Short 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 |
||||
|---|---|---|---|---|---|---|
| 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 |
||||
|---|---|---|---|---|---|---|
| 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.
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 https://orcid.org/0000-0002-1997-3959
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