Results and discussion

Head and neck cancer

Head and Neck Cancer represents one of the most frequently diagnosed malignancies. These malignancies originate in the UADT, affecting the mucosal lining of the oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx [2, 3]. Other less common sites include the skin of the head and neck area, the salivary glands, the nasal cavities, and the paranasal sinuses [2]. From a histopathological perspective, more than 90% of all cancers in the head and neck region are squamous cell tumors. Men experience a higher incidence of HNC compared to women, and it typically arises between the ages of 50 and 60 years [2]. Cancer of different types of salivary glands can also begin in HNCs, but this category of HNC is comparatively infrequent. Depending on the site in which cancer begins, HNCs are classified into different cancer groups, namely, oral cavity, salivary glands, pharynx, larynx, nasal cavity, and paranasal sinus [23].

Head and neck cancers consists of a heterogeneous group of malignancies arising from anatomically distinct sites, each characterised by specific ICD-O-3 topography codes and varying epidemiological patterns. As presented in Table 1, the major HNC sites include the lip and oral cavity (C00–C06), larynx (C32), hypopharynx (C12–C13), oropharynx (C01, C05.1–C05.2, C09–C10), nasopharynx (C11), and salivary glands (C07–C08). The lip and oral cavity encompass the lips and commissures, tongue (excluding the base of the tongue), gingiva, floor of the mouth, hard palate, buccal mucosa, and retromolar region whereas the larynx comprises the supraglottis, glottis, and subglottis. The hypopharynx includes the pyriform sinus, postcricoid region and posterior pharyngeal wall, while the oropharynx comprises the tonsillar fossae and pillars, vallecula, lateral and posterior oropharyngeal walls, base of the tongue, and soft palate. The major salivary glands include the parotid, submandibular, and sublingual glands, whereas the nasopharynx comprises its anterior, superior, posterior, and lateral walls. Although these anatomical subsites are clinically distinct, GLOBOCAN 2022 does not provide subsite-specific ASIR or ASMRs; therefore, epidemiological estimates for the individual subsites could not be included.

Types of HNC | Anatomical subsite of HNC | ICD-O-3 Codes | ASIR (100,000) | ASMR (100,000)
India | Asia | World | India | Asia | World
Lip & Oral cavity | • Lips & Commissures,• All surfaces of the tongue except the base of tongue,• Gingiva (upper and lower),• Floor of mouth,• Hard palate,• Buccal mucosa,• Retromolar trigone | C00 – C06 | 9.8 | 3.2 | 4.1 | 5.4 | 1.6 | 3.9
Larynx | • Supraglottis,• Glottis,• subglottis | C32 | 2.4 | 1.2 | 0.9 | 1.7 | 0.7 | 2.1
Hypopharynx | • Pyriform sinus,• Postcricoid region,• posterior pharyngeal wall | C12 – C13 | 2.1 | 0.6 | 1.2 | 1.6 | 0.4 | 0.8
Oropharynx | • Tonsillar fossae,• Tonsillar pillars (faucial arch),• Vallecula,• Lateral and posterior walls of oropharynx,• Base of tongue,• Soft palate | C01,C05.1 – C05.2,C09 – C10 | 1.5 | 0.7 | 1.3 | 1.1 | 0.5 | 1.1
Nasopharynx | • Anterior, superior, posterior, and lateral walls of nasopharynx | C11 | 0.4 | 1.9 | 0.6 | 0.3 | 1.1 | 1.6
Salivary glands | • Parotid,• Submandibular or submaxillary,• Sublingual glands | C07 – C08 | 0.6 | 0.5 | 2.0 | 0.3 | 0.3 | 0.5

Considerable geographical variation exists in the ASIR and ASMR of HNC subsite across India, Asia, and the world (Table 1). Lip and OCC exhibit the highest ASIR in India (9.8 per 100,000) which is considerably higher than the Asian (3.2 per 100,000) and global (4.1 per 100,000) averages, accompanied by a relatively high ASMR of 5.4 per 100,000 in India. Similarly, laryngeal, hypopharyngeal, and oropharyngeal cancers demonstrate higher incidence and mortality rates in India than in both Asia and the global population. In contrast, nasopharyngeal cancer has lower ASIR and ASMR in India, exhibits substantially greater disease burden in Asia. Salivary gland cancers contribute minimally to the overall HNC burden, accounting lowest incidence and mortality rates across all geographical region. These regional variations highlight the importance of subsite-specific epidemiological patterns, which are influenced by different environmental exposures, lifestyle factors, oncogenic viral infections, and healthcare access. The epidemiological burden of HNCs in India is discussed in the following section.

Incidence of HNC in India

Recent WHO statistics (2022) revealed that, HNSCC is the fifth most predominant cancer type globally, with the highest incidence and mortality rate being observed in the Asia region. Compared to other countries in Asia, India has seen a significant increase in the incidence of HNCs (Fig. 2a), accounting for approximately 30–40% of all cancer cases [24]. According to the IARC report, HNC statistics of India indicate an annual incidence of 2,51,613 cases, comprising 1,43,759 cases of lip and OCC, 35,855 of the larynges, 30,510 of the hypopharynxes, 23,174 of the oropharynges, 8,107 of the salivary glands, and 6,519 of the nasopharynges, respectively. The percentage distribution of HNCs in India is diagrammatically represented in Fig. 4. In men, around 28% of all cancers are HNCs, compared to 8% in women, with a lifetime risk of 1 in 33 for men and 1 in 107 for women. India experiences a higher HNC burden compared to the USA, UK, Australia, Africa, and Brazil [25]. More than 12,00,000 individuals were diagnosed with HNSCC around the world in 2022 [26]. However, in India, they generally include one-third of all the cancer cases and the number is anticipated to twofold by 2030. HNC is the commonest malignancy experienced in Indian males. Moreover, OCC is the foremost prevalent type among males and one of the most noteworthy over the globe. Across central, eastern, northern, southern, and western regions of India, mouth cancer has emerged as the predominant cancer site compared to the cancers of the tongue, larynx, and hypopharynx [25].

Fig. 4: Percentage distribution of HNC incidence in India as reported in GLOBOCAN, 2022

A number of factors play a role in elevating the risk of HNC. As per the Indian Council of Medical Research (ICMR), the sharp upward trend in HNC cases is due to extensive smoking and the use of tobacco, alcohol consumption, pan masala (which includes BQ, areca nut, and slaked lime), and gutkha [3, 24, 27]. Moreover, poor oral hygiene, micronutrient deficiencies, and HPV infection are reported to play a role in elevating the risk of HNC. In India, cases of oral and tongue cancers are elevated due to the widespread habit of tobacco chewing [28]. As previously mentioned, India’s global contribution of HNC patients is 57% [28]. Over the years, the rising use of tobacco has resulted in India accounting for nearly 60% of global HNC cases.

Age-standardised incidence and mortality rates of HNC in India

Figure 5 (a and b) illustrates the substantial burden of HNCs in India, revealing a significant gender disparity in disease distribution based on GLOBOCAN 2022 data [29]. Although both genders share similar high-risk sub-sites, the absolute burden is considerably higher in males [30]. Lip and OCC emerge as predominant sites for both genders; however, the ASIR for males (14.7) and ASMR (8.1) are approximately three times higher than female equivalents (ASIR: 4.9; ASMR: 2.9) in India [29]. Other important sites in males, like the larynx (4.2) and hypopharynx (3.5), exhibit significantly higher incidence rates than in females (0.6 and 0.7, respectively). This is probably due to males’ increased exposure to primary carcinogens such as tobacco use [29, 30].

Fig. 5: Estimated ASIR and ASMR in India for (a) Males and (b) Females

A high Mortality-to-Incidence Ratio (MIR) is still present in both sexes especially in cases with late-stage oral diagnoses and pharyngeal cancers, indicating systemic difficulties in early detection and timely intervention [29]. With ASIR values below 1.0, minor salivary gland and nasopharyngeal cancers are still comparatively uncommon in both populations. This epidemiological profile highlights the urgent need for inclusive public health initiatives in India that guarantee all-encompassing care and encourage early screening and prompt detection based on the population’s distinct risk profiles [29].

Comparison of ASIR and ASMR for HNC’s in India and Asia

Based on GLOBOCAN 2022 data, the comparative analysis reveals a notable difference in the burden of HNC between India and Asia (Fig. 6). With an overall ASIR of 9.8, which is higher than the Asian average of 3.2, Lip and OCC are the most predominant subsite in India. Indian males bear a significantly higher burden with an ASIR of 14.7, nearly three times the rate seen in females (4.9), highlighting a critical public health crisis [29, 30].

Fig. 6: Estimated ASIR and ASMR for India and Asia

India reports a notably lower burden of nasopharyngeal cancer with an overall ASIR of 0.4 compared to 1.9 for the rest of Asia, despite leading in the majority of HNC subsites, including the larynx and hypopharynx [31]. Across all subsites, MIR persist in India and Asia, indicating many cases are diagnosed at advanced, often fatal stages, emphasizing the need for aggressive, tailored tobacco cessation and early screening programs [32].

The comprehensive risk profile of HNC in India

The prevalence of cancer is still rising dramatically worldwide. Tobacco use continues to be the primary cause of HNC, accounting for about 45% of cases globally. In India, however, tobacco and alcohol drive nearly 75% of HNC cases (Fig. 7); current data indicates that 38% of men and 9% of women aged 15 to 49 utilize high-risk products, such as bidis and smokeless tobacco [33]. Individuals who have used tobacco in chewing form are estimated to have an 80% higher risk of developing OCC [34].

Fig. 7: Risk factors of HNC in India

Alcohol consumption is another critical independent risk factor, contributing to roughly 17.5% of HNC cases, particularly in the hypopharynx, with higher risks associated with potent spirits and heavy daily intake [35]. Individuals who both smoke heavily and drink frequently have a considerably higher risk of HNC, that are projected to be major contributors to the growing global incidence of HNSCC with the greatest impact seen in developing nations [36].

In addition to smoking and alcohol, the widespread habit of chewing BQ, is responsible for nearly 35% of HNC cases in India. BQ with tobacco, a traditional mixture of areca nut and lime, is a primary driver of the high HNC rates in India due to its potent carcinogenic properties [35, 37].

Infections like HPV now account for roughly 10% of cases; as of 2020, India contributed to 24% of all HPV related cancer cases globally. High-risk strains like 16 and 18, is a major driver of oropharyngeal cancers, specifically target the tonsils and the base of the tongue, often affecting younger populations regardless of tobacco history [38, 39].

Additionally, 12.5% of cases are caused by poor oral hygiene, which includes gum infections, missing teeth, and ill-fitting dentures. These conditions cause chronic physical trauma to the oral mucosa, which can trigger malignant transformations The risk spectrum completed by dietary habits and environmental exposures, with unhealthy diets linked to approximately 15% of cases [33]. An additional 3% of the burden comes from occupational hazards in sectors like construction and textiles where workers are exposed to formaldehyde, asbestos, and wood dust. When coupled with environmental factors like prolonged UV light exposure on the lips and genetic predispositions associated with Asian ancestry, these factors create a multifaceted public health challenge that necessitates targeted prevention strategies for the Indian population [33, 37]. The global burden, risk factors, anatomical sites, and advances in radiotherapy techniques for managing HNC are presented in the schematic Fig. 8.

Fig. 8: Overview of global burden, risk factors, anatomical sites, and advances in the management of HNC

Advances in radiotherapy for HNC

The choice of the treatment is mainly based on the tumor stage, anatomical location, extent of disease and patients’ overall health and personal condition. Aim of the curative treatment is to completely eliminate cancer in order to achieve long-term survival or complete cure. It is commonly indicated for patients with early stage or advanced-stage HNCs. Successful curative treatment requires high dose of radiation delivered to the tumor with minimum irradiation of adjacent healthy tissues. Following are the various techniques used in curative treatment.

Conventional radiotherapy and three-dimensional conformal radiotherapy (3D-CRT)

Before 2000, RT was typically delivered using a simple conventional technique called 2DRT, which involved a single photon beam administered from two to four beam angles to treat the target volume [40]. However, this approach often resulted in significant side effects, particularly in HNC sites. Over the past three decades, radiotherapy planning has advanced from 2D to 3D image guided treatment planning. Even though 2DRT provided acceptable clinical outcomes, due to its limitations in target localization and normal tissue sparing resulted in the widespread adoption of 3D imaging based radiotherapy techniques for the curative management of HNSCC [26]. In 3DCRT, radiation beams are conformed to the shape of the tumor volume and an appropriate adjacent tissue margin is given to address microscopic disease spread. The design and delivery of RT treatment plans based on 3D image data with highly focused beams of radiation, allows precise dose to irregular tumour volume and reduces exposure to surrounding tissues when compared to traditional 2DRT [41].

Intensity modulated radiation therapy (IMRT)

Intensity modulated radiation therapy is the preferred radiotherapy technique for the HNC treatment, because of its complex anatomy and high risk of radiation induced toxicities. It is an advanced form of 3DCRT, that provides improved dose conformity around the irregularly shaped tumors while reducing the dose to the adjacent normal structures, introduced in the early 2000s [42]. It has become the standard method due to its ability to precisely target the primary tumor and regional lymph node while minimising the dose to brain, brain stem, optic nerves, parotid and salivary gland, thus achieving adequate target volume coverage and locoregional control [43].

Image guided radiation therapy (IGRT)

Image guided radiation therapy, another sophisticated advancement in the field of oncology, significantly utilizes imaging methods such as X-ray, CT, MRI with RT equipment to improve the precision in dose delivery. The core principle of IGRT is the integration of real-time imaging throughout treatment, allowing immediate corrections to beam alignment and patient positioning. This reduces margins around the tumor, minimising damage to healthy tissue. IGRT is now an integral part of RT delivery for HNC patients [44].

Volumetric modulated arc therapy (VMAT)

Although IMRT is widely used in the management of HNC treatment, concerns remain regarding the increased monitor units and prolonged treatment delivery times. VMAT is a technique that involves continuous delivery of radiation at various angles of a treatment beam as a linear accelerator rotates around the patient [45]. Using techniques of dynamic adjustments of multiple leaf collimator (MLC) positions, gantry rotation, and dose rate, it is possible to prescribe dose distributions highly conformal to complex target volumes, sparing the most sensitive critical structures such as the brain, brainstem, oral cavity, and parotid glands [46]. The lower monitor requirement and faster treatment delivery of VMAT increases patient comfortability, reduces intrafraction motion and improves efficiency, therefore is now emerged as one of the standard radiotherapy treatments for the HNCs.

Stereotactic radiosurgery (SRS) and Stereotactic radiotherapy (SRT)

Stereotactic radiosurgery is the highly precise radiotherapy technique that delivers a single high dose or few high dose fractions to small intracranial lesions using advanced image guidance. It is a non-invasive treatment, initially designed to treat small brain tumors and functional neurological disorders. The purpose is to deliver high radiation dose to eradicate the tumor while achieving durable local control [47]. Although SRS consists of a single treatment session, multiple stereotactic treatment sessions are more preferred for larger tumors (over approximately 1 inch in size). This is because to improve treatment safely and provide sufficient time for healthy tissues to recovery between treatment fractions. This technique is known as fractionated SRT, typically consists of two to five fractions of highly focused radiation delivered over non-consecutive treatment days [48]. In the care of patients with HNCs, its application is generally restricted to small, well-defined intracranial targets like skull-base tumours, cranial nerves, recurrent HNCs and brain metastases from primary HNC rather than for primary extracranial HNCs. Both SRS and SRT offer effective management of patients with local recurrence, achieving tumor control with a lower risk of cognitive toxicity.

Stereotactic body radiation therapy (SBRT)

An advanced non-invasive technique for delivering a high dose of targeted radiation therapy to a small, well-defined target and spare the surrounding tissue is SBRT. It delivers high doses of radiation to the tumor in a few fractions over a treatment course of one to two weeks. SBRT is primarily used for extracranial tumors, including selected HNCs rather than as a routine treatment for newly diagnosed disease [49]. Its principal applications include re-irradiation of recurrent HNCs, treatment of medically inoperable patients, small unresectable tumors, and management of small localized recurrences. This highly conformal radiation delivery is achieved through advanced imaging techniques including CT and MRI, which provide accurate tumor visualization and precise beam targeting [50]. SBRT can be particularly beneficial for patients who cannot tolerate lengthy treatment courses and reduces the likelihood of toxicities associated with conventional RT. Recent developments in treatment planning and radiation therapy technologies are improving the precision and efficiency of SBRT delivery for patients with HNC [51].

Tomotherapy

Another innovative technique in cancer care is Tomotherapy, a IGRT platform that combines helical IMRT with integrated daily megavoltage computed tomography (MVCT) imaging. The combination of these technologies allows the radiation beam to accurately target the tumor according to its shape, size and location [52]. During the treatment, exact location of the tumour and normal structures is verified with the help of a CT scan and these tumours, whether they are large or small, one or many, can be treated in the same session. In HNCs, Tomotherapy is particularly beneficial for patients with extensive primary tumours, or irregular target volumes located adjacent to multiple organs at risk (OAR) [53]. Compared to conventional radiotherapy, tomotherapy was found to be beneficial by improvement of OAR sparing and more homogeneous dose distributions.

Proton therapy (PT)

Proton therapy is another form of radiotherapy that utilizes proton particles in place of conventional photon beams. Its principal advantage lies on the characteristic Bragg peak, where protons deliver most of their energy at a specific depth, thereby minimising the exit dose outside the target region. It is increasingly used for selected patients with skull base tumours, HNCs, and cases requiring re-irradiation. In the treatment of HNCs, because of the close anatomical location of critical OARs, the radiation dose must be strictly limited [54]. Due to its unique physical properties, PT has the ability to reduce treatment-related toxicities and patient side effects while ensuring tumor control comparable to modern photon-based techniques [55]. So compared to conventional photon radiotherapy, PT improves the capability of protecting surrounding healthy tissue, but has the limitations in high costs of installation, availability and the need for specialized treatment facilities.

Adaptive radiotherapy (ART)

Although IMRT and VMAT are widely implemented for the treatment of HNCs in most healthcare settings, it has steeper dose fall-off beyond the target. These dose gradients signify that even small variations in the tumor volume, OAR location or anatomical changes, will have the effect of causing insufficient target coverage and increased dose to OARs [56]. During HNC treatment, anatomical modifications usually happen as from the initial therapy sessions, which includes the shrinking of tumors and even healthy tissues leading to organ movement and position changes relative to other structures. These minimal changes results in large variations in the dosimetric distribution. The one potential option to mitigate such events is called adaptive radiotherapy (ART), which necessitates re-scanning patient by CT and modifying plan according to the new anatomy [57].

Palliative radiotherapy

Although many advances in RT have improved the outcomes in curative-intent treatment, universal guidelines for palliative treatment remain lacking. Palliative care, “treatable but not curable cancers”, an integral component of supportive oncology, which aims to relieve tumour-related symptoms including pain, bleeding, dysphagia, airway obstruction, tumor ulceration or foul-smelling lesions, preserve organ function. It is commonly offered to minimise treatment burden in patient with locally recurrent, metastatic disease, and unresectable HNCs [58]. Compared with curative treatment, palliative radiotherapy generally involves shorter treatment courses and lower total radiation doses, allowing rapid symptom relief, reduction in tumor size, and treatment-related toxicity. In selected patients, modern treatment modalities like IMRT, VMAT, or SBRT may be used to optimize dose distribution and spare adjacent normal tissues, particularly in re-irradiation. Palliative radiotherapy is a cost-effective and widely available treatment modality, plays a pivotal role in effective symptom management and improved quality of life in patients with incurable HNC [59]. Although the advent of immunotherapy, particularly immune checkpoint inhibitors has improved survival rates and long-term protection with fewer side-effects, their high cost, limited affordability and availability for specialized healthcare settings continues to pose significant challenges in many low and middle-income countries, including India. Consequently, despite advances in immunotherapy, palliative radiotherapy is generally more affordable, accessible and effective option for symptom control and quality of life improvement in patients with advanced HNCs [60, 61]. Optimal outcomes of the treatment depend on appropriate patient selection, timely access to treatment, and comprehensive multidisciplinary supportive care.

Advancements in radiation therapy are vital to overcome challenges in treating HNCs to improve therapeutic outcomes and reduce adverse effects [62]. Tumor complexity and anatomical challenges arise because HNCs often occur near vital structures like the spinal cord, salivary glands, and optic nerves; advancements in radiotherapy enable precise tumor targeting, reducing radiation dose to these critical organs and lowering the risk of severe side effects. Personalization of treatment through integration of radiomics and artificial intelligence enables individualized planning by analysing imaging data to predict tumor response and toxicity risk, moving beyond a one-size-fits-all approach and improving both efficacy and safety [63]. Technological advances in imaging, treatment delivery, and computing power make it possible to monitor in real-time and adjust treatments during radiotherapy, which increases treatment precision and patient safety. Overall, these improvements address the limitations of traditional radiation therapy, boost tumor control, minimize treatment-related toxicity, and ultimately enhance survival and quality of life for patients with HNCs [62].