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Conrad Notes
a timely medical meeting newsletter
NEW THERAPIES FOR ADVANCED COLORECTAL CANCER (CRC)
E. Cvitkovic, MD, Paul Brouse Hospital, Villejuif, France, gave a balanced report on treating CRC with ralitrexed, CPT-11 (irinotecan), and oxaliplatin compared with 5-fluorouracil (FU) regimens. The new drugs, given alone, produce survival rates similar to those seen with 5-FU-based schedules. Combined use of 5-FU with CPT-11 or oxaliplatin increases survival significantly. (Please consult the package insert on irinitecan).

Treating CRC with 5-FU and leucovorin (LV) There are many simple and complicated treatment schedules for 5-FU (J Clin Oncol 1992;10:896-903). In general, best supportive care gives 5 months of added life in advanced CRC. Combined use of 5-FU plus LV increases survival to about 10 or 11 months.

Cytotoxic activity of new medications Ralitrexed interferes with the DNA synthesis phase (S) of cell division by blocking thymidylate synthase. CPT-11 disrupts the S phase by inhibiting topoisomerase I needed to maintain DNA shape during translation, transcription, and replication. Oxaliplatin cross-links DNA to prevent replication and transcription.

Treatment of CRC with ralitrexed Infusion of ralitrexed every 3 weeks leads to a 2 or 3 months' improvement in survival compared with 5-FU/LV therapy. One of the three studies in the latest metanalysis showed some modest benefit in the quality of life, according to Cvitkovic. Drug-induced mucositis and leukopenia seemed less severe and less frequent with ralitrexed.

Oxaliplatin, a replacement for cisplatin? Indeed oxaliplatin is more potent than cisplatin but has the same mechanism of action of other platinum drugs. In 5-FU refractory patients, oxaliplatin alone led to a response rate of 10%. Oxaliplatin combined with 5-FU shows a median survival of 15-19 months and a response rate of 35-60% as first and second line treatment.

CPT-11 alone and in combination Sponsor-provided unpublished data on CPT-11 alone helped in estimating response rates (RR) and survival times. Approved dosing in Europe (up to 350 mg/sqm every 3 weeks) and in the United States (up to 150 mg/sqm weekly) in previously untreated patients produced RRs of 20% and 29% with corresponding median survival of 14.7 and 11.4 months, respectively.

First line therapy of advanced CRC using combined CPT-11 and 5-FU/LV led to encouraging results. Rothenberg alternated CPT-11 and 5-FU/LV in untreated CRC (ASCO,1997-Conrad Notes). Data on 71 patients showed a 6.9 months' median time to tumor progression and 17.8 months' survival time. The combination added about 7 months' survival to the 10 to 11 months seen with 5-FU/LV in other studies.

Pozzo gave CPT-11 alternating with 5-FU/folinic acid (ASCO,1997-Conrad Notes). Preliminary results on 33 CRC patients show good tolerance and a RR of 30.3%. In Cvitkovic's opinion, the combined use of noncross resistant agents presents a unique opportunity to increase survival and RRs in advanced CRC.

Rating anticancer treatments Guidelines help oncologists and other clinicians judge the value of cancer therapies. The American Society of Clinical Oncology adopted a set of guidelines, including therapeutic outcomes, which conclude that:

  • Survival is the most important outcome.

  • An improvement in disease-free survival or quality of life merits using adjuvant therapy.

  • Toxicity is important, particularly in children.

  • Cost effectiveness is especially important when benefits are modest or costs are high.

"In general, there is no minimum benefit above which treatments are justified; rather, benefits should be balanced against toxicity and cost" (J Clin Oncol 1996;14:671-679).

Cvitkovic comments The current approach in treating CRC resembles that seen 20 years ago with breast cancer when the anthracyclines became available. Clinical investigators and practitioners need not waste time by repeating errors of the past. A major priority is the exploration of combination and sequential therapy over the natural history of the disease. Also, earlier identification of relevant treatment outcome variables is needed. There are opportunities independent of the delays of waiting for metanalyses, statistics and consensus decision-making.

For professional correspondence, contact Dr. Cvitkovic by Fax at: 33 1 4515 4045

Eugene A. Conrad

Presented at The European Cancer Conference (ECCO 9), September 14-18, 1997
Copyright © 1997 Conrad Group, Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / November 1997
Send comments to: ConradNote@aol.com

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