Our study showed that biweekly dose-dense TPF ICT in locally advanced SCCHN had a promising treatment response. The overall response rate and complete response rate were 89.7% and 31%, respectively. The 3-year OS and PFS were 56.3% and 34.3%, respectively. Compared to the data from TAX323 and TAX324 trials, standard triweekly TPF ICT regimen achieved 68% and 72% post-induction RR, respectively[5, 6]. The 3-year OS and PFS for patients in TAX 323 were 37% and 17%, and those for stage IV patients in TAX 324 were 58.6% and 25.1%, respectively[5, 6]. Particularly, 25.9% of the grade 3–4 neutropenia in our study is markedly lower than previously reported. For example, TAX323 trial reported 76.9% of the grade 3–4 neutropenia, and TAX324 trial reported 83% of the grade 3–4 neutropenia[5, 6].
Toxicity is a major issue of ICT, with up to 6% toxic deaths and 11% of febrile neutropenia[4, 20]. Some studies had tried to find fewer toxic regimens by reducing chemotherapy dose[21, 22]. HM. Wang et al. reduced the dose to 90% of the original TPF dosage (docetaxel 67.5 mg/m2 on Day 1, cisplatin 67.5 mg/m2 on Day 1 and 5FU 675 mg/m2 on Day 1–5) as the induction treatment. The grade 3–4 neutropenia was 35%, and the overall response rate was 73.1% after induction therapy[21]. A retrospective study from J Fayette et al. in France used the modified TPF regimen of docetaxel and cisplatin at 40 mg/2 on day 1 and a bolus of 5FU at 400 mg/m2, then 1000 mg/m2 on Day 1–2 every 2 weeks. The authors reported 10% of febrile neutropenia, 83% of overall response rate and 19% of complete response[22]. Notably, the regimen adopted by J Fayette et al. was similar to that our study used, such as biweekly administration, and 48-hour infusion of high-dose 5FU. Biweekly administration of docetaxel might be better tolerated due to the reduced peak drug concentrations[23]. Data from colon cancer and gastric cancer had shown that biweekly 48 hour infusion of 5FU can increase the response rate with fewer side effects of myelotoxicity[24, 25]. However, the inherent bias of the retrospective study, the heterogenous post-ICT treatment (including surgery and radiotherapy) and the reduced dose intensity of cisplatin and docetaxel compared to the standard TPF regimen made the interpretation of the results difficult.
Dose-Dense Chemotherapy aims to achieve maximum tumor kill by shortening the interval of chemotherapy delivery. Several clinical trials and metastasis from breast cancer, bladder cancer, and lymphoma had revealed that dose-dense regimen improved response rate and survival outcomes[26, 27]. However, the associated studies in head and neck cancer are scarce. Our TPF regimen included 50, 50, 2,500, and 250 mg/m2 of docetaxel, cisplatin, 5-fluorouracil, and leucovorin, respectively. We maintained the average dose intensity of the traditional TPF, with less toxicity than triweekly TPF and similar rates of neutropenia (25.86%) compared with the weekly TPF regimen. Additionally, 94.8% of patients completed 6 cycles of treatment without dose reduction. The high rate of treatment completion may explain the better response rate and survival outcomes in our study.
ICT also was a predictor of survival for locally advanced SCCHN. A recent meta-analysis study showed the ICT responders had better survival than nonresponders[28]. Moreover, a phase II study demonstrated that responders after one cycle of split-dose TPF ICT were a survival predictor for oral and oropharyngeal squamous cell carcinoma (OPSCC)[29]. A review article that recruited seven studies displayed that the standardized uptake value (SUV) reduction in interim PET scan may predict ICT response, PFS, and OS[30]. In our study, biweekly TPF ICT demonstrated around 90% RR and a high CR rate (31.0%). Also, the patients with CR had better OS and PFS than those with non-CR. Accordingly, patients with metabolic non-CR may need a different treatment after ICT.
Limitations of our study include the lack of a comparator group and the relatively small sample size. Although the primary objective of this study is to investigate the response rate of ICT, the heterogeneous treatment during radiotherapy could have introduced major biases in the analysis of overall survival. Additionally, 14 of 54 (25.9%) patients could receive radiotherapy only, which raised the concern that the administration of ICT may compromise the completion of subsequent concomitant administration of chemotherapy or biotherapy. To draw definitive conclusions is difficult in this regard because compliance and toxicity data are differently reported. However, according to the Spanish TTCC trial, which used standard triweekly TPF regimen followed by concomitant CRT regimen, 30% of patients would never receive radiotherapy, 41% of patients needed dose reduction, and 17% of patients discontinued CRT treatment[31]. In our study, 4/58 (6.9%) patients did not receive the following radiotherapy, and 3/54 (5.6%) patient discontinued CRT treatment. The relative tolerability of the dose-dense TPF regimen may be attributed to fewer grade 3–4 adverse effects and shortened treatment duration. Finally, our study design is unlikely to answer the question of whether the combination of dose-dense induction therapy plus the following radiotherapy can beat conventional concomitant CRT therapy.
In conclusion, biweekly dose-dense TPF ICT proves good RR and CR for locally advanced SCCHN. This regimen had fewer grade 3/4 hematologic adverse events including neutropenia, anemia, and thrombocytopenia than the triweekly TPF. Also, the survival figures were not inferior to the reported studies of triweekly TPF ICT. The patients with CR after ICT had superior survival outcomes than those with non-CR. Thus, future studies should focus on whether further treatments are necessary for patients with non-CR after ICT.
Declarations