Safety of pegylated interferon-alpha-2a in adjuvant therapy of intermediate and high-risk melanomas

ARTICLE

Auteur(s) : Carmen Loquai¹, Dorothee Nashan², Peter Hensen³, Thomas A Luger³, Stephan Grabbe¹, Cord Sunderkötter³, Meinhard Schiller³

¹Department of Dermatology, University of Mainz, Mainz, Germany
²Department of Dermatology, University of Freiburg, Freiburg, Germany
³Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, 48149 Münster, Germany

accepté le 27 Août 2007

Among the numerous therapeutic modalities investigated so far, recombinant IFN-α is the only single drug that has a reproducible and significant adjuvant effect in adjuvant therapy of high-risk melanoma. In 1996, Kirkwood et al. demonstrated that high-dose IFN-α-2b significantly prolongs not only disease-free survival (DFS), but also limited overall survival rates in patients with lymph node metastasis or with melanomas thicker than 4.0 mm [1, 2]. Since then, several meta-analyses of pooled results of 3 randomized trials conducted by the Eastern Cooperative Oncology Group clearly confirmed reductions in the recurrence of high-risk melanoma, though they failed to prove a reproducible and significant survival benefit [3, 4]. Adjuvant therapy with low-dose IFN-α for resected primary melanoma thicker than 1.5 mm without clinically detectable lymph node metastases, demonstrated a significant benefit in terms of disease-free survival, though they did not reveal a significant increase in overall survival [5, 6]. Therapy with IFN-α is associated with considerable side effects, such as a flu-like syndrome, fatigue, myelosuppression and hepatotoxicity. Other clinically relevant side effects – such as depression, anxiety, agitation and anorexia – occur less frequently, but are still of major relevance as they lead to substantial dose reduction and even discontinuation of therapy [5-10].

Fluck and colleagues have shown in their retrospective analysis on patients treated with high dose IFN-α in their single institution, that the absolute dosage of IFN-α tolerated by patients was a transient, independent predictor of relapse-free and overall survival [11]. Although this result needs further evaluation by prospective randomized studies it further justifies efforts to optimize dosage schemes and duration of therapy with IFN-α in order to further improve disease free survival or to attain a significant increase in overall survival. With standard IFN-α-2a, a highly variable drug concentration is present throughout the dosing interval due to the high systemic clearance and a serum half-life of less than 3 hours [12]. One might speculate that these pharmacokinetic properties are responsible for reduced efficacy and increased side effects. By contrast, a new pegylated formulation of IFN-α, i.e. PEG-IFN-α-2a, presents a more sustained high blood level due to its prolonged absorption half-life (50 h), restricted volume of distribution (8-12 l), and decreased clearance (94 ml h^–1) [13, 14]. These qualities were associated with a significantly higher efficacy of PEG-IFN-α-2a in combination with ribavirin in the treatment of chronic hepatitis C when compared to standard IFN-α/ribavirin therapy [15, 16]. These significantly superior, sustained, virological response rates have made the combination of ribavirin with both of the commercially available PEG-IFN-α formulations the current standard of care in hepatitis C [15-17]. In these studies the tolerability of standard IFN-α and PEG-IFN-α were similar [12].

In melanoma, the adjuvant antitumoural rather than the antiviral effects of IFN-α come into play. In light of the importance that cumulative or sustained IFN-α dosages have on the antitumour efficacy, dose limiting side effects may become a major factor for the clinical outcome. In this context the advantages of the pharmacokinetics of PEG-IFN-α have not been explored yet for melanoma patients. One should assume, however, that a reduction of side effects allows a more constant administration of the intended target dose and thus secures the antineoplastic efficacy for a high number of patients. As such, there has been initial evidence that pegylated IFN-α was very well tolerated in therapy of renal cell cancer [18, 19] and neuroendocrine gastroenteropancreatic carcinomas [20], with no decrease in efficacy.

Therefore, the aim of this retrospective study was to evaluate if PEG-IFN-α-2a would have a more favourable safety profile with less side effects in adjuvant treatment of high-risk melanoma patients than is usually experienced with high doses of standard IFN-α or also with low doses of standard IFN.

Materials and methods

Patients

Treatment schedule

Statistical analyses

Results

Definition of study population

^bNo known primary.

Side effects

Mild gastrointestinal symptoms (Grade I) were reported in 33% (n = 6) of patients. Two patients (11%) experienced weight loss (Grade I/II), which in 1 patient was associated with tumour progression. Fourteen patients (78%) experienced a mild to moderate degree of neutropenia (Grade I/II). Two cases of erysipelas requiring intravenous antibiotics and hospitalization were rather due to lymphedema subsequent to lymph node dissection (LAD) than to PEG-IFN. Both patients had undergone LAD prior to start of treatment. Anemia (56%) and thrombocytopenia (72%) occurred with a lower frequency and were not severe (Grade I/II) except for 1 patient, who developed Grade III thrombocytopenia. In this case a dose reduction by 25% was performed. Hepatotoxicity, i.e. increases in AST/ALT, GGT and alkaline phosphatase, occurred in 72%, 72%, and 17% of the patients, respectively. Only 3 patients experienced Grade III hepatotoxicity.

Depression and anxiety as psychiatric side effects occurred in 33% and 6% of patients, respectively. Two of them required anti-depressant medication for Grade III symptoms and they discontinued the treatment course (tables 1 and 4).

Further side effects which occurred in mild to moderate degrees (Grade I/II) were: dizziness (33%), arthralgia (22%), increased sweating (28%), hair loss (17%), chills (11%), rash (11%), local skin reaction (11%), erectile dysfunction (11%), dyspnea (6%) and blurred vision (6%) (table 2).

Mild (Grade I) sicca-symptoms occurred in 7 patients (39%): in 1 patient it was associated with dysgeusia. Taste alteration (Grade I/II) was reported by 2 patients during treatment. Four patients developed thyroid dysfunction with clinically apparent hyperthyroidism accompanied by the induction of thyroidal antibodies (anti-thyreoglobulin-antibodies (anti-TG-AB (n = 4)), anti-TSH-receptor-AB (n = 4), anti-thyroidperoxidase (TPO)-AB (n = 3)). During the course of therapy, 3 of them were complicated by clinically apparent hypothyroidism, requiring thyroid hormone supplementation. One patient turned positive for anti-TG-AB and anti-TPO-AB without any thyroid dysfunction.

Three patients were positive for ANAs before therapy. Five patients became ANA-positive under PEG-IFN-α2a therapy. However, only 1 of them developed an autoimmune thyroiditis as mentioned above. Another patient showed an erythematous rash with slight scaling located on the face and décolleté. No further clinical symptoms occurred and the exanthema faded after cessation of therapy.
Table 2 Adverse events in patients treated with Peg-IFN-α-2a

^bSevere (grade III) infections defined as infections requiring intravenous antibiotics or hospitalization.

^cHyper- and Hypothyroidism (more details are given in the results section).

^dNeuropsychiatric symtoms include anxiety and agitation.

Table 4 Dose modification and discontinuation of therapy

^bReasons for dose modification: hematotoxicity grade II (n = 1) and III (n = 1), hepatotoxicity grade II (n = 2) and III (n = 1).

IFN-α-2a therapy: analysis of dose delivered

Dose modification and discontinuation of therapy

Comparison of the most common adverse events between PEG-IFN-α-2a and standard IFN

On the other hand, fatigue and depression were seen less frequently in PEG-IFN-α-2a treated patients compared to a low-dose IFN-α treated group, but did not reach statistic significance (Fisher’s exact test; P = 0.063, and P = 0.091, respectively).

PEG-IFN-α-2a versus high dose standard IFN: PEG-IFN-α-2a treated patients collectively experienced less frequently, fatigue (P < 0.001), neutropenia (P < 0.068) and neuropsychiatric (statistically not significant) adverse events compared to patients treated with high-dose IFN-α as reported by Kirkwood and colleagues [8], the only exception was a statistically insignificant, slightly higher occurrence of hepatotoxicity after PEG-IFN-α-2a.
Table 5 Comparison of the most common adverse events in different adjuvant IFN-α treatment schemes

^bHigh-dose toxicity profile data taken from Kirkwood et al., 2002 [8]. When ranges were reported, the midpoint was used for statistical comparisons c Data not available.

Discussion

When PEG-IFN-α-2a (180 μg) was compared to high dose schemes with standard IFN-α, its side effect profile became markedly more favourable [8]. While it revealed no grade III and IV toxicities with regard to neutropenia, anemia, fatigue, the high dose IFN-α was reported to result in 26-60% of patients grade III and IV toxicities with regard to neutropenia and in 21-24% with regard to fatigue. Liver toxicity did not show significant differences between the two IFNs and neither did depression.

In a recent Phase II dose escalation trial with weekly PEG-IFN-α-2a monotherapy in metastatic melanoma (i.e. stage IV), an overall tumour/tumour response rate was shown in a range similar to the results that can be obtained by monochemotherapy, using the standard drug dacarbazine, at the end of the 24-week study period in the 3 dosage-defined treatment cohorts (180 μg, 360 μg, 450 μg) [24]. However, similarly to natural IFN-α [3], a significant dose related response of PEG-IFN-α-2a monotherapy in metastatic melanoma could not be demonstrated [24].

With regard to efficacy in other tumours, PEG-IFN-α-2a (180 μg/wk) was similarly as effective as standard IFN-α-2a in renal cell cancer [18, 19] and neuroendocrine gastroenteropancreatic carcinomas [20] while PEG-IFN-α-2a (450 μg/wk) resulted in higher response rates than standard IFN-α-2a (9 MU/day) in therapy of chronic myelogenous leukemia [25].

The incidence and severity of many side effects have clearly been related to the dosage, and some adverse events occur more frequently and are more severe with a longer duration of IFN-α therapy [26]. The 1-year course with high-dose IFN-α is associated with significant adverse events. According to Kirkwood et al., the majority of adult patients who underwent treatment with high-dose IFN-α experienced toxicities, resulting in interruption, delay or dose reduction of IFN-α in about 50% of patients [1]. Based on data from ECOG trials, Grade III or IV toxicities secondary to fatigue, fever, myalgia, nausea, vomiting, myelosuppression, increased transaminases, and neuropsychiatric symptoms frequently occur [8].

Interestingly, hepatotoxicity was experienced more frequently in patients receiving PEG-IFN-α-2a than high-dose IFN-α (of note, statistically not significant). The mechanisms responsible for adverse effects on the liver, resulting in increased circulating levels of hepatic enzymes, are poorly understood. Most likely, the relative risk of experiencing toxicity increases proportionally with the degree of inhibition of hepatic CYP450 isoenzyme [27, 28]. Given that more than 90% of drug metabolism in humans is dependent on hepatic CYP450 isoenzymes, the effects of IFN-α on these enzymes have important clinical implications with regard to potential drug interactions [28]. There are no data yet available regarding the impact of PEG-IFN-α-2a on the CYP450 isoenzyme systems, but sustained presence of PEG-IFN-α may well lead to a more sustained inhibition of CYP450 isoenzymes.

Regardless of the side effects studied, the percentage of adverse events reported as severe (Grade III/IV) was lower with PEG-IFN-α-2a. As the pharmacokinetic properties of low-dose IFN-α differ substantially from those of PEG-IFN-α-2a, it is not surprising that the proportion of patients suffering from myelosuppression (i.e. neutropenia, anemia, and thrombocytopenia), and liver toxicity (any Grade) was significantly higher among those receiving PEG-IFN-α-2a than those undergoing low-dose IFN-α treatment. Interestingly, fatigue and depression was seen less frequently in PEG-IFN-α-2a treated patients than in the low-dose IFN-α treated group. However the comparisons with published low-dose and high-dose IFN-α controls must be interpreted with caution, as our retrospective patient population was very limited. Indeed, a recent study showed that if a lowered availability of tryptophan and a consequent decrease of serotonergic neurotransmission may be the mechanism underlying the neuropsychiatric side effects of treatment with IFN-α, patients on PEG-IFN-α are most likely to have the same risk of developing neuropsychiatric side effects as patients on standard IFN-α [7].

Most data on PEG-IFN-α-2a (180 μg/wk) were obtained from patients treated for chronic hepatitis C. Here the side effect profile is the same as that of standard IFN-α (3 MU 3 times/wk, plus Ribavarin (1000-1200 mg/d) for 48 wk) with some difference in frequencies between different dosages and formulations. Hematological abnormalities (especially neutropenia) occur more frequently in chronic hepatitis C patients treated with PEG-IFN-α (PEG-IFN-α-2b or PEG-IFN-α-2a) than with standard IFN-α [29].

In our study there were only 2 patients with dose reduction because of hematological toxicity (i.e. Grade III thrombocytopenia; the other patients had only mild to moderate myelosupression). The difference between occurrence of neutropenia in chronic hepatitis C patients and our patients treated with PEG-IFN-α-2a may be due to the different patient populations, with pre-existent hematological abnormalities in chronic hepatitis C patients compared to melanoma patients.

A considerable number of melanoma patients in our retrospective trial developed ANAs under treatment with PEG-IFN-α-2a (27.7%); four patients (22.2%) developed an autoimmune thyroiditis during therapy. Elicitation of autoantibodies has been described in patients under IFN-α therapy [30, 31] and the induction of many autoimmune diseases has been reported in connection with the use of this cytokine – mainly thyroiditis [32] and connective tissue disorders such as systemic lupus erythematous (SLE) [33]. IFN-α therapy has also been implicated in the exacerbation of other autoimmune diseases, such as psoriasis [34] or chronic autoimmune hepatitis [35].

The incidence of ANA developed under PEG-IFN-α-2a treatment in our series was comparable to that under adjuvant high-dose IFN-α-2b in melanoma patients (28% vs 26%) [36]. However, clinical signs of autoimmune disease related to these antibodies are rare in both groups and ANA positivity is mostly reversible after cessation of therapy. Autoimmune thyroiditis is known to occur in treatment with standard IFN-α [8, 37] or PEG-IFN-α-2b [37, 38]. Thyroiditis, if undiagnosed, can cause significant problems, thus our findings of induced autoimmunity due to PEG-IFN-α-2a treatment are of clinical relevance. On the other hand standard IFN-induced autoimmunity has been recognized as a parameter of immune stimulation and effectiveness in adjuvant treatment with standard IFN-α [39].

In our study, the rate of dose reductions (27.8%) and therapy discontinuations (27.8%) due to toxicity is somewhat higher than the frequencies reported with 48-week PEG-IFN-α-2a in patients with chronic hepatitis C [15, 16]. This finding might be at least partially explained by investigators exercising particular caution in this study, because this represented the first melanoma patient experience with PEG-IFN-α-2a in an adjuvant stetting. Also, detailed dose-modification schemes were not put in place. As investigators gained more clinical experience, they were more likely to reduce or withhold doses, rather than to discontinue therapy. Yet, rate of dose reductions or therapy discontinuations was still lower than for high dose standard IFN.

One question is whether the efficacy of PEG-IFN-α-2a (180 μg) is similar to that of standard IFN-α and if it may even be similar to that of high dose schemes with standard IFN-α – rather than to the low dose schemes. The reason would be that, due to its continuously high blood levels, Peg-IFN-α cannot and need not be raised 10 fold as is done for standard IFN-α-2a in the HDI schemes. Whether the continuous blood level of PEG-IFN-α level (180 μg) does improve disease free survival and overall survival in patients with malignant melanoma in stage IIA to IIIB (as compared to low-dose IFN-α treatment) cannot be addressed in this study and is the subject of a current prospective randomized trial by the German Society of Dermatological Oncology (ADO).

One clue that PEG-IFN-α-2a 180 μg once weekly could indeed have an efficacy more similar to that of HDI schemes than to low dose schemes with IFN alpha 2a (3×3 MU weekly) comes from the evaluation of studies comparing both types of IFN in chronic hepatitis C. Here PEG-IFN-α-2a in a dosage of 180 μg once weekly revealed a significantly (3 to 10 fold) higher viral response rate than IFN-α-2a (3×3 MU weekly) [22, 40].

In conclusion, prolonged treatment with PEG-IFN-α-2a in patients with melanoma is feasible. Furthermore, tolerance was good and we did not face any serious adverse events related to treatment. The rate of dose reduction was substantial lower than in previous trials with high-dose IFN-α. Drug-induced autoimmunity as a parameter of relevant immune stimulation or surrogate marker for monitoring the efficacy of adjuvant treatment with PEG-IFN-α-2a warrants further evaluation.

The reduced rates of certain, e.g. dose-limiting side effects may allow schemes equivalent to higher dosages of IFN-α than the 3×3 Mill given for low dose adjuvant therapy. This may well support the search for more effective dosage schemes in an adjuvant setting.

Acknowledgements

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