Recent advances in the treatment of metastatic renal cell carcinoma (RCC) have dramatically changed the understanding of the current state of RCC treatment. For a long time, there was no effective systemic treatment for RCC because of the high level of resistance to chemotherapy and the marginal benefit of biologic therapy. However, the recent emergence of targeted agents has led to a significant change in the understanding of systemic therapy for RCC. As such drugs continue to emerge, a number of clinical issues continue to be mentioned. In this paper, we briefly review some of the clinical issues raised so far.
I. Important targets of RCC targeted therapy
In recent years, one of the key advances in the field of basic oncology research is the discovery of important cellular signaling pathways on which tumor cells depend. Signaling blockers targeting these pathways can effectively lead to impaired survival of tumor cells. Of course, such pathways are often not unique. This is an important basis for generating the concept of molecularly targeted therapy, which has two basic theoretical premises: first, that the discovered cellular signaling pathway is indeed necessary for the survival of tumor cells, and second, that blockers targeting this signaling pathway can effectively lead to the death of tumor cells when they are acted upon. Fortunately, two signaling pathways with the above requirements were identified in RCC: the vascular endothelial growth factor (VEGF) pathway and the mammalian target of rapamycin pass (mTOR) pathway.
The VEGF pathway and the mTOR pathway intersect at the level of hypoxia-inducible factor (HIF) when signaling occurs intracellularly. hIF activity is regulated in part by the VHL gene. vHL is an oncogene and heterozygous deletion of VHL (LOH) is present in 90% of patients with sporadic clear cell RCC, and residual VHL alleles can be inactivated by two mechanisms. Approximately 80% of them are inactivated by mutation, while the remaining 5% to 10% result in gene silencing through methylation [1]. Under physiological conditions, VHL is involved in the hydrolysis process of HIF; when VHL is functionally inactivated, HIF cannot be degraded in a timely manner, therefore leading to a continuous activation of the intracellular hypoxic response pathway. For the mTOR pathway, in fact, there are many of its downstream molecules intracellularly, including the overexpression of HIF [2]. mTOR can phosphorylate p70S6 kinase and activate it, leading to increased levels of certain ribosomal proteins and transcription elongation factors, which in turn lead to increased levels of HIF expression; mTOR can also promote the dissociation of the eukaryotic eIF-4E complex, thus freeing mTOR can also promote the dissociation of the eukaryotic eIF-4E complex, thereby freeing up the eIF-4E protein, which is now known to promote the increase of several cell cycle regulatory proteins at the translational level, including c-myc, cyclin D1, and ornithine decarboxylase. Activated HIF can localize to the nucleus, leading to a sustained increase in VEGF transcript levels. In fact, RCC has the highest levels of circulating VEGF levels in vivo and VEGF expression in the tumor tissue itself of all patients with solid tumors [3]. In turn, VEGF can act on VEGF receptors expressed on the surface of vascular endothelial cells to promote increased vascular permeability and endothelial cell proliferation and migration.
II. Determination of overall therapeutic goals in patients with RCC
The appropriate therapeutic goal for patients with RCC should be to slow down tumor progression as much as possible and maximize the time required for patients to reach lethal tumor burden, while maximizing the quality of life of patients. Among the means to achieve this goal, the ideal is of course to achieve a tumor-free state with curative criteria, but this is not realistic for the vast majority of RCC patients in terms of current clinical tools; in fact, the process of achieving this goal requires clinicians to be very familiar with the selection criteria and risk/benefit ratio of each treatment strategy for patients, but this is also very difficult because for these new concepts of current treatments, which are still not clearly defined, require clinicians to continuously draw from practice and closely follow the latest advances in the relevant field. In addition, the specifics of the lethal tumor load vary for different patients, thus requiring a high degree of individualization in the development of specific treatment strategies.
III. Clinical significance of subtractive nephrectomy in metastatic RCC
Debulking nephrectomy in patients with metastatic RCC is clinically feasible based on the requirement to achieve overall treatment goals for RCC, and in fact it has become the current standard of care for patients with metastatic RCC in individual oncology centers around the world [4,5]. This conclusion was confirmed by two large clinical trials, a pooled analysis of which showed [6] that patients with metastatic RCC treated with subtractive nephrectomy + IFN-α had an overall survival advantage compared with IFN-α alone, with a median survival of 13.6 months vs. 7.8 months, but no significant difference was seen between the two groups in terms of objective efficiency. The reasons why patients benefited from undergoing surgery are unclear, and possible explanations are: (i) patients had their tumor load reduced by surgery, effectively prolonging the time to develop a lethal tumor load again; (ii) it is possible that surgery altered the local immune microenvironment of the tumor, allowing the reversal of immune tolerance that was previously present locally (this hypothesis has been supported by clinical evidence) [7]; (iii) in some patients, surgery was found to be associated with mild renal insufficiency and a chronically acidic internal environment in patients, which favors the suppression of tumor infiltration [8]; (4) in addition, nephrectomy reduces the levels of endogenous pro-angiogenic proteins, especially VEGF, thus favoring the control of vascularization of tumor tissue and improving the efficacy of anti-VEGF therapy. Of course, the above view lacks evidence support from randomized, controlled clinical studies.
Thus, two different clinical treatment strategies could theoretically be adopted. One is for patients to undergo subtractive nephrectomy followed by systemic therapy. The inclusion criteria include: ECOG score of 0 to 1; tumor load predominantly located in the kidney and resectable; small and relatively stable tumor load in extrarenal lesions; and no other significant organ dysfunction. As can be seen, this so-called selection criterion is actually quite subjective; therefore, it often requires repeated communication between patients and clinicians, weighing the pros and cons, as well as good communication between physicians of different disciplines before specific implementation. Another strategy is for patients to receive systemic drug therapy before undergoing subtractive nephrectomy depending on the situation. The advantage of this is to have a better assessment of the patient’s treatment responsiveness and tumor progression before performing the surgery in order to facilitate better selection of patients who can undergo the surgery. However, it is not possible to determine the exact timing of surgical treatment. Two clinical trials are currently underway in patients with metastatic RCC to evaluate this treatment concept: one comparing the difference between surgery + sunitinib and sunitinib treatment alone; the other is the difference between sunitinib monotherapy and sunitinib + surgery.
IV. Timing of initiation of drug therapy in patients with metastatic RCC
Although drugs with definite efficacy for the treatment of RCC have emerged, none of these drugs can produce the desired CR response. The most important feature of treatment is that they all focus on controlling disease progression, and the time required for treatment is relatively long, so the possible benefits for the patient, the patient’s tumor load status, possible toxic side effects, the patient’s quality of life, and the associated treatment costs must be carefully measured before drug administration. Clinically, there does exist a small proportion of RCC patients with a small tumor load and a long disease duration, for which the overall treatment goal should be to control the tumor load and preserve the patient’s quality of life to the greatest extent possible, without recommending premature initiation of drug therapy. This has been supported by corresponding clinical evidence: in this case, patients can maximize clinical benefit even if antitumor therapy is started after definite tumor progression. For example, in the clinical trial of sorafenib [9], 28 patients were treated with sorafenib for 12 weeks followed by placebo and then restarted sorafenib treatment after disease progression. The median time to progression after reapplication of sorafenib in these patients was 24 weeks, which was generally consistent with the time to PFS in patients on continuous uninterrupted sorafenib treatment. This suggests that some patients may not require continuous drug therapy and may be able to obtain the same clinical benefit by starting drug therapy again after clinical confirmation of disease progression. However, this treatment concept should be applied with special care in clinical practice because the patient’s tumor load status, the rate of disease progression are highly individualized and may produce different outcomes depending on the drugs applied, and there is insufficient clinical evidence in this regard to fully elucidate the specific situation.
V. Systemic therapeutic strategies currently considered effective in patients with metastatic RCC
(i) Cytokine therapy
A considerable number of past clinical trials have confirmed that the use of endocrine therapy and chemotherapy is largely ineffective in patients with metastatic RCC, whereas treatment with IFN-α and IL-2 may result in marginal gains. Multiple phase III clinical trials and meta-analyses have shown that treatment with IFN-α can result in some survival advantage for patients compared to no treatment. (See Table-1). With high-dose IL-2 therapy, a significant overall control rate is achieved compared to low-dose IL-2 therapy (subcutaneous injections or outpatients) and CR is achieved in 5-7% of patients [10]. The clinical characteristics of patients who can achieve CR are generally young patients with no previous treatment, pathological type mostly clear cell carcinoma, ECOG score of 0, and only lightly loaded pulmonary metastases. High-dose IL-2 therapy has not been widely performed because of the very small patient population that can achieve CR and the difficulty of treatment implementation.
Regarding the combination of cytokines, many clinical trials have also been carried out, but none of them have confirmed the superiority of the combination, and of these, only positive results have been observed with the combination of IFN-α and bevacizumab [11]. The main direction of current research is to identify the characteristics of patient populations that benefit most from receiving cytokine therapy; for example, a retrospective analysis found that patients expressing carbonic anhydrase IX (also known as G250) achieved higher objective remission rates when treated with IL-2 [12], and relevant prospective trials are currently underway to confirm this idea. In addition, the combination of cytokine therapy with targeted therapies is one of the current hot topics of research.
Therefore, in general, the therapeutic status of cytokine therapy in patients with metastatic RCC is still not fully established and needs further refinement. However, as mentioned earlier, despite the overall lack of efficacy of cytokine therapy, the elucidation of the clinical characteristics of this group of patients is an extremely important clinical issue since it does produce significant and durable CR responses in a very small number of patients. In addition, the combination of high-dose IL-2 with targeted therapies needs to be further explored, but at least some studies may not support the combination of the two [13].
(ii) Targeted therapy
The more studied targeted therapeutic targets in metastatic RCC are the VEGF pathway and the mTOR pathway. Small molecule inhibitors targeting the VEGF receptor intracellular tyrosine kinase have been widely used in clinical practice, including sunitinib (SUTENTTM, sotan) and sorafenib (NEXAVARTM, doxorubicin). It is important to clarify that these two drugs do not target only the VEGF receptor system; in fact, both sunitinib and sorafenib are multi-target tyrosine kinase inhibitors, but the propensity to act on the targets differs slightly between the two, which leads to differences in clinical efficacy and variability in toxic side effects. Clinical studies have shown that sunitinib remains effective in patients who have failed prior cytokine therapy and that sunitinib also has a significant PFS and OS advantage over IFN-α in untreated patients [14]; although sorafenib also observed efficacy in patients who failed prior cytokine therapy, it failed in untreated patients be confirmed due to IFN-α [15]. Similarly, efficacy was observed with bevacizumab monotherapy in patients who had failed prior cytokine therapy, and the combination of bevacizumab with IFN-α was superior to IFN-α treatment in untreated patients in terms of PFS and OR [16]. The biological mechanism of the combination of the two is currently unknown. In high-risk patients, treatment with temsirolimus (TORISELTM) was superior to IFN-α monotherapy in terms of PFS and OS [17], while in patients who failed treatment with sunitinib and sorafenib, treatment with everolimus, another mTOR inhibitor, was still observed in comparison to placebo with a PFS advantage [18].
VI. Clinical treatment strategies for patients with metastatic RCC.
According to the RECIST evaluation criteria in clinical trials, the objective remission rates of targeted agents in metastatic RCC can be broadly classified as follows: only 1% with everolimus, close to 10% with sorafenib, bevacizumab and temsirolimus, and close to 40% with sunitinib. despite the different objective remission rates, the above All of these agents can result in some reduction in tumor load after initiation of drug therapy in 60% to 75% of patients; and all can double the PFS of patients in the treatment group compared with the control group. Therefore, one of the keys to treatment selection is the degree of tumor reduction needed by the patient. For patients with a high tumor load and more severe symptoms, treatment with sunitinib is more appropriate and can control the tumor load more rapidly. Alternatively, sunitinib may be appropriate in patients who have the potential to control their tumor load with drug therapy, thereby increasing the likelihood of undergoing consolidative metastasectomy for tumor reduction. A growing body of clinical evidence is beginning to support a treatment strategy of targeted therapy + consolidative metastasectomy [19], a treatment paradigm that has the potential to increase the proportion of patients who can undergo surgical tumor reduction and the proportion of patients who are tumor-free after surgical tumor reduction. Another issue that needs to be considered is how to maintain the quality of life of those patients who have undergone prolonged treatment, which includes the choice of dosing regimen, the control of toxic side effects, and how to effectively control tumor load.
Another thing to consider when making treatment decisions is the number and extent of adverse prognostic risk factors for the patient. The most applied algorithm is the MSKCC center algorithm [20], which requires consideration of factors such as KPS score less than 80, LDH 1.5 times higher than normal, hemoglobin below the lower limit of normal, blood calcium level greater than 100 mg/L, less than 1 year from diagnosis to the start of treatment, and more than 3 metastatic lesions. The algorithm allows to classify the clinical benefit of patients receiving targeted therapy into three categories. Most notably, clinical trials confirmed that temsirolimus resulted in a definite OS benefit for patients when more than three of the above risk factors were present; additional clinical trials suggested that sunitinib also had the potential to result in significant benefits for high-risk patients, but further confirmation is needed.
The histopathological type of RCC patients is also important. As mentioned earlier, VEGF expression levels are significantly elevated in RCC due to the presence of VHL mutations, but this appears to be seen only in large-cell RCC; therefore, the best clinical outcomes with anti-VEGF therapy should also be in patients with pathologically simple large-cell RCC. However, clinical studies have found better clinical outcomes in patients with non-large cell RCC, presumably related to HIF activation [21]. mTOR-mediated HIF activation may explain why effective treatment with targeted mTOR drugs has been observed in patients with non-large cell RCC, a phenomenon that was confirmed in a phase III clinical trial of temsirolimus. This phenomenon was confirmed in a phase III clinical trial of temsirolimus. The current trend is to recommend participation in the latest clinical trials for maximum benefit in patients with non-large cell RCC.
The most important starting point for choosing a therapeutic strategy is the ability to maximize the time to OS for the patient. However, for targeted therapies, the reality is more complex. In the phase III clinic with sunitinib it was observed that the OS was 26.4 months in the sunitinib treatment group and 21.8 months in the IFN treatment group compared to the control IFN treatment (p=0.051). Although the p-value does not seem to reach a statistically significant level, this may be mainly due to the fact that patients in the group receiving IFN therapy were treated with other targeted agents after disease progression, thus reducing statistical power [22]. In a trial on sorafenib, for patients who had failed previous treatment, the OS was 17.8 months vs. 15.2 months in the sorafenib-treated versus placebo group, p=0.51; however, after cross-over inclusion of control patients and then analyzed, the OS was 17.8 months vs. 14.3 months, p=0.03 [23]. It is thus evident that the approach taken in the III clinical trial on targeted therapy conducted in the current state, in which the control group was unblinded and then crossed into the treatment group, may have caused bias in the observed values of OS. However, although the data thus obtained do not allow us to conclude which drug, or which dosing sequence, resulted in the greatest OS benefit, we can still determine with some confidence that targeted therapies are effective in prolonging survival in patients with metastatic RCC by comparing them with historical control data.
VII. How to maximize the benefit for patients receiving treatment
Maintenance therapy is important in order to maximize the clinical benefit for patients. For example, the AUC values of sunitinib and its metabolites were found to correlate significantly with the clinical objective remission rates and PFS of patients in selected phase II clinical trials. Although this phenomenon is not currently observed in other drugs for the time being, it is certain that adequate doses of the drug are needed to maintain optimal blood concentrations for the best possible therapeutic effect. Usually, the first month after starting targeted therapy is very important, when drug toxicities are actively managed and necessary dose adjustments are made. Table-2 lists the dosing strategies for selected drugs. There are some rare but serious side effects that limit the use of targeted drugs in RCC patients at full doses, and the mechanisms of these side effects are not yet well understood, but require significant clinical attention, including possible cardiovascular toxicity, bleeding, and intestinal perforation with anti-VEGF agents, and interstitial pneumonia with mTOR inhibitors. It is currently believed that 30-40% of patients receiving targeted therapy in phase III clinical trials may require dose adjustment, and it is estimated that the proportion of patients requiring dose adjustment in large-scale clinical applications will be higher than this figure. However, no matter how patients make dose adjustment, under the condition of ensuring adequate efficacy, possible toxic side effects should be actively dealt with so that patients can receive long-term maintenance therapy to the greatest extent possible.
VIII. Timing of termination of treatment and selection of subsequent treatment
In addition to maintenance treatment, when patients can terminate treatment or the choice of next treatment after certain treatment failure is also a very important issue in clinical practice. Although the most objective evidence of tumor progression is the change in tumor volume observed on imaging, for targeted therapy, the change in lesion appearance is often observed, rather than significant change in tumor volume, and therefore cannot be generalized by the traditional RECIST criteria. In fact, in a significant number of patients with tumor progression reported on previous imaging, re-evaluation reveals a corresponding increase in the internal necrotic site, although accompanied by an increase in the tumor shape, which is currently considered to be a sign of good prognosis. This prompts clinicians to read conventional imaging reports and to personally review the films themselves to avoid bias in their determination. It has been found that many patients undergoing targeted therapy often experience a process of localized tumor regression followed by slow enlargement, which can easily meet the progression criterion of 20% tumor enlargement under the RECIST criteria, but these patients are actually benefiting from targeted therapy because the rate of tumor progression is significantly suppressed. In metastatic RCC, there are virtually no specific criteria to determine whether targeted therapy has become resistant. Treatment decisions depend in large part on the clinical experience of the physician, and in particular require the physician to make iterative trade-offs between the toxic side effects associated with continued use of the drug, the risk/benefit ratio, and the available options for subsequent therapy. It is often the case that patients undergoing targeted therapy have excellent control of the primary lesion, but develop new distant organ metastases, especially in CNS. The therapeutic decision in this situation is not yet sufficiently experienced, and the extensive experience in clinical implementation is required for flexible management at this time.
Currently, both retrospective and prospective clinical studies support the strategy of sequential application of targeted drug therapy in patients with RCC [24], but specific clinical guidelines are lacking. There is no evidence on which drugs are superior to each other in sequential order and which sequential order makes more sense. In a phase III clinical trial of Everolimus, it was demonstrated that treatment with everolimus was superior to placebo in patients with RCC who failed sunitinib or/and sorafenib, but the PFS benefit was marginal [25]. Moreover, although theoretically feasible, it is not practically possible to clinically validate the effectiveness of all possible sequential combinations of targeted agents. However, the high dependence of renal cancer cells on the VEGF pathway and the mTOR pathway has been demonstrated, at least in RCC, and therefore it is possible to achieve a state of maximal clinical benefit for patients through the inhibition of these two pathways. Relevant prospective clinical trials are currently underway to validate this idea.
IX. Outlook
Currently, the risk/benefit analysis of therapeutic strategies targeting VEGF and mTOR pathways in metastatic RCC is relatively adequate, and further in-depth studies are needed to find effective molecular markers that suggest prognosis or clinical response to treatment. In addition, a number of new drugs targeting the VEGF and mTOR pathways are progressing into the phase III clinic and are likely to be approved for RCC treatment, including pazopanib (GW-786034, GSK) and axitinib (AG-13736, Pfizer). The assessment of the clinical effectiveness and superiority of these agents needs to be fully evaluated on the basis of a large patient population. There are no clinical conclusions on whether the use of targeted agents can be used as adjuvant agents to reduce the risk of postoperative recurrence in patients with limited RCC. The current standard clinical strategy for this group of patients remains close follow-up after surgery, and there is no basis for using targeted therapy as adjuvant therapy, even for patients at high clinical risk. Relevant clinical trials are currently underway to answer this question. In addition, the combination of targeted therapeutic agents is also being tested in clinical trials. Preliminary clinical trial results found that quite a few combination strategies could not be effectively tolerated in terms of drug dose, and only a few combination regimens were observed to be relatively effective, but this is at least an encouraging direction, as the clinical benefit of combination therapy is clearly theoretically higher than that of sequential treatment strategies, and therefore, a more mature combination regimen is not yet available. Another issue to keep in mind is the issue of treatment decisions for specific patient populations (e.g., patients presenting with CNS metastases). Evidence suggests that treatment with sunitinib or sorafenib may be effective in patients presenting with CNS metastases after local management measures (surgery, conformal radiotherapy). A final issue that requires attention is the question of how to determine a safe drug dose in patients with hepatic or renal dysfunction.