Induction cisplatin (P) and fluorouracil (F) with or without docetaxel (T) followed by chemoradiation (CTRT) and surgical resection as indicated for locally advanced squamous cell carcinoma (LASCC) of the head & neck: preliminary results from the TAX 324 study

Reviewer: Charles Wood, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2006

Presenter: Posner MR
Presenter's Affiliation: Dana-Farber Cancer Institute, Boston, MA
Type of Session: Scientific

Background

PF induction chemotherapy has thus far proven to be the sole induction chemotherapeutic regimen to be effective in locally advanced squamous cell carcinoma and has been shown to confer an absolute 5% overall survival (OS) advantage per a recent meta-analysis study
Definitive concurrent chemoradiation has previously been shown by meta-analysis to confer an absolute OS advantage of 8% at 5 years
TPF is known to be highly active in the treatment of LASCC of the head & neck
This study was conducted to compare TPF and PF as induction chemotherapy regimens followed by chemoradiation with surgery as indicated in patients with LASCC of the head & neck

Materials and Methods

This was a multicenter phase III prospective randomized trial
Data was analyzed on an intent-to-treat basis
The primary endpoint of this study was OS
Secondary endpoints included progression-free survival (PFS), toxicity, response rate, duration of response, and quality of life
Eligibility requirements included Stage III or IV squamous cell carcinoma of the head & neck (oral cavity, oropharynx, larynx, and hypopharynx), a performance status of 0 or 1, no primary surgical resection, no alcohol addiction, no hospital admissions for COPD exacerbations within the previous 12 months, and weight loss not equal to or greater than 20% over the previous 3 months
Patients were randomized to induction PF versus TPF for 3 cycles given every 3 weeks; both arms then underwent definitive concurrent radiation and weekly carboplatin, with surgery as indicated for residual or initially bulky (N3) neck disease
Patients were stratified according to primary site, treatment center, and nodal (N) stage
The study was powered to 90% to detect an increase in OS with a 2-sided alpha of 0.05

Results

501 patients were included in the ITT analysis
494 patients received treatment and were included in the toxicity evaluation
median follow-up was 42 months
patients characteristics were well-balanced between treatment arms
the median dose and duration of RT was 70 Gy over 7.1 weeks
Comparison of OS:

	TPF	PF	P	HR
median OS	70.6 months	30.1 months	0.0058	0.70
OS (%)	59	47
1-year OS (%)	80	69
2-year OS (%)	67	54
3-year OS (%)	62	48

Comparison of PFS:

	TPF	PF	0.004	0.71
2-year PFS (%)	53	42
3-year PFS (%)	49	37

The overall response rate (ORR) after induction chemotherapy was significantly greater in the TPF arm versus PF arm (72% versus 64%, p=0.07)
The complete response rate (CRR) after induction chemotherapy was similar between the TPF and PF arms (17% vs. 15%, p=0.66)
There was no significant difference in the CRR between the TPF and PF arms following definitive CTRT (35% versus 28%, p=NS)
Toxicity was overall similar during induction chemotherapy, with increased neutropenia and febrile neutropenia in the TPF arm
There was no difference in toxicity between the 2 arms during CTRT
There were more deaths < 30 days after treatment in the PF versus TPF arms (12 vs. 4)

Author's Conclusions

TPF significantly increased OS versus PF (14% absolute OS advantage at 3 years with a 30% decrease in mortality)
TPF is a tolerable and safe regimen
TPF is the best induction combination and now the standard of care for induction chemotherapy in LASCC of the head & neck
The TPF arm represents the new standard of care for treatment of LASCC of the head & neck
The TPF arm is an appropriate platform for the addition of targeted molecular agents

Clinical/Scientific Implications

The combination of induction chemotherapy and CTRT is sound from a theoretical standpoint, as induction chemotherapy aids in decreasing distant metastases (DM) but not locoregional failure (LRF), and CTRT decreases LRF but not DM. Although there is increased alopecia and neutropenia with TPF, there is no overall evidence to suggest poorer tolerance, and the regimen appears to be reasonable with regards to toxicity.

Previous trials of induction chemotherapy have failed to show such robust results, and this is likely due to a combination of factors: underpowered trials, ineffective induction chemotherapy regimens, role of treatment intent, differential effects of induction chemotherapy when followed by radiation versus surgery, and patient selection factors. Indeed, there are several differences in eligibility requirements among cooperative group trials in this setting, and a consensus definition of high-risk squamous cell carcinoma of the head & neck would be most helpful in comparing across trials.

Preliminary data regarding local control, distant metastases, and late toxicity are not yet available; nevertheless, it is not unreasonable to consider the TPF arm the new standard of care in LASCC of the head & neck. Though subset analyses were not prospectively built in to the trial, such analyses in retrospect may prove beneficial in more definitively determining which patient need this aggressive treatment, and which patients could avoid such a regimen (e.g. T2N1 or laryngeal tumors).