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Randomized Phase II/III Trial of Interferon Alfa-2a With and Without 13-cis-Retinoic Acid in Patients With Progressive Metastatic Renal Cell Carcinoma: The European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC 30951)

From the Department of Clinical Cancer Research, The Norwegian Radium Hospital, Oslo, Norway; Departments of Internal Medicine and Urology, University Medical Centre Nijmegen, Nijmegen; Department of Urology, Erasmus Medical Center, Rotterdam, the Netherlands (current address: Centrum Fuer Operative Urologie Bremen, Bremen, Germany); Department of Oncology, U.Z. Gasthuisberg; Department of Urology, U.Z. Gasthuisberg, Leuven; European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium

Address reprint requests to Nina Aass, MD, PhD, The Norwegian Radium Hospital, 0310 Oslo, Norway; e-mail: ninaaass{at}radium.uio.no

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: A randomized phase II/III trial was conducted to determine whether combination treatment with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFN--2a) was superior to IFN--2a alone in patients with progressive metastatic renal cell carcinoma.

PATIENTS AND METHODS: Three hundred twenty patients were randomly assigned to treatment with IFN--2a plus 13-CRA or to IFN--2a alone. IFN--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. Patients randomly assigned to combination therapy received oral 13-CRA 1 mg/kg/d plus IFN--2a.

RESULTS: Median time to progression was 5.1 months for patients treated with the combination and 3.4 months for patients on IFN--2a alone (P = .008). Progression-free survival rates at 6 months were 43% for patients receiving combined therapy and 30% for patients on IFN--2a, and at 12 months, 27% and 17%, respectively. Median overall survival was 17.3 months for patients on IFN--2a and 13-CRA, and 13.2 months for patients treated with IFN--2a (P = .048). Twenty-two percent of the patients receiving the combination stopped treatment due to toxicity, as compared with 16% on IFN--2a.

CONCLUSION: Progression-free and overall survival for patients with progressive metastatic renal cell carcinoma treated with IFN--2a plus 13-CRA were significantly longer compared with patients on IFN--2a alone (P = .007 and P = .048, respectively). Improvement in efficacy in the combination arm was accompanied by increased, though not serious, toxicity.

	INTRODUCTION

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Metastatic renal cell carcinoma is highly resistant to chemotherapy and hormone therapy.^1-3 Treatment with cytokines (ie, interferon [IFN] or interleukin-2 [IL-2]) leads to responses in 10% to 20% of patients.^4-7 Two phase III trials have shown prolonged survival in patients treated with IFN- compared with "placebo-equivalent" therapy.^8,9 Combination of IFN and IL-2 suggested a synergism in preclinical studies.¹⁰ However, no survival benefit has been found for the combination compared with IFN- or with IL-2 alone.¹¹ Therefore, other therapeutic options in this group of patients are being explored, among them the use of retinoids. From preclinical data there is evidence that combined treatment with IFN and retinoids can result in enhanced antiproliferative and differentiation effects compared with either single agent.^12-14 Lippman et al showed the beneficial effect of the combination in patients with advanced squamous cell carcinoma of the skin and cervix.^15,16 From a clinical point of view, it is also important that the two drugs have nonoverlapping toxicity.

When the present study was planned, only one phase II trial combining IFN--2a with 13-cis-retinioc acid (13-CRA) in patients with metastatic renal cell carcinoma had been reported.¹⁴ In that trial, a 30% response rate was found. Responses were achieved in bone metastases as well as in the primary tumor, sites known to be resistant to systemic therapy. Due to these promising results, the European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC GU Group) designed a large randomized phase II/III study, with IFN--2a as the control arm looking at survival as the main end point. We now present the phase III results of this trial.

	PATIENTS AND METHODS

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The trial was started as a randomized phase II study in March 1996. The phase II part was closed in June 1997.¹⁷ The trial was reopened as a randomized phase III study in November 1998 and was finally closed to patient entry in January 2001. In the phase II part of the study, all patients had to have bidimensionally measurable metastases, whereas in the phase III part, clinically or radiologically detectable metastases were requested, omitting the requirement of measurability. The diagnosis of renal cell carcinoma had to be histologically proven, and all patients had previously undergone radical nephrectomy. Furthermore, progression had to be demonstrated in the 2 months preceding entry. Other eligibility requirements were: age between 18 and 75 years, WHO performance status 0 to 1, WBC count greater than 3 x 10⁹/L, granulocyte count more than 1.5 x 10⁹/L, platelet count more than 100 x 10⁹/L, adequate renal function (creatinine 150 µmol/L), adequate liver function (bilirubin 20 µmol/L), blood lipid values 1.5 x upper limit of normal range. Previous surgery, radiotherapy and/or hormonal therapy were allowed, but not previous chemotherapy or immunotherapy. Exclusion criteria included brain metastases, serous effusions, second tumors except basal cell carcinoma, cardiac disease, active uncontrolled infection, autoimmune disease, gastrointestinal dysfunction that might interfere with drug absorption, seizure disorder or compromised central nervous function, significant psychiatric disorder, or other serious intercurrent medical disorders. Females of childbearing potential were to use effective contraception, whereas pregnant or lactating women were excluded.

All participating institutions were members of the EORTC GU Group. Their local institutional review committees and/or regional or national ethics committees had approved the protocol. The patients gave their written informed consent before study enrollment.

The local investigators contacted the EORTC Data Center by telephone or the Internet to randomly assign their patients (central random assignment). Patients were stratified by institution and performance status using the minimization technique. Only after verification of all the eligibility criteria was the treatment assignment generated by computer and communicated to the investigator.

The patients were randomly assigned to treatment with IFN--2a (Roferon-A; Roche, Nutley, NJ) alone or IFN--2a plus 13-CRA (Roaccutane; Roche). IFN--2a was given as a single daily subcutaneous injection starting at a dose of 3 million units (MU). The dose was escalated every 7 days by increments of 3 MU, to 9 MU. Patients randomly assigned to combination treatment also received oral 13-CRA 1 mg/kg/d rounded up to the closest 10 mg. Side effects were graded according to the National Cancer Institute of Canada (NCIC) Clinical Trials Group Expanded Common Toxicity Criteria (revised December 21, 1994). If grade 3 granulocytopenia, grade 2 thrombocytopenia, or grade 2 nonhematologic toxicity occurred during the dose escalation period, the dose of IFN--2a was kept unchanged until the toxicity subsided.

Treatment duration was to be at least 3 months unless prior progression or toxicity had occurred. Patients with objective response or no change and with stable performance status were to be treated until objective evidence of progression or development of severe toxicity. Optimally, the treatment could be continued for 12 months. If grade 3 granulocytopenia or grade 2 thrombocytopenia occurred, the IFN--2a dose was reduced one dose level (by 3 MU). Grade 4 granulocytopenia or grade 3 thrombocytopenia led to discontinuation of IFN--2a and reduction of 13-CRA to 0.5 mg/kg. If infection or bleeding secondary to thrombocytopenia were reported, both drugs were stopped temporarily. With regard to nonhematologic toxicity (except CNS toxicity), the following dose modifications were made: IFN--2a: continuous grade 2, one dose level reduction; grade 3, two dose levels reduction; grade 4, interruption of treatment. 13-CRA: continuous grade 2, dose was halved; grade 3 or 4, discontinuation of treatment. If grade 2 CNS toxicity occurred, the dose of IFN--2a was decreased by one dose level, and the treatment was stopped if grade 3 CNS toxicity was reported. In case of dose modification or discontinuation of drugs, re-treatment was to be given at doses that were reduced by one dose level. If a patient had not recovered from drug-related toxicity within 3 weeks after the last dose, the patient was withdrawn from the study.

Patients were monitored biweekly for the first month of therapy (hematologic and serum chemical analysis), at weeks 8 and 12, and thereafter, every second month and at treatment discontinuation (clinical examination, performance status, disease evaluation, hematologic and serum chemical analysis). All patients were followed up until death or until July 2003.

The primary end point was overall survival. Rate of progression, progression-free survival, and toxicity were secondary end points. A total of 252 deaths were required to detect a 10% difference in overall 1-year survival from 10% to 20% (hazard ratio = 0.699), at error rates = .05 and ß = .20, based on a two-sided log-rank test. A total of 296 patients were to be entered.

All randomly assigned patients were included in the treatment efficacy comparisons (intent to treat analysis). All patients who started their treatment were included in the toxicity analyses. Time to event (duration of survival, progression-free survival) was estimated in each treatment group using the Kaplan-Meier technique, taking the random assignment date as the starting date, and compared using a two-sided log-rank test.

Based on an article by Jones et al,¹⁸ the following variables were used to retrospectively create risk groups: performance status, 0 v 1; time from diagnosis to start of cytokine treatment, 2 years versus more than 2 years; number of metastatic sites, one versus more than 1. Patients with 0 or 1 poor risk factors and patients with two or three poor risk factors were combined to create two risk groups (good-prognosis group and poor-prognosis group, respectively).

	RESULTS

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From March 1996 to January 2001, 320 patients were randomly assigned, 161 to treatment with IFN--2a alone, and 159 to IFN--2a combined with 13-CRA. One hundred thirteen patients were enrolled on the phase II part of the trial, and 207, on the phase III part. Twenty-three patients were found to be ineligible, 14 in the IFN--2a arm and nine in the combination arm. The main reasons for ineligibility were: Pleural effusion was the only sign of metastatic disease, eight patients; no target lesion (phase II), five patients; no metastases, two patients; symptomatic brain metastases, two patients; treatment with prednisolone at entry, two patients; WHO performance status more than 1, two patients; increased lipid values, one patient; second malignancy, one patient. Two patients never started treatment with IFN--2a (one ineligible patient, one patient refused), and five patients never started the combination therapy (three ineligible patients, one patient refused, one intercurrent death).

The median time from diagnosis to random assignment was 46 weeks for the whole study group (^{Table 1}). The median age at random assignment was 60 years, and 57% of the patients had performance status 0 according to the WHO criteria. In general, patient characteristics were well balanced between the two treatment groups; however, patients treated with the combination tended to have less lymph node metastases than patients on IFN--2a alone. Twenty percent of the patients in the IFN--2a group had previously received radiotherapy, and 2.5% had been treated with hormone therapy. The corresponding percentages for the patients who received combined treatment were 10% and 4%, respectively.

View larger version (15K): [in this window] [in a new window]   Fig 1. Time to progression for patients with progressive metastatic renal cell carcinoma treated with interferon alfa-2a (IFN) versus IFN plus 13-cis-retinoic acid (13-CRA). O, number observed; N, total number.

View larger version (15K): [in this window] [in a new window]   Fig 2. Overall survival for patients with progressive metastatic renal cell carcinoma treated with interferon alfa-2a (IFN) versus IFN plus 13-cis-retinoic acid (13-CRA). O, number observed; N, total number.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

Two other randomized phase III trials^20,21 have included the combination of retinoids and cytokines in patients with advanced renal cell carcinoma. In the study by Motzer et al,²⁰ the median overall survival time was 15 months, which is consistent with our results, but there was no difference between the patients treated with IFN--2a compared with the patients treated with IFN--2a and 13-CRA. However, duration of response and progression-free survival at 2 years were significantly longer in patients who received the combination compared with patients treated with IFN--2a alone. The authors suggest that one possible explanation may be that 13-CRA lengthens response to IFN--2a in the small proportion of patients with IFN--2a–sensitive tumors. Selection of these patients therefore seems crucial. In a previous study, Motzer and collaborators analyzed survival and prognostic factors in nearly 700 patients with metastatic renal cell carcinoma.²² In a multivariate analysis, Karnofsky performance status less than 80 and absence of prior nephrectomy were among the factors associated with shorter survival. In the phase III trial conducted by Motzer et al, only 50% of the patients had been nephrectomised, and 15% had Karnofsky performance status less than 80.²⁰ This may partly explain why no survival advantage was found for the combined therapy. Also another recently published study showed improved survival in patients with metastatic renal cell carcinoma who underwent nephrectomy before treatment with IFN- compared with patients who only received IFN-.²³ Thus, it seems to be important that patients who are to be treated with cytokines have been nephrectomised and have a good performance status. This was the case for all patients included in the present series. We did not find any additional information with regard to treatment efficacy when the patients were divided in two risk groups according to other well-known prognostic criteria (number of metastatic sites and time from diagnosis to start of cytokine therapy).¹⁸

Atzpodien et al²¹ conducted a three-arm study comparing patients receiving a triple combination of IL-2, IFN--2a, and fluorouracil, and patients receiving the combination combined with retinoids, with a control group treated with IFN--2a and vinblastine. Both the progression-free and overall survival were significantly longer for patients in the two former groups than in the control group, but there was no survival advantage for the patients receiving retinoids. The median overall survival for the control patients was longer in Atzpodien et al's trial compared with most other previously published studies with IFN, indicating highly selected patients.^8,11,24 Thus, the applicability of these results for patients with metastatic renal cell carcinoma in general is uncertain.

The present study has shown that the therapy was toxic for patients treated with IFN--2a alone and even more so for patients who received IFN--2a plus 13-CRA. This is mirrored by the high number of patients who had dose modifications, interruption of treatment, or who stopped therapy due to toxicity. Although few serious adverse effects were reported, the majority of patients experienced lethargy, anorexia, arthralgia/myalgia, and/or nausea/vomiting. In addition, many of the patients treated with 13-CRA suffered from stomatitis, dryness in mouth and nose, and dermatologic toxicity. All these symptoms have an influence on daily life activities and may also reduce quality of life in this group of patients who all are in a palliative situation. A high level of toxicity has also been reported in other studies applying the combination of IFN--2a and 13-CRA. In a phase II study by Wong et al, therapy was stopped in seven of 22 patients treated with this combination due to side effects.²⁵ In the same study, 12 patients reported a worsening of quality of life during the treatment period. Another phase II study including 29 patients reported nausea, anorexia, weight loss, dermatologic toxicity, and myelotoxicity occurring in most of the patients.²⁶ In the phase III trial by Motzer et al, a lower overall incidence and grade of side effects were observed than in our study and with no difference between the treatment arms.²⁰ However, at all times of evaluation, patients in both treatment groups reported reduced quality of life compared with the pretreatment situation. The patients receiving combined therapy had a significantly lower quality of life compared with patients treated with IFN--2a alone at 8, 17, and 34 weeks after start of therapy. The reduction in quality of life was most pronounced for patients with poor-risk treatment features irrespective of the therapy received.²² This underlines the importance to carefully select the patients to receive cytokine therapy.

In conclusion, the present trial has shown a small, but statistically significant improvement in both progression free and overall survival for patients with progressive metastatic renal cell carcinoma treated with IFN--2a plus 13-CRA compared with patients treated with IFN--2a alone. The small prolongation in survival must be balanced against an increased frequency and grade of treatment adverse effects, though not of serious character. Providing adequate information to the patients about toxicity before treatment decisions are taken is therefore very important. New treatment strategies are still highly warranted in patients with metastatic renal cell carcinoma.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Allan T. van Oosterom, Aventis, Novartis, Pfizer, Pharmamar, Roche; Sophie D. Fossa, Bayer. Research Funding: Allan T. van Oosterom, Amgen, Aventis, Novartis, Pfizer, Pharmamar, Roche, Schering-Plough; Sophie D. Fossa, Aventis. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.

	NOTES

 
Supported by an Educational Grant from Hoffman-La Roche and grant Nos. 2U10 CA11488-25 through 5U10 CA11488-34 from the National Cancer Institute (Bethesda, MD).

This article’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted July 19, 2004; accepted February 24, 2005.

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