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Randomized phase III trial comparing induction chemotherapy using cisplatin (P) fluorouracil (F) with or without docetaxel (T) for organ preservation in hypopharynx and larynx cancer. Preliminary results of GORTEC 2000-01

Reviewer: Charles Wood, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 5 de junio del 2006

Presenter: Calais G
Presenter's Affiliation: Centre Henry S. Kaplan, Tours, France
Type of Session: Scientific

Background

• Induction chemotherapy followed by radiation treatment (RT) provides a potential for functional laryngeal preservation in patients with locally advanced laryngeal and hypopharyngeal cancer
• PF is the standard induction regimen in locally advanced head & neck cancer, and data have suggested to the addition of T may increase efficacy
• This trial was undertaken to determine whether the addition of T to PF as induction treatment could increase the rate of laryngeal preservation in patients with locally advanced cancer of the larynx or hypopharynx

Materials and Methods

• This was a prospective multicenter randomized trial, and analysis was via intention-to-treat
• The primary endpoint was 3-year larynx preservation rate, and secondary endpoints included overall survival (OS), disease-free survival (DFS), and toxicity
• Eligibility criteria included larynx or hypopharynx primary sites, T3-T4 tumors or T2 tumors not suitable for partial laryngectomy, adequate organ function, WHO PS of 0 or 1, age from 18 to 70, lack of macroscopic residual tumor; both squamous cell carcinoma and undifferentiated histologies were allowed
• Patients requiring total laryngectomy (TL) were randomized to receive induction PF (P 100 mg/m 2 d1 and F 1000 mg/m 2 continuous infusion d1-5) or induction TPF (T 75 mg/m 2 d1, P 75 mg/m 2 d1, and F 750 mg/m 2 continuous infusion d1-5)
• Induction chemotherapy was given every 21 days for a total of 3 cycles
• 3-5 weeks following induction treatment, patients with partial (≥50%) or complete response (PR or CR) and normal laryngeal mobility went on to receive RT to a dose of 70 Gy; nonresponders underwent TL followed by post-operative RT to a dose of 54-66 Gy
• Response was determined via physical examination, endoscopic examination, and CT/MR imaging
• The study was powered to detect a 15% difference in larynx preservation rate (from 35% to 50%)

Results

• 220 patients were randomized (108 to PF, 112 to TPF) among 14 French centers, and an additional 15 patients were excluded because of ineligibility or missing data
• median follow-up was 35 months
• treatment arms were well-balanced with respect to age, gender, PS, and primary site, though a greater number of patients on the PF arm had less advanced tumors, and a greater number of patients on the TPF arm had increased nodal involvement
• there was more grade 3-4 alopecia (19% vs. 2%) and neutropenia (57% vs. 35%) in the TPF arm; there was more grade 3-4 mucositis (9% vs. 4%) and febrile neutropenia (6% vs. 2%) in the PF arm
• compliance to TPF was greater versus PF, and the intended treatment was delivered in the TPF arm to 81.2% of patients versus 67.4% of patients in the PF arm
• the average time between the last cycle of chemotherapy and first fraction of RT was approximately 4 weeks
• between the 2 arms, 73% of patients received the intended chemotherapy and 96.4% received the intended RT
• more patients in the TPF arm versus the PF arm were offered larynx preservation (80.0% versus 57.6%, p not specified)
• there was a significantly higher rate of larynx preservation at 3 years in the TPF arm (73% vs. 63%, p=0.036)
• there were significantly more responses (CR + PR) to treatment in the TPF arm (82.8% vs. 60.8%, p=0.0013)
• smaller tumors, pre-treatment Hgb > 14, treatment arm, and compliance with chemotherapy were significant predictors of response to treatment
• there was a trend for increased OS in the TPF arm (p=0.096)
• there was a trend for increased DFS in the TPF arm (p=0.105)
• there were no significant differences in acute toxicity between the 2 arms
• there were no significant differences in distant metastases (DM) between the 2 arms

Author's Conclusions

• TPF induction chemotherapy has an increased response rate, an increased compliance rate, and an increased larynx preservation rate versus PF induction chemotherapy

Clinical/Scientific Implications

This laryngeal preservation trial is somewhat unique in that it includes a mix of larynx and hypopharynx patients. The goal of the trial was the achievement of a 50% functional laryngeal preservation rate. Though there were more T3-T4 tumors in the TPF arm, more patients in this group (80% vs. 67%) were able to move on to RT. To be sure, an 80% rate of potential larynx preservation in the TPF arm in such advanced tumor patients borders on astounding, and is certain to generate skepticism as to its validity. More patients in the TPF arm did achieve functional larynx preservation at the 3-year mark, and the authors should be commended for applying a definition of "functional" larynx preservation in lieu of any sort of larynx preservation, functional or not.

Though there were significantly more responses in the TPF arm, this did not translate into an OS or DFS as of yet; however, the curves appear to diverge at 18 months in favor of TPF, such that differences between the groups with respect to OS and DFS may become statistically significant with further follow-up. Fortunately, there were no chemotherapy-related deaths in either arm, and similar acute toxicity rates were observed between the 2 groups; late toxicity reporting remains pending.

It is somewhat problematic to compare this study with previous laryngeal preservation trials, as the patient inclusion and treatment criteria are different (hypopharynx patient inclusion and stipulation of functional larynx). Additionally, the protocol specified RT alone following induction treatment as opposed to concurrent chemoradiation which might affect patient outcome.

Ultimately, however, the literature has shown an improvement in response rates with TPF that has not as of yet translated into an increase in locoregional control. Nevertheless, TPF appears to be the standard of care as an induction regimen in head & neck cancer.