Thirteen-year, long-term efficacy of interferon 2α and interleukin 2-based home therapy in patients with advanced renal cell carcinoma

Authors


Abstract

BACKGROUND

The goal of the current report was to demonstrate the long-term efficacy of outpatient subcutaneous (sc) interferon α (IFN-α) and sc interleukin 2 (IL-2)-based combination regimens in patients with metastatic renal cell carcinoma.

METHODS

In three consecutive clinical trials, 443 patients received combined sc IFN-α and sc IL-2 (n = 97 patients); combined sc IFN-α, sc IL-2, and intravenous (iv) 5-fluorouracil (5-FU) (n = 260 patients); or combined sc IFN-α, sc IL-2, and iv 5-FU with oral 13cis-retinoic acid (n = 86 patients).

RESULTS

The median overall survival was 21+ months. The 2-year, 5-year, and 13-year survival rates were calculated at 45.26%, 15.96%, and 8.96%, respectively. The median time to disease progression was 6 months. The 2-year, 5-year, and 13-year progression free survival rates were 17.84%, 9.54%, and 9.20%, respectively.

CONCLUSIONS

The current data suggest that combined outpatient sc IFN-α and sc IL-2, according to the Atzpodien regimen, achieves long-term survival benefits in a subset of patients with metastatic renal cell carcinoma, both with and without 13-cis-retinoic acid and/or 5-fluorouracil. Cancer 2002;95:1045–50. © 2002 American Cancer Society.

DOI 10.1002/cncr.10783

Renal cell carcinoma (RCC) represents the most common malignancy of the kidney in adults in the United States and is diagnosed in approximately 30,000 patients per year. Patients with untreated metastatic RCC carcinoma have an overall median survival of no more than 10 months. With little or no efficacy of conventional treatment strategies, including single-agent chemotherapy and hormonal therapy, new approaches are needed.1–3

High-dose interleukin 2 (IL-2) is currently the only drug for the treatment of patients with metastatic RCC that has been approved by the United States Food and Drug Administration. However, at high doses, intravenous (iv) recombinant IL-2 (rIL-2) invariably induced a wide spectrum of serious adverse effects. Treatment regimens using rIL-2 through subcutaneous (sc) injection at European Union-approved dose levels (approximately 10–30 times lower than in previous regimens) have demonstrated significant therapeutic efficacy while drastically reducing treatment-induced toxicity.4, 5 Single-agent efficacy of rIL-2 has been reported at objective response rates of 6–31%.6–8 Recombinant interferon α (INF-α) at sc doses of three or more mega units three to five times per week has produced objective regressions of metastatic RCC in 5–27% of patients treated, with a mean response rate of approximately 16%.2, 9 In addition, an enhanced antineoplastic activity has been demonstrated for the combination of recombinant cytokines and 5-fluorouracil (5-FU).10–12

Retinoids are known to play an important role in many biologic processes, including differentiation, morphogenesis, growth, and tissue homeostasis. More recently, an antiproliferative effect of 13cis-retinoic acid (13cRA) has been reported in patients with RCC who were treated with IFN-α or with combined IFN-α and IL-2 in clinical and preclinical trials.13–15 The goal of the current report was to evaluate the long-term therapeutic efficacy of metastatic RCC outpatient combination therapy employing combined sc IFN-α and sc IL-2, both with and without oral 13cRA and/or iv 5-FU.

MATERIALS AND METHODS

Patients

Between November 1988 and February 1998, 443 patients with progressive metastatic RCC received the present outpatient sc IFN-α and IL-2-based regimens in sequential, single-institution trials (Table 1). The median follow-up of these patients was 21 months (range, 1–158 months). Pretreatment variables included radical tumor nephrectomy (n = 430 patients), chemotherapy (n = 5 patients), immunotherapy (n = 53 patients), chemoimmunotherapy (n = 8 patients), and hormone therapy (n = 33 patients).

Table 1. Patients Characteristics
CharacteristicsIL-2/IFN-αIL-2/IFN-α/5-FUIL-2/IFN-α/5-FUAll
  1. IL-2: interleukin 2; IFN-α: interferon α; 5-FU: 5-fluorouracil.

No. of patients9726086443
Gender    
 Men6918866323
 Women287220120
Age (yrs)    
 Median58585758
 Range27–7022–7830–7422–78
Tumor nephrectomy9325384430
Systemic pretreatment    
 No5914255256
 Yes    
  Chemotherapy1405
  Immunotherapy10321153
  Chemoimmunotherapy0448
  Hormone therapy1019433
  Others17591288

Because all treatment regimens were designed for administration at home, this required the selection of patients with good or excellent performance status. Criteria for entry into the study were: histologically confirmed, progressive, metastatic RCC; an expected survival duration > 3 months; Karnofsky performance status > 80%; age between 18 years and 80 years; white blood cell count > 3500/μL; platelet count > 100,000/μL; hematocrit > 30%; and serum bilirubin and creatinine levels < 1.25 of the upper normal limit. Exclusion criteria included evidence of congestive heart failure, severe coronary artery disease, cardiac arrhythmias, symptomatic central nervous system disease or seizure disorders, human immunodeficiency virus infections, positivity for hepatitis B surface antigen or chronic hepatitis, and concomitant corticosteroid therapy. In all patients who were treated, no chemotherapy or immunomodulatory treatment had been performed during the previous 4 weeks. Pregnant and lactating woman were excluded.

The treatment regimens were approved by the institutional review board of the Medizinische Hochschule Hannover, where all patients were treated. Written informed consent was obtained from all patients prior to therapy.

Treatment Design

Patients were treated in an outpatient setting. Treatment 1 consisted of IFN-α and IL-2. Sc IFN-α2 was administered at a dose of 5 × 106 IU/m2 on Day 1 during Weeks 1 and 4 and on Days 1, 3, and 5 during Weeks 2, 3, 5, and 6. Sc IL-2 was administered at a dose of 10 × 106 IU/m2 twice daily on Days 3–5 during Weeks 1 and 4 and at a dose of 5 × 106 IU/m2 on Days 1, 3, and 5 during Weeks 2, 3, 5, and 6. Weeks 7 and 8 were therapy free.

Treatment 2 consisted of IFN-α, IL-2 and 5-FU. Sc IFN-α2 was administered at a dose of 5 × 106 IU/m2 on Day 1 during Weeks 1 and 4; on Days 1, 3, and 5 during Weeks 2 and 3; and at a dose of 10 × 106 IU/m2 on Days 1, 3, and 5 during weeks 5–8. Sc IL-2 was administered at a dose of 10 × 106 IU/m2 twice daily on Days 3–5 during Weeks 1 and 4 and at a dose of 5 × 106 IU/m2 on Days 1, 3, and 5 during Weeks 2 and 3. Iv bolus 5-FU was administered at a dose of 1000 mg/m2 on Day 1 during Weeks 5–8.

Treatment 3 consisted of IFN-α, IL-2, and 5-FU, as described for Treatment 2. In addition, patients received oral 13cRA at a dose of 35 mg/m2 daily.

Eight-week treatment cycles were repeated for up to three courses unless disease progression occurred. Revaluation of the patients' tumor status was performed between treatment cycles. Concomitant medication was given as needed to control adverse effects of immunochemotherapy.

Assessment of Response and Survival

Response to therapy was evaluated according to World Health Organization criteria as follows: A complete response (CR) was defined as the disappearance of all signs of disease for a minimum of 8 weeks; a partial response (PR) was defined as a reduction ≥ 50% in the sum of the products of the greatest perpendicular dimensions of measurable lesions with no increase in lesion size and no new lesions for a minimum of 8 weeks; stable disease was less than a PR with no disease progression for at least 8 weeks; and progressive disease was defined as an increase ≥ 25% in the sum of the products in the greatest perpendicular dimensions of measurable lesions or the development of new lesions. Progression free survival was measured from start of therapy. In patients with early disease progression, progression free survival was calculated at 0 months. Survival was measured from the start of therapy to the date of death or to the last known date alive. Treatment efficacy was assessed on an intent-to-treat basis.

Statistical Analysis

Probabilities of overall survival and progression free survival were plotted over time according to the method of Kaplan and Meier.

RESULTS

Four hundred forty-three patients received outpatient sc IFN-α and sc IL-2 (n = 97 patients); sc IFN-α, sc IL-2, and iv 5-FU (n = 260 patients); and sc IFN-α, sc IL-2, iv 5-FU, and oral 13cRA (n = 86 patients) in sequential, single-institution trials.

Objective Treatment Response

Overall, 37 patients (8.4%) achieved a CR, and 89 patients (20.1%) had a PR (Table 2). The objective response rate (CR and PR) was 28.5% (95% confidence interval [95%CI], 20.7–36.5%), with a median response duration of 18 months. One hundred fifty-seven patients (38.4%) had stable disease, and 160 patients (36.1%) exhibited continuous disease progression despite therapy.

Table 2. Response and Survival
ResponseNo. of patientsPercent of patientsMedian progression free survival (months)Median overall survival (months)
  1. CR: complete remission; PR: partial remission; SD: stable disease, PD: progressive disease.

CR378.4Not reachednot reached
PR8920.11336
SD15738.41023
PD16036.1010
Total443100.0621

Progression Free Survival

The median progression free survival was 6 months (95%CI, 5–7 months) in all patients (Fig. 1). The 2-year, 5-year, and 13-year progression free survival rates were calculated at 17.84%, 9.54%, and 9.20%, respectively.

Figure 1.

(A,B) Progression free survival (prog F. surv) of 443 patients (pts) who were treated with combined subcutaneous (sc) interleukin 2 (IL-2) and sc interferon α (IFN-α) (Treatment 1); with combined sc IL-2, sc IFN-α, and intravenous (iv) 5-fluorouracil (5-FU) (Treatment 2); or with combined sc IL-2, sc IFN-α, iv 5-FU, and oral 13cis-retinoic acid (13cRA) (Treatment 3). Survival was calculated from the start of therapy using the Kaplan–Meier method.

In patients who achieved a CR, the median progression free survival was not reached at 158 months (range, 7–158 months), whereas patients who achieved a PR and patients with stable disease reached a median progression free survival of 13 months (range, 4–101 months) and 10 months (range, 3–126 months), respectively (Table 2).

Patients who were treated with IFN-α and IL-2; with IFN-α, IL-2, and 5-FU; and with IFN-α, IL-2, 5-FU, and 13cRA achieved a median progression free survival of 6 months (range, 0–158 months; 95%CI, 4–8 months), 6 months (range, 0–115 months; 95%CI, 4–8 months), and 12 months (range, 0–93 months; 95%CI, 8–16 months), respectively. The 2-year, 5-year, and 13-year progression free survival rates were 12.37%, 8.25%, 7.22% for patients who received IFN-α and IL-2; 16.04%, 7.36%, and no denominator in patients who received IFN-α, IL-2, and 5-FU; and 29.55%, 17.52%, and no denominator in patients who received IFN-α, IL-2, 5-FU, and 13cRA.

Overall Survival

The overall median survival of all patients entered into the study was 21+ months (95%CI, 18–24 months), with a range from 1 month to 158 months (Fig. 2). The 2-year, 5-year, and 13-year survival rates were calculated at 45.26%, 15.96%, and 8.96%, respectively.

Figure 2.

(A,B) Overall survival of 443 patients (pts) who were treated with combined subcutaneous (sc) interleukin 2 (IL-2) and sc interferon α (IFN-α) (Treatment 1); with combined sc IL-2, sc IFN-α, and intravenous (iv) 5-fluorouracil (5-FU) (Treatment 2); or with combined sc IL-2, sc IFN-α, iv 5-FU, and oral 13cis-retinoic acid (13cRA) (Treatment 3). Survival was calculated from the start of therapy using the Kaplan–Meier method.

In patients who achieved a CR, the median survival was not reached at 158 months (range, 11–158 months) (Table 2). Patients who achieved a PR and patients with stable disease had a median survival of 36 months (range, 9–101 months; 95%CI, 30–42 months) and 23 months (range, 4–126 months; 95%CI, 19–27 months), respectively, compared with a median survival of 10 months (range, 1–132 months; 95%CI, 8–12 months) in patients with progressive disease.

Patients who were treated with IFN-α and IL-2; with IFN-α, IL-2, and 5-FU; and with IFN-α, IL-2, 5-FU, and 13cRA achieved a median survival of 17 months (range, 3–158 months; 95%CI, 13–21 months), 19 months (range, 1–115 months; 95%CI, 16–22 months), and 32 months (range, 3–93 months; 95%CI, 20–44 months), respectively (Fig. 2). The respective 2-year, 5-year, and 13-year survival rates were 39.12%, 17.53%, and 9.16% in patients who received IFN-α and IL-2; 42.31%, 11.46%, and no denominator in patients who received IFN-α, IL-2, and 5-FU; and 61.18%, 27.87%, and no denominator in patients who received IFN-α, IL-2, 5-FU, and 13cRA.

DISCUSSION

This is the first report on the long-term efficacy (13 years) of outpatient therapy regimens with sc IFN-α and IL-2 in patients with advanced RCC. Previously, the prognosis of untreated patients with metastatic RCC was poor, with a 5-year survival rate of less than 10% and a median overall survival of no more than 10 months.1

Here, we have demonstrated an overall objective response rate of 28.5%, which is comparable with previous results of other authors ranging from 18.6–29.4% (IFN-α and IL-2),4, 5, 10, 16, 17 1.8–48.6% (IFN-α, IL-2, and 5-FU),10–12, 18–20 and 17–31% (IFN-α, IL-2, 5-FU, and 13cRA),21, 22 with largely overlapping 95%CIs. The discrepancy in Phase I–II results may be explained best by at least three uncontrolled and often demonstrated variables: 1) patient selection and clinical/biologic risk distribution, 2) variations in the rIL-2-based regimen (e.g., reconstitution of drug, route, and dose of administration or the use of rIL-2 with concomitant chemotherapy), and 3) different standards of patient care (e.g., prior surgery and supportive care with cytokine therapy).

Among the 443 patients who were treated in our studies, we observed 2-year, 5-year, and 13-year-survival rates of 45.26%, 15.96%, and 8.96%, respectively, with a median overall survival of 21+ months (95%CI, 18–24 months), clearly demonstrating that outpatient sc IFN-α/sc IL-2-based therapies have long-term therapeutic efficacy in a subset of patients with advanced RCC. In addition to patients who achieved a CR (median survival not reached), patients who achieved a PR (median survival, 36 months) and patients with stable disease (median survival, 23 months) experienced a substantial survival benefit.

To date, no prospectively controlled trial has confirmed the long-term efficacy of iv bolus 5-FU when combined with outpatient sc IFN-α and sc IL-2, compared with sc IFN-α and sc IL-2 alone. In addition, although retinoids may augment the antitumor effect of INF-α and IL-2 against RCC21, 23 and may reverse IFN-α resistance in RCC,24, 25 this has not been demonstrated prospectively in randomized studies.

The current results provide evidence of long-term benefits in a subset of patients with good or excellent performance status who had metastatic, progressive RCC and received sc IFN-α and sc IL-2-based home therapy. Augmented benefits from the addition of iv 5-FU and oral 13cRA will require evaluation in prospectively randomized trials. Also, prognostic factors that may predict survival in patients with metastatic RCC will be useful for an improved understanding of the relative benefits of outpatients receiving combined sc IFN-α and IL-2 compared with natural history and patient selection.

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