Trial Title:
Metronomic Chemotherapy With Tegafur/Uracil for Head and Neck Squamous Cell Carcinoma
NCT ID:
NCT00855881
Condition:
Head and Neck Cancer
Conditions: Official terms:
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Squamous Cell Carcinoma of Head and Neck
Tegafur
Conditions: Keywords:
adjuvant chemotherapy for head and neck cancer
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Unknown status
Study design:
Allocation:
Non-Randomized
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
tegafur-uracil
Description:
tegafur-uracil 1 cap, bid for 1 year
Arm group label:
Treatment arm
Other name:
UFUR
Summary:
It is the investigators understanding that the combination of clinical trial with
laboratory cellular/molecular assay is relevant to the current promising mainstream, the
translational research. The design of this trial fulfills this concept and would be a
good example conducting in Mackay Memorial hospital.
Detailed description:
Head and neck squamous cell carcinoma (HNSCC) (excluding nasopharyngeal cancer) accounts
for 4% to 5% of the cancer incidence in Taiwan.1 Localized disease is curable by surgery
and irradiation. Two-thirds of patients present with advanced stages of the disease
(stage III and IV), and are treated with multimodality therapy, including surgery,
radiation and chemotherapy. Despite the achievement of complete responses in patients who
receive multimodality therapy, however, recurrences might occur in some of patients
within two years after multimodality therapy.
HNSCC has been regarded as a chemosensitive tumor since the early 1980s.Cisplatin-based
combination therapy with fluorouracil (5-FU) is the most common chemotherapy regimen for
patients with HNSCC. Concomitant chemoradiotherapy (CCRT) is conceptually supported by
the natural history of head and neck cancer, which indicates a primary need to improve
locoregional therapy and only a secondary need to improve systemic therapy. CCRT has
frequently been studied in inoperable patients or in those with unresectable disease4.
Several recent studies and meta-analyses have indicated superior locoregional control
and/or survival rates after CCRT when compared with radiotherapy alone3-12.
"Two similar, large-scale, prospective randomized independent trials designed by the
European Organization for Research and Treatment of Cancer (EORTC) and the Radiation
Therapy Oncology Group (RTOG) were conducted to evaluate the role of concurrent
administration of cisplatin with radiation in the postoperative treatment of high-risk
head and neck tumors. The EORTC (#22931) 29 study revealed that combination therapy was
more efficacious than radiotherapy alone in patients with locally advanced head and neck
cancer and that the treatment did not cause an undue number of late complications. The
RTOG (#9501)30 trial found that postoperative CCRT significantly improved the rates of
local and regional control and disease-free survival in high-risk patients with resected
head and neck cancer; however, the combined treatment was associated with a substantial
increase in adverse effects.
Multimodality therapy may achieve higher complete response rate for patients with locally
advanced HNSCC, however, patients still face high recurrent rate that might decrease
survival time. For these reasons, the development of reliable methods (for example) and
metronomic therapy to prevent relapse at locally advanced setting may improve the outcome
of treatment.
Uracil-tegafur (UFT), an oral fluoropyrimidine prodrug, is available commercially in
Japan and in several other countries. It is composed of
1-(2-tetrahydrofuryl)-5-fluorouracil (5-FU) (FT; also ftorafur or tegafur) and uracil in
a molar ratio of 1:4. FT is readily absorbed through the gut without degradation and is
converted in the liver to 5-FU and subsequently degraded to 2-fluoro-b-alanine. Thus, UFT
shares the chemotherapeutic mechanism of action of 5-FU. The 5-FU metabolite FdUMP binds
and inhibits the enzymatic activity of thymidylate synthase (TS), thereby inhibiting DNA
synthesis.13-17 Uracil strongly inhibits the degradation of 5-FU to 2-fluoro-b-alanine by
competitive inhibition of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme
in the metabolism of 5-FU.18,19 This alteration of 5-FU disposition seems to be tumor
selective. When taken orally, UFT and FT give a comparable distribution of 5-FU in blood
and other normal tissues, but UFT results in 5-10 times greater distribution of 5-FU in
tumors.20 Co-administration of uracil and/or FT, therefore, enhances the anti-tumor
activity of FT.21 The cytotoxic effects of 5-FU (and, thus, FT) can be enhanced markedly
if sufficient amounts of reduced folate cofactor, such as leucovorin (LV), are present.
Cellular folate pools are considered an important biochemical determinant of FdUMP enzyme
binding.22-28 One basic study has shown that in mice bearing RENCA tumors, tegafur/uracil
treatment resulted in significant prolongation of their life span, which was associated
with the inhibition of angiogenesis. This should be recomposed. For example,
"Tegafur/uracil treatment of mice with RENCA tumors has been shown to inhibit
angiogenesis, leading to a significant prolongation of life span.Two metabolites of
tegafur/uracil, namely, GHB33,34 and GBL were found to be responsible for these effects.
In another study, the formation of cancer vasculature, essential for the initiation of
metastasis and the inhibition of tumor angiogenesis, is one of the targets in tumor
dormancy therapy. The efficacy of tegafur/uracil in postoperative adjuvant chemotherapy
has been demonstrated in several clinical trials. The basic data from these studies
indicate a possible contribution of the anti-angiogenic activity of tegafur/uracil to its
overall anti-tumor activity, which until now has been thought to be mediated by the
cytotoxic effects of 5-FU. Thus, tegafur/uracil seems to be particularly useful in a
chronic postoperative adjuvant chemotherapy regimen to control metastasis.
Lam et31al. conducted a prospective randomized study of post-operative chemotherapy with
levamisole and UFT for treatment of head and neck carcinoma. A trend towards better
distant control in post-operative oral chemotherapy was observed. The side effects were
minimal. Masato Fujii also reported that adjuvant chemotherapy with UFT was efficacious
for treating maxillary sinus carcinoma. The 5-year survival was 76.2% for the UFT group
and 17.9% for the control group32.
Metronomic chemotherapy refers to the close, regular administration of a chemotherapeutic
drug, over prolonged periods, with no extended drug-free break periods38. As such, it is
a form of "dose dense" chemotherapy but differs from most forms of the latter in several
ways35,36. First, it is not "dose intense" when the goal remains to deliver high, toxic
levels of drug over shorter periods of time. Second, because metronomic regimens are much
less toxic, they do not usually require supportive growth factor, or other supportive
care measures39,40. Metronomic chemotherapy can thus be viewed as a form of efficiently,
low dose, and long term 'maintenance' chemotherapy that can be used on its own36,38, or
more importantly, combined with long-term biologic targeted therapies, especially with
antiangiogenic drugs such as anti-VEGFR-2 antibodies41 or small molecule multi-targeted
VEGFR-2 antagonist receptor tyrosine kinase inhibitors42. It can also be integrated with
standard MTD-type (maximum tolerated dose) chemotherapy where brief courses of such
therapy, 'upfront', is followed by long-term maintenance metronomic chemotherapy combined
with concurrent targeted therapies41,42, called "chemo-switching"40. The advantages of
metronomic chemotherapy include reduced acute toxicities, such as high grade
myelosuppression, vomiting, nausea, and mucotitis, 39,40 and sometimes surprisingly good
activity against drug resistant tumors38, reduced costs when using off patent
chemotherapeutic drugs, and increased convenience when using oral drugs that can be taken
at home36,39. These potential advantages could be useful for long term adjuvant therapy
of early stage cancers, e.g. long-term daily oral administration of a drug such as
UFUR(UFT; a 5-FU prodrug) for 1~2 years with no breaks43,45,46,50.
The reason why standard chemotherapy, using a maximum tolerated dose (MTD), separated by
long 2-3 week drug-free break periods is not as effective as an antiangiogenic treatment
regimen is that the damage inflicted upon the dividing endothelium cells of the tumor is
largely reversed during the extended drug-free break periods, perhaps by a massive
hemopoiesis-like mobilization ('rebound') of CEPs which then home to damaged tumor
endothelium and set about repairing the damage44. Thus shortening the break periods is
critical to ensure that the repair process is prevented or minimized38. This in turn
requires relatively low doses of drug to be used38.
The anti-tumor effects of single versus two chemotherapeutic drug combinations, dosed and
administered in a metronomic fashion, i.e., daily (by oral delivery) in a model of
advanced high volume (end stage) visceral metastatic disease where therapy is initiated
in terminal stages of disease47.
Metronomic chemotherapy regimens combined with an antiangiogenic drug have moved into
phase II clinical trial testing both in the adjuvant and metastatic settings. Some
interim results of phase II clinical trials involving metastatic breast cancer or
advanced, recurrent ovarian cancer looked extremely promising48,49,50. Ongoing, planned
or recently completed phase II clinical trials of metronomic chemotherapy combined with
an agent such as bevacizumab or thalidomide should indicate whether or not this treatment
strategy is promising in the treatment of metastatic and/or early stage human cancer.
Although when low-dose cytotoxic drugs combined with targeted agents may have potential
benefits as explained previously. There remain several significant challenges that must
be overcome to increase the success in the clinical setting. Foremost among these is the
current empiricism associated with trying to determine the optimal dose and schedule for
administration of chemotherapeutics. The challenge lies in finding the smallest dose that
will control the growth of target cells and then the most frequent dosing that will
maximize this control. the discovery and application of functional surrogate markers
might be one of the solutions to overcome the problem of metronomic-dose determination,
such as determining the So, detecting changes in levels of circulating TSP1 levels in
serum or plasma after administration of various low doses of chemotherapeutics might be
useful in determining the optimal low dose for a drug such as cyclophosphamide51.
In addition to TSP1 level, the most important approach in determining the optimal
metronomic low dose for a given metronomic chemotherapy regimen is evaluation of the
activities of CEPs or circulating endothelial cells (CECs). As previously discussed, CEPs
mobilization from the bone marrow into the peripheral circulation is strongly inhibited
by low-dose cyclophosphamide, as is CEP viability52. It might be conferred that there
could be a direct relationship between the relative efficacy of different (low) doses of
metronomic chemotherapy and the ability of these doses to reduce levels of CEPs in the
peripheral circulation. In a study by Shaked et al., using 4 distinct metronomic
chemotherapy regimens in 4 different preclinical tumor models to establish optimal
biological dose (OBD) without causing excessive toxicity demonstrated that the OBDs in
each tumor models were strikingly correlated with the maximum reduction in CEPs53. The
results of this study suggested that these results suggested that CEPs may serve as a
pharmacodynamic biomarker to determine the OBD of metronomic chemotherapy regimens.
It is our understanding that the combination of clinical trial with laboratory
cellular/molecular assay is relevant to the current promising mainstream, the
translational research. The design of this trial fulfills this concept and would be a
good example conducting in Mackay Memorial hospital.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Histologically confirmed non-nasopharyngeal head and neck squamous cell carcinoma
- Complete response(CR) to previous treatment
- White blood cell (WBC) count greater than 3,000/mm3 and absolute neutrophil count
(ANC) greater than 1,500/mm3, and platelets greater than 50,000/mm3
- Serum bilirubin less than 2 times the upper limit of normal range (ULN)
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
- Serum creatinine less than 2.0 times the ULN
- ECOG performance status 0, 1, 2
- Age, 20 years or older
Exclusion Criteria:
- Other malignancy, with the exception of curatively treated non-melanoma skin cancer
or cervical carcinoma in situ prior to commencement of the study
- CR was confirmed more than 6 weeks prior to commencement of the study
- Concurrent treatment which may interfere with evaluation
- Pregnancy or breast feeding
Gender:
All
Minimum age:
20 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Mackay Memorial Hospital
Address:
City:
Taipei
Country:
Taiwan
Status:
Recruiting
Contact:
Last name:
Ching Lin, BS
Phone:
+886-2543-3535
Investigator:
Last name:
Y.F. Chang
Email:
Sub-Investigator
Start date:
December 2008
Completion date:
December 2016
Lead sponsor:
Agency:
Mackay Memorial Hospital
Agency class:
Other
Source:
Mackay Memorial Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT00855881
