Head and neck cancers account for the seventh most common malignancy worldwide with 890,000 estimated new cases and 450,000 estimated deaths in 2018 (1). Although early head and neck cancers are curable with radical surgery or radiotherapy and have favorable prognosis, more than 60% of patients present with advanced disease that require multidisciplinary treatment and carry high risk of local regional recurrence and distant metastasis (2). For inoperable locally advanced head and neck cancer (LAHNC) patients, high-dose cisplatin-based concurrent chemoradiotherapy (CCRT) remains standard of care (3–5). However, this treatment modality is associated with increased toxicities and is less tolerated in elderly patients or patients with poorer performance status. Main toxicities include Mucositis, hematological, gastrointestinal, renal and neurological toxicities, etc. Therefore, other less toxic platinum-based chemoradiotherapy and alternative concurrent regimens have also been actively investigated.

Nedaplatin is a cisplatin analog with decreased nephrotoxicity and gastrointestinal toxicity (6). Nedaplatin-based concurrent chemotherapy showed comparable effectiveness to cisplatin in terms of disease control and patient survival in nasopharyngeal carcinoma and head and neck cancers (7–9). Importantly, while nedaplatin led to less gastrointestinal toxicities, nephrotoxicity, ototoxicity, and neurotoxicity compared with cisplatin, more hematologic toxicities such as grade 3/4 neutropenia and thrombocytopenia were seen in nedaplatin-treated patients (7, 8). Lobaplatin is another platinum compound showing anti-tumor activity in multiple solid tumors such as breast cancer, small-cell lung cancer, and hepatocellular carcinoma (10–12). Lobaplatin-based induction chemotherapy followed by lobaplatin-radiotherapy showed comparable survival outcomes but less acute toxicities than cisplatin-based concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma and might be a promising alternative to cisplatin-based treatment (13). Importantly, leucopenia, neutropenia, and gastrointestinal toxicities were more documented in cisplatin-treated patients (14). For elderly patients or those who are intolerant to platinum-based concurrent chemotherapy, anti-EGFR antibodies have also shown semblable effectiveness and could be used as concurrent treatments in head and neck cancers (15–21). Cetuximab is a chimeric anti-EGFR monoclonal antibody. Although cetuximab-based CCRT showed superiority than radiotherapy alone in LAHNC (22), it did not outperformed cisplatin-based CCRT (23). Nimotuzumab is a humanized anti-EGFR antibody. The addition of nimotuzumab to weekly cisplatin-based concurrent chemoradiotherapy resulted in improved progression-free survival, locoregional control in locally advanced head and neck cancer (19, 20, 24). In head and neck cancer patients unfit for chemoradiotherapy, nimotuzumab plus radiotherapy yielded higher complete response and favorable overall survival compared with radiotherapy alone (25).

Although multiple alternative approaches are under investigation, cisplatin-based CCRT still remain the mainstay for LAHNC. Whereas in cases unfit for cisplatin treatment, platinum-analogs and anti-EGFR antibodies might be an attractive choice. However, direct comparison of toxicity profiles among these drugs has not been performed. In this study, we aimed to compare the hematological toxicities in nimotuzumab-, cisplatin-, nedaplatin- and lobaplatin-based concurrent chemoradiotherapy in locally advanced head and neck cancer.

Platinum-based concurrent chemotherapy showed better response rates and overall survival rates than radiotherapy alone, surgery alone or surgery plus radiotherapy in locally advanced head and neck cancers (LAHNC). However, the optimal concurrent chemotherapy regimen with or without induction chemotherapy is still inconclusive (27–30). Cisplatin-based concurrent chemoradiotherapy improved patient survival compared with radiotherapy alone in inoperable LAHNC, although it also increases toxicities such as gastrointestinal, hematological, renal and auditory toxicities (31–33). In those unfit or intolerant to cisplatin treatment, less toxic platinum analog and anti-EGFR antibodies might provide comparable effectiveness and could be alternative choices. However, the toxicity profiles and in particular the hematological toxicity differences among those treatments have not been fully demonstrated.

In this retrospective study, we found substantial differences in hematological toxicities among cisplatin-, nedaplatin-, lobaplatin-, and nimotuzumab-based concurrent chemoradiotherapy in LAHNC. Our results demonstrate that nimotuzumab had the lightest hematological toxicity, followed by cisplatin, nedaplatin, while lobaplatin had the most severe hematological toxicity. To our knowledge, this is the first study that compares these four commonly used chemotherapeutic agents in this setting.

Platinum salt was firstly developed by chemotherapist Peyrone in 1844 and since played central roles in anti-cancer chemotherapy. In 1965, Rosenberg et al. reported that cisplatin had potential anti-tumor activity. Subsequently, second-generation (carboplatin, nedaplatin) and third-generation platinums (oxaliplatin, lobaplatin) were also developed, with varied antitumor activities in different malignancies (34). In addition, these reagents were characterized with different toxicity profiles. Cisplatin (cis-dichlorodiamine platinum) was mainly metabolized by the kidneys and a large amount of oxygen free radicals were produced during the metabolic process, which could cause kidney injury. The glycolic acid on the structure of nedaplatin (Cis-glycolic acid diamine platinum) replaced two chloride ions, which had high solubility in water and thus changed the distribution in the kidneys. As a result, nedaplatin had less nephrotoxicity. In addition, nedaplatin induced lower ototoxicity and gastrointestinal toxicity (14). Lobaplatin (Chemical name: 1,2-Diamino-cyclobutane-lactate platinum) was a 1:1 diastereomers mixture of platinum complexes containing a 1,2-bis (aminomethyl) cyclobut ane stables ligand and lactic acid as the leaving group. As the latest third-generation platinum-derived anti-cancer drug, lobaplatin showed favorable antitumor activity, good solubility and stability in water. Moreover, lobaplatin carried tolerable toxicity and could potentially overcome tumor resistance to cisplatin (35). The component and structural difference among these platinum analogs gave rise to their distinct pharmaco-mechanisms and pharmacokinetic, which helped to explain their difference on hematological toxicity profiles observed in both clinical trials and real-world studies.

One of the main toxicities of platinum is dose limiting hematological toxicity. In line with our results, similar reports that compare either two of these drugs have showed varied hematological toxicities, although no direct comparison among four agents has yet been reported (7, 8, 10). Nedaplatin was more prone to induce grade 3/4 thrombocytopenia than cisplatin. In addition, grade 3 or worse adverse events of leucopenia, neutropenia and thrombocytopenia were more frequently observed in nedaplatin-treated patients than in cisplatin-treated ones (36). Likewise, lobaplatin was reported to result in more severe thrombocytopenia than cisplatin (13). In fact, during the course of lobaplatin-radiotherapy of locally advanced nasopharyngeal carcinoma, main grade 3/4 acute adverse events included thrombocytopenia, leucopenia, neutropenia, anemia (10, 37). A phase II randomized clinical trial comparing docetaxel plus lobaplatin induction chemotherapy combined with lobaplatin chemoradiotherapy versus TPF induction chemotherapy combined with cisplatin chemoradiotherapy in locally advanced head and neck squamous cell carcinoma (NCT03117257) is going on and might provide more convincing comparative data on their toxicity profiles.

In this study, we compared hematological toxicities of nimotuzumab-, cisplatin-, nedaplatin-, and lobaplatin-based concurrent chemoradiotherapy of head and neck cancers. Our research results show that lobaplatin had the most severe hematological toxicity, followed by nedaplatin, cisplatin and nimotuzumab. Specifically, lobaplatin was likely to produce more serious leukopenia and thrombocytopenia compared with cisplatin. The hematological toxicity of nedaplatin was more severe than that of cisplatin but lighter than that of lobaplatin. Given that there still lacks prospective comparative study showing a superiority of other platinums over cisplatin in concurrent chemoradiotherapy in LAHNC, cisplatin should be considered in priority in cases that patients have good liver and kidney function, and tolerable gastrointestinal reaction to cisplatin (5, 38). What’s more, cisplatin is economically available. However, cisplatin treatment must be supplemented with adequate prior hydration, which may lengthen the hospital stay. Cisplatin can also cause severe gastrointestinal reactions such as nausea and vomiting, leading to decreased patient compliance. In cases of intolerance to the toxicities of cisplatin, we should consider nedaplatin that induced less gastrointestinal reaction and lower liver and kidney toxicities. Although nedaplatin caused less nausea, vomiting, liver and kidney toxicities, some patients still suffered from these events. Furthermore, a small part of patients showed allergy to nedaplatin, limiting its use in many cases (39). For patients who cannot tolerate the above-mentioned two platinum salts, lobaplatin might be an alternative choice. Lobaplatin has good water solubility, broad anti-cancer spectrum, high anti-cancer activity, and no cross-resistance with other platinums. However, lobaplatin is more toxic to the hematopoietic system. Our study demonstrated highest risk of grade 3/4 hematological toxicities associated with lobaplatin. Therefore, during the use of lobaplatin in concurrent chemoradiotherapy, patients should be given closer and more frequent monitoring of white blood cells and platelets, especially for patients older than 65, and those who have undergone multiple chemotherapies and those who have experienced previous grade 3/4 myelosuppression. In addition, lobaplatin was the most expensive among the three platinum salts. For elderly patients with poor general health conditions, or those who cannot tolerate platinum-based chemotherapy, nimotuzumab with best hematological toxicity profiles could be considered. But it was quite expensive, and was not yet covered by current medical insurance system. Therefore, in patients tolerable to platinum, we still suggest platinum-based concurrent chemotherapy.

Cisplatin and nedaplatin have been commonly used clinically and the standard dose of concurrent chemotherapy is 30 mg/m² once a week or 100 mg/m² once every three weeks which converting to a single dose is respectively 50 mg once a week or 160 mg once every three weeks, respectively. The effectiveness and safety results of them are also relatively mature. Previous clinical trials have evaluated the toxicities of tri-weekly treatment regimen and weekly treatment regimen and found that tri-weekly treatment regimen was associated with more hematological toxicities in terms of leukopenia, neutropenia (40, 41). In our study, the cisplatin group had the more patients using tri-weekly treatment regimen, compared with nedaplatin. Grade 3/4 thrombocytopenia occurred more frequently in weekly nedaplatin-treated patients compared with tri-weekly nedaplatin-treated patients. There was no significant difference in hematological toxicity between the weekly regimen and tri-weekly regimen in cisplatin-treated patients. As for lobaplatin, the maximum tolerated dose is 60 mg/m² and the recommended dose is 30-50 mg/m², and the standard dose of lobaplatin in western countries is 50 mg/m². Due to ethnic and geographic differences, this dose level may not be suitable for Chinese. In our center, 23 patients received a dose of 35 mg/m² and 10 patients were given a dose of 50 mg/m² every three weeks.

Our study further identified induction chemotherapy prior to concurrent chemoradiotherapy was a risk factor of developing grade 3/4 hematological toxicities. These results indicated that for patients who have received induction chemotherapy, closer attention should be paid concerning potential severe myelosuppression, especially when use nedaplatin or lobaplatin as concurrent drug. Given less hematological toxicity and gastrointestinal side effects, nimotuzumab could be a safe alternate. Otherwise, cisplatin could also be considered with proper management of its adverse effects.

There were some limitations in this study. First, the sample size of eligible patients in this study was small. Second, the retrospective nature made it evitable to create selection and information bias that render the study less rigorous. Therefore, these results are supposed to provide reference to clinical decision-making and should be validated in prospective randomized trials. In addition, we did not take into account of other frequent toxicities but particularly focused on hematological side effect. More comprehensive analysis on treatment effectiveness, toxicity and patient quality of life is warranted.

In conclusion, our study revealed the hematological differences among cisplatin-, nedaplatin-, lobaplatin- and nimotuzumab-based concurrent chemoradiotherapy for locally advanced head and neck cancers. Choice of concurrent regimens should take into considerations of their potential toxicities, patient tolerability, economic concerns and should pay specific attention to treat-related side effect that fits each regimen delivered.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The clinical research projects were approved by Zhongnan Hospital of Wuhan University (Clinical Research Ethics Number: 2019130). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

Conceptualization, QW, CZ, YFZ, and YHZ. Methodology, QW, CZ, YFZ, and YHZ. Software and data analysis, QW and CZ. Validation, QW, CZ, YFZ, and YHZ. Writing, review, and editing, QW, CZ, SZ, YFZ, and YHZ. Supervision, YFZ and YHZ. All authors have read and agreed to the published version of the manuscript.

This study was supported by a grant from the Leading Discipline Construction Project of Oncology of Zhongnan Hospital of Wuhan University, a grant from the Scientific Research Project of Hubei Provincial Health and Family Planning Commission (grant no. WJ2019H064) and a grant from the Science, Technology and Innovation Seed Fund of Zhongnan Hospital of Wuhan University (Grant no. znpy2018123).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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