Clin Exp Metastasis (2015) 32:7–14 DOI 10.1007/s10585-014-9686-x
RESEARCH PAPER
Bone metastases in gastrointestinal cancer Fabienne Portales • Simon The´zenas • Emmanuelle Samalin • Eric Assenat • Thibault Mazard • Marc Ychou
Received: 30 April 2014 / Accepted: 20 October 2014 / Published online: 9 November 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Colorectal (CRC) and gastroesophageal (GEC) cancers unusually spread to the bone. However, bone metastases (BM) are responsible for skeletal-related events (SREs) associated with an altered quality of life. Aiming to describe the characteristics and prognostic influence of BM from gastro-intestinal cancers, we performed a retrospective analysis of prospectively collected data in patients treated in our institution (1996–2006). 189 patients (5.5 %) developed BM: 79 with GEC and 110 with CRC. 57 patients had bone-exclusive metastases. In univariate analyses, the median time to BM occurrence was correlated with the primary tumour (PT) localisation, surgery, histology and TNM staging. However, in multivariate analyses, the occurrence delay was significantly shorter only for patients with GEC (HR 2.1), N1–2 status (HR 1.9), M1 status (HR 2.4), and epidermoid carcinoma (HR 6.0). Pain was the most frequent clinical sign leading to BM diagnosis (77.2 %). SRE occurred in 55 % of patients. Median overall survivals (OSs) of patients with CRC and GEC were 9.4 months [95 % confidence interval (95 % CI) 6.4–11.1] and 3.4 months (95 % CI 2.5–9.0), respectively. In univariate analyses, OS was correlated with PT surgery F. Portales (&) E. Samalin E. Assenat T. Mazard M. Ychou Department of Digestive Oncology, Institut re´gional du Cancer de Montpellier (ICM) – Val d’Aurelle, 208 avenue des Apothicaires, 34298 Montpellier Cedex 5, France e-mail: [email protected] S. The´zenas Biostatistics Unit, Institut re´gional du Cancer de Montpellier (ICM) – Val d’Aurelle, Montpellier, France E. Assenat T. Mazard Medical and Digestive Oncology Unit, Hoˆpital Saint-Eloi, CHU de Montpellier, Montpellier, France
and NM staging, and the number of BM. In multivariate analyses, only the PT surgery and the number of BM remained correlated with OS. Our results suggest that there may be a subset of patients associated with a quicker development of BM. Given their higher risk of SRE, they could benefit from an early screening, calling for further prospective studies encompassing patients with and without BM. Keywords Colorectal cancer Gastric cancer Esophageal cancer Metastasis Bone metastasis Skeletal-related event
Introduction Cancers of the gastrointestinal (GI) tract are some of the most common incident forms of cancer in Europe, with more than half of cases arising from the colon [1]. If bone metastases (BM) are especially common in multiple myeloma, breast, prostate, lung, bladder, thyroid and renal cell carcinomas, their occurrence from GI tumours is rare, accounting for about 3–5 % [1–4]. Recent advances in GI cancer care including widespread screening programs, the rising use of combined multimodal therapeutic strategies, and the development of targeted therapies in metastatic disease, have led to changes in the natural history of disease [5]. Indeed, survival significantly improved, and an increased number of patients with GI cancer are likely to develop unusual metastatic sites, especially in the late stages. Although colorectal (CRC) and gastroesophageal (GEC) cancers usually spread to the liver, lung and peritoneum [6–8], bone may also be affected. Currently, neither bone scan nor X-rays are routinely used in patients with GI cancer to detect BM, often discovered due to
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clinical signs. Indeed, BM cause bone pain and substantial skeletal-related events (SREs) defined as spinal-cord compression, pathological fractures, radiotherapy and/or surgery to bone [9, 10] and hypercalcemia [11, 12]. Generally the pelvis, vertebrae and ribs are more often affected than distal bones. The most frequent complication of BM is bone pain resulting from structural damage, periosteal irritation, and nerve entrapment. Recent evidence suggests that pain caused by BM may also be related to the rate of bone resorption. Clinical consequences are decreased mobility, progressive loss of autonomy and significant alteration of quality of life [13]. Therefore, a better evaluation of the incidence and metastatic pattern of BM would be clinically relevant nowadays [14]. To our knowledge, there have been few studies evaluating BM from primary GI cancer [15]. The aim of this single-institution study was to describe the incidence and prognostic influence of BM from GI cancer, over a 10-year period, as well as to define a particular tumour profile which could benefit from an early screening.
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considered as the date of the radiological or clinical examination that established the diagnosis, to the date of death from any cause. The closing date of the study analysis was used as the endpoint measure. OS rates and median values were estimated according to the Kaplan– Meier method and presented with their 95 % confidence intervals (95 % CIs). The median length of follow-up was estimated using a reverse Kaplan–Meier method and presented with associated 95 % CI. Survival curves were drawn and the log-rank test was performed to assess differences between two groups: CRC versus GEC. To investigate prognostic factors (on the median time to onset of BM), multivariate analyses were carried out using the Cox’s proportional hazards regression model with a stepwise selection procedure. All P-values reported are twosided, and the significance level was set at 5 % (P \ 0.05).
Results Study population
Patients and methods Patient selection and evaluation We performed a retrospective analysis of prospectively collected data of patients with BM originating from GI carcinoma treated in the Montpellier Cancer Institute (ICM, Montpellier, France) between 1996 and 2006. We distinguished two different groups of patients according to primary tumour (PT) site: CRC or GEC. BM were primarily detected clinically by bone pain, neurological compression, hypercalcemia, and/or pathological fractures. Diagnosis confirmation was obtained using bone scan, X-ray, computed tomography (CT) scan or magnetic resonance imaging. A dedicated computerised form was created to collect demographic data, clinical and pathological characteristics including PT site, histological type, number and location of BM, occurrence pattern and therapeutic management. The time between PT diagnosis and BM occurrence was recorded as well as the patients’ outcome. This study was approved by the Institutional Review Board of the ICM. Statistical analysis Categorical variables were reported by means of contingency tables. For continuous variables, median and range values were computed. To investigate the association between study features, univariate statistical analyses were performed using the Pearson’s v2 test. Overall survival (OS) time was measured from the date of BM diagnosis,
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Over a 10-year period, a total of 3,438 patients with primary GI tumours were treated at the ICM. Among them, 2,434 (71 %) were diagnosed with CRC and 1,004 (29 %) with GEC. We identified 189 patients (5.5 %) who developed BM with a higher incidence in patients with GEC (7.9 %) than with CRC (4.5 %). Patient and tumour characteristics are detailed in Table 1. Characteristics of metastases At cancer diagnosis, 103 patients (54.5 % of the total group) had synchronous metastatic disease (diagnosed within 6 months after PT diagnosis) referred as the ‘‘M1’’ group (Fig. 1). Among the latter, 69 patients (67.0 % of the M1 group) had visceral metastases, 50 (48.5 %) in the liver and 26 (25.2 %) in the lung. Those synchronous metastases were exclusively visceral in 31 patients (30.1 %), and bone-exclusive in 34 patients (33.0 %). Patients with metachronous metastases (n = 86) are referred as the ‘‘M0’’ group. At BM diagnosis, patients from the M0 group had developed either bone-exclusive or mixed (bone and viscera) metastases (Fig. 1). In total, 57 patients (30.2 % of the total group) had bone-exclusive metastases, of whom 23 from esophageal PT (40 %), 8 from gastric PT (14 %), 15 from colic PT (26 %), and 11 from rectal PT (19 %). In this bone-exclusive subset of patients, males were more represented (79 %) than in the non-bone-exclusive subset (59 %, P = 0.009). Likewise, oesophageal PT (40 vs. 20 %, P = 0.035) and epidermoid carcinoma (32 vs. 9 %, P \ 0.001) spread more frequently exclusively to the bone. On the contrary, the T and N status were not significantly
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Table 1 Patients’ characteristics (n = 189) Characteristics Median age, years (range)
n
(%) 60
(27–92)
66
(34.9)
123
(65.1)
Sex Female Male PT localisation Colon
69
(36.5)
Rectum
41
(21.7)
Cardia-stomach
29
(15.3)
Oesophagus
50
(26.5)
19 107
(15.1) (84.9)
Tumour size (T) T0–2 T3–4 Txa
63
(33)
Nodal status (N) N0
32
(29.4)
N1–2
77
(70.6)
Nxa
80
Metastasis at diagnosisb (M) M0 M1
c
86
(45.5)
103
(54.5)
157
(83.1)
30
(15.9)
2
(1.1)
1
(1–4)
PT histology Adenocarcinoma Epidermoid carcinoma Undifferentiated Median number of metastatic sites at metastatic stage diagnosis (range) PT primary tumour a
Non-operated patients
b
Date of diagnosis of the primary tumour
c
Considered as M1 if discovery delay B6 months from PT diagnosis
different between these two subsets. At the end of the study, the metastases of 43 patients had remained completely bone-exclusive (i.e., 14 patients who were boneexclusive at BM diagnosis developed other metastases during follow-up such as visceral lesions). Among these 43 patients, 84 % were males (n = 36) versus 59.6 % in the non-bone-exclusive subset (n = 87/146, P = 0.004). On the contrary, PT localisation and histology were not different (P = 0.287 and 0.111, respectively). Median time from PT diagnosis to BM diagnosis was shorter for GEC than for CRC (4.0 vs. 25.1 months, P \ 0.001). In univariate analyses, several factors significantly influenced the median time to BM occurrence such as the PT localisation, histology and TNM staging, the most advanced cancer leading to faster diagnosis of BM (Table 2). A curative treatment of the PT, especially surgical, significantly lengthened this delay. However, in multivariate analyses, the number of significant prognostic
Fig. 1 Metastatic disease at cancer diagnosis (black) and during the course of the disease (grey)
parameters was lower. Indeed, the occurrence delay was significantly shorter for patients with GEC (HR 2.1, 95 % CI 1.0–4.3), positive N (HR 1.9, 95 % CI 1.1–3.4) and positive M (HR 2.4, 95 % CI 1.3–4.6) status, and epidermoid carcinoma (HR 6.0, 95 % CI 1.6–23.2). Diagnosis circumstances and treatment Overall, pain was the most frequent clinical sign leading to BM diagnosis (77.2 %), followed by neurological signs (5.8 %), which were significantly higher in GEC than in CRC (P \ 0.001, see Table 3). Conversely, hypercalcemia and fractures were very uncommon (two and three patients, respectively). BM were confirmed at bone scan in 173 patients (91.5 %). Among those patients, the median number of lesions was 2 (range 0–17), with no significant difference according to PT site (P = 0.082), and secondary diffuse BM were observed in 35 patients (20.2 %). Bone lesions were primarily located to the hip (48.6 %), the lumbar vertebrae (40.5 %), the dorsal rachis (39.3 %), the ribs (37.0 %) and the femur (28.9 %). Other sites included cervical vertebrae, skull and humerus. Clinical characteristics of BM at the CT scan was available for 92 patients (48.7 %) and revealed that lesions were more often osteolytic (59.8 %) rather than condensing (10.3 %) or mixed (4.7 %). SRE occurred in 59 patients (53.6 %), with significantly more fractures in GEC than in CRC (8.9 vs. 0.9 %; P = 0.007; Table 3). However, no significant difference was observed in terms of applied treatment between CRC and GEC. BM-induced pain was mostly managed with the use of analgesic drugs, bisphosphonates, and localised radiation therapy whereas surgery was performed after pathological fracture or spinal cord compression.
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Table 2 Bone metastasis occurrence delay according to disease and treatment characteristics
n
Delay (months)
P-value
Median
[95 % CI]
Univariate analyses*
Multivariate analyses**
\0.001
0.041
[17.9–34.1] 0.032
0.323
0.019
0.024
\0.001
0.006
\0.001
0.009
\0.001
0.404
\0.001
0.562
PT localisation CRC
110
25.1
GEC
79
4.0
T0–2
19
21.1
[10.5–59.4]
T3–4
107
17.9
[11.1–22.6]
[2.2–6.4]
PT size (T)
Nodal status (N) N0
32
34.1
[16.5–44.8]
77
18.7
[12.1–23.4]
M0
86
29.9
[21.5–39.1]
M1b
103
2.5
157
17.9
30
2.2
[1.7–5.1]
No
74
2.3
[1.0–5.3]
Yes
115
20.2
No
67
2.0
Yes
122
23.6
N1–2 Metastasis at diagnosisa (M)
[1.9–4.0]
PT histology CI confidence interval, PT primary tumour * Log-rank test, ** Cox regression model a
Date of diagnosis of the primary tumour
b
Considered as M1 if discovery delay B6 months from PT diagnosis
Adenocarcinoma Epidermoid carcinoma Curative treatment of PT
[16.5–29.8]
Surgery of PT
Treatment of PT and metastases included surgery for 122 patients (64.6 %), radiotherapy for 95 patients (50.3 %) and chemotherapy for 168 patients (88.9 %) with an average of two lines of treatment (range 1–5). Only 22 patients (13.1 %) received targeted therapies. Survival analysis At the time of analysis, the median follow-up from BM diagnosis was 39.8 months (range 0.2–91.7). Median OS for patients with CRC and GEC were 9.4 months (95 % CI 6.4–11.1) and 3.4 months (95 % CI 2.5–9.0), respectively (P = 0.111; Fig. 2). Univariate analyses highlighted that several parameters had a significant influence on patients’ outcome (Table 4). Patients whose PT was resected had a longer OS of 9.9 months (95 % CI 7.2–11.4) as compared with non-operated patients (3.4 months [95 % CI 2.6–5.5], P = 0.011). Furthermore, the number of BM was also a significant prognostic factor (\3: 9.9 months [95 % CI 6.4–12.2 vs. C3: 4.7 months [95 % CI 2.7–9.0], P = 0.015). As with time to BM occurrence, a positive nodal status and the presence of metastasis at PT diagnosis were significantly associated with lower OS rates. In addition, patients who develop BM within 6 months after PT diagnosis also have a poorer prognosis. However, PT size, histology and curative treatment did not significantly
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[12.5–21.5]
[0.8–2.8] [19.1–32.6]
influence patients’ OS. On multivariate analyses, only the surgical treatment of PT (yes: HR 0.3, 95 % CI 0.1–0.8) and the number of BM (C3: HR 1.7, 95 % CI 1.0–2.9) remained correlated with OS (Table 4). In addition, patients with bone-exclusive metastases at BM diagnosis (n = 57) had a longer median OS than those with mixed metastases (9.8 months, 95 % CI 3.3–20.4 vs. 7.0 months, 95 % CI 4.8–9.1, respectively, P = 0.007). However, when considering OS rates at 1 and 5 years, no statistical difference was observed.
Discussion This retrospective study aimed to determine the frequency of BM in patients with GI tumours, and to identify possible subsets of patients who should undergo investigation for BM. Results showed a 5.5 % incidence of BM originating from GI tumours, confirming that bone is an unusual site for primary GI tumour spread. The observed incidence of BM from CRC (4.5 %) is close to those of two American studies with an incidence of 6.9 % (8.9 and 5.1 % in rectal and colon cancer, respectively between 1960 and 1970) [16] and 6.6 % in a retrospective study (1970–1995) [17]. Except for a retrospective American study of 252 patients
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Table 3 Metastatic disease diagnosis circumstances, complication occurrence and treatment administration for patients with colorectal cancer (CRC, n = 110) and gastroesophageal cancer (GEC, n = 79) CRC
GEC
P-value*
Signs leading to bone metastasis suspiciona Pain Neurological sign Fracture
84
(97 %)
62
(81 %)
0.732
1 1
(1 %) (1 %)
10 2
(10 %) (3 %)
\0.001 0.379
Hypercalcemia
0
–
2
(3 %)
0.093
Other
1
(1 %)
1
(1 %)
0.813
(57 %)
0.650
(10.1 %)
0.220
Missing One SREb or more during the course of the disease
25
15
59
(53.6 %)
45
Neurological compression
18
(16.4 %)
8
Hypercalcemia
3
(2.7 %)
7c
(8.9 %)
0.085
Fracture
1
(0.9 %)
7
(8.9 %)
0.007
Analgesic drugs
95
(86.4 %)
73
(92.4 %)
0.192
Radiotherapy
56
(50.9 %)
39
(49.4 %)
0.834
Bisphosphonates
8
(7.3 %)
11
(13.9 %)
0.134
Surgery of PT
6
(5.5 %)
6
(7.6 %)
0.552
Treatment
PT primary tumour, SRE skeletal-related event * Difference between primary tumour localisation a
There may have been several signs for one single patient
b
SRE, skeletal-related events including neurological compression, hypercalcemia, need for bone surgery or radiation therapy, and pathological fractures
c
One missing data for calcemia in this subset
with CRC (2000–2008) reporting a 5.5 % of incidence (all patients had benefited from a FDG-PET [14]), the observed incidence of our study remains lower than many of those published in studies from the same period. The actual incidence of BM is probably underestimated in GI cancer, because a large proportion of patients remain asymptomatic. Indeed, bone pain is often the first clinical sign that leads to diagnosis as seen in our study. In an Italian retrospective multicentre observational study, authors reported a 10 % incidence of BM in patients with CRC treated between 1989 and 2000 (n = 264) [15]. Likewise, the incidence was 10.4 % in American patients with metastatic CRC and systematically undergoing bone scan between 1993 and 2002 [5]. Finally, 23.7 % (n = 28/118) and 30 % (n = 43/145) patients with CRC had BM in a Japanese [18] and an American [19] autopsy studies, respectively, such values being certainly overestimated due to the stage of the disease at the date of death. However, in gastric cancer, the observed incidence (7.9 %) was higher than in previous reports. In a Korean retrospective study, BM were detected in 30 patients out of 1,683 with gastric cancer (1.8 %) [20]. Likewise, a retrospective study (1998–2008) on 8,633 patients with gastric cancer reported only 2.4 % of BM [21]. These results contrast with those recently published from a retrospective study (1998–2011) on more than 2,000 patients with gastric cancer that reported 10 % of BM [12]. Diagnosis circumstances and study types seem to greatly impact reported incidences. The observed median time to BM was different than those published, namely lower in gastric cancer and higher
Fig. 2 Overall survival curves of patients with colorectal cancer (CRC) and gastroesophageal cancer (GEC). Survival was calculated from the date of bone metastases diagnosis
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Table 4 Overall survival rates at 1 year and correlation to tumour characteristics n
OS rate at 1 year (%)
PT size (T) T0–2
19
48
T3–4
107
35
N0
32
50
N1–2
77
27
Nodal status (N)
Metastasis at diagnosisb (M) M0
86
46
M1a
103
22
Synchronous BM (within 6 months after PT diagnosis) No
117
39
Yes
72
23
157
35
30
30
\3
85
42
C3
84
26
PT histology Adenocarcinoma Epidermoid carcinoma Number of BM
Curative treatment of PT No
74
25
Yes
115
39
Surgery of PT No
67
23
Yes
122
39
P-value* Univariate analyses*
Multivariate analyses**
0.406
0.831
0.038
0.068
0.003
0.257
0.021
0.142
0.301
0.997
0.015
0.040
0.072
0.473
0.011
0.017
BM bone metastasis, OS overall survival, PT primary tumour * Log-rank test, ** Cox regression model a
Considered as M1 if discovery delay B6 months from PT diagnosis
b
Date of diagnosis of the primary tumour
in CRC. Indeed, in gastric cancer, Silvestris et al. reported a median time to BM diagnosis of 8 months (95 % CI 6.1–9.9 months) [12]. In CRC, Santini et al. reported a median time to BM diagnosis of 11 months (95 % CI 4.7–13.1 months). An explanation could be that PT stages were different between the studied populations. Moreover, 55 % of patients developed one or more SRE, as expected in breast, prostate or lung cancer. SRE reduce quality of life and require more supportive care, with antalgic, surgery of pathologic bone fractures or palliative radiotherapy treatment [22]. Bisphosphonates and denosumab (a RANK ligand inhibitor) are not usually used in GI cancer as indicated in
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breast, prostate and lung cancers, in which they reduce SRE by 16–41 % [23, 24], 11 % [25], and 10 % [26], respectively. However, the use of strong analgesic drugs, palliative radiotherapy, and surgery is frequent in the event of fractures or medullar compression. Regarding bone-exclusive metastases the observed rate in CRC (26 patients, 23.6 % of our CRC patients) was somewhat higher than the one reported in the retrospective study of Kanthan et al. (1970–1995, 16.9 %) [17]. However, the observed rate in gastric cancer (14 %) was close to the one published by Park et al. in the same period (1998–2008, 15.3 %) [21]. This results contrast with those of the Roth retrospective study with no exclusive BM at all [14]. Kanthan et al. also observed that patients with boneexclusive metastases survived longer at 5 years than patients with mixed localisations (38 vs. 16 %, respectively) but this difference was not maintained at 10 years [17]. OS rates at 5 years were higher in our cohort both for bone-exclusive and mixed subsets (54.1 vs. 58.7 %, respectively). Moreover, we observed a similar difference but only when comparing median OS. One explanation of the longer survival of patients with bone-exclusive metastases is that bone is not a vital organ. BM undeniably impact patients’ quality of life, though. Another explanation could lie in the metastatic process and efficiency that differ according to the tumour biology. Indeed, metastases develop after the release of tumour cells that spread via the blood or lymphatic system [27–29]. This process is not bone-specific in itself and generally relates to the proportion of cells released [13]. However, some tumour types also display a genetic profile gearing the disseminated cells especially towards the bone by enhancing the cell mobility and adhesion to this tissue [27]. Consequently, boneexclusive metastases could originate from a peculiar tumour type—with a specific tumour biology—whereas, when associated with other metastases, BM may reflect the aggressive nature of observed GI cancers rather than a particular bone tropism. In accordance with the literature, a poor median survival of 3.4 months was observed for patients with GEC and BM [21]. At the same study period (2000–2005) in previously untreated patients with advanced GEC, median survival times were 9.9, 9.9, 9.3 and 11.2 months if treated by ECF, ECX, EOF and EOX, respectively [30]. The presence of BM has already been associated with a poorer prognosis in a Korean [31] and a Danish study [32]. A recent phase II prospective study in 70 patients with epidermoid oesophageal metastatic cancer found that the absence of BM is correlated with a better tumour control at 6 weeks [33]. Likewise, patients with BM from CRC had a poorer prognosis (median survival of 9.4 months) than reported in a study performed at the same period (1999–2001) in previously untreated metastatic CRC: median survivals of 15.0, 17.4 and 19.5 months if
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treated with IFL,1 IROX2 and FOLFOX,3 respectively [34]. However, this comparison is limited by the different definitions considered for survival times. In addition, Santini et al. reported a median OS of 7.0 months (95 % CI 5.6–8.7) for patients with CRC and BM [15]. In accordance with our results, they also highlighted the significant correlation of the number of BM with OS (P = 0.004). Our results have clinical consequences, suggesting that there may be a subset of patients with GI cancers of a particular profile associated with a quicker development of BM, and thus a BM-related poorer quality of life. Specifically, BM occurred more rapidly in patients with GEC, epidermoid carcinoma, a positive nodal status and synchronous metastases at diagnosis. When BM are diagnosed, the number of lesions and the resection of the PT are the factors significantly impacting survival. Such characteristics could constitute the basis for a future prospective study encompassing patients with and without BM. Accordingly, there is a need to provide effective early screening of this population, which raises the question of extending the use of bone scan in a systematic manner in these patients. With increasing numbers of patients with GI cancer eventually developing bone metastatic disease, clinicians aim to provide them with suitable bone-targeted therapy, thereby reducing the risk of complications and ensuring a satisfying functional level and quality of life [35, 36]. Although limitations of this analysis include its retrospective nature, these results warrant further prospective studies to more precisely pattern BM in GI cancer. The development of a predictive score would provide a valuable tool to better identify those patients with GI cancer who are most likely to develop BM and to help physicians to tailor treatment options. Acknowledgments We would like to acknowledge the editorial assistance of Dr. Vanessa Guillaumon and Dr. Julie Courraud. Conflict of interest of interest.
The authors declare that they have no conflict
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31. Lee J, Lim T, Uhm JE et al (2007) Prognostic model to predict survival following first-line chemotherapy in patients with metastatic gastric adenocarcinoma. Ann Oncol 18:886–891. doi:10. 1093/annonc/mdl501 32. Hernandez RK, Maegbaek ML, Liede A et al (2014) Bone metastases, skeletal-related events, and survival among children with cancer in Denmark. J Pediatr Hematol Oncol. doi:10.1097/ MPH.0000000000000106 33. Peugniez C, Hiret S, Galais M-P et al (2014) Les facteurs pre´dictifs de controˆle tumoral des carcinomes e´pidermoı¨des me´tastatiques de l’oesophage traite´s par chimiothe´rapie a` base de sels de platine: premiers re´sultats de l’e´tude E-DIS. In: JFHOD congress, Paris, France, p 108, #CO.87. http://www.snfge.org/sites/ default/files/SNFGE/JFHOD/livre-resumes-jfhod-2014-vfinale. pdf 34. Goldberg RM, Sargent DJ, Morton RF et al (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30. doi:10.1200/ JCO.2004.09.046 35. Henry DH, Costa L, Goldwasser F et al (2011) Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29:1125–1132. doi:10.1200/JCO.2010.31.3304 36. Aapro M, Abrahamsson PA, Body JJ et al (2008) Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 19:420–432. doi:10.1093/ annonc/mdm442
RESEARCH PAPER
Bone metastases in gastrointestinal cancer Fabienne Portales • Simon The´zenas • Emmanuelle Samalin • Eric Assenat • Thibault Mazard • Marc Ychou
Received: 30 April 2014 / Accepted: 20 October 2014 / Published online: 9 November 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Colorectal (CRC) and gastroesophageal (GEC) cancers unusually spread to the bone. However, bone metastases (BM) are responsible for skeletal-related events (SREs) associated with an altered quality of life. Aiming to describe the characteristics and prognostic influence of BM from gastro-intestinal cancers, we performed a retrospective analysis of prospectively collected data in patients treated in our institution (1996–2006). 189 patients (5.5 %) developed BM: 79 with GEC and 110 with CRC. 57 patients had bone-exclusive metastases. In univariate analyses, the median time to BM occurrence was correlated with the primary tumour (PT) localisation, surgery, histology and TNM staging. However, in multivariate analyses, the occurrence delay was significantly shorter only for patients with GEC (HR 2.1), N1–2 status (HR 1.9), M1 status (HR 2.4), and epidermoid carcinoma (HR 6.0). Pain was the most frequent clinical sign leading to BM diagnosis (77.2 %). SRE occurred in 55 % of patients. Median overall survivals (OSs) of patients with CRC and GEC were 9.4 months [95 % confidence interval (95 % CI) 6.4–11.1] and 3.4 months (95 % CI 2.5–9.0), respectively. In univariate analyses, OS was correlated with PT surgery F. Portales (&) E. Samalin E. Assenat T. Mazard M. Ychou Department of Digestive Oncology, Institut re´gional du Cancer de Montpellier (ICM) – Val d’Aurelle, 208 avenue des Apothicaires, 34298 Montpellier Cedex 5, France e-mail: [email protected] S. The´zenas Biostatistics Unit, Institut re´gional du Cancer de Montpellier (ICM) – Val d’Aurelle, Montpellier, France E. Assenat T. Mazard Medical and Digestive Oncology Unit, Hoˆpital Saint-Eloi, CHU de Montpellier, Montpellier, France
and NM staging, and the number of BM. In multivariate analyses, only the PT surgery and the number of BM remained correlated with OS. Our results suggest that there may be a subset of patients associated with a quicker development of BM. Given their higher risk of SRE, they could benefit from an early screening, calling for further prospective studies encompassing patients with and without BM. Keywords Colorectal cancer Gastric cancer Esophageal cancer Metastasis Bone metastasis Skeletal-related event
Introduction Cancers of the gastrointestinal (GI) tract are some of the most common incident forms of cancer in Europe, with more than half of cases arising from the colon [1]. If bone metastases (BM) are especially common in multiple myeloma, breast, prostate, lung, bladder, thyroid and renal cell carcinomas, their occurrence from GI tumours is rare, accounting for about 3–5 % [1–4]. Recent advances in GI cancer care including widespread screening programs, the rising use of combined multimodal therapeutic strategies, and the development of targeted therapies in metastatic disease, have led to changes in the natural history of disease [5]. Indeed, survival significantly improved, and an increased number of patients with GI cancer are likely to develop unusual metastatic sites, especially in the late stages. Although colorectal (CRC) and gastroesophageal (GEC) cancers usually spread to the liver, lung and peritoneum [6–8], bone may also be affected. Currently, neither bone scan nor X-rays are routinely used in patients with GI cancer to detect BM, often discovered due to
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clinical signs. Indeed, BM cause bone pain and substantial skeletal-related events (SREs) defined as spinal-cord compression, pathological fractures, radiotherapy and/or surgery to bone [9, 10] and hypercalcemia [11, 12]. Generally the pelvis, vertebrae and ribs are more often affected than distal bones. The most frequent complication of BM is bone pain resulting from structural damage, periosteal irritation, and nerve entrapment. Recent evidence suggests that pain caused by BM may also be related to the rate of bone resorption. Clinical consequences are decreased mobility, progressive loss of autonomy and significant alteration of quality of life [13]. Therefore, a better evaluation of the incidence and metastatic pattern of BM would be clinically relevant nowadays [14]. To our knowledge, there have been few studies evaluating BM from primary GI cancer [15]. The aim of this single-institution study was to describe the incidence and prognostic influence of BM from GI cancer, over a 10-year period, as well as to define a particular tumour profile which could benefit from an early screening.
Clin Exp Metastasis (2015) 32:7–14
considered as the date of the radiological or clinical examination that established the diagnosis, to the date of death from any cause. The closing date of the study analysis was used as the endpoint measure. OS rates and median values were estimated according to the Kaplan– Meier method and presented with their 95 % confidence intervals (95 % CIs). The median length of follow-up was estimated using a reverse Kaplan–Meier method and presented with associated 95 % CI. Survival curves were drawn and the log-rank test was performed to assess differences between two groups: CRC versus GEC. To investigate prognostic factors (on the median time to onset of BM), multivariate analyses were carried out using the Cox’s proportional hazards regression model with a stepwise selection procedure. All P-values reported are twosided, and the significance level was set at 5 % (P \ 0.05).
Results Study population
Patients and methods Patient selection and evaluation We performed a retrospective analysis of prospectively collected data of patients with BM originating from GI carcinoma treated in the Montpellier Cancer Institute (ICM, Montpellier, France) between 1996 and 2006. We distinguished two different groups of patients according to primary tumour (PT) site: CRC or GEC. BM were primarily detected clinically by bone pain, neurological compression, hypercalcemia, and/or pathological fractures. Diagnosis confirmation was obtained using bone scan, X-ray, computed tomography (CT) scan or magnetic resonance imaging. A dedicated computerised form was created to collect demographic data, clinical and pathological characteristics including PT site, histological type, number and location of BM, occurrence pattern and therapeutic management. The time between PT diagnosis and BM occurrence was recorded as well as the patients’ outcome. This study was approved by the Institutional Review Board of the ICM. Statistical analysis Categorical variables were reported by means of contingency tables. For continuous variables, median and range values were computed. To investigate the association between study features, univariate statistical analyses were performed using the Pearson’s v2 test. Overall survival (OS) time was measured from the date of BM diagnosis,
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Over a 10-year period, a total of 3,438 patients with primary GI tumours were treated at the ICM. Among them, 2,434 (71 %) were diagnosed with CRC and 1,004 (29 %) with GEC. We identified 189 patients (5.5 %) who developed BM with a higher incidence in patients with GEC (7.9 %) than with CRC (4.5 %). Patient and tumour characteristics are detailed in Table 1. Characteristics of metastases At cancer diagnosis, 103 patients (54.5 % of the total group) had synchronous metastatic disease (diagnosed within 6 months after PT diagnosis) referred as the ‘‘M1’’ group (Fig. 1). Among the latter, 69 patients (67.0 % of the M1 group) had visceral metastases, 50 (48.5 %) in the liver and 26 (25.2 %) in the lung. Those synchronous metastases were exclusively visceral in 31 patients (30.1 %), and bone-exclusive in 34 patients (33.0 %). Patients with metachronous metastases (n = 86) are referred as the ‘‘M0’’ group. At BM diagnosis, patients from the M0 group had developed either bone-exclusive or mixed (bone and viscera) metastases (Fig. 1). In total, 57 patients (30.2 % of the total group) had bone-exclusive metastases, of whom 23 from esophageal PT (40 %), 8 from gastric PT (14 %), 15 from colic PT (26 %), and 11 from rectal PT (19 %). In this bone-exclusive subset of patients, males were more represented (79 %) than in the non-bone-exclusive subset (59 %, P = 0.009). Likewise, oesophageal PT (40 vs. 20 %, P = 0.035) and epidermoid carcinoma (32 vs. 9 %, P \ 0.001) spread more frequently exclusively to the bone. On the contrary, the T and N status were not significantly
Clin Exp Metastasis (2015) 32:7–14
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Table 1 Patients’ characteristics (n = 189) Characteristics Median age, years (range)
n
(%) 60
(27–92)
66
(34.9)
123
(65.1)
Sex Female Male PT localisation Colon
69
(36.5)
Rectum
41
(21.7)
Cardia-stomach
29
(15.3)
Oesophagus
50
(26.5)
19 107
(15.1) (84.9)
Tumour size (T) T0–2 T3–4 Txa
63
(33)
Nodal status (N) N0
32
(29.4)
N1–2
77
(70.6)
Nxa
80
Metastasis at diagnosisb (M) M0 M1
c
86
(45.5)
103
(54.5)
157
(83.1)
30
(15.9)
2
(1.1)
1
(1–4)
PT histology Adenocarcinoma Epidermoid carcinoma Undifferentiated Median number of metastatic sites at metastatic stage diagnosis (range) PT primary tumour a
Non-operated patients
b
Date of diagnosis of the primary tumour
c
Considered as M1 if discovery delay B6 months from PT diagnosis
different between these two subsets. At the end of the study, the metastases of 43 patients had remained completely bone-exclusive (i.e., 14 patients who were boneexclusive at BM diagnosis developed other metastases during follow-up such as visceral lesions). Among these 43 patients, 84 % were males (n = 36) versus 59.6 % in the non-bone-exclusive subset (n = 87/146, P = 0.004). On the contrary, PT localisation and histology were not different (P = 0.287 and 0.111, respectively). Median time from PT diagnosis to BM diagnosis was shorter for GEC than for CRC (4.0 vs. 25.1 months, P \ 0.001). In univariate analyses, several factors significantly influenced the median time to BM occurrence such as the PT localisation, histology and TNM staging, the most advanced cancer leading to faster diagnosis of BM (Table 2). A curative treatment of the PT, especially surgical, significantly lengthened this delay. However, in multivariate analyses, the number of significant prognostic
Fig. 1 Metastatic disease at cancer diagnosis (black) and during the course of the disease (grey)
parameters was lower. Indeed, the occurrence delay was significantly shorter for patients with GEC (HR 2.1, 95 % CI 1.0–4.3), positive N (HR 1.9, 95 % CI 1.1–3.4) and positive M (HR 2.4, 95 % CI 1.3–4.6) status, and epidermoid carcinoma (HR 6.0, 95 % CI 1.6–23.2). Diagnosis circumstances and treatment Overall, pain was the most frequent clinical sign leading to BM diagnosis (77.2 %), followed by neurological signs (5.8 %), which were significantly higher in GEC than in CRC (P \ 0.001, see Table 3). Conversely, hypercalcemia and fractures were very uncommon (two and three patients, respectively). BM were confirmed at bone scan in 173 patients (91.5 %). Among those patients, the median number of lesions was 2 (range 0–17), with no significant difference according to PT site (P = 0.082), and secondary diffuse BM were observed in 35 patients (20.2 %). Bone lesions were primarily located to the hip (48.6 %), the lumbar vertebrae (40.5 %), the dorsal rachis (39.3 %), the ribs (37.0 %) and the femur (28.9 %). Other sites included cervical vertebrae, skull and humerus. Clinical characteristics of BM at the CT scan was available for 92 patients (48.7 %) and revealed that lesions were more often osteolytic (59.8 %) rather than condensing (10.3 %) or mixed (4.7 %). SRE occurred in 59 patients (53.6 %), with significantly more fractures in GEC than in CRC (8.9 vs. 0.9 %; P = 0.007; Table 3). However, no significant difference was observed in terms of applied treatment between CRC and GEC. BM-induced pain was mostly managed with the use of analgesic drugs, bisphosphonates, and localised radiation therapy whereas surgery was performed after pathological fracture or spinal cord compression.
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Table 2 Bone metastasis occurrence delay according to disease and treatment characteristics
n
Delay (months)
P-value
Median
[95 % CI]
Univariate analyses*
Multivariate analyses**
\0.001
0.041
[17.9–34.1] 0.032
0.323
0.019
0.024
\0.001
0.006
\0.001
0.009
\0.001
0.404
\0.001
0.562
PT localisation CRC
110
25.1
GEC
79
4.0
T0–2
19
21.1
[10.5–59.4]
T3–4
107
17.9
[11.1–22.6]
[2.2–6.4]
PT size (T)
Nodal status (N) N0
32
34.1
[16.5–44.8]
77
18.7
[12.1–23.4]
M0
86
29.9
[21.5–39.1]
M1b
103
2.5
157
17.9
30
2.2
[1.7–5.1]
No
74
2.3
[1.0–5.3]
Yes
115
20.2
No
67
2.0
Yes
122
23.6
N1–2 Metastasis at diagnosisa (M)
[1.9–4.0]
PT histology CI confidence interval, PT primary tumour * Log-rank test, ** Cox regression model a
Date of diagnosis of the primary tumour
b
Considered as M1 if discovery delay B6 months from PT diagnosis
Adenocarcinoma Epidermoid carcinoma Curative treatment of PT
[16.5–29.8]
Surgery of PT
Treatment of PT and metastases included surgery for 122 patients (64.6 %), radiotherapy for 95 patients (50.3 %) and chemotherapy for 168 patients (88.9 %) with an average of two lines of treatment (range 1–5). Only 22 patients (13.1 %) received targeted therapies. Survival analysis At the time of analysis, the median follow-up from BM diagnosis was 39.8 months (range 0.2–91.7). Median OS for patients with CRC and GEC were 9.4 months (95 % CI 6.4–11.1) and 3.4 months (95 % CI 2.5–9.0), respectively (P = 0.111; Fig. 2). Univariate analyses highlighted that several parameters had a significant influence on patients’ outcome (Table 4). Patients whose PT was resected had a longer OS of 9.9 months (95 % CI 7.2–11.4) as compared with non-operated patients (3.4 months [95 % CI 2.6–5.5], P = 0.011). Furthermore, the number of BM was also a significant prognostic factor (\3: 9.9 months [95 % CI 6.4–12.2 vs. C3: 4.7 months [95 % CI 2.7–9.0], P = 0.015). As with time to BM occurrence, a positive nodal status and the presence of metastasis at PT diagnosis were significantly associated with lower OS rates. In addition, patients who develop BM within 6 months after PT diagnosis also have a poorer prognosis. However, PT size, histology and curative treatment did not significantly
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[12.5–21.5]
[0.8–2.8] [19.1–32.6]
influence patients’ OS. On multivariate analyses, only the surgical treatment of PT (yes: HR 0.3, 95 % CI 0.1–0.8) and the number of BM (C3: HR 1.7, 95 % CI 1.0–2.9) remained correlated with OS (Table 4). In addition, patients with bone-exclusive metastases at BM diagnosis (n = 57) had a longer median OS than those with mixed metastases (9.8 months, 95 % CI 3.3–20.4 vs. 7.0 months, 95 % CI 4.8–9.1, respectively, P = 0.007). However, when considering OS rates at 1 and 5 years, no statistical difference was observed.
Discussion This retrospective study aimed to determine the frequency of BM in patients with GI tumours, and to identify possible subsets of patients who should undergo investigation for BM. Results showed a 5.5 % incidence of BM originating from GI tumours, confirming that bone is an unusual site for primary GI tumour spread. The observed incidence of BM from CRC (4.5 %) is close to those of two American studies with an incidence of 6.9 % (8.9 and 5.1 % in rectal and colon cancer, respectively between 1960 and 1970) [16] and 6.6 % in a retrospective study (1970–1995) [17]. Except for a retrospective American study of 252 patients
Clin Exp Metastasis (2015) 32:7–14
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Table 3 Metastatic disease diagnosis circumstances, complication occurrence and treatment administration for patients with colorectal cancer (CRC, n = 110) and gastroesophageal cancer (GEC, n = 79) CRC
GEC
P-value*
Signs leading to bone metastasis suspiciona Pain Neurological sign Fracture
84
(97 %)
62
(81 %)
0.732
1 1
(1 %) (1 %)
10 2
(10 %) (3 %)
\0.001 0.379
Hypercalcemia
0
–
2
(3 %)
0.093
Other
1
(1 %)
1
(1 %)
0.813
(57 %)
0.650
(10.1 %)
0.220
Missing One SREb or more during the course of the disease
25
15
59
(53.6 %)
45
Neurological compression
18
(16.4 %)
8
Hypercalcemia
3
(2.7 %)
7c
(8.9 %)
0.085
Fracture
1
(0.9 %)
7
(8.9 %)
0.007
Analgesic drugs
95
(86.4 %)
73
(92.4 %)
0.192
Radiotherapy
56
(50.9 %)
39
(49.4 %)
0.834
Bisphosphonates
8
(7.3 %)
11
(13.9 %)
0.134
Surgery of PT
6
(5.5 %)
6
(7.6 %)
0.552
Treatment
PT primary tumour, SRE skeletal-related event * Difference between primary tumour localisation a
There may have been several signs for one single patient
b
SRE, skeletal-related events including neurological compression, hypercalcemia, need for bone surgery or radiation therapy, and pathological fractures
c
One missing data for calcemia in this subset
with CRC (2000–2008) reporting a 5.5 % of incidence (all patients had benefited from a FDG-PET [14]), the observed incidence of our study remains lower than many of those published in studies from the same period. The actual incidence of BM is probably underestimated in GI cancer, because a large proportion of patients remain asymptomatic. Indeed, bone pain is often the first clinical sign that leads to diagnosis as seen in our study. In an Italian retrospective multicentre observational study, authors reported a 10 % incidence of BM in patients with CRC treated between 1989 and 2000 (n = 264) [15]. Likewise, the incidence was 10.4 % in American patients with metastatic CRC and systematically undergoing bone scan between 1993 and 2002 [5]. Finally, 23.7 % (n = 28/118) and 30 % (n = 43/145) patients with CRC had BM in a Japanese [18] and an American [19] autopsy studies, respectively, such values being certainly overestimated due to the stage of the disease at the date of death. However, in gastric cancer, the observed incidence (7.9 %) was higher than in previous reports. In a Korean retrospective study, BM were detected in 30 patients out of 1,683 with gastric cancer (1.8 %) [20]. Likewise, a retrospective study (1998–2008) on 8,633 patients with gastric cancer reported only 2.4 % of BM [21]. These results contrast with those recently published from a retrospective study (1998–2011) on more than 2,000 patients with gastric cancer that reported 10 % of BM [12]. Diagnosis circumstances and study types seem to greatly impact reported incidences. The observed median time to BM was different than those published, namely lower in gastric cancer and higher
Fig. 2 Overall survival curves of patients with colorectal cancer (CRC) and gastroesophageal cancer (GEC). Survival was calculated from the date of bone metastases diagnosis
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Clin Exp Metastasis (2015) 32:7–14
Table 4 Overall survival rates at 1 year and correlation to tumour characteristics n
OS rate at 1 year (%)
PT size (T) T0–2
19
48
T3–4
107
35
N0
32
50
N1–2
77
27
Nodal status (N)
Metastasis at diagnosisb (M) M0
86
46
M1a
103
22
Synchronous BM (within 6 months after PT diagnosis) No
117
39
Yes
72
23
157
35
30
30
\3
85
42
C3
84
26
PT histology Adenocarcinoma Epidermoid carcinoma Number of BM
Curative treatment of PT No
74
25
Yes
115
39
Surgery of PT No
67
23
Yes
122
39
P-value* Univariate analyses*
Multivariate analyses**
0.406
0.831
0.038
0.068
0.003
0.257
0.021
0.142
0.301
0.997
0.015
0.040
0.072
0.473
0.011
0.017
BM bone metastasis, OS overall survival, PT primary tumour * Log-rank test, ** Cox regression model a
Considered as M1 if discovery delay B6 months from PT diagnosis
b
Date of diagnosis of the primary tumour
in CRC. Indeed, in gastric cancer, Silvestris et al. reported a median time to BM diagnosis of 8 months (95 % CI 6.1–9.9 months) [12]. In CRC, Santini et al. reported a median time to BM diagnosis of 11 months (95 % CI 4.7–13.1 months). An explanation could be that PT stages were different between the studied populations. Moreover, 55 % of patients developed one or more SRE, as expected in breast, prostate or lung cancer. SRE reduce quality of life and require more supportive care, with antalgic, surgery of pathologic bone fractures or palliative radiotherapy treatment [22]. Bisphosphonates and denosumab (a RANK ligand inhibitor) are not usually used in GI cancer as indicated in
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breast, prostate and lung cancers, in which they reduce SRE by 16–41 % [23, 24], 11 % [25], and 10 % [26], respectively. However, the use of strong analgesic drugs, palliative radiotherapy, and surgery is frequent in the event of fractures or medullar compression. Regarding bone-exclusive metastases the observed rate in CRC (26 patients, 23.6 % of our CRC patients) was somewhat higher than the one reported in the retrospective study of Kanthan et al. (1970–1995, 16.9 %) [17]. However, the observed rate in gastric cancer (14 %) was close to the one published by Park et al. in the same period (1998–2008, 15.3 %) [21]. This results contrast with those of the Roth retrospective study with no exclusive BM at all [14]. Kanthan et al. also observed that patients with boneexclusive metastases survived longer at 5 years than patients with mixed localisations (38 vs. 16 %, respectively) but this difference was not maintained at 10 years [17]. OS rates at 5 years were higher in our cohort both for bone-exclusive and mixed subsets (54.1 vs. 58.7 %, respectively). Moreover, we observed a similar difference but only when comparing median OS. One explanation of the longer survival of patients with bone-exclusive metastases is that bone is not a vital organ. BM undeniably impact patients’ quality of life, though. Another explanation could lie in the metastatic process and efficiency that differ according to the tumour biology. Indeed, metastases develop after the release of tumour cells that spread via the blood or lymphatic system [27–29]. This process is not bone-specific in itself and generally relates to the proportion of cells released [13]. However, some tumour types also display a genetic profile gearing the disseminated cells especially towards the bone by enhancing the cell mobility and adhesion to this tissue [27]. Consequently, boneexclusive metastases could originate from a peculiar tumour type—with a specific tumour biology—whereas, when associated with other metastases, BM may reflect the aggressive nature of observed GI cancers rather than a particular bone tropism. In accordance with the literature, a poor median survival of 3.4 months was observed for patients with GEC and BM [21]. At the same study period (2000–2005) in previously untreated patients with advanced GEC, median survival times were 9.9, 9.9, 9.3 and 11.2 months if treated by ECF, ECX, EOF and EOX, respectively [30]. The presence of BM has already been associated with a poorer prognosis in a Korean [31] and a Danish study [32]. A recent phase II prospective study in 70 patients with epidermoid oesophageal metastatic cancer found that the absence of BM is correlated with a better tumour control at 6 weeks [33]. Likewise, patients with BM from CRC had a poorer prognosis (median survival of 9.4 months) than reported in a study performed at the same period (1999–2001) in previously untreated metastatic CRC: median survivals of 15.0, 17.4 and 19.5 months if
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treated with IFL,1 IROX2 and FOLFOX,3 respectively [34]. However, this comparison is limited by the different definitions considered for survival times. In addition, Santini et al. reported a median OS of 7.0 months (95 % CI 5.6–8.7) for patients with CRC and BM [15]. In accordance with our results, they also highlighted the significant correlation of the number of BM with OS (P = 0.004). Our results have clinical consequences, suggesting that there may be a subset of patients with GI cancers of a particular profile associated with a quicker development of BM, and thus a BM-related poorer quality of life. Specifically, BM occurred more rapidly in patients with GEC, epidermoid carcinoma, a positive nodal status and synchronous metastases at diagnosis. When BM are diagnosed, the number of lesions and the resection of the PT are the factors significantly impacting survival. Such characteristics could constitute the basis for a future prospective study encompassing patients with and without BM. Accordingly, there is a need to provide effective early screening of this population, which raises the question of extending the use of bone scan in a systematic manner in these patients. With increasing numbers of patients with GI cancer eventually developing bone metastatic disease, clinicians aim to provide them with suitable bone-targeted therapy, thereby reducing the risk of complications and ensuring a satisfying functional level and quality of life [35, 36]. Although limitations of this analysis include its retrospective nature, these results warrant further prospective studies to more precisely pattern BM in GI cancer. The development of a predictive score would provide a valuable tool to better identify those patients with GI cancer who are most likely to develop BM and to help physicians to tailor treatment options. Acknowledgments We would like to acknowledge the editorial assistance of Dr. Vanessa Guillaumon and Dr. Julie Courraud. Conflict of interest of interest.
The authors declare that they have no conflict
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1 2 3
IFL (irinotecan, 5-fluorouracile and leucovorin). IROX (irinotecan and oxaliplatin). FOLFOX (5-fluorouracile, oxaliplatin and leucovorin).
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