Neoadjuvant therapy of renal cell carcinoma: A novel treatment option in the era of targeted therapy?
Andres Jan Schrader M.D., Ph.D., Department of Urology, Ulm University Medical Center, Prittwitzstrasse 43, D-89075 Ulm, Germany. Email: email@example.com
The study was carried out to evaluate the effectiveness, toxicity and optimal duration of neoadjuvant therapy for patients with organ-confined or locally advanced renal cell carcinoma in the era of targeted agents. A literature review was carried out using Medline/Pubmed articles, as well as congress reports from the last five American Society of Clinical Oncology, American Urological Association and European Association of Urology Annual Meetings. Neoadjuvant targeted therapy is feasible and shows toxicity similar to that seen in a palliative setting. Most studies recommend an application for 2–4 months. The current data situation is best for sunitinib. Surgery can apparently be carried out the day right after discontinuing the drug. However, even sunitinib leads to only a mean 10% decrease in primary tumor size, and one-quarter to one-fifth of all patients show local tumor progression during treatment. Few patients (approximately 12%) with a vena cava tumor thrombus achieve a significant decrease in its level under neoadjuvant therapy; here too, progression is observed in a significant number of cases. Even the new targeted agents show limited effectiveness in achieving relevant remissions of the primary tumor. Furthermore, tumor progression is seen in a significant percentage of patients during neoadjuvant therapy. Thus, even today in the era of targeted agents, a neoadjuvant approach should only be made in patients with localized or locally advanced renal cell carcinoma, which primarily seem to be absolutely inaccessible by (partial) nephrectomy.
Abbreviations & Acronyms
- IQR =
- IVC =
inferior vena cava
- NA =
- NSS =
- RCC =
renal cell carcinoma
- RECIST =
response evaluation criteria in solid tumors
- TKI =
tyrosine kinase inhibitors
In oncology, the term neoadjuvant therapy refers to a type of treatment used to improve the outcome of potentially curative management – usually definitive surgery – by (previous) tumor volume reduction.1 Thus, in the strict sense of the word, neoadjuvant therapy is not used to designate primary tumor downsizing in a palliative metastatic setting, even though the aim in both cases is to reduce the (primary) tumor mass.
The neoadjuvant approach had no status in the era of cytokine-based systemic therapy of RCC. These treatment regimens were considerably less effective in the management of metastases, as long as the primary tumor remained in situ;2 accordingly, a significant reduction of primary tumor size was not observed under cytokine-based therapy. Today, in the era of targeted therapy, attention has again focused on the role of neoadjuvant treatment strategies.3–5 Possible or conceivable indications for neoadjuvant use of the new agents include: (i) locally advanced tumors to facilitate surgery; (ii) large (bilateral) tumors to enable a nephron-sparing procedure; and (iii) vena cava thrombus to achieve downsizing and thus enable a simpler surgical technique associated with lower morbidity.
The present review article attempts to evaluate potential indications for the new agents, taking into consideration the balance between toxicity and effectiveness. The article also examines the following: (i) whether neoadjuvant systemic therapy complicates the intra- and/or postoperative course; (ii) how long it should continue and when potentially curative surgery is best carried out; and (iii) what drug currently seems most promising for neoadjuvant therapy of RCC.
Neoadjuvant therapy to downsize a large or locally advanced RCC and thus facilitate surgery
In recent months and years, a number of studies in the literature have described successful downsizing of primary tumors. Gorin et al., for example, reported the case of a 49-year-old man with bilateral clear cell RCC that the authors regarded as too large for NSS.6 Four cycles of neoadjuvant sunitinib therapy achieved a 34.7–54.9% reduction of the tumors, and the patient could subsequently undergo bilateral partial nephrectomy (Table 1). Silberstein et al. recently published a multicenter retrospective review of 12 patients undergoing neoadjuvant (n = 7) or palliative presurgical (n = 5) sunitinib for 2 months before NSS.7 The mean primary tumor diameter before and after sunitinib was 7.1 and 5.6 cm, respectively (mean reduction of 21.1%). Four patients had a partial response, none experienced progressive disease and all 14 tumors could be treated by partial nephrectomy. Similar cases were reported by Ansari et al.15 However, not all studies show such an impressive effect of the novel targeted agents on the primary tumor. Hellenthal et al. prospectively treated 20 patients with sunitinib, 16 neoadjuvantly and four presurgically in a cytoreductive/palliative setting.8 Of the 20 patients, 17 showed a mean 11.8% decrease in primary tumor size (growth rate under sunitinib −27% to +11%). Eight patients in this group could subsequently undergo partial nephrectomy. Comparison with a control group (n = 97) showed no increase in perioperative complications.
Table 1. Efficacy and safety of neoadjuvant and presurgical targeted therapy in patients with advanced disease
|Gorin et al. (2012)6||Sunitinib, 4 cycles, n = 1||57.9% primary tumor diameter reduction prior to NSS||NA|
|Silberstein et al. (2010)7||Sunitinib, 2 cycles, n = 12||21.1% (3.2–45%) decrease in primary tumor diameter||3 patients developed delayed urinary leaks after NSS|
|Hellenthal et al. (2010)8||Sunitinib, 2 cycles, n = 20||11.8% mean decrease in primary tumor diameter; 3/20 progressed up to 23%||no specific complications|
|Bex et al. (2009)9||Sunitinib, 1–8 cycles, n = 10||10% mean decrease in primary tumor diameter; 3/10 progressed up to 11%||NA|
|Powles et al. (2011)10||Sunitinib, 2–3 cycles, n = 52||Median 12% (8 to 35%) decrease in primary tumor size||16% impaired wound healing, marked sunitinib-induced intra- and perirenal fibrosis|
|Cowey et al. (2010)11||Sorafenib, 1–2 cycles, n = 30||Median 9.6% decrease in primary tumor size (range, −40 to +16%)||no specific complications|
|Abel et al. (2011)12||Sunitinib, n = 75||Median percentage change or primary tumor diameter: −10.2% (−21.1 to −2.8%)||NA|
|Abel et al. (2011)12||Bevacizumab, n = 25||Median percentage change or primary tumor diameter: 0.1% (−4.2 to −4.6%)||NA|
|Abel et al. (2011)12||Sorafenib, n = 16||Median percentage change or primary tumor diameter: −6.0% (−12.3 to 0.4%)||NA|
|Abel et al. (2011)12||Temsirolimus, n = 16||Median percentage change or primary tumor diameter: −4.0% (−8.6 to −0.5%)||NA|
|Jonasch et al. (2009)13||Bevacizumab (n = 27) or Bevacizumab + erlotinib (n = 23), 2 cycles||52% of patients showed some degree of primary tumor reduction, 23% had ≥10% reduction in diameter||No specific complications|
|Harshman et al. (2011)14||Sunitinib or sorafenib, n = 11||6/11 primary tumor shrinkage, 3/11 with significant primary tumor progression prior to surgery (12 to 55%)||Marked TKI-induced intra- and perirenal fibrosis, otherwise no specific complications|
Bex et al. evaluated the effect of sunitinib on large primary tumors that had already metastasized and were classified by the authors as inoperable.9 All 10 patients had surgery-limiting tumor sites, including liver invasion. They were treated with sunitinib, which led to a median 10% shrinkage of the primary tumor (growth −20 to +11%); no primary tumor showed partial remission. An 11% median size reduction was observed at the surgery-limiting tumor sites (−20% to +46%). The metastases of the patients involved responded better to sunitinib. A 22% median size reduction was documented here (−100% to +50%), and three of these patients showed partial remission of metastatic sites according to RECIST criteria. Interestingly, this study also showed that the response of the primary tumor and metastases can differ markedly in the same patient. In the study by Bex et al., just three of the 10 patients could ultimately undergo surgery after upfront systemic therapy.9 Significant primary tumor shrinkage was seen after 2–4 months, if at all. The authors concluded that primary tumor downsizing can only be recommended in selected patients; that is, those deemed absolutely inoperable.
Powles et al. prospectively investigated the effectiveness of preoperative sunitinib in patients with metastatic RCC; that is, in a palliative setting.10 A total of 52 patients received two or three cycles of sunitinib before primary tumor surgery. All patients suffered from clear cell RCC; the median tumor diameter was 9.45 cm. Six patients showed partial remission of the primary tumor (i.e. 30% shrinkage). This study reported a median 12% (8–35%) decrease in primary tumor size. The effectiveness, toxicity and perioperative morbidity did not correlate with the number of preoperative sunitinib cycles. This study also showed once again the greater effect of targeted therapy on the metastases than on the primary tumor in the same patient. The partial remission rate under sunitinib was 27% for metastases, but just 6% for the primary tumor. Ultimately, 37 of the 53 (70%) patients in the study by Powles et al. underwent surgery after sunitinib pretreatment.10
Although surgical tumor resection after targeted therapy is feasible, with low morbidity in most cases, significant complications can occur as a potential consequence of compromised tissue or vascular damage.16 Margulis et al. even reported a complication rate of up to 39% for cytoreductive nephrectomy after targeted therapy.17 In accordance, Chapin et al., who evaluated the safety of presurgical targeted therapy in the setting of metastatic RCC concluded that patients who underwent surgery after presurgical TKI therapy (n = 70) had an increased risk for wound-related complications (HR 4.14, 95% CI 1.6–10.6; P < 0.001) and multiple complications (P = 0.013).18 However, overall surgical complications and the risk of severe complications (Clavien ≥3) were not greater after presurgical targeted therapy in comparison with upfront cytoreductive surgery (n = 103). Powles et al. did not report a distinctly higher complication rate due as a result of the pretreatment, even though they also observed impaired wound healing in 16% of all cases.10 Furthermore, the authors mentioned difficult surgical conditions caused by sometimes marked sunitinib-induced intra- and perirenal fibrosis. Furthermore, it appeared to be irrelevant whether sunitinib was discontinued 1 day or 14 days before surgery.10 Half of all patients showed largely vital tumor components in the nephrectomy specimen; just 49% had more than 50% necrotic components in the resection material, which again points to a limited effect of the agent on the primary tumor.10 Wood et al. also compared the safety of presurgical targeted therapy and compared a group of 44 pretreated patients (bevacizumab, sunitinib, sorafenib) with 58 matched patients who underwent initial surgical resection.19 They found no significant differences between the study groups in the type and length of surgical procedure, extent of lymph node dissection, estimated blood loss, incidence of blood transfusions, amount of blood products given, or the length of hospital stay.
Sorafenib can also be given before surgery. In a study by Cowey et al., 30 RCC patients received sorafenib for a median of 33 days before nephrectomy: 17 in a neoadjuvant setting and 13 in a palliative situation before cytoreductive surgery.11 A median tumor shrinkage of 9.6% was observed here (growth −40% to +16%). The authors did not find sorafenib to be associated with increased intra- or postoperative complications. All 30 patients were able to undergo surgery after this preoperative systemic therapy.
A study recently published by Abel et al. retrospectively analyzed 168 patients who received systemic targeted therapy in Wisconsin or Texas for a primary tumor in situ (sunitinib n = 75; bevacizumab n = 25; bevacizumab + erlotinib n = 26; sorafenib n = 16; temsironiums n = 16; others n = 10).12 Of those patients, 4% were in a neoadjuvant setting; 96% already had metastases or refused surgery. This study had a median follow up of 15 months, and the median primary tumor diameter was 9.6 cm (IQR 6–20 cm). A median primary tumor shrinkage of 7.1% was seen in this large patient population. The median time to maximum remission was 62 days. The largest subgroup in this patient population described by Abel et al. received sunitinib (n = 75), which resulted in a median 10.2% decrease in primary tumor size (IQR −21.1% to −2.8%).12 The second largest subgroup received bevacizumab (n = 25). No significant tumor shrinkage was observed here (median +0.1%; IQR −4.2% to +4.6%). Just 6% of all 168 patients achieved partial remission according to RECIST criteria. A tumor size regression of at least 10% was seen in 38% of the patients. However, the primary tumor was progressive, even under treatment in approximately one-quarter of the patients.
Harshman et al. recently presented a retrospective analysis of surgical outcomes and complications in 11 patients pretreated with TKI: two in a neoadjuvant and nine in a palliative setting.14 They had a median primary tumor diameter of 11 cm (6.7–24.2 cm), a median TKI treatment duration of 4 months and a median 2-week TKI-free interval before surgery. Just six of the 11 patients included in this study showed tumor shrinkage under sorafenib or sunitinib treatment. Three patients were significantly progressive under treatment, primary tumor size progressing by 39% in one patient and even by 55% in another one. Harshman et al. found no difference between sunitinib and sorafenib treatment.14 They also observed that TKI-pretreated patients developed adhesions in the surgical field more often than controls during the same time period. Peri- and intrarenal fibrosis occurred more often (86 vs 58%) and in a more severe form (median, grade III vs grade I). Pretreated patients did not differ from controls in any other way and did not have a higher complication rate.
Neoadjuvant therapy in patients with a vena cava tumor thrombus
Karakiewicz et al. were the first to describe a significant reduction of the thrombus extension in the inferior vena cava after sunitinib therapy, enabling an easier surgical procedure.20 Other reports of individual cases followed, showing similar results5,21–24 (Table 2). However, neoadjuvant systemic therapy was not always successful in patients with tumor thrombi in the inferior vena cava.25,26
Table 2. Effect of targeted drugs on the tumor thrombus level in patients with IVC RCC thrombi
|Karakiewicz et al. (2008)20||Sunitinib, 3 months (n = 1)||Level VI→II thrombus|
|Di Silverio et al. (2008)21||Sorafenib, 6 months (n = 1)||Level II→I thrombus, 90% necrotic tissue|
|Shuch et al. (2008)5||Sunitinib, 6 months (n = 1)||Level II→I thrombus, regression of pulmonary and mediastinal metastasis|
|Harshman et al. (2009)23||Sunitinib, 4 months (n = 1)||Level II→I thrombus|
|Robert et al. (2009)24||Sunitinib, 6 months (n = 1)||Level II/III thrombus → complete IVC thrombus necrosis, 35% remission of the primary tumor|
|Kondo et al. (2010)22||Sorafenib, 2.5 months (n = 1)||Level III→II thrombus|
|Bex et al. (2010)25||Sunitinib, 2 months (n = 1)||Level II→IV thrombus|
|Bex et al. (2010)25||Sunitinib, 3 months (n = 1)||Level 0→II thrombus|
|Cost et al. (2011)26||Sunitinib (n = 12), bevacizumab (n = 9), temsirolimus (n = 3), sorafenib (n = 1)||Increase in level (II→III), n = 1; stable thrombi, n = 21; decrease in level (IV→III, III→II, II→0), n = 3; median change in thrombus height: 0 cm (−8.5 to +5 cm)|
In 2011, Cost et al. published an interesting (and for the first time, larger) retrospective large study examining the ability of targeted agents to effectively downsize a vena cava tumor thrombus.26 The 25 patients included were treated in Dallas or Houston. The thrombus level according to Belgrano et al. was II in 18 patients, III in five patients and IV in two patients.27 Sunitinib was applied in 12 cases, bevacizumab in nine cases, temsirolimus in three cases and sorafenib in one case. Patients received a median of two to three cycles of the targeted therapy. The thrombus level remained unchanged in 21 patients (84%) and increased under treatment in one patient (4%; I to III). Three patients (12%) achieved a lower thrombus level (IV to III, III to II, and II to 0). Accordingly, the thrombus height remained constant in seven patients (28%), increased in seven patients (28%) and decreased in 11 patients (44%). The median change in thrombus height was 0 cm. All three decreases in thrombus level were seen in the group treated with sunitinib. Thrombus size was reduced in 58% of the patients treated with sunitinib, but in just 31% of those who received other agents. Cost et al. also evaluated primary tumor size, and found an increase in 10 patients (40%), a decrease in 12 (48%) and no change in three (12%).26 Just nine of the 25 patients ultimately underwent surgical resection and thrombectomy after initial systemic therapy with the various targeted agents. The authors concluded that the currently available targeted agents generally have a limited cytoreductive effect on a tumor thrombus and that a high percentage of patients might even progress under targeted therapy.
Neoadjuvant targeted therapy in patients with organ-confined or locally advanced RCC is feasible and shows toxicity similar to that seen in a palliative setting. Surgery after neoadjuvant targeted therapy is safe, but sometimes complicated by increased peri- and intrarenal fibrosis. If neoadjuvant therapy is applied, it should be given for approximately 2–4 months. Sunitinib is currently the most extensively investigated agent and – as a result of its tumor-shrinking effect – probably the most suitable agent for neoadjuvant therapy. However, as neoadjuvant targeted therapy can also result in progression of a local tumor or tumor thrombus (in about one-quarter or one-fifth of all patients), it should only be considered in exceptional cases or in patients deemed absolutely inoperable. In addition, targeted therapy in a palliative setting usually has a less marked effect on the primary tumor and the tumor thrombus than on metastases in the same patient.
Conflict of interest