Clinical Cancer Research Meeting Calendar Advances in Breast Cancer
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dutcher, J. P.
Right arrow Articles by Atkins, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dutcher, J. P.
Right arrow Articles by Atkins, M.
Clinical Cancer Research Vol. 6, 3442-3450, September 2000
© 2000 American Association for Cancer Research

Clinical Trials

Phase II Trial of Interleukin 2, Interferon {alpha}, and 5-Fluorouracil in Metastatic Renal Cell Cancer: A Cytokine Working Group Study1

Janice P. Dutcher2, Theodore Logan3, Michael Gordon4, Jeffrey Sosman5, Geoffrey Weiss, Kim Margolin, Terry Plasse, James Mier6, Michael Lotze, Joseph Clark and Michael Atkins6

Albert Einstein Cancer Center, Bronx, New York [J. P. D.]; University of Pittsburgh, Pittsburgh, Pennsylvania 15260 [T. L., M. L.]; Indiana University, Indianapolis, Indiana 85012 [M. G.]; Loyola University, Chicago, Illinois 60612 [J. S., J. C.]; University of Texas, San Antonio, Texas [G. W.]; City of Hope Medical Center, Duarte, California 91010 [K. M.]; Chiron Corp., Emeryville, California 94608 [T. P.]; and Tufts-New England Medical Center, Boston, Massachusetts 02111 [J. M., M. A.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-{alpha}2B followed by 4 weeks of 5-fluorouracil plus IFN-{alpha}2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1–4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3–5, and the dosage for IFN-{alpha}2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-{alpha}2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5–8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-{alpha}2B (9 MIU/m2) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated.

There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10–25). The median response duration was 8 months (range, 3–51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1–53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4- week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts are directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment versus treatment with outpatient s.c. injection of IL-2 plus IFN.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
rIL-27 has been shown to produce partial and CRs in a minority of good-performance-status patients with metastatic renal cell carcinoma (1, 2, 3, 4, 5, 6) . The high-dose regimen originally described by Rosenberg et al. has been associated with durable responses in a number of follow-up analyses (1, 2, 3, 4) . The concerns regarding the high-dose regimen have always been the restriction of the regimen to highly selected patients and the potential for severe toxicity (1, 2, 3, 4, 5, 6, 7) . Subsequent studies of lower-dose regimens of rIL-2 alone have suggested a lower therapeutic potential, but only one Phase III comparative study has been reported (8 , 9) .

Because preclinical data suggested synergy when IL-2 was combined with IFN-{alpha} (10, 11, 12, 13, 14, 15, 16) , a variety of doses and schedules have been tested and have demonstrated tolerability and clinical response (17, 18, 19, 20, 21, 22) . Additional Phase II studies of this combination with prolonged follow-up have yielded response rates similar to those produced by high-dose rIL-2 (23, 24, 25, 26, 27, 28) . Response duration has yet to be assessed for comparability, but there have been long-term survivors with lower-dose, combination cytokine regimens (23, 24, 25, 26, 27, 28) .

The addition of IFN-{alpha} to 5FU therapy in gastrointestinal malignancies is based on preclinical work demonstrating the biochemical modulation of 5FU by IFN (29) . In a recent study of this combination in mice carrying the RENCA renal cell tumor model, IFN was shown to reduce thymidine kinase activity (30) . Although the applicability of this mechanism to the treatment of human renal cancer is unknown, 2'-deoxy-5-fluorouridine, a 5FU derivative, has yielded a response rate in metastatic renal cell carcinoma that suggests a possible basis for 5FU-plus-cytokine therapy in renal cell cancer (31) . On the basis of these data and others, studies of the combination of 5FU and IFN have been performed in metastatic renal cell carcinoma with variable results (32, 33, 34, 35) . Subsequent studies have combined IL-2 with IFN and 5FU, either simultaneously (36, 37, 38, 39, 40, 41, 42) or sequentially, alternating IL-2/IFN with 5FU/IFN (43, 44, 45, 46, 47, 48) . Results demonstrate response rates ranging from 2 to 39% and median survival ranging from 11.9 to more than 42 months (36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48) .

In this report by the CWG, we have attempted to reproduce the results reported with an alternating regimen of rIL-2/IFN with 5FU/IFN (43, 44, 45, 46) , to evaluate the response rate and response duration and survival, and to assess the quality of life of patients during administration of this therapy. Similar to previous CWG studies, we have used strict patient eligibility criteria, including only patients who would otherwise be eligible for high-dose rIL-2 studies (2 , 3 , 7) . Quality-of-life assessment was a new evaluation technique for patients with renal cell cancer and was conducted at baseline and periodically throughout the treatment period. Two standardized, well-established questionnaires that evaluate various functional and symptom parameters were used in an attempt to assess the impact of treatment and disease on patient symptoms and function. This analysis will be reported in a separate publication.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection.
Eligible patients were required to meet the criteria used in our previous high-dose IL-2 studies (2 , 3 , 7) . These include histologically confirmed bidimensionally measurable and clearly progressive metastatic renal cell cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; adequate organ function, with normal hematological parameters; serum creatinine <= 1.5 mg/dl or calculated creatinine clearance >60 ml/min; forced expiratory volume in 1 sec >2.0 liter/sec or 75% of predicted value; no evidence of congestive heart failure, serious cardiac arrhythmias, symptoms of coronary artery disease, or ischemia on a cardiac stress test; negative serological testing for human immunodeficiency virus type I antibody and hepatitis B surface antigen; no contraindications to the use of pressor agents; no evidence of active infection requiring antibiotic therapy; and no medical condition requiring corticosteroids. Patients who had received prior treatment with either rIL-2 or type I IFNs and those with brain metastases, seizure disorders, organ allografts, history of another malignancy, or concurrent corticosteroid therapy were ineligible.

Treatment Plan.
Patients were treated in an outpatient setting, based on a report from Europe (43, 44, 45, 46) , using the drug administration schedule depicted in Table 1Citation . During the first 4 weeks of treatment, patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) in weeks 1 and 4 (10 MIU/m2 twice daily on days 3–5) and IFN-{alpha}2B (Intron; Schering Plough, Kenilworth, NJ; 6 MIU/m2 on day 1). During weeks 2 and 3, dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and for IFN-{alpha}2B was 6 MIU/m2 on days 1, 3, and 5. During weeks 5–8, 5FU (750 mg/m2 ) was administered once weekly by a bolus i.v. injection, and IFN-{alpha}2B (9 MIU/m2 ) was administered as a s.c. injection three times weekly. All of the patients were taught self-administration of s.c. rIL-2 and IFN-{alpha}2B in anticipation of outpatient administration.


View this table:
[in this window]
[in a new window]

  		Table 1 Treatment schema

 
Patients were evaluated for tumor response at the end of each 8-week cycle. Patients with progressive disease after a course of therapy were removed from study treatment. Patients with evidence of objective tumor response or stable disease were able to continue on treatment for two courses beyond maximal regression or until progression. A rest period of 2–4 weeks was permitted after each 8-week treatment to allow for recovery and tumor assessment. Patients could discontinue therapy at their request. Several patients underwent surgical resection of residual disease after one or two courses of therapy or after the completion of therapy at the discretion of their physician. In the case of responders who underwent resection of residual disease while in response, the response duration was censored at the time of surgery.

This protocol was approved by the institutional review committee of each participating institution, and all of the patients provided voluntary written informed consent.

Dose Modification and Toxicity Monitoring.
Toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria. Treatment modifications for dose-limiting toxicities were determined by the part of the course in which the patient was being treated. During the first 4 weeks, criteria for holding doses were related to marked changes in performance status or grade 3/4 toxicity associated with the inability to perform normal activities of daily living, and/or a requirement for hospitalization. During weeks 1–4 of a course, both IFN and rIL-2 were withheld for any DLT until there was improvement to a grade 1 or less, and then therapy was reinstituted, with 50% reduction of both drugs. Patients were evaluated at the end of week 4 for their readiness to continue to week 5. Treatment was delayed until toxicities from week 1–4 were resolved to a clinically acceptable level. Delays of greater than 2 weeks prior to the initiation of week 5 led to dose reduction of the subsequent rIL-2/IFN 4-week therapy of the next cycle. Even if dose adjustments were required during the initial 4 weeks of rIL-2/IFN, the second 4-week segment of 5FU/IFN was started at full-dose. Subsequent dose adjustments were made based on the segment of therapy in which toxicity occurred, i.e., dosages of 5FU were adjusted for each course.

During weeks 5–8, IFN dose reductions, which followed the above guidelines, were not influenced by 5FU toxicities or 5FU dose modifications. After DLT (myelosuppression) attributable to 5FU, all of the subsequent doses of 5FU were delivered at 75% of the initial dose. For a second DLT, the 5FU was reduced to 50%. Patients requiring dose reductions more than twice were removed from study. No doses were recovered nor was dose reescalation allowed.

Response Assessment.
Standard response criteria were used. CR was defined as the complete absence of all clinical evidence of malignant disease for at least two determinations 4 weeks apart. PR required >50% decrease in the sum of the products of the perpendicular diameters of all measurable lesions for at least two measurements at least 4 weeks apart. MR was <50% but >25% reduction but was in fact considered stable disease. Stable disease was defined as including MR, no change, or <25% increase in disease and no new disease. Clinically relevant stable disease must be durable, at least 6 months. Progressive disease was defined as a greater than 25% increase in the sum of the products of perpendicular diameters of all lesions, or the appearance of any new lesion. Response duration was measured from the date of PR or CR, and survival was measured from the date of entry into the study.

Quality of Life Evaluation.
Because there was concern about the toxicity of chronic cytokine therapy, a health-related quality of life assessment was performed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 evaluation instrument (49) and the McCorkle and Young symptom-distress scale (50) . These provided patient self-evaluation of symptoms and level of function, as well as an assessment of the financial impact of the disease and its treatment. The QLQ-C30 and symptom-distress scale questionnaires were completed at three time points during course 1, and at the beginning of subsequent courses and off study. The full evaluation of the quality of life assessment as a reporting instrument in patients with metastatic renal cell cancer will be published separately.

Statistical Considerations.
This Phase II study was designed to evaluate the response rate, duration of response, and long-term follow-up of patients treated with a regimen of IL-2/IFN alternating with 5FU/IFN. The goal was to detect a result in which data demonstrated with 95% confidence that the response rate was >=20% and that the CR rate was >=10%, as was described in the original report of this regimen (10% CR and 29% PR; Refs. 43, 44, 45, 46 ). We set a high standard in the attempt to demonstrate whether this is a substantially more active regimen. These results could constitute an incremental improvement of this combined regimen over the regimen of rIL-2/IFN alone. To achieve this power, the accrual of 50 patients was required and met. In view of the expected rapid rate of accrual, there were no early-stopping rules applied.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics.
Table 2Citation outlines the patient demographics and disease characteristics. Fifty patients (41 males and 9 females; median age, 54 years; range, 31–77 years) who met the eligibility criteria outlined were entered in the study. All of them were evaluable for response and toxicity. Thirty-six patients had Eastern Cooperative Oncology Group performance status 0, and 12 had performance status 1. On review, two patients with performance status 2 were treated. Thirty-seven (74%) had undergone nephrectomy before IL-2-based therapy, and 20% had lung metastases as the only site of metastatic disease, which is a distribution similar to that reported in previous CWG studies. The sites of disease are also shown in Table 2Citation .


View this table:
[in this window]
[in a new window]

  		Table 2 Patient characteristics (n = 50)

 
Treatment Course and Dose Alterations.
Patients received full-dose treatment as prescribed until progression, a maximum of 4 courses, or unless undue toxicity required a dose adjustment or cessation. Table 3Citation demonstrates the numbers of patients beginning each course of therapy and the number requiring dose adjustments during treatment. All of the 50 patients completed nearly all of the first 4 weeks of rIL-2 and IFN in course 1 (Ia). However, five patients did not go on to the 5FU/IFN segment of course 1 (Ib) for the reasons noted in Table 3Citation . Six patients required dosage alterations during Ia, and nine required alterations during Ib.


View this table:
[in this window]
[in a new window]

  		Table 3 Treatment administration

 
Twenty-six patients began course 2 of rIL-2/IFN (IIa), and 25 went on to the 5FU/IFN segment of course 2 (IIb). Seventeen patients progressed between course 1 and course 2 as noted in Table 3Citation . One patient progressed after IIa and did not receive 5FU/IFN. Dose adjustments were required in six patients during IIa and in 13 patients during IIb.

Nine patients began course 3 of rIL-2/IFN (IIIa) and 8 began the 5FU/IFN (IIIb) segment of course 3. Between courses 2 and 3, 13 patients discontinued protocol therapy because of progressive disease. One patient who achieved PR and was eligible for course 3 became a surgical complete responder after course 2 and did not receive further therapy, and two other eligible patients refused further therapy. Dose adjustments from prior courses were continued in two patients during IIIa and in seven patients during IIIb. Only two patients began course 4, and one completed it with markedly reduced doses of 5FU.

Toxicity.
All of the 50 patients were evaluable for toxicity. Toxicity was primarily constitutional in the rIL-2/IFN segments of the courses and was granulocytopenia during the 5FU/IFN segments (Table 4)Citation . There appeared to be cumulative myelotoxicity, requiring multiple 5FU dosing adjustments in most patients who received more than one cycle of therapy. The most common toxicities during rIL-2/IFN were fatigue, nausea/vomiting, anorexia, skin rash, injection site inflammation, diarrhea, fever, and liver transaminase function abnormalities. One-third of patients experienced some form of central nervous system toxicity, including headache and depression. In the 5FU/IFN segment of the first course, 48 of 50 patients experienced grade 2/3 granulocytopenia, and one other experienced thrombocytopenia. Less frequent grade 2/3 toxicities included diarrhea, nausea, vomiting, fatigue, and thrombocytopenia. During the course of the study, eight patients experienced nine grade 4 toxicities, including nausea/vomiting (one patient), diarrhea (three patients), central nervous system (one patient), liver function (one patient), shortness of breath (one patient), and hypotension and shortness of breath in one patient who developed sepsis (Table 5)Citation .


View this table:
[in this window]
[in a new window]

  		Table 4 Toxicity—course 1

 

View this table:
[in this window]
[in a new window]

  		Table 5 Grade 4 toxicity—all courses

 
Quality of Life Evaluation.
At baseline, all of the patients were quite close in performance status, as required by protocol. In view of the somewhat rapid fall-off in patient numbers per cycle of therapy, hard numerical comparisons cycle-by-cycle are difficult. However, any subsequent quality-of-life functional scales and symptomatology scores generally correlated with clinical outcome, when the patients were divided into either progressive disease or those with response. There were substantial declines in functional scales in the progressive disease group versus stabilization or smaller declines in the other patients even during treatment. Most of the symptoms that were measured worsened more for the progressive disease group than for the other patients (51) . This will be reported in detail in a subsequent publication.

Response and Survival.
There were two complete and seven partial responders for an overall response rate of 18%, (95% confidence interval, 10–25; Table 6Citation ). The median response duration was 8 months (range, 3–51+ months). Patients rendered disease-free by subsequent surgery were censored at the time of surgery, and their response is listed as the best response to protocol therapy alone. The CR durations were 5 months and 51+ months. The patient who remains disease-free had disease in the lung and kidney. Other responding patients had disease in the lung, renal bed masses, lymph nodes, and adrenal masses. The PR durations ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three PRs, one minor responder, and four with stable disease) were rendered disease-free by resection of remaining metastatic disease. Six of the eight remain alive at 43+ to 53+ months, and four remain disease-free since surgery. Twenty-one patients were classified with stable disease as best response. Six of these remained stable for 6 or more months (range, 6–18 months).


View this table:
[in this window]
[in a new window]

  		Table 6 Response and survival in CWG studies

 
The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1 to 53+ months. This median survival in part reflects the excellent performance status of the patients entered and is consistent with the median survival of patients entered in previous CWG studies who met the same eligibility criteria. It is also consistent with the median survival reported for IL-2 plus IFN by Negrier et al. (28) in a randomized study in which the combination had a longer median survival than did either arm with IL-2 or IFN alone. In our study, eight patients remain alive at 43+ to 53+ months after starting treatment; five are disease-free. This is also similar to our results with outpatient s.c. rIL-2 plus IFN given at monthly cycles without 5FU (Refs. 25, 26, 27 , 47 ; Table 6Citation ).


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study attempted to confirm and further evaluate the toxicity and efficacy of a complex biochemotherapy regimen reported from a multicenter European trial (43, 44, 45, 46) . The regimen consisted of alternating 4 weeks each of rIL-2/IFN with 5FU/IFN. The criteria for entry into this trial were similar to those for patients entered into previous CWG trials of high-dose rIL-2 based therapy. The first 8-week course of the regimen was administered almost in full, but only one-half of the patients began the second course, primarily because of progressive disease.

Table 7Citation summarizes other reports of therapy of metastatic renal cell cancer using 5FU/IL-2/IFN. The initial report by Atzpodien et al. (52) generated interest in this approach, reporting a response rate of 47.6%. Since that report, others have reported variable results (36, 37, 38, 39, 40, 41, 42) . However, in view of the high response rate and low toxicities reported, we chose to duplicate the regimen exactly as published (43, 44, 45, 46 , 52) .


View this table:
[in this window]
[in a new window]

  		Table 7 Summary of phase II/III trials of IL-2/IFN/5FU in metastatic renal cell carcinomaa

 
Our results differ from those of Atzpodien et al. (43 , 46 , 52) using this regimen, both in terms of response rate and in toxicity. In our study, 18.5% achieved CR or PR, whereas Atzpodien et al. and Hanninen et al. reported a response rate of 39% when they included larger numbers of patients (43 , 44) . Although the patient populations in general appear to be similar, one possibility that has been raised for this difference is the rate of prior nephrectomies in the two studies. In our study, 13 patients (26%) had their primary tumor in place, although it did not represent the bulk of the disease at the time of treatment, whereas in the later report by Atzpodien et al. (46) , 96% had had prior surgery (not specifying nephrectomy). In our previous CWG studies, the percentage of patients with affected kidney in place was one-half of the rate in this study, 13% in the outpatient IL-2/IFN study and 14% in the high-dose IL-2 study (3 , 27) . However, the response rate achieved in this study is consistent with our previous results as is the median survival for this patient population (Table 6Citation ; 3 , 27 ), and these results are consistent with other reports of this combination (Table 7Citation ; Refs. 36, 37, 38, 39, 40, 41, 42 ). In a recent update of the European continuous infusion IL-2 data, Negrier et al. (53) reviewed three studies, including the randomized French study, using either this combination or IL-2 plus IFN, and response rates were consistent with our data. The overall median survival for all of the patients in the three trials was somewhat shorter (10 months) despite 93% having had prior nephrectomy (53) . Still, in view of recent data which suggests improved survival in patients who underwent nephrectomy prior to receiving IFN (54) , the lower rate of nephrectomy in our study, or the ability of the study-patients entered to undergo nephrectomy, cannot be excluded as a potential factor in determining the response rate and overall outcome.

With respect to differences in toxicity observed, in the initial reports by Atzpodien et al. (43, 44, 45, 46) of this regimen, toxicity was remarkably mild and in substantial contrast to the toxicity observed in our study of this regimen. We very carefully reproduced the schema of the regimen, despite its complexity, so it is unlikely that differences in administration account for the differences in toxicity reporting. In addition, the patients were comparable, with all but two of our patients having performance status of 0 or 1. Of note, in the >German study (43, 44, 45, 46) , patients were responsible for self-assessing and grading their own toxicity through a form that they completed. They were followed by general practitioners, and results of the assessments were reported to the oncology center. It is not stated how frequently laboratory tests were obtained. Thus, the difference in toxicity may be in the reporting and capturing of various grades of toxicity and in the familiarity with a specific grading scale. Additionally, patients may not have reported all toxicities, and infrequent blood testing may not have captured laboratory abnormalities. Certainly the toxicities reported in our study with this regimen are consistent with other reports of this combination of agents in this patient population (37, 38, 39) .

The studies listed in Table 7Citation provide a background of the overall response and survival data achieved with a variety of dosages and schedules of 5 FU and IL-2, including bolus or continuous infusion 5FU and s.c. and i.v. continuous infusion IL-2 (36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47) . Pharmacokinetics of IL-2 by either s.c. injection or i.v. continuous infusion route are quite similar. Most of the studies listed demonstrate increased myelosuppression with the addition of 5FU. The dosages of 5FU have ranged from 200 to 1000 mg/m2 .

Overall response rates have been reported from 1.8 to 39%, and in a recent review by Bukowski and Dutcher (48) , the response rate in 836 patients treated with some combination of IL-2/IFN and 5FU was 25.3%. CR rates and median survival data are also widely variable but fall within the range of that seen with IL-2/IFN alone (21, 22, 23, 24 , 27 , 28) .

Negrier et al. (42) have conducted the only randomized study currently available of IL-2/IFN with or without 5FU, including 131 patients, 70 in the IL-2/IFN-alone arm and 61 in the arm with 5FU added. The schedule was every other week, with IL-2 given for 6 days and IFN for 3 days. 5FU was given by continuous infusion during weeks 1 and 5. The response rate for IL-2/IFN was 1.8% and for that plus 5FU, 8.2%, and they concluded that neither arm was active. Others who use weekly administration of IL-2/IFN alone have consistently reported response rates of 15–25% (21, 22, 23, 24 , 27 , 28) .

Ellerhorst et al. (37) , using i.v. continuous infusions of both IL-2 and 5FU with s.c. administered IFN, report a response rate of 31% accompanied by substantial toxicity. Similarly, regimens such as that reported by Kirchner and Tourani (38 , 45) are associated with significant toxicity, such that delays or reductions in dosage occur in more than 50% of patients treated.

The overall response rate of 18% and median survival of 17.5 months observed in the present study are similar to that reported in previous CWG trials, including those using high-dose i.v. bolus rIL-2 alone and those using outpatient s.c. rIL-2/IFN (Table 6Citation ; Refs. 2 , 3 , 27 , 28 ). In this study, the addition of an alternating month of 5FU/IFN per course did not appear to augment either the response rate or the median survival as previously reported for rIL-2/IFN alone (21, 22, 23, 24 , 27 , 28) . It may be that the first 4 weeks of therapy is the critical treatment period, but that cannot be ascertained from this study, although one-half of patients progressed within the first 8–12 weeks.

It is important to note that, as with previous rIL-2 based trials, there are long-term survivors among the patients treated in this study, with eight patients (16%) still alive after 53 months of follow-up. In studies of high-dose bolus IL-2, the long-term survivors are primarily the drug-induced complete responders (4) . However, in this study, of the eight long-term survivors, one was a complete responder to IL-2/IFN/5FU alone, but six were rendered disease-free with surgery after IL-2/IFN/5FU after having achieved a PR (n = 3) or stable disease (n = 5), and 5 have remained disease-free after surgery with all of them having prolonged survival.

In summary, the CWG has shown in this study and in the previous outpatient study of rIL-2/IFN (25, 26, 27 , 47) that outpatient rIL-2 based therapy has activity against metastatic renal cell carcinoma. This type of treatment still requires goodperformance-status patients, however, and does not enhance access to this therapy by virtue of ease of administration of a lower-dose regimen. The outcome of this study is not dissimilar to our previous study of every-4-week rIL-2/IFN-alone, and that regimen is considerably less complex. Despite the absence of randomized trial data, it is extremely unlikely that the addition of alternating 5FU/IFN to rIL-2/IFN is superior to rIL-2/IFN alone, in terms of response rate or survival, based on our data and on the cumulative experience with this combination (Table 7Citation ; 47 , 48 ). The CWG does not recommend the addition of 5FU/IFN to the above outpatient rIL-2/IFN regimen. Others have demonstrated the lack of benefit from the simultaneous administration of 5FU with rIL-2/IFN, but in doses and schedule somewhat different from the earlier reports (38 , 39) . In terms of the combination of IL-2 plus IFN, with outpatient s.c. administration, the combination appears to be more efficacious than either agent alone. This has been demonstrated in a randomized trial by Negrier et al. (28 , 53) , which showed improved one-year survival with the combination compared with either drug alone. They have not, however, seen synergy with the addition of 5FU (42) .

This study, once again, points to the potential value of surgical resection after maximal response or stable disease with cytokine therapy, with six of eight patients remaining disease-free after surgery for residual metastatic disease at 43+ to 53+ months from the start of treatment (55 , 56) . Surgery for metastatic renal cell cancer during the first year of treatment appears to also have a role in overall management and, in conjunction with cytokine therapy, is capable of producing prolonged disease-free survival.

This study does not help to answer the question of the relative benefit of high-dose, short-course inpatient bolus rIL-2 compared with outpatient, prolonged rIL-2/IFN therapy for metastatic renal cell cancer. The relative toxicities are well demonstrated, but the relative efficacy in terms of long-term disease-free survival is not yet known. The major question remains whether outpatient IL-2/IFN is comparable with high-dose IL-2 in terms of response duration, progression-free survival, or overall survival. The response rate in this study is similar to that seen with high-dose IL-2, but the response duration and progression-free survival at 3 years from drug alone are considerably less than that reported with high-dose bolus IL-2 (Table 6)Citation . Of the long-term disease-free survivors, only one is disease-free solely from the effect of the drugs administered. The others were rendered disease-free with surgery after treatment with the study regimen. The median survival is 17.5 months with a range of 1 to 53+ month, and further follow-up will provide an initial comparison to the original high-dose IL-2 regimen. However, only the results of a large, ongoing Phase III randomized study can attempt to fully answer a comparative question. Such a study is currently underway in the CWG in which high-dose IL-2, using the CWG dosage and schedule (600,000 IU/kg every 8 h in weeks 1 and 3 every 12 weeks) is compared with the CWG outpatient regimen of IL-2 (5 MIU/m2 daily for 5 days) plus IFN (5 MU/m2 three times per week), both for 4 weeks, every 6–8 weeks for up to 6 months. This study will provide important answers regarding optimal dose and schedule of IL-2-based therapy for metastatic renal cell cancer. Finally, we must continue to seek new treatment approaches for metastatic renal cell cancer, alone or in combination with other agents.


   FOOTNOTES
 
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.

1 Supported in part by grants to each institution from Chiron Therapeutics, Division of Chiron Corporation, Emeryville, CA and Schering Plough Corporation, Kenilworth, N. J., and by the Cancer Center Support Grant P30CA13330 awarded by the National Cancer Institute. Presented in part at the 1997 meeting of the American Society of Clinical Oncology. Back

2 Present address and to whom requests for reprints should be addressed, at Comprehensive Cancer Center, Our Lady of Mercy Medical Center, 600 East 233rd Street, Bronx, NY 10466. Phone: (718) 920-1112; Fax: (718) 920-1123. Back

3 Present address: Indiana University, Indianapolis, IN. Back

4 Present address: University of Arizona, Phoenix, AZ. Back

5 Present address: University of Illinois Medical Center, Chicago, IL. Back

6 Present address: Beth Israel Deaconess Medical Center, Boston, MA. Back

7 The abbreviations used are: rIL-2, recombinant IL-2; IL-2, interleukin 2; 5FU, 5-fluorouracil; CWG, cytokine working group; DLT, dose-limiting toxicity; CR, complete response; PR, partial response; MR, minor response. Back

Received 11/ 5/99; revised 6/16/00; accepted 6/21/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Rosenberg S. A., Yang J. C., Topalian S. L., Schwartentruber D. J., Weber J. S., Parkinson D. R., Seipp C. A., Einhorn J. H., White D. E. The treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high dose bolus interleukin-2. J. Am. Med. Assoc., 271: 907-913, 1994.[Abstract/Free Full Text]
  2. Fisher, R. I., Coltman, C. A, Jr., Doroshow, J. H., Rayner, A. A., Hawkins, M. J., Mier, J. W., Wiernik, P. H., McMannis, J. D., Weiss, G. R., Margolin, K. A., Gemlo, B. T., Hoth, D. F., Parkinson, D. R., and Paietta, E. Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells—a Phase II clinical trial. Ann. Intern. Med., 108: 518–523, 1988.
  3. Atkins M. B., Sparano J., Fisher R. I., Weiss G. R., Margolin K. A., Fink K. I., Rubinstein L., Louie A., Mier J. W., Gucalp R., Sosman J. A., Boldt D. H., Doroshow J. H., Aronson F. R., Sznol M. Randomized Phase II trial of high dose interleukin-2 either alone or in combination with interferon {alpha}-2b in advanced renal cell carcinoma. J. Clin. Oncol., 11: 661-670, 1993.[Abstract]
  4. Fyfe G., Fisher R. I., Rosenberg S. A., Sznol M., Parkinson D. R., Louie A. C. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J. Clin. Oncol., 13: 688-696, 1995.[Abstract/Free Full Text]
  5. West W. H., Tauer K. W., Yanelli J. R., Marshall G. D., Orr D. W., Thurman G. B., Oldham R. K. Constant infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N. Engl. J. Med., 316: 898-905, 1987.[Abstract]
  6. Bukowski R. M., Goodman P., Crawford E. D., Sergi J. S., Redan B. G., Whitehead R. P. A Phase II trial of high dose intermittent interleukin-2 in metastatic renal cell carcinoma. A Southwest Oncology Group Study. J. Natl. Cancer Inst., 82: 1202-1206, 1990.[Abstract/Free Full Text]
  7. Margolin K., Rayner A. A., Hawkins M., Atkins M., Dutcher J. P., Fisher R. I., Weiss G. R., Doroshow J. H., Jaffe H. S., Roper M., Parkinson D. R., Wiernik P. H., Creekmore S. P., Boldt D. H. Toxicity of interleukin-2 and lymphokine-activated killer (LAK) cell therapy. J. Clin. Oncol., 7: 486-489, 1989.[Abstract]
  8. Yang J. C., Topalian S. L., Parkinson D., Schwartzentruber D. J., Weber J. S., Ettinghausen S. E., White D. E., Steinberg S. M., Cole D. J., Kim H. I., Levin R., Guleria A., MacFarlane M. P., White R. L., Einhorn J. H., Seipp C. A., Rosenberg S. A. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J. Clin. Oncol., 12: 1572-1576, 1994.[Abstract/Free Full Text]
  9. Yang J. C., Rosenberg S. A. An ongoing prospective randomized comparison of interleukin-2 regimens for the treatment of metastatic renal cell cancer. Cancer J. Sci. Am., 3(Suppl.1): S79-S84, 1997.
  10. Iigo M., Sakurai M., Tamura T., Saijo N., Hoshi A. 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: 260-264, 1988.[Abstract/Free Full Text]
  11. Brunda M. J., Bellantoni D., Sulich V. In vivo antitumor activity of combinations of interferon-{alpha} and interleukin-2 in a murine model. Correlation of efficacy with the induction of cytotoxic cells resembling natural killer cells. Int. J. Cancer, 40: 365-371, 1987.[Medline]
  12. Kim B., Warnaka P. Indomethacin-enhanced immunotherapy of pulmonary metastases using IL-2 and IFN-{alpha}. Surgery, 106: 248-256, 1989.[Medline]
  13. Cameron R. B., McIntosh J. K., Rosenberg S. A. Synergistic antitumor effects of combination immunotherapy with recombinant interleukin-2 and a recombinant hybrid {alpha}-interferon in the treatment of established murine hepatic metastases. Cancer Res., 48: 5810-5817, 1988.[Abstract/Free Full Text]
  14. Weber J. S., Rosenberg S. A. Modulation of murine tumor major histocompatibility antigens by cytokines in vivo and in vitro. Cancer Res., 48: 5818-5824, 1988.[Abstract/Free Full Text]
  15. Guadagni F., Schlom J., Johnston W. W., Szpak C. A., Goldstein D., Smalley R., Simpson J. F., Borden E. C., Pestka S., Greiner J. W. Selective interferon-induced enhancement of tumor-associated antigens on a spectrum of freshly isolated human adenocarcinoma cells. J. Natl. Cancer Inst., 81: 502-511, 1989.[Abstract/Free Full Text]
  16. Winklehake J. L., Stampfl S., Zimmerman R. J. Synergistic effects of combination therapy with human recombinant interleukin-2 and tumor necrosis factor in murine tumor models. Cancer Res., 47: 3948-3953, 1987.[Abstract/Free Full Text]
  17. Rosenberg, S. A., Lotze, M. T., Yang, J. C., Linehan, W. M., Seipp, C., Calabro, S., Karp, S. E., Sherry, R. M., Steinberg, S., and White, D. E. Combination therapy with interleukin-2 and {alpha}-interferon for the treatment of patients with advanced cancer. J. Clin. Oncol., 7: 1863–1874. 1989.
  18. Lee K. H., Talpaz M., Rothberg J. M., Murray J. L., Papadopoulos N., Plager C., Benjamin R., Levitt D., Gutterman J. Concomitant administration of recombinant human interleukin-2 and recombinant interferon {alpha}-2A in cancer patients: a Phase I study. J. Clin. Oncol., 7: 1726-1732, 1989.[Abstract]
  19. Sznol M., Mier J. W., Sparano J., Gaynor E. R., Weiss G. R., Margolin K. A., Bar M. H., Hawkins M. J., Atkins M. B., Dutcher J. P., Fisher R. I., Boldt D. H., Doroshow J. H., Louie A., Aronson F. R. A Phase I study of high-dose interleukin-2 in combination with interferon-{alpha}2b. J. Biol. Response Modif., 9: 529-537, 1990.[Medline]
  20. Hirsh M., Lipton A., Harvey H., Givant E., Hopper K., Jones G., Zeffren J., Levitt D. 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.[Abstract]
  21. Ilson D. H., Motzer R. J., Kradin R. L., Vogelzang N. J., Bajorin D. F., Scher H. I., Nanus D., O’Moore P., Marathias K., Bosl G. J. A Phase II trial of interleukin-2 and interferon {alpha}-2a in patients with advanced renal cell carcinoma. J. Clin. Oncol., 10: 1124-1130, 1992.[Abstract]
  22. Mittelman A., Puccio C., Ahmed T., Zeffren J., Choudhury A., Arlin Z. A Phase II trial of interleukin-2 by continuous infusion and interferon by intramuscular injection in patients with renal cell carcinoma. Cancer (Phila.), 68: 1699-1702, 1991.[CrossRef][Medline]
  23. Atzpodien J., Hanninen E. L., Kirchner H., Bodenstein H., Pfreundschuh M., Rebmann U., Metzner B., Illiger H. J., Jakse G., Niesel T. Multi-institutional home-therapy trial of recombinant human IL-2 and IFN-{alpha}-2 in progressive metastatic renal cell carcinoma. J. Clin. Oncol., 13: 497-501, 1995.[Abstract/Free Full Text]
  24. Figlin R. A., Belldegrun A., Moldawer N., Zeffren J., deKernion J. Concomitant administration of recombinant human interleukin-2 and recombinant interferon {alpha}-2a: an active outpatient regimen in metastatic renal cell carcinoma. J. Clin. Oncol., 10: 414-421, 1992.[Abstract/Free Full Text]
  25. Dutcher J. P., Fisher R. I., Weiss G., Aronson F., Margolin K., Louie A., Mier J. An outpatient regimen of subcutaneous interleukin-2 plus {alpha}-interferon in metastatic renal cell cancer. Proc. Am. Soc. Clin. Oncol., 12: 248 1993.
  26. Dutcher J. P., Fisher R., Weiss G., Aronson F., Margolin K., Louie A., Mier J. Outpatient subcutaneous interleukin-2 plus {alpha}-interferon in metastatic renal cell cancer: 3 year follow-up of the Cytokine Working Group study. Proc. Am. Soc. Clin. Oncol., 14: 332 1995.
  27. Dutcher J. P., Fisher R. I., Weiss G., Aronson F., Margolin K., Louie A., Mier J., Caliendo G., Sosman J. A., Eckardt J. R., Ernest M. L., Doroshow J., Atkins M. Outpatient subcutaneous interleukin-2 and interferon-{alpha} for metastatic renal cell cancer: five year follow-up of the Cytokine Working Group Study. Cancer J. Sci. Am., 3: 157-162, 1997.[Medline]
  28. Negrier S., Escudier B., Lasset C., Douillard J-Y., Savary J., Chevreau C., Ravaud A., Mercatello A., Peny J., Mousseau M., Philip T., Tursz T. Recombinant human interleukin-2, recombinant human interferon {alpha}-2a, or both in metastatic renal cell carcinoma. N. Engl. J. Med., 338: 1272-1278, 1998.[Abstract/Free Full Text]
  29. Schwartz E. L., Hoffman M., O’Connor C., Wadler S. Stimulation of 5-fluorouracil metabolic activation by interferon-{alpha} in human colon carcinoma cells. Biochem. Biophys. Res. Commun., 182: 1232-1239, 1991.
  30. Marumo K., Oya M., Murai M. Biochemical modulation of 5-fluorouracil with murine interferon-{alpha}/ß against murine renal cell carcinoma. Int. J. Urol., 4: 163-168, 1997.[Medline]
  31. Damascelli B., Marchiano A., Spreafico C., Lutman R., Salvetti M., Bonalumi M. G., Mauri M., Garbagnati F., DelNero A., Comeri G., Conti G., Coppoli S., Benetti G., Tralongo P., Belussi D. Circadian continuous chemotherapy of renal cell carcinoma with an implantable, programmable infusion pum. p. Cancer (Phila.), 66: 237-241, 1990.
  32. Hanninen E. L., Poliwoda H., Atzpodien J. Interferon-{alpha}/5-fluorouracil: a novel outpatient chemo/Immunotherapy for progressive metastatic renal cell carcinoma. Cancer Biother., 10: 21-24, 1995.[Medline]
  33. Sparano, J. A., Dutcher, J. P., Wiernik, P. H., Wadler, S., Caliendo, G., and Nobile, L. A Phase II trial of low-dose continuous infusion 5-fluorouracil plus interferon-{alpha} in patients with advanced renal cell carcinoma. Proc. Soc. Biol. Ther., 1993.
  34. Gebrosky N. P., Koukol S., Nseyo U. O., Carpenter C., Lamm D. L. Treatment of renal cell carcinoma with 5-fluorouracil and {alpha}-interferon. Urology, 50: 863-868, 1997.[CrossRef][Medline]
  35. Elias L., Blumenstein B. A., Kish J., Flanigan R. C., Wade J. L., Lowe B. A., Goodwin J. W., Crawford E. D. A Phase II trial of interferon-{alpha} and 5-fluorouracil in patients with advanced renal cell carcinoma: a Southwest Oncology Group study. Cancer (Phila.), 78: 1085-1088, 1996.[CrossRef][Medline]
  36. Hofmockel G., Langer W., Theiss M., Gruss A., Frohmuller H. G. W. Immunochemotherapy for metastatic renal cell carcinoma using a regimen of interleukin-2, interferon-{alpha} and 5-fluorouracil. J. Urol., 156: 18-21, 1996.[CrossRef][Medline]
  37. Ellerhorst J. A., Sella A., Amato R. J., Tu S-M., Millikan R. E., Finn L. D., Banks M., Logothetis C. J. Phase II trial of 5-fluorouracil, interferon-{alpha} and continuous infusion interleukin-2 for patients with metastatic renal cell carcinoma. Cancer (Phila.), 80: 2128-2132, 1997.[CrossRef][Medline]
  38. Tourani, J-M., Pfister, C., Berdah, J-F., Benhammouda, A., Salze, P., Monnier, A., Paule, B., Guillet, P., Chretien, Y., Brewer, Y., DiPalma, M., Untereiner, Malaurie, E., Tadrist, Z., Pavlovitch, J-M., Hauteville, D., Mejean, A., Azagury, M., Mayeur, D., Lucas, V., Krakowski, I., Larregain-Fournier, D., Abourachid, H., Andrieu, J-M., and Chastang, C. Outpatient treatment with subcutaneous interleukin-2 and interferon {alpha} administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: results of a sequential nonrandomized Phase II study. J. Clin. Oncol., 16: 2505–2513, 1998.
  39. Ravaud A., Audhuy B., Gomez F., Escudier B., Lesimple T., Chevreau C., Douillard J-Y., Caty A., Geoffrois L., Ferrero J-M., Linassier C., Drevon M., Negrier S. Subcutaneous interleukin-2, interferon {alpha}-2a, and continuous infusion of fluorouracil in metastatic renal cell carcinoma: a multicenter Phase II trial. J. Clin. Oncol., 16: 2728-2732, 1998.[Abstract]
  40. Savage P., Costelna D., Moore J., Gore M. E. A Phase II study of continuous infusional 5-fluorouracil (5-FU) and subcutaneous interleukin-2 (IL-2) in metastatic renal cell cancer. Eur J. Cancer, 33: 1149-1151, 1996.[CrossRef]
  41. Joffe J. K., Banks R. E., Forbes M. A., Hallam S., Jenkins A., Patel P. M., Hall G. D., Velikova G., Adams J., Crossley A., Johnson P. W., Whicher J. T., Selby P. J. A Phase II study of interferon-{alpha}, interleukin-2 and 5-fluorouracil in advanced renal carcinoma: clinical data and laboratory evidence of protease activation. Br. J. Urol., 77: 638-649, 1996.[Medline]
  42. Negrier S., Escudier B., Douillard J. Y., Lesimple T., Rossi J. F., Viens P., DiStefano-Louineau D., Drevon M., Gomez F., Caty A. Randomized study of interleukin-2 and interferon with or without 5-FU (FUCY study) in metastatic renal cell carcinoma. Proc. Am. Soc. Clin. Oncol., 16: 326 1997.
  43. Atzpodien J., Kirchner H., Hanninen E., Deckert M., Fenner M., Poliwoda H. Interleukin-2 in combination with interferon-{alpha} and 5-fluorouracil for metastatic renal cell carcinoma. Eur J. Cancer, 29A: 56-58, 1993.
  44. Hanninen E. L., Kirchner H., Atzpodien J. Interleukin-2 based home therapy of metastatic renal cell carcinoma: Risks and benefits in 215 consecutive single institution patients. J. Urol., 155: 19-25, 1996.[CrossRef][Medline]
  45. Kirchner H., Buer J., Probst-Kepper M., Franzke A., Hoffmann R., Wittke F., Ganser A., Atzpodien J. Risk and longer-term outcome in metastatic renal cell carcinoma patients receiving SC interleukin-2, SC interferon-{alpha} 2A, and IV 5-fluorouracil. Proc. Am. Soc. Clin. Oncol., 17: 310 1998.
  46. Atzpodien J., Kirchner H., Duensing S., Hanninen E. L., Franzke A., Buer J., Probst M., Anton P., Poliwoda H. Biochemotherapy of advanced metastatic renal-cell carcinoma: results of the combination of interleukin-2, {alpha}-interferon, 5-fluorouracil, vinblastine, and 13-cis-retinoic acid. World J. Urol., 13: 174-177, 1995.[Medline]
  47. Dutcher J. P., Atkins M., Fisher R., Weiss G., Margolin K., Aronson F., Sosman J., Lotze M., Gordon M., Logan T., Mier J. Interleukin-2-based therapy for metastatic renal cell cancer: The Cytokine Working Group Experience, 1989–1997. Cancer J. Sci. Am., 3(Suppl.1): S73-S78, 1997.
  48. Bukowski R. M., Dutcher J. P. Low dose interleukin-2: single agent and combination regimens Vogelzang N. J. Scardino P. T. Shipley W. U. Coffey D. S. eds. . Comprehensive Textbook of Genitourinary Oncology, Ed 2, : 218-234, Williams & Wilkins Philadelphia 2000.
  49. Aaronson N. K., Ahmedzai S., Bergman B., Bullinger M., Cull A., Duez N. J., Filiberti A., Flechtner H., Fleishman S. B., DeHaes J. C. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical trials in oncology. J. Natl. Cancer Inst., 85: 365-376, 1993.[Abstract/Free Full Text]
  50. McCorkle R. The measure of symptom distress. Sem. Oncol. Nursing, 3: 248-256, 1987.
  51. Plasse T., Goss T., Dutcher J., Logan T., Gordon M., Clark J., Weiss G., Margolin K., Atkins M. Quality of life (QOL) assessment of renal cancer patients treated with interleukin-2, interferon-{alpha} and 5-fluorouracil. Proc. Am. Soc. Clin. Oncol., 17: 67 1998.
  52. Atzpodien J., Kirchner H., Hanninen E. L., Deckert M., Franzke A., Poliwoda H. European studies of interleukin-2 in metastatic renal cell cancer. Proc. Am. Soc. Clin. Oncol., 13: 247 1994.
  53. Negrier S., Maral J., Drevon M., Vinke J., Escudier B., Philip T. Long-term follow-up of patients with metastatic renal cell carcinoma treated with intravenous recombinant interleukin-2 in Europe. Cancer J. Sci. Am., 6(Suppl.1): S93-S98, 2000.
  54. Flanigan R. C., Blumenstein B. A., Salmon S., Crawford E. Cytoreduction nephrectomy in metastatic renal cancer: the results of Southwest Oncology Group Trial 8949. Proc. Am. Soc. Clin. Oncol., 19: 2 2000.
  55. Sherry R. M., Pass H. I., Rosenberg S. A., Yang J. C. Surgical resection of metastatic renal cell carcinoma and melanoma after response to interleukin-2-based immunotherapy. Cancer (Phila.), 69: 1850-1855, 1992.[CrossRef][Medline]
  56. Kavolius J. P., Mastorakos D. P., Pavlovich C., Russo P., Burt M. E., Brady M. S. Resection of metastatic renal cell carcinoma. J. Clin. Oncol., 16: 2261-2266, 1998.[Abstract]



This article has been cited by other articles:


Home page
 JCOHome page
J. A. Gollob, W. K. Rathmell, T. M. Richmond, C. B. Marino, E. K. Miller, G. Grigson, C. Watkins, L. Gu, B. L. Peterson, and J. J. Wright
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line Therapy in Patients With Metastatic Renal Cell Cancer
J. Clin. Oncol., August 1, 2007; 25(22): 3288 - 3295.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
M. Parton, M. Gore, and T. Eisen
Role of Cytokine Therapy in 2006 and Beyond for Metastatic Renal Cell Cancer
J. Clin. Oncol., December 10, 2006; 24(35): 5584 - 5592.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C.-L. Law, K. A. Gordon, B. E. Toki, A. K. Yamane, M. A. Hering, C. G. Cerveny, J. M. Petroziello, M. C. Ryan, L. Smith, R. Simon, et al.
Lymphocyte Activation Antigen CD70 Expressed by Renal Cell Carcinoma Is a Potential Therapeutic Target for Anti-CD70 Antibody-Drug Conjugates
Cancer Res., February 15, 2006; 66(4): 2328 - 2337.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
D. F. McDermott and M. M. Regan
In Reply:
J. Clin. Oncol., September 1, 2005; 23(25): 6268 - 6269.
[Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. B. Atkins, M. Regan, and D. McDermott
Update on the Role of Interleukin 2 and Other Cytokines in the Treatment of Patients with Stage IV Renal Carcinoma
Clin. Cancer Res., September 15, 2004; 10(18): 6342S - 6346S.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
J. I. Clark, M. B. Atkins, W. J. Urba, S. Creech, R. A. Figlin, J. P. Dutcher, L. Flaherty, J. A. Sosman, T. F. Logan, R. White, et al.
Adjuvant High-Dose Bolus Interleukin-2 for Patients With High-Risk Renal Cell Carcinoma: A Cytokine Working Group Randomized Trial
J. Clin. Oncol., August 15, 2003; 21(16): 3133 - 3140.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
E. M. Messing, J. Manola, G. Wilding, K. Propert, J. Fleischmann, E. D. Crawford, J. E. Pontes, R. Hahn, and D. Trump
Phase III Study of Interferon Alfa-NL as Adjuvant Treatment for Resectable Renal Cell Carcinoma: An Eastern Cooperative Oncology Group/Intergroup Trial
J. Clin. Oncol., April 1, 2003; 21(7): 1214 - 1222.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
J. I. Clark, T. M. Kuzel, T. M. Lestingi, S. G. Fisher, P. Sorokin, B. Martone, M. Viola, and J. A. Sosman
A multi-institutional phase II trial of a novel inpatient schedule of continuous interleukin-2 with interferon {alpha}-2b in advanced renal cell carcinoma: major durable responses in a less highly selected patient population
Ann. Onc., April 1, 2002; 13(4): 606 - 613.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dutcher, J. P.
Right arrow Articles by Atkins, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dutcher, J. P.
Right arrow Articles by Atkins, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online