Palliative radiotherapy for bone metastases from lung cancer: Evidence-based medicine?

Table 1 Search strategy

Step	String	Results
1	Exp Bone Neoplasms/sc OR Bone Neoplasms/rt OR [(boneCarcinoma/sc OR exp Neoplasm Metastasis/rt) AND exp “Bone and Bones”/] OR [(osseous OR skeletal) ADJ3 metastasis$] OR (bone ADJ3 metastasis$)	26956
2	Exp *Lung Neoplasms/OR exp Lung Neoplasms/pa OR lung cancer.mp	188189
3	Exp Radiotherapy/OR exp Dose Fractionation/OR exp Radiotherapy Dosage/	133052
4	Exp Palliative Care/OR exp Pain/RT OR Pain Management/mt OR (palliative OR palliation).mp OR painful adj3 metastasis$ OR (palliative$ ADJ3 radiotherapy).mp	94404
5	1 AND 2 AND 3 AND 4	88 Limit 10 yr: 28
6	1 AND 3 AND 4 Exclusion criteria: non-lung primary site cancers	608 Limit 10 yr: 256
7	(1 AND 4 AND radiotherapy.mp AND combined modality therapy/OR analgesics/OR treatment outcome/OR quality of life/OR exp Antineoplastic Combined Chemotherapy Protocols) NOT 6	129 Limit 10 yr: 50
8	Total	156

Table 2 Evidence supporting recommended dose-fractionation schedules

Indication	Recommended schedule	Selected references	Level of evidence
Uncomplicated bone metastases (spine, non-spine)		[15]	1
	8Gy/1	[10,32,39,41,60,61]	5
Neuropathic pain	8Gy/1 or 20Gy/5	[38]	1
Impending SCC, RT alone	Multifraction	[41]	5
		[36]	4
Impending pathologic fracture, RT alone	20-40Gy/5-20	[45]	1

RT: Radiotherapy; SCC: Spinal cord compression.

Table 3 Hypothetical cases utilized by previous surveys

Ref.	Case history	Methodology	Responserate
Nakamura et al[46] Case 1 (Japan, 2012)	A 65 yr old man was diagnosed with squamous cell lung cancer one year earlier and was treated by radical surgery. He now has pain in his right shoulder. Radiologic examinations detected osteolytic bone metastasis at the right scapula and multiple lung metastases. ECOG 1	Radiation Oncologist members of JROSG completed an internet-based survey Presumed trainees were excluded Not anonymous	NR
Nakamura et al[46] Case 2 (Japan, 2012)	A 65 yr old man was diagnosed with squamous cell lung cancer one year earlier and was treated by radical surgery. He now has back pain. Radiologic examinations detected osteolytic bone metastasis at L1 and multiple lung metastases. There is no evidence of vertebral collapse or spinal or thecal sac compression. ECOG 1
Nakamura et al[46] Case 3 (Japan, 2012)	Same setting as in case 2 with the addition of paresthesias in a distribution consistent with the L1 dermatome, compatible with neuropathic pain
De Bari et al[47] Case 21 (Italy, 2011)	68yo woman ECOG 1, right lung cancer in 2005, pT2N1M0 underwent lobectomy -> adjuvant chemotherapy. No previous RT. Negative F/U to today. Lumbar pain (L2-L3) underwent bone scan and spinal MRI, total body CT and CT brain. 3 new liver lesions. Bone scan: multiple sites of pathological uptake. MRI: multiple osteolytic spinal metastases including at symptomatic sites. No clinical or radiologic evidence of SCC and no risk of immediate fracture. VAS: 8 without analgesics, 3 after regular weak opioids	Questionnaires given to ROs attending the national congress at the time of registration and collected at the end of the congress Trainees included Anonymous Prespecified list of dose fractionation schedules provided as answer choices, or ‘other’ Factors influencing dose were sought for each case	122/300 (40.6%)3
De Bari et al[47] Case 41 (Italy, 2011)	78yo man ECOG 2, left lung cancer in 2007, pT3NOM0 post left pneumonectomy -> adjuvant chemo x6. Negative f/u until today. Sudden thoracic (D5/D6, D10) and lumbar (L4) pain. No clinical signs of cord compression. No other symptomatic sites. MRI spine: multiple spinal secondary lytic lesions. Radiological signs of D10 spinal cord compression. Risk of pathologic fracture at C3. CT body: multiple liver and lung metastases. VAS: 9 without analgesics, 3 after regular opiods analgesics (transdermal fentanyl 50 ug) and prn nSAIDS
Fairchild et al[9] Case 3 (Intl, 2009)	A 55-year-old male was diagnosed with stage IIIA (T3N2) non-small cell lung cancer one year ago, and was treated radically with chemotherapy and thoracic radiotherapy. He now has pain in the lower back, and a bone scan shows a lesion at L3. His pain localizes to an area consistent with L3, and motor and sensory exams are unremarkable. There is a lytic lesion present and evidence of mild vertebral collapse, but no cauda equina or thecal sac compression on MRI scan	Web-based survey distributed to Radiation Oncologist members of ASTRO, CARO and RANZCR Anonymous Trainees, retirees excluded No prespecified list of dose fractionation schedules provided General factors influencing dose were sought (not case-by-case) Bonferroni used	962/6110 (15.7%)
Fairchild et al[9] Case 4 (Intl, 2009)	Same setting as in case above, with the addition of paresethesias in a distribution consistent with the L3 dermatome, compatible with neuropathic pain
Chow et al[48] Case 2 (Canada, 2000)	A 45 yr old male was diagnosed with stage IIIA (T3N2) large cell carcinoma of the lung one year ago, and was treated with chemotherapy and thoracic irradiation. He now has pain in his lower back, and a bone scan shows a lesion in the third lumbar vertebra. His pain localizes to an area consistent with L3, and does not radiate. Motor and sensory examinations are unremarkable. A CT scan of this area shows a lytic lesion, but no evidence of compression of the cauda equina or thecal sac	Survey mailed to all ROs in active practice in Canada Excluded retirees or those practicing outside of Canada No mention of including trainees Did not specify whether anonymous No prespecified list of dose fractionation schedules provided Factors influencing dose not explored	172/300 (57.3%)
Chow et al[48] Case 3 (Canada, 2000)	Same setting as above, but instead of L3, the lesion is at L1 with no evidence of cord compression. Assume the external beam irradiation to the painful site in L1 would not overlap the previous radiation field
Roos et al[6] Case 3 (Aust/NZ, 2000)	Male, age 63 with disseminated large cell lung cancer and bone scan positive L1-L3, several ribs and skull. There is pain in the upper lumbar spine only and no neurologic dysfunction	Survey distributed to delegates at 1998 Royal ANZ College of Radiologists Annual Scientific Meeting and returned before a presentation on bone pain Anonymous Trainees included Presumed no prespecified list of dose fractionation schedules were provided since cases were designed based on previous surveys Factors influencing dose sought for each case Used Bonferonni correction	53/114 (46.5%)3
Roos et al[6] Case 4 (Aust/NZ, 2000)	Male, age 63 with disseminated large cell lung cancer and bone scan positive L1-L3, several ribs and skull. There is pain in the upper lumbar spine as well as pain and tingling in the right L2 distribution consistent with neuropathic pain
Hartsell et al[49] Case 22 (United States, 1998)	A 45 yr old male was diagnosed with stage IIIA (T3N2) large cell carcinoma of the lung one year ago, and was treated with chemotherapy and thoracic irradiation. He now has pain in his lower back, and a bone scan shows a lesion in the third lumbar vertebra. His pain localizes to an area consistent with L3, and does not radiate. Motor and sensory examinations are unremarkable. A CT scan of this area shows a lytic lesion, but no evidence of compression of the cauda equina or thecal sac	Survey mailed to randomly selected radiation oncologists in United States Factors influencing dose not reported Did not specify whether prespecified list of doses was given Presumed trainees excluded Did not report whether anonymized	229/362 (63.3%)

¹Only surveys containing all the answers for at least 3 of the 4 clinical cases in the wider survey were analyzed;

²Few case details provided in abstract but Chow et al[48] reports using the same case so clinical history is as described by Chow et al;

³Including trainees. NR: Not reported; CT: Computed tomography; MRI: Magnetic resonance imaging; SCC: Spinal cord compression; Intl: International; ECOG: Eastern Cooperative Oncology Group.

Table 4 Grey shading indicates dose-fractionation schedules which would be supported by current evidence

Case	N treating with EBRT	8Gy/1	20Gy/5	30Gy/10	Other	Median (Range)
Uncomplicated-non-spine
Nakamura case 1 (Japan, 2012)	51	13.70%	9.80%	66.70%	9.80%	NR (NR)
Uncomplicated-spine
Hartsell case 2 (United States, 1998)	229	4% recommended < 30Gy		76% recommended 30-35Gy 20% recommended > 35Gy		NR (15Gy/5 – 47.5Gy/25)
Nakamura case 2 (Japan 2012)	51	5.90%	3.90%	78.40%	11.80%	NR (NR)
Chow case 3 (Canada, 2000)	171	15.80%	66.10%	8.80%	9.4%3	NR (8Gy/1 – 30Gy/10)
Chow case 2 (Canada, 2000)	170	15.90%	64.70%	8.20%	11.2%3	NR (8Gy/1 – 30Gy/10)
Fairchild case 3 (Intl, 2009)	867	18.3%2	19.8%2	41.9%2	20.00%	30Gy/10 (3Gy/1 - 55Gy/22)
De Bari case 2 (Italy, 2011)	107€	22.20%	50.10%	26.80%	0.90%	NR (NR)
Roos case 3 (Aust/NZ, 2000)	531€	39.6%€	35.8%€	15.1%€	9.4%€	NR (8Gy/1 - 40Gy/18)
Complicated-neuropathic pain
Nakamura case 3 (Japan, 2012)	52	0%	5.80%	78.80%	15.40%	NR (NR)
Fairchild case 4 (Intl, 2009)	844	6.6%2	29.0%2	42.8%2	21.60%	30Gy/10 (3Gy/1 – 45Gy/18)
Roos case 4 (Aust/NZ, 2000)	531€	13.2%€	52.8%€	24.5%€	9.4%€	NR (8Gy/1 - 40Gy/20)
Complicated-impending spinal cord compression and impending pathologic fracture
De Bari case 4 (Italy, 2011)	113€	30.60%	25.80%	28.20%	15.4%3	NR (NR)

¹41 specialists/12 trainees;

²Takes into account multiple dose fractionation schemes listed per respondent;

³Includes unknown/missing responses; €: Extrapolated from data reported or from figure. EBRT: External beam radiotherapy; Intl: International; NR: Not reported.

Table 5 Factors influencing choice of dose fractionation scheme based on direct questioning of respondents

Case	Most impact	Least impact
Uncomplicated-spine
Nakamura Case 2 (Japan, 2012)	Factors influencing those who chose MF: Time until first increase in pain Incidence of spinal cord compression Incidence of pathologic fracture	NR
De Bari Case 21 (Italy, 2011)	Prognosis Performance status Radiologic appearance of lesions	Financial aspects Personal habits Waiting list
Roos Case 32 (Aust/NZ, 2000)	Factors influencing those who chose SF: Literature results Patient convenience Resource limitations Factors influencing those who chose MF: Minimize chance of recurrent pain Minimize risk of neurologic progression (tie) Optimize tumour regression Patient convenience	NR
Complicated-neuropathic pain
Roos Case 42 (Aust/NZ, 2000)	Factors influencing those who chose SF: Literature results Patient convenience Resource limitations Factors influencing those who chose MF: Minimize risk of neurologic progression Minimize chance of recurrent pain Optimize tumour regression	NR
Complicated – impending spinal cord compression and impending pathologic fracture
De Bari Case 41 (Italy, 2011)	Radiologic appearance of lesions Site of metastasis Prognosis	Financial aspects Personal habits (tie) Waiting list
Overall
Fairchild (Intl, 2009)	Prognosis Risk of spinal cord compression Performance status Previous RT Published evidence	Departmental policy Waiting list Future retreatment Age Late toxicity

¹Literature results were not one of the prespecified options;

²Includes specialist and trainee responses. Intl: International; MF: Multiple fractions; NR: Not reported; SF: Single fractions.

Table 6 Statistical predictors of use of single fraction schedules

Case	Factor	OR for use of SF (95%CI)	P
Uncomplicated-spine
Hartsell Case 2 (1998, United States)	Respondents recommending doses < 30Gy:	NR	NR
	Longer time in practice
	Academic practice
	Practice in the Southwest
Chow Case 2 (Canada, 2000) Chow Case 3 (Canada, 2000)	No differences based on country of specialty training or year training completed	NR	NR
Fairchild Case 3	University practice	2.08 (1.35-3.19)	0.001
(Intl, 2009)	Private practice	0.27 (0.12-0.61)	0.002
	Trained in United States	0.17 (0.10-0.28)	< 0.001
	Practice in Aust/NZ	2.44 (1.43-4.18)	0.001
Roos Case 3 (Aust/NZ, 2000)	No difference based on trainees vs specialists, public vs private practice, years of experience, % workload palliative, between Aust vs NZ or between Aust states	NR	NR
Complicated-neuropathic pain
Fairchild Case 4	University practice	2.31 (1.33-4.00)	0.003
(Intl, 2009)	Trained in US	0.22 (0.11-0.43)	< 0.001
Roos Case 4 (Aust/NZ, 2000)	No difference based on trainees vs specialists, public vs private practice, years of experience, % workload palliative, between Aust vs NZ or between Aust states	NR	NR

Aust: Australia; Intl: International; NR: Not reported; NZ: New Zealand.

Table 7 Reasons for reticence in use of single fractions

Factor	Ref.
Patient-related
Neuropathic pain	[6]
Prevent or address neurologic symptoms	[46]
Maximize time to first increase in pain	[6]
Patient selection	[7]
Prognosis	[7]
Patient wishes	[7]
Fear of toxicity (acute/late)	[6]
Site of bone metastasis	[9]
Comorbidities	[9]
Physician-related
Influence of global opinion leaders	[52]
Presumed dose-response	[7]
Professional membership affiliation	[9]
Country of training	[9]
Country of practice	[9]
Lack of experience with large fraction sizes	[9]
Lack of participation in related trials	[6]
Disbelief of early trial results due to quality	[48]
Institution-related
Departmental policy	[9]
Longer wait times for RT delivery	[62]
Type of centre	[9]
Health care system-related
Retreatment more often required	[35]
Increased costs due to retreatment	[14]
Reimbursement system	[24]