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Role of cetuximab in recurrent and/or metastatic head and neck cancer (R/M-HNC) in the era of immunotherapy: Consensus from India
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Received: ,
Accepted: ,
How to cite this article: Chandrakanth MV, Bajaj R, Bakshi C, Deshmukh C, Dubey AP, Ghosh J, et al. Role of cetuximab in recurrent and/or metastatic head and neck cancer (R/M-HNC) in the era of immunotherapy: Consensus from India. South Asian J Cancer. 2026;15:123-37. doi: 10.25259/SAJC_39_2025
Abstract
Recurrent or metastatic squamous cell carcinoma of the head and neck (R/M-HNSCC) is a difficult-to-treat cancer. Indian patients with R/M-HNSCC are very different from Western patients as they have oral primaries, tobacco-driven aetiology, and high tumour burden. Historically, platinum-based chemotherapy has been the most used and guideline-recommended treatment for R/M-HNSCC in India. However, platinum-based chemotherapy does not demonstrate a median overall survival beyond nine months and results in high haematological toxicity. Targeted therapies such as cetuximab-based regimens and immunotherapy have recently been added to Indian R/M-HNSCC guidelines. Immunotherapy is not feasible in the Indian setting due to a unique patient population with highly symptomatic disease and high tumour burden. Immunotherapy is also costly and not affordable to several patients in India. On the other hand, cetuximab is effective in Indian R/M-HNSCC patients with high tumour burden and highly symptomatic disease, and Indian guidelines recommend adding cetuximab to platinum-based regimens in R/M-HNSCC to improve survival. Though cetuximab is an expensive drug, the availability of cetuximab biosimilar in India has significantly improved the affordability of cetuximab-based regimens in Indian patients with R/M HNSCC. This expert opinion from India drafted ten consensus statements highlighting the various clinical settings where cetuximab-based regimens can benefit Indian R/M HNSCC patients.
Keywords
Cetuximab
Anti-epidermal growth factor receptor
Cetuximab
Extreme regimen
Head and neck cancer
High tumor burden
TPExtreme regimen
Paclitaxel
carboplatin
and cetuximab regimen
INTRODUCTION
Head and neck cancers (HNC) are the third most prevalent cancers worldwide.[1] Overall, 57.5% of HNCs worldwide occur in Asia [2], and especially in India, where HNCs account for ~30-40% of all cancers.[2-5] The high HNC incidence (20.9 to 25.9/100,000 for males and 6.1 to 8.0/100,000 for females) in India is primarily because of the prevalent use of tobacco.[4,5]
Though a disease of the sixth or seventh decade of life, HNC is increasingly seen in the younger population in India.[4,6] However, 20 to 39% of HNC patients are ≥60 years.[6,7] The age-standardised HNC incidence rate for patients ≥60 years is reported to be 114.9 and 36.9 per 100,000 population for males and females, respectively.[4]
Squamous cell carcinomas of the head and neck (HNSCC) account for 90% of all HNCs.[3,6,8] About 10% of HNC patients have distant metastasis at diagnosis.[9,10] Sixty percent of the HNSCC patients experience locoregional recurrence, and 20% experience distant metastasis while on treatment.[11]
Recurrent or metastatic HNSCC (R/M-HNSCC) is a difficult-to-treat cancer. The treatment choice in R/M-HNSCC depends on the performance status, comorbid conditions, prior treatment, recurrence-free interval, symptom burden, tumour burden, patient preference, and logistics.[9,12,13]
Historically, platinum-based chemotherapy (cisplatin or carboplatin) with 5-fluorouracil (5-FU) or taxane had been the first-line treatment for inoperable R/M- HNSCC patients with good performance status.[9,14] However, the regimen failed to demonstrate an improved overall survival (mOS typically around 9 months) and resulted in high haematological toxicity.[9,14]
The epidermal growth factor receptor (EGFR) is overexpressed in >90% of HNSCCs, and 10%–30% of HNSCCs show EGFR gene amplification; EGFR expression is associated with more aggressive disease.[15] Hence, strategies targeting EGFR expression were considered to improve OS and reduce the toxic effects of chemotherapies. However, none of the EGFR inhibitors (nimotuzumab, panitumumab, or zalutumumab), except cetuximab (EGFR-inhibiting immunoglobulin G1 chimeric monoclonal antibody), showed appreciable response in R/M-HNSCC.[15,16]
Cetuximab added to platinum–5-FU chemotherapy (EXTREME regimen) demonstrated a 2.7-month increase in the mOS (10.1 vs. 7.4 months), 2.3-month increase in progression-free survival (PFS) (5.6 vs. 3.3 months), a 16% increase in objective response rate (ORR) (36% vs 20%), and reduced the relative risk of death by 20% compared with platinum–5-FU chemotherapy alone.[17] The US Food and Drug Administration (FDA) approved cetuximab in 2006 in combination with platinum-5FU for treating R/MHNSCC.[18] Further, cetuximab added to platinum-taxane (TPEx regimen) improved the mOS to 14.5 months, and demonstrated fewer toxicities.[19]
Based on the Keynote-048 study[20], pembrolizumab-platinum-5FU (immuno-chemotherapy or IC) became the National Comprehensive Cancer Network (NCCN) guidelines recommended preferred systemic therapy for R/M HNSCC, irrespective of programmed death-ligand 1 (PD-L1) status.[21] Further, the NCCN also preferred immunotherapy alone (IO) with pembrolizumab for patients with PD-L1 combined positive score (CPS)≥ 1, especially for those with CPS ≥20.[21]
However, despite the OS advantage and PFS-2 of 11 months in the Keynote-048 study, first-line[20] IC/IO may not be feasible for Indian patients who have different profiles (e.g., oral primaries, tobacco-driven aetiology, and high tumour burden [HTB]) than patients recruited in the Keynote-048 study (human papillomavirus [HPV]-related aetiology.[22] Further, the OS benefit in Keynote-048 was primarily seen in the CPS ≥20 subgroup. The cost and accessibility of IC/IO and PD-L1 CPS testing can be a notable barrier to adopting immunotherapy in India's front-line treatment paradigm of R/M-HNSCC.[23] Hence, in metastatic disease at initial presentation, Indian guidelines still recommend first-line chemotherapy with a single agent or a combination of docetaxel/paclitaxel/cisplatin/carboplatin/5-FU/cetuximab.[24,25] In patients with recurrent or persistent disease, the Indian guidelines recommend adding cetuximab to chemotherapy regimens such as cisplatin plus 5-FU, carboplatin plus paclitaxel / or docetaxel to improve the overall survival.[24,25]
Though targeted therapies like cetuximab are also costly[26,27], the approval of high-quality cetuximab biosimilar by the Drugs Controller General of India (DCGI)(7) is expected to improve access and affordability of cetuximab-based treatments for R/M-HNSCC.[23] The biosimilar was found to be non-inferior to the innovator drug in Indian patients with R/M-HNSCC.[23]
In light of these challenges in treating R/M-HNSCC, leading oncologists from India convened to conceptualise and draft a consensus on the role of cetuximab in R/M-HNSCC in an era of immunotherapy.
MATERIAL AND METHODS
Consensus process
This consensus was derived after two online advisory board meetings held during November 2024, attended by 16 eminent oncologists from India.
The consensus statements were generated through a modified Delphi method as shown in Figure 1.[28] The steps included a comprehensive literature search carried out before the meeting. MEDLINE (PubMed) and Google Scholar free databases were searched using keywords such as cetuximab, 'recurrent/metastatic head and neck cancer', R/M-HNC, 'recurrent/metastatic squamous cell carcinoma of head and neck', R/M-HNSCC, 'cetuximab in the era of immunotherapy', and 'India'. Data and literary evidence on the management of R/M-HNC/R/M-HNSCC were collected from Indian and international guidelines, randomised controlled trials (RCTs), landmark trials, real-world, and observational studies, and shared with the oncologists. Evidence-based statements supporting the role of cetuximab in /R/M-HNC/R/M-HNSCC were generated. The literature and statements were presented during the meeting and discussed in detail.
After moderator-mediated discussion on each statement, voting was carried out (agree/disagree). A statement was accepted as the “Consensus Statement” only if ≥80% of the panel members voted in favour (agreed).
If <80% of panellists voted in favour of any statement, it was re-discussed and modified according to the suggestions of the panellists and accepted as consensus only if ≥80% of panellists agreed with the statement.
Cetuximab-guideline recommendations
Indian and International guidelines recommend cetuximab-based regimens in R/M-HNSCC [Box 1].[7,21,24,25]
| NCCN 2024 | Indian (very advanced HNSCC) | Indian (cetuximab use in HNSCC) |
|---|---|---|
| Recommends the KEYNOTE-048 regimen as the preferred regimen in first-line | For metastatic (M1) disease at initial presentation: Recommends single agent or combination therapies with docetaxel paclitaxel/cisplatin/carboplatin/5- FU/cetuximab in metastatic (M1) disease at initial presentation (EL I; Grade A). Also recommends immunotherapy with pembrolizumab or pembrolizumab + platinum |
Recommend cetuximab-based regimen in 1L R/M-HNSCC |
| Cetuximab-based regimens are also recommended in first- and subsequent lines: • Combination regimens • Cetuximab/platinum (cisplatin or carboplatin)/5- FU (EXTREME)(category 1) • Cisplatin/cetuximab • Cisplatin or carboplatin/docetaxel/cetuximab (TPEx) • Cisplatin or carboplatin/paclitaxel/cetuximab (PCC) • Cetuximab/pembrolizumab/nivolumab Single Agents • Cetuximab |
Recommend TPEx over EXTREME regimen and CHANGE-2 | |
| For recurrent or persistent disease: Recommends addition of cetuximab to cisplatin plus 5-FU (EXTREME), carboplatin plus paclitaxel (PCC/CETMET), or cisplatin/carboplatin plus docetaxel (TPEx) to improve overall survival. | Consider cetuximab-based regimens effective and safe in geriatric patients fit to receive systemic therapy. | |
| Recommend use of 1L cetuximab-based | ||
| regimens followed by ICI in 2L to improve OS and ORR | ||
| Recommends immunotherapy (pembrolizumab or nivolumab) for patients who progress on first-line chemotherapy (with or without cetuximab) | Suggests the use of cetuximab biosimilar as it has received DCGI approval, and its efficacy and safety data meet international standards |
DCGI: Drugs Controller General of India, NCCN: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, R/M-HNSCC: Recurrent/metastatic squamous cell carcinoma of the head and neck, ICI: Immune checkpoint inhibitor, 2L: Second line, OS: Overall survival, ORR: Objective response rate. CHANGE-2 = Modified EXTREME regimen (Cetuximab + Cisplatin + 5-FU) with 25% dose reduction of cisplatin and a 6.25% total dose reduction of 5-FU for 5 days.
Overview of the consensus statements
Ten statements received >80% consensus in favour of the statement and were accepted by the expert panel. The ten statements and their voting results are shown in Figure 2.
Statement 1: In Indian patients, the oral cavity is the most commonly affected site with R/M- HNSCC
Statement 2: More than 25% of patients with HNSCC have recurrent/metastatic disease in India.
Statement 3: The majority of patients with HNSCC in India have a high tumour burden.
Literary evidence presentation and discussion
Indian HNSCC patients seen in routine clinical practice have unique characteristics and have different genetic and etiological factors compared to those in the western world.[7,22,29]
Lip and oral cavity cancer is the most common HNC (varies from 41% to 58.4% to as high as 72%) in India, followed by larynx (varies from 17.2% to 20% to as low as 6.5%), and naso/oro/hypo-pharynx (24.4% to 34%).[2,7,30] The GLOBOCAN 2022 data showed that HNC (lip and oral cavity) was the second most frequent cancer in India, with the highest frequency in males and the fourth highest frequency in females.[31] The 5-year prevalence of lip and oral cavity cancer in India is 26.3%[31], and the number of oral cavity cancer cases is projected to increase from 57,380 in 2020 to 64,519 in 2025.[32] The GLOBOCAN 2022 data also show that lip and oral cavity cancer is the second most common cause of cancer-related deaths in India.[31] Oral cavity cancer was present in 55.6% of Indian R/M-HNSCC patients treated with a cetuximab-based PCC regimen.[22]
Further, 66% of HNCs in India are diagnosed at a locally advanced stage (III or IV), and 50% of them develop locoregional recurrence at 2 years.[10,33] Indian patients with R/M-HNSCC have an aggressive disease course, high tumour burden (HTB), and high symptom burden.[7] Despite advances in multimodal treatments, approximately 10%-11.7% of HNC patients have distant metastases at diagnosis, while 20%–30% (25-30% for N3 disease and 18-20% for N2 disease) develop distant metastasis during the disease course.[9,10,34-36]
Patients with poorly differentiated cancers and higher nodal burden (N2/3) have a higher rate of distant metastasis.[35,37] The literature shows that the OS in R/M-HNSCC decreases with the number of distant metastases (5-year OS: 35% for single vs. 4% for multiple metastases).[38] The prognosis of R/M - HNSCC is generally poor, with a median overall survival (mOS) between 6 and 15 months.[9,10]
Medical oncologists who helped formulate the 'Practical Consensus Guidelines on the use of Cetuximab in HNSCC' reported that >50% of their patients had high-risk features at initial presentation, and 20 to 39% of their patients were in the geriatric age group (≥60 years).[7] The most common high-risk features in HNSCC reported by Indian studies include smoking, smokeless tobacco, and alcohol consumption.[2,39-42] Tobacco use in any form is the single most common risk factor for oral cancer in India, identified in 80 to 90% of the patients.[2] Cigarette smoking is a less common method of using tobacco in India compared to the Western world.[43] Bidi smoking is more prevalent in India than cigarette smoking. Further, chewing some form of tobacco(smokeless tobacco) is also very common in India, and is considered to be a major health risk and associated with increased mortality risk.[43]
HPV is the most common etiological factor for HNCs in the Western world.[7,22] On the contrary, various Indian studies have shown a low association between HPV and HNSCC, including oral cancer.[5,39] In general, HPV-positive patients have more favourable outcomes compared to HPV-negative patients.[7,44]
Another differentiating factor in Indian HNSCC patients is the high burden of comorbidities.[3,45,46] A Tata Memorial Hospital study from India reported that 56.6% of HNC patients presented with comorbidities such as hypertension (29.1%), diabetes mellitus (25.5%), cardiac diseases (6.2%), and respiratory diseases (6.0%).[45] The study showed that 20.6% of the patients with comorbidities did not receive the ideal guideline-recommended therapy and had lower survival rates than patients without comorbidities who received guideline-recommended therapy.[3,45]
Another Indian study of R/M-HNSCC patients treated with the first-line paclitaxel, carboplatin, and cetuximab (PCC) regimen showed that 50% of the patients had comorbidities. The most frequent comorbidities were hypertension (35.2%), diabetes mellitus (25.9%), cardiac dysfunction (11.1%), and renal dysfunction (13%).[22]
Panel disposition and voting results
Poll question 1: A poll was conducted during the discussion of the literary evidence for the first three statements for the question: “Which key characteristics of the Indian R/M HNSCC patients make them different from the Western population?”
The oncologists were asked to select all options that applied to the question. Four options were given: smoking/smokeless tobacco aetiology, HPV-ve disease, presence of comorbidities, and high tumour burden. The combined poll results of the two meetings are shown in Figure 3. According to 31% of the experts, all the options (smoking/smokeless tobacco aetiology, HPV-ve disease, presence of comorbidities, and high tumour burden) differentiated the Indian HNSCC population from the Western population.
The voting results for the first three consensus statements are shown in Figure 2.
Statement 4: When using cetuximab-based regimen in R/M HNSCC patients, TPEx, PCC and CHANGE-2 are the preferred regimens
Literary evidence presentation and discussion
EXTREME trial
The EXTREME trial (Erbitux in first-line treatment of recurrent or metastatic head and neck cancer) was pathbreaking in the treatment milieu of R/M-HNSCC. For the first time in 30 years of treating R/M-HNSCC with platinum-based chemotherapy, Vermorken et al. (2008) demonstrated that the addition of cetuximab to the standard cisplatin-5FU significantly improved the outcomes in patients with R/M HNSCC without adversely affecting the safety profile [Table 1].[13,17,19,47,48] There was a 2.7-month increase in OS (20% reduction in the relative risk of death) and a 2.3-month prolongation of PFS (46% reduction in the risk of disease progression) as compared with platinum– fluorouracil chemotherapy alone [17]
| Parameters | EXTREME | TPEx/TPExtreme vs. EXTREME | CETMET EXTREME vs. TPEx | CHANGE2 (Modified EXTREME) |
|---|---|---|---|---|
| Regimen | Cetuximab + cisplatin + 5-FU vs. chemotherapy alone | Cetuximab + cisplatin + docetaxel (TPEx) vs. Cetuximab + cisplatin + 5-FU (EXTREME) | Cetuximab + 5-FU/cisplatin or carboplatin (arm A: EXTREME) vs. cetuximab + paclitaxel/carboplatin (arm B: TPEx-like regimen) | Cetuximab + cisplatin + 5-FU vs. chemotherapy alone |
| Cetuximab dosing | Cetuximab on days 1, 8, and 15 (IV 400 mg/m2 on day 1 of cycle 1 and 250 mg/m2 weekly subsequently; even for maintenance) | Cetuximab on days 1, 8, and 15 (IV 400 mg/m2 on day 1 of cycle 1 and 250 mg/m2 weekly subsequently; cetuximab 500 mg/m2 every 2 weeks as maintenance) | Cetuximab on days 1, 8, and 15 (IV 400 mg/m2 on day 1 of cycle 1 and 250 mg/m2 weekly; cetuximab 500 mg/m2 every 2 weeks as maintenance) | Cetuximab dosing same as used in the EXTREME trial. The dose of chemotherapy was modified |
| ORR (%) | 36 vs. 20 (OR: 2.33; p <0.001) | 57 vs. 59 | 20 vs 22 patients | 50.0% vs 26.6% |
| DCR (%) | 81 vs. 60 (OR: 2.88; p <0.001) | NE | NE | NE |
| OS (months) | 10.1 vs. 7.4 (HR: 0.80; p= 0.04) | 14.5 vs. 13.4 (HR: 0.89; p= 0.23) | 8.4 vs. 10.2 (HR: 0.71; p= 0.166) | 11.1 vs. 8.9 (HR: 0.69) |
| PFS (months) | 5.6 vs. 3.3 (HR: 0.54; p <0.001) | 6.0 vs. 6.2 (HR: 0.88; p= 0.14) | 4.37 vs. 6.5 (HR: 0.65; p= 0.063) | 5.5 vs. 4.2 (HR: 0.57) |
ORR: Objective response rate, OR: Odds ratio, DCR: Disease control rate, NE: Not evaluated, OS, Overall survival, HR: Hazards ratio, PFS: Progression-free survival.
Patients with good performance status (Karnofsky score ≥80) had a significant reduction in the risk of death by 49% compared to those with poor performance status (Karnofsky score <80) (HR: 0.51;p <0.001).[17] No new safety signals were identified with the platinum-5FU group, and cetuximab's addition did not adversely affect the safety profile. Grade 3-4 adverse events, such as skin reactions, were consistent with those reported earlier for cetuximab.[17] Five-year data of the EXTREME trial reported lower incidence of toxicities during the cetuximab maintenance (grade 3-4 adverse events decreased from 81% during the combination with chemotherapy to 49% during cetuximab maintenance, and grade 3 skin toxicity decreased from 9% to 5%).[49] With these results, the EXTREME regimen became the first-line standard regimen to be used in R/M HNSCC patients.[13]
An adapted EXTREME regimen in older (≥ 70 years) fit R/M-HNSCC patients showed that this regimen provided the same ORR and survival benefits as seen in younger patients without any new safety concerns.[50] The mOS was 15.8 months, and the best ORR was 46%. The median age of the patients was 75 years (IQR: 72-79 years; range 70-89 years), and 18% were ≥80 years. Cardiovascular disease was present in 77% of the patients, and 22% had diabetes.[50] The adapted EXTREME regimen used 5-FU 4000 mg/m2 on days 1–4 instead of 1000 mg/m2 used in the EXTREME regimen; carboplatin was used as the platinum of choice, and there was no change in the initial cetuximab dose. After six cycles, cetuximab maintenance therapy at 500 mg/m2 was continued once every 2 weeks until disease progression or unacceptable toxicity instead of the 250 mg/m2 weekly maintenance dose followed in the EXTREME regimen.
One Indian study by Tiwari et al.,[48] evaluated the efficacy and safety of the EXTREME regimen as 1L in 50 Indian patients with R/M HNSCC. The disease control rate (DCR) was 92%, the median PFS was 5.3 months, and the mOS was 9.93 months.[51] The most common Grade 3/4 side effects were either haematological (88%) or gastrointestinal (56%).[51] The study showed that the EXTREME regimen can be effectively and safely used as 1L in Indian patients with R/M HNSCC.
CHANGE-2 (Modified EXTEME regimen)
The outcomes of the CHANGE-2 (CHANGE-2 = Modified EXTREME regimen [Cetuximab + Cisplatin + 5-FU] with 25% dose reduction of cisplatin and a 6.25% total dose reduction of 5-FU for 5 days.) trial in Chinese patients with R/MHNSCC are captured in Table 1. This trial evaluated a modified EXTREME regimen with reduced doses of chemotherapy (cisplatin dose was reduced by 25% from 100 mg/m2 to 75 mg/m2 intravenously on day 1 and the 5-FU dose was reduced by 6.25% from 1000 mg/m2 to 750 mg/m2 intravenously for Day 1-5 instead of the four-day schedule used in EXTREME trial) and the same dose of cetuximab as used in EXTREME trial.[52] Both arms of the CHANGE-2 trial had lower-grade 3-4 adverse events as compared to the respective arms of the EXTREME trial, primarily driven by the lower chemotherapy dose.
However, despite the chemotherapy dose reduction, the efficacy parameters were not compromised and were numerically better in the CHANGE-2 trial, as shown in Table 1. Further, all patients in the cetuximab arm of CHANGE-2 received cisplatin as the initial platinum compound, as compared to 67% of patients in the cetuximab arm of the EXTREME trial. The CHANGE-2 trial showed that a modified EXTREME regimen was effective, safe, and well-tolerated. Hence, the CHANGE-2 regimen with a modified chemotherapy dose can be used instead of the EXTREME regimen in Indian patients who cannot tolerate 5-FU and in patients who need effective therapies due to older age, HTB, and symptomatic disease.
Replacing the 5-FU in the EXTREME regimen with a taxane
The 5-FU component of the EXTREME regimen is less likely to be tolerated by Indian R/M-HNSCC patients with comorbidities due to serious 5-FU toxicities.[45] Further, 5-FU resistance is seen in approximately 40% of Indian patients.[52] Patients with contraindications to 5-FU cannot be administered the EXTREME regimen.[19] On the other hand, 5-FU infusion in the EXTREME regimen requires hospital admission for four days, thereby increasing the per-cycle treatment cost.
Hence, first-line 5-FU-sparing R/M-HNSCC cetuximab-based regimens are frequently used in Asian and Indian patients.[22,53-58] A retrospective Indian study in R/M-HNSCC patients receiving palliative chemotherapy noted that the majority (61.1%) of patients received cetuximab-based chemotherapy; of these, only 18.34% received cetuximab + cisplatin + 5-FU, whereas 36.24% received cetuximab + paclitaxel + carboplatin.[58] Of the 38.9% of patients who received chemotherapy without cetuximab, only 4.8% received a regimen that included 5-FU.[58] This suggests that many oncologists in India are omitting 5-FU from palliative R/M HNSCC treatment settings.
R/M-HNSCC patients treated with the cetuximab-platinum-5-FU combination versus those treated with the cetuximab-platinum-taxane combination demonstrated similar survival outcomes. The cetuximab-platinum-taxane combinations in the TPExtreme regimen ( docetaxel used as the taxane), and the cetuximab-platinum-paclitaxel (taxane) regimen followed in the CETMET trial, and the phase III, randomised, multicentre trial by Gibson et al., demonstrated similar mOS and ORR as the EXTREME regimen with cetuximab-platinum-5-FU combination.[19,47,48,59,60] In the trial by Gibson et al., the mOS in the 5-FU group was 8.7 months versus 8.1 months in the paclitaxel group. The corresponding ORR values were 27% and 26%, respectively. The toxicity profile of the two regimens was also similar.[60] The FU-sparing PCC regimen (paclitaxel + cetuximab+ cisplatin/carboplatin) has been effectively and safely used in several Indian studies.[22,55,56,61]
GORTEC 2014-01 (TPExtreme) trial
The outcomes of the TPEx trial are outlined in Table 1. Unlike the trial by Gibson et al., the adverse event profile of the TPEx regimen was significantly better than the EXTREME regimen (Grade ≥3 AEs: 81% vs. 93%; P<0.0001). Serious adverse events were also more common in the EXTREME versus TPEx group (54% vs. 45%). The EXTREME group in the GORTEC 2014-01 trial had significantly more delays in chemotherapy, more dose adjustments, more frequent switch to carboplatin, and a lower proportion of patients receiving the planned treatment than the TPEx group.[19]
The authors concluded that the TPEx regimen could be a good alternative to the EXTREME regimen in first-line treatment R/M-HNSCC, especially in patients with combined positive score (CPS) <1 (PD-L1 negative), contraindication for 5-FU, and in patients not suitable for first-line pembrolizumab due to HTB, high symptom burden, and presence of immunologically relevant comorbidities, necessitating a rapid response.[19] Further, an analysis of the GORTEC 2014-01 trial showed that patients who received second-line ICI with PD-1 inhibitors or PD-L1 inhibitors after cetuximab-based regimens showed improved mOS.[62] The mOS was 21.9 months when IO was given after the TPEx regimen and 19.4 months when IO was given after the EXTREME regimen.[62]
PCC regimen
An Indian study compared six cycles of cetuximab, cisplatin, and 5-FU (EXTREME regimen) with the PCC regimen.[61] The study showed that the PCC regimen resulted in higher PFS (9 months vs 6 months) and OS (13 months vs. 12 months) than the EXTREME regimen. However, the results were not statistically significant.[62]
Other Indian studies, too, have consistently shown the efficacy and safety of the PCC as 1L in R/M HNSCC [Table 2].[22,55,56,61]
| Study (no of participants; year) | Median OS | Median PFS | ORR | Grades ≥2 adverse events (AEs) |
|---|---|---|---|---|
| Chandrakanth et al.[22], 2024 (n = 54) | 15.01 months | 7.03 months | 59.3% | 1L Grade 3/4 AEs: neutropenia (31.4%), anemia (35.1%), thrombocytopenia (7.4%), febrile neutropenia (11.1%) and skin reaction (16.6%) |
| Rangaraju et al.[55], 2012 (n = 53) | 9.2 months (10 months among responders) | 5.87 months (6.43 months in responders) | 82.9% | No 2L Grade 3/4 AEs. Grade 2/3 AE: cetuximab-induced rash; No grade 4 AE |
PCC: Paclitaxel, carboplatin, cetuximab, 1L: First line, R/M HNSCC: Recurrent/metastatic squamous cell carcinoma of head and neck, OS: Overall survival: PFS: Progression-free survival, ORR: Objective response rate, 2L: Second line.
CETMET trial
The outcomes of the CETMET trial are captured in Table 1. The trial showed that just like the TPEx regimen, the cetuximab + paclitaxel/carboplatin (TPEx-like) regimen had similar efficacy as cetuximab + 5-FU/cisplatin or carboplatin (EXTREME) but with significantly less toxicity (Grade ≥ 3 adverse events: 40% vs. 60%; p = 0.034).[47] The TPEx-like regimen was easier to administer than the EXTREME regimen.[47]
Literary evidence presented above shows that various cetuximab-based regimens, such as the EXTREME, CHANGE-2, TPEx, and PCC, have an important place as first-line in R/M-HNSCC.
Panel disposition and voting results
The panel discussed that R/M-HNSCC treatment cost is a major consideration in a developing nation like India and other Asian countries due to out-of-pocket expenditures during treatment.[26,63-65] The panel stressed that while cetuximab-based regimens can be costly.[26,27], the availability of cetuximab biosimilar in India can reduce the cost of treatment, with the added benefit of improved survival and faster response in symptomatic patients and patients with HTB.[7,23,66,67]
After presenting the literary evidence for Statement 4, two polls were conducted during both meetings. For both the poll questions, the experts could select all the options they considered appropriate for the query.
Poll question 2: Which regimen do you prefer among R/M HNSCC? Four options were given: EXTREME, TPEx, PCC, CHANGE 2. The poll results are shown in Figure 4. The TPEx regimen was preferred by 62% of the experts, and 38% preferred the PCC regimen.
Poll question 3: Which R.M-HNSCC patient population in your clinical practices is suitable for first-line cetuximab therapy? Six options were given: Elderly, HPV- ve, HTB, high symptomatic disease, oral cavity, all of the above. The majority of the experts (88%) considered that all the types of patient population (elderly, HPV-ve, HTB, high symptomatic disease, and oral primary) are suitable for first-line cetuximab therapy.
The voting result for consensus statement 4 is shown in Figure 2.
Statement 5: Cetuximab-based regimens show rapid symptomatic improvement (in four weeks of treatment) in patients with R/M HNSCC
Literary evidence presentation and discussion
Indian patients with R/M-HNSCC, especially those with oral cavity cancers, have a high symptom burden, distress level, and poor outcomes.[7,30,46,68,69] Multimodality treatment (including chemotherapy, radiotherapy, and immunotherapy) and HTB increase symptom burden due to haematological toxicities, pain, fatigue, loss of appetite, insomnia, mucositis, xerostomia, and aspiration.[46,70–73] Treatment-related nutritional disturbances are seen in 74.2% of patients, and approximately 20% of patients succumb to these nutritional disturbances.[70]
The consensus guidelines from India on 'the use of cetuximab in HNSCC' note that, generally, in India, a rapid response becomes a prerequisite in patients who have HTB, aggressive disease, and a compromised nutritional status.[7] Especially in patients with bulky disease, achieving symptomatic relief (e.g., from pain and foul odour) is as important as improving OS.[7] A study from India showed that symptom relief was the primary expectation from palliative chemotherapy (administered primarily for recurrent/metastatic disease) in 58.5% of HNC patients.[30]
Though immunotherapy improves OS in R/M-HNSCC, its response rate compared to the cetuximab EXTREME regimen is much lower (19% vs. 35%).[66] This could be a problem in Indian patients with high symptom burden, where a quick response is a prerequisite.[7]
Literary evidence from the SOCCER trial showed that R/MHNSCC patients who responded to a cetuximab-based regimen had lower symptom burden as early as 4 weeks after treatment initiation.[66] In the SOCCER trial, cetuximab was administered with platinum-based chemotherapy (EXTREME) in 79% of the patients, while 20% received cetuximab + radiotherapy, and 1% received both regimens. Reduction of symptom burden was analysed every four weeks using a visual analogue score (VAS), and patients with worse VAS had the worst OS.[66] Patients responding to a cetuximab-based regimen reported a significant improvement in pain (p = 0.001) and swallowing (p = 0.002) compared to nonresponders at the best post-line assessment, which was scheduled after the first four weeks. Thus, the improvement appeared fast, as it was visible after four weeks.[66]
Other literary evidence also reports that the addition of cetuximab to a platinum-based chemotherapy (EXTREME regimen) resulted in a significant improvement in pain and swallowing, speech, and social eating, and did not adversely affect the quality of life (QoL).[26,66,74] A significant improvement in the symptom scores of 'pain, swallowing, speech problems, and social eating' was seen in the cetuximab arm as early as cycle 3.[74]
Symptomatic relief from pain and dysphagia was also reported after palliative paclitaxel and cetuximab (PaCe) in 79.8% and 50% of Indian patients with advanced HNC, respectively.[27] The study evaluated the symptoms weekly and reported at 2 months of treatment. Symptom relief was noted in both platinum-sensitive and platinum-insensitive patients. Pain decreased by at least one CTCAE grade in 89.5% of platinum-insensitive and 71.7% of platinum-sensitive patients. The corresponding values for dysphagia were 55.0% and 45.8%, respectively.[27] Another Indian study evaluating the efficacy of the PCC regimen every two weeks for six months noted that 88.2% (30/34 evaluable) had symptomatic benefits.[55]
Panel disposition and voting results
The panel concurred with the literary evidence presented. The voting result for the consensus statement 5 is shown in Figure 2.
Statement 6: Cetuximab-based regimens are preferred over immunotherapy-based regimens in patients with the oral cavity subset of R/M HNSCC
Statement 7: Cetuximab-based regimens are preferred over immunotherapy-based regimens in RM HNSCC patients with high tumour burden and rapidly progressive disease.
Statement 8: In the Indian context, in R/M HNSCC, in comparison with IO, a Cetuximab-based regimen is preferred 1L therapy in oral cavity cancer, CPS < 20, high tumour burden, and highly symptomatic disease
Literary evidence presentation and discussion
First-line cetuximab-based chemotherapy: Factors associated with improved OS
Literature shows that longer OS in R/M-HNSCC patients treated with first-line cetuximab-based chemotherapy has a significant association with oral cavity primary (p = 0.003)[74] high tumour burden (multiple locations) (p = 0.0134)[66]; high visual analogue score (VAS, indicative of high symptom burden) (p = 0.0009)[66] European Cooperative Oncology[74], Group-Performance Status (ECOG-PS) of 0 (p = 0.01)[75] 1 (p = 0.0133)[66], and ≥ 2 (p = 0.0001)[66] response to cetuximab (complete/partial) (p <0.0001)[75] cetuximab-induced skin toxicity (grade 2-4; indirect indication of cetuximab response) (p = 0.037)[75] continuing cetuximab until disease progression or unacceptable toxicity (p = 0.037).[75] Longer OS had a borderline significant association with the Charlson comorbidity index (p = 0.559).[66]
Thus, the first-line cetuximab-based regimen is a valuable systemic treatment across a broad range of medically fit R/M-HNSCC patients. Moreover, the treatment has a well-tolerated toxicity profile.[75]
Cetuximab preferred for oral primaries
The EXTREME trial showed that compared to other HNSCC sites (oropharynx, larynx, and hypopharynx), oral cavity cancer had the best OS with cetuximab + CT versus CT alone. The OS with cetuximab + CT in the EXTREME regimen was 11.0 months (oral cavity), 10.9 months (oropharynx), 8.6 months (larynx), and 8.4 months (hypopharynx).[17] On the other hand, another study showed that immune checkpoint inhibitor-treated R/M-HNSCC patients with oral cavity cancer had worse overall survival compared with patients with RM-HNSCC of other subsites.[76]
Cetuximab preferred for high tumour burden R/M-HNSCC
As discussed earlier, Indian patients with RM-HNSCC have HTB.[7] A retrospective study from India reported that the cetuximab-based PCC regimen was effective and safe in HTB HNSCC patients (55.6% had loco-regional and distant metastases, and 7.4 % had distant metastases at the study start).[22]
The results of CheckMate 141[77] and Keynote 048[20] Trials showed that ICIs (nivolumab and pembrolizumab, respectively) improved survival in R/M-HNSCCC; however, more than 50% of R/M-HNSCC patients fail to benefit from these drugs.[78] This is because HTB reduces the efficacy of ICI in R/M-HNSCC and other cancers.[78] Though the exact mechanism behind this is unclear, HTB impacts immune cell infiltration.[78]
A retrospective study from Asia showed that HTB measures, high baseline number of metastatic lesions (BNML), a high baseline sum of the longest diameters of the target lesions (BSLD), and a high standardised uptake value (SUVmax), were associated with the worst clinical outcomes in ICI-treated RM-HNSCC patients.[78] The median progression-free survival (mPFS) was 7.1 and 9.1 months in the low-BNML and low-BSLD groups and 3.1 months and 3.5 months in the high-BNML and high-BSLD groups, respectively. The mPFS was statistically significantly higher in the low-BNML and low-BSLD groups (p = 0.010 and p = 0.004, respectively). High SUVmax levels were associated with worse overall survival (OS) and PFS.[78]
Hence, calculating the tumour burden in R/M-HNSCC is important to drive treatment decisions. Tumour burden is usually expressed as tumour burden score (TBS), which is calculated using the formula TBS2=(maximal diameter of largest tumor)2 + (number of tumor lesions)2.[67]
A retrospective study from China in 252 R/M-HNSCC patients demonstrated that patients with HTB (high TBS) had significantly poorer survival outcomes compared to those with low tumour burden (LTB). The mOS of LTB vs. HTB was 14.2 vs. 9.2 months (p = 0.001), and the median PFS was 7.1 vs. 3.9 months (p <0.001).[67] The significantly poor survival in HTB versus LTB was seen irrespective of the PD-L1 expression.[67] The median PFS (LTB vs. HTB) for PD-L1 negative patients was 5.0 vs. 1.6 months (p <0.001), and the mOS was 14.2 vs. 5.0 months, respectively (p <0.001). The median PFS (LTB vs. HTB) for PDL1 positive patients was 11.2 vs. 4.8 months (p <0.001), and the mOS was 20.0 vs. 8.5 months, respectively (p <0.001).[67]
In these HTB patients with poor survival, a cetuximab-based regimen significantly improved survival compared to a pembrolizumab-based regimen, irrespective of their PD-L1 expression.[67] The study showed that 68% of patients with HTB were treated with the EXTREME regimen (cetuximab+5FU+cisplatin), and 32% were treated with the KEYNOTE-048 regimen (pembrolizumab +5FU+cisplatin). The mOS in patients with HTB was significantly higher in patients treated with the EXTREME regimen (9.9 months) than those treated with the KEYNOTE-048 regimen (6.4 months; p = 0.002). PFS was also significantly higher with cetuximab (5.8 months) than with pembrolizumab (4.8 months; p = 0.042).[67]
Cetuximab preferred for R/M-HNSCC with CPS<20
Literature shows that cetuximab-based regimens play an important role in treating R/M-HNSCC patients with CPS < 1 (also considered PD-L1 negative) and CPS 1-19.[13,79] The phase III EXTREME trial demonstrated significant improvement in OS by the addition of cetuximab to platinum/5-FU in PD-L1 negative patients (HR 0.80; p = 0.04).[80]
A subgroup analysis of the KEYNOTE 048 trial reported the survival and ORR outcomes of pembrolizumab, pembrolizumab-chemotherapy arms versus the EXTREME arm (cetuximab-chemotherapy) in patients with PD-L1 CPS < 1, and > 1 and < 20 [Table 3].[13,79] The analysis showed that cetuximab-based chemotherapy could be a better treatment strategy than pembrolizumab-chemotherapy in CPS < 1 and better than pembrolizumab in PD-L1 sub-group with CPS < 1 and CPS > 1 and < 20 (1-19).[13] Cetuximab-based chemotherapy had the best ORR across CPS < 1 and CPS > 1 and < 20.[13]
| Treatment comparision | PD-L1 subgroup CPS <1 | PD-L1 subgroup CPS 1–19 | PD-L1 subgroup CPS ≥20 | |||||
|---|---|---|---|---|---|---|---|---|
| mOS | mPFS | ORR | mOS | mPFS | ORR | mOS | mPFS | |
| Pembrolizumab vs cetuximab- chemotherapy | 7.9 vs 11.3 mo (HR: 1.51; p= 0.96) | 2.1 vs 6.2 mo (HR: 4.31; p= 1.00000) | 4.5% vs 42.2% | 10.8 vs 10.1 mo (HR: 0.86; p= 0.1287) | 2.2 vs 4.9 mo (HR: 1.25; P=0.95) | 14.5% vs 33.8% | 14.8 vs 10.7 mo (HR: 0.58; p= 0.001*) | 3.4 vs 5.3 mo (HR: 0.99; p = 0.46791) |
| Pembrolizumab- chemotherapy vs cetuximab- chemotherapy | 11.3 vs 10.7 mo (HR: 1.21; =0.789) | 4.7 vs 6.2 mo (HR: 1.46; p= 0.94898) | 30.8% vs 39.5% | 12.7 vs 9.9 mo (HR: 0.71; p= 0.007*) | 4.9 vs 4.9 mo (HR: 0.93; p = 0.29189) | 29.3% vs 33.6% | 14.7 vs 11 mo (HR: 0.60; p= 0.0004*) | 5.8 vs 5.3 mo (HR: 0.76; p = 0.0295*) |
PD-L1 (Programmed Death-Ligand 1), CPS: Combined Positive Score, mOS: Median overall survival, mPFS: Median progression free-survival, ORR: Objective response rate, HR: Hazard ratio.
Vitale et al. reviewed treatment-related literature in HNSCC and recommended first-line cetuximab-based chemotherapy for patients with CPS<1 and CPS 1-19 and for patients with symptomatic disease.[13] They concluded that cetuximab-based regimens have a role in rapid tumour shrinkage in patients with CPS<1 and CPS 1-19.[13]
Panel disposition and voting results
After presenting the literary evidence for Statements 6, 7, and 8, a poll was conducted during both meetings for the question: According to you, what percentage of patients with R/M HNSCC have CPS <20? The poll results are shown in Figure 5. The majority of experts (44%) stated that they saw CPS<20 patients in 50-70% of their R/M-HNSCC patients.
The voting results for statements 6, 7, and 8 are shown in Figure 2.
Statement 9: Hyperprogression is an underrecognized issue associated with IO, and it is particularly relevant in Indian patients with R/M HNSCC due to heavy tumour burden
Literary evidence presentation and discussion
Hyperprogressive disease (HPD) after ICI has been commonly reported in certain cancers such as HNSCC, urothelial cancer, and non-small cell lung cancer.[81,82] HPD is characterised by rapidly worsening and paradoxically accelerated growth of malignancy after ICI initiation.[82]
An Indian guideline notes that the risk of hyper-progression with ICI in RM-HNSCC is underestimated.[7] Of the solid tumours exhibiting HPD after ICI, R/M-HNSCC has the highest risk of HPD, ranging from 9-29%.[82] A Korean study identified R/M-HNSCC patients with tumour growth kinetics (TGK) ratio (TGKr) >2 as having HPD; 54.4% of the study participants had progressive disease, and 26.5% of patients with progressive disease had HPD.[83] Those with HPD constituted 14.4% of the study population. A retrospective French study measured TGK after ICI and noted hyperprogression in 29% of R/M HNSCC patients; 39% had at least a locoregional recurrence, and 9% had only distant metastases.[84]
Several clinicopathological factors are associated with HPD after ICI, including elderly (>65 years), high metastatic burden, EGFR/ALK mutation, and MDM2/4 gene amplification.[81,82] A Korean study reported that HPD was associated with younger age (p = 0.040), oral HNSCC (p = 0.027), and prior irradiation (p = 0.015).[83] As discussed earlier, several of these clinicopathological factors are seen in Indian patients, including younger age, elderly, oral HNSCC, and HTB.
HPD is associated with worse survival outcomes (OS and PFS).[7,83] A Korean study also reported significantly shorter PFS (1.2 vs. 3.4 months; p <0.001)) and OS (3.4 vs. 10.7 months; p = 0.047).[83] However, subsequent salvage therapy after hyperprogression on ICI is feasible.[83] As discussed earlier, a cetuximab-based regimen improved ORR, OS, and PS in Japanese R/M-HNSCC patients progressing on ICI.[85]
Panel disposition and voting results
The panel concurred with the literary evidence presented. The voting result for the consensus statement 9 is shown in Figure 2.
Statement 10: Sequencing with a cetuximab-based regimen in the first line, followed by immunotherapy in the second line, has shown impressive overall survival
Literary evidence presentation and discussion
Though immunotherapy has been approved as the first-line treatment for R/M-HNSCC based on the KEYNOTE-048 study, the hazard ratio for survival did not favour pembrolizumab for patients with recurrent disease (recurrent-only subset).[86] Cetuximab-based regimens have a valuable place in the management of Indian patients with R/M-HNSCC due to their unique characteristics.[7] Right sequencing of the cetuximab-based regimen followed by an immunotherapy-based regimen in R/M-HNSCC is important as it improves the survival outcomes.[7]
A retrospective Indian study in patients of platinum-sensitive R/M HNSCC showed that first-line weekly PCC regimen followed by second-line immunotherapy (nivolumab) significantly improved OS (from 15.01 months to 20.6 months) compared to second-line oral metronomic chemotherapy (OMCT) [Box 2].[22] First-line PCC was generally well tolerated, and there were no grade 3/4 treatment-related adverse events with second-line nivolumab or OMCT.
| PCC dosing: Paclitaxel (80 mg/m2) + carboplatin (AUC2) + cetuximab (loading dose: 400 mg/m2 followed by 250 mg/m2) for a maximum of 12 weeks. | |||
| Category | First line | The second line of therapy for disease progression | |
| Regimens | PCC followed by cetuximab maintenance 250 mg/m2 (until disease progression or intolerable adverse effects) | Nivolumab | Oral metronomic chemotherapy (OMCT) |
| ORR | 59.3% | 26.3% | 10% |
| mPFS | PFS-1: 7.03 months | 6.5 months | 2 months |
| mOS | 15.01 months | 20.6 months | 7 months |
AUC2 represents a dose adjusted to achieve a total drug exposure (area under the curve) of 2 mg•min/mL. ORR: Objective response rate, mPFS: Median progression free-survival, mOS: Median overall survival.
An Asian study from Japan demonstrated that weekly paclitaxel, carboplatin, and cetuximab (PCE) followed by nivolumab had favourable survival and response outcomes compared to those who did not receive second-line nivolumab (HR: 0.47; p = 0.084) [Box 3].[87]
| Category | First line | Second line |
|---|---|---|
| Regimens | PCE | Nivolumab |
| ORR | 48.6% | 10.8% |
| mPFS | 4.4 months | 6.8 months |
| mOS | 19.5 mo (since PCE initiation) | |
ORR: Objective response rate, mPFS: Median progression-free survival, mOS: Median overall survival.
A study in R/M HNSCC patients comparing Cet-IO sequencing versus IO-Cet (40 patients in Cet-IO and 35 patients in IOCet) found no significant difference in survival between the two sequences, but the overall response rate (ORR) significantly favoured Cet-IO over IO-Cet [Box 4].[88] The significantly higher ORR of Cet-IO and the significantly higher DCR after IO following first-line cetuximab show that this sequencing may be helpful in patients with HTB and urgent needs for treatment responses.[88]
| Sequencing | Cet-IO | IO-Cet | p-value |
|---|---|---|---|
| ORR (%) after first line | 73% | 37% | 0.002* |
| ORR (%) after second line | 63% | 37% | 0.028* |
| DCR (%) after first line | 78% | 63% | 0.165 |
| DCR (%) after the second line | 78% | 51% | 0.018* |
| mPFS-1 after first line(months) | 5.1 | 4.5 | 0.777 |
| mPFS-2 after second line (months) | 16.5 | 11.4 | 0.566 |
| mOS (months) | 23.7 | 22.8 | 0.484 |
The therapeutic decision for treatment sequencing in R/M-HNSCC depends on patient characteristics such as tumour location, disease burden, symptom burden, CPS, performance status, and patient preferences, and the treating oncologist's priority to achieve rapid response, survival, or quality of life.[13] Further, the toxicity profile of the regimen should be considered to assess if the patient is fit for the regimen.[13] Vitale et al. suggest that a cetuximab-based regimen should be preferred in R/M-HNSCC patients because it opens the possibility of using IO, such as pembrolizumab, for the second line with good outcomes.[13] The sequencing algorithm recommended by Vitale et al. is based on literary evidence and captured in [Table 4].[13]
| Category | Preferred 1st line option | Preferred 2nd line option | Preferred 3rd line option |
|---|---|---|---|
| CPS <1 | Cetuximab-based chemotherapy | Nivolumab or mono-chemotherapy | Single agent-chemotherapy |
| CPS 1–19 | Either cetuximab-based chemotherapy or IO (Pembrolizumab) ± chemotherapy | IO (Pembrolizumab or Nivolumab) or Cetuximab ± Taxane | Single agent-chemotherapy |
| CPS ≥20 | Pembrolizumab ± chemotherapy | Cetuximab ± Taxane or chemotherapy | Cetuximab or chemotherapy |
| Symptomatic disease | Chemotherapy or RT + Cetuximab | Pembrolizumab | Single agent-chemotherapy |
| ECOG >2 | Cetuximab or Pembrolizumab | Cetuximab or Pembrolizumab | Single agent-chemotherapy |
R/M-HNSC: Recurrent/metastatic head and neck squamous cell carcinoma, CPS: Combined Positive Score, IO: Immunotherapy, ECOG: Eastern Cooperative Oncology Group.
Panel disposition and voting results
The panel concurred with the literary evidence presented. The voting result for the consensus statement 10 is shown in Figure 2.
TAKE HOME MESSAGE
The experts agreed that cetuximab-based regimens are preferred as first-line therapy in R/M-HNSCC patients, specifically in patients with PD-L1-negative (CPS<1), low PDL1 CPS (1-19), oral cavity primary, high tumour burden, and highly symptomatic disease. The experts stressed that in this unique R/M-HNSCC patient population from India, quicker response and symptom control are as important as improving OS and concurred that using a cetuximab-based regimen is ideal. The experts also agreed that cetuximab-based regimens in the first line, followed by immunotherapy-based regimens in subsequent lines, offer promising survival outcomes for Indian cancer patients. The cetuximab biosimilar can reduce treatment costs, making it more accessible to our patients.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient's consent not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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