Cancer Chemother Pharmacol DOI 10.1007/s00280-014-2413-0
Review Article
Recommendations from the Spanish Oncology Genitourinary Group for the treatment of patients with renal cell carcinoma Xavier García del Muro · Enrique Gallardo · Iciar García Carbonero · Nuria Laínez · María José Méndez · Pablo Maroto · María Ochoa de Olza · Javier Puente · Gaspar Reynes · José Rubio · Carmen Santander · Cristina Suárez · Sergio Vázquez Estévez · Daniel Castellano
Received: 3 December 2013 / Accepted: 7 February 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Clear-cell renal cell carcinoma (RCC) is the most common kidney cancer. New treatment options of localized RCC recently incorporated include laparoscopic surgery, nephron-sparing surgery, ablative techniques and active surveillance. But 50 % of patients may develop disease recurrence attributable to subclinical metastases. In these cases, and considering the low benefits of chemotherapy, new targeted therapies such as tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors have been developed as first- and second-line
treatment. Both sunitinib and pazopanib are TKIs that constitute the first-line treatment option in patients with metastatic RCC. As second-line treatment, sequential therapy with a second TKI or a mTOR inhibitor is recommended. This review has collected together a series of recommendations issued by the Spanish Oncology Genitourinary Group with the aim of facilitating the treatment of these patients. Each recommendation is accompanied by the level of evidence and grade of recommendation on the basis of the available data.
X. García del Muro (*) Genitourinary and Sarcoma Unit, Department of Medical Oncology, Institut Català d’Oncologia L’Hospitalet, Gran Via de L’Hospitalet, 199‑203, 08908 L’Hospitalet, Barcelona, Spain e-mail: [email protected]
J. Puente Hospital Universitario San Carlos, c/Profesor Martín Lagos, s/n, 28040 Madrid, Spain
E. Gallardo Hospital Parc Taulí, c/Parc Taulí, 1, 08208 Sabadell, Barcelona, Spain I. García Carbonero Hospital Virgen de la Salud, Avda. de Barber, 30, 45071 Toledo, Spain N. Laínez Hospital de Navarra, c/Irunlarrea, 3, 31008 Pamplona, Navarra, Spain M. José Méndez Hospital Universitario Reina Sofía, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain P. Maroto Hospital de la Santa Creu i Sant Pau, Carrer Sant Quintí, 89, 08026 Barcelona, Spain
G. Reynes Hospital Universitario La Fe, Avda. Campanar, 21, 46009 Valencia, Spain J. Rubio Instituto Valenciano de Oncología, c/del Profesor Beltrán Bàguena, 8, 76009 Valencia, Spain C. Santander Hospital Universitario Miguel Servet, Pº Isabel la Católica, 1‑3, 50009 Zaragoza, Spain C. Suárez Hospital Vall d’Hebron, Pº Vall d’Hebron, 119‑129, 08035 Barcelona, Spain S. Vázquez Estévez Hospital Lucus Agusti, c/San Cibrao, s/n, 27003 Lugo, Spain D. Castellano Hospital Universitario 12 de Octubre, Madrid, Spain
M. Ochoa de Olza Institut Català d’Oncologia L’Hospitalet, Gran Via de L’Hospitalet, 199‑203, 08908 L’Hospitalatet, Barcelona, Spain
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Keywords Diagnosis · Nephrectomy · Renal cell carcinoma · Tyrosine kinase inhibitor
Cancer Chemother Pharmacol
Abbreviations ASCO American Society of Clinical Oncology CT Computed tomography DFS Disease-free survival ECOG Eastern Cooperative Oncology Group EORTC European Organization for Research and Treatment of Cancer ESMO European Society of Medical Oncology HIFU High-intensity focused ultrasound HR Hazard ratio IL Interleukin mTOR Mammalian target of rapamycin OS Overall survival PFS Progression-free survival PS Performance status RCC Renal cell carcinoma SOGUG Spanish Oncology Genitourinary Group SWOG Southwest Oncology Group TKI Tyrosine kinase inhibitor ULN Upper limit of normal VEGF Vascular endothelial growth factor VEGFR Vascular endothelia growth factor receptor WHO World Health Organization
the Renal Cancer Working Group of the SOGUG. A bibliographic search of articles published until April 2013 was performed in the Medline database (PubMed) and the Cochrane Library using MeSH terms whenever possible. Search terms were “renal cell carcinoma” OR “renal neoplasms” AND “metastatic” OR “advanced” AND “clear cell” AND “diagnosis” OR “treatment” OR “management.” Other specific terms were set up to perform a bibliographic search for each topic. Searches were limited to human studies, clinical trials, meta-analyses, clinical guidelines and consensus statements. Additionally, a review of abstracts of relevant, still non-published, phase III studies focused on RCC therapy presented in three relevant international oncology meetings [American Society of Clinical Oncology (ASCO) meeting, ASCO Genitourinary Cancers Symposium and European Society of Medical Oncology (ESMO) meeting], in the last 3 years, was performed. In a first face-to-face working meeting, the structure of the guideline was laid down, the experts responsible for each section were selected together with the working method to be followed, and deadlines were set. In a second meeting, the findings of the different sections were presented to the entire group. The members then discussed the results and determined the level of evidence and the grade of recommendation for each recommendation according to the ASCO guidelines [2].
Introduction
Treatment of localized RCC
The incidence of renal cell carcinoma (RCC) has risen over the last 50 years, having an estimated age-adjusted rate of 15 new cases per 100,000 men and women. According to the World Health Organization (WHO) classification, RCC has three major histological subtypes: clear cell (75 %), papillary 1 and 2 (15 %) and chromophobic (5 %). Currently, the majority of patients can be treated by surgery, but one-third of them will present either with locally advanced tumor or with metastases. In addition, another third of patients may develop metastatic disease after initial treatment [1]. In recent years, the understanding of RCC biology has improved, which has been translated into major advances in the treatment of these patients. Several new molecular-targeted agents have been identified that have led to significant improvements in progression-free survival (PFS) and a general increase in overall survival (OS). These agents include inhibitors of the vascular endothelial growth factor (VEGF) pathway and inhibitors of the mammalian target of rapamycin (mTOR) pathway. The Spanish Oncology Genitourinary Group (SOGUG) has a responsibility to issue recommendations to ensure the optimal management of patients with RCC. These recommendations have been developed by the members of
From its beginnings in the 1950s with open radical nephrectomy, the treatment of localized RCC has dramatically changed in the last 10–15 years due to new approaches such as laparoscopic surgery, nephron-sparing surgery, ablative techniques and active surveillance. Laparoscopic surgery, either as radical or partial nephrectomy, has achieved equivalence in terms of oncological results with open surgery [3–6]. The good results of laparoscopic radical nephrectomy offer better recovery and cosmetic results, as well as less blood loss compared with open radical nephrectomy. In contrast, laparoscopic partial nephrectomy is known to be one of the most difficult procedures, whether it is performed through both pure or robotic laparoscopic access, and with longer ischemic periods, so it should only be performed in highvolume referral centers. For nephron-sparing surgery, in retrospective and epidemiological studies, a close relationship has been shown between the loss of nephrons and the decline in estimated glomerular filtration rate, and this fact has been shown to be a risk factor for cardiovascular events and may have a possible relationship with a worse OS rate. Although this hypothesis has not been confirmed prospectively [7],
13
Cancer Chemother Pharmacol
retrospective evidence is so strong that nowadays nephronsparing surgery is preferred to radical nephrectomy to preserve the best estimated glomerular filtration rate possible. Surgical complications are slightly more frequent with partial nephrectomy than with radical nephrectomy, but this is counterbalanced by better long-term preservation of renal function [8]. Ablative techniques have been developed during the last decade as an alternative to partial nephrectomy. There are not ischemic periods during this procedure, so there is potentially less morbidity associated with them, and they can be used on high-risk patients. Its best indication is in incidental exophytic small renal mass in elderly patients or patients with severe comorbidities and in hereditary RCC syndromes, bilateral tumors or single kidney. They are strongly not recommended in tumors >3 cm if they are close to renal hilum or collecting system, and are questionable in young patients with incidental RCC, who are candidates for nephron-sparing surgery. The most fully developed ablative techniques are radiofrequency ablation and cryotherapy, although data on long-term follow-up are lacking. Renal biopsy is recommended before use to reveal tumor histology. Both ablative techniques can be performed percutaneously or by laparoscopic guidance, and percutaneous radiofrequency ablation and laparoscopic computed tomography (CT) are the most frequently used. Local recurrence is more frequent with radiofrequency ablation compared with cryotherapy, and both have less cancer-specific survival compared with partial nephrectomy or radical nephrectomy [9]. Patients must be informed about the lack of long-term follow-up results and relatively slightly worse results than for a conventional surgical approach. The remainder of ablative techniques tested [microwave, laser, high-intensity focused ultrasound (HIFU), etc.] are nowadays considered experimental. With regard to active surveillance, as a result of the great increase in detection of small renal masses, and the finding of benign pathology in around 25 % of them, there has been debate about the risk of overtreatment because they are common in people over the age of 65. Results from a series of retrospective studies cast doubt on a correlation between local tumor progression and an increased risk of metastatic disease. With short- to medium-term followup, these results have shown that active surveillance is an initial strategy for elderly or patients with comorbidities and presenting small renal masses, and possible surgical rescue in the case of local progression [10]. However, the patient has to be counseled about the low, but definite, risk of cancer progression and the possible loss of a window for nephron-sparing surgery along with the risk of failure to cure if metastasis occurs.
Recommendations 1. Surgery is the only curative approach of RCC. cT1 RCC should be managed with open or laparoscopic nephron-sparing surgery depending on surgeon expertise (level of evidence: I; grade of recommendation: A). 2. Partial nephrectomy should be performed in all cT1a, but if tumor localization is difficult, laparoscopic radical nephrectomy would be the alternative. Including a healthy tissue rim of 1–2 mm is sufficient in nephronsparing surgery (level of evidence: III; grade of recommendation: B). 3. In instances of positive margins, close follow-up and no immediate nephrectomy are recommended (level of evidence: III; grade of recommendation: B). 4. In cT1b RCC, partial nephrectomy is oncologically safe (level of evidence: IIb; grade of recommendation: A) and its indication has to be discussed depending on tumor characteristics and surgeon experience. 5. The standard treatment of cT2 RCC is laparoscopic radical nephrectomy, with open radical nephrectomy as an alternative (level of evidence: III; grade of recommendation: B). 6. Radical nephrectomy is the standard option for cT3a RCC. The open or laparoscopic access will again depend on tumor characteristics and surgeon experience. Open radical nephrectomy is the best choice for c≥T3b. The tumor thrombus has to be completely excised (level of evidence: III; grade of recommendation: B). 7. Extended lymphadenectomy has to be restricted to those cases where nodes are present in CT/magnetic resonance imaging or when they are palpable during surgery. For the remainder of patients, hilar lymphadenectomy is an option for staging purposes (level of evidence: I; grade of recommendation: A). 8. Adrenalectomy can be avoided if the adrenal gland is not involved (level of evidence: III; grade of recommendation: B). 9. Open partial nephrectomy remains the standard of care and is the preferred approach in patients with a single kidney (level of evidence: III; grade of recommendation: C). 10. Initial active surveillance in elderly or high-risk patients with small renal masses is an option that should be discussed with the patient, where very few risks of metastatic spread can be assumed (level of evidence: II; grade of recommendation: B). 11. Radiofrequency ablation or cryotherapy can also be considered in elderly or high-risk patients with small renal masses (level of evidence: III; grade of recommendation: A).
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Cancer Chemother Pharmacol
Adjuvant and neoadjuvant treatment of localized RCC
Neoadjuvant treatment
Radical nephrectomy is a potentially curative procedure for patients with localized RCC. However, up to 50 % of patients may go on to develop disease recurrence attributable to subclinical metastases.
In the new era of systemic therapy for RCC, the adequate integration of surgery and targeted therapies in the management of locally advanced and metastatic RCC is being evaluated. Neoadjuvant treatment of RCC with vascular endothelial growth factor receptor (VEGFR) inhibitors is being studied in two different situations of patients with metastatic tumors who could be candidates for cytoreductive nephrectomy and patients with localized tumors who could benefit from more limited surgery. The concept of neoadjuvant or presurgical treatment has several potential advantages and disadvantages that required further investigation. Potential advantages were primary tumor downstaging, with decreased surgical morbidity, and permitting more nephron-sparing surgery. The antitumoral response could be used as selection criteria for the indication of cytoreductive surgery, avoiding morbid surgery in patients with poor prognosis. Other objectives should be to make resectable those tumors which were previously unresectable. Possible risks of a neoadjuvant approach include increased surgical morbidity (wound healing) and locally or metastatic progression of disease during treatment. Several retrospective studies using sorafenib, sunitinib or bevacizumab before surgery suggest that neoadjuvant treatment is feasible, safe and does not increase surgical morbidity or perioperative complications [15]. In a retrospective study, primary tumor response to targeted agents was examined in patients with metastatic RCC. Most patients demonstrated little if any response in either the primary tumor or in the venous thrombus when it was present. There were some patients with impressive tumor response, but there were also a significant number of patients with tumor progression during therapy [16]. Additional small prospective phase II studies with neoadjuvant-targeted therapies have addressed the feasibility and efficacy of this approach [17, 18]. Nevertheless, randomized trials are required to know whether this approach is beneficial.
Adjuvant treatment Several studies have addressed the potential role of adjuvant treatment after nephrectomy using different therapeutic drugs in patients with RCC and high risk of recurrence. Two large phase III trials using vaccine therapy have been performed. A randomized study tested adjuvant autologous renal tumor cell vaccine compared results with a control group in patients with pT2-3 pN0-3 RCC. A reduced risk of tumor progression was noted in favor of the vaccine group (at 5 year, hazard ratio [HR] for tumor progression was 1.58; p = 0.0204 with 5-year PFS rates of 77.4 % in the vaccine group and 67.8 % in the control group) [11]. Another recent study using an autologous therapeutic vaccine (HSPPC-96; vitespen) showed no differences in terms of recurrence-free survival between patients given vitespen and those who received no treatment after nephrectomy. However, a possible improvement in the recurrence-free survival was observed in the subgroup of patients with early-stage disease (recurrence events in patients with stage I or II disease were reported in 15.2 % of patients in the vitespen group and in 27 % of patients in the control group; HR 0.576; p = 0.056) [12]. Adjuvant interferon-alpha or high-dose interleukin (IL)-2 showed no delay in time to relapse or any improvement in terms of survival. A phase III trial that tested biochemotherapy (IL-2, interferon-alpha and 5-fluorouracil) showed no statistically significant benefits for the regimen in terms of disease-free survival (DFS) or OS [13]. A recent meta-analysis of ten randomized studies shows that adjuvant therapy provided no benefits in terms of OS (HR 1.07; 95 % CI 0.89–1.28; p = 0.48) or DFS (HR 1.03; 95 % CI 0.87–1.21; p = 0.77) when compared with no treatment. No subgroup analysis (immunotherapy, vaccines, biochemotherapy) had relevant results [14]. Currently, several randomized trials are ongoing to test the role of targeted therapies such as sunitinib, sorafenib, pazopanib and everolimus in the adjuvant setting of RCC. Until these trials yield results, adjuvant therapy cannot be recommended for patients who undergo surgical resection of RCC. Patients with high risk of relapse, pT3-4 or any pT pN1-2, should be encouraged to participate in clinical trials, if available.
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Recommendations 1. To date, reported randomized controlled trials comparing adjuvant therapy with observation after surgery have not yielded benefits in terms of OS or DFS. Therefore, adjuvant treatment following surgery is not recommended outside of clinical trials (level of evidence: I; grade of recommendation: A). 2. Neoadjuvant treatment in localized renal tumors remains experimental and cannot be recommended as a standard of treatment (level of evidence: IV; grade of recommendation: B).
Cancer Chemother Pharmacol
3. However, in patients with metastatic tumors, neoadjuvant treatment prior to nephrectomy could be an alternative to immediate surgery in selected cases in order to improve the selection of candidates to cytoreductive nephrectomy (level of evidence: III; grade of recommendation: B).
Surgery in metastatic RCC Patients with metastatic RCC at diagnosis or those with recurrent disease after nephrectomy may benefit from surgery, integrated as a part of the therapeutic approach, in several clinical situations. Surgery may be considered in these patients in terms of cytoreductive or palliative nephrectomy or in terms of metastasectomy. Cytoreductive nephrectomy Cytoreductive nephrectomy in metastatic RCC patients has been associated with spontaneous regression of metastases in 1 year, single versus multiple sites of metastases, Eastern Cooperative Oncology Group (ECOG) 0-1, absence of prior cytotoxic chemotherapy or significant weight loss [22]. Resection of residual metastases after partial response to systemic therapy with IL-2 may increase 2-year PFS rate up to 37 %, with some patients maintaining DFS beyond 10 years [23]. However, there is limited information in patients treated with targeted therapies, with small observational studies reporting median DFS of 43 weeks after surgery [24]. Surgical resection of isolated lung metastases has been associated with 5-year OS rate of 20–50 % [25]. Fewer pulmonary nodules predict a higher probability of complete resection. Lymph node involvement is an important negative prognostic factor in this setting, although surgery could still be considered if no more than 3 intrapulmonary or hilar lymph nodes are affected. Surgical resection of local recurrence could be associated with clinical benefit when complete resection is achieved. Excision of solitary liver, bone and brain metastasis prolongs survival in selected patients, especially when they are metachronous. Extensive staging study, including thoracoabdominal CT scan and bone scintigraphy, is recommended in case of apparent solitary metastasis. Surgery of metastases should be specially considered in patients with solitary metastasis, long disease-free interval from nephrectomy and in whom complete surgical resection is amenable. In the group of selected candidates to surgery of metastasis, medical therapy is not advisable until a subsequent recurrence after the surgical procedure. Recommendations 1. Cytoreductive nephrectomy may be considered in patients with metastatic RCC, with clear-cell histology, ECOG 0-1, resectable primary tumor, and adequate pulmonary and cardiac function. Laparoscopic nephrectomy may be useful to minimize morbidity. This approach, however, should be avoided in the majority of patients with poor prognostic features (level of evidence: III; grade of recommendation: B). 2. Surgery of metastases in patients with RCC should be considered in the case of clinically solitary metastasis (metachronous or selected synchronous cases), or limited number of metastases confined to one organ, provided that complete surgical resection is amenable, patient has good performance status (PS), and there are not contraindications for surgery or other adverse prognostic indicators (level of evidence: III; grade of recommendation: B).
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8.6 versus 8.1 versus 4.8
First‑line treatment of good and intermediate risk patients Table 1 summarizes phase III trials in first-line treatment of metastatic RCC. In this setting, either sunitinib [26], bevacizumab plus interferon-alpha [27, 28], pazopanib [29] or tivozanib [30] have improved PFS compared with either interferon-alpha or placebo, and all except tivozanib are currently approved as first-line treatment for patients with metastatic RCC. Although interferon-alpha plus bevacizumab is approved by the regulatory agencies as first-line therapy for patients with metastatic RCC, it has been progressively abandoned and oral monotherapy with a tyrosine kinase inhibitor (TKI) has become the standard of care in this setting. Interferon-alpha has been shown to be inferior to any TKI in all phase III trials in terms of both toxicity and PFS. As a result, the use of immunotherapy with interferon-alpha as first-line therapy cannot be justified. For selected patients with good prognosis features such as no lymph node or lung involvement, low tumor burden, clearcell type, ECOG 0-1 and young age, and in selected centers with experience in its management, high-dose IL-2 may still be an option. However, no predicted biomarker for response has been prospectively validated. Therefore, selection of the first-line treatment remains on clinical criteria and mainly based on the toxicity profile.
Temsirolimus versus temsirolimus/interferon-alpha versus interferon-alpha
Comparison between TKIs
* p
Review Article
Recommendations from the Spanish Oncology Genitourinary Group for the treatment of patients with renal cell carcinoma Xavier García del Muro · Enrique Gallardo · Iciar García Carbonero · Nuria Laínez · María José Méndez · Pablo Maroto · María Ochoa de Olza · Javier Puente · Gaspar Reynes · José Rubio · Carmen Santander · Cristina Suárez · Sergio Vázquez Estévez · Daniel Castellano
Received: 3 December 2013 / Accepted: 7 February 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Clear-cell renal cell carcinoma (RCC) is the most common kidney cancer. New treatment options of localized RCC recently incorporated include laparoscopic surgery, nephron-sparing surgery, ablative techniques and active surveillance. But 50 % of patients may develop disease recurrence attributable to subclinical metastases. In these cases, and considering the low benefits of chemotherapy, new targeted therapies such as tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors have been developed as first- and second-line
treatment. Both sunitinib and pazopanib are TKIs that constitute the first-line treatment option in patients with metastatic RCC. As second-line treatment, sequential therapy with a second TKI or a mTOR inhibitor is recommended. This review has collected together a series of recommendations issued by the Spanish Oncology Genitourinary Group with the aim of facilitating the treatment of these patients. Each recommendation is accompanied by the level of evidence and grade of recommendation on the basis of the available data.
X. García del Muro (*) Genitourinary and Sarcoma Unit, Department of Medical Oncology, Institut Català d’Oncologia L’Hospitalet, Gran Via de L’Hospitalet, 199‑203, 08908 L’Hospitalet, Barcelona, Spain e-mail: [email protected]
J. Puente Hospital Universitario San Carlos, c/Profesor Martín Lagos, s/n, 28040 Madrid, Spain
E. Gallardo Hospital Parc Taulí, c/Parc Taulí, 1, 08208 Sabadell, Barcelona, Spain I. García Carbonero Hospital Virgen de la Salud, Avda. de Barber, 30, 45071 Toledo, Spain N. Laínez Hospital de Navarra, c/Irunlarrea, 3, 31008 Pamplona, Navarra, Spain M. José Méndez Hospital Universitario Reina Sofía, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain P. Maroto Hospital de la Santa Creu i Sant Pau, Carrer Sant Quintí, 89, 08026 Barcelona, Spain
G. Reynes Hospital Universitario La Fe, Avda. Campanar, 21, 46009 Valencia, Spain J. Rubio Instituto Valenciano de Oncología, c/del Profesor Beltrán Bàguena, 8, 76009 Valencia, Spain C. Santander Hospital Universitario Miguel Servet, Pº Isabel la Católica, 1‑3, 50009 Zaragoza, Spain C. Suárez Hospital Vall d’Hebron, Pº Vall d’Hebron, 119‑129, 08035 Barcelona, Spain S. Vázquez Estévez Hospital Lucus Agusti, c/San Cibrao, s/n, 27003 Lugo, Spain D. Castellano Hospital Universitario 12 de Octubre, Madrid, Spain
M. Ochoa de Olza Institut Català d’Oncologia L’Hospitalet, Gran Via de L’Hospitalet, 199‑203, 08908 L’Hospitalatet, Barcelona, Spain
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Keywords Diagnosis · Nephrectomy · Renal cell carcinoma · Tyrosine kinase inhibitor
Cancer Chemother Pharmacol
Abbreviations ASCO American Society of Clinical Oncology CT Computed tomography DFS Disease-free survival ECOG Eastern Cooperative Oncology Group EORTC European Organization for Research and Treatment of Cancer ESMO European Society of Medical Oncology HIFU High-intensity focused ultrasound HR Hazard ratio IL Interleukin mTOR Mammalian target of rapamycin OS Overall survival PFS Progression-free survival PS Performance status RCC Renal cell carcinoma SOGUG Spanish Oncology Genitourinary Group SWOG Southwest Oncology Group TKI Tyrosine kinase inhibitor ULN Upper limit of normal VEGF Vascular endothelial growth factor VEGFR Vascular endothelia growth factor receptor WHO World Health Organization
the Renal Cancer Working Group of the SOGUG. A bibliographic search of articles published until April 2013 was performed in the Medline database (PubMed) and the Cochrane Library using MeSH terms whenever possible. Search terms were “renal cell carcinoma” OR “renal neoplasms” AND “metastatic” OR “advanced” AND “clear cell” AND “diagnosis” OR “treatment” OR “management.” Other specific terms were set up to perform a bibliographic search for each topic. Searches were limited to human studies, clinical trials, meta-analyses, clinical guidelines and consensus statements. Additionally, a review of abstracts of relevant, still non-published, phase III studies focused on RCC therapy presented in three relevant international oncology meetings [American Society of Clinical Oncology (ASCO) meeting, ASCO Genitourinary Cancers Symposium and European Society of Medical Oncology (ESMO) meeting], in the last 3 years, was performed. In a first face-to-face working meeting, the structure of the guideline was laid down, the experts responsible for each section were selected together with the working method to be followed, and deadlines were set. In a second meeting, the findings of the different sections were presented to the entire group. The members then discussed the results and determined the level of evidence and the grade of recommendation for each recommendation according to the ASCO guidelines [2].
Introduction
Treatment of localized RCC
The incidence of renal cell carcinoma (RCC) has risen over the last 50 years, having an estimated age-adjusted rate of 15 new cases per 100,000 men and women. According to the World Health Organization (WHO) classification, RCC has three major histological subtypes: clear cell (75 %), papillary 1 and 2 (15 %) and chromophobic (5 %). Currently, the majority of patients can be treated by surgery, but one-third of them will present either with locally advanced tumor or with metastases. In addition, another third of patients may develop metastatic disease after initial treatment [1]. In recent years, the understanding of RCC biology has improved, which has been translated into major advances in the treatment of these patients. Several new molecular-targeted agents have been identified that have led to significant improvements in progression-free survival (PFS) and a general increase in overall survival (OS). These agents include inhibitors of the vascular endothelial growth factor (VEGF) pathway and inhibitors of the mammalian target of rapamycin (mTOR) pathway. The Spanish Oncology Genitourinary Group (SOGUG) has a responsibility to issue recommendations to ensure the optimal management of patients with RCC. These recommendations have been developed by the members of
From its beginnings in the 1950s with open radical nephrectomy, the treatment of localized RCC has dramatically changed in the last 10–15 years due to new approaches such as laparoscopic surgery, nephron-sparing surgery, ablative techniques and active surveillance. Laparoscopic surgery, either as radical or partial nephrectomy, has achieved equivalence in terms of oncological results with open surgery [3–6]. The good results of laparoscopic radical nephrectomy offer better recovery and cosmetic results, as well as less blood loss compared with open radical nephrectomy. In contrast, laparoscopic partial nephrectomy is known to be one of the most difficult procedures, whether it is performed through both pure or robotic laparoscopic access, and with longer ischemic periods, so it should only be performed in highvolume referral centers. For nephron-sparing surgery, in retrospective and epidemiological studies, a close relationship has been shown between the loss of nephrons and the decline in estimated glomerular filtration rate, and this fact has been shown to be a risk factor for cardiovascular events and may have a possible relationship with a worse OS rate. Although this hypothesis has not been confirmed prospectively [7],
13
Cancer Chemother Pharmacol
retrospective evidence is so strong that nowadays nephronsparing surgery is preferred to radical nephrectomy to preserve the best estimated glomerular filtration rate possible. Surgical complications are slightly more frequent with partial nephrectomy than with radical nephrectomy, but this is counterbalanced by better long-term preservation of renal function [8]. Ablative techniques have been developed during the last decade as an alternative to partial nephrectomy. There are not ischemic periods during this procedure, so there is potentially less morbidity associated with them, and they can be used on high-risk patients. Its best indication is in incidental exophytic small renal mass in elderly patients or patients with severe comorbidities and in hereditary RCC syndromes, bilateral tumors or single kidney. They are strongly not recommended in tumors >3 cm if they are close to renal hilum or collecting system, and are questionable in young patients with incidental RCC, who are candidates for nephron-sparing surgery. The most fully developed ablative techniques are radiofrequency ablation and cryotherapy, although data on long-term follow-up are lacking. Renal biopsy is recommended before use to reveal tumor histology. Both ablative techniques can be performed percutaneously or by laparoscopic guidance, and percutaneous radiofrequency ablation and laparoscopic computed tomography (CT) are the most frequently used. Local recurrence is more frequent with radiofrequency ablation compared with cryotherapy, and both have less cancer-specific survival compared with partial nephrectomy or radical nephrectomy [9]. Patients must be informed about the lack of long-term follow-up results and relatively slightly worse results than for a conventional surgical approach. The remainder of ablative techniques tested [microwave, laser, high-intensity focused ultrasound (HIFU), etc.] are nowadays considered experimental. With regard to active surveillance, as a result of the great increase in detection of small renal masses, and the finding of benign pathology in around 25 % of them, there has been debate about the risk of overtreatment because they are common in people over the age of 65. Results from a series of retrospective studies cast doubt on a correlation between local tumor progression and an increased risk of metastatic disease. With short- to medium-term followup, these results have shown that active surveillance is an initial strategy for elderly or patients with comorbidities and presenting small renal masses, and possible surgical rescue in the case of local progression [10]. However, the patient has to be counseled about the low, but definite, risk of cancer progression and the possible loss of a window for nephron-sparing surgery along with the risk of failure to cure if metastasis occurs.
Recommendations 1. Surgery is the only curative approach of RCC. cT1 RCC should be managed with open or laparoscopic nephron-sparing surgery depending on surgeon expertise (level of evidence: I; grade of recommendation: A). 2. Partial nephrectomy should be performed in all cT1a, but if tumor localization is difficult, laparoscopic radical nephrectomy would be the alternative. Including a healthy tissue rim of 1–2 mm is sufficient in nephronsparing surgery (level of evidence: III; grade of recommendation: B). 3. In instances of positive margins, close follow-up and no immediate nephrectomy are recommended (level of evidence: III; grade of recommendation: B). 4. In cT1b RCC, partial nephrectomy is oncologically safe (level of evidence: IIb; grade of recommendation: A) and its indication has to be discussed depending on tumor characteristics and surgeon experience. 5. The standard treatment of cT2 RCC is laparoscopic radical nephrectomy, with open radical nephrectomy as an alternative (level of evidence: III; grade of recommendation: B). 6. Radical nephrectomy is the standard option for cT3a RCC. The open or laparoscopic access will again depend on tumor characteristics and surgeon experience. Open radical nephrectomy is the best choice for c≥T3b. The tumor thrombus has to be completely excised (level of evidence: III; grade of recommendation: B). 7. Extended lymphadenectomy has to be restricted to those cases where nodes are present in CT/magnetic resonance imaging or when they are palpable during surgery. For the remainder of patients, hilar lymphadenectomy is an option for staging purposes (level of evidence: I; grade of recommendation: A). 8. Adrenalectomy can be avoided if the adrenal gland is not involved (level of evidence: III; grade of recommendation: B). 9. Open partial nephrectomy remains the standard of care and is the preferred approach in patients with a single kidney (level of evidence: III; grade of recommendation: C). 10. Initial active surveillance in elderly or high-risk patients with small renal masses is an option that should be discussed with the patient, where very few risks of metastatic spread can be assumed (level of evidence: II; grade of recommendation: B). 11. Radiofrequency ablation or cryotherapy can also be considered in elderly or high-risk patients with small renal masses (level of evidence: III; grade of recommendation: A).
13
Cancer Chemother Pharmacol
Adjuvant and neoadjuvant treatment of localized RCC
Neoadjuvant treatment
Radical nephrectomy is a potentially curative procedure for patients with localized RCC. However, up to 50 % of patients may go on to develop disease recurrence attributable to subclinical metastases.
In the new era of systemic therapy for RCC, the adequate integration of surgery and targeted therapies in the management of locally advanced and metastatic RCC is being evaluated. Neoadjuvant treatment of RCC with vascular endothelial growth factor receptor (VEGFR) inhibitors is being studied in two different situations of patients with metastatic tumors who could be candidates for cytoreductive nephrectomy and patients with localized tumors who could benefit from more limited surgery. The concept of neoadjuvant or presurgical treatment has several potential advantages and disadvantages that required further investigation. Potential advantages were primary tumor downstaging, with decreased surgical morbidity, and permitting more nephron-sparing surgery. The antitumoral response could be used as selection criteria for the indication of cytoreductive surgery, avoiding morbid surgery in patients with poor prognosis. Other objectives should be to make resectable those tumors which were previously unresectable. Possible risks of a neoadjuvant approach include increased surgical morbidity (wound healing) and locally or metastatic progression of disease during treatment. Several retrospective studies using sorafenib, sunitinib or bevacizumab before surgery suggest that neoadjuvant treatment is feasible, safe and does not increase surgical morbidity or perioperative complications [15]. In a retrospective study, primary tumor response to targeted agents was examined in patients with metastatic RCC. Most patients demonstrated little if any response in either the primary tumor or in the venous thrombus when it was present. There were some patients with impressive tumor response, but there were also a significant number of patients with tumor progression during therapy [16]. Additional small prospective phase II studies with neoadjuvant-targeted therapies have addressed the feasibility and efficacy of this approach [17, 18]. Nevertheless, randomized trials are required to know whether this approach is beneficial.
Adjuvant treatment Several studies have addressed the potential role of adjuvant treatment after nephrectomy using different therapeutic drugs in patients with RCC and high risk of recurrence. Two large phase III trials using vaccine therapy have been performed. A randomized study tested adjuvant autologous renal tumor cell vaccine compared results with a control group in patients with pT2-3 pN0-3 RCC. A reduced risk of tumor progression was noted in favor of the vaccine group (at 5 year, hazard ratio [HR] for tumor progression was 1.58; p = 0.0204 with 5-year PFS rates of 77.4 % in the vaccine group and 67.8 % in the control group) [11]. Another recent study using an autologous therapeutic vaccine (HSPPC-96; vitespen) showed no differences in terms of recurrence-free survival between patients given vitespen and those who received no treatment after nephrectomy. However, a possible improvement in the recurrence-free survival was observed in the subgroup of patients with early-stage disease (recurrence events in patients with stage I or II disease were reported in 15.2 % of patients in the vitespen group and in 27 % of patients in the control group; HR 0.576; p = 0.056) [12]. Adjuvant interferon-alpha or high-dose interleukin (IL)-2 showed no delay in time to relapse or any improvement in terms of survival. A phase III trial that tested biochemotherapy (IL-2, interferon-alpha and 5-fluorouracil) showed no statistically significant benefits for the regimen in terms of disease-free survival (DFS) or OS [13]. A recent meta-analysis of ten randomized studies shows that adjuvant therapy provided no benefits in terms of OS (HR 1.07; 95 % CI 0.89–1.28; p = 0.48) or DFS (HR 1.03; 95 % CI 0.87–1.21; p = 0.77) when compared with no treatment. No subgroup analysis (immunotherapy, vaccines, biochemotherapy) had relevant results [14]. Currently, several randomized trials are ongoing to test the role of targeted therapies such as sunitinib, sorafenib, pazopanib and everolimus in the adjuvant setting of RCC. Until these trials yield results, adjuvant therapy cannot be recommended for patients who undergo surgical resection of RCC. Patients with high risk of relapse, pT3-4 or any pT pN1-2, should be encouraged to participate in clinical trials, if available.
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Recommendations 1. To date, reported randomized controlled trials comparing adjuvant therapy with observation after surgery have not yielded benefits in terms of OS or DFS. Therefore, adjuvant treatment following surgery is not recommended outside of clinical trials (level of evidence: I; grade of recommendation: A). 2. Neoadjuvant treatment in localized renal tumors remains experimental and cannot be recommended as a standard of treatment (level of evidence: IV; grade of recommendation: B).
Cancer Chemother Pharmacol
3. However, in patients with metastatic tumors, neoadjuvant treatment prior to nephrectomy could be an alternative to immediate surgery in selected cases in order to improve the selection of candidates to cytoreductive nephrectomy (level of evidence: III; grade of recommendation: B).
Surgery in metastatic RCC Patients with metastatic RCC at diagnosis or those with recurrent disease after nephrectomy may benefit from surgery, integrated as a part of the therapeutic approach, in several clinical situations. Surgery may be considered in these patients in terms of cytoreductive or palliative nephrectomy or in terms of metastasectomy. Cytoreductive nephrectomy Cytoreductive nephrectomy in metastatic RCC patients has been associated with spontaneous regression of metastases in 1 year, single versus multiple sites of metastases, Eastern Cooperative Oncology Group (ECOG) 0-1, absence of prior cytotoxic chemotherapy or significant weight loss [22]. Resection of residual metastases after partial response to systemic therapy with IL-2 may increase 2-year PFS rate up to 37 %, with some patients maintaining DFS beyond 10 years [23]. However, there is limited information in patients treated with targeted therapies, with small observational studies reporting median DFS of 43 weeks after surgery [24]. Surgical resection of isolated lung metastases has been associated with 5-year OS rate of 20–50 % [25]. Fewer pulmonary nodules predict a higher probability of complete resection. Lymph node involvement is an important negative prognostic factor in this setting, although surgery could still be considered if no more than 3 intrapulmonary or hilar lymph nodes are affected. Surgical resection of local recurrence could be associated with clinical benefit when complete resection is achieved. Excision of solitary liver, bone and brain metastasis prolongs survival in selected patients, especially when they are metachronous. Extensive staging study, including thoracoabdominal CT scan and bone scintigraphy, is recommended in case of apparent solitary metastasis. Surgery of metastases should be specially considered in patients with solitary metastasis, long disease-free interval from nephrectomy and in whom complete surgical resection is amenable. In the group of selected candidates to surgery of metastasis, medical therapy is not advisable until a subsequent recurrence after the surgical procedure. Recommendations 1. Cytoreductive nephrectomy may be considered in patients with metastatic RCC, with clear-cell histology, ECOG 0-1, resectable primary tumor, and adequate pulmonary and cardiac function. Laparoscopic nephrectomy may be useful to minimize morbidity. This approach, however, should be avoided in the majority of patients with poor prognostic features (level of evidence: III; grade of recommendation: B). 2. Surgery of metastases in patients with RCC should be considered in the case of clinically solitary metastasis (metachronous or selected synchronous cases), or limited number of metastases confined to one organ, provided that complete surgical resection is amenable, patient has good performance status (PS), and there are not contraindications for surgery or other adverse prognostic indicators (level of evidence: III; grade of recommendation: B).
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8.6 versus 8.1 versus 4.8
First‑line treatment of good and intermediate risk patients Table 1 summarizes phase III trials in first-line treatment of metastatic RCC. In this setting, either sunitinib [26], bevacizumab plus interferon-alpha [27, 28], pazopanib [29] or tivozanib [30] have improved PFS compared with either interferon-alpha or placebo, and all except tivozanib are currently approved as first-line treatment for patients with metastatic RCC. Although interferon-alpha plus bevacizumab is approved by the regulatory agencies as first-line therapy for patients with metastatic RCC, it has been progressively abandoned and oral monotherapy with a tyrosine kinase inhibitor (TKI) has become the standard of care in this setting. Interferon-alpha has been shown to be inferior to any TKI in all phase III trials in terms of both toxicity and PFS. As a result, the use of immunotherapy with interferon-alpha as first-line therapy cannot be justified. For selected patients with good prognosis features such as no lymph node or lung involvement, low tumor burden, clearcell type, ECOG 0-1 and young age, and in selected centers with experience in its management, high-dose IL-2 may still be an option. However, no predicted biomarker for response has been prospectively validated. Therefore, selection of the first-line treatment remains on clinical criteria and mainly based on the toxicity profile.
Temsirolimus versus temsirolimus/interferon-alpha versus interferon-alpha
Comparison between TKIs
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