The rescue agents include CSFs, erythropoietin(Drug information on erythropoietin) (Epogen, Procrit), and folinic acid (leucovorin). The available CSFs--granulocyte CSF, or G-CSF (filgrastim [Neupogen]), and granulocyte-macrophage CSF , or GM-CSF (molgramostim [Leucomax], sargramostim(Drug information on sargramostim) [Leukine, Prokine]), are lineage-specific for neutrophils and macrophages, respectively. Erythropoietin is specific for red blood cell production. Leucovorin is a rescue agent that bypasses the enzymatic blockade of the antifolates (methotrexate and trimetrexate(Drug information on trimetrexate)).
Colony-stimulating factors, glycoproteins that stimulate the growth and differentiation of myeloid cells from the bone marrow, and cytokines, polypeptides that stimulate or inhibit the chemotaxis and proliferation of white blood cells involved in the immune response, have the potential to lessen the complications associated with chemotherapeutic agents. The identification, cloning, and industrial production of the hematopoietic CSFs have fostered an intense interest in their use to treat myelosuppression and to overcome the dose-limiting toxicity associated with some forms of chemotherapy. Current treatment regimens have focused primarily on G-CSF and GM-CSF. Erythropoietin is also widely used to treat anemia associated with renal disease and has recently been approved for chemotherapy-associated anemia.
Clinical Trials--The ability of G-CSF and GM-CSF to reduce the duration of chemotherapy-induced neutro- penia has been evaluated in clinical trials. In an open-label crossover trial of patients with transitional-cell carcinoma of the urothelium, a randomized trial of patients with non-Hodgkin's lymphoma receiving chemotherapy alone or chemotherapy plus G-CSF, and a randomized, placebo-controlled trial of patients with small-cell lung cancer, G-CSF significantly reduced the incidence of febrile neutropenia and hastened neutrophil recovery following the first cycle of chemotherapy. In two of these studies, G-CSF resulted in a decrease in hospitalization and antibiotic use.[55,57]
The efficacy of G-CSF in reducing the duration of chemotherapy-induced neutropenia and resulting complications was assessed in a multicenter, randomized, placebo-controlled, double-blind study of 211 patients with small-cell lung cancer. Patients received a combination of cyclophosphamide(Drug information on cyclophosphamide), doxorubicin(Drug information on doxorubicin), and etoposide(Drug information on etoposide) (VePesid), with or without G-CSF. In addition to being well tolerated, G-CSF reduced the incidence of complications caused by neutropenia during the first cycle of therapy from 57% to 28% and decreased antibiotic use and hospitalizations by 47% and 45%, respectively.
Granulocyte CSF has also been used in the setting of high-dose chemotherapy and autologous bone marrow transplantation. In patients with Hodgkin's disease, G-CSF significantly accelerated the recovery of granulocyte counts. In another study of patients receiving chemotherapy, G-CSF also hastened neutrophil recovery and reduced mucositis after autologous bone marrow transplantation.
Randomized studies of GM-CSF have been conducted after myelosuppressive chemotherapy (standard-dose chemotherapy) and after myeloablative therapy (high-intensity chemoradiation followed by autologous bone marrow transplantation or peripheral stem-cell infusion).[61-65] In trials of myelosuppressive chemotherapy, GM-CSF has not consistently reduced febrile neutropenic events. In one such trial comparing GM-CSF vs placebo in patients with small-cell lung cancer treated with platinum and etoposide and concurrent chest irradiation, GM-CSF failed to cause significant differences in neutrophil recovery; furthermore, an increased incidence of fever and thrombocytopenia was noted in the GM-CSF-treated patients.
Granulocyte-macrophage CSF has also been assessed in patients treated with myeloablative regimens. In several phase III trials evaluating the efficacy of GM-CSF in autologous bone marrow transplantation procedures, neutrophil recovery occurred 4 to 7 days earlier with GM-CSF than with placebo. The incidence of infection, duration of hospitalization, and days of IV antibiotic use were significantly reduced in patients receiving GM-CSF.
The use of G-CSF or GM-CSF has allowed physicians to maintain chemotherapy doses. Trillet-Lenoir et al reported that only 29% of patients with small-cell lung cancer who received cyclophosphamide, doxorubicin, and etoposide with G-CSF support required reductions of 15% or more in their target dose, whereas 61% of patients in the control group required such reductions.
Similar results were achieved in a trial of patients with non-Hodgkin's lymphoma who received sequential combinations of vincristine, Adriamycin, prednisolone(Drug information on prednisolone), etoposide, cyclophosphamide, and bleomycin(Drug information on bleomycin) (VAPEC-B), either alone or with G-CSF. Patients treated with G-CSF had significantly fewer dose reductions and treatment delays than did controls and maintained a median dosage intensity of 95% (as compared with 83% in controls).
Despite these positive results with G-CSF and GM-CSF, none of the randomized trials has reported a significant difference in overall response rates or survival between CSF- and placebo-treated patients.
Clinical Use--Stimulation of myeloid progenitors by CSFs may increase the pool of granulocyte precursors susceptible to destruction by chemotherapeutic agents. Indeed, it has been shown that CSFs given concurrently with chemotherapy increases the severity of neutropenia and thrombocytopenia. As a result, administration of GM-CSF or G-CSF should not begin until at least 24 hours after the last dose of chemotherapy.[61,66,67] Recent data also show that the efficacy of CSFs decreases with repeated courses of chemotherapy.
At currently used subcutaneous doses (5 mcg/kg/d of G-CSF and 125 mcg/kg/d of GM-CSF), the CSFs are well tolerated. The only common toxicity is medullary bone pain, which can usually be controlled with nonnarcotic analgesic agents. Medullary bone pain typically arises when CSF therapy is initiated and again just before the occurrence of neutrophil recovery.
Therapy with GM-CSF is often associated with low-grade fever, nausea, fatigue, chills, and myalgia. Other less common side effects with the first dose of GM-CSF include arthralgia, capillary leakage, and, rarely, dyspnea. It remains unclear whether the side-effect profiles of G-CSF and GM-CSF differ significantly from each other.
Leucovorin Leucovorin (folinic acid, citrovorum factor) is used as a rescue agent in patients receiving high-dose methotrexate(Drug information on methotrexate) or trimetrexate regimens. Methotrexate- or trimetrexate-induced cytotoxicity results from inhibition of dihydrofolate reductase (DHFR), followed by depletion of intracellular folate pools and impaired biosynthesis of purines and pyrimidines.
Leucovorin is a reduced folate that can prevent the toxic effects of methotrexate or trimetrexate, including myelosuppression and GI toxicity. The mechanism of leucovorin rescue of normal cells is repletion of reduced intra-cellular folate levels. In addition, leucovorin competes with methotrexate polyglutamates to overcome the inhibition of thymidylate synthetase. The timing of leucovorin administration relative to methotrexate or trimetrexate is critical to avoid tumor cell rescue.
Leucovorin is available for both oral and IV use. To prevent toxicity from high-dose methotrexate, leucovorin, 15 mg (approximately 10 mg/m²) is administered every 6 hours for 10 doses beginning 24 hours after the initiation of the methotrexate infusion. In the presence of nausea or vomiting, leucovorin should be administered parenterally.
Serum creatinine and methotrexate levels should be determined once daily. Leucovorin should be continued until the serum methotrexate level is less than 45 ×10-8 M (0.05 mcM). Additional modification of the leucovorin dose and duration of therapy may be necessary depending on methotrexate levels.
The major question that arises with the use of any chemoprotective agent is whether the protection of normal tissues extends to protection of tumor cells from the cytotoxic effects of chemotherapy and radiotherapy. Similarly, with cytokines, one must address the question of whether they stimulate the growth of both tumor cells and stem cells. Obviously, there is little benefit to be gained from a drug that protects or stimulates normal tissue and tumor tissue comparably.
Several large, randomized clinical trials have evaluated the use of amifostine(Drug information on amifostine) with chemotherapy and/or radiotherapy. In these studies, amifostine selectively protected against hematologic and nonhematologic adverse events without compromising the efficacy of the anticancer therapies.[24,40]
More recently, amifostine has been combined with cisplatin(Drug information on cisplatin), vinblastine(Drug information on vinblastine), and irradiation to treat advanced non-small-cell lung cancer. Patients with stage IV disease who received amifostine had a response rate of 64% and median survival of 17 months. This high tumor-response rate in non-small-cell lung cancer when amifostine is given with platinum is significantly better than response rates customarily seen with traditional therapies.
Dexrazoxane is currently indicated for use as a cytoprotector against anthracycline-induced cardiotoxicity. However, this drug was originally tested as an anticancer agent. Its weak activity in this domain is apparently related to the ability of certain bisdioxopiperazines to inhibit DNA topoisomerase II.
Recent studies have focused on the potential use of this class of compounds as facilitators of cancer therapies. In vitro assays have demonstrated that dexrazoxane can enhance the antiproliferative effect of cisplatin on ovarian cancer cells in a synergistic and dose-dependent manner, resulting in a decrease in cisplatin inhibitory concent (IC50). In addition, dexrazoxane has been used recently with good results as a sensitizer of radiation therapy in patients with inoperable rectal cancer. This suggests that this agent may, under certain circumstances, be used as both a cardioprotector and a facilitator of therapy in cancer cells.
Mesna has been tried successfully as an orally administered uroprotective agent.[74,75] This type of administration is advantageous in therapeutic settings where outpatient chemotherapy is likely to increase.
Colony-stimulating factors can reduce the incidence of febrile neutropenia after myelosuppressive chemotherapy. In addition, CSFs can shorten the period of neutropenia and reduce infectious complications after myeloablative therapy with autologous bone marrow transplantation or peripheral stem-cell transplantation and perhaps after allogeneic bone marrow transplantation. Overall, G-CSF and GM-CSF have little effect on platelet nadir or duration of thrombocytopenia. Colony-stimulating factors do not protect stem cells and are not to be given concurrently with chemotherapy or radiotherapy, as they have enhanced bone marrow toxicity in this setting.
Recent clinical data obtained from patients with head and neck cancer who were treated with combination cisplatin-fluorouracil-leucovorin chemotherapy suggest that GM-CSF may reduce mucositis, another dose-limiting toxicity of chemotherapy. There is increasing evidence that maintenance of GI epithelial structure and function is regulated by a cytokine network, analogous to that present in bone marrow.
Several cytokines with potential epithelial activity have been described, including GM-CSF, G-CSF, interleukin-1 (IL-1), IL-11, and transforming growth factor-beta (TGF-beta). These cytokines are now in preclinical or clinical development as mucosal protectants. Interleukin-11 has recently been shown to stimulate recovery of mucosal cells of the small intestine after cytoablative therapy. Similarly, TGF-beta3 slows the proliferation rate of mucosal cells, making them less vulnerable to chemotherapeutic agents.
The use of hematopoietic CSFs in patients with myeloid malignancies (acute myeloblastic leukemia and myelodysplastic syndromes) has been a concern because most myeloid leukemia cells express CSF receptors. Several clinical trials that address this issue have been completed, and results vary with respect to the interference of CSFs with antitumor efficacy.[80,83]
Evidence suggests that GM-CSF may also act as a growth activator on a variety of tumor cells of nonhematopoietic origin. However, in a trial of patients with ovarian cancer receiving carboplatin(Drug information on carboplatin)-cyclophosphamide therapy and GM-CSF, the patients in the GM-CSF arm showed less severe neutropenia and thrombocytopenia but no difference in tumor response rate when compared with controls.
Cytoprotective Plus Rescue Agents
Preclinical studies show that the combination of amifostine pretreatment, irradiation, and G-CSF after radiation enhances hematologic recovery.[86,87] Assessment of these combined effects merits clinical investigation. Cytoprotection with amifostine can reduce the extent of toxic damage to normal tissues, including proliferating cell populations, kidneys, and peripheral nerves. Once the chemotherapeutic or radiotherapeutic treatment phase has been accomplished, myeloid progenitors (now present at a higher baseline) can be stimulated by growth factors (CSFs or cytokines).
Cytoprotective and rescue agents can reduce the acute and cumulative toxicities associated with more intensive and more effective therapeutic regimens. Oncologists must learn how to use these agents in order to improve the quality and duration of life of cancer patients.