Cisplatin, Docetaxel and Cetuximab (TPEx) as First-line Treatment for Patients With Recurrent or Metastatic Head and Neck Cancer: A Multicenter Real-World Study


 BACKGROUNDThe association of platinum, taxanes, and cetuximab has proven to be an effective and safe strategy for head and neck cancer treatment. Here we present a multi-institutional real-world experience of the TPEx schema as first-line therapy in advanced squamous cell carcinoma of the head and neck (SCCHN).METHODS This retrospective multicenter cohort study included patients with histologically confirmed recurrent or metastatic SCCHN treated with first-line TPEx regimen at five medical centers in Argentina between January 1, 2017, and April 31, 2020. Chemotherapy consisted of four cycles of docetaxel, cisplatin, and cetuximab, followed by cetuximab maintenance. Clinical outcomes and toxicity profiles were evaluated. RESULTSTwenty-four patients were included. Median age at diagnosis was 58 years (range 36-77). The majority of patients (83.3%) received at least four chemotherapy cycles in the initial part. In the included group, overall response rate was 62.5%, and three patients achieved a complete response (12.5%). The median time to response was 2.4 months (95% CI 1.3-3.5). With a median follow-up of 12.7 months (95% CI 8.8-16.6), the median progression-free survival was 6.9 months (95% CI: 6.5-7.3), and the overall survival rate at 12 months was 82.4%. Two-thirds of patients reported at least one treatment-related adverse event, and 25% presented grade 3-4 toxicities.CONCLUSIONSTPEx was an adequately tolerated regimen in our population. Median progression-free survival and overall response rates were consistent with recent reports in clinical trials evaluating this treatment combination.


Introduction
Squamous cell carcinoma of the head and neck (SCCHN) represents 5% of all newly diagnosed cancers, leading to over 300,000 deaths per year 1 . Despite appropriate primary treatments, in about 50% to 60% of patients with stage III to IV disease, loco-regionally relapse is evidenced 2 . Given that a signi cant proportion of these cases are not suitable for surgery or radiotherapy, systemic treatments and best supportive care are the preferred therapeutic options.
Up to the early 2000s, the median overall survival (OS) of patients with metastatic disease was only 6 months 3,4 . This poor prognosis has encouraged signi cant research efforts in the last 15 years for developing novel drugs. In this setting, targeted therapy against the epidermal growth factor receptor (EGFR) cetuximab has proved substantial e cacy for recurrent or metastatic (R/M) SCCHN treatment in combination with 5-uorouracil and platinum-based chemotherapy (EXTREME regimen) 3 . More recently, a new strategy using the immune checkpoint inhibitor pembrolizumab alone, or in combination with 5uorouracil and platinum, became an appropriate rst-line treatment for R/M SCCHN patients [5][6][7] .
Under these circumstances, the EXTREME regimen still represents a recommended rst-line treatment option in selected scenarios, such as cases with PDL-1-negative tumors or when immunotherapy is contraindicated. Noteworthy, this treatment regimen may represent an attractive approach for patients with disease progression after rst-line immune checkpoint inhibitors given as monotherapy 8 .
Taxanes have maintained widespread clinical use, particularly in solid tumors, since their discovery in the early 1970s and several clinical trials have shown its antineoplastic activity against SCCHN 9-11 .
The uorouracil substitution by a taxane seeks to take advantage of the potential immunogenic and proapoptotic synergy between cetuximab and docetaxel or paclitaxel 12,13 . Cetuximab, platinum, and taxane-based schedules were associated with promising survival results and cytoreductive properties in clinical studies [14][15][16][17][18] . In this context, TPExtreme was the rst large, phase 3, randomized trial comparing the TPEx regimen (cetuximab, taxane, and platinum) with the EXTREME schema at rst-line setting 19 .
This trial demonstrated similar e cacy outcomes in 539 R/M HNSCC patients, showing a median OS of 14.5 and 13.4 months using TPEx and EXTREME regimen, respectively. Furthermore, the TPEx arm had a more favorable toxicity pro le, leading to better compliance of the planned treatment (72% vs. 44%), with fewer dose interruptions (10 vs. 27%).
Based on these considerations and given the scarce real-world studies including patients that underwent this schema, we retrospectively evaluated the e cacy and safety of the TPEx regimen as rst-line therapy in patients with R/M SCCHN.

Study population and treatment characteristics.
This retrospective multicenter cohort study included patients between January 1, 2017, and April 31, 2020, with histologically con rmed diagnosis of R/M SCCHN, that received TPEx as rst-line treatment at ve medical centers in Argentina. Chemotherapy consisted of four cycles of docetaxel 75mg/m², cisplatin 75mg/m² every three weeks, and cetuximab (400mg/m2 on day 1 of cycle 1, then 250mg/m2 weekly), with systematic granulocyte colony-stimulating factor (GCSF) support at each cycle. Patients with controlled disease continued with weekly 250 mg/m2 or every-2-weeks cetuximab 500mg/m² maintenance until disease progression or unacceptable toxicity. Demographic and clinicopathological characteristics, including age, ECOG performance status, smoking status, alcohol consumption, primary site tumor, and previous treatments were collected from medical charts and entered in a prede ned centralized database. E cacy and safety information was also retrieved, and treatment strategies, responses, adverse events, and discontinuation were also documented.
Disease progression and treatment response were collected from medical charts. Treatment response was assessed by the investigator using CT or MRI scans in accordance with Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0).

Statistical analysis
Data was summarized by frequency and percentage for categorical variables and by median and range for continuous variables. Progression-free survival (PFS) and OS of TPEx as rst-line treatment were calculated from the date of therapy initiation to rst documented relapse or death due to any cause, respectively. Data was censored on the last follow-up if the patient was alive. The duration of response (DOR) was de ned as the time from rst complete response (CR) or partial response to progressive disease or death. Survival curves were performed using the Kaplan-Meier method, and differences between groups were calculated using the log-rank test. All statistical analyses were performed using SPSS software version 23.0 (SPSS, Inc., Chicago, IL, USA).

Patients characteristics
In this multicenter retrospective study, 24 patients with R/M SCCHN were included from ve Argentinian medical centers. All patients received rst-line chemotherapy with TPEx. Median age at diagnosis was 58 years (range 36-77), males represented 62.5% of the sample (n=15), and the majority had ECOG 0-1 (22, 91.7%) ( Table 1). Smoking history was reported in 13 patients (54.2%), and around one-third of the cases reported alcohol consumption. Of note, only two patients (8.3%) had a body mass index (BMI) < 18.5.

E cacy
A total of three patients achieved a complete response (12.5%), and in half of the cases a partial response was documented (Table 2). Remarkably, most of the cases bene ted from TPEx therapy since the overall response rate (ORR) and disease control rate (DCR) were 62. 5

Safety and adverse events
Two-third of the patients reported at least one treatment-related adverse event and 25% at least one grade 3-4 adverse event. A summary of the safety pro le is listed in table 3. The most commonly reported hematological adverse events were febrile neutropenia (12.5%), anemia (12.5%), and hyponatremia/hypokalemia (12.5%). Among non-hematological events, acne-like rash was the most frequent (33.3%) related adverse event. Grade 3-4 nausea-vomiting, asthenia, and renal failure were noted in 4.2% of the cases. Only one patient experienced a grade 1 hypersensitivity reaction during taxane infusion.
Overall, serious adverse events were reported in ve patients (20.8%). Three of them developed febrile neutropenia, one acute renal failure, and the remaining patient was hospitalized due to grade 3 vomiting that required intravenous hydration. All cases continued treatment after resolving the toxicity. The median duration of hospitalization among patients with severe adverse events was six days (range 2-22).

Discussion
Despite substantial advances in the last decade, R/M SCCHN remains a signi cant clinical issue, given its associated high mortality rate. In this context, tumor response rate is an important goal in these patients given its association with symptoms improvement and better quality of life.
Over the past years, the EXTREME regimen became a preferred rst-line strategy in R/M SCCHN patients 3 .
While signi cant improvement in OS, PFS, and ORR was demonstrated in the cetuximab plus platinumuorouracil arm of the pivotal phase 3 trial, 82% of the included patients experienced grade 3-4 adverse events, mostly related to 5-uorouracil continuous infusion. Of note, all these ndings were observed in t patients, hence treatment decisions in this setting should be analyzed on a case by case basis. Clinical comorbidities, performance status, nutritional assessments, access to infusion pumps, or even availability for patient hospitalization are some of the considerations made in clinical practice before treatment de nition.
Given that not all patients can tolerate the EXTREME regimen, alternative treatment protocols were developed, mostly replacing 5-uorouracil by taxanes. The phase 2 GORTEC study evaluated fty-four patients with R/M SCCHN using cisplatin, docetaxel, and cetuximab in the rst-line setting 14  To the best of our knowledge, our study represents the rst multicenter real-world data, including South-American patients treated with the TPEx schema. Notably, PFS and ORR were consistent with the previous clinical trials. Intriguingly, two patients with complete responses were associated with longer PFS, which may support that depth of response could be studied as a prognostic factor in patients with R/M HNSCC.
In our experience, the TPEx regimen was adequately tolerated by most of the analyzed patients. The incidence of grade 3-4 adverse events was surprisingly lower than expected (25%), but it should be noted that ve patients had treatment-related hospitalizations. Fortunately, no fatal toxicities were experienced.
Our experience con rms that the substitution of 5-uorouracil by docetaxel may be a reasonable treatment strategy for R/M SCCHN patients. TPEx was incorporated as a standard regimen in our centers, considering that this regimen is associated with a lower duration of treatment infusions, lower total number of cycles, and the recent reports of safety and quality of life outcomes. These particularities are essential in low-and middle-income countries with limited access to infusion pumps. Furthermore, the instauration of simpli ed regimens has become of extreme importance during the COVID-19 pandemic 23 .
Our results should be interpreted with caution considering study limitations. This real-world data study was conducted in ve private care centers, which can impact the high proportion of patients with access to immunotherapy after disease progression (92.9%). The low number of included patients and the study retrospective nature may also hamper the extrapolation of our results to Hispanic and Latino-American populations. Additionally, our follow-up is not long enough to adequately analyze OS in our sample.
Finally, it should also be highlighted that the landscape in R/M SCCHN is evolving. First-line treatment strategies currently include immunotherapy given alone or in combination with chemotherapy 7 . Nevertheless, TPEx represents an adequate alternative for patients with R/M HNSCC without PDL-1 expression or as a subsequent treatment after disease progression with immune checkpoint inhibitors given as a monotherapy. It should be emphasized that drugs combination regimens, such as TPEx, have proven to be associated with higher ORR, which is particularly bene cial in patients with high tumor burden.

Conclusions
TPEx was a well-tolerated regimen in our population. Clinical outcomes, such as PFS and ORR, were comparable to the recently reported clinical trial using the same treatment schema. This regimen may be considered an attractive therapeutic strategy due to its more simpli ed administration, the total number of chemotherapy cycles, treatment tolerability. In this context, quality of life, cost of hospitalizations, and adverse event management should be carefully analyzed before deciding the best therapeutic plan for patients with R/M SCCHN. Availability of data and materials

Abbreviations
The datasets used and analyzed in the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
This study was approved by the Institutional Review Board of Alexander Fleming Institute. The requirement for written informed consent was waived owing to the retrospective nature of the study Consent for publication Not applicable.  a. Objective response was considered to be a con rmed complete or partial response, as assessed by investigator.
b. The disease-control rate was considered to be a con rmed complete response, a partial response, or stable disease, as assessed by investigator.
c. Time to response was calculated with the use of the Kaplan-Meier method from the date of TPEx initiation to the date of the rst documentation of a partial or complete response.
d. Duration of response was calculated with the use of the Kaplan-Meier method from the date of the rst documented response until the date of documented disease progression, death, or the last response assessment in the absence of disease progression. a. The investigators determined whether adverse events were related to the treatment.
b. Adverse events that leaded hospitalization.
c. This category includes patients who interrupted or discontinued cisplatin, docetaxel, or cetuximab because of an adverse event at any time and patients who interrupted or discontinued cetuximab maintenance for an adverse event after completing the cycles of chemotherapy. Events were attributed to the speci c treatment by the investigator.