Adjuvant Chemoradiation With Weekly Oxaliplatin in Resected Head and Neck Cancer
| Status: | Terminated |
|---|---|
| Conditions: | Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 5/3/2018 |
| Start Date: | February 2005 |
| End Date: | October 2011 |
A Phase II Study of Adjuvant Chemoradiation With Weekly Oxaliplatin in Patients With High Risk Resected Squamous Cell Carcinoma of the Head and Neck Region
Oxaliplatin-containing regimens have been safely and successfully used in combination with
concurrent radiation in treatment of solid tumors such as rectal and esophageal cancers. The
Lyon R0-04 phase II trial utilized the combination of Oxaliplatin, infusional 5-fluorouracil
(5-FU) and radiation in the treatment of rectal cancer. The trial showed a combined
preoperative chemoradiotherapy and Oxaliplatin-containing regimen is well tolerated with no
increase surgical toxicity. The good response rate observed warrants its use in further
clinical trials.
The combination of oxaliplatin, 5-FU, and radiation also have been used in a Phase I/II trial
in esophageal cancer. In this particular trial, eligibility included therapeutically naïve
esophageal cancer subjects with clinical disease stages II to IV. Initial doses and schedules
for cycle 1 consisted of Oxaliplatin 85 mg/m2 on days 1, 15, and 29; continuous infusion of
5-FU 180 mg/m2 for 24 hours for 35 days; and radiation therapy (RT) 1.8 Gy in 28 fractions
starting on day 8. At completion of cycle 1, eligible subjects could undergo an operation or
begin cycle 2 without RT. Postoperative subjects were eligible for cycle 2. Stage IV subjects
were allowed three cycles in the absence of disease progression. 38 subjects were treated (22
stage IV, 16 stage II-III). 38 eligible subjects received therapy: 22 non-invasively staged
as IV and 16 non-invasively staged as IV and 16 non-invasively staged as II and III. 36
subjects completed cycle 1, 29 subjects started cycle 2, and 24 subjects completed cycle 2.
The combined-modality therapy was well tolerated, but dose limiting toxicity (DLT) prevented
Oxaliplatin and 5-FU escalation. No grade 4 hematologic toxicity was noted. Eleven grade 3
and two grade 4 clinical toxicities were noted in eight subjects. After cycle 1, 29 subjects
(81%) had no cancer in the esophageal mucosa. 13 subjects underwent an operation with intent
to resect the esophagus and 5 subjects (38%) exhibited pathologic complete responses. There
was no surgical mortality. Only 1 subject developed post-operative tracheoesphageal fistula.
The results of these trials described above indicated that combination of oxaliplatin and
radiation is safe and efficacious and dose not compromise surgical wound healing, repair and
clinical outcome.
concurrent radiation in treatment of solid tumors such as rectal and esophageal cancers. The
Lyon R0-04 phase II trial utilized the combination of Oxaliplatin, infusional 5-fluorouracil
(5-FU) and radiation in the treatment of rectal cancer. The trial showed a combined
preoperative chemoradiotherapy and Oxaliplatin-containing regimen is well tolerated with no
increase surgical toxicity. The good response rate observed warrants its use in further
clinical trials.
The combination of oxaliplatin, 5-FU, and radiation also have been used in a Phase I/II trial
in esophageal cancer. In this particular trial, eligibility included therapeutically naïve
esophageal cancer subjects with clinical disease stages II to IV. Initial doses and schedules
for cycle 1 consisted of Oxaliplatin 85 mg/m2 on days 1, 15, and 29; continuous infusion of
5-FU 180 mg/m2 for 24 hours for 35 days; and radiation therapy (RT) 1.8 Gy in 28 fractions
starting on day 8. At completion of cycle 1, eligible subjects could undergo an operation or
begin cycle 2 without RT. Postoperative subjects were eligible for cycle 2. Stage IV subjects
were allowed three cycles in the absence of disease progression. 38 subjects were treated (22
stage IV, 16 stage II-III). 38 eligible subjects received therapy: 22 non-invasively staged
as IV and 16 non-invasively staged as IV and 16 non-invasively staged as II and III. 36
subjects completed cycle 1, 29 subjects started cycle 2, and 24 subjects completed cycle 2.
The combined-modality therapy was well tolerated, but dose limiting toxicity (DLT) prevented
Oxaliplatin and 5-FU escalation. No grade 4 hematologic toxicity was noted. Eleven grade 3
and two grade 4 clinical toxicities were noted in eight subjects. After cycle 1, 29 subjects
(81%) had no cancer in the esophageal mucosa. 13 subjects underwent an operation with intent
to resect the esophagus and 5 subjects (38%) exhibited pathologic complete responses. There
was no surgical mortality. Only 1 subject developed post-operative tracheoesphageal fistula.
The results of these trials described above indicated that combination of oxaliplatin and
radiation is safe and efficacious and dose not compromise surgical wound healing, repair and
clinical outcome.
Adjuvant treatment of resected head and neck cancers The incidence of locoregional failures
and distant metastasis is high after primary resection of squamous cell carcinoma of the head
and neck (HNSCC), especially in patients with unfavorable prognostic factors such as residual
disease, histological evidence of extracapsular spread, and/or multiple neck nodes. RT is
indicated as an adjuvant therapy to surgery. In the past 2 decades, RT was mainly delivered
post-operatively, and the therapeutic gain with this combination is now well documented.
Despite an overall 2-year freedom of recurrance of approximately of 70-75%, survival rates
are usually poor in the whole HNSCC patient population, and they usually do not exceed 30 to
35% at 5 years. The incidence of metastases in locally advanced but resectable head and neck
cancer can reach 15 to 20%. The role of systemic chemotherapy has been tested in clinical
trials to determine if the addition of chemotherapy can decrease locoregional and distant
failure and improve survival.
Oxaliplatin and radiation in solid tumors Oxalipaltin-containing regimens have been safely
and successfully used in combination with concurrent radiation in treatment of solid tumors
such as rectal and esophageal cancers. Results of previous trials indicated that combination
of oxaliplatin and radiation is safe and efficacious and dose not compromise surgical wound
healing, repair and clinical outcome.
Oxaliplatin and radiation in head and neck cancer Oxaliplatin and radiation has been used in
a randomized phase II study comparing standard radiation with or without weekly oxaliplatin
in the treatment of locally advanced nasopharyngeal carcinoma. Radiation was administered at
70-74 Gy to the primary tumor site, 60-64 Gy to the involved areas of the neck and 50 Gy to
the uninvolved area of the neck. Chemotherapy with oxaliplatin at 70 mg/m2 was given weekly
for 6 courses with standard radiation in the investigational arm. Interim results concurrent
radiation with weekly oxaliplatin resulted in a higher complete response in the primary tumor
site and in the cervical lymph nodes. There was no difference in the incidences of dry mouth,
stomatitis, skin reaction, peripheral neuropathy or hematological toxicities between the 2
treatment arms. Patients receiving the concurrent radiation and oxaliplatin treatment did
experience more gastrointestinal toxicities mostly nausea and vomiting. The only grade 3
toxicities are thrombocytopenia (5.1%), nausea/vomiting (12.8%) and skin reaction (25.6%).
Microscopically involved margins, involvement of two or more nodes, extracapusular spread,
presence of perineural involvement, and vascular embolisms are associated with an
approximately 25% to 30% probability of developing locoregional failure. The addition of
cisplatin to radiation reduces the locoregional failure and distant metastasis. We propose to
investigate the toxicities of using weekly oxaliplatin with radiation in the treatment of
high risk resected head and neck patients since oxaliplatin has a better side effects
profile. The high risk factors will be the same criteria utilized in both RTOG 9501 and EORTC
22931. They include microscopically involved margins, involvement of two or more nodes,
extracapusular spread, presence of perineural involvement, vascular embolisms, and oral
cavity or oropharyngeal carcinoma with lymph nodes metastasis at level IV or V.
and distant metastasis is high after primary resection of squamous cell carcinoma of the head
and neck (HNSCC), especially in patients with unfavorable prognostic factors such as residual
disease, histological evidence of extracapsular spread, and/or multiple neck nodes. RT is
indicated as an adjuvant therapy to surgery. In the past 2 decades, RT was mainly delivered
post-operatively, and the therapeutic gain with this combination is now well documented.
Despite an overall 2-year freedom of recurrance of approximately of 70-75%, survival rates
are usually poor in the whole HNSCC patient population, and they usually do not exceed 30 to
35% at 5 years. The incidence of metastases in locally advanced but resectable head and neck
cancer can reach 15 to 20%. The role of systemic chemotherapy has been tested in clinical
trials to determine if the addition of chemotherapy can decrease locoregional and distant
failure and improve survival.
Oxaliplatin and radiation in solid tumors Oxalipaltin-containing regimens have been safely
and successfully used in combination with concurrent radiation in treatment of solid tumors
such as rectal and esophageal cancers. Results of previous trials indicated that combination
of oxaliplatin and radiation is safe and efficacious and dose not compromise surgical wound
healing, repair and clinical outcome.
Oxaliplatin and radiation in head and neck cancer Oxaliplatin and radiation has been used in
a randomized phase II study comparing standard radiation with or without weekly oxaliplatin
in the treatment of locally advanced nasopharyngeal carcinoma. Radiation was administered at
70-74 Gy to the primary tumor site, 60-64 Gy to the involved areas of the neck and 50 Gy to
the uninvolved area of the neck. Chemotherapy with oxaliplatin at 70 mg/m2 was given weekly
for 6 courses with standard radiation in the investigational arm. Interim results concurrent
radiation with weekly oxaliplatin resulted in a higher complete response in the primary tumor
site and in the cervical lymph nodes. There was no difference in the incidences of dry mouth,
stomatitis, skin reaction, peripheral neuropathy or hematological toxicities between the 2
treatment arms. Patients receiving the concurrent radiation and oxaliplatin treatment did
experience more gastrointestinal toxicities mostly nausea and vomiting. The only grade 3
toxicities are thrombocytopenia (5.1%), nausea/vomiting (12.8%) and skin reaction (25.6%).
Microscopically involved margins, involvement of two or more nodes, extracapusular spread,
presence of perineural involvement, and vascular embolisms are associated with an
approximately 25% to 30% probability of developing locoregional failure. The addition of
cisplatin to radiation reduces the locoregional failure and distant metastasis. We propose to
investigate the toxicities of using weekly oxaliplatin with radiation in the treatment of
high risk resected head and neck patients since oxaliplatin has a better side effects
profile. The high risk factors will be the same criteria utilized in both RTOG 9501 and EORTC
22931. They include microscopically involved margins, involvement of two or more nodes,
extracapusular spread, presence of perineural involvement, vascular embolisms, and oral
cavity or oropharyngeal carcinoma with lymph nodes metastasis at level IV or V.
Inclusion Criteria:
- All subjects must have histologically or cytologically confirmed diagnosis of squamous
cell carcinoma of the head and neck region. Primary tumor sites include: oral cavity,
pharynx (oropharynx, hypopharynx), or larynx (supraglottis, glottis subglottis).
Nasopharynx primary will be excluded.
- The resected tumor must have one or more of the following high risk features:
histologic extracapsular nodal extension involvement of ≥ 2 regional lymph nodes,
mucosal margin of resection with invasive cancer (limited to microscopic detection
only), tumor with perineural invasion, tumor with lymphovascular invasion, oral cavity
and oropharynx carcinomas with positive lymph nodes metastasis at level IV or V.
- Radiation must begin within 28 to 56 days after surgical resection.
- All subjects must be 18 years of age or older.
- Subjects must have a Zubrod performance of 0-2.
Exclusion Criteria:
- Subjects must not have distant metastatic disease (M1).
- Subjects must NOT have prior therapy with oxaliplatin.
- Subjects with any evidence of active or uncontrolled infection, recent myocardial
infection, unstable angina, or life-threatening arrhythmia are not eligible.
- Patients with severe psychiatric disorder are not eligible.
- No other prior malignancy is allowed except for adequately treated basal cell or
squamous cell carcinoma, in situ cervical cancer, or adequately treated Stage I and II
cancer from which the patient is in complete remission, or any other malignancy from
which the patient has been disease-free for 5 years.
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