|Year : 2019 | Volume
| 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
Xing Wang1, Jianmin Gu2, Cuiling Shao2, Kun Han2, Jian Meng2
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 Publication||1-Apr-2019|
Dr. Jian Meng
Department of Oromaxillofacial Head and Neck Surgery, College of Medicine, Affiliated Xuzhou Hospital, Southeast University, Xuzhou, Jiangsu 221000
Source of Support: None, Conflict of Interest: None
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 Apr 21];15:312-6. Available from: http://www.cancerjournal.net/text.asp?2019/15/2/312/255108
| > Introduction|| |
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., Surgery has been the principal treatment for early-stage HNSCC. However, the long-term survival of patients with advanced HNSCC remained poor.,,
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., In a randomized phase II study, concurrent chemoradiotherapy provided an improved survival rate as opposed to simple radiotherapy. However, the benefit of chemotherapy with platinum and 5-fluorouracil was not significant, and in fact, it led to additional toxicities.
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). 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. After adding nimotuzumab to chemotherapy, the efficacy could be improved over single chemotherapy in HNSCC., 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.
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|| |
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. Adverse events were described in accordance with the CTC v3.0 guidelines. During chemotherapy, laboratory tests were performed at 15-day interval.
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|| |
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%).
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].
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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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.
| > Discussion|| |
Several systemic treatment approaches for patients with advanced HNSCC have recently become available, of which the standard therapy has been platinum-based chemotherapy. 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. 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. 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.
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.,
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. 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. 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. 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.
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. For instance, the incidence of skin rash was low, which was a specific adverse effect of cetuximab., 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|| |
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.
| > References|| |
Dwivedi RC, Kazi RA, Agrawal N, Nutting CM, Clarke PM, Kerawala CJ, et al.
Evaluation of speech outcomes following treatment of oral and oropharyngeal cancers. Cancer Treat Rev 2009;35:417-24.
Al-Swiahb JN, Chen CH, Chuang HC, Fang FM, Tasi HT, Chien CY, et al.
Clinical, pathological and molecular determinants in squamous cell carcinoma of the oral cavity. Future Oncol 2010;6:837-50.
Chinn SB, Spector ME, Bellile EL, Rozek LS, Lin T, Teknos TN, et al.
Efficacy of induction selection chemotherapy vs. primary surgery for patients with advanced oral cavity carcinoma. JAMA Otolaryngol Head Neck Surg 2014;140:134-42.
Agarwal JP, Nemade B, Murthy V, Ghosh-Laskar S, Budrukkar A, Gupta T, et al.
Hypofractionated, palliative radiotherapy for advanced head and neck cancer. Radiother Oncol 2008;89:51-6.
Das S, Thomas S, Pal SK, Isiah R, John S. Hypofractionated palliative radiotherapy in locally advanced inoperable head and neck cancer: CMC Vellore experience. Indian J Palliat Care 2013;19:93-8.
] [Full text]
Mohanti BK, Umapathy H, Bahadur S, Thakar A, Pathy S. Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and incurable head and neck cancer: AIIMS study. Radiother Oncol 2004;71:275-80.
Meng J, Gu QP, Meng QF, Zhang J, Li ZP, Si YM, et al.
Efficacy of nimotuzumab combined with docetaxel-cisplatin-fluorouracil regimen in treatment of advanced oral carcinoma. Cell Biochem Biophys 2014;68:181-4.
Fayette J, Fontaine-Delaruelle C, Ambrun A, Daveau C, Poupart M, Ramade A, et al.
Neoadjuvant modified TPF (docetaxel, cisplatin, fluorouracil) for patients unfit to standard TPF in locally advanced head and neck squamous cell carcinoma: A study of 48 patients. Oncotarget 2016;7:37297-304.
Keil F, Selzer E, Berghold A, Reinisch S, Kapp KS, De Vries A, et al.
Induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy with cetuximab for locally advanced squamous cell carcinoma of the head and neck. Eur J Cancer 2013;49:352-9.
Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, et al.
Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: Long-term results of the TA×324 randomised phase 3 trial. Lancet Oncol 2011;12:153-9.
Qi D, Cui Y, Wang Q, Huang C, Xu J, Yang Y, et al.
Aclinical trial on docetaxel and carboplatin therapy with or without nimotuzumab for the treatment of advanced nonsmall cell lung cancer. J Cancer Res Ther 2015;11 Suppl 1:C32-7.
Crombet-Ramos T, Rak J, Pérez R, Viloria-Petit A. Antiproliferative, antiangiogenic and proapoptotic activity of h-R3: A humanized anti-EGFR antibody. Int J Cancer 2002;101:567-75.
Xu S, Ramos-Suzarte M, Bai X, Xu B. Treatment outcome of nimotuzumab plus chemotherapy in advanced cancer patients: A single institute experience. Oncotarget 2016;7:33391-407.
Verduzco-Rodríguez L, Aguirre-González EH, Verduzco-Aguirre HC. Durable complete response induced by paclitaxel-nimotuzumab-methotrexate chemotherapy in a patient with metastatic head and neck squamous cell carcinoma. Hematol Oncol Stem Cell Ther 2011;4:182-4.
Gomez-Roca C, Koscielny S, Ribrag V, Dromain C, Marzouk I, Bidault F, et al.
Tumour growth rates and RECIST criteria in early drug development. Eur J Cancer 2011;47:2512-6.
Denis F, Garaud P, Bardet E, Alfonsi M, Sire C, Germain T, et al.
Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: Comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol Phys 2003;55:93-8.
Soulières D, Aguilar JL, Chen E, Misiukiewicz K, Ernst S, Lee HJ, et al.
Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: A randomized, double-blind safety study comparing cetuximab produced from two manufacturing processes using the EXTREME study regimen. BMC Cancer 2016;16:19.
Ahn JS, Cho SH, Kim OK, Lee JK, Yang DH, Kim YK, et al.
The efficacy of an induction chemotherapy combination with docetaxel, cisplatin, and 5-FU followed by concurrent chemoradiotherapy in advanced head and neck cancer. Cancer Res Treat 2007;39:93-8.
Kataria T, Gupta D, Bisht SS, Goyal S, Basu T, Srivastava A, et al.
Chemoradiation in elderly patients with head and neck cancers: A single institution experience. Am J Otolaryngol 2015;36:117-21.
Mukhopadhyay S, Kwatra G, Alice KP, Badyal D. Role of olanzapine in chemotherapy-induced nausea and vomiting on platinum-based chemotherapy patients: A randomized controlled study. Support Care Cancer 2017;25:145-54.
Posch D, Fuchs H, Kornek G, Grah A, Pammer J, Aretin MB, et al.
Docetaxel plus cetuximab biweekly is an active regimen for the first-line treatment of patients with recurrent/metastatic head and neck cancer. Sci Rep 2016;6:32946.
Pfister DG, Su YB, Kraus DH, Wolden SL, Lis E, Aliff TB, et al.
Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: A pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006;24:1072-8.
Cohen RB. Current challenges and clinical investigations of epidermal growth factor receptor (EGFR)- and ErbB family-targeted agents in the treatment of head and neck squamous cell carcinoma (HNSCC). Cancer Treat Rev 2014;40:567-77.
Reddy BK, Lokesh V, Vidyasagar MS, Shenoy K, Babu KG, Shenoy A, 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.
Caudell JJ, Sawrie SM, Spencer SA, Desmond RA, Carroll WR, Peters GE, et al.
Locoregionally advanced head and neck cancer treated with primary radiotherapy: A comparison of the addition of cetuximab or chemotherapy and the impact of protocol treatment. Int J Radiat Oncol Biol Phys 2008;71:676-81.
Gupta M, Madholia V, Gupta N, Bhowmik KT. Results from a pilot study of nimotuzumab with concurrent chemoradiation in patients with locally advanced squamous cell carcinoma of head and neck. J Clin Oncol 2010;28:5565. [Abstract].
Cetina L, Crombet T, Jiménez-Lima R, Zapata S, Ramos M, Avila S, et al.
Apilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer. Cancer Biol Ther 2015;16:684-9.
[Table 1], [Table 2], [Table 3]