The present trial showed that ICT with a split-dose regime of TPF was safe and did not jeopardize curative surgery of primary head and neck cancer and neck metastasis as well as postoperative radiotherapy or radiochemotherapy. The feasibility of such a complex trimodal treatment approach for patients with locally advanced head and neck cancer was proven. The primary objective, the determination of MTD of the split-dose regime, was achieved: a split-dose regime of 30 mg/m2 docetaxel, 40 mg/m2 cisplatin and 2000 mg/m2 5-fluorouracil was recommended for the subsequent and still ongoing phase II study.
The regimen was moderately well tolerated. The rate of DLT in form of grade 3 and 4 neutropenia was not higher than expected. Using the presented split-dose regimen neutropenia grade 3 and 4 was observed in 56% of the cases. In comparison, the two large phase III studies with a standard TPF regimen observed this hematologic toxicity in 38% and 76% of the cases, respectively
]. Safety is a major concern when subjecting patients with head and neck cancer to ICT prior to a standard therapy consisting of curative surgery and postoperative radiotherapy. It is very important to emphasize that other relevant acute toxicities were very rare in the present study as it was also shown for a comparable split-dose strategy in gastric cancer
]. In turn, the acceptable acute toxicity is the reason that treatment delays were a rare event. Surgery was performed 14 – 50 days after end of ICT. Hence, ICT causes a treatment delay in comparison to standard therapy, i.e. to perform the tumor surgery directly without ICT. The prognostic role of a treatment delay on the outcome of head and neck cancer is controversially discussed. There are studies showing a negative effect of a delay on the survival but other studies not
]. We have to await the follow-up data to see if the time interval between end of ICT and surgery has influence on the final outcome. Finally, the satisfactory treatment tolerance caused that all but one patient finished the complete protocol. Most of the patients ended therapy with nearly normal swallowing function. This might be a benefit in comparison to surgery and postoperative radiotherapy in combination with postoperative chemotherapy. We conclude that the strategy with a split-dose regimen of TPF has favorable toxicity profile using it if ICT is planned prior to surgery of a locally advanced head and neck cancer. Alternatively, it might be also a feasible strategy for further clinical trials to omit fluorouracil. This might allow higher dosages of docetaxel
The presented neoadjuvant setting with subsequent surgery allowed an evaluation of the pathologic response to the split-dose TPF regime. To our knowledge, we present the first pathologic response data for TPF as it was used so far mainly prior to radiotherapy or radiochemotherapy. In such a setting, the clinicoradiologic overall response rate to TPF for head and neck cancer is about 70% (complete response: 9-17%;
]. The present study limited to oral and oropharyngeal cancer gives comparable results with a clinicoradiologic overall response of 83% (complete response: 16%). Interestingly, histopathologic results revealed a complete tumor regression of the primary tumor in 50% of the patients and for primary and neck metastasis in 27% of the cases. It seems that the clinicoradiologic assessment underestimates the complete tumor response. The HPV positive tumors showed all a complete histopathologic tumor response. Nevertheless, at least two third of the patients (in our study all HPV negative) present viable tumor cells after ICT and neck metastasis and primary tumor in the same patients must not respond equally. The tumor cells remnants in the primary seem to be randomly distributed in the necrotic former tumor area (data not shown). Therefore, it has to be emphasized that tumor surgery has to be orientated on the initial extension of the tumor. Surgery seems to be an effective therapeutical option to treat such tumor remnants as R0 resection was achieved in all cases. Downstaging of the primary oral and oropharyngeal cancer for surgery is not allowed after ICT with split-dose TPF. On the other hand, ICT using split-dose TPF plus surgery resulted in a low risk postoperative constellation in 3 out of 4 patients, i.e. this presented ICT strategy seem to decrease the rate of high-risk constellations after surgery as we would expect about half of the patients with high risk post-surgical constellation after standard surgery without ICT
The results of the two large phase III studies (TAX 323 and TAX 324;
] led to a renaissance of ICT prior to radiotherapy or radiochemotherapy and there is an ongoing debate of the effectivity in comparison to concurrent radiochemotherapy. The present study and the meanwhile initiated phase II study adopt the idea to a trimodal concept including surgery. This is the first ongoing phase II trial including TPF as ICT prior to surgery in a trimodal therapy concept. There are two recent large randomized studies investigating the outcome of ICT prior to surgery. The one from the GETTEC group is showing that overall survival after ICT with PF prior to surgery and postoperative radiotherapy is better than after surgery and postoperative radiotherapy alone
]. In this study, PF induction achieved in 56% of patients an objective response. This is accordance to large TAX 323 and 324 trials showing a much less response for PF than for TPF
]. Unfortunately, the GETTEC study did not present data on the histopathologic response. Hence, a comparison of the histopathologic response effect after PF in the GETTEC study versus the effect of TPF in the present study is not possible. In contrast to the GETTEC trial, the addition of primary chemotherapy with PF to standard surgery was unable to improve survival in the other recent randomized trial from Italy
]. The Italian study was restricted to cancer of the oral cavity. The objective response rate restricted to this tumor location was higher with 82%. A pathologic complete response of the primary tumor was observed in 27% of patients, i.e. half as effective like the TPF regimen in the present study. Unfortunately, the publication of the Italian trial does not give clear data on the pathologic complete response of the neck. Hence, a more detailed comparison is not possible. In the Italian trial only high-risk patients received postoperative radiotherapy. As one third of patients in the ICT group received postoperative radiotherapy, it could be concluded that PF is also able to decrease the number of high risk patients. But the present study with only a quarter of high risk patients gives some evidence that TPF is more effective than PF to decrease the number of postoperative high risk patients.