Abstract
Twenty-two patients with metastatic renal cell carcinoma and removal of the primary tumor were treated with subcutaneous pegylated interferon alfa-2b (PEG-Intron) to evaluate toxicity and efficacy. Start dose was 3.0 μg/kg/week, escalated to 6.0 μg/kg/week. After 2 months, therapy was extended in case of response or stable disease (SD) until progressive disease (PD) or relapse for a maximum of 2 years. National Cancer Institute common toxicity criteria (NCI-CTC) were monitored every 2–4 weeks. After 2 months, nine patients did not continue (8 PD, 1 SD with grade 4 CTC) and 13 extended treatment [three partial response (PR), 10 SD], of these, 11 progressed. One patient with PR developed a durable complete response later. Overall response rate was 13.6% (3/22). Median overall survival is 13 months (range 3–35 months). Dosage was escalated to 6 μg/kg/week in three patients . NCI-CTC grade 2 and 3 required dose attenuation in 12 patients during escalation, and reduction in 10 during the trial. Three patients discontinued because of grade 4 CTC (two fatigue, one hyperglycemia). Fatigue was the major dose-limiting toxicity. These results suggest an efficacy and toxicity of PEG-Intron comparable to standard interferon alfa-2b in patients with mRCC and removal of the primary tumor.
Keywords: Immunotherapy, Renal cell carcinoma, Interferon, Pegylated, Metastatic
Introduction
Safety, administration on an outpatient basis and ease of patient selection have made IFN-alfa an attractive immunotherapeutic treatment for patients with metastatic renal cell carcinoma (mRCC) [10, 12]. In two phase-III studies, IFN-alfa has shown a survival benefit compared to either vinblastine or medoxyprogesterone [8, 16]. The complete and partial response rates recorded from adequate trials with more than 20 patients and a dose of at least 5×106 IU/m2 IFN-alfa 3 times a week vary from 5–26% with a mean of 17%. It is well recognized that the primary tumor rarely responds to immunotherapy. Nephrectomy is currently part of the multimodality treatment of synchronous metastatic disease, after two phase-III trials in patients with primary metastatic renal cell carcinoma have demonstrated a significant—albeit limited—survival benefit for nephrectomy and adjuvant IFN-alfa compared to IFN-alfa alone [3, 11].
Commercially available IFN-alfa preparations (IFN-alfa 2a Roferon, Hoffmann-LaRoche, IFN-alfa 2b, Intron, Schering-Plough) are characterized by a relatively short plasma half life that necessitates frequent dosing. A recent formulation of IFN-alfa is pegylated IFN-alfa 2b (PEG-Intron, Schering Plough) and a higher molecular-weight pegylated IFN-alfa 2a (Pegasys, Hoffmann-LaRoche), which both give slow release with adequate serum levels because of covalent linkage of IFN-alfa to the polyethylene glycol (PEG) polymer. Pharmakokinetic data show a lower peak serum concentration, a longer half life and exposure allowing weekly injections [2, 13]. It has been argued that the longer half life may translate into improved efficacy compared with non-pegylated IFN-alfa [2]. There is already considerable experience in the treatment of hepatitis C with PEG-Intron 1.0 μg/kg/week, which is well tolerated at that dose [4, 7]. Studies were performed in chronic myelogenous leukemia (CML), melanoma, renal cell carcinoma (RCC) and myeloma. A phase-I study in patients with CML revealed 6.0 μg/kg/week as the maximum tolerated dose (MTD) [18]. In a phase-I/II study in patients with metastatic melanoma and RCC, PEG-Intron was well tolerated at a dose of up to 6.0 μg/kg/week [1]. Pharmacokinetic profiles of PEG-Intron and interferon alfa-2b doses have been compared in a multidose, dose-ranging study in patients with chronic hepatitis C infection [7] and revealed a dramatically increased exposure to pegylated IFN alfa-2b. Comparison of PEG-Intron and non-pegylated IFN-alfa 2b demonstrated that a weekly dose of 0.5–1.0 μg/kg PEG-Intron is similar to the most common dose schedules of 3×5–10×106 IU IFN-alfa 2b/week while the toxicity profile is comparable [2]. It has been estimated that PEG-Intron at 6.0 μg/kg/week may achieve exposure comparable to that of 180×106 IU/week of IFN alfa-2b [1]. Additionally, a phase-I dose escalation trial in 27 CML patients demonstrated that PEG-Intron accumulated by a factor of 1.5 after multiple doses regardless of the dose [2, 18]. Thus, PEG-Intron at 6.0 μg/kg/week resulted in an exposure that was estimated to be 80 times that observed after IFN alfa-2b at 9×106 IU/week [18] while tolerability was comparable to IFN alfa-2b at 3–5×106 IU/m2 per day [5].
As two recent phase-II studies of pegylated IFN-alfa in metastatic renal cell carcinoma [1, 14] revealed an efficacy comparable to non-pegylated IFN-alfa but with only mild to moderate toxicity, we conducted a similar phase-II study with high doses of PEG-Intron to investigate whether the reported data can be reproduced in a more homogenous patient population.
Patients and methods
Patients
The trial has been carried out with the approval of the ethics committee of the Netherlands Cancer Institute. All patients signed an informed consent. Patients were eligible if they had measurable, histologically documented, progressive metastatic RCC. Progression was defined according to RECIST criteria [19]. All patients had prior nephrectomy, either before the onset of metastasis (metachronous) or after the diagnosis of systemic disease (synchronous). Prior chemotherapy, immunotherapy or hormonal therapy was not allowed. Eligibility criteria included a World Health Organization (WHO) performance status of 0 or 1, age >18 and <70 years, a life expectancy of >12 weeks, adequate bone marrow function (WBC >4.0/nl, platelets >100/nl), adequate renal function (creatinine clearance >50 ml/min) and hepatic function (bilirubin <3 × ULN; <5 × ULN with liver metastases), adequate contraception and written informed consent. Patients were ineligible if they had severe cardiac, pulmonary, metabolic, psychiatric or other serious co-morbid conditions. Also ineligible were pregnant or lactating women, those with active infections requiring antibiotics, patients with only bone metastases, presence of brain metastases, other uncontrolled malignancies and the use of systemic steroids.
Statistical considerations
The study was designed as a Simon optimal two stage phase-II unicenter trial [17]. Study endpoints were durable tumor response of at least 6 months (primary) and toxicity (secondary). It was estimated that 22 patients were required to determine whether the true response rate was <10 vs. >25%. The study was to be discontinued if 2 or fewer (<10%) out of 22 patients showed a durable response. If three or more patients developed a durable response (≥6 months), the study would continue until the full accrual of 40 patients. This statistical hypothesis had an error rate of 5% with a power of 80% (the probability of type I error selected, i.e., recommending the treatment for further trials when in fact the response rate is as low as 10%, that is, 0.05; the probability of type II error selected, i.e., rejecting the treatment for further trials, when in fact the response rate is as high as 25%, that is, 0.20). Statistical analysis for response rates and adverse effects was descriptive. Patient characteristics were subdivided into performance status 0 or 1, metachronous or synchronous metastasis, metastasis <1 or >1 year after nephrectomy in metachronous disease, number of metastatic sites as a parameter of tumor burden, and metastatic sites.
Dose and treatment
Twenty-two patients were treated with subcutaneous injections of PEG-Intron with escalating dose levels from 3.0 to 6.0 μg/kg/week. Start dose was 3.0 μg/kg/week, intentionally escalated to 4.5 μg/kg/week after 2 weeks and subsequently to 6.0 μg/kg/week after another 2 weeks unless grade 2 CTC toxicity occurred, except fever or flu-like symptoms (see toxicity and dose modifications for details). The rationale for stepping up to 6.0 μg/kg/week was based on the results of dose-ranging trials performed to assess the maximum-tolerated dose (MTD) in patients with melanoma, RCC or chronic myeloid leukemia [1, 18]. Patients who completed the initial 2 months of treatment and showed response [complete (CR) or partial (PR)] or stable disease (SD) were eligible to continue at the dose level reached during escalation until progression or relapse occurred for a maximum period of 2 years (extended treatment).
Toxicity and dose modifications
Toxicities were graded according to the National Cancer Institute common toxicity criteria (NCI-CTC). Patients were monitored for toxicity every 2 weeks in the initial 2 months, followed by every 4 weeks in the case of extension. Monitoring consisted of physical examination, hematology, biochemistry and patient history focusing on constitutional symptoms of the NCI-CTC. In case of hematologic and/ or non-hematologic toxicity grade 2 during escalation, except for fever or flu-like symptoms (rigors, chills, arthralgia, myalgia), the dose was attenuated, that is, not further escalated but continued on the level reached. With persisting toxicity grade 2, during escalation or at any time during the trial, treatment was reduced by one dose level each time (reduction in decrements of 1.5 μg/kg/week) until a minimum of 1.5 μg/kg/week. In the case of grade 3 non-hematologic toxicity, apart from fever or flu-like symptoms, treatment was withdrawn temporarily and restarted at a lower dose level (4.5, 3, 1.5 μg/kg/week). If grade 3 leukopenia or thrombocytopenia occurred, the treatment would be stopped transiently and resumed one dose level lower only after restoration to normal levels. If any grade 4 hematologic or non-hematologic toxicity occurred, the treatment was discontinued. Supportive care consisted of acetaminophen 500–1,000 mg 30 min before administration of PEG-Intron.
Response assessment
To assess tumor response as primary endpoint, the RECIST criteria were applied [19]. Patients who had completed 2 months of PEG-Intron were evaluated for response. Response evaluation was continued every 8 weeks for 1 year. Tumor response was assessed by physical examination, chest X-ray, bone scan and computed tomography and the responses observed were confirmed.
Results
Patient characteristics
Twenty-two patients with metastatic renal cell carcinoma were enrolled between January 2001 and December 2002. All patients had the primary tumor removed, either with curative intent before the onset of metastasis (metachronous disease; n=12) or prior to immunotherapy together with removal of all intraabdominal metastases (synchronous disease; n=10). All tumors were of the conventional clear-cell subtype. Overall, 19 patients had lung metastases, in 8 of whom the lung was the only metastatic site. Two had additional bone lesions and three had liver metastases without elevation of serum bilirubin. The median age was 55 years. Sixteen patients had a performance status of WHO 0 and 6 of WHO 1. Patient characteristics at baseline are listed in Table 1.
Table 1.
Patient characteristics at baseline
| Characteristics | No. |
|---|---|
| Patients | 22 |
| Males | 16 |
| Females | 6 |
| Age (years) | |
| Median | 55 |
| Range | 41–68 |
| Performance status (WHO) | |
| 0 | 16 |
| 1 | 6 |
| Nephrectomy | |
| Synchronous | 10 |
| Metachronous | 12 |
| Time to metachronous disease | |
| <1 years | 3 |
| 1–2 years | 4 |
| >2 years | 5 |
| Number of metastatic sites | |
| 1 | 11 |
| 2 | 8 |
| ≥3 | 3 |
| Metastatic sites | |
| Lung | 19 |
| Lymph nodes retroperitoneal | 3 |
| Lymph nodes mediastinal | 6 |
| Liver | 3 |
| Bone | 2 |
| Other | 4 |
| Memorial Sloan Kettering prognostic index classification | |
| Favorable | 5 |
| Intermediate | 15 |
| Poor | 2 |
Response
All patients (n=22) completed the initial phase of 2 months’ PEG-Intron. Eight patients revealed PD at 2 months and were not eligible for extended treatment, and one patient with SD did not continue because of adverse effects. Characteristics of patients with PD were compared to patients eligible for extension, but no distinctive pattern emerged. Thirteen patients qualified for extended treatment with PEG-Intron: 3 patients had a PR [13.6%, 95% Clopper–Pearson confidence interval (C-P CI): 3–35%] and 10 SD after 2 months’ escalation. Of the 3 patients with PR, one developed a CR 2 months after extension and remains free of disease after 11 months. Only two patients (9%) had a major response longer than 6 months (95% C-P CI: 1–29%). Characteristics of patients with major response are listed in Table 2. Of the ten patients with SD, only one remains stable at 26 months and none developed a response during extended treatment. Eleven of 13 on extension have progressed with a median time to progression of 6 months (range 4–18 months). Median duration of extended treatment was 4 months (range 2–24 months). Eight patients continued for less than or equal to 4 months (range 2–4 months) and five for more than 4 months (range 7–24 months) with one ongoing for 13 months. Only three continued for more than 1 year, with one still continuing. One patient has completed the 2-year phase. Twelve patients died of disease-related complications, 9 are alive with disease with a median follow-up of 20 months (range 12–35 months) and one remains free of disease after 11 months. Fifteen (68%) patients were alive at 12 months. The median overall survival for the entire group is 13 months (range 3–35 months).
Table 2.
Details of patients with best responses
| Age (years) | Sex | Maximum dose (μg/kg/week) | Extension dose (minimum) | Metastases (synchronous/metachronous) | Metastatic sites | Response | Duration (months) |
|---|---|---|---|---|---|---|---|
| 63 | M | 6 | 1.5 | Synchronous | Lung | CR | 11+ |
| 52 | F | 6 | 4.5 | Synchronous | Lung, adrenal | PR | 4 |
| 59 | F | 6 | 3 | Metachronous | Mediastinal LN | PR | 18 |
Toxicity and dose
During the treatment, fatigue and chronic fatigue was the major dose-limiting event in this trial. Overall, 12 patients (54.5%) required dose attenuation during escalation and 10 (45.4%) reduced the dose maximally achieved at step-up during the entire study; generally, there was one decrement. The median time from the start of treatment to first dose reduction was 4 months (range 0.5–11 months). Three patients discontinued because of grade-4 toxicity (one initial escalation, two extension therapy). The most frequently reported adverse effects potentially related to PEG-Intron during initial escalation and the 2-year extension are listed in Tables 3 and 4.
Table 3.
Reported adverse effects by severity in the initial phase (n=22, possible or probable relation to treatment) (NCI-CTC toxicity scale)
| Adverse effect | No. of patients | |||
|---|---|---|---|---|
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
| Constitutional symptoms | ||||
| Fatigue | 11 | 6 | 4 | 1 |
| Fever | 1 | 17 | 3 | 0 |
| Rigors, chills | 2 | 17 | 2 | 0 |
| Sweating | 3 | 13 | 0 | 0 |
| Weight loss | 3 | 3 | 0 | 0 |
| Gastrointestinal | ||||
| Nausea | 7 | 7 | 0 | 0 |
| Vomiting | 5 | 2 | 0 | 0 |
| Diarrhea | 4 | 3 | 0 | 0 |
| Skin | ||||
| Dry skin | 3 | 0 | 0 | 0 |
| Injection site reaction | 7 | 0 | 0 | 0 |
| Rash | 2 | 0 | 0 | 0 |
| Pain | ||||
| Myalgia/arthralgia | 5 | 3 | 2 | 0 |
| Headache | 6 | 3 | 1 | 0 |
| Pulmonary | ||||
| Cough | 3 | 1 | 0 | 0 |
| Dyspnea | 2 | 2 | 0 | 0 |
| Neurology | ||||
| Mood alteration | 1 | 1 | 0 | 0 |
| Blood | ||||
| Neutropenia | 1 | 1 | 0 | 0 |
| Leukopenia | 3 | 4 | 0 | 0 |
| Lymphopenia | 2 | 0 | 0 | 0 |
| Thrombocytopenia | 2 | 3 | 0 | 0 |
| Elevated liver enzymes | 4 | 1 | 0 | 0 |
Table 4.
Adverse effects reported in order of frequency by severity in the maintenance phase (n=13, possible or probable relation to treatment) (NCI-CTC toxicity scale)
| Adverse effect | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
|---|---|---|---|---|
| Fatigue | 2 | 4 | 3 | 1 |
| Sweating | 2 | 2 | 0 | 0 |
| Headache | 0 | 3 | 0 | 0 |
| Myalgia/arthralgia | 0 | 2 | 0 | 0 |
| Fever | 1 | 1 | 0 | 0 |
| Rigors, chills | 1 | 1 | 0 | 0 |
| Nausea | 1 | 1 | 0 | 0 |
| Diarrhea | 1 | 1 | 0 | 0 |
| Injection site reaction | 2 | 0 | 0 | 0 |
| Rash | 0 | 0 | 1 | 0 |
| Neutropenia | 0 | 1 | 0 | 0 |
| Leukopenia | 0 | 1 | 0 | 0 |
| Thrombocytopenia | 0 | 1 | 0 | 0 |
| Hyperglycemia | 0 | 0 | 0 | 1 |
Dosage was escalated to 6 μg/kg/week in ten patients, seven reached 4.5 μg/kg/week and five did not increase above 3 μg/kg/week. Overall, three patients reduced one decrement during escalation due to grade-2 toxicity, but none of them had reached 6 μg/kg/week. One patient, despite SD, discontinued treatment at the end of the initial phase because of grade-4 fatigue at 3 μg/kg/week with a reduction of performance status from WHO 1 to WHO 3. Of the 13 patients eligible for extended treatment, eight continued on 6 μg/kg/week. Seven patients reduced dosage during extension due to grade-2 toxicity. The patient with a durable CR reduced from 6 to 4.5 μg/kg/week after 2 months’ extended therapy and subsequently via 3 to 1.5 μg/kg/week after 9 months. Two patients discontinued extended treatment after 1 month because of grade-4 adverse effects (fatigue and hyperglycemia at 4.5 and 6 μg/kg/week, respectively).
One patient who continued on 1.5 μg/kg/week finished the 2-year extended therapy and remains stable at 26 months’ follow-up.
Discussion
The only phase-I/II study of pegylated interferon alfa-2b for patients with solid tumors, including renal cell carcinoma, is heterogenous and therefore difficult to interpret [1]. Of the 57 patients with metastatic renal cell cancer, 35 were previously untreated with cytokines and enrolled to assess the activity of pegylated IFN alfa-2b at the two highest dose levels without prior escalation (6.0 and 7.5 μg/kg/week for 12 weeks). Twenty-three RCC patients continued on the extension protocol (6.0 or 7.5 μg/kg/week for 1 year) of whom five completed the treatment. Prior surgical excision was acceptable, but was not required in this multicenter trial. The report does not make a distinction between synchronous metastatic RCC with or without nephrectomy or metachronous RCC and the time interval to metastasis, though these factors may bias the response rates and median survival reported [9]. Therefore, we accrued patients with metachronous and synchronous metastatic renal cell cancer following nephrectomy to exclude a bias stemming from removal of the primary tumor. In patients with synchronous metastasis, the influence of cytoreductive surgery has been well documented in two randomized phase-III trials comparing nephrectomy and interferon alfa-2b with interferon alfa-2b alone [3, 11]. It has been argued that synchronous disease reflects a different tumor biology than metachronous disease. In patients with metachronous metastases, a time interval of more than 2 years between primary tumor and metastasis was accompanied by a longer disease-specific survival in patients who underwent surgical cytoreduction of metastases [20]. Similarly, a short interval from renal tumor to metastases of less than 1 year was predictive for rapid progression under cytokine treatment [15].
Table 1 shows that only a few patients in this trial had an unfavorable prognosis: none of the patients had the primary tumor in situ, only three had more than two metastatic sites, three developed metastatic disease less than 1 year after nephrectomy and five had metastatic sites associated with a poor prognosis (three liver, two bone). According to the Memorial Sloan Kettering Prognostic Index Classification based on five pretreatment clinical features (low Karnofsky performance status, high lactate dehydrogenase, low serum hemoglobin, high corrected serum calcium and time from initial RCC diagnosis to start of interferon therapy of less than 1 year) [12], the majority of the patients were assigned to the intermediate-risk group. With regard to the limited number of patients, no distinctive pattern emerged predicting qualification for extended treatment. In contrast to progressing patients, considerably more patients qualifying for extension reached the maximum dose of 6.0. In our view, this may be a consequence of a better performance score, which independently influences prognosis, rather than reflecting a higher effectivity of the maximum dose.
In another multicenter phase-II trial, 40 patients with metastatic RCC were treated with pegylated interferon alfa-2a (Pegasys, Hoffmann-LaRoche) at a dose of 450 μg once weekly for 24 weeks [14]. Pegylated IFN-alfa 2a was previously studied in a phase-I dose escalation study in untreated advanced RCC [13]. The maximum-tolerated dose was defined as 540 μg/week with dose-limiting toxicities of fatigue and elevated hepatic transaminase. Twenty-five patients had a prior nephrectomy, but no distinction was made between prior nephrectomy in synchronous metastatic disease or nephrectomy before the onset of metastasis. The time interval between surgery and metastases is not known. Fifteen patients had no nephrectomy, which is an adverse prognostic factor as opposed to prior surgery in patients with metastatic disease.
Despite these limiting factors, the overall response rates and survival were surprisingly similar in both trials. In the PEG-Intron phase-I/II trial, the objective response rate was 14% among the previously untreated RCC patients with a 1-year survival rate of 50% and a median survival of 13.2 months [1]. In the Pegasys trial, 13% achieved a major response with a 1-year survival rate of 63% [14].
The results of this trial do not differ from these earlier phase-I/II trials on pegylated IFN alfa. Major response was observed in 13.6% with 68% being alive at 1 year and a median survival of 13 months. However, only two patients developed a durable response (≥6 months). According to protocol requirements, the trial was therefore not continued until the full accrual of 40 patients.
It has been concluded from the phase-I/II PEG-Intron trial [1] that the maximum tolerated dose at 12 weeks was 6.0 μg/kg/week and that this dose was well tolerated for 1 year with appropriate dose modification. Among 70 patients treated with a range of 0.75–7.5 μg/kg/week PEG-Intron in the 12-week core phase, including patients with melanoma and gastric cancer, ten adverse events were classified as (NCI-CTC) grade 3 (fatigue, diarrhea and myalgia) and two as grade 4 (chills and hyperbilirubinemia). Grade 3 and 4 hematologic toxicity occurred in four patients. They observed grade 3–4 toxicity in 28% (8/29) over the 1-year extension phase (arthralgia, fever, headache, rigors, pain and rash) with grade 3–4 hematological toxicity in six (neutro-,leuko- and thrombocytopenia). No grade 3 or 4 fatigue occurred. We observed fewer instances of hematological toxicities, which may be partly explained by the higher doses of 7.5 μg/kg/week and the lack of an escalation phase in 35 patients with RCC in the study of Bukowski et al. As this trial contained an escalation phase, early grade-2 toxicity was used to halt further escalation and to continue on the level reached in order to prevent likely grade 3 or 4 toxicity with increasing dose levels. However, we observed pronounced constitutional symptoms at all dose ranges. Five of 22 patients (22.7%) reported grade 3–4 fatigue (1 grade 4) during the initial phase and 4 of 13 (30.7%) during extended treatment, again with one grade 4. It has been argued from data presented in the phase-I/II PEG-Intron trial that PEG-Intron allows patients to achieve the same or even higher exposure to interferon alfa than high-dose non-pegylated IFN alfa regimens without reaching dose-limiting toxicity. On the contrary, grade 3 or 4 fatigue has been reported in up to 25% of patients with metastatic RCC treated with the registered dose of non-pegylated IFN alfa 18×106 IU three times weekly and in patients with melanoma who were treated for 1 year with the approved high-dose non-pegylated IFN alfa-2b regimen (subcutaneous 10×106 IU/m2 three times weekly) [6]. However, we conclude from our data that a similar percentage of patients experience dose-limiting fatigue with PEG-Intron 3.0–6.0 μg/kg/week. In fact, fatigue was the major dose-limiting event in this trial and was not exclusively associated with the higher dose ranges.
Weekly administration of PEG-Intron was associated with a shorter duration of flu-like symptoms limited to the day of administration in the majority of patients [5]. This may be beneficial in contrast to patients who experience frequent acute flu-like symptoms during the week with non-pegylated interferon alfa regimens with daily or three times weekly injections. In this trial, flu-like symptoms (fever, rigors, chills, sweating, myalgia, arthralgia and headache) were indeed mostly grade 1 or 2 and limited to the initial days following subcutaneous injection of PEG-Intron.
It has been argued that the future direction should not be to achieve exposure equivalent to that with standard interferon alfa-2b, but rather to focus on the greater tolerability of PEG-Intron to achieve dose intensification and thereby potentially increasing efficacy [2]. The response rates in metastatic RCC reported in larger contemporary trials achieved with non-pegylated IFN alfa have been observed with doses of 5×106 IU/m2 or 9×106 IU daily, three or five times weekly [10]. These regimens and intervals have revealed less toxicity than the originally described regimen of 18×106 IU three times weekly, which is currently less widely used. From the various contemporary phase-II trials for metastatic RCC, the fact emerges that oncologic efficacy with response rates of 15% and median survival of 15 months can be similarly achieved regardless of the individual doses and intervals as long as weekly total doses of 25–45×106 IU IFN alfa are gained [10]. PEG-Intron at 3.0–6.0 μg/kg/week constitutes an intensified dose range compared to standard IFN alfa-2b. We could not produce evidence that PEG-Intron at this dose range was more effective than treatment with non-pegylated IFN alfa-2b with total weekly doses of 25–45×106 IU. For patients with metastatic RCC and removal of the primary tumor, response rates and especially survival were in line with results published in the literature.
We therefore conclude that a high dose range of PEG-Intron of 3.0–6.0 μg/kg/week appears to have a tolerability and efficacy comparable to that reported for standard non-pegylated interferon alfa 2b in patients with metastatic RCC; however, a true comparison would require a randomized trial comparing both toxicity and efficacy in patients with equivalent prognostic categories of metastatic RCC. If response rates and survival are not improved with intensified PEG-Intron, it may be preferable to aim at exposure equivalent to non-pegylated interferon alfa-2b to potentially reduce adverse effects.
Footnotes
Author disclosure declaration: None of the authors has a relationship with pharmaceutical companies, biomedical device manufacturers or other corporations whose products or services are related to the subject matter of the submission, nor do the authors have financial interests such as investments, licensing, or other commercial interest in any drugs, goods, or services in connection with the matter under consideration.
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