Cancer of the Larynx, Cancer of the Nasal Cavity, Cancer of the Oral Cavity, Cancer of the Pharynx, Paranasal Sinus Neoplasms
Conditions
Keywords
Cancer of the Pharynx (Nasopharynx, Oropharynx, Hypopharynx), Cancer of the Nasal Cavity and Paranasal Sinuses
Brief summary
The combined use of chemotherapeutic drugs with radiation has proven to be effective in improving overall survival and local control among patients with locally advanced head and neck cancer. Induction chemotherapy given before receiving local treatment has been shown to reduce the rate of distant failure. Many drugs have been found to prevent tumor cells from growing or dividing, although it has yet to be determined which agent, or specific combination of agents, is most effective in treating head and neck cancer. Docetaxel is a drug which has been reported to show promising activity in Phase II head and neck cancer studies. Therefore, the purpose of this trial is to compare the effectiveness of induction chemotherapy followed by chemoradiotherapy versus the same chemoradiotherapy alone in patients with locally advanced head and neck cancer.
Detailed description
TRIAL DESIGN: Phase III trial of induction therapy with docetaxel followed by chemoradiotherapy versus chemoradiotherapy alone in patients with nodal stage N2 or N3 head and neck cancer OBJECTIVES: Primary * To determine the effect on overall survival when induction chemotherapy is administered prior to chemoradiotherapy in patients with N2 or N3 disease. Secondary * To determine the effect of induction chemotherapy when administered prior to chemoradiotherapy on distant failure-free survival, failure pattern, progression free survival and quality of life. TREATMENT PLAN: * After eligibility is confirmed, patients will be randomized to one of two treatment arms: Arm A - Induction + chemoradiotherapy Arm B - Chemoradiotherapy alone * Induction therapy: Two 21-day cycles of chemotherapy consisting of docetaxel (day 1), cisplatin (day 1), and 5-fluorouracil (days 1-5). Total duration of 6 weeks. * Chemoradiotherapy: Five 14-day cycles of docetaxel (day 1), 5-fluorouracil (day 0-4), and hydroxyurea (days 0-4) with twice daily radiation (days 1-5). Total duration of 10 weeks. * All patients will undergo surgical evaluation after chemoradiation for possible neck dissection. * Upon completion of treatment, patients will be monitored every three months during the first year, every six months during the second and third years, and annually thereafter, up to seven years. * Patients will be followed for Quality of Life (QOL) during the course of treatment, as well as annually thereafter, up to five years. PROJECTED ACCRUAL: * An expected sample size of 400 patients will be enrolled for this study (200 per treatment arm).
Interventions
DRUGfluorouracil
750 mg/m2/day on days 1-5 (induction phase); 600 mg/m2/day, day 0-4 (chemoradiotherapy phase)
DRUGdocetaxel
75 mg/m2 on day 1 (induction phase); 25 mg/m2 on day 1 (chemoradiotherapy phase)
DRUGcisplatin
75 mg/m2 on day 1
DRUGhydroxyurea
Each cycle: 500 mg PO q 12 hours x 6 days (11 doses)
PROCEDUREchemotherapy
See protocol for details
PROCEDUREradiotherapy
See protocol for details
Sponsors
University of Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years or older * Histologically or cytologically confirmed diagnosis of squamous cell or poorly differentiated carcinomas of the head and neck (excluding lip), or lymphoepithelioma * No prior chemotherapy or radiotherapy * Prior surgical therapy will consist only of incisional or excisional biopsy, and organ sparing procedures such as debulking of airway-compromising tumors or neck dissection in a patient with an existing primary tumor * Karnofsky performance status of \>= 70% * Intact organ and bone marrow function * Obtained informed consent
Exclusion criteria
* Demonstration of metastatic disease (i.e. M1 disease). * Patients with a history of severe allergic reaction to docetaxel or other drugs formulated with polysorbate 80. History of allergic reactions attributed to compounds of similar chemical or biologic composition to cisplatin, 5-fluorouracil, or hydroxyurea * Other coexisting malignancies or malignancies diagnosed within the previous 3 years with the exception of basal cell carcinoma, cervical cancer in situ, and other treated malignancies with no evidence of disease for at least 3 years. * Prior surgical therapy other than incisional or excisional biopsy and organ-sparing procedures such as debulking of airway-compromising tumors or neck dissection in a patient with an unknown primary tumor. Any non-biopsy procedure must have taken place less than 3 months from initiating protocol treatment. * Incomplete healing from previous surgery * Pregnancy or breast feeding (men and women of child-bearing potential are eligible but must consent to using effective contraception during therapy and for at least 3 months after completing therapy) * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Patients with clinically significant pulmonary dysfunction, cardiomyopathy, or any history of clinically significant CHF are excluded. The exclusion of patients with active coronary artery disease will be at the discretion of the attending physician. * Uncontrolled active infection unless curable with treatment of their cancer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival: Time From Randomization to Death From Any Cause | Up to 6 years | Survival rates over 6 years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence Free Survival: Time From Randomization to Local/Regional/Distant Recurrence or Death From Any Cause | Up to 6 years | Recurrence-free survival rates over 6 years. Recurrence-free survival is time from randomization to local, regional, or distant recurrence or death from any cause |
| Failure Pattern (Local/Regional Recurrence) | Up to 6 years | Percentage of patients with local/regional recurrence |
| Failure Pattern (Distant Recurrence) | Up to 6 years | Percentage of patients with distant recurrence |
| Distant Failure-free Survival (DFFS): Time From Randomization to Distant Recurrence or Death From Any Cause | Up to 6 years | DFFS rates over 6 years. DFFS is time from randomization to distant recurrence or death from any cause |
| Quality of Life (Normalcy of Diet) | Change from baseline to post-CRT (post-pre). This corresponds to week 16 in the induction arm and week 10 in the CRT alone arm. | Performance Status Score (0-100 point scale with negative numbers indicating worsening of function) |
| Quality of Life (Speech) | Change from baseline to post-CRT (post-pre). This corresponds to week 16 in the induction arm and week 10 in the CRT alone arm. | Performance Status Score (0-100 point scale with negative numbers indicating worsening of function) |
| Quality of Life (McMaster) | Change from baseline to post-CRT (post-pre). This corresponds to week 16 in the induction arm and week 10 in the CRT alone arm. | McMaster RT Questionnaire (4-28 point scale with negative numbers indicating worsening of function) |
| Quality of Life (FACT H&N) | Change from baseline to post-CRT (post-pre). This corresponds to week 16 in the induction arm and week 10 in the CRT alone arm. | FACT Hand-and-neck subscale(b) (0-40 point scale with negative numbers indicating worsening of function) |
Countries
Croatia, France, Russia, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Induction Plus Chemoradiotherapy Induction therapy: Two 21-day cycles of chemotherapy consisting of docetaxel (75 mg/m2, day 1), cisplatin (75 mg/m2, day 1), and 5-fluorouracil (750 mg/m2/day, days 1-5). Total duration of 6 weeks.
Chemoradiotherapy: Five 14-day cycles of docetaxel (25 mg/m2, day 1), 5-fluorouracil (600 mg/m2/day, day 0-4), and hydroxyurea (500 mg PO q 12 hours x 6 days (11 doses)) with twice daily radiation (150 cGy given bid, days 1-5). Total duration of 10 weeks.
docetaxel: 75 mg/m2 on day 1 (induction phase); 25 mg/m2 on day 1 (chemoradiotherapy phase)
cisplatin: 75 mg/m2 on day 1
hydroxyurea: Each cycle: 500 mg PO q 12 hours x 6 days (11 doses)
fluorouracil: 750 mg/m2/day on days 1-5 (induction phase); 600 mg/m2/day, day 0-4 (chemoradiotherapy phase)
chemotherapy: See protocol for details
radiotherapy: See protocol for details | 138 |
| Chemoradiotherapy Chemoradiotherapy: Five 14-day cycles of docetaxel (25 mg/m2, day 1), 5-fluorouracil (600 mg/m2/day, day 0-4), and hydroxyurea (500 mg PO q 12 hours x 6 days (11 doses)) with twice daily radiation (150 cGy given bid, days 1-5). Total duration of 10 weeks.
docetaxel: 75 mg/m2 on day 1 (induction phase); 25 mg/m2 on day 1 (chemoradiotherapy phase)
hydroxyurea: Each cycle: 500 mg PO q 12 hours x 6 days (11 doses)
fluorouracil: 750 mg/m2/day on days 1-5 (induction phase); 600 mg/m2/day, day 0-4 (chemoradiotherapy phase)
chemotherapy: See protocol for details
radiotherapy: See protocol for details | 135 |
| Total | 273 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Site withdrew before starting treatment | 2 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Chemoradiotherapy | Total | Induction Plus Chemoradiotherapy |
|---|---|---|---|
| Age, Continuous | 56.9 years | 56.8 years | 56.7 years |
| Region of Enrollment Croatia | 4 Participants | 9 Participants | 5 Participants |
| Region of Enrollment France | 3 Participants | 7 Participants | 4 Participants |
| Region of Enrollment Russia | 5 Participants | 13 Participants | 8 Participants |
| Region of Enrollment Spain | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 123 Participants | 243 Participants | 120 Participants |
| Sex: Female, Male Female | 17 Participants | 42 Participants | 25 Participants |
| Sex: Female, Male Male | 118 Participants | 231 Participants | 113 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 39 / 138 | 42 / 135 |
| other Total, other adverse events | 132 / 138 | 129 / 135 |
| serious Total, serious adverse events | 65 / 138 | 38 / 135 |
Outcome results
Primary
Overall Survival: Time From Randomization to Death From Any Cause
Survival rates over 6 years.
Time frame: Up to 6 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Induction Plus Chemoradiotherapy | Overall Survival: Time From Randomization to Death From Any Cause | 74.9 percentage of participants |
| Chemoradiotherapy | Overall Survival: Time From Randomization to Death From Any Cause | 72.8 percentage of participants |
Comparison: Comparison of overall survival curvesp-value: 0.6895% CI: [0.59, 1.41]Log Rank
Secondary
Distant Failure-free Survival (DFFS): Time From Randomization to Distant Recurrence or Death From Any Cause
DFFS rates over 6 years. DFFS is time from randomization to distant recurrence or death from any cause
Time frame: Up to 6 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Induction Plus Chemoradiotherapy | Distant Failure-free Survival (DFFS): Time From Randomization to Distant Recurrence or Death From Any Cause | 69.3 percentage of participants |
| Chemoradiotherapy | Distant Failure-free Survival (DFFS): Time From Randomization to Distant Recurrence or Death From Any Cause | 63.8 percentage of participants |
p-value: 0.3795% CI: [0.55, 1.25]Log Rank
Secondary
Failure Pattern (Distant Recurrence)
Percentage of patients with distant recurrence
Time frame: Up to 6 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Induction Plus Chemoradiotherapy | Failure Pattern (Distant Recurrence) | 13.8 percentage of participants |
| Chemoradiotherapy | Failure Pattern (Distant Recurrence) | 21.5 percentage of participants |
p-value: 0.11Fisher Exact
Secondary
Failure Pattern (Local/Regional Recurrence)
Percentage of patients with local/regional recurrence
Time frame: Up to 6 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Induction Plus Chemoradiotherapy | Failure Pattern (Local/Regional Recurrence) | 10.1 percentage of participants |
| Chemoradiotherapy | Failure Pattern (Local/Regional Recurrence) | 12.6 percentage of participants |
p-value: 0.57Fisher Exact
Secondary
Quality of Life (FACT H&N)
FACT Hand-and-neck subscale(b) (0-40 point scale with negative numbers indicating worsening of function)
Time frame: Change from baseline to post-CRT (post-pre). This corresponds to week 16 in the induction arm and week 10 in the CRT alone arm.
Population: Survivors who completed the questionnaire. (Patients with missing data excluded.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Induction Plus Chemoradiotherapy | Quality of Life (FACT H&N) | -11.41 units on a scale | Standard Error 1.11 |
| Chemoradiotherapy | Quality of Life (FACT H&N) | -12.34 units on a scale | Standard Error 1.1 |
p-value: 0.55t-test, 2 sided
Secondary
Quality of Life (FACT H&N)
FACT Hand-and-neck subscale(b) (0-40 point scale with negative numbers indicating worsening of function)
Time frame: Change from baseline to 1 year (1 year-pre)
Population: Survivors who completed the questionnaire. (Patients with missing data excluded.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Induction Plus Chemoradiotherapy | Quality of Life (FACT H&N) | -7.60 units on a scale | Standard Error 1.14 |
| Chemoradiotherapy | Quality of Life (FACT H&N) | -7.34 units on a scale | Standard Error 1.31 |
p-value: 0.88t-test, 2 sided
Secondary
Quality of Life (McMaster)
McMaster RT Questionnaire (4-28 point scale with negative numbers indicating worsening of function)
Time frame: Change from baseline to post-CRT (post-pre). This corresponds to week 16 in the induction arm and week 10 in the CRT alone arm.
Population: Survivors who completed the questionnaire. (Patients with missing data excluded.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Induction Plus Chemoradiotherapy | Quality of Life (McMaster) | -9.72 units on a scale | Standard Error 0.9 |
| Chemoradiotherapy | Quality of Life (McMaster) | -9.79 units on a scale | Standard Error 0.86 |
p-value: 0.96t-test, 2 sided
Secondary
Quality of Life (McMaster)
McMaster RT Questionnaire (4-28 point scale with negative numbers indicating worsening of function)
Time frame: Change from baseline to 1 year (1 year-pre)
Population: Survivors who completed the questionnaire. (Patients with missing data excluded.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Induction Plus Chemoradiotherapy | Quality of Life (McMaster) | -3.29 units on a scale | Standard Error 1.08 |
| Chemoradiotherapy | Quality of Life (McMaster) | -6.00 units on a scale | Standard Error 1.15 |
p-value: 0.09t-test, 2 sided
Secondary
Quality of Life (Normalcy of Diet)
Performance Status Score (0-100 point scale with negative numbers indicating worsening of function)
Time frame: Change from baseline to 1 year (1 year-pre)
Population: Survivors who completed the questionnaire. (Patients with missing data excluded.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Induction Plus Chemoradiotherapy | Quality of Life (Normalcy of Diet) | -10.22 units on a scale | Standard Error 4.49 |
| Chemoradiotherapy | Quality of Life (Normalcy of Diet) | -8.89 units on a scale | Standard Error 4.09 |
p-value: 0.83t-test, 2 sided
Secondary
Quality of Life (Normalcy of Diet)
Performance Status Score (0-100 point scale with negative numbers indicating worsening of function)
Time frame: Change from baseline to post-CRT (post-pre). This corresponds to week 16 in the induction arm and week 10 in the CRT alone arm.
Population: Survivors who completed the questionnaire. (Patients with missing data excluded.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Induction Plus Chemoradiotherapy | Quality of Life (Normalcy of Diet) | -54.00 units on a scale | Standard Error 3.95 |
| Chemoradiotherapy | Quality of Life (Normalcy of Diet) | -41.51 units on a scale | Standard Error 4.3 |
p-value: 0.034t-test, 2 sided
Secondary
Quality of Life (Speech)
Performance Status Score (0-100 point scale with negative numbers indicating worsening of function)
Time frame: Change from baseline to 1 year (1 year-pre)
Population: Survivors who completed the questionnaire. (Patients with missing data excluded.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Induction Plus Chemoradiotherapy | Quality of Life (Speech) | -1.70 units on a scale | Standard Error 1.7 |
| Chemoradiotherapy | Quality of Life (Speech) | -3.41 units on a scale | Standard Error 1.74 |
p-value: 0.49t-test, 2 sided
Secondary
Quality of Life (Speech)
Performance Status Score (0-100 point scale with negative numbers indicating worsening of function)
Time frame: Change from baseline to post-CRT (post-pre). This corresponds to week 16 in the induction arm and week 10 in the CRT alone arm.
Population: Survivors who completed the questionnaire. (Patients with missing data excluded.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Induction Plus Chemoradiotherapy | Quality of Life (Speech) | -10.67 units on a scale | Standard Error 2.77 |
| Chemoradiotherapy | Quality of Life (Speech) | -7.35 units on a scale | Standard Error 2.21 |
p-value: 0.35t-test, 2 sided
Secondary
Recurrence Free Survival: Time From Randomization to Local/Regional/Distant Recurrence or Death From Any Cause
Recurrence-free survival rates over 6 years. Recurrence-free survival is time from randomization to local, regional, or distant recurrence or death from any cause
Time frame: Up to 6 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Induction Plus Chemoradiotherapy | Recurrence Free Survival: Time From Randomization to Local/Regional/Distant Recurrence or Death From Any Cause | 68.6 percentage of participants |
| Chemoradiotherapy | Recurrence Free Survival: Time From Randomization to Local/Regional/Distant Recurrence or Death From Any Cause | 58.6 percentage of participants |
p-value: 0.1695% CI: [0.51, 1.12]Log Rank