Modified biweekly cisplatin, docetaxel plus cetuximab (TPEx) as first-line treatment for patients with recurrent/metastatic head and neck cancer

For stage III/IV squamous cell carcinoma of the head and neck (SCCHN), the locoregional recurrence rate after curative therapy was reported to be 30–40% [1]. Distant metastases at diagnosis (mainly pulmonary) are detected only in a minority of patients [2]. Additionally, second primaries occur at a constant rate of 2–3% per year [3, 4]. Attempts to implement adjuvant treatment strategies after chemoradiation in order to improve outcomes such as the epidermal growth factor receptor (EGFR) inhibitor afatinib have not been successful so far [5].

For patients, who are not amenable to salvage surgery, only limited palliative treatment options exist: globally, systemic combination therapy is the category I recommendation for patients with locoregionally unresectable recurrent or metastatic (R/M) disease and excellent performance status.

During the last decade, chemotherapy regimens have been constantly improved and novel drugs such as the EGFR antibodies panitumumab or cetuximab were evaluated in clinical trials for the treatment of R/M SCCHN patients. However, the median overall survival (OS) in this setting is still about 8–10 months employing the EXTREME regimen, which is containing a platinum drug, 5-FU and weekly cetuximab and regarded as the standard of care [6].

Apart from platinum drugs and cetuximab, taxanes were shown to exert significant anti-tumor activity against SCCHN cells. Numerous clinical trials demonstrated the efficacy of both docetaxel and paclitaxel as single agents and in combination with platinum drugs in R/M SCCHN [7].

The molecular basis of clinical reports, which showed synergistic effects of taxanes in combination with cetuximab, is not fully understood. Various molecular mechanisms such as the prevention of taxane induced EGFR phosphorylation or modulation of the EGFR downstream pathways by taxanes might contribute to the beneficial activity profile of this particular combination [8, 9]. From the clinical point of view, both docetaxel and paclitaxel in combination with cetuximab are an effective regimen for R/M SCCHN patients both in the first-line and in the second-line setting accompanied with a beneficial side-effect profile [10, 11].

A recent phase II study demonstrated that the substitution of 5-FU by docetaxel in combination with cisplatin given every 3 weeks plus weekly cetuximab might be as effective as the EXTREME regimen in R/M SCCHN patients and is well tolerated [12]. However, further streamlining and simplifying this dosing regimen would be of particular value with respect to patients’ quality of life in the palliative setting.

Based on these considerations, we performed this retrospective analysis in order to evaluate the efficacy and safety of modified cisplatin, docetaxel plus cetuximab (TPEx) administered every other week as first-line therapy in patients suffering from R/M SCCHN.

Despite recent advances in immunotherapy and extensive research efforts, R/M head and neck cancer is still a clinical challenge. Since no curative treatment options are available in this setting, prolonging OS and symptom control is the ultimate treatment goal. In this retrospective analysis, we show that a modified TPEx regimen administered biweekly is a feasible, safe and effective regimen in unselected patients suffering from R/M SCCHN.

In the first-line platinum-sensitive setting, a combination chemotherapy according to the EXTREME regimen is regarded as the standard of care worldwide, although considerable shortcomings are linked to this protocol such as the high amount of patients (82%) suffering from severe grade 3/4 adverse events or the continuous administration of 5-FU for four days [6]. Two recently published phase II studies demonstrated that substitution of 5-FU by a taxane might be equi-effective with respect to OS but yield in higher ORR and better toxicity profile [12, 13]. The first study enrolled 54 patients and reported that conventional TPEx consisting of cisplatin/docetaxel given every 3 weeks plus cetuximab administered weekly results in an OS of 14 months (95% CI 11.3–17.3) and an ORR of 44% [12]. However, two infectious events leading to death were observed [12]. The second study compared three weekly cisplatin plus weekly cetuximab with or without paclitaxel resulting in a median OS of 11 month, a median PFS of 7 months and an ORR of 51.7% in the cisplatin/paclitaxel plus cetuximab group [13]. Given the limitations of inter-trial comparisons, the low patient number and the retrospective nature of our analysis these results are completely in line with our findings. Patients receiving off-protocol modified biweekly TPEx had a median OS of 10.8 months (95% CI 6.7–14.2) and a median PFS of 6.3 months (95% CI 5.7–6.8) indicating a comparable efficacy of the biweekly TPEx regimen. Tumor shrinkage is a crucial issue for head and neck cancer patients leading to symptom relief and quality of life improvement, although response rates do not always translate into a prolonged OS as shown in the aforementioned trial. While the ORR of biweekly TPEx was 50% in our analysis, conventional TPEx was reported to yield in an ORR of 44.4%. ORR with cisplatin in combination with paclitaxel and cetuximab was numerically higher (51.7%), whereas the standard of care EXTREME regimen achieved tumor response in 36% of the patients [6]. Of note, we observed four complete responders, whereas in the conventional TPEx regimen, no CRs were reported [12]. This finding further supports the activity of modified TPEx given every other week. Interestingly, the DCR of 53.5%, we observed in our analysis was inferior compared to the other two cisplatin/taxane/cetuximab trials, which reported a DCR of 79.6 and of 76.4%, respectively [12, 13]. Additionally, compared to the conventional TPEx study, a higher amount of patients were not assessable for response due to early death (26 vs. 11%) in our analysis. We are aware that making assumptions for the definitive reasons for this discrepancy is speculative and no final conclusions can be drawn given the retrospective nature of this analysis. However, we have to point out that a higher fraction of our patients received salvage treatment for recurrence (34%) and/or upfront multimodality treatment such as surgery plus radiotherapy or chemoradiation (44%), thus representing a patient population at increased risk for rapid disease progression.

Modified biweekly TPEx was very well tolerated and no new safety issues arose. Although the majority of patients suffered from a grade 3/4 adverse event, the side effects were well manageable. As compared to the conventional TPEx study, we observed lower rates of severe neutropenia (13%), which is in line with other trials employing a biweekly platinum/taxane protocol [14].

However, the main advantage of biweekly TPEx should be considered both under quality of life and health economic aspects: Minimizing the number of outpatient visits will reduce health care costs and the need for health care staff and is more convenient for the patient than weekly infusions. From the pharmacological point of view, several trials have shown that biweekly schedules are feasible and might be equivalent to weekly or three weekly regimens in the palliative setting: For cetuximab, it was shown that there is no difference between biweekly and weekly cetuximab in target regulation, pharmacokinetics and pharmacodynamic parameters in colorectal cancer and head and neck cancer patients [15, 16]. Likewise, it has been demonstrated that cisplatin/docetaxel biweekly is as effective as cisplatin/docetaxel triweekly accompanied with fewer side effects in non-small cell lung cancer patients [14].

In conclusion, modified biweekly TPEx is a feasible and effective regimen for the first-line therapy of R/M SCCHN patients. Non-inferiority trials are warranted in order to establish this regimen as a standard of care treatment protocol for R/M SCCHN.