Comparative Analysis between Immunochemotherapy and Target Therapy for Metastatic Renal Cell Carcinoma: Overview of Treatment-Related Adverse Events and the Dropout Rate in Korea

Due to the more widespread practice of regular health examinations and advancements in diagnostic imaging technology, the rate of diagnosis of asymptomatic, early stage renal cell carcinoma (RCC) has been increasing [1]. However, owing to the absence of characteristic symptoms, metastases are observed in 30% of initial diagnoses, and even in cases diagnosed with localized RCC and in which nephrectomy with curative intent is carried out, a recurrence/metastasis rate of 20-40% is observed during follow-up [2]. Consequently, most patients with RCC require systemic therapy; however, metastatic RCC (mRCC) shows an extremely poor response to conventional therapeutic strategies such as chemotherapy, curative radiation therapy, and hormone therapy, and the prognosis is reported to be very poor, with a mean survival period of 12 months and a 2-year survival rate of 10-20%. As a result, until recently, the only effective treatment of metastatic disease was cytokine-based immunotherapy with interferon (IFN)-alpha and interleukin (IL)-2, which unfortunately produces only relatively low objective response rates of 10-20%. In addition, among other problems, severe systemic toxicities have been observed at therapeutic doses, in some cases requiring inpatient treatment including admission into intensive care units, but no suitable replacement has been available to date [2].

Recent advances in our understanding of the biology and genetics of RCC have led to the emergence of novel molecular targeted approaches for the treatment of mRCC. Sunitinib malate is the current first-line targeted therapeutic agent for favorable and intermediate-risk groups with mRCC [3]. Toxicities observed at therapeutic doses are associated with a distinct pattern of adverse events in mRCC, which are different from those observed with conventional chemotherapy or immunotherapy [4, 5]. As such, it is important for physicians treating mRCC patients with targeted agents to be aware of potential treatment-related adverse events and to initiate management strategies promptly to avoid deleterious effects on the clinical outcome and patient's quality of life. However, few studies have been published to date in Korea regarding the clinical efficacy and treatment-related toxicities of sunitinib [6]. Although studies overseas have reported the treatment-related toxicities to be relatively mild, clinical experience has shown the adverse effects to be quite significant.

In light of this situation, we carried out a comparative analysis of treatment-related adverse events and the dropout rate in Korean patients who have undergone treatment with either sunitinib, currently the first-line therapeutic agent for mRCC, or IL-2- or INF-alpha-based immunochemotherapy, the mainstay over the past 20 years [7].

Treatment of advanced RCC has recently undergone a major change with the development of novel molecular targeted agents and potent angiogenesis inhibitors. Sunitinib is an orally administered, low-molecular-weight inhibitor of multiple receptor kinases. The antitumor effect of sunitinib is mediated through interference with platelet-derived growth factor receptor and vascular endothelial growth factor receptor [11]. In the two phase II open trials in patients with mRCC refractory to immunotherapy, unexpected and significant improvements in the response rate and overall survival with partial response were seen in 40-44% of patients; the median progression-free survival was 8.7 months, and the disease-specific survival was 16.4 months [5, 12]. On the basis of these promising data, a subsequent large-scale randomized phase III clinical trial comparing the relative efficacies of sunitinib and IFN-2a showed the former to be superior in terms of objective response rate to treatment (31% vs. 6%), median progression-free survival (11 months vs. 5 months), and overall survival (26.4 months vs. 21.8 months) in all prognosis groups as classified according to the Memorial Sloan-Kettering Cancer Center criteria [13]. Supported by such superior clinical results, sunitinib is currently used as the drug of choice in the treatment of mRCC [14]; nevertheless, due to significant therapy-related adverse events, reductions in dosage, postponements in treatment schedules, and ultimately complete cessation of treatment are common in actual clinical usage, despite the excellent rate of response to treatment [15-17].

In previous studies, immunotherapy and targeted molecular therapy were shown to differ in their treatment-related toxicities as a result of the different mechanisms responsible for their antitumor activities. Adverse events associated with immunotherapy largely consist of those due to cytokines released by activated T lymphocytes and natural killer cells, such as fever, myalgia, and general malaise, among other systemic symptoms, and those due to increased vascular wall permeability, including generalized and pulmonary edema and hypotension. The more frequently encountered toxicities associated with target therapy include hypertension, reduced left ventricular ejection fraction, hemorrhage, dermatological symptoms, and diarrhea. Likewise, in the present study, systemic constitutional symptoms such as fever, chill, and general malaise and pulmonary symptoms were the more frequently encountered nonhematologic adverse effects in the immunochemotherapy subjects. On the other hand, symptoms such as hypertension, hand-foot syndrome, mucositis-stomatitis, diarrhea, and nausea were more frequently observed in the sunitinib therapy group, similar to the results of previous studies. In addition, although hematologic toxicities were observed in both groups, the incidence was relatively lower compared with the results of other studies, and in most cases, the toxicities were of lower grades not requiring any special intervention.

Furthermore, whereas some studies have reported incidence rates as high as 85% for thyroid function test anomalies in patients receiving sunitinib treatment, the incidence rate observed in the present study was considerably lower at 27% [18]. A decrease in the left ventricular ejection fraction is a rare but potentially threatening complication. Chu et al reported that the incidence rate of cardiovascular toxicity associated with sunitinib treatment was 21% [19]; the figure obtained in the present study did not differ much at 13%, and most of the patients with newly developed treatment-related hypertension were successfully managed by commencement of standard antihypertensive drugs without any demonstrable vascular event. In patients already receiving medical therapy for hypertension, blood pressure was also adequately controlled with dose escalation of the currently prescribed antihypertensive medication. However, one of these subjects developed symptomatic congestive heart failure with a more than 20% decrease in the left ventricular ejection fraction from baseline; the subject's cardiac function returned to the pretherapeutic level subsequent to cessation of treatment.

Furthermore, in the present study, although an impressive superior objective response rate was observed in targeted therapy subjects, approximately 60% of the patients with mRCC did not respond to sunitinib. Response duration in sunitinib therapy subjects was relatively shorter than in the immunochemotherapy subjects, although without statistical significance, probably because of the limited number of patients. Complete remission was not seen, although long-term complete remission spanning 6 years was observed in one subject who received immunochemotherapy; this finding is similar to those of previously published studies. These results can be explained by tumor cell adaptation and compensation with overexpression of nontargeted oncogenic growth factor or receptor tyrosine kinase that confer resistance to the tumor cell.

In a study assessing satisfaction with treatment in patients receiving sunitinib or IFN-alpha treatment by use of self-filled questionnaires, Cella et al stated that at all stages, the physical, functional, psychological, and social satisfaction was greater in patients receiving sunitinib treatment [20]. Similarly, in this study, although the overall incidence of therapy-related adverse events and high-grade nonhematologic toxicities was higher for targeted therapy, most of the adverse events were low-grade, manageable toxicities, and potentially lethal high-grade toxicities were relatively less common. Even when toxicities did occur, they were usually resolved during the 2-week break at the end of each cycle. These off-dosage periods, along with the greater convenience of sunitinib because of its once daily oral dosing on an outpatient basis and the possibility of toxicity prevention through stepwise dose reduction, accounted for the greater patient compliance in the target therapy subjects.

One limitation of the present study is that it rests on retrospective examination of medical reports. Although a relatively accurate assessment of therapeutic toxicities, based on clinicians' observations and review of systems charts, was possible for the most part, some reliance on the limited recollections of the subjects was still present. Furthermore, because CTCAE, which was used in evaluating nonhematological adverse effects, uses the impact on daily life activities as the criterion in differentiating between low-grade and high-grade toxicities, an embedded limitation in the objectivity of assessing the severity of toxicities was present. In addition, identifying whether a particular symptom bore direct association to the systemic treatment of metastatic renal carcinoma or whether it occurred as part of the natural course of the disease or another co-morbidity was impossible in reality.

Sunitinib, which is currently used as the first-line treatment for metastatic renal cell carcinoma, was shown to be superior to immunochemotherapy in terms of objective therapeutic response and also demonstrated acceptable tolerability. The adverse events with sunitinib were predictable, relatively less severe, and stereotypical in general, and the dropout rate with sunitinib was relatively lower than that for immunotherapy in Korea.