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Journal of Clinical Oncology, Vol 18, Issue 16 (August), 2000: 2972-2980
© 2000 American Society for Clinical Oncology

Phase III Trial of Interferon Alfa-2a With or Without 13-cis-Retinoic Acid for Patients With Advanced Renal Cell Carcinoma

By Robert J. Motzer, Barbara A. Murphy, Jennifer Bacik, Lawrence H. Schwartz, David M. Nanus, Tania Mariani, Patrick Loehrer, George Wilding, Diane L. Fairclough, David Cella, Madhu Mazumdar

From the Genitourinary Oncology Service, Division of Solid Tumor Oncology, and the Departments of Medical Imaging and Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center; Joan and Sanford I. Weill Medical College of Cornell University; and New York Presbyterian Hospital, New York, NY; Vanderbilt University, Nashville, TN; Indiana University, Indianapolis, IN; University of Wisconsin, Madison, WI; AMC Cancer Research Center, Denver, CO; and Evanston Northwestern Healthcare and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.

Address reprint requests to Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: A randomized phase III trial was conducted to determine whether combination therapy with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFN{alpha}2a) is superior to IFN{alpha}2a alone in patients with advanced renal cell carcinoma (RCC).

PATIENTS AND METHODS: Two hundred eighty-four patients were randomized to treatment with IFN{alpha}2a plus 13-CRA or treatment with IFN{alpha}2a alone. IFN{alpha}2a was given daily subcutaneously, starting at a dose of 3 million units (MU). The dose was escalated every 7 days from 3 to 9 MU (by increments of 3 MU), unless >= grade 2 toxicity occurred, in which case dose escalation was stopped. Patients randomized to combination therapy were given oral 13-CRA 1 mg/kg/d plus IFN{alpha}2a. Quality of life (QOL) was assessed.

RESULTS: Complete or partial responses were achieved by 12% of patients treated with IFN{alpha}2a plus 13-CRA and 6% of patients treated with IFN{alpha}2a (P = .14). Median duration of response (complete and partial combined) in the group treated with the combination was 33 months (range, 9 to 50 months), versus 22 months (range, 5 to 38 months) for the second group (P = .03). Nineteen percent of patients treated with IFN{alpha}2a plus 13-CRA were progression-free at 24 months, compared with 10% of patients treated with IFN{alpha}2a alone (P = .05). Median survival time for all patients was 15 months, with no difference in survival between the two treatment arms (P = .26). QOL decreased during the first 8 weeks of treatment, and a partial recovery followed. Lower scores were associated with the combination therapy.

CONCLUSION: Response proportion and survival did not improve significantly with the addition of 13-CRA to IFN{alpha}2a therapy in patients with advanced RCC. 13-CRA may lengthen response to IFN{alpha}2a therapy in patients with IFN{alpha}2a-sensitive tumors. Treatment, particularly the combination therapy, was associated with a decrease in QOL.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
METASTATIC RENAL CELL carcinoma (RCC) is characterized by a high level of resistance to systemic treatment.1-3 Cytotoxic chemotherapy and hormonal therapy are ineffective treatments for advanced RCC.4 Interest in biologic response modifiers has been fostered by a low rate of response to interferon alfa-2a (IFN{alpha}2a) and interleukin-2 therapy.5,6

13-cis-retinoic acid (13-CRA) increased the antiproliferative effects of IFN{alpha}2a in several interferon-sensitive renal cancer cell lines.7 The combination resulted in a 30% response proportion in a phase II trial conducted at our center, which was higher than the proportion earlier achieved with IFN{alpha}2a alone.8 In three other phase II trials, treatment of RCC with IFN{alpha}2a plus retinoid was associated with relatively high response rates.9-11 One treatment program included interleukin-2 with 13-CRA and IFN{alpha}2a, and a 22% major response rate was reported.10 The combination of IFN{alpha}2a, 13-CRA, interleukin-2, and fluorouracil was associated with a 44% major response rate.11 The in vitro and clinical studies provided the rationale for the present randomized trial.

The influence of cytokine treatment on quality of life (QOL) is an important aspect in the management of advanced RCC. The Functional Assessment of Cancer Therapy (FACT) scale12 was used to assess QOL. Items were appended to the general questionnaire (Functional Assessment of Cancer Therapy-General [FACT-G]) to address the impact of side effects associated with treatment with IFN{alpha}2a and the retinoid.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
Between April 1994 and July 1996, 284 patients were entered onto this randomized trial. Participating centers were Memorial Sloan-Kettering Cancer Center (MSKCC) and member institutions of the Eastern Cooperative Oncology Group (ECOG). All patients gave informed consent. Eligibility requirements included the following: histologic confirmation of RCC, bidimensionally measurable disease, Karnofsky performance status (KPS) >= 70%, estimated life expectancy more than 3 months, WBC count >= 3,000/µL, platelet count >= 100,000/µL, serum total bilirubin level less than 1.5 mg/dL (normal, < 1.0 mg/dL), and serum creatinine level less than 2 mg/dL (normal, < 1.1 mg/dL) or creatinine clearance more than 50 mL/min. Patients were excluded if they had received prior systemic chemotherapy or immunotherapy, had received radiation within 4 weeks of study entry, or had brain metastases.

Each patient was evaluated before initiation of treatment. A history was obtained and a physical examination, chest radiography, ECG, automated complete blood cell count, comprehensive blood chemistry panel including determination of cholesterol and triglyceride levels, and appropriate radiographic imaging of measurable disease were performed. A negative pregnancy test result was required for women with childbearing potential.

Treatment Plan
Recombinant human IFN{alpha}2a (Roferon-A) and 13-CRA (Accutane) were obtained from Hoffmann-La Roche (Nutley, NJ) through the Division of Cancer Treatment, National Cancer Institute, Bethesda, MD. IFN{alpha}2a was provided in 3–million unit (MU) and 18-MU vials and was mixed with sterile water. 13-CRA was available in 10- and 40- mg tablets.

Patients were randomized to daily treatment with IFN{alpha}2a plus 13-CRA or IFN{alpha}2a alone. IFN{alpha}2a was given as a single daily subcutaneous injection, starting at a dose of 3 MU, and the dose was escalated every 7 days by increments of 3 MU, to 9 MU. During escalation, if >= grade 2 nonhematologic toxicity or grade 3 hematologic toxicity was noted, dose escalation was stopped. Patients randomized to combination therapy received oral 13-CRA 1 mg/kg/d in two divided doses (rounded to the nearest 10 mg) plus IFN{alpha}2a.

Treatment was continued until progression of disease, complete response, or development of toxicity occurred. Dose modifications during therapy were dictated by an attenuation schedule. The IFN{alpha}2a dose was attenuated by 3-MU increments in patients with >= grade 2 nonhematologic toxicity and grade 3 or 4 leukopenia or thrombocytopenia. In cases of grade 3 or 4 neurologic toxicity (except mood-affecting neurotoxicity), treatment was discontinued and the patient taken off study. In cases of grade 3 or 4 mood-affecting neurotoxicity, the IFN{alpha}2a dose was attenuated by 3-MU increments. Patients with fatigue that resulted in a decrease in KPS to <= 50% underwent sequential dose reduction and were removed from the study if the participating investigator deemed removal appropriate. If toxicity resulted in an interruption of therapy, patients treated with IFN{alpha}2a plus 13-CRA had both drugs withheld. The 13-CRA dose was reduced by 50% in cases of grade 4 dermatologic toxicity or any other grade 3 or 4 toxicity associated with 13-CRA administration.

Patients were monitored weekly for the first 4 weeks of therapy and every 2 weeks thereafter (physical examination, complete blood cell count, and serum chemical analysis). All patients underwent reassessment of measurable disease every 4 weeks until maximum response and every 2 months thereafter. All patients kept daily logs in which they documented symptoms and medications taken.

Standard response and toxicity criteria were used.13 Stable disease was defined as disease that remained stable for at least 3 months from the day of evaluation after the first cycle of therapy.

Biostatistical Analysis
This trial was designed with response proportion as the major end point. Two hundred eighty-four patients were accrued to detect a 15% difference in response proportion with a power of >= 85% and a significance level of 5%. The design included an O’Brien and Fleming stopping rule.14 As the data accumulated, two interim analyses were undertaken and the data were reviewed by an independent data and safety monitoring committee. Randomization was performed at a centralized office at MSKCC using the method of random permuted block, with center (MSKCC v ECOG), lung-only disease, prior nephrectomy, and KPS (70% or 80% v 90%) used as stratification factors.15 All analyses were intent-to-treat analyses. Fisher’s exact test was used to compare the response proportions in each treatment arm. Survival curves were estimated using the Kaplan-Meier method16 and were compared using the log-rank test. The Wilcoxon rank sum test17 was used to compare the duration of response by treatment arm for patients who achieved a complete or partial response. Durations of best response and survival were measured from the date of initiation of therapy. Toxicity data are summarized as frequency tables, with each patient’s worst-grade toxicity over all cycles used in calculations.

QOL Study
Patients enrolled after February 1995 were asked to undergo assessment of QOL. The baseline assessment was performed before therapy, with other assessments performed 2, 8, 17, 34, and 52 weeks after initiation of therapy.

The trial used FACT Version 3 as the tool for QOL assessment.12 For this trial, 17 disease- and treatment-specific items were developed and appended to the core questionnaire to address symptoms related to treatment with interferon and retinoids. The composite questionnaire was titled the Functional Assessment of Cancer Therapy-Biologic Response Modifier (FACT-BRM). Using an approach combining conceptual input and principal components factor analysis followed by checks on internal consistency, the original pool of 17 statements was reduced to a 16-item measure to assess toxicity related to treatment with biologic response modifiers. The 16-item measure consisted of two subscales to assess toxicity having a physical effect (10 items) and toxicity affecting mood or cognition (six items) (Table 1).


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  		Table 1. Two BRM Subscales Formed From Items Appended to the FACT-G Scale*
 
The Trial Outcome Index (TOI), calculated by adding the physical well-being score, functional well-being score, and the two biologic response modifier subscale scores, was used in the following analysis as a summary measure of physical and functional well-being. Time intervals around each scheduled assessment were defined so that each questionnaire received was included in an interval. The compliance rate for each interval was then calculated as the number of questionnaires received divided by the number expected.

A joint mixed-effects and survival model that accounts for unignorable missing data was used to capture changes in QOL over time.18 Estimates of QOL at baseline and at 2, 8, 17 and 34 weeks were obtained for each arm, and differences between the arms were tested. No estimate of QOL at 52 weeks was obtained for the treatment arms, because there was a paucity of data from that assessment time.

MSKCC Prognostic Model
A prognostic factor model was previously developed using data from 670 patients with advanced RCC treated in 24 MSKCC clinical trials of immunotherapy and chemotherapy between 1975 and 1996.19 Pretreatment features associated with shorter survival in the multivariate analysis were low KPS (< 80%), high lactate dehydrogenase level (> 1.5 times upper limit of normal), low hemoglobin level (below lower limit of normal), high corrected serum calcium level (> 10 mg/dL), and absence of nephrectomy. These prognostic factors were used to categorize patients by risk into three groups: those with no risk factors (favorable risk), those with one or two risk factors (intermediate risk), and those with three or more risk factors (poor risk).19 This risk categorization was applied to the patients on our trial.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Two hundred eighty-four patients were registered onto the trial: 145 received IFN{alpha}2a alone and 139 received IFN{alpha}2a and 13-CRA. The two treatment arms were similar in terms of patient characteristics (Table 2). Overall median age was 60 years, and 61% of study patients had a KPS of 90%. One hundred seventy-eight patients (63%) had two or more metastatic sites, and 144 (51%) had undergone nephrectomy. Twenty-nine patients (20%) treated with IFN{alpha}2a both had undergone nephrectomy and had lung-only metastases, compared with 33 patients (24%) treated with IFN{alpha}2a plus 13-CRA. One hundred nine (38%) were registered by MSKCC and 175 (62%) by ECOG.


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  		Table 2. Patient Characteristics
 
Response and Survival
Twenty-five (9%) of the 284 patients registered onto the trial had a complete or partial response (Table 3). Complete or partial responses were achieved by 12% of patients treated with IFN{alpha}2a plus 13-CRA (five complete responses, 11 partial responses) and 6% of patients treated with IFN{alpha}2a (one complete response, eight partial responses; P = .14). Five patients (4%) treated with IFN{alpha}2a plus 13-CRA achieved a complete response, compared with one (1%) treated with IFN{alpha}2a alone (P = .11). Median duration of response (complete and partial combined) from the start of treatment in the group treated with the combination was 33 months (range, 9 to 50 months), versus 22 months (range, 5 to 38 months) for the group treated with IFN{alpha}2a alone (P = .03).


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  		Table 3. Response and Patient Status
 
Thirty-seven patients remained progression-free after follow-up: 21 after treatment with IFN{alpha}2a plus 13-CRA and 16 after treatment with IFN{alpha}2a alone. The median progression-free survival time was 5 months, with no difference in progression-free survival between the two arms (P = .13; Fig 1). However, the progression-free survival curves started to separate after 1 year of follow-up. Nineteen percent of patients treated with IFN{alpha}2a plus 13-CRA were progression-free at 24 months, compared with 10% of patients treated with IFN{alpha}2a alone (P = .05).



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  		Fig 1. Progression-free survival for patients with advanced RCC treated with IFN{alpha}2a versus IFN{alpha}2a plus 13-CRA.

 
Fifty-six of 284 patients remained alive, and the median survival time for all patients was 15 months (95% confidence interval, 12 to 17 months). The median follow-up for survivors was 38 months (range, 1 to 62 months); one of these patients was lost to follow-up at 1 month, another at 2 months. There was no difference in survival between the two treatment arms (P = .26; Fig 2).



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  		Fig 2. Survival for patients with advanced RCC treated with IFN{alpha}2a versus IFN{alpha}2a plus 13-CRA. Tick mark indicates last follow-up.

 
Toxicity
There was no difference in incidence of grade 2, 3, or 4 toxicities between treatment arms (Table 4). Grade 2 toxicities reported in 20% to 40% of patients were leukopenia, anemia, fever, and gastrointestinal toxicity. Grade 3 hematologic toxicities were reported in 60 patients (21%), and grade 4 hematologic toxicities were reported in three patients (1%). A total of 82 grade 3 and 10 grade 4 nonhematologic toxicities were reported in 284 patients.


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  		Table 4. Grade 2 to 4 Toxicity by Treatment Arm
 
QOL Analysis
Two hundred thirty patients were asked to participate in the QOL assessment portion of the protocol. A total of 213 patients completed and returned at least one questionnaire; 735 questionnaires were received. The rate of compliance with baseline assessments was 81% in the IFN{alpha}2a treatment arm and 86% in the IFN{alpha}2a plus 13-CRA treatment arm (Table 5). Over time, compliance rates decreased; by the 52-week assessment, the rates were 24% and 39% in the IFN{alpha}2a and IFN{alpha}2a plus 13-CRA treatment arms, respectively. There were similar dropout rates in the two arms at each of the assessment times.


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  		Table 5. Compliance With QOL Assessment
 
The estimates of change in TOI scores are displayed in Fig 3. There was a pattern of decrease in QOL from baseline to 2 weeks and a smaller decrease from 2 to 8 weeks, especially in the IFN{alpha}2a plus 13-CRA treatment arm, making the difference between the arms significant at 8 weeks (P = .02). After 8 weeks, there was some recovery of scores in the IFN{alpha}2a treatment arm and stabilization of scores in the IFN{alpha}2a plus 13-CRA treatment arm, with TOI scores significantly lower at 17 and 34 weeks in the IFN{alpha}2a plus 13-CRA treatment arm (P < .001 and P = .01, respectively). However, scores never recovered to baseline values in either arm.



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  		Fig 3. QOL (TOI) for patients with advanced RCC treated with IFN{alpha}2a versus IFN{alpha}2a plus 13-CRA.

 
TOI scores were compared according to risk group as classified by the MSKCC model.19 Each risk group had a dramatic decrease from baseline to 2 weeks, with the favorable- and intermediate-risk groups having a smaller decrease from 2 to 8 weeks (Fig 4). However, these two groups began to recover after 8 weeks, although a full recovery never occurred. In contrast, the poor-risk group experienced a decrease after 8 weeks, followed by a stabilization of scores at a very low level after 17 weeks. This group never experienced a recovery in scores, and although stabilization did occur after 17 weeks, it was at a level approximately 20 points lower than baseline. The differences between the intermediate- and poor-risk groups at 17 and 34 weeks were significant at the .05 level (P = .01 and P = .03, respectively).



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  		Fig 4. QOL (TOI) according to risk criteria for patients with advanced RCC treated with IFN{alpha}2a versus IFN{alpha}2a plus 13-CRA according to risk criteria for patients with RCC.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Response proportion and survival did not improve significantly with the addition of 13-CRA to IFN{alpha}2a therapy in patients with advanced RCC. The response proportion for patients treated with IFN{alpha}2a plus 13-CRA was greater than that for patients treated with IFN{alpha}2a, with more complete responses in the combination therapy arm. Moreover, the duration of response for patients who achieved a complete or partial response was longer after treatment with IFN{alpha}2a plus 13-CRA than after treatment with IFN{alpha}2a alone. However, the overall response proportion for all patients treated on the trial was low (9%), with no significant difference in major response proportion (complete and partial combined) between arms. Two phase III trials are being conducted by others20,21 and may provide further insight into the role of retinoid-cytokine combination therapy against RCC.

Response proportions in individual phase II trials involving patients with advanced RCC range from 0% to 30% for single-agent IFN{alpha} therapy,5 0% to 37% for combinations of IFN{alpha}2a plus interleukin-2,22 and 0% to 37% for the three-drug combination of IFN{alpha}, interleukin-2, plus fluorouracil.23 Responsible factors include differences in treatment schedules, sample size, and patient selection. The impact of IFN{alpha}2a treatment on survival is controversial, but the two larger phase III trials found IFN{alpha}2a therapy to be associated with longer survival than vinblastine or medroxyprogesterone therapy.24,25 In contrast, no randomized phase III trial has shown a survival benefit for combination therapy compared with treatment with IFN{alpha}2a or interleukin-2 alone in patients with advanced RCC.26-31 Each combination therapy showed promise in phase II trials but lacked survival benefit compared with monotherapy in the randomized trial. The outcome of these trials reaffirms the necessity to conduct phase III trials to evaluate the efficacy of combination therapies compared with treatment with IFN{alpha}2a or interleukin-2 alone in patients with metastatic RCC.

Additional items were appended to the FACT-G scale12 in this study, to address the impact of biologic treatment on patients with advanced RCC. Patients treated with IFN{alpha}2a alone showed a pattern of initial decrease in TOI scores followed by some recovery, although not to baseline values. Patients treated with the combination of IFN{alpha}2a and 13-CRA also experienced an initial decrease, although scores stabilized after 8 weeks. Treatment with the combination was associated with lower TOI scores, presumably because of side effects of retinoid therapy.

In a QOL study using the Rotterdam Symptom checklist, patients were randomized to treatment with IFN{alpha}2a or medroxyprogesterone.25 IFN{alpha}2a was given at a dose of 10 MU 3 days per week, and the pattern of QOL was likewise characterized by initial decrease and recovery. There was no detected difference in symptoms between treatment arms after 6 months of therapy. The intensive schedule of IFN{alpha}2a therapy used in our trial may played a role in the overall decrease of QOL. Treatment was administered daily, rather than 3 or 5 days per week, which is standard practice.5

We have reported on a risk classification undertaken in 670 patients with advanced RCC treated on clinical trials with cytotoxic therapy or cytokines.19 Patients treated on that trial who had poor-risk pretreatment features for survival had inferior QOL compared with patients with intermediate or favorable prognostic features. Patients with poor-risk features have a short survival regardless of whether they are treated with cytokine therapy or chemotherapy.19 Also, patients with intermediate- or favorable-risk features may be more likely to derive therapeutic benefit from cytokine therapy.32 In the current study, the poor-risk group of patients experienced the most symptoms associated with IFN{alpha}2a therapy. The poor survival and decrease in QOL associated with cytokine therapy suggest that patients with poor-risk features should be considered for novel treatment strategies on clinical trials or supportive care.

Two outcomes from this trial suggest that 13-CRA augmented response to IFN{alpha}2a therapy. First, duration of complete or partial response was significantly longer in patients treated with 13-CRA plus IFN{alpha}2a compared with those treated with IFN{alpha}2a alone. Second, progression-free survival at 2 years was greater in the combination therapy arm compared with patients treated with IFN{alpha}2a alone. One possible explanation is that 13-CRA lengthens response to IFN{alpha}2a therapy in the relatively small proportion of patients with IFN{alpha}2a-sensitive tumors.

This hypothesis is consistent with findings of our previous in vitro studies on renal cancer cell lines, in which 13-CRA enhanced the antiproliferative effect of IFN{alpha}2a in IFN{alpha}2a-sensitive but not IFN{alpha}2a-resistant renal cancer cells.8 The manner by which 13-CRA augments the effect of IFN{alpha}2a is unknown. Recent studies have shown that renal cancer cells in vitro and in vivo contain low levels of intracellular retinoids compared with normal kidney and that treatment with IFN{alpha}2a plus retinoic acid results in an approximately eight-fold increase in intracellular retinoid levels.33 Higher levels of intracellular retinoic acid may play an important role in the generation of a more complete antitumor response in IFN{alpha}2a-sensitive RCC, because an increase in expression of retinoid acid receptor beta in renal tumor cells is associated with growth inhibition in vitro7 and tumor regression in vivo.34 Although these studies suggest that retinoic acid may somehow augment the antitumor effects of IFN{alpha}2a therapy, this benefit has not been convincingly achieved using oral formulations of retinoic acid, as indicated by the results of the current trial. Continued studies are warranted and should focus on the mechanisms of IFN{alpha}2a-retinoid interaction in renal cancers. Clinical trials of more potent retinoids should be conducted.

In summary, response proportion and survival did not improve significantly with the addition of 13-CRA to IFN{alpha}2a therapy in patients with advanced RCC. 13-CRA may lengthen response to IFN{alpha}2a therapy in the relatively small proportion of patients with IFN{alpha}2a-sensitive tumors. Treatment, particularly the combination therapy, was associated with a decrease in QOL as assessed by the FACT-BRM.


   ACKNOWLEDGMENTS
 
Supported by grant no. CA 05826 from the National Cancer Institute and by Hoffman-La Roche, Nutley, NJ.

We thank Patricia Fischer for providing nursing care and Carol Pearce for reviewing the manuscript.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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34. Berg WJ, Nanus DM, Leung A, et al: Up-regulation of retinoic acid receptor beta expression in renal cancers in vivo correlates with response to 13-cis-retinoic acid and interferon-alfa-2a. Clin Cancer Res 5:1671–1675, 1999[Abstract/Free Full Text]

Submitted January 31, 2000; accepted April 26, 2000.




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