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© 2003 American Society for Clinical Oncology Phase III Study of Interferon Alfa-NL as Adjuvant Treatment for Resectable Renal Cell Carcinoma: An Eastern Cooperative Oncology Group/Intergroup Trial
From the University of Rochester School of Medicine and Dentistry, Rochester, NY; Dana-Farber Cancer Institute, Boston, MA; University of Wisconsin Comprehensive Cancer Center, Madison, WI; University of Pennsylvania School of Medicine, Philadelphia, PA; Einstein and New York Westchester Square, Bronx; Roswell Park Cancer Institute, Buffalo, NY; University of Colorado School of Medicine, Denver, CO; Wayne State University School of Medicine, Detroit, MI; The Mayo Clinic, Rochester, MN. Address reprint requests to Edward M. Messing, MD, University of Rochester, 601 Elmwood Ave, Box 656, Rochester, NY 14642; email: edward_messing{at}urmc.rochester.edu.
Purpose: To evaluate the role of adjuvant interferon alfa after complete resection of locally extensive renal cell carcinoma. Patients and Methods: A total of 283 eligible patients with pT3–4a and/or node-positive disease were randomly assigned after radical nephrectomy and lymphadenectomy to observation or to interferon alfa-NL (Wellferon, Burroughs-Wellcome, Research Park, NC) given daily for 5 days every 3 weeks for up to 12 cycles. Patients were stratified on the basis of pathologic stage. Patients remained on treatment until documented recurrence, excessive toxicity, or patient/physician preference deemed removal appropriate. Results: At median follow-up of 10.4 years, median survival was 7.4 years in the observation arm and 5.1 year in the treatment arm (log-rank P = .09). Median recurrence-free survival was 3.0 years in the observation arm and 2.2 years in the interferon arm (P = .33). Performance status (P = .003), nodal status (N2 v N0, P < .0001), and tumor stage (P = .0002) were significant prognostic factors in multivariate analysis. A proportional hazards model examining the effects of treatment arm and time to recurrence on survival after recurrence among patients who recurred found that random assignment to interferon treatment (P = .009) and shorter time to recurrence (P < .0001) were independent predictors of shorter survival after recurrence. Although no lethal toxicities were observed, severe (grade 4) toxicities including neutropenia, myalgia, fatigue, depression, and other neurologic toxicities occurred in 11.4% of those randomly assigned to interferon treatment. Conclusion: Adjuvant treatment with interferon did not contribute to survival or relapse-free survival in this group of patients.
LOCALLY EXTENSIVE renal cell carcinoma, even if entirely resected, has a worse prognosis than organ-confined disease.1 In these circumstances (using the tumor-node-metastasis system of classification, stage T3–4a, and/or N+, M0), the majority of patients who succumb to renal cell carcinoma do so from distant metastases.2,3 The standard approach to patients with completely resected local or regional disease is observation with the use of systemic therapies only on documented recurrence. In the last 15 years, a variety of biologic therapies4–18 have been demonstrated to provide objective responses in 15% to 35% of patients with disseminated metastases. One of the most widely used of these agents has been interferon alfa.16,17,19–21 In view of the reported activity of this agent in metastatic renal cancer and the high risk of recurrence for patients with locally advanced disease, we evaluated the role of adjuvant interferon alfa after complete resection in this setting.
From May 1987 to April 1992, 294 patients who had undergone radical nephrectomy and were found to have unilateral, locally advanced (pathological stage T3–4a), and/or node-positive renal cell carcinoma, and who were free of disseminated metastases by radiographic and intraoperative assessments, were randomly assigned to receive up to 12 cycles of interferon alfa-NL (Wellferon) administered daily for 5 days every 3 weeks (3 million U/m2 day 1, 5 million U/m2 day 2, 20 million U/m2 days 3, 4, and 5 by intramuscular injection) or observation until recurrence or progression was identified (at which point patients would be treated at investigator option). Patients were randomly assigned to a treatment within 30 days of surgery and were assessed before random assignment and then every 3 months for the first year with physical examinations, complete blood counts (CBCs), creatinine levels, liver function tests, and chest x-rays. Computer tomographic (CT) scans of the chest, abdomen, and pelvis and radionuclide bone scans were performed before random assignment to treatment and semiannually. After 1 year, all examinations were performed semiannually. In subjects receiving treatment, CBC, creatinine, and liver function tests were monitored on days 1, 8, and 15 during cycle 1 and repeated 2 weeks after the last injection of each cycle. If granulocyte counts were below 250/mm3 or platelet counts were less than 25,000/mm3; AST or bilirubin were more than five times or 1.5 times the normal levels, respectively; or the creatinine level was more than 2.1 ng/mL, treatment was withheld until levels returned to these parameters.
Fatigue consistent with Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4, weight loss of Radiographic evidence of solitary lesions was not considered sufficient to document recurrence without histologic or cytologic confirmation. Causes of death were determined by autopsy when possible, but for the majority of patients, causes were based on death certificate and confirmed by evidence at the most recent follow-up visit before death.
Patients were ineligible for this study if their tumors were confined to the kidney without renal vein or regional node involvement (stage T1, T2, N0, M0), if disease extended above the diaphragm (even if just by vena caval extension), if they had mediastinal or pelvic node involvement, or if they had hematogenous metastases (M1), even if these lesions were completely resected. On the basis of clinical assessment and pathologic evaluation, clinicians had to believe that tumors were completely resected. In the case of stage T3c disease, for which pathologic examination alone cannot assess the thoroughness of removal of a vena caval thrombus, clinical impression was considered adequate evidence of complete resection. Staging criteria are summarized in Table 1
Patients were also considered ineligible if they had ever received prior radiation or chemotherapy for their renal tumor or other malignancies; had experienced any other malignancy except for in situ carcinoma of the cervix or superficial basal cell or squamous cell carcinomas of the skin; had ongoing angina, congestive heart failure, or seizure disorders; had a serum creatinine above 2.0 ng/mL, bilirubin greater than 1.4 mg/dL, AST (or comparable hepatic enzyme) above three times the normal value, WBC counts less than 4,000/mm3, platelet counts less than 100,000/mm3, or ECOG performance status 2 or greater. Documented recurrence, intolerable toxicity, or patient or physician desire were considered reasons to discontinue treatment with interferon alfa-NL. Management at the time of failure was at investigator and patient option, but cross-over of the observed patients to interferon alfa-NL was not a part of the trial.
Central pathology review was not used for this study, so pathologic classification, staging, and confirmation of the completeness of resection were based on review by each institution’s pathologists to determine study eligibility and stratification. Patients were stratified on the basis of histological tumor extent into four categories (T3a,b,c, N0, M0; T4a, N0–1 to 3M0; T1–2, N1–3, M0; and T3a,b,c, N1–3, M0 ([Tables 1
The surgical techniques, the extent of lymphadenectomy, the degree of radicalness of the nephrectomy, and the thoroughness of the original histopathologic examinations that determined eligibility and stratification category were not identical. Despite this, an extra-Gerotal nephrectomy that included perinephric fat, ipsilateral adrenal gland, perihilar fatty nodal packet, and negative surgical margins was required. The study was carried out by ECOG with centralized randomization, data collection, and statistical analysis. All research review boards from participating institutions approved this study, and all participants gave written informed consent.
Statistics and Study Design
Of the 294 patients who were originally entered and randomly assigned to treatment, 11 were excluded from the primary analysis because of entry errors (n = 2), metastatic disease or incompletely resected primary tumors (n = 5), serum creatinine above 2.0 ng/mL (n = 2), poor performance status (n = 1), or absence of all follow-up data (n = 1). The courses of 283 patients were analyzed with a median follow-up of 10.4 years and a maximum follow-up of 13.7 years (143 patients in the observation arm and 140 patients in the treatment arm). The arms were well matched for patient age, sex and race, tumor size, preoperative clinical stage, and histologic subtype (Table 2  ). The observation group had a somewhat higher proportion of individuals with poorer ECOG performance status, but this did not reach statistical significance (P = .10).
Four years after the study closed (median follow-up of 5.3 years), a survival advantage for observed patients was identified (P = .0096).25 At 8.8 years median follow-up, when 50% mortality had been reached in the observation arm and exceeded in the interferon arm, the survival advantage for observed patients had lost its statistical significance (P = .056). Now, at a median follow-up of 10.4 years, there have been 174 deaths in 81 observed and 93 treated patients. Thus, at least 56% mortality has been reached in both groups. There continues to be no statistically significant difference in survival between treatment arms (log-rank P = .09; Table 3
A multivariate proportional hazards model was developed that included treatment arm, age, sex, performance status (ECOG performance status 0 v 1), histology (clear-cell v other), local tumor stage (T1, T2, T3a, -b v T3c, T4), and lymph node status (none or unknown [N0/NX] v [N1] v [N2, N3]). In terms of the extent of nodal involvement, although no patient had involved nodes more than 5 cm in diameter (N3), 40 of the 50 patients with N2 disease had multiple bulky nodal metastases, three had multiple micrometastases, one had a single involved node more than 2 cm in diameter, and in six patients, the pathologic description was inadequate to ascertain the size of nodal metastases other than that there were multiple nodes involved. Performance status (P = .003), nodal status (N0/NX v N2; P < .0001), and tumor stage (P = .002) each significantly predicted survival independent of treatment. Survival was similar between N0/NX and N1 patients (P = .68). To test for differences in effect of nodal status and tumor stage by treatment arm, treatment-by-nodal status and treatment-by-tumor stage interaction terms were tested in the model. Differences attributable to the interaction term were not statistically significant, signifying that effect of treatment did not differ by nodal status or tumor stage. Figures 3  through 5 show overall survival by these three significant factors, and the final models are shown in Table 4. Sex, age, race, histology, and number of nodes sampled (not shown) did not significantly affect survival. Although clear-cell histology was associated with abbreviated survival in a univariate analysis (47.3 v 95.4 months; log-rank P = .006), the proportion of patients with positive nodes among those with clear-cell histology was higher than the proportion among patients with other histologies (30.3% v 12.9%; Fisher’s exact P = .001). In the multivariable model, histology was not a significant prognostic factor (Table 4; P = .17).
We used a proportional hazards model to examine the effects of treatment arm and time to recurrence on survival following recurrence. After controlling for time to recurrence, there was a significant difference between treatment arms (favoring observed patients) in survival following recurrence among the 177 patients who experienced recurrence (Table 4 ; P = .009). However, patients who had longer times to recurrence had reduced risk of death following recurrence, regardless of treatment.
No patient died from treatment toxicity. However, 16 patients (11.4%) experienced grade 4 toxicity, including neutropenia (n = 6), myalgia (n = 5), fatigue (n = 3), depression (n = 2), and neurologic toxicity (n = 2). Multiple grade 4 toxicities occurred in two patients. Descriptions of grade 3 and 4 neurologic toxicity included "depression with paranoia," "couldn’t be aroused," "fainting spells, weakness, and fuzziness," "confusion, amnesia for 3 days," and "violent behavior and depression." The summary of grade 3 and 4 toxicities for all patients randomly assigned to treatment (n = 294) appears in Table 5
The study was designed so that patients randomly assigned to receive interferon alfa-NL would receive a cycle of therapy every 3 weeks for 36 weeks (a total of 12 cycles) or would have treatment discontinued on tumor recurrence. If one eliminates the 52 patients who relapsed or died before receiving 12 cycles, only 70% (59 of 84 for whom the number of cycles were known) received complete therapy. The remainder withdrew at various time points, the overwhelming majority from grade 3 and 4 toxicities. Number of cycles received was not associated with prolonged survival (P = .09). Of the 81 patients in the observation arm who died, renal cancer was thought to be the cause in 63 patients (44% of the 143 observed patients and 78% of deaths in this group), cancer was believed not to be the cause in eight patients (6% of patients and 10% of deaths), and the cause was unknown in 10 patients (7% of patients and 12% of deaths). Of the 93 deaths in the interferon group, 65 deaths (46% of patients randomized to interferon and 70% of deaths in this group) were believed to be due to renal cancer, 15 deaths (11% of patients and 16% of deaths) were not caused by cancer, and the cause of death for 13 patients (6% of patients and 12% of deaths) was unknown (P = .25 for renal cancer as cause of death in observed versus interferon-treated patients). The sites of first failure (known for 159 of 177 patients who experienced treatment failure) were overwhelmingly distant metastases, regardless of original tumor or node stage. One hundred thirty-three (84%) of the 159 patients had distant metastases as the first site, 20 patients (13%) had metastases in regional nodes only (three of the 20 were NX at original surgery), and six patients (4%) had isolated local recurrences. Twelve patients who died without evidence of disease were considered to have experienced treatment failure. All but one of the 26 patients with initially isolated local or regional failure had died by the latest follow-up: most (n = 22) of progressing renal cancer. Twenty patients with distant metastases also had simultaneous local and/or regional recurrences, and 26 additional patients had subsequent local and/or regional recurrences (together 35% of the 133 initially distant failures). Thus, of the 159 patients in whom sites of recurrence were known, 72 (45%) developed local or regional recurrences eventually. Treatment randomization did not predict site of first recurrence among patients who experienced treatment failure (P = .48).
Locally advanced renal cell carcinoma is a challenging oncologic management problem. Even with widespread use of abdominal imaging to assess nonspecific symptoms, stage T3+ and/or N+ disease still occurs in 21% to 25% of patients at presentation.18,27 This study confirms that these patients are at high risk for recurrence and death: more than 30% of even the most favorable stratum (T3a, b, or c, N0) died within 5 years following nephrectomy (Fig 3 ). By the same token, 45% of these patients are alive at 10 years, 70% of whom have not experienced any recurrences with complete local resection. Furthermore, in patients in whom the first site of failure could be determined, recurrences consisted of distant metastases alone (71%) or occurred with concomitant local or regional recurrences (13%). Few (16%) patients who experienced treatment failure at known sites had local or regional recurrences as the initial site(s), and less than 25% (n = 72) of all evaluable patients ever experienced a local or regional recurrence. However, in view of recurrences being primarily at distant sites, indicating the likely presence of micrometastases at the time of surgery (or tumor dissemination by the surgical procedure), the inability of interferon alfa-NL to improve outcome is disappointing, particularly in view of reports of at least modest efficacy in distant metastatic disease.16 The specific form of alpha interferon chosen for this trial, interferon alfa-NL, was purified from supernatants of cultures of lymphoblastoid cells after Sendai virus stimulation. This interferon, which contained at least 16 alfa interferon subtypes, was one of the two most widely tested preparations in the mid-1980s when the study was planned.28 The other most widely used form, Hoffman-LaRoche’s (Nutley, NJ) recombinant form, was thought to be more likely to induce the development of neutralizing substances that adversely affected response. Interferon alfa-NL was also being studied at that time by the ECOG Melanoma Committee. There was no compelling evidence for differential in vivo biologic activity or antineoplastic activity at the time. This perception, along with ECOG’s prior experience with interferon alfa-NL, provided the rationale for selecting interferon alfa-NL for this study.29 However, the dose and schedule were modified in the current protocol from that used for known metastatic disease because the 10-day regimens employed in the former study were believed to be too toxic for the adjuvant setting.29
It is possible that this reduction in total dose and duration of each cycle of treatment explain in part the lack of efficacy seen with this regimen in this trial; however, in view of the considerable toxicity we observed even at this modified schedule (Table 5
The reasons patients treated with interferon alfa-NL tended toward worse initial survival30 are not readily apparent from toxicity data because there were no lethal toxicities from treatment. Also, although any prolongation of survival seen in observed patients was more in the time from first recurrence to death rather than in the time to first recurrence, in reality, longer survival after recurrence reflected a longer time to first recurrence rather than treatment assigned (Table 4
Intriguingly, in a similar group of patients randomly assigned to 6 months of 3 million units recombinant interferon alpha 2B three times weekly or observation after radical nephrectomy, Pizzocaro et al18 found a worse outcome in N0 patients who received interferon, but a protective effect in those with extensive nodal metastases (N2, 3), so that overall 5-year survival was identical in both arms. As in our cohort, more than 80% of deaths in their study occurring by 5 years were due to renal cancer. In our patients, extensive nodal disease was an independent poor prognostic factor (Fig 5 It could be argued that our results might have been different had another therapeutic regimen been employed. Examples of such regimens include high-dose interleukin 2 (IL-2),12,15 a combination of IL-2 and interferon alfa,17,20 other interferon alfa preparations,18,31 other interferons alone5,32 or with interferon alfa,11 lymphokine-activated killer cells with systemic IL-2,33,34 or combinations of either interferons or IL-2 with chemotherapy35–37 or biologic therapy (eg, cis-retinoic acid).14,38 However, at the time of the study’s inception, interferon alfa-NL had the substantial phase II evidence of efficacy and at least modest tolerance that make an agent appropriate for use in the adjuvant setting.39 In addition, the design of the study, in which patients were only entered after surgery and final histopathologic inspection had been completed, would have rendered it far more difficult to carry out more personalized therapeutic approaches including use of tumor infiltrating lymphocytes along with immunomodulators40 or tumor vaccination strategies.41,42 Another issue to be considered is that variable surgical practices and the absence of a required surgical technique in our study may have had an unrecognized influence on outcome. However, it would appear that for the primary lesion and the tumor’s direct extensions, at least adequate resection was the rule, because treatment failures exclusively with local or regional recurrences, despite the extensive nature of these cancers, occurred in only 8.5% of evaluable participants and were equally distributed in each arm (P = .67). In addition, randomization and stratification should have equally balanced such influences in each arm.
In this regard, the finding that patients who had extensive regional node dissections (as determined by surgical reviews and number of lymph nodes removed) did not fare significantly better than those undergoing more limited dissections might lead one to question the value of such surgeries. However, that 40% of the subjects with N1 disease were alive at last follow-up (similar [P = .86] to the 43% of those with N0 disease who were alive at last follow-up; Fig 5
Another issue that has not been addressed in prior studies is whether the histologic types of renal cell cancer were equally balanced and/or could explain results. Recently, molecular abnormalities, particularly alterations of key genetic loci, have been ascribed to clear-cell, papillary, chromophobe, and oncocytic varieties, each being associated with somewhat different degrees of indolence and aggressiveness.45 In addition, renal cell carcinomas with a major sarcomatoid component have been recognized to have particularly aggressive behavior.46 Because of the lack of central pathology review and less appreciation of these (potential) correlations between tumor behavior and histologic type at the time of the study’s inception and conduct, stratification was not based on these factors, and even by retrospective analysis of pathology reports, this information cannot be accurately retrieved for about 10% of the patients. However, by retrospective review, histologic types were equally distributed between treatment arms, with roughly two thirds being clear-cell carcinomas in each group and another 12% having mixed histologies consisting of sizable proportions of clear-cell carcinoma. Because all patients had locally and/or regionally extensive tumors, clear-cell and sarcomatoid varieties may have been overrepresented (accounting for roughly 85% of all tumors in this study; Table 4 In conclusion, adjuvant lymphoblastoid interferon alfa-NL, in the dosage used, did not provide a benefit for patients with locally or regionally extensive, completely resected renal cell carcinomas.
It is important to note that ostensibly complete surgical resection, even in the face of locally extensive disease, led to nearly an 8-year median survival in patients without multiple nodal metastases, most of whom maintained their disease-free status. This should be remembered when making treatment recommendations to patients with locally extensive disease (the overwhelming majority of our patients were known to have stage T3 disease preoperatively; Table 1
Levels of Interferon Toxicity
Supported by grant no. CA-23318, awarded by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
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43. Flanigan RC, Salmon S, Blumenstein BA, et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 345:1655–1659, 2001 44. Mikisch GH, Garin A, van Poppel H, et al: Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: A randomized trial. Lancet 358:966–970, 2001[CrossRef][Medline] 45. Zambrano NR, Lubensky IA, Merino MJ, et al: Histopathology and molecular genetics of renal tumors toward unification of a classification system. J Urol 162:1246–1258, 1999[CrossRef][Medline] 46. Dickerson G, Colvin R: Pathology of renal tumors, in Skinner D, Lieskovsky G (eds): Diagnosis and Management of Genitourinary Cancer. Philadelphia, PA, WB Saunders, 1988, pp 118–149 Submitted February 2, 2001; accepted November 21, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5%, diarrhea, intractable vomiting, and neurologic toxicities also mandated a dose reduction. Toxicities are defined in the Appendix. For level 1 fatigue or anorexia, doses were reduced to 50% for that and all subsequent cycles. For level 2 fatigue or anorexia, interferon alfa-NL was discontinued for the remainder of that cycle, and treatment was delayed until toxicity decreased to a level less than 1. If toxicity returned to level 1 with resumption of therapy, doses were reduced another 50% during that and all subsequent cycles. If level 2 toxicity was again reached, interferon was withheld for the remainder of that cycle and only resumed if toxicity less than level 1 was reached. The dose could be diminished by 50% again if level 1 toxicity was reached, but further toxicity or repetition of level 1 toxicity during future cycles mandated discontinuation of treatment. Level 2 neurotoxicity required removal from treatment. For all other toxicities, dose modifications as for fatigue were followed. Patients who experienced grade 3 toxicity on 25% of the specified study dose or who did not have toxicities reverse within 3 weeks of discontinuation of treatment were removed from protocol therapy. 
