Neoadjuvant systemic therapy for urological malignancies

Authors

  • Guru Sonpavde,

    1. Texas Oncology,
    2. the Michael E. DeBakey Veterans Affairs Medical Center,
    3. Department of Medicine, Section of Medical Oncology, Baylor College of Medicine, Houston, TX, USA, and
    Search for more papers by this author
  • Cora N. Sternberg

    Corresponding author
    1. Department of Medical Oncology, San Camillo Forlanini Hospitals, Rome, Italy
    Search for more papers by this author

Cora N. Sternberg, Department of Medical Oncology, San Camillo and Forlanini Hospitals, Nuovo Padiglione IV, Circonvallazione Gianicolense 87, 00152 Rome, Italy.
e-mail: csternberg@scamilloforlanini.rm.it

Abstract

Neoadjuvant cisplatin-based combined chemotherapy is an established standard for muscle-invasive bladder cancer and pathological complete remission is an excellent intermediate surrogate endpoint for survival. Phase III trials are ongoing to elucidate the role of neoadjuvant combined androgen deprivation and docetaxel-based chemotherapy for localized high-risk prostate cancer. Neoadjuvant therapy with biological agents targeting angiogenesis preceding cytoreductive nephrectomy for metastatic renal cell carcinoma is a novel approach, although ongoing randomized trials are validating this paradigm and attempting to establish the timing and necessity of cytoreductive nephrectomy. Neoadjuvant trials provide a window of opportunity to evaluate and screen novel agents for biological activity by using brief therapy preceding surgery and provide a rationale to further develop the most promising agents in larger trials. The neoadjuvant therapy approach followed by surgery is acceptable and feasible with a wide array of agents in urological cancers and provides a paradigm for evaluating the activity, mechanism of action and resistance to new treatments. Urological cancers are initially characterized by localized presentation in the vast majority of cases, coupled with a substantial risk of distant relapses following surgical resection. Therefore, the paradigm of neoadjuvant therapy preceding surgery may expedite the development of novel systemic agents and improve outcomes.

Abbreviations
(p)CR

(pathological) complete response

ADT

androgen-deprivation therapy

DFS

disease-free survival

TMPRSS2

transmembrane protease, serine 2

ER

oestrogen receptor

XRT

radiotherapy

CRPC

castration-resistant prostate cancer

RP

radical prostatectomy

CUOG

The Canadian Urologic Oncology Group

DFCI

Dana Farber Cancer Institute

VEGF

vascular endothelial growth factor

EMP

estramustine phosphate

MRC

the British Medical Research Council

EGFR

epidermal growth factor receptor

HR

hazard ratio

KAVE

ketoconazole plus doxorubicin alternating with vinblastine, estramustine

TEC

paclitaxel, estramustine, carboplatin

CALGB

The Cancer and Leukaemia Group-B

SWOG

Southwest Oncology Group

COX-2

cyclooxygenase 2

PI3K

phosphatidylinositol-3-kinase

PDGFR

platelet-derived growth factor receptor

MDACC

M.D. Anderson Cancer Centre

GM-CSF

granulocyte macrophage colony-stimulating factor

mTOR

mammalian target of rapamycin

RC

radical cystectomy

PFS

progression-free survival

EORTC

European Organization for the Research and Treatment of Cancer

(DD)-MVAC

(dose-dense) methotrexate, vinblastine, doxorubicin and cisplatin

GC

gemcitabine and cisplatin

CMV

cisplatin, methotrexate and vinblastine

MSKCC

Memorial Sloan-Kettering Cancer Center

PCaG

paclitaxel, carboplatin, gemcitabine

CTLA-4

cytotoxic T-lymphocyte antigen 4

ICOS

inducible costimulator

IFN

interferon

CN

cytoreductive nephrectomy

ccRCC

clear cell RCC

UCLA

University of California, Los Angeles

INTRODUCTION

 Systemic therapy for metastatic RCC has witnessed dramatic advances fuelled by an understanding of the central role of angiogenesis in its pathogenesis. Advances in the arena of systemic therapy in the setting of other metastatic urological cancers including prostate cancer and TCC of the urothelium are also emerging. However, there is a need for effective and tolerable systemic therapy for urological cancers, given that the vast majority of advanced urological cancers are generally incurable with currently available systemic therapy. The conventional paradigm for the development of novel regimens is to initially evaluate them for advanced disease. Upon demonstrating feasibility and activity in the advanced setting, agents are subsequently applied in the adjuvant setting. In contrast, neoadjuvant systemic therapy preceding definitive surgery for organ-confined resectable disease permits the rapid in vivo assessment of antitumour activity. Neoadjuvant systemic therapy, defined as preoperative systemic therapy preceding surgery, is established as a standard for several other malignancies including breast cancer, where the efficacy appears similar to the efficacy of adjuvant therapy (and in some cases a trend in favour of neoadjuvant therapy has even been observed) [1]. In addition, the aforementioned urological cancers are generally characterized by organ-confined and surgically curable presentation in most cases. At the same time, they are associated with a substantial risk of distant recurrence (implying a high frequency of distant microscopic metastases at presentation), which warrants effective perioperative systemic therapy. Therefore, the paradigm of neoadjuvant therapy preceding surgery may expedite the development of new systemic agents and simultaneously improve long-term clinical outcomes by the early delivery of systemic therapy. This review will discuss neoadjuvant systemic therapy preceding surgery for urological cancers as well as its use as a paradigm to develop novel agents.

NEOADJUVANT THERAPY AS A PARADIGM TO DEVELOP NOVEL SYSTEMIC THERAPY

Repetitive cycles of combination regimens to evaluate pathological down-staging

Neoadjuvant therapy permits the in vivo assessment of tumour response and pathological down-staging in several malignancies. The down-staging/sizing of localized malignancy may also facilitate complete surgical resection. Since pathological complete response (pCR) and biological activity can be rapidly determined after surgery, the efficacy of a systemic regimen can become evident with a small number of patients and relatively short follow-up. The incorporation of anatomical, functional and molecular imaging and biological markers may complement pathological endpoints. Neoadjuvant therapy may be more feasible than adjuvant therapy owing to slow postoperative recovery in some patients, and therefore may be feasible in more patients. Given that both pCR and an excellent partial response (near-pCR, i.e. low residual tumour burden) correlate with improved clinical outcomes in other malignancies (e.g. breast cancer), this finding may also apply to urological malignancies [2]. A higher pCR rate with chemotherapy has been reported in oestrogen receptor (ER)-negative as opposed to ER-positive breast cancer, which parallels differential long-term benefits in the adjuvant and advanced disease settings [3]. In one neoadjuvant study using sequential paclitaxel plus anthracycline, all pCRs occurred in patients with high Oncotype DX® (breast cancer assay; Genomic Health Inc., Redwood City, CA, USA) recurrence scores, which parallels data from adjuvant therapy trials suggesting that patients with ER-positive cancers with a high recurrence score benefit preferentially [4,5]. Thus, in principle, data gleaned from neoadjuvant therapy may be applicable in the adjuvant and advanced disease settings. While the primary goal of neoadjuvant therapy is to improve long-term outcomes for high-risk localized disease, this paradigm has the potential to accelerate the pace of development of systemic therapy. It may also be possible to determine baseline molecular and biological characteristics that predict both prognosis and sensitivity, knowing quite well that activity of regimens in early disease may not necessarily translate to efficacy in patients with more advanced metastatic disease and a poorer performance status. Additionally, pathological stage is not available before surgery and some low-risk patients may receive unnecessary systemic therapy. Neoadjuvant therapy may inherently complicate surgery and increase the risk of postoperative complications by increasing fibrosis. A malignancy that is resistant to neoadjuvant therapy may potentially progress due to delay of surgery. The threshold of pathological and clinical response predictive for improved long-term clinical outcomes is unclear and certainly needs refinement for different regimens and tumours. Biologically indolent malignancies may exhibit favourable long-term outcomes despite a poor pathological response. High pathological response optimally also needs validation in terms of enhanced long-term outcomes in the perioperative setting before embarking on a phase III trial.

Brief therapy with novel agents to evaluate tumour tissue pharmacodynamic activity

Guided by promising preclinical activity of novel agents, early studies may also have a primary objective of evaluating pharmacodynamic endpoints. Brief therapy for 1–4 weeks while awaiting surgery can provide access to tumour tissue before (biopsy) and after therapy (from surgery). This design may enable the potential identification of a signal of biological activity and provide proof-of-principle from a small number of patients by examining the modulation of validated biomarkers (e.g. proliferation, apoptosis, microvessel density, signalling pathways, etc.). For example, Ki-67 down-regulation within 2 weeks of hormonal therapy appears to be highly predictive of improved long-term outcomes in women with localized breast cancer [6]. In another trial using brief neoadjuvant trastuzumab for locally advanced human epidermal growth factor receptor 2 (HER2)-expressing breast cancer, tumours with a lower baseline proliferation displayed greater apoptosis, providing a rationale for synergism with chemotherapeutic agents, which primarily target a different population of rapidly proliferating cells [7]. Elucidation of emerging mechanisms of resistance may also be feasible. However, the threshold of pharmacodynamic activity predictive of improved clinical outcomes is unclear and will require refinement for each agent and tumour. Proteomic and genomic analyses need separate analysis in tumour and stromal cells to gain better insight. The optimal timing of safe surgery to evaluate activity also needs refinement and the design may need to incorporate a gradual shortening of the interval between the last dose of drug and surgery. A placebo or untreated control population is also ideally necessary, as there might be variations in biomarkers from biopsy to surgery independent of the impact of intervening therapy. Modulation of the primary molecular target in the tumour tissue in target-enriched populations to provide proof-of-concept should also be of importance. Selecting the proper dose that is clinically active and associated with improved clinical outcomes, and may also avoid off-target activity is also of high priority. While formalin-fixed paraffin embedded tissue is the easiest to obtain, fresh tissue often yields better or complementary information.

NEOADJUVANT THERAPY FOR PROSTATE CANCER

While androgen-deprivation therapy (ADT) is the conventional initial systemic therapy for prostate cancer, there is increasing evidence of its deleterious effects [8]. Even short-term use of ADT may lead to numerous side-effects such as osteoporosis, obesity, sarcopenia, lipid alterations, insulin resistance, and increased risk of diabetes and cardiovascular morbidity [9]. Adverse effects on quality of life and eventual progression to castration-resistant prostate cancer (CRPC) is the general rule. Treatment options are limited in patients with metastatic CRPC and only docetaxel-based chemotherapy has until now shown a modest extension of survival [10,11]. Clearly, there is a need for novel, effective and tolerable systemic therapies for prostate cancer. Since the advent of PSA screening, prostate cancer is commonly detected when still localized. Hence, the paradigm of neoadjuvant therapy preceding radical prostatectomy (RP) may improve outcomes and facilitate the development of new agents. A high-risk population of patients with localized prostate cancer is likely to optimally benefit from effective neoadjuvant therapy. High-risk patients have commonly been identified as those with a high T stage, Gleason score or PSA level, although trials have used heterogeneous definitions rendering across-trial comparisons difficult. A preoperative nomogram that incorporates all of these parameters enhances prediction of the risk of PSA recurrence and selection of a relatively homogeneous population [12]. Although a relatively high threshold of PSA recurrence to determine eligibility is reasonable, high-risk patients are often considered to be better treated by definitive radiotherapy (XRT).

Neoadjuvant ADT

Both brief and long duration neoadjuvant ADT have been evaluated. Three randomized trials of brief ADT for 3 months have shown some evidence of clinical and pathological down-staging (e.g. decreased positive margins and extracapsular extension), but no pCR or improvement of long-term outcomes [13–16]. A longer 6–8 month course of ADT also induced a higher rate of clinical and pathological down-staging, evidence for enhanced long-term outcomes is unfortunately lacking. The Canadian Urologic Oncology Group (CUOG) trial is the largest randomized trial evaluating ADT and randomized 549 patients with T1b–T2 clinical disease to 3 or 8 months of combined ADT [17]. Positive surgical margins (12% vs 23%, P= 0.01), pathological T2 stage (80% vs 68%, P= 0.002) and pCR rate (9.3% vs 5.1%, P= 0.07) were better in the 8-month group. Prostate volume measured by TRUS decreased by 37% with 3 months of ADT and by a further 13% with 8 months of ADT (P= 0.03), which suggests the utility of imaging as a surrogate for biological activity. There were no significant differences in intraoperative or perioperative morbidities. Another smaller trial randomized 393 patients to either RP alone or 12 or 24 weeks of neoadjuvant therapy, those receiving neoadjuvant therapy had an increased proportion of patients with organ-confined disease and negative margins [18]. These trials were underpowered to detect realistic differences and included patients who did not have high-risk disease, which can dilute the impact of neoadjuvant therapy on outcomes. Potentially, longer follow-up durations may uncover some differences in long-term outcomes. A Cochrane database systematic review reported the efficacy of neoadjuvant ADT [19]. As expected, neoadjuvant ADT preceding RP reduced positive surgical margin rates and lymph node invasion rates, and increased organ-confined tumour rates. However, overall and disease-free survival (DFS) did not improve. Signals of biological activity and resistance have been reported in small trials of neoadjuvant ADT that may assist future drug development. In one trial, gene expression was evaluated at baseline and after 3, 6 and 9 months of neoadjuvant ADT in RP samples from men with localized prostate cancer [20]. ADT reduced tissue androgens and the expression of many androgen-regulated genes (N-myc downstream-regulated gene 1 [NDRG1], FK506 binding protein 5 [FKBP5], and transmembrane protease, serine 2 [TMPRSS2]). However, other androgen-responsive genes, including the androgen receptor and PSA were not suppressed after 9 months of ADT. These data suggest that resistance mechanisms may allow prostate cancer cells to survive in a low-androgen environment.

Neoadjuvant chemotherapy

Published data concerning neoadjuvant chemotherapy alone before RP are sparse. A brief course of 6 weekly doses of docetaxel was evaluated in 29 patients with high-risk localized disease showing PSA level declines in 79% (24% exhibited a >50% reduction) with an unchanged testosterone level, but no pCR [21]. Increased tumour tissue expression of p53 and Bcl-2 was detected in a subset of 11 patients after treatment (compared with baseline tumour), suggesting that the apoptosis pathway may be an important target [22]. Another phase II study of 19 men at the Dana Farber Cancer Institute (DFCI) evaluated a longer course of weekly docetaxel (36 mg/m2 for up to 6 months) in patients with high-risk localized prostate cancer [23]. Tumour volume measured by endorectal MRI was reduced ≥25% in 13 patients (68%) and ≥50% in four (21%). There were PSA level decreases of ≥50% in 11 of 19 patients (58%), but there was no pCR. Gene-expression analysis showed up-regulation of genes involved in androgen metabolism. In a recent report, 19 patients with high-risk localized prostate cancer received two cycles of nanoparticle albumin bound-paclitaxel 150 mg/m2 weekly for 3 weeks of a 4-week cycle followed by RP [24]. Despite the lack of pCRs, cytoplasmic vacuolization was evident in all but one patient and the PSA level decreased in 18 of 19 patients. Combinations of docetaxel with mitoxantrone or capecitabine have also been evaluated in phase I or II trials without any pCRs [25,26]. In a recent update, 57 patients were enrolled in a phase 1/2 study of weekly docetaxel 35 mg/m2 and escalating mitoxantrone to 4 mg/m2 before RP [27]. Patients were treated with 16 weeks of chemotherapy administered weekly on a 3 of every 4 week schedule. There was no pCR but there was some evidence of pathological down-staging with negative surgical margins in 67% of cases and lymph node involvement in 18.5% of cases. With a median follow-up of 63 months, the recurrence-free survival was 49.8% at 5 years. Pretreatment serum PSA level, lymph node involvement, and postchemotherapy tissue vascular endothelial growth factor (VEGF) expression were independent predictors of early recurrence. This finding appears to support the hypothesis that VEGF signalling may partly mediate chemoresistance. The expression of post-therapy tumour Ki-67, CD10 and p16, and plasma VEGF concentrations were not predictive of clinical outcomes. While these trials show feasibility and modest biological activity for chemotherapy, the lack of pCRs and definitive evidence of improved clinical outcomes dampens the enthusiasm for chemotherapy regimens without ADT. This situation may be similar to ER-expressing breast cancer, where systemic chemotherapy exhibits modest activity and a low pCR rate [3]. Conversely, chemotherapy may confer a benefit in the absence of pCR. Neoadjuvant docetaxel every 3 weeks is being evaluated in a phase II trial (Table 1). Randomized trials to evaluate adjuvant docetaxel for high-risk localized prostate cancer after RP are being conducted in Sweden and by the Veterans Affairs Medical Center system in the USA [28].

Table 1.  Ongoing phase II trials of neoadjuvant novel agents without ADT for prostate cancer
InstitutionAgentTumour tissue correlative studies
  • *

    randomized phase II trial; Dex, dexamethasone; UCI, University of California; OHSU, Oregon Health and Science University.

UCIDocetaxel every 3 weeksResponse
Brown U.IxabepiloneRegression, pCR
MDACCFinasteride*Gene expression analysis
UCSFGM-CSFImmune response
UCSFSipuleucel-TImmune response
MDACC, UCLATemsirolimusmTOR signalling pathway
Johns HopkinsSirolimusmTOR signalling pathway
IsraelEverolimusmTOR signalling pathway
UCLASunitinibVEGF/PDGF pathway, apoptosis, proliferation
U. WashingtonSorafenibSignalling pathways, apoptosis, proliferation, angiogenesis
NorthwesternGenistein*Tumour PSA expression
U. New MexicoVitamin EBiomarker modulation
TorontoMetforminBiomarkers
OHSUSimvastatin vs. placeboMevalonate pathway, serum lipids
Roswell ParkCalcitriol + Dex*Biomarkers
VancouverCP-751871IGF-1 pathway
VancouverEnzastaurinProtein kinase C-β and AKT pathways

Neoadjuvant combined ADT and chemotherapy

The largest phase II trial of combined therapy by the CUOG evaluated weekly docetaxel (35 mg/m2 weekly for 6 of 8 weeks × three cycles) plus ADT for localized high-risk disease followed by RP [29]. The trial attempted to detect a pCR rate of interest of 20% as opposed to a low pCR rate of ≤5%. In all, 72 men were enrolled and 64 were evaluable. Two men (3%) displayed a pCR and 16 additional had ≤5% tumour volume (including three with microfoci of tumour) in the RP specimen. The caveat is that the rate of pCR plus near-pCR with RP or neoadjuvant ADT alone followed by RP is unknown. After a median follow-up of 42.7 months, there were 19 relapses (30%). This compares favourably to the results from the CUOG randomized study of 3 vs 8 months of ADT [17]. In that study, 97 of the 502 patients had high-risk disease and after a mean follow-up of 37.7 months, PSA recurrence occurred in 52.6%. As estramustine phosphate (EMP) induces biochemical castration owing to its oestrogenic activity, it may be appropriate to consider EMP-containing chemotherapy (without conventional ADT) as a subcategory of chemohormonal therapy. Phase II trials have evaluated ketoconazole plus doxorubicin alternating with vinblastine, estramustine (KAVE) and paclitaxel, estramustine, carboplatin (TEC) combined with ADT, or EMP combined with docetaxel or etoposide, but no pCRs have been reported [30–34].

The Cancer and Leukaemia Group-B (CALGB) is conducting an important phase III randomized trial that will enroll 750 patients to assess the efficacy (recurrence-free survival) of neoadjuvant therapy with leuprolide acetate plus six cycles of docetaxel every 3 weeks before RP (compared with RP alone). Eligibility criteria include localized disease with a nomogram predicted probability of ≤60% freedom from PSA recurrence at 5 years [12]. GETUG-12 (phase III trial of docetaxel-estramustine in high-risk localized prostate cancer) is a similar French randomized multicentre study that has completed the accrual of 413 patients. After lymph node dissection for pathological staging, patients with high-risk localized prostate cancer receive combination ADT for 3 months with or without four cycles of docetaxel plus EMP followed, at least 3 weeks later, by definitive local therapy with RP or XRT for N0 disease, and XRT or no definitive local therapy for lymph node-positive disease. While awaiting these results, it might be reasonable to conduct smaller phase II trials using novel regimens with a pCR or near-pCR rate of 10–20% being of significant interest. Randomized trials of adjuvant chemohormonal therapy after RP have been unsuccessful at accruing (e.g. the TAX 3501 trial) or have been aborted due to toxicity (the Southwest Oncology Group [SWOG]-9921 trial of adjuvant mitoxantrone plus ADT vs ADT was closed due to an increase in acute leukaemia in the mitoxantrone arm) [35]. The Radiation Therapy Oncology Group is evaluating the impact of adjuvant docetaxel after combined XRT and ADT in a randomized phase III trial.

Reported trials of novel agents and regimens as neoadjuvant therapy for prostate cancer

A phase II trial of men with localized low-risk prostate cancer were randomized to RP alone or two doses of neoadjuvant dutasteride (an antiandrogen agent that inhibits 5α-reductase) for 4 months [36]. Dutasteride reduced tissue dihydrotestosterone levels by ≈95% and increased tissue testosterone. Gene profiling showed significant changes in gene expression consistent with androgen inhibition. Notably, the higher-dose dutasteride treatment group had fewer cancers with TMPRSS2-ERG genetic fusions, which are driven by androgen receptor signalling. TMPRSS2 was over-expressed in cancer compared with benign epithelium, and dutasteride reduced its expression in both benign and cancer tissue. Previous data in the chemoprevention setting (Prostate Cancer Prention Trial) have shown that finasteride reduced prostate volume and selectively inhibited the development of low-grade cancer, which may have contributed to the increase in high-grade cancers [37,38].

Two small randomized studies randomized patients with localized prostate cancer to 4–6 weeks of celecoxib (cyclooxygenase 2 [COX-2] inhibitor) 400 mg twice daily vs no drug before RP [39,40]. Celecoxib decreased tumour proliferation, microvessel density, angiogenesis and hypoxia-inducible factor 1 and enhanced apoptosis [39]. In the other trial, tumour tissue surprisingly had significantly lower COX-2 expression than benign prostatic tissue (P= 0.01), but did show higher levels of proliferation, i.e. Ki-67 (P < 0.001) [40]. Celecoxib was measurable in prostate tissue, but had no effect on pharmacodynamic biomarkers (e.g. prostaglandins, COX-1/2 mRNA, Ki-67), although there was a trend toward statistical significance with the apoptotic marker p21waf1. Notably, in men with PSA-recurrent disease, 90% of patients had a reduction in PSA-slope and 19 of 40 patients had a stable or declining PSA level at 3 months [41]. The large STAMPEDE trial being conducted by the British Medical Research Council (MRC) is recruiting men with metastatic prostate cancer to evaluate the role of ADT alone or with docetaxel or celecoxib or zoledronic acid.

The antiangiogenesis strategy has been evaluated with both monoclonal antibodies and tyrosine kinase inhibitors. The DFCI evaluated neoadjuvant docetaxel plus bevacizumab, a monoclonal antibody against VEGF [42]. Docetaxel and bevacizumab were administered every 3 weeks for five cycles (without ADT) followed by a sixth cycle of docetaxel alone before RP. There was clinical evidence of activity, with a 36% partial response rate by endorectal MRI and PSA level declines in 76% (22% had ≥50% declines) with pathological analysis still pending. Unfortunately, data from a frontline CALGB phase III trial in the setting of metastatic CRPC comparing docetaxel-based chemotherapy with or without bevacizumab were recently announced to show no survival benefit with the addition of bevacizumab [43]. Sunitinib malate is being evaluated, either alone or combined with ADT in separate trials (Table 1). These data will complement promising data from the advanced CRPC setting, which has triggered an ongoing phase III trial comparing second-line placebo with sunitinib after docetaxel in patients with metastatic disease [44,45].

Neoadjuvant docetaxel plus gefitinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, without ADT was evaluated in a phase II trial of 31 men [46]. In all, 29 (94%) patients achieved a clinical partial response, including 35% of patients who had radiographic improvement on endorectal MRI, but there was no pCR. Gefitinib also displayed poor activity alone and when combined with docetaxel (with concurrent ADT) in CRPC, suggesting that gefitinib may not appreciably alter the natural course of the disease, or better patient selection may be necessary [47,48]. Cetuximab, is being evaluated, either alone or combined with docetaxel as neoadjuvant therapy, with correlative and efficacy endpoints (Table 1). A randomized phase II trial of mitoxantrone-prednisone with or without cetuximab as second-line therapy for metastatic CRPC has completed accrual and will provide complementary data in the advanced setting.

Inhibition of platelet-derived growth factor receptor (PDGFR), which is highly expressed in prostate cancer, by imatinib enhances preclinical drug delivery by decreasing interstitial fluid pressure [49]. Neoadjuvant studies with imatinib either alone or combined with docetaxel and ADT have been conducted [50,51]. Preliminary analysis by gene expression analysis and immunohistochemistry showed apoptosis of microvascular endothelial cells with 6 weeks of neoadjuvant imatinib. Disappointingly, there was no pCR when using a combination of neoadjuvant imatinib, docetaxel and ADT. Imatinib also did not detectably enhance the activity of docetaxel in a randomized phase II trial of 116 evaluable patients with metastatic CRPC and bone metastasis, despite evidence of systemic pharmacodynamic activity (down-regulation of phosphorylated PDGFR in peripheral blood leukocytes) [52]. Thus, the disappointing data from neoadjuvant trials appear to parallel data in the advanced CRPC setting, and do not corroborate promising preclinical data.

The M.D. Anderson Cancer Centre (MDACC) reported a Phase I/II study of neoadjuvant thalidomide (200–600 mg/day for up to 12 weeks in 18 men), an agent with antiangiogenic and antiproliferative properties [53]. There was a median reduction in PSA levels of 41% with no decline in testosterone levels. Tissue microarray analyses indicated modulation of vascular markers accompanied by a reduction in microvessel density compared with untreated controls. Comparison of stromal–epithelial interaction markers suggested a transition to a less aggressive phenotype. There was a favourable ratio of matrix metalloproteinases to E-cadherin (marker of cell adhesion) and ‘hedgehog’ signalling was attenuated. However, there were no differences in proliferation or apoptosis. Notably, the combination of docetaxel-based chemotherapy and thalidomide for metastatic CRPC suggested improved outcomes in a randomized phase II trial, and further development of this combination may be warranted [54]. The phase III Mainsail trial is evaluating the impact of combining lenalidomide with docetaxel for metastatic CRPC.

Granulocyte macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine with immune-modulating activity. A phase II neoadjuvant trial in high-risk localized prostate cancer administered GM-CSF at 250 µg s.c. three times weekly and thalidomide escalated to 200 mg/day for a maximum of 8 weeks [55]. RP tumour tissue showed significant CD3 and S100 over-expression when compared with pretreatment biopsies, but there were no changes in macrophage infiltration. There were increased serum dendritic cells, interleukin 8, basic fibroblast growth factor and VEGF. Some PSA decline occurred in 81% of patients. No pCR was reported, although pCR may not be a legitimate endpoint with 8 weeks of immunotherapy. Administration of GM-CSF plus thalidomide has also induced PSA declines ≥50% in 23% of patients with metastatic CRPC, which shows the activity of this regimen across a spectrum of stages of prostate cancer [56]. An ongoing trial at the University of California, San Francisco (UCLA)is evaluating GM-CSF alone for 4 weeks followed by RP within 3 days of the last dose, with tumour tissue immune studies as the primary endpoint (Table 1).

Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance. OGX-011 (custirsen) is a second-generation methoxy-ethyl modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA and inhibits clusterin expression. In all, 25 men with localized high-risk prostate cancer were treated with OGX-011 by 2-h i.v. infusion on days 1, 3, and 5 and then weekly from days 8–29 combined with ADT followed by RP within 7 days of the last dose of OGX-011 [57]. OGX-011 was well tolerated and the quantity in prostate tissue increased with dose to biologically effective concentrations accompanied by decreases in clusterin expression. The apoptotic index of prostate cancer cells was significantly increased in a dose-dependent fashion. Thus, this neoadjuvant design permitted a proof-of-principle demonstration of the biological effectiveness of OGX-011 and established dosing for future phase II studies. Indeed, a recent randomized phase II trial showed improved survival for the addition of OGX-011 to docetaxel-based chemotherapy in metastatic CRPC, and further study is planned in a randomized phase III trial [58].

The Baylor College of Medicine evaluated 4 weeks of bortezomib (proteasome inhibitor) followed by RP within 72 h of the last dose of bortezomib in a 40-patient phase II trial with primarily correlative endpoints [59,60]. Cytopathic effects (cytolysis, nuclear pyknosis) were commonly seen compared with baseline. There was up-regulation of apoptosis, proliferation and pAkt, providing a rationale to evaluate the combination of bortezomib and Akt inhibitors or chemotherapeutic agents. Indeed, a randomized phase II trial by US Oncology is being planned to evaluate mitoxantrone with or without bortezomib as second-line therapy for metastatic CRPC. Another neoadjuvant trial is planned by the Baylor College of Medicine to evaluate the combination of bortezomib and an inhibitor of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Stanford University reported the activity of 2 weeks of neoadjuvant oral placebo (n= 12) or genistein (n= 13), a soy isoflavone with antiproliferative and antiangiogenic properties [61]. There were decreases in COX-2 mRNA and increases in p21 mRNA in prostate tissue, which correlated with serum isoflavone levels. Thus, the mechanism of action was studied by exploiting the neoadjuvant paradigm in a small number of patients. Many of these trials will provide complementary data in the early hormone-naïve setting and help delineate the mechanism of activity.

Ongoing trials of neoadjuvant therapy with novel agents for prostate cancer

A panoply of novel agents is undergoing evaluation in the neoadjuvant setting of prostate cancer. The Department of Defense Prostate Cancer Clinical Trials Consortium in the USA is conducting trials of several novel agents. Most ongoing trials are evaluating novel agents (e.g. sipuleucel-T, mammalian target of rapamycin [mTOR] inhibitors, enzastaurin, IGF-1 receptor inhibitors, ipilimumab, finasteride, ixabepilone) without concurrent ADT to obtain a clear signal of activity with these agents (Table 1) [62–64]. This paradigm of monotherapy with novel agents (without concurrent ADT) preceding RP may deserve special attention to enable the detection of an early signal of biological antitumour activity and expedite the discovery of novel active agents. Some trials are attempting to primarily detect an increase in pCR rate with the combination of ADT and novel agents (e.g. dasatinib, sunitinib, abiraterone, vorinostat, ipilimumab), with other supportive pharmacodynamic endpoints (Table 2) [65].

Table 2.  Ongoing phase II trials of neoadjuvant combinations of novel agents with ADT for prostate cancer
InstitutionAgentTumour tissue correlative studies
  1. Cixutumumab, IGF receptor monoclonal antibody; HOG, Hoosier Oncology Group.

MulticentreAbiraterone + LHRH vs. LHRHHormone levels
MDACCAnti-CTLA-4 + LHRHImmune response
DukeImatinib ± (docetaxel + LHRH)Gene expression analysis
HOGDasatinib + LHRHpCR
MDACCSunitinib + LHRHpCR, biomarkers
U. WashingtonCixutumumab + LHRHpCR
MSKCCVorinostat + LHRHAR signalling

NEOADJUVANT THERAPY FOR BLADDER CANCER

Radical cystectomy (RC) has yielded excellent outcomes for organ-confined pT2N0 muscle-invasive TCC of the bladder [66]. Unfortunately, extravesical disease pT3–T4 disease confers a relatively poor progression-free survival (PFS) of 40–60%, while lymph node involvement is associated with a dismal PFS of 15–35%[67]. The incidence of distant recurrence (20–50%) is greater than that of locoregional recurrence (5–15%), which suggests that perioperative systemic therapy, particularly in patients with pathological extravesical and lymph node-positive disease, may eradicate distant micrometastases and improve survival. In metastatic disease, methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), dose-dense (DD)-MVAC and gemcitabine and cisplatin (GC) appear similar in efficacy and extend survival [68–70]. However, the median survival of patients with metastatic TCC eligible for clinical trials is only ≈15 months, and patients should be ideally enrolled on trials evaluating novel front-line regimens. The addition of paclitaxel to GC did not show a statistical improvement in survival in a large phase III trial [71]. Additionally, second-line therapy for metastatic TCC is suboptimal and novel agents are desperately needed for this unmet need [72–74]. Renal dysfunction (usually defined as a calculated creatinine clearance <60 mL/min), advanced age and poor performance status are quite common in patients with TCC and frequently render patients ineligible for cisplatin. More than 40% of postoperative patients aged >70 years are in this category [75]. Carboplatin-based and non-platinum regimens have been used in patients with advanced urothelial cancer and renal dysfunction or poor performance status. However, small randomized trials suggest that carboplatin-based regimens are inferior to cisplatin-based regimens [76–78]. Therefore, this population requires a special focus employing tolerable regimens

Data supporting neoadjuvant chemotherapy for bladder cancer

The advantage of adjuvant therapy is that it treats a population of patients whose risk of relapse is clearly defined by pathological stage at RC. However, all of the available data from clinical trials conducted to evaluate adjuvant chemotherapy are underpowered and do not provide definitive evidence for benefit. Although recent meta-analyses have been reported in support of adjuvant chemotherapy, they are flawed due to the inclusion of few patients in trials with methodological problems, which were often stopped early due to preliminary appearance of benefit [79,80]. Besides the lack of definitive data from prospective trials, the primary disadvantage of the adjuvant chemotherapy paradigm may be that it does not appear feasible in a third of patients within 90 days after RC due to postoperative complications [81,82]. Fortunately, accumulated data support neoadjuvant cisplatin-based combined chemotherapy as a standard. The International Collaboration of Trialists study from the European Organization for the Research and Treatment of Cancer (EORTC) and the MRC is the single largest trial of neoadjuvant chemotherapy for bladder cancer with accrual of 976 patients (Table 1) [83]. Eligible patients included those with clinical T2 grade 3, T3 or T4a node-negative disease who were candidates for local therapy with RC or external-beam radiation. Patients were randomized to local therapy with or without three cycles of neoadjuvant cisplatin, methotrexate and vinblastine (CMV). During the initial report, the difference between the 3-year survivals with neoadjuvant chemotherapy and local therapy alone approached, but did not reach, statistical significance (55.5% vs 50%, P= 0.075). The median survival for chemotherapy was 44 months vs 37.5 months for the local therapy alone group. After a longer median follow-up of 7 years, the difference achieved statistical significance (P < 0.05). The 3-year DFS was significantly longer with neoadjuvant chemotherapy (46% vs 39%, P= 0.019). After neoadjuvant chemotherapy, pCR was found in 32.5%. Chemotherapy-related mortality was 1% and postoperative complications did not increase. The chemotherapeutic regimen used in this study is not considered standard, albeit CMV has never been compared with MVAC. Although, the improvement in survival was less than the magnitude originally sought, this trial is considered a positive trial in favour of neoadjuvant CMV.

In all, 317 patients with operable T2N0M0 to T4aN0M0 disease were enrolled on the Intergroup trial (Table 1) [84]. The patients were randomized to RC alone or three cycles of MVAC before RC. At 5 years, 57% of patients in the neoadjuvant chemotherapy group were alive compared with 43% of those in the RC-alone group (two-sided P= 0.06). The median survival was 77 months for the neoadjuvant chemotherapy group and 46 months for the RC-alone group. Improved survival was associated with pCR defined as absence of all residual tumour. The 5-year survival for all patients with pCR was an impressive 85%. The neoadjuvant chemotherapy group displayed a significantly higher pCR rate (38% vs 15%, P < 0.001). The planned RC was performed in 82% of patients in the neoadjuvant chemotherapy group compared with 81% of patients in the RC-alone group. Reasons for not performing RC (39 patients) in all patients enrolled were aborted RC at time of exploration due to unresectability or positive nodes, patient refusal and progression of malignancy. In all, 87% of patients in the chemotherapy group received at least one cycle of MVAC. Chemotherapy induced grade 4 neutropenia in 33% and grade 3 gastrointestinal toxicities occurred in 17%. However, no life-threatening toxicities or deaths occurred from chemotherapy, and there was no increase in postoperative complications. Although the two-sided P value for the difference in survival was 0.06, the original goal of a statistically significant difference defined as a one-sided P < 0.05 was achieved. Survival was associated with neoadjuvant chemotherapy (hazard ratio, HR 1.39; P= 0.06), completion of RC (HR 2.88; P < 0.001) and removal of ≥10 pelvic lymph nodes (HR 2.38; P < 0.001) [85]. The 5-year survival and freedom from local relapse were 81% and 91%, respectively, in patients who had neoadjuvant chemotherapy/RC and ≥10 lymph nodes removed (n= 66), 66% and 90% in patients with RC alone and ≥10 lymph nodes removed (n= 60), 55% and 73% in chemotherapy/RC and <10 lymph nodes removed (n= 49), and 39% and 66% in RC alone with <10 lymph nodes removed (n= 44). The 5-year survival of patients with positive surgical margins (n= 25) and those who did not undergo RC (n= 39) was dismal at 0% and 11%, respectively. In another analysis of the SWOG trial, those with residual nonmuscle-invasive disease (pTa, pT1, pCarcinoma in situ) appeared to have worse survival (P= 0.054) than those with no residual disease (pT0), while survival was significantly worse for patients with residual muscle-invasive compared with residual pT0 disease (P < 0.001) [86]. Lymph node-positive disease was associated with worse survival than node-negative disease (P < 0.001). Patients with node-negative disease and <10 nodes removed appeared to have worse survival compared with those with ≥10 nodes removed (P= 0.079). The combination of baseline clinical stage and post-RC pathological stage was predictive of overall survival (P < 0.001). These data also suggest that patients with residual disease at RC should probably be offered clinical trials evaluating non-cross-resistant biological agents.

A meta-analysis was initiated by the MRC Clinical Trials Unit and reported by the Advanced Bladder Cancer Meta-analysis Collaboration [87,88]. In all, 2688 patients were analysed from 10 trials and information for individual patients was updated. Platinum-based combined chemotherapy (the vast majority received cisplatin) significantly improved 5-year overall survival compared with local therapy alone (50% vs 45%, P= 0.016; HR 0.87). Combined chemotherapy also showed an improvement in DFS (P < 0.001), locoregional DFS (P= 0.012) and metastasis-free survival (P= 0.001) compared with no neoadjuvant therapy. Combined chemotherapy also yielded significantly improved survival (P= 0.044) and DFS (P= 0.046) compared with cisplatin alone. However, single-agent cisplatin did not show an improvement in survival (P= 0.26) compared with no neoadjuvant therapy. As all platinum-based combination trials were analysed as a group, it is not possible to discern the best combination for use in neoadjuvant therapy. Additionally, new regimens (e.g. GC) were not evaluated in the included trials. While not tested in a prospective fashion, recent retrospective data from the Memorial Sloan-Kettering Cancer Center (MSKCC) show that the GC regimen produces a pCR rate of 35%, similar to MVAC [89]. The caveat is that phase III trials have not compared neoadjuvant MVAC with GC. In contrast to the above MSKCC study, data from the Cleveland Clinic showed that only 7% of patients achieved a pCR with mostly GC and other non-MVAC-based regimens [90]. However, these poor outcomes may be related to excessive delay in performing RC, as the median time from diagnosis to RC was ≈7 months. These investigators opined that in the absence of definitive supportive data for GC in the neoadjuvant setting, MVAC remained the preferred regimen. Adjuvant GC has been used in small non-randomized studies from the University of Chicago and appeared to improve long-term outcomes compared with contemporaneous patients that did not receive adjuvant chemotherapy [91,92]. Notably, most ongoing and planned trials in the neoadjuvant and advanced disease settings use GC as the backbone of therapy in combination with biological agents, given its greater tolerability (Table 2).

In a phase II trial of 68 patients with adequate renal function and clinical T3 or T2 with hydronephrosis, N0, M0 bladder cancer received three cycles of neoadjuvant paclitaxel, carboplatin, gemcitabine (PCaG) with a primary endpoint of pCR. Patients with T4 or node-positive patients received six cycles of PCaG with an endpoint of resectability [93]. There was pCR in 32% of evaluable patients in the T2–T3 group and 17% in the T4/node-positive group. Unfortunately, toxicities were unexpectedly common and 79% of all patients had grade 3/4 haematological toxicities. Seven patients died during chemotherapy or after RC (only one death clearly attributable to chemotherapy), which led to premature closure of the trial. In selected cisplatin-ineligible patients with good performance status, neoadjuvant PCaG may be considered based on these data. The caveat is that this regimen was fairly toxic in a population with adequate baseline renal function and may often warrant prophylactic granulocyte growth factors in accordance with guidelines [94]. SWOG conducted a phase II trial of three cycles of neoadjuvant PCaG followed by cystoscopic surveillance or immediate RC for patients with cT0 status after chemotherapy [95]. Patients with cT0 status could elect immediate RC or cystoscopic surveillance, and those with > cT0 status underwent immediate RC. Of 77 patients, 74 were assessable, and cT0 status was achieved in 34 patients (46%). Of the 34 patients with cT0 status 10 underwent immediate RC, six of whom had persistent cancer. There was persistent tumour at transurethral bladder tumour resection in 28 patients (38%) and 21 of them underwent RC. With a median follow-up of 22 months the 2-year overall survival was 59% (95% CI 45–72) and among cT0 cases it was 75% (95% CI 57–93). Thus, there was an unacceptably high rate (60%) of persistent cancer at RC in patients presumed to have pT0 status, which suggests that RC is a critical component of therapy. Myelosuppression was seen frequently with one death from neutropenic infection, again suggesting the necessity of routine prophylactic growth factor support. Trials have not addressed perioperative chemotherapy specifically targeting patients ineligible for cisplatin (due to renal dysfunction and/or poor performance status).

Other potential but unproven benefits of neoadjuvant therapy include earlier therapy for micrometastases before development of drug resistance, and superior efficacy compared with adjuvant chemotherapy. A disadvantage of the neoadjuvant approach is the possibility that some low-stage low-risk patients may unnecessarily receive neoadjuvant chemotherapy. The delay in RC in non-responders may adversely affect their long-term outcomes, as delay of RC has been reported in some, but not all studies, to negatively affect outcomes [96,97]. For these reasons, many urologists have not embraced neoadjuvant chemotherapy [98]. Among 7161 analysable patients in the National Cancer Data Base with stage III bladder cancer diagnosed between 1998 and 2003, perioperative chemotherapy was administered to 11.6% of patients with 10.4% receiving adjuvant chemotherapy and 1.2% receiving neoadjuvant chemotherapy. Whether these patterns are changing more recently needs further study.

Novel agents as neoadjuvant therapy for bladder cancer

Trials are building upon combinations of GC or DD-MVAC with novel biological agents administered in three to four cycles in the neoadjuvant setting with pCR as a key intermediate endpoint (Table 2). The induction of pCR significantly higher than that induced by MVAC or GC may rapidly provide a signal of more efficacious regimens. For example, separate phase II trials are evaluating the combination of DD-MVAC with bevacizumab, and GC with sunitinib (Table 3). The residual tumour tissue after neoadjuvant chemotherapy may be enriched for stem cell-like cells, similar to the finding in breast cancer [99]. Several novel agents and regimens are being evaluated in the brief window between cystoscopic biopsy and RC with correlative pharmacodynamic endpoints (Table 3). A signal of antitumour activity (reduced proliferation or increased apoptosis) coupled with down-regulation of the molecular target may warrant further development of the agent. Potentially, several new agents can be evaluated in randomized phase II trials to enable the selection of the most promising agents for further development. The cytotoxic T-lymphocyte antigen 4 (CTLA-4) antagonist monoclonal antibody when used as neoadjuvant therapy showed that CD4 T-cells from peripheral blood and tumour tissues of all treated patients had markedly increased expression of inducible costimulator (ICOS) [100]. These CD4(+)ICOS(hi) T-cells produced interferon γ (IFNγ) and could recognize the tumour antigen NY-ESO-1. Increase in CD4(+)ICOS(hi) cells led to an increase in the ratio of effector to regulatory T-cells. Ongoing trials are evaluating novel biological agents including sunitinib, dasatinib and erlotinib (Table 3). A preliminary report of the trial evaluating brief erlotinib administration (150 mg daily for 4 weeks) found this to be safe and suggested that baseline HRas, p85, and fibroblast growth factor receptor 3 (FGFR3) pathways may be associated with lack of response to EGFR inhibition [101,102].

Table 3.  Ongoing and planned nonrandomized neoadjuvant trials for bladder cancer
InstitutionRegimenPrimary end-point
  1. Nab paclitaxel, nanoparticle albumin-bound paclitaxel; MUSC, Medical University of South Carolina; UNC, University of North Carolina; HOG, Hoosier Oncology Group.

MSKCCIfosfamide-cisplatin-nab paclitaxelpCR
U. MichiganCarboplatin-gemcitabine-nab paclitaxelpCR
MUSCGC-bevacizumabpCR
DFCIDD-MVACpCR
MDACCDD-MVAC-bevacizumabpCR
UNCErlotinibCorrelative
Cleveland ClinicSunitinibpCR
Baylor-HOGGC-sunitinibpCR
MSKCCGC-sunitinibpCR
SWOGGC-cetuximabpCR
Baylor-HOGDasatinibCorrelative
MDACCIpilimumabCorrelative

Development of personalized therapy for bladder cancer with the neoadjuvant paradigm

Baseline tumour genomics and proteomics appear promising preliminarily as predictors of pCR [103]. Fourteen predictive genes separated the responder group (no muscle-invasive disease) from the non-responder group in a retrospective study of patients with invasive bladder cancer who received neoadjuvant MVAC chemotherapy. This system accurately predicted the drug responses of eight of nine test cases. Among those genes, topoisomerase IIa, a target of doxorubicin, was down-regulated in the non-responder group. Because real-time reverse transcription-PCR data were highly concordant with the cDNA microarray data for those 14 genes, a quantitative reverse transcription-PCR-based prediction system was developed. To further validate the clinical significance of the system, the investigators applied it to 22 additional cases of patients with bladder cancer and found that the scoring system correctly predicted clinical response for 19 of the 22 test cases [104]. There was also correlation between low/intermediate tumour breast cancer susceptibility gene 1 (BRCA1) mRNA levels (which mediates DNA repair) with long-term outcomes with neoadjuvant cisplatin-based combined chemotherapy [105]. These data suggest that the neoadjuvant paradigm may be optimal to rapidly attain the goal of personalized medicine.

NEOADJUVANT THERAPY FOR RCC

In the era of cytokines, cytoreductive nephrectomy (CN) before the institution of cytokines was shown to improve outcomes significantly in patients with metastatic clear cell (cc)RCC. In all, 331 patients were randomized in two similar trials conducted by the SWOG and the EORTC comparing CN plus IFNα-2b vs IFNα-2b alone in patients with metastatic RCC [106,107]. Patients were stratified at pre-randomization by performance status (0 or 1), site of metastases (lung only vs other) and disease measurability. The combined analysis of these two trials yielded a median survival of 13.6 months for CN + IFN vs 7.8 months for IFN alone [108]. There was no evidence of a difference in the size of the treatment effect according to pre-randomization stratification factors. Although the rates of tumour regression were not increased by up-front CN, it appeared that the delay of progression and early death by undefined mechanisms were the primary benefits [109]. Perioperative morbidity and mortality were low and the average time for patients to begin IFN treatment after CN was 19 days, and only 5.6% of the CN patients did not receive IFN compared with 1.8% in the non-CN group. Another retrospective study has also reported a similar benefit for CN in the context of high-dose interleukin 2 [110]. However, the antitumour activity of IFN is modest with overall response rates of ≈5%, and high-dose interleukin 2 is suitable only for a few patients. A panoply of novel VEGF and mTOR inhibiting agents have received approval and supplanted cytokines for the therapy of metastatic RCC. These novel agents have substantial activity compared to IFN, which has led investigators to question the current role of CN.

Current systemic therapy for metastatic RCC

Sunitinib, temsirolimus and the combination of bevacizumab-IFN are all accepted as conventional first-line regimens for metastatic RCC [111–114]. In addition, pazopanib was recently approved for advanced RCC, and sorafenib and everolimus have improved outcomes after cytokines or sorafenib/sunitinib, respectively [115–117]. All of the prospective phase III trials that evaluated these agents were performed largely in the setting of previous nephrectomy. The pivotal sunitinib vs IFN trial showed a median PFS of ≈1 year, a median survival of ≈26 months and an impressive response rate of 39% with sunitinib in patients that had low- and intermediate-risk disease, 90% of whom had undergone previous nephrectomy [111]. A subset of patients on this trial that received IFN alone without crossover to sunitinib or other novel biological agents had a median survival of ≈13 months, which is similar to the historical survival of these patients. Temsirolimus extended survival compared with IFN in patients with high-risk disease and most (≈67%) of this population had also undergone previous nephrectomy [112]. On subset analysis, the lack of previous nephrectomy did not appear to confer poorer outcomes. When examining the bevacizumab-IFN phase III trials, the AVOREN trial mandated a previous nephrectomy, while ≈90% of patients in the similar CALGB trial had undergone a nephrectomy [113,118]. The response rate with bevacizumab-IFN was ≈25% and the median PFS was 8.5–10.5 months. Similarly, the phase III trials that evaluated pazopanib, sorafenib and everolimus mostly enrolled patients that had undergone nephrectomy.

Neoadjuvant therapy with novel agents preceding cn for metastatic RCC

Recommendations were published on the role of CN in patients with metastatic RCC using the RAND/University of California, Los Angeles (UCLA) Appropriateness Method [119]. The panel was uncertain if CN was appropriate with targeted agents except in patients with symptomatic primary tumours and limited metastases.

Notably, there are no data to definitively support the role of CN in patients with non-ccRCC [120,121]. Recent data has emerged that show the feasibility and activity of novel VEGF-targeting agents administered as neoadjuvant therapy before CN. Van der Veldt et al. [122] described a series of 22 patients treated with sunitinib with the primary tumour in situ. They reported only two partial responses in the primary tumour when using Response Evaluation Criteria in Solid Tumors, although some response to therapy (18–60% decrease in tumour volume) was recorded in 13 primary tumours overall. Other preliminary reports also suggest that sunitinib has substantial activity on the primary renal tumour mass and concurrently controls metastatic sites [123,124]. Notably, in one study, 32% of nephrectomy patients had progression of disease during the treatment break with surgery, but 63% of these responded or stabilized on continued postoperative sunitinib [123]. A series of 19 patients deemed to have unresectable tumours before therapy was recently reported from the Cleveland Clinic [125]. The patients were placed on a standard sunitinib regimen with the primary tumour in situ, but only three (16%) of 19 patients had a partial response in the primary tumour. Four patients were able to undergo nephrectomy, and there was viable tumour in all the nephrectomy specimens. Grade 3 or 4 adverse effects from treatment occurred in seven (37%) of the 19 patients, and five patients died during the median 6-month follow-up. A recent preliminary report, does report the slight increase in perioperative complications after neoadjuvant sunitinib (haemorrhage, delayed wound healing and altered surgical field) [126].

Patients with untreated ccRCC whose primary tumours were enrolled in a trial by Jonasch et al. [127] at the MDACC to receive bevacizumab plus erlotinib (n= 23) or bevacizumab alone (n= 27) for 8 weeks followed by re-staging. In all, 42 patients underwent nephrectomy and the median PFS was 11.0 months with a median overall survival of 25.4 months. Cytoreduction occurred in both primary and metastatic sites of disease. Therefore, these outcomes appear similar to outcomes in patients that received bevacizumab-IFN and had undergone nephrectomy in the aforementioned large phase III trials. Two perioperative deaths occurred, which were not attributable to the study drug. Wound dehiscence resulted in treatment discontinuation for three patients and treatment delay for two others, suggesting a modest adverse impact on wound healing. Frozen nephrectomy-tumour specimens were subjected to correlative studies and compared with untreated controls [128]. High tumour total AMP-activated protein kinase (which regulates the PI3K pathway) and low PI3K pathway expression (low pAkt, low pS6K, high phosphatase and tensin homolog [PTEN]) correlated with longer survival, which may be a candidate pathway that interacts with the VEGF pathway and is a potential resistance mechanism. The investigators hypothesized that agents targeting the PI3K pathway may provide clinical benefits in bevacizumab-treated patients. However, baseline pre-treatment tumour tissue analyses were not presented and it is unclear if this tumour tissue profile is present at baseline or is induced by bevacizumab. Phase II trials have also shown that the administration of preoperative sorafenib is safe and affects the size and density of the primary tumour as well as metastatic sites [129,130]. Future tissue-based studies are planned to evaluate whether pharmacodynamic changes in the nephrectomy-tumour specimens reflect the addition of erlotinib to bevacizumab. Notably, the addition of erlotinib to bevacizumab did not enhance long-term outcomes in another randomized phase II front-line trial [131]. Clearly, the field of neoadjuvant therapy for metastatic RCC is in its infancy and further development of this paradigm is necessary.

A recent retrospective report of 314 patients suggests that CN may continue to play a role in the setting of novel antiangiogenic agents after adjusting for prognostic factors, although the limitations of a retrospective study do not allow firm conclusions [132]. The paradigm of neoadjuvant systemic therapy for metastatic RCC followed by CN requires prospective evaluation and is being evaluated in comparison with up-front CN followed by systemic therapy in large randomized trials. In addition to questioning the timing of CN, the value of performing a CN is also being evaluated. The French CARMENA trial is designed as a non-inferiority trial with a target accrual of 576 patients with metastatic ccRCC. The trial is designed to show that overall survival is not different in patients treated with sunitinib therapy alone vs CN followed by sunitinib. A separate study (SURTIME), designed by EORTC, has been proposed to evaluate the timing of therapy and nephrectomy. This study will enroll 458 patients and is designed to assess PFS in patients with advanced RCC who will receive either sunitinib after nephrectomy or two to three cycles of sunitinib before nephrectomy.

Brief neoadjuvant therapy preceding cn as a paradigm to develop tailored therapy

A phase II trial is planned by a consortium of Texas Oncology, Baylor College of Medicine and the University of Texas Southwestern to evaluate front-line everolimus administered before CN for metastatic RCC (Fig. 1). Patients undergo a baseline biopsy of the renal tumour followed by 3–5 weeks of everolimus before CN. After CN, everolimus is resumed and continued until progression or intolerable toxicity. Modulation of the mTOR signalling pathway and downstream proliferation, apoptosis and angiogenesis in the nephrectomy-tumour specimen is correlated with time to progression. Potentially, baseline markers as well as biological alterations in the tumour with brief therapy will predict long-term outcomes. Additionally, this design will evaluate the feasibility of neoadjuvant everolimus before CN and is a potentially important paradigm for developing tailored therapy. Brief neoadjuvant therapy before excision of localized high-risk RCC (i.e. non-metastatic) may also be feasible to obtain signals of biological activity.

Figure 1.

Design of planned phase II trial of neoadjuvant frontline everolimus followed by CN and correlative studies for metastatic RCC.

CONCLUSIONS AND FUTURE DIRECTIONS

While neoadjuvant cisplatin-based combined chemotherapy is an established standard for muscle-invasive bladder cancer, phase III trials are ongoing to elucidate the role of neoadjuvant combined ADT and docetaxel-based chemotherapy for localized high-risk prostate cancer. Neoadjuvant therapy with VEGF- and mTOR-targeting biological agents preceding CN for metastatic RCC is a reasonable approach, although ongoing randomized trials are validating this paradigm and attempting to establish the timing and necessity of CN. Neoadjuvant trials using brief therapy preceding surgery can be supported to screen novel agents for biological activity and build a rationale to evaluate the most promising agents in larger trials. The neoadjuvant therapy design should be used thoughtfully and should be guided by preclinical data. A committed multidisciplinary team is imperative to deploy this design. Given scant resources, the proliferation of numerous novel agents and frequent presentation of urological cancers in an organ-confined stage, the neoadjuvant paradigm holds considerable promise to aid the development of systemic therapy for urological cancers.

CONFLICT OF INTEREST

Guru Sonpavde receives research support from Eli Lilly, Pfizer, Bristol-Myers Squibb, Cytogen and AstraZeneca and is on the speakers’ bureau for Pfizer, Novartis and Sanofi-Aventis.

Cora N. Sternberg has received research support from Eli Lilly, Sanofi-Aventis, Cougar Biotech, and is on the advisory board/consultant for Bayer, Novartis, GlaxoSmithKline and Pfizer.

Ancillary