Combination Chemotherapy and Radiation in Treating Patients With Stage III or IV Head and Neck Cancer (Paradigm Trial)

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00095875
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 145
• Locations: 15
• Arms: 2
• Duration (Months): 92
• Patients Per Site: 9.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as docetaxel, cisplatin, fluorouracil, and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining chemotherapy with radiation therapy may kill more tumor cells. It is not yet known which regimen of chemotherapy and radiation therapy is most effective in treating head and neck cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of two different regimens of chemotherapy and radiation therapy in treating patients who have stage III or stage IV head and neck cancer.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Cancer	Drug: carboplatin; Drug: cisplatin; Drug: docetaxel; Drug: fluorouracil	Phase 3

Detailed Description

OBJECTIVES:

Primary

• Compare 3-year survival of patients with previously untreated stage III or IV squamous cell carcinoma of the head and neck treated with induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil followed by radiotherapy and carboplatin or docetaxel vs radiotherapy and cisplatin only.

Secondary

• Compare 2-year progression-free status in patients treated with these regimens.

• Compare 5-year survival of patients treated with these regimens.

• Compare 3- and 5-year progression-free survival of patients treated with these regimens.

• Compare the complete response rate in patients treated with these regimens.

• Compare tumor site-specific survival in patients treated with these regimens.

• Compare functional organ preservation in patients treated with these regimens.

• Compare the toxicity of these regimens in these patients.

• Compare the quality of life of patients treated with these regimens.

• Correlate tissue and germline markers with response, local/regional control, and the development of distant metastases in patients treated with these regimens.

OUTLINE: This is a randomized study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil. Treatment repeats every 21 days for 3 courses. Patients achieving a pathologic complete response at the primary site and a clinical complete response in the neck then receive carboplatin once weekly and undergo concurrent radiotherapy once daily, 5 days a week, for 7 weeks. Patients with a partial response at the primary site (i.e., positive biopsy), stable disease, or radiographic evidence of persistent disease in the neck receive docetaxel once weekly for 4 weeks and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks.

• Arm II: Patients receive cisplatin IV on weeks 1 and 4 and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks.

Quality of life is assessed at baseline and then at 3, 12, and 24 months.

Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1 year, and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 330 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 145 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase III Comparing Sequential Therapy With TPF/Chemoradiation (ST) To Cisplatinum-Based Chemoradiotherapy [PARADIGM TRIAL]
• Study Start Date: Aug 1, 2004
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil. Treatment repeats every 21 days for 3 courses. Patients achieving a pathologic complete response at the primary site and a clinical complete response in the neck then receive carboplatin once weekly and undergo concurrent radiotherapy once daily, 5 days a week, for 7 weeks. Patients with a partial response at the primary site (i.e., positive biopsy), stable disease, or radiographic evidence of persistent disease in the neck receive docetaxel once weekly for 4 weeks and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks.	Drug: carboplatin; Given IV; Other Names: Paraplatin ; Drug: cisplatin; Given IV; Other Names: Platinol ; Drug: docetaxel; Given IV; Other Names: Taxotere ; Drug: fluorouracil; Given IV; Other Names: Efudex
Experimental: Arm II Patients receive cisplatin IV on weeks 1 and 4 and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks.	Drug: cisplatin; Given IV; Other Names: Platinol

Outcome Measures

Primary Outcome Measures

1. Overall Survival [3-years]

   To compare the 3-year survival achieved by docetaxel/cisplatin/5-FU based sequential therapy with platinum based chemo radiotherapy in patients with locally advanced SCCHN. Overall survival is defined as the time from date of randomisation to death from any cause. Patients alive at the time of current analysis were censored at the date last known to be alive.Kaplan-Meier method was used to estimate overall survival

Secondary Outcome Measures

1. Progression-free Survival and Disease-specific Survival as Assessed by Disease Progression or Death and Log Rank Tests at the Median, and 2, 3, and 5 Years [5 years]

   Progression free survival was defined as the time from date of randomisation to disease progression or death from any cause without progression whichever occurred first; otherwise, patients were censored at the date last known to be free of progression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

List of Inclusion Criteria:

• Histologically or cytologically confirmed squamous cell carcinoma of the head and neck

• Stage III or IV* disease

• One of the following primary tumor sites:

• Oral cavity

• No mandible invasion

• Oropharynx

• Hypopharynx

• Larynx

• The following primary tumor sites are excluded:

• Nasal cavity

• Paranasal cavity

• Nasopharynx NOTE: *No evidence of distant metastases by chest x-ray, abdominal ultrasound, or CT scan (for patients with liver function test abnormalities) or bone scan (for patients with local symptoms)

• At least 1 uni- or bi-dimensionally measurable lesion

PATIENT CHARACTERISTICS:

Age

• Over 18

Performance status

• WHO 0-1

Life expectancy

• Not specified

Hematopoietic

• Neutrophil count > 1,500/mm^3

• Platelet count > 100,000/mm^3

• Hemoglobin > 10 g/dL

Hepatic

• Bilirubin normal

• AST or ALT within eligibility range

• Alkaline phosphatase within eligibility range

Renal

• Creatinine clearance > 60 mL/min

Cardiovascular

• No unstable cardiac disease despite treatment

• No myocardial infarction within the past 6 months

Pulmonary

• No chronic obstructive pulmonary disease, defined as requiring hospitalization for pneumonia or respiratory decompensation within the past year

• Obstruction caused by the tumor allowed

Neurologic

• No symptomatic peripheral neuropathy > grade 2

• No symptomatic altered hearing > grade 2

• No history of significant neurologic or psychiatric disorders, including dementia or seizures

Other

• No active drug addiction, including alcohol, cocaine, or intravenous drugs within the past 6 months

• No other malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, or other cancer curatively treated by surgery alone

• No active, clinically significant, uncontrolled infection

• No autoimmune disease requiring therapy

• No unhealed or clinically active peptic ulcer disease

• No hypercalcemia

• No other serious illness or medical condition

• No involuntary weight loss > 25% of body weight within the past 2 months

• HIV negative

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for at least 3 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy

Surgery

• No prior organ transplantation

• No prior surgery for this cancer

• Biopsy allowed

Other

• More than 30 days since prior participation in another investigational study

• No other concurrent anticancer therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rebecca and John Moores UCSD Cancer Center	La Jolla	California	United States	92093-0658
2	CCOP - Colorado Cancer Research Program	Denver	Colorado	United States	80224
3	Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - Main Campus	Boca Raton	Florida	United States	33486
4	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
5	Cardinal Bernardin Cancer Center at Loyola University Medical Center	Maywood	Illinois	United States	60153
6	Maine Center for Cancer Medicine and Blood Disorders - Scarborough	Scarborough	Maine	United States	04074
7	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
8	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
9	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
10	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0002
11	UMDNJ University Hospital	Newark	New Jersey	United States	07103
12	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York	United States	10461
13	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina	United States	28232-2861
14	UPMC Cancer Centers	Pittsburgh	Pennsylvania	United States	15232
15	Klinikum der J.W. Goethe Universitaet	Frankfurt		Germany	D-60590

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• National Cancer Institute (NCI)

Investigators

• Study Chair: Robert I. Haddad, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Robert I. Haddad, MD, Medical Oncology, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00095875
• Other Study ID Numbers: DFCI 04-006; P30CA006516; CDR0000393548; NCT00705068
• First Posted: Nov 9, 2004
• Last Update Posted: Nov 19, 2013
• Last Verified: Oct 1, 2013

• Keywords provided by Robert I. Haddad, MD, Medical Oncology, Dana-Farber Cancer Institute: stage III squamous cell carcinoma of the hypopharynx; stage III squamous cell carcinoma of the larynx; stage III squamous cell carcinoma of the lip and oral cavity; stage III squamous cell carcinoma of the oropharynx; stage IV squamous cell carcinoma of the hypopharynx; stage IV squamous cell carcinoma of the larynx; stage IV squamous cell carcinoma of the lip and oral cavity; stage IV squamous cell carcinoma of the oropharynx
• Additional relevant MeSH terms: Head and Neck Neoplasms; Carboplatin; Docetaxel; Fluorouracil

Study Results

Participant Flow

Recruitment Details	Between August 24, 2004 and December 29, 2008 145 patients were enrolled across 16 sites.
Pre-assignment Detail	Patients were randomly assigned in a 1:1 ratio to recieve either induction chemotherapy with 3 cycles of TPF followed by concurrent chemoradiotherapy with either docetaxel or carboplatin or concurrent chemoradiotherapy alone with 2 cycles of bolus cisplatin.

Arm/Group Title	Arm I	Arm II
Arm/Group Description	Patients receive induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil. Treatment repeats every 21 days for 3 courses. Patients achieving a pathologic complete response at the primary site and a clinical complete response in the neck then receive carboplatin once weekly and undergo concurrent radiotherapy once daily, 5 days a week, for 7 weeks. Patients with a partial response at the primary site (i.e., positive biopsy), stable disease, or radiographic evidence of persistent disease in the neck receive docetaxel once weekly for 4 weeks and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. cisplatin : Given IV radiation therapy : Patients undergo radiation therapy once or twice daily, 5 days a week, for up to 7 weeks carboplatin : Given IV fluorouracil : Given IV docetaxel : Given IV	Patients receive cisplatin IV on weeks 1 and 4 and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. cisplatin : Given IV radiation therapy : Patients undergo radiation therapy once or twice daily, 5 days a week, for up to 7 weeks
Period Title: Overall Study
STARTED	70	75
COMPLETED	56	66
NOT COMPLETED	14	9

Baseline Characteristics

Arm/Group Title	Arm I	Arm II	Total
Arm/Group Description	Patients receive induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil. Treatment repeats every 21 days for 3 courses. Patients achieving a pathologic complete response at the primary site and a clinical complete response in the neck then receive carboplatin once weekly and undergo concurrent radiotherapy once daily, 5 days a week, for 7 weeks. Patients with a partial response at the primary site (i.e., positive biopsy), stable disease, or radiographic evidence of persistent disease in the neck receive docetaxel once weekly for 4 weeks and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. cisplatin : Given IV radiation therapy : Patients undergo radiation therapy once or twice daily, 5 days a week, for up to 7 weeks carboplatin : Given IV fluorouracil : Given IV docetaxel : Given IV	Patients receive cisplatin IV on weeks 1 and 4 and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. cisplatin : Given IV radiation therapy : Patients undergo radiation therapy once or twice daily, 5 days a week, for up to 7 weeks	Total of all reporting groups
Overall Participants	70	75	145
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	59 84.3%	66 88%	125 86.2%
>=65 years	11 15.7%	9 12%	20 13.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55 (9)	54 (8)	55 (8.4)
Sex: Female, Male (Count of Participants)
Female	6 8.6%	12 16%	18 12.4%
Male	64 91.4%	63 84%	127 87.6%
Region of Enrollment (participants) [Number]
United States	69 98.6%	69 92%	138 95.2%
Germany	1 1.4%	6 8%	7 4.8%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	To compare the 3-year survival achieved by docetaxel/cisplatin/5-FU based sequential therapy with platinum based chemo radiotherapy in patients with locally advanced SCCHN. Overall survival is defined as the time from date of randomisation to death from any cause. Patients alive at the time of current analysis were censored at the date last known to be alive.Kaplan-Meier method was used to estimate overall survival
Time Frame	3-years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I	Arm II
Arm/Group Description	Patients receive induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil. Treatment repeats every 21 days for 3 courses. Patients achieving a pathologic complete response at the primary site and a clinical complete response in the neck then receive carboplatin once weekly and undergo concurrent radiotherapy once daily, 5 days a week, for 7 weeks. Patients with a partial response at the primary site (i.e., positive biopsy), stable disease, or radiographic evidence of persistent disease in the neck receive docetaxel once weekly for 4 weeks and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. cisplatin : Given IV radiation therapy : Patients undergo radiation therapy once or twice daily, 5 days a week, for up to 7 weeks carboplatin : Given IV fluorouracil : Given IV docetaxel : Given IV	Patients receive cisplatin IV on weeks 1 and 4 and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. cisplatin : Given IV radiation therapy : Patients undergo radiation therapy once or twice daily, 5 days a week, for up to 7 weeks
Measure Participants	70	75
Number (95% Confidence Interval) [percent of patients]	73	78

2. Secondary Outcome

Title	Progression-free Survival and Disease-specific Survival as Assessed by Disease Progression or Death and Log Rank Tests at the Median, and 2, 3, and 5 Years
Description	Progression free survival was defined as the time from date of randomisation to disease progression or death from any cause without progression whichever occurred first; otherwise, patients were censored at the date last known to be free of progression.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I	Arm II
Arm/Group Description	Patients receive induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil. Treatment repeats every 21 days for 3 courses. Patients achieving a pathologic complete response at the primary site and a clinical complete response in the neck then receive carboplatin once weekly and undergo concurrent radiotherapy once daily, 5 days a week, for 7 weeks. Patients with a partial response at the primary site (i.e., positive biopsy), stable disease, or radiographic evidence of persistent disease in the neck receive docetaxel once weekly for 4 weeks and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. cisplatin : Given IV radiation therapy : Patients undergo radiation therapy once or twice daily, 5 days a week, for up to 7 weeks carboplatin : Given IV fluorouracil : Given IV docetaxel : Given IV	Patients receive cisplatin IV on weeks 1 and 4 and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. cisplatin : Given IV radiation therapy : Patients undergo radiation therapy once or twice daily, 5 days a week, for up to 7 weeks
Measure Participants	70	75
Number (95% Confidence Interval) [percent of patients]	67	69

Adverse Events

Adverse Event Reporting Description	Only the following adverse events were records: mucositis, febrile neutropenia, pain, xerostomia, feeding tube placement, and neuropathy which was deemed pertinent to the comparision of regimens in this setting.
Arm/Group Title	Arm I		Arm II
Arm/Group Description	Patients receive induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil. Treatment repeats every 21 days for 3 courses. Patients achieving a pathologic complete response at the primary site and a clinical complete response in the neck then receive carboplatin once weekly and undergo concurrent radiotherapy once daily, 5 days a week, for 7 weeks. Patients with a partial response at the primary site (i.e., positive biopsy), stable disease, or radiographic evidence of persistent disease in the neck receive docetaxel once weekly for 4 weeks and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. cisplatin : Given IV radiation therapy : Patients undergo radiation therapy once or twice daily, 5 days a week, for up to 7 weeks carboplatin : Given IV fluorouracil : Given IV docetaxel : Given IV		Patients receive cisplatin IV on weeks 1 and 4 and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. cisplatin : Given IV radiation therapy : Patients undergo radiation therapy once or twice daily, 5 days a week, for up to 7 weeks
All Cause Mortality
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	56/70 (80%)		29/75 (38.7%)
Blood and lymphatic system disorders
Febrile Neutropenia	16/70 (22.9%)		1/75 (1.3%)
Gastrointestinal disorders
Mucositis	33/70 (47.1%)		12/75 (16%)
Xerostomia	5/70 (7.1%)		5/75 (6.7%)
General disorders
Pain	2/70 (2.9%)		9/75 (12%)
Nervous system disorders
Neurpathy	0/70 (0%)		2/75 (2.7%)
Other (Not Including Serious) Adverse Events
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/70 (100%)		75/75 (100%)
Gastrointestinal disorders
Mucositis	29/70 (41.4%)		44/75 (58.7%)
Xerostomia	42/70 (60%)		46/75 (61.3%)
General disorders
Pain	41/70 (58.6%)		35/75 (46.7%)
Immune system disorders
Neuropathy	22/70 (31.4%)		18/75 (24%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.