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Keywords:

  • neoadjuvant;
  • tyrosine kinase inhibitors;
  • sunitinib;
  • locally advanced;
  • kidney cancer;
  • RCC

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. POSSIBLE ROLE WITH LND, RENAL FOSSA RECURRENCE AND METASTASTECTOMY
  8. CONFLICT OF INTEREST
  9. REFERENCES

OBJECTIVE

To evaluate our early experience with neoadjuvant therapy (sunitinib or sorafenib) in advanced renal cell carcinoma (RCC), to explore the effect on both tumour biology and potential for downstaging advanced tumours, as systemic therapy for RCC has historically resulted in little if any primary tumour response, but recent experience with targeted therapy suggests otherwise.

PATIENTS AND METHODS

The preliminary experience with neoadjuvant therapy for the surgical management of RCC was reviewed at two large referral centres. Several unique patients were identified who had a novel response to systemic therapy that altered the surgical strategy.

RESULTS

Four patients who had targeted therapy before surgery are described and in whom there were effects on tumour biology not seen previously with chemotherapy and cytokine therapy. The selected patients who had neoadjuvant targeted therapy had shrinkage of a tumour thrombus in the inferior vena cava, nodal involvement, renal fossa recurrence and tumour within a solitary kidney.

CONCLUSIONS

The introduction of new molecular agents has revolutionized the treatment of patients with metastatic RCC. Responses to targeted therapy within the primary tumour, tumour thrombus, renal fossa recurrence, and lymph node metastases are novel findings not seen during treatment with immunotherapeutic-based strategies. This might be a signal for urological surgeons to re-evaluate the paradigm for the surgical management of advanced RCC. Potential applications are presented to encourage further investigations with targeted therapy in the neoadjuvant setting.


Abbreviations
IVC

inferior vena cava

(P)(R)(C)N

(partial) (radical) (cytoreductive) nephrectomy

NSS

nephron-sparing surgery

LND

lymph node dissection.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. POSSIBLE ROLE WITH LND, RENAL FOSSA RECURRENCE AND METASTASTECTOMY
  8. CONFLICT OF INTEREST
  9. REFERENCES

Neoadjuvant therapy is commonly used to downstage locally advanced tumours and to improve survival. In the field of kidney cancer, neoadjuvant studies have been limited during the cytokine era due to poor responses in the primary tumour and to significant toxicity associated with treatment. Furthermore, cytoreductive nephrectomy (CN) followed by interferon-α improved survival in patients with metastatic kidney cancer, shaping the current approach of surgery before systemic therapy [1,2].

The introduction of oral targeted therapies has revolutionized the treatment approach to metastatic RCC. Compared with cytokine-based immunotherapy, targeted therapy has higher response rates in primary and metastatic sites, and a favourable safety profile. These findings suggest that the concept of neoadjuvant therapy in RCC should be revisited, particularly in patients deemed to have unresectable disease. Furthermore, neoadjuvant therapy might extend beyond these uses to patients with localized or advanced disease. We reviewed recent experiences at two large academic institutions and selected several patients who had neoadjuvant targeted therapy, to highlight and discuss the potential applications of targeted therapy within the surgical management of RCC.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. POSSIBLE ROLE WITH LND, RENAL FOSSA RECURRENCE AND METASTASTECTOMY
  8. CONFLICT OF INTEREST
  9. REFERENCES

Unique patients were identified in whom oral neoadjuvant targeted therapy (sunitinib, sorafenib) had altered the tumour biology and/or surgical management, treated from 2006 to 2007 at the author’s institutions. Four of these patients were reviewed retrospectively, each being analysed for the type/duration of therapy, toxicity, response of the tumour and/or associated lymphadenopathy or tumour thrombus, surgical approach, intraoperative findings, pathology and outcome.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. POSSIBLE ROLE WITH LND, RENAL FOSSA RECURRENCE AND METASTASTECTOMY
  8. CONFLICT OF INTEREST
  9. REFERENCES

In patient no. 1 the neoadjuvant sunitinib resulted in a decrease in the extent of tumour thrombus. This 59-year-old man presented with haemoptysis and had a 7.5-cm right renal mass with an associated level II tumour thrombus (Fig. 1). The metastatic evaluation showed many small pulmonary and mediastinal metastases. A renal biopsy showed a high-grade clear cell RCC. An outside physician placed him on 50 mg of sunitinib. The dose was reduced to 25 mg after he developed thrombocytopenia, asthenia and hand-foot syndrome. After the second cycle, re-imaging showed a complete response of the lung nodules, a partial response of the mediastinal nodes, and a stable renal mass and level II tumour thrombus. After two more cycles of sunitinib there was a reduction in the extent of the tumour thrombus to level 0/I (Fig. 2). After stopping sunitinib for 4 weeks, a nephrectomy and thrombectomy was performed without a bypass. A level I thrombus was found to be adherent to the vena cava and a partial resection and primary closure was necessary. The patient was discharged with no complications. The final pathology revealed a grade 4, 7.6 cm clear cell RCC with sarcomatoid components; the final TMN stage was T3bN0M1.

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Figure 1. A level II IVC tumour thrombus at disease presentation.

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Figure 2. After neoadjuvant therapy, showing a level I IVC tumour thrombus.

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In patient no. 2, neoadjuvant sunitinib and sorafenib reduced the size of a large primary tumour in a solitary kidney, allowing nephron-sparing surgery (NSS). This 50-year-old women presented with flank pain and haematuria. Her history was significant for a solitary kidney secondary to a motor-vehicle accident. Imaging showed an 8.5-cm tumour in the lower pole of her left kidney and an ipsilateral 3.7 × 3.3 cm adrenal metastasis (Fig. 3). Chest CT showed multiple small pulmonary nodules. A renal biopsy showed a high-grade clear cell RCC. Because the tumour was large and central she was counselled that her tumour would not be amenable to a partial nephrectomy (PN). Concerns about her quality of life on dialysis led her to avoid nephrectomy. She was placed on 50 mg sunitinib for two 4-week cycles. Re-imaging showed a 30% reduction in the adrenal metastasis, a 30–40% reduction in the pulmonary nodules, and a 25% response of the primary tumour. After two more cycles of sunitinib she developed hand-foot syndrome and hypertension. She was subsequently changed to 800 mg daily sorafenib for 3 months, on which she developed diarrhoea and neuropathy. Repeat imaging showed a 1.5-cm adrenal mass and a 3–4 cm renal tumour.

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Figure 3. A large 9 cm mass in solitary left kidney before neoadjuvant therapy.

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Secondary to her significant response, she was offered PN and adrenalectomy. After stopping sorafenib for 4 weeks she had surgery; the adrenalectomy was completed with no complications. During surgery dissection through the parenchyma was difficult, as it appeared that the neoadjuvant therapy lead to fibrosis and scarring. The mass appeared somewhat larger than had appeared on the most recent imaging but the PN was completed with no complication. After surgery she recovered uneventfully and was discharged with a creatinine level of 1.3 mg/dL, increased from 1.2 mg/dL before surgery.

Pathology showed a grade 4, 5.1 cm clear cell RCC (Fig. 4). Two lymph nodes were replaced with tumour. The adrenal gland had a 1.0-cm area of scarring and inflammation but no evidence of malignancy. The TMN stage was T1bN2M1.

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Figure 4. A tumour specimen after PN showing a circumscribed RCC with degenerative changes.

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In patient no. 3, sunitinib therapy was followed by complete resection of massive lymphadenopathy not amenable to initial excision. This 53-year-old man presented with flank pain and haematuria and was diagnosed with a 15-cm left renal tumour. Massive lymphadenopathy was seen extending from the superior mesenteric artery to the aortic bifurcation (Fig. 5). Imaging showed no evidence of distant metastases. He had a radical nephrectomy (RN), completed with no difficulty, but several hours was required for the lymph node dissection (LND). Due to massive retroperitoneal disease and encasement of the great vessels and mesenteric vessels, a complete resection was judged impossible and was aborted. The patient recovered uneventfully. Pathology showed a grade 4, T3bN2M0 clear cell RCC.

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Figure 5. Initial images of a large left renal tumour and massive lymphadenopathy.

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The residual retroperitoneal disease was treated with sunitinib (Fig. 6). After two 50-mg cycles there was a 40% partial response; the patient continued on three more cycles until disease stabilization (Fig. 7). ‘Second-look’ surgery after the fifth cycle included a full bilateral retroperitoneal LND, with no complication, but the cleavage planes were difficult to identify between the great vessels and the nodes. Pathology showed viable clear cell carcinoma similar to the primary specimen.

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Figure 6. Sagittal CT images after left RN, showing residual paracaval, peri-aortic and left renal hilar lymphadenopathy.

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Figure 7. After sunitinib therapy and before ‘second look’ surgery, showing an excellent response of retroperitoneal lymphadenopathy.

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Patient no. 4 had adjuvant bevacizumab and sunitinib, with subsequent retroperitoneal LND and adrenalectomy. This 44-year-old man with polycystic kidney disease was diagnosed with two tumours in his left kidney of 9 and 5 cm. A left PN showed a T2, grade 4, unclassified/sarcomatoid tumour. Within 6 months he had a local recurrence and had a RN. Pathology showed an 8.5-cm T3a tumour of similar histology. He was placed on 10 mg/kg bevacizumab adjuvant therapy for six biweekly cycles. Follow-up imaging showed an isolated recurrence in the renal fossa of 3.5 cm, with an additional 2.5 cm peri-adrenal mass. Daily 50 mg sunitinib therapy was initiated but was later changed to 37.5 mg due to hypertension and thrombocytopenia. Repeat imaging showed a partial response of both lesions to 1.5 (renal fossa) and 0.8 cm (peri-adrenal).

After stopping therapy he had a retroperitoneal LND and adrenalectomy. A 4-cm mass adherent to the adrenal gland and a para-aortic/hilar mass were resected with no complication. Pathology showed no evidence of residual tumour, and only a foreign-body giant-cell reaction and the presence of necrotic tissue.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. POSSIBLE ROLE WITH LND, RENAL FOSSA RECURRENCE AND METASTASTECTOMY
  8. CONFLICT OF INTEREST
  9. REFERENCES

These selected cases illustrate the potential of neoadjuvant targeted therapy in the surgical management of RCC. Phase II trials with neoadjuvant bevacizumab and sunitinib have been initiated to address the role of preoperative therapy. Until these trials are completed, clinicians must rely on level IV evidence for the potential clinical utility of neoadjuvant therapy.

Questions must be answered about the toxicity and effects on surgery before the therapy can be considered safe for widespread use. In particular, the optimum duration of therapy and interval before surgery has yet to be elucidated. The duration of therapy will probably vary based on radiographic and/or biochemical measures. The perceived enlargement of the tumour from imaging to exploration in patient no. 2 might have occurred while the patient was off sorafenib, illustrating the quandary between potential complications related to perioperative usage and tumour response. Additionally, in patients 2 and 3 had fibrosis potentially related to the administration of systemic therapy.

While the expanded use of neoadjuvant treatment cannot currently be based on randomized trials, these approved agents have been safe and effective for metastatic RCC. Whether neoadjuvant therapy leads to increased rates of complications remains to be seen. Off-label use might aid selected patients with unique situations, but caution must be advised. With no data on safety in the neoadjuvant setting, surgery should be performed in centres that can manage the potential serious complications.

Based on the above clinical observations, we propose applications for future areas of research and clinical trials. These applications, if confirmed, might have major implications for managing RCC.

A possible role in tumour thrombectomy

The neoadjuvant use with nephrectomy/thrombectomy for localized disease: Recent studies have recognized that tumour characteristics, not the level of thrombus, determine the prognosis [3,4], but the level affects the surgical approach and need for bypass techniques. A higher level of thrombus leads to longer surgery, greater blood loss, higher perioperative mortality and complications, in addition to longer hospital stays [4,5].

Patient 1 illustrated the use of neoadjuvant therapy to aid thrombectomy by diminishing thrombus extent. Several centres use a similar strategy with embolization. For cases of extensive thrombus, angiography can determine arterialization and if present, embolization can diminish vascularity. This approach can shrink the thrombus and facilitate removal [6]. Thus neoadjuvant targeted therapy might function like a ‘medical angioinfarction’ of the thrombus. This approach could improve operative characteristics and decrease perioperative morbidity and mortality. A similar case was recently reported [7], showing a reduction of a thrombus from level IV to level II, averting the need for cardiopulmonary bypass.

Neoadjuvant use before CN/thrombectomy: Patients with extensive tumour thrombus in the setting of concomitant metastatic disease frequently cannot proceed to systemic therapy, and when they do, it is associated with a long delay. In addition, the appearance of difficult-to-resect tumours and metastatic disease raises concerns over the true benefit of CN. For these reasons, patients with suprahepatic inferior vena cava (IVC) thrombus were excluded from Southwest Oncology Group and European Organisation for Research and Treatment of Cancer CN trials [1,2]. For patients undergoing surgery, a higher level of thrombus is associated with a decreased response rate to systemic therapy, possibly due to the delay in administration and subsequent disease progression [4]. Neoadjuvant therapy for patients with extensive tumour thrombus enables all patients to receive therapy, as many are unable to do so after surgery. This might also ‘select’ those patients with a significant response to proceed with surgery. Furthermore, reductions in the level of tumour thrombus might allow a less extensive resection with a more rapid convalescence, hastening progress to the next phase of therapy.

Possible role in downstaging the primary tumour

Facilitating imperative NSS by downsizing large primary tumours: In the cytokine era, patients with the primary tumour in place had a 6% response rate to immunotherapy, with no responses in the primary tumour [8]. With no effective therapy, neoadjuvant therapy to facilitate PN was not feasible. For extensive disease in a solitary kidney, RN improves disease-specific survival; however, overall survival and quality of life are concerns due to renal failure. In cases where PN does not appear feasible, patients might benefit from neoadjuvant treatment. Patient 2 illustrates a partial response to therapy permitting subsequent PN. This approach might become applicable to anyone who requires imperative NSS.

Improving operative characteristics/decreasing complications for elective NSS by downstaging primary tumours: PN was initially reserved for cases of tumours in solitary kidneys, bilateral tumours, hereditary syndromes, and patients with renal insufficiency. However NSS results in similar cancer-specific survival [9]. Recent evidence also links RN with a decreased GFR and risk of chronic kidney disease [10]. The elective PN has gained popularity, with low rates of complications and a potential improvement in quality of life.

Patard et al.[11] reviewed the outcomes for PN based on tumour size. Patients undergoing elective NSS for tumours of ≥4 cm had significant differences in operative characteristics compared to those with tumours of <4 cm. Larger tumours were associated with greater blood loss, operative times, more frequent need for collecting-system repair and a higher incidence of urinary fistula formation. For larger tumours, downstaging with neoadjuvant therapy might lead to improved operative outcomes for PN.

Neoadjuvant therapy to facilitate NS-CN: A cytoreductive PN is feasible and results in equivalent survival [12]. Interleukin-2 is contraindicated in patients on dialysis and caution is needed in those with renal insufficiency. To maximize a patient’s ability to respond to systemic therapy, it might be feasible to use neoadjuvant therapy to make the primary lesion amenable to a NS-CN; this might afford the patient a chance for a complete response with interleukin-2 therapy.

Neoadjuvant therapy and laparoscopic RN for localized disease: A laparoscopic RN results in improved convalescence and is safe in patients with moderate-sized tumours. However, those with extremely large tumours frequently require open RN. Neoadjuvant therapy might permit large primary tumours to be downstaged, and thus allow a laparoscopic RN.

Neoadjuvant therapy and laparoscopic CN/RN: Initial experience with laparoscopic cytoreductive surgery showed poor results due to tumour invasion and obliteration of tissue planes. However, for moderate-sized tumours, laparoscopic CN is feasible in experienced hands [13]. If neoadjuvant downstaging allows a laparoscopic approach, more patients can proceed to systemic therapy by minimizing the morbidity of surgery. Earlier initiation of systemic therapy could limit disease progression during the recovery period.

POSSIBLE ROLE WITH LND, RENAL FOSSA RECURRENCE AND METASTASTECTOMY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. POSSIBLE ROLE WITH LND, RENAL FOSSA RECURRENCE AND METASTASTECTOMY
  8. CONFLICT OF INTEREST
  9. REFERENCES

Lymph node dissection for localized disease: In the setting of locally advanced disease, a complete LND can lead to long-term survival [14]. While a staging LND does not add much morbidity to a nephrectomy, surgery in the setting of high-volume retroperitoneal disease can be challenging. As illustrated in patients 3 and 4 the administration of sunitinib was successful in decreasing the retroperitoneal disease burden and potentially allowing a durable surgical cure. In retrospect, rather than adjuvant usage followed by a second-look surgery in patient 3, neoadjuvant use might have allowed a single-stage operation.

LND for metastatic disease: In the setting of metastatic disease, lymph node involvement is common. Pantuck et al.[14] reported worse survival in patients with M1N+ disease than in those with no lymph node involvement. An evaluation of the effect of lymphadenopathy during CN showed that complete LND led to improved survival [14,15]. While patients with lymph node involvement have a worse response to immunotherapy, those who have LND appear to have better response rates [14,16]. With massive lymphadenopathy a complete dissection is difficult if not impossible. If neoadjuvant therapy can decrease the retroperitoneal burden, a complete LND might be possible, thus improving the response to systemic therapy.

Neoadjuvant therapy before resecting renal fossa recurrence: Isolated renal fossa recurrence after nephrectomy occurs in 2% of patients [17]. Surgical excision can lead to extended survival and is recommended. However, due to invasion into the adjacent structures, surgery can be challenging and occasionally impossible. Also, up to 40% of patients who have a resection have a positive resection margin [17]. As shown in patient 4, perhaps local recurrences can be downstaged with targeted therapy, thus improving the likelihood of resection and decreasing the rate of positive margins.

Targeted therapy in conjunction with metastastectomy: Patients with isolated metastatic deposits that are resected can have prolonged survival [18]. In the cytokine era, occasionally patients would have an objective response to systemic therapy followed by stable residual disease. Resection of residual disease in these patients is thought to extend survival [19]. After targeted therapy the tumour burden can be diminished to an extent that permits complete excision of all metastatic deposits [20]. With high response rates to the oral agents, this type of multimodal treatment might become the standard for metastatic RCC.

In conclusion, the emergence of new therapeutic agents has revolutionized the medical treatment of patients with metastatic RCC. Initial observations suggest that targeted agents such as sunitinib and sorafenib are active in the primary tumour, tumour thrombus, renal fossa recurrence, and in involved lymph nodes. These findings suggest a possible role of these new drugs in combination with the surgical management of RCC. Future clinical trials are needed to assess the use of neoadjuvant therapy in both localized and advanced RCC.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. POSSIBLE ROLE WITH LND, RENAL FOSSA RECURRENCE AND METASTASTECTOMY
  8. CONFLICT OF INTEREST
  9. REFERENCES