Yonago Acta medica 2013;56:69–72

Original Article

Scoring of Prognostic Parameters in Patients with Unresectable Advanced or
Recurrent Colorectal Cancer Undergoing Chemotherapy
Masahide Ikeguchi, Ryugo Shimoda, Manabu Yamamoto, Yoshihiko Maeta, Keigo Ashida and Hiroaki Saito
Division of Surgical Oncology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504,
Japan

ABSTRACT

Key words

chemotherapy; colorectal cancer; inflammation; immunity; nutrition

Background

Suitable chemotherapy is needed to prolong the survival of patients with unresectable advanced
or recurrent colorectal cancer. We scored the periodical
changes of several prognostic markers during chemotherapy in patients with this type of cancer to discern theeffectiveness of chemotherapy.
Methods Twenty consecutive patients with unresectable advanced or recurrent colorectal cancer were enrolled. All patients underwent combination chemotherapy with oxaliplatin or irinotecan plus 5-fluorouracil/
leucovorin. Neutrophil/lymphocyte ratio (NLR), serum
C-reactive protein (CRP), serum carcinoembryonic antigen (CEA) and serum albumin (ALB) were compared
between the two periods (before chemotherapy and 3
months after it was started) in each patient. The scoring system was as follows: points are added when apatient shows a decrease of NLR, CRP and CEA and anincrease of ALB at 3 months after the start of chemotherapy with a possible final score of +4. On the other
hand, points are reduced if a patient shows an elevationof NLR, CRP and CEA and a decrease of ALB at 3
months after the start of chemotherapy with a possible
final score of –4.
Results At 3 months after the start of first line chemotherapy, 13 patients showed positive scores but 7 patients
showed zero or minus scores. According to our scoring
system, we found the mean survival time (MST) of the
13 patients with plus scores was 34 months and thiswas significantly better than that of the 7 patients who
showed zero or minus scores (P = 0.0008).
Conclusion Our new scoring system is useful but
when we find that first line chemotherapy is ineffective,
we need to change it to second line chemotherapy assoon as possible. That may be the best treatment for patients with unresectable advanced or recurrent colorectal
cancer.

5-Fluorouracil (5-FU) in combination with leucovorin(LV) (5-FU/LV) has been the standard systemic regimen for the treatment of unresectable advanced or recurrent colorectal cancer in most countries.1 Recently,
combination chemotherapies with oxaliplatin plus 5-FU/
LV (FOLFOX) or irinotecan plus 5-FU/LV (FOLFIRI)
have shown superior survival benefits when comparedwith 5-FU/LV, and led to a steady improvement in the
median overall survival of these patients.2 Also, a molecular target drug administered as a first-line treatment
showed efficacy, and these therapies are considered as
the standard treatment.3 However, irrespective of the
progress in chemotherapeutic drugs, the median overall
survival was about 2 years in several pivotal phase III
studies of chemotherapy for unresectable or metastatic
colorectal cancer.4 In order to improve the survival ofthese patients, it is important to decide the effectivenessof first line chemotherapy.
Several prognostic markers for patients with gastrointestinal carcinomas have been used for evaluating
patients’ response to chemotherapy. Neutrophil/lymphocyte ratio (NLR) of peripheral blood was detected as an
immunological marker.5 Serum albumin (ALB) level
and C-reactive protein (CRP) have been recognized as
the prognostic nutritional marker and marker of inflammation, respectively.6, 7 Also, serum carcinoembrionicantigen (CEA) level was a good indicator for progression of colorectal cancer.8 In the present study, we
compared the periodical changes of these four markers(NLR, CRP, ALB and CEA) between the point before
chemotherapy and at 3 months after the start of first line
chemotherapy in consecutive patients with unresectableadvanced or recurrent colorectal cancer. We scored increases or decreases of these markers and investigatedwhether or not these scores expressed reactivity of patients to anti-cancer chemotherapy.

Corresponding author: Masahide Ikeguchi, MD
masaike@med.tottori-u.ac.jp
Received 2013 June 13
Accepted 2013 June 20
Abbreviations: 5-FU, 5-fluorouracil; ALB, albumin; CEA, carcinoembryonic antigen; CRP, C-reactive protein; FOLFIRI, irinotecan plus 5-FU/LV; FOLFOX, oxaliplatin plus 5-FU/LV; LV, leucovorin; MST, mean survival time; NLR, neutrophil/lymphocyte
ratio

SUBJECTS AND METHODSPatients

Between April 2008 and June 2009, 20 patients werediagnosed with unresectable advanced or recurrent
69

M. Ikeguchi et al.
Table 1. Patients’ characteristics

NLR, CRP and CEA and with a decrease of ALB at 3
months after the start of chemotherapy, we gave a –4. If
the patient showed a decrease of NLR and CRP, and anincrease of CEA and ALB at 3 months after the start ofchemotherapy, his final score was +2. A “0 score” wasgiven when we found equal levels of NLR, CRP, CEA
and ALB before and after chemotherapy.

		Patients
Number		 20Age, mean (SD), yr		
70.5 (7.9)
Male/female		
13 /7
ECOG: PS 0/1		
9 /11
Tumor: primary/recurrent		
9 /11
Primary tumor: colon/rectum		
13 /7
Site of metastasis
Liver
9
Lung
4
Peritoneum5
Lymph node2
First line chemotherapy
FOLFOX/FOLFIRI
15 /5
Bevacizumab plus
12

Statistics

The chi-square test for independence, Fisher’s exact
probability test, and the Mann-Whitney U test were used
to compare the differences between the two parameters.
Spearman’s rank correlation coefficient was used to assess the correlation between the two parameters. Survival rates of the two groups were estimated by the KaplanMeier method, and the statistical differences between
survival curves were examined by the log-rank test. A P
value of < 0.05 was regarded as statistically significant.

ECOG: PS, Eastern Cooperative Oncology Group performancestatus; FOLFIRI, irinotecan plus 5-fluorouracil/ leucovorin;
FOLFOX, oxaliplatin plus 5-5-fluorouracil/leucovorin.

colorectal cancer and were scheduled to undergo
FOLFOX or FOLFIRI chemotherapy in our hospital.
The Eastern Cooperative Oncology Group performancestatus of these patients was 0 or 1, and they had adequate bone marrow (platelet count > 100,000/L, whiteblood cell count > 4000/L, granulocyte count > 1500/
L, haemoglobin > 10.0 mg/dL), renal (serum creatinine< 2.0 mg/dL), and hepatic (serum bilirubin < 2.0 mg/dL)
functions. Fifteen patients underwent FOLFOX treatment, but 5 patients wanted FOLFIRI treatment instead.
Bevacizumab was administered to 12 patients (FOLFOX,
9 patients and FOLFIRI, 3 patients). The Ethics Committee of Tottori University (approval number 1223)
approved this study in 2008. Informed consent was obtained from all 20 patients. They were followed up until
April 2013 and their details are shown in Table 1.

RESULTS
All patients were followed up at our hospital. The median follow-up period of the 20 patients was 28.3 months(range, 5–63 months). During the follow-up period, 17
patients died due to disease progression. The mean pretreatment levels of NLR, CRP, CEA and ALB were 2.7,
1.1 mg/dL, 237.7 ng/mL and 3.8 g/dL. And the mean
post-treatment levels were 2.0, 0.9 mg/dL, 153.6 ng/mL
and 3.7 g/dL each. At 3 months after the start of firstline chemotherapy, decreased NLR was detected in 14,
decreased CRP was detected in 15, decreased CEA wasdetected in 15, and increased ALB was detected in 8 patients.
According to our scoring system, we found that
6 were +4, 2 were +3, 3 were +2 and 2 patients were
+1. However, 3 were 0 and 4 patients were –4 and –3.
The mean survival time (MST) of 13 patients with plus

Blood samples

Blood samples were taken from each patient before startof the first line chemotherapy and at 3 months after thestart of chemotherapy. NLR, serum ALB, CRP and
CEA levels were compared between the two periods.
Scoring system

At 3 months after the start of chemotherapy, the NLR,
CRP, CEA and ALB levels were compared with thoseof before chemotherapy in each patient. Scoring was asfollows: decreased NLR, +1; increased NLR, –1; decreased CRP, +1; increased CRP, –1; decreased CEA,
+1; increased CEA, –1; increased ALB, +1; decreased
ALB, –1. In cases with a decrease of NLR, CRP and
CEA and with an elevation of ALB at 3 months after
the start of chemotherapy, we gave a score of +4. On theother hand, when we found cases with an elevation ofFig. 1. The survival curve of 13 patients with plus scores (solidline) is significantly better than that of 7 patients with minus orzero scores (dotted line). The difference is statistically significant(P = 0.0008).

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Prognostic score of colorectal cancer

specimens or bioptic samples, or we need to check theperiodical changes of tumors by using an imaging analyzer. These methods may be useful, but it will take lotsof time and money and/or require special techniques toperform these methods.
It is well known that circulating lymphocytes play
an important immunological role in various carcinomas.13, 14 In addition, a strong correlation between
cancer progression and lymphopaenia was detected inpatients with clear cell renal carcinoma.14, 15 Lissoni et
al. reported that independently of tumor histotype andchemotherapeutic regimen, lymphocytosis occurred inpatients who achieved an objective tumor regression in
response to chemotherapy, and the mean lymphocyte
count observed at the end of the chemotherapeutic treatment was significantly higher than that seen before theonset of treatment.16 They added that the mean lymphocyte count decreased with chemotherapy in patients withtumor progression. Based on this finding, we invented a
new scoring system using NLR, CRP, CEA and ALB to
decide the effectiveness of first line chemotherapy. Thissystem is very simple and we can use this system without special techniques.
Even though the total number of our investigatedcases was small, we found that this scoring system accurately predicted the prognosis of patients with unresectable advanced or recurrent colorectal cancer during chemotherapy in our study. Specifically, CEA should be agood indicator of tumor progression, but many colorectal tumors that did not express CEA elevation according
to the tumor progression have been reported.17, 18 In suchcases, peripheral lymphocytes counts, CRP and serum
ALB should be good indicators. In this paper, we discuss the usefulness of a scoring system as a parameter

Fig. 2. There is a significantly positive correlation between CEA
decreasing ratios (X axis) and NLR decreasing ratios (Y axis, =0.651, P = 0.0046). CEA, carcinoembryonic antigen; NLR, neutrophil/lymphocyte ratio.

scores was 34 months and this was significantly better
than that of the 7 patients who showed zero or minus (19months, Fig. 1, P = 0.0008).
We calculated the decrease ratio [(pre – post)/pre100%] of NLR, CRP and CEA in each case and calculated the increase ratio [(post – pre)/pre 100%] of ALB
in each case. We found strong correlations among theseratios [NLR and CRP: = 0.615, P = 0.0073; NLR and
CEA: ρ = 0.651, P = 0.0046 (Fig. 2); NLR and ALB: =0.59, P = 0.0102; CRP and CEA: = 0.497, P = 0.0303;
CRP and ALB: = 0.614, P = 0.0075 and CEA and
ALB: = 0.483, P = 0.0354].
We investigated the prognostic strength of eachparameter. Then, we divided the patients into two subgroups according to the median levels of each parameter. Table 2 shows that the CEA decrease ratio was agood parameter of prognosis of patients with unresectable advanced or recurrent colorectal cancer undergoing
chemotherapy.

Table 2. Prognostic analysis of 20 patientsDISCUSSION
For patients with unresectable advanced or recurrent
colorectal cancer, it is important to continue effective chemotherapy for as long as possible. FOLFOX or
FOLFOX plus bevacizumab has been recognized asa good first line chemotherapy for these patients,9 but
in cases where first line chemotherapy is ineffective,
we should change the treatment to second line chemotherapy as soon as possible. To find out whether firstline chemotherapy is effective or not, we looked for suitable markers. Another point is that several parameters
have been reported as useful markers to determine theeffectiveness of chemotherapeutic drugs in advanced
colorectal cancer.10, 11, 12 But when we use these markers, we need to do special immunostaining of resected

Mediann
MST(%)		(mo)		 High
1034
NLR decrease ratio 34.3						 Low
10
19
		 High
10
24
CRP decrease ratio 34.9						 Low
10
20
		 High
1034
CEA decrease ratio 47.4				
		 Low
10
19
		 High
1030
ALB increase ratio –2.5						 Low
10
23

P

0.30690.96850.01190.3873

ALB, albumin; CEA, carcinoembryonic antigen; CRP, C-reactive
protein; MST, mean survival time; NLR, neutrophil/lymphocyte
ratio.

71

M. Ikeguchi et al.

of effectiveness of first line chemotherapy for colorectal
cancer. For all patients, peripheral blood samples werechecked every month and these data are what our system used. NLR, serum ALB, CRP and CEA levels werecompared between the two periods (before the start offirst line chemotherapy and at 3 months after the startof chemotherapy). Usually, the response assessment has
been checked every 2 or 3 months during chemotherapy
in advanced colorectal cancers.19 Our scoring system
may indicate total patient conditions including immunological aspects of patients or tumor regression during chemotherapy. However, the prognostic differencesamong the patients who showed scores of +4, +3, +2, +1,0, –1, –2, –3 and –4 were unclear. In order to clarify this,we need to investigate our scoring system with a larger
scale study of colorectal cancer patients.
In conclusion, when we suspect that first line chemotherapy will be ineffective for patients, our scoring
system can help us to decide to change to the second line
chemotherapy as soon as possible. That may be the besttreatment for patients with unresectable advanced or recurrent colorectal cancer undergoing chemotherapy.

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The authors declare no conflict of interest.
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