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on Platelet Recovery after High-Dose Carboplatin
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Background Thrombocytopenia is a frequent side effect of cancer chemotherapy and commonly limits attempts to escalate drug doses. To determine whether interleukin-1
Methods High-dose carboplatin (800 mg per square meter of body-surface area) was administered alone to a control group. Subsequent patients were randomly assigned to receive the same dose of carboplatin with interleukin-1
Results Carboplatin alone consistently produced thrombocytopenia with a median nadir of 19,000 platelets per cubic millimeter and a median of 10 days with less than 100,000 platelets per cubic millimeter. All 15 patients receiving interleukin-1
Conclusions Interleukin-1
could ameliorate carboplatin-induced thrombocytopenia, we combined it with high-dose carboplatin in 43 patients with advanced neoplasms. , administered either before or after carboplatin. Interleukin-1 was given intravenously at a dose of 0.03, 0.1, or 0.3 µg per kilogram of body weight per day for five days. before carboplatin had similar findings. In contrast, 5 of the 15 patients given one of the two higher doses of interleukin-1 after carboplatin had minimal thrombocytopenia (nadir, 91,000 to 332,000 platelets per cubic millimeter). In the 10 patients given 0.3 µg of interleukin-1 per kilogram after carboplatin treatment, the platelet count recovered to 100,000 per cubic millimeter significantly earlier than in either the control group (P = 0.002) or the patients who received interleukin-1 before carboplatin (P = 0.003), with the median times to recovery in the three groups being 16, 21, and 23 days, respectively. At the highest dose of interleukin-1, toxicity was substantial (but reversible), requiring inpatient support for hypotension, supraventricular arrhythmias, and pulmonary-capillary leak. can accelerate the recovery of platelets after high-dose carboplatin therapy and may be clinically useful in preventing or treating thrombocytopenia induced by chemotherapy.
We designed a clinical trial to test whether interleukin-1 could ameliorate chemotherapy-induced thrombocytopenia. Carboplatin was chosen as the antineoplastic drug because it has activity against many cancers10 and because dose escalation is limited by thrombocytopenia. In addition, greater antitumor activity is observed with higher doses of carboplatin,4,11 and preclinical studies indicated that carboplatin and interleukin-1 had synergistic antitumor effects12. One group of patients in our trial received interleukin-1 before chemotherapy, because of preclinical studies indicating that it was capable of protecting the bone marrow from myelosuppression induced by chemotherapy or radiation therapy13,14. Interleukin-1 was given after chemotherapy in another group to test its ability to accelerate hematopoietic recovery.
Methods
Patients
The patients met the standard eligibility criteria for phase I trials9. In addition, they had had no previous radiation therapy or chemotherapy with nitrosoureas or mitomycin, and at least four weeks had passed since their most recent chemotherapy treatment. The study was approved by the institutional review boards of the Clinical Oncology Program of the National Cancer Institute and the Frederick Cancer Research and Development Center. Each patient voluntarily gave written informed consent before treatment.
Study Design
A control group of eight patients received carboplatin alone to ensure that a dose of 800 mg per square meter of body-surface area induced reproducible thrombocytopenia. All the other patients received interleukin-1 in combination with carboplatin. The dose of interleukin-1 was escalated in sequential cohorts of patients from 0.03 µg per kilogram of body weight per day to 0.1 µg per kilogram per day and 0.3 µg per kilogram per day, a range of doses that produced hematopoietic effects in our phase I trial9. At each dose level, five patients were randomly assigned to receive interleukin-1 before and five to receive it after carboplatin. After dose escalation had been completed, five more patients were added to the cohort that received 0.3 µg of interleukin-1 per kilogram after carboplatin treatment.
Treatment
All the patients were treated at the Biological Response Modifiers Program of the Frederick Cancer Research and Development Center between May 1990 and March 1992. In the first cycle of therapy all the patients received 800 mg of carboplatin per square meter by intravenous infusion over a 30-minute period. The patients received 250 ml of normal saline before carboplatin treatment and 750 ml of normal saline after treatment. The dose of carboplatin was reduced to 600 mg per square meter in subsequent cycles if the patient had had more than seven days of grade 4 granulocytopenia or more than seven days of grade 4 thrombocytopenia in an earlier course. Interleukin-1 was provided by Dainippon Pharmaceutical Company (Osaka, Japan) and was administered by intravenous infusion over a 15-minute period daily for five days, beginning one day after carboplatin treatment or ending two days before carboplatin treatment. Interleukin-1 was given for five days because shorter periods of treatment had not had a myeloprotective effect in preclinical studies13. The patients were given 150 ml of normal saline per hour for six hours immediately after the interleukin-1. The patients were observed closely for at least six hours after interleukin-1 treatment, which was given in an outpatient setting at the first two dose levels; all the patients who received 0.3 µg per kilogram per day were treated in the hospital. Platelet transfusions were planned for patients whose platelet counts dropped below 20,000 per cubic millimeter or who had clinical evidence of bleeding. Toxicity was graded according to the National Cancer Institute's Common Toxicity Criteria.
Laboratory Studies
Complete blood counts were obtained three times before the start of treatment, daily during interleukin-1 treatment, and every Monday, Wednesday, and Friday at home until the platelet count dropped below 100,000 per cubic millimeter, whereupon complete blood counts were obtained daily. Serum-chemistry values were monitored several times during interleukin-1 treatment and just before and one, five, and nine days after carboplatin treatment. Creatinine clearance was calculated on the basis of the patient's age, weight, and serum creatinine level15.
Statistical Analysis
The effect of interleukin-1 was evaluated during the first cycle. The number of days it took for the platelet count to fall below and rise to 100,000 per cubic millimeter, as well as the period during which the count remained below 100,000 per cubic millimeter, was estimated according to the Kaplan-Meier product-limit method16. Comparisons among groups of the distribution of days to decline and recovery were performed with the log-rank (Savage) and generalized Wilcoxon tests in stratified Kaplan-Meier time-to-event analyses16. For simplicity, only probability values from the log-rank test are reported. Comparisons among groups of the periods during which platelet counts remained below 100,000 per cubic millimeter were made primarily with the Wilcoxon rank-sum test and stratified time-to-event analyses. The data on one patient in the control group who died with thrombocytopenia were right censored in the time-to-event analyses and eliminated from the analyses requiring the Wilcoxon rank-sum test. Similar analyses were conducted with respect to granulocytes. Data from complete blood counts were not grouped. In the few cases in which data from a patient were missing for a particular day, data were linearly interpolated from values on previous and subsequent days. Patients were assigned a platelet count of 20,000 per cubic millimeter as long as they required platelet transfusions. We emphasize that the control group was not randomized in this study.
Results
The characteristics of the 43 patients enrolled in this trial are listed in Table 1. There were 15 patients with colon cancer, 13 with melanoma, 6 with renal-cell cancer, 4 with lung cancer, 3 with pancreatic cancer, 1 with liposarcoma, and 1 with adenocarcinoma with an unknown primary site. The various treatment groups had similar characteristics, except that a slightly higher percentage of the patients who received 0.1 or 0.3 µg of interleukin-1 per kilogram after carboplatin had previously received chemotherapy.
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per kilogram before treatment with carboplatin, the first-cycle platelet nadir, duration of thrombocytopenia, and time to a decrease below or recovery to a platelet count of 100,000 per cubic millimeter did not differ from values in the control group (data not shown). All 15 patients in these three groups had nadirs below 100,000 platelets per cubic millimeter (median, 17,000; range, 8000 to 36,000).
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per kilogram after carboplatin treatment and 3 of the 10 patients who received 0.3 µg per kilogram after carboplatin treatment had minimal thrombocytopenia. Figure 2 shows the evolution of platelet counts in the patients with the best response (mean nadir, 165,000 per cubic millimeter; range, 91,000 to 332,000). The median daily values of the control group are given for comparison.
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per kilogram before carboplatin and those who received 0.3 µg per kilogram after carboplatin. The distributions of times to decline were homogeneous (P = 0.76), but the distributions of times to recovery were significantly different (P = 0.003), with recovery occurring earlier in the after-carboplatin group. The median time to recovery was 16 days in the group that received interleukin-1 after carboplatin, and 23 days in the group that received interleukin-1 before carboplatin. The difference in the duration of thrombocytopenia between the two groups was tested directly with the Wilcoxon rank-sum test and found to be significant (P = 0.05). A time-to-event analysis of the distributions of duration of a platelet count below 100,000 per cubic millimeter yielded a comparable result (P = 0.05 by the log-rank test and P = 0.05 by the generalized Wilcoxon test). The median platelet counts of the groups that received the 0.3-µg dose of interleukin-1 before and after carboplatin are shown in Figure 4.
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per kilogram after carboplatin treatment revealed results similar to those described above. There was no significant difference between the groups in the lengths of time to a decline below 100,000 platelets per cubic millimeter (P = 0.63), but there was a significant difference in the lengths of time to recovery to that level (P = 0.002). The median time to recovery was 16 days in the interleukin-1 group and 21 days in the control group. Figure 5 shows the median platelet counts in the group given the 0.3-µg dose of interleukin-1 after carboplatin treatment and in the control group. The slight decrease in platelet counts during the five days of interleukin-1 treatment has been previously observed9 and is probably caused by the induction of adhesion molecules. The difference in the duration of thrombocytopenia between the group given the 0.3-µg dose after carboplatin and the control group was not significant (P = 0.26 by the Wilcoxon rank-sum test), nor was the difference in the distributions of duration of the platelet count below 100,000 per cubic millimeter (P = 0.14 by the log-rank test). No differences in the times to decline, times to recovery, or duration of thrombocytopenia were observed between the control group and the group given 0.3 µg of interleukin-1 per kilogram before carboplatin treatment.
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per kilogram before and after carboplatin treatment and in the control group. In the after-carboplatin group, the values in 5 of the 10 patients never fell below 50,000, resulting in median values of 1.5 days below 50,000 and 1 day below 25,000. In the before-carboplatin group, however, the values in all five patients fell below 50,000, and in four they fell below 25,000, resulting in median values of eight and five days, respectively.
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treatment there was a marked increase in the total white-cell count and the absolute neutrophil count, particularly at the highest dose. There were no significant differences among the groups in the length of time until the neutrophil count dropped below 500 per cubic millimeter, the time it remained below that level, and the time until it recovered to that level (data not shown). Overall, 40 percent of the patients required red-cell transfusions, 65 percent required platelet transfusions, and 23 percent were hospitalized for febrile neutropenia, with little difference among the treatment groups, except that a lower percentage of patients required platelet transfusions in the groups treated with the two higher doses of interleukin-1 after carboplatin. One patient with neutropenia in the control group died of pneumonia on day 15.
Nonhematologic toxic effects of carboplatin included nausea and vomiting of grade 2 or lower, as well as hearing loss in one patient and a transient elevation in the serum creatinine level in another. The toxic effects of interleukin-1 were similar to those observed in our previous trials. At the two lower doses, patients had chills, fever, nausea, vomiting, headache, myalgia, and fatigue of grade 2 or lower. More severe side effects were noted at the highest dose; although these effects were manageable and reversible, they did require hospitalization. Sixty percent of the patients given 0.3 µg of interleukin-1 per kilogram (9 of 15) required temporary blood-pressure support with intravenous fluids and pressors, although 5 of the 9 required pressors for only one day. Twenty-seven percent of the patients in the 0.3-µg groups had supraventricular arrhythmias, all of which were either self-limited or responsive to treatment. Forty percent had mild-to-moderate pulmonary-capillary leak that responded quickly to treatment with oxygen and furosemide. No patient receiving the 0.3-µg dose had to stop interleukin-1 treatment early. No toxic effects were observed with the combination of carboplatin and interleukin-1 that have not been observed with either agent alone.
Five patients had partial responses: one with non-small-cell lung cancer (duration, 10 months), one with pancreatic cancer (3 months), one with renal-cell carcinoma (2 months), one with colon cancer (more than 4 months), and one with melanoma (more than 2 months).
Discussion
This study demonstrates that interleukin-1 can accelerate platelet recovery and shorten the duration of thrombocytopenia in patients with cancer when it is given for five days starting 24 hours after high-dose carboplatin treatment. Interleukin-1 is a cytokine produced by a variety of human cells that has profound immunologic, physiologic, and hematopoietic effects17. Its two forms ( and 
) bind to the same receptors and have similar biologic activities, although they have only 26 percent homology18. In vitro and preclinical studies have shown that interleukin-1 induces bone marrow stromal cells (fibroblasts and endothelial cells) to produce a variety of colony-stimulating factors19,20 and interleukin-621. Interleukin-1 acts synergistically with the colony-stimulating factors to promote the proliferation and differentiation of hematopoietic progenitor cells in vitro22. In addition, interleukin-1 can up-regulate the expression of receptors for interleukin-1, granulocyte-macrophage colony-stimulating factor, and interleukin-3 on hematopoietic progenitor cells23. Preclinical studies have shown that interleukin-1 can accelerate the recovery of granulocytes and platelets if it is given after chemotherapy or sublethal radiation, and is myeloprotective if it is given before lethal radiation or chemotherapy13,14,24,25,26.
Accelerating the recovery of platelets would permit earlier initiation of the next cycle of carboplatin, thereby increasing the dose intensity. The reduction in the duration of severe thrombocytopenia might permit further escalation of the dose of carboplatin if granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor were given to ameliorate the neutropenia. In one third of the patients treated with the two higher doses of interleukin-1, there was minimal thrombocytopenia, suggesting that interleukin-1 can almost eliminate carboplatin-induced thrombocytopenia in some patients.
Phase I trials of interleukin-1 and interleukin-1 demonstrated increased serum levels of interleukin-67,9. Elevated serum levels of interleukin-6 and granulocyte colony-stimulating factor were also detected in patients in our study who received the two higher doses of interleukin-1 either before or after carboplatin treatment (data not shown). Although the mechanism of interleukin-1-induced thrombocytosis in vivo remains unclear, it is conceivable that the secondary induction of interleukin-6 may be responsible. Alternatively, interleukin-1 may induce the production of interleukin-11, a hematopoietic growth factor capable of increasing platelet counts that was not measured in this trial.
Serum interleukin-3 levels were not elevated either before or after chemotherapy in our patients (data not shown). This observation differs from the findings of others, who have correlated serum interleukin-3 levels with rebound thrombocytosis after chemotherapy27. Interleukin-1 can up-regulate the expression of interleukin-3 receptors on hematopoietic progenitor cells,23 and it is possible that after high-dose carboplatin treatment the local endogenous production of interleukin-3 may have augmented the thrombocytosis induced by interleukin-1, perhaps explaining why interleukin-1 enhanced platelet recovery only when it was given after carboplatin.
The fact that interleukin-1 did not have a beneficial effect when given before carboplatin may be related to the duration of exposure to the agent. The preliminary results of a trial of interleukin-1 given in a three-hour intravenous infusion for seven days before high-dose chemotherapy and autologous bone marrow transplantation are consistent with the notion that interleukin-1 could have an important myeloprotective effect28. More prolonged intravenous infusion or subcutaneous administration of interleukin-1 before chemotherapy may demonstrate a protective effect.
During the five-day course of interleukin-1 in our study, granulocyte counts were significantly increased, but the depth and duration of carboplatin-induced granulocytopenia were not affected. Measurable levels of granulocyte colony-stimulating factor have been detected in the serum of patients treated with interleukin-1 and interleukin-1 and probably account for the elevation in granulocyte counts7,9,29. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor have been shown to accelerate the recovery of granulocytes and reduce the duration of granulocytopenia after high-dose chemotherapy1,2. This effect was not observed in our study, possibly because the interleukin-1 was given for only five days; colony-stimulating factors are normally administered until granulocytopenia resolves.
This pilot study suggests that interleukin-1 may be clinically useful as a thrombopoietic agent. Although higher doses of interleukin-1 were associated in most cases with chills, fever, and hypotension, the fact that tachyphylaxis to these side effects develops rapidly9 suggests that more prolonged administration of interleukin-1 (5 days before chemotherapy plus 5 to 10 days after chemotherapy, or 10 to 15 days after chemotherapy) may prove feasible.
The merits of interleukin-1 as compared with interleukin-3, another potential thrombopoietic cytokine, remain undefined. Interleukin-3 has a number of side effects -- primarily chills, fever, malaise, headache, and rashes -- and occasional patients have had capillary leak, atrial fibrillation, meningismus, and an unusual syndrome of rigidity resembling Parkinson's disease30,31,32,33,34. Preliminary trials of interleukin-3 alone after chemotherapy have provided conflicting evidence of enhanced platelet recovery35,36,37,38,39,40,41,42. Perhaps, as other cytokines such as interleukin-6 and interleukin-11 become available for clinical trials, combinations of these agents will permit a substantial escalation of chemotherapy doses and the prospective study of the effect of dose-related variables on the outcome of treatment.
Supported in part by the National Cancer Institute under a contract (NO1-CO-74102) with Program Resources, Inc./DynCorp. This article does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does any mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.
We are indebted to the fellows, nursing staff, and administrative staff of the center for their help in conducting this clinical trial, to Frank Schaff for his skilled assistance in the laboratory, and to Sharon Lewis for assistance in the preparation of the manuscript.
Source Information
From the Biological Response Modifiers Program (J.W.S., D.L.L., J.E.J., W.H.S., B.L.G., B.D.C., S.P.C., J.T.H., R.G.F., J.J.O.) and Data Management Services (W.G.A.), Frederick Cancer Research and Development Center of the National Cancer Institute; Frederick Memorial Hospital (S.J.F., J.C.H.); and Program Resources, Inc./DynCorp. (G.C.P., W.J.U.) -- all in Frederick, Md.; the Cancer Treatment Evaluation Program, National Cancer Institute, Rockville, Md. (M. Sznol, L.L.M.); and Dainippon Pharmaceutical Co., Osaka, Japan (M. Shimizu).
Address reprint requests to Dr. Smith at NCI-FCRDC, BRMP, 501 W. Seventh St. Suite 3, Frederick, MD 21701.
References
alone and in combination with myelosuppressive doses of 5-fluorouracil in patients with gastrointestinal cancer. Blood 1991;78:1420-1427. administered in a phase I trial to patients with advanced malignancies. J Clin Oncol 1992;10:1141-1152. [Abstract]
with antitumor drugs on syngeneic tumors in mice. Cancer Res 1991;51:215-221. in cyclophosphamide-treated normal and tumor-bearing mice: protection from acute toxicity, hematologic effects, development of late mortality, and enhanced therapeutic efficacy. J Immunol 1990;145:4121-4130. [Abstract]
(IL-1) with ifosfamide (I), CBDCA (C), and etoposide (E) (ICE) and autologous bone marrow transplant (BMT). Proc Am Soc Clin Oncol 1992;11:335. abstract.
(Syntex). Proc Am Soc Clin Oncol 1991;10:211. abstract.
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