Introduction
More than half of patients with head and neck cancer (HNC) initially present with locoregionally advanced disease (stage III–IVb) (Chow
2020; Grunwald et al.
2020). Many of these patients develop a disease recurrence within the first 2 years following primary treatment. Primary distant metastatic HNC (Stage IVc) is uncommon (about 3.5% of newly diagnosed HNC). Patients with recurrent and/or metastatic HNC (R/M HNC) constitute a challenging population for systemic treatment because of tumor-related, patient-related and treatment-related factors (Oosting and Haddad
2019). If not amenable to curative intent treatment, the EXTREME regimen consisting of cisplatin or carboplatin with 5-fluorouracil (5-FU) and cetuximab followed by cetuximab maintenance has been the standard first-line treatment for the last decade (Vermorken et al.
2008). Head and neck cancer guidelines also recommend the inclusion of R/M HNC patients into ongoing clinical trials and, with a lower level of evidence, other chemotherapy combinations or single-agent treatment options (David et al.
2020). Recently it was shown treatment with immune checkpoint inhibitors like with anti-programmed death 1 (PD1) antibodies nivolumab or pembrolizumab improve overall survival in patients who progress after platinum containing chemotherapy compared to investigator’s choice systemic therapy (Ferris et al.
2018; Cohen et al.
2019). Recently, the Phase 3 KEYNOTE-048 trial demonstrated in the first-line R/M HNC setting, that the checkpoint inhibitor pembrolizumab in combination with chemotherapy and as monotherapy in patients with programmed death-ligand 1 (PD-L1) biomarker expression significantly improved OS compared to standard treatment with cetuximab in combination with platinum-based chemotherapy (Burtness et al.
2019). Therefore, the newest National Comprehensive Cancer Network (NCCN) guideline considers the combination of pembrolizumab + platinum + 5-FU as preferred first-line option for all patients with R/M disease who have no surgical or radiotherapeutic option (David et al.
2020). The NCCN guideline also considers pembrolizumab monotherapy as a preferred first-line option for patients with significant biomarker expression.
Actual epidemiologic population-based studies on the treatment of R/M HNC are sparse. Thuringia is a territorial state in Germany with approximately 2.2 million habitants. The Thuringian cancer registry database registers all new cases of head and neck cancer and the occurrence of R/M HNC. This provides an ideal platform for a population-based analysis of the systemic therapy in patients with R/M HNC in the years 2015–2018 in Thuringia. The focus was to collect data on current practices in daily routine and their outcome.
Discussion
Although palliative systemic therapy forms unfortunately a substantial part of the treatment of patients with R/M head and neck cancer, no international uniform treatment guideline exists. The results of the study showed a wide variation of regimens and drugs used for systemic therapy. Platinum-based combinations were most frequently used as first-line therapy (71.4%). Due to a recent survey on palliative treatment for head and neck cancer, the EXTREME protocol was the institutional standard of care for first-line treatment in most centers in Germany in the period of the present study (Laban et al.
2016). Nevertheless, the EXTREME protocol was used only for 32.9% of the patients for first-line systemic therapy. Taking into account the low comorbidity rate, this was surprising. Due to the retrospective design of the study, the reasons why not more patients received an EXTREME treatment that was considered standard in the study period, remain unclear. Furthermore, the recommendation from clinical trials is to give six cycles followed by maintenance of cetuximab (Vermorken et al.
2008). In this study presenting real-word data, only 8.6% of the patients with EXTREME first-line treatment received six cycles. Beyond progressive disease, the treatment was terminated in about 30% of the cases because of intolerance, allergy, side effect, or deterioration of the patient’s general condition. This cannot explain the early termination for all cases, but shows that the real-life settings do not guarantee an optimal setting to get most patients through the recommended number of cycles.
32.5% of the patients received a second-line therapy and even 13.1% a third-line therapy. Single-agent regimens were the most frequent second-line therapy (53% of all second-line therapies). Cetuximab, platinum, and taxanes were the three most used single agents for second-line therapy (45, 41, 27%, respectively, of all second-line therapies). Nivolumab was licensed in 2017 and pembrolizumab in 2019 for treatment of R/M head and neck cancer. This explains the low number of second-line treatments with nivolumab (21% of all second-line therapies), because treatment with this checkpoint inhibitor only started in 2017. Overall, the drugs and combinations used for first and further lines of systemic therapies for patients with R/M HNC varied significantly across the analyzed population. Such a high variation of different regimens was recently also across some countries in Europe, Asia Pacific and Latin/North America (Grunwald et al.
2020). A web-based survey performed between 2013 and 2014 on palliative treatment for head and neck cancer in German-speaking countries also revealed a large variation but no standards especially for second- and third-line treatments. The authors assume that reasons for this could be the physicians’ individual experience as well as the varying assessment regarding the toxicity of palliative systemic therapy (Laban et al.
2016). The valid NCCN guidelines for the years 2015–2018 clearly favored a combination of platinum, 5-FU, and cetuximab ahead of other combinations or a single-agent option (Adelstein et al.
2017). Nevertheless, the NCCN guideline and German guidelines do not give clear criteria for or against a specific protocol (Wolff et al.
2012; Bootz
2020). Not very old patients or patients with (more often felt than measured) better performance status might receive more aggressive protocols and more frequently combination therapy (La et al.
2018). This large scope for decision making might be the reason for the high variation of different systemic therapy regimens.
Median overall survival after start of first-line systemic therapy was 16.8 months. This is much longer than other recently published German real-world data from 2011 to 2013 in sample with comparable treatment regimens: 102 patients with probably lower general health status (ECOG performance status ≥ 2: 41%) than in the present study showed a median overall survival of only 7 months (Grunwald et al.
2020). In contrast, a retrospective data collection of 462 patients from a network of community oncology practices in the United States from 2007 to 2015 on effectiveness of systemic therapy for R/M HNC estimated a median overall survival of 21.0 months, i.e., even longer than in the present study (Fisher et al.
2018). In contrast, in trials on first-line systemic therapy, typically patients with an ECOG performance status > 1 are not included. In these studies, median overall survival ranges from about 8.2–10.7 months for cetuximab with chemotherapy, reach about 14.9 months for checkpoint inhibitors, and reach maximally 6.9 months for other single-agent regimens (Vermorken et al.
2008; Burtness et al.
2019). A direct comparison of the data is not possible. We can only conclude that first-line systemic therapy with the used protocols seemed to be, in general, effective in the clinical routine setting. The same holds true for second-line treatment. Median overall survival after start of second-line systemic therapy was 20.0 months. In trials using checkpoint inhibitors, median overall survival was about 7.5 months, and from 5.1 to 6.9 months for other combinations or monotherapies (Ferris et al.
2016; Pai et al.
2019; El Rassy et al.
2019). It is an important limitation of the present study that we cannot verify the correctness of the indication for any line of systemic therapy in retrospect. The series might include outliers with good prognosis not requiring systemic therapy.
A small amount of patients (12.4%) of the present study received the systemic therapy as primary treatment for stage IVc cancer. Overall survival of these patients was not significantly different from the patients receiving systemic therapy for a recurrent disease. In a recent population-based study analyzing patients from the National Cancer Database treated between 2003 and 2006 for primary stage IVc head and neck cancer, a 6-month and 12-month overall survival rate of about 70% and 50% was estimated, i.e. equivalent to the present data. Unfortunately, the drugs used for systemic therapy were not reported (Schwam et al.
2015).
Although presenting a large series of real-word data, the present study has important limitations. Due to the retrospective design, decision making for or against the selected systemic therapy regime remained unclear. The incidence of systemic therapy for HNC was 3.28/100,000 persons. The average incidence of newly diagnosed HNC in the years before was about 16–17/100,000 persons in Thuringia (Dittberner et al.
2020). Hence, about 20% of the patients receive directly or later on a systemic therapy for R/M HNC. If this proportion is low or high, cannot be answer as comparable study are missing. Standardized data on the performance status of the patients were missing. This might be the reason why the calculated comorbidity was low in our study sample (59.4%). It might be that the comorbidity was underestimated due to missing data. Alternatively, the study sample might represent a positive selection of good performers selected for systemic therapy, whereas bad performers might have had a lower probability to receive a systemic therapy. Instead, such patients might have had a higher probability to be selected for best supportive care and were not covered by the present study. Furthermore, the HPV status of the patients was unknown. It should, however, be stated that the HPV status does not play a role for treatment selection in the R/M HNC setting (Misiukiewicz et al.
2014). Furthermore, it seems that the HPV status has no predictive role when choosing a checkpoint inhibitor for treatment of R/M HNC. The prognostic role of HPV when using immunotherapy in the R/M HNC setting is undetermined (Bauml et al.
2017; Ferris et al.
2018; Cohen et al.
2019). An important strength of the study was the combination of population-based data and hospital-based data. The population-based approach allowed a representative reflection of the health care of R/M HNC patients in daily routine beyond clinical trials. The addition of data of the charts of all patients allowed a detailed analysis of the regimens, lines and cycles. This would not have been possible based on clinical cancer registry data.
The present study ended when a new era of systemic therapy just started. The phase 3 KEYNOTE-048 trial showed that pembrolizumab in combination with chemotherapy or as monotherapy improved overall survival compared to platinum-based chemotherapy with cetuximab in the first-line R/M HNC setting (Burtness et al.
2019). Therefore, pembrolizumab alone or in combination with chemotherapy is considered as the new first-line standard by many head and neck surgeons and oncologists. Cetuximab in combination with platinum-based chemotherapy is seen important in the future only for patients with no PD-L1 expression and as second-line treatment and all single-agent regimes for second or even third-line therapy. Fit patients with no PD-L1 expression might be good candidates for the TPExtreme protocol combining cetuximab with platinum and docetaxel (instead of 5-FU) (Guigay et al.
2019). We should not forget that only a minority of R/M HNC patients responds to immune-oncology therapies. Some important phase III trials are ongoing, for instance, the CheckMate 651 trial of nivolumab in combination with ipilimumab (NIH U.S. National Library of Medicine 2020), and the KESTREL trial of another PD-L1-inhibitor, durvalumab monotherapy or durvalumab in combination with tremelimumab (NIH U.S. National Library of Medicine 2020). The task now will be to collect and analyze large real-word dataset of patients treated with immune-oncology therapies.
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