General Information
We conducted a systematic review of articles published between 2000 and 2022 that focused on induction chemotherapy for oral squamous cell carcinoma. After excluding studies that did not meet the predefined screening criteria, our analysis comprised 227 English-language articles from 111 journals and 5,250 co-cited references originating from 372 institutions across 28 countries/regions.
Our findings indicate a gradual, albeit fluctuating, increase in research on induction chemotherapy for oral squamous cell carcinoma since 2000, although the overall publication output remains relatively low. Notably, three significant shifts emerged in 2008, 2013, and 2020. These turning points were characterized by substantial increases in publication volume compared to the preceding year. This can be attributed to the exploration of the efficacy and safety of various chemotherapy drugs, such as cisplatin and 5-fluorouracil, in multiple studies in 2008, along with corresponding phase I and II clinical trials[13-16]. In 2013, the phase III clinical trial of TPF regimen for oral squamous cell carcinoma by Zhong Laiping further advanced research in this field[17, 18]. In 2020, molecular biology and immunotherapy contributed to the development of personalized chemotherapy based on molecular targets and combination immunotherapy, bringing oral squamous cell carcinoma treatment back into the public[19-24].
China and the United States shared the top spot in terms of publication count. Notably, three of the top four countries are from Asia (China, India, and Japan), reflecting the high incidence of oral cancer in the region. The distribution of institutions matches the distribution of countries/regions. The top three institutions are from China, USA, and India. Close collaboration between countries/regions and institutions was observed, particularly between China and the United States, as well as multi-party collaborations centered around China and the United States.
Among the top ten active authors in terms of publication volume, each author has published at least five articles, and the top four authors have published more than ten articles, with citation counts of more than 300 for all articles. Among these thirteen prolific authors, twelve from Asia, comprising nine Chinese scientists affiliated with Shanghai Jiao Tong University and three researchers from India's Tata Memorial Hospital. This finding suggests that Asian researchers have played an important role and made significant contributions to the research on induction chemotherapy for oral squamous cell carcinoma.
Co-cited authors assume a pivotal role in this field. Among the top ten co-cited authors, only Posner MR and Vermorken JB have been co-cited more than 100 times (co-citations = 104). Zhong Laiping, who ranks first in terms of publication volume, ranks third with 89 co-citations. These three authors have conducted clinical trials on PF and TPF induction chemotherapy for oral squamous cell carcinoma. In addition, Posner MR and Vermorken JB further investigated the efficacy of induction chemotherapy regimens in combination with cetuximab, while Zhong Laiping conducted a pilot study on the neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib in 2022, opening new avenues for research in induction chemotherapy for oral squamous cell carcinoma[5, 6, 16, 17, 25].
The top ten journals accounted for only 94 papers, representing 41% of the total publications in this research domain. Oral Oncology claimed the top position with 24 publications, followed by Head and Neck-Journal for the Sciences and Specialties of the Head and Neck with 11 publications and Indian Journal of Cancer with eight publications. This indicates that these journals are particularly interested in articles related to induction chemotherapy research of oral squamous cell carcinoma. This data will help future scientists in selecting journals for submitting manuscripts in terms of this field.
Furthermore, following a thorough analysis of authorship, co-cited authors, and co-cited references, we identified Zhong Laiping as the sole researcher present in all three categories. This suggests that he is an accomplished author in the field, and his team is an excellent research team. His team has the potential to be excellent collaborators for researchers.
Knowledge base
When two publications are co-cited by a third publication, it establishes a co-citation relationship. The significance of a document in a specific field increases as it receives more citations. This reflects the knowledge base and primary concerns of researchers in that field[26]. Table 5 presents the top ten most cited articles, comprising 11 publications that originate from renowned international journals with high impact factors. Among these, nine articles are clinical trials, while the remaining two are meta-analyses. These clinical trials primarily investigate the selection of induction chemotherapy regimens for advanced oral squamous cell carcinoma and conduct phase II or III clinical trials to assess the effectiveness of induction chemotherapy. The first clinical trial conducted in 1994 showed that neoadjuvant chemotherapy reduced the incidence of distant metastases in operable patients and improved local control, distant metastasis incidence, complete remission, and overall survival in inoperable patients[27] (#9). The most cited article, a phase III clinical trial by Jan B Vermorken in 2007[6] (#1), compared the efficacy of two induction chemotherapy regimens (TPF and PF) in locally advanced, unresectable oral squamous cell carcinoma. It found that the TPF regimen significantly improved progression-free survival and overall survival compared to the PF regimen. In the same year, Marshall R Posner conducted a phase III clinical trial[5] (#2) that also concluded that the TPF induction chemotherapy regimen in combination with radiotherapy was more effective than the PF regimen. However, a study by Robert Haddad in 2013[7] (#5) compared the efficacy of concurrent chemoradiotherapy after induction chemotherapy with TPF versus concurrent cisplatin-based chemoradiotherapy alone in patients with locally advanced unresectable head and neck cancer. It found that preoperative induction chemotherapy with TPF did not significantly improve patient survival. Another study by Zhong Laiping[4] (#4) suggested that in patients with respectable stage III or IV oral squamous cell carcinoma, TPF-induced chemotherapy was not effective in improving survival compared to surgery. Similarly, Lisa Licitra's study [28] (#3) found that adding TPF chemotherapy to standard surgery did not improve survival. A subsequent study by Ezra E W Cohen[29] (#8) concluded that induction chemotherapy did not significantly improve overall survival in patients with advanced N2, N3 head and neck squamous cell carcinoma compared to chemoradiotherapy alone. Based on these co-citation relationships, it can be inferred that the efficacy of induction chemotherapy regimens for advanced oral squamous cell carcinoma is a topic of interest and discussion among researchers in the field.
Two meta-analyses investigating the effectiveness of chemotherapy in the treatment of head and neck squamous cell carcinoma indicated that concurrent chemotherapy was more beneficial for patients compared to induction chemotherapy[30] (#7). However, a previous study published in The Lancet presented opposing findings, suggesting that chemotherapy had limited impact on patient survival[31] (#6).
Overall, these ten highly cited papers provide a comprehensive evaluation and analysis of the efficacy of induction chemotherapy for advanced oral squamous cell carcinoma. Additionally, they delve into the exploration and enhancement of induction chemotherapy regimens. Furthermore, the application of co-citation analysis furnishes us with valuable insights into the evolution of the knowledge structure pertaining to induction chemotherapy for oral squamous cell carcinoma.
Research frontiers
To explore and identify new areas of research in induction chemotherapy for oral squamous cell carcinoma, we utilized CiteSpace to analyze co-cited references. Figure 7B demonstrates that earlier studies conducted between 2000 and 2005 mainly focused on investigating the effectiveness of sequential treatment involving chemotherapy combined with radiotherapy for OSCC, specifically referred to as "#5 radiochemotherapy". Notably, preoperative concurrent chemoradiotherapy followed by radical surgery has yielded promising long-term outcomes for advanced squamous cell carcinoma of the oral cavity. Studies conducted by Kirita et al. showcased high response rates both clinically and pathologically, along with impressive survival rates at 5 and 10 years[32, 33]. This treatment regimen also resulted in notable clinical tumor response rates, acceptable acute toxicity, and minimal late therapeutic complications[33]. Individuals who achieved favorable histopathological responses exhibited superior survival rates when compared to those with substantial residual tumors[34]. Furthermore, Klug et al.'s study discovered that preoperative radiochemotherapy combined with radical surgery led to a 5-year overall survival probability of 53.9%, along with a 5-year local control probability of 70.2%[35]. Similarly, Eich et al. reported positive outcomes with neoadjuvant radiochemotherapy followed by radical surgery, demonstrating an overall survival of 65% at 2 years and 45% at 5 years[36]. These findings strongly indicate that preoperative concurrent chemoradiotherapy followed by radical surgery serves as an effective and safe treatment option for advanced oral cavity squamous cell carcinoma.
Currently, the primary attention is directed towards the selection of induction chemotherapy regimens for OSCC. Additionally, new approaches involving the combination of induction chemotherapy and immunotherapy, such as "#0 paclitaxel", are under investigation. Paclitaxel (PTX), a member of the taxane family, has shown broad antitumor activity and is commonly used in the treatment of various solid tumors, including OSCC. Its primary mode of action is by disrupting microtubule dynamics, leading to mitotic arrest and eventual cell death[37]. Another taxane chemotherapeutic agent, docetaxel, is commonly used for induction chemotherapy in OSCC as a TPF regimen, which includes 5-fluorouracil and cisplatin, since it is a microtubule inhibitor like PTX. Data from randomized trials suggest that TPF sequential therapy may be a viable alternative to concurrent chemoradiotherapy in certain patients. TPF therapy is generally well-tolerated, but does have a higher incidence of hematologic adverse events, including neutropenia and complications linked with neutropenia, compared to PF therapy[38]. PTX has demonstrated broad antitumor activity as a stand-alone treatment or in combination with other chemotherapy agents. For instance, several scholars have conducted clinical studies in recent years, concentrating on the effectiveness of combining cetuximab with traditional TPF chemotherapy in advanced OSCC[39, 40]. Additionally, some basic experiments have confirmed that the combination of PTX and cetuximab boosts the antitumor activity of OSCC through inhibition of the NF-κB activity[41]. Yuta Sawatani et al. discovered that PTX increased the anti-cancer impact of cetuximab in vitro by improving antibody-dependent cytotoxicity (ADCC) in OSCC cells[42]. Tumor immunotherapy generates immune responses against tumors by enhancing the body's immune system. Recently, progress has been made in understanding the potential application of classical drugs in tumor immunotherapy. Numerous studies have shown that paclitaxel can directly kill tumor cells and modulate various immune cells, such as effector T cells, dendritic cells (DCs), natural killer cells (NK cells), regulatory T cells (Tregs), and macrophages[43]. Paclitaxel can inhibit the function of Tregs and reverse tumor immune escape. Therefore, the combination of paclitaxel and immunotherapy can enhance treatment efficacy[43]. Recent research has focused on combining paclitaxel with immunotherapies to improve treatment outcomes. The combination therapy of paclitaxel and immune checkpoint inhibitors has shown promising efficacy signals in clinical trials, with long-term disease control and favorable toxicity profiles[44, 45]. Overall, the combination of paclitaxel and immunotherapies holds the potential to improve the treatment outcomes of OSCC, but further research is needed to optimize treatment strategies.
In our study, we utilized CiteSpace to identify burst keywords that can serve as significant indicators of research hotspots or frontiers. The evolution of these burst keywords over the past 20 years, as presented in Figure 9B, reveals the research field's focus on clinically evaluating the efficacy of various induction chemotherapy regimens for patients with OSCC. Based on this analysis, it has been determined that "phase III clinical trials" is the most prominent burst keyword as of 2014. These pivotal phase III clinical trials have played a crucial role in advancing the exploration of induction chemotherapy for OSCC. One notable study, the TAX 324 trial, demonstrated the effectiveness of combining paclitaxel with cisplatin and fluorouracil as an induction chemotherapy regimen for OSCC, resulting in a significant increase in the surgical resection rate[46]. Likewise, the RTOG 1016 study found that induction chemotherapy improves the overall survival of patients with OSCC[47]. Another potential induction chemotherapy regimen involves the combination of docetaxel, cisplatin, and 5-Fu with radiotherapy. The RADPLAT study compared the effectiveness of induction chemotherapy with paclitaxel and cisplatin to direct surgical resection in individuals with oral squamous carcinoma[48]. The findings of this study demonstrated that induction chemotherapy led to a decrease in tumor stage and an increase in the frequency of surgical removal.
Strength and limitation
Our study provides an initial methodical and logical assessment of the literature on OSCC induction chemotherapy research and its trends. In order to gain a comprehensive understanding, we employed various bibliometric software to analyze research hotspots from multiple perspectives. However, it is important to acknowledge the limitations of our study. Firstly, the literature we evaluated may not be exhaustive as we exclusively examined data from WoSCC and excluded data from other major search engines such as PubMed, Embase, Scopus, etc. Secondly, there might be some linguistic bias since we only included articles published in English. Lastly, due to the systematic settings of the bibliometric software, we were unable to conduct a thorough analysis of articles published before 2000 or after 2022 in this paper. Consequently, our study may not fully capture all the relevant studies on induction chemotherapy of OSCC.
Role of the Funding Source
This work was sponsored by the Interdisciplinary Program of Shanghai Jiao Tong University (YG2021QN60), Shanghai Sailing Program (21YF1423500 and 20YF1423300).