What is the role of palliative care in symptom management for patients with lung cancer?

From Cancer Guidelines Wiki

Introduction

Palliative care is appropriate for all people facing life threatening disease, though in practice in Australia, most services are directed toward people with life limiting/terminal disease. While most studies reviewed to create the palliative care section are derived from studies relating to patients with NSCLC, it is likely that the themes and concepts are broadly applicable to those with SCLC.

Palliative care prioritises the early identification, assessment and management of pain and other symptoms and attention to the psychosocial and spiritual priorities. Substantial evidence demonstrates that palliative care-when combined with standard cancer care or as the main focus of care-leads to better patient and caregiver outcomes; improvement in symptoms, QOL, patient satisfaction, and reduced caregiver burden. Earlier involvement of palliative care also leads to more appropriate referral to and use of hospice, and reduced use of futile intensive care.[1] Expert consensus from the American Society of Clinical Oncology thus recommends that combined standard oncology care and palliative care should be considered early in the course of illness for any patient with metastatic cancer and/or high symptom burden.[2]

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Symptom management

The occurrence of multiple symptoms is common in cancer with high levels of distress occurring in patients with lung cancer.[3] These guidelines will address updates on the more common symptoms of pain, dyspnoea, constipation, cough and haemoptysis. It will not address the use of chemotherapy or radiation therapy for symptom management (refer to Radiotherapy to the lung primary in stage IV NSCLC). The majority of studies quoted involve a heterogeneous population and include data from non-cancer patients.

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Pain

Poorly controlled pain requires prompt attention. There is currently good evidence to support the use of nonsteroidals, opioids, bisphosphonates, radiotherapy and radiopharmaceuticals for the management of cancer pain.[4]

Morphine remains the recommended opioid based on familiarity, cost and ease of access.A systematic review of 54 randomised studies [5] demonstrated that both oral modified release (Mm/r) and immediate release (MIR) morphine is effective for cancer pain. Dose titration occurred with both MIR and Mm/r with studies comparing Mm/r with MIR, MIR of different strengths, MIR with other opioids and different routes of administration. Daily doses ranged form 25mg to 2000mg with an average of between 100mg and 250mg. There was insufficient comparable data for meta-analysis or number need to treat (NNT) for the analgesic effect.

The Cochrane reviews of 43 studies for hydormorphone for acute and chronic pain[6] and nine randomised studies methadone for cancer pain. A meta-analysis of four RCT’s[7] comparing oral oxycodone with oral morphine or oral hydromorphone showed that there was no evidence that mean pain scores differed between oxycodone and control drugs. The efficacy and tolerability of oxycodone was similar to morphine, supporting its use as an opioid for cancer-related pain.

A Cochrane review of the use of non-steroidal anti-inflammatory drugs (NSAIDS), alone or in combination with opioids for cancer pain.[8] showed a superiority of NSAID’s over placebo no superiority or efficacy of one NSAID over another.

Newer anticonvulsants such as gabapentin and pregabalin are recommended for the management of neuropathic pain.[9] The main body of evidence arises for its use in post herpetic neuralgia and diabetic neuropathy though there remains to be head to head trials of these agents.

Data from a systematic review of 30 randomised studies showed benefit for the use of bisphophonates for the relief of pain from bone metastasis.[10] Pooled data from the treatment group achieved a NNT at four weeks of eleven [95% CI 6-36], at twelve weeks of seven [95% CI 5-12] and a number need to harm (NNH) of 16 [95% CI 12-27] for discontinuation of therapy. Small study numbers and limited data precluded exploration of the most effective bisphosphonate and their relative effectiveness. In cases of pain from widespread bony metastasis, intravenous radiopharmaceuticals should be considered. A systematic review[11] which included 5-10% of patients with lung cancer concluded that single agent radiopharmaceuticals such as strontium-89 and samarium-153 were effective in the palliation of multiple site of bone pain when conventional treatment was unsatisfactory.

There remains a lack of high quality RCT’s to generate substantive evidence for the use of complementary therapies.[12][13][14] A systematic review of three RCT”s[12] showed the effect of auricular acupuncture compared with auricular acupuncture at ‘placebo’ points with significant decrease in pain intensity recorded on VAS at one month and two months (p<0.0001) and an over all 36% decrease in pain intensity. A systematic review of the benefits of aromatherapy and massage showed benefit but little evidence for the improvement of pain.[14]

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Dyspnoea

Dyspnoea is a subjective symptom with complex multifocal phenomenon. It occurs in up to 73% of patient with end stage lung cancer and is associated with a poor prognosis.

The use of oral or parenteral opioids to palliative dyspnoea are well established. Seven trials assessing opioids in a systematic review evaluating interventions for cancer related dyspnoea.[15] showed that the administration of subcutaneous morphine resulted in a significant reduction in dyspnoea compared to placebo. There was no benefit from nebulised morphine when compared to subcutaneous morphine.

Oxygen is frequently prescribed but a meta-analysis of 134 cancer patients [16] and a detailed systematic review of RCT’s involving adults with chronic end stage disease (including cancer) showed that oxygen failed to improve dyspnoea in mildly or non-hypoxemic cancer patients . A more recent international, multicentre, double blind RCT of 239 participants with life limiting illness once again showed no additional symptomatic benefit of oxygen compared to room air.[17]

Benzodiazepines are also commonly used in the management of breathlessness but a systematic review of seven studies showed no evidence for a beneficial effect.[18] There was a slight, non significant trend towards a beneficial effect, justifying its use as a second or third line treatment. The addition of benzodiazepines to morphine have been shown to be more beneficial than the use of morphine alone.[15]

Data from a systematic review of non-pharmacological interventions for breathlessness from 47 studies.[19] included complex interventions and were conducted in non-cancer patients and occasionally within a laboratory setting. There was a lack of strong evidence to support the interventions and it remains unclear as to which combinations of interventions are most appropriate.

A study of 30 lung cancer patients referred to a breathless clinic with physiotherapy led interventions showed improvements [20] in the frequency of dyspnoea, functional capacity (p<0.001) and degree of breathlessness with the percentage of patients experiencing breathlessness several times or more a day reduced from 73% to 27% four weeks later.

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Constipation

Data form a systematic review[21] evaluating the use of laxatives in 616 palliative care patients from seven studies concluded that insufficient RCT’s still limit recommendations as to which of the oral laxatives are most appropriate. No differences were demonstrated between lactulose and senna, lactulose and senna compared to magnesium hydrochloride and liquid paraffin or between misrakasneham and senna. Lactulose and senna were more favourable than co-danthramer in stool frequency but not in patient’s assessment of bowel function.

More promising results emerged form combined analysis (287 participants) of methylnaltrexone compared to placebo. It significantly induced laxation at four hours (odds ratio 6.95; 95% CI 3.83-12.61). Patients were more likely to experience flatulence and dizziness, but showed no evidence of opioid withdrawal. There is insufficient data about the long term effects of the use of opioid antagonists.

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Cough

A phase II study of hydrocodone[22] in patients with advanced cancer showed that it was effective in reducing the severity, frequency of cough and associated symptoms. A further detailed systematic review of interventions for cough in cancer[23] examined the results of 17 RCT’s. No practice recommendations were concluded due to the absence of credible evidence. No clear conclusions were possible form the use of pharmacological interventions though butamirate linctus, codeine (60mg), dihydrocodeine (10mg), cromoglycate and hydropropizine / levodroprozine seem to exercise positive benefits. Brachtherapy was shown to improve cough in selected patients and is possibly beneficial at the lowest effective dose to minimise side effects.

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Haemoptysis

A recent study reviewing the benefit of tranxemic acid in a randomised double-blinded placebo controlled trial failed to show its benefit in shortening the number of days of haemoptysis.[24] A low incidence of side effects confirmed the relative safety of this drug.

Low level evidence suggests the potential usefulness of transcathether arterial embolisation (TAE)[25] or bronchial artery embolisation.[26] Data for 128 TAE procedures completed in 58 patients showed high technical (100%) and clinical success (98%) with a 40% reoccurrence rate. BAE showed an 84% technical success rate though the survival rate in patients with cancer related haemoptysis remained poor. (Refer also to Radiotherapy to the Lung Primary in Stage IV)

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Evidence summary and recommendations

Evidence summary Level References
Oral morphine remains the gold standard for the management of moderate to severe cancer pain. It is possible to titrate to analgesic effect using immediate or modified release morphine.

Last reviewed December 2015

I [5]
Oxycodone, hydromorphone and methadone can provide comparable analgesia to morphine when titrated to effect.

Last reviewed December 2015

I [6], [7], [27]
NSAIDS alone is superior to placebo and adequate for the management of mild cancer pain

Last reviewed December 2015

I [8]
Bisphosphonates and radiopharmaceuticals should be considered where analgesics and /or radiotherapy are inadequate for the management of painful bone metastasis.

Last reviewed December 2015

I [10], [11]
Evidence-based recommendationQuestion mark transparent.png Grade
There is strong evidence from consistent randomised trials to support the use of NSAIDS and opioids for the management of pain in patients with NSCLC.

Last reviewed December 2015

B
Evidence-based recommendationQuestion mark transparent.png Grade
There is a role for the use of bisphosphonates and radiopharmaceuticals in a select group of patients with pain arising from multiple site of bony metastasis.

Last reviewed December 2015

B


Practice pointQuestion mark transparent.png

- It is advised that the use of methadone occurs with involvement of specialist palliative care or pain services, due to its complex pharmacodynamic properties.
- The choice of opioids used may consider issues of availability, cost and individual patient factors such as route of administration, metabolism and organ impairment such as renal failure.
- Anticonvulsants such as gabapentin and pregabalin may be considered in the management of neuropathic pain, based on substantive body of evidence generated in non-cancer patients.
- Non-pharmacological approaches and complementary therapies may be considered as part of a multimodal approach when pain remains poorly controlled.
Last reviewed December 2015


Evidence summary Level References
The evidence suggest that systemic opioids, administered orally or parenterally is beneficial for the management of dyspnoea in lung cancer patients.

Last reviewed December 2015

I [15]
The evidence suggests that both air and oxygen and administered intranasally provide equal symptomatic benefit for the relief of dyspnoea. The benefit of oxygen is better established in patients with hypoxemia.

Last reviewed December 2015

I [16], [28], [15]
Evidence-based recommendationQuestion mark transparent.png Grade
The use of opioids are recommended for the relief of dyspnoea in patients with NSCLC.

Last reviewed December 2015

B


Evidence-based recommendationQuestion mark transparent.png Grade
Following individual patient assessment and a therapeutic trial, oxygen administered intranasally may be administered to patients with advanced lung cancer to palliate the symptom of breathlessness.

Last reviewed December 2015

B



Practice pointQuestion mark transparent.png

The use of non-pharmacological strategies, such as breathing retraining, simple relaxation, activity pacing and psychosocial support from nursing or allied health, can be beneficial for the management of breathlessness.
Last reviewed December 2015


Practice pointQuestion mark transparent.png

Benzodiazepines can be used as a second or third line therapy in the treatment of breathlessness in patients with advanced lung cancer, when opioids and non-pharmacological measures have failed.
Last reviewed December 2015

Evidence summary Level References
The evidence suggests that opioid receptor antagonists such as methylnaltrexone, are effective in inducing laxation for opioid induced constipation.

Last reviewed December 2015

I [21]
Evidence-based recommendationQuestion mark transparent.png Grade
Subcutaneous methylnaltrexone should be considered in patients where conventional laxatives have failed.

Last reviewed December 2015

B


Practice pointQuestion mark transparent.png

Recommendations for the treatment of constipation in the palliative care population have been made based on expert opinion and currently suggest a combination of stimulant and softening agent.
Last reviewed December 2015


Practice pointQuestion mark transparent.png

-Centrally acting oral opioids may be considered for the suppression of cough in NSCLC

-Symptomatic treatment with antimuscuranic agents or antibiotics may be helpful by reducing the volume of secretions or mucopurulant sputum.

-Where appropriate and accessible, interventions such as brachytherapy may be beneficial for the management of cough in selected patients. (Refer to Brachytherapy section in Radiotherapy Stage IV)
Last reviewed December 2015


Practice pointQuestion mark transparent.png

Palliative measures for the management of haemoptysis include the use of oral haemostatics e.g. tranexamic acid, or radiotherapy, or laser treatment to the tumour site and the active management of underlying causes, such as infection, or pulmonary infarction.
Last reviewed December 2015

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References

  1. Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010 Aug 19;363(8):733-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20818875.
  2. Smith TJ, Temin S, Alesi ER, Abernethy AP, Balboni TA, Basch EM, et al. American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. J Clin Oncol 2012 Mar 10;30(8):880-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22312101.
  3. Cooley ME. Symptoms in adults with lung cancer. A systematic research review. J Pain Symptom Manage 2000 Feb;19(2):137-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10699541.
  4. Lorenz KA, Lynn J, Dy SM, Shugarman LR, Wilkinson A, Mularski RA, et al. Evidence for improving palliative care at the end of life: a systematic review. Ann Intern Med 2008 Jan 15;148(2):147-59 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18195339.
  5. 5.0 5.1 Wiffen PJ, McQuay HJ. Oral morphine for cancer pain. Cochrane Database Syst Rev 2007 Oct 17;(4):CD003868 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17943804.
  6. 6.0 6.1 Quigley C. Hydromorphone for acute and chronic pain. Cochrane Database Syst Rev 2009 Abstract available at http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD003447/pdf_fs.html.
  7. 7.0 7.1 Reid CM, Martin RM, Sterne JA, Davies AN, Hanks GW. Oxycodone for cancer-related pain: meta-analysis of randomized controlled trials. Arch Intern Med 2006 Apr 24;166(8):837-43 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16636208.
  8. 8.0 8.1 McNicol E, Strassels SA, Goudas L, Lau J, Carr DB. NSAIDS or paracetamol, alone or combined with opioids, for cancer pain. Cochrane Database Syst Rev 2005 Jan 25;(1):CD005180 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15654708.
  9. Dworkin RH, O'Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007 Dec 5;132(3):237-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17920770.
  10. 10.0 10.1 Wong R, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database Syst Rev 2002;(2):CD002068 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12076438.
  11. 11.0 11.1 Bauman G, Charette M, Reid R, Sathya J. Radiopharmaceuticals for the palliation of painful bone metastasis-a systemic review. Radiother Oncol 2005 Jun;75(3):258-70 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16299924.
  12. 12.0 12.1 Paley CA, Johnson MI, Tashani OA, Bagnall AM. Acupuncture for cancer pain in adults. Cochrane Database Syst Rev 2011 Jan 19;(1):CD007753 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21249694.
  13. Robb KA, Bennett MI, Johnson MI, Simpson KJ, Oxberry SG. Transcutaneous electric nerve stimulation (TENS) for cancer pain in adults. Cochrane Database Syst Rev 2008 Jul 16;(3):CD006276 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18646140.
  14. 14.0 14.1 Fellowes D, Barnes K, Wilkinson S. Aromatherapy and massage for symptom relief in patients with cancer. Cochrane Database Syst Rev 2004;(2):CD002287 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15106172.
  15. 15.0 15.1 15.2 15.3 Ben-Aharon I, Gafter-Gvili A, Paul M, Leibovici L, Stemmer SM. Interventions for alleviating cancer-related dyspnea: a systematic review. J Clin Oncol 2008 May 10;26(14):2396-404 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18467732.
  16. 16.0 16.1 Uronis HE, Currow DC, McCrory DC, Samsa GP, Abernethy AP. Oxygen for relief of dyspnoea in mildly- or non-hypoxaemic patients with cancer: a systematic review and meta-analysis. Br J Cancer 2008 Jan 29;98(2):294-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18182991.
  17. Abernethy AP, McDonald CF, Frith PA, Clark K, Herndon JE 2nd, Marcello J, et al. Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind, randomised controlled trial. Lancet 2010 Sep 4;376(9743):784-93 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20816546.
  18. Simon ST, Higginson IJ, Booth S, Harding R, Bausewein C. Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults. Cochrane Database Syst Rev 2010 Jan 20;(1):CD007354 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20091630.
  19. Bausewein C, Booth S, Gysels M, Higginson I. Non-pharmacological interventions for breathlessness in advanced stages of malignant and non-malignant diseases. Cochrane Database Syst Rev 2008 Apr 16;(2):CD005623 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18425927.
  20. Hately J, Laurence V, Scott A, Baker R, Thomas P. Breathlessness clinics within specialist palliative care settings can improve the quality of life and functional capacity of patients with lung cancer. Palliat Med 2003 Jul;17(5):410-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12882259.
  21. 21.0 21.1 Candy B, Jones L, Goodman ML, Drake R, Tookman A. Laxatives or methylnaltrexone for the management of constipation in palliative care patients. Cochrane Database Syst Rev 2011 Jan 19;(1):CD003448 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21249653.
  22. Homsi J, Walsh D, Nelson KA, Sarhill N, Rybicki L, Legrand SB, et al. A phase II study of hydrocodone for cough in advanced cancer. Am J Hosp Palliat Care 2002;19(1):49-56 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12171425.
  23. Molassiotis A, Bailey C, Caress A, Brunton L, Smith J. Interventions for cough in cancer. Cochrane Database Syst Rev 2010 Sep 8;(9):CD007881 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20824870.
  24. Tscheikuna J, Chvaychoo B, Naruman C, Maranetra N. Tranexamic acid in patients with hemoptysis. J Med Assoc Thai 2002 Apr;85(4):399-404 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12118485.
  25. Dave, B.R., Sharma, A., Kalva, S.P.,Wicky, S.. Nine-year single-center experience with transcatheter arterial embolization for haemoptysis:medium-term outcomes. Vasc. Endovascular. Surg. 2011;45, 258-268 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21444351.
  26. Wang GR, Ensor JE, Gupta S, Hicks ME, Tam AL. Bronchial artery embolization for the management of hemoptysis in oncology patients: utility and prognostic factors. J Vasc Interv Radiol 2009 Jun;20(6):722-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19406667.
  27. Nicholson AB. Methadone for cancer pain. Cochrane Database Syst Rev 2007 Oct 17;(4):CD003971 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17943808.
  28. Cranston JM, Crockett A, Currow D. Oxygen therapy for dyspnoea in adults. Cochrane Database Syst Rev 2008 Jul 16;(3):CD004769 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18646110.

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Appendices

Further resources

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