ORIGINAL ARTICLE
The Prognostic Significance of Pretreatment Hematologic Parameters in Patients Undergoing Resection for Colorectal Cancer Margaret M. Kozak, BS,* Rie von Eyben, MS,* Jonathan S. Pai, BS,* Eric M. Anderson, BS,* Mark L. Welton, MD,w Andrew A. Shelton, MD,w Cindy Kin, MD,w Albert C. Koong, MD, PhD,* and Daniel T. Chang, MD*
Objectives: The prognostic value of several hematologic parameters, including platelet, lymphocyte, and neutrophil counts, has been studied in a variety of solid tumors. In this study, we examined the significance of inflammatory markers and their prognostic implications in patients with colorectal cancer (CRC). Materials and Methods: Patients with stage I-III CRC who underwent surgical resection at the Stanford Cancer Institute between 2005 and 2009 were included. Patients were excluded if they did not have preoperative complete blood counts performed within 1 month of surgical resection, underwent preoperative chemotherapy or radiation, had metastatic disease at diagnosis, or had another previous malignancy. We included 129 eligible patients with available preoperative complete blood counts in the final analysis. Results: A preoperative neutrophil-to-lymphocyte ratio of > 3.3 was significantly associated with worse disease-free (DFS) and overall survival (OS) (P = 0.009, 0.003), as was a preoperative lymphocyte-tomonocyte ratio of r2.6 (P = 0.01, 0.002). Preoperative lymphopenia (P = 0.002) was associated with worse OS but not DFS (P = 0.09). In addition, preoperative thrombocytosis was associated with worse DFS (P = 0.006) and OS (P = 0.010). Preoperative leukocytosis was associated with worse OS (P = 0.048) but not DFS (P = 0.49). Preoperative hemoglobin was neither associated with OS (P = 0.24) or DFS (P = 0.15). Conclusions: Pretreatment lymphopenia, thrombocytosis, a decreased lymphocyte-to-monocyte ratio, and an elevated neutrophil-to-lymphocyte ratio independently predict for worse OS in patients with CRC. Key Words: colorectal, cancer, NLR
statistics available from the SEER cancer database, the 5-year survival rate for CRC is approximately 70% for stage III patients and 12.5% for stage IV patients (seer.cancer.gov). Therefore, active areas of research focus on determining predictors of prognosis to help individualize therapy and improve clinical outcomes. Of particular interest are the effects of the systemic inflammatory response on tumor progression and response to treatment. Rudolf Virchow1 first observed the link between inflammation and tumorigenesis in his description of leukocyte infiltrates in tumors. Since then, inflammation has been shown to influence cancer development in a wide range of tissues through processes that involve genomic destabilization and induction of invasion and metastasis. Several studies have shown the importance of a wide array of inflammatory markers on the prognosis of patients with lung,2 ovarian,3 nasopharyngeal,4 breast,5 and pancreatic cancer.6,7 Other authors have observed that the preoperative neutrophil-to-lymphocyte ratio (NLR) can be used as a prognostic marker in patients with CRC,8–10 although a standard cutoff value has yet to be determined.11,12 The lymphocyte-tomonocyte ratio (LMR) has been shown to predict for worse outcomes in patients with diffuse large B-cell lymphoma13 and nasopharyngeal carcinoma.14 However, its effects in patients with CRC remain undefined. A recent analysis by Stotz et al15 was the first of its kind to suggest a prognostic significance for the LMR in patients with CRC. In this study, we aim to examine the prognostic significance of the NLR and LMR, as well as other components of the systemic inflammatory response, in patients with CRC.
(Am J Clin Oncol 2015;00:000–000)
MATERIALS AND METHODS
C
olorectal cancer (CRC) is the third most common malignancy in the United States and the third leading cause of cancer-related deaths in both men and women. The American Cancer Society estimates a total of 142,820 new cases in 2013 and 50,830 deaths. CRC is frequently diagnosed at advanced stages, characterized by local invasion or metastasis to regional lymph nodes or distant sites. According to the most recent From the *Department of Radiation Oncology, Stanford Cancer Institute; and wDepartment of Surgery, Stanford University Medical Center, Stanford, CA. The authors declare no conflicts of interest. Reprints: Daniel T. Chang, MD, Department of Radiation Oncology, Stanford University, 875 Blake Wilbur Drive, Stanford CA 943055847. E-mail: [email protected]. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/000-000 DOI: 10.1097/COC.0000000000000183
American Journal of Clinical Oncology
Patients with biopsy-proven CRC who underwent surgical resection at the Stanford Cancer Institute between 2005 and 2009 were included in this retrospective institutional review board approved study. Patients were excluded if they lacked preoperative complete blood counts (CBCs) within 1 month of resection, underwent preoperative chemotherapy or radiation therapy, had metastatic disease at diagnosis, or had another previous malignancy. Patients were also excluded if they had or r10.0 K/mL), hemoglobin level (< or Z11.7 g/dL for females and < or Z13.5 g/dL for males), platelet count ( > or r400 K/mL), neutrophil count (1.7 to 6.7 K/mL, median 4.72), lymphocyte count (1.0 to 3.0 K/mL, median 1.31), LMR ( > or r2.6), and NLR ( > or r3.3) for correlation with these endpoints. Significance was determined as a P-value < 0.05. Multivariate analysis was performed with Cox proportional hazards regression using established prognostic clinical characteristics to determine independent variable for OS and DFS. Because of the sample size limitations, each hematologic parameter was analyzed separately in the Cox model. Hazard ratios were reported with a 95% confidence interval (CI). All statistical analyses were performed using Statistical Analysis Software (SAS Institute Inc., Cary, NC). A 2-sided P-value of 67 T stage T1 T2 T3 T4 N stage N0 N1 N2 Unknown Overall stage I II III Grade Well differentiated Well-to-mod differentiated Moderately differentiated Mod-to-poor differentiated Poorly differentiated Tumor location Right colon Transverse colon Left colon Rectum Unknown Resection margin status Positive Negative No. lymph nodes sampled < 12 LN sampled Z12 LN sampled Adjuvant chemotherapy Yes No Unknown NLR r3.3 > 3.3 LMR < 2.6 Z2.6 WBC count (K/mL) < 10.0 Z10.0 Platelet count (K/mL) < 400 Z400 Absolute lymphocyte count (K/mL) < 1.0 Z1.0 Hemoglobin < 11.7 g/dL for women (n = 74) < 13.5 g/dL for men (n = 55)
No. Patients (%)
OS
DFS
0.57
0.56
0.017
0.67
0.12
0.055
0.021
0.071
0.042
0.046
0.40
0.54
0.34
0.59
0.041
0.01
0.38
0.39
0.46
0.007
0.003
0.009
0.002
0.01
0.048
0.49
0.010
0.006
0.002
0.09
0.24
0.15
129 55 (43) 74 (57) 65 (50.4) 64 (49.6) 16 23 79 11
(12.5) (17.8) (61.2) (8.5)
74 35 19 1
(57.4) (27.1) (14.7) (0.8)
32 (24.8) 44 (34.1) 53 (41.1) 8 1 103 6 11
(6.2) (0.8) (79.8) (4.7) (8.5)
59 9 47 11 3
(45.7) (7.0) (36.5) (8.5) (2.3)
3 (2.3) 126 (97.7) 63 (48.8) 66 (51.2) 44 (34.1) 51 (39.5) 34 (26.4) 65 (50.4) 64 (49.6) 65 (50.4) 64 (49.6) 114 (88.4) 15 (11.6) 112 (86.8) 17 (13.2) 33 (25.6) 96 (74.4) 38 (51.4) 25 (45.5)
DFS indicates disease-free survival; LMR, lymphocyte-to-monocyte ratio; LN, lymph nodes; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; WBC, white blood cell count.
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2015
TABLE 2. Prognostic Parameters by Stage
n (%) Characteristics Tumor grade Well differentiated Well-to-mod differentiated Moderately differentiated Mod-to-poor differentiated Poorly differentiated No. LN sampled < 12 LN Z12 LN No. positive LN 0 1-5 6-10 > 10 NLR < 3.3 NLRZ3.3 LMRr2.6 LMR > 2.6
Stage I (N = 32)
Stage II (N = 44)
Stage III (N = 53)
4 (12.5) 0 (0)
0 (0) 1 (2.3)
4 (7.5) 0 (0)
26 (81.3)
35 (79.5)
42 (79.3)
1 (3.1)
3 (6.8)
2 (3.8)
1 (3.1)
5 (11.4)
5 (9.4)
5 (15.6) 27 (84.4)
3 (6.8) 41 (93.2)
9 (17.0) 44 (83.0)
32 (100) — — — 22 (68.8) 10 (31.2) 11 (34.4) 21 (65.6)
43 (97.8) 1 (2.2) — — 20 (45.5) 24 (54.5) 21 (47.7) 23 (52.3)
1 39 12 1 22 31 33 20
(1.9) (73.6) (22.6) (1.9) (41.5) (58.5) (62.3) (37.7)
LMR indicates lymphocyte-to-monocyte ratio; LN, lymph nodes; NLR, neutrophil-to-lymphocyte ratio.
NLR of >3.3. A preoperative NLR of >3.3 was significantly associated with worse OS (P = 0.003) and worse DFS (P = 0.009) (Figs. 1A, B). Patients with an NLR > 3.3 and r3.3 had a median OS of 53.4 and 101.7 months, respectively. When adjusting for overall stage using a Cox proportional hazards model, patients with an NLR > 3.3 had a significantly worse OS (P = 0.0098) and
Hematologic Parameters Predict Outcomes in CRC
DFS (P = 0.044). Patients with stage III disease and an elevated NLR > 3.3 had significantly worse OS and DFS compared with those patients with stage III disease and an NLRr3.3 (P = 0.0022, 0.0017) (Figs. 2A, B), as well as compared with the cohort as a whole (P = 0.0003, 0.0003) (Figs. 3A, B). We subsequently applied the NLR values published by other recent studies to our patient cohort, and found a significant association with OS for an NLR of 2.5 (P = 0.017), an NLR of 4.0 (P = 0.002), and an NLR of 5.0 (P = 0.002), but only an NLR of 4.0 (P = 0.043) showed a significant relationship with DFS. An NLR > 3.3 remained significant for OS on multivariate analysis (P = 0.006; HR, 1.05; 95% CI, 1.014-1.089) when taking into account factors of age, overall stage, and total number of lymph nodes sampled. NLR > 3.3 was not significant on multivariate analysis for DFS (P = 0.058; HR, 1.04; 95% CI, 0.9991.081). On multivariate analysis, NLR > 4.0 remained significant for OS (P = 0.003; HR, 3.08; 95% CI, 1.453-6.524) but not DFS (P = 0.072; HR, 2.20; 95% CI, 0.931-5.214) (Table 3).
LMR The median LMR for our cohort was 2.6 (range, 0.22 to 10.5). A total of 65 patients (50.4%) had an LMR < 2.6 and 64 patients (48.7%) had an LMRZ2.6. On univariate analysis, a preoperative LMR of 3.3 have significantly worse overall and disease-free survival than patients with NLR r3.3. Overall survival (C) and diseasefree survival (D) for patients with preoperative LMR < 2.6. Patients with a preoperative LMR < 2.6 have significantly worse overall and disease-free survival than patients with preoperative LMRZ2.6. LMR indicates lymphocyte-to-monocyte ratio; NLR, neutrophil-tolymphocyte ratio.
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.amjclinicaloncology.com |
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
3
Kozak et al
American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2015
FIGURE 2. Overall survival and disease-free survival for patients with stage III disease only. Patients with a neutrophil-to-lymphocyte ratio (NLR) > 3.3 have significantly worse overall survival (A) and disease-free survival (B) than patients with NLRr3.3. Overall survival (C) and disease-free survival (D) for patients with preoperative LMR < 2.6. Patients with a preoperative LMR < 2.6 have significantly worse overall survival and disease-free survival than patients with preoperative LMRZ2.6. LMR indicates lymphocyte-to-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio.
Patients with stage III disease and an LMR < 2.6 had significantly worse OS and DFS compared with the cohort as a whole (P = 0.0001, 0.013) (Figs. 3C, D).
Total Leukocyte Count Preoperative leukocytosis was identified in 15 patients (12%). WBC counts ranged from 10.2 to 19.0 K/mL. On univariate analysis, pretreatment leukocytosis was associated with worse OS (P = 0.048) but not DFS (P = 0.49) (Figs. 4A, B). Patients with
WBC count > 10.0 K/mL had a median OS of 45.5 months versus a median OS of 101.7 months in patients with a WBC count of 3.3 MVA for WBC Age Overall Stage Total LN WBC count MVA for ALC Age Overall Stage Total LN ALC MVA for LMR Age Overall Stage Total LN LMR MVA for platelet Age Overall Stage Total LN Platelet count MVA for hemoglobin Age Overall Stage Total LN Hemoglobin MVA for NLR > 4.0 Age Overall Stage Total LN NLR > 4.0
DFS
P
Hazard Ratio
95% CI
P
Hazard Ratio
95% CI
0.036 0.027 0.18 0.006
1.03 1.83 0.96 1.05
1.002-1.053 1.073-3.131 0.907-1.018 1.014-1.089
0.60 0.04 0.68 0.058
1.00 2.13 0.99 1.04
0.979-1.032 1.084-4.191 0.927-1.050 0.999-1.081
0.03 0.04 0.15 0.018
1.03 1.68 0.96 1.15
1.002-1.053 1.032-3.064 0.903-1.016 1.024-1.282
0.45 0.023 0.57 0.12
1.01 2.27 0.98 1.10
0.983-1.036 1.153-4.457 0.921-1.045 0.977-1.249
0.036 0.006 0.08 0.005
1.03 2.13 0.95 0.34
1.002-1.049 1.239-3.680 0.893-1.007 0.162-0.724
0.63 0.017 0.64 0.41
1.01 2.31 0.99 0.73
0.979-1.031 1.190-4.475 0.926-1.048 0.350-1.510
0.27 0.024 0.052 0.006
1.01 1.87 0.94 0.27
0.989-1.039 1.086-3.207 0.887-1.001 0.106-0.680
0.84 0.043 0.49 0.036
0.99 2.07 0.98 0.31
0.969-1.023 1.060-4.047 0.917-1.040 0.110-0.889
0.038 0.023 0.14 0.39
1.03 1.87 0.96 1.00
1.001-1.053 1.089-3.199 0.905-1.014 0.998-1.006
0.44 0.028 0.47 0.061
1.01 2.23 0.98 1.00
0.982-1.036 1.134-4.397 0.918-1.040 1.000-1.009
0.08 0.017 0.13 0.47
1.02 1.90 0.96 1.32
0.998-1.049 1.123-3.208 0.905-1.013 0.614-2.854
0.21 0.01 0.92 0.056
1.02 2.56 0.99 0.39
0.988-1.046 1.281-5.123 0.936-1.061 0.151-1.027
0.045 0.016 0.08 0.003
1.02 1.99 0.95 3.08
1.001-1.048 1.139-3.475 0.896-1.006 1.453-6.524
0.60 0.019 0.66 0.072
1.01 2.36 0.99 2.24
0.980-1.031 1.191-4.669 0.928-1.048 0.947-5.294
ALC indicates absolute lymphocyte count; CI, confidence interval; DFS, disease-free survival; LMR, lymphocyte-to-monocyte ratio; LN, lymph nodes; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; WBC, white blood cell count.
was predictive for both worse DFS (P = 0.006) and OS (P = 0.010) (Figs. 4C, D). Platelets did not remain significant on multivariate analysis as shown in Table 3.
Absolute Lymphocyte Count Preoperative lymphopenia was identified in 33 patients (25.6%). On univariate analysis, preoperative lymphopenia was significantly associated with worse OS (P = 0.002) but not DFS (P = 0.09). Patients with preoperative lymphopenia had a median OS of 45.5 months versus a median OS of 101.7 months in patients without lymphopenia. Lymphopenia remained significant on multivariate analysis (Table 3) for OS (P = 0.005; HR, 0.34; 95% CI, 0.162-0.724).
Hemoglobin Preoperative anemia, defined as a hemoglobin level of 3 dNLR > 2.2 NLR > 3.7 NLR > 2.5 NLR > 5 NLR > 5 NLR > 4 WBC > 10 K/mL Platelet count > 300 K/mL LMR LMR NLR > 3.3
< 0.001 — 0.001 — 0.028 — 0.004 0.045 — 0.010 0.002 0.0045
— 0.018 0.026 < 0.001 — < 0.001 — 0.036 0.007 0.008 0.007 < 0.001
dNLR indicates derived neutrophil-to-lymphocyte ratio; LMR, lymphocyteto-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio; WBC, white blood cell count.
stratify CRC patients undergoing surgery alone. COP-NLR ratios fell into 3 different groups, and patients with a COPNLR ratio of 1 or 2 had a significantly worse cancer-specific survival than those patients with a COP-NLR ratio of 0. Recently, Szkandera et al27 published the first report detailing the prognostic significance of the LMR in patients with solid tumors. They found that a low LMR was significantly associated with a decreased cancer-specific survival and DFS in patients with soft tissue sarcomas. Similarly, Stotz et al15 published a report on the prognostic significance of the preoperative LMR in patients with stage III CRC. They found that a decreased LMR predicted for shorter DFS and OS, and indicated that patients with decreased LMR may not benefit from 5-FU-based adjuvant treatment. Our report confirms these findings and is the second of its kind to suggest a role for the LMR in patients with CRC. Leukocytosis has been shown to be a negative prognostic indicator in patients with a variety of nonhematological malignancies—carcinomas of the lung and colorectum were shown to be most strongly associated.28 Banerjee et al29 showed that pretreatment leukocytosis in patients with anal cancer is associated with significantly worse DFS and OS; this association was augmented by concomitant anemia. Hernandez et al30 demonstrated that thrombocytosis is a frequent finding among patients with cervical cancer. These patients had larger tumors and more positive lymph nodes than patients without thrombocytosis. Patients with negative lymph nodes and thrombocytosis were found to have worse OS. Ishizuka et al31 studied the effects of thrombocytosis on survival in patients with CRC. They found that a preoperative platelet count was able to divide patients into 2 groups, those with a platelet count of 300 K/mL. Patients with an elevated presurgery platelet count had a significantly worse OS. A summary of recent literature can be found in Table 5. Some limitations to our study design include its retrospective nature and relatively small sample size. Our smaller sample size was due to limited availability of CBC data for other patients in our database. Although our institution requests blood work 1 month before resection, oftentimes a CBC with differential was not obtained, limiting our ability to calculate the NLR and LMR values for these patients. For this reason, our sample size was decreased to 129 patients from the original 448. Furthermore, we excluded patients with metastatic disease, and those that received neoadjuvant treatment, Copyright
r
Hematologic Parameters Predict Outcomes in CRC
to minimize the potentially confounding effects of these factors. In addition, we excluded 11 patients with 5 is a prognostic factor for recurrent colorectal cancer. Colorectal Dis. 2013;15:323–328. Cook EJ, Walsh SR, Farooq N, et al. Post-operative neutrophillymphocyte ratio predicts complications following colorectal surgery. Int J Surg. 2007;5:27–30. Carruthers R, Tho LM, Brown J, et al. Systemic inflammatory response is a predictor of outcome in patients undergoing preoperative chemoradiation for locally advanced rectal cancer. Colorectal Dis. 2012, Oct;14(10):e701–7.
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
The Prognostic Significance of Pretreatment Hematologic Parameters in Patients Undergoing Resection for Colorectal Cancer Margaret M. Kozak, BS,* Rie von Eyben, MS,* Jonathan S. Pai, BS,* Eric M. Anderson, BS,* Mark L. Welton, MD,w Andrew A. Shelton, MD,w Cindy Kin, MD,w Albert C. Koong, MD, PhD,* and Daniel T. Chang, MD*
Objectives: The prognostic value of several hematologic parameters, including platelet, lymphocyte, and neutrophil counts, has been studied in a variety of solid tumors. In this study, we examined the significance of inflammatory markers and their prognostic implications in patients with colorectal cancer (CRC). Materials and Methods: Patients with stage I-III CRC who underwent surgical resection at the Stanford Cancer Institute between 2005 and 2009 were included. Patients were excluded if they did not have preoperative complete blood counts performed within 1 month of surgical resection, underwent preoperative chemotherapy or radiation, had metastatic disease at diagnosis, or had another previous malignancy. We included 129 eligible patients with available preoperative complete blood counts in the final analysis. Results: A preoperative neutrophil-to-lymphocyte ratio of > 3.3 was significantly associated with worse disease-free (DFS) and overall survival (OS) (P = 0.009, 0.003), as was a preoperative lymphocyte-tomonocyte ratio of r2.6 (P = 0.01, 0.002). Preoperative lymphopenia (P = 0.002) was associated with worse OS but not DFS (P = 0.09). In addition, preoperative thrombocytosis was associated with worse DFS (P = 0.006) and OS (P = 0.010). Preoperative leukocytosis was associated with worse OS (P = 0.048) but not DFS (P = 0.49). Preoperative hemoglobin was neither associated with OS (P = 0.24) or DFS (P = 0.15). Conclusions: Pretreatment lymphopenia, thrombocytosis, a decreased lymphocyte-to-monocyte ratio, and an elevated neutrophil-to-lymphocyte ratio independently predict for worse OS in patients with CRC. Key Words: colorectal, cancer, NLR
statistics available from the SEER cancer database, the 5-year survival rate for CRC is approximately 70% for stage III patients and 12.5% for stage IV patients (seer.cancer.gov). Therefore, active areas of research focus on determining predictors of prognosis to help individualize therapy and improve clinical outcomes. Of particular interest are the effects of the systemic inflammatory response on tumor progression and response to treatment. Rudolf Virchow1 first observed the link between inflammation and tumorigenesis in his description of leukocyte infiltrates in tumors. Since then, inflammation has been shown to influence cancer development in a wide range of tissues through processes that involve genomic destabilization and induction of invasion and metastasis. Several studies have shown the importance of a wide array of inflammatory markers on the prognosis of patients with lung,2 ovarian,3 nasopharyngeal,4 breast,5 and pancreatic cancer.6,7 Other authors have observed that the preoperative neutrophil-to-lymphocyte ratio (NLR) can be used as a prognostic marker in patients with CRC,8–10 although a standard cutoff value has yet to be determined.11,12 The lymphocyte-tomonocyte ratio (LMR) has been shown to predict for worse outcomes in patients with diffuse large B-cell lymphoma13 and nasopharyngeal carcinoma.14 However, its effects in patients with CRC remain undefined. A recent analysis by Stotz et al15 was the first of its kind to suggest a prognostic significance for the LMR in patients with CRC. In this study, we aim to examine the prognostic significance of the NLR and LMR, as well as other components of the systemic inflammatory response, in patients with CRC.
(Am J Clin Oncol 2015;00:000–000)
MATERIALS AND METHODS
C
olorectal cancer (CRC) is the third most common malignancy in the United States and the third leading cause of cancer-related deaths in both men and women. The American Cancer Society estimates a total of 142,820 new cases in 2013 and 50,830 deaths. CRC is frequently diagnosed at advanced stages, characterized by local invasion or metastasis to regional lymph nodes or distant sites. According to the most recent From the *Department of Radiation Oncology, Stanford Cancer Institute; and wDepartment of Surgery, Stanford University Medical Center, Stanford, CA. The authors declare no conflicts of interest. Reprints: Daniel T. Chang, MD, Department of Radiation Oncology, Stanford University, 875 Blake Wilbur Drive, Stanford CA 943055847. E-mail: [email protected]. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/000-000 DOI: 10.1097/COC.0000000000000183
American Journal of Clinical Oncology
Patients with biopsy-proven CRC who underwent surgical resection at the Stanford Cancer Institute between 2005 and 2009 were included in this retrospective institutional review board approved study. Patients were excluded if they lacked preoperative complete blood counts (CBCs) within 1 month of resection, underwent preoperative chemotherapy or radiation therapy, had metastatic disease at diagnosis, or had another previous malignancy. Patients were also excluded if they had or r10.0 K/mL), hemoglobin level (< or Z11.7 g/dL for females and < or Z13.5 g/dL for males), platelet count ( > or r400 K/mL), neutrophil count (1.7 to 6.7 K/mL, median 4.72), lymphocyte count (1.0 to 3.0 K/mL, median 1.31), LMR ( > or r2.6), and NLR ( > or r3.3) for correlation with these endpoints. Significance was determined as a P-value < 0.05. Multivariate analysis was performed with Cox proportional hazards regression using established prognostic clinical characteristics to determine independent variable for OS and DFS. Because of the sample size limitations, each hematologic parameter was analyzed separately in the Cox model. Hazard ratios were reported with a 95% confidence interval (CI). All statistical analyses were performed using Statistical Analysis Software (SAS Institute Inc., Cary, NC). A 2-sided P-value of 67 T stage T1 T2 T3 T4 N stage N0 N1 N2 Unknown Overall stage I II III Grade Well differentiated Well-to-mod differentiated Moderately differentiated Mod-to-poor differentiated Poorly differentiated Tumor location Right colon Transverse colon Left colon Rectum Unknown Resection margin status Positive Negative No. lymph nodes sampled < 12 LN sampled Z12 LN sampled Adjuvant chemotherapy Yes No Unknown NLR r3.3 > 3.3 LMR < 2.6 Z2.6 WBC count (K/mL) < 10.0 Z10.0 Platelet count (K/mL) < 400 Z400 Absolute lymphocyte count (K/mL) < 1.0 Z1.0 Hemoglobin < 11.7 g/dL for women (n = 74) < 13.5 g/dL for men (n = 55)
No. Patients (%)
OS
DFS
0.57
0.56
0.017
0.67
0.12
0.055
0.021
0.071
0.042
0.046
0.40
0.54
0.34
0.59
0.041
0.01
0.38
0.39
0.46
0.007
0.003
0.009
0.002
0.01
0.048
0.49
0.010
0.006
0.002
0.09
0.24
0.15
129 55 (43) 74 (57) 65 (50.4) 64 (49.6) 16 23 79 11
(12.5) (17.8) (61.2) (8.5)
74 35 19 1
(57.4) (27.1) (14.7) (0.8)
32 (24.8) 44 (34.1) 53 (41.1) 8 1 103 6 11
(6.2) (0.8) (79.8) (4.7) (8.5)
59 9 47 11 3
(45.7) (7.0) (36.5) (8.5) (2.3)
3 (2.3) 126 (97.7) 63 (48.8) 66 (51.2) 44 (34.1) 51 (39.5) 34 (26.4) 65 (50.4) 64 (49.6) 65 (50.4) 64 (49.6) 114 (88.4) 15 (11.6) 112 (86.8) 17 (13.2) 33 (25.6) 96 (74.4) 38 (51.4) 25 (45.5)
DFS indicates disease-free survival; LMR, lymphocyte-to-monocyte ratio; LN, lymph nodes; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; WBC, white blood cell count.
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2015
TABLE 2. Prognostic Parameters by Stage
n (%) Characteristics Tumor grade Well differentiated Well-to-mod differentiated Moderately differentiated Mod-to-poor differentiated Poorly differentiated No. LN sampled < 12 LN Z12 LN No. positive LN 0 1-5 6-10 > 10 NLR < 3.3 NLRZ3.3 LMRr2.6 LMR > 2.6
Stage I (N = 32)
Stage II (N = 44)
Stage III (N = 53)
4 (12.5) 0 (0)
0 (0) 1 (2.3)
4 (7.5) 0 (0)
26 (81.3)
35 (79.5)
42 (79.3)
1 (3.1)
3 (6.8)
2 (3.8)
1 (3.1)
5 (11.4)
5 (9.4)
5 (15.6) 27 (84.4)
3 (6.8) 41 (93.2)
9 (17.0) 44 (83.0)
32 (100) — — — 22 (68.8) 10 (31.2) 11 (34.4) 21 (65.6)
43 (97.8) 1 (2.2) — — 20 (45.5) 24 (54.5) 21 (47.7) 23 (52.3)
1 39 12 1 22 31 33 20
(1.9) (73.6) (22.6) (1.9) (41.5) (58.5) (62.3) (37.7)
LMR indicates lymphocyte-to-monocyte ratio; LN, lymph nodes; NLR, neutrophil-to-lymphocyte ratio.
NLR of >3.3. A preoperative NLR of >3.3 was significantly associated with worse OS (P = 0.003) and worse DFS (P = 0.009) (Figs. 1A, B). Patients with an NLR > 3.3 and r3.3 had a median OS of 53.4 and 101.7 months, respectively. When adjusting for overall stage using a Cox proportional hazards model, patients with an NLR > 3.3 had a significantly worse OS (P = 0.0098) and
Hematologic Parameters Predict Outcomes in CRC
DFS (P = 0.044). Patients with stage III disease and an elevated NLR > 3.3 had significantly worse OS and DFS compared with those patients with stage III disease and an NLRr3.3 (P = 0.0022, 0.0017) (Figs. 2A, B), as well as compared with the cohort as a whole (P = 0.0003, 0.0003) (Figs. 3A, B). We subsequently applied the NLR values published by other recent studies to our patient cohort, and found a significant association with OS for an NLR of 2.5 (P = 0.017), an NLR of 4.0 (P = 0.002), and an NLR of 5.0 (P = 0.002), but only an NLR of 4.0 (P = 0.043) showed a significant relationship with DFS. An NLR > 3.3 remained significant for OS on multivariate analysis (P = 0.006; HR, 1.05; 95% CI, 1.014-1.089) when taking into account factors of age, overall stage, and total number of lymph nodes sampled. NLR > 3.3 was not significant on multivariate analysis for DFS (P = 0.058; HR, 1.04; 95% CI, 0.9991.081). On multivariate analysis, NLR > 4.0 remained significant for OS (P = 0.003; HR, 3.08; 95% CI, 1.453-6.524) but not DFS (P = 0.072; HR, 2.20; 95% CI, 0.931-5.214) (Table 3).
LMR The median LMR for our cohort was 2.6 (range, 0.22 to 10.5). A total of 65 patients (50.4%) had an LMR < 2.6 and 64 patients (48.7%) had an LMRZ2.6. On univariate analysis, a preoperative LMR of 3.3 have significantly worse overall and disease-free survival than patients with NLR r3.3. Overall survival (C) and diseasefree survival (D) for patients with preoperative LMR < 2.6. Patients with a preoperative LMR < 2.6 have significantly worse overall and disease-free survival than patients with preoperative LMRZ2.6. LMR indicates lymphocyte-to-monocyte ratio; NLR, neutrophil-tolymphocyte ratio.
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.amjclinicaloncology.com |
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
3
Kozak et al
American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2015
FIGURE 2. Overall survival and disease-free survival for patients with stage III disease only. Patients with a neutrophil-to-lymphocyte ratio (NLR) > 3.3 have significantly worse overall survival (A) and disease-free survival (B) than patients with NLRr3.3. Overall survival (C) and disease-free survival (D) for patients with preoperative LMR < 2.6. Patients with a preoperative LMR < 2.6 have significantly worse overall survival and disease-free survival than patients with preoperative LMRZ2.6. LMR indicates lymphocyte-to-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio.
Patients with stage III disease and an LMR < 2.6 had significantly worse OS and DFS compared with the cohort as a whole (P = 0.0001, 0.013) (Figs. 3C, D).
Total Leukocyte Count Preoperative leukocytosis was identified in 15 patients (12%). WBC counts ranged from 10.2 to 19.0 K/mL. On univariate analysis, pretreatment leukocytosis was associated with worse OS (P = 0.048) but not DFS (P = 0.49) (Figs. 4A, B). Patients with
WBC count > 10.0 K/mL had a median OS of 45.5 months versus a median OS of 101.7 months in patients with a WBC count of 3.3 MVA for WBC Age Overall Stage Total LN WBC count MVA for ALC Age Overall Stage Total LN ALC MVA for LMR Age Overall Stage Total LN LMR MVA for platelet Age Overall Stage Total LN Platelet count MVA for hemoglobin Age Overall Stage Total LN Hemoglobin MVA for NLR > 4.0 Age Overall Stage Total LN NLR > 4.0
DFS
P
Hazard Ratio
95% CI
P
Hazard Ratio
95% CI
0.036 0.027 0.18 0.006
1.03 1.83 0.96 1.05
1.002-1.053 1.073-3.131 0.907-1.018 1.014-1.089
0.60 0.04 0.68 0.058
1.00 2.13 0.99 1.04
0.979-1.032 1.084-4.191 0.927-1.050 0.999-1.081
0.03 0.04 0.15 0.018
1.03 1.68 0.96 1.15
1.002-1.053 1.032-3.064 0.903-1.016 1.024-1.282
0.45 0.023 0.57 0.12
1.01 2.27 0.98 1.10
0.983-1.036 1.153-4.457 0.921-1.045 0.977-1.249
0.036 0.006 0.08 0.005
1.03 2.13 0.95 0.34
1.002-1.049 1.239-3.680 0.893-1.007 0.162-0.724
0.63 0.017 0.64 0.41
1.01 2.31 0.99 0.73
0.979-1.031 1.190-4.475 0.926-1.048 0.350-1.510
0.27 0.024 0.052 0.006
1.01 1.87 0.94 0.27
0.989-1.039 1.086-3.207 0.887-1.001 0.106-0.680
0.84 0.043 0.49 0.036
0.99 2.07 0.98 0.31
0.969-1.023 1.060-4.047 0.917-1.040 0.110-0.889
0.038 0.023 0.14 0.39
1.03 1.87 0.96 1.00
1.001-1.053 1.089-3.199 0.905-1.014 0.998-1.006
0.44 0.028 0.47 0.061
1.01 2.23 0.98 1.00
0.982-1.036 1.134-4.397 0.918-1.040 1.000-1.009
0.08 0.017 0.13 0.47
1.02 1.90 0.96 1.32
0.998-1.049 1.123-3.208 0.905-1.013 0.614-2.854
0.21 0.01 0.92 0.056
1.02 2.56 0.99 0.39
0.988-1.046 1.281-5.123 0.936-1.061 0.151-1.027
0.045 0.016 0.08 0.003
1.02 1.99 0.95 3.08
1.001-1.048 1.139-3.475 0.896-1.006 1.453-6.524
0.60 0.019 0.66 0.072
1.01 2.36 0.99 2.24
0.980-1.031 1.191-4.669 0.928-1.048 0.947-5.294
ALC indicates absolute lymphocyte count; CI, confidence interval; DFS, disease-free survival; LMR, lymphocyte-to-monocyte ratio; LN, lymph nodes; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; WBC, white blood cell count.
was predictive for both worse DFS (P = 0.006) and OS (P = 0.010) (Figs. 4C, D). Platelets did not remain significant on multivariate analysis as shown in Table 3.
Absolute Lymphocyte Count Preoperative lymphopenia was identified in 33 patients (25.6%). On univariate analysis, preoperative lymphopenia was significantly associated with worse OS (P = 0.002) but not DFS (P = 0.09). Patients with preoperative lymphopenia had a median OS of 45.5 months versus a median OS of 101.7 months in patients without lymphopenia. Lymphopenia remained significant on multivariate analysis (Table 3) for OS (P = 0.005; HR, 0.34; 95% CI, 0.162-0.724).
Hemoglobin Preoperative anemia, defined as a hemoglobin level of 3 dNLR > 2.2 NLR > 3.7 NLR > 2.5 NLR > 5 NLR > 5 NLR > 4 WBC > 10 K/mL Platelet count > 300 K/mL LMR LMR NLR > 3.3
< 0.001 — 0.001 — 0.028 — 0.004 0.045 — 0.010 0.002 0.0045
— 0.018 0.026 < 0.001 — < 0.001 — 0.036 0.007 0.008 0.007 < 0.001
dNLR indicates derived neutrophil-to-lymphocyte ratio; LMR, lymphocyteto-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio; WBC, white blood cell count.
stratify CRC patients undergoing surgery alone. COP-NLR ratios fell into 3 different groups, and patients with a COPNLR ratio of 1 or 2 had a significantly worse cancer-specific survival than those patients with a COP-NLR ratio of 0. Recently, Szkandera et al27 published the first report detailing the prognostic significance of the LMR in patients with solid tumors. They found that a low LMR was significantly associated with a decreased cancer-specific survival and DFS in patients with soft tissue sarcomas. Similarly, Stotz et al15 published a report on the prognostic significance of the preoperative LMR in patients with stage III CRC. They found that a decreased LMR predicted for shorter DFS and OS, and indicated that patients with decreased LMR may not benefit from 5-FU-based adjuvant treatment. Our report confirms these findings and is the second of its kind to suggest a role for the LMR in patients with CRC. Leukocytosis has been shown to be a negative prognostic indicator in patients with a variety of nonhematological malignancies—carcinomas of the lung and colorectum were shown to be most strongly associated.28 Banerjee et al29 showed that pretreatment leukocytosis in patients with anal cancer is associated with significantly worse DFS and OS; this association was augmented by concomitant anemia. Hernandez et al30 demonstrated that thrombocytosis is a frequent finding among patients with cervical cancer. These patients had larger tumors and more positive lymph nodes than patients without thrombocytosis. Patients with negative lymph nodes and thrombocytosis were found to have worse OS. Ishizuka et al31 studied the effects of thrombocytosis on survival in patients with CRC. They found that a preoperative platelet count was able to divide patients into 2 groups, those with a platelet count of 300 K/mL. Patients with an elevated presurgery platelet count had a significantly worse OS. A summary of recent literature can be found in Table 5. Some limitations to our study design include its retrospective nature and relatively small sample size. Our smaller sample size was due to limited availability of CBC data for other patients in our database. Although our institution requests blood work 1 month before resection, oftentimes a CBC with differential was not obtained, limiting our ability to calculate the NLR and LMR values for these patients. For this reason, our sample size was decreased to 129 patients from the original 448. Furthermore, we excluded patients with metastatic disease, and those that received neoadjuvant treatment, Copyright
r
Hematologic Parameters Predict Outcomes in CRC
to minimize the potentially confounding effects of these factors. In addition, we excluded 11 patients with 5 is a prognostic factor for recurrent colorectal cancer. Colorectal Dis. 2013;15:323–328. Cook EJ, Walsh SR, Farooq N, et al. Post-operative neutrophillymphocyte ratio predicts complications following colorectal surgery. Int J Surg. 2007;5:27–30. Carruthers R, Tho LM, Brown J, et al. Systemic inflammatory response is a predictor of outcome in patients undergoing preoperative chemoradiation for locally advanced rectal cancer. Colorectal Dis. 2012, Oct;14(10):e701–7.
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
