Nasopharyngeal carcinoma (NPC), a malignant tumor, originates from the epithelial cells of the nasopharynx, and is characterized by a unique geographical location with particular prevalence in East and Southeast Asia (1). The incidence can be as high as 25 to 50 cases per 100,000 in southern China (2). According to the International Agency for Research on Cancer (IARC), approximately 129,000 people were diagnosed with nasopharyngeal cancer in 2018, which only accounts for 0.7% of total cancers diagnosed (3). Gender differences exist in the incidence of nasopharyngeal cancer, with a higher incidence in males than in females, and the ratio was approximately 2.5:1 in China in 2015 (4).

The World Health Organization (WHO) classifies nasopharyngeal carcinoma into three histological subtypes, namely keratinizing squamous cell carcinoma, nonkeratinizing (differentiated or undifferentiated) carcinoma, and basal-like carcinoma. Undifferentiated carcinomas are the most common in high prevalence areas, accounting for about 95% or more (1, 5, 6). Nasopharyngeal carcinoma may be associated with Chinese salt cured fish, passive smoking, oral health and oral microbiota as well as with infection of Epstein-Barr virus (EBV) of infection (7).

Compared with computed tomography (CT), magnetic resonance imaging (MRI) can better identify early-stage nasopharyngeal carcinoma, with greater sensitivity and discrimination of infiltration of adjacent soft tissue, skull base and cranial nerve infiltration, and involvement of retropharyngeal lymph nodes. With its advantages of high soft tissue resolution, multiparametric imaging and non-ionizing radiation, MRI has replaced CT as the first choice for diagnosis, staging, efficacy assessment and follow-up of nasopharyngeal carcinoma (8). Surgery is difficult to operate owing to its specific anatomical location. In contrast, nasopharyngeal carcinoma is highly sensitive to radiotherapy (RT), making it the primary treatment modality. Radical radiotherapy is the first-line treatment for early-stage nasopharyngeal carcinoma and the cornerstone of multi-disciplinary treatment for patients with locally advanced nasopharyngeal carcinoma (9, 10).

Conventional two-dimensional radiotherapy (2DCRT) was the main radiotherapy technique until the 1990s. 2DCRT is principally based on contraction field radiation techniques, where the target field is gradually reduced or modified to deliver the desired dose (11). However, conventional radiotherapy of the head and neck is associated with severe acute and late toxicity due to the limitations of its degree of consistency. Mucositis is the most common acute side effect caused by radiation to the oral mucosa, accompanied by severe pain, dysphagia and malnutrition. Other acute and late effects include xerostomia and taste disturbances, hearing loss, persistent xerostomia, radiological osteonecrosis of the mandible, and dysphagia (12–14). Although there is no significant impact on survival outcomes, quality of life can be severely diminished.

Over the past decade, intensity-modulated radiotherapy (IMRT) has replaced 2DCRT, which uses a dynamic multileaf collimator to adjust the shape and intensity of individual beams to achieve optimal dose distribution in the tumor region. A more conformal dose distribution allows IMRT to minimize dose delivery to organs at risk (OAR), including the brainstem, spinal cord, and optic cross (15–17). The application of daily image guidance (image-guided radiation therapy) also reduces the dose in the planned target volume (PTV), which further reduces normal tissue exposure (18). Compared to conventional two-dimensional (2D) or three-dimensional (3D) radiotherapy, IMRT provides high doses of radiation for nasopharyngeal cancer while protecting adjacent vital structures and reducing treatment toxicity (19–23). Moreover, due to dosimetric advantages (24), IMRT is also superior to 2DCRT in terms of preservation of parotid gland, improvement of quality of life (17, 21) and reduction of temporal lobe neuropathy (TLN) rate (20, 25) in patients with nasopharyngeal carcinoma. Patients with nasopharyngeal carcinoma treated with IMRT can achieve local control and overall survival rates of up to 90% and 80%, respectively (26, 27), which are better than those of 2DCRT (19, 22, 23, 28). Table 1 summarized the clinical data on IMRT versus 2D-CRT (29).

In order to achieve better prognosis, an uninterrupted routine radiotherapy schedule is an essential necessity for precise radiotherapy of nasopharyngeal carcinoma (36). Disruptions in radiotherapy, however, are inevitable for several unavoidable factors, such as public holidays (37) (the largest share, about 39-46%), machine failures, patient compliance, and adverse effects of treatment (38). Similarly, because of the pandemic of Corona Virus Disease 2019, confirmed positive patients had longer treatment interruptions, which led to fewer patients completing radiotherapy, thus increasing local disease progression (39).

The length of delayed treatment is a key indicator of the severity of treatment interruption (36, 40). It has been shown that 5-year survival is reduced by 10-20% in patients with squamous head and neck cancer who are treated for a total duration of up to 10 days beyond the original schedule, and even a one-day interruption results in 1.4% reduction in local control (41). The timing of radiotherapy interruption is of course important (42). Skladowsky et al. (43) reported that patients with supraglottic laryngeal carcinoma who interrupted radiotherapy on day 19 had lower local tumor control than those without a treatment gap. Generally speaking, nasopharyngeal cancer is extremely sensitive to radiotherapy. Interruption of radiotherapy or prolongation of treatment can have an adverse effect on the prognosis of patients (44, 45).

Tumor tissue regenerates at a faster rate than normal tissue, and the onset of rapid cell regeneration in tumor tissue during the treatment interval results in a lower radiobiologic dose to the planned target volume (PTV) (64). Radiotherapy interruption for nearly a full workweek and reduction in radiation service utilization may compromise the therapeutic benefit for patients because of the reduction in biological activity, which can lead to sublethal loss of repair (65).

At the beginning of radiotherapy, numerous tumor cells will be far from the capillaries and will therefore be in various states of oxygen deprivation. They will either be in a quiescent state or multiply at a much slower rate than when they were initially created. In addition, cell loss factor (CLF) is usually high while treatment is starting, especially in larger tumors. Tumors become smaller as radiotherapy proceeds, vascular distribution begins to improve, and CLF decreases. As a result, any cells that have not been killed by radiation begin to become better oxidized and begin to grow (repopulate) at or near their fastest rate (66). This involves the well-known 4R principles of radiotherapy, namely regeneration, repair, reoxygenation and redistribution. The kinetics of tumor regeneration are graphically summarized in Figure 1 , where the characteristic “dog-leg” shape shows that tumor repopulation remains close to zero after the start of treatment, meaning that the dose required to maintain TCP is essentially constant (horizontal line). After a delay of several weeks, the remaining cells begin to repopulate rapidly, and the additional dose required to kill new cells and maintain TCP increases linearly with time. Therefore, the uncompensated interruptions that lead to the extension of treatment to this period are particularly problematic (67). Unless additional doses are added, eradication of newly generated cells becomes unlikely and tumor progression is thus possible.

The time to tumor multiplication (Tpot) is an important issue in cancer treatment. A study by Delahaut et al. revealed a mean absolute tumor progression rate of 0.23 ± 0.2 cm³/day in 19 patients with squamous cell carcinoma of the head and neck (68). In more aggressive tumors, Tpot values may be surprisingly low, usually much less than 7 days, and re-proliferation rates are much faster (69–71). The delay of starting radiotherapy may lead to residual tumor proliferation after surgery. Besides, any tumor cells which were still existing at the end of the treatment are likely to grow at the fastest rate. If treatment is prolonged at this point, the increased time will allow for the generation of more cells.

Unless additional doses are added, eradication of newly generated cells becomes unlikely and tumor progression is thus possible. The kinetics of tumor regeneration are graphically summarized in Figure 1 , where the characteristic “dog-leg” shape shows that tumor repopulation remains close to zero after the start of treatment, meaning that the dose required to maintain TCP is essentially constant (horizontal line). After a delay of several weeks, the remaining cells begin to repopulate rapidly, and the additional dose required to kill new cells and maintain TCP increases linearly with time. Therefore, the uncompensated interruptions that lead to the extension of treatment to this period are particularly problematic (67).

Radiotherapy interruption can have varying degrees of impact on patient outcomes, and the possibility of such interruptions should be minimized in actual clinical practice. However, due to the existence of some irresistible factors, sometimes radiotherapy interruption cannot be avoided. When radiotherapy is interrupted, remedial measures should be taken as much as possible. For example, increase the number or dose of radiotherapy, or combine other treatment modalities to reduce the adverse effects caused by radiotherapy interruption.

FZ drafted the article. DY revised it critically. XL did final approval of the version to be submitted. All authors contributed to the article and approved the submitted version.