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ReseaRch aRticle

Drug anD ChemiCal ToxiCology 2024, Vol. 47, no. 4, 365–371

The incidence rate of allergic reactions induced by oxaliplatin is higher in patients with rectal cancer compared with colon cancer

tong liu, Yao Jin, Xu Yang, Zhiqiang tong and Mei Dong

Department of Pharmacy, harbin medical university Cancer hospital, no.150 haping rd, nangang District, harbin, 150081, P.r. China

ABSTRACT Aim:  to explore the diverse profiles of adverse reactions caused by oxaliplatin between colon and rectal cancer, we investigated the toxicity of oxaliplatin in patients with colon and rectal cancer. Methods:  From January 2017 to December 2021, 200 cases of sporadic cRc patients with adverse reactions after oxaliplatin were collected from harbin Medical University cancer hospital, harbin, china. all patients received a chemotherapy regimen containing oxaliplatin (100 colon cancer and 100 rectal cancer). We reviewed the adverse reactions induced by oxaliplatin in patients with colon and rectal cancer. Results:  We found there was no significant difference in gastrointestinal toxicity, hematotoxicity, neurotoxicity, hepatotoxicity, respiratory toxicity, and cardiotoxicity caused by oxaliplatin between patients with colon cancer and patients with rectal cancer, but patients with rectal cancer were more prone to allergic reactions than patients with colon cancer after oxaliplatin. in addition, we found neutrophil-to-lymphocyte ratios (NlR) and platelet-to-lymphocyte ratios (PlR) were higher in patients with colon cancer than in patients with rectal cancer. this may reflect differences in immune status and inflammatory responses between colon cancer and rectal cancer, which might be the reason for more allergic reactions caused by oxaliplatin in colon cancer patients compared to rectal cancer patients. Conclusion:  except for a higher incidence of allergic reactions in patients with rectal cancer, no significant difference in the incidence of adverse drug reactions associated with oxaliplatin was noted between patients with colon cancer and rectal cancer. Our results suggested more attention should be paid to the allergic reaction caused by oxaliplatin in patients with colon cancer.

1.  Introduction

colorectal cancer (cRc) is the third most common cause of cancer mortality worldwide with more than 1.85 million cases and 850 000 deaths annually (Biller and schrag 2021). For the treatment of cRc patients with stage iii or ii, who have high-risk factors of recurrence or distant metastasis, adjuvant systemic chemotherapy is chosen (NccN guidelines version 3. 2021 colon cancer, Buccafusca et  al. 2019). the current management of disseminated metastatic colon cancer involves various active drugs. these drugs could be used either in combination or as a single agent based on many factors (Buccafusca et  al. 2019). at present, the combination of 5-fluorouracil/leucovorin with oxaliplatin or capecitabine with or without oxaliplatin is the main therapeutic regime as neo- adjuvant or adjuvant therapy for cRc or the first-line treat- ment for metastatic colorectal cancer (mcRc) (O’Neil and Goldberg 2008, National comprehensive cancer Network, 2022). Due to the neurotoxicity of oxaliplatin, the time to start chemotherapy for the patients is often delayed (andré et  al. 2009). hence, it is important to explore the toxicity profile of oxaliplatin for the treatment of cRc.

Many biological and clinical hallmarks are different between colon and rectal cancer (heald and Moran 1998). there are also several differences in the treatment of colon and rectal cancer. in patients with rectal cancer, neoadjuvant radiotherapy or chemoradiotherapy is widely used compared to colon can- cer. in addition, the expression of related genes varies in dif- ferent locations of the colon and rectum (tamas et  al. 2015). Moreover, metastatic patterns are different notably between colon and rectal cancers. Rectal cancer more frequently metas- tasized into thoracic organs and the nervous system and less frequently within the peritoneum (Riihimäki et  al. 2016). the 5-year disease-specific overall survival rate of colon cancer and rectal cancer are also dissimilar (Dutch comprehensive cancer centres, 2015 May 04), therefore, it is very important to explore the difference between colon cancer and rectal cancer.

Oxaliplatin is a third-generation platinum-based chemothera- peutic agent commonly administered in combination with leu- covorin and fluorouracil for neoadjuvant and adjuvant treatment of cRc (andré et  al. 2004). Oxaliplatin is an alkylating agent that interacts with DNa to form intrastrand/interstrand DNa crosslinks that affect DNa base pairing, replication, and gene transcription,

© 2023 informa uK limited, trading as Taylor & Francis group

CONTACT mei Dong [email protected] Department of Pharmacy, harbin medical university Cancer hospital, no.150 haping rd, nangang District, harbin, P.r. China

https://doi.org/10.1080/01480545.2023.2217700

ARTICLE HISTORY Received 13 July 2022 Revised 10 april 2023 accepted 13 april 2023

KEYWORDS colon cancer; rectal cancer; oxaliplatin; adverse reactions; allergic reactions

366 t. liU et al.

ultimately causing cell death (Rogers et al. 2019). a range of side effects is associated with oxaliplatin including fatigue, nausea, peripheral neuropathy, and hematological toxicity (hong et  al. 2014). studies have demonstrated that oxaliplatin controls voltage-gated Na+ and K+ channels, which might be the mech- anism of acute neuropathy caused by oxaliplatin (Benoit et  al. 2006, Kagiava et al. 2008). in order to explore the diverse profiles of adverse reactions caused by oxaliplatin between colon cancer and rectal cancer, we investigated the toxicity of oxaliplatin in patients with colon cancer and patients with rectal cancer.

2.  Material and methods

2.1.  To explore the adverse reactions of oxaliplatin in colon cancer and rectal cancer

Patients. From January 2017 to December 2021, 200 cases of sporadic cRc patients with adverse reactions after oxaliplatin were collected from harbin Medical University cancer hospital, harbin, china. all patients received a chemotherapy regimen containing oxaliplatin (100 colon cancer and 100 rectal cancer). the demo- graphic characteristics of the patients included were extracted from the electronic medical records (table 1). all methods were performed in accordance with the relevant guidelines and regulations.

adverse reaction assessment. adverse events were graded using the National cancer institute common terminology criteria for adverse events (common terminology criteria for adverse events (ctcae) Version 5, 2017). We reviewed the adverse reactions induced by oxaliplatin in patients with colon and rectal cancer after evaluating the adverse drug reaction by Naranjo adverse Drug Reaction Probability scale (Naranjo et  al. 1992). the adverse drug reactions are assigned to a probability category from the total score as follows: definite if the overall score is 9 or greater, probable for a score of 5–8, possible for 1–4, and doubtful if the score is 0.

2.2.  To explore possible differences in blood cell counts between colon cancer and rectal cancer

Patients. 156 patients with histopathologically confirmed col- orectal cancer for the first time were included from harbin

Medical University cancer hospital, harbin, china. (78 colon cancer and 78 rectal cancer). None of the included patients with colorectal cancer had distant metastasis. there was no significant difference in age and gender between the colon cancer group and rectal cancer group (table 2).

Detection method. We used an autoanalyzer (sysmex Xe-2100, Kobe, Japan) to detect white blood cell (WBc), neu- trophil, lymphocyte, and platelet counts. We collected the whole blood samples in eDta-containing tubes and processed the samples within 30 minutes. the platelet-to-lymphocyte ratio (PlR) or neutrophil-to-lymphocyte ratio (NlR) was cal- culated as the platelet count divided by the lymphocyte count or the neutrophil count divided by the lymphocyte count measured (Wang et  al. 2017).

2.3.  Meta-analysis to explore the potential adverse reactions of oxaliplatin for the treatment of CRC

Based on the guidelines of the preferred reporting items for systematic reviews and meta-analysis (PRisMa) statements, we conducted the meta-analysis to investigate the adverse reac- tions profile of oxaliplatin (liberati et  al. 2009, liu et  al. 2023).

Many international and chinese databases were searched to find information about adverse reactions of capecitabine monotherapy and capecitabine combined with oxaliplatin for the treatment of cRc (liu et  al. 2023). the search terms were “capecitabine”, “oxaliplatin”, “XelOX” and “colorectal cancer”. the search deadline is 10 February 2022. Data extraction and meta-analysis. two reviewers independently screened all stud- ies to extract data. Review manager 5.3 software was used to perform a meta-analysis to investigate the toxicity of oxaliplatin.

2.4.  Statistical analysis

statistical analysis was performed using iBM sPss Version 23. the descriptive statistics are presented as means ± sD for con- tinuous variables. We applied the Kolmogorov-smirnov test to verify the normal distribution of data. the enumeration data and measurement data were analyzed by χ2 and t-test, respec- tively. P < 0.05 was considered to be statistically significant. to estimate the severe adverse reactions (iii-iV) of oxaliplatin, we applied the pooled ORs with 95% cis as an evaluation index. I2 statistic and the p values from the χ2-based cochran’s Q test were the assessment criteria to judge the heterogeneity. if the i2 statistic was above 25%, 50%, or 75%, the heterogeneity among studies was low, moderate, or high. For the low hetero- geneity, we applied the fixed effects model to assess the effect value. For the moderate or high heterogeneity, a random effect model was employed (higgins et  al. 2003, liu et  al. 2023).

3.  Results

3.1.  The profiles of adverse reactions of oxaliplatin between patients with colon cancer and patients with rectal cancer

We observed some common adverse reactions in patients with colon and rectal cancer treated with oxaliplatin. the

Table 1. The basic characteristics of the patients included and different adverse reactions between colon and rectal cancer.

Colon cancer (n = 100)

rectal cancer (n = 100) P

Demographic variables gender (m/F) 44/56 55/45 0.12 age (year) 57.86 (9.00) 55.97 (9.99) 0.16 Weight (Kg) 62.10 (9.30) 63.65 (9.44) 0.24 adverse reactions gastrointestinal toxicity 21 26 0.40 hematotoxicity 42 34 0.24 neutropenia 23 21 0.54 Thrombocytopenia 19 12 0.38 neurotoxicity 17 13 0.43 hepatotoxicity 2 3 0.65 respiratory toxicity 5 3 0.47 Cardiotoxicity 4 3 0.70 allergic reaction 5 13 0.04

DRUG aND cheMical tOXicOlOGY 367

common adverse reactions included gastrointestinal toxicity, hematotoxicity, neurotoxicity, hepatotoxicity, respiratory tox- icity, cardiotoxicity, and allergic reaction. the gastrointestinal toxicity was mainly nausea and vomiting. the hematotoxicity included neutropenia and thrombocytopenia. as shown in Figure 1, there was no difference in the profile of adverse reactions to oxaliplatin between patients with colon cancer and patients with rectal cancer. Furthermore, there was no significant difference in gastrointestinal toxicity, hematotox- icity, neurotoxicity, hepatotoxicity, respiratory toxicity, and cardiotoxicity between patients with colon cancer and patients with rectal cancer. to our surprise, we found that patients with rectal cancer were more prone to allergic reac- tions than patients with colon cancer after oxaliplatin (table 1). the allergic responses in both colon and rectal cancer groups were mainly skin rash and pruritus, accompanied by mild dyspnea.

3.2.  NLR and PLR were lower in patients with rectal cancer than in patients with colon cancer

as shown in Figure 2, there was no statistical difference in white blood cell count, neutrophil count, and lymphocyte count between patients with colon cancer and patients with rectal cancer, but the platelet count was lower in the patients with rectal cancer compared with patients with colon cancer. in addition, we found that NlR and PlR were lower in patients with rectal cancer than in patients with colon cancer, indi- cating the different immune status and inflammatory response between colon cancer and rectal cancer. the diverse immune status and inflammatory response might be the reason for distinct allergic reactions caused by oxaliplatin between patients with colon cancer and patients with rectal cancer.

3.3.  Meta-analysis to explore the potential adverse reactions of oxaliplatin for the treatment of CRC

in order to find the potential adverse reactions of oxaliplatin for the treatment of cRc, we conducted a meta-analysis to compare the adverse reactions caused by capecitabine com- bined with oxaliplatin and capecitabine monotherapy. through searching the international and chinese databases, we found 7 literature assessing the adverse reaction profiles of oxalipla- tin in cRc patients (Xu et  al. 2013, Jiao et  al. 2015, Gao 2017, he 2017, Yaghobi Joybari et al. 2019, Xie et al. 2020, Zhang et al. 2020, liu et  al. 2023). Based on the results of our meta-analysis, no significant toxicity difference was observed between oxaliplatin combined with capecitabine and capecit- abine, suggesting that oxaliplatin was relatively safe or that oxaliplatin and capecitabine alone might have a common mechanism in the occurrence of adverse reactions (Figure 3).

4.  Discussion

Our previous study found that there were differences in tumor markers between patients with colon cancer and rectal cancer (liu et  al. 2021), indicating the different prognosis between colon cancer and rectal cancer. Oxaliplatin is a common che- motherapeutic drug for the treatment of colorectal cancer, and the difference in the occurrence of adverse reactions caused by oxaliplatin between colon cancer and rectal cancer needs to be studied. Our study found that there was no sig- nificant difference in gastrointestinal toxicity, hematotoxicity, neurotoxicity, hepatotoxicity, respiratory toxicity, and cardio- toxicity between patients with colon cancer and patients with rectal cancer. the occurrence rate of allergic reactions in patients with rectal cancer was higher than in patients with colon cancer, suggesting the immune status might be different

Table 2. The basic characteristics of the patients included and the difference in blood cell count between colon and rectal cancer.

Colon cancer (n = 78) rectal cancer (n = 78) P age (year) 62.09 (11.29) 62.68 (8.43) 0.71 gender (male/female) 47/35 51/27 0.10 White blood cell (109/l) 6.83 (2.29) 6.80 (2.53) 0.95 neutrophils (109/l) 4.20 (1.95) 4.12 (2.04) 0.80 Platelet (109/l) 275.00 (76.26) 249.62 (78.67) 0.04 lymphocyte (109/l) 1.93 (0.65) 2.01 (0.68) 0.48

Figure 1. The profiles of adverse reactions of oxaliplatin between colon cancer and rectal cancer. (a) Colon cancer (B) rectal cancer.

368 t. liU et al.

between colon cancer and rectal cancer. the allergic responses were judged according to the clinical criteria for diagnosing anaphylaxis from the european academy of allergy and clinical immunology (Muraro et  al. 2014), which is the acute onset of an illness (minutes to several hours) with involvement of the skin or mucosal tissue and at least one of the following: (1) respiratory compromise. (2) reduced blood pressure or

associated symptoms of end-organ dysfunction. the allergic responses in both colon and rectal cancer groups were mainly skin rash and pruritus, accompanied by mild dyspnea. the symptoms of anaphylaxis in the two groups were generally similar, only the occurrence rates were different.

in order to further explore whether the difference in adverse reactions of oxaliplatin between colon cancer and rectal cancer

Figure 2. The difference of blood cell count between colon cancer and rectal cancer. (a) White blood cell; (B) neutrophils; (C) Platelet; (D) lymphocyte; (e) neutrophil-to-lymphocyte ratio; (F) Platelet-to-lymphocyte ratio.

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is related to the pathological condition of patients, we included 78 patients with colon cancer and 78 patients with rectal cancer to test white blood cell count, neutrophil count, platelet count, and lymphocyte count. there was no statistical difference in white blood cell count, neutrophil count, and lymphocyte count between patients with colon cancer and patients with rectal cancer, but the platelet count was lower in patients with rectal

cancer compared with patients with colon cancer. inflammation is currently considered a hallmark of cancer development (hanahan and Weinberg 2011). the neutrophil-to-lymphocyte ratio (NlR) and platelet-to-lymphocyte ratio (PlR) are two readily available serologic biomarkers that are felt to be surrogates for the degree of systemic inflammation and have been studied as prognostic markers in a range of malignancies (templeton et al.

Figure 3. meta-analysis to explore the potential adverse reactions of oxaliplatin for the treatment of CrC. (a) gastrointestinal toxicity; (B) neutropenia; (C) Thrombocytopenia; (D) neurotoxicity; (e) hand foot syndrome.

370 t. liU et al.

2014a, 2014b). NlR and PlR play a predictive role in many diseases. in thyroid cancer, preoperative NlR was associated with pathological prognosticators such as tumor size and lateral lymph node metastasis (cheong et al. 2021). in ulcerative colitis, NlR was associated with active disease (Posul et  al. 2015). a study reported that PlR might be useful in predicting the devel- opment and control levels of type 2 diabetes mellitus (atak et  al. 2019). Besides, it was reported NlR could be also used as a marker of the development of atrial fibrillation in diabetic patients (lee et  al. 2021). in the coronavirus 2019 disease (cOViD-19), NlR and PlR could aid clinicians to identify poten- tially severe cases at early stages and initiate effective manage- ment in time which may reduce the overall mortality of cOViD-19 patients (Khalid et  al. 2021). therefore, exploring the expression of NlR and PlR plays an important role in the occur- rence and prognosis of diseases. Our study showed NlR and PlR were higher in patients with colon cancer than in patients with rectal cancer, indicating the different immune status and inflammatory response between colon cancer and rectal cancer, which might be the reason for higher allergic reactions in rectal cancer, and more specific mechanisms needed to be explored.

We applied meta-analysis to search for potential adverse reactions of oxaliplatin. since there are few colorectal cancer patients treated with oxaliplatin monotherapy, we compared the toxicity between capecitabine combined with oxaliplatin and capecitabine monotherapy, which were the common chemotherapy regimen for the treatment of cRc. We found there was no significant difference with respect to gastroin- testinal toxicity, neutropenia, thrombocytopenia, neurotoxicity, and hand-foot syndrome between capecitabine combined with oxaliplatin and capecitabine monotherapy. Gastrointestinal toxicity, neutropenia, thrombocytopenia, and neurotoxicity also appeared in our study, but hand-foot syndrome was not found in our study. the meta-analysis indicated that oxalipla- tin was relatively safe or that oxaliplatin and capecitabine might have a common mechanism in the occurrence of adverse reactions.

5.  Conclusion

except for a higher incidence of allergic reactions in patients with rectal cancer, no significant difference in the incidence of adverse drug reactions associated with oxaliplatin was noted between patients with colon cancer and rectal cancer. Our results suggested more attention should be paid to the allergic reaction caused by oxaliplatin in patients with colon cancer.

Ethical statement

ethical approval was waived by the local ethics committee of harbin Medical University cancer hospital in view of the retrospective nature of the study and all the procedures being performed were part of the routine care.

Author contributions

tong liu: Drafting the manuscript Yao Jin: Data analysis

Xu Yang: Data analysis Zhiqiang tong: Data analysis Mei Dong: Design of this study

Patient consent

informed consent was obtained from all individual participants included in the study.

Consent to publish

the participant has consented to the submission of the report to the journal.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Funding

this study was supported by the haiyan Foundation of harbin Medical University cancer hospital (JJQN2023-09), Project of Beijing Medical award Foundation (YXJl-2022-0187-0013), Beijing hongdingxiang Public Welfare Development center (BJ-hDX-20220437).

Data availability statement

all data generated or analyzed during this study are included in this published article.

References

andré, t., et  al., 2004. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. The New England Journal of Medicine, 350 (23), 2343–2351.

andré, t., et al., 2009. improved overall survival with oxaliplatin, fluoroura- cil, and leucovorin as adjuvant treatment in stage ii or iii colon cancer in the MOsaic trial. Journal of Clinical Oncology, 27 (19), 3109–3116.

atak, B., et  al., 2019. Diabetes control could through platelet-to-lympho- cyte ratio in hemograms. Revista da Associacao Medica Brasileira, 65 (1), 38–42.

Benoit, e., Brienza, s., and Dubois, J.M., 2006. Oxaliplatin, an anticancer agent that affects both Na + and K + channels in frog peripheral my- elinated axons. General Physiology and Biophysics, 25 (3), 263–276.

Biller, l.h., and schrag, D., 2021. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA, 325 (7), 669–685.

Buccafusca, G., et  al., 2019. early colorectal cancer: diagnosis, treatment and survivorship care. Critical Reviews in Oncology/Hematology, 136, 20–30.

cheong, t.Y., et  al., 2021. the diagnostic predictive value of neutrophil-to-lymphocyte ratio in thyroid cancer adjusted for tumor size. PLoS One, 16 (5), e0251446.

common terminology criteria for adverse events (ctcae) Version 5. Published: November 27, 2017. Us department of health and human services National institutes of health National cancer.

Dutch comprehensive cancer centres. http://www.cancerregistry.nl (cited 2015 May 04).

Gao, Z.Y., 2017. effect and clinical nursing experience of XelOX and capecitabine in patients with colorectal cancer. Strait Pharmacy, 29 (01), 172–173.

hanahan, D., and Weinberg, R.a., 2011. hallmarks of cancer: the next generation. Cell, 144 (5), 646–674.

DRUG aND cheMical tOXicOlOGY 371

he, Y. J., 2017. Prospective randomized controlled study of capecitabine vs capecitabine + oxaliplatin concurrent radiotherapy and chemother- apy after radical resection of stage ii/iii rectal cancer. Dalian Medical University.

heald, R.J., and Moran, B.J., 1998. embryology and anatomy of the rec- tum. Seminars in Surgical Oncology, 15 (2), 66–71.

higgins, J.P., et  al., 2003. Measuring inconsistency in meta-analyses. BMJ, 327 (7414), 557–560.

hong, Y.s., et  al., 2014. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally ad- vanced rectal cancer after preoperative chemoradiotherapy (aDORe): an open-label, multicentre, phase 2, randomised controlled trial. The Lancet Oncology, 15 (11), 1245–1253.

Jiao, D., et  al., 2015. Fluorouracil-based preoperative chemoradiother- apy with or without oxaliplatin for stage ii/iii rectal cancer: a 3-year follow-up study. Chinese Journal of Cancer Research , 27 (6), 588–596.

Kagiava, a., et  al., 2008. the effects of oxaliplatin, an anticancer drug, on potassium channels of the peripheral myelinated nerve fibres of the adult rat. Neurotoxicology, 29 (6), 1100–1106.

Khalid, a., et  al., 2021. hematological and biochemical parameters as di- agnostic and prognostic markers in saRs-cOV-2 infected patients of Pakistan: a retrospective comparative analysis. Hematology, 26 (1), 529–542.

lee, s., et  al., 2021. Glycemic and lipid variability for predicting compli- cations and mortality in diabetes mellitus using machine learning. BMC Endocrine Disorders, 21 (1), 94.

liberati, a., et  al., 2009. the PRisMa statement for reporting systemat- ic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Medicine, 6 (7), e1000100.

liu, t., et  al., 2021. increased serum ca125 ii, but not cea, ca19-9, aFP or ca72-4 in colon cancer compared to rectal cancer. British Journal of Biomedical Science, 78 (4), 218–220.

liu, t., et  al., 2023. a comparison of panitumumab and cetuximab in the treatment of KRas wild-type metastatic colorectal cancer: a system- atic review and meta-analysis. Immunopharmacology and Immunotoxicology, 45 (1), 1–9.

Muraro, a., et  al., 2014. anaphylaxis: guidelines from the european academy of allergy and clinical immunology. Allergy, 69 (8), 1026– 1045.

Naranjo, c.a., shear, N.h., and lanctôt, K.l., 1992. advances in the diag- nosis of adverse drug reactions. Journal of Clinical Pharmacology, 32 (10), 897–904.

National comprehensive cancer Network. 2022. NccN clinical Practice Guidelines in Oncology: Rectal cancer, version 4.2022.

NccN guidelines version 3. 2021. colon cancer. O’Neil, B.h., and Goldberg, R.M., 2008. innovations in chemotherapy for

metastatic colorectal cancer: an update of recent clinical trials. The Oncologist, 13 (10), 1074–1083.

Posul, e., et  al., 2015. Does neutrophil-to-lymphocyte ratio predict active ulcerative colitis? Wiener Klinische Wochenschrift, 127 (7-8), 262–265.

Riihimäki, M., et  al., 2016. Patterns of metastasis in colon and rectal cancer. Scientific Reports, 6, 29765.

Rogers, B.B., et  al., 2019. Oxaliplatin: detection and management of hy- persensitivity reactions. Clinical Journal of Oncology Nursing, 23 (1), 68–75.

tamas, K., et  al., 2015. Rectal and colon cancer: not just a different an- atomic site. Cancer Treatment Reviews, 41 (8), 671–679.

templeton, a.J., et  al., 2014a. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst, 106 (6), dju124.

templeton, a.J., et  al., 2014b. Prognostic role of platelet to lymphocyte ratio in solid tumors: a systematic review and meta-analysis. Cancer Epidemiology, Biomarkers & Prevention , 23 (7), 1204–1212.

Wang, X., et  al., 2017. Decreased mean platelet volume predicts poor prognosis in invasive bladder cancer. Oncotarget, 8 (40), 68115– 68122.

Xie, X., li, M., and Wu, Y., 2020. Observation on the clinical efficacy and quality of life of patients with colorectal cancer treated with XelOX and capecitabine. Heilongjiang Medicine, 33 (2), 326–327.

Xu, s.s., et  al., 2013. effect comparison and nursing of XelOX and capecit- abine in the treatment of colorectal cancer patients. Chinese Journal of Modern Nursing, 48 (32), 3985–3988.

Yaghobi Joybari, a., et  al., 2019. comparison of capecitabine (Xeloda) vs. combination of capecitabine and oxaliplatin (xelox) as neoadjuvant crt for locally advanced rectal cancer. Pathology Oncology Research, 25 (4), 1599–1605.

Zhang, D.Z., et  al., 2020. efficacy and safety of XelOX regimen versus capecitabine monotherapy in postoperative adjuvant chemotherapy for elderly patients with colorectal cancer. Chinese Journal of Clinical Pharmacology and Therapeutics, 25 (08), 926–936.

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