Squamous cell carcinoma of the head and neck (SCCHN) is one of the most frequent causes of cancer-related deaths, with more than 500,000 cases diagnosed annually (1). SCCHN is typically observed in the oropharynx, oral cavity, hypopharynx, or larynx, being a complex disease influenced by genetic and environmental factors (2). Although alcohol and smoking represent the major etiological risk factors, human papillomavirus (HPV) and poor oral hygiene also play a relevant role (3, 4).

Patients with locally advanced (LA) SCCHN (stage III or IVA/B) represent approximately 60% of the SCCHN cases at diagnosis (5). Despite improvements in overall survival due to therapy innovation, patients with HPV-negative LA-SCCHN continue to have poor prognoses (6). Thus, concurrent cisplatin-based chemotherapy (CRT) has been used with improved outcomes (7–9).

CRT with high-dose cisplatin is the standard of care for LA-SCCHN. Bolus cisplatin 100 mg/m² x 3 cycles Q21 days concomitant with radiotherapy (RT) represents the standard of care for LA-SCCHN. The efficacy of cisplatin-based radiochemotherapy (RCT) seems to be correlated with the cumulative dose received (10, 11). Still, compliance with platinum-based RCT treatment might be lower due to the significant toxicity caused by this regimen (12, 13).

HPV-positive cancers are typically associated with better outcomes compared to HPV-negative tumors (14). Hence, the clinical benefit of cisplatin-based RCT has been shown to decrease with lower total dosage in patients with HPV-negative LA-SCCHN. Notably, a cumulative cisplatin dose of <200 mg/m² has been associated with lower overall survival than a cumulative dose of ≥200 mg/m² (15).

This retrospective observational study assessed compliance with cisplatin-based RCT in real-world patients with LA-SCCHN. This study also evaluated the potential factors associated with treatment compliance, the compliance impact on clinical response, and the main toxicities.

This study revealed that patients with LA-SCCHN achieved a high compliance rate with cisplatin concomitantly administered with RT, which is adversely affected by poor ECOG PS. This study also disclosed that non-compliance might be associated with lower tumor response.

Though the clinical characteristics of these patients are heterogeneous, as they were collected in a real-world scenario, they are similar to populations studied in previous clinical trials. Regarding the TNM stage at diagnosis, most patients had T3 to T4 (78.2%) and were N2 (52.5%), respectively, similar to that of the GORTEC 2007-02 trial (14). Only 53 (16.3%) patients were tested for HPV and 80 (24.5%) for p16, values slightly lower than those previously published (17). The lower level of testing might be explained by the inclusion dates of the study, as HPV testing has only in recent years been recommended and implemented. Notably, it should be highlighted that performing HPV testing in oropharyngeal cancer patients is critical since HPV-positive cancers are commonly associated with better outcomes compared with HPV-negative tumors (14).

This international multicentered study disclosed a high treatment compliance rate (84%) among patients with LA-SCCHN. This compliance rate is notably higher than the one reported in a previous retrospective study (37%, COMPLY) conducted in patients with LA-SCCHN (stage III or IVA/B) who received a cumulative dose of ≥200 mg/m², based on their age, ECOG, and renal function (17). While the most common regimen used in our study was 100 mg/m² q3w, in the COMPLY study, the most common regimen was 40 mg/m² q1w, aiming to prevent toxicity (17). Of note, in the COMPLY study, the compliance rates were higher for lower-dose weekly schedules (77.8% for 40 mg/m² and 65% for 30 mg/m²) than those obtained with a high-dose schedule (54.8% for 100 mg/m²). Still, in another retrospective study, nearly half of all patients completed three cycles of high-dose cisplatin (18).

The high-dose cisplatin regimen used in this study is considered the most adequate, as it promotes better locoregional and overall survival relative to RT following international clinical guidelines (19, 20). Still, it was associated with a higher incidence of AEs, as most toxicities are dose and schedule-dependent (17), which, in turn, might potentiate dose reductions and treatment delays with this intensive regime (12).

Identifying risk factors in patients who do not tolerate high cisplatin doses could enable physicians to identify ineligible patients for cisplatin-based RCT and prevent excessive toxicities and severe AEs (21). Accordingly, this study assessed the factors potentially affecting treatment compliance with cisplatin, such as demographic and clinical features and other SCCHN-related characteristics. The ECOG PS was the only factor identified by the multivariate model as an independent factor associated with compliance with cisplatin during RCT. Patients with an ECOG PS of 2 were less likely to comply with cisplatin-based RCT, suggesting that it should be considered a risk factor for compliance, and, thus, alternative treatments might be considered. These results are consistent with the international guidelines recommending that patients older than 70 years with an ECOG PS of ≥2 should not be treated with cisplatin (22, 23). Accordingly, most studies on CRT excluded patients older than 70 years. Nonetheless, in this model, age was considered a continuous variable; perhaps stratification of this variable could have revealed certain significant age ranges as predictors of compliance with cisplatin-based RCT. Another possible explanation is that as biological age per se is currently not recognized as a good predictor of benefit and/or toxicity in elderly patients, it should not guide treatment decisions and the functional age should be adopted instead (24). Decision-making in older patients requires a multidisciplinary evaluation and risk assessment provided by a comprehensive geriatric assessment.

The association between compliance and objective response to cisplatin-based RCT was also assessed. Suboptimal compliance with the cisplatin regimen might negatively impact patient outcomes. Regardless of the treatment regimen, it has been suggested that a cumulative dose of 200 mg/m² has to be achieved to allow a therapeutic benefit (12). A higher objective response was obtained in compliant patients (82.0%) who received a total dose of cisplatin ≥200 mg/m² compared with non-compliant patients (69.8%) who received a total dose of cisplatin <200 mg/m², with an estimated odds ratio of 1.974. These results suggest that the cumulative cisplatin dose might correlate with clinical response to cisplatin-based RCT.

The compliance to cisplatin plus RT is frequently lowered due to toxicity (17). Despite the high treatment compliance in this study, 62.6% (n= 599) of reported AEs were cisplatin-related. Most were low grade (grade 1 or 2) and aligned with those previously reported, including oral mucositis, neutropenia, and renal impairment (14). Strategies such as more frequent lower RT doses could potentially circumvent high-dose related toxicities, thereby improving compliance. A recent Japanese study found that weekly RCT was not inferior to 3-weekly RCT for post-operative high-risk patients with LA-SCCHN and had a favorable toxicity profile, leading the authors to conclude that this could be a new strategy in these patients (25, 26). Although there is lack of robust scientific evidence, weekly lower dose RCT may also benefit elderly patients who are frail (27). Other strategies such as accelerated fractionation with concomitant boost and RCT with concurrent split-dose cisplatin are also being explored as alternatives for patients who cannot safely tolerate high-dose RCT (28, 29). The main limitation of this study is its retrospective nature, as all the available data depends on the information already registered on the medical records. Still, this population represents the real-world setting, with a high prevalence of comorbidities and risk factors. Furthermore, this study was performed during the COVID pandemic, which impacted the recruitment period as the workload of clinicians/researchers increased considerably. Lastly, as HPV testing was not the diagnostic standard of SCCHN during the period the patients were diagnosed, we were unable to do subgroup analysis by HPV status due to the low number of patients with data available.

To our knowledge, this is the most extensive study that has provided up-to-date real-world data on compliance with cisplatin during RCT in patients with LA-SCCHN. The cisplatin regimen was administered according to each country’s site and local practices without being biased by screening criteria. Thus, the results from our retrospective study might be extrapolated to the general population of patients with LA-SCCHN receiving cisplatin.

This study shows a high cisplatin compliance rate (median cumulative dose ≥200 mg/m²) in patients with LA-SCCHN receiving cisplatin-based RCT, which is negatively influenced by ECOG PS. The absence of cisplatin compliance during RCT adversely affects tumor response.