Despite substantial advances in the last decade, R/M SCCHN remains a significant 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 first-line strategy in R/M SCCHN patients3. While significant improvement in OS, PFS, and ORR was demonstrated in the cetuximab plus platinum–fluorouracil arm of the pivotal phase 3 trial, 82% of the included patients experienced grade 3-4 adverse events, mostly related to 5-fluorouracil continuous infusion. Of note, all these findings were observed in fit 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 definition.
Given that not all patients can tolerate the EXTREME regimen, alternative treatment protocols were developed, mostly replacing 5-fluorouracil by taxanes. The phase 2 GORTEC study evaluated fifty-four patients with R/M SCCHN using cisplatin, docetaxel, and cetuximab in the first-line setting14. Median OS, PFS, and ORR were 14 months, 6.2 months, and 44.4%, respectively. In this selected population, only 12 patients (22.2%) experienced grade 4 adverse events. In another phase 2 trial, Bossi et al. randomized 201 patients with R/M SCCHN to first-line cetuximab plus cisplatin with or without paclitaxel15. Authors reported a median PFS of 7 months and an ORR of 51.7% in the cetuximab, cisplatin, and paclitaxel arm. With this regimen, 72.5% and 33% of the included patients presented grade ≥3 and 4 adverse events, respectively.
Guigay and collaborators have recently published the results of a phase 3 trials that compared TPEx with EXTREME as first-line treatment in 539 patients19. Overall survival, PFS and ORR were 14.5 vs. 13.4 months, 6.0 vs. 6.1 months, and 46 vs. 40%, respectively, not finding significant differences between both arms. TPEx regimen was associated with 30% grade 4 adverse events, which was significantly lower than the 43% incidence reported with the EXTREME schema. Furthermore, an exploratory analysis of this trial showed a better quality of life in patients who received TPEx, mainly in global health status, physical functioning, role functioning, and scores of appetite20.
Remarkably, real-world data in this setting is scarce. Before the GORTEC trial, Guigay and collaborators presented the results of 30 patients treated with TPEx at Gustave Roussy Institute between 2011 and 201321. In this group of patients, median PFS and OS were 6.0 and 13.6 months, respectively. A total of eight grade 3-4 adverse events were documented, including vomiting, mucositis, skin rash, diarrhea, hypersensitivity, and neutropenia. Additionally, Fuchs et al. reported similar results in a retrospective single-institution study, including 38 R/M SCCHN patients treated with TPEx at the Medical University of Vienna22. In this study, the median OS, PFS, and ORR were 10.8 months, 6.3 months, and 50%, respectively.
To the best of our knowledge, our study represents the first 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 five patients had treatment-related hospitalizations. Fortunately, no fatal toxicities were experienced.
Our experience confirms that the substitution of 5-fluorouracil 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 simplified regimens has become of extreme importance during the COVID-19 pandemic23.
Our results should be interpreted with caution considering study limitations. This real-world data study was conducted in five 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 chemotherapy7. 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 beneficial in patients with high tumor burden.