[Doi 10.1159%2F000355906] Peters, S.; Stahel, R.a. -- [Progress in Tumor Research] Successes and...

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Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy. Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 98–112 (DOI: 10.1159/000355906) Abstract Until recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific im- munotherapy based on interleukin-2 or interferon-α. This was associated with a modest survival benefit and with significant clinical toxicities. The understanding of numerous molecular pathways in RCC, including HIF, VEGF, mTOR, and the consecutive use of targeted therapies since the begin- ning of 2005 have significantly improved outcomes for patients with metastatic RCC with an overall survival greater than 2 years. At present, at least 7 targeted agents are approved for first and con- secutive lines of treatment of clear cell metastatic RCC. Long-term benefit and extended survival may be achieved through the optimal use of targeted therapies: optimal dosing, adverse event manage- ment and treatment duration and compliance. Advances in the finding of prognostic factors high- light the potential for personalizing treatment for patients with metastatic RCC. Data regarding the best sequencing of targeted therapies, predictive biomarkers, best timing of surgery, patient risk profiles, understanding of resistance mechanisms and safety of targeted therapies are growing and will provide a further step ahead in the management of advanced RCC. In parallel, a new class of therapeutics is emerging in RCC: immunotherapy; in particular check-point blockade antibodies are showing very promising results. © 2014 S. Karger AG, Basel Introduction Epidemiology Renal cell carcinoma (RCC) represents the sixth most frequent cancer in developed countries [1]; there are about 209,000 new cases of RCC and more than 102,000 deaths worldwide. This corresponds to about 2–3% of all malignant tumors in the adult [2]. Successes and Limitations of Targeted Therapies in Renal Cell Carcinoma Marc Pracht · Dominik Berthold Medical Oncology Unit, Department of Oncology, CHUV, Lausanne, Switzerland Downloaded by: UCSF Library & CKM 169.230.243.252 - 1/10/2015 12:24:59 AM

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  • Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy.Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 98112 (DOI: 10.1159/000355906)

    AbstractUntil recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific im-munotherapy based on interleukin-2 or interferon-. This was associated with a modest survival benefit and with significant clinical toxicities. The understanding of numerous molecular pathways in RCC, including HIF, VEGF, mTOR, and the consecutive use of targeted therapies since the begin-ning of 2005 have significantly improved outcomes for patients with metastatic RCC with an overall survival greater than 2 years. At present, at least 7 targeted agents are approved for first and con-secutive lines of treatment of clear cell metastatic RCC. Long-term benefit and extended survival may be achieved through the optimal use of targeted therapies: optimal dosing, adverse event manage-ment and treatment duration and compliance. Advances in the finding of prognostic factors high-light the potential for personalizing treatment for patients with metastatic RCC. Data regarding the best sequencing of targeted therapies, predictive biomarkers, best timing of surgery, patient risk profiles, understanding of resistance mechanisms and safety of targeted therapies are growing and will provide a further step ahead in the management of advanced RCC. In parallel, a new class of therapeutics is emerging in RCC: immunotherapy; in particular check-point blockade antibodies are showing very promising results. 2014 S. Karger AG, Basel

    Introduction

    Epidemiology

    Renal cell carcinoma (RCC) represents the sixth most frequent cancer in developed countries [1]; there are about 209,000 new cases of RCC and more than 102,000 deaths worldwide. This corresponds to about 23% of all malignant tumors in the adult [2].

    Successes and Limitations of Targeted Therapies in Renal Cell Carcinoma

    Marc Pracht Dominik BertholdMedical Oncology Unit, Department of Oncology, CHUV, Lausanne, Switzerland

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    On average, metastatic dissemination is seen in 30% of new cases [3] and about 40% of patients relapse locally after nephrectomy [4]. The incidence of RCC has been ris-ing over the last decades, most likely due to improved imaging leading to earlier di-agnosis of small tumors [5]. The mortality, however, has not changed significantly since 2005.

    Risk Factors

    Classic risk factors are tobacco and arterial hypertension. Obesity and chronic renal insufficiency (in particular in the papillary subtype) might also be contributing factors [2]. Two to 4% of RCC are attributed to hereditary syndromes which most of the time are transmitted in an autosomic dominant manner. The most frequent syndrome is the Von Hippel-Lindau disease, which is linked to the tumor suppressor gene VHL, and in patients with this syndrome clear cell RCC (ccRCC) is the principle cause of death [6].

    Histology

    There are three frequent histological subtypes and others which are much rarer. The subtypes are not only characterized by their anatomical pathologic features, but also specific oncogenic properties (table1). ccRCC is the most common type representing 7085% followed by papillary RCC, which represents 1015%. The chromophobe type represents less than 10%, while collecting duct RCC (Bellini tumor) represents

    Table 1. Genetic abnormalities, oncogenic pathways and prevalence associated with sporadic RCC

    RCC subtype Geneticabnormality

    Oncogenic pathway

    Prevalence(sporadic RCC)

    Hereditary predisposition syndrome

    ccRCC VHL VHL/HIF/VEGFPI3K/AKT/mTOR

    7085% Von Hippel-Lindau disease

    Papillary type 1 RCC cMET cMET/RAF/MEK/ERK 1015% 6075% type 1 40% type 2

    Hereditary papillary RCC

    Papillary type 2 RCC fumarate hydratase

    VHL/HIF/VEGFPI3K/AKT/mTOR

    Hereditary leiomyomatosis and RCC

    Chromophobe RCC BHD1 cKIT/RAF/MEK/ERK

  • 100 Pracht Berthold

    less than 1% of all RCC. Further divisions can be made: the papillary type has been divided into type 1 and type 2, and this subdivision has been supported by genetic mutations. This translates also into clinical behavior where the papillary subtype 2 is generally more aggressive [2].

    Prognosis before the Introduction of Targeted Agents

    Before the arrival of the 2 first targeted agents approved for RCC in 2007 [7, 8], RCC was considered highly resistant to medical treatments. The overall survival of the metastatic cases was 1020% at 5 years. Only passive immune therapies with interferon- (IFN) or interleukin-2 (IL-2) had shown a low proportion of objective responses [9, 10]. Long-term remissions were rare, and only occasionally achieved with high-dose IL-2. High-dose IL-2 has been offered only in few centers, with a treat-ment-related mortality of about 3%.

    Clear Cell Renal Carcinoma Biology

    ccRCC is dependent on two main oncogenic pathways, the VHL/HIF/VEGF pathway and the PI3K/AKT/mTOR pathway (fig.1).

    The VHL/HIF/VEGF PathwayThe tumor suppressor gene VHL is an early and central element of ccRCC carcino-genesis [11]. Inactivation by mutation, deletion or hypermethylation of his promoter is detected in 60% of sporadic ccRCCs [12]. The VHL mutation is closely related to the hypoxia-inducible factor (HIF-). In the normal cell with an active VHL gene, HIF- is regulated by hydroxylation in the presence of oxygen. In hypoxic conditions, HIF is a transcription factor that activates genes that encode for proteins such as VEGF, PDGF and TGF-, GLUT1 and EPO, which all act as angiogenic factors [13]. Therefore, the inactivation of VHL implies overexpression of these new angiogenic factors. Given the fact that VEGF as well as PDGF are central mechanisms in the de-velopment and progression of RCC [14], these pathways seemed appropriate as tar-gets for new therapeutic strategies [15].

    The PI3K/AKT/mTOR PathwayThis pathway is downstream to many growth factor receptors such as VEGF, PDGF and others. If the receptors are activated, the first mediator consecutively activated is PI3K, which then activates AKT, while PTEN represents an inhibitor of AKT. AKT itself is an activator of mTOR which acts on the transduction of multiple mRNAs, particularly on those interfering with cell survival. mTOR induces the expression of HIF- which then leads to the induction of growth factors such as VEGF, PDGF,

    Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy.Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 98112 (DOI: 10.1159/000355906)

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  • Targeted Therapies in RCC 101

    TGF-, EGF, and others. This leads to enhance survival of cancer cells as well as an-giogenesis [16]. The PI3K pathway is frequently overactivated in ccRCC [17]. There-fore, mTOR-inhibitors exerts their therapeutic activity by reducing VEGF signaling and decreasing survival signals.

    Success of Targeted Therapies in a Clear Cell Renal Carcinoma

    Prognostic Factors

    Before discussing the systemic treatment options of RCC, the prognostic factors need to be understood as they have guided the recent drug development.

    Retrospective data of the cytokine era [18] were used to generate prognostic factors for metastatic RCC also known as the MSKCC criteria or Motzer criteria. Unfavorable prognostic factors include high LDH, low Karnofsky performance status, low hemo-globin levels, high corrected calcium levels as well as the time from initial diagnosis to start of systemic treatment (> or < than one year). Patients were divided into groups of low, intermediate or high risk. The risk group was correlated with a medium life expectancy of 30, 14 or 5 months respectively [19].

    Fig. 1. Biological pathways targeted for therapy in RCC. From Vasudev et al. [64].

    Cell growth and survival

    Cyclic D1c-Myc

    mRNA translation

    HIF

    HIF

    HIF

    HIF

    HIFHIF

    HIF

    HIFeIF-4E

    eIF-4E

    RaptormLST8

    mTORC1

    p70S6K

    GL

    P P

    Proteasome-mediateddegradation of HIF

    Normoxiaand normalVHL gene VEGF

    VHL

    Tumour cell

    Bevacizumab

    Cell stimuli(eg: growth factors)

    InactivatedVHL tumor

    suppressor geneVEGFR

    PDGF

    PDGFR

    Endothelial cell

    SunitinibSorafenibAxitinibPazopanibHypoxia

    Akt

    PI3-K

    PTEN

    TemsirolimusEverolimus

    VHLE3 Ligase

    4E-BP1

    4E-BP1

    Transcriptionalactivation of

    HIF target genesPro

    ProPro

    Pro Pro

    Pro

    Pro

    UbUbUbUb

    OH

    OH

    OH

    Pro

    FKBP

    Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy.Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 98112 (DOI: 10.1159/000355906)

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    An updated prognostic model has been presented by Heng et al. [20] based on pa-tients treated with VEGF-targeted therapy. This analysis confirmed the previously reported MSKCC criteria, adding high neutrophil and platelet counts as additional unfavorable prognostic factors (table2).

    Systemic Therapy

    First-Line TreatmentFor patients with a good or intermediate risk and metastatic RCC with clear cell com-ponent, the treatment options today are sunitinib [7, 21], sorafenib [8, 22], bevacizum-ab combined with IFN [2326] as well as pazopanib [27, 28]. The choice between these agents is not always based on objective criteria but might be influenced by the approval of national health authorities or by a physician or patients preference (oral vs. i.v.). The main results of the pivotal phase III trials are summarized in table3. When these agents became first available in 2005, they revolutionized the treatment of mRCC. Sunitinib, until recently the most frequently used first-line treatment, was compared against IFN in a study including 750 patients [7, 21]. The median progression-free survival (PFS) and median overall survival were respectively longer in the sunitinib group than in the IFN group (11.0 vs. 5.0 months, p< 0.001, and 26.4 vs. 21.8, p=

    Table 2. Heng criteria and prognosis according to Heng criteria

    a Heng criteria

    Prognostic risk factor Cutoff value

    Karnovsky performance status N

    b Prognosis according to Heng criteria

    Number ofrisk factors

    Risk group

    Median OS,months

    Two-yearOS, %

    0 Favorable 43.2 7512 Intermediate 22.5 5336 Poor 7.8 7

    OS= Overall survival.

    Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy.Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 98112 (DOI: 10.1159/000355906)

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    0.051). Sunitinib was also associated with a higher objective response rate than IFN (31 vs. 6%, p< 0.001). The proportion of patients with grade 3 or 4 treatment-related fatigue was significantly higher in the group treated with IFN, whereas diarrhea was more frequent in the sunitinib group (p< 0.05). Patients in the sunitinib group report-ed a significantly better quality of life than did patients in the IFN group (p< 0.001).

    Pazopanib [27, 28] was studied in 435 patients: 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median PFS 9.2 vs. 4.2 months; hazard ratio, HR, 0.46; 95% CI: 0.340.62; p< 0.0001), in the treatment-naive sub-population (median PFS 11.1 vs. 2.8 months; HR, 0.40; 95% CI: 0.270.60; p< 0.0001) and in the cytokine-pretreated subpopulation (median PFS, 7.4 vs. 4.2 months; HR, 0.54; 95% CI: 0.350.84; p< 0.001). The objective response rate was 30% with pazo-panib compared to 3% with placebo (p< 0.001).

    Bevacizumab plus IFN was compared to placebo plus IFN [23, 24]. Median du-ration of PFS was significantly longer in the bevacizumab plus IFN group than it was in the control group (10.2 vs. 5.4 months; HR, 0.63; 95% CI: 0.520.75; p= 0.0001). Increases in PFS were seen with bevacizumab plus IFN irrespective of risk group or whether reduced-dose of IFN have been administered. Three deaths in the bevaci-zumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue [40 (12%) patients in the bevacizumab group vs. 25 (8%) in the control group] and asthenia [34 (10%) vs. 20 (7%)]. A study by American investigators gave similar results as shown in table3 [25, 26].

    Table 3. Results from pivotal phase 3 trials of targeted therapies in first-line treatment of metastatic RCC

    Agents Ref. n Risk group Median PFS,months

    Median OS,months

    Objectiveresponse rate, %, RECIST1.0

    Sunitinib vs. IFN [7, 21] 750 favorableintermediate (

  • 104 Pracht Berthold

    The PISCES trial was a randomized phase 2 trial [29] which compared sunitinib with pazopanib. Patients were blinded to the drug medication and received for 10 weeks one drug and subsequently the other. Allowed to choose the agent of their pref-erence, 70% of patients preferred to be treated with pazopanib compared to sunitinib. The noninferiority of pazopanib as compared to sunitinib with regard to PFS has been documented in a phase III trial with 1,100 patients (COMPARZ Study) [30].

    For patients with poor risk disease, temsirolimus has been studied in a randomized controlled phase 3 trial comparing temsirolimus with IFN [31]. In a three-arm trial, 626 patients with mRCC were randomized 1: 1:1 (temsirolimus 25 mg vs. IFN alone vs. temsirolimus 15 mg and IFN). At least three of the following six predictors of short survival were required: a serum lactate dehydrogenase level of more than 1.5 times the upper limit of the normal range, a hemoglobin level below the lower limit of the normal range, a corrected serum calcium level of more than 10 mg per deciliter (2.5 mmol per liter), a time from initial diagnosis of renal-cell carcinoma to randomization of less than 1 year, a Karnofsky performance score of 60 or 70%, or metastases in multiple organs. Of note, 20% of patients with non-clear cell pathology were allowed to enter the trial. The trial favored temsirolimus with 5.5 versus 3.1 and 4.7 months of median PFS for the IFN and the combination therapy group, respectively (p< 0.001), and with regard to overall survival with 10.9 months for temsirolimus versus 7.3 and 8.4 months for the IFN and the combination therapy group, respectively (p= 0.008).

    About 510% of patients with poor risk disease have been included in the phase 3 trials cited above with sunitinib [7, 21], pazopanib [27, 28] and bevacizumab/IFN [2326]. Even if these studies were not designed to support or reject the use of these agents in high-risk patients, they give credit to target poor-risk disease by anti-VEGF therapy.

    Second-Line TreatmentMost patients receive a VEGF-directed therapy as first-line treatment. The best evi-dence for second-line treatment is available for everolimus [32, 33] as well as axitinib [34, 35]. The main results of phase 3 trials are summarized in table4. Everolimus has been studied versus placebo showing a medium PFS of 4.9 versus 1.9 months (p< 0.001). Serious adverse events with everolimus, occuring, in 5% of patients included infections (all types, 10%), dyspnea (7%), and fatigue (5%). The median OS was 14.8 months (everolimus) versus 14.4 months (placebo; HR, 0.87; p= 0.162), with 80% of patients in the placebo arm who crossed over to everolimus [32, 33].

    Axitinib has been studied against sorafenib in a patient population with 723 pa-tients [34, 35]. Most patients were pretreated with anti-VEGF-targeted therapy, but about 35% had a cytokine-based treatment previously. The overall survival in this population was comparable (20 vs. 19 months). There was a significant difference for patients treated with cytokines favoring axitinib (12.1 vs. 6.5 months, p< 0.001), while the difference for patients who received antiantigenic treatment before was less strik-ing (4.8 vs. 3.4 months, p= 0.01).

    Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy.Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 98112 (DOI: 10.1159/000355906)

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    Two studies gave remarkable insights into the use of mTOR inhibitors. The INTORSECT study was a randomized phase III trial comparing temsirolimus with sorafenib in the second-line setting. The primary end point was PFS, and this was comparable for both drugs (4.3 months for temsirolimus vs. 3.9 for sorafenib). How-ever, overall survival, which was a secondary end point, showed a significant differ-ence in favor of sorafenib with 16.6 versus 12.3 months [36].

    Everolimus and sunitinib were alternatively studied in first and second line in a sequential manner (plannified cross-over after progression in first line) in the Re-cord-3 trial [37]. This randomized phase 2 trial included 471 patients and showed a median PFS of 10.7 months for sunitinib noninferiority compared to 7.8 months for everolimus first line. Interestingly, the median overall survival in first line with evero-limus was 22 months compared to 32 months for sunitinib. The noninferiority of everolimus for PFS in first line was not achieved in this trial. mTOR inhibitors there-fore represent an option in second line.

    Third-Line TreatmentCurrently there are few prospective third-line data available. Dovitinib is a candidate for third-line therapy currently evaluated in the treatment of metastatic RCC. Patients who treated with one VEGF-targeted therapy and one mTOR inhibitor were randomized to

    Table 4. Results from pivotal phase 3 trials of targeted therapies in second-line or more treatment of metastatic RCC

    Agents Ref. n Previous line(s) Median PFS,months

    Median OS,months

    Objectiveresponse rate,%, RECIST1.0

    Sorafenib vs. placebo [8, 22] 903 cytokinesno TKIs/mAb

    5.5 vs. 2.8 17.8 vs. 15.2 10 vs. 2

    p

  • 106 Pracht Berthold

    dovitinib or sorafenib in a phase 3 study. The study called GOLD, has fully recruited and early results have just been reported at ECCO-ESMO 2013 showing the same efficacy for both tyrosine kinase inhibitors (TKIs) and establishing for the first time the efficacy and safety profile of those compouds in third line after one VEGF-targeted therapy and one mTOR inhibitor [38]. The RECORD1 trial [32, 33] included patients with one or two previous TKIs and showed a significant PFS benefit in either group. Therefore, everolimus can be considered as a third-line therapy after two TKIs. The currently ap-proved options in first, second and third lines of treatment are summarized in table5.

    Limitations of Targeted Therapies

    Despite the significant development in recent years, many questions remain open and many challenges need to be addressed. Particularly toxicity, absence of predictive fac-tors of response, the difficulty of evaluating the response as well as resistance to the first or second line are still open questions.

    Toxicity

    Despite the targeted mechanism of reaction, targeted therapeutics have a broad range of side effects. Table6 summarizes the most important grade 3 and 4 toxicities in the major randomized trials. Asthenia, GI toxicity, anorexia, mucositis and cutaneous al-

    Table 5. Algorithm for systemic treatment in metastatic RCC according to ESMO Clinical Practice Guidelines [5]

    Treatment line Risk group first line Standard Option

    First good/intermediate sunitinibbevacizumab-IFNpazopanib

    cytokinessorafenib

    poor temsirolimus sunitinibsorafenib

    Second post-cytokines sorafenibpazopanibaxitinib

    sunitinib

    post-TKIs everolimusaxitinib

    sorafenib

    Third post-2 TKIs everolimus

    post-one TKI and one mTOR-inhibitor sorafenib

    Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy.Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 98112 (DOI: 10.1159/000355906)

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    terations stand out. Much has been published to reduce the incidence or intensity of side effects and to help the patient with supportive measures [39, 40]. The manage-ment of toxicity is of crucial importance as dose interruptions and delays in treatment due to toxicity have been related to poor outcome. Some side effects are rare but rel-evant if they lead to organ damage and death. For example, the following side effects have been related to sunitinib: multi-organ failure, disseminated intravascular coagu-lation, rhabdomyolysis, cerebrovascular accident, adrenal insufficiency, shock and sudden death.

    Predictive Factors

    Unfortunately, today there is no accepted predictive factor which could be used to select patients for systemic treatment. Examples of factors that have been investigated are summarized below.

    VEGF blood levels were not found to be predictive for efficacy [41]. The data were somewhat more encouraging with the tissue inhibitor of metalloproteinase 1 as it has been reported from the TARGET study using sorafenib [42]. A protein signature based on VEGF, osteopontin, carbonic anhydrase 9, VEGFR2 and TNF appears to be correlated with the PFS for patients treated with sorafenib [43].

    Clinical side effects have been associated with treatment effects. Hypertension, hyperthyroidism and hand-food syndrome have been evaluated and a predictive value has been shown based on retrospective data [4446]. However, there are a significant number of patients that do not have many side effects and still re-spondreasonably well to treatment; therefore, these indicators are of limited clini-cal value.

    Table 6. Main side effects of targeted therapies for RCC

    Targeted therapy Toxicityall grades (20%) Toxicity grade 3/4 Remarks

    Bevacizumab + IFN asthenia, diarrhea, hypertension,anorexia, bleeding, influenza-like illness, headache, proteinuria

    asthenia (1137%), hypertension (310%), anorexia (317%), proteinuria (715%), neutropenia (49%)

    fatal bleeding and GI perforations are described

    VEGF TKIs asthenia, GI disorders, anorexia, hypertension, mucosal inflammation, nausea, hair color changes, hand and foot syndrome, several laboratory abnormalities

    asthenia (7%), hypertension (8%), lymphopenia (12%), neutropenia (11%)

    risk of bleeding or cardiovascular severe adverse events

    mTOR TKIs asthenia, rash, anemia, nausea, anorexia, stomatitis, pain, dyspnea, hyperlipidemia, hyperglycemia, peripheral edema, GI disorders, pneumonitis, infection, raised creatinine, leucopenia, hypophosphatemia

    asthenia (411%) anemia (1020%), hyperglycemia (1112%), dyspnea (19%), lymphopenia (115%)

    acute respiratory failure and opportunistic infections are described

    Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy.Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 98112 (DOI: 10.1159/000355906)

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    Radiological Response Criteria

    RECIST criteria have been developed in the area of cytotoxic treatments [47]. How-ever, they might be of limited utility in evaluating antiangiogenic treatments as they only consider size reduction and not the tumor necrosis mostly induced by these agents. New criteria, proposed by Choi et al. [48] have initially been used for gastro-intestinal trauma tumors. They take into account the tumor volume but also the changes in tumor attenuation on contrast-enhanced CT scan (in Hounsfield units) which reflect the tumor viability. Those criteria based on CT scans as well as other imaging modalities such as dynamic contrast-enhanced MRI or US and diffusion MRI are currently investigated in clinical trials [49]. Recent developments in nuclear medicine with new radiotracers such as 18F-fluoromisonidazole (FMISO) as a marker of hypoxia or as 18F-fluoro-L-thymidine (FLT) as a marker of proliferation, could lead to obtaining a new predictive tool for predicting response to targeted therapies in RCC: FMISO PET and FLT PET, for example [50].

    Resistance

    A minority of patients exhibit intrinsic tumor resistance, but the majority will develop resistance after initial response, frequently after 612 months [7, 35]. Usually, revas-cularization precedes tumor progression. The mechanism is not completely elucidat-ed, but the HIF1 is released by the necrotic center of the tumor leading to increased VEGF and PGF concentrations [51, 52].

    Similar considerations can be made to the resistance of mTOR inhibitors as they also target angiogenesis. However, other mechanisms such as activation, mutation or phosphorylation of AKT via insulin-like growth factor-1 receptor may ultimately lead to mTOR resistance [53]. Determination of mechanisms of resistance is crucial, to determine the best sequence for patients with tumors that resist to first- or second-line treatment.

    Adjuvant and Neo-Adjuvant Therapies

    Patients diagnosed with locally advanced RCCs have a significant risk of systemic relapse. Several models for predicting the risk of relapse have been established, and for some patients the risk of relapse can be as high as 90% after local treatment. Therefore, it is unsatisfactory for patients and physicians not to have treatment op-tions to reduce the risk of relapse as used routinely in many tumor types with early adjuvant treatment. Unfortunately, currently there are no data to support such a strategy. Several randomized phase 3 trials are ongoing, with sorafenib, sunitinib, bevacizumab and everolimus. The results are eagerly awaited but will not be available

    Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy.Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 98112 (DOI: 10.1159/000355906)

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    for the next 1236 months. In the absence of solid evidence, adjuvant treatment can-not be recommended.

    The same is true for the neoadjuvant treatment. Patients with locally advanced tu-mors, particularly those with a vena cava thrombus benefit only occasionally in terms of downstaging or downsizing [54]. Therefore, the neoadjuvant approach should be limited to those with initially nonoperable disease, hoping that the lesion might sig-nificantly regress to subsequently allow radical nephrectomy. Neoadjuvant treatment is currently investigated to explore the potential for nephron-sparing strategies such as cryotherapy [55].

    Non-Clear Cell Histology

    The significant progress which has been made in targeting the VEGF signaling path-way or the mTOR pathway is restricted to RCC with clear cell histology. Patients with less frequent histologies such as papillary RCC, chromophobe RCC and others have only been marginally evaluated. The European recommendations [5] as well as the National Comprehensive Cancer Network [56] recommendations currently do not give much guidance for those non-clear cell subtypes. Well-designed large clinical tri-als should be prioritized for these patients.

    Outlook

    Looking at the recent results from randomized trials with new TKIs such as tivozanib [57], it seems that the ceiling has been reached in terms of PFS with VEGF-targeted therapies. Therefore, new pathways need to be explored. The c-Met [58] inhibitors such as cabozantinib [59] as well as tivantinib are currently in clinical trials. Of par-ticular interest are the check point blockade-inhibitor PD1 and PDL1 antibodies [60]. For example, BMS-936559 has shown a significant preliminary activity in the treat-ment of RCC and is currently investigated in a randomized phase III trial versus everolimus in patients previously treated with TKI [61]. The development is very promising because these agents may produce long-lasting responses in contrast to the targeted approach with transitory disease stabilization.

    Conclusion

    Since 2005, the treatment of RCC has rapidly evolved with currently 7 new targeted therapies registered. This has led to significant improvement in PFS and overall sur-vival. The mechanisms of action as well as mechanisms of resistance have been eluci-dated partially. Many challenges remain as our patients progress after a limited time

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    Dominik BertholdMedical Oncology Unit, Department of Oncology, CHUVBugnon 46CH1011 Lausanne (Switzerland)E-Mail [email protected]

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