Carcinoma of Unknown Primary Clinical Trial
Official title:
A Phase II Trial Evaluating the Combination of Carboplatin, Gemcitabine, and Capecitabine in Patients With Carcinoma of Unknown Primary Site
This study is for patients with a type of cancer called carcinoma of unknown primary site
(CUP), meaning that the site of the body where the tumor has originated is not clear.
Currently, carcinoma of unknown primary site (CUP) accounts for about 5% of all newly
diagnosed malignancies. The stage of the tumor is such that it is not treatable by surgery.
Currently, the standard treatment for such a type of cancer at that stage is chemotherapy.
However, the overall prognosis for patients with metastatic CUP remains poor, even if
treated with conventional chemotherapy. Through ongoing research at medical centers around
the world, doctors are trying to improve on the presently available chemotherapy regimens.
The purpose of the investigators' study is similar: it is trying to determine whether a
combination of three chemotherapy drugs - carboplatin, gemcitabine, and capecitabine - will
improve the treatment of patients with metastatic CUP. The reason the investigators are
interested in the above combination of chemotherapy agents is that each one of them is
already used in patients with a variety of specific tumors, such as lung cancer, breast
cancer, pancreatic cancer, colon cancer, etc.
This research study will help determine whether the combination of carboplatin, gemcitabine
and capecitabine can be used and is effective in patients with carcinoma of unknown primary
site.
Carcinoma of unknown primary site (CUP) accounts for approximately 5% of all newly diagnosed
malignancies. The overall prognosis for patients with CUP remains poor, with median survival
less than one year with modern chemotherapy combinations and virtually no long-term
survivors.
It has been recognized that patients with CUP represent a heterogeneous group of tumors.
Managing patients with CUP requires a complete medical history, careful consideration of
findings on physical exam, targeted radiologic studies and pathologic analysis of biopsy
and/or surgical specimens. Within this heterogeneous group there exist at least four subsets
of patients with CUP, that based on clinicopathologic features are treated with regimens
which have demonstrated efficacy in tumors originating in the most likely primary site of
that CUP; squamous carcinoma involving mid or high levels of cervical lymph nodes, women
with isolated axillary adenopathy containing adenocarcinoma, women with a predominant
presentation of peritoneal carcinomatosis and young men with extragonadal germ cell
syndrome.
Unfortunately, a majority of patients with CUP do not fall into any of the above subsets and
these represent a therapeutic dilemma, as there is no single regimen to date that has shown
significant activity or has resulted in prolonged survival for these patients with
particularly poor prognosis. Thus, new therapeutic combinations need to be investigated for
treatment of these patients with CUP.
Platinum compounds have been the cornerstone of chemotherapy regimens for a wide variety of
solid tumors, including lung, urothelial, head and neck, ovarian and endometrial carcinomas,
as well as testicular carcinomas. Cisplatin and its analog carboplatin are currently used in
chemotherapy combinations to treat CUP. Carboplatin has fewer non-hematologic side effects
compared to cisplatin including less nausea and vomiting, peripheral neuropathy,
nephrotoxicity and ototoxicity making it an attractive agent to combine with other drugs.
In recent years, new agents active in solid malignancies have been developed. Gemcitabine is
one such agent. It is a deoxycytidine analogue structurally related to cytosine arabinoside.
Gemcitabine is activated by deoxycytidine kinase in three steps of phosphorylation into
difluorodeoxycytidine triphosphate, which when incorporated into DNA, leads to chain
termination. Gemcitabine has been shown to have activity in pancreatic, breast, non-small
cell lung carcinomas as well as in carcinomas of unknown primary site. Because of its mild
toxicity profile, gemcitabine has been used in combination with other chemotherapy agents.
There is evidence of in vitro and in vivo synergy between gemcitabine and the platinum
compounds.
Capecitabine is an orally administered fluoropyrimidine that undergoes a three-step
conversion into 5-FU, with pharmacokinetics that mimic low dose continuous infusion 5-FU.
The oral formulation allows for convenient continuous therapy, avoiding a need for central
venous catheters and external infusion pumps.
The final step of conversion of capecitabine into 5-FU is catalyzed by thymidine
phosphorylase (TP), an enzyme which has been shown to be over expressed in colorectal
tumors. This selective tumor activation has been demonstrated to lead to higher
concentrations of 5-FU in tumor cells as compared to normal tissue, suggesting tumor
targeting by the oral drug. Capecitabine was initially approved by the FDA for treatment of
refractory breast carcinoma and has shown activity in metastatic colorectal carcinoma.
Capecitabine is an attractive agent for use in combination chemotherapy due to its
non-overlapping toxicity profile with many agents and lack of hematologic toxicity.
Gemcitabine has been combined with 5-FU, and may enhance the activity of 5-FU in vivo.
Gemcitabine is an inhibitor of ribonucleotide reductase, an enzyme needed for synthesis of
deoxynucleotides, and 5-FU interferes with dTTP synthesis by inhibition of thymidylate
synthase (TS). It is plausible that concomitant administration of gemcitabine and
capecitabine, may result in increased cytotoxicity by reducing intracellular dTTP thru two
different mechanisms, thereby inhibiting DNA replication and repair. Platinum compounds lead
to cell death by forming DNA adducts and causing double strand breaks. By inhibiting DNA
synthesis and repair, both gemcitabine and 5-FU analogues could potentiate the activity of
carboplatin. These interactions may underlie the clinical synergism that has been observed
with platinum/5-FU and platinum/gemcitabine combinations.
We propose to combine carboplatin, gemcitabine and capecitabine as a palliative treatment
for patients with CUP. Programs evaluating the incorporation of newer chemotherapy agents
into combinations are reasonable in an attempt to improve outcome in patients with CUP. In
addition to anticipated anti-tumor activity, the proposed combination provides a convenient
schedule of brief intravenous treatment, the use of the oral agent capecitabine, and a
toxicity profile which is expected to be mild, characteristics which are important in
palliative treatment programs.
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Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label
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