Tag Archive for: tyrosine kinase inhibitors

Posts

Article of the month: Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

Every month, the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urological community and the authors have also kindly produced a video describing their work. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

Cedric Lebacle* , Karim Bensalah, Jean-Christophe Bernhard§, Laurence AlbigesBrigitte Laguerre**, Marine Gross-Goupil††, Herve Baumert‡‡, Herve Lang§§, Thibault Tricard§§, Brigitte Duclos¶¶, Armelle Arnoux***, Celine Piedvache***, Jean-Jacques Patard††† and Bernard Escudier

 

*Department of Urology, Bicêtre University Hospital, Assistance Publique-Hôpitaux de Paris, APHP, University Paris-Saclay, Le Kremlin-Bicêtre, Department of Urology, Pontchaillou University Hospital, Rennes, Department of Urology, Bordeaux University Hospital, Pellegrin Hospital, §French Research Network on Kidney Cancer UroCCR, Bordeaux, Department of Medicine, Gustave Roussy, University Paris-Saclay, Villejuif, **Department of Oncology, Eugene Marquis Centre, Rennes, ††Department of Medical Oncology, Bordeaux University Hospital, Saint-André Hospital, Bordeaux, ‡‡Department of Urology, Saint-Joseph Hospital, Paris, §§Department of Urology, Nouvel Hôpital Civil, ¶¶Department of Oncology, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, ***Paris-Sud Clinical Research Unit, Department of Statistics, Bicêtre University Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre and †††Department of Urology, Mont de Marsan Hospital, Mont de Marsan, France

 

Abstract

Objective

To evaluate the ability of neoadjuvant axitinib to reduce the size of T2 renal cell carcinoma (RCC) for shifting from a radical nephrectomy (RN) to a partial nephrectomy (PN) indication, offering preservation of renal function.

Patients and Methods

Patients with cT2aN0NxM0 clear‐cell RCC, considered not suitable for PN, were enrolled in a prospective, multicentre, phase II trial (AXIPAN). Axitinib 5 mg, and up to 7–10 mg, was administered twice daily, for 2–6 months before surgery, depending on the radiological response. The primary outcome was the number of patients receiving PN for a tumour <7 cm in size after neoadjuvant axitinib.

Results

Eighteen patients were enrolled. The median (range) tumour size and RENAL nephrometry score were 76.5  (70–98) mm and 11 (7–11), respectively. After axitinib neoadjuvant treatment, 16 tumours decreased in diameter, with a median size reduction of 17% (64.0 vs 76.5 mm; P < 0.001). The primary outcome was considered achieved in 12 patients who underwent PN for tumours <7 cm. Sixteen patients underwent PN. Axitinib was tolerated in the present study, as has been previously shown in the metastatic setting. Five patients had grade 3 adverse events. Five patients experienced Clavien III–V post‐surgery complications. At 2‐year follow‐up, six patients had metastatic progression, and two had a recurrence.

Conclusion

Neoadjuvant axitinib in cT2 ccRCC is feasible and, even with a modest decrease in size, allowed a tumour shrinkage <7 cm in 12 cases; however, PN procedures remained complex, requiring surgical expertise with possible morbidity.

Editorial: Expanding the feasibility of nephron‐sparing surgery: time for a paradigm shift?

With the rapid implementation of ‘targeted’ therapies, kidney cancer has entered a new era where old paradigms are being challenged, and new ones can be explored. The idea of delivering ‘neoadjuvant’ systemic therapy to alter the surgical treatment of advanced RCC was suggested in this same journal ~10 years ago as a proof‐of‐concept study [1]. Since then, a plethora of small case series has investigated the safety and feasibility of different targeted agents in the preoperative setting to facilitate surgical resection of locally advanced disease, mostly with a ‘cytoreductive’ (rather than ‘curative’) intent.

In this issue of the BJU Int, Lebacle et al. [2] evaluated the role of neoadjuvant axitinib, an oral tyrosine kinase inhibitor currently recommended as a second‐line option for metastatic clear cell RCC, to downstage cT2 kidney cancer and allow a partial nephrectomy (PN). In this multicentre prospective study, 18 patients with RCC (median tumour size 7.6 cm and R.E.N.A.L. [Radius; Exophytic/Endophytic; Nearness; Anterior/Posterior; Location] score 11) were enrolled. A median tumour size reduction of 17% was obtained, and the primary outcome (‘clinical downstaging’ to cT1 to allow PN) was achieved in 12 patients (67%). Overall, 16 patients underwent PN, as this was successfully done also in four of six (67%) patients who were not ‘down‐staged’ by the drug. Notably, about half of the PNs were performed with a robotic approach. Whilst axitinib was well tolerated, five patients experienced a high‐grade complication after surgery, including one death. Interestingly, final pathology showed upstaging to pT3a disease in seven patients, and two positive margins. Moreover, about a third of patients had metastatic progression and two had recurrence at 2 years. Thus, while the authors noted axitinib to be effective in reducing tumour size and achieving a clinical downstaging in most patients, the significant presence of pT3a disease calls into question the overall efficacy (to truly pathologically downstage) or desirability (most of the tumours that were not downstaged still successfully underwent PN) of the study’s main stated aim.

The rapid adoption of robotic surgery and the increasing experience with PN techniques translated into expanding indications for minimally invasive nephron‐sparing surgery (NSS), to include also T1b and T2 renal masses [3], and the field is primed for a possible paradigm shift. Whether or not a PN is doable, regardless of the technique, remains in the hands of the surgeon, who makes that decision based on previous personal experience. This is also the case for the present study, where the primary outcome was simply represented by the number of patients who could get a PN (instead of a radical nephrectomy). As such, is such a subjective endpoint (feasibility of PN) clinically meaningful? While disagreement may occur over the risk of PN in complex and elective cases, the desirability of nephron preservation in imperative and most elective circumstances is supported by evidence that largely suggests that PN translates into better renal function. In addition, recent findings suggest that estimated GFR preservation might translate into better cancer‐specific survival [4]. Certainly, this type of endpoint (whether a PN is feasible) is prone to intrinsic bias and limitations.

Only a limited number of studies have specifically explored the role of neoadjuvant therapy to enable NSS with variable results [5] (Table 1) [2, 6, 7, 8, 9]. Overall, these studies suggest that even a modest tumour size reduction can facilitate kidney preservation in a significant number of cases. Amongst these studies, only one had assessed axitinib in this specific setting [9]. Differences in outcomes between that trial and the present one by Lebacle et al. [2] could be explained by differences in study populations and/or drug regimens. A more recent study by Karam et al. [10], showed that inter‐observer agreement regarding the feasibility of a PN is quite variable, which is not surprising. For this reason, those authors advocated the need for a ‘resectability score’.

In conclusion, utility of neoadjuvant therapy to modify tumour size and facilitate NSS is an active and exciting area of clinical investigation, fuelled by the rapidly changing landscape of systemic therapies for RCC. It is too early to call for a paradigm shift, but a few ongoing studies might provide some meaningful answers soon. Amongst these, the PADRES (Prior Axitinib as a Determinant of Outcome of REnal Surgery) is an ongoing North American multicentre phase II study of axitinib with the aim of recruiting 50 patients [5]. While waiting for more robust evidence, the use of neoadjuvant therapy to facilitate NSS should still be deemed as investigational.

References

  1. Shuch, BRiggs, SBLaRochelle, JC et al. Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm. BJU Int 2008102692– 6
  2. Lebacle, CBensalah, KBernhard, JC et al. Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study. BJU Int 2019123804– 10
  3. Bertolo, RAutorino, RSimone, G et al. Outcomes of robot‐assisted partial nephrectomy for clinical T2 renal tumors: a multicenter analysis (ROSULA Collaborative Group). Eur Urol 201874:226– 32
  4. Antonelli, AMinervini, ASandri, M et al. Below safety limits, every unit of glomerular filtration rate counts: assessing the relationship between renal function and cancer‐specific mortality in renal cell carcinoma. Eur Urol 201874661– 7
  5. Bindayi, AHamilton, ZAMcDonald, ML et al. Neoadjuvant therapy for localized and locally advanced renal cell carcinoma. Urol Oncol 20183631– 7
  6. Silberstein, JLMillard, FMehrazin, R et al. Feasibility and efficacy of neoadjuvant sunitinib before nephron‐sparing surgery. BJU Int 20101061270– 6
  7. Rini, BIPlimack, ERTakagi, T et al. A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. J Urol 2015194297– 303
  8. Lane, BRDerweesh, IHKim, HL et al. Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma. Urol Oncol 201533112.e15–21.
  9. Karam, JADevine, CEUrbauer, DL et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. Eur Urol 201466874– 80
  10. Karam, JADevine, CEFellman, BM et al. Variability of inter‐observer agreement on feasibility of partial nephrectomy before and after neoadjuvant axitinib for locally advanced renal cell carcinoma (RCC): independent analysis from a phase II trial. BJU Int 2016117629– 35

 

Video: Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

Abstract

Objective

To evaluate the ability of neoadjuvant axitinib to reduce the size of T2 renal cell carcinoma (RCC) for shifting from a radical nephrectomy (RN) to a partial nephrectomy (PN) indication, offering preservation of renal function.

Patients and Methods

Patients with cT2aN0NxM0 clear‐cell RCC, considered not suitable for PN, were enrolled in a prospective, multicentre, phase II trial (AXIPAN). Axitinib 5 mg, and up to 7–10 mg, was administered twice daily, for 2–6 months before surgery, depending on the radiological response. The primary outcome was the number of patients receiving PN for a tumour <7 cm in size after neoadjuvant axitinib.

Results

Eighteen patients were enrolled. The median (range) tumour size and RENAL nephrometry score were 76.5  (70–98) mm and 11 (7–11), respectively. After axitinib neoadjuvant treatment, 16 tumours decreased in diameter, with a median size reduction of 17% (64.0 vs 76.5 mm; P < 0.001). The primary outcome was considered achieved in 12 patients who underwent PN for tumours <7 cm. Sixteen patients underwent PN. Axitinib was tolerated in the present study, as has been previously shown in the metastatic setting. Five patients had grade 3 adverse events. Five patients experienced Clavien III–V post‐surgery complications. At 2‐year follow‐up, six patients had metastatic progression, and two had a recurrence.

Conclusion

Neoadjuvant axitinib in cT2 ccRCC is feasible and, even with a modest decrease in size, allowed a tumour shrinkage <7 cm in 12 cases; however, PN procedures remained complex, requiring surgical expertise with possible morbidity.

Article of the Week: Combining Nanotech Drug Delivery and Thermoablation in an in vivo mouse model of RCC

Every week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Nanotechnology combined therapy: tyrosine kinase-bound gold nanorod and laser thermal ablation produce a synergistic higher treatment response of renal cell carcinoma in a murine model

James Liu*, Caleb Abshire*, Connor Carry*, Andrew B. Sholl, Sree Harsha Mandava*, Amrita Datta*, Manish Ranjan*, Cameron Callaghan*, Donna V. Peralta, Kristen S. Williams, Weil R. Lai*, Asim B. Abdel-Mageed*, Matthew Tarr and Benjamin R. Lee§

 

Departments of *Urology, Pathology, Tulane University School of Medicine, Department of Chemistry, University of New Orleans, New Orleans, LA, and §Division of Urology, University of Arizona College of Medicine, Tucson, AZ, USA

 

Abstract

Objectives

To investigate tyrosine kinase inhibitors (TKI) and gold nanorods (AuNRs) paired with photothermal ablation in a human metastatic clear cell renal cell carcinoma (RCC) mouse model. Nanoparticles have been successful as a platform for targeted drug delivery in the treatment of urological cancers. Likewise, the use of nanoparticles in photothermal tumour ablation, although early in its development, has provided promising results. Our previous in vitro studies of nanoparticles loaded with both TKI and AuNRs and activated with photothermal ablation have shown significant synergistic cell kill greater than each individual arm alone. This study is a translation of our initial findings to an in vivo model.

Materials and Methods

Immunologically naïve nude mice (athymic nude-Foxn1nu) were injected subcutaneously bilaterally in both flanks (n = 36) with 2.5 × 106 cells of a human metastatic renal cell carcinoma cell line (RCC 786-O). Subcutaneous xenograft tumours developed into 1-cm palpable nodules. AuNRs encapsulated in human serum albumin protein (HSA) nanoparticles were synthesised with or without a TKI and injected directly into the tumour nodule. Irradiation was administered with an 808-nm light-emitting diode laser for 6 min. Mice were humanely killed 14 days after irradiation; tumours were excised, formalin fixed, paraffin embedded, and evaluated for size and the percentage of necrosis by a genitourinary pathologist. The untreated contralateral flank tumours were used as controls.

Results

In mice that did not receive irradiation, TKI alone yielded 4.2% tumour necrosis on the injected side and administration of HSA-AuNR-TKI alone yielded 11.1% necrosis. In the laser-ablation models, laser ablation alone yielded 62% necrosis and when paired with HSA-AuNR there was 63.4% necrosis. The combination of laser irradiation and HSA-AuNR-TKI had cell kill rate of 100%.

aotw-22-2-17

Conclusions

In the absence of laser irradiation, TKI treatment alone or when delivered via nanoparticles produced moderate necrosis. Irradiation with and without gold particles alone also improves tumour necrosis. However, when irradiation is paired with gold particles and drug-loaded nanoparticles, the combined therapy showed the most significant and synergistic complete tumour necrosis of 100% (P < 0.05). This study illustrates the potential of combination nanotechnology as a new approach in the treatment of urological cancers.

 

 

Editorial: Synergistic effects in combinational drug delivery and thermal ablation using nanotechnology

Chemotherapy, the dominant therapeutic approach to the treatment of a wide variety of cancers, is intrinsically inefficient because its drug delivery is non-specific. This leads to a trade-off between undesirable cytotoxic effects in healthy cells and associated side effects and lower efficacy in killing cancerous cells at lower concentrations.

The study in the present issue of BJUI by Lui et al. [1], from the University of Arizona College of Medicine, attempts to circumvent these undesirable side effects by employing nanoparticles as drug delivery vectors, isolating chemotherapeutic agents from the systemic environment while allowing them to accumulate in solid tumours with leaky vasculature and impaired lymphatics, and improving cellular uptake both passively and through targeted therapy. In recent years, this therapeutic approach has been extended by combining targeted drug delivery via nanoparticles with temperature-based treatments. In the combined therapy, either the nanoparticles exhibit strong absorption in the human tissue transparency window in the near infra-red, enabling laser excitation, or alternatively, via the absorption of ultrasound. Synergy implies more than a simple linear addition of chemotherapeutic agents and high temperature ablation, and it has been suggested previously that the efficacy of chemotherapeutic agents is improved at elevated temperatures [2].

A wide variety of nanoparticle vectors has been investigated, but gold nanoparticles have been shown to be biocompatible and elementally stable, while possessing the ability to bind various compounds for immune system evasion, and are a malleable structure for further design considerations [3] as well as exhibiting a strong and wavelength-tunable absorption resonance for near infra-red laser excitation.

In genitourinary oncology, the use of nanotechnology as a carrier for drug delivery, laser ablation, gene therapy and imaging has grown rapidly in the past decade. The work reported in the present study follows one of the first studies on synergistic therapeutic treatments, which was conducted by Stern et al. [4] from the University of Texas Southwestern. They used a combination of gold and tyrosine kinase inhibitor (TKI) nanotechnology with laser ablation. Their work was performed in an in vivo metastatic RCC mouse model [4] and shows that gold nanoparticles improve heat delivery to cancer while both sparing local benign tissues and also significantly improving tumour necrosis.

A previous study by Lui’s group [5] has already demonstrated the efficacy of using gold nanorods loaded with human serum albumin (HSA) and a TKI (sorafenib) as effective drug delivery vectors, as well as gold nanorods (AuNR) for tumour ablation. The purpose of the study was to explore the synergistic effects when gold ablation is also paired with chemotherapeutics; therefore, in each individual experimental arm low amounts of HSA-AuNR and HSA-AuNR-TKI were used to further magnify any co-acting effect when combined with thermal ablation.

For that study, immunologically naïve nude mice (Athymic Nude-Foxn1nu) were injected bilaterally on the flanks (= 36) with 2.5 × 106 cells of a human metastatic RCC cell line (RCC 786-O). Subcutaneous xenograft tumours developed 1-cm palpable nodules. AuNR encapsulated in HSA protein nanoparticles were synthesized with or without a TKI and injected directly into the tumour nodule. Once tumours reached an appropriate size, they were directly injected with 0.1 mL of 10 mM sorafenib solution in PBS, 0.1 mL suspension of HSA-AuNR stock, or 0.1 mL of HSA-AuNR-TKI stock. In the treatment groups, laser ablation was performed 24 h later to allow the cellular uptake of the particle with irradiation, administered with an 808-nm LED diode laser for 6 min. The mice were killed 14 days after irradiation. The tumours were then excised, formalin-fixed, paraffin-embedded and evaluated for size and percent necrosis by a genitourinary pathologist. Untreated contralateral flank tumours were used as controls. The area of laser treatment was 1 cm in diameter, completely covering the tumours. The mice were anaesthetized during laser treatment with continuous isoflurane.

The results of the final percentage tumour necrosis and average tumour size are shown in Fig. 1. To be able to infer synergistic effects, a careful study design was used, such that neither HSA-AuNR vs sorafenib alone, nor HSA-AuNR vs laser treatment alone showed statistically significant differences, which showed that nanoparticles concentrations were insufficient in each individual experimental arm to result in any statistical improvement when compared with control settings (Fig. 1). In mice that did not receive irradiation, a TKI alone yielded 4.2% tumour necrosis on the injected side and administration of HSA-AuNR-TKI alone yielded 11.1% necrosis. In laser ablation models, laser ablation alone yielded 62% necrosis and, when paired with HSA-AuNR, yielded 63.4% necrosis; however, the combination of laser irradiation and HSA-AuNR-TKI had cell kill of 100%. The clear conclusion is that in the absence of laser irradiation, TKI treatment alone or when delivered via nanoparticle produced moderate necrosis. Irradiation with and without gold particles alone also improves tumour necrosis. When irradiation is paired with gold particle and drug-loaded nanoparticle treatment, however, the combination therapy showed the most significant and synergistic complete tumour necrosis of 100% (P < 0.05). The overwhelming tumour necrosis of combinational nanotechnology shows synergistic kill rather than simple additive effects of each treatment method.

aotw-ed-22-2-17

This significantly improved efficacy of combination nanotechnology can be explained by the complementary mechanisms of action for each individual arm. By combining AuNR and sorafenib in an albumin vehicle, better delivery of both chemotherapeutic drug and thermal ablative particle to the tumour site is possible. Likewise, when tumour cells are activated by laser there is not only cell lysis, attributable to rapid temperature increase, but also cells that do survive upregulate heat shock proteins, such as FasL which mediate apoptosis [6]. Studies have found that TKIs play a critical part in intracellular pathways that enhance this effect, possibly by upregulating FasR and thereby accelerating apoptosis [7]. A laser-induced temperature increase may disrupt albumin construction and facilitates intracellular drug delivery. The verification of synergistic tumour necrosis from combination nanotechnology is an exciting springboard for future experiments, while the translation of this effective in vitro model into a murine tumour model illustrates that nanotechnology is a reliable platform demanding future clinical evaluation.

The present study beautifully illustrates the enormous potential of combination nanotechnology as a new approach in the treatment of urological cancers. The next step in pursuing more effective combination nanotechnology is to better calibrate factors such as drug load, AuNR load and laser settings. In particular, narrow size distribution of the gold nanoparticles, fully optimizing their absorption resonance optimized at the irradiation wavelength will enable lower nanoparticle loading and either lower irradiation thresholds or deeper tissue activation. These studies will not only help find new ways to eradicate tumours but will also add to the precision of minimally invasive surgical technology.

Wayne Dickson
Department of Physics, King’s College London, London, UK

References

 

2 Zhang W, Guo Z, Huang D et al. Synergistic effect of chemo- photothermal therapy using PEGylated graphene oxide. Biomaterials 2011; 32: 855561

 

3 Stern JM, Staneld J, Lotan Y, Park S, Hsieh JT, Cadeddu JA. Efcacy of laseractivated gold nanoshells in ablating prostate cancer cells in vitro. J Endourol 2007; 8: 93

 

 

© 2019 BJU International. All Rights Reserved.