Current Role of Protective Agents in Cancer Treatment
Current Role of Protective Agents in Cancer Treatment
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.
Although rejuvenated with the introduction of cytokines, the rescue strategy was introduced decades ago when leucovorin was used with escalating (high) doses of methotrexate. Leucovorin rescue was extensively, albeit mostly 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-dose metho-trexate and leucovorin rescue over conventional doses of methotrexate was never demonstrated,[1-3] and only in patients with osteosarcoma are such regimens still employed on a wide scale--but not without continuing controversy.
The experience with high-dose methotrexate exemplifies many of the difficulties surrounding the testing of cytoprotective strategies; in particular, proving that dose escalation (or dose intensification) with protection or rescue is therapeutically superior to simply following toxicity-driven dose modifications at the expense of maintaining dose intensity. More discussion of this point in the article would have been helpful to convey the complexity of adopting and using these drugs.
The strengths of this review article lie in its broad coverage of the potential clinical applications of amifostine (Ethyol) and the author's practical experience with its administration. The most mature clinical data supporting the amelioration of chemotherapy-induced toxicities following pretreatment with amifostine come from a randomized clinical trial of cyclophosphamide (Cytoxan, Neosar) plus cisplatin (Platinol) with and without the cytoprotector in ovarian cancer. Randomized studies are also ongoing in the Netherlands using weekly cisplatin with or without amifostine in patients with advanced head and neck cancer.
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 neurotoxicity is difficult to explain, but accelerated marrow recovery may be a general property of amifostine, in view of its effects on hematopoietic colony-forming units.
In addition to the fact that some information about amifostine cytoprotection is quite preliminary, widespread adoption of this agent into clinical practice is unlikely because of the acute toxicities and cumbersome requirements for nursing supervision and premedications accompanying its use. Introducing this agent into a regimen requires antiemetics, other premedications (such as lorazepam and phenothiazines), hydration, and monitoring of vital signs. Even with these maneuvers, some patients continue to experience substantial subjective intolerance. On the other hand, since the use of cisplatin-based regimens often require this degree of intensive monitoring, the addition of amifostine does not represent an overwhelming escalation of labor. However, these problems may discourage the use of amifostine unless evidence of its advantage in specific circumstances is demonstrated in phase III trials.
We have recently employed amifostine with gemcitabine (Gemzar) and cisplatin in very heavily pretreated patients with ovarian cancer, including two who had undergone bone marrow transplantation, and have demonstrated tolerance of this regimen. Randomizing patients to cycles with or without amifostine may provide an indication of whether marrow tolerance is improved by its use.
The indication of dexrazoxane (Zinecard) reviewed by Dr. Schuchter is confined to the study setting that led to its approval: patients with advanced breast cancer who have received 300 mg/m²of doxorubicin. While such an indication is reasonable, it may not be the optimal way to use the drug.
The evidence that dexrazoxane is a topoisomerase II inhibitor does raise the concern of interference with antitumor effects.[8,9] However, cardiac protection by its chelating properties is the most apparent clinical effect, whereas protection of hematologic toxicities and alopecia would be expected to be even more prominent than tumor protection since the antagonism occurs at the level of topoisomerase II alpha during cell division. Protection of toxicities to proliferating tissues has not, in fact, been observed. Blunting of objective tumor response in breast cancer is suggested in one large study, in addition to the one quoted by Dr. Schuchter. However, this should not negate the possible therapeutic gains derived from achieving cardioprotection nor should it discourage exploration of expanded clinical applications of dexrazoxane in randomized studies.
The recommendation of instituting dexrazoxane after a 300-mg/m² cumulative doxorubicin dose has been reached stems from the design of the study ultimately leading to its approval. Placebo-pretreated patients were crossed over, after a 300-mg/m² dose of doxorubicin, to pretreatment with dexrazoxane; such a design confirmed the cardioprotective effects of dexrazoxane upon crossover relative to patients in parallel studies who were not crossed over to the cytoprotector. Certainly, the delay in instituting dexrazoxane minimizes the risk of interference with antitumor effects. However, additional data should be sought to define the optimal timing of treatment with dexrazoxane, particularly in populations who are at especially high risk for anthracycline cardiotoxicity, such as children.
As a better understanding of the actions of cytotoxic drugs is gained, other cytoprotectors will undoubtedly be introduced. Such understanding will lead to attempts to manipulate biochemical pathways to achieve greater cytotoxicity in tumor cells (biochemical modulation) or lesser toxicity to normal tissues (cytoprotection).
Fluoropyrimidines under development rely heavily on both of these concepts. For example a new preparation from Japan (S-1) soon to begin testing here combines the fluorouracil (5-FU) prodrug tegafur, an inhibitor of 5-FU catabolism, and an inhibitor of phosphorylation (oxonic acid) that, when given by the oral route, diminishes 5-FU gastrointestinal toxicity.
Cytoprotection and Quality of Life
This leads me to comment on the concept of cytoprotection as a way to improve quality of life in relation to chemotherapy. The focus should be on the prevention of toxicities and common complications resulting from treatment. The case for improving the quality of life of patients by treating them with amifostine, as an example, has not been made. More plausible is the possible use of amifostine to protect selected populations against platinum toxicities. This may be readily apparent during retreatment of patients with ovarian cancer, and underlies the proposed use with gemcitabine and cisplatin described above. In turn, under these specific circumstances, one might be able to demonstrate improved quality of life, as compared with patients treated without such protection.
In summary, the concepts of cytoprotection and rescue from toxicity have had recent clinical applications leading to drug approval. Such concepts emanate from our expanding knowledge of chemotherapy mechanisms in normal and tumor tissues, and are theoretically attractive. However, it is imperative to address each promising area preferably through randomized clinical trials covering specific indications to fill the large gaps present in the evaluation of end results.
1. Von Hoff DD, Rozencweig M, Penta JS, et al: Incidence of drug-related deaths 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 not a conventional treatment. Cancer Treat Rep 62:178-180, 1978.
3. Von Hoff DD, Rozencweig M, Louie AC, et al: "Single" agent activity of high-dose metho- trexate with citrovorum factor rescue. Cancer Treat Rep 62:233-235, 1978.
4. Graf N, Winkler K, Betlemovic M, et al: Methotrexate pharmacokinetics and prognosis in osteosarcoma. J Clin Oncol 12:1443-1450, 1994.
5. Glick J, Kemp G, Rose P, et al: A randomized trial of cyclophosphamide and cisplatin + amifostine in the treatment of advanced epithelial ovarian cancer (abstract). Proc Am Soc Clin Oncol 13:432, 1994.
6. Planting AST, Vermorken JB, Catimel G, et al: Randomized phase II study of weekly cis- platin with or without amifostine in patients with advanced 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 stimulant of hematopoietic progenitors (abstract). Proc Am Assoc Cancer Res 36:291, 1995.
8. Ishida R, Miki T, Narita T, et al: Inhibition of intracellular topoisomerase II by antitumor bis (2,6-dioxopiperazine) derivatives: Mode of cell growth inhibition 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 Randomized Controlled Clinical Trial to Evaluate Cardioprotection of Dexrazane vs No Cardioprotection in Women Receiving Epirubicin Chemotherapy for Advanced Breast Cancer. J Clin Oncol 14(12)3112-3120, 1996.
10. Muggia FM: Cytoprotection: Concepts and challenges. Support Care Cancer 2:377-379, 1994.
11. Shirasaka T, Shimamoto Y, Fukushima M: Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res 53:4004-4009, 1993.