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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 2  |  Page : 312-316

Nimotuzumab plus chemotherapy with docetaxel, cisplatin, 5-fluorouracil for locally advanced head and neck squamous cell carcinoma: A clinical study


1 Department of Oromaxillofacial Head and Neck Surgery, College of Medicine, Affiliated Xuzhou Hospital, Southeast University, Xuzhou, Jiangsu 221000; Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing 100081, China
2 Department of Oromaxillofacial Head and Neck Surgery, College of Medicine, Affiliated Xuzhou Hospital, Southeast University, Xuzhou, Jiangsu 221000, China

Date of Web Publication1-Apr-2019

Correspondence Address:
Dr. Jian Meng
Department of Oromaxillofacial Head and Neck Surgery, College of Medicine, Affiliated Xuzhou Hospital, Southeast University, Xuzhou, Jiangsu 221000
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_889_17

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 > Abstract 


Background: A clinical study was conducted to determine the efficacy of nimotuzumab combined with docetaxel, cisplatin, and 5-fluorouracil (TPF) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) after surgery and conformal radiotherapy.
Methods: Thirty-one HNSCC patients received three courses of chemotherapy every 21 days, at a dose of 75 mg/m2 of docetaxel and cisplatin on day 1 and 750 mg/m2 of 5-fluorouracil on days 1–5 followed by 200 mg/m2/week of nimotuzumab on week 1–2 (day 6–21).
Results: After sequential therapy, complete and partial responses were observed in 10 (32.3%) and 17 (54.8%) patients, respectively. The overall response rate was 87.1%. A progression-free survival of 71.2% (95% confidence interval [CI] 51.6%–93.7%) and an overall survival of 78.3% (95% CI 58.9%–89.5%) were achieved at 2nd year. The most common Grade 3–4 toxicities during the complete treatment were lymphopenia (25.8%), neutropenia (22.6%), anemia (12.9%), and diarrhea (16%). In addition, no rash and treatment-related death occurred during this study.
Conclusions: Nimotuzumab in combination with TPF has been well tolerated as a treatment program for locally advanced HNSCC.

Keywords: Chemotherapy, epidermal growth factor receptor, head and neck squamous cell carcinoma


How to cite this article:
Wang X, Gu J, Shao C, Han K, Meng J. Nimotuzumab plus chemotherapy with docetaxel, cisplatin, 5-fluorouracil for locally advanced head and neck squamous cell carcinoma: A clinical study. J Can Res Ther 2019;15:312-6

How to cite this URL:
Wang X, Gu J, Shao C, Han K, Meng J. Nimotuzumab plus chemotherapy with docetaxel, cisplatin, 5-fluorouracil for locally advanced head and neck squamous cell carcinoma: A clinical study. J Can Res Ther [serial online] 2019 [cited 2019 Jul 18];15:312-6. Available from: http://www.cancerjournal.net/text.asp?2019/15/2/312/255108




 > Introduction Top


Head and neck squamous cell carcinoma (HNSCC) has been one of the most common malignancies worldwide, which accounted for >90% of all cases of head and neck cancer.[1],[2] Surgery has been the principal treatment for early-stage HNSCC.[3] However, the long-term survival of patients with advanced HNSCC remained poor.[4],[5],[6]

Concomitant platinum-based chemotherapy has played an important role in the treatment of advanced HNSCC patients. It showed that tumor regression was correlated with improved outcomes in patients.[7],[8] In a randomized phase II study, concurrent chemoradiotherapy provided an improved survival rate as opposed to simple radiotherapy.[9] However, the benefit of chemotherapy with platinum and 5-fluorouracil was not significant, and in fact, it led to additional toxicities.[10]

More recently, the efficacy of platinum-based concomitant chemotherapy has been improved by the addition of nimotuzumab, a humanized monoclonal IgG1 antibody that specifically binds to the extracellular domain of the epidermal growth factor receptor (EGFR).[11] EGFR-targeted monoclonal antibody is the first humanized monoclonal antibody approved for cancer therapy in China. Ninety percent of HNSCC patients showed high expression of EGFR, which was crucial for proliferation, metastasis, and apoptosis inhibition.[12] After adding nimotuzumab to chemotherapy, the efficacy could be improved over single chemotherapy in HNSCC.[13],[14] A multicenter study was conducted in Austria, and it aimed to evaluate the effectiveness and morbidity of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by radiotherapy in 49 patients with locally advanced HNSCC. The complete remission (CR)/ partial remission (PR) rate in the 1st and 2nd year of therapy was 61% and 51%, respectively.[9]

However, there were still several limitations in nimotuzumab for HNSCC treatment. Information regarding the concomitant administration of nimotuzumab and TPF has been limited although it may be a potential second-line or higher therapy for patients with advanced HNSCC. In this study, the feasibility and safety of combining nimotuzumab administration with the TPF regimen were determined. The primary endpoints of this study were the response rate, survival benefits, and adverse events.


 > Methods Top


Patients and data collection

From September 2009 to July 2013, we recruited 31 patients aged ≥18 years with histologically proved locally advanced HNSCC. The patients were classified according to the TNM staging criteria established by the International Union Against Cancer. These patients had received surgery followed by radiotherapy and were clinically in remission after the last treatment. All patients experienced a tumor recurrence or metastasis. The main inclusion criteria were Karnofsky performance status of >70, expected survival time of ≥6 months, white blood cell count of ≥3 × 109/L, platelet count of ≥100 × 109/L, and hemoglobin level of at least 90 g/L. Signed informed consent form was obtained before their enrollment in the study. The entire study protocol was approved by the ethics committee of our hospital (20090720).

Scheme of treatment

On day 1, nimotuzumab (loading dose: 200 mg/m2) was intravenously administered 1 h before chemotherapy once a week for six successive courses. Before chemotherapy, dexamethasone (8 mg) was administered every morning for 3 consecutive days. Docetaxel and cisplatin (dose: each 75 mg/m2) were intravenously administered on day 1 for 1 h followed by continuous infusion of 5-fluorouracil (dose: 750 mg/m2) from days 1–5. This regimen was periodic (every 21 days) and a total of three cycles were administered.

Evaluation of treatment

To explore alterations in therapeutic efficacy, computed tomography or magnetic resonance imaging was performed at the end of the trial at 3-month intervals after the last treatment. The response was evaluated based on the RECIST.[15] Adverse events were described in accordance with the CTC v3.0 guidelines.[16] During chemotherapy, laboratory tests were performed at 15-day interval.

Statistical analysis

Progression-free survival (PFS) was defined as the time from the start of the treatment until disease progression or death. Overall survival (OS) was calculated from the data of first chemotherapy administration to death due to any cause. Data were analyzed with the statistical software SPSS 17.0 (SPSS Inc., Chicago, IL, USA). P < 0.05 was considered statistically significant. Univariate and multivariate analysis were performed to assess the significant prognostic factors with Cox regression models. Survival curves were plotted with Kaplan–Meier method, and survival rates were estimated and calculated with a 95% confidence interval (CI).


 > Results Top


Patient characteristics

A total of 31 patients, including 25 males and six females, were enrolled in this trial. No patient dropped out during the study. The patient characteristics are summarized in [Table 1]. The age of patients ranged from 28 to 88 years (median 59.3 years). Eight patients (25.8%) were evaluated as tumor Stage III and 23 (74.2%) as Stage IV. The common tumor sites included the floor of mouth, tongue, gum, mandible, buccal mucosa, tonsil, base of the tongue, and larynx. All the patients had histopathological-proved locally advanced carcinoma. Of 31 patients, 21 patients experienced a long history of smoking (74.2%).
Table 1: Baseline and demographic data of patients

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Clinical response

After conducting nimotuzumab-TPF combined chemotherapy in 31 patients, we observed complete response (CR) in 10 patients, partial response (PR) in 17 patients, and stable disease in four patients. No incidence of progressive disease (PD) was observed. The overall response rate was 87.1%, including both CR and PR. The mean follow-up duration in our study was 30.6 months. The 2-year PFS and OS rates were 71.2% (95% CI: 51.6%–93.7%) and 78.3% (95% CI: 58.9%–89.5%), respectively [Figure 1].
Figure 1: Overall survival and progression-free survival

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Prognostic factors

Some potential prognostic factors were evaluated including age, sex, tumor stage, smoking habits, and tumor response at the end of treatment. Univariate analysis showed that tumor stage and smoking habits were significant prognostic factors for OS, while tumor stage and tumor response at the end of treatment were significant prognostic factors for PFS [Table 2]. Multivariate analysis indicated poorer OS and PFS for Stage IV patients, as well as smoking habits for OS and tumor response for PFS (P < 0.05).
Table 2: Univariate analysis of prognostic factors on overall survival and progression-free survival in patients

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Adverse events

The details of toxicities in patients are provided in [Table 3]. Treatment was generally well-tolerated throughout the study. Myelosuppression was one of the most common toxicities after nimotuzumab-TPF combined chemotherapy, but no Grade 4 adverse events were observed. The most common Grade 3 adverse events during chemotherapy included lymphopenia (25.8%), neutropenia (22.6%), anemia (12.9%), and diarrhea (16%). Importantly, no rash and treatment-related death occurred during this study.
Table 3: Acute toxicity according to CTC criteria

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 > Discussion Top


Several systemic treatment approaches for patients with advanced HNSCC have recently become available, of which the standard therapy has been platinum-based chemotherapy.[17] A retrospective study of advanced HNSCC patients treated with TPF followed by simultaneous chemoradiotherapy was conducted in Korea. The overall response rate was 95.4%; OS rate at 1st and 2nd year was 93.6% and 88.7%, respectively.[18] In another single-institution study, 32 elderly patients who received chemoradiation showed locoregional control, and their OS rate at 1st and 2nd year was 71.6% and 88.9%, respectively. The toxicities resulted from therapy were moderate.[19] In the last 30 years, despite continued advances in therapeutic strategies, the incidences of adverse reactions have not been reduced, leading to less than optimal survival and poor functional outcomes.[20]

The focus of HNSCC therapy has shifted to targeted therapy, particularly the EGFR or vascular endothelial growth factor receptor pathway. Targeted therapy can potentially reduce tumor cell proliferation and tumor progression, as well as increasing chemosensitivity. The curative effects of cetuximab were enhanced when combined with platinum-based chemotherapy and 5-fluorouracil for treating recurrent and metastatic cancer. However, some clinical studies had to be stopped early owing to significant cetuximab-related toxicity.[21],[22]

Nimotuzumab is another recombinant humanized anti-EGFR monoclonal antibody, which differs from cetuximab in the following aspects. First, it exhibits a reduced binding affinity for EGFR compared to that of other anti-EGFR antibodies. Second, at the same dose, nimotuzumab has a longer half-life than cetuximab. Finally, nimotuzumab rarely leads to severe skin toxicities. Our preliminary studies demonstrated that nimotuzumab did not cause any new toxicities in patients with advanced oral carcinoma.[7] This observation was consistent with another report that showed a trend toward improved life quality after delayed effects of nimotuzumab could be optimally detected with statistical analysis.[23] From the perspective of safety, it would be beneficial to further explore the clinical applications of nimotuzumab. The results obtained in this study should be further validated with large-scale clinical trials.

We investigated the potential clinical merits of concurrent administration of nimotuzumab and TPF chemotherapy. Our present data revealed an overall response rate of 87.1% for included patients. Reddy et al. evaluated the clinical utility of nimotuzumab concurrent with radiotherapy and chemoradiotherapy in HNSCC, and their data agreed with that of ours. According to the report, the overall response rate was the highest at 6 months after treating with nimotuzumab plus chemoradiotherapy. The risk of death was lower than that of with chemoradiotherapy and nimotuzumab plus radiotherapy.[24] Patients in our study showed a survival advantage, with the median PFS and OS of 71.2% (95% CI 51.6%–93.7%) and 78.3% (95% CI 58.9%–89.5%), respectively. These results were comparable with the efficacy of cetuximab plus chemotherapy, suggesting that nimotuzumab could be an effective drug in combination chemotherapy for patients with locally advanced HNSCC.[25]

Our toxicity profile was similar to that of in previous reports: Nimotuzumab did not cause any unexpected adverse events and no treatment-related death occurred during this trail. In another study on the squamous cell carcinoma of head and neck, a small population size of 17 patients were included and administered with nimotuzumab plus concurrent chemotherapy; no Grade 3–4 adverse event was reported.[26] For instance, the incidence of skin rash was low, which was a specific adverse effect of cetuximab.[22],[27] Conclusively, our results suggested nimotuzumab plus TPF an alternative regimen, not only guaranteeing efficacy but also reducing side effects. Owing to the small sample size and shortage of long-term observation, this regimen could only provide a potential remedy for some specific patients.


 > Conclusions Top


Our findings provided evidence that nimotuzumab combined with the TPF regimen has been safe and feasible for locally advanced HNSCC. Randomized controlled studies with a larger sample size and extended follow-up data will be necessary to confirm the benefits of the scheme described in the current study.

Financial support and sponsorship

This work has been financially supported by Jiangsu Province Medical Youth Talent Project (QNRC2016390) and Xuzhou Medical Creative Team Program (XWCX201604).

Conflicts of interest

There are no conflicts of interest.



 
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