•The existing continuum of cancer care extends the expected survival over one year.•Local ablation should be considered in oligometastatic and oligoprogressive disease.•Traditional chemotherapy ...improves response with no impact on overall survival.•Cetuximab/platinum/5-fluorouracil improves survival preferentially in oral cancer.•Immune checkpoint inhibition of PD-1 represents the standard second-line therapy.
In recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN), the armamentarium of systemic anti-cancer modalities continues to grow in parallel with innovations in and better integration of local approaches. The backbone of cytotoxic chemotherapy remains cisplatin with 5-fluorouracil or a taxane. In contrast to cisplatin, the tumoricidal activity of carboplatin monotherapy is debatable. Adding the epidermal growth factor receptor (EGFR) inhibitor cetuximab to a platinum/5-fluorouracil doublet (the so-called EXTREME regimen) produced a statistically but also clinically significant improvement of survival and became thus the standard first-line palliative treatment in adequately fit patients. Interestingly, three large randomized trials (EXTREME, SPECTRUM, and ZALUTE) evaluating different anti-EGFR monoclonal antibodies (cetuximab, panitumumab, and zalutumumab, respectively) demonstrated preferential anti-tumour efficacy in patients with primary cancer in the oral cavity. Modern immunotherapy with immunomodulating antibodies, dubbed immune checkpoint inhibitors, such as anti-programmed cell death protein-1 (anti-PD-1) inhibitors nivolumab and pembrolizumab, showed unprecedented activity in one first-line (KEYNOTE-048) and several second-line trials (CheckMate-141, KEYNOTE-012, KEYNOTE-055, and KEYNOTE-040). In a minority of also heavily-pretreated patients, these agents generate long-lasting responses without the typical chemotherapy-related toxicity, however, at a price of a low overall response rate, rare but potentially life-threatening immune-related adverse events, the risk of hyperprogression, and high costs. In oligometastatic disease, emerging data indicate long-term benefit with locally ablative techniques including metastasectomy and stereotactic radiotherapy of pulmonary but also hepatic and other distant lesions. In the frame of highly-individualized cancer care, a particularly intriguing approach is a combination of systemic and local therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Locoregionally advanced, recurrent, and metastatic squamous cell carcinomas of the head and neck (SCCHN) remain difficult to treat disease entities, in which systemic treatment often forms an ...integral part of their management. Immunotherapy is based on functional restoration of the host immune system, helping to counteract various tumour evasion strategies. Broadly, immunotherapeutic approaches encompass tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating agents. Until 2015, the epidermal growth factor receptor inhibitor cetuximab, a tumour-specific antibody, represented the only Food and Drug Administration (FDA)-approved targeted therapy for SCCHN. Subsequently, in 2016, the results from two prospective trials employing the immune-modulating antibodies nivolumab and pembrolizumab heralded a new era of anticancer treatment.
Nivolumab and pembrolizumab are monoclonal antibodies against programmed cell death protein-1 (PD-1), an 'immune checkpoint' receptor. Found on the surface of T-cells, PD-1 negatively regulates their activation and can thus be exploited during carcinogenesis. The second-line phase III trial CheckMate-141 randomly assigned 361 patients with recurrent and/or metastatic SCCHN in a 2:1 ratio to receive either single-agent nivolumab (3 mg/kg intravenously every 2 weeks) or standard monotherapy (methotrexate, docetaxel, or cetuximab). Nivolumab improved the objective response rate (13% versus 6%) and median overall survival (OS; 7.5 versus 5.1 months, p = 0.01) without increasing toxicity. Exploratory biomarker analyses indicated that patients treated with nivolumab had longer OS than those given standard therapy, regardless of tumour PD-1 ligand (PD-L1) expression or p16 status. In the non-randomised, multicohort phase Ib study KEYNOTE-012, treatment with pembrolizumab achieved comparable results. Importantly, most of the responding patients had a long-lasting response.
Based on recent results, nivolumab and pembrolizumab have been approved by the FDA as new standard-of-care options for the second-line treatment of recurrent and/or metastatic SCCHN. Generally well tolerated, these novel drugs demonstrated modest response rates, with tumour regressions usually being durable, even in platinum-resistant/refractory cases. The next step will be to extend the observed benefit to first-line treatment, currently dominated by the EXTREME regimen (platinum/5-fluorouracil/cetuximab), and to the locoregionally advanced setting, where concurrent chemoradiation with cisplatin is standard. Regimens combining immunotherapy with other modalities will probably further improve outcomes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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, undertreatment 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 randomized 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.
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 level of evidence for the use of weekly cisplatin chemoradiation in locally advanced squamous cell carcinoma of the head and neck is limited. This systematic review of the literature compares the efficacy, toxicity, and compliance of low‐dose cisplatin given once a week during external beam irradiation with the standard, three‐weekly high‐dose treatment schedule.
Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage and has a dismal prognosis. Nearly 10 years after the approval of cetuximab, anti-PD1/PD-L1 checkpoint inhibitors ...are the first drugs that have shown any survival benefit for the treatment on platinum-refractory recurrent/metastatic (R/M) HNSCC. Furthermore, checkpoint inhibitors are better tolerated than chemotherapy. The state of the art in the treatment of R/M HNSCC is changing, thanks to improved results for checkpoint inhibitors. Results for these treatments are also awaited in curative settings and for locally advanced HNSCC. Unfortunately, the response rate of immunotherapy is low. Therefore, the identification of predictive biomarkers of response and resistance to anti-PD1/PD-L1 is a key point for better selecting patients that would benefit the most from immunotherapy. Furthermore, the combination of checkpoint inhibitors with various agents is being currently evaluated to improve the response rate, prolong response duration, and even increase the chances for a cure. In this review, we summarize the most important results regarding immune targeting agents for HNSCC, predictive biomarkers for resistance to immune therapies, and future perspectives.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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•Macrophages are frequently reported in the microenvironment of head and neck cancers.•Macrophages may harbor two phenotypes: antitumoral M1 or protumoral M2.•Macrophages in head and ...neck cancers have been associated with a poor prognosis.•Different strategies are developed toward macrophages as a therapeutic target.•Macrophages modulators are investigated alone or in combination with standard Therapies.
The microenvironment of solid tumors has become a promising target for future therapies modulating immune cells. Patients with advanced head and neck cancer, which still portends a poor outcome, are particularly in need of innovative approaches. In oral squamous cell carcinoma, high density of tumor-associated macrophages (TAMs) appears consistently associated with poor prognosis, whereas data are currently limited for other head and neck sites. Several approaches to block TAMs have been investigated, including TAMs inactivation by means of the colony stimulating factor 1 (CSF-1)/CSF-1 receptor (CSF-1R) inhibitors or strategies to reprogram TAMs from M2 protumoral phenotype toward M1 antitumoral phenotype. This review focuses on both prognostic and therapeutic aspects related to TAMs in head and neck carcinomas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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/m
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.
Hematogenous dissemination represents a common manifestation of squamous cell carcinoma of the head and neck, and the recommended therapeutic options usually consist of systemically administered ...drugs with palliative intent. However, mounting evidence suggests that patients with few and slowly progressive distant lesions of small size may benefit from various local ablation techniques, which have already been established as standard-of-care modalities for example in colorectal and renal cell carcinomas and in sarcomas. In principle, serving as radical approaches to eradicate cancer, these interventions can be curative. Their impact on local control and overall survival has been shown in numerous retrospective and prospective studies. The term oligometastatic refers to the number of distant lesions which should generally not surpass five in total, ideally in one organ. Currently, surgical resection remains the method of choice supported by the majority of published data. More recently, stereotactic (ablative) body radiotherapy (SABR/SBRT) has emerged as a viable alternative. In cases technically amenable to such local interventions, several other clinical variables need to be taken into account also, including patient-related factors (general health status, patient preferences, socioeconomic background) and disease-related factors (primary tumor site, growth kinetics, synchronous or metachronous metastases). In head and neck cancer, patients presenting with late development of slowly progressive oligometastatic lesions in the lungs secondary to human papillomavirus (HPV)-positive oropharyngeal cancer are the ideal candidates for metastasectomy or other local therapies. However, literature data are still limited to say whether there are other subgroups benefiting from this approach. One of the plausible explanations is that radiological follow-up after primary curative therapy is usually not recommended because its impact on survival has not been unequivocal, which is also due to the rarity of oligometastatic manifestations in this disease. At the same time, aggressive treatment of synchronous metastases early in the disease course should be weighed against the risk of futile interventions in a disease with already multimetastatic microscopic dissemination. Therefore, attentive treatment sequencing, meticulous appraisal of cancer extension, refinement of post-treatment surveillance, and understanding of tumor biology and kinetics are crucial in the management of oligometastases.
In locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN), concurrent chemoradiotherapy is an integral part of multimodality management both in the adjuvant and in the definitive ...settings. Although de-intensification strategies have been propelled to the forefront of clinical research in human papillomavirus (HPV) positive oropharyngeal cancer, three cycles of 100 mg/m
cisplatin given every 3 weeks concurrently with conventionally fractionated external beam radiotherapy represent a cost-effective and globally accessible treatment option for the majority of LA-SCCHN cases. Based on four large randomized trials, this regimen has become the non-surgical standard of care for cisplatin-eligible patients. Nevertheless, the outcomes in terms of efficacy, toxicity, and compliance have been rather disappointing. Therefore, there is an unmet need to find a better alternative. With limited support from randomized trials, weekly low-dose cisplatin regimens have replaced the standard high-dose schedule at some institutions. Four prospective trials exploring radiotherapy with and without weekly low-dose cisplatin have been published. Two of them were conducted in the 1980s, one of which had a negative outcome, the third study provided insufficient information on toxicity, and the fourth trial had to be prematurely terminated due to poor accrual. Moreover, the findings of two phase III trials comparing the two concurrent cisplatin regimens favored the high-dose protocol. We performed a composite meta-analysis of 59 prospective trials enrolling a total of 5,582 patients. The primary endpoint was overall survival. Reflecting different radiotherapy fractionation schemes and treatment intents, three meta-analyses were carried out, one for postoperative conventional chemoradiotherapy, one for definitive conventional chemoradiotherapy, and one for definitive altered fractionation chemoradiotherapy. In the former two settings, both high- and low-dose regimens yielded similar survival outcomes, thus, the primary objective was not met. When given concurrently with altered fractionation radiotherapy, patients treated with high-dose cisplatin had significantly longer overall survival than those who received low-dose cisplatin. In this article we provide a synthetic view of the results, discuss the issue of cumulative dose, compare two vs. three cycles of high-dose cisplatin, and present our three-step recommendations for use of the current standard of care, high-dose cisplatin, in clinical practice.
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