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On September 28, the FDA approved a new indication for docetaxel injection concentrate (Taxotere; sanofi-aventis) to use in combination with cisplatin and 5-fluorouracil for induction therapy before chemotherapy and surgery for locally advanced squamous cell carcinoma of the head and neck.

The approval was based on data from a phase 3, randomized, open-label, international trial (TAX324; n = 494), showing that the addition of docetaxel to cisplatin and 5-fluorouracil infusions significantly increased median overall survival by more than 3 years relative to use of standard 5-fluorouracil alone (70.6 vs 30.1 months; hazard ratio for mortality, 0.70; P = .0058).

In the study, patients were treated every 3 weeks for 3 cycles with docetaxel 75 mg/m2 plus cisplatin 100 mg/m2 and 5-fluorouracil 1000 mg/m2 a day for 4 days, or intravenous cisplatin 100 mg/m2 and 5-fluorouracil 1000 mg/m2 a day for 5 days. All patients went on to receive weekly chemotherapy (carboplatin) with radiation therapy for 7 weeks, followed by surgery when applicable.

The overall rate of grade 3 to 4 adverse events was similar between patients receiving docetaxel with cisplatin and 5-fluorouracil (65%) and those receiving just cisplatin and 5-fluorouracil (62%); the incidence of nausea, anorexia, and constipation was comparable.

However, patients receiving docetaxel plus cisplatin and 5-fluorouracil experienced greater rates of febrile neutropenia (12% vs 7%), neutropenic infection (12% vs 8%), grade 3 to 4 neutropenia (84% vs 56%), dizziness (4% vs 2%), alopecia (4% vs 1%), and diarrhea (7% vs 3%). Decreased rates were observed with respect to grade 3 to 4 thrombocytopenia (4% vs 11%), stomatitis (21% vs 27%), lethargy (15% vs 10%), and vomiting (8% vs 10%).

Docetaxel previously was approved for use in the treatment of breast cancer, non–small-cell lung cancer, hormone-refractory prostate cancer, and gastric adenocarcinoma.

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The United States Food and Drug Administration (FDA) recently approved the chemotherapy agent Taxotere® (docetaxel), in combination with Platinol® (cisplatin) and 5-fluorouracil, for use prior to surgery and chemoradiation therapy for the treatment of locally advanced squamous cell head and neck cancer. Taxotere is also approved for breast, lung, gastric, and prostate cancers.

Head and neck cancers originate in the oral cavity (lip, mouth, tongue), salivary glands, paranasal sinuses, and nasal cavity, pharynx (upper back part of the throat), larynx (voice box), and lymph nodes in the upper part of the neck. Worldwide, head and neck cancer is diagnosed in approximately 640,000 people and is responsible for approximately 350,000 deaths annually.

Locally advanced head and neck cancer refers to cancer that has spread from its site of origin to nearby tissues in the head and/or neck, but not to distant sites in the body. Patients are often treated with several different treatment modalities, including chemotherapy, radiation therapy, and/or surgery.

Pre-operative therapy including chemotherapy and/or radiation therapy is referred to as neoadjuvant therapy. Neoadjuvant therapy is often used to shrink the size of the cancer prior to the surgical removal, both to allow for a greater chance of complete removal and to provide initial systemic (full-body) therapy to kill cancer cells that may have already spread. If treatment is not administered until after surgery, the patient must wait until he/she has healed from surgery; this waiting period may allow cancer cells to grow and spread further.

The trial that prompted FDA approval of Taxotere for head and neck cancer is referred to as the TAX 324 trial. This international trial included patients with head and neck cancer that was considered potentially operable though not likely to be cured with surgery. Patients were treated with either Taxotere/Platinol/5-fluorouracil (TPF) or Platinol/5-fluorouracil (PF) as initial (induction) therapy. All patients were then treated with Paraplatin® (carboplatin) plus radiation therapy followed by surgery, for those eligible at that point.

• Overall survival was significantly improved for patients treated with TPF compared with those treated with PF.
• Overall median survival was 70.6 months for patients treated with TPF compared with only 30.1 months for those treated with PF.
• At three years survival was 62% for those treated with TPF compared with only 48% for those treated with PF.
• Severe side effects occurred in 65% of patients treated with TPF and 62% of patients treated with PF.

Patients diagnosed with locally advanced head and neck cancer may wish to speak with their physician regarding their individual risks and benefits of treatment with Taxotere.

Reference: Sanofi-Aventis. Taoxtere® (docetaxel) Granted FDA Approval to Treat Locally Advanced Head and Neck Cancer Prior to Chemoradiotherapy and Surgery.
Download the pdf of press release dated October 1, 2007 :

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According to two articles recently published in the New England Journal of Medicine, the addition of the chemotherapy agent Taxotere® (docetaxel) to Platinol® (cisplatin) and 5-fluorouracil (5-FU) improves survival over cisplatin/5-FU alone in the treatment of head and neck cancer.

Head and neck cancers originate in the oral cavity (lip, mouth, tongue), salivary glands, paranasal sinuses, and nasal cavity, pharynx (upper back part of the throat), larynx (voice box), and lymph nodes in the upper part of the neck. Worldwide, head and neck cancer is diagnosed in approximately 640,000 people annually and is responsible for approximately 350,000 deaths each year.

Advanced head and neck cancer refers to cancer that has spread from its site of origin. Patients are often treated with several different modalities, including chemotherapy, radiation therapy, and/or surgery.

Preoperative therapy including chemotherapy and/or radiation therapy is referred to as neoadjuvant therapy. Neoadjuvant therapy is often used to shrink the size of the cancer prior to the surgical removal, which may allow for a greater chance of complete removal and provide initial systemic (full-body) therapy to kill cancer cells that may have already spread. If treatment is not administered until after surgery, the patient must wait until he/she has healed from surgery; this waiting period may allow cancer cells to grow and spread further.

The first trial was conducted by researchers affiliated with the TAX 324 group.[1] This trial included 501 patients with advanced head and neck cancer who were not considered eligible for surgery. Patients were treated with either Taxotere plus Cisplatin and 5-FU (TPF) or Cisplatin/5-FU (PF) only as initial therapy. All patients then received treatment with the chemotherapy agent Paraplatin® (carboplatin) plus radiation therapy, referred to as chemoradiotherapy. Minimum follow-up was two years.

At three years overall survival was 63% for patients treated with TPF compared with 48% for patients treated with PF.
Cancer spread that was at or near the site of the original cancer was significantly reduced among patients treated with TPF versus those treated with PF; however, cancer spread to distant sites in the body did not differ between the two treatment groups.
Low levels of immune cells (neutropenia) occurred more frequently among patients treated with TPF than among patients treated with PF.

The researchers concluded that patients with “[advanced] head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy.”

The second trial was conducted by researchers affiliated with the EORTC 24971/TAX 323 Study Group. This trial also compared TPF to PF among 358 patients with advanced, inoperable head and neck cancer with no spread to distant sites in the body.[2] Patients were treated with either TPF or PF, and those whose cancer did not progress while receiving chemotherapy were treated with subsequent radiation within four to seven weeks of completing chemotherapy. The median follow-up was 32.5 months.

• Median progression-free survival was 11 months for those treated with TPF compared with 8.2 months for those treated with PF.
• Patients treated with TPF had a 27% reduced risk of death compared with patients treated with PF.
• Median overall survival was 18.8 months for patients treated with TPF compared with 14.5 months for patients treated with PF.
• Death rates from treatment-related side effects occurred in 2.3% of patients treated with TPF compared with 5.5% of patients treated with PF.

The researchers concluded: “As compared with the standard regimen of cisplatin and fluorouracil, induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with [advanced, inoperable] head and neck [cancer].”

Patients diagnosed with advanced head and neck cancer may wish to speak with their physician regarding their individual risks and benefits of treatment that includes Taxotere.
Reference:

• [1] Posner M, Hershock D, Blajman c, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. New England Journal of Medicine. 2007;357:1705-1715.
• [2] Vermorken J, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. New England Journal of Medicine. 20007;357:1695-1704.

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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.