NEW YORKPatients with advanced colorectal cancer have a median
survival of only 12 months with single-agent chemotherapy. New drugs
and new drug combinations are being tested in an attempt to find more
effective treatments for the disease. A panel of researchers
discussed trials of raltitrexed (Tomudex) in combination with other
drugs at the Chemotherapy Foundation Symposium XVII.
Raltitrexed, a thymidylate synthase (TS) inhibitor, has been approved
for use in Europe and Canada, but not yet in the United States, said
panel moderator Joseph R. Bertino, MD, chairman of the Department of
Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering
Early findings of a phase I trial of raltitrexed with fluorouracil
(5-FU) revealed a synergistic effect between the two drugs when
raltitrexed is administered followed by 5-FU, but an antagonistic
effect when the order of drug administration is reversed, reported
Gary K. Schwartz, MD, of the Division of Solid Tumor Oncology,
In the trial, 59 patients (51 of whom had had prior therapy with
5-FU) received escalating doses of the two drugs, with raltitrexed
delivered as a 15-minute infusion, followed 24 hours later by a 5-FU
bolus. Treatment was repeated every 21 days. The maximum tolerated
doses that emerged are 5.5 mg/m² of raltitrexed and 1,200
mg/m² of 5-FU.
The combination is well tolerated, Dr. Schwartz said, with prolonged
neutropenia the dose-limiting toxicity. Grade IV mucositis and
diarrhea were also seen.
We observed antitumor response in this heavily pretreated
patient population, with an impressive degree of stable disease,
Dr. Schwartz said. The results, he said, warrant phase II studies,
but he added that the phase I trial continues and is still enrolling
Raltitrexed Plus Oxaliplatin
Philippe Rougier, MD, professor of hepatogastroenterology and
digestive oncology, Hôpital Ambroise Paré, Boulogne,
France, reported results of a multicenter phase II French trial of
raltitrexed combined with oxaliplatin. Oxaliplatin (investigational
in the United States) is a new, platinum-based drug that is
structurally and functionally different from carboplatin (Paraplatin)
and cisplatin (Platinol). It has been studied as a single agent and
in combination with 5-FU, with and without leucovorin, Dr. Rougier said.
In this open-label trial, 3 mg/m² of raltitrexed was delivered
as a 15-minute infusion, followed by a 2-hour infusion of
oxaliplatin, 130 mg/m², every 3 weeks for six cycles. The study
included 62 patients with previously untreated metastatic colorectal
The regimen was well tolerated, Dr. Rougier said, with
only three patients discontinuing treatment because of toxicity.
Grade 1-2 neurotoxicity was seen in 97% of patients for a few days
following each cycle. Grade 4 neutropenia was seen in 16.5%. There
were two treatment-related deaths.
Although only 1.6% of patients achieved a complete response, 61%
showed a partial response, for an overall response rate of 62.6%, Dr.
Rougier said. The median duration of response was 8.5 months and
median time to progression, 6.5 months.
Dr. Rougier called the combination of raltitrexed and oxaliplatin
highly active, convenient, tolerable, and feasible, but
cautioned that it is necessary to monitor neutropenia and diarrhea to
avoid severe complications in this patient population.
Irinotecan Plus Raltitrexed
Irinotecan (Camptosar), a topo-isomerase I inhibitor with
broad-spectrum activity in a wide variety of cancers, is being tested
in combination with raltitrexed in metastatic colorectal cancer in an
ongoing phase I trial. Jean Maroun, MD, head of medical oncology,
Ottawa Regional Cancer Center, said that the trial aims to establish
the maximum tolerated dose in preparation for a phase II trial.
Thus far, 18 patients have been enrolled. In addition to the standard
inclusion criteria, participants must have adequate renal function,
because raltitrexed is excreted through the kidneys, he said. Prior
treatment with a thymidylate synthase inhibitor is permitted.
Irinotecan is administered as an IV infusion over 90 minutes. After a
15-minute break, raltitrexed is given as a 15-minute infusion. The
cycle is repeated every 3 weeks. Irinotecan doses were escalated from
300 to 350 mg/m² and raltitrexed doses from 2.5 to 3.5
Although clinical benefit was not the primary study objective, Dr,
Maroun said that stable disease has been observed in 53% of
participants, with disease progression in only four (24%). Time to
disease progression has ranged from 5 to 30 weeks. Dose-limiting
toxicities have included febrile neutropenia, grade 3 fatigue, and diarrhea.
Dr. Bertino concluded the discussion on an optimistic note, observing
that these three studies of raltitrexed in combination with a drug
shown to be active in colorectal cancer give hope for future
progress. Each combination deserves further study.