- Email: [email protected]
Brain Metastasis in Colorectal Cancer Patients: Survival and Analysis of Prognostic Factors
Original Study
Brain Metastasis in Colorectal Cancer Patients: Survival and Analysis of Prognostic Factors Marlies Michl,1 Johannes Thurmaier,1 Gabriele Schubert-Fritschle,2 Max Wiedemann,2 Rüdiger P. Laubender,3 Natascha C. Nüssler,4 Reinhard Ruppert,4 Jörg Kleeff,5 Wolfgang Schepp,6 Clemens Reuter,7 Florian Löhe,8 Meinolf Karthaus,9 Jens Neumann,10 Thomas Kirchner,10 Jutta Engel,2,3 Volker Heinemann1 Abstract To our knowledge, this is the largest number of patients with colorectal cancer and brain metastasis (BM) analyzed to date (n [ 228; 134 male [59%]; 94 female [41%]; median age 63 years). Most primary tumors were staged as T3/4, ND, Grade 2. BM occurred 29.2 months after initial diagnosis. Overall survival from the time of first diagnosis was 35.6 months, from the time of metastatatic disease 16.5 months, and from BM 2.0 months. Solitary BM were found in 13.6%. 80.7% of all BM occurred sequentially. Background: The purpose of the study was to characterize the rare cohort of patients (pts) with metastatic colorectal cancer (mCRC) and brain metastasis (BM) and to identify prognostic subgroups. Patients and Methods: In collaboration with the Munich Cancer Registry, pts with mCRC and BM who were diagnosed between 1998 and 2011 were identified. Survival from the time of first diagnosis of colorectal cancer (CRC) (OS-1), from the time of diagnosis of metastatic disease (OS-2) and of BM (OS-3) was calculated regarding (1) the temporal occurrence of extra- and intracranial metastasis (meta- vs. synchronous) and (2) tumor and patient characteristics. For survival analysis the KaplaneMeier estimator and Cox regression models were used. Results: A total of 228 pts (134 male [59%], 94 female [41%]) were identified. The median age was 63 years (142 pts [62%] were 65 years of age or younger). Most pts presented with primary tumors staged T3/4, Nþ, Grade 2. The primary tumor was located predominantly in the left colon (155 pts; 68%), especially in the rectum (95 pts; 42%). Median OS-1 was 35.6 months (95% confidence interval [CI], 30.1-41.1 months), OS-2 was 16.5 months (95% CI, 13.9-19.1 months), and OS-3 was 2.0 months (95% CI, 1.52.5 months). Median time from first CRC diagnosis to BM was 29.2 months. Subsequent BM after extracranial metastasis were observed in 184 pts (80.7%), whereas 31 pts (13.6%) presented with solitary BM. Univariate analysis did not reveal a prognostic variable for overall survival after diagnosis of BM. Conclusion: This study presents the largest number of pts with mCRC and BM analyzed to date. The results show that most mCRC pts develop BM as a late step in the course of disease. Median time from first CRC diagnosis to BM is 29.2 months. Only a few pts were diagnosed with BM early in the disease or with solitary BM. When BM is present survival is poor. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Brain metastasis, CNS metastasis, Metastatic colorectal cancer, Subgroups, Survival
1 Department of Hematology and Medical Oncology, Klinikum Grosshadern and Comprehensive Cancer Center Munich (CCCM), Ludwig-Maximilians-University of Munich, Munich, Germany 2 Munich Cancer Registry (MCR), IBE / Klinikum Grosshadern, Ludwig-MaximiliansUniversity of Munich, Munich, Germany 3 Institute of Medical Informatics, Biometry and Epidemiology (IBE), LudwigMaximilians-University of Munich, Munich, Germany 4 Department of Surgery, Klinikum Neuperlach, Städtisches Klinikum München, Munich, Germany 5 Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany 6 Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, Klinikum Bogenhausen, Städtisches Klinikum München, Munich, Germany
1533-0028/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2015.05.009
7 Department of Surgery, Krankenhaus Barmherzige Brüder München, Munich, Germany 8 Department of Surgery, Klinikum Landshut, Landshut, Germany 9 Department of Hematology, Oncology and Palliative Care, Städtisches Klinikum Harlaching und Neuperlach, Munich, Germany 10 Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany
Submitted: Feb 25, 2015; Revised: May 25, 2015; Accepted: May 29, 2015 Address for correspondence: Marlies Michl, MD, Department of Hematology and Oncology, CCC - Comprehensive Cancer Center Munich, Klinikum der Universität München, Campus Grosshadern, Marchioninistr 15, D-81377 Munich, Germany Fax: þ49-(0)89-4400-72208; e-mail contact: [email protected]
Clinical Colorectal Cancer Month 2015
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Brain Metastasis in Colorectal Cancer Patients Introduction Colorectal cancer (CRC) represents one of the most common malignancies in women and men (prevalence 8% and 9%, respectively1), and is responsible for 12% of all cancer-related deaths.2 Approximately 20% of all CRC patients are diagnosed with primary metastatic disease. Another 25% will develop metastases during the course of the disease, most commonly in the liver, lung, and lymphatic tissue. Only approximately 1% of all CRC patients develop brain metastasis (BM).3,4 The present work focused on this uncommon metastatic site in CRC. Knowledge about onset, prognosis, and survival of CRC patients with BM is very limited.5,6 Compared with other solid organ tumors such as breast cancer, lung cancer, or melanoma, BM in CRC represents a rare and late event.5,6 Only 4% to 6% of all secondary brain malignancies are attributed to CRC.7 Most available information is obtained from postmortem studies,8,9 by neurosurgeons10,11 or by radiotherapists,12 who focus on local treatment options for BM. Most studies are retrospective single-center analyses with descriptive character and in sample sizelimited cohorts. In the literature, median survival calculated from the date of initial diagnosis of CRC ranges between 26 and 38 months.10,13 However, when BM occur, prognosis is poor with median survival ranges from 1.0 to 5.7 months.10,12,14,15 Some authors report longer overall survival (OS) in a highly selected patient cohort intensively treated for BM.3,13,15-19 Farnell et al observed long-term survivors.17 The question as to whether BM simply occur as a final step in a gradually progressive polymetastatic disease in a small fraction of CRC patients or whether a biologically distinct CRC cohort exists who phenotypically present with BM is unanswered. To our knowledge, the present study represents the largest patient number with CRC and BM analyzed to date. We aimed to
characterize this patient cohort, to evaluate survival, and to identify prognostic subgroups or factors.
Patients and Methods Patient Selection In collaboration with the Munich Cancer Registry (MCR), a systematic database search was conducted on patients with histologically proven CRC and BM in or around Munich between 1998 and 2011. The MCR covers an estimated population of 2.8 million inhabitants of southern Germany. The following data were evaluated: patient and tumor characteristics including age, sex, primary colorectal tumor site, tumor, node, metastases (TNM) stage, grading, Union Internationale Contre le Cancer (UICC) stage, date of initial diagnosis of CRC, date of diagnosis of metastatic disease, date of diagnosis of BM, and date of death. Patients were excluded if nonCRC or nonadenocarcinoma histology was present. The study was approved by the local ethics committee (approval number 505-11).
Patient Subgrouping and Survival Probabilities According to the clinical course of the disease and the onset of extra- and intracranial metastasis over time, patients were categorized into 6 subgroups (Figure 1). Cutoff time for the assignment to the meta-/synchronous or the concurrent/subsequent category was 30 days. Categorization of extracranial metastasis (EM) and solitary BM is temporally referred to the initial diagnosis of CRC, and that of BM to EM. Survival probabilities were calculated using the KaplaneMeier estimator: from the date of initial diagnosis of CRC until death from any
cause (OS-1), from the date of diagnosis of metastatic disease until death from
any cause (OS-2), and from the date of diagnosis of BM until death from any cause (OS-3).
Figure 1 Assignment of Patients to 6 Survival Subgroups Regarding Occurrence of Metachronous Versus Synchronous Extracranial Metastasis (EM) and Subsequent Versus Concurrent Intracranial Metastasis (BM). Patients With Solitary BM Hold a Special Position. Cutoff Time for the Assignment to the Meta- or Synchronous and Subsequent or Concurrent Category Was 30 Days. Corresponding Categorization of EM and Singular BM Is Referred to as the Initial Diagnosis of Colorectal Cancer (CRC), and That of Subsequent or Concurrent BM to EM
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Marlies Michl et al Table 1 Baseline Patient Demographic and Tumor Characteristics of the Analyzed Patient Cohort Baseline Patient and Tumor Characteristics (n [ 228)
Table 1 Continued Baseline Patient and Tumor Characteristics (n [ 228)
n
%
Age at Time of Initial Diagnosis, Years Median
63
Range
27-94
n
%
Metastatic Status M0
126
55
M1
102
45 4
UICC Stage
65
142
62
I
10
>65
86
38
II
21
9
III
56
25
IV
102
45
39
17
Age at Time of BM Diagnosis, Years Median
66
Range
28-97
Unknown
Sex Female
94
41
134
59
Right colon
49
21
Cecum
16
7
Colon ascendens
25
11
Right colon flexure
4
2
Colon transversum
4
2
155
68
Left colon flexure
2
1
Colon descendens
9
4
Sigma
39
16
Rectosigmoidal transition
10
6
Rectum
95
42
Male Primary Tumor Site
Left colon
Upper third (>12 cm)
25
11
Middle third (7.5 and 12 cm)
38
17
Lower third (>4 and <7.5 cm)
30
13
Unknown
2
1
Double/multifocal primary
5
2
19
8
T1
9
4
T2
13
6
T3
99
43
T4
45
20
Tx
1
Unknown T Stage (Primary)
Unknown
0.4
61
27
N0
40
18
N1
55
24
N2
68
30
Nx
3
1
62
27
Regional Lymph Node Status
Unknown
The percentage values are rounded. Abbreviation: UICC ¼ Union Internationale Contre le Cancer.
Patients with solitary BM (group 1-1 and 2-1) occupied a special position. In case of subsequent solitary BM, OS-2 was identical to OS-3 (group 1-1), and in case of concurrent solitary BM, OS-1 was identical to OS-2 and OS-3 (group 1-1; Figure 1).
Uni- and Multivariate Testing Uni- and multivariate Cox proportional hazards models were used to explore the effect of independent variables on OS. Some variables were dichotomized for analysis when patient numbers per category were too small. For this model, the hazard ratio, its 95% confidence interval, and the P value (2-sided) resulting from the Wald test are reported. Because of the large number of tests performed P values are reported rather than tests performed with adjustment for multiple testing at the .05 level of statistical significance. Statistical evaluations were carried out using statistical software SPSS version 21 (SPSS Inc, Chicago, IL).
Results Patient and Tumor Characteristics Overall, 228 patients with metastatic CRC (mCRC) and BM were identified (134 male [59%], 94 female [41%]). Baseline patient demographic and tumor characteristics are summarized in Table 1. Median age at the time of initial diagnosis was 63 years (range, 27-94 years) and at diagnosis of BM 66 years (range, 28-97 years). Two-thirds of all patients were initially diagnosed with tumors staged T3 or T4 (144 patients; 63%), graded G2 (145 patients; 64%) and without distant metastases (M0; 126 patients; 55.3%). Regarding the primary tumor sites, two-thirds were localized in the left colon (155 patients; 68%) and there predominantly in the rectum (95 patients; 42%). Within the rectum, primary tumor was distributed most equally throughout the 3 thirds with a slight predominance in the middle third.
Grade 1
1
2
145
64
3
66
29
X
6
3
10
4
Unknown
0.4
Survival Data in the Entire Patient Cohort Median survival times (in months) and probabilities (in %) are listed in Table 2. Overall, OS-1 was 35.6 months (95% CI, 30.141.1 months), OS-2 16.5 months (95% CI, 13.9-19.1 months), and OS-3 2.0 months (95% CI, 1.5-2.5 months) irrespective of prognostic subgroups. Median time from first diagnosis of CRC to
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Brain Metastasis in Colorectal Cancer Patients Table 2 Median OS and Survival Probabilities for OS-1, OS-2, and OS-3 in All Patients Irrespective of Prognostic Group (n [ 228) Median OS, Months
95% CI, Months
35.6 16.5 2.0
30.1-41.1 13.9-19.1 1.5-2.5
OS-1 OS-2 OS-3
Survival Probability, % From Initial Diagnosis of CRC From Diagnosis of Metastatic Disease From Diagnosis of Brain Metastasis
6 Months
1 Year
2 Years
5 Years
94.3 76.3 26.8
83.3 57.5 11.0
63.6 36.8 2.6
17.5 5.7 0.4
Abbreviations: CRC ¼ colorectal cancer; OS ¼ overall survival; OS-1 ¼ overall survival from time of first diagnosis of colorectal cancer; OS-2 ¼ overall survival from time of diagnosis of metastatic disease; OS-3 ¼ from time of diagnosis of brain metastasis.
diagnosis of BM was 29.2 months (95% CI, 23.1-35.3 months). From diagnosis of mCRC, 1-year survival was 57.5%, 2-year survival 36.8%, and 5-year survival 5.7%. From diagnosis of BM, 6-month survival was 26.8%, 1-year-survival 11%, 2-year-survival 2.6% and 5-year-survival 0.4% (1 patient survived more than 5 years after diagnosis of BM).
Survival According to Clinical Subgroup Extracranial metastasis was present in 197 patients (86.4%), when BM became apparent. One hundred eighty-four patients (80.7%) developed subsequent BM, 158 patients (69.3%) had existing EM that evolved metachronously (77 patients; 33.8%) or synchronously (81 patients; 35.5%). Thirty-one patients (13.6%) presented with solitary BM, namely, 26 patients (11.4%) with subsequent solitary BM and 5 patients (2.2%) with concurrent solitary BM (group 2-1). No patient developed EM after the diagnosis of BM. Survival data (OS-1, OS-2, and OS-3) of the 6 clinically assigned patient subgroups (Figure 1) are presented in Table 3 and Figures 2, 3, and 4. Median Survival From Initial Diagnosis of CRC. OS-1 was longer in patients with metachronous metastasis (group 1; n ¼ 126) compared with those with synchronous metastasis (group 2; n ¼ 102). Within group 1, OS-1 did not differ significantly in the 3 subgroups, however, all patients in group 1 showed a significantly longer OS-1 than those in group 2 (Table 3). OS-1 was longest in patients with metachronous EM and subsequent BM (group 2-1; 77 patients; 49.0 months; 95% CI, 43.3-54.6 months) and shortest in patients with synchronous EM and concurrent BM (group 2-3; 16 patients; 4.0 months; 95% CI, 0.2-7.7 months). Median Survival From Diagnosis of Metastatic Disease. OS-2 did not differ between patients with metachronous EM (group 1-2; 28.6 months) and those with synchronous EM (group 2-2; 22.2 months; P ¼ .26). Patients who developed subsequent BM (group 1-2 and 2-2) showed significantly longer OS-2 compared with those with synchronous BM (group 1-3 and 2-3; Table 3) regardless of whether EM developed metachronously or synchronously.
in group 2-1 with solitary synchronous BM with an OS-3 of 14.3 months (in detail: 0.6 months, 1.9 months, 14.3 months, 15.1 months, and 45.5 months). The shortest OS-3 was observed in patients with synchronous EM and metachronous BM (group 2-2: 0.8 months), which differed significantly from all other groups (Table 3). In patients with solitary BM, OS-3 was longer when BM developed synchronously (group 2-1; 5 patients; 14.3 months) than metachronously (group 1-1; 26 patients; 2.0 months).
Effect of Patient and Tumor Characteristics on Survival Several patient and tumor characteristics were analyzed for prognostic value on OS-1, OS-2, and OS-3 and revealed a significant effect as follows (Table 4; data for multivariate analysis not shown): Median Survival From Initial Diagnosis of CRC. As independent prognostic factors for OS-1, T-status (T1/2/3 vs. T4; P ¼ .031), N-status (N0 vs. N1 vs. N2; P < .0001; global testing), M-status (M0 vs. M1; P < .0001), grading (G1/2 vs. G3; P ¼ .002), and UICC stage (I/II/III vs. IV; P < .001) were identified in univariate analysis. N-status (P < .0001) and UICC stage (P < .0001) also were identified in multivariate analysis. Median Survival From Diagnosis of Metastatic Disease. In univariate analysis, as independent prognostic factors for OS-2, age ( 65 years vs. > 65 years; P ¼ .001), N-status (N0 vs. N1 vs. N2; P ¼ .033; global testing), M-status (M0 vs. M1; P ¼ .005), Grade (Grade 1/2 vs. Grade 3; P ¼ .021) and UICC stage (I/II/III vs. IV; P ¼ .015) were identified. Age (P ¼ .01), N-status (P ¼ .027) and Mstatus (P < .0001) were also identified in multivariate analysis. Median Survival After Diagnosis of BM. M-status (M0 vs. M1; P ¼ .027) and site of primary (colon vs. rectum; P ¼ .034) were identified as independent prognostic factors for OS-3 in univariate analysis; age (P ¼ .004) and M-status (P < .0001) were identified in multivariate analysis. Sex was found to have no effect on OS-1, -2, or -3, neither did primary tumor site categorized as right versus left colon.
Discussion
4
-
Median Survival After Diagnosis of BM. OS-3 ranged between 0.8 and 4.0 months in all subgroups with exception of the 5 patients
Clinical Colorectal Cancer Month 2015
Overall survival in CRC patients has improved in particular with the introduction of a more personalized approach and with the advent
Table 3 Median Survival Time in Months (95% CI) for OS-1, OS-2, and OS-3 According to the Shaped Patient Groups, and a Comparison of Patient Subgroups Regarding OS-1, OS-2, and OS-3 (n [ 228) Group 1: CRC -> Metachronous Metastasis Metachronous Extracranial Metastasis
1-1: Metachronous Solitary BM Patient n OS-1 OS-2 OS-3
Group 2: CRC With Synchronous Metastasis
26 39.2 (34.4-44.1) 2.0 (0.0-5.7)
1-2: Subsequent BM
1-3: Concurrent BM
77 49.0 (43.3-54.6) 28.6 (22.6-34.7) 3.3 (2.1-4.4)
23 35.0 (22.1-47.9) 2.3 (0.0-4.7)
)/ )/ )/ )/ )/ )/ )/ )/ )/ )/ )/ )/ )/ )/ )/
1-2 1-3 2-1 2-2 2-3 1-3 2-1 2-2 2-3 2-1 2-2 2-3 2-2 2-3 2-3
P .16 .68 .009 .049 <.001 .06 .001 <.001 <.001 .02 .17 <.001 .07 .10 <.001
2-3a: Concurrent BM
5 14.3 (0.0-41.0)
81 22.2 (17.2-27.2)
16 4.0 (0.2-7.7)
OS-2 HR (95% CI) 0.72 1.13 3.62 1.57 8.39 1.57 5.01 2.18 11.61 3.20 1.39 7.42 0.44 2.32 5.33
(0.46-1.14) (0.64-2.00) (1.38-9.51) (1.00-2.47) (4.40-15.98) (0.98-2.51) (2.01-12.51) (1.59-2.99) (6.60-20.44) (1.21-8.47) (0.87-2.22) (3.86-14.27) (0.18-1.08) (0.85-6.36) (3.07-9.27)
P <.001 .13 .03 <.001 .19 <.001 .29 .26 <.001 .002 <.001 .01 .14 .18 <.001
OS-3 HR (95% CI) 0.20 1.55 0.33 0.17 0.66 7.62 1.63 0.83 3.24 0.21 0.11 0.43 0.51 1.98 3.9
(0.13-0.32) (0.88-2.74) (0.13-0.87) (0.11-0.27) (0.35-1.23) (4.59-12.65) (0.66-4.05) (0.60-1.14) (1.87-5.60) (0.08-0.58) (0.65-0.18) (0.22-0.81) (0.21-1.26) (0.72-5.42) (2.25-6.76)
P .95 .41 .19 .004 .36 .29 .18 <.001 .32 .08 .08 .11 .006 .49 .001
HR (95% CI) 0.99 1.27 0.53 1.94 0.75 1.29 0.53 1.97 0.76 0.41 1.53 0.59 3.70 1.42 0.39
(0.63-1.54) (0.72-2.23) (0.20-1.38) (1.23-3.06) (0.40-1.4) (0.81-2.06) (0.21-1.33) (1.42-2.72) (0.44-1.31) (0.16-1.10) (0.96-2.44) (0.31-1.12) (1.47-9.33) (0.52-3.91) (0.22-0.67)
Significant P values are shown in bold (P < .05, Cox regression). Abbreviations: BM ¼ brain metastases; CRC ¼ colorectal cancer; HR ¼ hazard ratio; OS ¼ overall survival; OS-1 ¼ overall survival from time of first diagnosis of colorectal cancer; OS-2 ¼ overall survival from time of diagnosis of metastatic disease; OS-3 ¼ from time of diagnosis of BM. a For these groups OS-1 is identical with OS-2 and OS-3, because the date of diagnosis of BM corresponds to the time of first diagnosis.
Marlies Michl et al
Clinical Colorectal Cancer Month 2015
1-1 1-1 1-1 1-1 1-1 2-2 2-2 1-2 1-2 1-3 1-3 1-3 2-1 2-1 2-2
2-2: Subsequent BM
0.8 (0.1-1.5)
OS-1 Comparison Groups
Synchronous Extracranial Metastasis
2-1a: Synchronous Solitary BM
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Brain Metastasis in Colorectal Cancer Patients Figure 2 Kaplan-Meier Survival Curves for OS-1 According to the 6 Clinical Subgroups (See Figure 1). Data Are Presented as Median Months (Range)
of newer cytostatic drugs and biological agents since the late 1990s, ranging from 26 to 30 months as recent randomized trials report (PEAK, FIRE-3).20,21 Although mCRC represents one of the most frequent solid malignancies, knowledge on BM in CRC is limited.
Few analyses with limited patient numbers were published in the past decades and mainly focused on treatment options for BM.3,10,16 In the present study we aimed to characterize this rare patient cohort and to identify prognostic subgroups regarding survival. We
Figure 3 Kaplan-Meier Survival Curves for OS-2 According to the 6 Clinical Subgroups (See Figure 1). Data Are Presented as Median Months (Range)
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Clinical Colorectal Cancer Month 2015
Marlies Michl et al Figure 4 Kaplan-Meier Survival Curves for OS-3 According to the 6 Clinical Subgroups (See Figure 1). Data Are Presented as Median Months (Range)
identified 228 patients with mCRC and BM who were diagnosed between 1998 and 2011. That represents the largest BM cohort in mCRC patients analyzed to date. Overall, OS-1 was 35.6 months and 1-, 2-, and 5-year survival probabilities were 83.3%, 63.6%, and 17.5%, respectively, and thus shorter than in large CRC collectives without BM.22 Regarding OS2, with a focus on patients with subsequent BM after meta- or synchronous EM (group 1-2: 28.6 months; group 2-2: 22.2 months; Table 3), OS-2 was comparable with the latest survival data in stage IV CRC patients (FIRE-3, CALGB/SWOG).21,23 Median time from first diagnosis of CRC to diagnosis of BM was 29.2 months and slightly exceeded the time period described in the literature (24-28 months).10,13,16,24 However, OS-3 was short irrespective of subgroup (0.8-4.0 months). Nearly 73.2% of all patients died within the first 6 months after BM was diagnosed. From diagnosis of BM, 1-year survival was only 11% and a single patient survived more than 5 years (Table 2). These data strongly confirm previous reports of dramatically dismal survival when BM is present.6,11,13,14,16,18,25,26 In addition, the present results underline the previous publication data from Berghoff et al in which patients with BM of colorectal histology demonstrated the shortest OS compared with other histologies, which could be shown with high Ki-67 staining.27 An exception was observed in patients with synchronous solitary BM. The outstanding long OS-3 in 3 patients might be because of the shorter duration of systemic disease and lack of pretreatments resulting in a better performance status and therefore optimal conditions for intensive BM therapy.24,26 Regarding the presented clinical subgroups, by far most patients (197 patients; 86.4%) were diagnosed with BM when EM were already present. Similar observations were described by other
authors.13,15-17,26,28 The frequency of subsequent BM after metachronous or synchronous EM was comparable (33.8% vs. 35.5%). Only 31 patients presented with solitary BM, most of which also occurred subsequently. Primary tumors were located throughout the whole colon and rectum, but predominantly left-sided (155 patients; 68%) including in the rectum (95 patients; 42%; Table 1), which is in line with the expected distribution of colorectal carcinomas.13,16,19,29,30 Regarding the influence of patient baseline characteristics (Table 1) on OS-1, OS-2, and OS-3, one can summarize that (1) the effect of age, TNM status, grading, and UICC stage on OS-1, which is long known and approved in large CRC patient collectives, remains valid when BM develop later during course of metastatic disease; (2) that the effect of age, N- and M-status, grading, and UICC stage on OS-2 continues with less strong significance; and (3) that the effect of tumor and patient characteristics on survival dissolves in most instances when BM occur (OS-3; Table 4). Age at the time of initial diagnosis was the sole variable that constantly revealed a significant effect on survival suggesting a better performance status in younger patients. Although there was a trend towards a longer OS-1 for men compared with for women (38.1 vs. 29.1 months), statistical significance was not reached. This is in concordance with more recent data, which also suggested a disadvantage in response and survival for certain CRC subgroups (eg. female sex), which however, needs to be further investigated.10,16,31 The present analysis is unfortunately limited by lack of information on patient performance status, applied systemic or local treatments for CRC or BM, and lack of information on intracranial metastatic sites and numbers, which certainly limit the significance of the present data, but are owed to the data source in a registry. In addition, the numbers of patients in certain subgroups was small,
Clinical Colorectal Cancer Month 2015
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8
OS-1 Patient and Tumor Characteristic Agea
n
Months
228
OS-2
HR
95% CI
P
1.27
0.97-1.67
.08
Months
65 years
142
37.9
19.6
>65 years
86
26.7
10.3
Sex
228
Female Male
1.25
0.96-1.62
.10
OS-3
HR
95% CI
P
1.57
1.20-2.06
.001
Months
HR
95% CI
P
1.31
1.00-1.72
.06
0.94
0.72-1.22
.62
1.03
0.73-1.46
.86
e
e
2.3 1.5 0.93
0.71-1.22
.60
94
29.1
14.9
2.2
134
38.1
17.1
1.9
TNMa T status T 1þ2þ3 T4 Lymph node status N0 (reference)
166
1.46
22
39.5
144
24.3
1.03-2.06
1.08
0.76-1.52
1.9
11.8
1.7
<.001 52.4
.68
16.5
163 40
.03
e
e
.03
e
34.5
e
e
e
.68 2.2
e
N1
55
35.0
1.50
0.99-2.26
.06
11.8
1.63
1.08-2.46
.02
1.5
0.89
0.59-1.35
.60
N2
68
23.6
2.32
1.56-3.47
<.001
14.2
1.63
1.09-2.43
.02
2.3
1.05
0.71-1.55
.82
2.22
1.70-2.90
<.001
0.68
0.52-0.89
.005
1.35
1.03-1.75
.03
1.14
0.85-1.53
.38
1.26
0.94-1.68
.12
0.75
0.57-0.98
.03
0.79
0.57-1.09
.15
Metastatic Status
228
M0
126
44.2
M1
102
17.5
Gradinga
212
Grade 1þ2 Grade 3 UICCa UICC I þ II þ III UICC IVb Localization Primary (1)
1.20-2.16
.002
39.5
17.4
66
24.4
11.2 2.31
87
44.4
102
17.5
228 31.0
Rectum
126
37.6
204
<.001
1.05-1.90
.02 2.0 1.6
0.70
0.52-0.93
.02
11.1
2.4
17.5 0.88
102
1.72-3.09
1.5 1.42
146 189
2.7
17.5 1.61
Colon Localization Primary (2)
11.1
0.68-1.15
.36
1.5 0.90
0.69-1.16
.41
14.3
1.7
17.7 0.81
0.58-1.12
.20
2.3 0.73
0.53-1.01
.06
Right colon
49
22.2
11.2
1.5
Left colon
155
36.5
17.8
2.0
P values < .05 are in bold. Indicated number of patients corresponds to the number of observations of 228. Regarding assignment of primary tumor site to left or right sided colon; see Table 1. Abbreviations: CRC ¼ colorectal cancer; HR ¼ hazard ratio; OS ¼ overall survival; OS-1 ¼ overall survival from time of first diagnosis of CRC; OS-2 ¼ overall survival from time of diagnosis of metastatic disease; OS-3 ¼ from time of diagnosis of brain metastases; TNM ¼ tumor, node, metastases; UICC ¼ Union Internationale Contre le Cancer. a At time of initial diagnosis of CRC. b In multiple testing OS-1 showed significant differences depending on UICC IV versus II and III (P ¼ .004, respectively).
Brain Metastasis in Colorectal Cancer Patients
Clinical Colorectal Cancer Month 2015
Table 4 Univariate Cox Proportional Hazards Modeling OS for OS-1, OS-2, and OS-3 According to Patient and Tumor Characteristics
Marlies Michl et al which means confidence intervals are wide and the reliability of the results is less certain.
Conclusion To our knowledge, this is the largest analysis of patients with mCRC and BM up to this date. The results presented show that most patients develop BM as a late step in disease when EM is already present. Only a small fraction of patients are diagnosed with BM early in disease or with solitary BM. Data further show that survival is poor when BM is diagnosed irrespective of subgroup and tumor characteristics with the exception of patients with synchronous solitary BM. As previous studies show, survival can increase with early BM detection and intensive treatment with combined surgical resection and radiation therapy for which best results were reported. Therefore, there is an urgent need to intensify the search for prognostic or predictive markers and to identify patients who are at risk.
Clinical Practice Points Although CRC represents one of the most common malig-
nancies in women and men, knowledge about onset, prognosis, and survival of CRC patients with BM is very limited to date. In the literature BM in CRC is described as a rare and late event (approximately 1%-4%). Most available information is obtained from postmortem studies, by neurosurgeons, or by radiotherapists, who focus on local treatment options for BM in solid tumors. In the literature, median survival time counted from the date of initial diagnosis of CRC ranges between 26 and 38 months. When BM occurs, prognosis is poor with median survival time ranges from 1.0 to 5.7 months. Results of this work offer a precise description of this rare patient cohort: Median age at initial diagnosis (63 years) was comparable with those in recent large prospective clinical trials, but younger compared with registry data in the Western world. Most patients are initially diagnosed with tumors staged T3/4, Nþ, Grade 2, and without distant metastases. Regarding the primary tumor sites, most are located in the left colon and there predominantly in the rectum. We also presented survival data regarding OS from the time of initial diagnosis (35.6 months), from diagnosis of metastatic disease (16.5 months), and from diagnosis of BM (2.0 months). First described herein was time from initial diagnosis of CRC to occurrence of BM (29.2 months). We also included a proposal for clinical prognostic subgrouping of these patients dependent on occurrence of synchronous or metachronous extra- and intracranial metastasis. Most patients develop sequential BM (> 80%). Only a small fraction of patients are diagnosed with BM early in disease or with solitary BM (13.4%). Univariate analysis revealed no effect of patient and tumor characteristics on survival when BM has been diagnosed. To our knowledge, we included the largest number of patients with CRC and BM analyzed to date. Results of this study might sensitize clinicians for the potential development of BM in late-stage CRC with a consequence on diagnostic imaging of the brain.
It is an appeal to consider this rare cohort (announce to clinical
registries, need for further research including molecular diagnostics, etc). When BM is present, certain patients (subgroups) show longer survival compared with others (also long-term survivors), so there might be a need for different treatment strategies.
Acknowledgments This publication is part of the doctoral thesis of Johannes Thurmaier. This work is part of a DKTK (German Consortium for Translational Cancer Research) funded project.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics 2012. CA Cancer J Clin 2012; 62:220-41. 2. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010; 46:765-81. 3. Go PH, Klaassen Z, Meadows MC, Chamberlain RS. Gastrointestinal cancer and brain metastasis: a rare and ominous sign. Cancer 2011; 117:3630-40. 4. Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002; 94:2698-705. 5. Cante D, Girelli G, La Porta MR, Sciacero P, La Sala S, Ozzello F. Late brain metastases from colorectal cancer a case report and review of the literature. Tumori 2005; 91:280-2. 6. Bartelt S, Momm F, Weissenberger C, Lutterbach J. Patients with brain metastases from gastrointestinal tract cancer treated with whole brain radiation therapy: prognostic factors and survival. World J Gastroenterol 2004; 10:3345-8. 7. Rahmathulla G, Toms SA, Weil RJ. The molecular biology of brain metastasis. J Oncol 2012; 2012:723541. 8. Temple DF, Ledesma EJ, Mittelman A. Cerebral metastases. From adenocarcinoma of the colon and rectum. N Y State J Med 1982; 82:1812-4. 9. Weiss L, Grundmann E, Torhorst J, et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol 1986; 150:195-203. 10. Wronski M, Arbit E. Resection of brain metastases from colorectal carcinoma in 73 patients. Cancer 1999; 85:1677-85. 11. Suzuki Y, Yamaguchi T, Matsumoto H, et al. Prognostic factors and treatment effects in patients with curatively resected brain metastasis from colorectal cancer. Dis Colon Rectum 2014; 57:56-63. 12. Windsor AA, Koh ES, Allen S, et al. Poor outcomes after whole brain radiotherapy in patients with brain metastases: results from an international multicentre cohort study. Clin Oncol (R Coll Radiol) 2013; 25:674-80. 13. Hammoud MA, McCutcheon IE, Elsouki R, Schoppa D, Patt YZ. Colorectal carcinoma and brain metastasis: distribution, treatment, and survival. Ann Surg Oncol 1996; 3:453-63. 14. Alden TD, Gianino JW, Saclarides TJ. Brain metastases from colorectal cancer. Dis Colon Rectum 1996; 39:541-5. 15. Jiang XB, Yang QY, Sai K, Zhang XH, Chen ZP, Mou YG. Brain metastases from colorectal carcinoma: a description of 60 cases in a single Chinese cancer center. Tumour Biol 2011; 32:1249-56. 16. Damiens K, Ayoub JP, Lemieux B, et al. Clinical features and course of brain metastases in colorectal cancer: an experience from a single institution. Curr Oncol 2012; 19:254-8. 17. Farnell GF, Buckner JC, Cascino TL, O’Connell MJ, Schomberg PJ, Suman V. Brain metastases from colorectal carcinoma. The long-term survivors. Cancer 1996; 78:711-6. 18. Kye BH, Kim HJ, Kang WK, Cho HM, Hong YK, Oh ST. Brain metastases from colorectal cancer: the role of surgical resection in selected patients. Colorectal Dis 2012; 14:e378-85. 19. Ko FC, Liu JM, Chen WS, Chiang JK, Lin TC, Lin JK. Risk and patterns of brain metastases in colorectal cancer: 27-year experience. Dis Colon Rectum 1999; 42: 1467-71. 20. Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014; 32:2240-7. 21. Heinemann V, Fischer von Weikersthal L, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15:1065-75.
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Brain Metastasis in Colorectal Cancer Patients 22. (MCR) MCR survival statistics in colorectal cancer. 1988-2012. Available at: http://www.tumorregister-muenchen.de/fact/specific_analysis.php. Accessed: June 23, 2015. 23. Venook AP, Niedzwiecki D, Lenz HJ, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC) (abstract LBA3). J Clin Oncol 2014; 32(suppl 15). 24. Chyun Y, Hayward E, Lokich J. Metastasis to the central nervous system from colorectal cancer. Med Pediatr Oncol 1980; 8:305-8. 25. Khattak MA, Martin HL, Beeke C, et al. Survival differences in patients with metastatic colorectal cancer and with single site metastatic disease at initial presentation: results from South Australian clinical registry for advanced colorectal cancer. Clin Colorectal Cancer 2012; 11:247-54. 26. Kruser TJ, Chao ST, Elson P, et al. Multidisciplinary management of colorectal brain metastases: a retrospective study. Cancer 2008; 113:158-65.
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27. Berghoff AS, Ilhan-Mutlu A, Dinhof C, et al. Differential role of angiogenesis and tumour cell proliferation in brain metastases according to primary tumour type: analysis of 639 cases. Neuropathol Appl Neurobiol 2015; 41: e41-55. 28. Noura S, Ohue M, Shingai T, et al. Brain metastasis from colorectal cancer: prognostic factors and survival. J Surg Oncol 2012; 106:144-8. 29. Cascino TL, Leavengood JM, Kemeny N, Posner JB. Brain metastases from colon cancer. J Neurooncol 1983; 1:203-9. 30. Mongan JP, Fadul CE, Cole BF, et al. Brain metastases from colorectal cancer: risk factors, incidence, and the possible role of chemokines. Clin Colorectal Cancer 2009; 8:100-5. 31. Heinemann V, Fischer von Weikersthal L, Decker T, et al. Gender and tumor location as predictors for efficacy: influence on end points in first-line treatment with FOLFIRI in combination with cetuximab or bevacizumab in the AIO KRK 0306 (FIRE3) trial (abstract 3600). J Clin Oncol 2014; 32(suppl 15).
Brain Metastasis in Colorectal Cancer Patients: Survival and Analysis of Prognostic Factors Marlies Michl,1 Johannes Thurmaier,1 Gabriele Schubert-Fritschle,2 Max Wiedemann,2 Rüdiger P. Laubender,3 Natascha C. Nüssler,4 Reinhard Ruppert,4 Jörg Kleeff,5 Wolfgang Schepp,6 Clemens Reuter,7 Florian Löhe,8 Meinolf Karthaus,9 Jens Neumann,10 Thomas Kirchner,10 Jutta Engel,2,3 Volker Heinemann1 Abstract To our knowledge, this is the largest number of patients with colorectal cancer and brain metastasis (BM) analyzed to date (n [ 228; 134 male [59%]; 94 female [41%]; median age 63 years). Most primary tumors were staged as T3/4, ND, Grade 2. BM occurred 29.2 months after initial diagnosis. Overall survival from the time of first diagnosis was 35.6 months, from the time of metastatatic disease 16.5 months, and from BM 2.0 months. Solitary BM were found in 13.6%. 80.7% of all BM occurred sequentially. Background: The purpose of the study was to characterize the rare cohort of patients (pts) with metastatic colorectal cancer (mCRC) and brain metastasis (BM) and to identify prognostic subgroups. Patients and Methods: In collaboration with the Munich Cancer Registry, pts with mCRC and BM who were diagnosed between 1998 and 2011 were identified. Survival from the time of first diagnosis of colorectal cancer (CRC) (OS-1), from the time of diagnosis of metastatic disease (OS-2) and of BM (OS-3) was calculated regarding (1) the temporal occurrence of extra- and intracranial metastasis (meta- vs. synchronous) and (2) tumor and patient characteristics. For survival analysis the KaplaneMeier estimator and Cox regression models were used. Results: A total of 228 pts (134 male [59%], 94 female [41%]) were identified. The median age was 63 years (142 pts [62%] were 65 years of age or younger). Most pts presented with primary tumors staged T3/4, Nþ, Grade 2. The primary tumor was located predominantly in the left colon (155 pts; 68%), especially in the rectum (95 pts; 42%). Median OS-1 was 35.6 months (95% confidence interval [CI], 30.1-41.1 months), OS-2 was 16.5 months (95% CI, 13.9-19.1 months), and OS-3 was 2.0 months (95% CI, 1.52.5 months). Median time from first CRC diagnosis to BM was 29.2 months. Subsequent BM after extracranial metastasis were observed in 184 pts (80.7%), whereas 31 pts (13.6%) presented with solitary BM. Univariate analysis did not reveal a prognostic variable for overall survival after diagnosis of BM. Conclusion: This study presents the largest number of pts with mCRC and BM analyzed to date. The results show that most mCRC pts develop BM as a late step in the course of disease. Median time from first CRC diagnosis to BM is 29.2 months. Only a few pts were diagnosed with BM early in the disease or with solitary BM. When BM is present survival is poor. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Brain metastasis, CNS metastasis, Metastatic colorectal cancer, Subgroups, Survival
1 Department of Hematology and Medical Oncology, Klinikum Grosshadern and Comprehensive Cancer Center Munich (CCCM), Ludwig-Maximilians-University of Munich, Munich, Germany 2 Munich Cancer Registry (MCR), IBE / Klinikum Grosshadern, Ludwig-MaximiliansUniversity of Munich, Munich, Germany 3 Institute of Medical Informatics, Biometry and Epidemiology (IBE), LudwigMaximilians-University of Munich, Munich, Germany 4 Department of Surgery, Klinikum Neuperlach, Städtisches Klinikum München, Munich, Germany 5 Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany 6 Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, Klinikum Bogenhausen, Städtisches Klinikum München, Munich, Germany
1533-0028/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2015.05.009
7 Department of Surgery, Krankenhaus Barmherzige Brüder München, Munich, Germany 8 Department of Surgery, Klinikum Landshut, Landshut, Germany 9 Department of Hematology, Oncology and Palliative Care, Städtisches Klinikum Harlaching und Neuperlach, Munich, Germany 10 Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany
Submitted: Feb 25, 2015; Revised: May 25, 2015; Accepted: May 29, 2015 Address for correspondence: Marlies Michl, MD, Department of Hematology and Oncology, CCC - Comprehensive Cancer Center Munich, Klinikum der Universität München, Campus Grosshadern, Marchioninistr 15, D-81377 Munich, Germany Fax: þ49-(0)89-4400-72208; e-mail contact: [email protected]
Clinical Colorectal Cancer Month 2015
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Brain Metastasis in Colorectal Cancer Patients Introduction Colorectal cancer (CRC) represents one of the most common malignancies in women and men (prevalence 8% and 9%, respectively1), and is responsible for 12% of all cancer-related deaths.2 Approximately 20% of all CRC patients are diagnosed with primary metastatic disease. Another 25% will develop metastases during the course of the disease, most commonly in the liver, lung, and lymphatic tissue. Only approximately 1% of all CRC patients develop brain metastasis (BM).3,4 The present work focused on this uncommon metastatic site in CRC. Knowledge about onset, prognosis, and survival of CRC patients with BM is very limited.5,6 Compared with other solid organ tumors such as breast cancer, lung cancer, or melanoma, BM in CRC represents a rare and late event.5,6 Only 4% to 6% of all secondary brain malignancies are attributed to CRC.7 Most available information is obtained from postmortem studies,8,9 by neurosurgeons10,11 or by radiotherapists,12 who focus on local treatment options for BM. Most studies are retrospective single-center analyses with descriptive character and in sample sizelimited cohorts. In the literature, median survival calculated from the date of initial diagnosis of CRC ranges between 26 and 38 months.10,13 However, when BM occur, prognosis is poor with median survival ranges from 1.0 to 5.7 months.10,12,14,15 Some authors report longer overall survival (OS) in a highly selected patient cohort intensively treated for BM.3,13,15-19 Farnell et al observed long-term survivors.17 The question as to whether BM simply occur as a final step in a gradually progressive polymetastatic disease in a small fraction of CRC patients or whether a biologically distinct CRC cohort exists who phenotypically present with BM is unanswered. To our knowledge, the present study represents the largest patient number with CRC and BM analyzed to date. We aimed to
characterize this patient cohort, to evaluate survival, and to identify prognostic subgroups or factors.
Patients and Methods Patient Selection In collaboration with the Munich Cancer Registry (MCR), a systematic database search was conducted on patients with histologically proven CRC and BM in or around Munich between 1998 and 2011. The MCR covers an estimated population of 2.8 million inhabitants of southern Germany. The following data were evaluated: patient and tumor characteristics including age, sex, primary colorectal tumor site, tumor, node, metastases (TNM) stage, grading, Union Internationale Contre le Cancer (UICC) stage, date of initial diagnosis of CRC, date of diagnosis of metastatic disease, date of diagnosis of BM, and date of death. Patients were excluded if nonCRC or nonadenocarcinoma histology was present. The study was approved by the local ethics committee (approval number 505-11).
Patient Subgrouping and Survival Probabilities According to the clinical course of the disease and the onset of extra- and intracranial metastasis over time, patients were categorized into 6 subgroups (Figure 1). Cutoff time for the assignment to the meta-/synchronous or the concurrent/subsequent category was 30 days. Categorization of extracranial metastasis (EM) and solitary BM is temporally referred to the initial diagnosis of CRC, and that of BM to EM. Survival probabilities were calculated using the KaplaneMeier estimator: from the date of initial diagnosis of CRC until death from any
cause (OS-1), from the date of diagnosis of metastatic disease until death from
any cause (OS-2), and from the date of diagnosis of BM until death from any cause (OS-3).
Figure 1 Assignment of Patients to 6 Survival Subgroups Regarding Occurrence of Metachronous Versus Synchronous Extracranial Metastasis (EM) and Subsequent Versus Concurrent Intracranial Metastasis (BM). Patients With Solitary BM Hold a Special Position. Cutoff Time for the Assignment to the Meta- or Synchronous and Subsequent or Concurrent Category Was 30 Days. Corresponding Categorization of EM and Singular BM Is Referred to as the Initial Diagnosis of Colorectal Cancer (CRC), and That of Subsequent or Concurrent BM to EM
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Marlies Michl et al Table 1 Baseline Patient Demographic and Tumor Characteristics of the Analyzed Patient Cohort Baseline Patient and Tumor Characteristics (n [ 228)
Table 1 Continued Baseline Patient and Tumor Characteristics (n [ 228)
n
%
Age at Time of Initial Diagnosis, Years Median
63
Range
27-94
n
%
Metastatic Status M0
126
55
M1
102
45 4
UICC Stage
65
142
62
I
10
>65
86
38
II
21
9
III
56
25
IV
102
45
39
17
Age at Time of BM Diagnosis, Years Median
66
Range
28-97
Unknown
Sex Female
94
41
134
59
Right colon
49
21
Cecum
16
7
Colon ascendens
25
11
Right colon flexure
4
2
Colon transversum
4
2
155
68
Left colon flexure
2
1
Colon descendens
9
4
Sigma
39
16
Rectosigmoidal transition
10
6
Rectum
95
42
Male Primary Tumor Site
Left colon
Upper third (>12 cm)
25
11
Middle third (7.5 and 12 cm)
38
17
Lower third (>4 and <7.5 cm)
30
13
Unknown
2
1
Double/multifocal primary
5
2
19
8
T1
9
4
T2
13
6
T3
99
43
T4
45
20
Tx
1
Unknown T Stage (Primary)
Unknown
0.4
61
27
N0
40
18
N1
55
24
N2
68
30
Nx
3
1
62
27
Regional Lymph Node Status
Unknown
The percentage values are rounded. Abbreviation: UICC ¼ Union Internationale Contre le Cancer.
Patients with solitary BM (group 1-1 and 2-1) occupied a special position. In case of subsequent solitary BM, OS-2 was identical to OS-3 (group 1-1), and in case of concurrent solitary BM, OS-1 was identical to OS-2 and OS-3 (group 1-1; Figure 1).
Uni- and Multivariate Testing Uni- and multivariate Cox proportional hazards models were used to explore the effect of independent variables on OS. Some variables were dichotomized for analysis when patient numbers per category were too small. For this model, the hazard ratio, its 95% confidence interval, and the P value (2-sided) resulting from the Wald test are reported. Because of the large number of tests performed P values are reported rather than tests performed with adjustment for multiple testing at the .05 level of statistical significance. Statistical evaluations were carried out using statistical software SPSS version 21 (SPSS Inc, Chicago, IL).
Results Patient and Tumor Characteristics Overall, 228 patients with metastatic CRC (mCRC) and BM were identified (134 male [59%], 94 female [41%]). Baseline patient demographic and tumor characteristics are summarized in Table 1. Median age at the time of initial diagnosis was 63 years (range, 27-94 years) and at diagnosis of BM 66 years (range, 28-97 years). Two-thirds of all patients were initially diagnosed with tumors staged T3 or T4 (144 patients; 63%), graded G2 (145 patients; 64%) and without distant metastases (M0; 126 patients; 55.3%). Regarding the primary tumor sites, two-thirds were localized in the left colon (155 patients; 68%) and there predominantly in the rectum (95 patients; 42%). Within the rectum, primary tumor was distributed most equally throughout the 3 thirds with a slight predominance in the middle third.
Grade 1
1
2
145
64
3
66
29
X
6
3
10
4
Unknown
0.4
Survival Data in the Entire Patient Cohort Median survival times (in months) and probabilities (in %) are listed in Table 2. Overall, OS-1 was 35.6 months (95% CI, 30.141.1 months), OS-2 16.5 months (95% CI, 13.9-19.1 months), and OS-3 2.0 months (95% CI, 1.5-2.5 months) irrespective of prognostic subgroups. Median time from first diagnosis of CRC to
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Brain Metastasis in Colorectal Cancer Patients Table 2 Median OS and Survival Probabilities for OS-1, OS-2, and OS-3 in All Patients Irrespective of Prognostic Group (n [ 228) Median OS, Months
95% CI, Months
35.6 16.5 2.0
30.1-41.1 13.9-19.1 1.5-2.5
OS-1 OS-2 OS-3
Survival Probability, % From Initial Diagnosis of CRC From Diagnosis of Metastatic Disease From Diagnosis of Brain Metastasis
6 Months
1 Year
2 Years
5 Years
94.3 76.3 26.8
83.3 57.5 11.0
63.6 36.8 2.6
17.5 5.7 0.4
Abbreviations: CRC ¼ colorectal cancer; OS ¼ overall survival; OS-1 ¼ overall survival from time of first diagnosis of colorectal cancer; OS-2 ¼ overall survival from time of diagnosis of metastatic disease; OS-3 ¼ from time of diagnosis of brain metastasis.
diagnosis of BM was 29.2 months (95% CI, 23.1-35.3 months). From diagnosis of mCRC, 1-year survival was 57.5%, 2-year survival 36.8%, and 5-year survival 5.7%. From diagnosis of BM, 6-month survival was 26.8%, 1-year-survival 11%, 2-year-survival 2.6% and 5-year-survival 0.4% (1 patient survived more than 5 years after diagnosis of BM).
Survival According to Clinical Subgroup Extracranial metastasis was present in 197 patients (86.4%), when BM became apparent. One hundred eighty-four patients (80.7%) developed subsequent BM, 158 patients (69.3%) had existing EM that evolved metachronously (77 patients; 33.8%) or synchronously (81 patients; 35.5%). Thirty-one patients (13.6%) presented with solitary BM, namely, 26 patients (11.4%) with subsequent solitary BM and 5 patients (2.2%) with concurrent solitary BM (group 2-1). No patient developed EM after the diagnosis of BM. Survival data (OS-1, OS-2, and OS-3) of the 6 clinically assigned patient subgroups (Figure 1) are presented in Table 3 and Figures 2, 3, and 4. Median Survival From Initial Diagnosis of CRC. OS-1 was longer in patients with metachronous metastasis (group 1; n ¼ 126) compared with those with synchronous metastasis (group 2; n ¼ 102). Within group 1, OS-1 did not differ significantly in the 3 subgroups, however, all patients in group 1 showed a significantly longer OS-1 than those in group 2 (Table 3). OS-1 was longest in patients with metachronous EM and subsequent BM (group 2-1; 77 patients; 49.0 months; 95% CI, 43.3-54.6 months) and shortest in patients with synchronous EM and concurrent BM (group 2-3; 16 patients; 4.0 months; 95% CI, 0.2-7.7 months). Median Survival From Diagnosis of Metastatic Disease. OS-2 did not differ between patients with metachronous EM (group 1-2; 28.6 months) and those with synchronous EM (group 2-2; 22.2 months; P ¼ .26). Patients who developed subsequent BM (group 1-2 and 2-2) showed significantly longer OS-2 compared with those with synchronous BM (group 1-3 and 2-3; Table 3) regardless of whether EM developed metachronously or synchronously.
in group 2-1 with solitary synchronous BM with an OS-3 of 14.3 months (in detail: 0.6 months, 1.9 months, 14.3 months, 15.1 months, and 45.5 months). The shortest OS-3 was observed in patients with synchronous EM and metachronous BM (group 2-2: 0.8 months), which differed significantly from all other groups (Table 3). In patients with solitary BM, OS-3 was longer when BM developed synchronously (group 2-1; 5 patients; 14.3 months) than metachronously (group 1-1; 26 patients; 2.0 months).
Effect of Patient and Tumor Characteristics on Survival Several patient and tumor characteristics were analyzed for prognostic value on OS-1, OS-2, and OS-3 and revealed a significant effect as follows (Table 4; data for multivariate analysis not shown): Median Survival From Initial Diagnosis of CRC. As independent prognostic factors for OS-1, T-status (T1/2/3 vs. T4; P ¼ .031), N-status (N0 vs. N1 vs. N2; P < .0001; global testing), M-status (M0 vs. M1; P < .0001), grading (G1/2 vs. G3; P ¼ .002), and UICC stage (I/II/III vs. IV; P < .001) were identified in univariate analysis. N-status (P < .0001) and UICC stage (P < .0001) also were identified in multivariate analysis. Median Survival From Diagnosis of Metastatic Disease. In univariate analysis, as independent prognostic factors for OS-2, age ( 65 years vs. > 65 years; P ¼ .001), N-status (N0 vs. N1 vs. N2; P ¼ .033; global testing), M-status (M0 vs. M1; P ¼ .005), Grade (Grade 1/2 vs. Grade 3; P ¼ .021) and UICC stage (I/II/III vs. IV; P ¼ .015) were identified. Age (P ¼ .01), N-status (P ¼ .027) and Mstatus (P < .0001) were also identified in multivariate analysis. Median Survival After Diagnosis of BM. M-status (M0 vs. M1; P ¼ .027) and site of primary (colon vs. rectum; P ¼ .034) were identified as independent prognostic factors for OS-3 in univariate analysis; age (P ¼ .004) and M-status (P < .0001) were identified in multivariate analysis. Sex was found to have no effect on OS-1, -2, or -3, neither did primary tumor site categorized as right versus left colon.
Discussion
4
-
Median Survival After Diagnosis of BM. OS-3 ranged between 0.8 and 4.0 months in all subgroups with exception of the 5 patients
Clinical Colorectal Cancer Month 2015
Overall survival in CRC patients has improved in particular with the introduction of a more personalized approach and with the advent
Table 3 Median Survival Time in Months (95% CI) for OS-1, OS-2, and OS-3 According to the Shaped Patient Groups, and a Comparison of Patient Subgroups Regarding OS-1, OS-2, and OS-3 (n [ 228) Group 1: CRC -> Metachronous Metastasis Metachronous Extracranial Metastasis
1-1: Metachronous Solitary BM Patient n OS-1 OS-2 OS-3
Group 2: CRC With Synchronous Metastasis
26 39.2 (34.4-44.1) 2.0 (0.0-5.7)
1-2: Subsequent BM
1-3: Concurrent BM
77 49.0 (43.3-54.6) 28.6 (22.6-34.7) 3.3 (2.1-4.4)
23 35.0 (22.1-47.9) 2.3 (0.0-4.7)
)/ )/ )/ )/ )/ )/ )/ )/ )/ )/ )/ )/ )/ )/ )/
1-2 1-3 2-1 2-2 2-3 1-3 2-1 2-2 2-3 2-1 2-2 2-3 2-2 2-3 2-3
P .16 .68 .009 .049 <.001 .06 .001 <.001 <.001 .02 .17 <.001 .07 .10 <.001
2-3a: Concurrent BM
5 14.3 (0.0-41.0)
81 22.2 (17.2-27.2)
16 4.0 (0.2-7.7)
OS-2 HR (95% CI) 0.72 1.13 3.62 1.57 8.39 1.57 5.01 2.18 11.61 3.20 1.39 7.42 0.44 2.32 5.33
(0.46-1.14) (0.64-2.00) (1.38-9.51) (1.00-2.47) (4.40-15.98) (0.98-2.51) (2.01-12.51) (1.59-2.99) (6.60-20.44) (1.21-8.47) (0.87-2.22) (3.86-14.27) (0.18-1.08) (0.85-6.36) (3.07-9.27)
P <.001 .13 .03 <.001 .19 <.001 .29 .26 <.001 .002 <.001 .01 .14 .18 <.001
OS-3 HR (95% CI) 0.20 1.55 0.33 0.17 0.66 7.62 1.63 0.83 3.24 0.21 0.11 0.43 0.51 1.98 3.9
(0.13-0.32) (0.88-2.74) (0.13-0.87) (0.11-0.27) (0.35-1.23) (4.59-12.65) (0.66-4.05) (0.60-1.14) (1.87-5.60) (0.08-0.58) (0.65-0.18) (0.22-0.81) (0.21-1.26) (0.72-5.42) (2.25-6.76)
P .95 .41 .19 .004 .36 .29 .18 <.001 .32 .08 .08 .11 .006 .49 .001
HR (95% CI) 0.99 1.27 0.53 1.94 0.75 1.29 0.53 1.97 0.76 0.41 1.53 0.59 3.70 1.42 0.39
(0.63-1.54) (0.72-2.23) (0.20-1.38) (1.23-3.06) (0.40-1.4) (0.81-2.06) (0.21-1.33) (1.42-2.72) (0.44-1.31) (0.16-1.10) (0.96-2.44) (0.31-1.12) (1.47-9.33) (0.52-3.91) (0.22-0.67)
Significant P values are shown in bold (P < .05, Cox regression). Abbreviations: BM ¼ brain metastases; CRC ¼ colorectal cancer; HR ¼ hazard ratio; OS ¼ overall survival; OS-1 ¼ overall survival from time of first diagnosis of colorectal cancer; OS-2 ¼ overall survival from time of diagnosis of metastatic disease; OS-3 ¼ from time of diagnosis of BM. a For these groups OS-1 is identical with OS-2 and OS-3, because the date of diagnosis of BM corresponds to the time of first diagnosis.
Marlies Michl et al
Clinical Colorectal Cancer Month 2015
1-1 1-1 1-1 1-1 1-1 2-2 2-2 1-2 1-2 1-3 1-3 1-3 2-1 2-1 2-2
2-2: Subsequent BM
0.8 (0.1-1.5)
OS-1 Comparison Groups
Synchronous Extracranial Metastasis
2-1a: Synchronous Solitary BM
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Brain Metastasis in Colorectal Cancer Patients Figure 2 Kaplan-Meier Survival Curves for OS-1 According to the 6 Clinical Subgroups (See Figure 1). Data Are Presented as Median Months (Range)
of newer cytostatic drugs and biological agents since the late 1990s, ranging from 26 to 30 months as recent randomized trials report (PEAK, FIRE-3).20,21 Although mCRC represents one of the most frequent solid malignancies, knowledge on BM in CRC is limited.
Few analyses with limited patient numbers were published in the past decades and mainly focused on treatment options for BM.3,10,16 In the present study we aimed to characterize this rare patient cohort and to identify prognostic subgroups regarding survival. We
Figure 3 Kaplan-Meier Survival Curves for OS-2 According to the 6 Clinical Subgroups (See Figure 1). Data Are Presented as Median Months (Range)
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Clinical Colorectal Cancer Month 2015
Marlies Michl et al Figure 4 Kaplan-Meier Survival Curves for OS-3 According to the 6 Clinical Subgroups (See Figure 1). Data Are Presented as Median Months (Range)
identified 228 patients with mCRC and BM who were diagnosed between 1998 and 2011. That represents the largest BM cohort in mCRC patients analyzed to date. Overall, OS-1 was 35.6 months and 1-, 2-, and 5-year survival probabilities were 83.3%, 63.6%, and 17.5%, respectively, and thus shorter than in large CRC collectives without BM.22 Regarding OS2, with a focus on patients with subsequent BM after meta- or synchronous EM (group 1-2: 28.6 months; group 2-2: 22.2 months; Table 3), OS-2 was comparable with the latest survival data in stage IV CRC patients (FIRE-3, CALGB/SWOG).21,23 Median time from first diagnosis of CRC to diagnosis of BM was 29.2 months and slightly exceeded the time period described in the literature (24-28 months).10,13,16,24 However, OS-3 was short irrespective of subgroup (0.8-4.0 months). Nearly 73.2% of all patients died within the first 6 months after BM was diagnosed. From diagnosis of BM, 1-year survival was only 11% and a single patient survived more than 5 years (Table 2). These data strongly confirm previous reports of dramatically dismal survival when BM is present.6,11,13,14,16,18,25,26 In addition, the present results underline the previous publication data from Berghoff et al in which patients with BM of colorectal histology demonstrated the shortest OS compared with other histologies, which could be shown with high Ki-67 staining.27 An exception was observed in patients with synchronous solitary BM. The outstanding long OS-3 in 3 patients might be because of the shorter duration of systemic disease and lack of pretreatments resulting in a better performance status and therefore optimal conditions for intensive BM therapy.24,26 Regarding the presented clinical subgroups, by far most patients (197 patients; 86.4%) were diagnosed with BM when EM were already present. Similar observations were described by other
authors.13,15-17,26,28 The frequency of subsequent BM after metachronous or synchronous EM was comparable (33.8% vs. 35.5%). Only 31 patients presented with solitary BM, most of which also occurred subsequently. Primary tumors were located throughout the whole colon and rectum, but predominantly left-sided (155 patients; 68%) including in the rectum (95 patients; 42%; Table 1), which is in line with the expected distribution of colorectal carcinomas.13,16,19,29,30 Regarding the influence of patient baseline characteristics (Table 1) on OS-1, OS-2, and OS-3, one can summarize that (1) the effect of age, TNM status, grading, and UICC stage on OS-1, which is long known and approved in large CRC patient collectives, remains valid when BM develop later during course of metastatic disease; (2) that the effect of age, N- and M-status, grading, and UICC stage on OS-2 continues with less strong significance; and (3) that the effect of tumor and patient characteristics on survival dissolves in most instances when BM occur (OS-3; Table 4). Age at the time of initial diagnosis was the sole variable that constantly revealed a significant effect on survival suggesting a better performance status in younger patients. Although there was a trend towards a longer OS-1 for men compared with for women (38.1 vs. 29.1 months), statistical significance was not reached. This is in concordance with more recent data, which also suggested a disadvantage in response and survival for certain CRC subgroups (eg. female sex), which however, needs to be further investigated.10,16,31 The present analysis is unfortunately limited by lack of information on patient performance status, applied systemic or local treatments for CRC or BM, and lack of information on intracranial metastatic sites and numbers, which certainly limit the significance of the present data, but are owed to the data source in a registry. In addition, the numbers of patients in certain subgroups was small,
Clinical Colorectal Cancer Month 2015
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8
OS-1 Patient and Tumor Characteristic Agea
n
Months
228
OS-2
HR
95% CI
P
1.27
0.97-1.67
.08
Months
65 years
142
37.9
19.6
>65 years
86
26.7
10.3
Sex
228
Female Male
1.25
0.96-1.62
.10
OS-3
HR
95% CI
P
1.57
1.20-2.06
.001
Months
HR
95% CI
P
1.31
1.00-1.72
.06
0.94
0.72-1.22
.62
1.03
0.73-1.46
.86
e
e
2.3 1.5 0.93
0.71-1.22
.60
94
29.1
14.9
2.2
134
38.1
17.1
1.9
TNMa T status T 1þ2þ3 T4 Lymph node status N0 (reference)
166
1.46
22
39.5
144
24.3
1.03-2.06
1.08
0.76-1.52
1.9
11.8
1.7
<.001 52.4
.68
16.5
163 40
.03
e
e
.03
e
34.5
e
e
e
.68 2.2
e
N1
55
35.0
1.50
0.99-2.26
.06
11.8
1.63
1.08-2.46
.02
1.5
0.89
0.59-1.35
.60
N2
68
23.6
2.32
1.56-3.47
<.001
14.2
1.63
1.09-2.43
.02
2.3
1.05
0.71-1.55
.82
2.22
1.70-2.90
<.001
0.68
0.52-0.89
.005
1.35
1.03-1.75
.03
1.14
0.85-1.53
.38
1.26
0.94-1.68
.12
0.75
0.57-0.98
.03
0.79
0.57-1.09
.15
Metastatic Status
228
M0
126
44.2
M1
102
17.5
Gradinga
212
Grade 1þ2 Grade 3 UICCa UICC I þ II þ III UICC IVb Localization Primary (1)
1.20-2.16
.002
39.5
17.4
66
24.4
11.2 2.31
87
44.4
102
17.5
228 31.0
Rectum
126
37.6
204
<.001
1.05-1.90
.02 2.0 1.6
0.70
0.52-0.93
.02
11.1
2.4
17.5 0.88
102
1.72-3.09
1.5 1.42
146 189
2.7
17.5 1.61
Colon Localization Primary (2)
11.1
0.68-1.15
.36
1.5 0.90
0.69-1.16
.41
14.3
1.7
17.7 0.81
0.58-1.12
.20
2.3 0.73
0.53-1.01
.06
Right colon
49
22.2
11.2
1.5
Left colon
155
36.5
17.8
2.0
P values < .05 are in bold. Indicated number of patients corresponds to the number of observations of 228. Regarding assignment of primary tumor site to left or right sided colon; see Table 1. Abbreviations: CRC ¼ colorectal cancer; HR ¼ hazard ratio; OS ¼ overall survival; OS-1 ¼ overall survival from time of first diagnosis of CRC; OS-2 ¼ overall survival from time of diagnosis of metastatic disease; OS-3 ¼ from time of diagnosis of brain metastases; TNM ¼ tumor, node, metastases; UICC ¼ Union Internationale Contre le Cancer. a At time of initial diagnosis of CRC. b In multiple testing OS-1 showed significant differences depending on UICC IV versus II and III (P ¼ .004, respectively).
Brain Metastasis in Colorectal Cancer Patients
Clinical Colorectal Cancer Month 2015
Table 4 Univariate Cox Proportional Hazards Modeling OS for OS-1, OS-2, and OS-3 According to Patient and Tumor Characteristics
Marlies Michl et al which means confidence intervals are wide and the reliability of the results is less certain.
Conclusion To our knowledge, this is the largest analysis of patients with mCRC and BM up to this date. The results presented show that most patients develop BM as a late step in disease when EM is already present. Only a small fraction of patients are diagnosed with BM early in disease or with solitary BM. Data further show that survival is poor when BM is diagnosed irrespective of subgroup and tumor characteristics with the exception of patients with synchronous solitary BM. As previous studies show, survival can increase with early BM detection and intensive treatment with combined surgical resection and radiation therapy for which best results were reported. Therefore, there is an urgent need to intensify the search for prognostic or predictive markers and to identify patients who are at risk.
Clinical Practice Points Although CRC represents one of the most common malig-
nancies in women and men, knowledge about onset, prognosis, and survival of CRC patients with BM is very limited to date. In the literature BM in CRC is described as a rare and late event (approximately 1%-4%). Most available information is obtained from postmortem studies, by neurosurgeons, or by radiotherapists, who focus on local treatment options for BM in solid tumors. In the literature, median survival time counted from the date of initial diagnosis of CRC ranges between 26 and 38 months. When BM occurs, prognosis is poor with median survival time ranges from 1.0 to 5.7 months. Results of this work offer a precise description of this rare patient cohort: Median age at initial diagnosis (63 years) was comparable with those in recent large prospective clinical trials, but younger compared with registry data in the Western world. Most patients are initially diagnosed with tumors staged T3/4, Nþ, Grade 2, and without distant metastases. Regarding the primary tumor sites, most are located in the left colon and there predominantly in the rectum. We also presented survival data regarding OS from the time of initial diagnosis (35.6 months), from diagnosis of metastatic disease (16.5 months), and from diagnosis of BM (2.0 months). First described herein was time from initial diagnosis of CRC to occurrence of BM (29.2 months). We also included a proposal for clinical prognostic subgrouping of these patients dependent on occurrence of synchronous or metachronous extra- and intracranial metastasis. Most patients develop sequential BM (> 80%). Only a small fraction of patients are diagnosed with BM early in disease or with solitary BM (13.4%). Univariate analysis revealed no effect of patient and tumor characteristics on survival when BM has been diagnosed. To our knowledge, we included the largest number of patients with CRC and BM analyzed to date. Results of this study might sensitize clinicians for the potential development of BM in late-stage CRC with a consequence on diagnostic imaging of the brain.
It is an appeal to consider this rare cohort (announce to clinical
registries, need for further research including molecular diagnostics, etc). When BM is present, certain patients (subgroups) show longer survival compared with others (also long-term survivors), so there might be a need for different treatment strategies.
Acknowledgments This publication is part of the doctoral thesis of Johannes Thurmaier. This work is part of a DKTK (German Consortium for Translational Cancer Research) funded project.
Disclosure The authors have stated that they have no conflicts of interest.
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