Background. Three‐weekly high‐dose cisplatin (100 mg/m²) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA‐SCCHN). However, due to unsatisfactory patient tolerance, various weekly low‐dose schedules have been increasingly used in clinical practice. The aim of this meta‐analysis was to compare the efficacy, safety, and compliance between these two approaches. Materials and Methods. We systematically searched literature for prospective trials of patients with LA‐SCCHN who received postoperative or definitive conventionally fractionated concurrent chemoradiation. Radiation doses were usually 60–66 gray (Gy) in the postoperative setting and 66–70 Gy in the definitive setting. Standard, three‐weekly high‐dose cisplatin (100 mg/m², 3 doses) was compared with the weekly low‐dose protocol (≤50 mg/m², ≥6 doses). The primary endpoint was overall survival. Secondary outcomes comprised response rate, acute and late adverse events, and treatment compliance. Results. Fifty‐two studies with 4,209 patients were included in two separate meta‐analyses according to the two clinical settings. There was no difference in treatment efficacy as measured by overall survival or response rate between the chemoradiation settings with low‐dose weekly and high‐dose three‐weekly cisplatin regimens. In the definitive treatment setting, the weekly regimen was more compliant and significantly less toxic with respect to severe (grade 3–4) myelosuppression (leukopenia p = .0083; neutropenia p = .0024), severe nausea and/or vomiting (p < .0001), and severe nephrotoxicity (p = .0099). Although in the postoperative setting the two approaches were more equal in compliance and with clearly less differences in the cisplatin‐induced toxicities, the weekly approach induced more grade 3–4 dysphagia (p = .0026) and weight loss (p < .0001). Conclusion. In LA‐SCCHN, current evidence is insufficient to demonstrate a meaningful survival difference between the two dosing regimens. Prior to its adoption into routine clinical practice, the low‐dose weekly approach needs to be prospectively compared with the standard three‐weekly high‐dose schedule. Implications for Practice. Given concurrently with conventional radiotherapy in locally advanced head and neck cancer, high‐dose three‐weekly cisplatin has often been replaced with weekly low‐dose infusions to increase compliance and decrease toxicity. The present meta‐analysis suggests that both approaches might be equal in efficacy, both in the definitive and postoperative settings, but differ in toxicity. However, some toxicity data can be influenced by unbalanced representation, and the conclusions are not based on adequately sized prospective randomized studies. Therefore, low‐dose weekly cisplatin should not be used outside clinical trials but first prospectively studied in adequately sized phase III trials versus the high‐dose three‐weekly approach.

The demographics of squamous cell carcinoma of the head and neck (SCCHN) is marked by a growing number of patients aged 65 and over, which is in line with global projections for other cancer types. In developed countries, more than half of new SCCHN cases are diagnosed in older people and in 15 years from now, the proportion is expected to rise by more than 10%. Still, a high-level evidence-based consensus to guide the clinical decision process is strikingly lacking. The available data from retrospective studies and subset analyses of prospective trials suffer from a considerable underrepresentation of senior participants. The situation is even more challenging in the recurrent and/or metastatic setting, where usually only palliative measures are employed. Nevertheless, it is becoming clear that if treated irrespective of chronological age, fit elderly patients in a good general condition and with a low burden of comorbidities may derive a similar survival advantage as their younger counterparts. Despite that, under-treatment represents a widespread phenomenon and together with competing non-cancer mortality is suggested to be an important cause of the worse treatment outcomes observed in this population. Due to physiological changes in drug metabolism occurring with advancing age, the major concerns relate to chemotherapy administration. In locally advanced SCCHN, concurrent chemoradiotherapy in patients over 70 years remains a point of controversy owing to its possibly higher toxicity and questionable benefit. However, accumulating evidence suggests that it should, indeed, be considered in selected cases when biological age is taken into account. Results from a randomised trial conducted in lung cancer showed that treatment selection based on a comprehensive geriatric assessment (CGA) significantly reduced toxicity. However, a CGA is time-consuming and not necessary for all patients. To overcome this hurdle, geriatric screening tools have been introduced to decide who needs such a full evaluation. Among the various screening instruments, G8 and Flemish version of the Triage Risk Screening Tool were prospectively verified and found to have prognostic value. We therefore conclude that also in SCCHN, the application of elderly-specific prospective trials and integration of clinical practice-oriented assessment tools and predictive models should be promoted.

Well-designed randomized trials provide the highest level of scientific evidence to guide clinical decision making. In chemoradiotherapy of locally advanced squamous cell carcinoma of the head and neck (SCCHN), data support the use of three cycles of 100 mg/m² cisplatin given every 3 weeks concurrently with conventionally fractionated external beam radiotherapy, although a full compliance with all three cycles is reserved to only about two thirds of initially eligible cases. On an individual patient level, practicing oncologists have to determine whether the patient is a suitable candidate for this treatment or whether contraindications exist. In the latter case, an adequate alternative has to be offered. In this regard, to facilitate triaging of medical information, we reviewed available publications on this topic and prepared practice-oriented recommendations for systemic treatment concurrent to definitive and post-operative radiotherapy. Even if no contraindications for the standard-of-care cisplatin apply, clinicians may opt for alternative regimens by adjusting the peak dose, cumulative dose, or timing of cisplatin. Relative contraindications pose the major issue in clinical practice, as very limited data is available in the literature and final decisions are usually based on an expert opinion or retrospective cohort studies. In the case of absolute interdiction of cisplatin, several alternative regimens incorporating carboplatin, 5-fluorouracil, cetuximab, and docetaxel are available. At the same time, it should be kept in mind that radiotherapy alone represents a viable option with hyperfractionation being particularly beneficial in the definitive management of limited nodal disease. Ideally, all treatment propositions should be discussed within multidisciplinary tumor boards taking into account the patient- and disease-related characteristics as well as local logistics and reimbursement policies.