Head and neck squamous cell carcinoma (HNSCC) is ranked as the seventh most common cancer in the world and has been frequently linked to tobacco and alcohol use, as well as human papillomavirus (HPV), Helicobacter pylori and Candida albicans infections (1–3). In cases of recurrent or metastatic cancer, conventional therapeutic approaches such as surgery, radiation and systemic chemotherapy frequently result in considerable morbidity and have poor efficacy (4, 5). Oral metronomic chemotherapy (OMCT) has become a viable option due to its ability to suppress tumor angiogenesis, modulate the immune system, and minimize toxicity (6). It entails frequently administering low-dose chemotherapy drugs without extended intervals.

Angiogenesis is a process by which new blood vessels proliferate to deliver nourishment to the tumor cells (7). Additionally, alternate mechanisms such as vasculogenic mimicry have been described in various human malignancies (8). Inhibiting angiogenesis is the main mechanism by which metronomic chemotherapy functions (9). The anti-angiogenic action of metronomic chemotherapy relies upon targeting the endothelial cells in the tumor vasculature, which are more susceptible to continual low-dose chemotherapy. Furthermore, it is believed that metronomic chemotherapy has immunomodulatory effects, specifically through the reduction of regulatory T-cells (Tregs), which are responsible for inhibiting the body's immune response against tumors (6). These processes differ from the classic cytotoxic effects of chemotherapy, which are designed to destroy rapidly dividing tumor cells.

Oral metronomic chemotherapy has been researched in several therapeutic contexts, especially for patients with recurrent or metastatic HNSCC who have few alternative options for treatment. OMCT could be a better alternative for patients who are not promising candidates for aggressive therapy, according to a phase II study assessing the use of low-dose oral cyclophosphamide in combination with celecoxib in patients with advanced HNSCC (10). The study found that a subset of patients experienced a significant reduction in tumor size with minimal toxicity. Patients receiving OMCT also experienced fewer adverse effects, such as neutropenia and mucositis, which are common in standard chemotherapy (11).

OMCT has also been explored as a maintenance therapy to prolong disease control following induction chemotherapy or chemoradiation (12). A study reported that patients with HNSCC who received maintenance OMCT with methotrexate and celecoxib had a longer median PFS compared to those who received no further treatment after completing standard therapy (13). This suggests that OMCT may help in sustaining the therapeutic response and delaying disease progression. An area of growing attention is the use of immune checkpoint inhibitors in conjunction with OMCT. Metronomic chemotherapy has been demonstrated in preclinical investigations to increase the effectiveness of immunotherapy by altering the tumor microenvironment and promoting the infiltration of cytotoxic T-cells (1). Many clinical trials are now underway to assess the synergistic effects of OMCT in HNSCC (14).

The present systematic review was thus designed to evaluate the efficacy of oral metronomic chemotherapy in the management of head and neck squamous cell carcinoma in comparison to other standard chemotherapy regimens.

The literature search strategy revealed 147 articles published until 2024 in various electronic scientific databases. Out of these 147 articles, forty papers were excluded after reading the titles and abstracts for eligibility, along with 55 duplicate papers, yielding 52 articles for inclusion in the review. These 52 articles were further evaluated by reading the full text for eligibility. At this stage, three articles were excluded as the full texts could not be retrieved. From the 49 full-text articles that were retrieved, 25 articles were again excluded based on the eligibility criteria. Finally, 24 articles were included in the present systematic review (Figure 1) (18–41).

With few treatment options and a poor prognosis, head and neck squamous cell carcinoma (HNSCC) is still a serious health concern, particularly in underdeveloped and developing nations where the resources are limited, with added financial burden and diagnosis of the disease at an advanced stage (42–44). Although surgery, with adjuvant chemotherapy and radiotherapy (CTRT), remains the mainstay treatment for head and neck squamous cell carcinoma, the high dosage and repeated cycles of CTRT are usually linked to serious side effects, which makes them unsuitable for patients with advanced or recurrent disease (45, 46). This has raised interest in metronomic chemotherapy, a method of administering chemotherapeutics continuously at low doses to modify immune responses, lower angiogenesis, and target the tumor microenvironment without the significant toxicity of traditional regimens (47–49). OMCT is not only advantageous in the advanced clinical stage or recurrent diseases but could also be provided to patients where the waiting period is long or in large unresectable tumors with difficulty in obtaining free margins. This holds particularly true for the malignancies of the posterior part of the oral cavity. Preliminary studies suggest that OMCT may offer an effective and less toxic alternative for advanced HNSCC, though robust clinical evidence is still needed (18–22). The present systematic review was performed to evaluate the efficacy of OMCT in HNSCC, aiming to expand treatment options for this challenging patient population and to investigate its potential as a sustainable, less invasive therapeutic approach.

From the systematic review conducted, it was found that the studies where controls were included for comparison of the efficacy of OMCT in head and neck squamous cell carcinoma, most studies demonstrated that the overall survival with OMCT was better as compared to the control groups (20, 21, 23, 24, 29, 32, 34, 38, 39, 41). Few studies, however, showed a reverse trend (22, 27, 40). Owing to the fact that the values of end point determination were expressed variably in percentage, months, years or days, homogeneous data could not be generated to assess the significance and to perform a meta-analysis. The longest duration of overall survival was 26 months observed with the weekly administration of 15 mg/m² of Methotrexate and twice-daily administration of 200 mg of Celecoxib (23). In contrast, the control group showed an overall survival of only 14 months. Similar results were obtained from other studies. The highest percentage of overall survival was 98% observed with the daily administration of 100–400 mg of Tegafur-Uracil, contrasting with the 82% OS in the control group (39). Similarly, the longest duration of progression-free survival was 11.4 months, which was observed with the combination of neoadjuvant chemotherapy (175 mg/m² of Paclitaxel with Carboplatin every 3 weeks) and oral metronomic chemotherapy (9 mg/m² of Methotrexate weekly with 200 mg of Celecoxib twice daily, and 150 mg of Erlotinib once daily) (35). The highest percentage of progression-free survival was 60.8% observed with the weekly administration of 15 mg/m² of Methotrexate and twice-daily administration of 200 mg of Celecoxib (40). The longest duration of disease-free progression was 54.5 months observed with weekly administration of 15 mg/m² of Methotrexate and twice-daily administration of 200 mg of Celecoxib (33). The highest percentage of disease-free survival was 91% observed with the twice-daily administration of 120 mg of S-1 for 2 weeks (41) (Table 1).

The highest degree of suitable results was obtained with the oral metronomic administration of the combination of Methotrexate and Celecoxib. The mechanism of action of Methotrexate is due to its ability to inhibit the enzymes responsible for nucleotide synthesis, including dihydrofolate reductase (DHFR), thymidylate synthase (TS), aminoimidazole carboxamide ribonucleotide transformylase (AICART), and amido phosphoribosyl transferase (APRT) (50). As a result, methotrexate prevents tumor cells from proliferating and also has additional anti-inflammatory effects through several mechanisms, including adenosine signaling, the generation of reactive oxygen species (ROS), the decrease of pro-inflammatory cytokine levels, and the enhancement of immune balance through the increase in Treg cells (51).

The usage of a combination of celecoxib with methotrexate was commonly administered as OMCT and showed better outcome measures, as evidenced in the present review (33). Celecoxib inhibits the 3-phosphoinositide-dependent kinase-1 (PDK-1) signaling pathway and binds to the cadherin-11 (CDH11) protein, which is believed to be involved in the development of cancers, to provide anticancer effects (52). It mainly regulates the proliferation, migration, and invasion of tumor cells by inhibiting the cyclooxygenase 2 (COX2)- prostaglandin E2 (PGE2) signal axis, thereby inhibiting the phosphorylation of nuclear factor-κ-gene binding and the expression of matrix metalloproteinases 2 (MMP2) and 9 (MMP9). Celecoxib also promotes the apoptosis of tumor cells by enhancing mitochondrial oxidation, thereby activating the mitochondrial apoptotic process. Celecoxib further reduces drug resistance by increasing the sensitivity of cancer cells to chemotherapy drugs (6). The above mechanisms of methotrexate and celecoxib show that these suppress tumor growth by inhibiting cell division and promoting apoptosis of tumor cells, respectively. These two mechanisms work hand in hand to provide the heightened anticancer effect.

Our compiled results are in line with earlier studies that demonstrated the possible advantages of OMCT in HNSCC (25–30). A better overall immunological response may result from the persistently low dosage, which may lessen immune cell suppression (47). Low-dose, continuous chemotherapy is given orally as part of OMCT, which makes administration simpler and increases patient compliance. According to earlier research, metronomic chemotherapy may be able to control tumor growth with fewer side effects than traditional high-dose regimens by targeting the tumor microenvironment, namely by preventing angiogenesis and regulating the immune response (48, 53).

The current review has, however, a few limitations, including a small sample size and limited follow-up, indicating the need for larger randomized trials. The reporting of survival results, such as the duration of survival in some studies and the percentage of surviving patients in other studies, makes it difficult to effectively compare the results of the studies and also hinders the conduct of a meta-analysis of the extracted data. 67% of the included studies were conducted in India, which may have affected the results, as previous research shows that pharmaco-ethnicity impacts the treatment outcomes of patients undergoing various forms of anti-cancer therapy, primarily through polymorphism within the genes responsible for metabolism (54).

Standardization of reporting criteria is the next step in the systematic analysis of studies into oral metronomic chemotherapy, as it facilitates the proper comparison of treatment outcomes and statistical analysis of the efficacy of various metronomic drug dosages and multidrug combinations. Future studies should also explore biomarkers to identify patients most likely to benefit from OMC and examine combinations with immunotherapies for enhanced efficacy (8). The evidence supporting the efficacy of OMCT in HNSCC is promising, particularly in the context of recurrent or metastatic disease, where traditional treatments often fail. The advantages of OMCT include its favorable toxicity profile, ease of administration, and potential to be combined with other therapeutic modalities, such as immunotherapy. However, challenges remain, including identifying the optimal dosing regimens, understanding the long-term effects, and determining the patient populations that would benefit the most from this approach.

Based on the data collected and analyzed, oral metronomic chemotherapy showed a comparatively better survival compared to the standard chemotherapy regimens, particularly in the case of squamous cell carcinomas of the head and neck. However, it must be noted that there was heterogeneity in the usage of drug regimen and dosages among various studies, necessitating large scale multicentric studies for affirmation of the findings. The anti-angiogenic and immunomodulatory effects of OMCT, combined with its low toxicity, make it an attractive alternative to conventional chemotherapy. The utilization of OMCT for anti-cancer treatment has the added advantage of producing decreased drug resistance, which thereby increases the efficacy of the administered treatment.