Annals of Oncology

Association of performance status and pain in metastatic

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bone pain management in the Spanish clinical setting
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Journal: Annals of Oncology

Manuscript ID: ANNONC-2015-0503

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Manuscript Type: Original Article

Date Submitted by the Author: 30-Mar-2015

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Complete List of Authors: Dómine, Manuel; Fundación Jimenez Díaz, Medical Oncology
Diaz, Nieves; Hospital San Juan de Alicante, Medical Oncology
Cantos, Blanca; University Hospital Puerta de Hierro, Medical Oncology
Zugazabeitia, Luis; Hospital de Povisa, Radiation Oncology
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Martínez, Joaquina; Clínica Nuestra Sra de Belén, Medical Oncology

Poza de Celis, Raul; HOSPITAL TXAGORRITXU, 6. Radiation Oncology
Department
TRUJILLO VILCHEZ, RAFAEL; XANIT HOSPITAL INTERNACIONAL, 7. Medical
Oncology Department
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Pelaez, Ignacio; Hospital de Cabueñes, medical Oncology

CAPDEVILA CASTILLÓN, JAUME; Hospital de la Vall D´Hebrón, Medical
Oncology Department
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Traseria, Susana; MUNDIPHARMA PHARMACEUTICALS, medical department

Gonzalez, Emilio; Hospital Central de Asturias, Oncologiia Medica

Keywords: Pain, ECOG, metastasis, cancer, bone

Background
We studied the association of pain management in bone metastatic
oncologic patients and their performance status in the Spanish clinical
setting.
Patients and methods
A 3-month follow-up prospective, epidemiologic, multicenter study was
conducted with 579 patients to assess the evolution of their performance,
Abstract: the impact of pain control on sleep and functionality, and the degree of
pain control according to analgesic treatment.
Results
ECOG (1.5 ±0.7 to 1.3 ±0.7 and 1.3 ±0.8; p<0.001) and pain (6.5 ±1.4 to
2.8 ±1.9 and 2.1 ±1.9; p<0.001) improved significantly from baseline to
months 1 and 3, as did functionality and sleep, after a treatment change
consisting in increasing the administration of opioids. Evolution of ECOG
and pain were closely related. ECOG and pain outcomes were significantly
Page 1 of 44 Annals of Oncology

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4 more favorable in patients treated with opioids vs. non-opioid treatment,
and in patients who did not need rescue medication vs. those who did.
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Conclusions
6 Metastatic bone pain (MBP) is currently poorly managed in Spain. ECOG
7 improvement is closely and directly related to pain management in MBP.
8 Opioid treatment and no need for rescue medication are associated with
9 better ECOG and pain outcomes in MBP patients.
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 Annals of Oncology Page 2 of 44

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6 1 Original article:
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8 2 Association of performance status and pain in metastatic bone
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3 pain management in the Spanish clinical setting
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5 M. Dómine Gómez1, N. Díaz Fernández2, B. Cantos Sánchez de Ibargüen3, L.
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6 Zugazabeitia Olabarría4, J. Martínez Lozano5, R. Poza de Celis6, R. Trujillo
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7 Vílchez7, I. Peláez Fernández8, J. Capdevila9, S. Traseira10, E. Esteban11
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9 1. Medical Oncology Department, Fundación Jiménez Díaz, Madrid, Spain
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10 2. Medical Oncology Department, Hospital San Juan de Alicante, Alicante,
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11 Spain
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12 3. Medical Oncology Department, Hospital Puerta de Hierro de
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13 Majadahonda, Madrid, Spain
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14 4. Radiation Oncology Department, Hospital de Povisa, Vigo, Spain
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15 5. Medical Oncology Department, Clínica Nuestra Señora de Belén, Murcia,
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16 Spain
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17 6. Radiation Oncology Department, Hospital Txagorritu, Vitoria-Gasteiz,
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18 Spain
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19 7. Medical Oncology Department, Clínica Santa Elena, Torremolinos, Spain
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20 8. Medical Oncology Department, Hospital de Cabueñes, Gijón, Spain
28 21 9. Medical Oncology Department, Hospital de la Vall D´Hebrón, Barcelona,
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22 Spain
30 23 10. Medical Department, Mundipharma Pharmaceuticals S.L., Madrid, Spain
31 24 11. Medical Oncology Department, Hospital Universitario Central de
32 25 Asturias, Oviedo, Spain
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35 27 Corresponding author:
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28 Dr. Manuel Dómine Gómez

38 29 Medical Oncology Department, Fundación Jiménez Díaz.
39 30 Avda de los Reyes Católicos, 2
40 31 28040 Madrid (Spain)
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32 Tel: 915504800
42 33 FAX: 915443625
43 34 e-mail: mdomine@fjd.es
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46 36 Abbreviations: MBP: Metastatic bone pain, RT: radiation therapy, NP:
47 37 neuropathic pain, PS: performance status
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Page 3 of 44 Annals of Oncology

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6 39 SUMMARY
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8 40 Background
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10 41 We studied the association of pain management in bone metastatic oncologic
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12 42 patients and their performance status in the Spanish clinical setting.
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14 43 Patients and methods
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16 44 A 3-month follow-up prospective, epidemiologic, multicenter study was
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18 45 conducted with 579 patients to assess the evolution of their performance, the
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20 46 impact of pain control on sleep and functionality, and the degree of pain control
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22 47 according to analgesic treatment.
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24 48 Results
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26 49 ECOG (1.5 ±0.7 to 1.3 ±0.7 and 1.3 ±0.8; p<0.001) and pain (6.5 ±1.4 to 2.8
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28 50 ±1.9 and 2.1 ±1.9; p<0.001) improved significantly from baseline to months 1
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30 51 and 3, as did functionality and sleep, after a treatment change consisting in

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32 52 increasing the administration of opioids. Evolution of ECOG and pain were
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34 53 closely related. ECOG and pain outcomes were significantly more favorable in
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36 54 patients treated with opioids vs. non-opioid treatment, and in patients who did
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38 55 not need rescue medication vs. those who did.

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40 56 Conclusions
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42 57 Metastatic bone pain (MBP) is currently poorly managed in Spain. ECOG

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44 58 improvement is closely and directly related to pain management in MBP. Opioid
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46 59 treatment and no need for rescue medication are associated with better ECOG
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48 60 and pain outcomes in MBP patients.
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50 61 Keywords: Pain, ECOG, cancer, bone, metastasis
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6 63 INTRODUCTION
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8 64 Bone metastasis is the most common cause of cancer-related pain [1, 2], and
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10 65 metastatic bone pain (MBP) is not only severe but also progressive in many
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12 66 patients [3]. As the tumor grows and tumor-induced bone remodeling
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14 67 progresses, skeletal-related events (SREs) occur. These include not only pain
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16 68 and “breakthrough pain” but also hypercalcemia, anemia, skeletal fractures,
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18 69 compression of the spinal cord, and decreased mobility and activity [4], all of
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20 70 which compromise the patient’s functional status, quality of life, and survival [5].
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22 71 Furthermore, chronic pain is frequently associated with anxiety, depression and
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24 72 sleep disorders [6]. All these comorbidities have a negative impact on response
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26 73 to analgesic treatment, which in turn contributes to loss of quality of life. Hence,
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28 74 pain treatment is crucial for these patients [7].
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30 75 Since MBP responds poorly to non-steroidal anti-inflammatory drugs (NSAIDs),

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32 76 the WHO therapeutic guidelines for cancer pain recommend opioids [8]. These
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34 77 include drugs such as oxycodone, which is effective for pain relief in patients
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36 78 with bone metastases [3] and has a specific effect on neuropathic pain (NP) [9],
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38 79 a frequent complication in vertebrae metastases [3]. Other therapies are

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40 80 currently used for MBP: surgical therapy [3], palliative radiation therapy (RT),
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42 81 and radiopharmaceuticals [10, 11]; bisphosphonates, which delay the onset and
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44 82 reduce the risk of SREs in patients with bone metastases [12]; denosumab,
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46 83 which is a fully monoclonal antibody recently approved for the prevention of
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48 84 SREs [13]; and rescue medication, i.e., supplemental analgesia for
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50 85 “breakthrough pain” [14].
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52 86 We studied the association of pain management with evolution of overall status
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54 87 (ECOG) in cancer patients with bone metastases, plus the degree of pain
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6 88 control according to analgesic treatment, to determine the quality of MBP
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8 89 management in the Spanish clinical setting.
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10 90 METHODS
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14 92 Study design
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16 93
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18 94 This was a 3-month follow-up, observational, prospective, Spanish multicentre
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20 95 study performed in accordance with the revised Declaration of Helsinki. The
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22 96 protocol was approved by the ethics committee, and patients provided informed
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24 97 consent before inclusion in the study.
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26 98 The primary endpoint was to assess the correlation between pain relief and
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28 99 performance status (PS) of oncologic patients with bone metastases.
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30 100 Secondary endpoints were to assess pain control on sleep quality, functionality,
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32 101 as well as pain relief depending on the type of treatment.
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34 102 Eligible patients were ≥ 18 years old diagnosed with cancer with bone
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36 103 metastases, life expectancy ≥ 3 months and pain intensity ≥ 4 on a numerical
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38 104 rating scale (NRS). Patients were excluded if they were scheduled for palliative
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40 105 surgery or the investigator considered them to have insufficient cognitive
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42 106 capacity to understand the study.

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44 107
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46 108 Outcome measures
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48 109
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50 110 Basic demographic variables were collected at baseline, along with clinical
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52 111 variables. Patient-reported outcomes were collected at baseline and at months
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54 112 1 and 3 during the study follow-up, including pain severity and pain control on
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6 113 sleep and functionality recorded on a 0-10 NRS. PS was evaluated at baseline
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8 114 and at months 1 and 3, and rated according the Eastern Cooperative Oncology
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10 115 Group (ECOG) scale.
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12 116
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14 117 Statistical analysis
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16 118
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18 119 Statistically significant differences for ECOG, pain, functionality and sleep
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20 120 between baseline and months 1 and 3 were determined using the Wilcoxon
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22 121 signed-rank test. The influence of pain management on ECOG during follow-up
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24 122 was assessed using the Spearman correlation, Kruskal Wallis test and the Chi 2
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26 123 test.
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28 124
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32 126 RESULTS
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36 128 Evolution of ECOG, pain, functionality and sleep
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40 130 Baseline demographics and disease characteristics are shown in Table I. PS,
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42 131 pain, functionality and sleep improved significantly over the study (Table II).
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44 132 ECOG evolution, measured by the change in PS score and by the proportion of
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46 133 patients with better/stable/worse ECOG over baseline, was compared to pain
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48 134 evolution, which was measured by 5 pain parameters (degree of change;
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50 135 patients with improved/stable/worsened pain; those with ≥ 20% of pain
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52 136 improvement; those with ≥ 50% of pain improvement; and those ending with
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54 137 NRS ≤3). Tests results were significant (p< 0.001), and data indicated that pain
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6 138 and ECOG outcomes were closely and directly related. All patients with ECOG
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8 139 improvement over baseline also had a better evaluation of pain; most patients
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10 140 with stable ECOG also showed stable pain(75%), and most patients with worse
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12 141 ECOG over baseline also showed worse pain (77%) (data not shown).
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14 142 Treatments
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16 143 As shown in Table II, 7 different treatment modalities were used during the
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18 144 study. Chemotherapy was indicated in 68% of patients: as first line in nearly half
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20 145 of these (43.4%), second line in 20.4%, and third or more in 18%. Most
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22 146 common therapies used were vinorelbine (11.7%), cisplatin (11.7%), carboplatin
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24 147 (11.4%), gemcitabine (10.7%) and taxotere (10.4%) (data not shown).
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26 148 Mean doses of the 4 most frequent opioids used were: fentanyl 56.6 mg every 3
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28 149 days; tramadol 101.7 mg every 8 or 12 h; oxycodone 22.1 mg every 12 h and
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30 150 morphine 46 mg every 12 h.

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32 151 Bisphosphonates, almost exclusively zolendronic acid (96.7%), were taken by
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34 152 51.7% of patients. Palliative radiotherapy to alleviate pain was given to 20.9%,
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36 153 with the spinal column being the most frequent application area (56.2%),
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38 154 followed by pelvis (30.6%) and femur (10.7%). Mean dose was 71.1 Gy (median
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40 155 30 Gy), with 10x300 cGy in 57.9% of cases (data not shown). Finally, surgery
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42 156 and non-pharmacological treatment were considered for 4.1% and 0.7% of
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44 157 patients, respectively.
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46 158
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48 159 Change in treatment during follow-up
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50 160 Chemotherapy and bisphosphonates remained stable over the study, and had
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52 161 no effect on ECOG and pain (p=0.801 and p=0.172; and p=0.462 and p=0470,
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54 162 respectively); however, there was an increase in palliative RT at baseline and a
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6 163 decrease at the following months, with no effect on ECOG or pain (p=0.321 and
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8 164 p=0.715) (Table II). Non-opioids or coadjuvant administration decreased over
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10 165 the study, while opioids almost doubled at baseline and remained at the same
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12 166 high levels thereafter. Mean doses of fentanyl and oxycodone increased slightly
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14 167 from 56 to 62 mg and 22 to 25 mg, respectively. Rescue treatment was
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16 168 prescribed in 71.4% of patients at baseline (immediate release (IR) oxycodone
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18 169 capsules 60.4%, IR oxycodone solution 11.7%, morphine 13.8%, fentanyl 7.5%,
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20 170 and others 6.6%) and in 66.2% at month 1, in similar proportions. Laxatives and
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22 171 antiemetics were prescribed in 71.5% and 54.7% of patients, respectively, at
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24 172 baseline and in 71.8% and 44.4%, respectively, at month 1 (data not shown).
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26 173 Treatment at month 3 basically replicated month 1 treatments.
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28 174 Treatment compliance was high at 1- and 3-month visits. At month 1, 76.5% of
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30 175 patients complied with RT, 92.6% with CT, 86.8% with bisphosphonates, and
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32 176 95.3% with analgesic medication. At month 3, percentages were: RT 79.5%, CT
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34 177 86.5%, bisphosphonates 79.9% and analgesic medication 93.2%. Rescue
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36 178 medication was taken by 44.4% of patients at month 1 (mainly oxycodone
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38 179 [66.8%] or morphine [16%]), and by a significantly smaller proportion of patients

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40 180 at month 3 (35%; p=0.001).
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42 181 Regarding adverse events (AE) to analgesic treatment: 37 (6.4%) patients

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44 182 experienced some baseline AEs; 53 (9.8%) patients at month 1, and 44 (9.3%)
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46 183 patients at month 3. The most frequent AEs, for the first and third months, were
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48 184 constipation (27.4% and 36.5%), nausea (23.8% and 19.5%), and somnolence
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50 185 (12.3% and 14.6%), respectively (Supplementary Figure 1). There were no
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52 186 grade 4 adverse events, six 6 were grade 3 (15.8 %), with opioids AEs being
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54 187 the most common.
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6 188
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8 189 ECOG evolution according to treatment
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10 190 Patients treated with a specific analgesic treatment (prescribed at baseline and
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12 191 with confirmed compliance at the specific time point analyzed) were compared
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14 192 with those who did not receive it in terms of ECOG. At both time points, patients
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16 193 treated with opioids showed significantly more favorable ECOG outcomes than
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18 194 those who did not (p<0.001). Similarly, patients who did not need rescue
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20 195 medication showed more favorable ECOG outcomes than those who did
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22 196 (p<0.001; Table III).
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26 198 Pain evolution according to treatment
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28 199 The pain parameters of patients treated with a specific analgesic treatment
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30 200 (prescribed at baseline and with confirmed compliance at the specific analyzed
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32 201 time point) were compared with those that did not. Opioids and rescue
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34 202 medication showed significant differences depending on whether they were
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36 203 used or not. Since opioids seemed to have an effect on pain evolution, the 2
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38 204 most commonly used (oxycodone and fentanyl) were analyzed specifically
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40 205 (Table IV).
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42 206 At month 1 there was a significant difference in pain between patients taking
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44 207 and not taking opioids. Similarly, there were significant differences in all pain
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46 208 parameters in favor of patients not taking rescue medication. Mean decrease in
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48 209 pain (-3.9 vs. -3.2; p=0.003) and the proportion of patients with ≥ 50%
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50 210 improvement in pain (72.9% vs. 59.3%; p=0.007) were significantly larger in
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52 211 patients taking oxycodone than in those taking other opioids. The proportion of
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54 212 patients with ≥ 50% improvement in pain was significantly lower in patients
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6 213 taking fentanyl than in those taking other opioids (59.1% vs. 71.5%; p=0.041)
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8 214 (data not shown). After 3 months, mean reduction in pain was significantly
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10 215 greater in patients treated with opioids (-4.4 vs. -3.6; p=0.014). Mean decrease
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12 216 in pain, and the proportion of patients with ≥ 20% improvement, ≥ 50%
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14 217 improvement, and those ending with NRS ≤ 3 were significantly in favor of
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16 218 patients not taking rescue medication. Mean decrease in pain (-4.7 vs. -3.6;
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18 219 p < 0.001) and the proportion of patients with ≥ 50% improvement (84.6% vs.
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20 220 71.3%; p=0.002) were significantly larger in patients taking oxycodone than in
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22 221 those taking other opioids. In terms of fentanyl, 83% of patients taking this drug
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24 222 decreased pain by ≥ 20%, and 66% by ≥ 50% vs. 93.2% (p=0.015) and 83.1%
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26 223 (p= 0.005) of patients taking other opioids (Table IV).
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28 224 DISCUSSION
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30 225 Good management of bone metastases has been shown to considerably relieve
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32 226 pain [7]. However, although baseline pain values in this study (mean NRS=6.5)
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34 227 were moderate-severe, and up to 43.5% of patients suffered from NP, which is
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36 228 difficult to treat [15], only 59% of patients were being treated with opioids. The
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38 229 WHO analgesic ladder recommends administration of a minor opioid in the

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40 230 second step (for moderate pain) and a major opioid in the third step (for severe
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42 231 pain).
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44 232 During the study, the percentage of patients treated with chemotherapy and
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46 233 bisphosphonates hardly varied, whereas palliative RT and non-opioids or
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48 234 coadjuvants decreased from baseline to follow-up visits. The percentage of
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50 235 patients treated with opioids almost doubled compared with previous
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52 236 treatments, baseline, and follow-up. Opioids have been successfully used for
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54 237 NP since the early 90s [16], with oxycodone specifically being reported as a
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6 238 beneficial drug in benign NP, and as efficacious as morphine in treating
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8 239 oncologic pain [9].
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10 240 Significant improvements in pain, sleep and functionality found during the first
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12 241 month were similar to another Spanish oncologic NP study [17]. In that study,
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14 242 88% of patients were treated with oxycodone, and pharmacologic cancer pain
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16 243 treatment had a greater effect in patients with metastases than in those with no
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18 244 metastases, evidencing its importance in metastatic cancer pain. Analgesic
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20 245 treatment response depended on the specific treatment used, with patients on
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22 246 oxycodone or other opioids showing a greater improvement in pain than
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24 247 patients on treatment other than opioids.
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26 248 In addition to PS being dependent on patient’s overall response, our results
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28 249 show that ECOG improvement is closely related to pain. The response to
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30 250 analgesic treatment for palliation of MBP has been found to be significantly
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32 251 related to PS [18] . Furthermore, the association between pain and PS seems to
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34 252 be reciprocal, since patients with poor PS (ECOG ≥ 2), among other variables,
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36 253 are more likely to have SREs, including pain [19]. The change from previous
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38 254 treatment consisted in a decrease in non-opioids or coadjuvants and a two-fold

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40 255 increase in opioids, due to oxycodone increase (6-fold). Therefore, pain and
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42 256 ECOG improvements observed at months 1 and 3 seem to be the result of the
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44 257 increase in opioid administration. Although RT treatment increased at baseline,
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46 258 it decreased subsequently, and hence would not explain the improvement
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48 259 observed during the follow-up period. Furthermore, statistical analyses were not
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50 260 significant. One limitation of our study is the large difference in sample sizes
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52 261 among specific opioid drugs (452 patients received oxycodone, 75 patients
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54 262 received fentanyl) which prevented reliable statistical comparisons. Although no
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6 263 differences were observed between oxycodone and the rest of opioids for
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8 264 ECOG, significant differences were observed in pain outcomes. Thus, decrease
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10 265 in pain was significantly greater in patients taking oxycodone, while the
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12 266 proportion of patients with a ≥ 50% improvement in pain was significantly larger
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14 267 in patients taking oxycodone, and significantly smaller in those taking fentanyl.
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16 268 This suggests that in patients with MBP, oxycodone, specifically, might improve
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18 269 pain more than other opioids.
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20 270 In conclusion, management of MBP in Spain is currently poor. In fact, pain,
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22 271 sleep, functionality and ECOG improvements were achieved after changing
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24 272 treatment to a wider range of opioids. Pain and ECOG outcomes are directly
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26 273 related. Opioid treatment seems to have a favorable effect on ECOG and pain
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28 274 evolution in patients with MBP, while the opposite is true of the need for rescue
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30 275 treatment.
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6 279 Acknowledgements
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8 280 We would like to thank the following investigators that participated in the BMP
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10 281 (Bone Metastatic Pain) Study: Eva María Ciruelos, H. 12 de Octubre, Madrid;
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12 282 Mónica Corral, H. Alcañiz, Alcañiz; Purificación Martínez del Prado, H. Basurto,
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14 283 Bilbao; Francisco J. Carabantes, H. Carlos Haya, Málaga; Manuel Cobo, H. Carlos
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16 284 Haya, Málaga; Luis Olay, H. Central de Asturias, Oviedo; Diego Soto, H. Clínico de
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18 285 Valladolid, Valladolid; Isabel Blancas, H. Clínico Granada, Granada; Javier Puente, H.
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20 286 Clínico San Carlos, Madrid; José Miguel, H. Clínico San Cecilio, Granada; Dolores
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22 287 Isla, H. Clínico Zaragoza, Zaragoza; Julio José Lambea, H. Clínico Zaragoza, Zaragoza;
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24 288 Yolanda López, C. A. de Zamora, Zamora; Irma Muruzabal, H. de Cruces, Barakaldo;
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26 289 José Miguel Martín, H. de Getafe, Getafe; Salvador Garcerá, H. de la Ribera, Alzira;
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28 290 Natalia Lupión, H. de Mérida, Mérida; Enrique Martínez, H. de Navarra, Pamplona;
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30 291 Núria Calvo, H. de Sant Pau, Barcelona; Sonia Maciá, H. Elda, Alicante; Ana Blasco,
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32 292 H. General de Valencia, Valencia; José María García, H. General de Albacete,
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34 293 Albacete; Enric Carcereny, H. Germans Trias I Pujol, Badalona; Esperanza Blanco, H.
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36 294 Infanta Cristina, Badajoz; Ana Belén Custodio, H. la Paz, Madrid; Juan Bayo, Clin. los
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38 295 Naranjos, Huelva; Carmen Velilla, H. Lozano Blesa, Zaragoza; Almudena García, H.
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40 296 Marqués de Valdecilla, Santander; Miguel Méndez, H. Móstoles, Móstoles; Román
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42 297 Bastus, H. Mutua de Terrassa, Terrassa; Ana María Tortorella, H. Naval, Murcia;
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44 298 Yolanda García, C. Parc Taulí, Sabadell; José María Puerto, H. Perpetuo Socorro,
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46 299 Badajoz; Cristina López, H. Povisa, Vigo; Fátima Navarro, H. Príncipe de Asturias,
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48 300 Alcalá de Henares; Javier Munárriz, H. Provincial Castellón, Castellón; Ramón de las
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50 301 Peñas, H. Provincial Castellón, Castellón; Miguel Ruiz, H. Punta de Europa, Algeciras;
51
52 302 María Fernández, H. Ramón y Cajal, Madrid; Laura Murillo, H. Reina Sofía, Tudela;
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54 303 Isabel Palomo, H. Río Hortega, Valladolid; Christian Rolfo, Clin. Rotger, Palma de
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6 304 Mallorca; Antonia Perello, H. Son Dureta, Palma de Mallorca; Aránzazu González del
7
8 305 Alba, H. Son Dureta, Palma de Mallorca; José Manuel Pérez, H. Vall d'Hebron,
9
10 306 Barcelona; Miguel Marín, H. Virgen de la Arrixaca, Murcia; Javier Medina, H. Virgen
11
12 307 de la Salud, Toledo; Ruth Álvarez, H. Virgen de la Salud, Toledo; Francisco de Asís, H.
13
14 308 Virgen de los Lirios, Alcoy; David Vicente, H. Virgen Macarena, Sevilla; Manuel
15
16 309 Codes, H. Virgen Macarena, Sevilla; Guillermo Quintero, C. Xeral-Calde, Lugo; Sergio
17
18 310 Vázquez, C. Xeral-Calde, Lugo; Silvia Antolín, CHUAC, A Coruña; Rafael López,
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20 311 CHUS, Santiago; Bernardo Queralt, ICO-Girona, Girona.
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22 312
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24 313 We would also like to thank Mayte Martín Fuentes from Mundipharma
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26 314 Pharmaceuticals S.L. for managing the study, and Almudena Pardo and Luis
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28 315 Santamaria for helping in the medical writing of the manuscript.
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30 316
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32 317 Funding
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34 318 This work was sponsored by Mundipharma Pharmaceuticals S.L.
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36 319
37 320 Disclosure
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38 321
39 322 Susana Traseira is a Medical Director at Mundipharma Pharmaceuticals S.L,
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41 323 sponsor of this study. All remaining authors have declared no conflicts of
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43 324 interest.
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6 329
7 330 FIGURE LEGENDS
8 331
9 332
10 333 Supplementary Figure 1. Adverse events in analgesic treatment at
11 334 different study time points
12 335
13 336
14 337
15 338
16 339
17 340
18 341 REFERENCES
19 342
20 343 1. Cleeland CS, Gonin R, Hatfield AK et al. Pain and its treatment in
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21 344 outpatients with metastatic cancer. N Engl J Med 1994; 330: 592-596.
22 345 2. Caraceni A, Portenoy RK. An international survey of cancer pain
23 346 characteristics and syndromes. IASP Task Force on Cancer Pain. International
24 347 Association for the Study of Pain. Pain 1999; 82: 263-274.
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25 348 3. Hara S. Opioids for metastatic bone pain. Oncology 2008; 74 Suppl 1: 52-
26 349 54.
27 350 4. Ford JA, Mowatt G, Jones R. Assessing pharmacological interventions for
28 351 bone metastases: the need for more patient-centered outcomes. Expert Rev Clin
29 352 Pharmacol 2012; 5: 271-279.
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30 353 5. Jimenez-Andrade JM, Mantyh WG, Bloom AP et al. Bone cancer pain. Ann
31 354 N Y Acad Sci 2010; 1198: 173-181.
32 355 6. Castro MM, Daltro C. Sleep patterns and symptoms of anxiety and
356 depression in patients with chronic pain. Arq Neuropsiquiatr 2009; 67: 25-28.
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34 357 7. Vassiliou V, Kardamakis D. The management of metastatic bone disease
35 358 with the combination of bisphosphonates and radiotherapy: from theory to clinical
36 359 practice. Anticancer Agents Med Chem 2009; 9: 326-335.
37 360 8. Raphael J, Ahmedzai S, Hester J et al. Cancer pain: part 1:
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38 361 Pathophysiology; oncological, pharmacological, and psychological treatments: a

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362 perspective from the British Pain Society endorsed by the UK Association of
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363 Palliative Medicine and the Royal College of General Practitioners. Pain Med
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365 9. Nunez Olarte JM. Oxycodone and the challenge of neuropathic cancer pain:
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366 a review. Oncology 2008; 74 Suppl 1: 83-90.
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367 10. Chow E. Update on radiation treatment for cancer pain. Curr Opin
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368 Support Palliat Care 2007; 1: 11-15.
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369 11. Fairchild A, Chow E. Role of radiation therapy and radiopharmaceuticals
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370 in bone metastases. Curr Opin Support Palliat Care 2007; 1: 169-173.
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371 12. Jansen DR, Krijger GC, Kolar ZI et al. Targeted radiotherapy of bone
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372 malignancies. Curr Drug Discov Technol 2010; 7: 233-246.
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373 13. Iranikhah M, Wilborn TW, Wensel TM, Ferrell JB. Denosumab for the
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374 prevention of skeletal-related events in patients with bone metastasis from solid
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375 tumor. Pharmacotherapy 2012; 32: 274-284.
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376 14. Zeppetella G. Impact and management of breakthrough pain in cancer.
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377 Curr Opin Support Palliat Care 2009; 3: 1-6.
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6 378 15. Stacey BR. Management of peripheral neuropathic pain. Am J Phys Med
7 379 Rehabil 2005; 84: S4-16.
8 380 16. Mercadante S, Gebbia V, David F et al. Tools for identifying cancer pain of Formatted: Spanish (International Sort)

9 381 predominantly neuropathic origin and opioid responsiveness in cancer patients. J Formatted: Spanish (International Sort)
10 382 Pain 2009; 10: 594-600.
11 383 17. Garcia de Paredes ML, del Moral Gonzalez F, Martinez del Prado P et al.
12 384 First evidence of oncologic neuropathic pain prevalence after screening 8615
13 385 cancer patients. Results of the On study. Ann Oncol 2011; 22: 924-930.
14 386 18. Campos S, Presutti R, Zhang L et al. Elderly patients with painful bone
15 387 metastases should be offered palliative radiotherapy. Int J Radiat Oncol Biol Phys
16 388 2010; 76: 1500-1506.
17 389 19. Sun JM, Ahn JS, Lee S et al. Predictors of skeletal-related events in non-
18 390 small cell lung cancer patients with bone metastases. Lung Cancer 2011; 71: 89-93.
19 391
20 392
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6 1 Original article: Formatted: Numbering: Continuous
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9 2 Association of performance status and pain in metastatic bone
10 3 pain (MBP) management in the Spanish clinical setting
11 4
12 5 M. Dómine Gómez1, N. Díaz Fernández2, B. Cantos Sánchez de Ibargüen3, L.
13 6 Zugazabeitia Olabarría4, J. Martínez Lozano5, R. Poza de Celis6, R. Trujillo
14 7 Vílchez7, I. Peláez Fernández8, J. Capdevila Castillón9, S. Traseira10, E.
15 8 Esteban11
16 9
17
18 10 1. Fundación Jiménez Díaz. Medical Oncology Department. , Fundación
11 Jiménez Díaz,. Madrid, Spain
Fo
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20 12 2. Hospital San Juan de Alicante. Medical Oncology Department,. Hospital
13 San Juan de Alicante., Alicante, Spain
21
14 3. Medical Oncology Department, Hospital Puerta de Hierro de Formatted: Spanish (International Sort)
22
15 Majadahonda,. Medical Oncology Department. Madrid, Spain
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Formatted: Spanish (International Sort)
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16 4. Radiation Oncology Department, Hospital de Povisa,. Radiation
24
17 Oncology Department. Vigo, Spain
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18 5. Medical Oncology Department, Clínica Nuestra Señora de Belén,
26
19 Medical Oncology Department. Murcia, Spain Formatted: Spanish (International Sort)
27 20 6. Radiation Oncology Department, Hospital Txagorritu, Radiation
28 21 Oncology Department, Vitoria-Gasteiz, Spain
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29 22 7. Medical Oncology Department, Clínica Santa Elena, , Medical Oncology

30 23 Department, Torremolinos, Spain
31 24 8. Medical Oncology Department, Hospital de Cabueñes, Medical Oncology
32 25 Department. Gijón, Spain
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33 26 9. Medical Oncology Department, Hospital de la Vall D´Hebrón, Medical

34 27 Oncology Department, Barcelona, Spain
35 28 10. Medical Department, Mundipharma Pharmaceuticals S.L., Medical
36 29 Department, Madrid, Spain
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37 30 11. Medical Oncology Department, Hospital Universitario Central de

38 31 Asturias, Medical Oncology Department. Oviedo, Spain
39 32
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41 33 Corresponding author:
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43 34 Dr. Manuel Dómine Gómez
44 35 Medical Oncology Department, Fundación Jiménez Díaz. Medical Oncology
45 36 Department
46 37 Avda de los Reyes Católicos, 2
47 38 28040 Madrid (Spain)
48 39 Tel: 915504800
49 40 FAX: 915443625
50 41 e-mail: mdomine@fjd.es Field Code Changed
51 42
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53 43 Abbreviations: MBP: Metastatic bone pain, RT: radiation therapy, NP:
54 44 neuropathic pain, PS: performance status
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6 46 SUMMARY
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8 47 Background
9
10 48 We studied the association of pain management in bone metastatic oncologic
11
12 49 patients with and their performance status, plus the degree of pain control
13
14 50 according to analgesic treatment in the Spanish clinical setting.
15
16 51 Patients and methods
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18 52 A 3-month follow-up prospective, epidemiologic, multicenter study was carried
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20 53 conducted with 579 patients to assess the evolution of their performance status,
21
22 54 the impact of pain control on sleep and functionality, and the degree of pain
r
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24 55 control according to analgesic treatment.
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26 56 Results
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28 57 ECOG (1.5 ±0.7 to 1.3 ±0.7 and 1.3 ±0.8; p<0.001) and pain (6.5 ±1.4 to 2.8 Formatted: Font: Italic
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30 58 ±1.9 and 2.1 ±1.9; p<0.001) improved significantly from baseline to 1 and 3 Formatted: Font: Italic

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32 59 months 1 and 3, and as so did functionality and sleep, after a treatment change
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34 60 consisting in increasing the administration of opioids. Evolution of ECOG and
35
36 61 pain were closely related. ECOG and pain outcomes were significantly more
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62 favorable to in patients treated with opioids vs. non-opioid treatment, and to in
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63 patients who did not need rescue medication vs. those who did.
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64 Conclusions
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43
65 Metastatic bone pain (MBP) in Spain is currently not properlypoorly managed in
44
45 66 Spain. ECOG improvement is closely and directly related to pain management
46
47 67 in MBP. Opioid treatment and not need foring rescue medication are associated
48
49 68 to with better ECOG and pain outcomes in MBP patients.
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51 69 Keywords: Pain, ECOG, cancer, bone, metastasis
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53 70
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6 71 INTRODUCTION
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8 72
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10 73 Metastatic cancer spreads most frequently to the bone[1, 2], with vertebrae
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12 74 being the most frequent site [1], followed by pelvis and ribs [2]. Breast, prostate,
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14 75 thyroid, lung, and kidney primary tumors are the most frequent tumors
15
16 76 spreading to the bone [1,3].
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18 77
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20 78 Although Bbone metastasis does not always cause pain, it is the most common
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22 79 cause of cancer-related pain [3, 4] [4], being and involved in 40% of cancer pain Field Code Changed
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23 Field Code Changed
24 80 cases [5]. Mmetastatic bone pain (MBP) is is not only severe and sometimes
Pe

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26 81 intolerable but also progressive in many patients [5] [2]., becoming chronic in Field Code Changed

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28 82 most of them[2] [3]. As the tumor grows and tumor-induced bone remodeling
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30 83 progresses, they result in skeletal-related events (SREs) occur. These that
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32 84 include not only pain and “breakthrough pain” but also hypercalcemia, anemia,
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34 85 skeletal fractures, compression of the spinal cord, and decreased mobility and
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36 86 activity [6] [6], all of which compromise the patient’s functional status, quality of Field Code Changed
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87 life, and survival [7][7, 8] [7,8]. Furthermore, chronic pain is frequently Field Code Changed
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88 associated to with anxiety, depression and sleep disorders [9] [9]. All ; these Field Code Changed
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41
89 comorbidities have , all of them, with a negative impact on the response to
42
43
90 analgesic treatment, which in turn contributes to the decrease inloss of quality
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45 91 of life.
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47 92
48
49 93 Since bone metastases do not only cause pain but also mean a decrease in
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51 94 performance status (PS) and quality of life Hence, pain treatment is crucial forin
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53 95 these patients [10].[10, 11] [10,11]. Field Code Changed
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6 96
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8 97 Metastatic bone painSince MBP hardly responds poorly to the non-steroidal
9
10 98 anti-inflammatory drugs (NSAIDs), and the WHO therapeutic guidelines for
11
12 99 cancer pain opioids combination are recommended opioids by the WHO
13
14 100 therapeutic guidelines for cancer pain [12]. [12] These include , with drugs such Field Code Changed
15
16 101 as oxycodone, which is effective for pain relief in patients with bone metastases
17
18 102 [5] and has a specific effect on neuropathic pain (NP) [13], which is a frequent Field Code Changed
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19 Field Code Changed
20 103 complication in case of vertebrae metastases [5]. Other therapies are currently Field Code Changed
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22 104 used for MBP: sSurgical therapy [5] [2], palliative radiation therapy (RT), and Field Code Changed
r
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24 105 radiopharmaceuticals [14, 15];. bBisphosphonates, which delay the onset and Field Code Changed
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25 Field Code Changed

26 106 reduce the risk of SREs in patients with bone metastases [16] [15];. Field Code Changed
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28 107 dDenosumab, which is a fully monoclonal antibody with high affinity and
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30 108 specificity for human RANKL recently approved for the prevention of SREs [17] Field Code Changed

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32 109 [16];. Opioid-based drug therapy [2] with drugs such as oxycodone, which is
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34 110 effective for pain relief in patients with bone metastases [2] and has a specific
35
36 111 effect on neuropathic pain (NP) [17], which is a frequent complication in case of
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112 vertebrae metastases [2]and r. Rescue medication, which isi.e., supplemental
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113 analgesia for “breakthrough pain” [18] [18].

40
41
114
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115 Since pain is so frequent in bone metastases and has such a negative impact
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45 116 on PS, Wwe wanted to studiedy the association of pain management in
46
47 117 oncologic patients with bone metastases with the evolution of their overall
48
49 118 status (ECOG), in oncologiccancer patients with bone metastases, plus the
50
51 119 degree of pain control according to analgesic treatment, to find out
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53 120 whetherdetermine the quality of MBP is or not being properly managementd in
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6 121 the Spanish clinical setting, to identify putative deficiencies and best strategies
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8 122 to overcome them.
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10 123
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12 124
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6 125 METHODS
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8 126
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10 127 Study design
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12 128
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14 129 This was a 3-month follow-up, observational, prospective, Spanish multicentre
15
16 130 study to assess the relationship between PS and pain relief in patients with
17
18 131 Bone Metastatic Pain (BMP study) in Spain. The study was performed in
Fo
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20 132 accordance with the revised Declaration of Helsinki. T and the protocol was
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22 133 approved by the ethics committee, and p. Patients provided informed consent
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24 134 before any inclusion in the study procedure.
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26 135 The primary endpoint was to assess the correlation between pain relief and
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28 136 performance status (PS) of oncologic patients with bone metastases.
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30 137 Secondary endpoints were to assess pain control on sleep quality, functionality,
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32 138 as well as pain relief depending on the type of treatment.
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36 140 Patients
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142 Eligible patients were ≥ 18 years old diagnosed with cancer with bone
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143 metastases, life expectancy ≥ 3 months and pain intensity ≥ 4 with on a
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144 numerical rating rate scale (NRS) ≥ 4. Patients were excluded if they had were
44
45 145 scheduled for palliative surgery or the investigator considered that them to have
46
47 146 they did not presentinsufficient enough cognitive capacity to understand the
48
49 147 study.
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51 148
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53 149 Outcome measures
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6 150
7
8 151 Basic demographic variables were collected at baseline, along with clinical
9
10 152 variables including: cancer diagnosis, site of primary tumour and metastasis,
11
12 153 type of pain, and treatment. Patient-reported outcomes were collected at the
13
14 154 baseline and at months 1 and 3 during the study follow-up, including of the
15
16 155 study. These included pain severity with 0-10 NRS scale and p. Pain control on
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18 156 sleep and functionality, was recorded by on a 0-10 visual analogue scale (NRS)
Fo
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20 157 of 0-10 points. PS was evaluated at baseline and at months 1 and 3, and
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22 158 scored rated by according the Eastern Cooperative Oncology Group (ECOG)
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24 159 scale.
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26 160
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28 161 End points
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30 162
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32 163 The primary endpoint of the study was to assess the correlation between pain
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34 164 relief and PS of oncologic patients with bone metastases. Secondary endpoints
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36 165 were to study pain control on sleep quality, functionality, as well as, pain relief
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166 depending on the treatment type.
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168 Statistical analysis
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169
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45 170 Statistically significant differences for ECOG, pain, functionality and sleep
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47 171 between baseline and months 1 and 3 were determined with using the Wilcoxon
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49 172 signed-rank test. The influence of pain management on ECOG during the
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51 173 follow-up was assessed by using the Spearman correlation, Kruskal Wallis test
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53 174 and the Chi2 test.
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6 175
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18 181
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20 182 RESULTS
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22 183
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24 184 Patients
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26 185
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28 186 A total of 587 patients were recruited in 56 centres, and 579 of them were
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30 187 included in this study. Baselines demographics and diseases characteristics are
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32 188 presented in Table I. Mean age was 63.2 ± 11.4 with 53.2 % of males. Most
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34 189 frequent primary tumors were lung (33.2%), breast (30.1%) and prostate
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36 190 (13.6%). Bone metastases occurred with higher percentage in spinal column
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191 (68%), pelvis (43%), ribs (38%), and femur (22.8%). Bone metastases led to
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192 spinal compression in 7.8 % of patients. As for of the nature of pain, the
40
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193 percentages of somatic pain or neuropathic were 83.2% and 43.5%,
42
43
194 respectively. Pain was caused by bone metastases in 96% of patients, being
44
45 195 the dorso-lumbar area the most frequent painful area, see supplementary figure
46
47 196 1. At baseline, patients presented a mean NRS value for pain of 6.5 ± 1.4 and
48
49 197 an ECOG of 1.5 ± 0.7. NRS values for functionality and sleep were 4.8 ± 2.3
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51 198 and 4. 8 ± 2.4, respectively.
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53 199
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6 200 Prescribed treatments at the baseline, as percentage patients, were the
7
8 201 following: opioids (94.8 %), non-opioids or coadjuvants (72.3 %), chemotherapy
9
10 202 (62.6%), bisphosphonates (54.5%), palliative radiotherapy (31.3%), non-
11
12 203 pharmacological treatment (1%) and surgery (1%). Detailed information on
13
14 204 treatment can be found in Table II.
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16 205
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18 206
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20 207 Evolution of ECOGPS, pain, functionality and sleep during along the study
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22 208
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24 209 Baselines demographics and diseases characteristics are presentedshown in
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26 210 Table I. In comparison to their mean values at the baseline, PS, pain,
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28 211 functionality and sleep improved significantly at the first and third months of the
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30 212 studyalongover the study (Table II). ECOG´s values were 1.5 ± 0.7, 1.3 ± 0.7,
31
32 213 and 1.3 ± 0.8, at baseline, first and third month, respectively p<0.001 (Figure
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34 214 1A). Pain also decreased along the study, starting by a moderate mean value of
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36 215 6.5 ± 1.4 and being reduced to 2.8 ± 1.9, and 2.1 ± 1.9 for the second and third
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216 month respectively (p<0.01), Figure 1B. In parallel to the pain relief, the values
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217 for functionality and sleep quality also improved significantly (p<0.001) along
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218 the study, as it is shown in Figure 2.
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219
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45 220 ECOG evolution according to pain
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47 221
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49 222 ECOG evolution, from baseline to 3 months, measured by the change in ECOG
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51 223 PS score change (in number of points) and by the proportion of patients with
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53 224 better/stable/worse ECOG than over baseline, was was compared to pain
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6 225 evolution, which was measured by 5 pain parameters (degree of change;
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8 226 patients with improved/stable/worsened pain; those with ≥ 20% of pain
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10 227 improvement; those with ≥ 50% of pain improvement; and those ending with
11
12 228 NRS ≤3). Tests results were significant (p< 0.001), and data indicated that pain Formatted: Font: Italic
13
14 229 and ECOG outcomes were closely and directly related. (table III). As can be
15
16 230 seen in figure 3 for ECOG evolution at month 3, aAll patients showing with
17
18 231 better ECOG improvement than over baseline, also had a better evaluation of
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20 232 pain; among most patients with stable performance status (ECOG) also showed
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22 233 stable pain, most patients (75%) also showed stable pain, and most among
r
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24 234 patients with worse ECOG than over baseline, also showed worse pain most
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26 235 patients (77%) showed worse pain as well (data not shown).
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28 236
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32 238 Treatments
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34 239 As shown in Table II,
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36 240 There were seven 7 different treatment modalities employed were used during
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241 the study. as it is shown in Ttable II. Previous treatments were as follows:
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242 90.8% of patients were taking some non-opioid or coadjuvant medication, being
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243 the most frequent of them NSAIDs (71.5%), paracetamol (32.9%), and
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244 corticoids (23.8%). Chemotherapy was indicated for in 68% of patients: as first
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45 245 line in , nearly half of them these (43.4%) on first line, second line in 20.4% in
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47 246 second line, and 18% in third or more line in line18%(data not shown). Most
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49 247 frequent common therapies used were vinorelbinea (11.7%), cisplatin (11.7%),
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51 248 carboplatin (11.4%), gemcitabine (10.7%) and taxotere (10.4%) (data not
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53 249 shown).
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6 250
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8 251 Opioids were taken by 59.4% of patients being fentanyl and tramadol the most
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10 252 frequent ones (28.2% and 25.6%, respectively), followed by oxycodone and
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12 253 morphine (13.11% and 11.6%, respectively). Mean doses of the four 4 most
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14 254 frequent opioids used were: fentanyl 56.6 mg every 3 days; tramadol 101.7 mg
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16 255 every 8 or 12 h; oxycodone 22.1 mg every 12h,12 h and morphine 46 mg every
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18 256 12 h.
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20 257
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22 258 Bisphosphonates were taken by 51.7% of patients, and almost exclusively
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24 259 zolendronic acid (96.7%),. were taken by 51.7% of patients. Palliative
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26 260 radiotherapy to alleviate pain was taken given to by 20.9%, with the spinal
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28 261 column being the most frequent application area (56.2%), followed by pelvis
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30 262 (30.6%) and femur (10.7%). (data not shown). Mean dose was 71.1 Gy (median
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32 263 30 Gy), with a fractioning 10x300 cGy in 57.9% of cases. (data not shown).
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34 264 Finally, surgery and non-pharmacological treatment were considered for 4.1%
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36 265 and 0.7% of patients, respectively.
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269 Chemotherapy and bisphosphonates remained stable along over the study, and
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45 270 did nothad no have any influenceeffect on ECOG and pain (p=0.801 and
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47 271 p=0.172; and p=0.462 and p=0470, respectively); howeveron the other
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49 272 handhowever, there was an increase in palliative RT at baseline (from 20.9% to
50
51 273 31.3%) and a decrease at 1 monththe following months, with no effect without
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53 274 influence on ECOG or pain (p=0.321 and p=0.715) (to 9.7%), (Ttable II). Non-
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6 275 opioids or coadjuvants administration decreased alongover the studyfrom
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8 276 90.8% to 72.3% at baseline and to 67.2% at 1 month, while opioids almost
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10 277 doubled from 59.4% to 94.8% at baseline and stayed remained at thosethe
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12 278 same high levels at month 1afterwardsthereafter. Mean doses for of fentanyl
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14 279 and oxycodone discretely increased slightly from 56 to 62 mg and 22 to 25 mg,
15
16 280 respectively. Rescue treatment was prescribed to in 71.4% of patients at
17
18 281 baseline (immediate release (IR) oxycodone capsules 60.4%, IR oxycodone
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20 282 solution 11.7%, morphine 13.8%, and fentanyl 7.5%, and others 6.6%) and toin
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22 283 66.2% at month 1, with in similar proportions of the specific drugs. Laxatives
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24 284 and antiemetics were prescribed for in 71.5% and 54.7% of patients,
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26 285 respectively, at baseline and for in 71.8% and 44.4%, respectively, at month 1
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28 286 (data not shown). Treatments at month 3 basically replicated month -1
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32 288
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34 289 Treatment compliance was high at 1- and 3-month visits. At 1 month 1, 76.5%
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36 290 of patients complied with RT, 92.6% complied with CT, 86.8% complied with
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291 bisphosphonates, and 95.3% complied with analgesic medication. At 3 month
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292 s3, percentages were: RT 79.5%, CT 86.5%, bisphosphonates 79.9% and

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293 analgesic medication 93.2%. Rescue medication was taken by 44.4% of
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294 patients at 1 month 1 [(mainly oxycodone ([66.8%]) or morphine ([16%]),] and
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45 295 by a significantly smaller proportion of patients at 3 months 3 (35%; p=0.001). Formatted: Font: Italic
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47 296
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49 297 Regarding adverse events (AE) to analgesic treatment: At baseline, 37 (6.4%)
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51 298 patients experienced some baseline AEs; at 1 month 1, 53 (9.8%) patients at
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53 299 month 1,, and at 3 months 3, 44 (9.3%) patients at month 3. The most frequent
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6 300 AEs, for the first and third months, were constipation (27.4% and 36.5%),
7
8 301 nausea (23.8% and 19.5%), and somnolence (12.3% and 14.6%), respectively
9
10 302 (Supplementary Figure 41). There were no grade 4 adverse events, and six
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12 303 events 6 were grade 3 (15.8 %), being with the opioids AE´s being the most
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14 304 common.
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16 305
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18 306 ECOG evolution according to treatment
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20 307 Patients treated with a specific analgesic treatment (prescribed at baseline and
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22 308 with confirmed compliance at the specific analyzed time point analyzed) were
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24 309 compared with those who did not receive that treatmentit in terms of ECOG. At
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26 310 both time points, Only patients treated with opioids showed significantly more
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28 311 favorable ECOG outcomes than patients those who did notnot treated with
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30 312 them, at 1 month compared to baseline (p=0.012), as well as at 3 months
31
32 313 compared with baseline (p=0.047), see t (p<0.001able IV). Significant (p<0.001)
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34 314 differences were also observed between patients needing or not rescue
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36 315 medication at 1, as well as at 3 months. At both time pointsSimilarly, patients
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316 who did not need rescue medication showed more favorable ECOG outcomes
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317 than those who did, (p<0.001; T table IVIII). Formatted: Font: Italic
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319
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45 320 Pain evolution according to treatment
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47 321 The pain parameters of pPatients treated with a specific analgesic treatment
48
49 322 (prescribed at baseline and with confirmed compliance at the specific analyzed
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51 323 time point) were also compared with those who that did not receive that
52
53 324 treatmentit, in terms of pain parameters. Opioids and rescue medication
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6 325 showed significant differences depending on whether they were used or not.
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8 326 Since opioids seemed to have an effect on pain evolution, the two 2 most
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10 327 commonly used frequent ones (oxycodone and fentanyl) were again
11
12 328 lookedanalyzed at specificallyspecifically ,(T table IV)..
13
14 329
15
16 330 At 1 month 1 there was a significant difference in pain between patients taking
17
18 331 and not NRS change patient´s proportions to those taking opioids vs. those not
Fo
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20 332 taking them. Similarly, there were significant differences in all pain parameters
21
22 333 favorable in favor of to those patients not taking rescue medication vs. those
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24 334 taking it. The two specific opioids most frequently used (oxycodone and
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26 335 fentanyl) were compared vs. other opioids. MThe mean decrease in pain NRS (-
27
28 336 3.9 vs. -3.2; p=0.003) and the proportion of patients improving pain inwith ≥ Formatted: Font: Italic
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30 337 50% improvement in pain (72.9% vs. 59.3%; p=0.007) were significantly larger Formatted: Font: Italic

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32 338 in patients taking oxycodone than in those taking other opioids. The proportion
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34 339 of patients with ≥ 50% improvement in painproportion of patients improving pain
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36 340 in ≥50% was significantly smaller lower in patients taking fentanyl than in those
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341 taking other opioids (59.1% vs. 71.5%; p=0.041) (data not shown). Aftert three 3 Formatted: Font: Italic
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342 months, (table V), the mean reduction in pain NRS was significantly greater in
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343 patients treated with opioids than in those not treated with opioids (-4.4 vs. -3.6;
42
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344 p=0.014). MThe mean decrease in pain NRS, and the proportion of patients Formatted: Font: Italic
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45 345 with improving ≥ 20% improvement, improving ≥ 50% improvement, and those
46
47 346 ending with NRS ≤ 3 were significantly favorable in favor of to patients not
48
49 347 taking rescue medication vs. those taking it. MThe mean decrease in pain (-4.7
50
51 348 vs. -3.6; p < 0.001) and the proportion of patients showing a pain reductionwith Formatted: Font: Italic
52 Formatted: Font: Italic
53 349 ≥ 50% improvement (84.6% vs. 71.3%; p=0.002) were significantly larger in Formatted: Font: Italic
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6 350 patients taking oxycodone than in those takingon other opioids. In terms of
7
8 351 fentanyl, 83% of patients takingon this drug fentanyl decreased pain in by ≥
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10 352 20%, and 66% in by ≥ 50% vs. 93.2% (p=0.015) and 83.1% (p= 0.005) of Formatted: Font: Italic
11 Formatted: Font: Italic
12 353 patients takingon other opioids (Table IV).
13
14 354
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16 355
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6 356 DISCUSSION
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8 357 Formatted: Font: Not Bold
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10 358 This study showed that ECOG improvement was directly related to pain, and
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12 359 that pain was not adequately managed in MBP patients in Spain. An
13
14 360 appropriateGood management of bone metastases has been been shown to Formatted: Font: Not Bold
15
16 361 relief pain considerably relieve pain [10] [11]. However, although baseline pain Field Code Changed
17
18 362 values of in this study (mean NRS=6.5) were moderate-severe, and up to
Fo
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20 363 43.5% of patients suffered from NP, which is difficult to treat [19], only 59% of Field Code Changed
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22 364 patients were being treated with opioids. The WHO analgesic ladder
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24 365 recommends administration of a minor opioid already in the second step (for
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26 366 moderate pain) and a major opioid in the third step (for severe pain). In addition,
27
28 367 up to 43.5% of patients suffered from NP , which is difficult to treat [19]. This
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30 368 might also partly explain the lack of analgesic treatment response in this
31
32 369 population.
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34 370
35
36 371 During the study, the percentage of patients treated with chemotherapy and
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372 bisphosphonates stayed within similar valueshardly varied, whereas palliative
38
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373 RT and non-opioids or coadjuvants decreased from baseline to follow-up visits.

40
41
374 The treatment established at baseline differed from previous treatment in an
42
43
375 increase in palliative RT (from 20.9% to 31.3%), although it decrease at 1
44
45 376 month (9.7%), a decrease in non-opioids or coadjuvants (from 90.8% to 72.3%
46
47 377 at baseline and to 67.2% at 1 month). TIn our study, the percentage of patients
48
49 378 treated with opioids almost doubled compared withing previous treatments, and
50
51 379 baseline, and follow-up, due mainly to an increase in oxycodone (6 fold
52
53 380 increase). We consider that opioids should be the first symptomatic treatment in
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6 381 moderate to severe cancer pain. In fact, they Opioids have been successfully
7
8 382 used for NP since the early 90s [20] [20], with oxycodone specifically being Field Code Changed
9
10 383 reported as a beneficial drug in benign NP, and as efficacious as morphine in
11
12 384 treating oncologic pain [17][13].
13
14 385
15
16 386 SThe significant improvements in pain, sleep and functionality found during the
17
18 387 first month were similar to another Spanish oncologic NP study [21] [21]. In that Field Code Changed
Fo
19
20 388 study, 88% of patients were treated with oxycodone, and pharmacologic cancer
21
22 389 pain treatment had a greater effect in patients with metastases than in those
r
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24 390 without with no metastasesthem, evidencing its importance for in metastatic
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26 391 cancer pain. Analgesic treatment response depended on the specific treatment
27
28 392 used, with patients on oxycodone or other opioids showing a greater decrease
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30 393 improvement in pain than patients on treatment other than opioids.
31
32 394
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34 395
35
36 396 In addition to being PS being dependent on patient’s overall response, oOur
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397 results show that ECOG improvement isdecreased significantly from baseline
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398 and its evolution was closely related to pain. The response to analgesic
40
41
399 treatment for palliation of metastatic bone pain MBP has been found to be
42
43
400 significantly related to PS [22] [22]. Furthermore, the association between pain Field Code Changed
44
45 401 and PS seems to be reciprocal, since patients with poor PS (ECOG ≥ 2), among
46
47 402 other variables, are more likely to have SREs, including pain [23] [23]. As we Field Code Changed
48
49 403 have mentioned, tThe change from previous treatment consisted in a decrease
50
51 404 in non-opioids or coadjuvants and an two-fold increase by in two fold of opioids,
52
53 405 due to oxycodone increase (6- fold). Therefore, pthe pain and ECOG
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6 406 improvements observed at 1 and 3 months 1 and 3 seem to be the result of the
7
8 407 increase in opioid administration. Although RT treatment increased from 20.9%
9
10 408 to 31.3% at baseline, it decreased to 9.7% at 1 month;subsequently, thusand
11
12 409 hence , it would not explain the improvement observed also at 3 monthsduring
13
14 410 the follow-up period. Furthermore, statistical analyses were not significant.
15
16 411
17
18 412 One limitation of our study is the large difference in sample sizes among
Fo
19
20 413 specific opioid drugs (i.e. 452 patients received oxycodone, 75 patients received Formatted: Font: Italic
21 Formatted: Font: Italic
22 414 fentanyl) which prevented. From of all the patients receiving opioids during the
r
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24 415 study (~94% =544), 78% received oxycodone (i.e. 452 patients), with fentanyl
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26 416 being the second most frequent opioid used, at the low percentage of 13% (i.e.
27
28 417 75 patients). Due to this difference in number of patients, reliable statistical
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30 418 comparisons cannot be performed. Although no differences were observed
31
32 419 between oxycodone and the rest of opioids for ECOG, significant differences
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33
34 420 were observed for in pain outcomes. Thus, the mean decrease in pain was
35
36 421 significantly largergreater in patients taking oxycodone, whileNRS and the
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422 proportion of patients improving pain inwith a ≥ 50% improvement in pain were
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423 was significantly larger in patients taking oxycodone, in patients taking

40
41
424 oxycodone than in those taking other opioids, while the proportion of patients
42
43
425 improving pain in ≥50% wasand significantly smaller in patients taking
44
45 426 oxycodone in those taking or fentanyl, respectively than in those taking other
46
47 427 opioids, at 1 and 3 months. Therefore it can be suggestedThis suggests that in
48
49 428 patients with MBP, oxycodone, specifically, might improve pain more than other
50
51 429 opioids.
52
53 430
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6 431 As aIn conclusion, management of metastatic bone pain MBP in Spain is
7
8 432 currently not properly managedpoor. IndeedIn fact, pPain, sleep, functionality
9
10 433 and ECOG improvements were observed achieved after changing treatment to
11
12 434 a wider use range of opioids. Pain and ECOG outcomes are closely and directly
13
14 435 related. Opioid treatment seems to exert have a favorable effect on ECOG and
15
16 436 pain evolution in patients with metastatic bone painMBP, while the opposite is
17
18 437 true of the need for rescue treatment exerts a negative impactdoes the
Fo
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20 438 opposite.
21
22 439
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23 440
24 441 Formatted: Spanish (International Sort)
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6 442 Acknowledgements Formatted: Spanish (International Sort)
7
8 443 We would like to thank the following investigators that participated in the Study Formatted: Spanish (International Sort), Not
9 Highlight

10 444 BMP (Bone Metastatic Pain): Study: Eva María Ciruelos, H. 12 de Octubre, Madrid; Formatted: Spanish (International Sort), Not
Highlight
11
Formatted: Justified, Line spacing: Double,
12 445 Mónica Corral, H. Alcañiz, Alcañiz; Purificación Martínez del Prado, H. Basurto, Don't adjust space between Latin and Asian
13 text, Don't adjust space between Asian text
and numbers
14 446 Bilbao; Francisco J. Carabantes, H. Carlos Haya, Málaga; Manuel Cobo, H. Carlos
15
16 447 Haya, Málaga; Luis Olay, H. Central de Asturias, Oviedo; Diego Soto, H. Clínico de
17
18 448 Valladolid, Valladolid; Isabel Blancas, H. Clínico Granada, Granada; Javier Puente, H.
Fo
19
20 449 Clínico San Carlos, Madrid; José Miguel, H. Clínico San Cecilio, Granada; Dolores
21
22 450 Isla, H. Clínico Zaragoza, Zaragoza; Julio José Lambea, H. Clínico Zaragoza, Zaragoza;
r
23
24 451 Yolanda López, C. A. de Zamora, Zamora; Irma Muruzabal, H. de Cruces, Barakaldo;
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26 452 José Miguel Martín, H. de Getafe, Getafe; Salvador Garcerá, H. de la Ribera, Alzira;
27
28 453 Natalia Lupión, H. de Mérida, Mérida; Enrique Martínez, H. de Navarra, Pamplona;
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29
30 454 Núria Calvo, H. de Sant Pau, Barcelona; Sonia Maciá, H. Elda, Alicante; Ana Blasco,
31
32 455 H. General de Valencia, Valencia; José María García, H. General de Albacete,
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34 456 Albacete; Enric Carcereny, H. Germans Trias I Pujol, Badalona; Esperanza Blanco, H.
35
36 457 Infanta Cristina, Badajoz; Ana Belén Custodio, H. la Paz, Madrid; Juan Bayo, Clin. los
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458 Naranjos, Huelva; Carmen Velilla, H. Lozano Blesa, Zaragoza; Almudena García, H.
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459 Marqués de Valdecilla, Santander; Miguel Méndez, H. Móstoles, Móstoles; Román

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460 Bastus, H. Mutua de Terrassa, Terrassa; Ana María Tortorella, H. Naval, Murcia;
42
43
461 Yolanda García, C. Parc Taulí, Sabadell; José María Puerto, H. Perpetuo Socorro,
44
45 462 Badajoz; Cristina López, H. Povisa, Vigo; Fátima Navarro, H. Príncipe de Asturias,
46
47 463 Alcalá de Henares; Javier Munárriz, H. Provincial Castellón, Castellón; Ramón de las
48
49 464 Peñas, H. Provincial Castellón, Castellón; Miguel Ruiz, H. Punta de Europa, Algeciras;
50
51 465 María Fernández, H. Ramón y Cajal, Madrid; Laura Murillo, H. Reina Sofía, Tudela;
52
53 466 Isabel Palomo, H. Río Hortega, Valladolid; Christian Rolfo, Clin. Rotger, Palma de
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6 467 Mallorca; Antonia Perello, H. Son Dureta, Palma de Mallorca; Aránzazu González del
7
8 468 Alba, H. Son Dureta, Palma de Mallorca; José Manuel Pérez, H. Vall d'Hebron,
9
10 469 Barcelona; Miguel Marín, H. Virgen de la Arrixaca, Murcia; Javier Medina, H. Virgen
11
12 470 de la Salud, Toledo; Ruth Álvarez, H. Virgen de la Salud, Toledo; Francisco de Asís, H.
13
14 471 Virgen de los Lirios, Alcoy; David Vicente, H. Virgen Macarena, Sevilla; Manuel
15
16 472 Codes, H. Virgen Macarena, Sevilla; Guillermo Quintero, C. Xeral-Calde, Lugo; Sergio
17
18 473 Vázquez, C. Xeral-Calde, Lugo; Silvia Antolín, CHUAC, A Coruña; Rafael López,
Fo
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20 474 CHUS, Santiago; Bernardo Queralt, ICO-Girona, Girona. Formatted: Font: Arial
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22 475
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24 476 We would also like to thank Mayte Martín Fuentes from Mundipharma
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26 477 Pharmaceuticals S.L. for managing the study, and Almudena Pardo and Luis
27
28 478 Santamaria for helping in the medical writing of the manuscript.
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30 479
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32 480 Funding
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34 481 This work was sponsored by Mundipharma Pharmaceuticals S.L.
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36 482
483 Disclosure Formatted: Font: Bold, English (U.S.)
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484 Formatted: English (U.S.)
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485 Susana Traseira worksis a as Medical Director, inat Mundipharma Formatted: Justified
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486 Pharmaceuticals S.L, sponsor of this study. All remaining authors have declared
41
42
487 no conflicts of interest.
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6 492
7 493 FIGURE LEGENDS
8 494
9 495
10 496 Supplementary Figure 1. Adverse events to in analgesic treatment at the
11 497 different study time points
12 498
13 499
14 500
15 501
16 502
17 503
18 504 REFERENCES
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6 541 15. Fairchild A, Chow E. Role of radiation therapy and radiopharmaceuticals
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9 544 malignancies. Curr Drug Discov Technol 2010; 7: 233-246.
10 545 17. Iranikhah M, Wilborn TW, Wensel TM, Ferrell JB. Denosumab for the
11 546 prevention of skeletal-related events in patients with bone metastasis from solid
12 547 tumor. Pharmacotherapy 2012; 32: 274-284.
13 548 18. Zeppetella G. Impact and management of breakthrough pain in cancer.
14 549 Curr Opin Support Palliat Care 2009; 3: 1-6.
15 550 19. Stacey BR. Management of peripheral neuropathic pain. Am J Phys Med
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17 552 20. Mercadante S, Gebbia V, David F et al. Tools for identifying cancer pain of Formatted: Spanish (International Sort)
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19 554 Pain 2009; 10: 594-600.
20 555 21. Garcia de Paredes ML, del Moral Gonzalez F, Martinez del Prado P et al.
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22 557 cancer patients. Results of the On study. Ann Oncol 2011; 22: 924-930.
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23 558 22. Campos S, Presutti R, Zhang L et al. Elderly patients with painful bone
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26 561 23. Sun JM, Ahn JS, Lee S et al. Predictors of skeletal-related events in non-
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3 Table I. Demographic and clinical characteristics of the study population
4
5 N=579
6 Men 308 (53.2) Bone metastases (II)
Age 63.2 ± 11.4 Feet 1 (0.2)
7
≤ 50 83 (14.3) Hands 1 (0.2)
8
51-60 143 (24.7) Other bones 57 (9.8
9 61-70 186 (32.1) Metastases other than bone
10 71-80 142 (24.5) *Lung 156 (46.7)
11 >80 23(4) *Liver 149 (44.6)
12 No data 2 (0.3) *Lymph nodes 122 (36.5)
13 Primary tumor (>1.5%) *Cortico-adrenal 37 (11.1)
14 Lung 192 (33.2) *Pleural 36 (10.8)
15 Breast 174 (30.1) *Other 32 (9.6)
16 Prostate 79 (13.6) *Brain 22 (6.6)
17 Colon and/or rectum 34 (5.9) *Peritoneum 17(5.1)
18 Other 20 (3.5) Consequence of bone metastasis
Bladder 16 (2.6) Fracture 39(6.7)
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Kidney 12 (0.1) Spinal compression 45 (7.8)
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Pancreas 9 (1.6) Surgery 24 (4.1)
21 Sarcoma 8 (1.4) Splint or orthopedic corset 35 (6)
22 Bone metastases (I) Pain pathophysiology
r
23 Spinal column 393 (68) Somatic 482 (83.2)
24 Pelvis 249 (43) Neuropathic 252 (43.5)
Pe

25 Ribs 220 (38) Visceral 54 (9.3)

26 Femur 132 (22.8) Mixed 192 (33.2)
27 Sternum 73 (12.6) Cause of pain
28 Humerus 64 (11.1) Bone metastases 556 (96)
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29 Skull 62 (10.7) Primary tumor 49 (8.5)

30 Knees 5 (0.9) Other metastases 42 (7.3)
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*Percentages based on total number of other metastases (335)
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4 Table II. ECOG, pain, functionality and sleep at different study time points. Treatment
5 prior to start of study (% of patients) and treatment prescribed or continued at different
6 study time points.
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8
9
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11 Previous Baseline 1-month 3-month
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13 ECOG - 1.5 ±0.7 1.3 ±0.7* 1.3 ±0.8*
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16 Pain (NRS) - 6.5 ±1.4 2.8 ±1.9* 2.1 ±1.9*
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19 Functionality (NRS) - 4.8 ±2.3 3.0 ±2.1* 2.7 ±2.4*
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22 Sleep (NRS) - 4.8 ±2.4 2.5 ±1.9* 2.2 ±1.9*
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24
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25 Palliative RT 20.9% 31.3% 9.7% 5.7%

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27 Chemotherapy 68% 62.6% 68.1% 58.2%
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Bisphosphonates 51.7% 54.5% 51.9% 44.6%
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32 Surgery 4.1% 1% 1.3% 0.8%
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34 †
Non-opioids or coadjuvants 90.8% 72.3% 67.2% 61.4%
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36 NSAID 71.5% 66.8% 65.6% 65.7%
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39 Paracetamol 32.9% 16.0% 18.9% 17.3%
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41 Corticoid 23.8% 41.3% 31.4% 34.6%
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Pregabalin 8.2% 14.1% 14.7% 14.5%
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46 Gabapentin 6.1% 13.0% 13.3% 15.6%
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48 Benzodiazepine 5.7% 7.6% 10.3% 9.3%
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51 Other 5.3% 1.6% - -
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53 Muscle relaxant 4% 3.0% 4.4% 3.8%
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Amitriptyline 4% 6.5% 6.7% 6.6%
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Duloxetin 0.6% 1.6% 4.4% 5.9%
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5
†
6 Opioids 59.4% 94.8% 94.2% 90.7%
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8 Phentanyl 28.2% 12.8% 13.3% 14.3%
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11 Tramadol 25.6% 1.6% 1% -
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13 Oxycodone 13.1% 78.3% 77.8% 78.9%
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Morphine 11.6% 3.8% 4.6% 3.5%
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18 Tramadol (+Paracetamol) 7.3% - - -
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20 Codein (+Paracetamol) 7.0% 0.2% - -
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Hydromorphone
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23 5.2% 2.4% 2.0% 1.9%
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25 Buprenorphine 3.5% 0.7% 1.2% 0.9%

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27 Other 2.6% 0.7% - 0.9%
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29 ˆNon-pharmacologic
30 treatment 0.7% 1% 3.4% 3.2%
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32 *p<0.001 (Wilcoxon test) for differences over baseline
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34 Percentage of each specific drug based on number of patients that use that drug class
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36 ˆNon-pharmacologic treatment includes massage, rehabilitation and neural blockade.
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3 Table III. Patients (%) with better, stable or worse ECOG over baseline, according to
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5 whether or not (X) they received opioid treatment or rescue treatment
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10 ECOG 1 Month-Baseline 3 Month-Baseline
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13 Opioids No opioids p-value Opioids No opioids p-value
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15 Better 31.7% 23.1% 37.3% 28.1%
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18 Stable 58.6% 53.8% 0.012 48.7% 45.6% 0.047
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21 Worse 9.7% 23.1% 14.0% 26.3%
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23 Rescue No rescue Rescue No rescue
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medication medication medication medication
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27 Better 21.5% 38.3% 26.3% 39.5%
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30 Stable 64.1% 53.4% 0.001 47.5% 48.6% 0.001
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Worse 14.3% 8.4% 26.3% 11.9%
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4 Table IV. Significance (p-value) of the difference in pain parameters between patients
5 receiving opioid and rescue treatment or not. Oxycodone treatment vs. other opioids
6 and fentanyl treatment vs. other opioids were also analyzed.
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8
Opioids vs Oxy vs other Phen vs. other Rescue medication vs.
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no opioids opioids opioids no rescue medication
10
11 Pain at 1 month
12 †Change in pain (NRS) 0.026 0.003 0.055 <0.001
13 *Evolution (%
14 <0.001 0.707 0.817 <0.001
better/stable/worse)
15 *Evolution (%
16 0.013 0.306 0.267 <0.001
improving≥20%)
17 *Evolution (%
0.707 0.007 0.041 <0.001
18 improving ≥50%)
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19 *Evolution (% ending
0.571 0.062 0.084 <0.001
20 with NRS≤3)
21 Pain at 3 months
22
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23 †Change in pain (NRS) 0.014 <0.001 0.099 <0.001
24 *Evolution (%
0.12 0.148 0.051 0.185
Pe

25 better/stable/worse)
26 *Evolution (%
0.128 0.07 0.015 0.011
27 improving≥20%)
*Evolution (%
28 0.102 0.002 0.005 <0.001
improving ≥50%)
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29 *Evolution (% ending
30 0.13 0.375 0.031 <0.001
with NRS≤3)
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32 † Mann-Whitney test; *Chi2 test
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34 In bold: significant p-values
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32 Adverse events in analgesic treatment at different study time points
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33 254x190mm (96 x 96 DPI)

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