TPF induction in head and neck cancer – pro

A combined modality approach with chemotherapy and radiation has become standard treatment for head and neck carcinoma. The most notable prospective trial to date examined induction with 5-FU and cisplatin followed by radiation. The overall initial response rate was 93% and the 6 year survival was 67%.  Because of the poor results obtained with radiation therapy alone in patients with locally advanced disease, induction cisplatin-5FU before radiation therapy has been tested. The overall response rate to cisplatin-5FU is approximately 90%, and about 50% achieved CRs, with improved 5-year survival. Concurrent cisplatin/radiation therapy,which has been investigated by us and later by other investigators, produced higher CR rates and better 5-year survival rates. Since the introduction of effective chemotherapy as part of the salvage treatment after relapse in these patients with head and neck cancer, the 5-year survival rate in patients with stage IV disease who received radiation therapy as their initial treatment has risen to the 40% range.

5FU and cisplatin are standard therapy in most stage presentations of head and neck carcinoma. The issues here is the use of TPF first, before radiation, use of erbitux and, the concept of adding chemotherapy again after the chemoradiation.

Many radiation oncologists and some medical oncologists believe that induction chemotherapy is not effective for the treatment of patients with inoperable locally advanced squamous cell carcinoma of the head and neck. However, a growing body of data from randomized clinical trials has demonstrated that induction chemotherapy — in combination with chemoradiotherapy — may play an important role in the treatment of this patient population. The standard neoadjuvant chemotherapy regimen has consisted of a platinum agent and 5-fluorouracil (5-FU), a regimen known as PF. More recently, the addition of a taxane such as docetaxel (or, less commonly, paclitaxel) to the PF regimen (a triple combination known as TPF) is emerging as a more effective and less toxic standard for induction chemotherapy.

Two large, randomized trials — the Veterans Affairs Laryngeal Cancer Study Group trial[8] and a phase 3 trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) — have demonstrated the benefit of induction chemotherapy with PF (100 mg/m2 of cisplatin on day 1 and 1000 mg/m2 of 5-FU by continuous infusion on days 1-5) with respect to organ preservation. In these trials, overall survival rates were similar in patients receiving either induction PF chemotherapy and radiation or surgery and radiation therapy. In patients with more advanced unresectable tumors, PF induction therapy has been shown to produce long-term survival benefits, with overall survival times in a subset of inoperable patients receiving chemotherapy of 21% at 5 years and 16% at 10 years compared with 8% and 6%, respectively, in patients not receiving chemotherapy. In a phase 3 trial of neoadjuvant chemotherapy in patients with oropharyngeal cancer conducted by the French Groupe d’Etude des Tumeurs de la Tete et du Cou (GETTEC), the median overall survival time for patients with both resectable and unresectable tumors was 5.1 years when PF induction chemotherapy was followed by locoregional therapy vs 3.3 years for those who did not receive PF induction chemotherapy (P = .03).

A number of randomized trials have demonstrated improved organ preservation or survival with TPF compared with PF. The phase 3 TAX 323 trial, a direct comparison of PF and TPF induction chemotherapy conducted by the EORTC, included patients with locally advanced and unresectable squamous cell head and neck cancer who were randomized to receive induction therapy with either PF or TPF every 3 weeks for 4 cycles, followed by radiotherapy or surgery. The overall rate of response among patients who received TPF induction chemotherapy was 68%, compared with a 54% response rate in the group that received PF induction chemotherapy (P = .007). With a median follow-up of 32 months, TPF-treated patients demonstrated significantly superior progression-free survival (hazard ratio [HR] 0.72; 95% confidence interval [CI], 0.56, 0.91; P = .006), overall survival (HR 0.73; 95% CI 0.57, 0.94; P = .016), and response rate (67.8% vs 53.6%; P = .007). Patients treated with PF experienced more grade 3-4 nausea (7.3% vs 0.6%), vomiting (5.0% vs 0.6%), and stomatitis (11.2% vs 4.6%), and more toxic deaths occurred among patients in the PF arm (5.5% vs 2.3%).

The international TAX 324 trial assessed PF induction chemotherapy, with or without docetaxel, followed by chemoradiotherapy and surgical resection in patients with locally advanced head and neck cancer. The overall response rate following induction chemotherapy showed a trend toward improvement with the addition of docetaxel (72% vs 64%, P = .07). Survival data at 3 years posttreatment showed a highly significant (62% vs 48%) survival advantage for patients who received the TPF regimen. The HR was 0.70 (P = .0058), indicating a 30% reduction in mortality in the TPF arm. Less toxicity was noted in patients who received TPF compared with PF. Finally, a randomized phase 3 trial comparing PF induction chemotherapy with and without docetaxel in patients with laryngeal cancer demonstrated an improvement in organ preservation with the addition of the taxane to the PF regimen.

The DeCIDE trial — Docetaxel Based Chemotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer — a phase 3 trial sponsored by the University of Chicago, is currently recruiting patients with an expected total enrollment of 400. The trial’s primary objective is to determine the effect on overall survival when induction chemotherapy is administered prior to chemoradiotherapy in patients with nodal stage N2 or N3 head and neck cancer. A secondary goal is to evaluate the effect of induction chemotherapy when administered prior to chemoradiotherapy on distant failure-free survival, failure pattern, progression-free survival, and quality of life. Induction chemotherapy consists of two 21-day cycles of docetaxel (day 1), cisplatin (day 1), and 5-FU (days 1-5), for a total duration of 6 weeks. The chemoradiotherapy course is five 14-day cycles of docetaxel (day 1), 5-FU (days 0-4), and hydroxyurea (days 0-4) with twice-daily radiation on days 1-5, for a total duration of 10 weeks. Following chemoradiation, all patients will undergo surgical evaluation for possible neck dissection.

The Paradigm study, a randomized phase 3 trial, is under way internationally, led by the Dana-Farber Cancer Institute. The trial is comparing sequential therapy with TPF/chemoradiation vs cisplatin-based chemoradiotherapy with accelerated concomitant boost radiotherapy for locally advanced squamous cell cancer of the head and neck. Patients are randomized to receive an aggressive chemoradiotherapy course with cisplatin and accelerated concomitant boost radiotherapy or 3 cycles of TPF followed by radiotherapy. Patients who have a good response will then receive carboplatin and daily radiotherapy, whereas those who have a poor response will go on to receive accelerated boost radiotherapy with 4 weekly infusions of low-dose docetaxel. This trial is expected to accrue about 330 patients over the next 3 years.

Two European randomized trials comparing a sequential treatment approach including TPF induction chemotherapy and chemoradiotherapy vs standard chemoradiation were recently published in the October 25, 2007 issue of the New England Journal of Medicine (N Engl J Med. 2007; 357:1695-1704)1705-1715),  both randomized phase 3 trials, sponsored by Sanofi-Aventis, demonstrate the advantages of docetaxel.. The first study, by Dr. Posner and his team, is known as the European Organization for Research and Treatment of Cancer TAX 324 trial. The second study, led by author Jan Vermorken, MD, PhD, from the Universitair Ziekenhuis Antwerpen, in Edegem, Belgium, is known as 24971/TAX 323.

Jan B. Vermorken, M.D., Ph.D., Eva Remenar, M.D., Carla van Herpen, M.D., Ph.D., Thierry Gorlia, M.Sc., Ricard Mesia, M.D., Marian Degardin, M.D., John S. Stewart, M.D., Svetislav Jelic, M.D., Jan Betka, M.D., Joachim H. Preiss, M.D., Ph.D., Danielle van den Weyngaert, M.D., Ahmad Awada, M.D., Ph.D., Didier Cupissol, M.D., Heinz R. Kienzer, M.D., Augustin Rey, M.D., Isabelle Desaunois, M.Sc., Jacques Bernier, M.D., Ph.D., and Jean-Louis Lefebvre, M.D., for the EORTC 24971/TAX 323 Study Grou, *Cisplatin, Fluorouracil, and Docetaxel in Unresectable Head and Neck Cancer. N Engl J Med 2007; 357:1695-1704October 25, 2007

Al-Sarraf M, Reddy MS. Nasopharyngeal carcinoma. Curr Treat Options Oncol. 2002;3:21-32.

Mould RF,Tai TH. Nasopharyngeal carcinoma: treatments and outcomes in the 20th century. Br J Radiol. 2002;75:307-339.

Haddad R, Tishler RB, Norris CM, Mahadevan A, Busse P, Wirth L, Goguen LA, Sullivan CA, Costello R, Case MA, Posner MR. Docetaxel, cisplatin, 5-fluorouracil (TPF)-based induction chemotherapy for head and neck cancer and the case for sequential, combined-modality treatment.Oncologist. 2003;8(1):35-44.

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