New directions in the management of renal cell carcinoma
Marco Antonio Arap1, Ariel Galapo Kann2, Gustavo dos Santos Fernandes2, Antonio Carlos Buzaid2, Sami Arap1, Fernando Cotait Maluf2,*
1Department of Urology, University of Sao Paulo Medical School, São Paulo, Brazil
2Oncology Center, Sirio Libanês Hospital, São Paulo, Brazil
__________________________________________________________________________________
*Correspondence: Fernando Cotait Maluf, Rua Adma Jafet 91 CEP 01308-050, São Paulo, São Paulo, Brazil; Tel/Fax: 55-11-3155-0210; e-mail: maluffc@uol.com.br
Key words: Molecular target therapy, Motzer criteria, good, poor and intermediate prognosis, RCC patients, novel agents, Adjuvant therapy, cytoreductive nephrectomy
Abbreviations: central nervous system, (CNS); Eastern Cooperative Oncology Group, (ECOG); interleukin 6, (IL-6); mammalian target of rapamycin, (mTOR); platelet-derived growth factor, (PDGF); Renal clear cell carcinoma, (RCCC); vascular endothelial growth factor, (VEGF); von-Hippel-Lindau, (VHL)
Received: 29 October 2007; Revised: 24 December 2007
Accepted: 31 December 2007; electronically published: January 2008
Summary
Renal cell carcinoma represents nearly 3% of all cancers, frequently affecting patients at the age of 50 to 70 years. Few treatments options were available until recently for metastatic renal cell carcinoma. The 5-year median survival for those patients was estimated to be less than 10%. This review explored the data of the most relevant trials focused on new approaches with novel agents with several mechanisms of action such as: sunitinib, sorafenib, bevacizumab, temsirolimus and their combinations with traditional agents. We describe mechanism of action, activity and toxicity profile of all those agents as well as administration schedule. The surgical treatment was also revised, highlighting the data about nephrectomy in metastatic disease.
I. Introduction
Renal cell carcinoma represents nearly 3% of all cancers, frequently affecting patients at the age of 50 to 70 years. Renal clear cell carcinoma (RCCC) represents 60 to 70% of primary malignant renal tumors. In 2006, almost 35710 people in the United States developed renal cell carcinoma and 12480 died because of progression of disease (Cancer facts and figures, 1996). Epidemiologic data shows that in the last two decades the incidence of renal tumors has increased 2% to 4% each year (Kosary et al, 1993).
Few treatments options were available until recently for metastatic renal cell carcinoma. The 5-year median survival for those patients was estimated to be less than 10%. The objective response rate obtained with chemotherapy was only 5%. Higher objective responses were reported with interferon-a (objective response rate of 12%) as well as with high-dose interleukin-2 (objective response rate of 19%). After failure to prior cytokine based-therapy, the overall median survival was only 10 to 13 months (Motzer et al, 2004). Therefore, newer therapies were clearly necessary in order to improve outcome in this aggressive disease that is generally chemo and immunotherapeutic-resistant.
A relevant knowledge was provided by a study that showed that there is a similar genetic profile between sporadic renal clear cell carcinoma (non inherited and responsible for 60 to 70% of all renal tumors) and RCC secondary to the von-Hippel-Lindau (VHL) syndrome (hereditary disease characterized by vascular tumors including RCC representing 1% to 4% of all renal tumors) (Kondo et al, 2001, 2002). In the VHL syndrome, the mutation, deletion or chemical modifications of the VHL gene lead to lower protein levels or even inactivation of this protein with consequent higher levels of hypoxia inductible factor a. As a result, the expression of growth factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are markedly increased. Both VEGF and PDGF are intrinsically related to the promotion of angiogenesis, cancer invasiveness, and metastasis. Supporting prior findings, recent studies suggest that more than 60% of sporadic RCC have, as a critical point in their pathogenesis, somatically acquired mutations or methylation of the VHL gene (Kim WY et al, 2004), suggesting that may exist link between the VHL syndrome and sporadic RCC. In this review article we discuss the mechanisms of action, safety and role of novel agents both in the first-line and salvage, setting as well as the role of surgery in the treatment of advanced renal carcinoma (Schemes 1-3).
II. Molecular target therapy in previously untreated patients
A. Patients with good or intermediate prognosis according to Motzer criteria
Sunitinib is an oral drug that inhibits VEGF (types 1-3) and PDGF (a e β) receptors, as well as other tyrosine-kinase proteins. Sunitinib according to a phase I study (Faivre et al, 2006), Sunitinib was associated with an acceptable toxicity profile, easy schedule, and antitumoral activity. The use of sunitinib in patients with central nervous system (CNS) metastases was sometimes avoided because the potential risk of bleeding. However, this year one retrospective study suggested that anti-VEGF agents including sunitinib (13 patients) and sorafenib (10 patients) does not increase the risk of either intratumoral bleeding or any CNS bleeding when a local treatment, involving particularly radiation, was previously administered (Unnithan et al, 2007). Recently, two randomized phase III studies (Escudier et al, 2007b; Motzer et al, 2007b) and one randomized phase II study (Yang et al, 2003b) have been conducted comparing agents capable of VEGF inhibition (experimental arm) versus interferon-a (control arm) in metastatic renal cell
Scheme 1. Management of metastatic renal cell carcinoma regarding the role of surgery.
Scheme 2. Management of metastatic renal cell carcinoma in the first-line setting.
Scheme 3. Management of metastatic renal cell carcinoma in the second-line setting.
carcinoma patients with good or intermediate prognosis according to Motzer criteria. This muticenter phase III study conducted by Motzer and colleagues included 750 patients with metastatic or unresectable renal cell carcinoma and no prior systemic treatment (Motzer et al, 2007b). Patients were randomized to receive interferon-a or sunitinib. Treatment with subcutaneous interferon-a was administered at the initial dose of 3MU three times a week (tiw) with drug escalation, if no toxicity, until 9MU tiw. Treatment with oral sunitinib was given daily at the dose of 50mg for four consecutive weeks followed by two weeks of rest with cycles administered every six weeks. Patients were randomly assigned according to LDH (1.5 ≤ versus > 1.5 x normal superior limits), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), presence or absence of prior nephrectomy. The primary end point of this study, with an statistical power of 90%, was to demonstrate if the experimental arm would increase progression-free survival by 35% over to the control arm (from 4.6 to 6.2 months). Secondary endpoints included: overall survival, response rate and toxicity. The efficacy and safety data was evaluated by an independent committee in addition to the investigators. Patient characteristics were similar in both arms. Nearly 90% of the patients had prior nephrectomy, 14% had prior radiotherapy, 60% had ECOG 0, and 75% of patients had lung involvement. According to Motzer criteria nearly 36% of patients had good prognostic factors, 58% intermediate and only 6% had poor prognostic factors. Patients assigned to sunitinib had superior response rates (31% versus 6%, p < 0.000001) as well as progression-free survival rates (11 months versus 5 months, HR 0.41, 95% CI, 0.32-0.53, p < 0.000001) compared to the control arm (Figure 1). Also, patients on sunitinib had a trend towards improvement in overall survival, though the OS has not been reached in either groups (HR 0.65, 95% CI, 0.44-0.94, p = 0.02). Subgroup analysis revealed an advantage in progression-free survival both in good (not reached versus 8 months, HR 0.37, 95% CI, 0.21-0.64) and intermediate (11 months versus 4 months, HR 0.39, 95% CI, 0.28-0.54) prognostic groups treated with sunitinib. Update of these results confirmed prior findings (Motzer et al, 2007a). Sunitinib was associated with more frequent grade III and IV toxicities including diarrhea (5%), erythrodysesthesia (5%), fatigue (7%) and hypertension (8%). On the other hand, interferon-a was associated with more often grade III and IV fatigue (11%). It is important to recognize that sunitinib has been also associated with hypothyroidism. In one series fifteen of 42 patients (36%) who were receiving sunitinib developed clinically significant hypothyroidism during the course of treatment. Abnormal results on blood tests indicating at least some level of hypothyroidism occurred in a total of 26 of 42 patients (62%). The longer sunitinib was administered, the greater was the chance of developing suppression of thyroid function (Desai et al, 2006).
Figure 1. Kaplan-Meier analysis of progression-free survival of sunitinib and interferon-α.
Another study reported similar results (12 out of 55 patients) (Shaheen et al, 2006). Hypothyroidism can contribute to fatigue associated with sunitinib. Therefore, it is advised to monitor thyroid hormone levels in patients treated with this agent.
A randomized phase II trial (Yang et al, 2003b), including 116 previously treated patients evaluated the impact on progression-free survival of two different schedules of bevacizumab administered intravenously at 3mg/kg and 10mg/kg every two weeks in comparison to placebo. This trial demonstrated an advantage on progression-free survival rates for patients treated with high-dose bevacizumab compared to placebo (4.8 months versus 2.5 months, p < p="0.0670)" p =" 0.004)"> 2). Patients receiving the combination regimen had more grade III/IV toxicity (60%) when compared to the control group (45%) including fatigue (23% versus 15%), proteinuria (6.5% versus 0%), hypertension, (3.9% versus 0.7%) and hemorrhage (3.3% versus 0.3%). Despite that the combination arm was considered generally well tolerated. Based on these results, both sunitinib alone and bevacizumab plus interferon-α can be considered standard first-line therapy options in patients with unresectable or metastatic RCC with favorable or intermediate prognostic factors. Treatment costs, schedule profile, and patient’s and physician’s preferences must influence the regimen of choice between these two regimens. Is important to mention that the combination of bevacizumab and interferon-α has not yet been approved for the Food and Drug Administration, limiting the use of this therapy in some countries including the United States.
Sorafenib is a bi-aryl urea orally active characterized by Raf-1 serine-threonine kinase inhibition wich has inhibitory properties against VEGF (type 1-3) and PDGF receptors (a e β) (Mancuso et al, 2006). The activity of sorafenib was demonstrated in a phase III study including patients who failed prior systemic therapy (Escudier et al, 2007b). A randomized phase II study, including 189 patients, compared subcutaneous interferon-a at dose of 9MU tiw to oral sorafenib at the continuous dose of 400mg twice a day (bid) as first therapeutic line for RCC line. Primary end point included evaluation and comparison of progression-free survival between the two arms. Patient characteristics were similar in both arms. Despite the fact that sorafenib arm had superior quality of life outcomes over interferon-a (p = 0.02), there were no differences in response rates (5% versus 9%) and progression-free survival (5.7 months versus 5.6 months, HR 0.88, 95% CI, 0.61-1.27, p = 0.5). Sorafenib was associated with greater grade III and IV non-hematologic toxicities including diarrhea (6%), erythrodysesthesia (11%), and skin rash (6%). On the other hand, interferon-a was associated with more frequent grade III and IV fatigue (11%), nausea (6%), constitutional symptoms (6%) and confusion (4%) (Escudier et al, 2006). An update of this trial, recently presented, evaluated the role of sorafenib dose-escalation to 600mg bid for 44 patients who progressed on the standard dose dose (400mg bid). Surprisingly, patients on higher doses had a median progression-free survival of 4.1 months, any degree of tumor shrinkage in 44% of the cases, and reasonable tolerance (Szczylik et al, 2007). A phase II trial with intra-patient sorafenib dose-escalation up to 1200-1600mg a day (Amato et al, 2007) was presented this year. A total of 44 patients were included, 25 of them was not treated before, 91% of all patients could receive higher doses and the authors reported objective responses of 55%, including 19% of complete responses. These encouraging results suggest that higher doses of sorafenib might circumvent drug resistance of this agent administered at the conventional schedule, this trial also showed an increased dose dependent toxicity, the most common treatment related adverse events were: hand/foot syndrome, skin rash, diarrhea, alopecia, fatigue, hypertension, hypophosphatemia, and elevated amylase/lipase. These findings also raises the question regarding that the initial sorafenib doses evaluated in both phase II and III trials might be suboptimal and if this is true new studies should evaluate higher doses schedules.
B. Patients with poor and intermediate prognosis according to Motzer criteria
Other important pathway involved in the biological cascade in RCC carcinoma is represented by a serine/threonine protein kinase knowed as mammalian target of rapamycin (mTOR). Overexpression of mTOR is associated with prolonged tumor cell survival as well as high cell proliferation rates. Temsirolimus (CCI-779) is an mTOR inhibithor, such action is explained by the interaction of the drug with mTOR forming a complex that inactivates the kinase through phosphorylation phosphorilation inhibition. This effect induces apoptosis, cell cycle arrest at the G1 phase as well as cell response to growth factors and nutrients. Temsirolimus also inhibits one of the most important mTOR promoters, the AKT (serine-threonine kinase), as well as their regulators (PI3 kinase and tumor suppressor gene PTEN). Several studies have demonstrated that both AKT and mTOR play a critical role in renal cell carcinoma tumorigenesis and biologic behavior. Also, temsirolimus is known as an inhibitor of the hypoxia induced-a factor that is associated with direct effects on both VEGF and PDGF (Smolewski, 2006; Rubio-Viqueira et al, 2007). A phase III trial was conducted (Hudes et al, 2007), including 626 treatment-naïve patients with metastatic renal cancer associated with poor and intermediate prognostic characteristics. Patients were randomized among interferon-a versus temsirolimus versus the combination of both agents. Treatment with subcutaneous interferon-a was administered initially at the dose of 3MU tiw with dose escalation, if no toxicity, until 18MU tiw. Single-agent weekly temsirolimus was given intravenously at the dose of 25mg. In the combination arm interferon-a was administered initially at the dose of 6MU tiw associated to weekly temsirolimus at the dose of 15mg. Patients were stratified according to registration center and absence or presence of prior nephrectomy. Patients had to have at least three of the six unfavorable prognostic factors that included: performance status 60-70 (according to the Karnofsky scale), LDH > 1.5 x the superior normal limits, hemoglobin level lower than inferior normal limit, corrected serum calcium > 10mg/dL, time from the diagnosis to the study entry < 1 year, multiple sites of metastasis. The primary end point of this study was overall survival. With a statistical power of 90%, the design of this trial planned to show an increase in overall survival by 40%, in favor of temsirolimus arms (from 4.9 to 6.9 months, two-sided, p value < 0.025). Secondary end points included: progression-free survival, response rates (including stable disease for the clinical benefit analysis), and toxicity. This study also had an independent review committee for reviewing the efficacy and safety data. The three arms were well balanced. Nearly 67% of the patients had prior nephrectomy, 80% had clear cell histology, and more than 70% of the patients had unfavorable prognostic factors according to Motzer criteria. Overall survival in the combination arm was not superior compared to control arm (HR 0.96, 95% CI, 0.76-1.20; p = 0.70). Median overall survival rates in the interferon-a, temsirolimus, and combination arms were 7.3 months, 10.9 months, and 8.4 months, respectively (Table 1). Temsirolimus alone was associated with an advantage in overall survival (HR, 0.73, 95% CI, 0.58-0.92; p = 0.008) and progression-free survival (p < 0.001) over interferon-a alone. Single agent temsirolimus was well tolerated. Grade III or IV adverse events occurred in 67% of patients in the temsirolimus group, as compared with 78% of patients in the interferon group (P=0.02) and 87% of patients in the combination-therapy group (P=0.02). Most common grade III or IV toxicities from temsirolimus included hyperglycemia (10%) and anemia (12%) dyspnea and asthenia. Asthenia was most common in the two groups receiving interferon alone or in combination. Grade III or IV asthenia was reported in 11% of patients in the temsirolimus group, in 26% of those in the interferon group (P<0.001), and in 28% of those in the combination-therapy group (P<0.001). When compared with patients in the interferon group, mild to moderate rash, peripheral edema, and stomatitis affected more patients who received temsirolimus, either alone or in combination with interferon. Anemia, neutropenia, and thrombocytopenia were more common in the combination-therapy group than in the interferon group (P<0.001 for anemia, neutropenia, and thrombocytopenia) or in the temsirolimus group (P<0.001 for neutropenia and thrombocytopenia, and P=0.002 for anemia). Hyperglycemia, hypercholesterolemia, and hyperlipidemia were more common in the temsirolimus group and the combination-therapy group, reflecting inhibition of mTOR-regulated glucose and lipid metabolism. Based on these results single agent temsirolimus should be considered the standard first-line therapy for patients with poor prognosis characteristics according to Motzer criteria.
Table 1. Overall survival by treatment arm comparing interferon-α, temsirolimus, or both.
Overall Survival by Treatment Arm
IFN (Arm 1)
TEMSR (Arm 2)
TEMSR + IFN (Arm 3)
N
207
209
210
Deaths, n (%)
149 (34)
141 (32)
152 (34)
OS, median (95% CI), months
7.3 (6.1, 8.9)
10.9 (8.6, 12.7)
8.4 (6.6, 10.2)
Protocol-defined comparisons
NA
Arm 2: Arm 1
Arm 3: Arm 1
OS, hazard ratio (95% CI)
NA
0.73 (0.57, 0.92)
0.95 (0.76, 1.20)
OS, log-rank p
NA
0.0069
0.6912
INF = Interferon-α; TEMSR = Temsirolimus; OS = Overall Survival; N = number of patients; NA: Not Achieved
Confirming the activity of this class of agents, a phase II study evaluated everolimus at dose of 10mg orally and reported partial responses in 9 of 28 metastatic renal cell carcinoma patients exposed to prior systemic therapies (Amato et al, 2006).
Based on the fact that agents that inhibit multiple kinases involved on the VEGF and PDGF pathways have established activity in advanced disease, it is plausible as part of future strategies to evaluate synergistic interactions among them with other class of agents such as immunotherapeutic drugs. A phase II study, including 62 patients, evaluated the role of combining sorafenib 400mg orally bid continuously with interferon-a 10MU tiw as first-line therapy. Eligible patients had metastatic or unresectable renal carcinoma with a clear-cell component, no prior systemic therapy, performance status 0 to 1, and measurable disease. The primary end point was objective response. Twelve (19%) of 62 assessable patients achieved an objective confirmed response. An additional 31 patients (50%) had an unconfirmed partial response or stable disease as best response. The median progression-free survival was 7 months (95% CI, 4-11 months). The most common adverse events were fatigue, anorexia, anemia, diarrhea, nausea, rigors/chills, leukopenia, fever, and transaminases elevation (Ryan, 2007). Another phase II study was conducted including 40 patients who were treated with sorafenib and interferon-α, as first- or second-line therapy in metastatic renal cell cancer, on the same schedule of the previous study have the following results: response rate 33% (95% CI, 19% - 49%; 13 of 40 patients), including 28% partial responses (n = 11) and 5% complete responses (n = 2). The median duration of response was 12 months. With a median follow-up time of 14 months, median progression-free survival time was 10 months (95% CI, 8 - 18 months). Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss were the most common toxicities. Grade IV toxicities were uncommon but included hypophosphatemia, neutropenia, rash, fatigue, and anemia. Dose reductions were required in 65% of patients (Gollob et al, 2007). A phase III randomized study is ongoing, planning to accrual 499 patients with RCC, comparing daily sunitinib 50mg for 4 weeks followed by 2 weeks of rest versus daily sunitinib 37.5mg continuously for 6 weeks versus sunitinib at the conventional schedule combined with interferon-a. The primary goal of this trial is to evaluate if the combination arm will be associated with an improvement in time to progression from 8 to 12 months compared to the sunitinib alone arms (statistical power of 85%). This study will answer important questions regarding potential synergisms among different agents with distinct mechanisms of action as well as delineate the optimal sunitinib schedule. Another randomized phase II study has being conducted by ECOG, including 360 patients with RCC, comparing intravenous bevacizumab 10mg/kg given every 2 weeks versus bevacizumab at the same schedule associated with intravenous temsirolimus administered at the dose of 25mg weekly on days 1, 8, 15, and 22 or bevacizumab associated with sorafenibe 400mg bid continuously. The fourth arm of this trial consists of the combination of sorafenibe 400mg bid plus temsirolimus 25mg on days 1, 8, 15, and 22. The study primary end point includes the evaluation and comparison of progression free survival among the four arms.
III. Molecular target therapy in previously treated RCC patients
Patients with metastatic renal cell carcinoma who failed immunotherapy have a poor prognosis (Flanigan RC et al, 2007). The activity of other immunological agents as well as cytotoxic chemotherapy is minimal and clearly new agents are necessary in order to increase overall survival, palliate symptoms and improve quality of life. Two phase II studies including 168 patients were conducted to evaluate the activity of sunitinib in patients with RCC who failed prior cytokine therapy (interferon-a, interleukin-2, or both). Inclusion criteria included: ECOG 0 or 1, measurable disease, and absence of CNS involvement. Approximately 97% of patients had undergone prior nephrectomy. The response rates were classified according to the RECIST criteria and revised by an independent commission. The objective response rate was 42% with a median progression-free survival of 8.2 months (95% CI, 7.8-10.4 months). The toxicity profile of both trials evaluating sunitinib as second-line therapy is comparable to that observed with this agent in the first-line setting. (Motzer et al, 2006a,b).
An important phase III trial (Escudier et al, 2007b), in treatment refractory RCC, evaluated sorafenib at the standard schedule (400 mg BID) continuous orally) versus placebo. This study included 903 patients and the primary end point was overall survival. Secondary end points included the evaluation and comparison of progression-free survival, response rate, toxicity and quality of life. Inclusion criteria included: metastatic RCC, disease progression after one prior systemic treatment within the 8 months, ECOG 0 or 1, and absence of CNS involvement metastasis. Poor-risk patients according to Motzer prognostic score (Motzer et al 2004) were excluded from the trial. Patients were stratified according to Motzer criteria (low and intermediate) and country. Patients in both arms had a median age of 58 years, 77% had lung involvement, and 82% had received previous cytokine-based therapy. Prior radiotherapy and nephrectomy were performed in 25% and 94% of the patients, respectively. Approximately 51% of the patients were low and 49% intermediate-risk. Update of this trial showed an overall survival benefit of sorafenib over placebo, however those results were limited only to patients who did not cross-over to receive sorafenib after progression to placebo (17.8 months versus 14.3 months, HR 0.78, 95% CI, 0.62-0.97, p = 0.028) (Figure 2) (Bukowski et al 2007). The disease-free survival in the sorafenib group was also superior compared to placebo (5.5 versus 2.8 months; HR 0.44, 95% CI, 0.43-0.60, p < 0.001) (Figure 3). Sorafenib was associated with an advantage in progression-free survival among all subgroups including age (< 65 years or ≥ 65 years), Motzer criteria (low or intermediate-risk), previous systemic treatment (cytokine or others), presence or absence of lung or liver metastasis, and time since diagnosis (< 1.5 years or ≥ 1.5 years).The most common adverse effects (all grades) were diarrhea (43%), cutaneous reactions (40%), erythrodysesthesia (30%), fatigue (37%), nausea (23%), and hypertension (17%). Grade III and IV hematologic and non-hematological toxicities were uncommon (3%).
Figure 2. Kaplan-Meier analysis of overall survival sorafenib and placebo.
Figure 3. Kaplan-Meier analysis of progression-free survival sorafenib and placebo.
IV. Unresolved questions raised by novel agents in renal cell carcinoma
Despite the encouraging results both in the first- and second-line setting, clinical studies with sunitinib and sorafenib raise several questions regarding optimal doses and intervals, durability of response, impact on long-term survival, definition of biomarkers of response, efficacy in other histologies, safety of administration in patients with CNS metastasis, and whether the standard response criteria, such as RECIST, should be applied to this class of agents.
Despite daily dose of sunitinib at 50mg for 4 weeks every 6 weeks was reasonably well tolerated, fatigue occurred in 51% of the patients. Possibly, dose modifications may be necessary in order to maintain the safety drug profile in patients with a lower body surface area than the average patient population included in the sunitinib trials. Also, monitoring serum levels of this agent might help individualize the optimal dose for each patient (Houk et al, 2007). We agree with the reviewer comment and we re-wrote the sentence as a hypothesis.
Although a high number of patients achieved a response with sunitinib (and in a minor proportion with sorafenib), it seems that responses are not as durable as those observed with high-dose interleukin 2. Approximately 8% of patients treated with high-dose interleukin-2 achieve complete responses (Yang et al, 2003a), and in 80% of those patients response duration lasts over 8 years. Recently, it was demonstrated that the carbonic anhydrase IX over-expression evaluated by immuno-histochemical analysis (Atkins et al, 2005) and the alveolar component (Upton et al, 2005) in RCC predict the response rates in patients treated with high-dose interleukin 2. Thus high-dose interleukin-2 should still be considered the standard first-line treatment for patients ≤ 60 years, without significant co-morbidities and absence of CNS involvement in association with a favorable histological and molecular profile. Unfortunately, only a few patients meet these criteria. Prognostic features are under evaluation to predict the efficacy of agents that target VEGF and PDGF receptor tyrosine kinases.
The role of sunitinib and sorafenib in non clear-cell renal carcinoma and the safety of both agents in patients with brain metastasis are still uncertain. In a recent abstract (Plantade A et al, 2007), sunitinib (38%) and sorafenib (62%) were evaluated in patients with chromophobe (12 patients) and papillary (41 patients) renal cell carcinoma. The response rates achieved with both VEGF inhibitors in chromophobe and papillary subtypes were 25% and 4.8%, respectively.
The standard response criteria based on measurable disease (e.g. RECIST) were validated in large studies using cytotoxic agents and generally correlates with clinical benefit. However, it is uncertain whether these criteria are optimal to evaluate efficacy of these novel anti-angiogenic agents who have both cytostatic and cytotoxic properties (Gore et al, 2006). In a retrospective analysis (Escudier et al, 2007a), patients who had tumor reduction > 0% and ≤ 10% versus > 10% and ≤ 20% versus > 20% had similar progression-free survival rates. As an example, progression-free survival curves in patients treated with sorafenib were similar despite the degree of tumor reduction. On the other hand, patients who had no tumor reduction (assessed by the sum of tumor axis) showed inferior progression-free survival rates. Similarly, a phase II trial (Ratain et al, 2006) was designed to evaluate the outcome of patients based on the response according to sorafenib treatment. Three groups of patients were classified according to the response as assessed by RECIST criteria and managed accordingly. Sorafenib was maintained for patients who had tumor reduction ≥ 25%. On the other hand, sorafenib was discontinued for patients with tumor growth ≥ 25%. Patients who had tumor reduction < 25% or tumor increase < 25% were randomly assigned to sorafenib maintenance (32 patients) or placebo (33 patients) for an additional 12 weeks. Analyzing this last group of patients who were randomized, a total of 50% of patients on the sorafenib arm versus 18% on the placebo arm were progression-free at 6 months (p=0.007), respectively. These results reinforce previous findings that VEGF inhibitors should be probably maintained in patients without gross tumor progression or unacceptable toxicity, even if tumor size does not decrease dramatically. Some preliminary data suggest the appearance of necrotic component during VEGF inhibitors treatment in prior solid lesions may be useful to evaluate the efficacy of these agents (Figure 4). Other authors suggest that changes in tumor vascularization during treatment as assessed by MRI (De Bazelaire et al, 2003; Morgan et al, 2003) or doppler ultrasonography (Lamuraglia et al, 2005) may also be useful as a criteria of response. These parameters must be evaluated prospectively and compared to the standard response criteria in order to better establish a relationship between image response and clinical benefit with these novel agents.
Lastly, as sunitinib, bevacizumab plus interferon-α, sorafenib, and temsirolimus have a major impact both in the first- and second-line setting, it is crucial to evaluate the activity of these agents in patients who failed other VEGF-inhibitor. A retrospective study (Sablin et al, 2007) evaluated the role of sunitinib in patients who progressed on sorafenib (68 patients) or vice-versa (22 patients). The objective response rate in these two groups of patients was 22.7% and 17.6%, respectively, suggesting that both agents may target different pathways rather than the VEGF cascade. As a result, both agents can be considered second-line options after failure to a VEGF inhibitor. In order to better evaluate prospectively the non-cross resistance activity of these agents, dose-response schedules, and potential synergism among these novel agents to revert resistance a phase II randomized trial is ongoing. In this trial, patients who had disease progression on sunitinib at the standard dose are randomized to increase the sunitinib dose versus association of bevacizumab to sunitinib versus switch to sorafenib at standard doses. Similarly, randomization for patients who had disease progression on sorafenib at standard doses includes increasing the sorafenib dose versus association of bevacizumab to sorafenib versus switching to sunitinib at standard doses. Also, based on the two standard first-line therapies, it is extremely important to evaluate the activity of bevacizumab (plus or minus interferon-α) in patients who have progressed on sunitinib and vice-versa.
A phase II trial (George et al, 2007) involving 61 bevacizumab-resistant patients evaluated the efficacy of sunitinib and reported objective responses and stable disease rates of 23% and 57%, respectively. The median duration of response and progression-free survival were 30 weeks and 36 weeks, respectively. A retrospective study (Drabkin et al, 2007) evaluated the activity of sorafenib in patients previously treated with bevacizumab. The objective response and stable disease were 2.5% and 77%, respectively. There is no data available regarding the activity of bevacizumab-based regimens sunitinib- or sorafenib-refractory patients.
How do we compare the results of these novel agents to immunotherapy or chemotherapy in the second-line setting? Escudier and colleagues reported a response rate with interferon-a of only 2% in 48 patients previously treated with interleukin-2. Similarly, the response rate to interleukin-2 in 65 patients previously treated with interferon-a was only 4% (Escudier et al, 1999). Another study including 251 patients treated with second-line agents (including immunotherapy and chemotherapy) reported a response rate of only 4% (Motzer et al, 2002).
In summary, these novel agents that inhibit important pathways related to the mutation or methylation of the VHL gene represent a new paradigm in the treatment of metastatic RCC. The disease-free survival observed with sunitinib (8.2 months) or sorafenib (5.5 months) in prior treated patients are significantly better than those observed with other “old” agents (2.4 months). Therefore, these novel agents represent an important progress in the treatment of metastatic RCC (Table 2). Surprisingly, the response rates and progression-free survival seems not to correlate whether patients received prior treatment or not. These findings suggest that these agents may have non-cross resistance properties with other agents such as immunotherapy and chemotherapy.
Figure 4. Patient with metastatic renal clear cell carcinoma involving the pancreas. Pre- and post-treatment with sunitinib showing a significant difference of density among the lesions due to necrosis/liquefaction after treatment despite the fact that no change in tumor diameter.
Table 2. Summary of results of anti-VEGF therapies and conventional therapy as second-line treatment (Escudier et al, 1999, 2007; Motzer and Russo, 2000; Yang et al, 2003b; Motzer et al, 2006a,b, 2007b).
Treatment
Author
Number of patients
Response
Progression-free survival
Sunitinib
Motzer
168
40%
8.2 months
Sorafenib
Escudier
451
10%
5.5 months
Bevacuzimab (high dose)
Yang
39
10%
4.8 months
Several (historic data)
Motzer
251
4%
2.4 months
Immunotherapy (second-line)
Escudier
113
3%
NR
Interferon-a (first-line)
Motzer
463
11%
4.7 months
V. Adjuvant therapy with molecular target therapy
According to the established activity of the VEGF and PGDF tyrosine kinase inhibitors in metastatic disease, clinical studies are ongoing to explore the role of these agents in reducing tumor recurrence, improving survival, and changing (for the first time) the natural history of this disease for high-risk patients in the adjuvant setting. The study, coordinated by the ECOG, plans to accrual 1332 patients with ≥T1B renal cell carcinoma and randomized them among three arms: sorafenib (400 mg bid on days 1-42) versus sunitinib (50 mg qd on days 1-28 every 42 days) versus placebo. In all three arms, treatment was given for a total of 9 cycles. The primary end point of this study is to evaluate and compare the disease-free survival curve rates among the three arms. Patients have being stratified by pathologic staging and histological subtype (clear cell or non-clear cell). This trial aim to answer two important questions: if these novel agents are superior to placebo and define the VEGF inhibitor of choice. Another phase III three-arm trial ongoing, plan to accrue 1420 high or intermediate risk patients. The three arms of this trial include continuous three-year sorafenib (400 mg bid) versus one-year sorafenib (400 mg bid) versus placebo. The primary end point of this study is to evaluate and compare the disease-free survival rates among the three arms. This study raises two different questions: whether the target agent impacts on the natural history of disease and the optimal treatment duration these novels agents.
A third randomized trial involving another molecular target agent is ongoing, with a planned accrual of 600 patients, comparing the role of a chimeric antibody against carbonic anhydrase protein given intravenously weekly for 24 weeks versus placebo for patients with intermediate- and high-risk of relapse. The carbonic anhydrase protein is overexpressed in more than 80 to 95% of the renal tumors and has direct biologic implications in renal clear cell carcinoma biology and behavior. A recent phase II trial (Bleumer et al, 2004) reported response rate and stable disease in 33% of treated patients. The primary end point includes the evaluation and comparison of disease-free survival and overall survival rates between the two arms.
VI. The role of cytoreductive nephrectomy in metastatic renal cell carcinoma
To date, cytokine-based immunotherapy is still considered an option for patients with metastatic renal clear cell carcinoma. The role of nephrectomy in this situation, either before or after systemic treatment, remains controversial. The rationale for cytoreduction before immunotherapy is based on the ability of renal cell carcinoma to manipulate host’s natural immunity. It is known that the primary lesion rarely responds to systemic treatment, even in patients who present with regression of metastases (Rackley et al, 1994). Lymphocytes from patients with metastatic renal cancer have increased apoptosis (Cardi et al, 1998; Uzzo et al, 1999) defective T-cell receptors (Finke et al, 1993) and poor signal transduction (Li et al, 1994; Ng et al, 2002). In addition, immunologic responses may be impaired by the overproduction of interleukin 6 (IL-6), IL-8, IL-10, GM-CFS, and other cytokines.
Other hypothetical benefits of nephrectomy before systemic treatment are palliation of paraneoplastic syndromes, prevention of complications caused by locally advanced disease, the shed of tumor cells and the interruption of cytokine release by the primary tumor, which might be also involved in the growth of metastases. Many retrospective studies of pre-immunotherapy cytoreductive nephrectomy before systemic treatment have been reported. As the response to cytoreductive nephrectomy is variable, most authors reinforce the importance of patient selection and preoperative evaluation of different criteria believed to be predictive of good outcome, such as ECOG performance status and the presence of liver, bone or central nervous system metastasis (Fallick et al, 1997) Other studies showed that multiple organ metastasis (Han et al, 2003). low Karnofsky performance status, hemoglobin level lower than the normal limits, corrected serum calcium level >10 mg/dL (Motzer et al, 1999), tumor grade, preoperative white blood cell count, partial thromboplastin time, and lymph node metastases are also prognostic (Pantuck et al, 2003).
The most important problems associated to surgery are the peri-operative mortality rate (that varies from 0 to 17%) and the inability to receive post-operative systemic therapy due to poor performance status (Bennett et al, 1995). The largest retrospective series is from the National Cancer Institute and included 195 patients who underwent nephrectomy before undergoing interleukin-2 therapy. The overall response was 18%, mortality was 1% and 38% of patients were unable to undergo interleukin-2 treatment due to poor performance status, post-operative complications and tumor progression (Walther et al, 1997).
Two important prospective and randomized trials were reported regarding cytoreductive nephrectomy (Flanigan et al, 2001; Mickisch et al, 2001). The trials conducted by SWOG and EORTC used the same protocol (cytoreductive nephrectomy followed by interferon-a or interferon-a alone) and both demonstrated longer survival in the nephrectomy groups. In addition, the trials definitively showed in a well-selected patient population that surgery was rarely a limitation to start systemic therapy, and that the response rate to systemic therapy was similar in both groups. There is no data regarding a potential role for cytoreductive nephrectomy for patients with metastatic disease treated with VEGF tyrosine kinase inhibitors. However, all positive trials that showed a benefit of VEGF, PDGF, and mTOR kinase inhibitors over immunotherapy or placebo included mostly patients who had prior nephrectomy. In conclusion, the role of nephrectomy before systemic therapy for metastatic renal cancer is still to be defined. However, nephrectomy is justified in the palliation of local symptoms, in patients with solitary metastases or low disease burden and in patients with good performance status and limited disease who candidates to receive systemic therapy including newer agents.
VII. Conclusions
Recently several advances have been made on both basic and clinical knowledge about renal cell carcinoma, such data allows to see knew horizons and build a more positive future for those patients achieved for this severe disease. In spite of those advances, metastatic RCC is considered incurable and the continue development of knew strategies is mandatory.
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