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Abstract

Objective

To compare the clinical efficacy and safety of nimotuzumab combined with chemotherapy versus chemotherapy alone as first-line treatment for advanced colorectal cancer (ACRC).

Method

We retrospectively enrolled patients with ACRC treated with nimotuzumab plus chemotherapy (n = 40) or chemotherapy alone (n = 44). Responses were evaluated according to the Response Evaluation Criteria in Solid Tumors and adverse events according to the Common Terminology Criteria for Adverse Events 3.0.

Results

The objective overall response rate and disease control rate were higher in the combined-treatment group (55.0% vs 36.4% and 85.0% vs 75.0%, respectively), but the differences were not significant. There was no significant difference in median progression-free survival or median survival time between the combined-treatment and chemotherapy-alone groups (9.89 vs 7.86 months and 22.32 vs 18.10 months, respectively). There was no significant difference in adverse events between the two groups.

Conclusion

Nimotuzumab combined with chemotherapy had similar efficacy and safety to chemotherapy alone in patients with ACRC. The efficacy and safety of the combined treatment should be further studied in a randomized multicenter trial with a larger number of patients with ACRC.

Keywords

Advanced colorectal cancer nimotuzumab chemotherapy combined treatment adverse events survival

Introduction

Colorectal cancer (CRC) is the third most common malignancy worldwide, with serious effects on patient’s lives.¹ CRC also has the second highest mortality rate of all types of cancer, with more than 50% of patients having distant metastases at the time of diagnosis. However, the development of combined chemotherapy protocols has improved the curative effect in patients with advanced CRC (ACRC) and extended the median survival time to 20 months.²

Fluoropyrimidine chemotherapy (parenteral 5-fluorouracil/leucovorin or oral capecitabine) in combination with oxaliplatin (FOLFOX or XELOX) or irinotecan (FOLFIRI), or capecitabine combined with oxaliplatin (CapeOx) are currently the first-line therapies for ACRC.³ The clinical application of targeted drugs has further improved the efficiency and safety of ACRC chemotherapy.^4–7 The monoclonal antibodies cetuximab and panitumumab targeting the epidermal growth factor receptor (EGFR) have been approved for the treatment of refractory metastatic CRC in patients with wild-type KRAS.^8–10 However, the high costs of cetuximab and panitumumab mean that they are not reimbursed through medical insurance in China. Nimotuzumab is a humanized IgG1 monoclonal antibody targeting the extracellular domain of EGFR. It blocks the binding of EGF and transforming growth factor-alpha to EGFR and thus inhibits tumor cell growth, angiogenesis, and apoptosis.^11–14 In contrast to other approved anti-vascular endothelial growth factor agents including cetuximab and panitumumab, nimotuzumab needs bivalent binding for stable attachment to the cellular surface, leading to higher clinical efficiency and better safety.^15–21 Nimotuzumab has therefore been approved for the treatment of advanced head and neck cancer, nasopharyngeal cancer (NPC), glioma, and esophageal cancer in 30 countries.^22–28 In China, nimotuzumab was approved as a drug in combination with radiotherapy for the treatment of NPC in 2008 and was recommended by the Chinese edition of the National Comprehensive Cancer Network (NCCN) guidelines as a targeted therapy for NPC in 2009.¹¹

Nimotuzumab is cheaper than cetuximab or panitumumab, and a series of clinical trials has reinforced its safety and efficacy for treating NPC within the Chinese population.^29–31 Owing to its promising efficacy and relatively low price, the China Food and Drug Administration has approved several clinical trials in patients with different tumors of epithelial origin. However, information on the combination of first-line treatment with nimotuzumab and chemotherapy drugs for ACRC is currently lacking. We therefore compared the clinical efficacy and safety of nimotuzumab combined with chemotherapy and chemotherapy alone in Chinese patients with ACRC.

Materials and methods

Patients

We retrospectively enrolled patients treated in the Department of Abdominal Oncology of the Tumor Hospital Affiliated to Guizhou Medical University between January 2014 and June 2017. The patients’ clinical data were recorded retrospectively. The study was approved by the Institutional Ethics Committee of Tumor Hospital Affiliated to Guizhou Medical University and signed informed consent was obtained from each participant.

The inclusion criteria were as follows: 1) age 18 to 75 years with basically normal cardiopulmonary function; 2) diagnosis of rectal or colon adenocarcinoma; 3) first treatment for ACRC without radical surgery, ACRC with recurrence and metastasis after radical resection, postoperative adjuvant chemotherapy for metastatic colorectal cancer; 4) at least one double-diameter-measurable lesion; 5) good physical condition with an Eastern Cooperative Oncology Group score of 0 to 1 or Karnofsky Performance Scale (KPS) score of 70 to 100; 6) routine blood and biochemical examinations met certain criteria (hemoglobin ≥90 g/L, absolute neutrophil count ≥1.5 × 10⁹/L, platelets ≥100 × 10⁹/L, alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≤2.5 times upper limit of normal [ALT and AST ≤5 times upper limit of normal for patients with hepatic metastases], alkaline phosphatase [ALP] ≤2.5 times upper limit [ALP ≤5 times upper limit of normal for patients with hepatic or bone metastases], serum total bilirubin <1.5 times upper limit of normal, serum creatinine <1.5 times upper limit of normal, serum albumin ≥30 g/L); 7) non-active chronic hepatitis B; 8) received nimotuzumab plus FOLFOX/FOLFIRI chemotherapy or FOLFOX/FOLFIRI chemotherapy alone, and completed at least two cycles of chemotherapy and eight consecutive nimotuzumab treatments; 9) no previous treatment with EGFR monoclonal antibodies; and 10) wild-type RAS genes detected in pathological samples of primary tumor or metastasis. DNA was isolated using a TIANamp Genomic DNA Kit (Tiangen Co., Ltd., Beijing, China) and KRAS mutation status was detected by real-time polymerase chain reaction. KRAS mutation was accepted if the Ct value was <38 and the Ct difference between KRAS and RNaseP (i.e., the internal positive control) was <8, otherwise no KRAS mutation was detected.

Patients who met the following criteria were excluded: 1) malignancies other than CRC in the past 5 years; 2) RAS mutations or no RAS gene detection performed; 3) fewer than two chemotherapy cycles or eight nimotuzumab treatments; and 4) concomitant use of other anticancer drugs.

Treatment schedule

Nimotuzumab (Tai Xin Sheng®, Baitai Biological Pharmaceutical Co., Ltd., Beijing, China) was administered before the day of chemotherapy with the first dose administered as an intravenous infusion of 400 mg for 2 hours. Subsequent doses were administered by intravenous drip once a week over a period of >1 hour, for a total of eight treatments. No pretreatment was administered before nimotuzumab and no other drugs were given within 1 hour after infusion, except for normal saline.

Patients with primary metastatic CRC or recurrence and metastasis following radical surgery for ACRC (no adjuvant chemotherapy was performed) were administered FOLFOX and patients with metastatic CRC after radical surgery with adjuvant chemotherapy received FOLFIRI.

All patients received serotonin receptor antagonists to prevent nausea and vomiting. Patients receiving chemotherapy containing irinotecan also received atropine 0.25 mg injected subcutaneously 30 minutes before chemotherapy. Routine blood, liver, and kidney function tests were performed once a week during chemotherapy. Granulocyte colony-stimulating factor was given in the event of grade 2 leukopenia and neutropenia. Treatments to protect the gastric mucosa and improve liver and kidney function were administered if necessary.

Evaluation of treatment response

Treatment efficacy was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) was defined as disappearance of all target lesions and short diameter of all pathological lymph nodes (including target nodes and non-target nodes) reduced to <10 mm. Partial response (PR) was defined as total diameter of the target lesion decreased by at least 30% compared with baseline. Progressive disease (PD) was defined as the minimum value of the sum of the diameters of all target lesions measured during the whole research process, with a relative increase of at least 20%; if the baseline measurement value was the minimum, the baseline value was taken as the reference. In addition, the absolute diameter must be increased by at least 5 mm, and the presence of one or more new lesions was also considered as PD. Stable disease (SD) was defined as reduction of the target lesion less than PR but an increase less than the PD criteria. The objective overall response rate (ORR) was determined as CR + PR and the disease control rate (DCR) was CR+PR+ SD. Progression-free survival (PFS) was defined as the time from the beginning of treatment to the onset of tumor progression or death, and overall survival (OS) was defined as the interval between the start of treatment and death or last follow-up. Patients were followed-up at the end of treatment and then every 3 months.

Evaluation of adverse events

Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) 3.0. Adverse reactions were evaluated after each cycle of chemotherapy. Routine blood, liver, and kidney functions and electrolytes were reviewed before, during, and after each chemotherapy cycle. In the event of grade 4 myelosuppression or grade 3 diarrhea, oxaliplatin, irinotecan, and fluorouracil were reduced by 25% to 30% in the next cycle of treatment. If any grade 3 or worse adverse reactions remained after two dose reductions, the chemotherapy was stopped immediately.

Statistical analysis

All data were analyzed using SPSS for Windows, Version 17.0 (SPSS Inc., Chicago, IL, USA). Comparisons were carried out using χ² or Fisher’s exact tests. Survival probabilities were constructed using Kaplan–Meier survival estimates and compared by the log-rank test.

Results

Patient characteristics

Eighty-four well-documented patients with ACRC were included in this study, including 40 in the combined-treatment group and 44 in the chemotherapy-alone group. The patient characteristics are shown in Table 1. There were no significant differences between the combined-treatment and chemotherapy-alone groups with regard to age, sex, initial KPS before treatment, primary tumor site, pathologic pattern, metastatic site, chemotherapy regimen, previous surgery, and chemotherapy cycles (Table 1).

Table 1.

General clinical features of patients with advanced colorectal cancer

	Combined-treatment group (n=40)	%	Chemotherapy-alone group (n=44)	%	P value
Sex					0.749
Male	25	62.5	26	59.1
Female	15	37.5	18	40.9
Age, years					0.677
≤55	20	50	24	54.5
>55	20	50	20	45.5
Initial KPS score before treatment					0.666
70 points	11	27.5	14	31.8
≥80 points	29	72.5	30	68.2
Primary tumor site					0.807
Rectum	23	57.5	28	63.6
Colon	13	32.5	11	25.0
Multiple primary colorectal	4	10.0	5	11.4
Pathologic pattern					0.811
Adenocarcinoma (unknown)	13	32.5	17	38.6
High- or medium- differentiated adenocarcinoma	16	40.0	15	34.1
Poorly differentiated adenocarcinoma	11	27.5	12	27.3
Metastatic site					0.998
Liver	19	47.5	22	50.0
Lung	17	42.5	18	40.9
Peritoneum	7	17.5	8	18.2
Other	30	75.0	34	77.3
Number of metastatic organs					0.565
Single	17	42.5	16	36.4
≥2	23	57.5	28	63.6
Chemotherapy regimen					0.806
FOLFOX4	13	32.5	16	38.6
mFOLFOX6	6	15.0	8	15.9
FOLFIRI	21	52.5	20	45.5
Previous surgery					0.280
Yes	29	72.5	27	61.4
No	11	27.5	17	38.6
Chemotherapy cycles					0.641
2–3	10	25.0	13	29.5
4–6	30	75.0	31	70.5

KPS, Karnofsky Performance Scale

Condition of treatment completion

All patients completed the follow-up and treatment. All 40 patients in the combined-treatment group received eight doses of nimotuzumab, including 10 who received two to three cycles of treatment and 30 who received four to six cycles of treatment. Among the 44 patients in the chemotherapy-alone group, 13 received two to three cycles and 31 received four to six cycles of treatment. There was no significant difference in treatment completion between the two groups (Table 2).

Table 2.

Treatment completion in patients treated with nimotuzumab plus chemotherapy or chemotherapy alone

Group	2–3 Cycles			4–6 Cycles
Group	FOLFIRI	FOLFOX4	mFOLFOX6	FOLFIRI	FOLFOX4	mFOLFOX6
Combined treatment (n=40)	4	4	2	17	9	4
Chemotherapy alone (n=44)	6	3	4	14	13	4
P value			0.756			0.828

Treatment response evaluations

No patient in either group achieved CR. However, 22 patients in the combined-treatment group and 16 in the chemotherapy-alone group achieved PR. Compared with the combined-treatment group, a greater number of patients in the chemotherapy-alone group tended to have SD and PD; however, these differences were not statistically significant. There were no significant differences in ORR or DCR between the two groups (Table 3).

Table 3.

Curative effects of nimotuzumab plus chemotherapy and chemotherapy alone

Group	Number of cases	CR	PR	SD	PD	RR	DCR
Combined treatment	40	0	22	12	6	55.0%	85.0%
Chemotherapy alone	44	0	16	17	11	36.4%	75.0%
P value			0.293	0.561	0.352	0.087	0.255

CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective overall response rate; DCR, disease control rate

Survival analysis

The final follow-up was on 31 December 2017. All 84 patients (100%) fulfilled the follow-up criteria, and 71 patients (84.5%) died during the follow-up period. The median PFS rates were 9.89 months (95% confidence interval (CI): 5.733–14.407) and 7.86 months (95% CI: 3.446–12.274) in the combined-treatment and chemotherapy-alone groups, respectively. However, the difference between the groups was not significant (Figure 1).

Figure 1.

Kaplan–Meier curves of progression-free and overall survival in patients treated with combined treatment (blue) and chemotherapy alone (green)

The 1-, 2-, and 3-year survival rates were 80.0%, 39.1%, and 19.9% in the combined-treatment group and 72.7%, 27.5%, and 12.2% in the chemotherapy-alone group, respectively. The median OS was 22.32 months (95% CI: 18.363–26.257) in the combined-treatment group and 18.10 months (95% CI: 13.322–22.878) in the chemotherapy-alone group. There was no significant difference in OS between the groups (Figure 1).

Adverse events

The adverse events in this study included hematological and non-hematological toxicities (Table 4). The most common hematological toxicities included neutropenia and leukopenia. The incidence rates of grades 1 and 2 hematological toxicity in the combined-treatment and chemotherapy-alone groups were 65% and 70.5%, respectively, and the rates of grades 3 and 4 hematological toxicity were 27.5% and 31.8%, respectively. Two patients had grades 3 and 4 nausea and vomiting; the non-hematological toxicities (i.e., nausea, vomiting, diarrhea, abnormal liver function, abnormal renal function, peripheral neurotoxicity, and hand-foot syndrome) observed in all other patients were grades 1 and 2 adverse reactions. There were no significant differences between the two groups in terms of non-hematological toxicities. The main adverse reactions related to nimotuzumab were fever in one case and scattered skin rashes in three cases. The fever resolved and the skin rashes disappeared after symptomatic treatment.

Table 4.

Toxic effects of nimotuzumab plus chemotherapy and chemotherapy alone

Toxic side effect	Grade 1–2			Grade 3–4
Toxic side effect	Combined treatment n (%)	Chemotherapy alone n (%)	P value	Combined treatment n (%)	Chemotherapy alone n (%)	P value
Hematological toxicity
Leukocyte decrease	24 (242.0)	28 (282.6)	0.732	7 (72.5)	10 (102.7)	0.551
Granulocytopenia	21 (212.5)	22 (222.0)	0.819	3 (32.5)	5 (52.4)	0.818
Decreased hemoglobin	17 (172.5)	18 (182.9)	0.883	6 (62.0)	4 (42.0)	0.619
Thrombocytopenia	16 (162.0)	16 (162.4)	0.732	3 (32.5)	4 (42.0)	0.808
Non-hematological toxicity
Nausea/vomiting	31 (312.5)	33 (332)	0.788	1 (12.5)	1 (12.3)	0.947
Diarrhea	6 (62)	7 (72.9)	0.908	0 (02)	0 (02)	–
Liver dysfunction	24 (242.0)	28 (282.6)	0.732	0 (02)	0 (02)	–
Kidney dysfunction	4 (42.0)	5 (52.4)	0.856	0 (02)	0 (02)	–
Peripheral neurotoxicity	1 (12.5)	2 (22.5)	0.626	0 (02)	0 (02)	–
Hand-foot syndrome	1 (12.5)	1 (12.3)	0.947	0 (02)	0 (02)	–

Discussion

The EGFR signaling pathway has become an important target for drug therapy in patients with CRC. Drugs targeting the EGFR pathway currently include cetuximab and panitumumab, and studies of first-, second-, and third-line treatment (CRYSTAL,³² EPIC,³³ CO.17³⁴) have shown that cetuximab can effectively improve treatment efficiency and PFS in patients with ACRC. A similar conclusion was obtained in the PRIME study using panitumumab.³⁵ Only cetuximab is currently listed in China. However, acne-like rash and diarrhea have been reported to occur in 80% to 90% of patients taking cetuximab.^36–38 The toxic side effects are caused by the high affinity of cetuximab for EGFR leading to EGFR antagonism. Allergic reactions are also common adverse effects of monoclonal antibody targeted drugs, with an overall incidence of 19% to 23% for cetuximab, but only 2% to 3% for grade 3 to 4 allergic reactions.³⁹ However, given that cetuximab is not covered by medical insurance in China, its high price makes it inaccessible to most patients with ACRC in China.

Nimotuzumab is a novel EGFR monoclonal antibody. Numerous clinical studies have confirmed that nimotuzumab combined with chemotherapy significantly improves the disease control rate and survival benefit in patients with solid tumors.^22,28,40 Nimotuzumab has significantly lower affinity for the EGFR than panitumumab and cetuximab (dissociation constants: 10⁻⁹, 3.9 × 10⁻¹⁰, and 5 × 10⁻¹¹ mol/L for nicodoxidane, cetuximab, and panidane, respectively), meaning that it binds monovalently to tissues with normal EGFR expression and thus dissociates easily, compared with molecules that bind covalently to tumor tissues with high EGFR expression and are thus more difficult to dissociate. Nimotuzumab may thus have similar anti-tumor efficacy to cetuximab, but milder side effects in clinical practice.⁴¹ Preliminary studies have shown that radiotherapy combined with 200 mg nimotuzumab was safe and effective for the treatment of head and neck squamous cell carcinoma and pancreatic cancer. The recommended dose for subsequent studies of nimotuzumab is 200 to 400 mg. However, related clinical research in the context of CRC is currently lacking. In this study, we therefore retrospectively analyzed the efficacy and safety of nimotuzumab combined with chemotherapy in patients with ACRC.

All patients enrolled in the current study had ACRC with wild-type KRAS, because EGFR monoclonal antibodies are only used in patients with ACRC who have wild-type KRAS and NRAS alleles. Patients were treated with 400 mg nimotuzumab, which was the maximum dose in a phase I clinical trial.³¹ We found no significant differences in ORR, DCR, PFS, and median survival between the two groups, suggesting similar efficacies of chemotherapy plus nimotuzumab and chemotherapy alone for ACRC. Regarding the safety profiles, there were no significant differences between the two groups and no new adverse reactions. In the future, larger sample sizes are needed to confirm our findings.

In conclusion, the current study suggested that the addition of nimotuzumab had no additional effect on the efficacy and safety of chemotherapy in patients with ACRC. Further studies with larger sample sizes are needed to confirm the efficacy and safety of combined treatment for ACRC.

Footnotes

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

This clinical study was funded by the joint fund of Guizhou Provincial Department of Science and Technology in 2014 (LH[2014]7136).

ORCID iD

Wenling Wang

References

Gandon

Screening for colorectal cancer: the role of CT colonography.

Diagn Interv Imaging 2014; 95: 467–474.

Colucci

Gebbia

Paoletti

et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 2005; 23: 4866–4875.

Berlin

Bendell

Hart

et al. A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer. Clin Cancer Res 2013; 19: 258–267.

Sastre

Gravalos

Rivera

et al. First-line cetuximab plus capecitabine in elderly patients with advanced colorectal cancer: clinical outcome and subgroup analysis according to KRAS status from a Spanish TTD Group Study. Oncologist 2012; 17: 339–345.

Asmis

Powell

Karapetis

et al. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)–results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol 2011; 22: 118–126.

Rodriguez

Viudez

Ponz-Sarvise

et al. Improving disease control in advanced colorectal cancer: panitumumab and cetuximab. Crit Rev Oncol Hematol 2010; 74: 193–202.

Maughan

Adams

Smith

et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011; 377: 2103–2114.

Petrelli

Borgonovo

Barni

The predictive role of skin rash with cetuximab and panitumumab in colorectal cancer patients: a systematic review and meta-analysis of published trials.

Target Oncol 2013; 8: 173–181.

Douillard

Siena

Cassidy

et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010; 28: 4697–4705.

10.

Raoul

Van Laethem

Peeters

et al. Cetuximab in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) in the initial treatment of metastatic colorectal cancer: a multicentre two-part phase I/II study. BMC Cancer 2009; 9: 112.

11.

Ramos-Suzarte

Bai

et al. Treatment outcome of nimotuzumab plus chemotherapy in advanced cancer patients: a single institute experience. Oncotarget 2016; 7: 33391–33407.

12.

Wang

Gao

Wang

et al. Antiproliferative effects of selective cyclooxygenase-2 inhibitor modulated by nimotuzumab in estrogen-dependent breast cancer cells. Tumour Biol 2012; 33: 957–966.

13.

Akashi

Okamoto

Iwasa

et al. Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status. Br J Cancer 2008; 98: 749–755.

14.

Crombet-Ramos

Rak

Perez

et al. Antiproliferative, antiangiogenic and proapoptotic activity of h-R3: a humanized anti-EGFR antibody. Int J Cancer 2002; 101: 567–575.

15.

Talavera

Friemann

Gomez-Puerta

et al. Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation. Cancer Res 2009; 69: 5851–5859.

16.

Berger

Krengel

Stang

et al. Nimotuzumab and cetuximab block ligand-independent EGF receptor signaling efficiently at different concentrations. J Immunother 2011; 34: 550–555.

17.

Garrido

Tikhomirov

Rabasa

et al. Bivalent binding by intermediate affinity of nimotuzumab: a contribution to explain antibody clinical profile. Cancer Biol Ther 2011; 11: 373–382.

18.

Diaz Miqueli

Blanco

Garcia

et al. Biological activity in vitro of anti-epidermal growth factor receptor monoclonal antibodies with different affinities. Hybridoma 2007; 26: 423–431.

19.

Crombet

Osorio

Cruz

et al. Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. J Clin Oncol 2004; 22: 1646–1654.

20.

Allan

DG.

Nimotuzumab: evidence of clinical benefit without rash.

Oncologist 2005; 10: 760–761.

21.

Boland

Bebb

Nimotuzumab: a novel anti-EGFR monoclonal antibody that retains anti-EGFR activity while minimizing skin toxicity.

Expert Opin Biol Ther 2009; 9: 1199–1206.

22.

Reddy

Lokesh

Vidyasagar

et al. Nimotuzumab provides survival benefit to patients with inoperable advanced squamous cell carcinoma of the head and neck: a randomized, open-label, phase IIb, 5-year study in Indian patients. Oral Oncol 2014; 50: 498–505.

23.

Rodriguez

Rivero

del Castillo Bahi

et al. Nimotuzumab plus radiotherapy for unresectable squamous-cell carcinoma of the head and neck. Cancer Biol Ther 2010; 9: 343–349.

24.

Basavaraj

Sierra

Shivu

et al. Nimotuzumab with chemoradiation confers a survival advantage in treatment-naive head and neck tumors over expressing EGFR. Cancer Biol Ther 2010; 10: 673–681.

25.

Huang

Gao

et al. [Multi-center phase II clinical trial of humanized anti-epidermal factor receptor monoclonal antibody h-R3 combined with radiotherapy for locoregionally advanced nasopharyngeal carcinoma]. Zhonghua Zhong Liu Za Zhi 2007; 29: 197–201.

26.

Chong

Toh

et al. Combined treatment of Nimotuzumab and rapamycin is effective against temozolomide-resistant human gliomas regardless of the EGFR mutation status. BMC Cancer 2015; 15: 255.

27.

Bode

Massimino

Bach

et al. Nimotuzumab treatment of malignant gliomas. Expert Opin Biol Ther 2012; 12: 1649–1659.

28.

Ramos-Suzarte

Lorenzo-Luaces

Lazo

et al. Treatment of malignant, non-resectable, epithelial origin esophageal tumours with the humanized anti-epidermal growth factor antibody nimotuzumab combined with radiation therapy and chemotherapy. Cancer Biol Ther 2012; 13: 600–605.

29.

Yan

Jiang

Yang

et al. Radiotherapy for nasopharyngeal carcinoma and combined capecitabine and nimotuzumab treatment for lung metastases in a liver transplantation recipient: a case experience of sustained complete response. Cancer Biother Radiopharm 2012; 27: 519–523.

30.

Huang

Zou

Qian

et al. Intensity-modulated radiotherapy plus nimotuzumab with or without concurrent chemotherapy for patients with locally advanced nasopharyngeal carcinoma. Onco Targets Ther 2017; 10: 5835–5841.

31.

Zhao

et al. A phase I dose escalation study of Nimotuzumab in combination with concurrent chemoradiation for patients with locally advanced squamous cell carcinoma of esophagus. Invest New Drugs 2012; 30: 1585–1590.

32.

Ciardiello

Lenz

Kohne

et al. Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/without cetuximab. J Clin Oncol 2014; 32: 3506–3506.

33.

Sobrero

Maurel

Fehrenbacher

et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 2311–2319.

34.

Jonker

O’Callaghan

Karapetis

et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007; 357: 2040–2048.

35.

Douillard

Siena

Cassidy

et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 2014; 25: 1346–1355.

36.

Sommeijer

Karapetis

Zalcberg

et al. The relationship between rash, tumour KRAS mutation status and clinical and quality of life outcomes in patients with advanced colorectal cancer treated with cetuximab in the NCIC CTG/AGITG CO.17. Acta Oncol 2014; 53: 877–884.

37.

Cutsem

Nowacki

Lang

et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial. J Clin Oncol 2007; 25: 4000–4000.

38.

Peeters

Price

Cervantes

et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010; 28: 4706–4713.

39.

Schwartzberg

Stepanski

Fortner

et al. Retrospective chart review of severe infusion reactions with rituximab, cetuximab, and bevacizumab in community oncology practices: assessment of clinical consequences. Support Care Cancer 2008; 16: 393–398.

40.

Liu

Z G

Zhao

Tang

et al. Nimotuzumab combined with concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma: a retrospective analysis. Oncotarget 2016; 7: 24429.

41.

Tikhomirov

Hidalgo

Yang

et al. Bivalent binding properties of epidermal growth factor receptor targeted monoclonal antibodies: factors contributing to differences in observed clinical profiles. Cancer Biol Ther 2008; 14: A36–A36.

Clinical efficacy and safety of nimotuzumab plus chemotherapy in patients with advanced colorectal cancer: a retrospective analysis

Abstract

Objective

Method

Results

Conclusion

Keywords

Introduction

Materials and methods

Patients

Treatment schedule

Evaluation of treatment response

Evaluation of adverse events

Statistical analysis

Results

Patient characteristics

Condition of treatment completion

Treatment response evaluations

Survival analysis

Adverse events

Discussion

Footnotes

Declaration of conflicting interest

Funding

ORCID iD

References