Study type – Therapy (case series)
Level of Evidence 4
Study type – Therapy (case series)
To investigate efficacy of neoadjuvant tyrosine kinase-inhibitor therapy (TKI) before imperative nephron-sparing surgery (NSS), as NSS in patients with large locally advanced or centrally located tumours can be challenging, and TKI therapy might result in a reduction of primary tumour burden and increase the feasibility of NSS.
PATIENTS AND METHODS
This was a multicentre retrospective review and prospective pilot study of patients undergoing neoadjuvant sunitinib before planned NSS from February 2006 to February 2009. All patients underwent confirmatory biopsy for clear cell renal cell carcinoma. Patients received two 28-day cycles of sunitinib before NSS. Demographics/tumour characteristics, tumour response (by the Response Evaluation Criteria In Solid Tumors), outcomes and complications were analysed.
Twelve patients (seven men and five women; mean age 60.1 years, tumours on 14 renal units) were given TKI before NSS for imperative indications. The mean pretreatment tumour diameter was 7.1 cm; all patients had a decrease in size of the primary tumour after TKI, with a mean reduction in maximum diameter of 1.5 cm (21.1%). Four of 14 and 10 of 14 primary tumours had a partial response and stable disease after TKI. NSS was achievable in all 14 kidneys. Four patients had a concurrent metastasectomy. The mean warm ischaemia time was 22.5 min; postoperative dialysis was not required in any patients. Final pathology revealed negative tumour margins in all 14 tumours. The mean creatinine and estimated glomerular filtration rate (before/after NSS) were 1.34/1.40 mg/dL (P = 0.431) and 57.7/53.4 mL/min/1.73 m2 (P = 0.475), respectively. At a mean follow-up of 23.9 months, 10 of the 12 patients were alive, one died from metastatic RCC and none required dialysis. Three of the 14 renal units developed delayed urinary leaks, all in patients who also received postoperative sunitinib. All leaks resolved with conservative measures.
Neoadjuvant TKI followed by NSS is safe and feasible, with all patients achieving a reduction in maximum tumour diameter, and with NSS being achievable with negative margins and with no requirement for postoperative dialysis. Further investigation is required.
tyrosine kinase inhibitor
clear cell RCC
body mass index
- ECOG PS
Eastern Cooperative Oncology Group performance status
The incidence of kidney cancer is increasing; in 2009 it is estimated that 57 760 new cases of kidney cancer will be diagnosed, and 12 980 people will die from the disease in the USA . Despite a significant stage migration in RCC toward smaller, lower-stage lesions, the mortality rate from kidney cancer has remained relatively constant [2,3].
While surgical excision of RCC is the standard of care and results in excellent outcomes, an increased understanding of diminished renal function and its influence on cardiovascular morbidity and mortality has prompted the desire to preserve as much normal renal parenchyma as possible [4,5]. Nephron-sparing surgery (NSS) has become the standard for treating the clinical T1 mass, with equivalent oncological efficacy and superior renal functional outcomes [4–9]. However, NSS can be challenging in large tumours, a central location, with local invasion of surrounding structures, hilar lymphadenopathy or tumour thrombus. New strategies must be explored to reliably extract these complex tumours with good oncological outcomes, while preserving viable renal parenchyma and minimizing short and long-term morbidities.
Sunitinib malate (SutentTM; Pfizer, New York, NY, USA), a multitargeted tyrosine kinase inhibitor (TKI), has been shown to improve progression-free survival in patients with metastatic RCC (mRCC) . Although few data are available on the effect of TKI therapy when the primary tumour is not resected, 10% of the patients in the initial phase III trial comparing sunitinib to interferon had their tumour left in situ and still had improved tumour-specific survival . Since then some small series reported a reduction of tumour burden and perhaps improved technical feasibility with neoadjuvant administration of sunitinib before consolidating nephrectomy [11–14].
Patients with chronic renal insufficiency in the presence of bilateral bulky renal tumours, and those with metastatic/locally advanced disease in a solitary kidney or compromised renal function, might benefit from neoadjuvant TKI before NSS to reduce the primary tumour burden. In this combination of a retrospective review and a prospective pilot study, we assessed the effect of neoadjuvant sunitinib on the primary neoplasm, and assessed the technical feasibility and early outcomes of NSS after neoadjuvant TKI therapy.
PATIENTS AND METHODS
After obtaining institutional review board approval, this multi-institutional retrospective review and prospective pilot series included all patients who were considered for neoadjuvant sunitinib therapy followed by NSS between February 2006 and February 2009. Patients were considered eligible for neoadjuvant therapy followed by NSS if they were aged ≥18 years with evidence of mRCC, with renal insufficiency or a solitary kidney/bilateral renal tumours, or with bilateral renal tumours in the setting of locally advanced disease, or in locally advanced disease in a solitary kidney. Patients underwent a complete staging protocol including chest/abdominal/pelvic CT and when appropriate, brain imaging and bone scintigraphy. In all patients histological confirmation of clear cell RCC (cc-RCC) with percutaneous renal biopsy was obtained before initiating neoadjuvant therapy. The TNM stage was assessed as defined by the American Joint committee on Cancer 2002 classification , and pathology/Fuhrman histological grade was determined according to 2004 WHO criteria . Patients were excluded if they refused renal biopsy or the results of the biopsy indicated a lesion other then cc-RCC.
Sunitinib was administered orally at 50 mg once daily, in 6-week cycles consisting of 4 weeks of treatment followed by 2 weeks without treatment. Repeat imaging was obtained before surgical intervention to determine the tumour response to sunitinib (Fig. 1). The clinical response (complete response, CR; partial response, PR; stable disease; and progressive disease, PD) of primary and metastatic tumour burden was assessed according to Response Evaluation Criteria in Solid Tumors using CT/MRI after each cycle of treatment . Responses were assessed by treating physicians. A CR represented resolution of all lesions; a PR represented a ≥30% decrease in the sum of target lesions; PD represented a ≥20% increase in target lesion sum, non-target lesion progression, or appearance of new lesions; and stable disease represented neither a decrease for PR nor increase for PD .
Patients with a PR or stable disease at re-imaging after two cycles of treatment had surgery. If disease progression and metastatic disease were noted at re-imaging, further systemic therapy was indicated. If there was PD in the setting of localized disease, surgery was indicated. Surgery was performed at the end of a minimum 2-week ‘washout’ period with no treatment. All NSS was performed by one surgeon (I.H.D.), but the surgical technique differed depending on both the primary tumour size and location, as well as any concurrent resectable metastatic disease . Concurrent metastasectomy was done when deemed to be reasonable under a single anaesthetic. Patients with residual metastatic disease after NSS resumed sunitinib. Patients with no metastatic disease did not receive further sunitinib therapy. Some patients with a residual metastatic burden, inaccessible at the time of the initial NSS, had a subsequent metastasectomy after surgery and further systemic therapy. Patients with bilateral concurrent renal masses, when deemed feasible under a single anaesthetic, had concurrent bilateral NSS.
Data entered and reviewed included demographic factors, disease characteristics, response rates, perioperative outcomes and complications, and renal functional outcomes and survival rates. Demographic outcomes reviewed included: age, sex, race, body mass index (BMI), and Eastern Cooperative Oncology Group performance status (ECOG PS). Disease characteristics included maximum primary tumour diameter, TNM stage and tumour location. The overall objective response rate was defined as the proportion of patients with a confirmed CR or PR. Primary tumour shrinkage and adverse events associated with sunitinib administration were also assessed. Perioperative outcomes analysed included estimated blood loss, ischaemia time, requirement for dialysis or blood transfusion, and complications. Overall survival was taken as the proportion of patients who were alive until the last follow-up after treatment with neoadjuvant sunitinib. Disease-specific survival was the proportion of patients who had not died from mRCC. Renal functional outcomes analysed included serum creatinine level and estimated GFR (eGFR) calculated using the Modification of Diet in Renal Disease equation . Renal insufficiency was defined as an eGFR of <60 mL/min/1.73 m2. Renal functional outcomes before and after NSS were compared using a two-tailed t-test, with P < 0.05 taken to indicate statistical significance.
Tables 1 and 2 show the patient demographics, and disease and tumour characteristics, respectively; 12 patients (seven men and five women) were considered for neoadjuvant sunitinib followed by NSS. All tumours had tumour abutment/displacement of the collecting system, and 10 of 14 tumours had hilar vascular abutment or invasion.
|Variable||No. of patients/kidneys|
|Mean age, years||60.1|
|Median (sd) BMI, kg/m2||30.5 (29.9)|
|Mean ECOG PS||0.86|
|Tumour location (pole)|
|Indication for NSS|
|Bilateral renal tumours||2|
|Primary tumour stage before treatment|
|Primary tumour with:|
|Hilar vascular invasion/abutment||10|
|Proximity to vital structures||5|
|Mean (range) max tumour diameter, cm; before treatment||7.10 (2.4–14.5)|
|Patient||Age, years||Sex||Primary tumour size, cm||Clinical TNM stage before TKI||Sites of metastases||Indication for NSS||Primary tumour|
|Location||Size after TKI, cm||Shrinkage, %|
|1||55.9||M||7.8||T2N0M1||Lung, omentum||SK||UP, anterior||5.8||25.6|
|2||61.8||F||2.6||T1aN0M1||Lung, ipsilateral adrenal||SK, CKD||MP, central/endophytic||1.7||34.6|
|3||60.2||F||4.1||T1bN0M1||Lung||SK, CKD||MP, central/endophytic||2.2||46.3|
|5||52.1||F||7.3||T3bN0M0||SK, CKD||MP, central, renal vein thrombus||5.4||26|
|6||69.9||M||6.4/5.3||T1bN0M0/T1bN0M0||Bilateral CKD||MP, endophytic/MP, central||4.2/4.4||34.4/17|
|9||74.7||M||8.3||T2N0M0||SK, CKD||MP, central||5.1||38.6|
|10||68.7||F||4.3/5.6||T1bN0M0/T1bN0M0||Bilateral, CKD||UP, anterior/MP, central||4.1/5.3||4.7/5.4|
|11||57.1||M||6.9||T1bN0M1||Bilateral adrenal, thyroid||CKD||MP, central||6.2||10.1|
Primary outcomes directly related to the use of neoadjuvant TKI therapy are shown in Table 3. All patients completed sunitinib; after two cycles of sunitinib, there were CRs in no primary tumours, a PR in four and stable disease in 10 patients, with PD in none. The mean primary tumour size before and after sunitinib therapy was 7.10 and 5.60 cm, respectively, a mean reduction of 1.5 cm (21.1%). Of the five patients with mRCC, there were no CRs, two PRs, three with stable disease and none with PD. The two patients with PR had PRs in both their primary tumours and metastatic lesions. Of the side-effects, fatigue (9/12) and diarrhoea (4/12) were the most commonly reported.
|Variable, mean or n||No. of patients/kidneys (12/14)|
|Response of primary tumours:|
|Primary tumours with shrinkage||14|
|Primary tumour diameter before/after TKI, cm||7.10/5.60|
|Decrease in primary tumour maximum diameter (range), cm||1.5 (0.2–3.2)|
|% decrease in primary tumour (range)||21.1 (3.2–45)|
|Response of metastases|
|Metastases with shrinkage||5|
Table 4 shows the outcomes and complications. All patients in the study had successful NSS and two had bilateral concurrent NSS. All patients had cc-RCC with negative tumour margins on final pathological analysis. The mean warm ischaemia time was 22.5 min, the mean estimated blood loss was 318.2 mL and two of the 12 patients received a blood transfusion.
|Variable, mean or n||No. of patients/kidneys (12/14)|
|Number of kidneys treated by NSS||14|
|Warm ischaemia time, min||22.5|
|Estimated blood loss, mL||318.2|
|Bilateral partial nephrectomy||2|
|Patients requiring perioperative or postoperative dialysis||0|
|eGFR, mL/min/1.73 m2 (P)||57.7/53.4 (0.475)|
|Serum creatinine, mg/dL (P)||1.34/1.40 (0.431)|
|Alive with recurrence||1|
|Died from PD||1|
At a mean follow-up of 23.9 months the overall survival rate was 10/12, with one death from metastatic disease and another following a myocardial infarction in a patient who was clinically disease-free. The disease-free survival rate for all patients was 10/12, with all seven with nonmetastatic disease being disease-free at the last follow-up. Four of five patients with metastatic disease had a concurrent metastasectomy (two adrenalectomy, one omentectomy, distal pancreatectomy). The disease-free survival rate at the last follow-up was three of five, as one had progressed and died from mRCC 15 months later, and another developed a recurrence 51 months after the initial diagnosis of disease.
To date, no patients have required dialysis in the acute postoperative setting or during the follow-up. The mean creatinine levels and eGFR are shown in Table 4. Three of the 14 renal units treated with NSS developed delayed urinary leaks, all in patients with metastatic disease who resumed sunitinib after surgery. All leaks resolved with conservative measures (percutaneous perinephric drainage, ureteric stenting) and with no need for further intervention. In two patients sunitinib therapy was temporarily discontinued until clinical resolution of the leak, and for 2 and 4 weeks thereafter, and in the other patient, sunitinib therapy was not discontinued, and the leak ultimately resolved while on sunitinib. In the two patients in whom sunitinib was discontinued, the leaks lasted for 19 and 28 days, and in the patient in whom sunitinib was continued, the leak ultimately resolved after 73 days.
Primary treatment for RCC consists of surgical excision of the neoplasm, either with partial or radical nephrectomy, both of which result in excellent cancer-specific survival for localized disease [20,21]. Despite increased detection of RCC, ≈25% of patients present with locally advanced or mRCC, and 20–30% of patients who initially present with local disease progress to mRCC . There were no effective systemic therapies targeted at molecular pathways for mRCC until recently. The initial study showing the superiority of sunitinib over interferon-α for treating mRCC included 75 patients who had not had a previous nephrectomy .
Recent studies reported stability or reduction of the primary tumour when patients were placed on TKI therapy [11–14]. van der Velt et al.  examined 17 patients with mRCC with primary tumour in situ who received sunitinib; 16 (84%) had PR or stable disease, with a median reduction in tumour volume of 31%. In three patients the primary tumour became surgically resectable only after neoadjuvant therapy. Thomas et al.  reviewed 19 patients with locally advanced and/or mRCC deemed unsuitable for initial nephrectomy and treated with sunitinib. Most patients had either PR or stable disease, and there was primary tumour shrinkage in eight (42%), with a mean (range) decrease in primary tumour size of 24 (2–46)%. Three patients had a reduction of primary tumour size which facilitated subsequent nephrectomy. Shuch et al.  reviewed four patients in whom neoadjuvant TKI altered tumour biology and/or surgical management, including regression of inferior vena cava tumour thrombus, reduction of tumour burden in a solitary kidney to facilitate NSS, and reduction of lymphadenopathy to facilitate retroperitoneal lymph node dissection. Amin et al.  identified nine patients with locally advanced or mRCC treated with TKI before nephrectomy. They found that TKI therapy resulted in varied primary tumour response (reduction of 0.8–54%, mean 12.9%) and noted that neoadjuvant sunitinib had no negative effect on surgical outcomes. The present data showing a PR in five of 14 primary tumours, with a 21.1% reduction in primary tumour maximum diameter (Table 3) are consistent with these previous reports [10–14,22].
Our perioperative outcomes of a median warm ischaemia times of 22.5 min, estimated blood of 318 mL, and lack of requirement of perioperative dialysis (Table 4) show the feasibility and safety or NSS after TKI therapy, and are consistent with published large series [6,7,23]. While the present study had few patients and reflects a nascent and emerging experience of NSS after TKI, we believe our findings are significant, showing the efficacy (negative margins, excellent preservation of short-term renal function, lack of progression to end-stage renal disease, Table 3) in patients with advanced disease, imperative indications and with significant tumour burden (Tables 1,2).
Three kidneys (of 14 renal units undergoing NSS) in three patients developed delayed urinary leaks (Table 4). All had a bulky tumour burden (one T2, two T1b tumours) requiring extensive collecting-system reconstruction, all significant risk factors (in addition to imperative indications) for urinary leak and consistent with previous reports [24–26]. Also, all three patients had metastatic disease and resumed sunitinib 4 weeks after surgery. While conservative measures led to resolution of fistulae in all patients, in the two in whom sunitinib was temporarily discontinued the urinary leaks resolved within a month, while the patient who was kept on sunitinib had a persistent leak for >2 months before resolution. Angiogenesis is a necessary step in wound healing, and TKI therapy might impair revascularization, wound strength and epithelialization [27–29], all factors which might affect healing after NSS. Although some authors have noted that TKIs can cause no significant increase in surgical morbidity for patients undergoing radical nephrectomy , this is the first study to specifically address NSS. Additional studies are needed to clarify the duration of administration, and optimal timing of cessation and re-institution of TKI after surgery. Caution should be exercised in this setting, especially with coexisting metastatic disease that might require sustained TKI therapy.
We restricted offering neoadjuvant sunitinib to patients with confirmed cc-RCC in accordance with previous investigations which based selection criteria on potential susceptibility of cc-RCC to targeted agents, due to its specific genetic abnormalities. Indeed, papillary and chromophobe histological subtypes might not respond to sunitinib or sorafenib as robustly as cc-RCC . Sunitinib was chosen in this series because it was shown to be well-tolerated and increase overall survival in patients with mRCC . However, it is not yet known if this is the agent that will result in the largest reduction in tumour volume. The emergence of several novel biological agents acting on multiple molecular targets has resulted in many unanswered questions about efficacy, combination of agents, duration, dose and timing of therapy .
Administration of neoadjuvant sunitinib adds economic and medical burden, as shown by the toxicities outlined in Table 2. However, no patients required discontinuation of their therapy. NSS is under-used for treating RCC, and while exact causes have not been fully elucidated, increasing the ease with which laparoscopic or open NSS can be performed might increase their use . Neoadjuvant TKI therapy could have an emerging role to shrink bulky tumours before NSS and improve the ease with which NSS can be performed. Also, shrinking the tumour before resection might allow the preservation of a greater volume of normal renal parenchyma.
While the primary goal in conducting this analysis was to investigate the feasibility of NSS after TKI therapy (which was confirmed by the reduction of the primary tumour, complete resection, lack of dialysis requirement, and excellent renal functional preservation) for imperative indication in bulky and/or metastatic disease, our analysis is nonetheless limited by the few patients, limited follow-up, mix of retrospective and prospective investigation, and heterogeneous indication. Without a comparative control group undergoing NSS for imperative indications in bulky and/or mRCC, the benefits of neoadjuvant treatment are unclear. At this point, neoadjuvant TKI must be considered investigational and should be considered only when necessary (bulky metastatic disease requiring immediate systemic stabilization, imperative indications where NSS would be particularly morbid or impossible). Further prospective and randomized study is necessary to elucidate the role of TKIs before NSS for imperative indications.
In conclusion, neoadjuvant sunitinib can be administered before NSS, safely, effectively and reproducibly, with no discernible negative effect on outcomes. With an overall modest reduction in tumour burden, despite an imperative indication for NSS, no patients in this series required dialysis. At this point, this approach is investigational and should be considered only in imperative circumstances in the setting of advanced disease. Further studies are needed to help delineate the appropriateness of neoadjuvant TKI before NSS for imperative indications.
CONFLICT OF INTEREST
Frederick Millard is a study investigator for Pfizer.