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- MATERIALS AND METHODS
- FUNDING SUPPORT
- CONFLICT OF INTEREST DISCLOSURES
Radiation therapy is the only curative treatment modality for nonmetastatic squamous cell carcinoma of the nasopharynx. Concurrent chemoradiation is the standard treatment strategy for nasopharyngeal cancer (NPC) in locally advanced stages (defined as a tumor classification of T3/T4 or positive lymph node [N+] status).[1-6] However, the results after such treatment are suboptimal. Clearly, novel treatment strategies are needed to further improve patients' survival rates.
The addition of a taxane to cisplatin and 5-fluorouracil (5-FU) (ie, the TPF regimen) before radiotherapy or concurrent chemoradiation has resulted in significantly improved treatment outcomes, including overall survival, in patients with head and neck squamous cell carcinoma (HNSCC), excluding NPC.[7-9] Such synergistic effects provided by TPF chemotherapy are equally attractive for its use in locoregionally advanced NPC. Therefore, we initiated 2 prospective phase 2 clinical trials in 2007—1 for stage III NPC and another for nonmetastatic stage IV NPC—to evaluate the efficacy and safety of induction TPF chemotherapy followed by concurrent chemoradiation using 3-dimensional (3D)-conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT). Here, we report the 3-year outcomes from those trials.
- Top of page
- MATERIALS AND METHODS
- FUNDING SUPPORT
- CONFLICT OF INTEREST DISCLOSURES
The primary objective of the 2 phase 2 trials we are reporting here addressed the efficacy of induction docetaxel, cisplatin, and 5-FU (the TPF regimen) used with a standard chemoradiation regimen for stage III and stage IVA/IVB NPC. In particular, we focused on OS as the primary endpoint for patients who received the triple combination of TPF followed by concurrent chemoradiation. The results demonstrated a significant improvement in OS to 94.8% for patients with stage III NPC and to 90.2% for patients with nonmetastatic stage IV NPC after 3 years of follow-up. Furthermore, the triple combination of TPF was well tolerated when used before the standard chemoradiation strategy for NPC.
NPC is sensitive to both radiation and chemotherapy, and combined chemoradiation is the mainstay of treatment for advanced, nonmetastatic disease. The use of chemotherapy with radiation has been studied extensively. The results from several randomized phase 3 trials and meta-analyses have confirmed that adjuvant chemotherapy provides no significant improvement in patients' survival.[13-16] Induction cisplatin chemotherapy, when used before radiation alone, does improve local control and disease-free survival in patients with locally advanced NPC without affecting OS.[17-20] The receipt of radiation therapy and concurrent cisplatin-based chemotherapy with or without adjuvant chemotherapy, became the standard treatment of choice for T3 of T4 and/or N+ NPC after the publication of the pivotal Intergroup INT-0099 study and several confirming randomized trials.[2-6] However, adjuvant chemotherapy is poorly tolerated and has limited compliance. because patients suffer substantial toxicities from concurrent chemoradiation, and many are unfit and/or reluctant to receive further chemotherapy. Typically, only 60% of patients (range, 55%-76%) receive all 3 scheduled cycles of adjuvant chemotherapy, and 70% (range, 60%-81%) receive at least 2 cycles. The reported studies clearly illustrate that, with neoadjuvant chemotherapy, tolerance and compliance indeed are substantially better, and nearly 100% of patients (range, 97%-100%) can tolerate at least 2 cycles.
However, it has been suggested that the improvement in OS from concurrent chemotherapy is mostly because of the improvement in local disease control. On the basis of the published literature, the 5-year OS rates for patients with stage III and nonmetastatic stage IV NPC are approximately 65% and 45%, respectively. To further improve the outcome of patients with locally advanced NPC, an improvement in both local and distant control will be needed. However, induction chemotherapy using cisplatin or its combination, such as combined cisplatin, epirubicin, and paclitaxel, or adjuvant chemotherapy using cisplatin plus 5-FU failed to improve OS further according to the results from several randomized clinical trials.[13, 20, 22]
Docetaxel has demonstrated significant efficacy as a single agent or in combination with platinum in HNSCC. Compared with paclitaxel, it has less neurotoxicity, which supports its combined use with cisplatin. Its efficacy in the treatment of HNSCC, excluding NPC, has been demonstrated repeatedly in randomized clinical trials. The results from the TAX 323 and TAX 324 studies revealed that, when used with concurrent chemoradiation or radiation alone, the addition of docetaxel (T) to cisplatin and 5-FU (PF) (ie, TPF vs PF) reduced the risk of death by nearly 30%.
The effect of docetaxel used with cisplatin and without 5-FU (the TP regimen) for NPC has been addressed in 2 previously reported studies.[23, 24] A randomized phase 2 trial published in 2009 studied the toxicities and the primary outcome of patients with NPC who did or did not receive induction chemotherapy using the TP regimen followed by concurrent cisplatin chemotherapy and conventional radiation. In addition to the acceptable adverse-effect profile, the researchers demonstrated a significant improvement in OS for patients who received induction TP chemotherapy. The 3-year OS rate was 94.1% after induction chemotherapy followed by chemoradiation, compared with 65% after chemoradiation alone. This superb and exciting result was consistent with that reported in a more recently published, retrospective study: Ekenel et al reported their observation of 59 patients with NPC who received 3 cycles of induction cisplatin (75 mg/m2) and docetaxel (75 mg/m2) followed by combined cisplatin-based chemotherapy and conventional radiotherapy using cobolt-60 or a 4 to 6 megavolt linear accelerator. Impressive OS and PFS rates of 94.9% and 84.7%, respectively, were reported. In both studies, however, the numbers of patients in either stage were limited, especially those with stage IVA/IVB disease, who are at substantial risk for local and distant recurrence.
The findings from our trials confirm the encouraging results mentioned above and suggest that superior results are achieved in patients who receive TPF-based induction chemotherapy followed by concurrent chemotherapy and 3D-CRT or IMRT; ie, the current standard radiation technique. The local control rate in both studies reached >93%, including patients who were treated for T4 tumors. More important, the outcomes—especially OS and DMFS—after such treatment in patients with T4 and/or N3 disease are nearly identical to those observed in patients with stage III NPC. The OS and DFMS rates of approximately 90% in both stages indicate that TPF may substantially improve the control of systemic disease in patients with advanced NPC. The already initiated Radiotherapy Oncology Group for Head and Neck (GORTEC) multicenter phase 3 trial, in which patients are randomized to receive cisplatin plus radiation with or without neoadjuvant TPF chemotherapy (ie, TPFconcurrent cisplatin + RT vs cisplatin + RT), will confirm the efficacy of neoadjuvant TPF in a randomized fashion (registered online: http://www.clinicaltrials.gov/NCT00828386). However, that trial does not require IMRT, which is considered the current standard radiation technique for the treatment of NPC. Another ongoing randomized trial in collaboration with our institution will address the efficacy of neoadjuvant TPF (ie, TPF concurrent cisplatin + IMRT vs cisplatin + IMRT) in patients with NPC who receive IMRT (registered online: http://www.clinicaltrials.gov/NCT01245959).
It has been reported that TPF induces a high rate of severe neutropenia (range, 76%-97%). In our studies, neutropenia occurred in 55.2% patients, which is less than the incidence of neutropenia reportedly caused by G-CSF support. However, the compliance with TPF neoadjuvant chemotherapy was better, all patients tolerated at least 2 cycles, and 88.8% of patients completed 3 cycles.
In a recently published, large, retrospective series of 370 patients, Lin et al demonstrated that OS after induction chemotherapy with TP or PF followed by IMRT without concurrent chemotherapy was as good as concurrent chemotherapy. If the hypothesis that neoadjuvant TPF significantly improves distant and local control is confirmed by the 2 ongoing randomized trials described above,[25, 26] then, based on the finding that IMRT improves the local control rate to >95% for all tumor classifications, whether concurrent chemotherapy (ie, the current standard) remains necessary becomes a question. This question (ie, TPFconcurrent cisplatin + IMRT vs TPFIMRT) will be addressed further by a multi-institutional, randomized, noninferiority study that is in the planning stage; however, the initiation of that trial will depend on the results from the 2 ongoing randomized trials described above.[25, 26]
The results of our phase 2 trials have demonstrated that neoadjuvant TPF chemotherapy produces encouraging and potentially efficacious outcomes in terms of OS, PFS, and local control in patients with locoregionally advanced NPC. Furthermore, this regimen was well tolerated and had a manageable toxicity profile. However, this aggressive treatment combination remains investigational and can only be considered standard after confirmation by the already initiated phase 3 randomized trial.