A Phase II Trial of Interleukin-2 and Interferon Alfa-2a in Patients With Advanced Renal Cell Carcinoma By David H. Ilson, Robert J. Motzer, Richard L. Kradin, Nicholas J. Vogelzang, Dean F. Bajorin, Howard I. Scher, David Nanus, Paul O'Moore, Katerina Marathias, and George J. Bosl Purpose: A phase II trial that used a regimen of interleukin-2 (IL-2) and interferon alfa-2a (IFN-a) was undertaken to evaluate the efficacy of this combination in the treatment of metastatic renal cell carcinoma. Patients and Methods: Thirty-four assessable patients were treated with one to two induction cycles of IL-2 administered by continuous intravenous (IV) infusion at a dose of 3 x 106 p/m 2 /d for 4 days per week plus IFN-a administered by subcutaneous injection at a dose of 5 x 106 p/m 2 /d for 4 days per week for 3 consecutive weeks. 2 A maintenance regimen of IL-2 2 x 106 p/m /d given by continuous IV infusion for 5 days per week plus IFN-a subcutaneously at a dose of 6 x 106 tL/m 2 /d that was given 3 days per week for 3 weeks was administered for one to five cycles. Twenty-eight patients (82%) completed

METASTATIC resistant to conventional chemotherapy.

one to two induction cycles, and 14 patients (41%) received maintenance doses. Results: Major responses were achieved in four patients (12%), which included one complete response (CR) in a bone metastasis. Responses were observed in patients both with and without prior nephrectomy as well as in a primary tumor. Toxicity was moderately severe and included two treatment-related deaths. Conclusions: In view of the minimal antitumor activity and associated toxicity, the combination of IL-2 and IFN-a in this trial cannot be recommended. The investigation of new cytokines and the identification of biologic prognostic factors for a response to immunologic therapy are essential. J Clin Oncol 10:1124-1130. © 1992 by American Society of Clinical Oncology.

RENAL cell carcinoma (RCC) is

0% to 35% have been reported, with IL-2 given in

Sponta-

various schedules and doses, and with or without the infusion of autologous LAK cells.'6-28 Given the potential synergy of IL-2 and IFN-a demonstrated in animal models 29-3 1 and the different mecha-

1

neous remissions have been reported in up to 7% of patients,2-5 which suggests a role for host immunity in antitumor response and fosters an interest in immuno-

therapeutic approaches. Interferon alfa-2a (IFN-ac) is a glycoprotein that exhibits antiproliferative activity and immunomodulatory effects that include augmentation of natural-killer (NK)-cell activity and upregulation of

nisms of action of the two agents, a series of phase I

expression of major histocompatibility complex and 7 tumor-associated antigens.6, IFN-a has been investigated as a treatment for metastatic RCC, with major 3 responses observed in 10% to 21% of patients. ,8-11

The results of a phase II trial of IFN-a and continuous intravenous (IV) infusion IL-2 in patients with metastatic RCC that used a dose and schedule adapted from 3 34 two prior phase I trials are reported. 3, The goal of the

trials that combined therapy with IFN-at and IL-2 were

undertaken. 25,32-35 Major responses in patients with metastatic RCC were reported in 25 of 110 patients (23%).

Interleukin-2 (IL-2) is a glycoprotein produced by T

current trial was to evaluate the efficacy in RCC of an

lymphocytes that induces proliferation and functional

intensive inpatient induction treatment combined with a

changes in cytotoxic T lymphocytes, NK cells, and lymphokine-activated killer (LAK) cells.12-14 An initial

prolonged outpatient maintenance treatment.

trial reported a 33% response proportion in patients with metastatic RCC treated with IL-2-based therapy.15

In multiple subsequent trials, response proportions of

From the Memorial Sloan-KetteringCancer Center, New York, NY; Massachusetts General Hospital, Boston, MA; and University of Chicago, Chicago, IL. Submitted November 4, 1991; acceptedFebruary 20, 1992. Supportedby NationalInstitutesof Health grants no. CA-05826 and CM-57732, the Brian Piccolo Cancer Research Fund, and Hoffmann-La Roche, Nutley, NJ. R.J.M. is the recipient of an American Cancer Society Career DevelopmentAward. Address reprint requests to Robert J. Mortzer, MD, Memorial Sloan-Kettering CancerCenter, 1275 York Ave, New York, NY 10021. © 1992 by American Society of Clinical Oncology. 0732-183X/92/1007-0015$3.00/0

1124

PATIENTS AND METHODS PatientPopulation From March 1989 until March 1991, 35 patients with advanced RCC were treated with IL-2 and IFN-cs; treatment was administered at the Memorial Sloan-Kettering Cancer Center (MSKCC; 23 patients), the Massachusetts General Hospital (nine patients), and the University of Chicago (three patients). All patients were required to have bidimensionally measurable disease, a Karnofsky performance status - 70%, an age > 18 years, an estimated life expectancy of more than 12 weeks, an adequate hematologic function (granulocyte count > 1,500 mm 3, hemoglobin > 10 g/dL, 3 and platelet count > 100,000/mm ), an adequate hepatic function (SGOT < four times the upper limit of normal, a bilirubin level of < 1.6 mg/dL, partial thromboplastin time < 1.5 times control), an adequate renal function (serum creatinine level < 2.0 mg/dL or creatinine clearance > 50 mL/min), and the ability to provide signed informed consent. Patients with significant pulmonary or cardiac disease, serious intercurrent illness or active infection,

Journal of Clinical Oncology, Vol 10, No 7 (July), 1992: pp 1124-1130

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1125

IL-2 AND IFN-a€ IN RCC brain metastasis, psychiatric or seizure disorders, or prior malignancy other than basal cell carcinoma or carcinoma in situ of the cervix were excluded. Additional exclusionary criteria included concurrent treatment with corticosteroids, any prior therapy with IL-2 or IFN-a, or prior chemotherapy, radiotherapy, or immunotherapy within 4 weeks of entry onto the protocol. Recombinant human IL-2 and recombinant human IFN-a (Roferon-A) were provided by Hoffmann-La Roche, Inc (Nutley, NJ). The specific activities of IL-2 and IFN-a were 1.5 x 107 U/mg protein and 2 x 108 U/mg protein, respectively.

the sites of disease found during the initial evaluation. Standard response criteria were used."37 Toxicity was graded according to the NCI common toxicity scale. Duration of response was measured from the initial documentation of response to the most current evaluation, or to the documentation of progression. Patients were assessed for response after every two consecutive treatment cycles, at 2- to 3-month intervals. Patient survival was calculated by using the Kaplan-Meier method38 ; survival was measured from the date of entry onto the protocol. RESULTS

Treatment Plan

Patient Characteristics

Patients were treated with IL-2 and IFN-a according to the schedule shown in Table 1. Patients received one to two courses of induction therapy as inpatients. IL-2 was given by continuous IV infusion, and IFN-a was given by a single daily subcutaneous injection. Each 3-week course of induction therapy was followed by a 2- to 4-week rest period. Patients who achieved a response or had stable disease were considered for maintenance therapy. A rest period of 2- to 4-weeks was allowed after each 3-week course of maintenance therapy. Patients who had completed the first course of induction therapy, and who, in the opinion of the investigator, would not be able to continue treatment on the second induction regimen, initiated maintenance after the first induction. Maintenance therapy was given on an inpatient or outpatient basis depending on the patient's tolerance to the therapy. Patients were treated routinely with the following medications to abrogate the toxicity of treatment: acetaminophen 650 mg before treatment and every 4 hours for fever, indomethacin 25 mg every 6 hours or 50 mg every 8 hours for high fever, diphenhydramine 50 mg intramuscularly (IM) or orally before treatment and every 4 hours for rigors and pruritus, meperidine 25 mg IM or IV every 2 hours for chills or rigors, and prochlorperazine 10 mg IV or per rectum every 4 hours for nausea. Hypotension was managed with IV fluid boluses, infusions of salt-poor albumin, or an increase in the rate of infusion of 0.9% saline or Normosol (Abbott Laboratories, Chicago, IL). Response Assessment and Survival Determination Before treatment began, each patient was evaluated with a history and physical examination, chest roentgenogram, computed tomographic (CT) scan of the cranium, screening blood chemistries, and complete blood cell count. CT scans of the abdomen, pelvis, or chest and radionuclide scans were performed as indicated. Response was monitored by physical examination, chest roentgenogram, and other radiographic techniques depending on

Thirty-five patients were entered onto the study. One patient subsequently was declared ineligible because of prior IFN-a therapy, and was not considered assessable for either response or toxicity. Patient characteristics are outlined in Table 2. A nephrectomy had been performed before IL-2 and IFN-a in 20 patients. Twenty-eight patients (82%) completed one to two induction cycles, and 14 patients (41%) received maintenance doses. Discontinuation of therapy during the first or second cycle of induction equally was due to treatment intolerance (six patients; one taken off study at the patient's request) and progression of disease (six patients); six patients received only one induction cycle by decision of the investigator, but all went on to receive maintenance. Failure to proceed to maintenance therapy after the completion of induction was due to disease progression in six patients and toxicity in two patients. The majority of patients progressed on maintenance therapy (nine patients), and the remainder were taken off maintenance due to disease stabilization (one patient) or toxicity (two patients). Only two patients (6%) received the planned four to five cycles of maintenance. Response

The best response achieved in the 34 assessable patients is outlined in Table 3. Four of 34 patients (12%; 95% confidence interval [CI], 1% to 23%) achieved a major response (one complete response [CR], three

Table 1. Treatment Plan Study Day

1

2

3

4

Induction weeks 1-3, 6-8* IL-2 x x x x IFN-a x x x x Weeks 4, 5, 9, 10: No treatment (rest period) Maintenance weeks 11-13, 16-18, 21-23, 26-28, 31-33* IL-2 x x x x IFN-a x x Weeks 14, 15, 19, 20, 24, 25, 29, 30: no treatment (rest period)*

5 -

x x

6

7

Dose/Route/Frequency 2

-

-

3 x 106 ±/m /CIV/d 2 5 x 106 a/m /SC/d

-

-

2 x 106 ý/m /CIV/d 2 6 x 106f /m /SC/d

2

Abbreviations: CIV, continuous intravenous infusion; SC, subcutaneous. *Representative week of therapy.

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1126

ILSON ET AL Table 2. Patient Characteristics No.

Assessable patients No. of patients, n Males/females, n Median age (years) Range Median KPS* (%) Range Median interval (months) from diagnosis to therapy Range Prior therapy Nephrectomy Radiation therapy Immunotherapyt Chemotherapy Sites of disease Lung Lymph nodes Retroperitoneum Kidney primary Bone Other Liver No. of sites One site Two sites Three or more sites Area of tumor burden: 2 < 50 cm 2 2 50 cm < area 5 100 cm 2 > 100 cm Duration of therapy Cycles of induction received < one One Two Cycles of maintenance received One Two-three Four-five

partial responses [PRs]). One additional patient who achieved disease stabilization underwent complete surgical resection of the primary kidney tumor and lung metastases. A minor response was observed in four patients (12%) and stable disease was observed in 13 patients (38%). The prior experience in a MSKCCparticipating trial using a similar IL-2 dose with and without LAK cells 26 is included in Table 3. The characteristics of the responding patients are outlined in Table 4. CR was achieved in a patient with a measurable bone metastasis who had undergone prior nephrectomy and resection of a chest wall metastasis; in this patient, progressive sclerosis of a nonmeasurable pelvic bone metastasis also was observed. In the patient who achieved a PR in the primary tumor, complete resolution of a small pulmonary nodule also was achieved. Three of four patients who achieved a major response had a prior nephrectomy, and all had a Karnofsky performance status of 2 80. All patients with a major response had a tumor burden of less than 100 cm 2 . The area of tumor burden was less than 50 cm 2 in two patients and was between 50 and 100 cm 2 in three patients. Time to maximal response on therapy was 2, 3, 4, and 12 months on treatment, and the number of cycles of therapy delivered in these patients ranged from two inductions without further maintenance to induction with five maintenance cycles. Three patients remain free of disease after treatment with IL-2 and IFN-ct, with or without surgical resection of viable tumor, and a diseasefree duration of 4+, 7+, and 8+ months. Two patients underwent surgical exploration after they had achieved a PR. One patient with a PR in a retroperitoneal mass that extended into the inferior vena cava underwent resection. Viable cancer was found only in the intravascular thrombus. The patient remains without evidence of disease for 4+ months postsurgical excision of disease and 13+ months from the start of IL-2 and IFN-a therapy. The second patient underwent resection of the renal primary tumor, but relapsed with disease in the contralateral kidney 2 months later.

%

34 25/9 54 20-70 90 70-100 5.5 1-82 20 8 1 0 21 15 15 14 13 11 5 5 8 21 20 7 7

6 12 16 5 7 2

*Karnofsky performance status. tMonoclonal antibody therapy. ýMeasurable sites only.

Table 3. Results of Therapy With IL-2 in MSKCC-Participating Clinical Trials

No. of patients Response CR PR Minor/stable/progression

No.

No.

34

36

35

1 3 30

3 9 88

1 2 34

Total

IL-2/LAK*

IL-2*

IL-2/IFN-. No.

3 6 94

1 0 33

%

No.

%

105 3 0 94

3 5 97

26

*Results updated for presentation.

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3 5 92

1127

IL-2 AND IFN-a IN RCC Table 4. Characteristics of Patients With Major Response or Rendered Free of Disease Age (years)

Nephrectomy

70 55 56 54 64

Yes Yes Yes No No

Sites of Disease

Response

Duration (months)

Status

Bone Retroperitoneum, IVC Bone Kidney, lung Kidney, lung

CR PR PR PR* Stable

7+ 13+ 5 5 16+

NED NED* Deadt AWD NED*

Abbreviations: NED, no evidence of disease; AWD, alive with disease; IVC, inferior vena cava. *After surgical resection of disease. tTreatment-related death. *PR in kidney and CR in lung.

Survival Overall survival is shown in Fig 1. The median survival is 11 months. Thirteen patients (38%) are alive, and three (9%) are without evidence of disease. Toxicity Grade 1 or 2 fever, chills, tachycardia, hypotension, fatigue, skin rash, nausea, diarrhea, and reversible elevation of alkaline phosphatase and SGOT (threefold to 10-fold above normal) were noted in nearly all patients. Grade 3 or 4 toxicities are listed in Table 5. Overall, 19 of 34 patients (56%) experienced one or more grade 3 or 4 toxicities; nine patients were taken off study because of toxicity (26%), and six (18%) required dose reductions. Grade 3 or 4 pulmonary toxicity consisted of self-limited dyspnea at rest in five patients, and three patients were taken off of the study because of a respiratory insufficiency that required intubation, near respiratory arrest, and severe bronchospasm, respec-

28.

W

n,

a-

o

a.

0

4

8

12

16

20

24

Months from Protocol Entry Fig 1. Survival of RCC patients treated with IL-2/IFN-a (34 patients, 13 censored and alive).

tively. A weight gain of more than 10% was uncommon, but was observed in three patients (9%). Hematologic and renal toxicity are outlined in Table 5. RBC transfusion was required in three patients (9%). Dose reductions were made for renal toxicity (four patients, 15%), hypotension and renal toxicity (one patient), and hypotension and gastrointestinal toxicity (one patient). One patient experienced grade 4 cardiac toxicity and suffered a myocardial infarction in the setting of Staphylococcus aureus septicemia. An additional two patients experienced S aureus sepsis in the presence of a central venous catheter; none of the episodes were associated with neutropenia. Of the four patients who required intenTable 5. Toxicity Induction

Maintenance

or IVToxicity

No. of Patients

No. of Patients

Total

Toxicity Pulmonary Hypotension Renal Gastrointestinal Weight gain Hematologic CNS Cardiac Dose reduction Off therapy ICU admission Death Nadir WBC, median Range Nadir HG, median Range Nadir PLT, median Range Peak CREAT, median Range

8 8 5 3 3 3 1 1 6 7 4 0 5.1 2.4-10.5 9.5 6.9-14.7 159 49-578 2.1 0.7-10.7

0 0 0 1 0 0 2 0 0 2 0 2 5.5 2.0-7.6 10.6 8.2-14.6 165 57-299 1.8 1.0-7.4

8 8 5 4 3 3 3 1 6 9 4 2

Grade III

Abbreviations: ICU, intensive care unit; WBC, white blood count x 103 /mm 3; HG, hemoglobin in g/dL; PLT, plateletes x 105/mm 3 ; CREAT, creatinine in mg/dL.

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1128

ILSON ET AL

sive care unit monitoring during therapy, only one required intubation and pressor support. Two patients (6%) died of treatment-related causes. One patient died at home 3 days after the third cycle of maintenance was completed. Because permission for an autopsy was denied, the exact cause of death was not determined. Given the temporal association with treatment, the death is considered treatment-related. The second patient, who achieved a PR in a bone lesion, experienced severe depression during therapy and attempted suicide 6 weeks after a single cycle of maintenance was completed. Despite hospitalization and antidepressive therapy, the patient ultimately committed suicide 3 months after maintenance was completed. The patient had a distant history of depression 20 years earlier, but had no recurrence before therapy with IL-2 and IFN-a. DISCUSSION The initial enthusiasm generated by reports of major responses that included CR in patients with metastatic RCC treated with IL-2 with or without LAK cells 15,16 has been tempered by both the toxicity of therapy and the inability to confirm the high response proportions observed in the early trials. 17,27 IL-2 has been investigated at the MSKCC in collaboration with other participating institutions for use as a single agent and in combination with LAK cells or IFN-oa. An 8% response proportion (eight of 105; 95% CI, 3% to 13%) was achieved in two consecutive trials (Table 3). In the first trial, a randomized study of IL-2 with or without LAK cells, the addition of LAK cells had no therapeutic benefit. The second trial, which is reported here, showed no increase in response with the addition of IFN-a, and the response proportion was similar to a recent preliminary report of a phase II trial of IL-2 with IFN-a by the IL-2 group. 36 IL-2, at the dose and schedule used in the current trial, cannot be recommended as therapy for patients with advanced RCC as a single agent or in conjunction with LAK cells or IFN-ta. Differences in response proportions achieved with IL-2-based therapy may reflect several factors, including dose, patient selection, and the natural history of the disease. The more dose-intensive IL-2 regimens appar16 18 25 ently have yielded the highest response proportions. , , However, equally intensive therapy has been reported to have little or no antitumor activity. 17,27 Higher response proportions have been reported in trials in which the majority of patients had undergone prior nephrectomy and had minimal tumor bulk.16, 18,25 Most of the patients in the current trial had multiple sites of metastatic

disease, and 41% had a renal primary tumor in place, which partly may explain the low response proportion observed. Although all of the major responses were observed in patients with a tumor burden of less than 100 cm 2, one of four patients with a major response achieved a PR in the renal primary. Metastatic RCC is characterized by spontaneous remission or prolonged disease stabilization in some patients. The inclusion of such patients in clinical trials may inflate response proportions. To define better antitumor activity and spare some patients the morbidity of therapy, only patients who demonstrate progressive disease or who are symptomatic are encouraged to participate in clinical trials at the MSKCC. Given the resistance of RCC to systemic therapy, even minimal or moderate antitumor activity, such as the rare CR or PR reported with IL-2 and/or IFN-a, warrants continued investigation of these agents in the treatment of advanced RCC. Future trials will need to identify chemotherapeutic or immunotherapeutic agents that can effectively synergize with IL-2 or IFN-a. The identification of prognostic factors that predict response may be used to direct therapy to those patients who are most likely to benefit from it. A recent report has suggested that patients with lung metastases only achieve a higher response proportion to IFN-a. 39 The investigation of biologic prognostic factors may prove to be useful clinically. We recently have reported that the expression of a 160 kD glycoprotein (gpl60) in RCC cell lines correlated with resistance to the antiproliferative effects of IFN-a, which indicates that the absence of gpl60 expression may be predictive of sensitivity to the antitumor effects of IFN-a.40 A clinical trial is underway to investigate the efficacy of IFN-a in patients with gpl60negative tumors. The investigation of novel immunotherapeutic approaches is indicated. Tumor-cell recognition and host immune response may be enhanced by the localized secretion of cytokines by tumor cells; in animal models, the injection of tumor cells infected by retroviral vectors that bare genes for IL-241 or -y-interferon,42 which leads to constitutive secretion of these cytokines, resulted in potent antitumor responses and the induction of a long-lasting state of T-cell immunity. Finally, the investigation of new cytokines is warranted. REFERENCES 1. Linehan WM, Shipley WU, Longo DL: Cancer of the kidney and ureter, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott, 1989, pp 979-1007

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IL-2 AND IFN-a( IN RCC 2. Freed SZ, Halperin JP, Gordon M: Idiopathic regression of metastases from renal cell carcinoma. J Urol 118:538-542, 1977 3. Quesada JR: Biologic response modifiers in the therapy of metastatic renal cell carcinoma. Semin Oncol 15:396-407, 1988 4. Fairlamb DJ: Spontaneous regression of metastases of renal cancer. Cancer 47:2102-2106, 1981 5. Oliver RTD: Unexplained spontaneous regression and its relevance to the clinical behavior of renal cell carcinoma and its response to interferon. Proc Am Soc Clin Oncol 6:98, 1987 (abstr 383) 6. Gresser I: Commentary on varied biologic effects of interferon. Cell Immunol 34:406-415, 1977 7. Gracomni P, Aguzzi A, Petska S, et al: Modulation by recombinant DNA leukocyte (alpha) and fibroblast (beta) interferons by the expression and shedding of HLA- and tumor-associated antigens by human melanoma cells. J Immunol 54:2844-2849, 1984 8. Krown SE: Interferon treatment of renal cell carcinoma: Current status and future prospects. Cancer 59:647-651, 1987 9. Muss HB: Interferon therapy for renal cell carcinoma. Semin Oncol 13:36-42, 1987 (suppl 2) 10. Krown SE: Interferon and interferon inducers in cancer treatment. Semin Oncol 13:207-217, 1986 11. Fossa SD, Lien HH, Lindegaard M: Effect of recombinant interferon alpha on bone metastases of renal-cell carcinoma. N Engl J Med 324:633-634, 1991 12. Meir JW, Gallo RC: Human T cell growth factor (TCGF): Biochemical properties and interaction with and production by normal and neoplastic human T cells, in Pick E (ed): Lymphokines, vol 6. New York, NY, Academic Press, 1982, pp 137-163 13. Farrar JJ, Benjamin WR, Hilfiker ML, et al: The biochemistry, biology, and role of interleukin 2 in the induction of cytotoxic T-cell and antibody-forming B-cell responses. Immuno Rev 63:129166, 1982 14. Grimm EA, Mazumder A, Zhang HZ, et al: The lymphokineactivated killer cell phenomenon: Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med 155:1823-1841, 1982 15. Rosenberg SA, Lotze MT, Muul LM, et al: Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313:1485-1492, 1985 16. Rosenberg SA, Lotze MT, Muul LM, et al: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316:889-897, 1987 17. Fisher RA, Coltman CA, Doroshow JH, et al: Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells: A phase II clinical trial. Ann Int Med 108:518-523, 1988 18. Rosenberg SA: Clinical immunotherapy studies in the surgery branch of the U.S. National Cancer Institute: Brief review. Cancer Treat Rev 16:115-121, 1989 supplyl A) 19. West WH, Tauer KW, Yanelli JR, et al: Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316:898-905, 1987 20. Wang JCL, Walle A, Novogrodsky A, et al: A phase II clinical trial of adoptive immunotherapy for advanced renal cell carcinoma using mitogen-activated autologous leukocytes and continuous infusion interleukin-2. J Clin Oncol 7:1885-1891, 1989 21. Gaynor ER, Weiss GR, Margolin KA, et al: Phase I study of high-dose continuous infusion recombinant interleukin-2 and autologous lymphokine-activated killer cells in patients with metastatic

or unresectable malignant melanoma and renal cell carcinoma. J Natl Cancer Inst 82:1397-1402, 1990 22. Sosman JA, Kohler PC, Jank J, et al: Repetitive weekly cycles of recombinant human interleukin-2: Responses of renal carcinoma with acceptable toxicity. J Natl Cancer Inst 80:60-63, 1988 23. Parkinson DR, Fisher RI, Rayner AA, et al: Therapy of renal cell carcinoma with interleukin-2 and lymphokine-activated killer cells: Phase II experience with a hybrid bolus and continuous infusion interleukin-2 regimen. J Clin Oncol 8:1630-1636, 1990 24. Allison MAK, Jones SE, McGuffey D: Phase II trial of outpatient interleukin-2 in malignant lymphoma, chronic lymphocytic leukemia, and selected solid tumors. J Clin Oncol 7:75-80, 1989 25. Rosenberg SA, Lotze MT, Yang JC, et al: Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol 7:1863-1874, 1989 26. Bajorin DF, Sell KW, Richards JM, et al: A randomized trial of interleukin-2 plus lymphokine activated killer cells versus interleukin-2 alone in renal cell carcinoma. Proc Am Assoc Cancer Res 31:1106, 1990 (abstr C-1106) 27. Abrams JS, Rayner AA, Wiernik P, et al: High-dose recombinant interleukin-2 alone: A regimen with limited activity in the treatment of advanced renal cell carcinoma. J Natl Cancer Inst 82:1202-1206, 1990 28. Bukowski RM, Goodman P, Crawford ED, et al: A phase II trial of high-dose intermittent interleukin-2 in metastatic renal cell carcinoma. J Natl Cancer Inst 2:143-146, 1990 29. Brunda MJ, Bellantoni D, Sulich V: In vivo antitumor activity of combinations of interferon-a and interleukin-2 in a murine model. Correlation of efficacy with the induction of cytotoxic cells resembling natural killer cells. Int J Cancer 40:365371, 1987 30. Iiogo M, Sakurai J, Tamura T, et al: In vivo antitumor activity of multiple injections of recombinant interleukin-2, alone and in combination with three different types of recombinant interferon, on various syngeneic murine tumors. Cancer Res 48:5810-5817, 1988 31. Rosenberg SA, Schwartz S, Spiess PJ: Combination immunotherapy for cancer: Synergistic antitumor interactions of interleukin-2, alpha-interferon, and tumor-infiltrating lymphocytes. J Natl Cancer Inst 80:1393-1397, 1988 32. Budd GT, Osgood B, Barna B, et al: Phase I clinical trial of interleukin-2 and alpha-interferon: Toxicity and immunologic effects. Cancer Res 49:6432-6436, 1989 33. Lee KH, Talpaz M, Rothberg JM, et al: Concomitant administration of recombinant human interleukin-2 and recombinant human interferon alpha-2A in cancer patients: A phase I study. J Clin Oncol 7:1726-1732, 1989 34. Hirsh M, Lipton A, Harvey H, et al: Phase I study of interleukin-2 and interferon alpha-2A as outpatient therapy for patients with advanced malignancy. J Clin Oncol 8:1657-1663, 1990 35. Mittelman A, Huberman M, Puccio C, et al: A phase I study of recombinant human interleukin-2 and alpha-interferon-2a in patients with renal cell cancer, colorectal cancer, and malignant melanoma. Cancer 66:664-669, 1990 36. Atkins MB, Sparano J, Fisher RI, et al: Randomized phase II trial of high-dose IL-2 either alone or in combination with interferon alpha 2B in advanced renal cell carcinoma. Proc Am Soc Clin Oncol 10:166, 1991 (abstr C-526)

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ILSON ET AL

1130 37. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981 38. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 39. Neidhart J, Anderson SA, Harris JE, et al: Vinblastine fails to improve response of renal cancer to interferon alfa-nl: High response rate in patients with pulmonary metastases. J Clin Oncol 9:832-837, 1991 40. Nanus DM, Pfeffer LM, Bander NH, et al: Antiproliferative

and antitumor effects of a-interferon in renal cell carcinoma: Correlation with expression of a kidney-associated differentiation glycoprotein. Cancer Res 50:4190-4194, 1990 41. Gansbacher B, Bannerji R, Daniels B, et al: Retroviral vector-mediated gamma-interferon gene transfer into tumor cells generated potent and long lasting antitumor immunity. Cancer Res 50:7820-7825, 1990 42. Gansbacher B, Zier K, Daniels B, et al: Interleukin-2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J Exp Med 172:1217-1224, 1990

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A phase II trial of interleukin-2 and interferon alfa-2a in patients with advanced renal cell carcinoma.

A phase II trial that used a regimen of interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) was undertaken to evaluate the efficacy of this combin...
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