Current Role of Protective Agents in Cancer Treatment

April 1, 1997

Dr. Schuchter's article explores the theoretical and practical aspects underlying the concept of cytoprotection, which has been recently introduced into the therapeutic armamentarium. Cytoprotection is contrasted with the related strategy of rescue, which has been widely applied since the cytokines granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) and granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine, Prokine]) obtained FDA approval.

Dr. Schuchter's article explores the theoretical and practical aspectsunderlying the concept of cytoprotection, which has been recently introducedinto the therapeutic armamentarium. Cytoprotection is contrasted with therelated strategy of rescue, which has been widely applied since the cytokinesgranulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) andgranulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim[Leukine, Prokine]) obtained FDA approval.

Although rejuvenated with the introduction of cytokines, the rescuestrategy was introduced decades ago when leucovorin was used with escalating(high) doses of methotrexate. Leucovorin rescue was extensively, albeitmostly uncritically, pursued in the 1970s for the treatment of osteosarcoma,soft-tissue sarcoma, central nervous system tumors, head and neck cancers,and leukemia, among other malignancies. The therapeutic advantage of high-dosemetho-trexate and leucovorin rescue over conventional doses of methotrexatewas never demonstrated,[1-3] and only in patients with osteosarcoma aresuch regimens still employed on a wide scale--but not without continuingcontroversy.[4]

The experience with high-dose methotrexate exemplifies many of the difficultiessurrounding the testing of cytoprotective strategies; in particular, provingthat dose escalation (or dose intensification) with protection or rescueis therapeutically superior to simply following toxicity-driven dose modificationsat the expense of maintaining dose intensity. More discussion of this pointin the article would have been helpful to convey the complexity of adoptingand using these drugs.

Amifostine

The strengths of this review article lie in its broad coverage of thepotential clinical applications of amifostine (Ethyol) and the author'spractical experience with its administration. The most mature clinicaldata supporting the amelioration of chemotherapy-induced toxicities followingpretreatment with amifostine come from a randomized clinical trial of cyclophosphamide(Cytoxan, Neosar) plus cisplatin (Platinol) with and without the cytoprotectorin ovarian cancer.[5] Randomized studies are also ongoing in the Netherlandsusing weekly cisplatin with or without amifostine in patients with advancedhead and neck cancer.[6]

At present, only an abstract indicates that dose escalations of paclitaxel(Taxol) are possible with less toxicity when amifostine precedes its administration.Mechanistically, amifostine-induced protection against paclitaxel neurotoxicityis difficult to explain, but accelerated marrow recovery may be a generalproperty of amifostine, in view of its effects on hematopoietic colony-formingunits.[7]

In addition to the fact that some information about amifostine cytoprotectionis quite preliminary, widespread adoption of this agent into clinical practiceis unlikely because of the acute toxicities and cumbersome requirementsfor nursing supervision and premedications accompanying its use. Introducingthis agent into a regimen requires antiemetics, other premedications (suchas lorazepam and phenothiazines), hydration, and monitoring of vital signs.Even with these maneuvers, some patients continue to experience substantialsubjective intolerance. On the other hand, since the use of cisplatin-basedregimens often require this degree of intensive monitoring, the additionof amifostine does not represent an overwhelming escalation of labor. However,these problems may discourage the use of amifostine unless evidence ofits advantage in specific circumstances is demonstrated in phase III trials.

We have recently employed amifostine with gemcitabine (Gemzar) and cisplatinin very heavily pretreated patients with ovarian cancer, including twowho had undergone bone marrow transplantation, and have demonstrated toleranceof this regimen. Randomizing patients to cycles with or without amifostinemay provide an indication of whether marrow tolerance is improved by itsuse.

Dexrazoxane

The indication of dexrazoxane (Zinecard) reviewed by Dr. Schuchter isconfined to the study setting that led to its approval: patients with advancedbreast cancer who have received 300 mg/m²of doxorubicin. While suchan indication is reasonable, it may not be the optimal way to use the drug.

The evidence that dexrazoxane is a topoisomerase II inhibitor does raisethe concern of interference with antitumor effects.[8,9] However, cardiacprotection by its chelating properties is the most apparent clinical effect,whereas protection of hematologic toxicities and alopecia would be expectedto be even more prominent than tumor protection since the antagonism occursat the level of topoisomerase II alpha during cell division. Protectionof toxicities to proliferating tissues has not, in fact, been observed.Blunting of objective tumor response in breast cancer is suggested in onelarge study,[10] in addition to the one quoted by Dr. Schuchter. However,this should not negate the possible therapeutic gains derived from achievingcardioprotection nor should it discourage exploration of expanded clinicalapplications of dexrazoxane in randomized studies.

The recommendation of instituting dexrazoxane after a 300-mg/m²cumulative doxorubicin dose has been reached stems from the design of thestudy ultimately leading to its approval. Placebo-pretreated patients werecrossed over, after a 300-mg/m² dose of doxorubicin, to pretreatmentwith dexrazoxane; such a design confirmed the cardioprotective effectsof dexrazoxane upon crossover relative to patients in parallel studieswho were not crossed over to the cytoprotector. Certainly, the delay ininstituting dexrazoxane minimizes the risk of interference with antitumoreffects. However, additional data should be sought to define the optimaltiming of treatment with dexrazoxane, particularly in populations who areat especially high risk for anthracycline cardiotoxicity, such as children.

Other Cytoprotectors

As a better understanding of the actions of cytotoxic drugs is gained,other cytoprotectors will undoubtedly be introduced. Such understandingwill lead to attempts to manipulate biochemical pathways to achieve greatercytotoxicity in tumor cells (biochemical modulation) or lesser toxicityto normal tissues (cytoprotection).[11]

Fluoropyrimidines under development rely heavily on both of these concepts.For example a new preparation from Japan (S-1) soon to begin testing herecombines the fluorouracil (5-FU) prodrug tegafur, an inhibitor of 5-FUcatabolism, and an inhibitor of phosphorylation (oxonic acid) that, whengiven by the oral route, diminishes 5-FU gastrointestinal toxicity.[12]

Cytoprotection and Quality of Life

This leads me to comment on the concept of cytoprotection as a way toimprove quality of life in relation to chemotherapy. The focus should beon the prevention of toxicities and common complications resulting fromtreatment. The case for improving the quality of life of patients by treatingthem with amifostine, as an example, has not been made. More plausibleis the possible use of amifostine to protect selected populations againstplatinum toxicities. This may be readily apparent during retreatment ofpatients with ovarian cancer, and underlies the proposed use with gemcitabineand cisplatin described above. In turn, under these specific circumstances,one might be able to demonstrate improved quality of life, as comparedwith patients treated without such protection.

In summary, the concepts of cytoprotection and rescue from toxicityhave had recent clinical applications leading to drug approval. Such conceptsemanate from our expanding knowledge of chemotherapy mechanisms in normaland tumor tissues, and are theoretically attractive. However, it is imperativeto address each promising area preferably through randomized clinical trialscovering specific indications to fill the large gaps present in the evaluationof end results.

References:

1. Von Hoff DD, Rozencweig M, Penta JS, et al: Incidence of drug-relateddeaths secondary to high-dose methothrexate and citrovorum factor administration.Cancer Treat Rep 61:745-748, 1977.

2. Catane R, Bono V, Jr, Louie AC, et al: High dose methotrexate nota conventional treatment. Cancer Treat Rep 62:178-180, 1978.

3. Von Hoff DD, Rozencweig M, Louie AC, et al: "Single" agentactivity of high-dose metho- trexate with citrovorum factor rescue. CancerTreat Rep 62:233-235, 1978.

4. Graf N, Winkler K, Betlemovic M, et al: Methotrexate pharmacokineticsand prognosis in osteosarcoma. J Clin Oncol 12:1443-1450, 1994.

5. Glick J, Kemp G, Rose P, et al: A randomized trial of cyclophosphamideand cisplatin + amifostine in the treatment of advanced epithelial ovariancancer (abstract). Proc Am Soc Clin Oncol 13:432, 1994.

6. Planting AST, Vermorken JB, Catimel G, et al: Randomized phase IIstudy of weekly cis- platin with or without amifostine in patients withadvanced head and neck cancer (abstract). Proc Am Soc Clin Onc 15:314,1996.

7. List AF, Heaton R, Glinsmann-Gibson B: Amifostine is a potent stimulantof hematopoietic progenitors (abstract). Proc Am Assoc Cancer Res 36:291,1995.

8. Ishida R, Miki T, Narita T, et al: Inhibition of intracellular topoisomeraseII by antitumor bis (2,6-dioxopiperazine) derivatives: Mode of cell growthinhibition distinct from that of the cleavable complex-forming type inhibitors.Cancer Res 51:4909-4916, 1990.

9. Venturini M, Michelotti A, Del Mastro L, et al: Multicenter RandomizedControlled Clinical Trial to Evaluate Cardioprotection of Dexrazane vsNo Cardioprotection in Women Receiving Epirubicin Chemotherapy for AdvancedBreast Cancer. J Clin Oncol 14(12)3112-3120, 1996.

10. Muggia FM: Cytoprotection: Concepts and challenges. Support CareCancer 2:377-379, 1994.

11. Shirasaka T, Shimamoto Y, Fukushima M: Inhibition by oxonic acidof gastrointestinal toxicity of 5-fluorouracil without loss of its antitumoractivity in rats. Cancer Res 53:4004-4009, 1993.