Research ArticleClinical Studies

The Impact of Intraoperative Blood Loss on the Survival After Laparoscopic Surgery for Colorectal Cancer

MASATSUNE SHIBUTANI, KIYOSHI MAEDA, SHINICHIRO KASHIWAGI, KOSEI HIRAKAWA and MASAICHI OHIRA
Anticancer Research September 2021, 41 (9) 4529-4534; DOI: https://doi.org/10.21873/anticanres.15264

Abstract

Background/Aim: Blood transfusion and a large amount of intraoperative blood loss (IBL) have been reported to have a negative impact on long-term survival via immunosuppression. In recent years, thanks to the spread of laparoscopic surgery and the development of surgical devices, the average amount of IBL has decreased, as has the need for perioperative blood transfusion. Under such conditions, the prognostic significance of the amount of IBL is unclear. The aim of this study was to assess the impact of the amount of IBL on long-term survival. Patients and Methods: A total of 277 patients who underwent laparoscopic surgery for stage II/III colorectal cancer were enrolled. Results: The median amount of IBL was 30 ml, and 16 patients received blood transfusion. The overall survival rates were significantly better in the low-IBL (≤100 ml) group than in the high-IBL (>100 ml) group regardless of the blood transfusion. As the amount of IBL increased, the decline rate of the peripheral lymphocyte count increased. Conclusion: A large amount of IBL was associated with poor long-term survival, regardless of blood transfusion, in patients with colorectal cancer.

Key Words:

R0 resection is the only potentially curative treatment for colorectal cancer. However, recurrence is a significant concern, even after R0 resection. Tumor depth and lymph node metastasis, which are well-known prognostic factors, are routinely used for stratification of risk of recurrence in clinical practice. Recently, in addition to these factors associated with the tumor, factors associated with the host, such as the neutrophil-to-lymphocyte ratio and CONUT score (1, 2), have received attention. Furthermore, blood transfusion and a large amount of intraoperative blood loss (IBL) have been reported to have a negative impact on long-term survival via immunosuppression in patients with various malignancies (3-9).

In recent years, thanks to the spread of laparoscopic surgery and the development of surgical devices such as electrothermal bipolar-activated devices or ultrasonic systems, the average amount of IBL has decreased, as has the need for perioperative blood transfusion. Under these conditions, the prognostic significance of the amount of IBL is unclear. Furthermore, few studies have specifically investigated the mechanism by which immunosuppression caused by IBL worsens the prognosis.

The present study assessed the impact of the amount of IBL on the long-term survival and on the postoperative immune status of patients who underwent curative operation for colorectal cancer.

Patients and Methods

A total of 277 patients who underwent laparoscopic surgery for stage II/III colorectal cancer at Osaka City University Hospital between January 2012 and December 2016 were enrolled in this study. All patients enrolled in this study underwent curative resection. Patients who received preoperative therapy, such as neoadjuvant chemoradiotherapy, underwent emergency surgery for perforation or obstruction, and patients with ulcerative colitis or familial adenomatous polyposis were excluded from this study.

This retrospective study was approved by the Ethics Committee of Osaka City University (approval number: 4182) and was conducted in accordance with the Declaration of Helsinki. All patients provided their written informed consent.

The relationship between the amount of IBL and the overall survival rate were assessed. An appropriate cut-off value for the amount of IBL was determined based on a receiver operating characteristic (ROC) curve analysis, and the patients were then classified into the low- (≤100 ml) and high-IBL (>100 ml) groups based on the cut-off value. Furthermore, the relationships between IBL and the clinicopathological factors were assessed in order to identify the factors that were associated with an increasing amount of IBL. The preoperative absolute peripheral lymphocyte count-to-postoperative absolute lymphocyte count ratio (rate of decline in the peripheral lymphocyte count) was calculated by dividing the absolute peripheral lymphocyte count on postoperative day 7 by that within two weeks before the operation.

All statistical analyses were performed using the SPSS software package for Windows (SPSS, Chicago, IL, USA). The significance of differences in IBL and the clinicopathological factors were analyzed using a chi-squared test and Fisher’s exact test. Survival curves were estimated using the Kaplan–Meier method, and the differences in the survival curves were assessed with a log-rank test. A multivariate Cox proportional hazard model was used to evaluate the prognostic factors associated with the survival. Factors with a p-value of <0.1 on the univariate analysis were included in the multivariate analysis. p-values of <0.05 were considered to indicate statistical significance.

Results

Patient characteristics. The patient characteristics are shown in Table I. The median amount of IBL was 30 (range=5-2,120) ml. Sixteen patients (5.8%) received blood transfusion. The median duration of follow-up was 48.0 months. Fifty-four patients relapsed, and 54 died during the follow-up period. Among the patients enrolled in this study, no patients died within 30 days after surgery.

View this table:
Table I.

Patient characteristics.

Classifications according to the amount of IBL. We used the amount of IBL, which was a continuous variable, as the test variable and the five-year survival as the state variable. When we investigated the cut-off value for IBL using the ROC curve analysis, we found that the most appropriate cut-off value was 107 (sensitivity: 35.2%; specificity: 79.4%) (Figure 1). We therefore set 100 as the cut-off value and classified patients into the high-IBL group (n=66) or the low-IBL group (n=211).

Figure 1.
Figure 1.

A receiver operating characteristic curve analysis of the intraoperative blood loss. Area under the curve=0.600; 95% Confidence Interval=0.519-0.681; p=0.022.

Correlations between IBL and clinicopathological factors. The correlations between IBL and the clinicopathological factors are shown in Table II. The amount of IBL was significantly associated with depth, lymphatic involvement, and venous involvement (Table II).

View this table:
Table II.

Correlation between intraoperative blood loss and clinicopathological factors in patients without blood transfusion.

Survival analyses according to IBL and blood transfusion. The overall survival rates were significantly better in the low-IBL group than in the high-IBL group (p=0.0293) (Figure 2). The overall survival rates tended to be worse in patients who received blood transfusion than in those who did not receive blood transfusion (p=0.0880) (Figure 3).

Figure 2.
Figure 2.

Kaplan–Meier survival curves for the overall survival according to the intraoperative blood loss (IBL). The low-IBL group had a significantly better overall survival rate than the high-IBL group (p=0.0293).

Figure 3.
Figure 3.

Kaplan–Meier survival curves for the overall survival according to the blood transfusion. The overall survival rates tended to be worse in patients who received blood transfusion than in those who did not receive blood transfusion (p=0.0880).

Subgroup analyses limited to the patients without blood transfusion. The overall survival rates were significantly better in the low-IBL group than in the high-IBL group (p=0.0240) (Figure 4). The correlations between the overall survival and various clinicopathological factors are shown in Table III. According to the results of the univariate analyses, the overall survival was significantly associated with the amount of IBL and tumor depth and tended to be associated with age and histological type. The multivariate analyses indicated that the overall survival was significantly associated with age and tended to be associated with the amount of IBL and tumor depth.

Figure 4.
Figure 4.

Kaplan–Meier survival curves for the overall survival according to the intraoperative blood loss (IBL) in patients without blood transfusion. The low-IBL group had a significantly better overall survival rate than the high-IBL group (p=0.0240).

View this table:
Table III.

The correlation between the overall survival and various clinicopathological factors in patients without blood transfusion.

Comparison of the rate of decline in the peripheral lymphocyte count according to the amount of IBL. The decline rate of peripheral lymphocyte count was significantly higher in the high-IBL group than in the low-IBL group (Figure 5).

Figure 5.
Figure 5.

A comparison of the rate of decline in the peripheral lymphocyte count according to the amount of intraoperative blood loss (IBL). The rate of decline in the peripheral lymphocyte count was significantly higher in the high-IBL group than in the low-IBL group. *p=0.038.

Discussion

In previous reports, perioperative blood transfusion was reported to have a negative impact on the long-term survival via immunosuppression in various malignancies (7-9). However, many points concerning the impact of an increased amount of IBL on the prognosis have been unclear. As a large amount of IBL increases the need for blood transfusion, the relationship between a large amount of IBL and a poor prognosis may be influenced by blood transfusion. However, in the present study, an increased amount of IBL was associated with a poor prognosis even in patients who did not receive blood transfusion. Therefore, an increased amount of IBL was revealed to be associated with a poor prognosis, regardless of blood transfusion.

Several mechanisms could be responsible for the association between the amount of IBL and worse prognosis. First, an increasing amount of IBL may cause immunosuppression, resulting in a poor prognosis. The present study revealed that as the amount of IBL increased, the rate of decrease in the peripheral lymphocyte count increased. Although the degree of the effect of peripheral lymphocyte depletion on the immune status is unclear, considering the existence of reports on the correlation between the number of peripheral lymphocytes and the prognosis after potentially curative operation (10-13), it is possible that increasing the IBL may worsen the prognosis via immunosuppression. Second, excessive blood loss may promote intraoperative tumor spillage and hematogenous spread during the operation (14, 15). Third, the amount of IBL indirectly represents the degree of cancer progression, as can be seen from the correlation between the amount of IBL and the tumor depth. However, the amount of IBL itself is considered to be an important prognostic factor, since the amount of IBL tended to correlate with the survival time, even in the multivariate analysis including the tumor depth as a covariate. Fourth, an increased amount of IBL leads to excessive surgical stress, which promotes the production of inflammatory cytokines (16). Inflammatory cytokines provide a favorable environment for the proliferation of micrometastasis, resulting in a poor prognosis (17-20). Fifth, increasing the amount of IBL worsens the prognosis via postoperative complications. Increased IBL has been reported to be associated with increased postoperative complications (21, 22). Postoperative infectious complications as well as surgical stress are associated with worse survival outcomes due to the increased production of inflammatory cytokines (23-25).

The present study has several limitations. First, this was a retrospective study with a small cohort performed in a single center. Second, some of the proposed mechanisms by which increasing IBL worsens the prognosis remain a matter of debate. Specifically, the theory that excessive IBL may promote intraoperative tumor spillage and hematogenous spread during the operation is only speculation, and proof supporting this mechanism is lacking at present. Third, regarding immunosuppression, although this study revealed that the peripheral lymphocyte count decreases as the amount of IBL increases, other immunocompetent cells have not been evaluated.

In conclusion, it was revealed that a large amount of IBL is associated with a poor long-term survival outcome, regardless of blood transfusion, in patients with colorectal cancer. Preventing massive intraoperative bleeding may improve the prognosis after curative operation for colorectal cancer.

Footnotes

  • Authors’ Contributions

    MS designed the study, performed the statistical analysis and drafted the manuscript. KM, SK, KH and MO designed the study and critically reviewed the manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in association with the present study.

  • Received July 2, 2021.
  • Revision received July 23, 2021.
  • Accepted July 26, 2021.

References

  1. ↵
    1. Shibutani M,
    2. Maeda K,
    3. Nagahara H,
    4. Noda E,
    5. Ohtani H,
    6. Nishiguchi Y and
    7. Hirakawa K
    : A high preoperative neutrophil-to-lymphocyte ratio is associated with poor survival in patients with colorectal cancer. Anticancer Res 33(8): 3291-3294, 2013. PMID: 23898094.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Iseki Y,
    2. Shibutani M,
    3. Maeda K,
    4. Nagahara H,
    5. Ohtani H,
    6. Sugano K,
    7. Ikeya T,
    8. Muguruma K,
    9. Tanaka H,
    10. Toyokawa T,
    11. Sakurai K and
    12. Hirakawa K
    : Impact of the preoperative controlling nutritional status (CONUT) score on the survival after curative surgery for colorectal cancer. PLoS One 10(7): e0132488, 2015. PMID: 26147805. DOI: 10.1371/journal.pone.0132488
    OpenUrlCrossRefPubMed
  3. ↵
    1. Liang YX,
    2. Guo HH,
    3. Deng JY,
    4. Wang BG,
    5. Ding XW,
    6. Wang XN,
    7. Zhang L and
    8. Liang H
    : Impact of intraoperative blood loss on survival after curative resection for gastric cancer. World J Gastroenterol 19(33): 5542-5550, 2013. PMID: 24023499. DOI: 10.3748/wjg.v19.i33.5542
    OpenUrlCrossRefPubMed
    1. Ito Y,
    2. Kanda M,
    3. Ito S,
    4. Mochizuki Y,
    5. Teramoto H,
    6. Ishigure K,
    7. Murai T,
    8. Asada T,
    9. Ishiyama A,
    10. Matsushita H,
    11. Tanaka C,
    12. Kobayashi D,
    13. Fujiwara M,
    14. Murotani K and
    15. Kodera Y
    : Intraoperative blood loss is associated with shortened postoperative survival of patients with stage II/III gastric cancer: Analysis of a multi-institutional dataset. World J Surg 43(3): 870-877, 2019. PMID: 30377722. DOI: 10.1007/s00268-018-4834-0
    OpenUrlCrossRefPubMed
    1. Mörner ME,
    2. Gunnarsson U,
    3. Jestin P and
    4. Svanfeldt M
    : The importance of blood loss during colon cancer surgery for long-term survival: an epidemiological study based on a population based register. Ann Surg 255(6): 1126-1128, 2012. PMID: 22498893. DOI: 10.1097/SLA.0b013e3182512df0
    OpenUrlCrossRefPubMed
    1. Tamagawa H,
    2. Aoyama T,
    3. Yamamoto N,
    4. Kamiya M,
    5. Murakawa M,
    6. Atsumi Y,
    7. Numata M,
    8. Kazama K,
    9. Hara K,
    10. Yukawa N,
    11. Rino Y,
    12. Masuda M and
    13. Morinaga S
    : The impact of intraoperative blood loss on the survival of patients with stage II/III pancreatic cancer. In Vivo 34(3): 1469-1474, 2020. PMID: 32354948. DOI: 10.21873/invivo.11931
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Kanda M,
    2. Kobayashi D,
    3. Tanaka C,
    4. Iwata N,
    5. Yamada S,
    6. Fujii T,
    7. Nakayama G,
    8. Sugimoto H,
    9. Koike M,
    10. Nomoto S,
    11. Murotani K,
    12. Fujiwara M and
    13. Kodera Y
    : Adverse prognostic impact of perioperative allogeneic transfusion on patients with stage II/III gastric cancer. Gastric Cancer 19(1): 255-263, 2016. PMID: 25563579. DOI: 10.1007/s10120-014-0456-x
    OpenUrlCrossRefPubMed
    1. Bekki T,
    2. Abe T,
    3. Amano H,
    4. Hattori M,
    5. Kobayashi T,
    6. Nakahara M,
    7. Ohdan H and
    8. Noriyuki T
    : Impact of low skeletal muscle mass index and perioperative blood transfusion on the prognosis for HCC following curative resection. BMC Gastroenterol 20(1): 328, 2020. PMID: 33028209. DOI: 10.1186/s12876-020-01472-z
    OpenUrlCrossRefPubMed
  9. ↵
    1. Arima K,
    2. Hashimoto D,
    3. Okabe H,
    4. Inoue R,
    5. Kaida T,
    6. Higashi T,
    7. Taki K,
    8. Nitta H,
    9. Hayashi H,
    10. Chikamoto A,
    11. Beppu T and
    12. Baba H
    : Intraoperative blood loss is not a predictor of prognosis for pancreatic cancer. Surg Today 46(7): 792-797, 2016. PMID: 26302976. DOI: 10.1007/s00595-015-1238-8
    OpenUrlCrossRefPubMed
  10. ↵
    1. Iseki Y,
    2. Shibutani M,
    3. Maeda K,
    4. Nagahara H,
    5. Tamura T,
    6. Ohira G,
    7. Yamazoe S,
    8. Kimura K,
    9. Toyokawa T,
    10. Amano R,
    11. Tanaka H,
    12. Muguruma K,
    13. Hirakawa K and
    14. Ohira M
    : The impact of the preoperative peripheral lymphocyte count and lymphocyte percentage in patients with colorectal cancer. Surg Today 47(6): 743-754, 2017. PMID: 27783149. DOI: 10.1007/s00595-016-1433-2
    OpenUrlCrossRefPubMed
    1. Zhang YY,
    2. Li WQ,
    3. Li ZF,
    4. Guo XH,
    5. Zhou SK,
    6. Lin A and
    7. Yan WH
    : Higher levels of pre-operative peripheral lymphocyte count is a favorable prognostic factor for patients with stage I and II rectal cancer. Front Oncol 9: 960, 2019. PMID: 31612109. DOI: 10.3389/fonc.2019.00960
    OpenUrlCrossRefPubMed
    1. Oh SY,
    2. Heo J,
    3. Noh OK,
    4. Chun M,
    5. Cho O and
    6. Oh YT
    : Absolute lymphocyte count in preoperative chemoradiotherapy for rectal cancer: Changes over time and prognostic significance. Technol Cancer Res Treat 17: 1533033818780065, 2018. PMID: 29909729. DOI: 10.1177/1533033818780065
    OpenUrlCrossRefPubMed
  13. ↵
    1. Feng F,
    2. Zheng G,
    3. Wang Q,
    4. Liu S,
    5. Liu Z,
    6. Xu G,
    7. Wang F,
    8. Guo M,
    9. Lian X and
    10. Zhang H
    : Low lymphocyte count and high monocyte count predicts poor prognosis of gastric cancer. BMC Gastroenterol 18(1): 148, 2018. PMID: 30305076. DOI: 10.1186/s12876-018-0877-9
    OpenUrlCrossRefPubMed
  14. ↵
    1. Fisher ER and
    2. Turnbull RB Jr.
    : The cytologic demonstration and significance of tumor cells in the mesenteric venous blood in patients with colorectal carcinoma. Surg Gynecol Obstet 100(1): 102-108, 1955. PMID: 13238159.
    OpenUrlPubMed
  15. ↵
    1. Roberts S,
    2. Watne A,
    3. McGrath R,
    4. McGrew E and
    5. Cole WH
    : Technique and results of isolation of cancer cells from the circulating blood. AMA Arch Surg 76(3): 334-346, 1958. PMID: 13507823. DOI: 10.1001/archsurg.1958.01280210004002
    OpenUrlCrossRefPubMed
  16. ↵
    1. Shibutani M,
    2. En W,
    3. Okazaki Y,
    4. Maeda K,
    5. Hirakawa K and
    6. Ohira M
    : A high postoperative serum C-reactive protein level has a negative impact on long-term survival, regardless of postoperative infectious complications, in patients who undergo laparoscopic surgery for colorectal cancer. Anticancer Res 41(3): 1593-1598, 2021. PMID: 33788754. DOI: 10.21873/anticanres.14920
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Tsuchiya Y,
    2. Sawada S,
    3. Yoshioka I,
    4. Ohashi Y,
    5. Matsuo M,
    6. Harimaya Y,
    7. Tsukada K and
    8. Saiki I
    : Increased surgical stress promotes tumor metastasis. Surgery 133(5): 547-555, 2003. PMID: 12773983. DOI: 10.1067/msy.2003.141
    OpenUrlCrossRefPubMed
    1. Kumagai K,
    2. Saikawa Y,
    3. Takeuchi H,
    4. Suda K,
    5. Fukuda K,
    6. Nakamura R,
    7. Takahashi T,
    8. Kawakubo H,
    9. Wada N,
    10. Miyasho T and
    11. Kitagawa Y
    : The neutrophil elastase inhibitor sivelestat suppresses accelerated gastrointestinal tumor growth via peritonitis after cecal ligation and puncture. Anticancer Res 33(9): 3653-3659, 2013. PMID: 24023292.
    OpenUrlAbstract/FREE Full Text
    1. Shibutani M,
    2. Nakao S,
    3. Maeda K,
    4. Nagahara H,
    5. Fukuoka T,
    6. Iseki Y,
    7. Hirakawa K and
    8. Ohira M
    : Inflammation caused by surgical stress has a negative impact on the long-term survival outcomes in patients with colorectal cancer. Anticancer Res 40(6): 3535-3542, 2020. PMID: 32487655. DOI: 10.21873/anticanres.14342
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Shibutani M,
    2. Kimura K,
    3. Kashiwagi S,
    4. Wang EN,
    5. Okazaki Y,
    6. Maeda K,
    7. Hirakawa K and
    8. Ohira M
    : Elevated postoperative levels of serum C-reactive protein are associated with shorter long-term survival after resection of colorectal liver metastases, regardless of the occurrence of infectious complications. Anticancer Res 41(5): 2605-2610, 2021. PMID: 33952490. DOI: 10.21873/anticanres.15040
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Chiappa A,
    2. Zbar AP,
    3. Bertani E,
    4. Biella F,
    5. Audisio RA and
    6. Staudacher C
    : Surgical outcomes for colorectal cancer patients including the elderly. Hepatogastroenterology 48(38): 440-444, 2001. PMID: 11379328.
    OpenUrlPubMed
  22. ↵
    1. Sah BK,
    2. Zhu ZG,
    3. Chen MM,
    4. Xiang M,
    5. Chen J,
    6. Yan M and
    7. Lin YZ
    : Effect of surgical work volume on postoperative complication: superiority of specialized center in gastric cancer treatment. Langenbecks Arch Surg 394(1): 41-47, 2009. PMID: 18584204. DOI: 10.1007/s00423-008-0358-7
    OpenUrlCrossRefPubMed
  23. ↵
    1. Gamboa AC,
    2. Lee RM,
    3. Turgeon MK,
    4. Varlamos C,
    5. Regenbogen SE,
    6. Hrebinko KA,
    7. Holder-Murray J,
    8. Wiseman JT,
    9. Ejaz A,
    10. Feng MP,
    11. Hawkins AT,
    12. Bauer P,
    13. Silviera M,
    14. Maithel SK and
    15. Balch GC
    : Impact of postoperative complications on oncologic outcomes after rectal cancer surgery: an analysis of the US Rectal Cancer Consortium. Ann Surg Oncol 28(3): 1712-1721, 2021. PMID: 32968958. DOI: 10.1245/s10434-020-08976-8
    OpenUrlCrossRefPubMed
    1. Ma L,
    2. Pang X,
    3. Ji G,
    4. Sun H,
    5. Fan Q and
    6. Ma C
    : The impact of anastomotic leakage on oncology after curative anterior resection for rectal cancer: A systematic review and meta-analysis. Medicine (Baltimore) 99(37): e22139, 2020. PMID: 32925766. DOI: 10.1097/MD.0000000000022139
    OpenUrlCrossRefPubMed
  25. ↵
    1. Fujita Y,
    2. Hida K,
    3. Hoshino N,
    4. Sakai Y,
    5. Konishi T,
    6. Kanazawa A,
    7. Goto M,
    8. Saito S,
    9. Suda T,
    10. Watanabe M and Japan Society of Laparoscopic Colorectal Surgery
    : Impact of postoperative complications after primary tumor resection on survival in patients with incurable stage IV colorectal cancer: A multicenter retrospective cohort study. Ann Gastroenterol Surg 5(3): 354-362, 2021. PMID: 34095726. DOI: 10.1002/ags3.12433
    OpenUrlCrossRefPubMed
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The Impact of Intraoperative Blood Loss on the Survival After Laparoscopic Surgery for Colorectal Cancer
MASATSUNE SHIBUTANI, KIYOSHI MAEDA, SHINICHIRO KASHIWAGI, KOSEI HIRAKAWA, MASAICHI OHIRA
Anticancer Research Sep 2021, 41 (9) 4529-4534; DOI: 10.21873/anticanres.15264
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