Background
Oral squamous cell carcinoma (OSCC) is one of the most common and aggressive
malignancies of the head and neck region. Despite advances in surgery,
radiotherapy, and systemic chemotherapy, the prognosis of patients with advanced,
recurrent, or inoperable disease remains poor. Conventional maximum-tolerated-
dose (MTD) chemotherapy is often associated with significant toxicities, including
neutropenia, mucositis, gastrointestinal disturbances, and organ dysfunction, and
generally requires prolonged treatment-free intervals. These intervals may permit
tumour regrowth and contributes to the development of treatment resistance.
Concept and Mechanism
Oral metronomic chemotherapy (OMCT) involves the continuous administration of
chemotherapeutic agents at relatively low doses and at regular intervals, without
prolonged treatment interruptions. Unlike conventional MTD chemotherapy, OMCT is
thought to exert its effects through multiple mechanisms. These include direct
inhibition of tumour-cell proliferation and suppression of tumour angiogenesis,
thereby limiting the formation of new blood vessels required for tumour growth and
progression.
Recent research has also highlighted the importance of the tumour
microenvironment and immune regulation in OSCC. Studies such as that by Kina
and colleagues (2023) have suggested that EphA4 signalling may contribute to an
immunosuppressive tumour microenvironment in OSCC. Modulation of such
molecular and immunological pathways may therefore represent a potential strategy
for improving tumour control and reducing the risk of disease recurrence.
Methods
This systematic review evaluated the efficacy and safety of oral metronomic therapy
in OSCC and selected other malignancies, including non-small-cell lung cancer,
metastatic breast cancer, and prostate cancer, with evidence published up to
December 2024. Randomized controlled trials, phase I/II clinical trials, and
retrospective cohort studies were considered for inclusion. The methodological
quality of randomized and non-randomized studies was assessed using the

Cochrane Risk of Bias tool and the Newcastle–Ottawa Scale, respectively. The
certainty of the available evidence was evaluated using the GRADE framework.
A total of ten studies were included in the review, of which five specifically evaluated
OSCC or head and neck cancers, while the remaining studies investigated OMCT in
other malignancies.
Key Findings
Oral Squamous Cell Carcinoma
Kashyap et al. (2021) reported that an OMCT-based regimen combined with
paclitaxel and carboplatin produced tumour reduction in patients with OSCC who
were considered unsuitable for surgery. Similarly, Shenoy et al. (2024) demonstrated
that OMCT may be a feasible neoadjuvant treatment approach, with encouraging
tumour response rates.
Combination Therapy
The meta-analysis by Shih et al. (2021) suggested that the combination of oral S-1
and radiotherapy may improve treatment outcomes and survival in patients with
head and neck cancers. These findings support the potential role of metronomic or
orally administered chemotherapy as part of multimodal treatment strategies.
Evidence from Other Malignancies
Evidence from other cancers also suggests potential benefits of metronomic
treatment strategies. In metastatic breast cancer, combinations involving agents
such as Vinorelbine, Capecitabine, and Apatinib have demonstrated therapeutic
activity. Similarly, studies investigating oral Vinorelbine in combination with
Atezolizumab have reported clinical activity in selected patients with castration-
resistant prostate cancer and in relapsed paediatric solid tumours. Although these
findings cannot be directly extrapolated to OSCC, they provide supporting evidence
for the broader potential of metronomic chemotherapy.
Safety and Patient Experience
Overall, OMCT was generally well tolerated across the studies reviewed. The most
frequently reported adverse effects were mild to moderate which included
gastrointestinal disturbances, fatigue, and mild haematological abnormalities. Severe
treatment-related adverse events were comparatively uncommon.
The oral route of administration may offer additional practical advantages, including
the possibility of treatment in an outpatient or home-based setting, reduced hospital
visits, and greater convenience for elderly or frail patients. These characteristics may
also facilitate treatment adherence and improve the overall patient human care
experience.

Conclusion
Oral metronomic chemotherapy represents a potentially valuable therapeutic
strategy for patients with advanced, recurrent, or inoperable OSCC, particularly in
clinical situations where conventional treatment options are limited. Its anti-tumour
and anti-angiogenic effects, favourable tolerability profile, and convenience of oral
administration make it an area of increasing clinical interest.
However, the currently available evidence remains limited and heterogeneous.
Further well-designed, adequately powered randomized controlled trials are required
to establish the optimal drug combinations, dosing schedules, treatment duration,
patient selection criteria, and long-term efficacy and safety of OMCT in OSCC. Until
such evidence becomes available, OMCT should be considered a promising
investigational or adjunctive approach rather than a replacement for established
standard treatments.

Authors
1. Dr. B. Sreenu
Intern, Department of General Pathology
SRM Dental College, Bharathi Salai, Ramapuram, Chennai, Tamil Nadu, India
2. Dr. K. Viswaja
Head of the Department, Department of General Pathology
SRM Dental College, Bharathi Salai, Ramapuram, Chennai, Tamil Nadu, India
3. Dr. Deepa
Tutor, Department of General Pathology, SRM Dental College, Bharathi Salai,
Ramapuram, Chennai, Tamil Nadu, India