Three-Drug Combo Best for Head and Neck Cancer

Fran Lowry

January 13, 2011

January 13, 2011 — The addition of docetaxel to standard induction chemotherapy with cisplatin and fluorouracil (PF) significantly improves the long-term survival of patients with locally advanced squamous cell head and neck cancer, reducing their likelihood of dying by 26% over 6 years.

These long-term results from the TAX 324 trial, published online January 12 in the Lancet Oncology, confirm that the 3-drug regimen — docetaxel, cisplatin, and fluorouracil (TPF) — should become the standard of care for all patients with locally advanced squamous cell cancer of the head and neck who are candidates for induction chemotherapy, say the authors.

"This is the longest follow-up with this regimen, and it is the longest follow-up of any regimen in head and neck cancer," said lead author Jochen Lorch, MD, from Harvard Medical School in Boston, Massachusetts. "The results from our study will definitely lay the concerns as to whether TPF is truly superior to PF to rest."

This study with 6-year results confirms earlier data showing the superiority of the 3-drug regimen; the 2-year results were published in 2007 (N Engl J Med. 2007; 357:1705-1715).

Comparing 3- and 2-Drug Regimens

The TAX 324 trial involved 501 patients with stage 3 or 4 disease randomized to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin and radiotherapy for 5 days per week for 7 weeks.

The TPF regimen consisted of docetaxel 75 mg/m2, followed by intravenous cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2 per day, administered as a continuous 24-hour infusion for 4 days. The PF regimen consisted of intravenous cisplatin 100 mg/m2, followed by fluorouracil 1000 mg/m2 per day as a continuous 24-hour infusion for 5 days.

Most patients (69%) had 3 or more years of follow-up. Significantly more patients survived in the TPF group than in the PF group (hazard ratio, 0.70; P = .006). Median overall survival was 71 months in the TPF group and 30 months in the PF group (P = .006).

The study also found that patients treated with TPF had better locoregional control (P = .04), but the incidence of distant metastases did not differ significantly.

Benefits Endure With Time

To see whether these benefits endured with time, Dr. Lorch and his colleagues performed an analysis of data gathered retrospectively from the TAX 324 patients' medical records as of December 1, 2008.

With a median follow-up of 72.2 months (95% confidence interval [CI], 68.8 to 75.5), they found that the original survival advantage was sustained.

The median overall survival in the TPF group was 70.6 months (95% CI, 49.0 to 89.0); in the PF group, it was 34.8 months (95% CI, 22.6 to 48.0; P = .014).

The estimated survival at 5 years was 52% in the TPF group and 42% in the PF group. Progression-free survival was significantly longer for patients receiving TPF than for those receiving PF (median, 38.1 vs 13.2 months).

In a subgroup analysis, patients with hypopharyngeal and laryngeal tumors had significantly longer progression-free survival with TPF than with PF (median, 20.9 vs 10.1 months). They also had a significantly lower risk for disease progression than PF-treated patients.

Patients with larynx and hypopharynx disease also fared better if they received TPF. Their median overall survival was 51.9 months, compared with 23.5 months for those treated with PF.

Surrogates for Toxicity

In addition, the researchers looked at tracheostomy and dependence on a gastric feeding tube as surrogates for treatment-related long-term toxicity. They report that no significant differences in these measures were detected between the treatment groups.

In the TPF group, 3 of 91 patients (3%) remained feeding-tube dependent, compared with 8 of 71 patients (11%) in the PF group. Six (7%) of 92 patients had tracheostomies in the TPF group, compared with 8 of 71 patients (11%) in the PF group.

"The data suggest that TPF is at least not any worse, and if anything may be a little better in terms of the long-term toxicities of feeding tubes and tracheostomies, but those data were somewhat limited," Dr. Lorch said.

"It was a little difficult to get reliable data because often there was no mention of whether they had tracheostomies or feeding tubes. When patients are being followed for years, it may not always be mentioned in physicians' notes, so this was one limitation of our study," he told Medscape Medical News.

Nevertheless, Dr. Lorch said that the take-home message for oncologists is that TPF should be considered the regimen of choice in squamous cell head and neck cancer patients with large primary tumors or extensive lymphadenopathy.

In an accompanying editorial, June Corry, MD, and Danny Rischin, MD, from the Peter MacCallum Cancer Centre, East Melbourne, Australia, agree that the continued superior results with TPF over PF definitively answer the question of which regimen is better.

But Role of Induction Is Unclear

However, the editorialists point out that the role of induction chemotherapy in the overall treatment of locally advanced head and neck cancer is still unclear.

"Use of TPF requires a subsequent compromise in dose intensity of the chemotherapy that can be given concomitantly with radiation," they write. "Weekly low-dose carboplatin (as used in TAX 324) is not a recognized standard concomitant regimen, and no data are available showing it to be better than radiation alone."

The lack of comparative data raises concerns that subjecting patients to a protracted course of treatment "might compromise the delivery of the concomitant component, which has been shown to have the largest effect on locoregional control and overall survival in locally advanced head and neck cancer," they write.

Some trials comparing sequential regimens with induction TPF and concomitant chemoradiation have closed early. "Hopefully, other completed or ongoing trials will provide the answers we need to determine whether there is a role for TPF-induction chemotherapy," they write.

Drs. Corry and Rischin also note that oropharyngeal cancers that are associated with human papillomavirus (HPV) have better outcomes than HPV-negative cancers. They warn that not stratifying patients according to their HPV status might confound the interpretation of such trials.

The study was supported by Sanofi-Aventis. Dr. Lorch, Dr. Corry, and Dr. Rischin have have disclosed no relevant financial relationships.

Lancet Oncol. Published online January 12, 2011.


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