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Clinical Trials |
1 Hôpital Saint Louis, Paris, France; 2 Institut Gustave Roussy, Villejuif, France; 3 CAC, Le Kremlin-Bicetre, France; 4 Hôpital des Quinze-Vingt, Paris, France; 5 Centre René Huguenin, Saint Cloud, France; 6 Hôpital Cochin, Paris, France; 7 Cliniques Universitaire Saint Luc, Brussels, Belgium; 8 Elman Retina Group, Baltimore, Maryland; 9 Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio; and 10 MGI PHARMA, Inc., Bloomington, Minnesota
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Clinical data from 277 patients entered in single-agent Phase I to II clinical trials who received irofulven on days 1 and 15 every 4 weeks; days 1, 8, and 15 every 4 weeks; or days 1 and 8 every 3 weeks were included in this multiparameter analysis.
Results: Overall, 74 patients (27%) experienced visual symptoms. The most frequently reported symptoms were flashing lights (12% of patients), blurred vision (9%), and photosensitivity (8%). Grade 3 toxicity was observed in 12 patients (4%). The incidence and severity of visual events were dose dependent, with no grade 3 visual events occurring at doses 
0.50 mg/kg and grade 1 to 2 events in only 12% and 8% of patients, at doses of 0.50 mg/kg and 20 mg/m2, respectively. Grade 1 to 2 toxicity was reversible in most patients. Abnormal electroretinogram and abnormal visual fields were noted after irofulven treatment in 24 of 39 patients (62%) and 15 of 26 patients (58%), respectively. All but 1 patient who had electroretinogram assessment received doses >0.50 mg/kg. Clinical examination and visual field assessment were found to be better correlated with symptoms and appear to be more appropriate for surveillance of irofulven retinal symptoms than electroretinograms.
Conclusions: On the basis of retained antitumor activity and reversibility of grade 1 and 2 visual symptoms at lower doses, it appears that an irofulven dose of 0.50 mg/kg or 20 mg/m2, not to exceed 50 mg in a single dose, given as a 30-minute infusion on days 1 and 8 every 3 weeks or days 1 and 15 every 4 weeks minimizes the frequency and severity of visual symptoms.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the initial single-agent Phase I trial, reported by Eckhardt et al. (7) , irofulven was given as a 5-minute daily i.v. infusion for 5 consecutive days every 4 weeks. Delayed thrombocytopenia, reversible renal tubular acidosis, and refractory vomiting were dose-limiting toxicities. At the recommended dose of 11 mg/m2/day, subsequent Phase II studies showed no renal toxicity but consistent evidence of nausea and vomiting associated with anorexia and asthenia and/or delayed thrombocytopenia, leading to frequent dose reduction or treatment discontinuation. Although confirmed objective responses were observed in several tumor types, the tolerance of this regimen raised questions about its feasibility for additional exploration and for combination therapy. The toxicity profile suggested that exposure times <5 days might allow better tolerance of irofulven. Additionally, weekly or biweekly treatment schedule may facilitate the development of combination regimens with irofulven.
Because preclinical data showed no schedule dependency, alternative schedules based on 1-day administration of irofulven repeated weekly or every other week were investigated in an attempt to maximize administered dose intensity and efficacy while minimizing toxicity. In the Phase I study reported by Alexandre et al. (8) , treatment delays for thrombocytopenia were considered to occur too frequently under a schedule of days 1, 8, and 15 every 4 weeks to permit additional exploration, whereas schedules of days 1 and 8 every 3 weeks and days 1 and 15 every 4 weeks were associated with only mild nausea and vomiting. None of the patients withdrew consent or were dose-reduced for acute or delayed emesis. Although grade 1 to 2 thrombocytopenia was reported, it was infrequently associated with dose reduction or treatment delay at the recommended dose. However, in that study, visual symptoms occurred during the dose escalation, having been reported only sporadically during the clinical experience with the daily times 5 administration schedule. Predominant visual symptoms consisted of blurred vision, flashing lights, and color vision abnormalities. No cases of decreased visual acuity occurred. Although mild and generally reversible, these symptoms decreased patient quality of life in some cases and prevented additional dose-escalation of irofulven in this trial.
Previous experience with other agents inducing serious major organ toxicity has shown that an adequate characterization of the event, its pharmacodynamics, and proper dosing guidelines has allowed additional development as useful and manageable anticancer agents. Visual disturbance being a treatment-limiting event with higher doses of irofulven, we attempted to identify patient and treatment characteristics associated with the risk of toxicity to provide guidance in the dosing of irofulven and advice in proactive monitoring of patients exhibiting symptoms or at a risk for developing visual events.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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18 years, Eastern Cooperative Oncology Group (ECOG) performance status 2, life expectancy >3 months, all previous anticancer treatment discontinued at least 4 weeks before first dose of study drug (6 weeks for mitomycin C), adequate bone marrow function (absolute neutrophil count 1.5 x 103/mm3, platelets 100 x 103/mm3, hemoglobin 9 g/dL), hepatic function [bilirubin within normal range of institutional value, aspartate transaminases (AST) or alanine transaminases (ALT) 2.5 times the upper limit of normal], renal function (creatinine clearance, calculated after Cockroft and Gault, 60 mL/min), corrected serum calcium <2.7 mmol/L, and signed informed consent. Patients meeting any of the following criteria were prohibited from participating in these studies: past radiation therapy to >30% to 40% of total bone marrow; prior chemotherapy with nitrosoureas, high-dose carboplatin, or prior mitomycin C cumulative dose 25 mg/m2; prior bone marrow transplant or intensive chemotherapy with stem cell support; presence of any serious concomitant systemic disorders deemed incompatible with the study by the investigator; presence of any significant central nervous system or psychiatric disorder(s) that could impair patient compliance; history of another malignancy; treatment with any other investigational agent or participation in another clinical trial within 30 days before study entry; and child-bearing or lactating patients. All of the trial protocols were authorized by applicable national or local ethics committees.
Treatment Schedules.
Irofulven was administered through a central venous access line as a 5-minute infusion (Phase I trial) or 30-minute infusion (Phase I and II trials). The Phase I trial tested three administration schedules: days 1, 8, and 15 every 4 weeks (21 patients); days 1 and 8 every 3 weeks (33 patients); days 1 and 15 every 4 weeks (45 patients); and a total of nine dose levels ranging from 13 to 28 mg/m2 (Table 1)
. Four Phase II trials used a schedule of days 1 and 15 every 4 weeks, initiated using a dose per infusion of 24 mg/m2/day (84 patients total) and, after an analysis of visual events in the then ongoing Phase I trial (12)
, a dose per infusion of 0.55 mg/kg, limited to 50 mg per infusion (94 patients).
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90 x 103/mm3 or 75 x 103/mm3, depending on the patient population, and an absolute neutrophil count 1.0 x 103/mm3. Patients were allowed to continue treatment in the absence of disease progression, unacceptable toxicity, or delay >1 week of day 8 or 15 or delay >2 weeks of day 1.
Study Assessments.
Before inclusion and before each 3- or 4-week treatment cycle, evaluations of ECOG performance status, physical examinations, and assessment of concomitant medications were performed. Laboratory studies, including a complete blood count, differential, standard blood chemistry assessments, and standard urinalysis were assessed throughout the study. Severity of visual toxicity was determined according to National Cancer Institute Common Toxicity Criteria, version 2.0, taking the highest grade of investigator-determined treatment-related visual event reported during treatment or at follow-up. Electroretinogram assessments and visual field tests were undertaken in 39 patients from the various studies, using a variety of methods according to the standard practice in the ophthalmological reference centers.
Statistical Analysis.
Patients were included in the analysis of predictive factors for visual toxicity if they received any irofulven treatment. Factors that were investigated included demographic characteristics (age, sex, height, weight, body surface area, body mass index, and performance status), pretreatment characteristics (prior hormone therapy, radiotherapy, number of lines of prior chemotherapy, and chemotherapeutic agents received), baseline biological and clinical abnormalities, and treatment characteristics (schedule, infusion duration, dose level, dose in first infusion in mg, mg/m2 of body surface area, and mg/kg of body weight).
Categorical variables were compared using the 
2 or Fisher exact test, as appropriate. The correlation between continuous variables was determined using Spearman’s 
. Correlation of binomial factors with continuous variables was determined using the Mann-Whitney U test (Wilcoxon) and multinomial factors via the Kruskal-Wallis test. A logistic regression model was generated to identify independent prognostic factors, which included all of the potential factors associated with the occurrence of visual toxicity at the P < 0.20 level (13)
. Lactate dehydrogenase was not included in the logistic regression due to the high rate of missing data. Time-to-event data are summarized using the Kaplan-Meier method (14)
. All of the reported significance levels are two-sided. P < 0.05 was considered to represent a significant correlation, and no adjustment for multiple comparisons was made.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; ref. 10
). A total of 74 patients (27%) presented a variety of visual symptoms, including 12 patients (4%) with grade 3 events. The most frequently reported symptoms were flashing lights (12% of patients), blurred vision (9%), photosensitivity (8%), and darkening vision (5%; Table 3
). Six patients (2%) experienced decreased visual acuity, including 1 patient (0.4%) with a grade 3 event. A description of individual symptoms according to typical onset are as follows: (1)
flashing lights and blurred vision occurred as early as the first treatment day with a median of 16 days from treatment initiation, and (2)
darkening vision, color disturbance, and photosensitivity occurred after a median of 28 to 31 days from treatment initiation. Grade 1 visual symptoms first appeared after a median of 15 days from treatment initiation; grade 2 symptoms appeared after a median of 34 days; and grade 3 symptoms appeared after a median of 28 days. Duration of symptoms was strongly related to grade of symptoms; the median duration of symptoms, according to the Kaplan-Meier method, was 19 days for grade 2 symptoms and 138 days for grade 3 symptoms. No relationship was found between the occurrence of visual events and cumulative dose (mg/kg or mg/m2), time to onset, or number of infusions received. Fifty-eight of the 74 patients with visual symptoms continued to receive irofulven treatment after onset of symptoms, for a median of 3 infusions per patient after the first onset. Of these, 10 patients (17%) subsequently experienced a worsening of toxicity by 1 grade, and 1 patient (2%) experienced worsening by 2 grades. Forty-five patients (61%) experienced complete resolution of all of the visual symptoms, and 9 additional patients (12%) experienced resolution of some but not all of the symptoms. When divided by grade, all of the symptoms resolved in 77% of patients having a maximum of grade 1 symptoms, in 59% of patients having grade 2, symptoms and in 25% of patients having grade 3 symptoms.
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. Higher initial dose per infusion was strongly correlated with the occurrence of visual symptoms and their severity. This relationship held for total dose (mg), for dose per square meter of body surface area (mg/m2), and per kilogram of body weight (mg/kg). Dose intensity did not appear to influence the incidence of toxicity.
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Factors indicative of good patient condition were also associated with a higher rate of grade 1 to 3 toxicity, with 38% of patients with ECOG performance status 0 reporting symptoms compared with 20% of patients entering trials with performance status 1 or 2. Asthenia, abnormal lactate dehydrogenase, and abnormal AST at baseline were less frequent in patients with toxicity. Finally, patients with higher body mass index reported visual symptoms more often. Prior therapy characteristics, including type of prior chemotherapy, were not found to influence visual toxicity. None of the factors investigated were discriminative with respect to which patients would experience grade 3 rather than grade 1 or 2 symptoms.
Dose administered in the first infusion, good performance status, baseline visual disorders, and normal AST at baseline were retained in a multifactor analysis as significantly correlated independent prognostic factors for the occurrence of visual toxicity (Table 5)
. Dose per infusion was retained irrespective of the manner of calculation (mg, mg/kg, or mg/m2). Sixty-four percent of patients with visual events had performance status 0 and/or a history of visual disorders; 53% of patients with both factors experienced visual events.
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. Scotopic electroretinographic results were also modified, with no response observed in red light and reduced waves in both blue and white light. This evidence suggests an alteration at the level of the cone photoreceptors. Fifteen of 26 patients (58%) had abnormal visual field tests, consisting of paracentral scotomata; 13 of these patients (87%) reported visual symptoms. Unfortunately, it is not possible to evaluate the relation between abnormal visual examination and dose administered, because all but 1 patient who had electroretinogram assessment received doses >0.50 mg/kg. Sensitivity and specificity of electroretinogram to predict visual symptoms were 0.84 and 0.79, respectively, and 0.87 and 0.82 for visual fields, respectively. Importantly, however, electrophysiological alterations appeared rapidly after the first or second treatment infusion and, interestingly, were not correlated with either the severity or the reversibility of symptoms. For the 26 patients who underwent both examinations, visual field assessment had a higher sensitivity than electroretinogram assessment (0.87 and 0.80, respectively) and equivalent specificity (0.82). Therefore, visual field examination represents a reliable objective method of follow up of patients treated with irofulven. Electrophysiological examination is not recommended for systematic follow up, because this method implies good patient condition, greater inconvenience, and higher risk of complications, without any notable advantage.
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0.50 mg/kg and only 1 grade 3 event (2%) for doses 20 mg/m2 (Fig. 2
and Fig. 3
). A 12% rate of grade 1 to 2 events was observed at doses 0.50 mg/kg and an 8% rate at doses 20 mg/m2. By comparison, 12 patients experienced grade 3 events (5%) at doses >0.50 mg/kg and >20 mg/m2. Rates of 24% and 27% of grade 1 to 2 visual events were observed at doses >0.50 mg/kg and >20 mg/m2, respectively. It appears that a single-agent dose of irofulven of 0.50 mg/kg/infusion or 20 mg/m2/infusion, not to exceed 50 mg in a single infusion, minimizes the frequency and severity of visual events.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Irofulven-associated visual toxicity is a dysfunction of the cone-mediated system of the retina, with flashing lights, blurred vision, photosensitivity, and darkening vision as the most distinctive features. In the Phase I trial of weekly dosing schedules, mild to moderate visual symptoms were considered dose limiting and prevented escalation above 28 mg/m2 per infusion. In the original Phase I trial using a daily times five schedule, only sporadic cases of visual symptoms were reported and were attributed to concomitant analgesics or the general condition of the patient. The adverse event profile of irofulven appears to be schedule-dependent, with visual symptoms being observed using weekly or biweekly infusions and nausea/vomiting/asthenia and/or thrombocytopenia being dose-limiting with the daily times five schedule. In this analysis, we found that the overall rate of irofulven visual toxicity was 27%, with the rate of grade 3 events at 4%. The incidence and severity, as well as the recovery from visual events were strongly dose dependent. Most of the patients reporting visual symptoms had previous ophthalmological disorders and/or good baseline performance status. The impact of the subjective nature of visual symptoms may possibly be reflected in the fact that patients in good condition appeared to experience more toxicity, being in a better position to perceive it and more liable to feel its effects on their daily life. Patients with poor performance status frequently have disease-related symptoms and concomitant medications, such as analgesics, that can mask the perception and reporting of visual symptoms. Likewise, it is probable that abnormal baseline AST was associated with less frequent visual symptoms due to poorer condition of these patients, despite the absence of a correlation between performance status and AST.
In this evaluation, most instances of mild to moderate symptoms with sufficient follow-up were reversible within a few weeks to months of treatment discontinuation. Furthermore, increase in severity was infrequent with repeated infusions. However, given the potential impact of this toxicity on quality of life, the occurrence of grade 2 as well as grade 3 visual events requires reconsideration of the individual patient risk-to-benefit equation and may necessitate treatment discontinuation. Conversely, good adherence to treatment guidelines and careful surveillance should allow maintenance of irofulven therapy despite the presence of grade 1 to 2 visual disturbance.
Among commonly used anticancer agents, retinal toxicity has been reported with high-dose tamoxifen and very high-dose cisplatin (15, 16, 17)
. For these drugs, dose was the most important determinant of toxicity, with almost no reported toxicity at current recommended doses. Likewise, in our analysis, the exposure to irofulven as measured by dose per infusion was strongly correlated with incidence and severity of symptoms and was found to be an independent prognostic factor. Irofulven is a highly lipophilic drug with a very short plasma half-life (
5 minutes) and a large volume of distribution (19 to 50 L/m2). One may infer that the eye, as an organ that varies little in size for people of differing body volume or area, receives an exposure to irofulven that is essentially proportional to the dose infused, irrespective of body size. In patients receiving a 30-minute irofulven infusion (which allowed more accurate pharmacokinetic sampling of this very short half-life drug), a significant correlation was observed between the occurrence of visual events and area under the plasma concentration-time curve to infinity (12)
. Patients with an area under the plasma concentration-time curve to infinity above 60 ng/mL.h treated with >0.55 mg/kg/infusion of irofulven had a significantly increased rate of visual toxicity. As reported for a number of alkylating agents, dose administered according to body surface area is not always correlated with pharmacokinetics/pharmacodynamics of cytotoxicity (18
, 19)
. Modeling of irofulven pharmacokinetics showed that dosing according to body surface area and total body weight gave similar results (20)
. In this analysis, grade 3 visual toxicity occurred at doses >0.50 mg/kg and, in all but 1 case, >20 mg/m2 irofulven. It appears that the safety of irofulven may be optimized with a dose per infusion of 0.50 mg/kg or 20 mg/m2. At these doses, treatment should be associated with only a moderate rate of generally reversible grade 1 or 2 symptoms.
Various methods have been used to evaluate irofulven visual abnormalities during the Phase I/II program, including clinical examination, electroretinography, and visual field assessment. In our analysis, we showed that electroretinography, although very sensitive, does not provide the proper support for quantification and follow-up. In fact, alterations of the electroretinogram were observed in patients who do not report any symptoms of visual toxicity. Moreover, the severity of electroretinographic modifications was not correlated with the clinical grade of toxicity. Given that visual field measurements correlate better with symptoms than electroretinograms, without the inconvenience, discomfort, and necessity of focused patient cooperation, clinical examination and visual field measurements appear to be more suitable methods for monitoring irofulven-related visual events.
In summary, during Phase I and II trials, irofulven induced a dysfunction of the cone-mediated system of the retina that is reversible for mild to moderate events. Pre-existing visual disorders may complicate the risk to benefit assessment when considering irofulven therapy. On the basis of our multiparameter analysis of visual toxicity, it appears that an irofulven dose of 0.50 mg/kg or 20 mg/m2, not to exceed 50 mg per infusion, given days 1 and 15 every 4 weeks or given days 1 and 8 every 3 weeks minimizes the frequency and severity of visual symptoms. In this dose range, the estimated rate of grade 1 to 2 visual events was 10%, with no patient requiring treatment discontinuation for visual events. Antitumor activity of irofulven has been retained within this dose range as documented in recent Phase I combination studies with capecitabine or cisplatin (21
, 22)
. Additionally, considering that irofulven is likely to be used in combination regimens with other anticancer agents at doses 0.50 mg/kg, visual toxicity is unlikely to be a limiting factor for additional development of irofulven combination therapy.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: E. Raymond and C. Kahatt participated equally in this work and shall be regarded as joint first authors.
Requests for reprints: Eric Raymond, Chef de Service, Service Inter-Hospitalier de Cancérologie Beaujon-Bichat, Hôpital Beaujon, 100, Boulevard du Général Leclerc, 92118 Clichy Cedex, France. Phone: 33-1-4087 5614; Fax: 33-1-4087 5487; E-mail: sec.raymond{at}bjn.ap-hop-paris.fr
Received 5/ 3/04; revised 6/23/04; accepted 6/25/04.
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REFERENCES |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  S Faivre and E Raymond Management of neuromuscular dose limiting toxicity at the early stage of drug development. Ann. Onc., September 1, 2006; 17(9): 1343 - 1346. [Full Text] [PDF]
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, grade 1;
, grade 2;
, grade 3.