ill cancer patients (49 patients with lung cancer) observed that the potentially correctable causes of dyspnea included bronchospasm (in 52%) and hypoxia (in 40%). It is important to ensure that bronchodilator therapy is optimized if the patient has obstructive airways disease. Inhaled furosemide also has been studied in patients with obstructive airways disease and in those with terminal dyspnea, and has been shown to improve airflow and exercise tolerance.⁶¹

Systemic Corticosteroids: The role for systemic corticosteroids is limited for relieving dyspnea from lung cancer. As is the case with bronchodilator therapy, patients with obstructive airways disease may benefit from systemic corticosteroids to decrease mucus production and inflammatory changes in the airway mucosa. It is also important to recognize that patients with lung cancer who are actively receiving specific therapy, such as radiotherapy and/or chemotherapy, may experience varying degrees of dyspnea.⁶² This may reflect pulmonary toxicity to such therapies. Pulmonary parenchymal toxicity leading to dyspnea may require discontinuation of tumor-specific therapies and administration of systemic corticosteroids.

Analgesics: Dyspnea has been shown to be more severe in patients with severe pain.⁴⁶⁵⁰ Dyspnea caused or aggravated by cancer-induced pain may respond to nonnarcotic analgesic therapy. However, dyspnea due to pain caused by bony metastases, malignant pleural effusions, or fatigue is unlikely to respond to conventional analgesic therapy. Such circumstances require more aggressive pain control, including palliative radiotherapy for skeletal metastasis. In patients with dyspnea caused by milder pain and discomfort, nonnarcotic analgesics should be tried for a brief period.

Anxiolytics and Antidepressants: Anxiety can aggravate the sensation of dyspnea, but studies of anxiolytics used to treat dyspnea, including benzodiazepines, phenothiazines and buspirone, have not shown benefit over placebo. Similarly, although antidepressants such as nortriptyline, desipramine, paroxetine, and selective serotonin reuptake inhibitors can be used to treat depression, their use to treat dyspnea is not supported.⁴⁸

Opioid Treatment: Opioids are frequently used to alleviate dyspnea in patients with advanced lung cancer, advanced obstructive airway disease, and cardiac failure.⁶³ A wide variety of opioid analgesics have been used to control both dyspnea and pain in patients with cancer of the lung and other organs. They include hydrocodone, acetaminophen with codeine, morphine, oxycodone, hydromorphone, and others. Opioids have been used orally, parenterally, and by aerosol, although the latter technique has not produced reliable results.⁶⁴ It is unclear if all opioids are equally efficacious in decreasing dyspnea perception in patients with lung cancer. In a study⁴⁶ of 104 patients with lung cancer, opioids administered to treat pain did not decrease dyspnea, although one study⁶⁵ showed an improvement in dyspnea when a subcutaneous dose of morphine 50% above the pain-relief dose was administered.

An open, uncontrolled study⁶³ evaluated the role of oral morphine to relieve dyspnea in 15 patients with advanced malignancy receiving standard care and noted that regular, titrated oral morphine may improve dyspnea but can cause significant short-term adverse effects. The relief of dyspnea is usually noted within 24 h, and the relief stays at a plateau with continued opioid therapy.⁶³

A metaanalysis⁶⁶ of 18 RCTs revealed a statistically significant positive effect of opioids on breathlessness. Oxygenation and carbon dioxide did not change in the 11 studies that included those variables. Some patients withdrew because of nausea, vomiting, and/or constipation. The effect of nebulized opioids was not different from placebo. A subsequent RCT⁶⁷ also showed significant improvement in refractory dyspnea using a sustained-release, low-dose, oral morphine.

Continuous IV infusion of morphine has been used in patients with terminal lung cancer with severe dyspnea, unrelieved by oxygen, nonnarcotic drugs, or intermittent bolus narcotics.⁶⁸ Even when patients achieve good dyspnea relief, the major side effect is sedation. Health-care providers, the patient, and family should be cognizant of the possibility of severe hypoventilation and hypercarbic respiratory failure and death. This side effect has been described also with inhaled morphine.⁶⁹ Nonetheless, the ethical principle of "double effect" supports the palliative use of opioids to relieve symptoms such as dyspnea and pain.⁴⁷

Invasive Approaches to Palliation of Dyspnea
Airway Obstruction: Primary lung cancer or metastatic malignancy in the thoracic cage can lead to airway obstruction as a result of tumor growth inside the airway lumen (intraluminal or intramural), airway wall (luminal or mural), or outside the airway lumen (extraluminal or extramural).^70717273 Central airway obstruction refers to significant obstruction of the trachea and main bronchi. Patients with this complication are more likely to have significant dyspnea and hemoptysis, at times life threatening, and require urgent therapy. Onset of stridor and its progression indicates the possibility of impending airway obstruction. The obstruction caused by the neoplasm can be aggravated by associated factors such as excessive mucous secretion and formation of mucous plugs, and blood and blood clots in the airway lumen. Palliative bronchoscopy plays a major role in such situations.

Clinical evaluations including imaging techniques and flow-volume curves may indicate the degree of airway obstruction. However, bronchoscopy is the singularly important technique for the diagnosis as well as therapy of airway obstruction. Bronchoscopic visualization usually determines the nature and severity of the obstruction and helps determine the appropriate diagnostic and therapeutic procedures.

Almost all bronchoscopic therapies are palliative in patients with lung cancer involving the major airways. A small number of patients with in situ lung cancer who cannot undergo resection because of comorbid conditions may get cured with endobronchial therapies. Bronchoscopic relief of disabling dyspnea is the most beneficial effect of the procedure. The next important symptom that can be treated by bronchoscopy is hemoptysis. Cough relief by bronchoscopy is less satisfactory because none of the palliative therapies will totally eradicate the tumor that is responsible for the cough.

The type of bronchoscopic therapy should be determined by the type and severity of respiratory symptoms, and the overall condition of the patient. The types of bronchoscopic therapy include endotracheal intubation, bronchoscopic debulking of intraluminal tumor, balloon dilatation, laser therapy, electrocautery, cryotherapy, argon plasma coagulation (APC), endobronchial irradiation (brachytherapy), or airway stent insertion (Table 1 ).⁷⁴ Some patients require a combination of techniques to obtain complete and lasting relief of symptoms.⁷⁵ All of these therapeutic techniques will provide significant relief of dyspnea and hemoptysis in the majority of patients.⁷⁶ While most of the techniques provide rapid relief of these symptoms, some procedures take a longer time and repeated applications. Expertise in these specialized techniques is imperative.

Bronchoscopic Debridement: Bronchoscopic debridement (resection) of intraluminal tumor can quickly relieve airway obstruction and resultant dyspnea. In many patients, this technique alone may suffice to relieve dyspnea. The rigid bronchoscope is much quicker than the flexible bronchoscope in accomplishing this task. The most important advantage of the rigid bronchoscope is that the instrument itself can be used as a tumor-debulking instrument, much like coring an apple. The other important advantages of the rigid bronchoscope include the ability to secure and maintain the airway, delivery of oxygen and anesthetic gases, and the ability to employ other therapeutic techniques. One retrospective study⁷⁷ evaluated the role of urgent rigid bronchoscopy, including Nd-YAG laser resection or stenting, in patients with acute respiratory failure from malignant central airways obstruction. Airway obstructions were caused by lung cancer in 14 patients. Urgent therapeutic bronchoscopy permitted immediate discontinuation of mechanical ventilation in > 52% of these patients (including 19 patients with benign lesions).⁷⁷ A study⁷³ of 143 patients who underwent 309 stent procedures of which 67% were for malignant disease observed that 82% required urgent or emergency intervention, and 77% had compromise of more than three fourths of the airway lumen. Flexible bronchoscopic debridement requires longer time because of the limitation of the ancillary instruments to adequately resect the tumor. Bronchoscopic debridement is best suited for intraluminal tumor growth and not applicable for therapy of extrinsic compression. Rigid bronchoscopy is best accomplished under general anesthesia or deep IV sedation. The major complication of simple bronchoscopic debridement is the bleeding associated with tumor resection.

Balloon Dilatation: Bronchoscopic balloon dilatation has a limited role in the treatment of major airway obstruction by malignant tumors.⁸¹⁸² This technique is a preparatory procedure to dilate the obstructed airway prior to placement of stents. Balloon dilatation through either the flexible or rigid bronchoscope is best suited for stenoses that are short in length.⁸³ Complications are few; excessive dilatation has the potential to cause airway rupture.

Laser: Bronchoscopic laser therapy is useful in relieving obstruction caused by intraluminal lesions. It has no role in treatment of obstruction caused by extraluminal tumors. Either rigid or flexible bronchoscopy can be used for application of laser energy, even though the former accomplishes this more quickly.⁸⁴ Rigid bronchoscopy is recommended for the management of large tumors in the trachea and mainstem bronchi. Once the laser accomplishes the coagulation of the tumor, a rigid bronchoscope itself or large forceps can be deployed to rapidly remove the obstructing tissue. If significant bleeding is encountered during the procedure, a rigid bronchoscope can provide quick control of this problem by tamponading the bleeding source as well as permitting suctioning of large quantities of blood from the airway. Currently, various types of lasers are available for treatment of endobronchial tumors. These include Nd-YAG, potassium titanyl phosphate, and CO₂ laser units. The Nd-YAG laser is the most commonly employed type of laser to treat malignant lesions of major airways. Immediate relief of airway occlusion and obstructive symptoms can be expected in > 90% of patients. Laser therapy also helps in preparing the airway for insertion of airway stents as well as brachytherapy catheters. Complications from laser therapy include endobronchial fire, severe hemorrhage, perforation of the airway, pneumothorax, and pneumomediastinum.^85868788

Electrocautery: Electrocautery application through either a rigid or flexible bronchoscope employs alternating electrical current to produce coagulation and vaporization of endobronchial lesions.^899091929394 The result from electrocautery technique is similar to that achieved with laser therapy. Immediate relief of dyspnea can be achieved with electrocautery in 55 to 75% of patients.^9093959697 A prospective study⁹⁸ evaluated the impact of bronchoscopic electrosurgery on the need for bronchoscopic Nd-YAG laser in patients with symptomatic airway lesions and observed that of the 47 bronchoscopic electrosurgery procedures, 42 procedures (89%) were successful in alleviating the obstruction, thus eliminating the need for laser. All procedures were performed in the outpatient bronchoscopy suite with the patient under conscious sedation (morphine and midazolam) and topical anesthesia with 2% lidocaine.⁹⁸ The advantages of electrocautery include less-expensive equipment (compared to laser) and the ease of use through flexible or rigid bronchoscope. Complications are similar to those encountered in laser ablation, and inadvertent delivery of electrical shock to the operator or patient.

APC: APC applies a technique to achieve noncontact electrocoagulation of viable tissue. APC utilizes electrically conductive argon plasma as a medium to deliver high-frequency current via a flexible probe to coagulate tissue. APC devitalizes tissue gradually by producing temperatures that coagulate and desiccate tissue. One retrospective study⁹⁹ of 60 patients with bronchogenic carcinoma (n = 43), metastatic tumors of airways (n = 14), or benign bronchial disease (n = 3) employed APC therapy via flexible bronchoscopy to control hemoptysis, symptomatic airway obstruction, or both obstruction and hemoptysis. Patients with endoluminal airway lesions had an overall decrease in mean obstruction of 18 ± 22%. All patients with obstructive lesions had symptom improvement, and symptom control was maintained during a median follow-up period of 53 days.⁹⁹ The advantages of APC include low cost (compared to laser), noncontact mode of therapy, easy portability of equipment, and ease of use. The noncontact feature of APC allows rapid coagulation with minimal manipulation of and mechanical trauma to the target tissue. Complications are similar to those described for laser and electrocautery.

Cryotherapy: Cryotherapy employs cryoprobes through either a rigid or flexible bronchoscope to apply extremely cold temperatures to tumor tissue so that malignant cells are devitalized and killed by repeated cycles of cold application followed by thawing. Nitrous oxide or liquid nitrogen is most commonly used to produce temperatures of – 80°C.^100101102 As is the case with laser and electrocautery, cryotherapy can be used to treat only intraluminal tumors. Subjective improvements have been observed in > 75% of patients with malignant airway lesions.¹⁰³¹⁰⁴ In a study¹⁰⁵ of 476 consecutive patients with obstructive airway tumors treated by cryotherapy, significant improvements in hemoptysis, cough, and dyspnea were observed in 76%, 69%, and 59%, respectively. In this study,¹⁰⁵ the overall complication rate was 3.5% and included bleeding, pneumothorax, respiratory distress, and cardiac events. Repeat bronchoscopy is needed for continued therapy in many patients. Cryotherapy equipment is less expensive and easier to use than laser therapy. The major disadvantage of treating large tumors in major airways is that cryotherapy requires repeated applications and far more time to relieve obstruction. Therefore, cryotherapy is not an ideal technique to acutely relieve dyspnea caused by major airway lesions.

Brachytherapy: Brachytherapy is the term used to describe intraluminal radiation therapy to treat malignant tumors within the airways. The flexible bronchoscope is used to insert and place the brachytherapy catheter into the affected airway lumen. Brachytherapy can be used to treat airway obstruction caused by intraluminal, luminal, as well as extraluminal cancer located immediately adjacent to the airway.^{106107108109110} Usually, brachytherapy is aimed at palliating malignant airway lesions in patients who have already received a maximum dose of external-beam radiation. Brachytherapy can also be used as a stand-alone therapy or as complimentary or combined therapy following external beam radiation therapy, airway debulking (laser, mechanical removal), or after airway stent placement. Even though earlier experience demonstrated that brachytherapy alone resulted in adequate symptomatic relief in a considerable number of patients,^{1112111112113114115} current evidence indicates that brachytherapy as a complimentary therapy provides better relief of dyspnea and other symptoms than brachytherapy alone.^{112116117118119120121122123} Relief from dyspnea can be expected in > 60% of patients and can last for weeks to months. A phase II study¹²⁴ involving 30 patients with stage-III NSCLC treated with 60 Gy x-ray therapy also used brachytherapy and reported palliation rates of 80% for dyspnea and 43% for cough. One prospective study¹²³ of 342 patients with endobronchial tumors treated by the combination of external-beam radiation therapy (30 to 60 Gy) and concomitant brachytherapy during weeks 1, 3, and 5 observed a response rate of 85% for cough and 86% for dyspnea. Major complications of brachytherapy include fistula formation between the airways and other thoracic structures in up to 8% of patients. The risk of massive hemoptysis increases dramatically when a fraction size of 15 Gy is used.¹²¹

Photodynamic Therapy: Photodynamic therapy (PDT) consists of deploying tumor-tagging compounds such as hematoporphyrin derivative and porfimer sodium. When tumor cells thus tagged are exposed to the light of the proper wavelength, chemical reactions cause death of malignant cells through production of toxic radicals. Patients with small (< 3 cm²) epithelial cell malignancies are most likely to benefit from this therapy.¹²⁵ Complete response lasting for > 12 months has been observed in 50% of patients.¹²⁶¹²⁷ The effectiveness of PDT for symptom palliation, and survival benefit has been evaluated in patients with advanced inoperable bronchogenic cancer and endobronchial luminal obstruction. Among 100 such patients, 82% had received prior chemotherapy and/or radiotherapy. On an average, endoluminal obstruction diminished from 86 to 18%. This study suggests that PDT is effective in palliation of inoperable advanced lung cancer in a subset of patients. One study¹²⁸ has reported on the therapeutic efficacy of combined brachytherapy and PDT in patients with bulky endobronchial lung cancer. Another study¹²⁹ of 37 consecutive cases of inoperable cancer, either primary or metastatic to lung, used porfimer sodium as a primer before PDT and observed 32 complete or partial responders and five treatment failures.

When PDT alone is used, however, the relief from obstruction is slow¹³⁰; because of this slow response, there is no major role for PDT in the treatment of obstructing lesions of central airways. In locally advanced and symptomatic lung cancer, PDT with or without radiotherapy can contribute to the relief of airway obstruction and hemoptysis, but it has not exhibited a survival advantage when compared with current treatments, such as Nd-YAG laser therapy or radiotherapy alone.¹³¹ Complications from PDT include phototoxicity, hemoptysis, and obstruction of bronchi by thick necrotic material.

Stents: Airway prostheses or stents made of metal, silicone, or other materials can be used to relieve airway obstruction caused by malignant tumors.^{132133134135136137} Stent therapy is indicated in both intraluminal and extraluminal major airway obstructions. Stent therapy is more effective in patients with tracheal or main bronchial obstruction than in those with airway diseases that involve lobar and more distal bronchi. Either silicone or metallic stents can be used to treat malignant airway lesions. Malignancy involving the main carina is best treated with silicone stents designed for this anatomic location.¹³⁸ Uncovered metallic stents are not recommended in patients with malignant airway lesions because the growth of cancer through the wire mesh negates the benefits of stent placement.¹³⁹ After bronchoscopic debridement of tumor and laser therapy, stent placement should be considered to maintain long-term airway patency. Even though bronchoscopy is frequently used to deploy airway stents, tracheobronchial stent insertion can be accomplished using fluoroscopic guidance alone.¹⁴⁰

In a report¹³⁶ on clinical experience over a 10-year period with 307 Gianturco metal stents placed via the flexible bronchoscope in 162 patients (144 primary lung tumors, 18 secondary malignancy), the average survival following stent insertion was less for primary lung cancer than for secondary disease (103 days vs 431 days, p < 0.001). In a study¹⁴¹ of 22 patients with severe malignant strictures, 34 airway stents were implanted as a temporary measure before patients received irradiation or chemotherapy. Significant improvements of dyspnea and partial oxygen pressure were observed; and in 50% of patients, the stents were removed after successful tumor-specific therapy.¹⁴¹ In another study,⁷⁷ among 34 patients with inoperable malignant airway stenosis, covered metallic stents were implanted on emergency basis in 19 patients (56%) because of life-threatening airway obstruction. Immediate relief of dyspnea was achieved in 82% of the patients, and significant improvements were observed in airway diameter, vital capacity, and peak expiratory flow.⁷⁷

All silicone stents require rigid bronchoscopy for their insertion, manipulation, and removal,^142143144 whereas metal stents can be inserted with the aid of flexible bronchoscopy and/or fluoroscopic guidance. Frequently, multiple stents and multiple procedures will be necessary to maintain a satisfactory airway.⁷³ Complications from silicone stents include migration of stent and inspissations of thick mucus within the stent lumen. Metallic stents are more likely to promote growth of granulation tissue.

Surgery: Surgical resection of malignant tracheobronchial tumors should be considered when unusual types of malignant tumors are encountered. The types of tumors that are amenable to resection and anastomosis include carcinoid, cylindroma, and mucoepidermoid tumors. The length of involvement of trachea or major bronchus should be short enough for the surgeon to resect the tumor so that the anastomotic site is free of malignant cells. Malignancy involving the main carina is usually deemed advanced and thus unresectable. Such patients, if symptomatic, benefit from the bronchoscopic techniques described above. In recent years, surgical resection and reconstruction of the main carina is being performed in patients who can tolerate surgery.^145146147

	Recommendations

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12. For all lung cancer patients who complain of dyspnea, it is recommended that they be evaluated for potentially correctable causes, such as localized obstruction of a major airway, a large pleural effusion, pulmonary emboli, or an exacerbation of coexisting COPD or congestive heart failure. If one of these problems is identified, treatment with appropriate methods is recommended. Grade of recommendation, 1C

13. For all lung cancer patients whose dyspnea does not have a treatable cause, opioids are recommended. Also recommended are other pharmacologic approaches such as oxygen, bronchodilators, and corticosteroids. Grade of recommendation, 1C

14. For all lung cancer patients with dyspnea, it is recommended that nonpharmacologic and noninterventional treatments be considered, such as patient and family education, breathing control, activity pacing, relaxation techniques, fans, and psychosocial support. Grade of recommendation, 2C

Palliation of Cough
Cough is a frequent and distressing symptom in patients with lung cancer. Cough can be dry or associated with sputum production. Involvement of any part of the respiratory system can lead to cough. Among the initial symptoms of lung cancer, cough is present in > 65% and productive cough in > 25% of patients.¹⁴⁸ Cough can be the presenting or leading symptom of lung cancer. It is more likely among patients with lung cancer originating in the airways. As in the treatment of dyspnea, the principal cause of the cough needs to be identified and treated appropriately (such as pleural involvement by the tumor, and infection). Other factors can contribute, such as esophageal reflux, coexisting COPD, or congestive heart failure, and should be addressed.⁷

Even if complete cessation of cough is not possible, significant control of cough may help patients enjoy cough-free periods. In late stage cancer when no specific therapy can address the cancer itself, control of bothersome cough becomes a problem. The following commentary is a brief summary of methods available to manage cough in the setting of lung cancer; a more detailed review was recently published as part of the American College of Chest Physicians evidence-based clinical practice guidelines for cough.⁷

Pharmacologic Agents
Cough Suppressants: Nonopioid cough suppressants may work in a small group of patients with advanced lung cancer. Occasionally, even opioid-resistant cough may respond to agents such as the peripherally acting nonopioid drug benzonatate.¹⁴⁹

Bronchodilators: Bronchospasm can cause or contribute to cough. If the patient with lung cancer also has underlying bronchospastic obstructive airways disease, then standard bronchodilator therapy may help alleviate the cough.

One study¹⁵⁰ tested the role of inhaled sodium cromoglycate in 20 patients with NSCLC and cough resistant to conventional treatment. The patients were randomized to receive, in a double-blind trial, inhaled sodium cromoglycate or placebo. The results showed that inhaled sodium cromoglycate reduced cough in all patients with NSCLC.

Opioids: Opioids are the best cough suppressants in patients with lung cancer. Codeine is the most widely used opioid for cough suppression. In advanced stages of lung cancer, standard nonopioid cough suppressants may not control the cough. Intractable or troublesome cough should be treated with opioid agents. Caution should be exercised in prescribing graduated doses of these drugs because of the risk of respiratory depression and hypoventilation.

A double-blind RCT¹⁵¹ regarding the treatment of nonproductive cough was performed in 140 adults with primary lung cancer or metastatic cancer of the lungs. The therapeutic efficacy and the tolerability of a 7-day treatment with levodropropizine drops (75 mg tid) were evaluated in comparison with dihydrocodeine drops (10 mg tid). Efficacy was assessed on the basis of cough severity scores, number of night awakenings due to cough, and overall estimate of antitussive efficacy. Tolerability was evaluated by laboratory results, vital signs, and any adverse event occurring during the clinical trial, including the presence or absence of somnolence. Subjective cough severity was significantly reduced during treatment with levodropropizine and dihydrocodeine, the antitussive effect, and its time profile being similar for both drugs. Also, according to the investigator’s evaluation, both levodropropizine and dihydrocodeine produced a significant decrease in cough severity. Concurrently with the relief of cough, the number of night awakenings was decreased significantly by both drugs, with no difference between the two treatments. No change in laboratory test values was considered clinically relevant, and vital signs were not clinically affected. The number of patients reporting adverse events was similar in the levodropropizine (n = 6) and dihydrocodeine (n = 4) group. However, the percentage of patients with somnolence in the group receiving levodropropizine (8%) was significantly lower as compared with that of the dihydrocodeine group (22%). These results confirm the antitussive effectiveness of levodropropizine and suggest a more favorable benefit/risk profile when compared to dihydrocodeine.¹⁵¹ However, levodropropizine is not available for use in the United States.

Corticosteroids: There are no studies on steroids specifically for cough in lung cancer. If cough is caused by radiation-induced lung problems, then high-dose corticosteroid therapy may relieve a significant degree of cough.

Lidocaine: There are no studies on the role of inhaled lidocaine on cough in patients with lung cancer.

Chemotherapy: Newer agents such as gemcitabine and cisplatin-based chemotherapy have been studied with regard to their specific effects on cough frequency and severity among patients with NSCLC. Gemcitabine reduces cough in 44% of subjects so treated, and moderate or severe cough was improved in 73%.¹⁵²¹⁵³ Treatment of SCLC patients with chemotherapy is reported to improve cough in 7 to 80%.^154155156

Nonpharmacologic Treatment of Cough
Surgery: No systematic studies have addressed the effect of surgical resection of NSCLC on the specific symptom of cough, but clinical experience suggests that cough will improve when the cancer is resected. Palliative ipsilateral high intrathoracic vagotomy immediately below the origin of the recurrent laryngeal nerve was reported in a small case series¹⁵⁷ to improve cough when an exploratory thoracotomy was done but the cancer was not resectable.

Radiation Therapy: Two RCTs in the United Kingdom were designed to assess the effect of different external-beam radiation programs on specific symptoms, including cough.¹⁵⁸¹⁵⁹ The first study¹⁵⁸ was a comparison of a two-dose schedule (8.5 Gy each) to longer conventional external-beam multifractionated treatment; and the second study¹⁵⁹ was a comparison of two 8.5-Gy fractions to a single 10-Gy fraction. Relief of cough occurred in 48 to 95% of patients treated with one or another of these schedules.

Endobronchial Treatment Methods: Laser and electrocautery methods of endobronchial treatment are usually offered for the purpose of palliating dyspnea or hemoptysis. However, various series^{91111112113116122160161} that have reported on cough have noted improvement in 51 to 90% of patients. All such reports are case series; there are no RCTs that have specifically analyzed cough as an outcome variable for such methods of palliating symptoms. Brachytherapy is the one endobronchial treatment modality that specifically includes a mention of cough palliation.^{106111112113116122}

	Recommendations

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15. For all lung cancer patients who have troublesome cough, it is recommended that they be evaluated for treatable causes. Grade of recommendation, 1B

16. For all lung cancer patients who have troublesome cough without a treatable cause, it is recommended that opioids be used to suppress the cough. Grade of recommendation, 1B

Palliation of Bone Metastases
Metastatic lung cancer to bone is a manifestation of stage IV disease; thus, cure essentially is not possible, and care for the patient will be palliative in nature. Elimination or reduction of pain is the primary goal of treatment. There are no randomized prospective studies that directly compare radiation to pharmacotherapy for the management of pain due to bony metastases. If a metastasis occurs in a weight-bearing bone, prophylactic surgical stabilization should be considered before a pathologic fracture occurs.

Pain caused by bone metastases has multiple causes. Periosteal inflammation and elevation is the most common mechanism behind the pain from bone metastases. Lung cancer metastases to bone are predominantly lytic. After controlling pain with pharmacologic methods, treatment should be directed at managing the inflammation. External-beam radiation should therefore be considered as the initial nonpharmacologic method. This technique uses energy to diminish the local inflammatory response and thereby eliminates the source of the pain. Other nonpharmacologic methods to manage pain from bone metastases include radioactive isotope infusion, supportive measures for pain management, and direct local management (such as surgery and nerve blocks).

A majority of patients with symptomatic bone metastases obtain some pain relief with a low-dose, brief course of palliative radiation therapy. One half of the responding patients may experience complete pain relief.¹⁶² For short-term improvement in bone pain, 8 Gy in a single fraction is as effective as higher doses.¹⁵⁸¹⁵⁹ Single-fraction radiotherapy is less expensive than multiple-fraction radiotherapy, and it is more convenient from the patient’s perspective. A systematic review and metaanalysis¹⁶³ of 11 randomized trials involving 3,435 patients treated with single-fraction radiotherapy vs multiple fraction radiotherapy was conducted in 2005. Although the trials included patients with painful bony metastases from multiple primary sites, the majority were from prostate, breast, and lung cancers. Lung cancers compromised 19.9% of the total. The overall response for relief of pain was 60% for patients treated with a single fraction, and 59% for patients treated with multiple fractions. Complete pain relief was accomplished in 34% of patients treated with a single fraction vs 32% for those treated with multiple fractions (odds ratio [OR], 1.11; 95% confidence interval [CI], 0.94 to 1.30). Although a single dose of radiation is effective, the duration of pain relief is less than with higher fractionated doses of radiation therapy. Retreatment was needed in 21.5% vs 7.4% for patients treated with multiple fractions (OR, 3.44; 95% CI, 2.67 to 4.43).¹⁶³ The pathologic fracture rate was 3% among patients treated with a single fraction, compared to 1.6% for those treated with multiple fractions (OR, 1.82; 95% CI, 1.06 to 3.11). If large fields are required, local inflammation and edema may be a problem with a high single dose. A high single dose is appropriate for small extremity fields, provided internal organs are not included, and for patients whose expected survival is only a few months.

Bisphosphonates have assumed an important role in the treatment of patients with bone metastases, especially since the introduction of zoledronic acid. Bisphosphonates prevent bone resorption at sites of bone remodeling. In three large randomized phase III trials¹⁶⁴ with > 3,000 patients, 4 mg of zoledronic acid administered during a 15-min infusion was found to be a very effective treatment for bone metastases in patients with lung cancer, prostate cancer, and other solid tumors. Zoledronic acid is generally well tolerated, but it can be associated with increases in serum creatinine that require monitoring of renal function.¹⁶⁴ Zoledronic acid has also been shown to prevent skeletal related events (pathologic fractures, spinal cord compression, hypercalcemia, or pain requiring surgery).¹⁶⁵ In a multicenter RCT comparing zoledronic acid to placebo, there were 378 patients with NSCLC among the 773 subjects with solid tumors that had metastasized to bones. The incidence of skeletal related events was significantly reduced among patients treated with zoledronic acid (p = 0.039).¹⁶⁶

Adjunctive therapy with disodium pamidronate has demonstrated good therapeutic response by itself, but more importantly when it is used in combination with radiotherapy for bony metastases. Response rates of 92% were seen in a randomized study¹⁶⁷ with external-beam radiation and pamidronate, vs radiation alone (83%), pamidronate alone (85%), or pamidronate in combination with chemotherapy (87%).

IV radioisotope infusion can also be used to manage pain from bony metastases, and it is especially useful for patients with widespread bony metastases. In a systematic review, Bauman et al¹⁶⁸ identified six randomized phase III trials, two randomized phase II trials, and one randomized crossover trial of ⁸⁹Sr. Another three randomized phase III trials and two randomized phase II trials of ¹⁵³Sm were part of their review, as were additional randomized trials of rhenium, ^117mSn, and ³²P. As is true for most issues regarding the palliative management of a specific problem, the study groups contained mixtures of primary organ sites of the cancers. In these studies, only 5 to 10% of the patients had primary lung cancer, with the majority of other patients having breast or prostate primary sites. In most of these studies, pain relief in existing sites of metastases was significantly longer for patients treated with radiopharmaceuticals. This led to the conclusion that single-agent radiopharmaceuticals (⁸⁹Sr and ¹⁵³Sm) should be considered as a possible option for the palliation of multiple sites of bone pain from metastatic cancer, when pain control with conventional analgesic regimens is unsatisfactory, and when activity on a bone scan of the painful lesions is demonstrated.¹⁶⁸

Pathologic fractures may occur when lung cancer metastasizes to bones. Fracture of long bones significantly impairs functional status and quality of life. The femur is at special risk because of its role in weight bearing, and surgical intervention may be needed. Other bones that may require palliative surgical intervention include the tibia, hip (proximal femur plus acetabulum), vertebrae, and the humerus.

Prophylactic surgery is recommended for the following situations when long bones are involved: persistent or increasing local pain despite the completion of radiation therapy; a solitary well-defined lytic lesion circumferentially involving > 50% of the cortex; involvement of the proximal femur associated with a fracture of the lesser trochanter; and diffuse involvement of a long bone.¹⁶⁹ Contraindications to surgical treatment of metastatic disease to long bones include a survival expectancy < 4 weeks and a poor general condition that is an obstacle to a safe operation.¹⁷⁰

No randomized, prospective, controlled trials have compared surgery alone, surgery plus radiation therapy, or radiation therapy alone for metastatic long bone disease. Generally, however, postoperative radiotherapy is recommended regardless of the type of surgical procedure chosen for bony metastases.¹⁷¹ All series that have analyzed operative intervention have included metastatic bone disease from multiple primary organ sites, with breast cancer as the most common. Lung cancer usually is the second most common primary site in reported series. A retrospective study¹⁷⁰ of 60 patients compared adjuvant surgery plus radiation therapy (35 sites) to 29 sites that were treated with surgery alone. Univariate analysis revealed that combined therapy (p = 0.02) and prefracture functional status (p = 0.04) were the only predictors of patients achieving a good functional status after surgery. On multivariate analysis, only postoperative radiation therapy was significantly associated with attaining a good level of function after surgery (p = 0.02).¹⁷⁰

Intramedullary nailing is generally regarded as the preferred operative approach to deal with metastatic long bone disease. Standard total joint arthroplasty of the proximal femur is very useful for pathologic fractures of the femoral head and neck and for intertrochanteric fractures that have metastases in the neck and head of the femur.¹⁷¹ Operative intervention for metastatic fractures of long bones provides a good functional result in approximately 80 to 85% of patients; a good analgesic effect is accomplished in nearly all patients.

In summary, pain relief is complete after radiotherapy for bony metastases in only one-third of patients. An approach to the management of bony metastases that is multifactorial (radiotherapy, bisphosphonates, and radioisotopes) coupled with analgesics is recommended. Because such combination approaches are usually successful, older methods of treatment (calcitonin, percutaneous ethanol injection into metastatic lesions, and embolization of the bone tumor vasculature) have not been reported extensively in recent years.

	Recommendations

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