Literature Search
The systematic search is summarized in the QUOROM flowchart (Figure 1). Twelve trials were identified that were published or presented between 1987 and 2009[5–8, 14–21]. Two studies enrolled metastatic and non-metastatic patients but no separate information of non-metastatic was provided, which precluded their inclusion in analyses[8, 15]. The remaining ten trials comprised 2609 patients. Six trials, (1,997 patients) had mature OS data [7, 14, 16, 18–20] while DFS was reported in all studies.
Eligible trials enrolled high-risk patients. Approximately 60% of patients had lymph node positive disease while 86% had pT2 or more advanced disease. No patient had previously received systemic therapy. None of selected trials was a placebo-controlled, double-blind trial. The Wood trial demanded a minimum clear cells component (25%) in tumor burden[19]. The remaining trials accepted all pathological subtypes. Considering the selected studies, three were carried out in the United States, six in Europe, and one in Japan. Methodological details potentially related to bias are described in Table 1.
Three studies tested vaccine therapy[16, 17, 19], three interleukin/interferon therapy[7, 18, 20] without high dose therapy, one biochemotherapy[14], one hormone therapy[5], one thalidomide[21] and one chemotherapy alone[6]. A detailed description of treatment arms for all included studies is presented in Table 2.
Overall Survival
The impact of adjuvant treatment on OS was extracted directly or estimated indirectly from published data of six trials with mature data (1,997 patients)[7, 14, 16, 18–20]. No single study demonstrated a statistically significant improvement in OS. Funnel plots of all comparisons did not identify a publication bias.
As the trials whose results were analyzed involved the use a multitude of agents, some of them with limited activity in advanced disease, the subgroups are shown and described individually.
Vaccine therapy
Two trials identified (848 patients) provided OS data on vaccine therapy[16, 19]. Meta-analysis demonstrated that adjuvant therapy was not capable of improving OS (HR = 1.02; 95% CI 0.75 to 1.39; P = 0.89; Figure 2). There was no heterogeneity between trials (I2 = 0%).
Immunotherapy
Three trials (840 patients) with immunotherapy were gathered and there was no sign of OS improvement (HR = 1.18; 95% CI 0.90 to 1.56; P = 0.23; Figure 2)[7, 18, 20]. Again, no heterogeneity was found (I2 = 0%).
Other Therapies
The systematic review found only one trial testing biochemotherapy (5-fluorouracil associated with interferon alfa/interleukin 2)[14]. There was no survival gain with biochemotherapy (HR = 0.91; 95% CI 0.60 to 1.38; P = 0.66; Figure 2).
One study tested chemotherapy (UFT), one thalidomide, and another one hormone therapy (medroxiprogesterone)[5, 6, 21]. None presented OS data.
The meta-analysis of all studies demonstrated that the agents studied did not improved OS (HR = 1.07; 95%CI 0.89 to 1.28; P = 0.46; Figure 2). There was no heterogeneity between trials (I2 = 0%; P = 0.64).
Disease-free Survival
Information concerning DFS was available in all trials (ten trials, 2,609 patients). Only one study demonstrated a statistically significant result, favoring active therapy[17].
One more time, as the trials used many different agents, some of them with no activity in advanced disease, the subgroups are shown and described individually.
Vaccine Therapy
All three trials identified testing vaccines presented DFS data (1,227 patients)[16, 17, 19]. The meta-analysis could not identify a DFS gain (HR = 0.86; 95% CI 0.71 to 1.04; P = 0.13; I2 = 51%) (data not shown). Nevertheless an elevated heterogeneity was found that demanded a more detailed evaluation of this comparison.
Examining carefully the characteristics of each trial, the study conducted by Jocham et al[17] seemed to be the source of heterogeneity. Jocham et al applied autologous vaccine in radically resected renal cancer patients and was the unique trial identified with positive impact in survival, more specifically, DFS. However, this study had methodological restrictions. A large portion of patients (41%) were not properly followed due to histological incompatibilities, lost of follow-up, failure in vaccine production, and staging flaws. Taking all these into account, Jocham et al results must be viewed with great caution. Excluding this trial from analysis (848 patients left) meta-analysis did not identify a DFS gain while heterogeneity was eliminated (HR = 0.95; 95% CI 0.76 to 1.19; P = 0.68; I2 = 0%; Figure 3).
Immunotherapy
All three trials (840 patients) with immunotherapy provided DFS data[7, 18, 20]. The meta-analysis was performed with acceptable heterogeneity although no gain could be observed (HR = 1.13; 95% CI 0.80 to 1.60; P = 0.48; I2 = 40%; Figure 3).
Other Therapies
The situation of thalidomide, chemotherapy, hormone therapy, and biotherapy was identical: the systematic review identified just one trial testing each of these therapies and no study demonstrated a survival benefit of adjuvant treatment.
Naito[6] tested adjuvant UFT (HR = 0.85; 95% CI 0.26 to 2.82; P = 0.80); Pizzocaro[5] tested medroxiprogesterone (HR = 0.95; 95% CI 0.45 to 2.00; P = 0.90); Margulis[21] tested thalidomide (HR = 2.34; 95% CI 0.93 to 5.88; P = 0.07), and Aitchison[14] applied 5-fluorouracil and interferon alfa/interleukin 2 (HR = 0.87; 95% CI 0.64 to 1.19; P = 0.40).
The meta-analysis of all studies demonstrated that all agents studied did not improved DFS (HR = 1.03; 95%CI 0.87 to 1.21; P = 0.77) (Figure 3). There was no significant heterogeneity between trials (I2 = 15%; P = 0.31).
Toxicity
Eight trials presented toxicity data (1,910 patients)[5–7, 16, 17, 19, 20]. Adverse event descriptions were scarce and no single toxicity was described across all trials. Vaccine and immunotherapy caused mild but frequent skin induration, injection site pain, and flu-like symptoms. Just one trial, which tested vaccine therapy, described grade 3/4 neutropenia (RR = 62.33; P = 0.004) and anemia (RR = 3.06; P = 0.49)[7]. No trial described neutropenic fever, thrombocytopenia, or grade 5 events.
Despite the absence of details, most severe toxicities were presented in each trial and therefore worst toxicity meta-analysis was feasible. Table 3 depicts the number of grade 3/4 events among the patients at risk (safety population).