October 25, 2007 — Adding docetaxel to induction chemotherapy with cisplatin and fluorouracil improves the survival of patients with head and neck cancer, 2 new studies show. Published in the October 25 issue of the New England Journal of Medicine, both randomized phase 3 trials, sponsored by Sanofi-Aventis, demonstrate the advantages of docetaxel, sold under the brand name Taxotere.
"Docetaxel plus cisplatin/fluorouracil–based sequential therapy is feasible, effective, and makes sound biologic sense," lead author Marshall Posner, MD, from the Dana-Farber Cancer Institute, in Boston, Massachusetts, told Medscape Oncology.
Dr. Posner said that sequential therapy with docetaxel followed by chemoradiotherapy has a high cure rate for patients with locally advanced disease. He suggests the new combination is superior to cisplatin and fluorouracil alone and appears to be less toxic as well.
"This opens up sequential therapy as a reasonable and acceptable alternative to chemoradiotherapy or conventional induction chemotherapy and changes the standard," Dr. Posner said. He suggests this shifts the induction portion of therapy to cisplatin and fluorouracil with docetaxel.
Dr. Posner says these findings could have implications for other drugs, such as cetuximab ( Erbitux, ImClone Systems, Bristol-Myers Squibb) and panitumamab ( Vectibix, Amgen). "Sequential therapy is the platform upon which the new agents, such as cetuximab and panitumamab, can be added to improve outcomes," he said. "It is possible that adding cetuximab might be even more effective than the sequential therapy alone." He says studies exploring this new combination are ongoing.
But the Current Standard Promotes Chemoradiotherapy Instead
The current standard for patients with unresectable squamous-cell carcinoma of the head and neck and for organ preservation is still chemoradiotherapy — a combination of radiotherapy and concurrent chemotherapy. But new studies have suggested that induction chemotherapy with cisplatin and fluorouracil can also be beneficial.
The 2 new trials push this concept further by adding docetaxel to the regimen. 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.
In the first trial, Dr. Posner and colleagues looked at 501 patients with stage 3 or 4 head and neck cancer. Patients had no distant metastases, had tumors considered to be unresectable, or were candidates for organ preservation. More than 80% of the patients were men, and the predominant primary site of disease was the oropharynx.
The researchers randomly assigned patients to receive 1 of the induction chemotherapy regimens followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week. The primary end point for the trial was overall survival.
After randomization, the induction-chemotherapy group that had docetaxel added to its regimen had more patients with T4 lesions than did the conventional-therapy group (49% vs. 37%, P = .04). The researchers report the characteristics of the patients were otherwise well balanced between the 2 groups.
The investigators write that their subgroup analyses showed that in the group taking the docetaxel regimen there was a consistent trend toward improved survival, regardless of the primary site of disease, reason for therapy, nodal status, primary tumor stage, or surgical curability.
The researchers also observed longer overall and progression-free survival and a nonsignificant reduction in overall toxic effects in this group. At a median follow-up of 42 months, the sequential therapy was said to reduce the risk for death by 30%, compared with cisplatin and fluorouracil alone, which has estimated 3-year survival rates of 62% in the sequential-therapy group and 48% in the conventional-therapy group ( P = .002).
The investigators report that sequential therapy was associated with a nonsignificant decrease in mucositis. They point out, however, that there was also more myelotoxicity in this group. But in general, the sequential-therapy patients had significantly fewer treatment delays than conventional-therapy patients, reflecting reduced overall toxic effects.
Could One Day Have Implications for Cetuximab and Panitumamab
In the second trial, by Dr. Vermorken and colleagues, a similar induction regimen was compared with conventional therapy followed by radiotherapy alone in patients with unresectable tumors. This trial also demonstrated that sequential therapy improved survival with an acceptable toxicity profile.
The investigators conducted an open-label, randomized, stratified phase 3 study at 37 institutions in 15 European countries. Researchers randomly assigned eligible patients with stage 3 or 4 disease and no distant metastases to receive induction chemotherapy with cisplatin and fluorouracil or a similar regimen plus docetaxel. Patients without disease progression received radiotherapy 4 to 7 weeks after completing chemotherapy. The primary end point for the trial was progression-free survival.
Patients who were treated with sequential therapy had a reduction of 28% in the risk for disease progression or death, compared with those who received cisplatin and fluorouracil alone. They also had an extension of 2.8 months in median progression-free survival. This result was associated with significant improvements in overall survival, overall response rates, and time to treatment failure.
Patients in the sequential-treatment group had a reduction of 27% in the risk for death, an improvement in median overall survival of 4.3 months, and an absolute increase in 3-year survival of 10.9%.
"Our study and the study by Posner et al raise 2 questions," the researchers write. First, is induction sequential therapy followed by radiotherapy alone equivalent or superior to chemoradiotherapy? Second, do induction chemotherapy and chemoradiotherapy have complementary effects on overall control of disease? "At least 5 ongoing randomized trials evaluating induction chemotherapy followed by chemoradiotherapy may provide the answer," they note.
"Sequential therapy is a reasonable treatment for patients with locally advanced squamous-cell carcinoma of the head and neck — both for unresectable patients and patients who are candidates for organ preservation," Dr. Posner told Medscape Oncology.
He points out that comparisons between sequential therapy and chemoradiotherapy alone have yet to be published. "Those studies are ongoing," he said, but given that current data support conventional induction chemotherapy and chemoradiotherapy being equivalent for survival and organ preservation, it is highly likely that sequential therapy will prove to be so as well, he suggests.
The TAX 324 trial was sponsored by Sanofi-Aventis. Dr. Posner reports having received consulting and lecture fees from Sanofi-Aventis. A number of his colleagues on the trial also report having financial ties to the company. The 24971/TAX 323 trial was sponsored by Sanofi-Aventis and the National Cancer Institute. Dr. Vermorken reports having served on paid advisory boards for Sanofi-Aventis, and other investigators on the trial report similar financial disclosures.
N Engl J Med. 2007; 357:1695-1704, 1705-1715.
Medscape Medical News © 2007 Medscape
Cite this: Allison Gandey. Chemotherapy With Docetaxel Improves Head and Neck Cancer Survival - Medscape - Oct 25, 2007.