1 Department of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome; 2 Department of Obstetrics and Gynecology, University of Pisa; 3 Fondazione G. Pascale, National Cancer Institute, Naples; 4 Department of Gynecology, San Matteo Hospital, Pavia; 5 Department of Oncology, Mariano Santo Hospital, Cosenza; 6 Department of Oncology, San Carlo Hospital, Potenza; 7 Department of Obstetrics and Gynecology, University of Bari, Bari; 8 Department of Oncology, San Vincenzo Hospital, Taormina, Italy
Received 30 October 2002; revised 24 March 2003; accepted 1 April 2003
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Abstract |
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A phase III multicenter randomized trial has been designed in order to address whether amifostine (WR-2721, Ethyol), an organic thiophosphate cytoprotector, can protect ovarian cancer patients from toxicity induced by carboplatinpaclitaxel chemotherapy.
Patients and methods:
Patients were randomly assigned to receive carboplatin [area under the curve (AUC) 5 mg·min/ml] and paclitaxel (175 mg/m2) with (arm A) or without (arm B) amifostine (910 mg/m2) every 21 days for six cycles.
Results:
One-hundred and eighty-seven patients were accrued: 93 patients in arm A and 94 patients in arm B. There was no difference in terms of erythrocytopenia between the two arms; grade 34 thrombocytopenia was higher in arm A (3.3% versus 0.6%; P = 0.0010). There was no significant reduction of grade 34 leukopenia in arm A (11.8% versus 13.8%). The incidence of grade 34 neutropenia was lower in arm A (31.3% versus 37.9%; P = 0.03), as was the incidence of severe mucositis (4.7% versus 15.4% in arm A versus arm B, respectively; P <0.0001). Finally, amifostine appears to be protective against neurotoxicity (grade 34 neurotoxicity 3.7% versus 7.2%; P = 0.02). With a median follow-up of 24 months (range 241), time to progression was similar between the two groups.
Conclusions:
We showed that amifostine can exert some protection from the cumulative toxicity associated with this regimen. The results need to be confirmed in other randomized trials with this combination.
Key words: amifostine, carboplatin, ovarian cancer, paclitaxel
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Introduction |
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This compound is activated at the tissue site by dephosphorylation through the membrane-bound alkaline phosphatase and, intracellularly, is able to bind and detoxify cytotoxic drugs as well as exert scavenging actions against oxygen-free radicals. The selective facilitated transportation of the metabolite into normal cells, where membrane phosphatase activity is higher with respect to tumor, represents the biochemical basis for the selectively higher cytoprotective activity of amifostine in normal versus neoplastic tissues [2].
Amifostine has the ability to act as a multilineage cytoprotective agent able to prevent not only hematological toxicities but also cumulative organ damage which can heavily impact, in time, on tolerance of multiple cycles or regimens. Moreover, the peculiar mechanism of action of amifostine, which acts through hematopoietic progenitor rescue [3], allows circumvention of the drawbacks inherent with the use of colony-stimulating factors which, in time, can result in the exhaustion of hematopoietic recovery potential [4]. More importantly, several preclinical and clinical studies demostrated that amifostine does not interfere with the antitumor effect of ionizing radiation, alkylating agents or cisplatin, suggesting a role of this compound in the prevention of toxicity associated with anticancer therapy [5, 6].
The majority of the current data consistently agree that amifostine can effectively prevent the hematological and organ toxicity induced by DNA-damaging agents and cisplatin [712].
On the other hand, it has been reported that amifostine is less active in protecting against in vitro cytotoxicity of some chemotherapeutic agents, such as vinka alkaloids [13], and can even potentiate the cytotoxicity of anthracyclines in in vitro models of hematopoietic precursors [3], thus emphasizing the need to investigate the cytoprotective activity of amifostine with respect to combinations of drugs with different mechanisms of action.
In this context, the toxicity deriving from the combination carboplatinpaclitaxel, the standard of care for first-line medical treatment of advanced ovarian cancer, is expected to benefit from the addition of amifostine, which has been reported to increase the median platelet nadir [14], accelerate the time to platelet recovery [15] and diminish hospitalization time in patients administered carboplatin in phase II trials. Moreover, evidence suggests that amifostine can also exert a role in protecting normal tissues from paclitaxel-related toxicity in vitro [16] and in phase I studies [17].
To our knowledge, no clinical data have been reported until now concerning the efficacy of amifostine as cytoprotectant against the toxicity induced by the combination carboplatinpaclitaxel. Therefore, a phase III multicenter randomized trial conducted in advanced ovarian cancer patients has been designed to address this issue.
The effects of amifostine addition on the antitumor efficacy of the chemotherapeutic regimen have also been investigated.
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Patients and methods |
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Inclusion criteria were: histologically proven FIGO stage IC G3, IIIIIIV epithelial ovarian cancer, World Health Organization (WHO) performance status 2, age
75 years and no prior chemotherapy or radiation therapy. Patients were required to have adequate bone marrow function defined as platelet count
100 000/µl, hemoglobin level
9 g/dl, white blood cell count (WBC) >3500/µl and an absolute neutrophil count (ANC)
1500 cells/µl. Adequate renal and liver functions were required, defined as creatinine
2.5 mg/dl or estimated creatinine clearance >50 ml/min, and as aspartate aminotransferase and alanine aminotransferase <1.5x the upper limit of normal, alkaline phosphatase <1.5x the upper limit of normal, unless caused by tumor, and bilirubin
1.5 mg/dl, respectively.
Exclusion criteria were: absence of any previous or concurrent malignancies at other sites with the exception of basal or squamous cell carcinoma of the skin and/or cone biopsed carcinoma in situ of the uterine cervix; absence of co-morbidities which in the clinicians judgement preclude the possibility to administer the combination and the doses of the drugs planned for the study.
Before study entry all patients were to provide a written informed consent and underwent complete history and physical examination. Pretreatment laboratory tests included complete blood cell count (CBC) and serum chemistries, including blood urea nitrogen, creatinine, creatinine clearance, total bilirubin, alkaline phosphatase, total protein, albumin, sodium, chloride and potassium. A urinalysis was performed and serum pregnancy test was to be obtained in case of potential childbearing.
Treatment plan
On day 1 of each cycle patients received paclitaxel 175 mg/m2 given as a 3-h i.v. infusion diluted in 5% dextrose 500 ml, followed by amifostine 910 mg/m2 (WR-2721, Ethyol; Schering-Plough International) given as a 15-min i.v. infusion diluted in saline solution 100 ml, administered within 30 min preceding carboplatin infusion [area under the curve (AUC) 5 mg·min/ml] given as a 1-h i.v. administration diluted in saline solution 1000 ml. Infusion could be given through a peripheral or a central line. Premedication with methylprednisolone (20 mg p.o. 14 and 7 h before paclitaxel infusion) and clorphenamine (10 mg i.v. 15 min before paclitaxel administration) was recommended. In arm A amifostine was reconstituted with normal saline 9.5 ml and a dose of 910 mg/m2 was administered as a 15-min i.v. infusion to patients in a supine position. Patients of both arms received i.v. hydration with 0.45% normal saline at a rate of 200 ml/h for 5 h before treatment. Antiemetic therapy was given with granisetron 3 mg i.v. 30 min before chemotherapy infusion. During amifostine infusion arterial blood pressure was monitored every 5 min and the infusion was interrupted if arterial systolic pressure (ASP) significantly decreased compared to basal values (hypotensive threshold is defined as a 20% decrease of systolic blood pressure).
Amifostine administration was restarted in the absence of symptoms if arterial pressure returned to normal values within 5 min from the interruption. If it was not possible to administer the entire dose, amifostine dose was reduced to 740 mg/m2 in the next cycles. Antihypertensive therapy was discontinued 24 h before and was withheld 24 h after amifostine administration.
Cycles were planned at 21-day intervals for a total of six cycles until dose-limiting toxicity or disease progression occurred. Toxicity of this regimen was evaluated according to National Cancer Institute common toxicity criteria (NCI-CTC, Version 2.0). After administration of chemotherapy weekly CBCs were obtained and before each cycle complete serum chemistry, physical examination, urinalysis and monitoring of any adverse event were performed. The use of granulocyte colony-stimulating factor (5 µg/kg subcutaneously daily) was allowed only in patients developing prolonged grade 4 neutropenia (ANC <500/µl for 3 days) or febrile neutropenia. Blood or platelet transfusions were recommended for hemoglobin value
8 g/dl and platelet count
20 000/µl.
Dose reductions of 20% for each drug were considered for leukocyte count <2500/µl and platelet count <50 000/µl on day 1 of the planned subsequent cycle. Neurological toxicity was evaluated by a clinical examination performed before each cycle or on adverse events reported by the patient. Interval debulking surgery was allowed in responding patients after the first three cycles of induction chemotherapy. Laparoscopic and/or laparotomic second look was allowed in patients with complete response after six cycles of chemotherapy.
Follow-up examination consists of general and gynecological examination, abdominopelvic ultrasonography and serum CA 125 assay performed every 3 months from the end of treatment.
To investigate whether amifostine addition might have any impact on patient survival, time to progression was analyzed according to treatment arm.
Collection of toxicity and follow-up data was performed by dedicated physicians and by data managers in each center. Periodic assessment of the adherence of each center to centralized guidelines was performed.
Statistical methods
The primary end point of the study was to evaluate the ability of amifostine to protect from grade 34 hematological toxicities. The expected incidence of grade 34 leukopeniathrombocytopenia in patients administered this chemotherapeutic regimen is 25%.
This study, planned to accrue 200 patients, was designed with 80% power ( = 0.05) to demonstrate a statistical reduction of 40% of the events in the amifostine-treated group. Statistical analysis was performed by Fishers exact test for proportion or chi-square statistic.
Time to progression was calculated from the date of diagnosis to the date of death/progression or date last seen. Medians and life tables were computed using the product limit estimated by the KaplanMeier method [18], and the log-rank test was employed to assess statistical significance [19]. All P values are two-sided. Statistical analysis was performed by specific staff of the Statistical Center of the Coordinator Center.
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Results |
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The overall rate of grade 34 leukopenia was 12.8% (95% CI 10.8% to 16.8%). There was no statistically significant reduction in the incidence of grade 34 leukopenia in the patient population randomized to receive chemotherapy plus amifostine [11.8% (95% CI 9.0% to 14.6%) versus 13.8% (95% CI 10.8% to 16.8%) in arm A versus arm B, respectively; not significant], whereas analysis of the last three cycles shows a trend in favor of amifostine protection [grade 34 leukopenia 13.9% (95% CI 9.6% to 18.2%) versus 20% (95% CI 7.8% to 32.2%) in arm A versus arm B, respectively; P = 0.09].
The cumulative incidence of grade 34 neutropenia was 34.4% (95% CI 31.5% to 37.3%) and a trend in favor of arm A is evident when considering the rate of grade 34 neutropenia in the first three cycles [25.4% (95% CI 20.2% to 30.6%) versus 33.4% (95% CI 27.8% to 39.0%) in arms A and B, respectively; P = 0.051], in the last three cycles [37.7% (95% CI 27.3% to 36.3%) versus 42.8% (95% CI 33.7% to 42.1%) in arms A and B, respectively; P = 0.028] and in all cycles in which the statistical significance has been reached (31.3% versus 37.9% in arms A and B, respectively; P = 0.03).
The higher percentage of blood transfusions performed in arm A patients [2.7% (95% CI 1.3% to 4.1%) versus 0.4% (95% CI 0.1% to 0.9%); P = 0.0018] is likely due to surgery-related complications (five vessel injuries, two subcutaneous blood infiltrations, one severe wound infection), rather than to chemotherapy-induced anemia. These surgical complications, together with a higher incidence of intercurrent urinary and respiratory infections occurring in amifostine-treated patients, supports a more frequent use of antibiotics in arm A versus arm B [4.7% (95% CI 2.9% to 6.5%) versus 1.7% (95% CI 0.6% to 2.8%), respectively; P = 0.005]. There were no platelet transfusions in either of the two arms.
Accordingly, there was no difference in terms of neutropenic fever (0.4% versus 0.8% in arms A and B, respectively; not significant), hospitalization days (0.8% versus 1.4% in arms A and B, respectively; not significant) and growth factor use (10.4% versus 9.3% in arms A and B, respectively; not significant) between the two groups. Finally, no difference in terms of treatment delays (7.1% versus 6.4% in arms A and B, respectively; not significant) or discontinuation rate (0.2% versus 0.4% in arms A and B, respectively; not significant) was observed between the two groups. The dose intensity of chemotherapy was the same in both arms; for carboplatin the dose intensity was 135 mg/m2/week and for paclitaxel the dose intensity was 58 mg/m2/week.
As shown in Table 3, the incidence of severe mucositis was significantly lower in arm A [4.7% (95% CI 2.9% to 6.5%) versus 15.4% (95% CI 12.3% to 18.5%) in arm A versus arm B, respectively; P <0.0001] and amifostine was shown to be protective against severe neurotoxicity [grade 34 neurotoxicity 3.7% (95% CI 2.1% to 5.3%) versus 7.2% (95% CI 5.0% to 9.4%) in arm A versus arm B, respectively; P = 0.02].
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Finally, no hypocalcemia was observed (data not shown).
Survival analysis
Follow-up data were available for 172 patients. As of September 2002, the median follow-up period was 24 months (range 241). During the follow-up period, progression of disease was observed in 47 (55.9%) and 43 (48.8%) patients in arms A and B, respectively. There was no significant difference in time to progression between the two groups (Figure 1).
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Discussion |
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The profile of amifostine protection from paclitaxelcarboplatin-induced toxicity seems to differ from that reported for alkylantscisplatin-based regimens, since in our series, hematological toxicity was not prevented by amifostine while a statistically significant improvement of neurotoxicity and mucositis was documented.
Kemp et al. [12] reported hematological protection in terms of a 62% reduction in neutropenia-associated events in the amifostine-treated arm in a series of 242 ovarian cancer patients treated with cisplatincyclophosphamide combination chemotherapy. The cytoprotective effect of amifostine became increasingly evident during the latter cycles of therapy, which demonstrates the ability of amifostine to reduce cumulative toxicity. Our study failed to demonstrate a similar benefit even if it is conceivable that the weak myeloprotective effect could be also related to the relatively low toxicity of this drug combination, as suggested by the observation that a trend in favor of myeloprotection was nevertheless detectable when considering the last three cycles in which the incidence of severe leukopenia is, as expected, higher because of cumulative toxicity. Therefore, it cannot be excluded that the myeloprotective action of amifostine could be detected by utilizing a higher dose of the same combination studied in this trial.
However, it cannot be ruled out that the specific pattern of toxicity of each chemotherapeutic agent or combination of drugs with different mechanisms of action could produce an unexpected effect on the profile of cytoprotection exerted by amifostine.
Amifostine has been reported in several studies to reduce the incidence and severity of thrombocytopenia induced by carboplatin alone [15, 20]. With the current regimen it failed to exert any protection at platelet level, and was shown to increase thrombocytopenia to a relatively low degree. Indeed, the combination of paclitaxel with carboplatin seems to be characterized by a lower incidence of thrombocytopenia than would be expected with carboplatin alone [21], possibly because of the antagonistic interaction between the two drugs at the level of the platelet precursor [22]. Therefore, it is conceivable that amifostine could interfere with the peculiar carboplatinpaclitaxel interaction at the platelet progenitor level, thus leading to a reduction of the platelet sparing effect of paclitaxel. Alternatively, pharmacokinetic considerations can also be taken into account: amifostine has been reported to increase paclitaxel clearance with the reduction of paclitaxel AUC [23], while prolonging the terminal half-life of carboplatin [24], thus leading to the hypothesis that co-administration of amifostine could in turn reduce the platelet protective effect of paclitaxel and increase the carboplatin effect at platelet level. No activity of amifostine at the level of hemoglobin value was observed in the present study, according to that previously reported by Betticher et al. [15], Poplin et al. [25] and transfusion requirements.
Non-hematological toxicity was not a study end point. Nevertheless, even with the limit linked to the small number of events, our results suggest that amifostine can protect from carboplatinpaclitaxel-induced neurotoxicity. Neurotoxicity related to paclitaxel administration represents the dose-limiting toxicity of this drug when neutropenia is prevented by colony-stimulating factors [26] and was shown to be prevented by amifostine in an earlier phase I trial that increased paclitaxel dose to 310 mg/m2 [23]. In the study by Gelmon et al. [27] amifostine failed to prevent the toxicity related to paclitaxel (250 mg/m2), although the small size of the sample series could represent a major limitation. Moreover, it did not provide information about the activity of amifostine with combinations of paclitaxel and platinum compounds. The mechanisms through which amifostine could interfere with specific paclitaxel-sustained microtubular disruption responsible for peripheral sensory neuropathy have not yet been clarified. However, given the multiplicity of microtubule-independent mechanisms of paclitaxel action, as recently reviewed by Taylor et al. [16], it is conceivable that amifostine can impact on paclitaxel neurotoxicity by targeting biochemical pathways other than microtubules. However, at present no conclusion can be drawn and more studies are required.
Finally, our study confirms the ability of amifostine to provide significant protection against mucositis, which is a frequent patient complaint for worsening quality of life.
An extensive database for amifostine demonstrated no reduction in the cytotoxicity of chemotherapeutic agents, including anthracyclines, taxanes, alkylating agents, vinca alkaloids and other compounds, in a number of human cancer cell lines [28]. Similarly, in vivo studies on human tumor xenografts of ovarian, lung and breast cancer have demonstrated no reduction or even increased antitumor efficacy, while normal organs showed decreased toxicity [29]. As shown by the studies of Kemp et al. [12] and Poplin et al. [25], our study failed to show any protective effect of amifostine upon tumor cells; in contrast to the cytoprotection of normal organs, the co-administration of amifostine did not protect cancer cells against the antineoplastic effect of the carboplatinpaclitaxel regimen. Time to progression curves, with a median follow-up duration of 24 months, were comparable between the two groups.
Amifostine at the recommended dose and schedule was shown to be generally well tolerated: severe nausea and vomiting occurred in 22.2% of cycles, similar to the control arm, and did not show an increase in either frequency or severity with repeated cycles of treatment. Moreover, hypotension was observed in only 26.2% of cycles and never required discontinuation of treatment. In this context, the recent finding that administration of amifostine at lower dose levels [30] or subcutaneously [31] can further improve its safety profile without lessening its cytoprotective effects is of clinical relevance.
This study was not conceived as a double-blind study. Usually the physicians assessing toxicity, especially non-hematological toxicity, were not the same physicians who were in charge of administering the treatment, so they could not be influenced by the evaluation of symptoms such as alopecia, neurotoxicity, diarrhea, nausea and vomiting.
This issue is noteworthy in the light of economic concerns about the introduction of amifostine in clinical practice. Indeed, a recent costbenefit analysis [32] of amifostine as cytoprotectant in a phase III trial with cisplatincyclophosphamide in advanced ovarian cancer [12] showed that the cost/efficacy ratio of the drug was within commonly accepted limits and consequently confirmed a reasonable advantage by using amifostine. Moreover, it has to be taken into account that amifostine-sustained preservation of hemopoietic potential and organ functionality could occur and be clinically valuable later in the natural history of disease, when recurrence takes place. Finally, it has to be taken into account that costbenefit analysis would probably underestimate the social and individual impact on patients quality of life deriving from specific toxicities such as mucositis and neurotoxicity.
Therefore, an evaluation of the effectiveness of amifostine in the prevention of chemotherapy toxicity as well as a faithful cost-effectiveness analysis should be extended to include second-line treatment.
At present, while American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants [33] recommend the use of amifostine for the reduction of cisplatin-related nephrotoxicity and alkylating agents-related neutropenia, data are insufficient to recommend amifostine for protection of cisplatin-related thrombocytopenia, neurotoxicity and ototoxicity and for the prevention of paclitaxel-related neurotoxicity. Therefore, efforts to clarify whether the profile of amifostine cytoprotection could be more complex in relation to the specific chemotherapeutic agent or the pharmacodynamicpharmacokinetic interactions among drugs used in combination seem to be worthwhile.
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Acknowledgements |
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Footnotes |
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