G Model
BIOPHA-3376; No. of Pages 4 Biomedicine & Pharmacotherapy xxx (2014) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Original article
Basal proteinuria as a prognostic factor in patients with metastatic colorectal cancer treated with bevacizumab Mukremin Uysal a,*, Hakan Bozcuk b, Sema Sezgin Go¨ksu b, Ali Murat Tatlı b, Deniz Arslan b, Seyda Gu¨ndu¨z b, Hasan Senol Coskun b, Mustafa Ozdogan c, Burhan Savas b a b c
Afyon Kocatepe University Faculty of Medicine, Department of Medical Oncology, Izmir Karayolu 8.km, 03200 Afyon, Turkey Akdeniz University Faculty of Medicine, Department of Medical Oncology, Antalya, Turkey Medstar Antalya Hospital, Department of Medical Oncology, Antalya, Turkey
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 January 2014 Accepted 4 March 2014
Background: The beneficial effects of bevacizumab, a widely used agent in metastatic colorectal cancer (mCRC), on clinical survival have been proven. This study investigated the correlation of the clinical benefits and prognosis with proteinuria and other parameters. Methods: The study included mCRC patients receiving bevacizumab. Hypertension, 24-hour urine proteinuria, and other routine parameters were recorded at baseline and at certain intervals during treatment. Results: The study included 36 consecutive patients. The median progression-free survival (PFS) duration was 10.9 2.6 months, and the median overall survival (OS) was 23 3.1 months. The median PFS was 7.2 months among patients with basal proteinuria above 114 mg/day, whereas the median PFS was 12 months among patients with an equal or lower level (P = 0.010). Similarly, PFS was shorter in patients with high lactate dehydrogenase (LDH) or carcinoembryonic antigen (CEA) levels (LDH, P = 0.022; CEA, P = 0.014). Bevacizumab response’s performance status was good (P = 0.05) and was even better in patients with a single liver metastasis (P = 0.034) or hypertension (P = 0.034). Conclusions: We demonstrated that high basal proteinuria, LDH, or CEA levels may be negative prognostic factors in mCRC patients receiving bevacizumab. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Bevacizumab Metastatic colorectal cancer Prognostic and predictive factors Proteinuria
1. Introduction Colorectal cancer (CRC) is a significant cause of death worldwide. It is the third most common cause of cancer-related death in the United States [1] and is the 5th and 2nd most common cancer type among men and women in our country, Turkey, respectively [2]. In total, 25% of patients are in the metastatic stage upon diagnosis. CRC can be treated and is usually curable if detected in the localized stage. Surgery is the primary treatment method and results in a cure in almost 50% of patients. In advanced stages, metastasis is observed in 30–40% of patients. Bevacizumab is widely used as the first step for the treatment of the metastatic disease. Several randomized studies have demonstrated that a combination of bevacizumab and chemotherapy in metastatic CRC (mCRC) significantly improves the
* Corresponding author. Tel.: +90 27 22 46 33 22; fax: +90 27 22 46 27 07. E-mail address: [email protected] (M. Uysal).
response rate, progression-free survival (PFS), and overall survival (OS) [3,4]. In a pivotal approval study of bevacizumab, the median OS was significantly extended (from 15.6 months to 20.3 months, HR 0.66, P < 0.001) by the addition of bevacizumab to the first-line therapy, consisting of irinotecan, 5-fluorouracil, and leucovorin [4]. However, no predictor of bevacizumab’s clinical benefits in mCRC has been defined. Moreover, no correlation between the VEGF expression targeted by bevacizumab and the therapeutic response has been defined [5]. However, the response and survival of patients developing hypertension during bevacizumab therapy are reportedly better [6,7]. Whether there is such a relationship concerning bevacizumab-related proteinuria development in mCRC patients is unclear. Further predictive or prognostic indicators are required to demonstrate bevacizumab’s efficacy. Herein, we investigated possible predictive/prognostic parameters for bevacizumab response among all routine clinical measurements, including proteinuria, in mCRC patients receiving bevacizumab therapy.
http://dx.doi.org/10.1016/j.biopha.2014.03.002 0753-3322/ß 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Uysal M, et al. Basal proteinuria as a prognostic factor in patients with metastatic colorectal cancer treated with bevacizumab. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.03.002
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BIOPHA-3376; No. of Pages 4 M. Uysal et al. / Biomedicine & Pharmacotherapy xxx (2014) xxx–xxx
2
Table 1 Demographic data.
2. Materials and methods 2.1. Patient selection and treatments Patients receiving therapy at Akdeniz University, Faculty of Medicine, Department of Internal Diseases, Medical Oncology Clinics, between August 2010 and April 2011 due to mCRC were enrolled. This is a prospective study. The inclusion criteria were that the patients had previously completed staging examinations, exhibited proven metastasis, were receiving chemotherapy including bevacizumab, and had a performance score of Eastern Cooperative Oncology Group (ECOG) 0-2. The aim was to investigate whether the routine measurements, including proteinuria, of these patients could predict the response to or prognosis of chemotherapy with bevacizumab. Routine treatment included the FOLFIRI-B, XELIRI-B, and XELOX-B chemotherapy regimens. 2.2. Evaluated data In addition to basal biochemical data, 24-hour proteinuria was monitored for all patients. Proteinuria levels, arterial blood pressure, and serum carcinoembryonic antigen (CEA) levels were recorded three times prior to the study and during the 2nd and 3rd courses of treatment. In the 2nd month of the study, a therapeutic response was evaluated via diagnostic imaging. 2.3. Statistical analysis Approximately 3–9 months after patient inclusion, the obtained data were evaluated regarding the presence of any correlation of PFS and responses with the routine measurements of the patients, including proteinuria. The primary end point of this study was to assess factors of affecting the PFS. Progression-free survival is defined as the time from first bevacicumab based therapy until objective tumor progression or death. Routine computed tomographic images were assessed according to the RECIST criteria. Statistical analyses were performed using SPSS V.18 software. A logarithmic transformation was performed for non-normally distributed variables. In addition to the descriptive statistics used to evaluate the study data, the Kaplan-Meier
Parameters
n
%
Age
36
Gender Male Female
20 16
55.6 44.4
Tumor localization Colon Rectum
28 8
77.8 22.2
Chemotherapy regimen Including irinotecan Including oxaliplatin
29 7
80.6 19.4
Number of metastases Single metastasis Multiple metastases
17 19
47.2 52.8
Single liver metastasis
7
19.4
Mean 57.7
Min–Max 34–80
Proteinuria (mg/day), > 150 mg/day
36
150
8–560
LDH (U/L)
36
358
1651–154
CEA (ng/mL)
36
44
1.3–621
42
Min: minimum; Max: maximum; LDH: lactate dehydrogenase; CEA: carcinoembryonic antigen.
method was used for survival analyses, and Cox regression analysis was used to define the correlation between survival and measurement parameters and to perform the predictive analysis of critical factors. The correlation between the therapeutic response and other parameters was evaluated using logistic regression. Lastly, a repeated measures-analysis of responses was used to investigate the correlation between repeated measurements and responses. 3. Results In total, 36 consecutive mCRC patients were evaluated in our study. The mean age was 57 11. Twenty patients (55.6%) were male, and 16 (44.4%) were female. A total of 28 (77.8%) patients had colon cancer, and 8 (22.2%) had rectal cancer. A single liver metastasis
Fig. 1. Progression-free survival and overall survival curves for all patients.
Please cite this article in press as: Uysal M, et al. Basal proteinuria as a prognostic factor in patients with metastatic colorectal cancer treated with bevacizumab. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.03.002
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BIOPHA-3376; No. of Pages 4 M. Uysal et al. / Biomedicine & Pharmacotherapy xxx (2014) xxx–xxx
3
Table 2 Factors affecting progression-free survival. Parameters
P
Exp(B), 95% CI for Exp(B)
Gender
0.070
0.574 (0.260–1.054)
Age
0.713
1.006 (0.975–1.037)
Comorbidity
0.556
0.895 (0.619–1.295)
ECOG PS
0.935
1.016 (0.697–1.482)
Metastasis type (only liver or multiple)
0.224
0.576 (0.237–1.401)
Number of metastases
0.114
1.467 (0.912–2.362)
Chemotherapy regimen (irinotecan vs. oxaliplatin)
0.644
1.232 (0.975–1.037)
Basal proteinuria ( 114 mg/day vs. > 114 mg/day). Favor of low proteinuria
0.010a
2.701 (1.508–2.988)
LDH. Favor of low LDH
0.022a
1.002 (1.000–1.003)
MPV
0.732
1.592 (0.111–22.74)
CEA. Favor of low CEA
0.014a
1.003 (1.001–1.006)
ECOG PS: Eastern Cooperative Oncology Group performance status; LDH: lactate dehydrogenase; CEA: carcinoembryonic antigen; MPV: mean platelet volume; Exp(B): exponentiated logistic coefficients or odds ratio. a P < 0.05
was observed in 19.4% of patients. The patients’ baseline routine biochemical measurements did not reveal any abnormal findings. The basal LDH (358 U/L [Ref 135–214]) and CEA (44 ng/mL [Ref 0–4]) levels were elevated. The patients’ demographic characteristics are shown in Table 1. The median duration of follow-up was 22.8 months. The median PFS and OS were 10.9 2.6 and 23 3.1 months, respectively, according to survival analyses (Fig. 1). No correlation was observed between PFS and gender; comorbidity; performance score; metastasis type (such as single metastasis); the number of metastases; age; creatinine, ALT and bilirubin levels; and the mean platelet volume (MPV). It was observed that the chemotherapy regimen type did not affect PFS (P = 0.644). However, basal 24-hour urine proteinuria, LDH, and CEA levels affected PFS (P = 0.010, 0.022, and 0.014, respectively). The data are summarized in Table 2. It was observed that high basal LDH, CEA, and proteinuria levels were related to negative prognosis. The median PFS among patients with basal proteinuria above 114 mg/day (high) or below 114 mg/day (low) was 7.2 and 12 months, respectively (P = 0.010). Median OS values of 15.7 and 23 months were observed among patients with basal proteinuria above 114 mg/day (high) or equal to or below 114 mg/day (low), respectively. However, these findings were not statistically significant (P = 0.18) (Fig. 2). The pre- and post-treatment sizes of the targeted lesion were calculated according to the RECIST criteria. The rate of response to chemotherapy, including bevacizumab revealed no response in 7 of the 36 (19.4%) patients and clinical benefit (response and stabilization) in 29 of the 36 (80.6%) patients. When factors affecting and predicting the response were investigated, gender; age; the number of metastases; the MPV; ALT, total bilirubin, LDH, CEA and basal proteinuria levels; mean arterial blood pressure; and chemotherapy type had no effect on the response (Table 3). However, ECOG performance status and metastasis type positively affected the response, which was better in patients
Fig. 2. Correlation between progression-free survival (PFS) and proteinuria. PFS is worse in patients with high basal proteinuria (> 114 mg/day).
with a low performance score (P = 0.050) or only liver metastasis (P = 0.034). An investigation of the correlation of repeated CEA and proteinuria measurements with the response revealed that a change in CEA levels was not sufficient to predict the response (P = 0.43). A change in proteinuria levels between treatment courses, meaning a change in proteinuria over time, did not predict the response to chemotherapy (P = 0.865).
Table 3 Evaluation of the parameters that may affect the therapeutic response. Parameters
P-value
Exp(B)
Gender (male vs. female)
0.940
0.951
Age
0.312
1.033
ECOG (ordinal variable)
0.050
2.344
Metastasis type (only liver vs. other)
0.034
0.088
Number of metastases (ordinal variable)
0.118
2.372
Chemotherapy type (including irinotecan vs. oxaliplatin)
0.506
1.250
MPV
0.249
1.470
Total bilirubin
0.498
0.518
LDH
0.314
1.002
CEA
0.149
1.022
Basal spot proteinuria
0.367
0.940
Basal daily proteinuria
0.392
0.404
Basal proteinuria ( 114 mg/day vs. > 114 mg/day)
0.334
0.519
Basal systolic blood pressure
0.107
1.028
Basal diastolic blood pressure
0.160
1.052
Mean basal blood pressure
0.061
1.050
LDH: lactate dehydrogenase; CEA: carcinoembryonic antigen; ECOG: Eastern Cooperative Oncology Group; MPV: mean platelet volume; Exp(B): exponentiated logistic coefficients or odds ratio.
Please cite this article in press as: Uysal M, et al. Basal proteinuria as a prognostic factor in patients with metastatic colorectal cancer treated with bevacizumab. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.03.002
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An investigation of arterial blood pressure measurements revealed that the response was better in patients with a high systolic blood pressure pre- and post-course (P = 0.034). However, the P-value for diastolic blood pressure was 0.088. No correlation was observed between bevacizumab-related proteinuria and basal LDH levels (r2 = 0.247, P = 0.146). 4. Discussion We demonstrated that basal proteinuria, LDH, and CEA levels may be prognostic in mCRC patients receiving bevacizumab. No previous study has assigned a prognostic value to basal proteinuria in patients receiving bevacizumab therapy. We hypothesize that basal proteinuria may be prognostic because mCRC negatively affects the kidney’s glomeruli via various mechanisms, and bevacizumab is more effective in these patients. For example, tumor load-related increased VEGF may impair endothelial function and, subsequently, glomerular function, leading to both hypertension and proteinuria. Similarly, hypertension and proteinuria are reported to be parallel in these patients [8–10]. However, these two factors were unrelated in our study, so different mechanisms may have been involved in the development of these two factors. Whether proteinuria has a predictive role in these patients and in patients receiving bevacizumab is also important and clearly may be treatment related. The same investigation should be repeated in patients not receiving bevacizumab-based therapies (a pure chemotherapy group) to answer this question. Additionally, basal LDH and CEA levels were determined to be other prognostic indicators in our study. Patients presenting high LDH levels had a negative prognosis. Indeed, this information is already known for CRC patients not receiving bevacizumab and is explained by increased LDH levels in parallel with increased tumor load. It is clear that prognosis would be worse in patients with a higher tumor load. Preclinical and clinical data show that a high serum LDH level is a biomarker for highly angiogenic tumors as well. Therefore, increased LDH levels predict a negative prognosis [11– 13]. CEA is an accepted biomarker for colon cancer. High preoperative CEA levels have been demonstrated to have an impact on negative prognosis in CRC, independent of the tumor stage [14,15]. The response-related parameters in our study were performance status, metastasis type, and hypertension. Accordingly, patients with a good ECOG performance status, a single liver metastasis, and increased arterial blood pressure during treatment may be good responders. These parameters are already known as positive prognostic factors [6,7,10,16]. A meta-analysis by Sargent et al. demonstrated that an ECOG performance score of 2 (PS2) resulted in worse outcomes than did PS0 or PS1 regarding PFS, OS, response rates, and side effects [16]. It has also been demonstrated that patients who develop hypertension during bevacizumab therapy have better PFS and OS. In a study by Scartozzi et al. on 39 patients, hypertension development was observed in 20%, and PFS was found to be significantly higher in these patients compared with non-hypertensive patients (14.5 months vs. 3.1 months, P = 0.004) [6]. Ryanne Wu et al. evaluated 84 patients and observed better recovery in the hypertensive group in terms of both OS (92 vs. 76%, P = 0.03) and PFS (62 vs. 19%, P = 0.004) in a one-year follow-up [7]. We demonstrated that the standard prognostic factors performance status, metastasis type, and hypertension, were effective in our study group as well. We have concluded that basal proteinuria levels in mCRC patients receiving bevacizumab-based therapy may be a new,
unique indicator of treatment efficacy and survival. Additionally, we have demonstrated that the tumor response was more significant in patients prone to hypertension during treatment, consistent with published information. We believe that investigating the possible predictive role of basal proteinuria via additional studies is of practical and clinical importance. Further studies should confirm proteinuria levels as a predictor in mCRC patients receiving bevacizumab therapies. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements None. References [1] American Cancer Society. Cancer facts & figures 2013. Atlanta: American Cancer Society; 2013. [2] Ferlay J. In: Shin HRB, Forman D, Mathers C, Parkin DM, editors. GLOBOCAN 2008 v2. 0, cancer incidence and mortality worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. [3] Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007; 25(12):1539–44. [4] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335–42. [5] Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS, et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 2006;24(2):217–27. [6] Scartozzi M, Galizia E, Chiorrini S, Giampieri R, Berardi R, Pierantoni C, et al. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol 2009;20(2): 227–30. [7] Ryanne Wu R, Lindenberg PA, Slack R, Noone AM, Marshall JL, He AR. Evaluation of hypertension as a marker of bevacizumab efficacy. J Gastrointest Cancer 2009;40(3–4):101–8. [8] Martel CL, Ebrahimi B, Upadhyaya G, Vakil M, Yeon C, Bosserman LD, et al. Bevacizumab-related toxicities: association of hypertension and proteinuria. Community Oncol 2006;3(2):90–3. [9] Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349(5):427– 34. [10] Cai J, Ma H, Huang F, Zhu D, Bi J, Ke Y, et al. Correlation of bevacizumab-induced hypertension and outcomes of metastatic colorectal cancer patients treated with bevacizumab: a systematic review and meta-analysis. World J Surg Oncol 2013;11(1):306. [11] Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343(13):905–14. [12] Tournigand C, Andre´ T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22(2):229–37. [13] Dı´az R, Aparicio J, Girone´s R, Molina J, Palomar L, Segura A, et al. Analysis of prognostic factors and applicability of Kohne’s prognostic groups in patients with metastatic colorectal cancer treated with first-line irinotecan or oxaliplatin-based chemotherapy. Clin Colorectal Cancer 2005;5(3):197–202. [14] Harrison LE, Guillem JG, Paty P, Cohen AM. Preoperative carcinoembryonic antigen predicts outcomes in node-negative colon cancer patients: a multivariate analysis of 572 patients. J Am Coll Surg 1997;185(1):55–9. [15] Onetto M, Paganuzzi M, Secco GB, Fardelli R, Santi F, Rovida S, et al. Preoperative carcinoembryonic antigen and prognosis in patients with colorectal cancer. Biomed Pharmacother 1985;39(7):392–5. [16] Sargent D, Kohne C, Sanoff H, Bot B, Seymour M, De G, et al. Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer. J Clin Oncol 2009;27(20):3410–1.
Please cite this article in press as: Uysal M, et al. Basal proteinuria as a prognostic factor in patients with metastatic colorectal cancer treated with bevacizumab. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.03.002
BIOPHA-3376; No. of Pages 4 Biomedicine & Pharmacotherapy xxx (2014) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Original article
Basal proteinuria as a prognostic factor in patients with metastatic colorectal cancer treated with bevacizumab Mukremin Uysal a,*, Hakan Bozcuk b, Sema Sezgin Go¨ksu b, Ali Murat Tatlı b, Deniz Arslan b, Seyda Gu¨ndu¨z b, Hasan Senol Coskun b, Mustafa Ozdogan c, Burhan Savas b a b c
Afyon Kocatepe University Faculty of Medicine, Department of Medical Oncology, Izmir Karayolu 8.km, 03200 Afyon, Turkey Akdeniz University Faculty of Medicine, Department of Medical Oncology, Antalya, Turkey Medstar Antalya Hospital, Department of Medical Oncology, Antalya, Turkey
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 January 2014 Accepted 4 March 2014
Background: The beneficial effects of bevacizumab, a widely used agent in metastatic colorectal cancer (mCRC), on clinical survival have been proven. This study investigated the correlation of the clinical benefits and prognosis with proteinuria and other parameters. Methods: The study included mCRC patients receiving bevacizumab. Hypertension, 24-hour urine proteinuria, and other routine parameters were recorded at baseline and at certain intervals during treatment. Results: The study included 36 consecutive patients. The median progression-free survival (PFS) duration was 10.9 2.6 months, and the median overall survival (OS) was 23 3.1 months. The median PFS was 7.2 months among patients with basal proteinuria above 114 mg/day, whereas the median PFS was 12 months among patients with an equal or lower level (P = 0.010). Similarly, PFS was shorter in patients with high lactate dehydrogenase (LDH) or carcinoembryonic antigen (CEA) levels (LDH, P = 0.022; CEA, P = 0.014). Bevacizumab response’s performance status was good (P = 0.05) and was even better in patients with a single liver metastasis (P = 0.034) or hypertension (P = 0.034). Conclusions: We demonstrated that high basal proteinuria, LDH, or CEA levels may be negative prognostic factors in mCRC patients receiving bevacizumab. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Bevacizumab Metastatic colorectal cancer Prognostic and predictive factors Proteinuria
1. Introduction Colorectal cancer (CRC) is a significant cause of death worldwide. It is the third most common cause of cancer-related death in the United States [1] and is the 5th and 2nd most common cancer type among men and women in our country, Turkey, respectively [2]. In total, 25% of patients are in the metastatic stage upon diagnosis. CRC can be treated and is usually curable if detected in the localized stage. Surgery is the primary treatment method and results in a cure in almost 50% of patients. In advanced stages, metastasis is observed in 30–40% of patients. Bevacizumab is widely used as the first step for the treatment of the metastatic disease. Several randomized studies have demonstrated that a combination of bevacizumab and chemotherapy in metastatic CRC (mCRC) significantly improves the
* Corresponding author. Tel.: +90 27 22 46 33 22; fax: +90 27 22 46 27 07. E-mail address: [email protected] (M. Uysal).
response rate, progression-free survival (PFS), and overall survival (OS) [3,4]. In a pivotal approval study of bevacizumab, the median OS was significantly extended (from 15.6 months to 20.3 months, HR 0.66, P < 0.001) by the addition of bevacizumab to the first-line therapy, consisting of irinotecan, 5-fluorouracil, and leucovorin [4]. However, no predictor of bevacizumab’s clinical benefits in mCRC has been defined. Moreover, no correlation between the VEGF expression targeted by bevacizumab and the therapeutic response has been defined [5]. However, the response and survival of patients developing hypertension during bevacizumab therapy are reportedly better [6,7]. Whether there is such a relationship concerning bevacizumab-related proteinuria development in mCRC patients is unclear. Further predictive or prognostic indicators are required to demonstrate bevacizumab’s efficacy. Herein, we investigated possible predictive/prognostic parameters for bevacizumab response among all routine clinical measurements, including proteinuria, in mCRC patients receiving bevacizumab therapy.
http://dx.doi.org/10.1016/j.biopha.2014.03.002 0753-3322/ß 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Uysal M, et al. Basal proteinuria as a prognostic factor in patients with metastatic colorectal cancer treated with bevacizumab. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.03.002
G Model
BIOPHA-3376; No. of Pages 4 M. Uysal et al. / Biomedicine & Pharmacotherapy xxx (2014) xxx–xxx
2
Table 1 Demographic data.
2. Materials and methods 2.1. Patient selection and treatments Patients receiving therapy at Akdeniz University, Faculty of Medicine, Department of Internal Diseases, Medical Oncology Clinics, between August 2010 and April 2011 due to mCRC were enrolled. This is a prospective study. The inclusion criteria were that the patients had previously completed staging examinations, exhibited proven metastasis, were receiving chemotherapy including bevacizumab, and had a performance score of Eastern Cooperative Oncology Group (ECOG) 0-2. The aim was to investigate whether the routine measurements, including proteinuria, of these patients could predict the response to or prognosis of chemotherapy with bevacizumab. Routine treatment included the FOLFIRI-B, XELIRI-B, and XELOX-B chemotherapy regimens. 2.2. Evaluated data In addition to basal biochemical data, 24-hour proteinuria was monitored for all patients. Proteinuria levels, arterial blood pressure, and serum carcinoembryonic antigen (CEA) levels were recorded three times prior to the study and during the 2nd and 3rd courses of treatment. In the 2nd month of the study, a therapeutic response was evaluated via diagnostic imaging. 2.3. Statistical analysis Approximately 3–9 months after patient inclusion, the obtained data were evaluated regarding the presence of any correlation of PFS and responses with the routine measurements of the patients, including proteinuria. The primary end point of this study was to assess factors of affecting the PFS. Progression-free survival is defined as the time from first bevacicumab based therapy until objective tumor progression or death. Routine computed tomographic images were assessed according to the RECIST criteria. Statistical analyses were performed using SPSS V.18 software. A logarithmic transformation was performed for non-normally distributed variables. In addition to the descriptive statistics used to evaluate the study data, the Kaplan-Meier
Parameters
n
%
Age
36
Gender Male Female
20 16
55.6 44.4
Tumor localization Colon Rectum
28 8
77.8 22.2
Chemotherapy regimen Including irinotecan Including oxaliplatin
29 7
80.6 19.4
Number of metastases Single metastasis Multiple metastases
17 19
47.2 52.8
Single liver metastasis
7
19.4
Mean 57.7
Min–Max 34–80
Proteinuria (mg/day), > 150 mg/day
36
150
8–560
LDH (U/L)
36
358
1651–154
CEA (ng/mL)
36
44
1.3–621
42
Min: minimum; Max: maximum; LDH: lactate dehydrogenase; CEA: carcinoembryonic antigen.
method was used for survival analyses, and Cox regression analysis was used to define the correlation between survival and measurement parameters and to perform the predictive analysis of critical factors. The correlation between the therapeutic response and other parameters was evaluated using logistic regression. Lastly, a repeated measures-analysis of responses was used to investigate the correlation between repeated measurements and responses. 3. Results In total, 36 consecutive mCRC patients were evaluated in our study. The mean age was 57 11. Twenty patients (55.6%) were male, and 16 (44.4%) were female. A total of 28 (77.8%) patients had colon cancer, and 8 (22.2%) had rectal cancer. A single liver metastasis
Fig. 1. Progression-free survival and overall survival curves for all patients.
Please cite this article in press as: Uysal M, et al. Basal proteinuria as a prognostic factor in patients with metastatic colorectal cancer treated with bevacizumab. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.03.002
G Model
BIOPHA-3376; No. of Pages 4 M. Uysal et al. / Biomedicine & Pharmacotherapy xxx (2014) xxx–xxx
3
Table 2 Factors affecting progression-free survival. Parameters
P
Exp(B), 95% CI for Exp(B)
Gender
0.070
0.574 (0.260–1.054)
Age
0.713
1.006 (0.975–1.037)
Comorbidity
0.556
0.895 (0.619–1.295)
ECOG PS
0.935
1.016 (0.697–1.482)
Metastasis type (only liver or multiple)
0.224
0.576 (0.237–1.401)
Number of metastases
0.114
1.467 (0.912–2.362)
Chemotherapy regimen (irinotecan vs. oxaliplatin)
0.644
1.232 (0.975–1.037)
Basal proteinuria ( 114 mg/day vs. > 114 mg/day). Favor of low proteinuria
0.010a
2.701 (1.508–2.988)
LDH. Favor of low LDH
0.022a
1.002 (1.000–1.003)
MPV
0.732
1.592 (0.111–22.74)
CEA. Favor of low CEA
0.014a
1.003 (1.001–1.006)
ECOG PS: Eastern Cooperative Oncology Group performance status; LDH: lactate dehydrogenase; CEA: carcinoembryonic antigen; MPV: mean platelet volume; Exp(B): exponentiated logistic coefficients or odds ratio. a P < 0.05
was observed in 19.4% of patients. The patients’ baseline routine biochemical measurements did not reveal any abnormal findings. The basal LDH (358 U/L [Ref 135–214]) and CEA (44 ng/mL [Ref 0–4]) levels were elevated. The patients’ demographic characteristics are shown in Table 1. The median duration of follow-up was 22.8 months. The median PFS and OS were 10.9 2.6 and 23 3.1 months, respectively, according to survival analyses (Fig. 1). No correlation was observed between PFS and gender; comorbidity; performance score; metastasis type (such as single metastasis); the number of metastases; age; creatinine, ALT and bilirubin levels; and the mean platelet volume (MPV). It was observed that the chemotherapy regimen type did not affect PFS (P = 0.644). However, basal 24-hour urine proteinuria, LDH, and CEA levels affected PFS (P = 0.010, 0.022, and 0.014, respectively). The data are summarized in Table 2. It was observed that high basal LDH, CEA, and proteinuria levels were related to negative prognosis. The median PFS among patients with basal proteinuria above 114 mg/day (high) or below 114 mg/day (low) was 7.2 and 12 months, respectively (P = 0.010). Median OS values of 15.7 and 23 months were observed among patients with basal proteinuria above 114 mg/day (high) or equal to or below 114 mg/day (low), respectively. However, these findings were not statistically significant (P = 0.18) (Fig. 2). The pre- and post-treatment sizes of the targeted lesion were calculated according to the RECIST criteria. The rate of response to chemotherapy, including bevacizumab revealed no response in 7 of the 36 (19.4%) patients and clinical benefit (response and stabilization) in 29 of the 36 (80.6%) patients. When factors affecting and predicting the response were investigated, gender; age; the number of metastases; the MPV; ALT, total bilirubin, LDH, CEA and basal proteinuria levels; mean arterial blood pressure; and chemotherapy type had no effect on the response (Table 3). However, ECOG performance status and metastasis type positively affected the response, which was better in patients
Fig. 2. Correlation between progression-free survival (PFS) and proteinuria. PFS is worse in patients with high basal proteinuria (> 114 mg/day).
with a low performance score (P = 0.050) or only liver metastasis (P = 0.034). An investigation of the correlation of repeated CEA and proteinuria measurements with the response revealed that a change in CEA levels was not sufficient to predict the response (P = 0.43). A change in proteinuria levels between treatment courses, meaning a change in proteinuria over time, did not predict the response to chemotherapy (P = 0.865).
Table 3 Evaluation of the parameters that may affect the therapeutic response. Parameters
P-value
Exp(B)
Gender (male vs. female)
0.940
0.951
Age
0.312
1.033
ECOG (ordinal variable)
0.050
2.344
Metastasis type (only liver vs. other)
0.034
0.088
Number of metastases (ordinal variable)
0.118
2.372
Chemotherapy type (including irinotecan vs. oxaliplatin)
0.506
1.250
MPV
0.249
1.470
Total bilirubin
0.498
0.518
LDH
0.314
1.002
CEA
0.149
1.022
Basal spot proteinuria
0.367
0.940
Basal daily proteinuria
0.392
0.404
Basal proteinuria ( 114 mg/day vs. > 114 mg/day)
0.334
0.519
Basal systolic blood pressure
0.107
1.028
Basal diastolic blood pressure
0.160
1.052
Mean basal blood pressure
0.061
1.050
LDH: lactate dehydrogenase; CEA: carcinoembryonic antigen; ECOG: Eastern Cooperative Oncology Group; MPV: mean platelet volume; Exp(B): exponentiated logistic coefficients or odds ratio.
Please cite this article in press as: Uysal M, et al. Basal proteinuria as a prognostic factor in patients with metastatic colorectal cancer treated with bevacizumab. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.03.002
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BIOPHA-3376; No. of Pages 4 M. Uysal et al. / Biomedicine & Pharmacotherapy xxx (2014) xxx–xxx
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An investigation of arterial blood pressure measurements revealed that the response was better in patients with a high systolic blood pressure pre- and post-course (P = 0.034). However, the P-value for diastolic blood pressure was 0.088. No correlation was observed between bevacizumab-related proteinuria and basal LDH levels (r2 = 0.247, P = 0.146). 4. Discussion We demonstrated that basal proteinuria, LDH, and CEA levels may be prognostic in mCRC patients receiving bevacizumab. No previous study has assigned a prognostic value to basal proteinuria in patients receiving bevacizumab therapy. We hypothesize that basal proteinuria may be prognostic because mCRC negatively affects the kidney’s glomeruli via various mechanisms, and bevacizumab is more effective in these patients. For example, tumor load-related increased VEGF may impair endothelial function and, subsequently, glomerular function, leading to both hypertension and proteinuria. Similarly, hypertension and proteinuria are reported to be parallel in these patients [8–10]. However, these two factors were unrelated in our study, so different mechanisms may have been involved in the development of these two factors. Whether proteinuria has a predictive role in these patients and in patients receiving bevacizumab is also important and clearly may be treatment related. The same investigation should be repeated in patients not receiving bevacizumab-based therapies (a pure chemotherapy group) to answer this question. Additionally, basal LDH and CEA levels were determined to be other prognostic indicators in our study. Patients presenting high LDH levels had a negative prognosis. Indeed, this information is already known for CRC patients not receiving bevacizumab and is explained by increased LDH levels in parallel with increased tumor load. It is clear that prognosis would be worse in patients with a higher tumor load. Preclinical and clinical data show that a high serum LDH level is a biomarker for highly angiogenic tumors as well. Therefore, increased LDH levels predict a negative prognosis [11– 13]. CEA is an accepted biomarker for colon cancer. High preoperative CEA levels have been demonstrated to have an impact on negative prognosis in CRC, independent of the tumor stage [14,15]. The response-related parameters in our study were performance status, metastasis type, and hypertension. Accordingly, patients with a good ECOG performance status, a single liver metastasis, and increased arterial blood pressure during treatment may be good responders. These parameters are already known as positive prognostic factors [6,7,10,16]. A meta-analysis by Sargent et al. demonstrated that an ECOG performance score of 2 (PS2) resulted in worse outcomes than did PS0 or PS1 regarding PFS, OS, response rates, and side effects [16]. It has also been demonstrated that patients who develop hypertension during bevacizumab therapy have better PFS and OS. In a study by Scartozzi et al. on 39 patients, hypertension development was observed in 20%, and PFS was found to be significantly higher in these patients compared with non-hypertensive patients (14.5 months vs. 3.1 months, P = 0.004) [6]. Ryanne Wu et al. evaluated 84 patients and observed better recovery in the hypertensive group in terms of both OS (92 vs. 76%, P = 0.03) and PFS (62 vs. 19%, P = 0.004) in a one-year follow-up [7]. We demonstrated that the standard prognostic factors performance status, metastasis type, and hypertension, were effective in our study group as well. We have concluded that basal proteinuria levels in mCRC patients receiving bevacizumab-based therapy may be a new,
unique indicator of treatment efficacy and survival. Additionally, we have demonstrated that the tumor response was more significant in patients prone to hypertension during treatment, consistent with published information. We believe that investigating the possible predictive role of basal proteinuria via additional studies is of practical and clinical importance. Further studies should confirm proteinuria levels as a predictor in mCRC patients receiving bevacizumab therapies. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements None. References [1] American Cancer Society. Cancer facts & figures 2013. Atlanta: American Cancer Society; 2013. [2] Ferlay J. In: Shin HRB, Forman D, Mathers C, Parkin DM, editors. GLOBOCAN 2008 v2. 0, cancer incidence and mortality worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. [3] Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007; 25(12):1539–44. [4] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335–42. [5] Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS, et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 2006;24(2):217–27. [6] Scartozzi M, Galizia E, Chiorrini S, Giampieri R, Berardi R, Pierantoni C, et al. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol 2009;20(2): 227–30. [7] Ryanne Wu R, Lindenberg PA, Slack R, Noone AM, Marshall JL, He AR. Evaluation of hypertension as a marker of bevacizumab efficacy. J Gastrointest Cancer 2009;40(3–4):101–8. [8] Martel CL, Ebrahimi B, Upadhyaya G, Vakil M, Yeon C, Bosserman LD, et al. Bevacizumab-related toxicities: association of hypertension and proteinuria. Community Oncol 2006;3(2):90–3. [9] Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349(5):427– 34. [10] Cai J, Ma H, Huang F, Zhu D, Bi J, Ke Y, et al. Correlation of bevacizumab-induced hypertension and outcomes of metastatic colorectal cancer patients treated with bevacizumab: a systematic review and meta-analysis. World J Surg Oncol 2013;11(1):306. [11] Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343(13):905–14. [12] Tournigand C, Andre´ T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22(2):229–37. [13] Dı´az R, Aparicio J, Girone´s R, Molina J, Palomar L, Segura A, et al. Analysis of prognostic factors and applicability of Kohne’s prognostic groups in patients with metastatic colorectal cancer treated with first-line irinotecan or oxaliplatin-based chemotherapy. Clin Colorectal Cancer 2005;5(3):197–202. [14] Harrison LE, Guillem JG, Paty P, Cohen AM. Preoperative carcinoembryonic antigen predicts outcomes in node-negative colon cancer patients: a multivariate analysis of 572 patients. J Am Coll Surg 1997;185(1):55–9. [15] Onetto M, Paganuzzi M, Secco GB, Fardelli R, Santi F, Rovida S, et al. Preoperative carcinoembryonic antigen and prognosis in patients with colorectal cancer. Biomed Pharmacother 1985;39(7):392–5. [16] Sargent D, Kohne C, Sanoff H, Bot B, Seymour M, De G, et al. Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer. J Clin Oncol 2009;27(20):3410–1.
Please cite this article in press as: Uysal M, et al. Basal proteinuria as a prognostic factor in patients with metastatic colorectal cancer treated with bevacizumab. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.03.002
